@article {pmid42585284,
year = {2026},
author = {Aksoy Gündoğdu, A and Samancı, B and Alaylıoğlu, M and Şahin, E and Ulukan, Ç and Gürvit, İH and Dursun, E and Hanağası, HA and Gezen-Ak, D and Bilgiç, B},
title = {Prognostic significance of cerebrospinal fluid tau biomarkers in amyloid-negative A-T + N + neurodegeneration: A retrospective cohort study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261476236},
doi = {10.1177/13872877261476236},
pmid = {42585284},
issn = {1875-8908},
abstract = {BackgroundAmyloid-negative tau-related neurodegeneration represents a non-Alzheimer biomarker-defined profile; however, its clinical heterogeneity and prognostic relevance remain unclear within Alzheimer's disease-related frameworks.ObjectiveTo characterize the clinical spectrum and identify predictors of mortality in patients with this profile.MethodsIn this retrospective cohort study, 1280 patients evaluated at a tertiary neurology center were screened, and 130 with an amyloid-negative cerebrospinal fluid (CSF) pattern [amyloid-β (Aβ)42 normal, phosphorylated tau (pTau), and total tau (tTau) elevated] were included. Survival was assessed using Kaplan-Meier analysis, and predictors of mortality were evaluated using Cox models.ResultsThe cohort (mean age 68.8 ± 10.1 years; 45.4% female) showed heterogeneous diagnoses, mainly mild cognitive impairment and frontotemporal dementia (each 30%). Survival differed across diagnostic groups (log-rank p = 0.037), with more favorable outcomes in mild cognitive impairment. Male sex was more frequent among non-survivors (88.9% versus 45.6%, p < 0.001). Higher CSF tTau levels were associated with mortality in the joint Cox model (HR 1.003, 95% CI 1.001-1.006, p = 0.006) and faster clinical progression (r = 0.22, p = 0.011). When modeled separately, neither tTau nor pTau was independently associated with mortality; however, both became significant in opposite directions when included jointly.ConclusionsThe amyloid-negative A-T + N + profile represents a clinically heterogeneous subgroup with prognostic relevance. CSF tTau was associated with mortality and faster clinical progression, but the joint-model findings involving tTau and pTau should be interpreted cautiously as hypothesis-generating. Further studies are needed to clarify the prognostic value of tau-related biomarkers in this population.},
}
@article {pmid42585285,
year = {2026},
author = {Lu, YT and Guo, ZM and Liu, MY and Ji, CH and Luo, YT and Zhou, SY and Ma, T and Zhu, XC and , },
title = {Correlation analysis between complement proteins and Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261475358},
doi = {10.1177/13872877261475358},
pmid = {42585285},
issn = {1875-8908},
abstract = {BackgroundThe prominent pathological features of Alzheimer's disease (AD) are amyloid-β (Aβ) plaques and tau pathology. The complement cascade is closely related to AD-associated pathological processes; however, the precise mechanisms underlying its contributions remain incompletely elucidated.ObjectiveWe aim to investigate the changes in complement protein expression during AD progression.MethodsThis study enrolled 285 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Participants were classified into biomarker-defined groups based on predefined cutoff values for Aβ42 and phosphorylated tau (P-tau). We compared cerebrospinal fluid (CSF) levels of complement proteins (C1q, C2, C3, C4a, C5, C6, C8b, and factor B) across these subgroups. Furthermore, we explored their associations with core AD biomarkers (Aβ42, P-tau, and T-tau) and clinical characteristics. Additionally, we investigated age-related changes in complement gene expression within the cerebral cortex of 3xTg mice using single-nucleus RNA sequencing.ResultsComplement protein levels in the CSF of A + subjects were significantly lower than those in A- subjects, and complement protein levels were positively correlated with Aβ pathology. Complement protein levels were influenced by factors such as age, gender, body mass index, APOE genotype, and hypertension. Compared with control mice, the complement gene C1qa in microglia was upregulated throughout the entire pathological cycle in 3xTg AD mice.ConclusionsComplement proteins undergo significant changes during the pathogenesis of AD, and alterations in their levels may reflect early pathological changes in AD and warrant further investigation. Notably, our findings suggest that microglia may contribute to complement-mediated pathological processes associated with AD.},
}
@article {pmid42585316,
year = {2026},
author = {Gallego-Rudolf, J and Wiesman, AI and Yakoub, Y and Zetterberg, H and Blennow, K and Baillet, S and Villeneuve, S and , },
title = {Prediction of mild cognitive impairment progression using time-sensitive multimodal biomarkers.},
journal = {Science advances},
volume = {12},
number = {33},
pages = {eaee2305},
pmid = {42585316},
issn = {2375-2548},
mesh = {Humans ; *Cognitive Dysfunction/diagnosis/blood/diagnostic imaging/metabolism ; *Biomarkers/blood ; Disease Progression ; Female ; Aged ; Male ; Alzheimer Disease/diagnosis ; Positron-Emission Tomography ; Magnetic Resonance Imaging ; tau Proteins/metabolism ; Magnetoencephalography ; },
abstract = {Alzheimer's disease (AD) develops silently for years before symptoms emerge, making early identification of at-risk individuals essential for prevention trials and early intervention. We tested whether combining neurophysiological, imaging, and blood biomarkers improves prediction of progression to mild cognitive impairment (MCI) in cognitively unimpaired older adults with a family history of AD (n = 102; 31 progressors; mean follow-up of 5.9 years). Magnetoencephalography, magnetic resonance imaging, plasma biomarkers, and amyloid and tau positron emission tomography each captured complementary aspects of disease biology. Multimodal models predicted progression more accurately than demographic and genetic factors alone. Higher MEG alpha power was associated with increased near-term risk, whereas higher gamma activity predicted lower near-term risk; both effects weakened over time. Higher neocortical amyloid burden predicted increasing risk over follow-up, whereas plasma biomarkers and entorhinal tau predicted higher risk without significant time-varying effects. These findings support a time-sensitive multimodal framework for identifying cognitively unimpaired individuals at risk of MCI due to AD.},
}
@article {pmid42585344,
year = {2026},
author = {Yuan, R and Liao, G and Su, S and Shan, J and Tang, S},
title = {Identification of B-cell senescence-related key genes and mechanisms in Alzheimer's disease through transcriptomic sequencing combined with Mendelian randomization analysis and experimental verification.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261477008},
doi = {10.1177/13872877261477008},
pmid = {42585344},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia. Currently, no treatment method can treat AD completely successfully.ObjectiveThis work seeks to uncover new genetic signatures linking B-cell senescence to AD, elucidate the immune-related pathological mechanisms of AD.MethodsThe GSE85426 and GSE168813 for AD were obtained from public databases. Differential analysis of expression matrix in GSE85426 was conducted to screen differentially expressed genes (DEGs), WGCNA was explored to obtain B cell and cell senescence related hub genes. Then the key genes for AD were screened by intersection, Mendelian randomization (MR), receiver operating characteristic (ROC) curve, and Wilcoxon test. Additionally, enrichment analysis, immune infiltration analysis, and molecular docking were performed to investigate the molecular mechanism of key genes and drug targets related to key genes, respectively.ResultsIn this study, CCDC86 and PARP9 were identified as key genes, genetic association analysis suggested CCDC86 correlates with higher AD susceptibility while PARP9 tends to correlate with lowered AD risk. We also found that these two key genes were highly correlated with B cells, and the abundance of B cells in AD increased significantly. Finally, our calculation revealed that the binding free energy between PARP9 and bisphenol A was -7.6 kcal/mol, implying a favorable simulated binding tendency between the two molecules.ConclusionsThese findings suggest that PARP9 may serve as a promising and reliable drug target for clinical therapy, which may represent a tentative candidate worthy of further experimental validation for subsequent biomarker and therapeutic target research in AD.},
}
@article {pmid42585347,
year = {2026},
author = {Ferreira, LK and Westman, E and Wahlund, LO and Mohanty, R and , },
title = {Progression from mild cognitive impairment to dementia in Alzheimer's disease: Whole cortex voxelwise functional connectivity analysis with multivariate distance matrix regression.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261477016},
doi = {10.1177/13872877261477016},
pmid = {42585347},
issn = {1875-8908},
abstract = {BackgroundDifferentiating individuals with mild cognitive impairment who convert to dementia due to Alzheimer's disease (MCI-C) from those who do not convert (MCI-NC) is increasingly important. Functional connectivity (FC) derived from resting state functional MRI (rs-fMRI) has been investigated as a potential biomarker. However, improved data analysis strategies are needed. One underexplored approach is pairwise voxel-to-voxel analysis.ObjectiveTo describe differences in FC between amyloid positive MCI-C and MCI-NC using a whole-cortex voxel-to-voxel pairwise approach.MethodsBaseline rs-fMRI from the Alzheimer's Disease Neuroimaging Initiative was retrieved for amyloid positive MCI participants. Voxel-to-voxel, pairwise, cortical FC was computed. Multivariate distance matrix regression was used to identify voxels presenting FC patterns that were significantly different between MCI-C and MCI-NC.Results21 MCI-C and 28 MCI-NC were included. The primary analysis with voxel-level threshold at p < 0.001 combined with cluster-level p < 0.05 yielded no significant results. At voxel-level p < 0.01 and the same cluster-level threshold, three significant clusters on the right visual cortex were found. These clusters, however, were not robust to head motion, fMRI protocol and additionally clinical or biological severity.ConclusionsProgression from Alzheimer-related MCI to dementia was not significantly associated with FC in the primary analysis. However, a less stringent threshold yielded FC differences in the occipital lobe in alignment with previous studies but were not robust to methodological and biological covariates between groups. Our findings highlight the need for larger samples and careful control of covariates to identify robust FC alterations related to dementia conversion.},
}
@article {pmid42585348,
year = {2026},
author = {Petrović, V and Reas, ET and Reimer, RA and Barha, CK},
title = {Role of previous parity in the relationship between lifetime physical activity and later life cognition: The Rancho Bernardo study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261477010},
doi = {10.1177/13872877261477010},
pmid = {42585348},
issn = {1875-8908},
abstract = {BackgroundParity history influences dementia risk and cognitive aging, and recent evidence suggests it may also influence the association between physical activity and cognition in later life.ObjectiveTo examine associations between total lifetime and life-stage-specific physical activity and later life cognition in postmenopausal females with differing parity histories.MethodsThis cross-sectional analysis using data from the Rancho Bernardo Study included 867 postmenopausal females with complete data, categorized into three parity groups (number of pregnancies >6-months): nulliparous, 1-2 pregnancies, and grand-multiparous (≥3 pregnancies). Cognitive outcomes included executive functions and memory. Physical activity was assessed using a self-report questionnaire capturing retrospective activity during adolescence, age 30, age 50, and current activity in later life. Covariates included age, education, health composite score, body mass index, and hysterectomy status. Linear models examined associations between physical activity and domain-specific later life cognitive outcomes stratified by parity.ResultsGreater total lifetime physical activity was associated with higher executive functions in nulliparous and grand-multiparous females. Moderate activity in nulliparous females and high activity in grand-multiparous females during adolescence and at age 30 were associated with higher executive functions. High physical activity at age 50 and currently was associated with higher executive functions in nulliparous females.ConclusionsThe findings suggest the relationship between self-reported physical activity and cognition was strongest in the two groups at greater risk for cognitive decline and Alzheimer's disease, the nulliparous and grand-multiparous groups. Further research is needed to understand the mechanisms driving parity differences.},
}
@article {pmid42585351,
year = {2026},
author = {Bubu, OM and Mbah, AK and Bernard, MA and Briggs, A and Faustin, A and Gurin, L and Rao, JA and Tall, SO and Osorio, RS and Masurkar, AV},
title = {Risk factors and cognitive domain markers of progression in subjective cognitive decline.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261470393},
doi = {10.1177/13872877261470393},
pmid = {42585351},
issn = {1875-8908},
abstract = {BackgroundSubjective cognitive decline (SCD) is increasingly recognized in some cases as an early clinical stage in the Alzheimer's disease continuum, yet the factors that predict which individuals will progress to objective impairment remain poorly understood.ObjectiveWe evaluated risk factor differences and cognitive domain markers associated with progression in participants with subjective cognitive decline (SCD) at baseline from the NYU Alzheimer's Disease Research Center.MethodsWe included SCD non-decliners (n = 27), who remained stable, and decliners (n = 24), who progressed to mild cognitive impairment or worse, between the second to sixth yearly follow-up visits. Adjusted mixed-effects models examined group differences and associations between demographic, APOE status, psychometric test performance and comorbidities with longitudinal-decline.ResultsOverall, mean (SD) age was 67.4 (9.2) and total follow-up time was 5.1 (1.8) years. Lower education (14.9 (3.2) versus 17.3 (2.1)), Hispanic ethnicity (50.0% versus 11.0%), and hypercholesterolemia (adjusted odds ratio: 6.67) were risk factors for progression in SCD, p ≤ 0.05, whereas APOE status was not. Notably, SCD decliners were at increased risk for both amnestic and non-amnestic cognitive-decline with psychometric changes in memory, executive, and language domains (p < 0.001 for all).ConclusionsThese findings inform further work on SCD outcomes and related biomarkers, as well as preventive studies that target modifiable risk factors for SCD progression.},
}
@article {pmid42585605,
year = {2026},
author = {Hazan, J and Salemme, S and Liu, KY and Howard, R},
title = {Blood-Based Biomarkers for Alzheimer Disease in Primary Care: The Gap Between Biology and Clinical Utility.},
journal = {Neurology},
volume = {107},
number = {5},
pages = {e218403},
doi = {10.1212/WNL.0000000000218403},
pmid = {42585605},
issn = {1526-632X},
mesh = {Humans ; *Alzheimer Disease/blood/diagnosis ; *Biomarkers/blood ; Primary Health Care ; },
abstract = {Blood-based biomarkers (BBMs) for Alzheimer disease (AD) have accelerated the prospect of earlier and more accessible detection of AD pathology, potentially beyond specialist settings. However, their introduction in primary care raises important questions about clinical sequencing, interpretability, pathway consequences, and real-world utility. In this Personal View, we argue that the main barrier to responsible implementation is not analytical performance alone, but the absence of a sufficiently defined diagnostic infrastructure in which a test result has a clear and actionable role. In low-prevalence and clinically heterogeneous primary care populations, inadequate clinical anchoring and unstable pretest probability may undermine interpretability and promote category drift from diagnostic testing towards case-finding or quasiscreening. Moreover, the value of a rule-out strategy depends on whether a negative result meaningfully changes management. Until stronger evidence, clearer guidance, and appropriate service conditions are in place, primary care use of AD BBMs should remain selective, clinically anchored, and pathway-dependent.},
}
@article {pmid42585606,
year = {2026},
author = {Bruno, J and Shaw, JS and Hosseini, SMH and , },
title = {Association Between Menopausal Hormone Therapy and Alzheimer Disease Neuropathology.},
journal = {Neurology},
volume = {107},
number = {5},
pages = {e218413},
doi = {10.1212/WNL.0000000000218413},
pmid = {42585606},
issn = {1526-632X},
mesh = {Humans ; Female ; *Alzheimer Disease/pathology/diagnostic imaging ; *Estrogen Replacement Therapy/adverse effects ; Aged, 80 and over ; Aged ; Cohort Studies ; *Brain/pathology/diagnostic imaging/drug effects ; Middle Aged ; *Menopause/drug effects ; Biomarkers/cerebrospinal fluid ; Amyloid beta-Peptides/cerebrospinal fluid ; },
abstract = {BACKGROUND AND OBJECTIVES: Although evidence suggests that the neurophysiologic impact of estrogen decline during menopause may contribute to increased risk of Alzheimer disease (AD) in women, the effect of menopausal hormonal therapy (MHT) on AD risk requires further study. We sought to examine the associations between MHT use and neuropathologic, clinical, and imaging/fluid biomarker outcomes.<br><br>METHODS: In this cohort study, we tested the association between estrogen-only MHT use and dementia outcomes in female participants using 2 independent, large-scale data sets: National Alzheimer's Coordinating Center (NACC) and Alzheimer's Disease Neuroimaging Initiative (ADNI). Participants included women 50 years and older with self-reported use of estrogen-only MHT or no self-reported use of MHT. Clinical, imaging/fluid biomarker, and neuropathologic outcomes were examined. Research was performed at academic medical centers.<br><br>RESULTS: Neuropathologic data were collected from NACC for 258 MHT users (mean age of death = 81.9, SD = 19.5) and 2,701 non-MHT users (mean age of death = 82.2, SD = 11.0). The ADNI cohort included 110 MHT users (mean age = 76.5, SD = 7.5) and 1,948 non-MHT users (mean age = 73.2, SD = 8.9). The odds of increased AD pathology on autopsy (primary outcome) were significantly decreased in MHT users relative to nonusers (odds ratio [OR] 0.65, 95% CI 0.48-0.88, p = 0.005). MHT use was associated with secondary outcomes including significantly decreased amyloid pathologic load assessed through plasma (&#x3b2; = 0.44, 95% CI 0.16-0.73, p = 0.0025) and CSF (&#x3b2; = 0.07, 95% CI 0.002-0.13, p = 0.030). MHT use was associated with significantly lower odds of clinical dementia diagnoses (OR 0.61, 95% CI 0.55-0.67, p < 0.0001) and lower odds of symptoms of memory/functional decline (OR 0.67, 95% CI 0.61-0.74, p < 0.0001).<br><br>DISCUSSION: Our findings demonstrate small but significant associations between MHT use during later life and a range of AD-related neuropathologic and clinical outcomes in 2 large cohorts of female participants. Although our results do not address causality and have limited generalizability due to the retrospective nature of the study, they suggest a protective effect of MHT use in the dementia course.},
}
@article {pmid42585609,
year = {2026},
author = {Salemme, S},
title = {Menopausal Hormone Therapy and Alzheimer Disease: When, Which, and for Whom?.},
journal = {Neurology},
volume = {107},
number = {5},
pages = {e218503},
doi = {10.1212/WNL.0000000000218503},
pmid = {42585609},
issn = {1526-632X},
}
@article {pmid42585730,
year = {2026},
author = {Shu, K and Li, J and Zhang, R and Cheng, N and Yang, P and Song, X and Lei, B},
title = {From voxel discovery to regional interaction: A multi-level interpretable framework for Alzheimer's disease diagnosis.},
journal = {Medical image analysis},
volume = {114},
number = {},
pages = {104243},
doi = {10.1016/j.media.2026.104243},
pmid = {42585730},
issn = {1361-8423},
abstract = {Alzheimer's disease (AD) is an irreversible neurodegenerative disorder where early diagnosis serves as the only viable window for effective intervention. While Structural MRI (sMRI) is a primary clinical tool for this purpose, manual diagnosis is heavily constrained by clinician expertise and the difficulty of visually quantifying subtle, diffuse anatomical changes. Deep learning has emerged as a powerful solution to capture these complex patterns. However, the inherent black-box opacity of current models creates a trust deficit that severely impedes their clinical adoption. Furthermore, existing interpretability methods predominantly rely on post-hoc visualizations, which frequently suffer from significant background leakage and lack anatomical coherence. To overcome these barriers, we propose a novel multi-level interpretable framework that inherently integrates diagnostic reasoning into the model architecture. The framework operates through a progressive three-stage trajectory to bridge the gap between pixel-level signals and global pathology. First, to eliminate the ambiguity caused by background leakage, we introduce a voxel discovery module implemented via Hierarchical Evidential Masking (HiEM). By leveraging this iterative optimization strategy, the model actively filters out irrelevant background signals to autonomously discover AD-relevant voxel sets. Subsequently, to bridge the semantic gap between discrete voxels and clinical anatomy, these discovered signals are dynamically aggregated into coherent semantic regions. Finally, recognizing that AD pathology propagates through brain networks, we explicitly model the regional interaction among these defined areas using Graph Attention Network (GAT). This voxel-region-network progression allows the model to transparently zoom out from local cues to global interactions. Validated on the Alzheimer's Disease Neuroimaging Initiative (ADNI) and Australian Imaging, Biomarkers and Lifestyle Study (AIBL) datasets, our method achieves performance comparable to state-of-the-art black-box models while autonomously reconstructing established neuropathological trajectories. Crucially, by extracting high-fidelity pathological signals, it offers a trustworthy tool for precise disease diagnosis and potentially serves as a digital biomarker discovery instrument for localizing subtle prodromal lesions. The source code is publicly available at: https://github.com/k-Jayus/HiEM.},
}
@article {pmid42585761,
year = {2026},
author = {Juanlu, C and Chen, LH},
title = {Pharmacological targeting of neuroimmune-synaptic interactions in Alzheimer's disease: Integrating NETosis, microglia, and synaptic vulnerability.},
journal = {Current opinion in pharmacology},
volume = {90},
number = {},
pages = {102650},
doi = {10.1016/j.coph.2026.102650},
pmid = {42585761},
issn = {1471-4973},
abstract = {Alzheimer's disease (AD) is increasingly recognized as a disorder involving interacting neuroimmune, glial, vascular, and synaptic processes that are not fully captured by single-pathway therapeutic models. Although anti-amyloid monoclonal antibodies slow clinical progression in selected early amyloid-positive patients, their benefit remains stage-dependent, monitoring-intensive, and incomplete with respect to downstream neural dysfunction. Clinically, vulnerable older adults may show abrupt cognitive decline after pneumonia-related hospitalization or other severe infections. This observation raises a pharmacological question: whether infection-triggered peripheral immune events activate modifiable risk processes before they become sustained neuroimmune and synaptic dysfunction. NETosis is one candidate mechanism linking peripheral inflammatory stress to endothelial injury, blood-brain barrier vulnerability, myeloid priming, and microglial dysregulation. Acute infection may represent a high-intensity peripheral NETosis-related trigger, whereas periodontitis provides a chronic, low-grade, neutrophil-rich, microbially driven, clinically measurable, and modifiable peripheral inflammatory model. We propose a node-based pharmacological framework organized around NETosis-associated immune amplification, microglial state dysregulation, and synaptic vulnerability. Selected phytochemicals are examined as node-aligned pharmacological probes rather than validated AD therapeutics: baicalin and hesperidin for NETosis-associated immune amplification, berberine for microglial state modulation, and catalpol as a synapse-proximal candidate.},
}
@article {pmid42585804,
year = {2026},
author = {Sun, J and Yu, M and Li, H and Ma, L},
title = {Edaravone dexborneol alleviates neuronal senescence injury by mitigating the innate immune response.},
journal = {Tissue &amp; cell},
volume = {104},
number = {Pt 1},
pages = {103821},
doi = {10.1016/j.tice.2026.103821},
pmid = {42585804},
issn = {1532-3072},
abstract = {Aging is a key risk factor for neurodegenerative diseases, contributing to progressive neuronal damage and closely linked to the onset and progression of conditions like Alzheimer's and Parkinson's diseases. However, the effect of edaravone dexborneol (EDB) on neuronal senescence remains unclear, which is an urgent scientific question to be addressed. In this study, we established models of neuronal senescence induced by oxidative stress and OGD/R. EDB treatment partially restored the proliferation inhibition of senescent cells. EDB treatment significantly decreased senescence markers, as indicated by reduced senescence-associated β-galactosidase staining and lower p16 and p21 protein expression. Subsequent research demonstrated that EDB improved mitochondrial membrane potential and replenished intracellular ATP levels. In the OGD/R-induced neuronal injury model, EDB treatment notably decreased the expression of senescence markers (p16/p21/p53). Mechanistic studies revealed that EDB not only alleviated oxidative stress but also inhibited the cGAS-STING-mediated innate immune signaling pathway. This study is the first to demonstrate that EDB mitigates mitochondrial damage to exert anti-neuronal senescence effects, offering a novel intervention strategy for aging-related neurodegenerative diseases.},
}
@article {pmid42585890,
year = {2026},
author = {Şenol, H and Demir, Y and Tokalı, P and Şenol, AM and Akyıldırım, O and Tokalı, FS},
title = {Development of novel diaryl ether-phenolic Mannich Base derivatives with potent cholinesterase inhibition and low neuronal toxicity.},
journal = {Bioorganic chemistry},
volume = {181},
number = {},
pages = {110354},
doi = {10.1016/j.bioorg.2026.110354},
pmid = {42585890},
issn = {1090-2120},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cholinergic dysfunction, making acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) attractive therapeutic targets. In the present study, twelve novel phenolic Mannich base-derived hydrazones incorporating a diaryl ether scaffold were rationally designed, synthesized, and evaluated as cholinesterase inhibitors. All synthesized compounds exhibited potent nanomolar inhibition against both cholinesterases, with Ki values ranging from 24.27 to 98.56 nM for AChE and 28.68-148.41 nM for BChE. Compound 5 was identified as the most potent AChE inhibitor (Ki = 24.27 nM), whereas compound 6 showed the highest BChE inhibitory activity (Ki = 28.68 nM). Both compounds were considerably more potent than the reference inhibitors tacrine and donepezil. Enzyme kinetic studies revealed that all compounds acted as competitive inhibitors. Cytotoxicity evaluation against SH-SY5Y neuronal cells demonstrated low toxicity, with IC50 values ranging from 33.41 to 46.79 μM, indicating that effective cholinesterase inhibition occurred at concentrations far below those affecting neuronal cell viability. Molecular docking and MD simulations demonstrated stable binding of the most active compounds within the catalytic gorge of both enzymes through persistent hydrogen bonds, cation-π, and π-π interactions with key active-site residues. MM-GBSA and energy decomposition analyses further supported their favorable binding affinities. In addition, the synthesized compounds exhibited acceptable predicted pharmacokinetic properties, including favorable parameters related to blood-brain barrier permeability and oral absorption. These results identify phenolic Mannich base-derived hydrazones as promising lead compounds for the development of new cholinesterase inhibitors for the treatment of Alzheimer's disease.},
}
@article {pmid42586144,
year = {2026},
author = {Liu, X and Zhang, M and Wang, R and Sun, L and Hou, S},
title = {MDEEG-IMPA: Integrating multidimensional EEG features with an improved MPA for high-precision diagnosis neurodegenerative disease.},
journal = {Journal of neural engineering},
volume = {},
number = {},
pages = {},
doi = {10.1088/1741-2552/ae98ba},
pmid = {42586144},
issn = {1741-2552},
abstract = {OBJECTIVE: Current clinical differentiation of Alzheimer's disease (AD) and frontotemporal dementia (FTD) suffers from a misdiagnosis rate exceeding 40% due to overlapping symptomatology, and existing Electroencephalography (EEG)-based tools inadequately integrate multidimensional features or lack adaptive optimization. We aimed to develop a framework combining periodic and aperiodic EEG features with adaptive optimization for high-precision differential diagnosis.<br><br>APPROACH: We proposed a dual-branch neural network integrating multi-dimensional electroencephalogram (MDEEG) features with an improved Marine Predator Algorithm (IMPA). The MDEEG-IMPA model combines Convolutional Neural Network (CNN)-based power spectral density (PSD) feature extraction with a fully connected branch for aperiodic parameters (1/f offset and exponent), enhanced by IMPA for adaptive feature weighting. The model was evaluated on resting-state EEG from 88 subjects (36 AD, 23 FTD, 29 healthy controls (HC)).<br><br>MAIN RESULTS: MDEEG-IMPA achieved 99.20% accuracy in discriminating AD from FTD (Recall = 98.82%, F1-score = 99.02%), substantially outperforming comparative methods including STEADYNnet (84.59%) and SVM (93.5%). The MDEEG-IMPA model demonstrated robust performance in discriminating between AD and HC (Accuracy = 98.11%) and between FTD and HC (Accuracy = 98.95%). Ablation studies confirmed that 96.3% of the improvement in performance originated from the synergy between features and algorithms.<br><br>SIGNIFICANCE: The MDEEG-IMPA framework provides a reliable, high-precision computer-assisted diagnostic solution for neurodegenerative diseases with overlapping clinical presentations. By integrating periodic and aperiodic EEG features within an optimized multi-branch architecture, this work demonstrates that multidimensional electrophysiological characterization combined with adaptive optimization can substantially improve differential diagnostic accuracy, offering significant potential for clinical translation in early and accurate identification of AD and FTD.},
}
@article {pmid42586245,
year = {2026},
author = {Rathore, S and Gupta, A and Shah, K and Chauhan, NS and Gupta, SK},
title = {Targeting the Hallmarks of Ageing: Pharmacological Challenges and Breakthroughs in CRISPR Delivery Systems and Future Prospects.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103301},
doi = {10.1016/j.arr.2026.103301},
pmid = {42586245},
issn = {1872-9649},
abstract = {CRISPR has emerged as a next-generation gene-editing tool with the potential to target the molecular pathways associated with ageing and related disorders. It functions through RNA-guided Cas nucleases, directing DNA cleavage and utilizing the native DNA repair machinery for genetic manipulations. Advances in CRISPR technology have significantly enhanced the precision and flexibility of techniques for genome editing. The enzyme Cas9's ability to cut DNA at exact site has revolutionized genome editing by enabling accurate modifications within living eukaryotic cells. This review critically examines recent developments in CRISPR-based technologies, including Cas9, Cas12, base editing, prime editing, and CRISPR-mediated gene regulation. It highlights their rising applications in ageing research, with more emphasis on neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. The review also discusses the major pharmacological and translational challenges that currently limit clinical applications, including inefficient tissue-specific delivery, off-target genome editing, immunogenicity, manufacturing complexity, and long-term safety concerns. Also, recent progress in both, viral and non-viral delivery methods are critically evaluated, including adeno-associated viruses, lentivirus vectors, lipid nanoparticles, gold nanoparticles, exosomes, electroporation, and microinjection, is thoroughly discussed to highlight their therapeutic potential and translational limitations. Current studies indicate that CRISPR-based approaches have preclinical potential for targeting important hallmarks of ageing, particularly genomic instability, telomere attrition, and mitochondrial dysfunction. Other hallmarks of ageing, such as stem cell exhaustion, epigenetic modifications, and microbiome changes, are at earlier stages of development. Overall, this review describes future strategies for developing safe, precise, and clinically translatable CRISPR-based treatments to promote healthy ageing.},
}
@article {pmid42586290,
year = {2026},
author = {Zhang, C and Cheng, C and Wang, L and Zhang, H and Yu, Y and Zhang, J and Zhang, J},
title = {Bibliometric analysis in the field of photobiomodulation in the last two decades: research trends and evolution of hot topics.},
journal = {Photodiagnosis and photodynamic therapy},
volume = {},
number = {},
pages = {105610},
doi = {10.1016/j.pdpdt.2026.105610},
pmid = {42586290},
issn = {1873-1597},
abstract = {BACKGROUND: Photobiomodulation (PBM) has evolved into a vibrant interdisciplinary field. Despite rapid research expansion, a comprehensive quantitative mapping of its knowledge structure, key contributors, and emerging trends remains lacking.<br><br>METHODS: We conducted a bibliometric analysis of PBM publications from the Web of Science Core Collection (2006-2025). Knowledge mapping utilized CiteSpace, VOSviewer, and the bibliometrix R package. Additionally, PubMed clinical trial data were extracted to cross-validate bibliometric trends with actual clinical practice.<br><br>RESULTS: We identified 4,907 publications, exhibiting a compound annual growth rate of 14.67%. Michael R. Hamblin was the most prolific author (n=100, h-index=54), and Lasers in Medical Science was the core journal (n=1,180). Brazil dominated global output (32.2%, n=1,579), led by the University of S&#xe3;o Paulo (n=821). Thematic analysis highlighted "photobiomodulation" and "low-level laser therapy" as fundamental themes, while "Alzheimer's disease" emerged as a specialized, rapidly growing niche.<br><br>CONCLUSIONS: Over two decades, PBM has matured into a promising mainstream therapeutic modality. Future research must prioritize the standardization of treatment parameters, alongside deeper exploration of biological mechanisms and long-term clinical validation. This 20-year mapping provides a strategic roadmap to guide evidence-based PBM practice.},
}
@article {pmid42586342,
year = {2026},
author = {Kim, HJ and Kim, DH and Han, CW and Jeong, MS and Jang, SB},
title = {Structural basis of α-synuclein and DJ-1 complex.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {154021},
doi = {10.1016/j.ijbiomac.2026.154021},
pmid = {42586342},
issn = {1879-0003},
abstract = {The structure of α-synuclein is predominantly α-helical when bound to cellular membranes. However, under pathological or destabilizing conditions, this α-helical structure transitions into β-sheet-rich conformations, promoting protein aggregation and formation of Lewy bodies (LBs) in neurodegenerative disorders such as Parkinson's disease dementia (PDD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and Alzheimer's disease (AD). DJ-1 is a multifunctional brain protein acting as a chaperone or protease under oxidative stress and associating with abnormal protein aggregates. Although previous studies suggested DJ-1 inhibits α-synuclein aggregation, the structural basis remained elusive. Here, we elucidate the direct interaction between α-synuclein and DJ-1 using size-exclusion chromatography (SEC), fluorescence spectroscopy, and multi-angle light scattering (MALS), and determined their crystal structure by X-ray diffraction. The interaction interface was mapped to residues Q24, E28, A29, and N65 of α-synuclein and K148, N173, and Q180 of DJ-1, with Q180 forming strong hydrogen bonds (2.60-2.97 Å) with α-synuclein. Transmission electron microscopy (TEM) demonstrated DJ-1 suppresses α-synuclein fibril formation. Based on the structure, we designed a DJ-1-derived peptide (173-180) that significantly inhibited α-synuclein aggregation in TEM and ELISA assays, suggesting its potential as a therapeutic candidate for α-synucleinopathies.},
}
@article {pmid42586403,
year = {2026},
author = {Faieta, JM and Devos, H and Philippou, E and Negm, A and Vaduvathiriyan, P and Erickson, KI and Hirsch, MA and van Wegen, EEH and Fakorede, S and Dagne, MB and Wong, KLY and Krishnan, S and Kahya, M and Sood, P and Heyn, PC},
title = {Exercise Interventions for Older Adults with Alzheimer's Disease: A Systematic Review and Meta-Analysis.},
journal = {Archives of physical medicine and rehabilitation},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.apmr.2026.08.001},
pmid = {42586403},
issn = {1532-821X},
abstract = {OBJECTIVE: Increased Alzheimer's disease (AD) prevalence paired with improved ability to diagnose the disease at earlier stages now, more than ever, necessitates interventions that will support the AD population for extended periods of time. Even with the substantial body of literature available, the effectiveness of physical exercise (PE) on various cognitive domains and the optimal dosage of PE are yet to be confirmed. Therefore, our objectives were to determine 1) the effectiveness of PE on cognitive function in older adults with AD, and 2) the optimal PE dosage for targeted outcomes.<br><br>DATA SOURCES: The search was carried out across Embase, PsycInfo, and Ovid Medline databases.<br><br>STUDY SELECTION: Of an initial return of 1,001 articles, 142 remained after title and abstract review, and 21 after full text review.<br><br>DATA EXTRACTION: Primary outcomes extracted from included articles spanned four cognitive domain outcomes (global cognition, memory, language, attention, and executive function). Data on secondary outcomes included activities of daily living, emotional well-being, quality of life, and caregiver burden.<br><br>DATA SYNTHESIS: The 21 included studies were published between 1991 and 2020 and sample sizes ranged from 12 to 494. Results confirm significant improvement in 4 of 5 cognitive domains favoring PE versus control conditions. Similarly, results favored exercise over control conditions for activities of daily living, emotional well-being, and quality of life outcomes, but not caregiver burden. The optimal PE dose was determined to be less than 60 minutes at least 3 times per week as compared to fewer more intense bouts.<br><br>CONCLUSIONS: The results of this systematic review and meta-analysis provide important insight into the effectiveness of exercise on cognitive outcomes and guidance on the most effective PE parameters for optimizing cognitive function in AD.},
}
@article {pmid42586624,
year = {2026},
author = {},
title = {Expression of Concern: "Pharmacological activation of the Nrf2 pathway by 3H-1, 2-dithiole-3-thione is neuroprotective in a mouse model of Alzheimer disease'' [BBR, 336 (2018) pp 219-226].},
journal = {Behavioural brain research},
volume = {514},
number = {},
pages = {116388},
doi = {10.1016/j.bbr.2026.116388},
pmid = {42586624},
issn = {1872-7549},
}
@article {pmid42586939,
year = {2026},
author = {Sheng, S},
title = {Gait Disturbances and Alzheimer's Disease Pathology: Unresolved Causal-Temporal Ambiguities and Methodological Considerations for the Proposed Mechanistic Framework.},
journal = {Geriatrics &amp; gerontology international},
volume = {26},
number = {8},
pages = {e70799},
doi = {10.1111/ggi.70799},
pmid = {42586939},
issn = {1447-0594},
}
@article {pmid42587009,
year = {2026},
author = {Barnett, EJ and Hess, JL and Hou, J and Escott-Price, V and Fennema-Notestine, C and Kremen, W and Lin, SJ and Zhang, C and Demontis, D and Børglum, AD and Gaiteri, C and Elman, J and Holmans, P and Faraone, SV and Glatt, SJ},
title = {A novel method to disentangle tightly linked risk and resilience genes for brain disorders: application to Alzheimer's disease.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42587009},
issn = {1476-5578},
abstract = {Genetic risk factors for neuropsychiatric disorders are well documented. However, some individuals with high genetic risk remain unaffected, and the mechanisms underlying such resilience remain poorly understood. The presence of protective resilience factors that mitigate risk could help explain the disconnect between predicted risk and reality, particularly when genetic contributions are substantial but incompletely understood. Identifying and studying resilience factors could improve our understanding of pathology, enhance risk prediction, and inform preventive measures or treatment strategies. However, such efforts are complicated by the difficulty of identifying resilience that is separable from low risk. We developed a novel adversarial multi-task neural network model to detect genetic resilience markers. The model learns to separate high-risk unaffected individuals from affected individuals at similar risk while "unlearning" patterns found in low-risk groups using adversarial learning. In simulated and existing Alzheimer's disease (AD) datasets, we identified markers of resilience with a feature-importance-based approach that prioritized specificity, generated resilience scores, and analyzed associations with polygenic risk scores (PRS). In simulations, our model had high specificity and sensitivity in identifying resilience markers, significantly outperforming traditional approaches. Applied to AD data, the model generated genetic resilience scores protective against AD and independent of PRS. We identified five resilience-associated SNPs, including known AD-associated variants, underscoring their potential involvement in resilience. Our findings support the utility of resilience scores in modifying risk predictions, particularly for high-risk groups. Expanding this method could aid in understanding resilience mechanisms, potentially improving diagnosis, prevention, and treatment strategies for AD and other brain disorders.},
}
@article {pmid42587122,
year = {2026},
author = {Dolgin, E},
title = {A controversial Alzheimer's surgery is said to reverse symptoms - here's what scientists know.},
journal = {Nature},
volume = {656},
number = {8127},
pages = {286-289},
pmid = {42587122},
issn = {1476-4687},
}
@article {pmid42587138,
year = {2026},
author = {Feng, X and Jiang, BW and Zhai, SN and Liu, CX and Wu, H and Zhu, BQ and Wei, MY and Wei, J and Yang, L and Chen, LL},
title = {Author Correction: Circular RNA aptamers targeting neuroinflammation ameliorate Alzheimer disease phenotypes in mouse models.},
journal = {Nature biotechnology},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41587-026-03281-3},
pmid = {42587138},
issn = {1546-1696},
}
@article {pmid42587229,
year = {2026},
author = {Sahu, S and Chidamabaram, H and Ananthanarayanan, V and Qureshi, T and Desale, S and Chandrashekar, M and Santhoshkumar, R and Mishra, M and Chinnathambi, S},
title = {Oral Administration of Different Forms of Exogenous Tau Protein Induces Multi-Organ Defects Across Developmental Stages in Drosophila melanogaster.},
journal = {Neurotoxicity research},
volume = {44},
number = {4},
pages = {},
pmid = {42587229},
issn = {1476-3524},
mesh = {Animals ; *tau Proteins/administration &amp; dosage/toxicity ; Drosophila melanogaster ; Larva/drug effects ; Administration, Oral ; *Drosophila Proteins/administration &amp; dosage ; Apoptosis/drug effects ; Reactive Oxygen Species/metabolism ; Pupa/drug effects ; },
abstract = {Tau is a crucial protein involved in many neurodegenerative diseases, including Alzheimer's disease. Natively, Tau is an unfolded protein found predominantly in axons that play a vital role in maintaining and stabilizing microtubules. Under pathological circumstances, Tau disengages from microtubules and forms insoluble intracellular filaments on its own, building neurofibrillary tangles in the brains of Alzheimer's patients. Although Tau exists in aggregates found in the brain and gut of Alzheimer's patients, the function of Tau in the brain is well studied, while the role of Tau in the gut needs further investigation. We have investigated the effects of Tau monomer, oligomer, and aggregates at 10 µM concentration via feeding them to the third instar larvae. To evaluate the genotoxicity, we did 4', 6-diamidino-2-phenylindole staining, while dichloro-dihydro-fluorescein diacetate staining was performed to assess cytotoxicity. Furthermore, we performed a TUNEL assay to detect apoptotic cells. Additionally, we carry out an NBT assay for biochemical estimation of reactive oxygen species by extracting hemolymph. Phenotypes were examined in different stages, i.e., larvae, pupae, and adult flies. Histological studies were performed on eye, gut tissue and reproductive organs of D. melanogaster to check the cytoskeletal alterations. The current study finds that the administration of monomer, oligomer, and aggregate forms causes genotoxicity, cytotoxicity, and cytoskeletal defects in D. melanogaster.},
}
@article {pmid42587260,
year = {2026},
author = {Musaeus, CS and Hasselbalch, SG and Waldemar, G and Sellebjerg, F and Budtz-Jørgensen, E and Simonsen, AH},
title = {Cerebrospinal fluid/plasma albumin quotient in dementia: a systematic review of biomarker potential and clinical associations.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42587260},
issn = {2509-2723},
abstract = {The blood-cerebrospinal fluid barrier (BCB) maintains central nervous system homeostasis. Its dysfunction, reflected by an increased cerebrospinal fluid/plasma albumin ratio (Q-Alb), has been reported in several neurodegenerative diseases. However, the diagnostic utility of Q-Alb in dementia remains uncertain. This review aimed to systematically evaluate Q-Alb as a biomarker in dementia by examining inter-group differences, diagnostic performance, and associations with other biomarkers. To address this questions, PubMed was searched for observational and longitudinal studies reporting Q-Alb in patients with dementia and healthy controls (HC). Data on Q-Alb levels, diagnostic accuracy, and biomarker associations were extracted. Meta-analyses were performed for Alzheimer's disease (AD) and vascular dementia (VaD). The search identified forty-three studies, spanning AD, VaD, Parkinson's disease (PD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD). Q-Alb was significantly higher in VaD compared with HC (pooled standardized mean difference 0.69, 95% CI: 0.53-0.86) and moderately increased in AD compared with HC (0.25, 95% CI: 0.14-0.36). Only two studies directly investigated the diagnostic accuracy. Q-Alb correlated positively with IgG index, neurofilament light chain, and vascular and inflammatory markers. Taken together, these findings suggest that Q-Alb is not a reliable standalone diagnostic biomarker, particularly for AD, but is consistently elevated in VaD and disorders with subcortical or vascular pathology. Findings support its role as a supportive marker of blood-cerebrospinal fluid barrier dysfunction. Further large, multimodal studies integrating vascular imaging are warranted to clarify its diagnostic and prognostic utility.},
}
@article {pmid42587262,
year = {2026},
author = {Martínez-Flores, R and Zapata, LP and Del Campo Milan, M and Blasco-Forniés, H and Jiménez-Moyano, E and Torres-Torronteras, J and Suárez-Calvet, M and Ibáñez, A and Martín-Sobrino, I and Falgàs, N and Grau-Rivera, O and Cristi-Montero, C and Perone, C and Supèr, H},
title = {Attentionally directed oculomotor training produces disease-stage-dependent effects on plasma tau, cognition, and oculomotor signatures in patients with mild cognitive impairment.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42587262},
issn = {2509-2723},
support = {PID2022-139968OB-I00//Ministerio de Ciencia, Innovaci&#xf3;n y Universidades/ ; },
abstract = {Attentionally directed oculomotor training may engage circuits implicated in gamma-band modulation and early Alzheimer's disease (AD) pathophysiology, yet its effects across mild cognitive impairment (MCI) risk strata remain unclear. We aimed to determine whether this training, delivered through a gamified eye-tracking task, is associated with differential effects on plasma neurodegeneration biomarkers, cognitive performance, and oculomotor signatures in individuals with MCI at differential risk of conversion to Alzheimer's dementia. Twenty-nine participants with MCI were stratified into MCI-HR (n = 17) and MCI-LR (n = 12) based on validated MoCA and MoCA-MIS cut-off scores and completed 8 weeks of daily oculomotor training. Outcomes were assessed pre/post using permutation tests, bootstrapped Hedges' g, and linear mixed-effects models. Cognitive performance improved in both groups (MoCA: g = 1.27-2.17; MoCA-MIS: g = 1.02-1.68), with no between-group difference. Plasma tau diverged by stratum: MCI-LR showed reductions in pTau-181 (g = -0.64, 95% CI [-1.07, -0.15]) and pTau-217 (g = -0.72, 95% CI [-1.08, -0.36]), whereas MCI-HR showed an increase in pTau-181 (g = 0.82, 95% CI [0.53, 1.16]; between-group g = 1.31, 95% CI [0.89, 1.78], p = 0.001). Amyloid, GFAP, and NfL remained stable. MCI-HR showed reduced accuracy and increased reaction times (+196.4 ms, p < 0.001); MCI-LR maintained stable performance. Oculomotor signatures diverged between strata post-training (group × time × stimulus interactions, p = 0.013-0.045). In MCI-LR, oculomotor changes correlated with reductions in pTau-181 (ρ = -0.60, 95% CI [-0.96, -0.20]) and pTau-217 (ρ = -0.69, 95% CI [-0.95, -0.20]). Oculomotor training produced stratum-dependent responses: biomarker reductions and oculomotor-molecular coupling in MCI-LR, and dissociated physiological and behavioral outcomes in MCI-HR, suggesting disease-stage-specific neuroplasticity capacity linked to tau-related processes.},
}
@article {pmid42587389,
year = {2026},
author = {Grant, RA and Doser, RL and LaRocca, TJ},
title = {Distinct Transposable Element Transcript Patterns in Microglia Across Aging and Alzheimer's Disease.},
journal = {Aging cell},
volume = {25},
number = {8},
pages = {e70653},
doi = {10.1111/acel.70653},
pmid = {42587389},
issn = {1474-9726},
support = {AG078859/NH/NIH HHS/United States ; },
mesh = {*Alzheimer Disease/genetics/pathology/metabolism ; *Microglia/metabolism/pathology ; Humans ; Animals ; *Aging/genetics ; Mice ; *DNA Transposable Elements/genetics ; Aged, 80 and over ; Mice, Transgenic ; Female ; },
abstract = {Microglia, the brain's resident immune cells, are transcriptionally diverse and highly dynamic, but during aging and disease they lose their transcriptomic flexibility and adopt a chronically activated state that is associated with neuroinflammation and pathology. An emerging transcriptomic process that is also increasingly implicated in brain aging, neuroinflammation, and disease is the dysregulation of transposable elements (TEs), repetitive genomic sequences with the potential to cause cellular stress/dysfunction. However, there are limited data on microglial TE transcript patterns in these contexts. Here, we analyzed multiple RNA-seq datasets from isolated human and mouse microglia across aging, Alzheimer's disease (AD), and AD-associated pathology. In contrast to previous observations based on whole-brain tissue and other brain cell types, we found that microglial TE transcript levels remained relatively consistent throughout most of the human lifespan before increasing in late life. We also found that TE transcript levels in microglia from AD patients showed minimal changes compared to age-matched controls, and in RNA-seq analyses of transgenic AD mouse models we observed pathology-associated TE transcript decreases. Subsequent analyses identified inverse associations between TE transcript levels and autophagy/lysosome-related gene expression, and in vitro studies suggested that aging- and AD-relevant stimuli, as well as pharmacological autophagy inhibition, modulate TE transcript expression in cultured human microglia. Together, these data provide novel insight into TE transcript dynamics in microglia, highlighting TE transcript patterns that differ from those observed in whole-brain samples and other cell types in aging and AD.},
}
@article {pmid42587631,
year = {2026},
author = {Salluzzo, MG and Schillaci, FA and Zago, E and Fucile, S and Marcolungo, L and Schinocca, P and Lanza, G and Ferri, R and Leonardi, G and Salemi, M},
title = {Genetic Overlap Between Dilated Cardiomyopathy and Neurological Disorders: Insights from a Next-Generation Sequencing Study.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {16},
number = {15},
pages = {},
doi = {10.3390/diagnostics16152395},
pmid = {42587631},
issn = {2075-4418},
support = {"Ricerca Corrente" (RC n. 2795124)//Ministry of Health/ ; },
abstract = {Background/Objectives: Dilated cardiomyopathy (DCM) is a genetically heterogeneous myocardial disorder. Emerging evidence suggests that some genes implicated in DCM may also be associated with neurological disorders, supporting the concept of genetic pleiotropy. This study explored the intersection between cardiac and neurological genetics, with the aim of identifying candidate genes that may contribute to shared pathogenic pathways linking these clinically distinct conditions. Methods: We performed exome sequencing in 149 patients with echocardiographically confirmed DCM and subsequently applied an in silico filter to a predefined list of 211 genes associated with inherited cardiomyopathies. Variants were classified according to the American College of Medical Genetics and Genomics (ACMG) criteria. Genes with validated evidence for DCM according to the Clinical Genome Resource (ClinGen) were further investigated through the Human Gene Mutation Database (HGMD) and a focused literature review to identify reported associations with neurological disorders. Results: Genetic variants in DCM-associated genes were identified in 105 patients. Overall, 137 variants were detected, including pathogenic variants and variants of uncertain significance. The most frequently involved genes were TTN, FLNC, and MYH6. Several DCM-associated genes also showed reported associations with neurological disorders, including autism spectrum disorder, Alzheimer's disease, Parkinson's disease, epilepsy, and schizophrenia. Among them, TTN, FLNC, RYR2, and SCN5A displayed the broadest overlap between cardiac and neurological phenotypes. Conclusions: These descriptive findings show that variants were most frequently observed in TTN, FLNC, and MYH6 and that several genes included in the ClinGen DCM curation framework have also been independently reported in neurological disorders. Because most identified variants were VUS and no control group or systematic neurological phenotyping was available, the findings indicate gene-level co-annotation only and do not establish variant enrichment, shared pathogenic mechanisms, or clinical overlap.},
}
@article {pmid42587665,
year = {2026},
author = {Al-Hatab, MMM and Al-Mallah, RHA and Qasim, MA and Mohammed, MF and Rassem, TH and Ahmed, AA},
title = {PCA-Enhanced Deep Features for Alzheimer's Disease Stage Classification with EFMM.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {16},
number = {15},
pages = {},
doi = {10.3390/diagnostics16152428},
pmid = {42587665},
issn = {2075-4418},
abstract = {Background/Objectives: Alzheimer's disease (AD) is a progressive neurodegenerative disorder necessitating accurate and timely diagnosis for effective clinical intervention. While deep learning methods have shown promise in AD classification, many rely on computationally intensive architectures and high-dimensional feature representations. This study introduces a lightweight hybrid framework combining deep feature extraction, dimensionality reduction, and adaptive classification for MRI-based Alzheimer's disease stage classification. Methods: Utilizing MRI images from a publicly available Alzheimer's disease dataset encompassing four clinical stages (Non-Demented, Very Mild Demented, Mild Demented, and Moderate Demented), deep features were extracted using a pre-trained SqueezeNet model as a fixed feature extractor, generating 1000-dimensional feature vectors. Due to the computational complexity and for the improvement of the model efficiency, the dimensionality reduction technique, Principal Component Analysis (PCA) was then applied. This resulted in an optimum representation of 100 principal components, retaining about 96% of the variance. Then, the performances of various machine learning classifiers such as k-Nearest Neighbors (kNN), Support Vector Machine (SVM), Decision Tree (DT), Neural Network (NN), Naïve Bayes (NB), Logistic Regression (LR) and Enhanced Fuzzy Min-Max Neural Network (EFMM) were tested. The accuracy, precision, recall, F1-score, area under the receiver operating characteristic curve (AUC), and confusion matrices were used to evaluate the performance. Stratified 5-fold cross validation was used to ensure the strength of our results. Results: The findings show that PCA has a significant improvement in classification accuracy for most of the models. In particular, the EFMM classifier outperformed the other classifiers, with an accuracy of 97.19% on the independent test set. After PCA, the AUC values for classes such as Mild Demented, Moderate Demented, Non-Demented and Very Mild Demented were obtained as 97.12%, 99.97%, 93.79% and 95.26% respectively. We further validated our proposed framework using stratified 5-fold cross validation which further corroborated the robustness of our proposed framework. The EFMM achieved a mean accuracy of 98.38% ± 0.36 and a mean macro-F1 score of 98.48% ± 0.43. Friedman statistical testing demonstrated that there were significant differences between the performance of the classifiers evaluated (p < 0.001), which further validated the performance of the EFMM. Conclusions: To sum up, the proposed SqueezeNet-PCA-EFMM is an effective and efficient method for Alzheimer's disease stage classification under MRI images. The combination of SqueezeNet, PCA, and EFMM-led not only to high classification performance, but also to good cross validation results. Furthermore, this property of incremental learning is the intrinsic one of the EFMM and renders this framework interesting for its incorporation in the next-generation intelligent clinical decision supports in particular, as medical care evolves.},
}
@article {pmid42587775,
year = {2026},
author = {Krupa, JM and Medapati, MR and Naqvi, AM and Hallam, RD and Tsang, AR and Seah, C and Whitehead, SN and Pasternak, SH},
title = {Macropinocytosis of Amyloid Precursor Protein Is Regulated by the Recruitment and Activity of Fe65, Arf6 and Rho GTPases.},
journal = {Cells},
volume = {15},
number = {15},
pages = {},
doi = {10.3390/cells15151366},
pmid = {42587775},
issn = {2073-4409},
support = {N/A//Beaconbright Foundation/ ; },
mesh = {ADP-Ribosylation Factor 6/metabolism ; Humans ; *Amyloid beta-Protein Precursor/metabolism ; *Pinocytosis ; *rho GTP-Binding Proteins/metabolism ; Animals ; *Nerve Tissue Proteins/metabolism ; *ADP-Ribosylation Factors/metabolism ; Alzheimer Disease/metabolism ; Protein Binding ; cdc42 GTP-Binding Protein/metabolism ; Nuclear Proteins ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the buildup of aggregated amyloid-beta (Aβ) peptides. We previously demonstrated that Aβ is produced from APP following its lysosomal internalization via macropinocytosis. However, the regulation of APP macropinocytosis in neuronal cells remained uncharacterized. Arf6 and the Rho GTPases Rac1, Cdc42 and RhoA are known to regulate macropinocytosis in response to signaling at the cell surface. Fe65, an adaptor protein known to interact with APP, may link APP to these regulatory elements. We hypothesized that APP binding/crosslinking recruits Fe65, which recruits/activates Arf6 and then Rac1, Cdc42, and RhoA, driving APP macropinocytosis. We found that antibody-mediated binding/crosslinking APP resulted in the transient recruitment of Fe65 and Arf6 to APP within 30 s of APP binding/crosslinking. Rac1, Cdc42, and RhoA were also recruited at 30 s, but remained recruited through 2 min. The mutation of the APP 'YENPTY' sequence and Arf6 inhibition by NAV-2729 prevented the recruitment of Rac1, Cdc42, and RhoA. Together, these observations are the first to demonstrate that a network of regulatory proteins is recruited to bound/crosslinked APP and regulates its macropinocytosis. Targeting these regulatory proteins to modulate APP trafficking to the lysosome could be a therapeutic strategy to reduce Aβ production in AD.},
}
@article {pmid42587777,
year = {2026},
author = {Xiao, L and Green, JM and Mochizuki, M and Nakahara, T},
title = {Exercise as a Systemic Prevention and Management for Alzheimer's Disease: Restoring Brain-Body Homeostasis Through Metabolic, Neurovascular, Anti-Inflammatory, and Regenerative Mechanisms.},
journal = {Cells},
volume = {15},
number = {15},
pages = {},
doi = {10.3390/cells15151368},
pmid = {42587777},
issn = {2073-4409},
support = {26K12666//Japan Society for the Promotion of Science/ ; 25K13155//Japan Society for the Promotion of Science/ ; 23K21496//Japan Society for the Promotion of Science/ ; },
mesh = {Humans ; *Alzheimer Disease/prevention &amp; control/metabolism/therapy/physiopathology ; *Homeostasis ; *Brain/metabolism/physiopathology ; *Exercise/physiology ; Animals ; Inflammation ; *Regeneration ; Aging ; },
abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disorder worldwide and remains a major unmet medical challenge in aging societies. Although amyloid-β (Aβ) plaques and tau pathology are hallmark features of AD, the limited efficacy of many Aβ- and tau-targeted therapies suggests that AD arises from systemic and cerebral dysfunction. Aging-associated homeostatic failure-including hepatic metabolic, vascular, neuroendocrine, inflammatory, oxidative, and mitochondrial dysfunctions-promotes the accumulation of neurotoxic Aβ and tau species, ultimately driving neurodegeneration and impairing endogenous neuroregeneration. Emerging evidence suggests that regular physical exercise induces metabolic, cardiovascular, and neuroendocrine adaptations, improving hepatic metabolic function, cerebral blood flow, oxygen delivery, mitochondrial activity, waste clearance pathways, and brain health. Exercise-induced musculoskeletal-brain crosstalk further contributes to these benefits through the release of myokines and extracellular vesicles, which facilitate systemic intercellular communication to regulate neurovascular function, neuroplasticity, and neuroregeneration. Collectively, these adaptations reduce chronic inflammation and oxidative stress while enhancing resilience across interconnected peripheral and cerebral systems. Therefore, physical exercise may represent a multifaceted preventive and therapeutic strategy capable of restoring brain-body homeostasis and mitigating AD progression. This comprehensive review discusses aging-associated systemic mechanisms underlying AD pathogenesis and summarizes recent advances in the understanding of exercise-mediated protection against AD progression.},
}
@article {pmid42587788,
year = {2026},
author = {Zheng, C and Wen, K and Li, H and Zhang, T and Zhang, Y},
title = {Extracellular Aβ42 Oligomers Induce ROCK2 Hyperactivation Through Dual Mediation by RhoA and GzmB: Significance of Moderate ROCK2 Activity in Neural Cells.},
journal = {Cells},
volume = {15},
number = {15},
pages = {},
doi = {10.3390/cells15151379},
pmid = {42587788},
issn = {2073-4409},
support = {31970883//National Natural Science Foundation of China/ ; },
mesh = {*rho-Associated Kinases/metabolism ; Animals ; *Amyloid beta-Peptides/metabolism ; *Neurons/metabolism/pathology/drug effects ; Mice ; *rhoA GTP-Binding Protein/metabolism ; *Peptide Fragments/metabolism ; Alzheimer Disease/metabolism/pathology ; Humans ; Actin Cytoskeleton/metabolism ; Neurites/metabolism ; },
abstract = {Alzheimer's disease (AD) is characterized by neurite degeneration and neuronal death. Extracellular amyloid-β 1-42 (Aβ42) oligomers (EAO) not only disrupt the homeostasis and function of the extracellular matrix (ECM) but also damage neural cells through direct binding. Previous studies have demonstrated that EAO binding to membrane integrins reduces neuronal motility, adhesion, and neuritogenesis. To identify the key molecular switch(es) responsible for these actin cytoskeleton dysfunction-associated events, this study utilized neuronal and glial cell lines as well as AD model mice to investigate the cascade underlying EAO-induced actin cytoskeleton dysfunction. This study revealed that EAO induce the dual activation of ROCK2 through RhoA and granzyme B (GzmB) mediation, with GzmB-mediated ROCK2 activation constituting a significant component of this process. ROCK2 hyperactivation in response to EAO causes dynamic dysregulation of the actin cytoskeleton, defective neuritogenesis, and ultimately reduced cell survival, leading to disturbances in brain cell populations. However, the excessive inhibition of ROCK2 activity might cause excessive neurite outgrowth, which may disrupt intrinsic neuronal networks or normal neural transmission. Thus, the disruption of ROCK2 activity might lead to impaired neuritogenesis and disturbances in brain cell populations. The findings of this study may provide important insights into AD pathogenesis and feasible therapeutic targets.},
}
@article {pmid42588059,
year = {2026},
author = {Kupczyk, D and Bilski, R and Kozieł, I and Słota, A and Kurek, M and Stablewska, E and Baumgart, S and Słomka, A and Studzińska, R},
title = {Oxidative Stress in Alzheimer's Disease: Can Dietary Interventions Provide Neuroprotection?.},
journal = {Nutrients},
volume = {18},
number = {15},
pages = {},
doi = {10.3390/nu18152436},
pmid = {42588059},
issn = {2072-6643},
mesh = {Humans ; *Alzheimer Disease/diet therapy/metabolism/prevention &amp; control ; *Oxidative Stress/physiology ; Antioxidants ; Gastrointestinal Microbiome ; *Neuroprotection ; Animals ; Brain/metabolism ; *Diet ; Polyphenols ; *Neuroprotective Agents ; },
abstract = {Population aging is a growing problem. This process is driven not only by genetic factors but also by environmental factors, such as diet. Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia worldwide, characterized by cognitive decline, synaptic dysfunction, and neuronal loss. Despite extensive research, effective disease-modifying therapies remain limited. Increasing evidence indicates that oxidative stress plays a central role in AD pathogenesis, acting as a key link between β-amyloid accumulation, tau hyperphosphorylation, mitochondrial dysfunction, and neuroinflammation. Accordingly, dietary strategies have been proposed to mitigate these pathological processes and may represent an important component of Alzheimer's disease prevention. Moreover, emerging evidence on the gut-brain axis highlights the critical role of gut microbiota in regulating neuroinflammation and oxidative stress. Dysbiosis has been associated with increased permeability of the intestinal barrier, systemic inflammation, and accelerated neurodegeneration. Dietary patterns such as the Mediterranean, DASH, and MIND diets may exert beneficial effects by simultaneously influencing antioxidant status and microbial composition. This review aims to provide a comprehensive overview of the role of oxidative stress in Alzheimer's disease and evaluate the potential of dietary interventions in modulating mechanisms involved in Alzheimer's disease pathogenesis and supporting cognitive health. Particular attention is given to the neuroprotective effects of dietary antioxidants, including vitamins, polyphenols, and polyunsaturated fatty acids, which act through the reduction in reactive oxygen species, modulation of inflammatory pathways, and support of neuronal survival. Although current findings are promising, inconsistencies in clinical data indicate the need for further well-designed studies. Future research should focus on personalized nutritional strategies integrating dietary, genetic, and microbiome-related factors. Targeting oxidative stress through diet and microbiota modulation represents a promising complementary strategy for Alzheimer's disease prevention and supportive management, although further clinical studies are required to establish disease-modifying effects.},
}
@article {pmid42588063,
year = {2026},
author = {Justin Margret, J and Jain, SK},
title = {Vitamin D and L-Cysteine as Potential Regulators of Adiponectin in Alzheimer's Disease: A Narrative Review.},
journal = {Nutrients},
volume = {18},
number = {15},
pages = {},
doi = {10.3390/nu18152440},
pmid = {42588063},
issn = {2072-6643},
support = {5R33AT010637-01A1/NH/NIH HHS/United States ; 3R33AT010637-02S1/NH/NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy/blood ; *Adiponectin/metabolism/blood ; *Vitamin D/pharmacology ; *Cysteine/pharmacology ; Oxidative Stress/drug effects ; Animals ; Signal Transduction ; Dietary Supplements ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by amyloid-β buildup, tau pathology, neuroinflammation, and declining cognition. Adiponectin, a hormone produced by adipose tissue with insulin-sensitizing, anti-inflammatory, and antioxidant effects, may link peripheral metabolic health to brain function. Studies show that adiponectin helps neurons survive, improves synaptic plasticity, maintains blood-brain barrier integrity, and reduces amyloid-β and tau damage via AdipoR1/R2 signaling. Clinical studies evaluating circulating adiponectin have yielded inconsistent findings, giving rise to the 'adiponectin paradox' whereby elevated adiponectin levels in older adults and patients with AD may reflect frailty, weight loss, systemic inflammation, or compensatory responses rather than direct neuroprotective effects. Studies indicate that vitamin D (VD) and L-cysteine (L-Cys), a precursor to glutathione, act synergistically to modulate oxidative stress, inflammation, and adiponectin levels. VD increases circulating adiponectin and benefits metabolism, while L-Cys boosts glutathione, restores redox balance, and promotes adiponectin secretion by affecting fat cell function. Emerging experimental evidence, together with clinical observations from metabolic disorders, suggests that VD and L-Cys may influence adiponectin-related pathways, oxidative stress, and inflammation, which are implicated in AD pathogenesis. However, direct clinical evidence demonstrating that combined VD and L-Cys supplementation modulates these pathways or alters AD progression in humans is currently lacking. This narrative review covers current knowledge of adiponectin and its links to obesity, metabolic issues, and AD, and it also explores the roles of VD and L-Cys as regulators of adiponectin signaling. Overall, the available evidence supports the proposed interaction among VD-L-Cys and adiponectin, which warrants further mechanistic investigation and well-designed clinical studies to determine its therapeutic relevance in AD.},
}
@article {pmid42588092,
year = {2026},
author = {Dissanayaka, DMS and Rainey-Smith, SR and Sohrabi, HR and Jayasinghe, TN and Ho, V and Jayasena, V and Taddei, K and Masters, CL and Martins, RN and Fernando, WMADB},
title = {Gut Microbiome Changes in Preclinical Alzheimer's Disease.},
journal = {Nutrients},
volume = {18},
number = {15},
pages = {},
doi = {10.3390/nu18152469},
pmid = {42588092},
issn = {2072-6643},
mesh = {*Alzheimer Disease/microbiology/metabolism ; Humans ; *Gastrointestinal Microbiome/physiology ; Fatty Acids, Volatile/metabolism ; Animals ; Diet ; Brain/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder that develops many years before clinical symptoms appear. The biological changes involved in the earliest stages remain poorly understood, particularly during the preclinical stage. Our previous work has identified gradual gut microbial and metabolic changes during this stage, suggesting these may represent early biological shifts that precede disease progression. Recent studies suggest that the gut microbiome may contribute to early AD processes through its effects on immune regulation, metabolism, and gut-brain communication. Changes in gut microbial composition, including reduced levels of short-chain fatty acid (SCFA)-producing bacteria, such as Faecalibacterium, Roseburia, and Eubacterium, have been reported in individuals with AD and mild cognitive impairment. These microbial alterations have also been linked to disrupted metabolic activity, impaired gut barrier function, and increased neuroinflammatory responses. Diet is an important factor influencing gut microbial composition and metabolic activity. Mediterranean, DASH, and prudent dietary patterns are generally associated with beneficial microbial profiles and increased SCFA production, whereas Western dietary patterns are linked to lower microbial diversity and increased pro-inflammatory taxa. This review summarises the current evidence linking gut microbiota, SCFAs, microbial metabolism, and dietary patterns with early AD pathology, while highlighting important gaps in the existing literature.},
}
@article {pmid42588202,
year = {2026},
author = {Lai, MC and Tzeng, YS and Liu, IM},
title = {Phycocyanobilin Attenuates Oligomerized Amyloid β-Induced Neuronal Senescence Through SIRT1-Associated Mechanisms.},
journal = {Nutrients},
volume = {18},
number = {15},
pages = {},
doi = {10.3390/nu18152579},
pmid = {42588202},
issn = {2072-6643},
support = {MOST 111-2320-B-127-001//National Science and Technology Council/ ; },
mesh = {*Sirtuin 1/metabolism/genetics ; Humans ; *Amyloid beta-Peptides/toxicity/metabolism ; *Cellular Senescence/drug effects ; *Neurons/drug effects/metabolism ; *Phycocyanin/pharmacology ; *Phycobilins/pharmacology ; *Peptide Fragments/toxicity ; *Neuroprotective Agents/pharmacology ; Signal Transduction/drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Oxidative Stress/drug effects ; },
abstract = {Background/Objectives: Alzheimer's disease (AD) is associated with amyloid-β (Aβ)-induced neuronal injury, oxidative stress, inflammatory activation, and cellular senescence. Phycocyanobilin (PCB), an algae nutritive compound, has shown neuroprotective potential, but whether it attenuates Aβ-induced neuronal senescence remains unclear. This study investigated the protective effects of PCB against Aβ1-42 oligomer-induced senescence-like alterations in SH-SY5Y cells and examined the involvement of sirtuin 1 (SIRT1) signaling. Methods: Differentiated SH-SY5Y cells were pretreated with PCB (50 μmol/L) in the presence or absence of EX527 (10 μmol/L) for 24 h, followed by exposure to Aβ1-42 oligomers (20 μmol/L) for an additional 24 h. Cell viability, lactate dehydrogenase (LDH) release, senescence-associated β-galactosidase (SA-β-gal) staining, senescence-associated heterochromatin foci (SAHF)-associated di-/tri-methylated histone H3 lysine 9 (H3K9me2/3) fluorescence, senescence-associated secretory phenotype (SASP)-related cytokines, phosphorylated histone H2AX (γ-H2AX) accumulation, Ki67 expression, p53/p21/p16 signaling, and silent information regulator 1 (SIRT1) expression and activity were assessed using cell counting kit-8 assay, LDH assay, enzyme-linked immunosorbent assay, immunofluorescence staining, quantitative real-time PCR analysis, Western blotting, and fluorometric enzymatic activity assay. Results: Aβ1-42 oligomers reduced cell viability, increased LDH release, promoted SA-β-gal positivity, enhanced H3K9me2/3 and γ-H2AX signals, elevated IL-1β, IL-6, and IL-8 levels, suppressed Ki67 expression, and upregulated p53, p21, and p16. PCB pretreatment markedly attenuated these cytotoxic, senescence-associated inflammatory, and DNA damage-related responses while restoring SIRT1 mRNA, protein expression, and enzymatic activity. EX527 partially reversed these protective effects. Conclusions: PCB attenuates Aβ1-42 oligomer-induced neuronal senescence-like alterations, at least partly through SIRT1-associated regulation, supporting its potential as a naturally derived anti-senescent neuroprotective compound for AD-related neuronal aging.},
}
@article {pmid42588443,
year = {2026},
author = {Sun, L and Zhu, X and Fan, C and Wang, Y and Chen, Q and Zhang, L and Zhang, Y and Liu, Y},
title = {Pharmacological Effects and Molecular Mechanisms of Lignans in the Treatment of Alzheimer's Disease.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {15},
pages = {},
doi = {10.3390/molecules31152594},
pmid = {42588443},
issn = {1420-3049},
support = {82404834//National Natural Science Foundation of China/ ; 2024XJJ-QNCX022, 2024KYYWF-1391//the Youth Science and Technology Innovation Capacity Cultivation Project of Heilongjiang University of Chinese Medicine/ ; CYQN24014//Heilongjiang Chunyan Innovation Team Program/ ; TD2024H002//Heilongjiang Provincial Natural Science Foundation Team Project/ ; LJGXCG2022-096//Heilongjiang Province "Double First-Class" Discipline Collaborative Innovation Achievements Construction Project/ ; },
mesh = {*Lignans/pharmacology/chemistry/therapeutic use ; Humans ; *Alzheimer Disease/drug therapy/metabolism ; Animals ; *Neuroprotective Agents/pharmacology/therapeutic use/chemistry ; Signal Transduction/drug effects ; Oxidative Stress/drug effects ; },
abstract = {Alzheimer's disease (AD) is a complex, multifactorial neurodegenerative disorder whose core pathological hallmarks include Aβ aggregation, tau hyperphosphorylation, chronic neuroinflammation, oxidative stress, mitochondrial dysfunction, and gut microbiota dysbiosis. Lignans, a class of naturally occurring polyphenolic dimers widely distributed in medicinal plants and diet, exhibit multi-target neuroprotective effects with low toxicity. This review provides a systematic synthesis of the anti-AD pharmacological mechanisms underlying nine structurally distinct lignan subtypes-dibenzocyclooctadiene, tetrahydrofuran, bisepoxy, benzofuran, and biphenyl types-emphasizing scaffold-dependent structure-activity relationships. Key mechanistic pathways encompass direct inhibition of Aβ aggregation and tau phosphorylation, activation of the Nrf2 antioxidant signaling axis and PI3K/Akt pro-survival pathways, suppression of NF-κB-mediated neuroinflammation, restoration of cholinergic function, protection of mitochondria via SIRT3, inhibition of ferroptosis through Gsk3β/Nrf2/GPX4 signaling, and modulation of the gut-brain axis via microbiota-mediated conversion to enterolactone. This review addresses key pharmacokinetic limitations such as low oral bioavailability, rapid metabolism, and limited brain exposure, alongside strategies including structural modification, brain-targeted delivery systems, and gut microbiota modulation. Despite promising preclinical evidence, clinical translation remains limited. Future research priorities should focus on direct target validation, network pharmacology, optimized formulations, and well-designed clinical trials to develop lignans into next-generation anti-aging and anti-AD therapeutics.},
}
@article {pmid42588471,
year = {2026},
author = {Gao, J and Li, L and Liu, Q and Zhang, N and Li, Y},
title = {Plant Polysaccharides in Alzheimer's Disease: From Phytochemistry to Microbiota-Gut-Brain Axis Mechanisms-Resolving the Pharmacokinetic-Pharmacodynamic Paradox.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {15},
pages = {},
doi = {10.3390/molecules31152622},
pmid = {42588471},
issn = {1420-3049},
support = {81202638//National Natural Science Foundation of China/ ; PL2025T010//Natural Science Foundation of Heilongjiang Province Joint Fund Cultivation Project/ ; LBH-Q18115//Heilongjiang Postdoctoral Fund/ ; ZHY2024-012//Heilongjiang Province Traditional Chinese Medicine Scientific Research Project/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Polysaccharides/chemistry/pharmacology/pharmacokinetics/therapeutic use ; Animals ; *Gastrointestinal Microbiome/drug effects ; Blood-Brain Barrier/metabolism/drug effects ; Brain/metabolism/drug effects ; *Phytochemicals/pharmacology/chemistry/therapeutic use/pharmacokinetics ; Neuroprotective Agents/pharmacology/pharmacokinetics/chemistry/therapeutic use ; Drugs, Chinese Herbal/chemistry/pharmacology/pharmacokinetics ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by Aβ deposition, tau hyperphosphorylation, and neuroinflammation. No effective drugs can slow disease progression. Polysaccharides from traditional Chinese medicine (TCM) exhibit neuroprotective activities (e.g., antioxidant, anti-inflammatory) with good safety. However, their clinical application is limited by low oral bioavailability, poor blood-brain barrier (BBB) permeability, and a pharmacokinetic-pharmacodynamic paradox. The emerging role of the microbiota-gut-brain axis in AD offers a strategy to overcome this paradox. This review summarizes the structural features and classification of TCM polysaccharides (from plants, fungi, and roots/rhizomes) and highlights their anti-AD mechanisms via the gut-brain axis. Acting as prebiotics, these polysaccharides escape upper digestion and are fermented by gut microbiota into short-chain fatty acids (SCFAs) and other metabolites, which enter circulation, cross the BBB, and alleviate AD pathology through metabolic, immune, and neuronal pathways. Outcomes include reduced Aβ deposition and tau phosphorylation, suppressed neuroinflammation, restored synaptic function, and improved cognition. This review provides a theoretical framework for TCM polysaccharide intervention in AD via the gut-brain axis and a pharmacological basis for developing natural product-based AD therapies.},
}
@article {pmid42588505,
year = {2026},
author = {Stoyanov, BP and Georgiev, B and Stefanova, D and Tzankova, V and Kalcheva-Yovkova, E and Vassilev, N and Rangelov, M and Todorova, N and Zheleva-Dimitrova, D and Shivachev, B and Angelova, VT},
title = {Design, Synthesis, In Silico and In Vitro Pharmacological Profiling of Cannabidiol-like Synthetic Analogues as Multi-Target Anti-Alzheimer's Agents.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {15},
pages = {},
doi = {10.3390/molecules31152657},
pmid = {42588505},
issn = {1420-3049},
support = {KP-06-N63/11; 14.12.2022//Bulgarian Science Fund/ ; },
mesh = {Humans ; *Cholinesterase Inhibitors/pharmacology/chemistry/chemical synthesis ; *Alzheimer Disease/drug therapy ; Molecular Docking Simulation ; Butyrylcholinesterase/metabolism/chemistry ; *Cannabidiol/chemistry/pharmacology/analogs &amp; derivatives/chemical synthesis ; Antioxidants/pharmacology/chemistry/chemical synthesis ; *Drug Design ; Acetylcholinesterase/metabolism/chemistry ; Structure-Activity Relationship ; Neuroprotective Agents/pharmacology/chemical synthesis/chemistry ; Molecular Structure ; Computer Simulation ; Animals ; },
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder that requires therapeutic agents capable of targeting multiple pathological pathways. In this study, a series of cannabidiol (CBD)-like hydrazone derivatives (3a-i) was synthesized and characterized by NMR, HRMS, and single-crystal X-ray diffraction for compound 3i. In silico ADME analysis predicted favorable drug-like properties, including compliance with Lipinski's Rule of Five, oral bioavailability, and blood-brain barrier permeability. The compounds were evaluated for cholinesterase inhibition, antioxidant activity, cytotoxicity in neuronal cell lines, and binding interactions with human butyrylcholinesterase (hBChE) by molecular docking. Biological evaluation revealed a marked preference for BChE over acetylcholinesterase (AChE). Compound 3f was the most potent BChE inhibitor (IC50 = 1.67 ± 0.11 μM), while compounds 3b and 3f demonstrated high selectivity toward BChE. Antioxidant assays (DPPH, ABTS, FRAP, and FTC) indicated moderate, mechanism-dependent activity. Compounds 3b and 3e showed the strongest ABTS radical-scavenging effects, whereas compounds 3b and 3f provided the greatest protection against lipid peroxidation, surpassing CBD under the tested conditions. Several derivatives, particularly 3a, 3b, 3f, 3h, and 3i, exhibited favorable safety profiles in SH-SY5Y and Neuro-2a cells. Molecular docking supported the experimental findings. Overall, compounds 3b and 3f emerged as promising multifunctional leads for the development of multitarget-directed anti-Alzheimer agents.},
}
@article {pmid42589213,
year = {2026},
author = {Badawy, AAB and Dawood, S and Clanchy, FIL and Williams, RO and Stone, TW},
title = {Docking Analysis of Drugs Used in the Treatment of Alzheimer's Disease, Using Cell Membrane Receptors and Enzymes of the Kynurenine Pathway: A Pilot Study.},
journal = {International journal of molecular sciences},
volume = {27},
number = {15},
pages = {},
doi = {10.3390/ijms27156555},
pmid = {42589213},
issn = {1422-0067},
mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Kynurenine/metabolism ; *Molecular Docking Simulation ; Humans ; Pilot Projects ; Cholinesterase Inhibitors/chemistry/pharmacology ; Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism/chemistry ; },
abstract = {Molecular docking in silico techniques were used to assess the interactions between several drugs used in the treatment of Alzheimer's disease (AlzD) with neuronal receptors and with tryptophan and glycolytic pathway enzymes. AlzD drugs believed to act by inhibiting acetylcholinesterase (AChE) docked to that enzyme, whereas other drugs did not. No docking was observed to the nicotinic acetylcholine receptor (α-7-nAChR). All the drugs tested docked to the kainic acid receptor for glutamate, whereas donepezil, galantamine, tropisetron and N-acetylcysteine docked to the glutamate-NMDA receptor, but none docked to the glutamate-AMPA receptor. Two compounds docked to GABA receptors. Since the kynurenine pathway of tryptophan metabolism has been linked to AlzD, docking was examined with its various enzymes. Docking to tryptophan-2,3-dioxygenase (TDO2), indoleamine-2,3-dioxygenase-1 (IDO1) and 2-amino-3-carboxymuconic acid-6-semialdehyde decarboxylase was seen with most of the AlzD drugs. Donepezil docked to kynurenine monooxygenase, while rivastigmine, memantine and tropisetron docked to kynurenine aminotransferase-2. There was limited docking to the aryl hydrocarbon receptor and glycolytic enzymes, whereas most drugs docked to phosphoenolpyruvate carboxykinase (PEPCK). Despite their strong docking ability to IDO1 and TDO, none of the compounds tested inhibited their enzyme activity in an assay of kynurenine production. This pilot study highlights the varied pharmacological profile of drugs used in AlzD and suggests that a detailed examination of their functional effects should be considered to assist understanding of their different profiles at on- and off- target sites in human treatment.},
}
@article {pmid42589223,
year = {2026},
author = {Iskusnykh, IY and Kryl'skii, ED and Popova, TN and Zakharova, AA},
title = {Redox Molecules in Aging and Neurodegenerative Disorders.},
journal = {International journal of molecular sciences},
volume = {27},
number = {15},
pages = {},
doi = {10.3390/ijms27156567},
pmid = {42589223},
issn = {1422-0067},
mesh = {Humans ; Oxidation-Reduction ; *Neurodegenerative Diseases/metabolism/pathology ; *Aging/metabolism ; Animals ; Oxidative Stress ; Glutathione/metabolism ; NAD/metabolism ; NADP/metabolism ; Mitochondria/metabolism ; },
abstract = {Oxidative stress is a key player in the pathogenesis of aging and various neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and multiple sclerosis (MS), among others. Coupled molecules involved in chemical reduction-oxidation (redox) reactions regulate central signaling pathways and ensure the activation of cytoprotective mechanisms as needed. Such redox couples include oxidized and reduced forms of nicotinamide adenine dinucleotide (NAD[+]/NADH), nicotinamide adenine dinucleotide phosphate (NADP[+]/NADPH), and glutathione (GSSG/GSH), respectively. Under pathological conditions, concentrations of NAD[+], NADPH, and GSH decrease, and an imbalance between the oxidized and reduced forms of these molecules develops. The current review focuses on the mechanisms that underlie these changes and their potential consequences for neurodegenerative processes and aging. The review also evaluates experimental studies on metabolic and genetic abnormalities associated with alterations in NAD[+], NADPH, and GSH concentrations and highlights current research on strategies to regulate these compounds for neuroprotective purposes. Special attention is paid to understanding the interconnection between disturbed redox homeostasis and mitochondrial dysfunction, as this crosstalk is increasingly recognized as a crucial step in neurodegeneration. Integration of biochemical, genetic, and therapeutic perspectives provides a comprehensive understanding of redox imbalance in the pathogenesis of aging and neurodegenerative disorders. Therefore, these insights may contribute to the development of innovative interventions that target redox homeostasis, with the potential of increasing the human lifespan.},
}
@article {pmid42589253,
year = {2026},
author = {Forbes-Hernández, TY and Quiles-Ramírez, C and Giampieri, F and Godos, J and Grosso, G and Rodríguez-Velasco, CL and Xiao, J and Ding, M and Battino, M and Rivas-García, L and Sánchez-González, C},
title = {Integrative Metabolomic Evidence of Bioactive Food-Derived Compounds Targeting Alzheimer's Disease: A Cross-Study Analysis in Caenorhabditis elegans.},
journal = {International journal of molecular sciences},
volume = {27},
number = {15},
pages = {},
doi = {10.3390/ijms27156591},
pmid = {42589253},
issn = {1422-0067},
support = {PID2019-106778RB-I00//Government of Spain/ ; Visiting Scholars 2022//Universidad de Granada/ ; },
mesh = {Animals ; *Caenorhabditis elegans/metabolism/drug effects ; *Alzheimer Disease/metabolism/drug therapy ; *Metabolomics/methods ; Antioxidants/pharmacology ; Flavonoids/pharmacology ; Oxidative Stress/drug effects ; Neuroprotective Agents/pharmacology ; Amyloid beta-Peptides/metabolism ; *Metabolome ; Cholinesterase Inhibitors/pharmacology ; Disease Models, Animal ; Polyphenols/pharmacology ; },
abstract = {Alzheimer's disease (AD) is a major neurodegenerative condition with limited treatment options. Applications of food-derived products rich in bioactive compounds have emerged as promising strategies, yet comparative evidence across different matrices remains scarce. Here, we present an integrative metabolomic analysis of eleven food extracts previously tested in Caenorhabditis elegans models of AD. By combining chemical fingerprints and functional bioassay data-including oxidative stress resistance, β-amyloid-induced paralysis, and tau-associated locomotion-we employed multivariate statistics to uncover common patterns and correlations. Principal Component Analysis, PLS-DA, and hierarchical clustering revealed distinct groupings of extracts based on metabolite profiles and neuroprotective effects. Polyphenols, flavonoids, and iridoids were consistently associated with beneficial outcomes, while antioxidant capacity and acetylcholinesterase inhibition emerged as key functional traits. Correlation heatmaps highlighted extract-specific strengths, suggesting potential for rational combinations targeting complementary bioactivities. This work underscores the value of integrating metabolomics and functional biology to inform the design of food-based interventions for neurodegenerative diseases, paving the way for evidence-based innovation in brain health.},
}
@article {pmid42589276,
year = {2026},
author = {Kanagawa, H and Kawahara, A and Mikawa, N and Sugihara, K and Ueda, M and Nitta, A and Egi, M and Oda, R and Nonaka, S and Tozaki-Saitoh, H and Oda, K and Nakanishi, H},
title = {Candidalysin Inhibits Porphyromonas gingivalis Lipoprotein-Induced IL-1β Production in BV-2 Microglia via Hydrophobic Microbial Interactions.},
journal = {International journal of molecular sciences},
volume = {27},
number = {15},
pages = {},
doi = {10.3390/ijms27156614},
pmid = {42589276},
issn = {1422-0067},
support = {JP24K09808 (S.N.) and JP24K09787 (K.O.).//JSPS KAKENHI/ ; },
mesh = {*Interleukin-1beta/metabolism/biosynthesis ; *Microglia/metabolism/drug effects/microbiology ; *Porphyromonas gingivalis/metabolism/pathogenicity ; Hydrophobic and Hydrophilic Interactions ; Animals ; *Lipoproteins/metabolism ; Lipopolysaccharides/pharmacology ; Mice ; NF-kappa B/metabolism ; Cell Line ; },
abstract = {In postmortem Alzheimer's disease (AD) brains, Porphyromonas gingivalis (Pg), a major periodontal pathogen, and Candida albicans, one of the most common fungal pathogens, have been detected. Although it is important to better understand the effects of their co-infection in the brain for elucidating the pathogenesis of AD, little is known about the neuropathological significance of such co-infection. In the present study, we aimed to elucidate the effects of co-exposure to virulence factors derived from Pg and C. albicans on microglial inflammatory responses. We demonstrated, for the first time, that both candidalysin dissolved in dimethyl sulfoxide (CLd) and water (CLw) significantly suppressed Pg lipopolysaccharide (LPS)-induced interleukin-1β (IL-1β) production by 35-60% and nuclear factor-κB (NF-κB) activation by 20-40%. It should be noted that contaminating Pg outer membrane lipoproteins in Pg LPS were mainly responsible for IL-1β production. To examine the possible hydrophobic interactions between lipoproteins contaminating the Pg LPS preparation and CL, we used 8-anilino-1-naphthalenesulfonic acid sodium salt (ANS-Na), which can be excited to emit fluorescence by binding of hydrophobic molecules. The mean fluorescence intensity of ANS-Na was significantly reduced by approximately 26% following co-treatment with CLw and Pg LPS compared with CLw alone. Furthermore, we generated a mutant form of CL with reduced hydrophobicity (GRAVY index: 1.106 vs. 0.874) while preserving its predicted structural properties. This mutant CLd no longer inhibited Pg LPS-induced IL-1β production. Taken together, these findings indicate that hydrophobic interactions between lipoproteins contaminating the Pg LPS preparation and CL mediate the inhibitory effect of CL on Pg LPS-induced inflammatory responses. The present findings suggest that interactions between polymicrobial virulence factors in the brain may modulate microglia-mediated inflammatory responses during AD progression.},
}
@article {pmid42589300,
year = {2026},
author = {Selvaraj, NR and V, BS and Nandan, D and San, S and Nair, SS and Nair, BG and Venugopal, P and Aradhya, R and Nair, VA},
title = {2-(Arylamino)thiazol-4(5H)-ones Mitigate Oxidative Stress and Confer Neuroprotection in Cellular and Drosophila Models of Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {15},
pages = {},
doi = {10.3390/ijms27156642},
pmid = {42589300},
issn = {1422-0067},
mesh = {Animals ; *Oxidative Stress/drug effects ; *Alzheimer Disease/drug therapy/metabolism/pathology ; Humans ; *Neuroprotective Agents/pharmacology/chemistry/chemical synthesis ; Molecular Docking Simulation ; Disease Models, Animal ; Drosophila melanogaster ; *Thiazoles/pharmacology/chemistry/chemical synthesis ; Acetylcholinesterase/metabolism/chemistry ; Reactive Oxygen Species/metabolism ; *Neuroprotection/drug effects ; Amyloid beta-Peptides/metabolism ; Cell Survival/drug effects ; Oxidopamine ; Membrane Potential, Mitochondrial/drug effects ; Cell Line, Tumor ; Cholinesterase Inhibitors/pharmacology/chemistry ; },
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder with limited effective therapies. In this study, a series of 2-(arylamino)thiazol-4(5H)-one derivatives was synthesized using an efficient microwave-assisted protocol, and evaluated for neuroprotective effects against 6-hydroxydopamine (6-OHDA)-induced oxidative stress (OS) in SH-SY5Y neuronal cells and an Aβ42-expressing Drosophila melanogaster model of AD. Among the synthesized compounds, 3n, 3i, and 3b exhibited low cytotoxicity and significant neuroprotection, as evidenced by increased cell viability, reduced reactive oxygen species (ROS) production, and preserved mitochondrial membrane potential. Notably, compound 3n demonstrated the highest activity and effectively ameliorated Aβ42-induced behavioral deficits in vivo. Molecular docking studies predicted favorable binding affinity within the acetylcholinesterase (AChE) active site, with the thiazol scaffold and aryl substituents stabilizing ligand binding through π-π stacking and hydrophobic interactions; compound 3n also formed additional hydrogen bonds enhancing its affinity. Consistent with the docking predictions, in vitro AChE inhibition studies demonstrated that compounds 3n, 3i, and 3b inhibited AChE in a concentration-dependent manner. Network pharmacology predicted seven potential core targets implicated in AD pathogenesis and related pathways, including OS, neuroinflammation, and synaptic dysfunction. Furthermore, in silico pharmacokinetic analysis indicated compliance with Lipinski's and Veber's rules, supporting favorable drug-like properties. While further experimental validation is essential, these findings highlight 2-(arylamino)thiazol-4(5H)-one derivatives, particularly compound 3n, as promising multifunctional candidates for further preclinical development against AD.},
}
@article {pmid42589529,
year = {2026},
author = {Pritha, AN and Chouliaras, L and Swann, P and Prats-Sedano, M and McKeever, A and Heslegrave, A and Ashton, NJ and Zetterberg, H and Su, L and Malpetti, M and Rowe, JB and O'Brien, JT},
title = {Metabolism Pathway Blood Proteomic Differences in Lewy Body Dementia Compared to Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {15},
pages = {},
doi = {10.3390/ijms27156875},
pmid = {42589529},
issn = {1422-0067},
support = {NIHR203312//NIHR Cambridge Biomedical Research Centre/ ; MC_UU_00030/14/MRC_/Medical Research Council/United Kingdom ; MR/T033371/1/MRC_/Medical Research Council/United Kingdom ; ARUK-RADF2021A-010//Race Against Dementia Alzheimer's Research UK/ ; },
mesh = {Humans ; *Alzheimer Disease/blood/metabolism/diagnosis ; *Proteomics/methods ; *Lewy Body Disease/blood/metabolism/diagnosis ; Female ; Male ; Aged ; Biomarkers/blood ; *Proteome/metabolism ; Aged, 80 and over ; *Metabolic Networks and Pathways ; },
abstract = {Dementia with Lewy Bodies (DLB) is the most common neurodegenerative dementia after Alzheimer's disease (AD), but it remains challenging to diagnose due to overlapping symptoms and mixed pathologies. This pilot study tested whether DLB has different metabolic blood proteomic profiles compared to AD and controls. Serum was analysed from people with DLB (n = 20), a group with AD (either with Alzheimer's disease dementia or Mild Cognitive Impairment with a positive amyloid positron emission tomography scan (MCI+/AD) (n = 15), and similarly aged controls (n = 15) using the Olink Metabolism panel encompassing 92 proteins. Six proteins (PILRB, LRIG1, NECTIN2, TINAGL1, SSC4D, and FKBP4) were significantly different in DLB compared with the controls, and one protein (SERPINB8) was differentially expressed when compared with MCI+/AD. Receiver operating characteristic curves for biologically relevant proteins that have previously established roles in neurodegenerative and cognitive properties showed that RNASE3 levels could differentiate DLB from MCI+/AD (area under the curve (AUC) = 0.717, sensitivity = 0.850, and specificity = 0.600). A multimarker model incorporating RNASE3 with phosphorylated tau 217 (pTau217) and polygenic risk scores for LBD achieved improved accuracy in discriminating DLB from MCI+/AD (AUC = 0.963, sensitivity = 1.000, and specificity = 0.900). Pathway analyses revealed dysregulation in cortisol signalling, inflammation resolution, and ErbB4-mediated neuroplasticity, which point towards peripheral protein alterations related to the adaptation to stress, immune regulation, and synaptic integrity in DLB. The present exploratory study highlights potential pathophysiological mechanisms implicated in DLB, suggesting that a multimodal biomarker panel may perform better compared to single proteins. Considering the small sample sizes, the findings will need to be replicated in larger cohorts.},
}
@article {pmid42589569,
year = {2026},
author = {Tan, CL and Zheng, XM and Zhu, YF and Xiong, QQ and Li, H and Meng, XL},
title = {CellSwarm-AD: A Multi-Scale Agent-Based Framework for Virtual Alzheimer's Disease Trials.},
journal = {International journal of molecular sciences},
volume = {27},
number = {15},
pages = {},
doi = {10.3390/ijms27156915},
pmid = {42589569},
issn = {1422-0067},
support = {32400068//National Natural Science Foundation of China/ ; 2025T180738//China Postdoctoral Science Foundation/ ; 2024M750284//China Postdoctoral Science Foundation/ ; },
mesh = {*Alzheimer Disease/drug therapy/metabolism/pathology ; Humans ; Computer Simulation ; Amyloid beta-Peptides/metabolism ; Donepezil/therapeutic use/pharmacokinetics ; Memantine/therapeutic use/pharmacokinetics ; },
abstract = {Computational models of Alzheimer's disease (AD) rarely connect cellular heterogeneity, spatial tissue organization, pathology cascades, and pharmacological intervention within one auditable workflow. We present CellSwarm-AD, a four-layer framework comprising five cell agent classes, a spatial Aβ diffusion environment, an Aβ-Ca[2+]-tau-NF-κB-viability cascade with repository PK/PD models, and an optional experiment orchestration interface. Layer 3 was demonstrated with reproducible prompt templates and deterministic mock outputs; no live large language model was used to generate or modify the quantitative simulation outputs or statistical results. In a prespecified 78-week virtual trial (n = 200 per arm), patient-level repeated measurements were analyzed with Gaussian generalized estimating equations. Week-78 mean (SEM) MMSE-like changes were -1.747 (0.071) for the placebo, -1.368 (0.076) for lecanemab, -1.428 (0.067) for donepezil, and -1.369 (0.065) for independently simulated donepezil plus memantine. The corresponding single-trial Cohen's d values versus the placebo were 0.395, 0.354, and 0.426. Across 20 independent n = 200-per-arm trials, the mean d values were 0.337, 0.359, and 0.326, respectively; replicates were not pooled. Ablation removed most of the treatment contrast when PK/PD was disabled, and fixed-domain grid testing showed decreasing relative L2 error from 6.20% (100 × 100) to 1.49% (200 × 200) against a 400 × 400 reference. These results establish a reproducible proof-of-concept while identifying calibration dependence, weak cross-layer coupling, and the absence of individual-level external validation as current limitations.},
}
@article {pmid42589618,
year = {2026},
author = {Vazquez-Villaseñor, I and Benson, B and Richardson, CD and Waller, R and Castelli, LM and Simpson, JE and Matthews, FE and Brayne, C and Wharton, SB and , },
title = {Senescence Markers and Associated Transcriptomic Changes Are Expressed at Early Stages of Alzheimer's Neuropathology but Are Not Independently Related to Dementia.},
journal = {International journal of molecular sciences},
volume = {27},
number = {15},
pages = {},
doi = {10.3390/ijms27156964},
pmid = {42589618},
issn = {1422-0067},
support = {ARUK PG2013A-003//Alzheimer's Research UK/ ; MRC/G9901400, U.1052.00.0013, G0900582/MRC_/Medical Research Council/United Kingdom ; //National Institute for Health and Care Research/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/metabolism/genetics ; *Transcriptome ; *Dementia/pathology/metabolism/genetics ; Biomarkers/metabolism ; *Cellular Senescence/genetics ; Neuroglia/metabolism/pathology ; Male ; Female ; Cyclin-Dependent Kinase Inhibitor p16/metabolism/genetics ; Gene Expression Profiling ; Cyclin-Dependent Kinase Inhibitor p21/metabolism/genetics ; Aged, 80 and over ; Aging/genetics ; },
abstract = {Cellular senescence may affect the post-mitotic cells of the brain. We examined the expression of senescence markers, including p16, p21, γH2Ax and H3K9me3, in the frontal cortex of brain donations from the Cognitive Function and Ageing Study to assess their relationship to Alzheimer's disease neuropathological change (ADNC) and dementia. p21, γH2Ax and H3K9me3 were expressed in pyramidal neurons and glia, whilst p16 was confined to glial cells. p21 and γH2Ax were correlated in neurons, and with p16 in glia. They did not increase with ADNC, tending to be higher at early Braak neurofibrillary tangle stages. Transcriptomic profiling of pyramidal neuron-enriched samples at low Braak stages showed that higher neuronal p21 expression was associated with altered pathways for neuronal function, neurodegeneration, protein homeostasis, mitochondrial dysfunction and synaptic signalling. In conclusion, the different expression profile of senescence markers in neurons and glia suggest possible differences in senescence-related mechanisms. Expression at lower ADNC stages suggests senescence may be important at earlier stages of Alzheimer's pathogenesis, whilst transcriptomic changes suggest an impact on neuronal function. The lack of association of senescence markers with dementia status indicates that more work is needed to determine the value of senescence as a therapeutic target for dementia.},
}
@article {pmid42589625,
year = {2026},
author = {Štambuk, S},
title = {The Role of Cytochrome P450 Holoenzyme Metabolism in the Origin of Neuropathologies.},
journal = {International journal of molecular sciences},
volume = {27},
number = {15},
pages = {},
doi = {10.3390/ijms27156971},
pmid = {42589625},
issn = {1422-0067},
mesh = {Animals ; Humans ; *Cytochrome P-450 Enzyme System/metabolism ; Holoenzymes/metabolism ; Heme Oxygenase-1/metabolism ; Heme/metabolism ; *Nervous System Diseases/metabolism/pathology ; Iron/metabolism ; },
abstract = {The increased activity of δ-aminolevulinic acid synthase-1 (ALAS1) leads to the accumulation of δ-aminolevulinic acid (ALA), which may reduce the iron(III) retention ability of ferritin, resulting in iron(III) overload. The accumulation of ALA occurs in the condition of attenuation of the heme negative feedback loop over ALAS1 activity in concert with the induction of ALAS1 expression. Attenuation of the heme negative feedback loop is maintained by elevated quantities of the heme catabolizing enzyme, heme oxygenase-1 (HO-1), which, in turn, may be induced by highly increased heme concentration. The upregulation of brain HO-1 occurs in patients with Alzheimer's and Parkinson's diseases. A mouse with overexpressed human HMOX1 is a model of schizophrenia with concurrent iron overload. HO-1 inhibitors reduce oxidative damage to whole cells and mitochondrial compartments of rat astrocytes transfected with the HMOX1 gene. Iron reduction within the heme prosthetic moiety of P450 cytochromes in microsomes is facilitated by NADPH-cytochrome P450 oxidoreductase (CPR), while adrenodoxin reductase performs this function in the mitochondria. In partial CPR-deficient conditions, the half-life of apocytochromes is prolonged while HO-1 is induced due to the elevated heme release from unreduced cytochromes. This study posits that, before being degraded by HO-1, the released hemin triggers the oligomerization of cytochromes, as well as other oxidative damages, by producing hydroperoxyl radicals from hydrogen peroxide produced in uncoupling reaction. After reaching a specific level, iron(III) overload may trigger the saturation of CPR, resulting in the development of neuropathologies.},
}
@article {pmid42589655,
year = {2026},
author = {Qiu, T and Zhang, J and Zhao, J},
title = {Estrogen Withdrawal-Induced Cognitive Impairment in Menopausal Women: Mechanisms and Prospects for Integrated Interventions.},
journal = {International journal of molecular sciences},
volume = {27},
number = {15},
pages = {},
doi = {10.3390/ijms27157003},
pmid = {42589655},
issn = {1422-0067},
support = {82505314//National Natural Science Foundation of China/ ; 82274337//National Natural Science Foundation of China/ ; 82574855//National Natural Science Foundation of China/ ; ZB2025042//China Academy of Chinese Medical Sciences/ ; CI2023C018YL//China Academy of Chinese Medical Sciences/ ; ZB2025036//China Academy of Chinese Medical Sciences/ ; ZZ13-YQ-073//Fundamental Research Funds for the Central public welfare research institutes/ ; },
mesh = {Humans ; Female ; *Estrogens/deficiency/metabolism ; *Cognitive Dysfunction/metabolism/etiology ; Mitochondria/metabolism ; *Menopause/metabolism ; Animals ; Estrogen Receptor beta/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Inflammasomes/metabolism ; },
abstract = {A marked reduction in estrogen levels during perimenopause substantially elevates the risk of Alzheimer's disease (AD) and cognitive dysfunction in women. While the endocrine etiology is well established, applying this understanding to effective clinical prevention remains difficult. Recent findings of diminished cerebral glucose metabolism and lower mitochondrial cytochrome oxidase activity in menopausal women have shifted research attention toward mitochondrial homeostasis disruption and neuroimmune-inflammatory network imbalance as central mechanisms underlying menopausal cognitive decline. This article examines the characteristics and underlying mechanisms of mitochondrial and immune imbalances induced by estrogen withdrawal during menopause. Estrogen deficiency is shown to disrupt mitochondrial-immune homeostasis, particularly via ERβ-mediated mitochondrial oxidative phosphorylation system (OXPHOS) dysfunction and subsequent excessive activation of the NLRP3 inflammasome. The analysis further addresses enhanced inflammatory signaling resulting from excessive reactive oxygen species generation and mitochondrial DNA (mtDNA) release, as well as reduced synaptic plasticity due to impaired neurotransmitter synthesis and an inflammatory microenvironment. Additionally, the dysregulation of the estrogen-neuromodulatory system in menopausal cognitive decline is investigated. Recent studies demonstrate that intervention strategies targeting estrogen receptors, especially selective ERβ agonists, possess significant neuroprotective potential. Future approaches should incorporate biomarkers, including neuroimaging and genetic polymorphisms, to facilitate risk-stratified and individualized precision medicine. This integration may enhance the prevention or delay of menopause-associated cognitive decline in women.},
}
@article {pmid42589678,
year = {2026},
author = {Żebrowska-Gamdzyk, M and Maciejczyk, M},
title = {The Possible Association Between Bisphenol A (BPA) and the Neuropathological Processes Characteristic of Alzheimer's Disease-A Systematic Review of the Literature.},
journal = {International journal of molecular sciences},
volume = {27},
number = {15},
pages = {},
doi = {10.3390/ijms27157026},
pmid = {42589678},
issn = {1422-0067},
mesh = {*Benzhydryl Compounds/adverse effects/toxicity ; Bisphenol A Compounds ; *Phenols/adverse effects/toxicity ; *Alzheimer Disease/pathology/metabolism/chemically induced/etiology ; Humans ; Animals ; *Endocrine Disruptors/adverse effects/toxicity ; tau Proteins/metabolism ; Oxidative Stress/drug effects ; Amyloid beta-Peptides/metabolism ; },
abstract = {Bisphenol A (BPA) is a ubiquitous environmental endocrine-disrupting compound whose potential neurotoxicity is attracting increasing interest. A growing body of evidence suggests a possible link between BPA exposure and neurodegenerative processes; however, comprehensive analyses of its role in Alzheimer's disease (AD) are lacking. The aim of this systematic review was to evaluate the available scientific evidence regarding the association between BPA exposure and Alzheimer's disease. A systematic literature review was conducted in accordance with the PRISMA 2020 guidelines. The PubMed/MEDLINE, Scopus, and Web of Science databases were searched up to 23 July 2026. Original research articles and meta-analyses published in English were included, covering studies in humans and animal models that analyzed the effects of BPA on Alzheimer's disease or related mechanisms. Study selection and data extraction were performed independently by two reviewers. The risk of bias was assessed using the ROBINS-E and SYRCLE tools. Of the 70 publications identified, 12 studies were included in the analysis. Most data came from in vivo and in vitro studies, and one study was clinical in nature (autopsy-based). The findings indicate that BPA exposure is associated with cognitive dysfunction, increased oxidative stress and neuroinflammation, amyloid-β accumulation, and tau protein hyperphosphorylation. Identified mechanisms included, among others, disturbances in insulin signaling, activation of the NF-κB and STAT3 pathways, and mitochondrial dysfunction. Eighty percent of the studies were rated as having good methodological quality. The analysis was limited by study heterogeneity, the small number of clinical studies, and the inability to perform a meta-analysis. The predominance of animal models and the use of high BPA doses hinder the direct extrapolation of the results to the human population. The available evidence suggests a possible association between BPA exposure and neuropathological processes characteristic of Alzheimer's disease. However, further well-designed epidemiological studies are needed to assess the impact of long-term, low-dose BPA exposure on the risk of developing AD.},
}
@article {pmid42589967,
year = {2026},
author = {Simfukwe, C and An, SSA and Youn, YC},
title = {EEG Microstate Alterations in Eyes-Open and Eyes-Closed Resting States Across the Alzheimer's Disease Continuum.},
journal = {Journal of clinical medicine},
volume = {15},
number = {15},
pages = {},
doi = {10.3390/jcm15155863},
pmid = {42589967},
issn = {2077-0383},
support = {2021R1A6A1A03038996//National Research Foundation of Korea (NRF), funded by the Ministry of Education/ ; RS-2024-00507796//Technology Innovation Program/ ; },
abstract = {Background/Objective: Quantitative electroencephalography (qEEG) microstates, recorded under both eyes-open (EOR) and eyes-closed (ECR) resting conditions, provide a powerful neurophysiological approach for capturing the temporal dynamics of cognitive processing. Nevertheless, microstate syntax remains poorly delineated in mild cognitive impairment (MCI) and Alzheimer's disease (AD). The present study seeks to identify potential drivers of altered microstate topography and temporal dynamics across advancing stages of cognitive decline. Methods: Resting-state EEG (rEEG) was recorded from 60 participants (40-90 years old) in each of three groups: MCI, AD, and healthy controls (HC), under both EOR and ECR conditions. After artifact rejection with EEGLAB in MATLAB R2024a, the final dataset comprised 180 clean recordings per condition (EOR and ECR) and 360 recordings in total. Microstate analysis was performed using the MICROSTATELAB toolbox. Potential group differences in microstate topography were examined with topographic analysis of variance (TANOVA). Four canonical microstates were extracted and labeled A, B, C, and E, following the well-established classification scheme. Results: Analysis of microstate topographies revealed significant group-level differences in the EOR condition for Microstate A (auditory network; p = 0.003), Microstate C (salience network; p = 0.004), and Microstate E (executive network; p = 0.036). In contrast, no significant between-group differences emerged under the ECR condition (all p > 0.05). Within-group comparisons indicated that Microstate B (visual network) was the only class to differ between the two resting conditions in healthy controls and patients with MCI. In the AD group, however, condition-related differences extended to Microstates A, C, and E, suggesting a more distributed disruption of network dynamics in advanced disease. Temporally, Microstate B coverage was the only parameter to show a significant between-group difference, being greater in MCI than in AD under the EOR condition (p = 0.031); visual trends of increasing Microstate A duration and decreasing Microstate C occurrence toward AD did not reach statistical significance. Conclusions: This study's rEEG microstate analysis uncovered condition-dependent and disease-sensitive alterations across the HC, MCI, and AD groups. The EOR condition proved more diagnostically informative, with significant group-level topographic differences emerging for Microstates A, C, and E, whereas the ECR condition yielded no reliable between-group effects. Microstate B coverage showed the only significant temporal alteration, distinguishing MCI from AD under EOR, while Microstate A and Microstate C showed non-significant trends warranting replication in larger cohorts.},
}
@article {pmid42590850,
year = {2026},
author = {Pascual-Lucas, M and Lacosta, AM and Montañés, M and Canudas, J and Loscos, J and Monleón, I and Allué, JA and Sarasa, L and Fandos, N and Romero, J and Sarasa, M and Torres, M and Whyms, D and Terencio, J and Piñol-Ripoll, G and Boada, M},
title = {Long-term safety and immunogenicity of ABvac40 active immunotherapy in mild cognitive impairment and very mild Alzheimer's disease: Results from AB1601 phase 2 extension study.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71746},
doi = {10.1002/alz.71746},
pmid = {42590850},
issn = {1552-5279},
support = {//Araclon Biotech-Grifols./ ; },
mesh = {Humans ; *Alzheimer Disease/therapy/immunology/drug therapy ; Female ; Male ; Amyloid beta-Peptides/immunology ; Aged ; *Cognitive Dysfunction/therapy/immunology/drug therapy ; *Immunotherapy, Active/methods/adverse effects ; Peptide Fragments/immunology ; Double-Blind Method ; Treatment Outcome ; *Alzheimer Vaccines/therapeutic use/adverse effects ; Aged, 80 and over ; },
abstract = {INTRODUCTION: ABvac40 is an active immunotherapy targeting Aβ40, the main component of cerebrovascular deposition in Alzheimer's disease (AD). A 24-month randomized, placebo-controlled phase 2 study (Part A) showed favorable safety and robust immunogenicity, with exploratory signals of clinical efficacy. Here, we report results from Part B, an 18-month extension evaluating long-term safety and immunological memory.<br><br>METHODS: Participants treated with ABvac40 in Part A received placebo plus a delayed booster, whereas previous placebo participants received ABvac40. Exploratory endpoints included safety, tolerability, and immunogenicity.<br><br>RESULTS: Seventy-seven participants entered Part B. Treatment-emergent adverse events (TEAEs) occurred in 75.0% of participants in placebo + booster group and 81.1% in ABvac40 group; serious TEAEs were 5.0% and 16.2%, respectively. No ARIA-E or meningoencephalomyelitis were observed, with one ARIA-H event. ABvac40 induced robust antibody responses following delayed booster, with detectable anti-A&#x3b2;40 antibodies in CSF.<br><br>DISCUSSION: ABvac40 showed favorable long-term safety and durable immunogenicity, supporting further clinical development.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov: NCT03461276, registered March 2, 2018. EudraCT: 2016-004352-30, registered March 10, 2017.},
}
@article {pmid42590992,
year = {2026},
author = {Aiken, SG and Zarganes-Tzitzikas, T and Brennan, PE},
title = {Chemical probes for Alzheimer's disease targets.},
journal = {Essays in biochemistry},
volume = {},
number = {},
pages = {},
doi = {10.1042/EBC20260014},
pmid = {42590992},
issn = {1744-1358},
support = {ARUK-TERM3DDI-OX//Alzheimer's Research UK (ARUK)/ ; },
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder involving amyloid-β deposition, tau aggregation, neuroinflammation, synaptic dysfunction, and microvascular and epigenetic changes. Although recent therapeutic developments have energised the field, effective and widely accessible disease-modifying treatments remain limited. This reflects both the biological complexity of AD and the continuing challenge of validating drug targets in the central nervous system (CNS). Chemical probes are small molecules designed to investigate the function of specific proteins in biological systems. When selected and used carefully, they provide powerful tools for testing how particular targets and pathways contribute to AD biology. High-quality chemical probes for AD targets must have high selectivity, confirmed target engagement, and CNS exposure adequate for the specific biological question, with low efflux, and biomarker evidence that the intended target is engaged in brain-relevant tissue. CNS penetration should be interpreted alongside mechanism-appropriate pharmacodynamic biomarkers, since cerebrospinal fluid measurements and modelled Kp,uu do not always directly reflect brain exposure. Chemical probes have shaped current understanding of major AD-relevant pathways, including amyloid precursor protein processing by BACE1 and γ-secretase, tau phosphorylation and aggregation, epigenetic regulation, and neuroinflammatory signalling. Several compounds initially developed as potential therapies have provided valuable mechanistic insight, even where they did not translate into clinical benefit. New modalities, including targeted protein degradation, molecular glues, and peptides, are expanding the range of AD biology that can be studied. These developments illustrate the value and limitations of chemical probes and underline the need for rigorous probe selection, validation, and experimental design in AD research.},
}
@article {pmid42591150,
year = {2026},
author = {Sun, N and Celorrio, M and Zhang, Y and Chen, X},
title = {Editorial: Neuro-immune interaction in disease.},
journal = {Frontiers in cellular neuroscience},
volume = {20},
number = {},
pages = {1931155},
pmid = {42591150},
issn = {1662-5102},
}
@article {pmid42591225,
year = {2026},
author = {Vöhringer, K and Müller, MS and Yildiz, CB and Zimmer-Bensch, G},
title = {DNMT1 as an environmental sensor: epigenetic pathways linking environmental exposures, sex hormone signaling, and vulnerability to neurodevelopmental and neurodegenerative diseases.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1883887},
pmid = {42591225},
issn = {1664-2295},
abstract = {DNA methyltransferase 1 (DNMT1) has classically been viewed as the canonical maintenance methyltransferase, yet accumulating evidence positions it as a multifaceted hub that integrates environmental, hormonal, and metabolic signals with chromatin regulation in the developing and adult brain. This review highlights DNMT1 as an environmentally responsive epigenetic sensor across the lifespan. We examine how psychosocial stress, early-life adversity, inflammation, nutritional and microbiome-derived metabolites, and environmental toxicants modulate DNMT1 expression, subcellular localization, and post-translational modifications, thereby reshaping DNA methylation landscapes in neurons and glia. We further discuss how sex hormone signaling, particularly estrogen receptor alpha α (ERα)-DNMT1 feedback loops, introduces sex-specific dimensions to epigenetic responsiveness, and how lncRNAs serve as intermediaries linking environmental cues to targeted DNMT1 recruitment at specific genomic loci. Building on this framework, we review how DNMT1 dysregulation contributes to neurodevelopmental and neuropsychiatric disorders-including schizophrenia, autism spectrum disorder, and depression-and to neurodegenerative conditions such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and DNMT1-associated monogenic neurodegenerative disorders. By positioning DNMT1 as a molecular interface between genetic predisposition, environmental exposure, and circuit-level vulnerability, this review highlights the need for integrated, sex-stratified, and longitudinal approaches to understanding epigenetic risk in neurological disease.},
}
@article {pmid42591309,
year = {2026},
author = {Nguchu, BA and Han, J and Mwighusa, DN and Li, L and Su, K and Shaw, P},
title = {Improved YOLOv8 for early detection of Alzheimer's disease from magnetic resonance imaging.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1771536},
pmid = {42591309},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a life-threatening condition affecting 47 million people globally, with 13% of them over the age of 65. Despite ongoing efforts in drug development, the incidence of Alzheimer's disease is increasing, projected to reach 131 million new cases in the next two decades. Delayed diagnosis and failure to uncover the neuropathological pathways of AD contribute to the increasing incidence and sequelae of AD.<br><br>METHODS: Here, we address these challenges by developing a model derived from YOLOv8 for the early diagnosis of AD. We improve YOLOv8 by replacing the CBS convolution modules with the RepVGG (Reparameterized VGG) module and appending the Spatial Pyramid Pooling Enhanced with ELAN (SPPELAN) module and Simple Attention Module (SimAM) at the end of the YOLOv8 network. Additionally, we improve the model by introducing C2f_EMA module at YOLOv8 neck.<br><br>RESULTS: Our results demonstrate a significant improvement in our model's performance compared to the benchmark YOLOv8 for AD detection. While the benchmark YOLOv8 showed performance metrics of 0.794 accuracy, 0.876 recall, 0.881 mAP50, and 0.875 mAP50:95, our model demonstrated improved performance with 0.816 accuracy, 0.877 recall, 0.904 mAP50, and 0.898 mAP50:95, indicating improvements of 2.77, 0.11, 2.61, and 2.62%, respectively. These findings provide insights into the possibility of achieving an effective diagnosis at the early stage of AD, which may aid early personalized intervention and further assist researchers in conducting in-depth examinations to understand the early mechanisms underlying AD.},
}
@article {pmid42591319,
year = {2026},
author = {Boutajangout, A and Osorio, RS and Masurkar, AV and Debure, L and Ghuman, M and Ahmed, W and Pirraglia, E and Vedvyas, A and Links, J and Vega, B and Marsh, K and Chodosh, J and Shao, Y and Wisniewski, T},
title = {Biomarkers for Alzheimer's disease to differentiate normal, SCD, and MCI subjects and their correlation with cognitive function.},
journal = {Alzheimer's &amp; dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70419},
pmid = {42591319},
issn = {2352-8729},
abstract = {INTRODUCTION: We assessed plasma biomarkers for the diagnosis of early Alzheimer's disease (AD).<br><br>METHODS: Subjects were divided into three groups: cognitively unimpaired (CU) (without subjective cognitive decline [SCD]) (n&#xa0;=&#xa0;113), CU with SCD (n&#xa0;=&#xa0;152), and mild cognitive impairment (MCI, n&#xa0;=&#xa0;45). Plasma assays for amyloid beta (A&#x3b2;) 40, A&#x3b2;42, neurofilament light chain protein, glial fibrillary acidic protein, and phosphorylated tau181 levels were measured using single molecule array (Simoa) technology. Neuroinflammation and blood-brain barrier (BBB) biomarkers were measured using the Corplex cytokine 10-Plex kit and the angiogenesis 6-Plex kit, respectively.<br><br>RESULTS: Biomarker levels were regressed by cognitive group, age, sex, race, and apolipoprotein E apoE &#x3b5;4 status, yielded significant positive associations between age and numerous AD, neuroinflammation, cytokine, and BBB plasma markers.<br><br>DISCUSSION: Linear regression analysis, adjusted for age, sex, race, and ApoE status, revealed significant differences between cognitive groups in levels of several plasma biomarkers and associations with age and sex. Neuroinflammation and BBB dysfunction showed significant positive associations with age across different stages of AD.},
}
@article {pmid42591325,
year = {2026},
author = {Shin, J and Suh, SI and Park, YJ and Lee, S and Kang, J and Lee, ES and Jung, HN and Ryoo, I and Lee, S and Eo, JS and Oh, K and Koh, SB and Kang, SH},
title = {Real-world implementation of lecanemab in Korean patients at a tertiary memory clinic: Safety, ARIA risk, and early treatment patterns.},
journal = {Alzheimer's &amp; dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70447},
pmid = {42591325},
issn = {2352-8729},
abstract = {INTRODUCTION: Lecanemab has demonstrated clinical efficacy in early Alzheimer's disease (AD), but real-world data remain limited, particularly in Asian populations.<br><br>METHODS: We prospectively enrolled 127 patients across the AD continuum who initiated lecanemab at a tertiary memory clinic in Korea. Infusion-related reactions (IRRs), amyloid-related imaging abnormalities (ARIAs), and cognitive outcomes were evaluated through clinical assessments, serial magnetic resonance imaging (MRI), and longitudinal Mini-Mental State Examination (MMSE) follow-up.<br><br>RESULTS: Among 127 patients, 102 completed at least five infusions with follow-up MRI. IRRs occurred in 27 (21.3%) patients, primarily during the first infusion. ARIAs occurred in 9 of 102 (8.8%), including ARIAs with edema in 4 (3.9%) and ARIA with hemorrhage in 7 (6.9%); most events were mild or asymptomatic. Higher microbleed burden and white matter hyperintensity were associated with increased ARIA risk. MMSE scores remained stable over 6 months.<br><br>DISCUSSION: In this prospective Korean cohort, lecanemab was generally well tolerated. Longer term controlled studies are needed to clarify cognitive outcomes.},
}
@article {pmid42591376,
year = {2026},
author = {Boord, MS and Morrissey, S and Keage, HAD and Schinazi, VR and Hornberger, M and Wong, S},
title = {Development and validation of the Spatial Navigation and Memory Questionnaire (SPAM).},
journal = {Alzheimer's &amp; dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70441},
pmid = {42591376},
issn = {2352-8729},
abstract = {INTRODUCTION: Spatial navigation deficits may provide a sensitive and specific marker of early Alzheimer's disease pathology. However, few spatial navigation assessment tools are available for clinical practice that are accessible, time efficient, and sensitive to cognitive aging.<br><br>METHODS: Exploratory (n&#xa0;=&#xa0;470) and confirmatory factor analyses (n&#xa0;=&#xa0;470) were conducted to establish the factor structure of the Spatial Navigation and Memory Questionnaire (SPAM) in healthy older adults. A subset of participants (n&#xa0;=&#xa0;445) completed the Virtual Supermarket Test (VST) to assess convergent validity. Normative data were reported stratified by age and sex.<br><br>RESULTS: A two-factor structure reflecting spatial navigation and memory for both subscales of the SPAM was supported, with acceptable to good internal consistency across factors. SPAM spatial navigation scores and VST performance were significantly correlated.<br><br>DISCUSSION: The SPAM demonstrates a clear and interpretable factor structure, acceptable model fit, and preliminary evidence of validity with an objective measure of spatial navigation performance.},
}
@article {pmid42591604,
year = {2026},
author = {Nathea, R and Ghosh, K and Nisha, JS},
title = {Convolutional neural networks in brain disease diagnosis: a unified review of Alzheimer's, Parkinson's, and brain tumor classification.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1875642},
pmid = {42591604},
issn = {1662-4548},
abstract = {Neurological and neuro-oncological brain disorders like Alzheimer's disease (AD), Parkinson's disease (PD), and brain tumors are challenging to diagnose due to overlapping symptoms and the limitations of conventional imaging techniques. Magnetic resonance imaging (MRI) with convolutional neural networks (CNNs) has emerged as a powerful approach, enabling automated and high-precision detection and staging. This review critically integrates recent developments in CNN architectures, such as hybrid models, attention mechanisms, and 3D CNNs for MRI-based diagnosis of these disorders. It further examines preprocessing methods, datasets, and performance metrics across studies, with emphasis on innovations such as transformer-based models and lightweight architectures. While CNNs show impressive accuracy, issues remain in generalizability, interpretability, and clinical integration. This review highlights the need for multimodal data fusion, explainable artificial intelligence, and real-world validation to narrow the gap between research and clinical practice. By defining future directions, this review aims to guide the development of robust, scalable neurodiagnostic systems for early intervention and better patient outcomes.},
}
@article {pmid42591826,
year = {2026},
author = {Amin, A and Badenes, M},
title = {Epidermal growth factor receptor modulation for neural repair: Implications for neurodegenerative disease therapy.},
journal = {Frontiers in molecular neuroscience},
volume = {19},
number = {},
pages = {1891964},
pmid = {42591826},
issn = {1662-5099},
abstract = {The epidermal growth factor receptor (EGFR; ErbB1/HER1) is a receptor tyrosine kinase that regulates cell proliferation, survival, differentiation, and tissue repair. In the nervous system, EGFR is expressed in neural progenitors, astrocytes, oligodendrocyte precursor cells, and neuronal populations, where its functions are context dependent. EGFR signaling contributes to neural regeneration by promoting progenitor proliferation, neuronal survival, neurogenesis, and remyelination following injury. However, sustained or excessive EGFR activation can drive reactive astrogliosis, neuroinflammation, glial scar formation, and neurotoxicity. Emerging evidence suggests that transient, regulated EGFR activation supports neural repair, whereas chronic or dysregulated signaling may contribute to neurodegeneration. These apparently opposing effects likely reflect differences in timing, duration, cellular context, ligand availability, and downstream signaling pathways engaged by EGFR activation, rather than inherently contradictory biological functions. In experimental models of Parkinson's disease, Alzheimer's disease, and Multiple sclerosis-like conditions, EGFR modulation has shown therapeutic potential, although the mechanisms remain incompletely understood. While EGFR ligands often exert neurotrophic and pro-remyelinating effects, disease-associated EGFR activation may promote maladaptive signaling pathways. In this review, we summarize current knowledge of EGFR signaling in neural repair and neurodegenerative diseases, discuss the context-dependent roles of this pathway, and highlight therapeutic strategies. We further propose a conceptual framework in which EGFR functions as a context-dependent signaling hub, with its outcomes determined by the spatiotemporal regulation of receptor activation. Although challenges remain, including optimal timing, dosing, and safety considerations, preclinical evidence suggests that modulation of EGFR signaling may be a therapeutic approach to promote neural repair while limiting neurodegenerative pathology.},
}
@article {pmid42591921,
year = {2026},
author = {Farag, A and Mirshahvalad, SA and Ortega, C and Tartaglia, C and Veit-Haibach, P and Metser, U},
title = {Quantification of global gray matter amyloid-β plaque from [18]F-Florbetaben PET/MRI and correlation to BAPL score in patients with cognitive impairment.},
journal = {Alzheimer's &amp; dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70449},
pmid = {42591921},
issn = {2352-8729},
abstract = {INTRODUCTION: Multiple standardized uptake value ratio (SUVR) and Centiloid (CL) thresholds exist for amyloid‑β (Aβ) positron emission tomography (PET) to classify scans as negative or positive, yet none reliably stratify brain amyloid plaque load (BAPL). This study proposes a global gray matter-based SUVR/CL model to determine amyloid status and quantitatively differentiate BAPL scores.<br><br>METHODS: Two [18]F-Florbetaben (FBB) PET datasets were analyzed to derive SUVRs and CL values from global gray and white matter. SUVR/CL were integrated with visual assessment and BAPL scoring, resulting in CL thresholds to distinguish amyloid status and cognitive stage. The CL thresholds were validated in an independent local cohort.<br><br>RESULTS: Global gray-to-white matter CL best stratified amyloid status and BAPL scores, yielding CL thresholds of&#xa0;<&#xa0;21 and&#xa0;>&#xa0;38 and high diagnostic accuracy.<br><br>DISCUSSION: The integrated global CL-BAPL model reliably stratified amyloid positivity and BAPL level, suggesting that it could serve as a complementary tool to visual assessment.},
}
@article {pmid42592146,
year = {2026},
author = {Sharma, R and Shkirkova, K and Mack, WJ and Gopalakrishna, R},
title = {Low Brain Levels of Dietary Polyphenols and Their Conjugates: Reassessing Mechanisms of Alzheimer's Disease Prevention.},
journal = {Journal of dementia and alzheimer's disease},
volume = {3},
number = {2},
pages = {},
pmid = {42592146},
issn = {3042-4518},
abstract = {Dietary polyphenols such as quercetin, resveratrol, and (-)-epigallocatechin-3-gallate (EGCG) have shown neuroprotective effects in epidemiologic and experimental studies of Alzheimer's disease (AD), although clinical evidence remains limited. This review highlights the importance of investigating glucuronide and sulfate conjugates of these polyphenols, as well as their intestinal microbial metabolites, at bioavailable low nanomolar concentrations, particularly those capable of reaching the brain. Although many in vitro studies use micromolar concentrations of aglycones, the relevance of such concentrations to neuroprotection remains uncertain. While polyphenols are redox-sensitive, their direct antioxidant or prooxidant effects may be limited at nanomolar concentrations. Instead, their neuroprotective actions appear to be mediated through high-affinity interactions with molecular targets such as the 67-kDa laminin receptor (67LR). This receptor binds both aglycones and conjugates at low nanomolar concentrations through a peptide G region containing glycosaminoglycan- and palindromic sequence-related motifs. The same region also binds the prion-amyloid-β complex, suggesting that polyphenols may antagonize amyloid-β binding and thereby prevent its neurotoxicity. The peptide G region may also function as a redox sensor. Binding of polyphenols to 67LR activates cAMP signaling and downstream neuroprotective pathways involving CREB, SIRT1, and protein phosphatase 2A. In addition, nanomolar concentrations of resveratrol and quercetin inhibit quinone reductase 2, an enzyme associated with cognitive decline and reported to be elevated in AD. Given their low bioavailability in the brain and their distinct molecular targets, combining multiple polyphenols at low doses may produce additive or synergistic effects, enhance efficacy, and minimize potential toxicity in the prevention of AD.},
}
@article {pmid42592497,
year = {2026},
author = {Pal, S and Das, S and Biswas, S and Murugan, SD and Jana, NR and Chattopadhyay, AP and Singh, NDP},
title = {Exploring viscosity sensitivity of π-extended coumarin fluorogen-based PRPGs for precise photorelease of valproic acid: detection and defibrillation of TDP-43 aggregation.},
journal = {Chemical science},
volume = {},
number = {},
pages = {},
pmid = {42592497},
issn = {2041-6520},
abstract = {Alteration of cellular microenvironment viscosity by protein aggregation plays a crucial role as a biophysical parameter that reflects abnormal cellular behaviour, leading to neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), etc. Herein, we report the design and development of a series of coumarin fluorogen-based photoremovable protecting groups (PRPGs, 5a-d) with variations in substitutions tethered with a π-extended linker that integrate viscosity sensing with visible-light-triggered release of bioactive molecules. By introducing π-extended conjugation and systematic substitution, the coumarin fluorogen-based PRPGs exhibit twisted intramolecular charge transfer (TICT)-based fluorescence modulation in response to microenvironmental viscosity. Comprehensive photophysical and photochemical investigations, supported by theoretical calculations, identified PRPG 5d as the most sensitive viscosity-responsive system with green-light absorption. Under viscous conditions, restricted bond rotation suppresses nonradiative decay and photoisomerization, enabling efficient photorelease of the neuroprotective agent valproic acid. The versatility of PRPG 5d was demonstrated in biologically relevant in vitro models, including TDP-43 protein aggregation and Parkinson's disease induced SH-SY5Y neuroblastoma cells. In both extracellular and intracellular neurodegenerative environments, increased viscosity was effectively sensed, triggering light-mediated valproic acid release and subsequent defibrillation. Overall, this work establishes coumarin fluorogen-based PRPGs as a promising platform for viscosity-guided, spatiotemporally controlled drug release, offering potential applications in the diagnosis and targeted therapy of neurodegenerative diseases.},
}
@article {pmid42592659,
year = {2026},
author = {Emon, M and Rahaman, MM and Sarder, D and Shadin, M and Neela, SA and Wangchuk, P and Sarker, S},
title = {Microbiome-Phytochemical Crosstalk Along the Gut-Brain Axis in Alzheimer and Parkinson's Disease.},
journal = {MicrobiologyOpen},
volume = {15},
number = {4},
pages = {e70374},
doi = {10.1002/mbo3.70374},
pmid = {42592659},
issn = {2045-8827},
mesh = {Humans ; *Parkinson Disease/microbiology/metabolism/drug therapy ; *Alzheimer Disease/microbiology/metabolism/drug therapy ; *Phytochemicals/pharmacology/metabolism ; *Gastrointestinal Microbiome/drug effects ; *Brain/metabolism ; Animals ; Signal Transduction ; *Brain-Gut Axis/drug effects ; },
abstract = {Gut-brain axis (GBA) has emerged as a bidirectional communication network linking the gut microbiota with central nervous system function and contributing to the pathogenesis of Alzheimer's disease (AD) and Parkinson's disease (PD). This study aimed to critically evaluate the current evidence on how phytochemicals modulate gut microbiota and GBA signaling to influence the progression of AD and PD. A systematic literature search was conducted using major scientific databases, and preclinical studies investigating microbiota-mediated mechanisms of phytochemicals were synthesized according to predefined inclusion criteria. The available evidence demonstrates that phytochemicals consistently remodel the gut microbiota by increasing beneficial taxa such as Lactobacillus, Bifidobacterium, Akkermansia, and short-chain fatty acid (SCFA)-producing bacteria while suppressing pro-inflammatory Gram-negative microorganisms. These microbial alterations were associated with reduced lipopolysaccharide (LPS) production, inhibition of TLR4/NF-κB and NLRP3 inflammasome signaling, enhancement of brain-derived neurotrophic factor (BDNF) activity, restoration of intestinal barrier integrity, attenuation of oxidative stress, and activation of autophagy-related pathways, including PI3K/AKT/mTOR and AMPK/mTOR, leading to reduced amyloid-β, tau, and α-synuclein pathology. A major contribution of this review is the integration of current evidence demonstrating the bidirectional crosstalk between phytochemicals and the gut microbiota as a central mechanism regulating GBA signaling in AD and PD. Available evidence suggests that phytochemical-mediated modulation of the gut microbiota represents a promising therapeutic strategy for slowing disease progression in AD and PD. However, further mechanistic investigations and well-designed clinical trials are required to validate these findings and facilitate their translation into clinical practice.},
}
@article {pmid42592691,
year = {2026},
author = {Yaqoob, F and Sadeghian, N and Tokali, FS and Taslimi, P and Alkhedaide, AQ and Althobaiti, A and Ulucay, O and Ibrahim, MM and Zaki, MEA and Gomha, SM and Zhao, X and Şenol, H and Janjua, MU and Shafiq, Z},
title = {Design, Synthesis, and Biological Evaluation of Biphenylsulfonyl Indole-Based Thiosemicarbazones as Potential AChE and CA I-II Inhibitors.},
journal = {Archiv der Pharmazie},
volume = {359},
number = {8},
pages = {e70315},
doi = {10.1002/ardp.70315},
pmid = {42592691},
issn = {1521-4184},
support = {//Deanship of Graduate Studies and Scientific Research/ ; //Taif University/ ; },
mesh = {*Thiosemicarbazones/pharmacology/chemical synthesis/chemistry ; *Drug Design ; Structure-Activity Relationship ; *Cholinesterase Inhibitors/chemical synthesis/pharmacology/chemistry ; *Indoles/chemistry/pharmacology/chemical synthesis ; Acetylcholinesterase/metabolism ; Molecular Docking Simulation ; *Carbonic Anhydrase I/antagonists &amp; inhibitors/metabolism ; *Carbonic Anhydrase II/antagonists &amp; inhibitors/metabolism ; *Carbonic Anhydrase Inhibitors/chemical synthesis/pharmacology/chemistry ; Molecular Structure ; Humans ; Molecular Dynamics Simulation ; *Biphenyl Compounds/chemistry/pharmacology/chemical synthesis ; Animals ; },
abstract = {In this study, 20 novel biphenyl-sulfonamide-indole-based thiosemicarbazone derivatives (1-20) were synthesized and evaluated for their inhibitory activities against AChE, hCA I, and hCA II. Among the synthesized compounds, compound 20 (4-nitrophenyl substituted) exhibited the highest inhibitory activity against all three enzymes (AChE Ki = 54.24 nM; hCA I Ki = 12.75 nM; hCA II Ki = 8.72 nM) and behaved as a competitive inhibitor in enzyme kinetic studies. To further explore the experimentally observed AChE inhibition, induced fit docking (IFD), MM-GBSA calculations, and molecular dynamics simulations were performed for compound 20, suggesting a plausible binding mode within the AChE active site. In silico ADME analysis indicated generally favorable drug-like properties for the synthesized compounds. These findings identify biphenyl-sulfonamide-indole-based thiosemicarbazones as promising AChE and carbonic anhydrase inhibitors for further biological investigation.},
}
@article {pmid42592704,
year = {2026},
author = {McQuaid, GA and Lee, NR and Wallace, GL},
title = {Characterization of Anticholinergic Medication Use and Its Associations With Everyday Memory Problems and Cognitive Decline in Autistic Adults With Higher Support Needs.},
journal = {Autism research : official journal of the International Society for Autism Research},
volume = {},
number = {},
pages = {e70342},
doi = {10.1002/aur.70342},
pmid = {42592704},
issn = {1939-3806},
support = {//George Washington University/ ; K01MH129622/MH/NIMH NIH HHS/United States ; },
abstract = {Among older adults in the general population, medications with anticholinergic (AC) effects are associated with declines in cognitive functioning and with dementia and Alzheimer's disease. Autistic people have high rates of co-occurring medical conditions and polypharmacy across the lifespan; thus, they may be at particularly high risk of exposure to AC medications and their negative impacts on cognitive functioning, including earlier in adulthood. Consistent with this, a single study has shown AC medication use is prevalent among autistic adults without co-occurring intellectual disability and is associated with self-reported concurrent memory problems and declines in cognition. No study has examined AC medications and their associations with cognition among autistic adults with higher support needs. We therefore characterized AC medication use and its associations with caregiver-rated memory problems and changes in cognition and behavior that have been linked with cognitive decline. Caregivers of autistic adults (18-68 years; Mean ~31 years) recruited via Simons Powering Autism Research's (SPARK) Research Match service reported medication use (N = 512), memory complaints (N = 467), and a screener that probes behavior/cognitive changes (N = 466) that are associated with cognitive decline among persons with an intellectual disability. The majority (66.41%) of autistic adults were taking at least one AC medication and 31% were taking clinically-meaningful levels of these medications. After controlling for age and birth sex, greater potency of AC medications was associated with both caregiver-reported memory challenges and behavioral/cognitive changes associated with cognitive decline. Understanding AC medication use and its potential impacts on cognition among autistic adults with higher support needs is crucial.},
}
@article {pmid42592812,
year = {2026},
author = {Le Guen, Y and Park, J and Peña-Tauber, A and Greicius, MD},
title = {Proteomic signatures of protected APOE ε4 carriers reveal causal pathways associated with delayed Alzheimer's disease onset.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71688},
doi = {10.1002/alz.71688},
pmid = {42592812},
issn = {1552-5279},
support = {//National Institute of Health/ ; AG072290/AG/NIA NIH HHS/United States ; AG066515/AG/NIA NIH HHS/United States ; },
mesh = {*Alzheimer Disease/genetics/blood ; Humans ; *Proteomics ; *Apolipoprotein E4/genetics ; Female ; Male ; Heterozygote ; Aged ; Age of Onset ; Biomarkers/blood ; },
abstract = {INTRODUCTION: APOE ε4 is the strongest common genetic risk factor for Alzheimer's disease (AD), yet many carriers remain cognitively unimpaired into late life. We tested whether protected ε4-first plasma proteomics could identify proteins associated with delayed clinical onset.<br><br>METHODS: We analyzed harmonized Global Neurodegeneration Proteomics Consortium (GNPC) plasma proteomics. Protected &#x3b5;4 carriers (&#x3b5;3/&#x3b5;4 &#x2265;75 years; &#x3b5;4/&#x3b5;4 &#x2265;65 years; Clinical Dementia Rating [CDR] score&#xa0;=&#xa0;0; n&#xa0;=&#xa0;456) were compared with &#x3b5;4 carriers with AD (n&#xa0;=&#xa0;1096). Protein-wise models adjusted for age, sex, &#x3b5;4 dosage, and plasma proteomic principal components. Top signals were integrated with loss-of-function burden testing and plasma/cerebrospinal fluid Mendelian randomization.<br><br>RESULTS: Protected &#x3b5;4 status was associated with 721 protein measures. Integrated analyses prioritized LILRA5, DBI, BPNT1, PTEN, EPHA1, and PCDH10 as &#x3b5;4-modified candidates and OMG, SELENOW, VAT1, and TPPP3 as broader AD-related signals. TREM2 and ACE were also identified.<br><br>DISCUSSION: This strategy highlights immune, synaptic, metabolic-stress, and myelin/axonal pathways that may delay AD onset.},
}
@article {pmid42593033,
year = {2026},
author = {Değirmenci, S and Tırın, H and Arıkan, E and Andiç, K and Sezgin, E},
title = {Red cell distribution width and modified 5-item frailty index to predict short-term mortality in patients undergoing surgery for hip fracture.},
journal = {Ulusal travma ve acil cerrahi dergisi = Turkish journal of trauma &amp; emergency surgery : TJTES},
volume = {32},
number = {8},
pages = {998-1007},
doi = {10.14744/tjtes.2026.20432},
pmid = {42593033},
issn = {1307-7945},
mesh = {Humans ; Female ; *Hip Fractures/surgery/mortality/blood ; Aged, 80 and over ; Male ; *Erythrocyte Indices ; Aged ; *Frailty/mortality ; Intensive Care Units/statistics &amp; numerical data ; Hospital Mortality ; Prognosis ; Turkey ; },
abstract = {BACKGROUND: Hip fractures (HFs), which are common in the geriatric population and have a high mortality rate, are among the pathologies frequently encountered in emergency departments (EDs). The aim of this study was to investigate the prognostic value of red cell distribution width (RDW) and modified 5-item frailty index (mFI-5) scores in the prediction of short-term mortality and intensive care unit (ICU) admission in patients with HFs.<br><br>METHODS: Patients who presented to the ED due to HF between January 01, 2019, and December 31, 2023, were evaluated. Patients who underwent surgery for femoral neck, intertrochanteric, or subtrochanteric fractures were included in the study. Baseline demographics (age and sex), comorbidities, ICU admission status, and in-hospital and 30-day mortality rates were recorded. Univariate and multivariable logistic regression analyses were performed to identify independent predictors of ICU admission and 30-day mortality.<br><br>RESULTS: A total of 413 patients undergoing surgical treatment for HFs were included. The mean age of the patients was 80&#xb1;11 years, and 271 (65.6%) were female. ICU admission was required for 43 patients (10%), while in-hospital and 30-day mortality rates were 7% (n=30) and 9.9% (n=41), respectively. Multivariable logistic regression analysis identified RDW as an independent predictor of both ICU admission (odds ratio [OR] 1.22, 95% confidence interval [CI] 1.05-1.41; p=0.009) and 30-day mortality (OR 1.20, 95% CI 1.03-1.39; p=0.016). Atrial fibrillation (AF) and Alzheimer's disease were also identified as independent predictors of ICU admission, while AF and age independently predicted 30-day mortality. The mFI-5 score did not reach statistical significance in univariate analysis for either outcome. A predictive model incorporating RDW and other covariates achieved area under the curve values of 0.74 for ICU admission and 0.70 for 30-day mortality.<br><br>CONCLUSION: RDW emerged as an independent predictor of ICU admission and 30-day mortality in surgically managed HF patients, with improved discriminatory performance when integrated into a multiparametric model. Advanced age, Alzheimer's disease, and AF further contribute to increased risk and should be closely monitored in clinical management. These findings support the incor-poration of RDW into routine emergency risk stratification for this vulnerable population.},
}
@article {pmid42593101,
year = {2026},
author = {Zhang, Z and Zhou, Z and Xiang, L and Shankaranarayanan, A and Gong, E and Zaharchuk, G},
title = {Deep Learning-Based Enhancement of Already Diagnostic-Quality MRI for Alzheimer's Disease Classification: Effects on Model Performance and Training Data Requirements.},
journal = {Journal of magnetic resonance imaging : JMRI},
volume = {},
number = {},
pages = {},
doi = {10.1002/jmri.70507},
pmid = {42593101},
issn = {1522-2586},
support = {R44MH135725//NIH SBIR/ ; },
abstract = {BACKGROUND: Deep learning (DL)-based image enhancement is widely used to improve suboptimal medical imaging. Whether it also benefits diagnostic-quality MRI in downstream task performance and data-efficiency remains unclear.<br><br>PURPOSE: To investigate the impact of DL-based enhancement applied to diagnostic quality structural MRI for Alzheimer's disease (AD) classification.<br><br>STUDY TYPE: Retrospective.<br><br>POPULATION: A total of 2293 brain MRI scans from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were split into training (n&#x2009;=&#x2009;1605), validation (n&#x2009;=&#x2009;229), and internal test (n&#x2009;=&#x2009;459) sets. Two hundred and seventy scans from the National Alzheimer's Coordinating Center (NACC) served as an external test set.<br><br>FIELD STRENGTH/SEQUENCE: 1.5&#x2009;T; 3D T1-weighted gradient-echo.<br><br>ASSESSMENT: Each scan was enhanced by SubtleHD (SHD), an FDA-cleared DL-based MR enhancement tool. ResNet34 and DenseNet121 were trained on standard-of-care (SOC) and SHD-enhanced images to classify subjects as cognitively normal, mild cognitive impairment, or AD and evaluated by accuracy and macro-area under the receiver operating characteristic curve (macro-AUC). Data efficiency was assessed by retraining on stratified training subsets (50%-100%).<br><br>STATISTICAL TESTS: McNemar test for accuracy and DeLong test for macro-AUC in three-class one-versus-rest setting (p&#x2009;<&#x2009;0.05).<br><br>RESULTS: SHD enhancement increased ResNet34 accuracy from 85.2% to 88.7% and macro-AUC from 0.951 to 0.968 (both significant), and DenseNet121 accuracy from 90.2% to 92.2% (p&#x2009;=&#x2009;0.18) and macro-AUC from 0.978 to 0.982 (p&#x2009;=&#x2009;0.29). Models trained on 70% of SHD-enhanced dataset matched those trained on the full SOC dataset (accuracy: 85.9%, macro-AUC: 0.942), indicating improved data efficiency with enhancement. In NACC, the SOC-trained model achieved accuracy of 49.2% and macro-AUC of 0.679 versus 63.0% and 0.819 for the SHD-trained model (both significant); the SHD-trained model retained an advantage on unenhanced NACC images (macro-AUC: 0.772).<br><br>DATA CONCLUSION: DL-based enhancement of diagnostic-quality MRI improves downstream Alzheimer's disease classification performance and reduces the amount of training data required. This suggests that conventional definitions of image quality may underestimate the information content available for machine learning.<br><br>EVIDENCE LEVEL: 3.<br><br>TECHNICAL EFFICACY STAGE: 2.},
}
@article {pmid42593238,
year = {2026},
author = {Simmons, J and Greenwood-Hickman, MA and Barrett, TD and Gill, VA and Broussard, JM and Barnes, DE},
title = {Amplifying the Voice of a Community: A Scoping Review of Attitudes, Beliefs, and Perceptions Among Black and African Americans About Dementia.},
journal = {The Gerontologist},
volume = {},
number = {},
pages = {},
doi = {10.1093/geront/gnag100},
pmid = {42593238},
issn = {1758-5341},
abstract = {BACKGROUND AND OBJECTIVES: African Americans (AA) are twice as likely as White Americans to develop Alzheimer's disease and related dementias (ADRD) but half as likely to receive a timely diagnosis. Factors contributing to underdiagnosis among AA include lack of healthcare access and provider bias, but little is known about attitudes, beliefs, and perceptions that may be patient-related drivers of dementia underdiagnosis.<br><br>RESEARCH DESIGN AND METHODS: We performed a scoping review of attitudes, beliefs, and perceptions regarding ADRD among AA by searching PubMed, CINAHL, Web of Science, and Black Studies Periodicals Database from 2002-2024. Eligible studies were written in English and discussed attitudes, beliefs, or perceptions toward ADRD among AA in the U.S. A primary reviewer identified key themes, which were then discussed and summarized by the team.<br><br>RESULTS: 49 studies met inclusion/exclusion criteria after title, abstract, and full manuscript review. We identified six themes: AA display gaps in knowledge about dementia; inclusive resources and support can help address the knowledge gap; stigma and losing autonomy are important barriers to seeking care; uncertainty in the relationship between the AA and medical communities is an additional barrier; the AA community has strengths that can be leveraged to support earlier dementia diagnosis if used carefully; and the AA community is not monolithic.<br><br>DISCUSSION AND IMPLICATIONS: It may be possible to address dementia-related disparities in diagnosis by leveraging underlying barriers and facilitators within the AA community. Additional research is needed to understand variations in attitudes, beliefs, and perceptions toward ADRD among AA.},
}
@article {pmid42593278,
year = {2026},
author = {Mandal, PK and Perry, G and Maroon, JC and Corby, P and Patira, R and Lopez, OL},
title = {Bypassing the bottleneck: Gamma-glutamylcysteine supplementation for brain glutathione enrichment in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261474009},
doi = {10.1177/13872877261474009},
pmid = {42593278},
issn = {1875-8908},
abstract = {Alzheimer's disease (AD) is a major neurodegenerative disorder affecting more than 7 million Americans. Extensive studies have identified various factors associated with the development of AD, but the actual cause remains unknown. Transgenic mouse model and human studies strongly indicate that oxidative stress precedes amyloid-β plaque formation and tau phosphorylation in AD. GSH loss itself raises the Abeta42/Abeta40 ratio and promotes tau aggregation [5], placing GSH depletion upstream of classical AD pathology. Subsequently, the role of the master antioxidant, glutathione (GSH), came into focus for brain GSH level enrichment through supplementation with γ-glutamylcysteine (GGC), the immediate precursor of GSH. We present that GGC has an excellent safety record and bioavailability. GGC is a strong candidate to investigate for brain GSH enrichment (target engagement hippocampus, anterior cingulate cortex etc.) and subsequent cognitive enhancement for patients with mild cognitive impairment (MCI).},
}
@article {pmid42593281,
year = {2026},
author = {Townsend, RF and Hamill, LL and Farsi, DN and McCarthy, G and Dolan, C and McGuinness, B and Kennelly, SP and Regan-Moriarty, J and Kee, F and Passmore, P and Woodside, JV and McEvoy, CT},
title = {BRAIN-Diabetes: Acceptability of an adapted FINGER multidomain intervention among adults living with type 2 diabetes in rural border regions across the island of Ireland.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261471915},
doi = {10.1177/13872877261471915},
pmid = {42593281},
issn = {1875-8908},
abstract = {BackgroundIndividuals with type 2 diabetes mellitus (T2DM) face increased risk of cognitive decline and dementia. Multidomain lifestyle interventions offer a non-pharmacological strategy to support brain health in this high-risk group.ObjectiveThis study examined the acceptability of a culturally adapted FINGER-based intervention among adults living with T2DM in rural border regions of Ireland (BRAIN-Diabetes Trial).MethodsA 6-month pilot randomized controlled trial was conducted. The intervention group received a multidomain program targeting diet, physical activity, and computerized cognitive training (CCT). The control group received standard care. Acceptability was assessed using questionnaires (all participants) and semi-structured interviews (intervention participants). Quantitative data were analyzed descriptively and qualitative data using template analysis, guided by four a-priori themes: trial participation and engagement, dietary behavior change, exercise behavior change, and CCT behavior change.ResultsQuestionnaire data (intervention: n = 28; control: n = 36) indicated high overall acceptability. Dietary and exercise components were rated most positively, while CCT component was less well received. Interviews (n = 25) highlighted facilitators to trial engagement, including perceived health improvements, and social connection, with time constraints and limited personalization as barriers. Dietary change was supported by tailored guidance but hindered by cost and availability. Facilitators for exercise included accessible resources and perceived benefits, with barriers including competing priorities. CCT engagement was mixed, with challenges including digital access and repetitiveness.ConclusionsThe Brain-Diabetes intervention was acceptable and feasible among adults with T2DM. Personalized support and accessible resources were key to engagement. Future work should refine delivery to enhance scalability and long-term adherence among high-risk groups.},
}
@article {pmid42593291,
year = {2026},
author = {Zhang, QN and Wu, W and Zhou, YM and Yu, LK and Zhang, XY and Wu, JL and Song, SY and Yao, ZH and , },
title = {Decreased cerebrospinal fluid NDRG2 is associated with non-Alzheimer's disease derived mild cognitive impairment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261477113},
doi = {10.1177/13872877261477113},
pmid = {42593291},
issn = {1875-8908},
abstract = {BackgroundMild cognitive impairment (MCI) lacks clear clinical biomarkers. N-Myc downstream-regulated gene 2 (NDRG2) is predominantly localized in astrocytes and is implicated in cognitive function.ObjectiveThis study aims to explore whether cerebrospinal fluid (CSF) NDRG2 could predict MCI and investigate its underlying mechanisms of cognitive decline.MethodsA total of 650 CSF samples were collected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, comprising 157 normal individuals, 366 MCI patients, and 127 Alzheimer's disease (AD) patients. One-way analysis of covariance (ANCOVA) was employed to assess differences in CSF NDRG2 levels among groups. Linear regression was used to analyze the correlation between NDRG2 and amyloid-β (Aβ), phosphorylated tau (p-tau), [18]F-fluorodeoxyglucose positron emission tomography (FDG-PET), albumin quotient (Qalb), and growth-associated protein 43 (GAP43). Receiver operating characteristic (ROC) curves were used to examine the diagnostic performance of NDRG2 for MCI.ResultsCSF NDRG2 levels were significantly reduced in MCI, most prominently in non-Aβ and non-tau subgroups. NDRG2 discriminated Aβ-negative MCI with an area under the curve (AUC) of 0.719, but showed limited discriminatory capacity in Aβ+, tau+, and apolipoprotein E ε4 (APOE ε4) carrier groups. Furthermore, CSF NDRG2 levels were positively correlated with GAP-43, a marker of synaptic plasticity.ConclusionsThe present study demonstrates that NDRG2 is a potential biomarker for non-AD derived MCI and suggests its involvement in synaptic plasticity impairment.},
}
@article {pmid42593302,
year = {2026},
author = {Li, B and Han, J and Yang, M and Yang, W and Wang, L},
title = {Associations of television viewing, computer use, and Alzheimer's disease among United States adults: A cross-sectional study of NHANES.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261476960},
doi = {10.1177/13872877261476960},
pmid = {42593302},
issn = {1875-8908},
abstract = {BackgroundElectronic screen use has become increasingly prevalent in modern society; however, its relationship with Alzheimer's disease (AD) remains unclear and insufficiently characterized.ObjectiveTo examine the associations of television (TV) viewing time and computer use with AD among United States (U.S.) adults.MethodsThis cross-sectional study used data from the National Health and Nutrition Examination Survey (NHANES) 2003-2006 and 2011-2016. A total of 12,165 participants aged ≥45 years were included. Survey-weighted logistic regression models were used to evaluate the associations between screen time and AD. Restricted cubic spline (RCS) analyses were performed to explore potential nonlinear relationships.ResultsLonger TV viewing time was significantly associated with higher odds of AD (OR 1.18, 95% CI: 1.08-1.29, pFDR = 0.002). Computer use was not significantly associated with AD in the main models. RCS analyses showed that computer use had a significant nonlinear U-shaped association with AD (p for nonlinear <0.001), with the lowest odds observed at approximately two hours per day.ConclusionsAmong U.S. adults aged ≥45 years, longer TV viewing time was associated with higher odds of AD, whereas computer use showed a nonlinear association with the lowest odds observed at around two hours per day.},
}
@article {pmid42593346,
year = {2026},
author = {Champigny, J and Hogan, DB and Marrie, RA and Luo, J and Chen, X and Ekuma, O and Walld, R and Dvorani, E and Bolton, JM and Goodarzi, Z and Li, P and Seitz, D and Gruneir, A and Hoben, M and Herrmann, N and Mondor, L and Maxwell, CJ and , },
title = {Mental illness among persons with and without dementia in continuing care: A multi-jurisdictional, repeated cross-sectional study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261476238},
doi = {10.1177/13872877261476238},
pmid = {42593346},
issn = {1875-8908},
abstract = {BackgroundLimited epidemiologic data exists for mental illnesses among at-risk home care (HC) and residential long-term care (LTC) recipients.ObjectiveTo estimate the annual prevalence (April 1, 2012-March 31, 2023) of various mental illnesses among HC and LTC populations (versus matched comparators) with and without dementia in the Canadian provinces of Ontario, Alberta, and Manitoba.MethodsParallel repeated cross-sectional studies were conducted in each province using linked health administrative data. HC and LTC recipients aged ≥18 years were matched to comparators on demographics, dementia and comorbidity. Prevalence estimates were derived using validated case definitions for any mental illness, mood/anxiety disorders, depression and anxiety (with/without drug claims), schizophrenia, bipolar disorder and suicide attempt. Prevalence ratios (95% CIs) were estimated with modified Poisson regression models.ResultsIncluded were 682,466 HC clients and 233,499 LTC residents. Mental illnesses were common in HC and LTC settings across all three provinces. Prevalence estimates were typically higher among care recipients versus matched comparators and among persons with versus without dementia. Up to 70% of HC clients and 80% of LTC residents with dementia had any mental illness; in both settings, 40% had mood/anxiety disorders, 4% bipolar disorders, and between 2%-6% schizophrenia. Suicide attempts were rare (0.5-0.6%). Prevalence varied by province and was higher for case algorithms including drug claims.ConclusionsThe high prevalence of mental illness and its common co-occurrence with dementia in HC and LTC recipients illustrates the complexity and challenges of care in these populations and raises concerns about potential unmet mental health needs.},
}
@article {pmid42593347,
year = {2026},
author = {Edema, M and Popuri, K and Lee, H and Wang, L and Beg, MF and , },
title = {Development and validation of an amyloid PET dementia of the Alzheimer's type (DAT) score.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261476273},
doi = {10.1177/13872877261476273},
pmid = {42593347},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) can be debilitating if left untreated, but its progression may be altered through early detection.ObjectiveTo develop and evaluate a convolutional neural network (CNN) for detecting AD from amyloid PET brain images and to investigate the regions contributing to model predictions.MethodsA 3D CNN with residual connections was developed to classify amyloid PET brain volumes. Amyloid PET data were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI), with approximately 600 images from cognitively normal control (NC) and dementia of the Alzheimer's type (DAT) participants used for training, validation, and testing. Performance was assessed using repeated 5-fold cross-validation (10 total folds). The model was also evaluated across the AD continuum, including unstable normal control (uNC), progressive normal control (pNC), stable mild cognitive impairment (sMCI), progressive mild cognitive impairment (pMCI), and early DAT (eDAT). Saliency and class activation maps were generated to identify regions contributing to predictions.ResultsThe model achieved a mean testing accuracy of 92% across the 10 folds. Across the disease continuum, accuracies were 76% for uNC, 78% for sMCI, 24% for pNC, 65% for pMCI, and 78% for eDAT. Saliency and class activation maps highlighted the putamen, thalamus, hippocampus, corpus callosum, and posterior cingulate cortex, regions previously implicated in AD pathology.ConclusionsThe proposed 3D CNN accurately distinguished DAT from cognitively normal controls using amyloid PET imaging and showed promising performance across the AD continuum. Model interpretation identified biologically relevant brain regions, supporting the potential of deep learning for early AD detection and clinical decision support.},
}
@article {pmid42593354,
year = {2026},
author = {Jiang, P and Peng, S and Huang, Y and Wang, L and Lan, Y and Li, Y and Wang, C and Feng, C and Xie, H and Liu, L and Guo, H and Gao, X},
title = {Evidence from European ancestry genome-wide association studies and a case-control study suggests several selenoproteins are linked to a decreased risk of Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261476713},
doi = {10.1177/13872877261476713},
pmid = {42593354},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a neurodegenerative disorder resulting from a complex interplay of multiple factors. Recent hypotheses suggest a potential role of selenium and selenoproteins in AD pathogenesis. However, the causality relationship between them remains to be elucidated.ObjectiveThis study investigates the causal link between selenoproteins and AD risk.MethodsWe analyzed the data by leveraging genome-wide association studies from European cohorts (90,338 AD patients and 1,036,225 controls) and expression quantitative trait loci (eQTLs) from eQTLGen (31,684 individuals) and GTEx v8 (838 individuals). Mendelian randomization and summary data-based Mendelian randomization were applied to assess the potential causal associations between selenoproteins and AD. To further confirm these genetic associations at the clinical level, we conducted a case-control study to evaluate the levels of four differentially expressed selenoproteins in peripheral blood in individuals with AD and cognitively normal controls.ResultsOur analysis revealed that four selenoproteins, including selenoprotein S (SEPH2) and selenoprotein M (SELENOM), glutathione peroxidase 4 (GPX4) and thioredoxin reductase 2 (TXNRD2), were correlated with a decreased risk of AD. The levels of GPX4, SELENOM, and TXNRD2 were found to be significantly downregulated in AD patients compared to controls in the case-control validation study, supporting the change identified in our genetic analysis.ConclusionsThis study provides genetic and clinical evidence that specific selenoproteins are associated with a decreased risk of AD. The findings highlight the potential role of these proteins in AD pathophysiology and suggest their promise as biomarkers or therapeutic targets, warranting further investigation.},
}
@article {pmid42593420,
year = {2026},
author = {Rizwan Ali, A and Kumar, P and Patnana, AK and Shanmugam, S and Chugh, A and Chaudhry, K},
title = {Association Between Periodontitis and Mild Cognitive Impairment, Alzheimer's Disease, and Dementia: An Umbrella Review With Evidence Stratification.},
journal = {Special care in dentistry : official publication of the American Association of Hospital Dentists, the Academy of Dentistry for the Handicapped, and the American Society for Geriatric Dentistry},
volume = {46},
number = {4},
pages = {e70235},
doi = {10.1111/scd.70235},
pmid = {42593420},
issn = {1754-4505},
mesh = {Humans ; *Alzheimer Disease ; *Cognitive Dysfunction/etiology/complications ; *Periodontitis/complications ; *Dementia/etiology ; Risk Factors ; },
abstract = {AIM: The present umbrella review aims to assess the association between periodontitis and mild cognitive impairment(MCI), Alzheimer's disease and dementia.<br><br>METHODS AND RESULTS: MEDLINE(via PubMed), Scopus, EMBASE, Google Scholar, and Cochrane Library was searched. Risk of Bias(ROB) was performed using Risk of Bias in Systematic Reviews (ROBIS) tool. Metaumbrella software was used for performing quantitative analysis, evidence stratification and GRADE analysis. 12 of the 14 included studies were judged to have a high ROB, while two systematic reviews and meta-analyses (SRMAs) demonstrated a low ROB. Individuals with periodontitis had a 1.651 times higher risk of developing MCI (95% CI = 1.391 to 1.96; I2 = 0%; P < 0.001), a 1.525 times higher risk of Alzheimer's disease (95% CI = 1.149 to 2.023; I2 = 85.877%; P < 0.001), and a 1.535 times higher risk of dementia (95% CI = 1.119 to 2.107; I2 = 82.972%; P < 0.001), all supported by Class IV evidence. Furthermore, severe periodontitis was associated with a 2.138 times higher risk of MCI (95% CI = 1.59 to 2.875; I2 = 0%; P < 0.001), while moderate or severe periodontitis was associated with a 2.048 times higher risk of dementia (95% CI = 1.45 to 2.893; I2 = 0%; P < 0.001), supported by Class IV and Class III evidence, respectively. Despite these associations, the certainty of evidence for all outcomes was rated as very low according to the GRADE assessment.<br><br>CONCLUSION: A significant association was found between periodontitis and MCI, Alzheimer's disease and dementia with a "very low" evidence certainty.},
}
@article {pmid42593551,
year = {2026},
author = {Arriagada, J and Lantadilla, M and Lobos, P and Paz, AA and Herrera, EA and Muñoz, P and Paula-Lima, A},
title = {Metformin Enhances Antioxidant Defenses and Limits Lipid Peroxidation Through the Modulation of Nrf2/KEAP1 Pathway in Hippocampal Neurons Exposed to Amyloid-β Oligomers.},
journal = {Neurotoxicity research},
volume = {44},
number = {4},
pages = {},
pmid = {42593551},
issn = {1476-3524},
support = {Doctorate National Scholarship No. 2123 0993//Agencia Nacional de Investigaci&#xf3;n y Desarrollo/ ; FONDECYT Regular Grant No. 1241502//Agencia Nacional de Investigaci&#xf3;n y Desarrollo/ ; FONDECYT Regular Grants No. 1251980//Agencia Nacional de Investigaci&#xf3;n y Desarrollo/ ; FONDECYT Regular Grant No. 1261188//Agencia Nacional de Investigaci&#xf3;n y Desarrollo/ ; Universidad de Chile RS0925//Universidad de Chile/ ; Universidad de Chile RS0925//Universidad de Chile/ ; INACH 16-21//Institut chilien de l'Antarctique/ ; },
mesh = {Animals ; *NF-E2-Related Factor 2/metabolism ; *Amyloid beta-Peptides/toxicity ; *Metformin/pharmacology ; *Kelch-Like ECH-Associated Protein 1/metabolism ; *Hippocampus/drug effects/metabolism ; *Neurons/drug effects/metabolism ; *Lipid Peroxidation/drug effects/physiology ; Signal Transduction/drug effects ; *Antioxidants/metabolism/pharmacology ; Cells, Cultured ; Rats ; Peptide Fragments/toxicity ; Oxidative Stress/drug effects ; },
abstract = {Oxidative stress is an early and important feature of Alzheimer's disease (AD) that contributes to synaptic dysfunction and neurodegeneration. Soluble amyloid-β oligomers (AβOs) are major contributors to oxidative damage and have been shown to impair neuronal antioxidant defenses. The Nrf2/KEAP1 pathway is a central regulator of cellular redox homeostasis; however, its activity is compromised in AD, increasing neuronal vulnerability to oxidative stress. Metformin (Met), a widely used antidiabetic drug, has emerged as a potential modulator of antioxidant signaling pathways in the nervous system. In the present study, we investigated whether Met enhances antioxidant defenses in primary fetal rat hippocampal neurons exposed to AβOs. Neuronal cultures were treated with Met (2.5 mM for 24 h) prior to exposure to AβOs (500 nM for 6 h). We evaluated Nrf2 and KEAP1 protein levels, Nrf2 nuclear localization, antioxidant enzyme expression and activity, and lipid peroxidation. Met treatment promoted Nrf2 nuclear accumulation, preserved a favorable Nrf2/KEAP1 profile under amyloid stress, and enhanced the expression and activity of key antioxidant enzymes, including superoxide dismutase (SOD1 and SOD2), catalase (CAT), and glutathione peroxidase (GPx1/2). In addition, Met attenuated AβOs-induced lipid peroxidation, supporting its protective effects against amyloid-associated oxidative damage. Collectively, these findings indicate that Met strengthens neuronal antioxidant defenses and promotes redox resilience under amyloid-associated oxidative stress. Our results support modulation of the Nrf2/KEAP1 pathway as a mechanism contributing to the neuroprotective actions of Met and identify the coordinated enhancement of antioxidant defenses and reduction of lipid peroxidation as key components of neuronal redox resilience against AβOs-induced stress.},
}
@article {pmid42593576,
year = {2026},
author = {Jarco, J and Malek, N},
title = {GPR84 and Neuroinflammation: A Receptor Worth Targeting, or A Target Worth Reconsidering?.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42593576},
issn = {1559-1182},
mesh = {Animals ; *Receptors, G-Protein-Coupled/metabolism ; Humans ; *Neuroinflammatory Diseases/metabolism/drug therapy ; *Molecular Targeted Therapy ; Microglia/metabolism ; *Inflammation/metabolism ; },
abstract = {GPR84 is a medium-chain fatty acid (MCFA)-sensing G-protein-coupled receptor conditionally expressed on innate immune cells - neutrophils, monocytes, macrophages, and microglia - with expression strongly induced by inflammatory stimuli. Upon activation, GPR84 engages Gi/o signalling, MAPK/ERK, NF-κB, and NLRP3 inflammasome pathways, amplifying pro-inflammatory effector functions across peripheral and central myeloid populations. In microglia, receptor upregulation marks a disease-associated subpopulation linked to TNF-α and IL-1β production in models of neurodegeneration, traumatic CNS injury, and neuropathic pain. Yet the same receptor exhibits context-dependent protective roles: GPR84 deletion attenuates neuropathic hypersensitivity through peripheral macrophage reprogramming while leaving microglial activation intact, and Gpr84-deficient Alzheimer's disease mice show reduced microgliosis but paradoxically accelerated cognitive decline, demonstrating that the receptor's output is determined by cell type, disease stage, and local inflammatory context rather than by a fixed pro-inflammatory identity. Recent cryo-EM structural resolution of GPR84 has enabled the design of G-protein-biased agonists that preferentially engage pathways linked to motility and phagocytosis while sparing cytokine amplification, providing a rationale for selectively enhancing homeostatic clearance without exacerbating chronic inflammation. However, the most clinically advanced antagonist, GLPG1205, failed to meet primary endpoints in Phase II trials in ulcerative colitis and idiopathic pulmonary fibrosis. This review argues that these translational failures reflect deeper methodological limitations - including supraphysiological agonist concentrations, constitutive knockout models that conflate microglial and peripheral macrophage contributions, species selectivity gaps in available antagonists - that have produced conflicting preclinical evidence and impeded clinical translation. Resolving GPR84's context-dependent biology will require conditional genetic models, CNS-penetrant pharmacological tools, and integration of spatial and temporal multiomics approaches before the receptor's therapeutic potential can be meaningfully evaluated.},
}
@article {pmid42593621,
year = {2026},
author = {Sura, S and Jagadeesan, S and Moklas, MAM and Masrudin, SS and Dandala, KCR and Judson, JP and MohdNor, NH},
title = {Tau dysfunction in alzheimer's disease: molecular and cellular mechanisms, genetic modulation, and therapeutic perspectives.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42593621},
issn = {1573-4978},
support = {GP-IPM/2021/9700000//Universiti Putra Malaysia through the Institutional Grant Scheme/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/metabolism/pathology/therapy ; *tau Proteins/metabolism/genetics ; Animals ; Amyloid beta-Peptides/metabolism ; Phosphorylation ; Neurons/metabolism/pathology ; Neurofibrillary Tangles/metabolism/pathology ; Brain/metabolism/pathology ; Tauopathies/genetics/metabolism ; Protein Processing, Post-Translational ; Amyloid beta-Protein Precursor/genetics/metabolism ; Mutation ; Apolipoproteins E/genetics ; },
abstract = {Amyloid-beta (Aβ) plaque formation and tauopathy are two of several hallmarks of Alzheimer's disease (AD), a neurodegenerative disease. AD's widely known pathological hallmarks include extracellular amyloid-β deposition, neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein, synaptic dysfunction, neuroinflammation, and cognitive decline. These pathological hallmarks can be explained at the neurochemical level as a loss of biochemical homeostasis in the brain. Dysregulated kinase-phosphatase signalling, altered post-translational modifications, and disrupted synaptic neurochemistry eventually push tau protein towards its pathological aggregation-prone form. Among these hallmarks, recent research has found that tau pathology plays a major role in neurodegeneration and cognitive decline. Tau protein typically acts as a microtubule-stabilizing protein that helps maintain neuronal structure. In AD, pathological hyperphosphorylation, post-translational modifications, and redistribution of tau trigger its dysfunction and cytotoxicity. Pathological tau protein accumulates in neurons and undergoes a series of changes that include hyperphosphorylation, aberrant post-translational modifications, missorting, aggregation, fibrillization, and seeding as it spreads between cells. Mutations in APP, PSEN1, and PSEN2 can have downstream effects on tau pathology. Variants in APOE, BIN1, PICALM, CD2AP, and TREM2 also influence tau pathology through cellular pathways including lipid metabolism, endocytic trafficking, proteostasis, and synaptic and neuroimmune mechanisms. These findings support a model in which tau dysfunction results from the convergence of molecular aberrations and genetic susceptibility within a pathological network involving amyloid-β, neuroinflammation, and synaptic failure. This review summarizes tau molecular and cellular mechanisms of tau dysfunction in AD, genetic factors regulating tau pathology, and emerging therapeutic approaches to mitigate tau-mediated neurodegeneration.},
}
@article {pmid42593791,
year = {2026},
author = {Laukka, EJ and Ekström, I and Valletta, M and Winblad, B and Fredolini, C and Andersson, S and Fratiglioni, L and Vetrano, DL and Grande, G},
title = {Blood Biomarkers of Alzheimer Disease and Rates of Global and Domain-Specific Cognitive Decline.},
journal = {JAMA network open},
volume = {9},
number = {8},
pages = {e2628975},
doi = {10.1001/jamanetworkopen.2026.28975},
pmid = {42593791},
issn = {2574-3805},
mesh = {Humans ; Female ; *Biomarkers/blood ; Male ; *Alzheimer Disease/blood/diagnosis ; Sweden/epidemiology ; Aged ; Prospective Studies ; tau Proteins/blood ; *Cognitive Dysfunction/blood/diagnosis ; Amyloid beta-Peptides/blood ; Middle Aged ; Neurofilament Proteins/blood ; Glial Fibrillary Acidic Protein/blood ; Aged, 80 and over ; },
abstract = {IMPORTANCE: While evidence is accumulating on blood-based biomarkers of Alzheimer disease (AD) and future cognitive decline, community-based studies that include phosphorylated tau (p-tau) 217 are still scarce. Moreover, there is limited knowledge regarding associations with domain-specific cognitive decline and modifying effects of key individual characteristics.<br><br>OBJECTIVE: To investigate associations of blood biomarkers of AD with global and domain-specific cognitive decline.<br><br>This prospective cohort study included participants from the Swedish National Study on Aging and Care-Kungsholmen recruited between March 21, 2001, and August 30, 2004. Participants were aged 60 years or older, provided blood samples, and were free of dementia at baseline. Follow-up assessments were completed on December 19, 2019. The statistical analysis was conducted between April 1 and September 30, 2025.<br><br>MAIN OUTCOMES AND MEASURES: Baseline biomarkers, including amyloid &#x3b2; 42/40 ratio, p-tau217, p-tau181, total tau, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP), and cognitive performance (episodic memory, semantic memory, verbal fluency, perceptual speed) were assessed at baseline and across 15 years of follow-up. Linear mixed models were used to assess associations between biomarker quartiles and rates of change in specific cognitive domains and a global composite score. Interactions were explored for age, sex, and APOE &#x3b5;4 status.<br><br>RESULTS: In the 2008 participants (mean [SD] age at baseline,&#x2009;71.7 [10.1] years; 1215 female [60.5%]) included, associations with rate of change were observed across all cognitive domains for amyloid &#x3b2; 42/40 ratio (P for trend = .006), p-tau217, p-tau181, NfL, and GFAP (all P for trend < .001), but not total tau. Significant interactions were observed for APOE, for which higher levels of p-tau181 were associated with faster decline in &#x3b5;4 carriers vs noncarriers (&#x3b2;&#x2009;=&#x2009;-0.037 [95% CI, -0.047 to -0.026] vs -0.020 [95% CI, -0.025 to -0.015]). In contrast, higher levels of NfL and GFAP were associated with faster cognitive decline only in non-&#x3b5;4 carriers (&#x3b2;&#x2009;= -0.025 [95% CI, -0.031 to -0.020]) and -0.017 [95% CI, -0.022 to -0.012], respectively). Associations between NfL and GFAP and cognitive decline were exacerbated in females (&#x3b2; = -0.023 [95% CI, -0.029 to -0.018] and -0.021 [95% CI, -0.028 to -0.015], respectively).<br><br>CONCLUSIONS AND RELEVANCE: This cohort study in a general older population found that AD biomarkers were associated with long-term rates of cognitive decline. The observed patterns varied across biomarkers and individual characteristics and suggest that sex and genetic risk of AD should be considered in the interpretation of these biomarkers.},
}
@article {pmid42522369,
year = {2026},
author = {Hackshaw, KV},
title = {Central sensitization syndromes as a neuropsychiatric risk state for dementia: Clinical and epidemiologic perspectives.},
journal = {CNS spectrums},
volume = {31},
number = {1},
pages = {e29},
doi = {10.1017/S1092852926101114},
pmid = {42522369},
issn = {2165-6509},
support = {R61/R33 NS117211/NS/NINDS NIH HHS/United States ; },
mesh = {Humans ; *Dementia/epidemiology ; *Central Nervous System Sensitization/physiology ; Sleep Wake Disorders/epidemiology ; Risk Factors ; },
abstract = {Dementia prevention increasingly targets modifiable midlife risk states contributing to neurodegenerative vulnerability. While vascular and metabolic factors are established, a substantial proportion of risk remains unexplained. Central sensitization syndromes (CSS)-chronic conditions characterized by neural amplification-are highly prevalent, co-occur with depression and sleep disturbance, and involve neuroimmune and network-level mechanisms implicated in early Alzheimer's disease. To synthesize epidemiologic evidence linking CSS with incident dementia and evaluate competing causal explanations, including shared vulnerability, reverse causation, and medication-related confounding. A structured narrative review was conducted of longitudinal cohort and meta-analytic studies assessing incident dementia across CSS-related conditions. Multiple CSS-including migraine, fibromyalgia, irritable bowel syndrome, restless legs syndrome, and PTSD disorder-are associated with modest-to-moderate increases in dementia risk. Multisite chronic pain demonstrates dose-response relationships with hippocampal atrophy and incident dementia. However, many conditions lack dedicated longitudinal studies. Interpretation is limited by residual confounding, reverse causation, healthcare utilization bias, and medication effects. CSS are associated with increased dementia risk but causality remains unproven. Central sensitization may represent a clinically identifiable vulnerability state integrating pain, affective burden, and sleep disruption. This highlights a potentially high-risk population that may not be fully captured by traditional dementia risk models. Biomarker-integrated longitudinal studies and advanced causal modeling are needed to clarify mechanisms.},
}
@article {pmid42578825,
year = {2026},
author = {Wang, R and Yamasaki, T and Mitsudo, T and Matsuda, Y and Goto, S and Sugi, T},
title = {Individual alpha peak frequency tracks Alzheimer's disease progression: A longitudinal pilot study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261476331},
doi = {10.1177/13872877261476331},
pmid = {42578825},
issn = {1875-8908},
abstract = {BackgroundEarly and accurate tracking of Alzheimer's disease (AD) progression is critical for timely intervention. However, electrophysiological biomarkers capable of capturing long-term neurodegenerative changes remain largely underexplored.ObjectiveWe investigated whether individual alpha peak frequency (IAPF), an electroencephalography (EEG)-derived measure of dominant neural oscillatory activity, could serve as a longitudinal biomarker of AD progression.MethodsTwenty-seven patients with AD aged 63-91 years underwent annual EEG and cognitive assessments over 2-7 years. IAPF was extracted from eyes-closed resting-state EEG. Longitudinal associations among IAPF, Mini-Mental State Examination (MMSE) scores, age, and follow-up time were evaluated using repeated-measures correlation and linear mixed-effects models. Annual IAPF changes were compared with those of healthy controls (HC) aged 20-70 years, stratified by decade-based age subgroups. Longitudinal changes in relative spectral power were also analyzed.ResultsPatients with AD showed significant longitudinal declines in both IAPF and MMSE scores, with a positive longitudinal association between the two measures. Mixed-effects models indicated that these declines were better explained by follow-up time after accounting for baseline age than by age at assessment alone. Compared with all healthy-control age subgroups, patients with AD exhibited a significantly steeper annual IAPF decline. Relative theta power increased and alpha/beta power decreased over follow-up, consistent with spectral slowing. However, annualized spectral-power changes showed limited disease specificity, with significant AD-HC differences only for delta and alpha power relative to the oldest HC subgroup.ConclusionsThese findings support IAPF as a non-invasive, temporally sensitive, and clinically accessible biomarker for monitoring AD progression.},
}
@article {pmid42579090,
year = {2026},
author = {Filippi, L and Nuvoli, S and Spanu, A and Palumbo, B},
title = {Mapping the Synaptome in Neurodegeneration: Emerging Clinical Applications of SV2A PET Imaging.},
journal = {Molecular diagnosis &amp; therapy},
volume = {},
number = {},
pages = {},
pmid = {42579090},
issn = {1179-2000},
support = {Ricerca Corrente//Ministero della Salute/ ; },
abstract = {Synaptic loss is a core pathological feature of neurodegenerative disorders and closely relates to cognitive and functional decline. Positron emission tomography (PET) targeting synaptic vesicle glycoprotein 2A (SV2A) has recently emerged as a promising tool for the indirect assessment of presynaptic alterations in the living human brain. This leading article discusses the evolving clinical landscape of SV2A PET across the neurodegenerative spectrum, emphasizing its translational trajectory and emerging applications. Current evidence spans Alzheimer's disease (AD), other dementias, movement disorders, Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). The literature is currently dominated by PET with [[11]C]UCB-J, while [[18]F]-labeled tracers, particularly [[18]F]SynVesT-1, are expanding clinical feasibility through longer half-life and broader distribution potential. Across disorders, PET consistently detected SV2A reductions that frequently correlated with cognition, disease severity, and complementary biomarkers, including amyloid, tau, glucose metabolism, and dopaminergic imaging. Although the field remains limited by small cohorts, heterogeneous quantification strategies, and incomplete longitudinal validation, SV2A PET is rapidly evolving into a promising translational tool for studying synaptopathies and monitoring disease progression.},
}
@article {pmid42579211,
year = {2026},
author = {Wang, F and Wang, X and Chen, Y and Li, Q and Wang, S and Cai, M and Zhao, J},
title = {Integrative transcriptomic and genetic analysis implicates fatty acid metabolic reprogramming in perivascular macrophages in Alzheimer's disease.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42579211},
issn = {1573-7365},
support = {232102521029//International cooperation projects of Henan Province/ ; 182300410389//Natural Science Foundation of Henan Province/ ; },
mesh = {*Alzheimer Disease/metabolism/genetics ; *Fatty Acids/metabolism/genetics ; *Macrophages/metabolism ; Animals ; Humans ; *Transcriptome/genetics ; Mice ; Metabolic Reprogramming ; Gene Expression Profiling ; Lipid Metabolism/genetics ; Mice, Transgenic ; },
abstract = {Dysregulated lipid metabolism and neuroinflammation are increasingly recognized as interacting contributors to Alzheimer's disease (AD), but the cell-type-specific genetic links between fatty acid metabolism and AD remain incompletely defined. This study aimed to identify fatty acid metabolism-related genes associated with AD risk and to characterize their relevance to perivascular macrophage (PVM) states. Single-cell RNA-sequencing data from GSE160936 and bulk transcriptomic data from GSE270454 were integrated to evaluate cell-type-specific fatty acid metabolism activity in AD and control samples.The primary data sources, fatty acid metabolism gene set, AUCell scoring strategy, CellChat workflow, GSEA resources, and MR software settings were specified to improve reproducibility. PVMs were further analyzed for differential expression, ligand-receptor communication, pathway enrichment, transcription factor regulation, and pseudotime-associated transcriptional changes. Cis-eQTL-based two-sample Mendelian randomization was performed using eQTLGen exposure data and AD GWAS summary statistics, followed by sensitivity analyses, reverse MR, and Bayesian colocalization.The analyses were interpreted across three distinct evidence levels: cell-type-resolved transcriptional association, systemic genetic expression prioritization, and tissue-level protein expression. Nominal MR findings were interpreted alongside multiple-testing considerations and colocalization support.Candidate protein expression was examined in hippocampal tissue from APP/PS1 and wild-type mice by Western blotting. Single-cell analysis identified eight major cell populations and showed increased fatty acid metabolism activity in PVMs from AD samples. Mendelian randomization prioritized ten fatty acid metabolism-related genes associated with AD risk, among which ACSL1, EPM2AIP1, MALT1, and RASGRP3 showed strong colocalization support (PP.H4 > 0.9). Pathway analyses linked these genes to lipid metabolic regulation, inflammatory signaling, phagocytosis, and mitochondrial/peroxisomal fatty acid metabolism. Co-expression analysis suggested associations between MALT1 and fatty acid oxidation-related genes, including ACADM and ACOX1. Western blotting in whole hippocampal lysates from APP/PS1 mice provided exploratory tissue-level protein evidence, showing increased ACSL1 and MALT1 and decreased RASGRP3 expression; these findings should not be interpreted as confirmatory PVM-specific validation. This integrative analysis prioritizes ACSL1, EPM2AIP1, MALT1, and RASGRP3 as candidate genes connecting fatty acid metabolic dysregulation with AD-associated neuroinflammatory processes. Because the genetic instruments were blood-derived and the protein assays used whole hippocampal lysates, the findings should be interpreted as candidate-gene prioritization and hypothesis generation rather than proof of direct PVM-specific causality.Accordingly, the study supports a prioritized candidate framework for future functional testing, not validated therapeutic targets or direct causal proof.},
}
@article {pmid42579351,
year = {2026},
author = {Liu, S and Han, D and Bai, T and Chen, H and Li, JP},
title = {Interpreting Divergent Short-Chain Fatty Acid Effects in Alzheimer's Disease: A Seven-Axis Framework.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.0777},
pmid = {42579351},
issn = {2152-5250},
abstract = {Studies of short-chain fatty acids (SCFAs) in Alzheimer's disease (AD) report protective, neutral, and adverse findings, but the same class label often conceals non-equivalent exposures and endpoints. We propose an AD-specific interpretive framework that organizes this heterogeneity as a causal sequence: source or intervention → SCFA species, dose, and route → absorption and metabolic filtering → target-compartment exposure → host and disease state → responding cell type → endpoint. Seven interdependent axes-SCFA species, dose, route, compartment, exposure context, disease stage, and responding cell type-identify the coordinates needed to compare studies. This organization separates administered dose from achieved exposure, direct entry into the central nervous system from blood-brain barrier or peripheral gut-brain signaling, and stage-related disease biology from evidence of stage-specific treatment efficacy. It also requires symmetric interpretation of null findings according to exposure verification, target engagement, power, cellular resolution, and endpoint specificity. The framework integrates rather than replaces established microbiome, pharmacological, and neuroimmune principles and has not been validated as a predictor of effect direction. Its explanatory value can be tested by prespecified meta-regression, variance partitioning, interaction analysis, matched-exposure replication, and causal mediation. Persistent opposite effects under matched coordinates would indicate missing dimensions or failure of the framework. This Perspective therefore supports mechanism-linked, biomarker-informed research rather than nonspecific SCFA supplementation in unselected patients.},
}
@article {pmid42579359,
year = {2026},
author = {Marcinkowska, AB and Grzywińska, M and Winklewski, PJ},
title = {Glymphatic System Function and Cognition: Converging Evidence from DTI-ALPS Imaging - A Narrative Review.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.0511},
pmid = {42579359},
issn = {2152-5250},
abstract = {The glymphatic system, a brain-wide perivascular network mediating cerebrospinal fluid-interstitial fluid exchange, has emerged as a candidate determinant of cognitive health through its role in clearing metabolic waste, neurotoxic proteins, and neuroactive metabolites. The diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index provides a non-invasive means to assess glymphatic activity in vivo, yet no synthesis has consolidated what this marker captures, how reliably it predicts cognitive outcomes, and what pathways may account for observed associations. This narrative review, informed by selected principles from the PRISMA 2020 framework but not constituting a formal systematic review, synthesizes evidence linking DTI-ALPS to domain-specific cognitive performance in healthy aging and neurological disease, encompassing the Alzheimer's disease continuum, cerebral small vessel disease, Parkinson's disease, multiple sclerosis, stroke, and HIV-associated neurocognitive disorder. Lower DTI-ALPS values were consistently associated with worse cognitive performance. The strongest associations were observed for memory and global cognition, followed by executive functions and processing speed; evidence for language and visuospatial abilities was less consistent. Longitudinal data indicate that DTI-ALPS decline may precede detectable amyloid pathology, positioning this index as a candidate early prognostic marker. Three mechanistic pathways are discussed: disruption of sleep-dependent waste clearance; compromise of gray matter integrity through neurotoxic metabolite accumulation; and facilitation of amyloid-β and tau pathology via impaired perivascular protein clearance. Limitations include the indirect nature of DTI-ALPS as a clearance measure, predominance of cross-sectional designs, small samples, and absence of sex-stratified analyses despite known hormonal modulation of glymphatic function. Longitudinal studies, randomized trials of glymphatic-targeting interventions, and acquisition protocol standardization represent priority directions for future research.},
}
@article {pmid42579377,
year = {2026},
author = {Liu, B},
title = {Temporal dissociation of semantic degradation and interference in Alzheimer's disease: Evidence from Chinese character processing.},
journal = {Journal of neuropsychology},
volume = {},
number = {},
pages = {},
doi = {10.1111/jnp.70071},
pmid = {42579377},
issn = {1748-6653},
abstract = {Chinese characters serve as the psychological entry point for lexical recognition in reading. Over 80% of these characters are phonetic compounds containing a semantic radical. Understanding how individuals with Alzheimer's disease (AD) process these structurally distinct characters is crucial for revealing the underlying nature of their cognitive decline. This study examined 180 older adults (60 Healthy Controls, 60 Mild AD, 60 Moderate AD) in a semantic categorization task across four radical-character relationships: fully related (FR), fully unrelated (FU), radical-only related (RR) and radical-only, related (RO-R). To disentangle semantic degradation from executive control demands, this study employed signal detection theory (SDT) and mixed-effects modelling. Results demonstrated significant group-by-condition interactions for accuracy, reaction time and perceptual sensitivity (d'). AD patients exhibited globally reduced d' and prolonged reaction times. Crucially, an error pattern analysis revealed that Mild AD patients produced significantly more false alarms in the RR condition, a deficit strongly correlated with their Stroop Interference scores (r = .58), reflecting a pronounced susceptibility to semantic interference, exacerbated by atypical executive inhibitory control. Furthermore, a temporal dissociation emerged: while explicit semantic sensitivity (d') collapsed early in the disease, Mild AD patients partially preserved the automatic reaction time advantage for isolated radicals (RO-R), yet suffered an exacerbated reaction time interference effect when resolving radical-related semantic interference (RR > FU). These findings suggest that explicit semantic boundaries and executive conflict resolution abilities degrade early in AD, whereas automatic semantic spreading activation is briefly preserved but highly susceptible to multifaceted semantic interference.},
}
@article {pmid42579441,
year = {2026},
author = {Sun, F and Liu, Y and Zhou, Q and Hu, Q and Wang, W and Xiao, Y and Su, J and Liu, G and Sun, M and Chen, L and Li, H and Yang, Y and Wang, JZ},
title = {A Small-Molecule DEPTAC Rescues Cognitive Deficits by Targeted Dephosphorylation of Pathological Tau.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e77088},
pmid = {42579441},
issn = {2198-3844},
support = {82571635//National Natural Science Foundation of China/ ; 82230041//National Natural Science Foundation of China/ ; 82371436//National Natural Science Foundation of China/ ; YCJJ20252412//Fundamental Research Funds for the Central Universities/ ; 241111310400//Key R&amp;D Program of Henan Province/ ; },
abstract = {Accumulation of hyperphosphorylated Tau (p-Tau) is a central driver of neurodegeneration in Alzheimer's disease (AD). Addressing the limitations of current therapeutics, we developed TP2, a small-molecule DEPhosphorylation-TArgeting Chimera (DEPTAC). TP2 is engineered to physically tether endogenous PP2A to Tau, facilitating targeted dephosphorylation. Mechanistically, TP2 induces ternary complex formation and potently reduces p-Tau in neurons. Systemic administration of TP2 in distinct tauopathy mouse models (P301L and AAV-hTau-N368) significantly lowered brain p-Tau levels, oligomers, and neurofibrillary tangles without altering global PP2A activity. Crucially, by rebalancing the phosphorylation of Tau, TP2 restored Tau's physiological function, as evidenced by the preservation of neuronal morphology, synaptic integrity, and microtubule stability. TP2 also ameliorated the dysregulated neuroimmune microenvironment. Consequently, TP2 treatment robustly reversed cognitive deficits in multiple behavioral paradigms. These findings establish TP2 as a promising therapeutic candidate that targets upstream pathological phosphorylation to halt neurodegeneration and restore cognitive function.},
}
@article {pmid42579930,
year = {2026},
author = {Go, M and Reich, LA and Harris, DA and Daiello, LA and Berry, SD and D'Amico, AM and Zullo, AR and Hayes, KN},
title = {Drug-Drug Interactions in Nursing Home Residents With vs Without Dementia.},
journal = {Journal of the American Medical Directors Association},
volume = {27},
number = {10},
pages = {106417},
doi = {10.1016/j.jamda.2026.106417},
pmid = {42579930},
issn = {1538-9375},
abstract = {OBJECTIVES: To examine whether nursing home (NH) residents with Alzheimer's disease and related dementias (ADRD) are more likely than those without ADRD to be exposed to potential drug-drug interactions (DDIs) and to experience longer durations of exposure to DDIs.<br><br>DESIGN: Retrospective observational study.<br><br>SETTING AND PARTICIPANTS: Long-stay US NH residents.<br><br>METHODS: We leveraged Medicare Fee-for-Service enrollment and claims data linked to Minimum Data Set 3.0 clinical assessments from 2018 to 2020 and identified NH residents aged &#x2265;66 years with observable part D prescription drug data. We identified exposure to 98 potential DDIs during the duration of their NH stay. We described the number of DDIs with a clinically meaningful difference in prevalence and/or duration between groups, defined as a &#x2265;1% difference in prevalence and &#x2265;7 days' duration, respectively. We used a log-binomial model to estimate the association between ADRD and exposure to any DDI as an adjusted prevalence ratio with 95% CIs and predicted the marginal prevalence of exposure to any DDI for those with vs without ADRD, standardized to population covariate distributions.<br><br>RESULT: We identified 485,251 eligible NH residents (average age, 84.6 [SD, 8.1] years; 67.1% female; 70.1% with ADRD; 56.6% with a potential DDI). A diagnosis of ADRD was associated with a higher prevalence of DDI exposure (prevalence ratio, 1.09 [95% CI, 1.08, 1.09]; marginal predicted prevalence for those with vs without ADRD: 58.0% vs 53.3%). Twelve DDIs had different prevalences between groups, and 34 DDIs had different differences in duration. For example, 29.6% of residents with vs 21.2% without ADRD were exposed to &#x2265;3 central nervous system-active drugs.<br><br>CONCLUSIONS AND IMPLICATIONS: NH residents with ADRD had a higher prevalence and duration of potential DDIs. Future research should evaluate whether the interactions we identified have causal effects on adverse outcomes such as falls.},
}
@article {pmid42579954,
year = {2026},
author = {Fernandes, F and Dey, A and Ma, A and Churchill, NW and Fischer, CE and Graham, SJ and Munoz, DG and Schweizer, TA},
title = {Choroid plexus volume in pathology-confirmed Alzheimer's disease.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {9},
pages = {100648},
doi = {10.1016/j.tjpad.2026.100648},
pmid = {42579954},
issn = {2426-0266},
abstract = {INTRODUCTION: The choroid plexus (CP) increases in volume across the Alzheimer's disease (AD) continuum, suggesting its potential as a clearance-related biomarker. However, few studies have examined ante-mortem CP volume in relation to post-mortem AD pathology, the gold standard for diagnosis.<br><br>METHODS: Participants who had structural magnetic resonance imaging and post-mortem pathology, with an interval of &#x2264; 5 years between imaging and death, were examined. Normalized CP volume (NCPV) was semi-automatically segmented from the lateral ventricles and analyzed using Bayesian linear regression to estimate associations with cognitive impairment (CI), AD pathology, and relevant clinical/demographic data.<br><br>RESULTS: Intermediate and high levels of AD pathology and CI were associated with larger NCPV, whereas female sex was associated with lower NCPV. Subgroup analyses showed larger NCPV in individuals with greater CI despite comparable levels of AD pathology.<br><br>DISCUSSION: These findings link CP enlargement to neuropathologically confirmed AD burden and CI, supporting further investigation of CP structure and function in AD.},
}
@article {pmid42579974,
year = {2026},
author = {Cui, J and Ye, W and Wen, J and Zhu, Q},
title = {Dual-contrastive modality recovery for incomplete multi-modal brain disease diagnosis.},
journal = {Medical image analysis},
volume = {114},
number = {},
pages = {104259},
doi = {10.1016/j.media.2026.104259},
pmid = {42579974},
issn = {1361-8423},
abstract = {Multi-modal learning is extensively applied to diagnose brain diseases such as epilepsy and Alzheimer's disease. However, incomplete multi-modal data, where some imaging modalities are unavailable or difficult to collect, limits the application of conventional methods. Additionally, existing approaches primarily focus on reconstructing missing imaging data but rarely enforce cross-modal semantic alignment. To address these challenges, we propose BrainCLIP, a CLIP inspired two-stage framework designed for incomplete multi-modal learning, with a focus on diagnosing representative brain diseases, i.e., epilepsy and Alzheimer's disease. The key novelty of our framework lies in its joint design of dual contrastive modality recovery and multi-modal representation learning in a two-stage pipeline. Specifically, we introduce a multi-modal contrastive learning stage that aligns text, fMRI, and DTI representations in a shared embedding space using complete samples. The recovered features are then refined through a dual contrastive recovery strategy with modality level and sample level contrastive objectives, thereby ensuring that the recovered features are semantically consistent and discriminative. For multi-modal representation learning, the recovered and available modalities are fused with fixed textual embeddings to learn task aware representations for disease classification. Extensive experiments demonstrate the effectiveness of our method in diagnosing epilepsy and Alzheimer's disease.},
}
@article {pmid42580032,
year = {2026},
author = {Zhu, Y and Walker, AIB and Bekena, S and Singh, RK and Strain, JF and Phuah, CL and Millar, PR and Canfield, P and Hill, CV and Hudson, DL and Williams, MM and Mohamed, EA and Williams, JP and Harrison, K and Laurido-Soto, OJ and Lee, JM and Ances, BM and Trani, JF and Babulal, GM},
title = {Structural and social determinants of health shape the impact of neurodegeneration and cerebrovascular pathology on cognitive functioning in black adults.},
journal = {Social science &amp; medicine (1982)},
volume = {406},
number = {},
pages = {119636},
doi = {10.1016/j.socscimed.2026.119636},
pmid = {42580032},
issn = {1873-5347},
abstract = {INTRODUCTION: Black adults in the United States experience a disproportionately higher risk of dementia due to cumulative exposure to structural and social determinants of health (S/SDOH). Although structural neuroimaging provides markers of atrophy and cerebrovascular injury, less is known about how these biomarkers interact with S/SDOH to influence cognitive performance within minoritized populations. This study examined independent and interactive associations between a multidimensional S/SDOH Composite Index (S/SDOH-CI) and structural imaging-derived biomarkers among Black adults in an urban setting.<br><br>METHODS: We analyzed data from a community-based sample of Black adults aged &#x2265;45 who completed brain MRI, the Preclinical Alzheimer Cognitive Composite (PACC), the Montreal Cognitive Assessment (MoCA), and a comprehensive assessment of structural and social determinants of health (S/SDOH). Structural biomarkers included total brain volume, hippocampal volume, global and regional white matter hyperintensities (WMH), and brain-age gap (BAG). Linear regression models examined independent and interactive associations between the S/SDOH-CI and MRI biomarkers with cognitive performance, adjusting for demographic characteristics and Charleston comorbidity index.<br><br>RESULTS: Total brain volume and BAG were associated with MoCA. Significant interactions were observed between S/SDOH-CI and BAG for cognitive outcomes. Across S/SDOH factors, discrimination, and coping moderated associations between WMH and PACC, while education moderated associations between brain volume and MoCA.<br><br>DISCUSSION: These findings underscore that biological vulnerability cannot be fully understood without accounting for structural and social disparities. Differential sensitivity of MRI biomarkers highlights the need for neuroimaging research tailored to diverse populations and supports integrating S/SDOH to inform precision-equity approaches to dementia prevention.},
}
@article {pmid42580292,
year = {2026},
author = {Luca, A and Piccoli, T and Di Marco, S and Nicoletti, A and Lo Coco, D and Rolandi, E and Sensi, SL and Russo, M and Ferri, R and Sucapane, P and Bruni, AC and Perani, D and Guarnieri, B and , },
title = {Sleep quality and caregiver burden in Alzheimer's disease: focus on sex differences.},
journal = {Sleep medicine},
volume = {148},
number = {},
pages = {109185},
doi = {10.1016/j.sleep.2026.109185},
pmid = {42580292},
issn = {1878-5506},
abstract = {INTRODUCTION: The relationship between sleep characteristics in caregivers and care recipients with Alzheimer's disease (AD) and caregiver burden, especially regarding sex-related differences, still needs to be clarified. The aims of the present study were to examine associations between caregiver and patient sleep characteristics and caregiver burden, including sex-differences and menopausal status among female caregivers.<br><br>METHODS: The SexDemCare study is a multicenter Italian study conducted within the SINdem Study Group "Sex and Gender Differences in Dementia." Caregivers and their non-institutionalized care recipients with clinically diagnosed AD across different stages of disease severity were enrolled. The Caregiver Burden Inventory was administered. Sleep characteristics of both caregivers and care-recipients were assessed using the Pittsburgh Sleep Quality Index.<br><br>RESULTS: 238 caregivers (65.9% women; mean age 59.6&#x202f;&#xb1;&#x202f;12.4 years) and 238 care-recipients (153 women; mean age 77.5&#x202f;&#xb1;&#x202f;7.9 years) were enrolled. Caregiver burden was associated with snoring, daytime hypersomnolence, longer sleep latency, and use of sleep medication. In sex-stratified analysis, caregiver burden was associated with several sleep characteristics only among female caregivers.<br><br>DISCUSSION: Female caregivers may be especially vulnerable to the negative consequences of poor sleep on caregiving burden.},
}
@article {pmid42580332,
year = {2026},
author = {Dries, DR and Yu, G},
title = {Breathing new life into the rational design of Alzheimer's therapeutics.},
journal = {Cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.cell.2026.07.046},
pmid = {42580332},
issn = {1097-4172},
}
@article {pmid42580389,
year = {2026},
author = {Bu, J and Nie, X and Luo, H and Wang, J and Jiang, D and Xu, N and Zhuang, P and Zhang, Y and Yin, Q},
title = {Neuron-Derived Neuroinflammation in Neurodegenerative Diseases: Mechanisms and Intervention Prospects.},
journal = {Pharmacological research},
volume = {},
number = {},
pages = {108383},
doi = {10.1016/j.phrs.2026.108383},
pmid = {42580389},
issn = {1096-1186},
abstract = {Neurodegenerative diseases represent a major global public health challenge, imposing substantial societal and economic burdens. Their complex pathogenesis and limited therapeutic options underscore an urgent need for new paradigms. Emerging evidence indicates that dysregulation of the brain's immune microenvironment is a critical driver of disease progression. Conventional wisdom posits that peripheral immune cells and central glial cells serve as the primary initiators of neuroimmune responses, whereas neurons are regarded merely as passive recipients of inflammatory damage. Emerging evidence suggests that upon receiving pathological signals in the central nervous system, neurons may become more vulnerable and participate in the onset of neuroimmune processes, positioning them as potential targets for early intervention in neurodegenerative diseases. This article systematically reviews the contribution of neuron-derived immune-inflammatory responses in neurodegenerative diseases and potential intervention strategies. We first outline the capacity of neurons to regulate neuroimmune responses and detail the underlying molecular mechanisms. Then we compare the specific mechanisms by which neurons with different susceptibility drive and amplify neuroinflammation in various neurodegenerative diseases such as alzheimer's disease, parkinson's disease, amyotrophic lateral sclerosis, vascular cognitive impairment, and transformed these mechanisms into intervention strategies targeting neurons,. This article aims to break through the traditional concept of passive neuronal damage, systematically integrate intervention strategies that shift from targeting peripheral immune and glial cells to regulating neuron-derived immunity, thereby providing a new theoretical framework for overcoming current clinical limitations and identifying effective therapeutic targets for the prevention and treatment of neurodegenerative diseases.},
}
@article {pmid42580438,
year = {2026},
author = {Silva, AC},
title = {Current Clinical Evidence on Nose-to-Brain Drug Delivery.},
journal = {Drug discovery today},
volume = {},
number = {},
pages = {104765},
doi = {10.1016/j.drudis.2026.104765},
pmid = {42580438},
issn = {1878-5832},
abstract = {Intranasal delivery is increasingly recognised as a promising strategy for direct drug transport to the brain via the nose-to-brain pathway, bypassing the blood-brain barrier and improving therapeutic efficacy. This approach has shown potential in the treatment of neurological disorders, including Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, and acute psychiatric conditions, as well as in emergencies such as anxiety attacks and migraine episodes. Recent clinical studies investigating intranasal formulations of rivastigmine, insulin, and olanzapine, among other drugs, have provided encouraging evidence supporting the clinical translation of this delivery strategy. In addition, FDA-approved intranasal products indicated for central nervous system disorders, including diazepam and midazolam for seizure management, and triptans for migraine, demonstrate the growing clinical relevance of intranasal drug delivery. Both preclinical and clinical studies have reported encouraging outcomes, particularly when intranasal delivery is combined with nanoformulations and specialised delivery devices designed to enhance olfactory deposition. Intranasal administration is non-invasive, painless, and may improve patient adherence while enhancing brain bioavailability. Nevertheless, further well-designed clinical studies are required to establish the long-term safety, efficacy, and clinical applicability of this delivery strategy.},
}
@article {pmid42580461,
year = {2026},
author = {Murray, HC and Dieriks, BV and Dodd, S and Usdin, T and Hamlin, D and Highet, B and Sit, Z and Kim, M and Faull, R and Turner, C and Scadeng, M and Curtis, MA and Koretsky, A},
title = {High-field MRI correlates with immunohistochemical analysis of the normal and Alzheimer's disease anterior olfactory nucleus.},
journal = {NeuroImage},
volume = {},
number = {},
pages = {122166},
doi = {10.1016/j.neuroimage.2026.122166},
pmid = {42580461},
issn = {1095-9572},
abstract = {The human anterior olfactory nucleus (AON) is one of the earliest brain regions affected by tau and beta amyloid pathology in Alzheimer's disease, potentially serving as a conduit for the spread of aggregated proteins to downstream cortical regions. However, the architecture of the human AON remains poorly understood. Here, we applied a multimodal imaging framework combining ultra-high-field magnetic resonance (MR) microscopy, thin-section immunofluorescence, and whole-mount tissue clearing with confocal and light-sheet microscopy to characterise the three-dimensional architecture of the AON and its involvement in Alzheimer's disease (AD). In neurologically normal cases, we identified tear-shaped AON clusters using MR microscopy that aligned with cytoarchitectural boundaries defined by PGP9.5, CNPase, and UEA lectin immunolabelling in serial sections, confirming the validity of AON segmentation in intact bulbs. In AD cases, MR microscopy, immunofluorescence, and light-sheet imaging revealed concentrated tau and beta-amyloid pathology within the AON clusters. Despite this pathology burden, neither total olfactory bulb volume nor AON volume differed significantly between neurologically normal and AD groups, and pathology load did not correlate with either volumetric measure. These findings refine our understanding of the human olfactory bulb and AON structure and demonstrate that high-resolution MR microscopy is a reliable tool for investigating substructural changes in the olfactory system.},
}
@article {pmid42580472,
year = {2026},
author = {Chen, J and Chen, J and Chen, Y and Xia, J and Fang, H and Zhang, P and Ge, RS and Wang, Y},
title = {Chain-length-selective inhibition of human and rat steroid 5α-reductase type 1 by alkyltrimethylammonium chloride disinfectants: kinetic, surface plasmon resonance, computational, and network toxicology analyses with implications for neurosteroidogenesis.},
journal = {Chemico-biological interactions},
volume = {},
number = {},
pages = {112273},
doi = {10.1016/j.cbi.2026.112273},
pmid = {42580472},
issn = {1872-7786},
abstract = {Alkyltrimethylammonium chlorides (ATMAs) are a major subclass of cationic quaternary ammonium compound (QAC) surfactants whose human exposure has risen sharply since 2020, but their effect on the brain neurosteroidogenic enzyme steroid 5α-reductase type 1 (SRD5A1) is unknown. Eight ATMAs from C1 to C22 were tested on human and rat SRD5A1 microsomes using HPLC-MS/MS, complemented by surface plasmon resonance (SPR), molecular docking, three-dimensional quantitative structure-activity relationship (3D-QSAR) modelling, and a network toxicology workflow. Screening at 100 μM identified ATMA-C14 and ATMA-C16 as the only active inhibitors against either species. The C14 and C16 compounds inhibited human SRD5A1 with IC50 of 50.94 μM and 46.98 μM respectively (Ki 55.51 and 52.95 μM); against rat SRD5A1, ATMA-C16 retained equal potency (IC50 46.75 μM) but ATMA-C14 lost approximately half its activity (IC50 108.62 μM), revealing a species shift around the C14 homologue. An equimolar C14/C16 mixture was synergistic against the human enzyme but antagonistic against the rat enzyme, mirroring the species difference in single-agent potency. Both compounds behaved as mixed/non-competitive inhibitors with respect to testosterone, and cofactor-titration kinetics together with SPR competition data placed the binding site at the NADPH pocket. SPR returned KD of 52.8 and 59.3 μM with rapid dissociation, consistent with reversible non-covalent binding. In intact SF126 cells the order was reversed, ATMA-C14 suppressing DHT production more than ATMA-C16, in keeping with differential membrane permeability. Docking located both ligands in the NADPH pocket (ΔG -5.78 to -6.65 kcal/mol), and a 3D-QSAR pharmacophore emphasised one hydrogen-bond acceptor and four hydrophobic features. Network toxicology pointed, in silico, to Alzheimer's disease as the most enriched disease intersection. ATMA-C14 and ATMA-C16 thus emerge as moderate, reversible SRD5A1 inhibitors with chain-length and species-dependent potency, raising potential endocrine-disruption concerns that warrant exposure-relevant assessment.},
}
@article {pmid42580481,
year = {2026},
author = {Chen, P and Guo, L and Guo, X and Hong, W and Meng, W},
title = {A new method for the production of recombinant human Aβ(1-42) peptide.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106238},
doi = {10.1016/j.neuint.2026.106238},
pmid = {42580481},
issn = {1872-9754},
abstract = {BACKGROUND: The amyloid-β protein (Aβ) plays a central role in the pathogenesis of Alzheimer's disease (AD). Chemically synthesized Aβ(1-42) is the most widely employed resource for AD mechanistic research and drug screening. However, solid-phase synthesis introduces truncated and modified byproducts, causing batch-to-batch heterogeneity and compromised experimental reproducibility.<br><br>METHODS: Herein, we established an optimized recombinant expression system utilizing a thermal green protein (TGP) fusion tag combined with TEV protease site-specific cleavage to produce tag-free, authentic human A&#x3b2;(1-42) in Escherichia coli. We systematically performed side-by-side biophysical characterization, including secondary structural transition and amyloid aggregation kinetics, to compare purified recombinant A&#x3b2;(1-42) (RecA&#x3b2;) and conventional synthetic A&#x3b2;(1-42) (SynA&#x3b2;). Human iPSC-derived neurons (iNs) and primary murine microglia were further applied to evaluate and compare their neurotoxicity and microglial regulatory functions.<br><br>RESULTS: The optimized TGP-TEV platform enabled robust production of high-purity RecA&#x3b2;(1-42), yielding 6-7 mg intact peptide per liter of bacterial culture. Biophysical assays demonstrated that RecA&#x3b2; shares highly conserved secondary structural features with SynA&#x3b2; but exhibits significantly enhanced aggregation propensity. Functional assays revealed that RecA&#x3b2;- and SynA&#x3b2;-derived ADDLs exert equivalent neurotoxicity in human iNs. While both fibril preparations display comparable microglial binding recognition and lysosomal clearance kinetics with subtle temporal differences, RecA&#x3b2; fibrils induce more severe microglial phagolysosomal dysfunction than SynA&#x3b2; fibrils.<br><br>CONCLUSION: This work establishes a robust, reproducible recombinant strategy for generating authentic human A&#x3b2;(1-42). RecA&#x3b2; recapitulates core AD-relevant bioactivities of commercial SynA&#x3b2; while possessing stronger aggregation potency and enhanced capacity to disrupt microglial homeostatic function. This standardized recombinant A&#x3b2; preparation provides a useful tool for the investigation of A&#x3b2; biology and screening of AD therapeutic candidates.},
}
@article {pmid42580558,
year = {2026},
author = {Armoundas, AA and Piperi, C},
title = {Epigenetic Drift and LINE-1 Activation in Aging Brain: Implications for Neurodegenerative Disease.},
journal = {Mechanisms of ageing and development},
volume = {},
number = {},
pages = {112235},
doi = {10.1016/j.mad.2026.112235},
pmid = {42580558},
issn = {1872-6216},
abstract = {Brain aging and age-associated neurological diseases, such as Alzheimer's Disease (AD), Parkinson's Disease (PD), and Amyotrophic Lateral Sclerosis (ALS), are largely attributed to epigenetic drift which is characterized by the gradual accumulation of alterations in neural cell methylation patterns over time. These methylation changes are particularly evident in transposable element (TE)-derived sequences such as Long interspersed element-1 (LINE-1) which comprises approximately 17% of the human genome. During aging, LINE-1 elements gradually lose their methylation, as well as the regulatory safeguard mechanisms that usually keep them inactive. This repression loss can lead to LINE-1 reactivation, contributing to harmful effects including genomic instability, neuroinflammation, and more. Together these findings indicate that impaired epigenetic maintenance, especially in repetitive genome regions, plays a key role in biological aging of neurons and glial cells. In this narrative review, we discuss the methylation dynamics and regulatory mechanisms of LINE-1 retrotransposons, their activation processes during aging, and contribution to age-associated neurological diseases. We also highlight the potential of targeting LINE-1 methylation to restore methylation homeostasis, epigenetic stability and delay brain aging.},
}
@article {pmid42580680,
year = {2026},
author = {Gupta, P and Pozzilli, V and De Giovanni, A and Sapio, E and Motolese, F and Capone, F and Pozzilli, P},
title = {GLP-1 receptor agonists, metabolic syndrome, and Alzheimer's disease: Lessons and opportunities from the EVOKE trials.},
journal = {Journal of neuroendocrinology},
volume = {38},
number = {8},
pages = {e70246},
doi = {10.1111/jne.70246},
pmid = {42580680},
issn = {1365-2826},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Glucagon-Like Peptide-1 Receptor Agonists ; *Metabolic Syndrome/drug therapy/metabolism/complications ; Semaglutide ; Animals ; *Hypoglycemic Agents/therapeutic use/pharmacology ; Glucagon-Like Peptides/therapeutic use ; },
abstract = {Metabolic syndrome and Alzheimer's disease (AD) are increasingly recognised as interconnected, sharing vascular, metabolic and inflammatory pathways that accelerate brain ageing and cognitive decline. This review critically examines the evidence that glucagon-like peptide-1 receptor agonists (GLP-1RAs), initially developed for diabetes and obesity, may influence AD related pathways or reduce AD risk in metabolically vulnerable populations. Metabolic syndrome and AD related cognitive impairment share biological mechanisms including vascular damage, insulin resistance and chronic inflammation, suggesting that therapies targeting metabolic dysfunction could influence neurological outcomes. GLP-1RAs are notable for combining systemic benefits, like weight loss, improved glycaemic control, and reduced cardiovascular risk, with possible but incompletely established central nervous system effects. Experimental studies suggest that some GLP-1RAs may reduce amyloid and tau pathology, support mitochondrial function, and limit neuroinflammation, although recent preclinical studies and limited brain penetrance argue against a direct neuroprotective effect. Observational data suggest lower dementia rates among users compared with other antidiabetic treatments. However, the recent EVOKE and EVOKE + trials showed that oral semaglutide did not slow clinical progression in early symptomatic AD, despite positive biomarker effects. This highlights the challenge of translating biological plausibility into meaningful clinical benefit and refocuses attention on disease stage, target population, and mechanism. Beyond summarising evidence, this review advocates a more cautious and mechanism specific framework: preserving cognitive health may require addressing systemic metabolic dysfunction rather than targeting the brain alone. GLP-1 RAs have failed to show an effect in symptomatic AD, but their effects on metabolism might still be beneficial at earlier stages, such as the preclinical phase of AD. Future studies should determine whether earlier intervention in metabolically enriched groups can alter AD related cognitive, vascular, and biomarker trajectories.},
}
@article {pmid42580784,
year = {2026},
author = {Souza, HJBC and Souza, KM and Dos Santos, MB and Silva, MAP and Grassi, TF and Destro, MV and Braz, MG},
title = {Evaluation of genetic instability in patients with amyotrophic lateral sclerosis.},
journal = {Mutation research. Genetic toxicology and environmental mutagenesis},
volume = {913},
number = {},
pages = {503953},
doi = {10.1016/j.mrgentox.2026.503953},
pmid = {42580784},
issn = {1879-3592},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; Female ; Male ; Case-Control Studies ; Middle Aged ; *Genomic Instability ; Mouth Mucosa/pathology ; Micronucleus Tests ; Aged ; Chromosomal Instability ; Micronuclei, Chromosome-Defective ; },
abstract = {Genetic instability has been reported in several neurodegenerative diseases, such as Alzheimer's and Parkinson's, but only a few studies have addressed sclerosis. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Micronuclei (MNi) and nuclear buds (NBUDs) are established markers of chromosomal instability, yet no data are available regarding a possible link between genetic instability and ALS. The novelty of this case-control study lies in the assessment of genetic instability in oral exfoliated cells from ALS patients (n = 20) and matched controls (n = 20), contributing to the identification of potential novel markers related to the molecular pathogenesis of this severe disorder. Groups were matched for age, sex, and lifestyle (p > 0.05). No significant differences were observed in MNi or NBUD frequencies between groups (p > 0.05). These findings suggest no association between ALS and MN/NBUD frequencies in oral cells.},
}
@article {pmid42581113,
year = {2026},
author = {Jomova, K and Alomar, SY and Valko, R and Nepovimova, E and Kuca, K and Valko, M},
title = {Oxidative stress and inflammation in neurodegenerative disorders.},
journal = {Archives of toxicology},
volume = {},
number = {},
pages = {},
pmid = {42581113},
issn = {1432-0738},
abstract = {The brain's consumption of approximately 20% of the body's oxygen contributes to oxidative stress, a significant pathological factor in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. This oxidative stress, linked to low levels of antioxidant enzymes, drives neuronal death by facilitating membrane peroxidation of fatty acids, proteins, and DNA. Alzheimer's disease is characterized by amyloid-beta (Aβ) plaque accumulation and hyperphosphorylated tau aggregates, both of which interact with mitochondria to generate reactive oxygen species (ROS). Aβ peptides bind metals such as iron and copper, catalyzing the formation of damaging hydroxyl radicals. Peripheral markers of oxidative damage, such as elevated malondialdehyde and protein carbonyls, are correlated with these processes in affected patients. In Parkinson's disease, the loss of dopaminergic neurons in the substantia nigra is associated with pathological iron accumulation and mitochondrial complex I dysfunction, which are worsened by misfolded α-synuclein and mutations in antioxidant genes such as PINK1 and Parkin. The autooxidation of dopamine also drives oxidative stress through the generation of hydrogen peroxide and reactive quinones. Huntington's disease involves the degeneration of medium spiny neurons in the striatum due to a polyglutamine repeat expansion in the huntingtin gene, which disrupts mitochondrial function and downregulates antioxidants, leading to excitotoxicity and ROS spikes. Amyotrophic lateral sclerosis primarily affects motor neurons due to the mutations in SOD1, which result in the production of aggregates that impair mitochondria and generate reactive nitrogen species (RNS), such as peroxynitrite. Mitigating oxidative stress in neurodegenerative disorders presents a considerable translational challenge. While low-molecular-weight antioxidant therapies for neurodegenerative disorders have shown promising results in preclinical and animal studies because they mitigate oxidative stress, their clinical efficacy is hampered by low bioavailability and difficulty in penetrating the blood‒brain barrier. To overcome these limitations, current medical research is focused on alternative delivery systems. Innovations such as nanoparticle-based drug delivery are being actively studied to help transport low-molecular-weight antioxidants across the blood‒brain barrier more safely and effectively. Several promising epidemiological trials linked high dietary intake of vitamins C and E to a reduced risk of Parkinson's disease, and plant-derived antioxidants such as polyphenols were explored for their ability to combat neuroinflammation and reduce cognitive decline. Refined oxidative stress-suppressing strategies involve the (ii) application of mitochondrial-targeted agents to preserve ATP production; (ii) boosting the Nrf2 pathway may trigger a cascade of detoxifying enzymes; (iii) supplementation with polyphenols such as quercetin, resveratrol, and curcumin can suppress oxidative stress and dampen microglial activation (neuroinflammation); (iv) and the use of substances affecting the bidirectional network linking oxidative stress and autophagy can clear ROS-generating components. Despite some promising epidemiological data, translating oral or systemic antioxidant therapy into effective clinical treatments for humans requires further effort. A survey of current knowledge of oxidative stress and antioxidant therapy in neurodegenerative diseases is the main subject of this review.},
}
@article {pmid42581131,
year = {2026},
author = {Rahim, A and Zubair, SM and Ahamed, M and Das, S and Patel, R and Debnath, B and Porel, P},
title = {cGAS-STING as a Neuroimmune Traffic Molecule: Unraveling Pathogenic Mechanisms and Therapeutic Potential in Neurological Disorders.},
journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology},
volume = {21},
number = {1},
pages = {},
pmid = {42581131},
issn = {1557-1904},
mesh = {Humans ; cGAS-STING Signaling Pathway ; Animals ; *Nucleotidyltransferases/metabolism/immunology ; *Membrane Proteins/metabolism/immunology ; *Nervous System Diseases/immunology/metabolism/drug therapy ; Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase ; STING Protein ; Signal Transduction ; },
abstract = {The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is an essential cytosolic DNA-sensing system that plays an important role in the regulation of innate immune and inflammatory responses in the central nervous system (CNS). It was first discovered as a promising antiviral defense cascade and has since been shown to execute broader functions in neuroinflammation and neurodegeneration. The pathway can become hyperactive with the release of endogenous DNA from damaged nuclei, mitochondria, or genomic instability, leading to chronic production of type I interferon (TI-IFN), various pro-inflammatory cytokines, and eventually contributing to chronic neuroinflammatory diseases. Recent studies have found that dysregulated cGAS-STING signaling is associated with several neurological disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), traumatic brain injury (TBI), stroke, and age-related neurodegeneration. In the CNS, chronic activation of this pathway leads to activation of microglia, oxidative stress, breakdown of the blood-brain barrier (BBB), impaired function of the synapses, and neuronal death. Mitochondrial dysfunction and cytosolic release of mitochondrial DNA (mtDNA) further promote inflammatory signaling, thus perpetuating neurodegeneration. This review highlights the molecular and pathological mechanisms of cGAS-STING signaling in a broader aspect of neurological disorders and appraises the novel therapeutics already under development to inhibit this pathway to regulate neuroinflammation and enhance neurological outcomes.},
}
@article {pmid42581224,
year = {2026},
author = {Stefano, GB and Esch, T},
title = {Microbiome-Inflammation-Mitochondria Coupling in Neurodegeneration and Depression: An Integrative Opinion.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42581224},
issn = {1559-1182},
mesh = {Humans ; *Mitochondria/metabolism/pathology ; Animals ; *Inflammation/pathology/microbiology/metabolism ; *Depression/microbiology/metabolism/pathology ; *Neurodegenerative Diseases/microbiology/pathology/metabolism ; *Microbiota ; *Gastrointestinal Microbiome/physiology ; *Nerve Degeneration/pathology ; },
abstract = {There is increasing evidence that gut microbiome dysbiosis, systemic inflammation, and mitochondrial dysfunction interact in ways that influence psychiatric and neurodegenerative disease vulnerability. Recent findings indicate that microbial signaling, inflammatory activation, and mitochondrial stress responses form dynamic bidirectional networks that may influence neurotransmission, neuroplasticity, metabolism, and behavior. This integrative opinion article distinguishes major depressive disorder (MDD), Parkinson's disease (PD), and Alzheimer's disease (AD) as mechanistically distinct disorders while proposing that they may share overlapping upstream modulatory pathways involving inflammation, microbial dysregulation, and mitochondrial dysfunction. Importantly, the microbiome-inflammation-mitochondria axis is presented as a disease-modifying and vulnerability-associated framework rather than a singular unifying etiology. Current limitations including reverse causation, microbiome heterogeneity, and differences in treatment responsiveness are also discussed.},
}
@article {pmid42581253,
year = {2026},
author = {Berisha, DE and Benca, RM and Mander, BA},
title = {Sleep apnea in REM sleep as an amplifier of vascular contributions to Alzheimer's disease.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71735},
doi = {10.1002/alz.71735},
pmid = {42581253},
issn = {1552-5279},
support = {K01AG068353/AG/NIA NIH HHS/United States ; R21AG079552/AG/NIA NIH HHS/United States ; R01AG096669/AG/NIA NIH HHS/United States ; F31AG084308/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/physiopathology/etiology/complications ; *Sleep, REM/physiology ; *Sleep Apnea Syndromes/complications/physiopathology ; *Cerebrovascular Disorders/complications/physiopathology ; Hypoxia/physiopathology ; },
abstract = {Obstructive sleep apnea (OSA), a common though underdiagnosed disorder in older adults, represents a potential upstream vascular stressor linked to increased Alzheimer's disease (AD) risk. In this Perspective article, we propose a stage-informed framework in which rapid eye movement (REM) sleep-related respiratory events amplify vascular contributions to AD. This framework is unified across four linked lines of evidence suggesting that (1) REM sleep physiology magnifies the hypoxic and hemodynamic burden of OSA, (2) the cardiometabolic consequences of sleep apnea are heightened in REM sleep, (3) REM-related hypoxemia is associated with markers of cerebrovascular pathology, and (4) vascular effects associated with REM-related hypoxemia are associated with medial temporal lobe vulnerability and memory dysfunction: core features of AD. Although direct evidence linking REM-specific OSA to AD biomarkers is lacking, we highlight REM sleep as a potentially critical window through which sleep-disordered breathing may amplify vascular contributions to AD.},
}
@article {pmid42581297,
year = {2026},
author = {Iruela-Arispe, ML and Hinman, JD and Yang, AC and Dabertrand, F and Lee, JM and Howell, GR and , },
title = {A collaborative framework for uncovering molecular and cellular drivers of VCID: Foundations for future interventions in dementia.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71701},
doi = {10.1002/alz.71701},
pmid = {42581297},
issn = {1552-5279},
support = {NS139949//Northwestern CWOW/ ; NS139972//UCLA VIBRANT CWOW/ ; NS139975//The Gladstone/UCSF/UCI/Rush CWOW/ ; NS140137//The Colorado Neurovascular Energetics CWOW/ ; NS139970//The WashU UNWIND CWOW/ ; NS139948//JAX/Emory/Columbia/Rush MINT-VCID CWOW/ ; },
mesh = {Humans ; Animals ; *Dementia ; *Dementia, Vascular ; *Cognitive Dysfunction ; },
abstract = {Vascular-related factors are now considered major contributors to most forms of dementia, including Alzheimer's disease. However, the degree to which vascular deficits contribute to risk, onset, and progression of cognitive impairment and dementia has only recently been appreciated. Our understanding of the mechanisms by which vascular deficits drive cognitive decline in dementia is still limited. Further, the testing of therapeutic approaches to prevent vascular deficits to treat dementia are few. These factors motivated the establishment of the Vascular Contributions to Cognitive Impairment and Dementia (VCID) Center Without Walls (CWOW) network, comprising institutes across the United States. We describe the current gaps and opportunities, and how, in collaboration with other relevant groups, the VCID CWOW network is aiming to tackle the major unmet need of developing improved therapeutic approaches targeting vascular deficits to treat dementia.},
}
@article {pmid42581300,
year = {2026},
author = {Shen, X and Wang, S and Song, W},
title = {Alzheimer's disease: erasing the peptidyl-arginine deiminase 2 (PAD2) stamp to restore microglial defense.},
journal = {Signal transduction and targeted therapy},
volume = {11},
number = {1},
pages = {},
pmid = {42581300},
issn = {2059-3635},
support = {82230043//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
}
@article {pmid42581306,
year = {2026},
author = {Fyfe, I},
title = {Circular RNAs outperform established Alzheimer disease biomarkers.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {42581306},
issn = {1759-4766},
}
@article {pmid42581323,
year = {2026},
author = {Lee, D and Vicari, JM and Porras, C and Spencer, C and Pjanic, M and Wang, X and Kinrot, S and Weiler, P and Kosoy, R and Bendl, J and N M, P and Psychogyiou, K and Malakates, P and Hennigan, E and Monteiro Fortes, J and Zheng, S and Therrien, K and Mathur, D and Kleopoulos, SP and Shao, Z and Argyriou, S and Alvia, M and Casey, C and Hong, A and Beaumont, KG and Sebra, R and Kellner, CP and Bennett, DA and Yuan, GC and Voloudakis, G and Theis, FJ and Haroutunian, V and Hoffman, GE and Fullard, JF and Roussos, P},
title = {Plasticity of human microglia and brain perivascular macrophages in aging and Alzheimer's disease.},
journal = {Nature genetics},
volume = {},
number = {},
pages = {},
pmid = {42581323},
issn = {1546-1718},
support = {R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; P30AG10161, P30AG72975, R01AG15819, R01AG17917, U01AG46152, U01AG61356//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
abstract = {Myeloid cells, including microglia and perivascular macrophages, are central to Alzheimer's disease (AD) neurobiology, yet their role remains incompletely understood. We profiled 832,505 human myeloid cells from the prefrontal cortex of 1,607 donors spanning the lifespan and showing varying degrees of AD neuropathology. We delineated six subclasses comprising 13 transcriptionally distinct subtypes and identified adaptive changes associated with aging and AD progression. Here we show that a disease-associated microglial subtype, characterized by elevated GPNMB expression and enriched for polygenic AD risk, expands with AD pathology and shows increased phagocytic activity. We identify MITF as an upstream regulator required to maintain this microglial state. Cell-cell interaction analyses prioritize APOE-SORL1 and APOE-TREM2 signaling pairs associated with disease progression. Using human and mouse models, we demonstrate that the neuroprotective effects of this microglial subtype depend on TREM2. These findings provide mechanistic insights into myeloid cell function in aging and AD, aiding therapeutic discovery.},
}
@article {pmid42581442,
year = {2026},
author = {Chen, C and Cheng, J and Yang, M and Li, JP and Tao, SS and Wang, P and Pan, HF},
title = {Immunosuppressant Use Mediates Neuroprotection Against Alzheimer's Disease in Rheumatoid Arthritis-A Two-Step Mendelian Randomization and NHANES Study.},
journal = {International journal of rheumatic diseases},
volume = {29},
number = {8},
pages = {e70823},
doi = {10.1111/1756-185x.70823},
pmid = {42581442},
issn = {1756-185X},
support = {82404354//National Natural Science Foundation of China/ ; 82273710//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Alzheimer Disease/prevention &amp; control/genetics/diagnosis/psychology/epidemiology ; *Arthritis, Rheumatoid/drug therapy/genetics/diagnosis/epidemiology/psychology ; Female ; Mendelian Randomization Analysis ; Male ; *Immunosuppressive Agents/therapeutic use ; Aged ; *Cognition/drug effects ; Risk Factors ; Nutrition Surveys ; Middle Aged ; United States/epidemiology ; *Neuroprotection/drug effects ; Protective Factors ; Risk Assessment ; Genetic Predisposition to Disease ; *Neuroprotective Agents/therapeutic use ; Genome-Wide Association Study ; Phenotype ; },
abstract = {OBJECTIVES: To investigate whether immunosuppressant (IS) use contributes to the inverse association between rheumatoid arthritis (RA) and Alzheimer's disease (AD).<br><br>METHODS: We analyzed NHANES 2011-2014 data, including 217 RA patients aged &#x2265;&#x2009;60&#x2009;years on prescription medications. Cognitive function was assessed using the Digit Symbol Substitution Test (DSST), CERAD, Animal Fluency Test (AFT), and a global cognition z-score (Z-score). Associations between IS use and cognition were evaluated using multivariable linear regression. Additionally, two-sample Mendelian randomization (TSMR) and multivariable MR (MVMR) analyses were performed with GWAS datasets for RA, AD, and IS to examine potential causal effects.<br><br>RESULTS: We observed that patients with RA using IS performed better in z.DDST (&#x3b2;: 0.335, p&#x2009;=&#x2009;0.036) and Z-score (&#x3b2;: 0.214, p&#x2009;=&#x2009;0.032) after adjusting for covariates, with sex-specific differences in cognitive domains. TSMR indicated that genetically predicted RA was associated with lower AD risk (OR: 0.936, p&#x2009;=&#x2009;4.531E-04), and this effect was largely mediated by IS use. MVMR further validated the independent neuroprotective effect of IS on AD (OR&#x2009;=&#x2009;0.884, p&#x2009;=&#x2009;0.003) after adjusting for glucocorticoid and NSAID use, while these other medications showed no significant association with AD risk.<br><br>CONCLUSIONS: These results suggest that the reduced risk of AD observed in RA patients may be partly related to IS use, highlighting a potential role of IS in improving cognitive function and modulating AD risk.},
}
@article {pmid42581647,
year = {2026},
author = {Zhang, SY and Ren, HJ and Liu, HY and Xu, SY and Peng, YJ},
title = {Emerging Trends and Hot Spots in Tauopathy Research (2003-2025): A Bibliometric Analysis.},
journal = {Brain and behavior},
volume = {16},
number = {8},
pages = {e71645},
doi = {10.1002/brb3.71645},
pmid = {42581647},
issn = {2162-3279},
mesh = {*Bibliometrics ; *Tauopathies ; Humans ; *Biomedical Research/trends ; },
abstract = {PURPOSE: This study aimed to systematically analyze the developmental trajectory, research landscape, and thematic evolution of tauopathy research from 2003 to 2025 using bibliometric methods.<br><br>METHODS: A total of 6752 publications retrieved from the Web of Science Core Collection (WoSCC) were analyzed using the R package bibliometrix and VOSviewer to construct bibliometric networks, including co-authorship, co-citation, and keyword co-occurrence analyses. Scimago Graphica was used to visualize international collaboration patterns.<br><br>RESULTS: The annual number of publications on tauopathy increased markedly during the period 2003-2025, reflecting sustained global research interest. The United States was the leading contributor in both publication output and citation impact, while the University of Pennsylvania emerged as a key institution. Among individual researchers, the most productive authors and influential scholars were identified through publication output and citation-based metrics. Citation analysis highlighted the enduring impact of highly cited studies, particularly those establishing key biomarker frameworks for Alzheimer's disease research.Keyword-based analysis further revealed a shift from traditional mechanistic studies toward more integrative research themes, such as tau-amyloid-&#x3b2; interactions, neurodegeneration, and glial involvement, alongside continued interest in tau-targeted therapeutic strategies.<br><br>CONCLUSION: This bibliometric analysis provides a quantitative and structured overview of the global tauopathy research landscape. Beyond confirming established patterns, it captures the dynamic evolution of research priorities and identifies emerging directions, offering a data-driven basis for future investigations.},
}
@article {pmid42581666,
year = {2026},
author = {Williams, A and Reddy, ABS and Velayudhan, L},
title = {A Systematic Review of Effects of Cholinesterase Inhibitors and Memantine on Cognitive Domains in Alzheimer's Disease.},
journal = {Journal of geriatric psychiatry and neurology},
volume = {},
number = {},
pages = {8919887261470005},
doi = {10.1177/08919887261470005},
pmid = {42581666},
issn = {1552-5708},
abstract = {BackgroundAlzheimer's Disease (AD) is characterised by progressive cognitive decline. Cholinesterase inhibitors (ChEI) (donepezil, rivastigmine and galantamine) and memantine have been the mainstay treatment and have showed their effectiveness on total cognitive scores, but their effects on individual cognitive domains remain unclear. This systematic review examined their impact on individual cognitive domains.MethodPubMed, Cochrane, MEDLINE, Web of Science and PsycINFO were searched (1st January 1999 - 31st March 2025) for studies evaluating the effects of ChEI and memantine on cognitive domains using standardised cognitive scales in individuals with AD. The review followed PRISMA guidelines. Risk of bias was assessed using the Cochrane ROB1 tool and a narrative synthesis was used to report the main findings.ResultsSixteen studies were included. Rivastigmine demonstrated dose-dependent benefits across memory, language, and praxis domains, with higher-doses generally producing less cognitive decline and greater improvements than lower-dose patches or capsules. Donepezil yielded benefits in language, praxis, and visuospatial abilities. Galantamine showed significant improvements in memory, praxis, visuospatial function, and language, and was superior to donepezil in language in one comparative study. Memantine demonstrated benefits across memory, language, praxis, attention, and visuospatial domains, both as monotherapy and as an adjunct to donepezil, with adjunct therapy producing sustained improvements in language and praxis. Overall, higher treatment doses were consistently associated with greater preservation of cognitive function across domains.DiscussionChEIs and memantine provide domain-specific cognitive benefits beyond global cognitive improvement. Future studies should examine whether treatment tailored to domain-specific deficits improves patient outcome.PROSPEROCRD42024493998.},
}
@article {pmid42581716,
year = {2026},
author = {Dabour, Z},
title = {The NeuroCommunity Ageing Framework: A Nursing Model for Brain-Health Assessment Towards Diagnostic Justice in Minority Older Adults.},
journal = {Journal of advanced nursing},
volume = {},
number = {},
pages = {},
doi = {10.1111/jan.70723},
pmid = {42581716},
issn = {1365-2648},
abstract = {AIM(S): To propose the NeuroCommunity Ageing Framework as a nursing-centred theoretical model for integrated brain-health assessment towards diagnostic justice in minority ageing populations.<br><br>DESIGN: Discursive theoretical paper presenting a conceptual framework derived from cross-disciplinary synthesis.<br><br>METHODS: A structured theoretical synthesis integrated literature on gerontological nursing, dementia epidemiology, multidomain prevention, clinical pharmacology, family caregiving, culturally responsive care, service access and systemic factors relevant to blood-based Alzheimer's disease biomarkers.<br><br>RESULTS: The framework integrates metabolic-vascular, cognitive-clinical, pharmacological, family-caregiving, cultural-linguistic and systemic-service determinants of brain health. It positions nurses to recognise cognitive vulnerability earlier, conduct culturally informed medication review, support caregivers, address language and stigma barriers and navigate service access. Hepatic calibration is presented strictly as a hypothesis-generating research construct for future biomarker validation in multimorbid older adults, not as a clinical interpretation rule.<br><br>CONCLUSION: The framework offers a nursing-oriented model for culturally valid dementia assessment, medication safety, caregiver support and equitable service navigation.<br><br>The framework may support nurses in embedding brain-health case-finding within primary care, chronic disease and community settings.<br><br>IMPACT: The paper addresses delayed dementia recognition among minority older adults and proposes a practical nursing framework advancing diagnostic justice.<br><br>REPORTING METHOD: No specific reporting guideline directly applies to this discursive theoretical paper; it was prepared according to principles of transparent narrative synthesis.<br><br>This study did not include patient or public involvement in its design, conduct or reporting.},
}
@article {pmid42582058,
year = {2026},
author = {Yang, J and Wan, D and Ren, L and Lv, Y and Zhao, H},
title = {Revisiting TREM2: from multi-omics signaling networks to clinical translation.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1782384},
pmid = {42582058},
issn = {1664-3224},
mesh = {Humans ; *Receptors, Immunologic/genetics/metabolism/immunology/chemistry ; *Membrane Glycoproteins/genetics/metabolism/immunology/chemistry ; *Signal Transduction ; Animals ; Multiomics ; Neoplasms/immunology/metabolism ; Translational Research, Biomedical ; Alzheimer Disease ; },
abstract = {TREM2 is a cell surface receptor that plays a crucial role in regulating immune responses, particularly in myeloid cells such as macrophages, dendritic cells, and microglia. Initially studied for its involvement in neuroinflammation and neurodegenerative diseases, while recent evidence has highlighted its broader implications in cancer and various other diseases. Recent studies show that TREM2 plays an immunoprotective role prompted by central nervous system-enriched sphingolipids during GBM progression. TREM2 overexpression represses GBM and synergizes with anti-PD-1 therapy, suggesting a potential therapeutic avenue in cancer immunotherapy. This review provides a comprehensive overview of TREM2 biology, focusing on its molecular structure, signaling pathways, and functional roles in different disease contexts. In Alzheimer's disease, TREM2 mutations are associated with altered immune responses and impaired amyloid-beta clearance, suggesting a potential therapeutic target. In cancer, TREM2 contributes to immune evasion, tumor progression, and metastasis, with emerging strategies aiming to target TREM2 to enhance anti-tumor immunity. Additionally, TREM2 is implicated in a range of other conditions, including autoimmune diseases, multiple sclerosis, and Parkinson's disease, where it may regulate inflammatory responses and tissue damage. Despite promising findings, several challenges remain in understanding TREM2's complex role across diverse diseases. Future research directions include unraveling its precise mechanisms, validating its therapeutic potential, and exploring clinical interventions targeting TREM2. This review provides a comprehensive overview of TREM2 biology, synthesizing insights from recent single-cell transcriptomics and metabolic profiling. We focus on its molecular structure, complex signaling networks, and context-dependent functional roles across diverse disease landscapes.},
}
@article {pmid42582107,
year = {2026},
author = {Zou, DZ and Li, J and Long, QS and Zhang, RQ and Zhu, BL and Tan, JZ},
title = {CD22 regulates Aβ clearance in microglia through INPP5D signaling.},
journal = {Frontiers in cellular neuroscience},
volume = {20},
number = {},
pages = {1886995},
pmid = {42582107},
issn = {1662-5102},
abstract = {INTRODUCTION: Impaired microglial clearance of amyloid-β (Aβ) is a central driver of Alzheimer's disease (AD), yet the mechanisms governing intracellular Aβ degradation remain poorly defined.<br><br>METHODS: We investigated the role of CD22 in microglial A&#x3b2; processing using primary microglia, transcriptomic profiling, and hippocampal samples from AD patients and transgenic mice.<br><br>RESULTS: We identified CD22 as an A&#x3b2;-inducible signaling regulator that restrains microglial A&#x3b2; processing. CD22 expression was elevated in the hippocampus of AD patients and transgenic mice and was rapidly induced by A&#x3b2; in microglia. Functionally, CD22 knockdown enhanced intracellular A&#x3b2; degradation without affecting initial uptake. Transcriptomic profiling identified the AD risk gene INPP5D as a key downstream effector of CD22. Loss of CD22 suppressed INPP5D expression and promoted AKT activation, while INPP5D overexpression partially rescued the enhanced A&#x3b2; clearance phenotype. These findings define a CD22-INPP5D signaling axis that acts as a molecular brake on microglial A&#x3b2; processing. A&#x3b2; itself induces CD22 expression, revealing a feed-forward inhibitory loop in which amyloid accumulation limits its own clearance.<br><br>DISCUSSION: Collectively, these findings identify a regulatory mechanism controlling intracellular A&#x3b2; degradation and suggest the CD22-INPP5D axis as a potential therapeutic target for AD.},
}
@article {pmid42582162,
year = {2026},
author = {Zhang, Z and Zhang, P and Li, Y and Chu, J and Su, C and Hu, Z and Xiong, H and Xu, G},
title = {Associations of childhood-to-adulthood body size trajectories with dementia risk and brain structural imaging markers: a study from UK Biobank.},
journal = {Frontiers in nutrition},
volume = {13},
number = {},
pages = {1764658},
pmid = {42582162},
issn = {2296-861X},
abstract = {BACKGROUND: Childhood and adulthood adiposity may influence dementia risk and brain structure; however, their life-course interplay and potential sex-specific effects remain incompletely understood.<br><br>METHODS: We analyzed 488,397 UK Biobank participants with self-reported comparative body size at age 10 (categorized as thinner, average, or plumper relative to peers) and measured adulthood BMI, followed prospectively for incident dementia. Cox models estimated hazard ratios (HRs) with 95% confidence intervals (CIs). A subsample (n&#x202f;=&#x202f;45,759) underwent brain MRI.<br><br>RESULTS: Compared with average childhood body size, a plumper body size at age 10 was associated with a higher risk of all-cause dementia (HR 1.12, 95% CI 1.04-1.20), particularly among men (HR 1.15, 95% CI 1.04-1.28), whereas a thinner body size was not significantly associated with dementia risk. In adulthood, overweight was associated with lower risks of all-cause dementia (HR 0.86, 95% CI 0.81-0.92) and Alzheimer's disease (HR 0.83, 95% CI 0.76-0.91), while obesity was associated with a higher risk of vascular dementia (HR 1.38, 95% CI 1.19-1.59) but not all-cause dementia. For body size trajectories, transitioning from thinner childhood body size to overweight in adulthood was associated with lower risks of all-cause dementia (HR 0.82, 95% CI 0.75-0.90) and Alzheimer's disease (HR 0.77, 95% CI 0.67-0.88), whereas transitioning to obesity was associated with a higher risk of vascular dementia (HR 1.54, 95% CI 1.24-1.92). In addition, higher adiposity, particularly obesity, was associated with lower gray matter and total brain volumes and greater white matter hyperintensity burden.<br><br>CONCLUSION: Life-course adiposity patterns are associated with dementia risk and brain structural changes, with differences by subtype and sex. Childhood adiposity and weight gain may be linked to adverse outcomes, whereas moderate adiposity in adulthood was associated with lower dementia risk.},
}
@article {pmid42582182,
year = {2026},
author = {Bhargava, Y and Tripathi, S and Baths, V and Deshpande, BM},
title = {Navigation performance in virtual reality-based cognitive assessment games as a candidate digital cognitive marker of hippocampal vulnerability: a scoping review.},
journal = {Alzheimer's &amp; dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70434},
pmid = {42582182},
issn = {2352-8729},
abstract = {Virtual reality-based cognitive assessment games (VR-CAGs) are an emerging digital paradigm in dementia and Alzheimer's disease research. Although multiple studies report correlations between VR-CAG performance and standard neuropsychological assessments, clinical adoption remains limited, indicating that behavioral evidence alone is insufficient and that consolidated neuroimaging evidence is required. Existing neuroimaging studies link VR-CAG performance to regional brain activation, volumetric change, and brainwave dynamics, but this evidence remains scattered. We conducted a scoping review of 29 neuroimaging studies on VR-CAGs. Three functional neural systems were associated with VR-CAG performance: the spatial map system, the response system, and the executive control system. Two VR-CAG archetypes - hippocampal-based and adaptive navigation - were identified. A reporting and evaluation checklist is proposed to standardize VR-CAG research. Review findings indicate that VR-CAGs based on allocentric and egocentric tasks may be sensitive to hippocampal health, potentially acting as candidate digital markers of dementia-relevant functional cognitive decline.},
}
@article {pmid42582266,
year = {2026},
author = {Yang, X and Li, Y and Bibic, A and Wang, J and Wan, M and Duan, W and Lu, H and Wei, Z},
title = {Differential presence of cerebral microbleeds in an amyloid mouse model compared with a CADASIL mouse model.},
journal = {Alzheimer's &amp; dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70308},
pmid = {42582266},
issn = {2352-8737},
abstract = {INTRODUCTION: Cerebral microbleeds are commonly observed on susceptibility-based magnetic resonance imaging (MRI) in Alzheimer's disease (AD) and are often interpreted as markers of small-vessel disease. However, how microbleed occurrence differs between amyloid-associated vascular pathology and non-amyloid vascular conditions remains incompletely understood. In this study, we performed a comparative analysis between an amyloidosis mouse model and a non-amyloid arteriopathy cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) model to assess whether microbleed occurrence differs across these distinct vascular contexts.<br><br>METHODS: Multimodal in vivo MRI at 11.7T, including gradient echo (GRE), spin echo, and diffusion-weighted imaging, was performed in 5xFAD mice and a CADASIL mouse model across 9 to 20 months of age. Ex vivo high-resolution GRE imaging and Prussian blue staining were used to validate microbleeds. Quantitative analyses focused on microbleed counts, parenchymal and cerebrospinal fluid volumes, and regional apparent diffusion coefficient (ADC). In addition, blood-brain barrier (BBB) integrity was assessed in the CADASIL mice.<br><br>RESULTS: Both in vivo and ex vivo GRE MRI consistently revealed hippocampal microbleeds in 5xFAD mice, whereas no microbleeds were detected in CADASIL mice at any examined age. Microbleeds in 5xFAD mice occurred in the absence of brain atrophy or ventricular enlargement. ADC elevation was observed selectively in the midbrain of 5xFAD mice but not in other regions or in the CADASIL cohort. BBB permeability remained normal in CADASIL mice, indicating preserved vascular barrier integrity despite vascular smooth muscle cell loss.<br><br>DISCUSSION: Cerebral microbleeds emerged selectively in the amyloid model and were absent in a non-amyloid arteriopathy driven by vascular smooth muscle cell degeneration, suggesting that microbleed occurrence may depend on the underlying pathology. These findings show consistency with the possibility that cerebral microbleeds may reflect disease-associated vascular conditions, refining their interpretation as translational MRI biomarkers in AD.},
}
@article {pmid42582267,
year = {2026},
author = {Winzell, F and Arvidsson, I and Overgaard, NC and Heyden, A and Åström, K and Karlsson, L and Vogel, JW and Hansson, O and Mattsson-Carlgren, N and , },
title = {Benchmarking privacy and utility in synthetic tabular cohorts for Alzheimer's disease research.},
journal = {Alzheimer's &amp; dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70430},
pmid = {42582267},
issn = {2352-8729},
abstract = {INTRODUCTION: The scarcity of large, clinically relevant cohorts is becoming a bottleneck in Alzheimer's disease (AD) research, as their sensitive nature makes open data sharing difficult. Privacy-preserving synthetic datasets generated with machine learning may help address this challenge.<br><br>METHODS: We compared five frameworks for generating synthetic tabular data from the Alzheimer's Disease Neuroimaging Initiative and Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease cohorts, with a set of empirical privacy and utility metrics. Two of the methods, DataSynthesizer and TableDiffusion, provide &#x3b5; -differential privacy guarantees.<br><br>RESULTS: Methods with differential privacy achieved high privacy ratings but low levels of utility. Deep learning methods like Tabular Prior-data Fitted Network (TabPFN) and Conditional Generative Adversarial Network (CTGAN) also showed high privacy with limited utility. In contrast, non-private DataSynthesizer and Synthpop offered higher utility at a cost of lower privacy.<br><br>DISCUSSION: The evaluated methods demonstrated a clear trade-off between privacy and utility. High privacy was generally associated with insufficient utility, highlighting the need for further research into synthetic data generation for AD.},
}
@article {pmid42582435,
year = {2026},
author = {Wu, M and Zeng, X and Cai, Y and Chen, H and Li, Q and Yang, H},
title = {Parvalbumin interneurons in Alzheimer's disease: Physiological insights and pathophysiological mechanisms.},
journal = {Journal of cell communication and signaling},
volume = {20},
number = {3},
pages = {e70105},
pmid = {42582435},
issn = {1873-9601},
abstract = {Fast-spiking parvalbumin-positive (PV[+]) interneurons, a specialized class of inhibitory neurons, possess unique morphological and functional properties that govern spatiotemporal precision in local microcircuits, large-scale network synchronization, and memory-related computations. Since their initial identification in the late 19th century, technological innovations in cellular neuroscience have progressively elucidated the multifaceted roles of these neurons. In this review, we first delineate the embryonic origins and developmental trajectory of PV[+] interneurons, emphasizing their unique properties for high-frequency firing with remarkable temporal precision. These specialized features enable PV[+] interneurons to orchestrate network oscillations and critically modulate memory encoding, consolidation, and retrieval, despite their substantial metabolic demands. We subsequently integrate multiple lines of evidence implicating region- and subtype-specific PV[+] interneuron impairment as a pivotal pathological hallmark in Alzheimer's disease (AD). Furthermore, we dissect molecular and cellular mechanisms driving PV[+] interneuron dysfunction in AD, including numerical alterations, morphological remodeling, and electrophysiological disruptions. Critically, we propose that the pathological transformation of PV[+] interneuron physiology emerges as a key driver in AD progression, bridging cellular dysfunction to system-level cognitive failure.},
}
@article {pmid42582438,
year = {2026},
author = {Tan, M and Lan, X and Anayiti, X and Chen, P and Liu, Y and Lin, B and Wang, P},
title = {The role of glymphatic-related structural and functional imaging biomarkers in the pathological progression of Alzheimer's disease: a multimodal imaging-based study.},
journal = {Quantitative imaging in medicine and surgery},
volume = {16},
number = {8},
pages = {609},
pmid = {42582438},
issn = {2223-4292},
abstract = {BACKGROUND: The comparative utility of choroid plexus volume (CPV) and the diffusion tensor imaging-based perivascular space (DTI-ALPS) index as glymphatic biomarkers across the Alzheimer's disease (AD) continuum is unclear. This study aimed to perform a head-to-head comparison of their relationships with AD pathology, cognition, and diagnostic performance.<br><br>METHODS: This study analyzed data from 848 AD Neuroimaging Initiative (ADNI) participants [426 cognitively normal (CN), 309 with mild cognitive impairment (MCI), and 113 with AD dementia]. Group differences in CPV and the ALPS index were assessed using generalized linear models (GLM), and their associations with AD biomarkers and cognition were examined via partial correlation. Diagnostic performance using logistic regression, and longitudinal predictive value was assessed with linear mixed models.<br><br>RESULTS: Compared with the CN and MCI groups, patients with AD exhibited significantly increased CPV and reduced ALPS indices (all P<0.001). Amyloid-&#x3b2;-positive (A&#x3b2;[+]) participants also showed significantly higher CPV and lower ALPS indices than A&#x3b2;-negative (A&#x3b2;[-]) individuals (all P<0.001). Elevated CPV was associated with lower cerebrospinal fluid (CSF) A&#x3b2;42 (r=-0.15, P<0.001), poorer Mini-Mental State Examination (MMSE; r=-0.12, P<0.001), Montreal Cognitive Assessment (MoCA; r=-0.17, P<0.001), and reduced hippocampal volume (r=-0.21, P<0.001). Conversely, higher ALPS indices were associated with increased CSF A&#x3b2;42 (r=0.12, P<0.001), better MMSE (r=0.13, P<0.001), and preserved hippocampal volume (r=0.15, P<0.001). CPV achieved superior diagnostic performance for differentiating AD from MCI [area under the curve (AUC) =0.774] and CN (AUC =0.912). Moreover, integrating CPV, ALPS, and hippocampal volume further improved classification performance across diagnostic and A&#x3b2; stratification tasks. Longitudinal analyses demonstrated that higher baseline CPV was associated with better baseline cognitive performance and slower decline in executive, language, and memory functions, whereas lower baseline ALPS indices predicted accelerated memory decline over time.<br><br>CONCLUSIONS: Our findings identify CPV and the ALPS index as a pair of promising, complementary neuroimaging biomarkers for AD. Their synergistic integration into diagnostic models improves the precision of early detection and intervention strategies.},
}
@article {pmid42582463,
year = {2026},
author = {Trudel, L and Therriault, J and Macedo, AC and Rahmouni, N and Soucy, JP and Gauthier, S and Vitali, P and Guiot, MC and Hazrati, LN and Rosa-Neto, P},
title = {Posterior cortical atrophy and logopenic variant primary progressive aphasia are more specific for Alzheimer's disease pathology than probable Alzheimer's disease.},
journal = {Brain communications},
volume = {8},
number = {4},
pages = {fcag304},
pmid = {42582463},
issn = {2632-1297},
abstract = {Accurately diagnosing Alzheimer's disease is challenging, as 15-30% of individuals diagnosed clinically lack evidence of Alzheimer's disease neuropathological changes (ADNC) at autopsy. While the typical amnestic presentation of Alzheimer's disease may have limited specificity due to coexisting age-related pathologies, atypical presentations such as logopenic variant primary progressive aphasia (lvPPA) or posterior cortical atrophy (PCA) are often associated with ADNC. This study evaluated how well clinical diagnoses of amnestic and atypical Alzheimer's disease predict ADNC and how co-pathologies contribute to clinical-pathological discordance. To evaluate how clinical diagnosis predicts ADNC, we calculated positive predictive values (PPVs) and negative predictive values (NPVs) for clinical diagnoses of PCA, lvPPA, amnestic Alzheimer's disease or non-Alzheimer's disease dementia for ADNC, using four neuropathological thresholds defined by combinations of the Consortium to Establish a Registry for Alzheimer's disease (CERAD) neuritic plaque frequency (moderate or frequent) and Braak stage (III-VI or V-VI). Analyses were replicated in vivo using amyloid- and tau-PET positivity (A+T+) as a surrogate for Alzheimer's disease pathology. We also quantified the frequency of co-pathologies and assessed their contribution to false-positive Alzheimer's disease diagnoses. This study included 6363 autopsy-confirmed cases from the National Alzheimer's Coordinating Center (NACC) database (mean age: 80.0 ± 11.4 years; 46.0% female) and 76 participants from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort (mean age: 67.9 ± 9.94 years; 55.3% female). The PPV of probable Alzheimer's disease dementia ranged from 58 to 80%, while PCA and lvPPA showed higher PPVs (81-96% and 80-92%, respectively) for ADNC. The NPV of probable Alzheimer's disease dementia ranged from 66 to 83%, compared with 38-58% for PCA and lvPPA. In TRIAD, individuals with PCA or lvPPA had 100% PPV for Alzheimer's disease biomarker abnormality, whereas amnestic Alzheimer's disease dementia showed a PPV of 78.1%. Among Alzheimer's disease dementia cases, 20.2% were ADNC-negative, with a higher frequency of false-positive diagnoses in late-onset compared with early-onset cases (23.8% versus 6.9%). Among ADNC-negative Alzheimer's disease dementia cases, vascular pathology was the most common pathology (early-onset: 93%; late-onset: 98%). In the late-onset group, limbic-predominant age-related TDP-43 encephalopathy occurred in 31% of the cases, followed by Lewy body pathology (28.8%) and primary age-related tauopathy (24.3%). Visuospatial and language variants of clinical Alzheimer's disease offer excellent predictive value for underlying Alzheimer's disease pathology, both in vivo and at autopsy, outperforming the amnestic presentation classically associated with Alzheimer's disease. Clinical-pathological discordance in amnestic Alzheimer's disease dementia is frequently associated with coexisting age-related and vascular pathologies, highlighting the complexity of interpreting clinical Alzheimer's disease diagnoses in the absence of ADNC.},
}
@article {pmid42582587,
year = {2026},
author = {Eid, TM and Lashley, T and Warner, TT and Khan, A and Jantrachotechatchawan, C and Francis, PT and Hardy, J and Bandopadhyay, R},
title = {Altered synaptic and astrocytic proteins in Lewy body disorders associated with GBA mutations.},
journal = {Brain communications},
volume = {8},
number = {4},
pages = {fcag246},
pmid = {42582587},
issn = {2632-1297},
abstract = {Mutations in the glucocerebrosidase (GBA) gene, originally implicated in Gaucher's disease, are now recognized as a major risk factor for developing Parkinson's disease (PD). While up to 70% of PD patients eventually progress to dementia, GBA mutations further increase the risk of Lewy body dementias (LBD), an umbrella term encompassing both dementia with Lewy bodies and Parkinson's disease dementia. Collectively, these disorders are classified as synucleinopathies. To date, there is no clear understanding of the mechanistic relationships between GBA mutations and synucleinopathies, although, synaptic protein changes have been shown to correlate with cognitive change in LBD as well as in Alzheimer's disease (AD). The aim of this study was to examine synaptic dysfunction in α-synucleinopathies with GBA mutations. The research cohort consisted of 10 controls, 7 PD/LBD-GBA N370S, and 20 PD/LBD-wild type (WT) where seven synaptic markers including four pre-synaptic [synaptosomal-associated protein 25; (SNAP25), synaptophysin; (SYP), ras-related protein; (Rab3A), and vesicle associated membrane proteins 2; (VAMP2)], two post-synaptic [post-synaptic density protein 95; (PSD95), and neurogranin; (NRGN)], and one astrocytic [vesicle associated membrane proteins 3; (VAMP3)] protein were investigated in four cortical regions (prefrontal, temporal, anterior cingulate and parietal) using immunoblot technique. Four markers (NRGN, SNAP25, VAMP2, and VAMP3) were found to be significantly and regionally altered between the three groups. The expression of pre-synaptic (SNAP25), post-synaptic (NRGN), and the astrocytic protein (VAMP3) is different between PD/LBD with GBA mutation and PD/LBD-WT suggesting the potential role of GBA gene due to mutations which could alter the levels of some synaptic markers. Our study is the first to validate several synaptic markers in human post-mortem-associated GBA N370S mutation.},
}
@article {pmid42582950,
year = {2026},
author = {Budak, M and Heffernan, KS and Ishaq, M and Paruzel, V and Abdalla, D and Moallemian, S and Fausto, BA and Elahi, FM and Gluck, MA},
title = {ABCA7-80 moderates vascular stiffness-p-tau217 association in older African Americans.},
journal = {Alzheimer's &amp; dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70297},
pmid = {42582950},
issn = {2352-8737},
abstract = {INTRODUCTION: Compromised vascular health is increasingly linked to Alzheimer's disease (AD) risk. Estimated pulse wave velocity (ePWV), derived from age and blood pressure, and provides a practical, non-invasive index of vascular stiffness and overall vascular health. Older African Americans experience a disproportionate burden of vascular disease and AD. Genetic risk factors such as APOE ε4 and ABCA7-80 (rs115550680) further increase AD susceptibility. However, whether these genetic risks influence vascular stiffness and how that may interact with AD pathology remains unknown, especially in African Americans.<br><br>METHODS: A total of 143 older African Americans (mean age&#xa0;=&#xa0;71.10&#xa0;&#xb1;&#xa0;6.83 years; 109 women) were included. We examined the effects of both ABCA7-80 and APOE &#x3b5;4 genotypes on ePWV and plasma phosphorylated tau 217 (p-tau217). All regression models controlled for sex, education, pulse pressure, waist-to-hip ratio, global cognitive status, hypertension status, and APOE genotype (APOE genotype only used for ABCA7-80 regression models).<br><br>RESULTS: ABCA7-80 risk allele carriers exhibited higher ePWV (F (1,130)&#xa0;=&#xa0;8.16, p&#xa0;=&#xa0;0.005, &#x3b7;[2] p&#xa0;=&#xa0;0.064) and higher p-tau217 levels (F (1,130)&#xa0;=&#xa0;30.11, p&#xa0;<&#xa0;0.001, &#x3b7;[2] p &#xa0;=&#xa0;0.201). APOE &#x3b5;4 allele carriers also showed higher p-tau217 levels (F (1,131)&#xa0;=&#xa0;12.96, p&#xa0;<&#xa0;0.001, &#x3b7;[2] p&#xa0;=&#xa0;0.092). ABCA7-80 significantly moderated the relationship between ePWV and p-tau217 (F(1,130)&#xa0;=&#xa0;6.58, p&#xa0;<&#xa0;0.001), such that higher ePWV was associated with higher p-tau217 among ABCA7-80 risk carriers (&#x3b2;&#xa0;=&#xa0;0.52, t (130)&#xa0;=&#xa0;2.69, p&#xa0;=&#xa0;0.008).<br><br>DISCUSSION: ABCA7-80 risk, but not APOE &#x3b5;4, heightens susceptibility to the tau-related effects of compromised vascular health among older African Americans. These findings identify a genetically vulnerable subgroup in which vascular stiffness may disproportionately accelerate AD-related tau pathology and highlight vascular health as a modifiable target for reducing AD risk in African Americans.},
}
@article {pmid42583026,
year = {2026},
author = {Erdal, M and Arı, A and Emekli, AS and Yılmaz, N&#xc7; and Kürtüncü, M},
title = {Clinical Use of Interleukin-6 Blockade in Neuroimmunological Disorders.},
journal = {Noro psikiyatri arsivi},
volume = {63},
number = {},
pages = {482-494},
pmid = {42583026},
issn = {1300-0667},
abstract = {Interleukin-6 (IL-6) is a multifunctional cytokine that plays a critical role in immune regulation, host defense, and tissue repair. Within the central nervous system (CNS), IL-6 contributes to both neuroprotection and neuroinflammation, depending on the signaling pathway involved; classic signaling, trans-signaling, or trans-presentation. Dysregulation of IL-6, particularly through sustained overexpression, disrupts the blood-brain barrier (BBB) integrity, promotes glial activation, and amplifies chronic inflammation, thereby contributing to the pathophysiology of numerous neurological disorders. This review aims to evaluate the role of IL-6 in neuroinflammatory processes and its clinical implications across a spectrum of neurological diseases. It focuses on the therapeutic potential and safety profile of IL-6 inhibitors, particularly tocilizumab and satralizumab. Key conditions discussed include neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein-associated disease (MOGAD), autoimmune encephalitis (AE), neuro-Behçet's disease (NBD), myasthenia gravis (MG), epilepsy, multiple sclerosis (MS), and Alzheimer's disease (AD). Clinical trials have demonstrated the efficacy of IL-6 receptor blockade in reducing relapse rates in NMOSD, leading to regulatory approvals. Promising off-label results have also been reported in treatment-resistant cases of MOGAD, epilepsy, and autoimmune conditions. However, IL-6 inhibition carries risks such as serious infections and paradoxical inflammatory reactions. Targeting the IL-6 pathway represents a significant advancement in neuroimmunology, offering new therapeutic opportunities for otherwise refractory conditions. Future research should focus on large-scale randomized controlled trials and the development of IL-6 inhibitors capable of crossing the BBB to enhance CNS-specific efficacy. Cost-related accessibility also remains a major challenge for broader clinical application.},
}
@article {pmid42583149,
year = {2026},
author = {Binte Iqbal, H and Janjua, A and Mahato, RK},
title = {AI-driven neuroimaging for Alzheimer's disease: Addressing genetic and ethnic bias in diagnostic modeling.},
journal = {Journal of public health research},
volume = {15},
number = {3},
pages = {22799036261474536},
pmid = {42583149},
issn = {2279-9028},
}
@article {pmid42583477,
year = {2026},
author = {Jiakponnah, NN and Biose, IJ and Fischer, T and Cherry, K and Cronin, J and Jazwinski, SM and Kim, S},
title = {Alzheimer's Disease DNA Methylation Index (AD-DMI) and its Association with Late-Life Cognitive Function.},
journal = {NPJ dementia},
volume = {2},
number = {},
pages = {},
pmid = {42583477},
issn = {3005-1940},
abstract = {Alzheimer's disease (AD) is driven by genetic and epigenetic factors. A knowledge gap remains in applying DNA methylation (DNAm) to capture AD-specific signatures. We developed the AD DNA Methylation Index (AD-DMI), a brain-derived risk index constructed from 100 CpG sites identified by elastic-net logistic regression of methylation data from postmortem dorsolateral prefrontal cortex tissue. AD-DMI was evaluated in 722 older adults, including individuals with normal cognition (NC), mild cognitive impairment (MCI), and AD. AD-relevant associations were tested using generalized linear models, logistic regression, and path analyses, with applicable covariate adjustments. Higher AD-DMI scores were associated with lower global cognitive function, greater global AD neuropathologic burden, and increased odds of subjective memory complaints. AD-DMI predicted clinical diagnosis across the continuum, independent of cognition and pathology. Compared to the Cortical clock, AD-DMI showed stronger and more specific associations with both cognitive and pathological outcomes. Genes mapped to AD-DMI CpGs overlapped with eight genetic loci identified in AD genome-wide association studies, including RELN, LRP1B, and PDE9A. AD-DMI was significantly associated with increased methylation at CpGs in APOE, HOXA3, and ANK1. AD-DMI provides a biologically grounded framework for linking disease-relevant methylation changes with cognitive and pathological outcomes in AD.},
}
@article {pmid42583594,
year = {2026},
author = {Grady, ST and Andrews, RM and Peters, JL and Adar, SD and Levy, JI and Beck, T and Dhana, K and Desai, P and Haupt, BJ and Kaufman, JD and Szpiro, AA and Wilson, RS and Rajan, KB and Weuve, J},
title = {Residential aircraft and road noise exposure, cognition, and Alzheimer's dementia in a US cohort of older adults.},
journal = {Environmental epidemiology (Philadelphia, Pa.)},
volume = {10},
number = {4},
pages = {e518},
pmid = {42583594},
issn = {2474-7882},
abstract = {BACKGROUND: There is limited evidence of the associations between transportation noise and dementia risk. We examined associations of road and aircraft noise with cognitive function, cognitive decline, and Alzheimer's dementia (AD) in a cohort of older adults.<br><br>METHODS: We set our study in the Chicago Health and Aging Project, a longitudinal cohort of community-dwelling older adults from four Chicago, Illinois, neighborhoods, followed from 1993 to 2012. Every 3 years, participants underwent in-home cognitive assessments (episodic memory, perceptual speed, global cognition). A stratified random sample underwent clinical evaluation for AD diagnosis. We estimated 5-year time-weighted day-night average sound levels before baseline for road and, in analyses, we considered exploratory because of a limited exposure range, aircraft noise. We fit covariate-adjusted linear mixed models to estimate associations with cognitive performance and decline, and a multiple logistic regression model weighted by the sampling design to estimate incident AD odds ratios.<br><br>RESULTS: Of the 10,681 participants, an interquartile range increment in road noise (8.5 dBA) corresponded to a 0.06-SD unit lower baseline global cognitive score (95% confidence interval: -0.08, -0.03); there were no differences in cognitive decline. In exploratory analyses limited by power, higher aircraft noise was associated with a higher baseline score yet a faster rate of cognitive decline. Among 2147 participants evaluated for dementia (460 cases), road noise was not noticeably associated with greater AD risk, as there was substantial uncertainty (odds ratio per interquartile range = 1.17 [95% confidence interval: 0.86, 1.59]).<br><br>CONCLUSION: We observed mixed associations of transportation noise with cognitive functioning and dementia across noise sources. These findings underscore the need to better characterize noise sources relevant to the cognitive health of older adults.},
}
@article {pmid42583767,
year = {2026},
author = {Brewer, EH and Williams, CA and Cary, GA and Betarbet, R and Pranoto, IKA and Zoeller, EL and Fu, H and Levey, AI and Wiley, JC and Carter, GW and Young, JE and , },
title = {Inhibition of Moesin and CD44 in stem cell-derived neurons affects the pathological genetic signature associated with Alzheimer's disease.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71734},
doi = {10.1002/alz.71734},
pmid = {42583767},
issn = {1552-5279},
support = {U54AG065187/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/genetics/metabolism/pathology ; *Neurons/metabolism/pathology ; *Hyaluronan Receptors/genetics/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; Phosphorylation ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/metabolism ; Gene Knockdown Techniques ; Microfilament Proteins ; },
abstract = {INTRODUCTION: Post mortem proteomic analysis of Alzheimer's disease (AD) brain tissue has identified novel target genes and proteins for potential therapeutic development. Moesin (MSN) and CD44 were identified as candidate targets. Using human induced pluripotent stem cells (hiPSCs)-derived neurons, we assayed how reducing gene expression of MSN and CD44 affected amyloid beta secretion, tau phosphorylation, and transcriptional state.<br><br>METHODS: Knockdown of MSN and CD44 in hiPSC-derived neurons was performed using short hairpin RNA&#xa0;(shRNA). Amyloid precursor protein processing and intracellular tau phosphorylation was measured using chemiluminescent ELISA assays. Global gene expression was analyzed by bulk RNA sequencing (RNA-seq).<br><br>RESULTS: Knockdown of CD44 and MSN increased secretion of amyloid beta and soluble APP beta and differentially altered tau generation and phosphorylation. RNA-seq revealed diverse effects of CD44 and MSN knockdown and the reversal of some expression shifts found in late-onset AD.<br><br>DISCUSSION: These findings connect reduced CD44 and MSN expression to AD-related signatures in neurons and inform their role in the disease.},
}
@article {pmid42583778,
year = {2026},
author = {Lisgaras, CP and Jacobs, T and Figueredo, L and Pirraglia, E and Radtke, CH and Keller, JN and Karvelas, N and Bernal, J and Ruiz, J and Zetterberg, H and Glodzik, L and de Leon, MJ and McIntire, LB and Boutajangout, A and Wisniewski, T and Ramos-Cejudo, J and Alcolea, D and Giménez, S and Fortea, J and Akassoglou, K and Elahi, FM and Osorio, RS},
title = {CSF fibrinogen predicts longitudinal Tau accumulation in cognitively unimpaired older adults.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71720},
doi = {10.1002/alz.71720},
pmid = {42583778},
issn = {1552-5279},
support = {R01AG012101/AG/NIA NIH HHS/United States ; R01AG022374/AG/NIA NIH HHS/United States ; R01AG056031/AG/NIA NIH HHS/United States ; R01AG013616/AG/NIA NIH HHS/United States ; R01AG056531/AG/NIA NIH HHS/United States ; R01AG056682/AG/NIA NIH HHS/United States ; R01AG068248/AG/NIA NIH HHS/United States ; R01AG070821/AG/NIA NIH HHS/United States ; R01AG080609/AG/NIA NIH HHS/United States ; R01AG056850/AG/NIA NIH HHS/United States ; RF1AG080769/AG/NIA NIH HHS/United States ; P30AG066512/AG/NIA NIH HHS/United States ; R21AG086880/AG/NIA NIH HHS/United States ; R21AG056974/AG/NIA NIH HHS/United States ; R01AG061566/AG/NIA NIH HHS/United States ; R01AG081394/AG/NIA NIH HHS/United States ; R61AG066543/AG/NIA NIH HHS/United States ; R35NS143067/AG/NIA NIH HHS/United States ; R01AG092953/AG/NIA NIH HHS/United States ; R01AG079282/AG/NIA NIH HHS/United States ; //Cure Alzheimer's Fund/ ; //Citizens United for Research in Epilepsy/ ; A2025013S//Brightfocus Foundation Award/ ; 26-144745//Alzheimer's Association Zenith Award/ ; H2020-SC1-BHC-2018-2020//Horizon 2020-Research and Innovation Framework Programme from the European Union/ ; PI22/00611//Salud Carlos III (Ministerio de Asuntos Econ&#xf3;micos y Transformaci&#xf3;n Digital, Gobierno de Espa&#xf1;a)/ ; PI25/00422//Salud Carlos III (Ministerio de Asuntos Econ&#xf3;micos y Transformaci&#xf3;n Digital, Gobierno de Espa&#xf1;a)/ ; INT23/00048//Salud Carlos III (Ministerio de Asuntos Econ&#xf3;micos y Transformaci&#xf3;n Digital, Gobierno de Espa&#xf1;a)/ ; INT21/00073//Salud Carlos III (Ministerio de Asuntos Econ&#xf3;micos y Transformaci&#xf3;n Digital, Gobierno de Espa&#xf1;a)/ ; PI20/01473//Salud Carlos III (Ministerio de Asuntos Econ&#xf3;micos y Transformaci&#xf3;n Digital, Gobierno de Espa&#xf1;a)/ ; PI23/01786//Salud Carlos III (Ministerio de Asuntos Econ&#xf3;micos y Transformaci&#xf3;n Digital, Gobierno de Espa&#xf1;a)/ ; PI20/00836//Salud Carlos III (Ministerio de Asuntos Econ&#xf3;micos y Transformaci&#xf3;n Digital, Gobierno de Espa&#xf1;a)/ ; GBHI_ALZ-23-971107//Global Brain Health Institute/ ; 1801Cycle2020//J&#xe9;r&#xf4;me Lejeune Foundation/ ; 2023-00356//Swedish Research Council/ ; 2022-01018//Swedish Research Council/ ; 2019-02397//Swedish Research Council/ ; 201809-2016862//Alzheimer Drug Discovery Foundation (ADDF)/ ; ADSF-21-831376-C//Alzheimer's Disease Strategic Fund and the Alzheimer's Association/ ; ADSF-21-831381-C//Alzheimer's Disease Strategic Fund and the Alzheimer's Association/ ; ADSF-21-831377-C//Alzheimer's Disease Strategic Fund and the Alzheimer's Association/ ; ADSF-24-1284328-C//Alzheimer's Disease Strategic Fund and the Alzheimer's Association/ ; NEuroBioStand,22HLT07//European Partnership on Metrology/ ; //Bluefield Project/ ; //Olav Thon Foundation/ ; //Erling-Persson Family Foundation/ ; FO2022-0270//Familjen R&#xf6;nstr&#xf6;ms Stiftelse, Familjen Beiglers Stiftelse, Stiftelsen f&#xf6;r Gamla Tj&#xe4;narinnor, Hj&#xe4;rnfonden, Sweden/ ; //National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre/ ; UKDRI-1003//UK Dementia Research Institute at UCL/ ; IK2CX002180/VA/VA/United States ; 2019A012SUP//Larry L. Hillblom Foundation/ ; //New Vision Research/ ; //Rainwater Charitable Foundation/ ; //Chan Zuckerberg Initiative/ ; //Rockefeller Philanthropies/ ; },
mesh = {Humans ; *tau Proteins/cerebrospinal fluid ; *Fibrinogen/cerebrospinal fluid ; Aged ; Female ; Male ; Biomarkers/cerebrospinal fluid ; Amyloid beta-Peptides/cerebrospinal fluid ; Longitudinal Studies ; Alzheimer Disease/cerebrospinal fluid ; Blood-Brain Barrier ; Disease Progression ; Peptide Fragments/cerebrospinal fluid ; Chitinase-3-Like Protein 1/cerebrospinal fluid ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Blood-brain barrier (BBB) dysfunction is an early feature of Alzheimer's disease (AD). Fibrinogen represents a sensitive marker of BBB leakage, but whether it modifies longitudinal tau progression in cognitively unimpaired (CU) individuals remains unknown.<br><br>METHODS: CU older adults underwent clinical evaluation and cerebrospinal fluid (CSF) assessment of fibrinogen, A&#x3b2;42, total tau (tTau), phosphorylated tau 181 (pTau181), and YKL-40. Linear regression tested baseline associations. Linear mixed-effects models tested whether baseline fibrinogen predicted longitudinal pTau181 change.<br><br>RESULTS: Among 169 CU participants with baseline fibrinogen, 87 had longitudinal pTau181 measurements (mean follow-up 2.5-years). Higher fibrinogen was associated with elevated YKL-40 (&#x3b2;&#xa0;=&#xa0;0.28, 95% confidence interval [CI] [0.11, 0.45]) but not A&#x3b2;42, tTau, or pTau181 at baseline. Baseline fibrinogen modified longitudinal pTau181 trajectories (interaction &#x3b2;&#xa0;=&#xa0;0.11, 95% CI [0.04, 0.19]), with only participants above the median showing significant pTau181 increases (&#x3b2;&#xa0;=&#xa0;0.13, 95% CI [0.08, 0.18]).<br><br>DISCUSSION: CSF fibrinogen associates cross-sectionally with glial inflammation and predicts accelerated tau accumulation in preclinical AD.},
}
@article {pmid42583783,
year = {2026},
author = {Zufiria-Gerbolés, B and Vereb, D and Mijalkov, M and Passaretti, M and Volpe, G and Xu, Z and Hinault, T and Garcia-Ptacek, S and Pereira, JB and , },
title = {Vulnerability of locus coeruleus connections to aging and Alzheimer's disease.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71737},
doi = {10.1002/alz.71737},
pmid = {42583783},
issn = {1552-5279},
support = {2022-01108//Swedish Research Council/ ; //Alzheimer Foundation/ ; 2022-014//Brain Foundation/ ; //European Union - NextGenerationEU and the Romanian Government, under National Recovery and Resilience Plan for Romania/ ; //Romanian Ministry of Research, Innovation and Digitalization, within Component 9,Investment I8/ ; //Strategic Research Area Neuroscience (StratNeuro)/ ; //KIConsolidator grant/ ; //KID-funding/ ; //Center for Medical Innovation (CIMED)/ ; //KonungGustaf V:s och Drottning Victorias Stiftelse/ ; //Foundation for Geriatric Diseases at Karolinska Institutet/ ; //Gamla Tj&#xe4;narinnor/ ; //Stohnes Foundation/ ; //Lars Hiertas Memorial Foundation/ ; //Innovative ways to fight Alzheimer&#xb4;s disease - Leif Lundblad Family and others/ ; //National Academic Infrastructure for Super-computing in Sweden/ ; 2022-06725//Swedish ResearchCouncil/ ; //Karolinska Institutet/ ; },
mesh = {Humans ; *Locus Coeruleus/pathology/diagnostic imaging ; *Alzheimer Disease/pathology/diagnostic imaging/genetics ; *Aging/pathology ; Female ; Aged ; Male ; Neural Pathways/pathology ; Magnetic Resonance Imaging ; tau Proteins/metabolism ; Aged, 80 and over ; White Matter/pathology ; Middle Aged ; Adult ; },
abstract = {INTRODUCTION: The locus coeruleus (LC) is important in coordinating communication between brain regions through its widespread connections. However, the organization of its connections, and its changes with aging and Alzheimer's disease (AD), remains unclear.<br><br>METHODS: We mapped whole-brain white matter connections from the LC in two independent cohorts: one spanning the adult lifespan and another covering the AD continuum.<br><br>RESULTS: We identified a novel dorsal-ventral organization of LC connectivity that showed changes common to aging and AD or specific to AD, was linked to gene expression patterns, and was associated with cognitive performance and tau pathology in the entorhinal cortex. We also developed an imaging marker, LC gap, capturing LC connectivity deviations associated with slower tau accumulation in cognitively normal individuals at high risk for AD.<br><br>DISCUSSION: These findings provide new insights into LC connectivity in aging and AD, highlighting its potential role as a resilience marker against AD neurodegeneration.},
}
@article {pmid42583837,
year = {2026},
author = {Zhu, N and Xu, H and Garcia-Ptacek, S and Mitra, S and Eriksdotter, M},
title = {Oral anticoagulants, cognition, and clinical outcomes in atrial fibrillation and Alzheimer's disease: a Swedish nationwide study.},
journal = {European heart journal},
volume = {},
number = {},
pages = {},
doi = {10.1093/eurheartj/ehag584},
pmid = {42583837},
issn = {1522-9645},
support = {FoUI-1002840//Center for Innovative Medicine/ ; AF-1032116//Swedish Alzheimer's Foundation/ ; M24-0221//&#xc5;ke Wiberg Foundation/ ; 2022-01428//Swedish Research Council/ ; 2022-01425//Swedish Research Council/ ; 2024-03599//Swedish Research Council/ ; M-2024-2526//Petrus and Augusta Hedlund Foundation/ ; 2024-1370//Magnus Bergvall Foundation/ ; //Swedish Kidney Foundation/ ; //Karolinska Institutet internal funds/ ; //Karolinska Institutet/ ; //Emil and Wera Cornell Foundation/ ; //Swedish Dementia Foundation/ ; //Stockholm County Council and Karolinska Institutet/ ; //New Innovative Roads Call/ ; //Leif Lundblad/ ; //Loo and Hans Osterman Foundation/ ; //Gun and Bertil Stohne Foundation/ ; //Swedish Dementia Foundation/ ; //Tore Nilson Foundation/ ; //Gamla Tj&#xe4;narinnor Foundation/ ; //Lindh&#xe9;s Advokatbyr&#xe5; Foundation/ ; //Mats Paulsson Foundation/ ; FO2024-0339//Swedish Brain Foundation/ ; 2021-02680//PREDEM/ ; },
abstract = {BACKGROUND AND AIMS: Use of non-vitamin K oral anticoagulants (NOACs) is associated with reduced dementia risk in patients with atrial fibrillation (AF), but their impact on cognitive function and clinical outcomes in AF patients with Alzheimer's disease (AD) remains unclear.<br><br>METHODS: Based on the Swedish Registry for Cognitive/Dementia Disorders, individuals with incident AD during May 2007-December 2020 and pre-existing AF were identified. Anticoagulant use at baseline was categorized as non-use, warfarin, or NOACs. Inverse probability of treatment weighting was employed to balance covariates. Mixed-effects models were used to assess the association between anticoagulant use and cognitive decline measured by the Mini-Mental State Examination (MMSE). Cox proportional hazards models were used to examine risks of all-cause mortality, ischaemic stroke/systemic embolism, major bleeding, and fracture.<br><br>RESULTS: Among 7308 eligible individuals (3341 non-users, 2277 warfarin users, and 1690 NOAC users), NOAC users exhibited significantly slower cognitive decline compared to non-users (difference in MMSE scores &#x3b2; = 0.23 points/year, 95% confidence interval [CI] 0.11-0.36) and warfarin users (&#x3b2; = 0.21 points/year, 95% CI 0.10-0.33). Compared to non-use of anticoagulants, NOAC use was associated with significantly lower rates of mortality (hazard ratio [HR] 0.81; 95% CI 0.72-0.91), ischaemic stroke/systemic embolism (HR 0.66; 95% CI 0.53-0.82), and fracture (HR 0.79; 95% CI 0.64-0.97), without an increased rate of major bleeding (HR 1.05; 95% CI 0.84-1.32); in contrast, warfarin use was associated with significantly lower rates of mortality (HR 0.88; 95% CI 0.80-0.97) and ischaemic stroke/systemic embolism (HR 0.85; 95% CI 0.72-1.00), but a higher rate of major bleeding (HR 1.31; 95% CI 1.09-1.56). Compared to warfarin, NOAC use was associated with lower rates of ischaemic stroke/systemic embolism (HR 0.78; 95% CI 0.62-0.98) and major bleeding (HR 0.80; 95% CI 0.64-1.01), and non-significant reductions in mortality and fracture.<br><br>CONCLUSIONS: In patients with AF and AD, NOAC use was associated with modestly slower cognitive decline and more favourable effectiveness and safety profiles, compared to warfarin or no anticoagulation.},
}
@article {pmid42583902,
year = {2026},
author = {Laishram, D and Du, G and Kanekar, S and Nagaraja, N},
title = {White Matter and Perivascular Imaging Changes in Alzheimer's Disease and Cerebral Amyloid Angiopathy.},
journal = {Annals of clinical and translational neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/acn3.70506},
pmid = {42583902},
issn = {2328-9503},
abstract = {OBJECTIVE: Peak-width of skeletonized mean diffusivity (PSMD) and diffusion tensor imaging-analysis along the perivascular space (DTI-ALPS), reflecting white matter integrity and glymphatic function, are altered in Alzheimer's disease (AD). We evaluated whether these biomarkers differ between AD participants with and without concomitant cerebral amyloid angiopathy (CAA).<br><br>METHODS: The study included 50 AD participants with mild cognitive impairment/mild dementia, and intermediate to high AD neuropathologic change at autopsy. AD was categorized as AD with CAA and AD without CAA based on CAA neuropathology. We evaluated global and regional (frontal, parietal, temporal and occipital) PSMD; left, right and mean DTI-ALPS indices and their association with clinical measures [Clinical dementia rating sum-of-boxes (CDR-SB) from CDR Dementia Staging Instrument, mini mental state examination (MMSE), cognitive composites: memory, processing speed, executive function, and language].<br><br>RESULTS: AD participants with CAA (n&#x2009;=&#x2009;17) had higher global [4.02&#x2009;&#xb1;&#x2009;1.44 (mean&#x2009;&#xb1;&#x2009;SD&#x2009;&#xd7;&#x2009;10[-4]&#x2009;mm[2]/s) vs. 3.12&#x2009;&#xb1;&#x2009;0.91, &#x3b2;&#x2009;=&#x2009;-0.80, 95% CI (-1.42, -0.18), p&#x2009;=&#x2009;0.012] and occipital PSMD [4.02&#x2009;&#xb1;&#x2009;1.10 vs. 3.00&#x2009;&#xb1;&#x2009;1.08, &#x3b2;&#x2009;=&#x2009;-0.88, 95% CI (-1.51, -0.26), p&#x2009;=&#x2009;0.026] than those without CAA. No PSMD metric was associated with any clinical measure. However, imaging-by-group interactions showed global PSMD associated with language [&#x3b2;&#x2009;=&#x2009;-0.89, 95% CI (-1.53, -0.26), p&#x2009;=&#x2009;0.027] and parietal PSMD with language [&#x3b2;&#x2009;=&#x2009;-1.05, 95% CI (-1.74, -0.36), p&#x2009;=&#x2009;0.014] and memory [&#x3b2;&#x2009;=&#x2009;-0.83, 95% CI (-1.38, -0.28), p&#x2009;=&#x2009;0.015]. DTI-ALPS indices did not differ by group. Higher mean and right DTI-ALPS indices were associated with preserved language function [mean: &#x3b2;&#x2009;=&#x2009;9.33, 95% CI (2.05, 16.62), p&#x2009;=&#x2009;0.036; right: &#x3b2;&#x2009;=&#x2009;7.75, 95% CI (1.54, 13.95), p&#x2009;=&#x2009;0.043] without imaging-by-group interactions.<br><br>INTERPRETATION: Global and occipital PSMD may help identify AD participants with concomitant CAA.},
}
@article {pmid42583949,
year = {2026},
author = {Takahashi, M and Matsuoka, K and Yamamuro, K and Toritsuka, M and Makinodan, M},
title = {Facial Emotion Recognition Deficits in Alzheimer's Disease Are Associated With Bilateral Uncinate Fasciculus Abnormalities and Frontotemporal-Limbic Microstructural Disorganisation.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {26},
number = {5},
pages = {e70206},
pmid = {42583949},
issn = {1479-8301},
mesh = {Humans ; *Alzheimer Disease/psychology/diagnostic imaging/pathology/physiopathology ; Female ; Male ; Aged ; Cross-Sectional Studies ; Diffusion Tensor Imaging/methods ; *Emotions/physiology ; *Uncinate Fasciculus/pathology/diagnostic imaging ; *Facial Expression ; *Temporal Lobe/pathology/diagnostic imaging ; Neuropsychological Tests ; Aged, 80 and over ; *Facial Recognition/physiology ; *Limbic System/pathology/diagnostic imaging ; Gray Matter/pathology/diagnostic imaging ; Magnetic Resonance Imaging ; *Frontal Lobe/pathology ; White Matter/pathology ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is associated with memory impairment and social cognitive dysfunction, including facial emotion recognition (FER) deficits. Our previous diffusion tensor imaging (DTI) study linked poor recognition of negative facial emotions in patients with AD to increased mean diffusivity (MD) in the left uncinate fasciculus (UF). Whether FER deficits in AD reflect microstructural alterations in related grey matter regions remains unclear.<br><br>METHODS: In this cross-sectional study, 74 patients with AD and 28 cognitively normal (CN) subjects underwent behavioural assessments using the Facial Emotion Selection Test (FEST). A subset of 67&#x2009;AD patients and 23 CN patients underwent magnetic resonance imaging. DTI was used to assess the fractional anisotropy (FA) and MD of the bilateral UF, and neurite orientation dispersion and density imaging (NODDI) was used to evaluate the neurite density index (NDI) and orientation dispersion index (ODI) of the insula, amygdala and temporal lobe.<br><br>RESULTS: Patients with AD showed significantly lower FEST total, negative emotion, positive emotion and neutral expression scores. DTI revealed significantly lower FA and higher MD in the bilateral UF. In the AD group, higher bilateral UF MD was significantly associated with lower total FEST and negative emotional scores. NODDI analyses demonstrated significantly lower ODI in the insula, amygdala and temporal lobe in the AD group, whereas no significant between-group differences were observed in the NDI. In the uncorrected analyses, ODI showed trend-level positive associations with FEST performance; however, these associations did not remain significant after false discovery rate correction. Bilateral UF MD was negatively correlated with ODI in the insula and temporal lobes.<br><br>CONCLUSIONS: FER is broadly impaired in AD and is associated with bilateral UF abnormalities and reduced ODI in the frontotemporal-limbic regions. These findings suggest that social cognitive dysfunction in AD involves broader frontotemporal-limbic network disruption than isolated white matter abnormalities.},
}
@article {pmid42584422,
year = {2026},
author = {Chen, M and Zhang, Q and Wu, Z and Lei, Z and Ling, Y},
title = {Integrated UHPLC-Q-Orbitrap HRMS and Network Pharmacology Approach for Exploring Potential Active Ingredients and Pharmacological Mechanisms of Epimedii Folium Against Alzheimer's Disease.},
journal = {Biomedical chromatography : BMC},
volume = {40},
number = {9},
pages = {e70594},
pmid = {42584422},
issn = {1099-0801},
support = {82560886//National Science Foundation of China/ ; 20252BAC240556//Jiangxi Provincial Natural Science Foundation/ ; GJJ2401823//Science and the Educational Department of Jiangxi Province of China/ ; },
mesh = {Chromatography, High Pressure Liquid/methods ; Molecular Docking Simulation ; *Alzheimer Disease/drug therapy ; *Network Pharmacology/methods ; *Drugs, Chinese Herbal/chemistry/pharmacology/analysis ; Humans ; Flavonoids/chemistry/analysis/pharmacology ; *Epimedium/chemistry ; },
abstract = {Epimedii Folium has been widely used to treat Alzheimer's disease (AD) in China. However, the potential active components of Epimedii Folium and its mechanism against AD are still not clear. In this study, an ultra-high performance liquid chromatography coupled to quadrupole Orbitrap high-resolution mass spectrometry (UHPLC-Q-OrbitrapHRMS) method was applied to screen the ingredients of Epimedii Folium. Network pharmacology was utilized to explore the potential active components and pharmacological mechanisms of Epimedii Folium against AD. The binding affinity and conformation of key active ingredients and core targets were performed by molecular docking. Consequently, 72 chemical constituents were identified in Epimedii Folium, including four phenolic acids, two quinones, three 9,10-dihydrophenanthrenes, and 63 flavonoids. Network pharmacology analysis revealed that quercetin, apigenin, kaempferol, and luteolin exhibit favorable pharmacological activities. Molecular docking demonstrated that apigenin-TNF, kaempferol-TNF, kaempferol-TP53, and quercetin-TP53 represent compound-target pairs with strong binding affinities. These findings help elucidate the material basis and underlying mechanisms of Epimedii Folium against AD and offer valuable evidence supporting the further development and clinical application of Epimedii Folium.},
}
@article {pmid42584479,
year = {2026},
author = {Huang, CW and Chang, HI and Chang, TY and Lin, KJ and Hsu, SW and Lee, CC and Huang, SH and Chang, CC},
title = {Selective white matter tract vulnerability associated with tau burden in progressive supranuclear palsy and Alzheimer's disease.},
journal = {European journal of nuclear medicine and molecular imaging},
volume = {},
number = {},
pages = {},
pmid = {42584479},
issn = {1619-7089},
support = {NSTC113-2321-B-182A-005//National Science and Technology Council/ ; NSTC114-2321-B-182A-004 and 115-2321-B-182A-001//National Science and Technology Council/ ; },
abstract = {PURPOSE: Progressive supranuclear palsy (PSP) and Alzheimer's disease (AD) exhibit different tau distributions. We compared tract-specific associations between florzolotau(18F) retention, white matter (WM) microstructure, and clinical impairment.<br><br>METHODS: Forty-nine patients with PSP, 40 with AD, and 30 cognitively unimpaired controls underwent florzolotau(18F) PET. Tractography evaluated projection and association fibers, including the dentatorubrothalamic tract (DRTT) and superior longitudinal fasciculus (SLF). Regional SUVRs were calculated using WM-PERSI normalization. Associations among uptake, diffusion measures, brain volume, and clinical outcomes were evaluated using covariate-adjusted correlations with Bonferroni correction, partial canonical correlation, and exploratory path analyses.<br><br>RESULTS: PSP was characterized by predominantly subcortical and brainstem florzolotau(18F) retention and more extensive WM abnormalities, including DRTT involvement. AD showed predominantly cortical retention and microstructural abnormalities of SLF branches. In PSP, regional subcortical uptake was associated with DRTT microstructure, while DRTT mean diffusivity and frontal volume contributed most strongly to the canonical variate associated with motor impairment (canonical correlation&#x2009;=&#x2009;0.82, p&#x2009;=&#x2009;0.001). In AD, cortical uptake was associated with SLF microstructure, while cortical volume and SLF mean diffusivity contributed to the canonical variate associated with executive function (canonical correlation&#x2009;=&#x2009;0.83, p&#x2009;=&#x2009;0.001). Exploratory path models were consistent with indirect associations involving white matter microstructure and cortical volume.<br><br>CONCLUSION: PSP and AD showed distinct patterns of tract vulnerability associated with regional florzolotau(18F) retention and clinical impairment. These cross-sectional findings support further longitudinal investigation of disease-specific network degeneration.},
}
@article {pmid42584743,
year = {2026},
author = {Wani, OH and Dhaka, P and Pinky, and Choudhary, SS and Wani, AA and Iqbal, A and Parvez, S and Dar, TA},
title = {Majoon-e-Boolis as a neurotherapeutic agent: cognitive and neuronal restoration in alzheimer's disease model.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42584743},
issn = {1573-7365},
support = {3-67/2022-CCRUM/Tech//Central Council for Research in Unani Medicine/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/chemically induced ; Rats ; Oxidative Stress/drug effects ; Male ; Disease Models, Animal ; *Neuroprotective Agents/pharmacology/therapeutic use ; Amyloid beta-Peptides ; *Cognition/drug effects ; *Neurons/drug effects/metabolism ; Antioxidants/pharmacology/therapeutic use ; Peptide Fragments ; Rats, Wistar ; },
abstract = {Majoon-e-Boolis (MB), a traditional Unani formulation, has been used for neurological conditions; however, its molecular mechanism remains largely unexplored. The current study was designed to explore the novel mechanistic insights between antioxidant activity, anti-inflammatory effects, dopaminergic support and anti-aggregation properties of the formulation for modulating the pathogenesis of Alzheimer's Disease (AD). Behavioral deficits were studied via Novel Object Recognition, Elevated Plus Maze and Open Field Test. In addition, the study looked at the immunohistochemistry of superoxide dismutase 2, tumor necrosis factor-alpha, tyrosine hydroxylase and α-synuclein (α-Syn) against Aβ1-42-induced AD model. Additionally, histopathological alterations were also performed against the AD model. The observed findings demonstrated that MB treatment in Aβ1-42-induced AD in rat models significantly improved their cognitive impairments and alleviated anti-anxiety behaviour with enhanced locomotor activity. Moreover, MB induced significant reduction in oxidative stress and neuroinflammation with enhanced dopaminergic neuronal activity. GC-MS analysis of MB revealed the presence of bioactive phytochemicals such as thiophene, guanidinopropionic acid, 5-hydroxymethylfurfural etc. The findings underscore the potential of MB as a promising therapeutic agent in mitigating the multifaceted pathology of Aβ1-42-induced AD in a rat model by exerting its neuroprotective effects, cognition restoration and overall maintenance of neuronal architecture through a combination of antioxidant, anti-inflammatory and anti-aggregation mechanisms, making it a multifaceted therapeutic candidate for AD.},
}
@article {pmid42584831,
year = {2026},
author = {Perez, A and Hammer, HL and Andersson, V and Saarinen, T and Alfonsín, S and Giuffrè, GM and Caraglia, N and Martellacci, N and Ramírez-Toraño, F and Tveitstøl, T and Kinnunen, A and Liljeström, M and Hotta, J and Koivisto, AM and Quaranta, D and Quijano-Rubio, C and Kollmorgen, G and Zetterberg, H and Christensen, E and Renvall, H and Marra, C and Maestú, F and Rossini, PM and Hatlestad-Hall, C and Haraldsen, IH},
title = {Cognitive components derived from traditional neuropsychological tests and their associations with plasma p-tau217 and p-tau181 in mild cognitive impairment: a multisite analysis.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42584831},
issn = {2509-2723},
support = {964220//Horizon 2020/ ; 2024019//Helse S&#xf8;r-&#xd8;st RHF/ ; },
abstract = {BACKGROUND: Currently, no single biomarker can reliably identify preclinical Alzheimer's disease (AD), particularly at or before the mild cognitive impairment (MCI) stage. Given the heterogeneity of MCI, integrative approaches are needed to improve early risk stratification.<br><br>OBJECTIVES: (i) To derive robust latent cognitive components from a multicenter, clinically defined MCI cohort using principal component analysis (PCA); (ii) to investigate the associations between these components and plasma p-tau217 and p-tau181 levels.<br><br>METHODS: Data from 742 MCI participants in the AI-Mind cohort were analyzed. Cognitive domains were derived using PCA with varimax rotation and tested for associations with plasma p-tau biomarkers using site-specific linear regressions, adjusted for age, sex, and education.<br><br>RESULTS: A reproducible four-component cognitive structure emerged (memory, executive/processing speed, verbal fluency, visuospatial ability), with memory as the most p-tau-sensitive domain. The p-tau217 measure showed stronger associations with memory than p-tau181, though effects varied by site.<br><br>CONCLUSION: The findings indicate that a robust four-factor cognitive structure can be identified in clinically defined MCI cohorts without prior biological selection. The association between latent memory factors and plasma p-tau217, observed primarily in cohorts with higher biomarker burden or clearer amnestic profiles, highlights the potential for blood-based biomarkers to refine risk assessment in routine clinical practice.},
}
@article {pmid42584956,
year = {2026},
author = {Zhao, M and Zhou, N and Liu, R and Li, X and Li, J and Xue, F and Hou, Q},
title = {Biochemically Constrained Multi-Omics Integration Reveals Protein-Metabolite Dependencies Across Diseases.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e77067},
doi = {10.1002/advs.77067},
pmid = {42584956},
issn = {2198-3844},
support = {82473733//National Natural Science Foundation of China/ ; ZR2024ZD18//Shandong Provincial Natural Science Foundation/ ; },
abstract = {Integrating proteomic and metabolomic data is essential for understanding complex diseases, yet current approaches that rely primarily on statistical associations often overlook the structured biochemical relationships between molecular entities and suffer from discriminative instability in small clinical cohorts. Here, we present ProMetNet, a biochemically constrained framework that incorporates pathway-derived connectivity from the Reactome database into neural network architecture. By encoding protein-metabolite relationships based on reaction topology, ProMetNet models structured cross-omics dependencies rather than relying solely on statistical correlations, reducing spurious associations while preserving global molecular context and improving robustness in data-limited settings. Across four heterogeneous disease cohorts, including Alzheimer's disease, type 2 diabetes, COVID-19, and glioblastoma, ProMetNet consistently outperforms evaluated multi-omics integration methods, including MOGONET, P-NET, PEARL, and MOINER, maintaining high discriminative performance under substantial data downsampling. In addition to classification accuracy, the framework prioritizes biologically plausible protein-metabolite dependencies that are not captured by conventional differential or correlation-based analyses. Importantly, pathway-level signals identified by ProMetNet demonstrate consistent discriminative performance in independent large-scale population data from the UK Biobank (N = 47,507), supporting their robustness and generalizability. Together, these results establish ProMetNet as a biologically grounded and interpretable framework for multi-omics integration, enabling robust identification of structured molecular dependencies across diseases.},
}
@article {pmid42585241,
year = {2026},
author = {Majumder, R and Datta, P and Moolayadukkam, S and Puri, IK},
title = {Repurposing Alzheimer's and ovarian cancer drugs as sonosensitizers for glioblastoma via a positive-unlabeled learning and 3D bioprinting-based new approach methodology (NAM).},
journal = {PloS one},
volume = {21},
number = {8},
pages = {e0354981},
doi = {10.1371/journal.pone.0354981},
pmid = {42585241},
issn = {1932-6203},
mesh = {Humans ; *Glioblastoma/drug therapy/pathology/therapy ; Female ; *Drug Repositioning/methods ; *Bioprinting/methods ; *Ovarian Neoplasms/drug therapy/pathology ; Cell Line, Tumor ; *Antineoplastic Agents/pharmacology/therapeutic use ; *Brain Neoplasms/drug therapy/pathology ; *Alzheimer Disease/drug therapy ; Tumor Microenvironment/drug effects ; Ultrasonic Therapy/methods ; Spheroids, Cellular/drug effects ; },
abstract = {Glioblastoma (GBM) remains a lethal primary brain tumor, in part because therapeutic efficacy is limited by the blood-brain barrier (BBB) and the complex tumor microenvironment (TME). Sonodynamic therapy (SDT), i.e., use of ultrasound to activate chemical sensitizers and generate cytotoxic stress, offers a non-invasive strategy for treating deep-seated intracranial disease, but progress is constrained by the scarcity of validated sonosensitizers and the inefficiency of conventional in vitro screening methods. Here, we introduce a New Approach Methodology (NAM) that couples a neural network-based positive-unlabeled (PU) learning framework with a high-throughput, magnetic field-guided 3D bioprinting platform to accelerate identification and experimental validation of SDT-sensitizing agents. Using curated drug and small-molecule data and RDKit-derived molecular descriptors, the PU classifier identifies candidate ultrasound-responsive compounds without requiring reliable negative labels. We then validate the AI-based predictions in physiologically relevant U-87 MG glioblastoma spheroids that reproduce key TME features, including spatial heterogeneity and a hypoxic core. The NAM identifies two FDA-approved drugs, carboplatin (advanced ovarian cancer) and memantine hydrochloride (Alzheimer's disease), as effective ultrasound-responsive agents. In 3D spheroids, combining low-intensity pulsed ultrasound with either drug significantly reduces viability compared with drug-only controls, and both combinations outperform temozolomide (TMZ), the current standard chemotherapeutic. Time-resolved responses reveal distinct kinetics: memantine produces strong early cytotoxicity (24 h) enhanced by ultrasound, whereas carboplatin shows delayed but pronounced cytotoxicity (72 h), also improved by ultrasound. Together, these results establish an integrated computational-experimental NAM that enables rapid repurposing of approved drugs as SDT sensitizers and provides a scalable framework for advancing GBM therapeutic discovery while reducing reliance on animal studies.},
}
@article {pmid42585279,
year = {2026},
author = {Barnes, DE and Benjamin, C and Boscardin, WJ},
title = {Development and validation of machine learning models to predict risk of undiagnosed dementia using healthcare claims and electronic health record data.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261474534},
doi = {10.1177/13872877261474534},
pmid = {42585279},
issn = {1875-8908},
abstract = {BackgroundApproximately half of people living with Alzheimer's disease and related dementias are undiagnosed.ObjectiveTo develop and validate algorithms that predict risk of undiagnosed dementia using electronic health record (EHR) and/or healthcare claims data.MethodsStudy participants were adult patients aged 65 years or older without evidence of dementia (diagnosis/medication) at baseline in two U.S. data sources: 1) Medicare claims (2010 to 2021); 2) EHR and claims from a primary care network (2016 to 2023). We applied coefficients from an existing, validated EHR-based algorithm to predictors defined using Medicare claims and used machine learning to develop new EHR- and claims-based predictive models. We assessed model discrimination using c-statistics.ResultsStudy participants included 8,374,400 Medicare beneficiaries (mean [SD] age, 76 [7] years; 57% female) and 29,983 primary care patients (age: 75 [6] years; 56% female). Model discrimination was good when applying EHR-based coefficients to Medicare claims-based predictors (c-statistic [95% confidence interval]: 0.770 [0.767, 0.773]) and was improved by refitting the model (0.795 [0.792, 0.798]) with a small added benefit from incorporating new claims-based predictors (0.801 [0.799; 0.804]). Similarly, when both EHR and claims data were available, discrimination was improved by refitting the model with a small additional benefit from including new predictors, regardless of the data source (EHR, claims, or either).ConclusionsA validated EHR-based algorithm predicted risk of undiagnosed dementia in Medicare claims with good discrimination. Model accuracy was improved by refitting and, to a lesser extent, by including novel predictors.},
}
@article {pmid42585283,
year = {2026},
author = {Barker, CCH and Koza, LA and Almuhanna, L and Trujillo, KR and Linseman, DA},
title = {Lack of effect of repetitive mild traumatic brain injury early in life on the neuropathological and behavioral hallmarks of Alzheimer's disease in 3xTg-AD mice.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261476274},
doi = {10.1177/13872877261476274},
pmid = {42585283},
issn = {1875-8908},
abstract = {Repetitive traumatic brain injuries (rTBIs) are predicted to increase risk for neurodegenerative disorders including Alzheimer's disease (AD). Objective: By using a combination of behavioral tests and histopathology, we investigated whether brain trauma worsens cognitive dysfunction and brain pathology in 3xTg-AD mice subjected early in life to repetitive mild TBI (rmTBI). Methods: At 3 months old, mice in the rmTBI group were given 5 mTBIs, each separated by 48 h. Mice were aged to 10 months old and assessed for cognitive function using the Barnes maze and Novel Object Recognition behavioral tests. Hippocampal sections were stained for amyloid-β and phosphorylated-tau proteins that constitute pathological hallmarks of AD. Immunostaining for GFAP and Iba1 was also employed to assess glial reactivity in the hippocampus. Results: Results from the behavioral tests indicate that there are no significant differences in the severity of cognitive dysfunction between any of the 3xTg-AD mouse groups (naïve, SHAM, or rmTBI). As expected, wild-type mice perform better across all behavioral tests than any of the 3xTg-AD mice. Furthermore, we do not find any significant difference in the amount of amyloid-β aggregation, tau phosphorylation, or gliosis between rmTBI and control (naïve or SHAM) 3xTg-AD mouse groups. Conclusions: Collectively, our data show that rmTBIs early in life do not accelerate progression or enhance the magnitude of disease in mice that are genetically predisposed to developing AD. These findings suggest that the young brain is quite resilient to trauma and that an enhanced risk of neurodegeneration is not an inescapable conclusion of a history of rmTBI.},
}
@article {pmid42574716,
year = {2026},
author = {Watry, RA and Hadidi, NN and Kreitzer, MJ and Bhimani, R and Yu, F and Salisbury, DL},
title = {Exercise Impact on Affective/Cognitive Symptoms and QoL in Subjective Cognitive Decline: An RCT.},
journal = {American journal of Alzheimer's disease and other dementias},
volume = {41},
number = {},
pages = {15333175261476974},
doi = {10.1177/15333175261476974},
pmid = {42574716},
issn = {1938-2731},
mesh = {Humans ; Female ; Aged ; *Quality of Life/psychology ; *Cognitive Dysfunction/therapy/psychology ; *Anxiety/therapy/psychology ; Male ; *Depression/therapy/psychology ; *Exercise Therapy/methods ; Aged, 80 and over ; *Exercise/psychology ; COVID-19 ; },
abstract = {IntroductionThe purpose of this secondary data analysis of an RCT, was to examine the preliminary efficacy of moderate-intensity cycling exercise versus control on cognitive and affective symptoms (i.e., depressive and anxiety), and quality of life (QoL) in older adults with subjective cognitive decline (SCD).MethodsCommunity-dwelling older adults with SCD (N=38) were randomized to 12 weeks/36 sessions. For this secondary data analysis, between-group change was evaluated by analysis of covariance, adjusting for baseline values.ResultsThe participants' mean age was 74.6(7.4) years, and 69% female. There were no significant between-group changes in all outcomes (p-values ranged from .06-.70. Large and moderate between-group effect sizes were seen in favor of the control group for anxiety symptoms (between-group change=-5.36 [4.74], ηp[2]=0.11.DiscussionAttention and social interaction received by this secluded population of older adults and COVID-19 losses likely impacted results. Further mixed-methods research with larger groups that does not span a pandemic, is necessary.Clinical Trial RegistryConcurrent Aerobic Exercise and Cognitive Training to Prevent Alzheimer's in At-risk Older Adults (Exergames): NCT04311736.},
}
@article {pmid42574828,
year = {2026},
author = {Lin, X and Wei, Z and Dong, X and Sun, Y},
title = {A sequential photodynamic-antioxidation therapy against Alzheimer's β-amyloid enabled by a dual‑carbon dots nanomotor.},
journal = {Journal of colloid and interface science},
volume = {724},
number = {Pt 3},
pages = {141317},
doi = {10.1016/j.jcis.2026.141317},
pmid = {42574828},
issn = {1095-7103},
abstract = {Abnormal accumulation of β-amyloid protein (Aβ) in the brain is considered as the primary hallmark of Alzheimer's disease (AD). Beyond inducing neuronal metabolic disorders and apoptosis, Aβ activates oxidative stress pathways, thereby exacerbating reactive oxygen species (ROS) toxicity. Therefore, the design of effective multi-target synergistic therapeutics targeting Aβ and excessive ROS has emerged as a critical strategy for AD prevention and treatment. Herein, we propose a "Sequential Photodynamic-Antioxidation Therapy (SPAT)" against Alzheimer's Aβ, and the SPAT strategy is enabled by the design of a sub-10nm dual‑carbon dots Janus composite (SeRCD) composed of a newly designed and synthesized selenium-doped high-efficiency antioxidant carbon dot (SeCD) and a previously reported near-infrared (NIR) carbon dot (RCD) possessing both thermogenic and photodynamic functionalities. The thermogenic property of RCD in SeRCD endows the Janus composite with photo-propelled autonomous motion powered by "self-thermophoretic force" under NIR irradiation. Thus, SeRCD shows potent inhibition of Aβ fibrillization at low concentrations (0.5 to 5 μg/mL) via photooxygenation and the nanomotor effect under NIR irradiation for only 10 min. Under the subsequent NIR-off condition, SeCD in SeRCD effectively mitigates the oxidative damage to cells by scavenging ROS. Thus, the lifespan of AD nematodes is prolonged by the SPAT strategy from 12 to 19 d at 2 μg/mL. The results collectively demonstrate the effectiveness of the dual-CDs composite design and great potential of the SPAT strategy for application in fighting against AD.},
}
@article {pmid42574987,
year = {2026},
author = {Liu, Z and Li, P and Cecarini, V and Eleuteri, AM and Nan, B and Piao, C},
title = {Ginsenoside Rg2 attenuates Alzheimer-like phenotypes in 3xTg-AD mice: Associations with gut microbiota and brain metabolomic profiles.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {160},
number = {},
pages = {158678},
doi = {10.1016/j.phymed.2026.158678},
pmid = {42574987},
issn = {1618-095X},
abstract = {BACKGROUND AND PURPOSE: Alzheimer's disease (AD) is the most common form of dementia. The microbiota-gut-brain axis represents a critical pathway bridging peripheral metabolic signals and central AD pathology. This study aimed to evaluate the effects of ginsenoside Rg2 on AD-like phenotypes in 3xTg-AD mice and to examine its associations with gut microbiota and brain metabolomic profiles.<br><br>STUDY DESIGN AND METHODS: A 3xTg-AD mouse model was used to assess the effects of Rg2 intervention in vivo. Behavioral performance was assessed using open field and water maze tests, A&#x3b2; and inflammatory factors were detected by ELISA, gut microbial changes were analyzed by 16S rRNA sequencing, and brain metabolic alterations were investigated using untargeted metabolomics.<br><br>RESULTS: The results showed that Rg2 improved behavioral performance in mice, reduced A&#x3b2; deposition in the brain, and decreased serum and brain tissue inflammatory factors. Rg2 treatment was associated with alterations in gut microbial community characteristics. Metabolomics indicated that Rg2 was associated with alterations in the brain metabolic profile, with differential metabolites mainly involved in energy and lipid metabolism as well as inflammation-related pathways. The correlation network further revealed a close relationship between microbiota, SCFAs and brain metabolites, inflammation and behavioral indicators.<br><br>CONCLUSION: Rg2 attenuated AD-related pathology and functional impairment in 3xTg-AD mice. These protective effects were accompanied by changes in gut microbiota composition, brain metabolic profiles, and the inflammatory microenvironment. This study provides multi-omics evidence supporting the potential of Rg2 as a natural product for AD intervention and highlights its associations with gut microbiota and brain metabolism.},
}
@article {pmid42575163,
year = {2026},
author = {Thurber, KR and Lee, M and Tycko, R},
title = {Brain-seeded 42-residue amyloid-β fibrils that resemble fibrils directly extracted from Alzheimer's disease brain tissue.},
journal = {Journal of molecular biology},
volume = {},
number = {},
pages = {169983},
doi = {10.1016/j.jmb.2026.169983},
pmid = {42575163},
issn = {1089-8638},
abstract = {Fibrils formed by the 42-residue amyloid-β peptide (Aβ42) are known to be polymorphic, with molecular conformations and supramolecular structures that depend on conditions of nucleation, growth, seeding, or other factors. Structural studies of Aβ42 fibrils that develop in human brain tissue have been based on two different approaches, either direct extraction and partial purification of fibrils from brain tissue for characterization by cryogenic electron microscopy (cryo-EM) or growth of fibrils in vitro from seeds in amyloid-containing brain tissue extracts for characterization by solid state nuclear magnetic resonance (ssNMR) or cryo-EM. To date, studies of brain-extracted and brain-seeded Aβ42 fibrils have produced qualitatively different sets of structures. Here we report structures of two new brain-seeded Aβ42 fibril polymorphs, derived from cortical tissue of an Alzheimer's disease (AD) patient, that share certain structural features with previously characterized polymorphs extracted from AD brain tissue. These structures contribute to our understanding of the relationships between brain-seeded and brain-extracted fibril structures and expand our understanding of the full range of polymorphism in amyloid-β fibrils.},
}
@article {pmid42575313,
year = {2026},
author = {Fang, J and Wang, X},
title = {Opposing kinase signaling may underlie the inverse relationship between cancer and Alzheimer's disease.},
journal = {Journal of proteomics},
volume = {},
number = {},
pages = {105723},
doi = {10.1016/j.jprot.2026.105723},
pmid = {42575313},
issn = {1876-7737},
abstract = {Cancer and Alzheimer's disease (AD) are leading causes of mortality and exhibit an inverse relationship, where AD patients have reduced cancer risk and vice versa. However, the molecular basis of this relationship remains poorly understood. We reanalyzed published proteomic and phosphoproteomic datasets to investigate this relationship. Differentially abundant proteins were identified in lung adenocarcinoma and glioblastoma samples relative to controls and compared with proteins altered in AD brains, revealing 37 proteins with opposing abundance patterns. Protein-protein interaction and pathway analyses revealed enrichment in kinase signaling and phosphorylation pathways. Phosphoproteomic analysis identified 52 differentially phosphorylated sites with opposing patterns, while kinase-substrate enrichment analysis identified 44 kinases with opposing inferred activity profiles. Integration of kinase activity and phosphosite data identified 29 kinase-phosphosite pairs, including 4 prioritized pairs with opposing patterns relevant to both diseases. Across seven independent cancer cohorts, 17 of 20 statistically significant phosphosite-cohort comparisons (85%) were concordant with the discovery findings, supporting reproducibility of the prioritized phosphosites. Together, these findings highlight opposing kinase signaling as a prominent feature of the inverse relationship and suggest potential biomarkers and therapeutic targets. This study provides a novel systems-level framework for investigating inverse relationships, supported by an R Shiny application for data exploration (https://advscancer.shinyapps.io/advscancer/). SIGNIFICANCE: This study presents an integrated proteomic and phosphoproteomic framework for investigating the inverse relationship between cancer and Alzheimer's disease (AD). By integrating differential protein abundance, phosphosite phosphorylation, inferred kinase activity, and curated kinase-substrate relationships, we identified opposing signaling patterns and prioritized four kinase-phosphosite pairs. Independent evaluation across seven CPTAC cancer cohorts supported the reproducibility of the prioritized phosphosite patterns. These findings provide insight into molecular processes potentially associated with the inverse relationship between cancer and AD, identify candidate biomarkers and therapeutic targets, and demonstrate the value of systems-level, data-driven approaches for investigating shared and opposing disease processes.},
}
@article {pmid42575342,
year = {2026},
author = {Lobyntseva, A and Guz, LS and Galushkin, A and Gozes, I},
title = {Dramatic sex differences leading to different brain disease presentation: The requirement for sex-specific medications with ADNP/davunetide as a case study.},
journal = {Frontiers in neuroendocrinology},
volume = {},
number = {},
pages = {101274},
doi = {10.1016/j.yfrne.2026.101274},
pmid = {42575342},
issn = {1095-6808},
abstract = {Focusing on the brain-essential gene revealed in our laboratory, activity-dependent neuroprotective protein (ADNP) and its neuroprotective site, the investigational drug davunetide (NAP), we discuss ADNP regulating steroid hormone biosynthesis and sex chromosome genes coupled with sex-dependent shuttling between the nuclei and cytoplasm. Further coupled with sex-dependent transcriptional control, ADNP/davunetide cytoplasmic microtubule/Tau targeting is translated into differential sex regulation of key cellular processes including neurogenesis, synaptic function, and axonal transport, then decoded into sexual dichotomy in multicellular processes directing sex-dependent behavioral outcomes. ADNP regulation of these sex-specific processes serves as a target for davunetide intervention, toward sex-directed precision medicine, revealing sexually dichotomized neuroprotection against tauopathy risk and progression spanning from coronary artery bypass grafting (CABG) to prodromal Alzheimer's disease, progressive supranuclear palsy (PSP), and schizophrenia, as well as the pediatric ADNP syndrome. Sex-specific intranasal bioavailability of davunetide, regulated by the estrous cycle, provides a mechanistic foundation for these differential outcomes.},
}
@article {pmid42575373,
year = {2026},
author = {Ding, G and Liu, Y and Zhao, Y and Chen, X and He, Y and Li, Y and Chen, N and Cui, J},
title = {Metabolic Vulnerability Indices and Alzheimer's Disease Risk: A Prospective Analysis of the UK Biobank Cohort.},
journal = {The Journal of nutrition},
volume = {},
number = {},
pages = {101777},
doi = {10.1016/j.tjnut.2026.101777},
pmid = {42575373},
issn = {1541-6100},
abstract = {BACKGROUND: Metabolic dysfunction is implicated in Alzheimer's disease (AD) pathogenesis. Branched-chain amino acids (BCAAs) have been prospectively linked to dementia risk, yet prospective associations of composite metabolic vulnerability indices with incident AD remain untested.<br><br>OBJECTIVE: To examine associations of the Metabolic Vulnerability Index (MVX), Inflammatory Vulnerability Index (IVX), and Metabolic Malnutrition Index (MMX) with incident AD in the UK Biobank.<br><br>METHODS: Among 367,715 dementia-free UK Biobank participants (mean age 56.93 years, 54.3% female; 2006-2010 baseline), incident AD was ascertained through hospital and death registry linkage. Fully adjusted Cox models (Model 3) constituted the pre-specified primary analysis; three Bonferroni-corrected tests (&#x3b1; = 0.0167) addressed multiple comparisons. Restricted cubic splines characterized association shape; interaction analyses examined potential effect modification by sex, age group, diabetes status, BMI, inflammatory status, and polygenic risk.<br><br>RESULTS: Over 13.7 years, 2,615 participants developed AD. Per 1-SD increase, MMX (HR = 1.16, 95% CI: 1.12-1.21, p = 4.93&#xd7;10[-13]) and MVX (HR = 1.12, 95% CI: 1.07-1.17, p = 3.72&#xd7;10[-6]) were each associated with higher AD risk, both meeting the Bonferroni-corrected threshold; IVX showed no association (p = 0.108). Associations were approximately linear and monotonically increasing. Sex-specific associations were observed for MMX (stronger in males, p-interaction = 0.004) and MVX (stronger in females, p-interaction = 0.003). Sensitivity analyses confirmed robustness.<br><br>CONCLUSION: MMX and MVX are independently associated with incident AD, supporting the clinical relevance of metabolic health monitoring in neurodegeneration risk stratification.},
}
@article {pmid42575375,
year = {2026},
author = {Ali, S and Ayaz, A and Zaman, W},
title = {Establishing causality for protein lactylation in Alzheimer's disease: site validation, evidence standards, and experimental priorities.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {118343},
doi = {10.1016/j.bcp.2026.118343},
pmid = {42575375},
issn = {1873-2968},
abstract = {Protein lysine lactylation has emerged as a candidate interface between metabolic stress and Alzheimer's disease (AD), but the strength of individual claims varies. This focused review evaluates whether reported histone and non-histone lactylation events meet analytical and experimental requirements for causal interpretation. Direct AD evidence is more robust for plaque-associated microglial histone H4 lysine 12 lactylation (H4K12la)-pyruvate kinase M2 (PKM2) feedback in an amyloid model. Histone H3 lysine 18 lactylation (H3K18la)-nuclear factor-κB (NF-κB) signaling is supported principally in senescent microglia and ageing or AD-related models. Human tau K331 lactylation demonstrates disease-associated occurrence but not quantitative occupancy, temporal precedence or residue-specific necessity. Amyloid precursor protein (APP) K612 lactylation provides a potentially protective mechanism supported by site-resolved identification, cellular perturbation and in vivo rescue. Histone H3 lysine 9 lactylation (H3K9la) and additional substrates remain hypothesis-generating. We distinguish putative enzymatic L-lactylation from methylglyoxal-derived D-lactoylation and define minimum standards for antibody specificity, stereochemistry, site localization, occupancy, protein abundance, cell composition, post-mortem quality, isotope tracing, genetic substitution and rescue. A four-tier framework separates extrapolated evidence, human occurrence or relevant in vivo association, site-specific AD-model mechanisms supported by intervention and rescue, and quantified, cell-resolved, residue-causal evidence independently replicated in human-relevant systems. Six experimental stages are proposed for advancing a candidate site from detection to human relevance. Current evidence supports protein lactylation as a context-dependent disease-modifying layer rather than a single upstream driver. Therapeutic development should prioritize validated sites and biomarker-defined cell states rather than indiscriminate suppression of lactate metabolism or global lactylation.},
}
@article {pmid42575412,
year = {2026},
author = {Liu, Y and Peng, L and Li, M and Yan, W and Xiang, Q},
title = {Let-7d-5p improves mouse cognitive function by targeting bach1 in Alzheimer's disease.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115957},
doi = {10.1016/j.expneurol.2026.115957},
pmid = {42575412},
issn = {1090-2430},
abstract = {BACKGROUND: MicroRNAs (miRNAs) have emerged as critical modulators in Alzheimer's disease (AD) pathogenesis. The lethal-7 (let-7) family functions as key regulators of cell apoptosis, differentiation, and immune response. Herein, we explore the functions and underlying mechanisms of let-7d-5p in AD progression.<br><br>METHODS: Eight-month-old male APP/PS1 transgenic mice and wild-type C57BL/6&#x202f;J mice were assigned to the model and control groups, respectively. Model mice received intrahippocampal injections of either a negative control adenovirus (Ad-NC) or a let-7d-5p overexpression adenovirus (Ad-let-7d-5p). The Morris water maze test was conducted to assess cognitive function. Hippocampal histopathological changes were evaluated using hematoxylin and eosin staining. A&#x3b2; deposition was detected via immunohistochemical staining. SH-SY5Y cells were transfected with let-7d-5p mimics prior to treatment with 10&#x202f;&#x3bc;M A&#x3b2;1-42. Cell viability and apoptosis were examined using MTT assays and flow cytometry. The expression levels of let-7d-5p and bach1 were measured using RT-qPCR. Western blotting was conducted to evaluate bach1, Bcl-2, and cleaved caspase-3 protein levels. The binding relationship between let-7d-5p and bach1 was verified using luciferase reporter assays.<br><br>RESULTS: In vitro, A&#x3b2;1-42 treatment induced the downregulation of let-7d-5p and decrease of cell viability. However, overexpression of let-7d-5p significantly increased let-7d-5p level, enhanced cell viability and inhibited cell apoptosis of A&#x3b2;1-42-treated SH-SY5Y cells. Moreover, overexpression of let-7d-5p upregulated Bcl-2 protein levels and downregulated cleaved caspase-3 protein levels in A&#x3b2;1-42-treated SH-SY5Y cells. Furthermore, let-7d-5p overexpression ameliorated oxidative stress injury in A&#x3b2;1-42-treated SH-SY5Y cells. Importantly, bach1 upregulation counteracted the inhibitory effects of let-7d-5p overexpression on A&#x3b2;1-42-induced cellular injury. In vivo, let-7d-5p overexpression mitigated cognitive deficits of AD mice, as indicated by reduced escape latency and increased platform crossings. Additionally, let-7d-5p overexpression attenuated hippocampal histopathological changes and A&#x3b2; deposition in APP/PS1 mice. At the molecular level, let-7d-5p targeted bach1 3'UTR and repressed its mRNA and protein expression in vitro and in vivo. Rescue assays further validated that bach1 overexpression restored the protective effect of let-7d-5p on cognitive deficits and pathological injuries.<br><br>CONCLUSION: Let-7d-5p alleviates cognitive deficits in AD by inhibiting A&#x3b2; deposition and neuronal apoptosis through targeting bach1.},
}
@article {pmid42575452,
year = {2026},
author = {Dai, X and Ye, Z and Zhang, X and Huang, Y and Wang, C and Liu, Y and Gao, B and Zhang, J and Chen, X},
title = {SIK2-P300 axis Orchestrates the metabolic reprogramming and Immunological functions in microglia of Alzheimer's disease mice via a dual modulation of lactylation and Acetylation: An epigenetic Perspective.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {106953},
doi = {10.1016/j.bbi.2026.106953},
pmid = {42575452},
issn = {1090-2139},
abstract = {Metabolic dysfunction in microglia is increasingly recognized as a core driver of Alzheimer's disease (AD) pathogenesis, and yet the underlying mechanisms remain elusive. Here, we identified salt-inducible kinase 2 (SIK2) as a critical metabolic checkpoint that was downregulated in microglia across the AD mouse models (5 × FAD, APP/PS1, and SAMP8). We found that a loss of SIK2 in microglia induced a pro‑inflammatory phenotype, thus impairing amyloid β-protein (Aβ) phagocytosis and rewiring glucose and lipid metabolism toward enhanced glycolysis and lipid accumulation. Mechanistically, SIK2 directly interacted with the histone acetyltransferase P300; SIK2 deficiency increased the activity of P300, elevating H3K9 acetylation and H4K8/12 lactylation at promoters of metabolic genes. The microglia‑specific SIK2 overexpression in the 5 × FAD mice mitigated cognitive deficits, Aβ pathology, neuroinflammation, and aberrant histone modifications. A pharmacological inhibition of P300 regained these protective effects. Our findings highlight the SIK2-P300 epigenetic axis as a key regulator of the metabolic homeostasis in microglia and a potential therapeutic target for AD treatments.},
}
@article {pmid42575718,
year = {2026},
author = {Dzib, E and Hernández-Ayala, LF and Silva-Aguirre, S and Galano, A},
title = {Rational Design of Multifunctional Tacrine Derivatives as Candidates for the Treatment of Alzheimer and Parkinson Diseases.},
journal = {ChemMedChem},
volume = {21},
number = {15},
pages = {e70429},
doi = {10.1002/cmdc.70429},
pmid = {42575718},
issn = {1860-7187},
support = {CBF2023-2024-1141//SECIHTI/ ; },
mesh = {*Tacrine/chemistry/pharmacology/chemical synthesis/therapeutic use/analogs &amp; derivatives ; *Alzheimer Disease/drug therapy/metabolism ; *Drug Design ; Humans ; Monoamine Oxidase/metabolism/chemistry ; Acetylcholinesterase/metabolism/chemistry ; *Parkinson Disease/drug therapy/metabolism ; *Cholinesterase Inhibitors/chemistry/pharmacology/chemical synthesis/therapeutic use ; Receptors, N-Methyl-D-Aspartate/antagonists &amp; inhibitors/metabolism ; Structure-Activity Relationship ; *Monoamine Oxidase Inhibitors/chemistry/pharmacology/chemical synthesis ; Catechol O-Methyltransferase/metabolism ; Molecular Structure ; Molecular Docking Simulation ; Catechol O-Methyltransferase Inhibitors/chemistry/pharmacology/chemical synthesis ; },
abstract = {Alzheimer disease (AD) and Parkinson disease (PD) are multifactorial neurodegenerative disorders for which there is currently no therapy that prevents or slows their progress. Some drugs used to treat AD are inhibitors of acetylcholinesterase (AChE) and antagonists of N-methyl-D-aspartate receptor (NMDAr), while inhibitors of catechol-O-methyltransferase (COMT) and monoamine oxidase B (MAO-B) are used for PD. Tacrine was the first FDA (Food and Drug Administration) approved drug against AD. Although later withdrawn due to hepatotoxicity, it remains a pivotal scaffold for drug development. Herein, 1295 tacrine derivatives, meant to enhance therapeutic efficacy and safety of the parent compound, were designed through the CADMA-Chem protocol. The chemical space was screened using selection scores based on ADME properties, toxicity, and synthetic accessibility. Two derivatives with the best drug-like behavior were chosen for further investigation. Acid-base constants and reactivity descriptors were estimated for them. Our findings show that these derivatives are promising inhibitors of AChE, COMT, NMDAr, and MAO-B. Therefore, according to in silico predictions they are expected to be beneficial for AD and PD. One of the compounds investigated here is the first reported tacrine-derived compound with potential as COMT inhibitor.},
}
@article {pmid42575772,
year = {2026},
author = {Russo, AG and Hawkshaw, MJ and Sataloff, RT},
title = {Voice Disorders as Early Biomarkers of Cognitive Decline.},
journal = {Journal of voice : official journal of the Voice Foundation},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jvoice.2026.07.037},
pmid = {42575772},
issn = {1873-4588},
abstract = {BACKGROUND: Dementia affects greater than 57 million people worldwide. With an aging population and limited disease-curing treatments available, early identification of biomarkers is crucial. The 2020 Lancet Commission identified hearing loss as the largest modifiable risk factor for dementia globally, and a randomized controlled trial found that hearing intervention reduced 3-year cognitive change in older adults who were at increased risk for cognitive decline. Similarly, studies have found that abnormalities in acoustic measures of voice are correlated with cognitive status and can potentially predict decline. The association between hearing loss and cognitive decline might have both social and neurological mechanisms. Dysphonia might pose similar problems. Socially, voice disorders may reduce engagement in social and cognitively stimulating activities. Neurologically, one example is in Parkinson's disease in which the vagus nerve is one of the earliest sites of Lewy body pathology in Braak staging, and dysphonia and dysarthria can precede motor symptoms by years. Voice changes have been associated with different neurological conditions such as amyotrophic lateral sclerosis, multiple system atrophy, and Alzheimer's disease. Despite this, no prior large-scale study has examined whether diagnosed voice disorders are associated independently with incident cognitive decline. Our study is the first to examine this potential association, using the TriNetX US Collaborative Health Network platform to compare patients with diagnosed voice disorders and matched controls, with a hearing loss cohort as a standard of comparison given that it is the largest established modifiable risk factor for dementia, as dysphonia is also a modifiable condition.<br><br>RESULTS: This study included 833,417 total patients in the voice disorders and control cohorts. Voice disorders were associated with a significantly elevated risk of incident cognitive decline compared to controls (HR=1.291, 95% CI 1.155-1.443, P<0.0001). Hearing loss alone was associated with a slightly lower risk of cognitive decline (HR=1.267, 95% CI 1.203-1.334, P<0.0001). Voice disorders without concurrent hearing loss were associated with an elevated risk of incident cognitive decline compared to hearing loss alone (HR=1.261, 95% CI 1.121-1.419, P=0.0001), while voice disorders with hearing loss were associated with the highest risk among all cohorts (HR=2.038 vs controls; HR=1.545 vs hearing loss). Both voice disorder subgroups did not differ when compared with each other (HR=1.088, P=0.376).<br><br>CONCLUSION: The results from our study indicate that voice disorders are associated with an elevated risk of incident cognitive decline and may represent a stronger early biomarker than hearing loss alone. These findings highlight otolaryngology and family medicine/internal medicine encounters as potential entry points for cognitive assessment, and early voice treatment needs to be investigated for possible beneficial cognitive effect.},
}
@article {pmid42575819,
year = {2026},
author = {Despa, F and Lashley, T},
title = {Amyloidogenic amylin signaling links diabetes to dementia pathogenesis.},
journal = {Trends in pharmacological sciences},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tips.2026.07.009},
pmid = {42575819},
issn = {1873-3735},
abstract = {Recent studies identify amyloidogenic human amylin, secreted by the pancreas, as a potential link between type-2 diabetes and Alzheimer's disease. Evidence suggests that pathogenic amylin signaling impairs cerebral bioenergetics, promoting tau hyperphosphorylation and neurodegeneration. Selective targeting of circulating amyloidogenic amylin and its pathogenic signaling may enable biomarker development and disease-modifying therapies.},
}
@article {pmid42575873,
year = {2026},
author = {Frank, LE and Flack, N and Faulk, C and Block, AJ and Bartz, JC and Larsen, PA},
title = {Epigenetic changes associated with the progression of prion disease in Syrian hamsters (Mesocricetus auratus).},
journal = {Prion},
volume = {20},
number = {1},
pages = {52-65},
doi = {10.1080/19336896.2026.2710965},
pmid = {42575873},
issn = {1933-690X},
mesh = {Animals ; *Epigenesis, Genetic ; DNA Methylation/genetics ; *Prion Diseases/genetics/pathology ; Mesocricetus ; Cricetinae ; Disease Progression ; Brain/metabolism/pathology ; },
abstract = {Prion diseases are fatal neurodegenerative disorders characterized by abnormally folded prion proteins inducing misfolding of normal prion proteins, leading to neurotoxic fibrils and plaques. Epigenetic mechanisms, particularly DNA methylation, are increasingly implicated in prion-like diseases (e.g. Alzheimer's disease), but their role in prion pathogenesis remains unclear. To investigate, we used nanopore sequencing and RNAseq to measure genome-wide methylation and gene expression in the brains of Syrian hamsters (Mesocricetus auratus) experimentally infected with a hamster-adapted murine synthetic prion strain (n = 9) and age-matched mock-infected controls (n = 9) at 80, 120, and 160 days post-infection (dpi). We identified 1,586, 1,692, and 2,429 differentially methylated regions (DMRs) at 80, 120, and 160 dpi, respectively. Early- and mid-stage prion disease (80 and 120 dpi) skewed towards hypermethylation, whereas late-stage prion disease (160 dpi) skewed towards hypomethylation. Gene ontology (GO) of DMR-associated genes at 160 dpi included neuron regulation and signalling, neurodevelopment, and cellular stress pathways. We identified 178 differentially expressed genes (DEGs) at 80 dpi, 90 at 120 dpi, and 616 at 160 dpi. The majority of DEGs were downregulated at 80 dpi, and at 120 and 160 dpi, most were upregulated. Overlap in DEGs across timepoints was limited, and GO terms were related to upregulation of disease/injury response and cell death pathways in later timepoints. Overall, we found a stage-specific transcriptional shift from immune suppression to widespread immune and inflammation activation. These findings provide time-resolved data on methylation and transcriptional changes associated with impaired neuronal structure, function, and communication during disease.},
}
@article {pmid42575875,
year = {2026},
author = {Satake, Y and Kanemoto, H and Taomoto, D and Takeda, K and Katakami, S and Kobayashi, M and Matsunaga, K and Isohashi, K and Suehiro, T and Yoshiyama, K and Ikeda, M},
title = {Progression to Dementia in Very Late-Onset Schizophrenia-Like Psychosis Stratified by Alzheimer's Disease and Lewy Body Disease Biomarkers: A Retrospective Cohort Study.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {26},
number = {5},
pages = {e70205},
doi = {10.1111/psyg.70205},
pmid = {42575875},
issn = {1479-8301},
support = {TK21K15730//Japan Society for the Promotion of Science/ ; Overseas Study grant//SENSHIN Medical Research Foundation/ ; },
mesh = {Humans ; Disease Progression ; *Lewy Body Disease/diagnosis/psychology ; Retrospective Studies ; Female ; Biomarkers/blood ; Male ; *Alzheimer Disease/diagnosis/psychology ; *Schizophrenia/diagnosis ; Aged ; *Psychotic Disorders/diagnosis ; Age of Onset ; Aged, 80 and over ; *Dementia/diagnosis ; Japan ; },
abstract = {BACKGROUND: Very late-onset schizophrenia-like psychosis (VLOSLP) is clinically heterogeneous, and its relationship with dementia-related neurodegenerative disease remains unresolved. We examined whether Alzheimer's disease (AD) and Lewy body disease (LBD) biomarker status were associated with dementia progression in VLOSLP.<br><br>METHODS: We retrospectively identified patients who visited the University of Osaka Hospital between January 2018 and December 2023 and met criteria for VLOSLP. Twenty-two participants with AD and/or LBD biomarker data and at least one follow-up assessment within 775&#x2009;days were classified as biomarker-negative (BMs-neg; n&#x2009;=&#x2009;7) or biomarker-positive (BMs-pos; n&#x2009;=&#x2009;15). Group comparisons were performed using Mann-Whitney U tests and Fisher's exact tests.<br><br>RESULTS: The BMs-pos group showed older onset age and lower memory scores than the BMs-neg group. Dementia progression was more frequent in the BMs-pos group than in the BMs-neg group, although the difference was not statistically significant (8/15 [53.3%] vs. 1/7 [14.3%]; p&#x2009;=&#x2009;0.165; odds ratio 6.31; 95% CI 0.55-353.18). Five of eight participants with AD biomarker positivity progressed to AD dementia. Three of seven participants with LBD biomarker positivity progressed to dementia, including two diagnosed with dementia with Lewy bodies. Follow-up MMSE, CDR, and CDR-SB scores differed significantly between groups.<br><br>CONCLUSIONS: AD and/or LBD biomarker-positive VLOSLP may be associated with greater dementia progression and cognitive decline, although findings should be interpreted cautiously given the small sample size and retrospective design. These results support the clinical value of considering neurodegenerative biomarkers when evaluating the prognosis and underlying pathology of VLOSLP.},
}
@article {pmid42575917,
year = {2026},
author = {Jacob, T and Schützmann, MP and Gerhards, L and Hruby, L and Leprivier, G and Tamgüney, G and Hoyer, W},
title = {Liquid-liquid phase-separated tau colocalizes with and stabilizes Aβ oligomers.},
journal = {Communications chemistry},
volume = {9},
number = {1},
pages = {},
pmid = {42575917},
issn = {2399-3669},
support = {726368//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; },
abstract = {Protein aggregation is a hallmark of neurodegenerative diseases, where misfolded proteins accumulate into insoluble deposits. Emerging studies indicate that liquid-liquid phase separation (LLPS) may serve as a transient stage in the transition from monomers to amyloid fibrils for several proteins implicated in neurological disorders. In this study, we investigated the interplay between tau and off-pathway oligomers of amyloid-beta (Aβ), the two key proteins in Alzheimer's disease (AD). Our findings demonstrate that tau condensates act as reservoirs for Aβ oligomers under LLPS conditions. Inside the tau condensates, Aβ oligomers reduced tau dynamics and formed discrete puncta, indicating a conducive environment for Aβ oligomer clustering. In contrast, in the absence of LLPS conditions, tau and Aβ oligomers formed solid-like co-aggregates with distinct morphologies. Tau significantly affected the kinetics of Aβ assembly, stabilizing off-pathway oligomers and inhibiting their replacement by amyloid fibrils. Our results highlight interactions between higher-order assemblies of tau and Aβ that may contribute to AD pathology.},
}
@article {pmid42575945,
year = {2026},
author = {Keil, J and Hernandez-Urbina, V and Doherty, L and Bahmani, H and Holtkamp, M and Steinbart, D and Diall, AD and Hebel, JM and Brandt, C and Cloppenborg, T and Doll, A and Müschenich, M},
title = {High-frequency visual stimulation can increase medial temporal lobe ripple oscillation density.},
journal = {Communications medicine},
volume = {6},
number = {1},
pages = {},
pmid = {42575945},
issn = {2730-664X},
abstract = {BACKGROUND: Flickering visual stimulation can evoke neural oscillations, which can influence ongoing brain activity. Electrophysiological recordings of neural oscillations in the ripple band (80-180 Hz) show that these high-frequency oscillations occur in the neocortex and the hippocampus, that they phase-synchronize across long distances, and that ripple oscillations in the neocortex often precede those in the hippocampus during wakefulness. It is therefore possible that the neocortical ripple oscillations propagate beyond sensory areas to the hippocampus, inducing ripple oscillations.<br><br>METHODS: To test the hypothesis that neocortical ripple oscillations induced by visual stimulation induce hippocampal ripple oscillations, we conduct an exploratory experiment (N&#x2009;=&#x2009;8) in humans, using ultra-high frequency visual stimulation to induce ripple oscillations recorded through electrodes implanted in or near the hippocampus. Although hippocampal ripple oscillations, so-called sharp-wave-ripples, mostly occur during quiet rest or slow-wave sleep, we aim to increase their abundance using visual stimulation during wakefulness in this exploratory study. We hypothesize that ultra-high frequency visual stimulation increases the number of sharp-wave-ripples relative to an eyes-open resting-state baseline.<br><br>RESULTS: In this exploratory and preliminary study, we observe significantly more sharp-wave-ripples per second during periods of stimulation compared to a resting-state baseline before and after the stimulation.<br><br>CONCLUSIONS: The increased number of sharp-wave ripples during stimulation suggests that ultra-high-frequency visual stimulation can be used as a safe noninvasive tool to influence sharp-wave ripples, which offers the potential to improve memory.},
}
@article {pmid42576087,
year = {2026},
author = {Oyedokun, PA and Gbadero, JO and Ajao, DI and Olorunsesan, MD and Oyesiji, AI and Ayilara, GO and Ogunsina, MK and Justus, BS and Ademola, FM and Adetunji, EA and Okodio, PS and Amedu, NO},
title = {The Amino Acid-Neurodegeneration Axis: Excitotoxicity and Oxidative Stress as Context-Dependent Amplifiers of Metabolic Dysfunction.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42576087},
issn = {1559-1182},
mesh = {*Oxidative Stress/physiology ; Humans ; Animals ; *Amino Acids/metabolism ; *Neurodegenerative Diseases/metabolism/pathology ; *Nerve Degeneration/metabolism/pathology ; Mitochondria/metabolism ; },
abstract = {Homeostasis of amino acids is essential for the integrity of the CNS, and is maintained by a tightly regulated transport and metabolic circuit that ensures efficient neurotransmission, mitochondrial bioenergetics and redox homeostasis. Disruption of this equilibrium is associated with the pathogenesis of the major neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease and Amyotrophic lateral sclerosis. Excessive glutamatergic stimulation and impaired glycine or homocysteine metabolism result in pathological Ca[2][+] influx, loss of mitochondrial membrane potential and production of reactive oxygen species, which are hallmarks of these disorders. It also limits cysteine availability and causes glutathione depletion, which affects antioxidant defence, and disrupts tryptophan-kynurenine metabolism, further affecting neurotoxic and neuroprotective signalling. Though there are disease-specific molecular triggers, the convergent pathogenesis of metabolic disruption makes neurons susceptible to disease. The convergent pathways link amino acid dysregulation to the reinforcement of each other's mechanisms of excitotoxicity, oxidative stress, mitochondrial dysfunction, and protein aggregation. Correcting the amino acid balance has clear translational potential for developing new therapies, such as glutathione augmentation, modulation of NMDA receptors, targeting of transporters, and regulation of metabolic enzymes. In addition, the use of metabolic biomarkers alongside neuroprotective endpoints in clinical trials could improve detection rates, patient stratification, and therapeutic precision. The concept of amino acid metabolism as a mechanism of neurodegeneration, therefore, provides a systems-level perspective and targets potential areas for continued neuroprotection and disease modification.},
}
@article {pmid42576162,
year = {2026},
author = {Park, JH and Kim, B and Al-Amin, MM and Tate, MD and Sharify, AD and John, SK and Karahan, H and Lu, HC and Dabin, LC and Kim, J},
title = {Unique transcriptomic alterations in 5XFAD;PS19 mouse model identify glial lipid dysregulation and coordinated microglial-oligodendrocyte responses.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71742},
doi = {10.1002/alz.71742},
pmid = {42576162},
issn = {1552-5279},
support = {R01NS086794/NH/NIH HHS/United States ; R01AG077829/NH/NIH HHS/United States ; RF1AG074543/NH/NIH HHS/United States ; U01AG076804/NH/NIH HHS/United States ; },
mesh = {Animals ; Mice ; *Microglia/metabolism/pathology ; *Transcriptome ; Disease Models, Animal ; *Alzheimer Disease/genetics/metabolism/pathology ; *Oligodendroglia/metabolism/pathology ; *Lipid Metabolism/genetics ; Mice, Transgenic ; Humans ; Brain/metabolism/pathology ; Female ; *Neuroglia/metabolism ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) features amyloid beta (Aβ) plaques and tau tangles, yet how their coexistence reshapes brain transcriptomic programs remains unclear.<br><br>METHODS: We performed high-quality, sex-balanced single-nucleus RNA sequencing of 5XFAD (A&#x3b2;), PS19 (tau), and combined 5XFAD;PS19 mice.<br><br>RESULTS: We identified transcriptional programs that emerged most prominently under combined pathology. These programs included disruption of glial lipid metabolism and immune pathways at the network level, alongside immune and synaptic alterations coordinated between microglia and oligodendrocytes. Cross-species analyses further revealed that the pathway-level alterations under combined pathology, particularly in immune, lipid, and cell cycle programs, exhibited the strongest concordance with human AD datasets, underscoring their translational relevance.<br><br>DISCUSSION: Beyond benchmarking mouse models, this study provides a high-quality transcriptomic resource to dissect multicellular disease mechanisms in AD and to prioritize therapeutic targets for a network-level systems pharmacology approach.},
}
@article {pmid42576167,
year = {2026},
author = {Uruk, G and Gatto, RG and Hossain, N and Whitwell, JL and Reichard, RR and Josephs, KA},
title = {Structural Heterogeneity of TDP-43 Fragments in Alzheimer's Disease and Primary Age-Related Tauopathy by Artificial Intelligence (AI)-Based 3D Segmentation.},
journal = {Neuropathology and applied neurobiology},
volume = {52},
number = {4},
pages = {e70096},
doi = {10.1111/nan.70096},
pmid = {42576167},
issn = {1365-2990},
support = {R01-AG37491/NH/NIH HHS/United States ; },
mesh = {Humans ; *DNA-Binding Proteins/metabolism ; *Alzheimer Disease/pathology/metabolism ; *Tauopathies/pathology/metabolism ; Female ; Male ; Aged ; *Artificial Intelligence ; Aged, 80 and over ; *Brain/pathology/metabolism ; Imaging, Three-Dimensional/methods ; },
abstract = {TAR DNA-binding protein 43 (TDP-43) inclusions are defining pathological features of frontotemporal lobar degeneration (FTLD) but are also often observed in Alzheimer's disease (AD) and primary age-related tauopathy (PART). TDP-43 in AD is either associated with cognitive impairment or a protective-life prolonging impact, and yet the localization, cellular and fragment characteristics of TDP-43 need to be determined. We investigated the relationships between TDP-43 volumetric inclusion burden in low likelihood AD (lAD) and definite PART by immunostaining against phosphorylated TDP-43 (pTDP-43), TDP-43 C terminal (TDP-C) and TDP-43 N-terminal (TDP-N) fragments combined with 3D confocal imaging taken from eight regions: amygdala (basolateral [amygdala-BL] and centromedial amygdala [amygdala-CM]), the hippocampus (Cornu Ammonis [CA]-1, CA2/3, CA4, dentate gyrus [DG] and subiculum [SUB]) and entorhinal cortex (ERC) and artificial intelligence (AI)-based segmentation via object recognition, reconstruction and quantification. We found amygdala-CM in lAD and PART to have the overall greatest burden of pTDP-43 whereas TDP-N burden in amygdala-BL of PART cases was greater than other TDP-43 fragments. There was no difference in TDP-43 burden in hippocampal subfields in PART. However, CA2/3 region showed greater pTDP-43 burden while TDP-N stood out in DG and SUB. Multiple comparisons among the groups revealed that TDP-C was the only fragment showing differences among PART and lAD in CA2/3, DG and SUB regions. Overall, unbiased AI-based volumetric burden analysis pipeline demonstrated unique fragment aggregation patterns in the neurodegenerative processes of PART and AD.},
}
@article {pmid42576170,
year = {2026},
author = {Wan, L and Kang, C and Harrison, R and Solis-Urra, P and Sewell, KR and Oberlin, LE and Jain, S and Huang, H and Grove, G and Kamboh, MI and Sutton, BP and Snitz, BE and Kramer, AF and McAuley, E and Burns, JM and Hillman, CH and Vidoni, ED and Marsland, AL and Karikari, TK and Morris, J and Erickson, KI},
title = {Neurobiological markers across joint profiles of subjective cognitive decline and objective cognitive function in older adults.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71743},
doi = {10.1002/alz.71743},
pmid = {42576170},
issn = {1552-5279},
support = {R01 AG053952/NH/NIH HHS/United States ; R35 AG072307/NH/NIH HHS/United States ; },
mesh = {Humans ; Aged ; Male ; Female ; Biomarkers/blood ; Neurofilament Proteins/blood ; Magnetic Resonance Imaging ; *Cognitive Dysfunction/blood/diagnostic imaging/psychology ; Glial Fibrillary Acidic Protein/blood ; *Cognition/physiology ; tau Proteins/blood ; Brain/pathology/diagnostic imaging ; Neuropsychological Tests ; Aging ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Subjective cognitive concerns frequently diverge from objective cognitive performance in cognitively unimpaired (CU) older adults, yet the neurobiological basis of this mismatch remains unclear.<br><br>METHODS: In 648 participants from the Investigating Gains in Neurocognition in an Intervention Trial of Exercise (IGNITE), we defined four profiles by integrating subjective and objective cognitive status. We examined associations with plasma neurofilament light chain (NfL), phosphorylated tau 217 (p-tau217), glial fibrillary acidic protein (GFAP), a magnetic resonance imaging-based volumetric Alzheimer's disease (AD) signature reflecting atrophy, and brain-predicted age difference (brain-PAD).<br><br>RESULTS: Joint profiles were differentially associated with NfL (P&#xa0;=&#xa0;0.0427) and brain-PAD (P&#xa0;=&#xa0;0.0296). Follow-up contrasts further indicated higher NfL and lower volumetric AD signature in the concordant lower functioning profile, and higher brain-PAD in discordant profiles. p-tau217 and GFAP did not differ across profiles.<br><br>DISCUSSION: Joint subjective-objective cognitive profiles may capture biologically meaningful heterogeneity relevant to neurodegeneration and brain aging in older adults.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov: NCT02875301.},
}
@article {pmid42576193,
year = {2026},
author = {Saifullah, K and Ridwan, AR and Evia, AM and Leurgans, SE and Wagner, M and Bennett, DA and Schneider, JA and Arfanakis, K},
title = {Brain morphometry patterns in the presence of Alzheimer's disease and/or LATE neuropathologic changes.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71719},
doi = {10.1002/alz.71719},
pmid = {42576193},
issn = {1552-5279},
support = {R01AG064233/AG/NIA NIH HHS/United States ; R01AG067482/AG/NIA NIH HHS/United States ; R01AG017917/AG/NIA NIH HHS/United States ; R01AG015819/AG/NIA NIH HHS/United States ; RF1AG022018/AG/NIA NIH HHS/United States ; R01AG056405/AG/NIA NIH HHS/United States ; R01AG052200/AG/NIA NIH HHS/United States ; P30AG010161/AG/NIA NIH HHS/United States ; P30AG072975/AG/NIA NIH HHS/United States ; UH2-UH3NS100599//Institute of Neurological Disorders and Stroke (NINDS)/ ; U01NS100599//Institute of Neurological Disorders and Stroke (NINDS)/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/diagnostic imaging ; Magnetic Resonance Imaging ; *Brain/pathology/diagnostic imaging ; Aged ; Female ; Male ; Aged, 80 and over ; Image Processing, Computer-Assisted ; },
abstract = {INTRODUCTION: Alzheimer's disease neuropathologic change (ADNC) and limbic-predominant age-related transactive response DNA-binding protein 43 kDa (TDP-43) encephalopathy neuropathologic change (LATENC) are common in older adults, yet differences in brain morphometry patterns when one or both pathologies are present remain unclear.<br><br>METHODS: We used deformation-based morphometry on ex-vivo MRI from 912 community-based older adults to compare groups with or without ADNC and/or LATENC.<br><br>RESULTS: AD+LATE- and AD-LATE+ groups showed less tissue in the medial temporal lobe than AD-LATE-. The AD+LATE+ group had less tissue in temporal, frontal, and parietal lobes. The AD-LATE+ group exhibited smaller anterior hippocampi than the AD+LATE- group. These findings were less pronounced in individuals without dementia. Increments in LATENC stages were associated with smaller hippocampi than increments in ADNC severity, independent of the severity of comorbid ADNC or LATENC, respectively.<br><br>DISCUSSION: These findings reveal distinct and overlapping brain morphometry patterns associated with ADNC and/or LATENC, with possible implications for diagnosis in older adults.},
}
@article {pmid42576197,
year = {2026},
author = {Um, YJ and Cho, IY and Koo, HY and Park, YM and Kim, KM and Lee, CE and Han, K},
title = {Intellectual disabilities and risk of dementia: A Korean population-based cohort study.},
journal = {Journal of intellectual disabilities : JOID},
volume = {},
number = {},
pages = {17446295261476476},
doi = {10.1177/17446295261476476},
pmid = {42576197},
issn = {1744-6309},
abstract = {This retrospective cohort study assessed the risk of all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VaD) in individuals with intellectual disabilities compared to those without. Using data from the Korean National Disability Registry and National Health Insurance Service, individuals over 40 who underwent health examinations in 2009 were followed until 2020. Cox proportional hazards models estimated hazard ratios (HRs) for dementia outcomes, adjusting for confounders. Over a mean 8-year follow-up, 161 dementia, 111 AD, and 22 VaD cases occurred among individuals with intellectual disabilities. Adjusted HRs for all-cause dementia, AD, and VaD were 5.75, 5.23, and 4.66, respectively, compared to those without intellectual disabilities. The risk was especially elevated among those aged 40-64 years (P for interaction <0.01). In conclusion, individuals with intellectual disabilities have a significantly higher risk of dementia, particularly at younger ages, highlighting the need for increased awareness and targeted healthcare strategies.},
}
@article {pmid42576199,
year = {2026},
author = {Zheng, F and Guan, R and Yu, X and Yang, J and Zhao, H and Yang, F},
title = {ADAR-mediated RNA editing in CNS disorders: from pathogenic mechanisms to therapeutic opportunities.},
journal = {Cellular &amp; molecular biology letters},
volume = {31},
number = {1},
pages = {},
pmid = {42576199},
issn = {1689-1392},
mesh = {Humans ; *RNA Editing/genetics ; *Adenosine Deaminase/metabolism/genetics ; *Central Nervous System Diseases/genetics/therapy/pathology/metabolism ; Animals ; *RNA-Binding Proteins/metabolism/genetics ; },
abstract = {The adenosine deaminases acting on RNA (ADAR) family of enzymes (ADAR1 and ADAR2) catalyze adenosine-to-inosine (A-to-I) RNA editing. This post-transcriptional change is remarkably prevalent in the central nervous system (CNS). ADAR-mediated editing is critical for proper brain development, synaptic plasticity, and immunological homeostasis in the central nervous system (CNS) via recoding neurotransmitter receptors and ion channels. Conversely, a wide range of CNS disorders, such as neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis), neuropsychiatric conditions (schizophrenia, bipolar disorder, and major depression), cerebrovascular diseases, and gliomas, are now linked to dysregulation of ADAR activity, whether through loss-of-function mutations, altered expression, or mislocalization. To address the main question of whether altered RNA editing is a fundamental driver of pathogenesis, a compensatory response, or a context-dependent modulator, this review critically synthesizes existing evidence. The basic processes of ADAR enzymes and their regulation throughout neurodevelopment are first described. Next, we thoroughly assess the unique molecular fingerprints of ADAR dysregulation across several CNS disorders, emphasizing recurring themes such as Alu RNA hypo-editing, induction of innate immunity, and GRIA2 editing, which can cause excitotoxicity. Lastly, we examine new treatment approaches that use or reinstate ADAR activity, such as small-molecule modulators and site-directed RNA editing tools (leveraging endogenous ADAR for programmable editing of RNA [LEAPER], clustered ADAR-recruiting guide RNAs (gRNAs) for effective RNA editing [CLUSTER], and mimicking inverted repeats to recruit ADARs using engineered oligoribonucleotides [MIRROR]). We summarize by reviewing key obstacles to clinical translation, including crossing the blood-brain barrier, the risks of off-target editing, and the challenges of achieving spatiotemporal accuracy. We also list important open topics for further investigation.},
}
@article {pmid42576501,
year = {2026},
author = {Li, D and Li, Y and Yang, X and Wang, Y and Qu, Y},
title = {[Association between 473 gut microbiota and Alzheimer's disease: a Mendelian randomization mediation analysis of 233 circulating metabolites].},
journal = {Nan fang yi ke da xue xue bao = Journal of Southern Medical University},
volume = {46},
number = {8},
pages = {1926-1935},
doi = {10.12122/j.issn.1673-4254.2026.08.20},
pmid = {42576501},
issn = {1673-4254},
mesh = {*Alzheimer Disease/microbiology/genetics ; *Mendelian Randomization Analysis ; Humans ; *Gastrointestinal Microbiome ; Genome-Wide Association Study ; },
abstract = {OBJECTIVES: To investigate the causal associations between gut microbiota (GM) and Alzheimer's disease (AD) and the mediating role of circulating metabolites using Mendelian randomization (MR) analysis.<br><br>METHODS: A two-sample MR analysis was conducted based on genome-wide association study (GWAS) summary data. Valid instrumental variables for 473 GM taxa and 233 circulating metabolites were selected, and the inverse-variance weighted (IVW) method was used as the primary analytical approach, with MR-Egger regression and weighted median method as the complementary analyses. Multiple sensitivity analyses were conducted to assess the robustness of the results, and reverse MR analyses were used to verify the direction of causality. Mediation MR analyses were performed to determine the mediating effects of the circulating metabolites.<br><br>RESULTS: A positive causal association was identified between the abundance of Negativibacillus massiliensis and the risk of AD (OR=1.204, 95% CI: 1.020-1.421,P=0.028), and the results were stable and reliable as confirmed by sensitivity analyses (P>0.05). Reverse MR analysis revealed no significant causal effect of AD on the abundance of Negativibacillus massiliensis (P=0.678). Mediation MR analysis showed that the indirect effect mediated by free cholesterol to total lipid ratio in very small very-low-density lipoprotein (v-VLDL FC/TL) accounted for 6.63% of the total effect of Negativibacillus massiliensis on AD.<br><br>CONCLUSIONS: From a genetic causal inference perspective, Negativibacillus massiliensis is likely associated with an increased risk of AD, and v-VLDL FC/TL may partially mediate this association, suggesting their potential as targets for AD prevention and treatment.},
}
@article {pmid42576518,
year = {2026},
author = {Shakya, M and Patel, SK and Singh, M and Rao, H and Moorthy, NHN and Tiwari, A},
title = {An Overview of 1,2,4-Triazole-5-Thiol and 3-Thione Derivatives as Promising Scaffolds for Anti-Neuroinflammatory Drug Discovery.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575433269260710072055},
pmid = {42576518},
issn = {1875-5607},
abstract = {Neuroinflammation is a major complex reaction that causes Neurodegenerative Diseases (ND) and cognitive behavioural disorders such as Alzheimer's Disease (AD), Parkinson's disease, multiple sclerosis, and traumatic brain injury. Neuroinflammation can be regulated by different types of enzymes and proteins, including acetyl- and butyrylcholinesterases, cyclooxygenases, kinases, and the accumulation of Amyloid-beta (Aβ) plaques and hyperphosphorylated tau protein. Due to the complex physiology of enzymes and proteins, ND cannot be cured permanently yet. Therefore, we need to design and synthesise novel small molecules with high selectivity and inhibitory properties against enzymes and proteins associated with neuroinflammation. In recent decades, researchers have examined a range of different heterocyclic scaffolds for their ability to fight neuroinflammation. The 1,2,4-triazole scaffold, especially its 5-thiol and 3-thione derivatives, is a chemically flexible heterocyclic scaffold that has attracted significant attention due to its wide range of biological activities and promising drug-like properties. As a review methodology, comprehensive literature searches of the PubMed, Scopus, Web of Science (WoS), ScienceDirect, and DOAJ databases were conducted using keywords to gather information on synthesis, in vitro (IC50 values), in vivo biology, and in silico approaches related to the 1,2,4-triazole-targeted scaffold. This literature review highlights 1,2,4-triazole scaffold 5-thiol and 3-thione derivatives, potent compounds from the synthesised derivatives, presenting synthetic schemes, biological activity data, and in silico studies. Molecular docking, in silico predictions, and preclinical experiments are summarised in detail to show how they can be used in medicinal drug discovery. The goal of this review is to provide a source of information that will help with future efforts to design new neuroprotective agents based on the 1,2,4-triazole scaffold.},
}
@article {pmid42576561,
year = {2026},
author = {Kara, S and Özandaç, S and Sencar, L and Akillioglu, K and Polat, S},
title = {Transforming Growth Factor Beta-1 Alleviates Neurodegeneration by Regulating Aβ42 and VDAC1 Expression in the Temporal Lobe and Cerebellum in an Alzheimer's Disease-Like Model.},
journal = {Current molecular medicine},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115665240501722260724103809},
pmid = {42576561},
issn = {1875-5666},
abstract = {BACKGROUND: Alzheimer's Disease (AD) has a critical pathology that causes neurodegeneration and mitochondrial dysfunctions via the amyloid deposition. The temporal lobe plays a role in converting sensory input into derived meanings for appropriate processing of visual memory, language comprehension, and emotional association. The cerebellum plays a critical role in the control of motor systems, cognitive, and emotional functions. Aβ42 accumulates between nerve cells in the brain, disrupting synaptic functions and negatively affecting memory and other cognitive functions. VDAC1 is a protein located in the cell membrane that facilitates energy transport to the mitochondria. TGF-β1 is a cytokine that plays a role in many biological functions, including cell growth, differentiation, and tissue repair.<br><br>OBJECTIVE: The aim of the study was to investigate the effect of TGF-&#x3b2;1 on scopolamine-induced neurodegeneration of the temporal lobe and cerebellum in experimental AD.<br><br>METHODS AND RESULTS: The evaluation showed that, according to light and electron microscopic results, edema areas, cytoplasmic vacuolization, and cellular damage were increased in the scopolamine group, while these changes were significantly reduced in the treatment group. According to immunohistochemical findings, the expression levels of A&#x3b2;42 and VDAC1 were significantly higher in the scopolamine group than in the control and TGF-&#x3b2;1 groups, while in the treatment group, a low expression was observed compared to the scopolamine group.<br><br>CONCLUSION: When all these results are considered together, it has been concluded that TGF-&#x3b2;1 application may regulate the expression of A&#x3b2;42 and VDAC1 in critical control centers such as the temporal lobe and cerebellum in a Scopolamin-induced neurodegeneration model, potentially alleviating cellular damage.<br><br>DISCUSSION: Previous studies have reported that TGF-&#x3b2;1 exerts both antineurodegenerative and neuroprotective effects. In our study, evaluation of the effects of TGF-&#x3b2;1 demonstrated beneficial effects on both mitochondrial damage and amyloid accumulation. Nevertheless, further detailed investigations of these effects may provide valuable insights for future studies.},
}
@article {pmid42576562,
year = {2026},
author = {Kumar, D and Ashesh, AM and Gupta, S and Kumar, A and Lohidasan, S and Tosaramandani, TJ},
title = {WNT Signaling in Alzheimer's Disease: Mechanisms, Pathological Implications, and Therapeutic Potential.},
journal = {CNS &amp; neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273455895260722103746},
pmid = {42576562},
issn = {1996-3181},
abstract = {The WNT signaling pathway plays a significant role in various biological processes during embryonic development, childhood, and adulthood. It is involved in neurogenesis, synapse formation, and such cognitive processes as learning and memory in the CNS. Dysregulated WNT signaling is associated with cognitive decline, synaptic dysfunction, neuronal loss, and has been associated with diseases like leukemia and colorectal cancer. The studies show that WNT/β-catenin signaling affects the cellular, molecular, and metabolic mechanisms that promote disease progression. The WNT pathway is a potential therapeutic target because it helps maintain neuronal survival, supports the growth of new nerve cells, and enhances synaptic plasticity. WNT signaling is important for stem cell selfrenewal and differentiation. Research is being conducted on therapeutic methods targeting WNT signaling to treat neurological diseases and cancer. This review explores the connection between WNT signaling and the pathology of Alzheimer's disease. This review explores the role of WNT signaling in AD pathogenesis, with a focus on the Wnt/β-catenin pathway as a therapeutic target. It summarizes existing findings to demonstrate that WNT signaling is a context-dependent regulatory network in which a shift from protective canonical activity to dysregulated non-canonical and inflammatory pathways contributes to disease progression.},
}
@article {pmid42576583,
year = {2026},
author = {Ahmed, A and Fu, X and Khan, H and Li, P},
title = {A Narrative Review: Suvorexant's Role in Sleep Deprivation and Neurodegenerative Disease.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X468876260722063322},
pmid = {42576583},
issn = {1875-6190},
abstract = {Sleep loss is a major risk factor for neurodegenerative diseases like Alzheimer's disease (AD) and Parkinson's disease (PD), accelerating cognitive impairment with neuropathology. Cumulative sleep loss impairs the glymphatic system, reduces amyloid-β clearance, and enhances the neuroinflammatory response, all of which contribute to the development of neurodegeneration. Given the orexin system's essential role in modulating sleep-wake rhythms, orexin receptor antagonists such as Suvorexant are potent candidates for treating sleep disturbances and cognitive decline associated with neurodegenerative conditions. Suvorexant promotes sustained sleep without the side effects commonly associated with sleep-inducing drugs, such as drowsiness and cognitive impairment, potentially offering a neuroprotective approach by selectively antagonizing orexin receptors. By inhibiting excessive orexin signaling in the brain, Suvorexant may benefit other neurodegenerative diseases. Preclinical studies support the idea that improving sleep quality, as seen with Suvorexant, can normalize sleep architecture, leading to reduced tau phosphorylation and amyloid plaque deposition, both of which are pathological hallmarks of AD. Furthermore, enhanced sleep quality may bolster synaptic plasticity and aid in memory consolidation, potentially counteracting cognitive deterioration. Although most research has been conducted in AD, the putative applications of Suvorexant in PD and other tauopathies are worth exploring, especially given the common involvement of sleep disturbances in these diseases. Animal studies show that Suvorexant not only promotes sleep but also prevents neuronal damage, suggesting its dual therapeutic potential. Long-term clinical trials are necessary, however, to prove its effectiveness in humans, especially in populations at risk for sleep disorders and early neurodegenerative alterations. Suvorexant could be a novel approach to slow cognitive decline and improve quality of life in patients with AD, PD, and related diseases, highlighting the vital interplay between sleep and brain health.},
}
@article {pmid42576592,
year = {2026},
author = {Jeeru, TR and Palathoti, N and Swaminathan, G},
title = {The Multifaceted Role of the P2X7 Receptor in Alzheimer's Disease: A Unifying Pathological Link.},
journal = {CNS &amp; neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273460900260724035926},
pmid = {42576592},
issn = {1996-3181},
abstract = {Alzheimer's Disease (AD) is a neurodegenerative disorder that characterizes depletion of memory, cognition, and a change in behavioural patterns. There is no standard treatment that completely cures this prevalent disease. This review delves into the existing pathologies of AD, which include the Aβ plaques accumulation, neurofibrillary tangles and Lewy bodies formation, and the influence of the P2X7 receptor on cellular mechanisms of neuronal cells like microglial cells, astrocytes and oligodendrocytes and also its influence on pathways such as JAK2/STAT3, NGF signalling, (Transactive response DNA binding protein) TDP-43 Proteinopathy, Wnt/β-Catenin signalling, and FGF7/FGFR2/PI3K/Akt causing AD. It discusses the unifying role of the P2X7 receptor mediating these pathways that link to the occurrence and progression of AD. The role of the Purinergic receptor (P2X7 receptor), a ligand-gated ion channel activated by extracellular ATP, was examined across existing cellular mechanisms and possible pathways involved in AD, as well as the co-pathologies encompassed and their hypothetical relationship with the P2X7 receptor. Additionally, the current P2X7 receptor antagonists treating neurotoxicity are discussed along with existing pre-clinical and clinical data. This may further advance drug development by targeting the P2X7 receptor to mitigate AD across multiple mechanisms.},
}
@article {pmid42576595,
year = {2026},
author = {Maghsoudlou, F and Esteki, A},
title = {Audio‒Visual Gamma Stimulation for Alzheimer's Disease: Current Evidence and Future Directions.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050478693260720114427},
pmid = {42576595},
issn = {1875-5828},
abstract = {INTRODUCTION/OBJECTIVE: Alzheimer's Disease (AD) is characterized by progressive cognitive decline and disrupted neural oscillations. Recently, 40 Hz gamma stimulation has emerged as a potential non-invasive therapy. This review evaluates the safety, tolerability, and clinical outcomes of this intervention based on evidence from the past decade.<br><br>METHODS: A literature search was conducted across PubMed, Web of Science, Google Scholar, and ClinicalTrials.gov for studies published during the last ten years. Registered and ongoing studies were also identified through ClinicalTrials.gov. Extracted data included stimulation modality, stimulation parameters, safety and tolerability outcomes, and reported effects on functional connectivity, brain atrophy, cognitive performance, and sleep-related measures.<br><br>RESULTS: Thirty studies were identified, comprising eight sensory-based 40-Hz gamma stimulation approaches, 12 40-Hz transcranial Alternating Current Stimulation (tACS) protocols, and 10 ongoing clinical trials. Among the 20 completed studies, 40-Hz gamma stimulation was reported to be safe and well-tolerated. The synthesized evidence from these completed trials suggests potential beneficial effects on functional connectivity, brain atrophy progression, cognitive outcomes, and sleep-related measures.<br><br>DISCUSSION: Gamma stimulation may represent a promising approach for modulating neural network activity and cognitive function in AD. Nevertheless, current evidence remains limited by small sample sizes, methodological heterogeneity, differences in stimulation protocols, and short follow-up periods. These factors limit the ability to draw definitive conclusions regarding therapeutic efficacy.<br><br>CONCLUSION: 40-Hz gamma stimulation is a feasible and generally well-tolerated non-invasive intervention with potential relevance for AD treatment. Further large-scale, randomized, and controlled studies are required to establish standardized stimulation protocols, determine long-term efficacy, and clarify its clinical utility.},
}
@article {pmid42576606,
year = {2026},
author = {Ioakeimidis, V and Palombo, M and Casella, C and Layland, L and McNabb, C and Schubert, R and Pallmann, P and Busse, M and Drew, C and Alusi, S and Harrower, T and Davies, J and Rosser, A and Metzler-Baddeley, C},
title = {In vivo mapping of striatal neurodegeneration in Huntington's disease with Soma and Neurite Density Imaging.},
journal = {eLife},
volume = {14},
number = {},
pages = {},
doi = {10.7554/eLife.107661},
pmid = {42576606},
issn = {2050-084X},
support = {NIHR-FS(A)-2022/HCRW_/HCRW_/United Kingdom ; MR/T020296/2//UKRI/ ; 10.35802/204005/WT_/Wellcome Trust/United Kingdom ; 10.35802/104943/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Humans ; *Huntington Disease/pathology/diagnostic imaging/physiopathology ; Female ; Male ; *Neurites/pathology ; Middle Aged ; *Corpus Striatum/pathology/diagnostic imaging ; Adult ; Diffusion Magnetic Resonance Imaging/methods ; Basal Ganglia/pathology/diagnostic imaging ; Aged ; },
abstract = {Huntington's disease (HD) is an inherited neurodegenerative disorder characterised by progressive cognitive and motor decline driven by basal ganglia (BG) atrophy. Clinical trials of novel disease-modifying therapies are ongoing, creating a need for sensitive non-invasive imaging biomarkers. Soma and Neurite Density Imaging (SANDI) is a multi-shell diffusion MRI model that estimates intracellular signal fractions from sphere-shaped soma and shows promise as a marker of neurodegeneration. The objectives of this study were to characterise HD-related microstructural abnormalities in the BG using SANDI and to examine relationships between SANDI and volumetric measurements and motor performance. T1- and diffusion-weighted images (b-values 200-6000 s/mm[2]) were acquired on a 3T Siemens Connectom scanner (300 mT/m) in 56 individuals with HD and 57 age- and sex-matched controls. HD participants completed Quantitative Motor (Q-Motor) tasks, summarised using principal component analysis. SANDI estimated apparent soma and neurite density, apparent soma size, and extracellular signal fraction. Microstructural and volumetric indices were extracted from bilateral caudate, putamen, pallidum and thalamus regions, compared between groups, and correlated with Q-Motor performance. HD was associated with reduced apparent soma density and increased apparent soma size and extracellular signal fraction in the BG but not the thalami. No group differences were present for apparent neurite density. SANDI metrics correlated with Q-Motor performance and explained up to 63% of striatal atrophy in HD. SANDI indices detected HD-related striatal neurodegeneration, explained atrophy, and correlated with motor impairments, demonstrating its potential as an in vivo biomarker and surrogate clinical outcome measure for HD and other neurodegenerative diseases.},
}
@article {pmid42576610,
year = {2026},
author = {Yang, Y and Yang, Y and Tang, Y and Yang, W},
title = {Myokines, Microbiota, and Neuroinflammation: Physical Activity Modulates the Gut-Brain Axis.},
journal = {Immunological investigations},
volume = {},
number = {},
pages = {1-28},
doi = {10.1080/08820139.2026.2689670},
pmid = {42576610},
issn = {1532-4311},
abstract = {BACKGROUND: Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis are increasingly recognized as disorders influenced not only by intrinsic neural pathology but also by systemic physiological networks, including the gut-brain axis. Emerging evidence highlights physical activity as a potent modulator of this bidirectional communication system, with muscle-derived signals particularly myokines, metabolites, and extracellular vesicles playing a central role.<br><br>METHODS: This narrative review synthesizes current knowledge on how exercise-induced molecular mediators influence gut microbiota composition, intestinal barrier integrity, immune signaling, and neuroinflammatory pathways. Findings were integrated across the disciplines of neuroscience, microbiology, and exercise physiology to evaluate mechanistic links between muscle-secreted factors and gut-mediated responses.<br><br>RESULTS: Mechanistic links exist between muscle-secreted factors such as irisin, cathepsin B, BDNF-inducing pathways, and lactate with microbial metabolites including short-chain fatty acids. These interacting pathways demonstrate a combined impact on neuroprotection, synaptic plasticity, and the modulation of disease progression in neurodegenerative conditions.<br><br>CONCLUSION: Physical activity represents a promising non-pharmacological strategy for modulating the gut-brain axis in neurodegenerative conditions. Understanding the interplay between muscle-derived signals and gut-mediated pathways may open new avenues for targeted interventions aimed at slowing or preventing neurodegenerative decline.},
}
@article {pmid42576612,
year = {2026},
author = {Carrier, T and Rouleau, I and St-Georges, MA and Afrooz, P and Montembeault, M},
title = {Deficits in the knowledge of social norms and their correlates in Alzheimer's disease.},
journal = {The Clinical neuropsychologist},
volume = {},
number = {},
pages = {1-18},
doi = {10.1080/13854046.2026.2712921},
pmid = {42576612},
issn = {1744-4144},
abstract = {Objective: Compared to other components of social cognition, knowledge of social norms has received less attention in the scientific literature. While social cognitive and semantic memory deficits appear early in the course of Alzheimer's disease (AD), no study has examined knowledge of social norms at earlier stages of the disease. In addition, it is unclear whether the knowledge of social norms in AD is associated with socioemotional deficits, as may be seen in the behavioral variant of frontotemporal dementia (bvFTD). Method: This study included 136 participants with amnestic mild cognitive impairment (aMCI), 134 with AD, most of whom were younger than 65 years, 280 with bvFTD, and 361 older healthy controls (HC). All participants were selected from the National Alzheimer's Coordinating Center (NACC). They completed the Social Norms Questionnaire (SNQ), which assesses the tendency to break or overadhere to social norms. They also completed tests assessing executive, semantic, and socioemotional functions. Results: Between-group comparisons showed that individuals with AD and aMCI made significantly more Break and Overadhere errors than HC, while they demonstrated better social norms knowledge than individuals with bvFTD. In aMCI and AD, social norms overadherence errors were most consistently associated with executive functioning. In bvFTD, semantic memory was the most consistent correlate across all SNQ variables. Conclusions: These findings may help clinicians and researchers better understand social cognitive changes in patients, support the inclusion of social norms knowledge assessment within broader neuropsychological evaluations, and provide complementary insight into the cognitive correlates of social knowledge loss in major neurocognitive disorders.},
}
@article {pmid42576814,
year = {2026},
author = {Singh, N and Guha, L and Kumari, A},
title = {Exosome-based nanomedicine for neurological disorders: mechanisms, engineering, and therapeutic potential.},
journal = {Therapeutic delivery},
volume = {},
number = {},
pages = {1-40},
doi = {10.1080/20415990.2026.2715878},
pmid = {42576814},
issn = {2041-6008},
abstract = {Exosomes are naturally occurring extracellular vesicles that have emerged as promising bio-inspired nanocarriers for the treatment of neurological disorders owing to their intrinsic biocompatibility, low immunogenicity, and ability to cross the blood-brain barrier. This review highlights recent advances in exosome biology, cargo-sorting mechanisms, and engineering strategies designed to enhance therapeutic delivery and targeting within the central nervous system. Particular emphasis is placed on the application of engineered exosomes in neurodegenerative diseases, stroke, spinal cord injury, neuropathic pain, and neuroinflammatory disorders. In addition, we discuss how exosomes compare with conventional delivery platforms and critically examine the major barriers limiting their clinical translation, including heterogeneity, scalability, reproducibility, purity, and regulatory standardization. By integrating mechanistic insights with translational perspectives, this review provides a framework for the rational design and future clinical implementation of exosome-based nanomedicines for neurological disorders. Relevant literature was identified through searches of PubMed, Scopus, Web of Science, and Google Scholar. Publications available from database inception through [Month Year] were screened using combinations of keywords including "exosomes," "extracellular vesicles," "neurological disorders," "brain-targeted delivery," "exosome engineering," "drug delivery," and "clinical trials." Additional relevant articles were identified through manual searches of reference lists from selected studies and recent reviews.},
}
@article {pmid42577088,
year = {2026},
author = {Zheng, K and Tsitsos, FN and Konofagou, EE and Leong, KW},
title = {Focused ultrasound-mediated lipid nanoparticle delivery for brain gene editing.},
journal = {Molecular therapy. Nucleic acids},
volume = {37},
number = {3},
pages = {103012},
pmid = {42577088},
issn = {2162-2531},
abstract = {Efficient brain gene editing remains constrained by the lack of delivery platforms that combine efficacy, spatial precision, and translational potential. Compared with viral vectors, lipid nanoparticles (LNPs) offer larger cargo capacity and lower immunogenicity for repeat dosing. However, their brain delivery is restricted by the blood-brain barrier (BBB). Here, we show that focused ultrasound (FUS)-mediated BBB opening enables systemic delivery of CRISPR-encoding plasmid DNA (pDNA)-LNPs for brain gene editing. Using a pDNA construct containing astrocyte-targeting GfaABC1D promoter and dual guide RNAs targeting apolipoprotein E4 (APOE4), the strongest genetic risk factor for Alzheimer's disease, we achieved efficient APOE4 knockdown, with reduced APOE4 mRNA and apoE4 protein expression, and attenuated astrocytes and microglial activation. These results establish FUS-mediated pDNA-LNP delivery as a non-invasive, non-viral strategy for brain gene editing that provides spatial control and cell-type-specific expression, while accommodating large genetic payload and enabling repeatable dosing.},
}
@article {pmid42577096,
year = {2026},
author = {Gaborit, M and Arabi, A and Mariotti, L},
title = {The emerging role of astrocytes in spatial cognition, action and Alzheimer's disease.},
journal = {Frontiers in cellular neuroscience},
volume = {20},
number = {},
pages = {1811370},
pmid = {42577096},
issn = {1662-5102},
abstract = {Astrocytes sense synaptic activity, neuromodulation, and metabolic signals, and respond by modulating neurotransmission, excitability, and plasticity in neural networks. Increasing evidence demonstrates that these processes contribute to information processing and encoding across brain areas, thereby influencing perception, memory, cognition, and goal-directed behaviours. Notably, impairments in these functions represent some of the earliest hallmarks of ageing and neurodegenerative disorders such as Alzheimer's disease. Here we review molecular, cellular, and computational insights into astrocyte-neuron interactions, framing their importance at the system and behavioural level; then, we discuss the role of these interactions in spatial cognition, goal-directed behaviour, and their impairment in Alzheimer's disease, and review the mouse models used to investigate spatial deficits and associated astrocyte activity. Finally, we highlight major open questions in the field, outline future research directions, and discuss emerging strategies to address astrocyte role in cognitive function in health and disease.},
}
@article {pmid42577185,
year = {2026},
author = {Highet, B and Singh-Bains, M and Eszes, M and Parker, R and McShane, E and Webb-Robinson, C and Hubbard, K and Biggins, F and Sharma, S and Bell, P and Burnett, O and Lehnert, K and Jacobsen, JC and Ryan, B and Hu, M and Turner, C and Faull, RLM and Curtis, MA},
title = {Operational, molecular, and cultural perspectives at the Neurological Foundation Human Brain Bank, New Zealand.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1900088},
pmid = {42577185},
issn = {1664-2295},
abstract = {Post-mortem human brain tissue is an irreplaceable resource for advancing understanding of the brain and neurological disease. Brain banks that collect, preserve, and distribute this tissue underpin discoveries across neuropathology, genomics, and emerging molecular disciplines. Yet brain banking is a resource-intensive enterprise that faces distinct operational, cultural, and scientific challenges depending on the national context in which it operates. Here, we present the perspective of the Neurological Foundation Human Brain Bank (NFHuBB) - New Zealand's sole post-mortem human brain bank, based at The University of Auckland. Operating as the only such facility in the country, the NFHuBB confronts a unique convergence of challenges: the logistical complexity of coordinating donation across a dispersed population, the scientific imperative to preserve tissue for molecular-era multi-omics technologies, and a multi-cultural population that needs culturally informed consent practices. We describe the growth of the bank's donor registry and collection over 45 years with specific emphasis on donations in the last five calendar years (2021-2025), outline recent advances in tissue processing, including the development of formalin-fixed paraffin-embedded (FFPE) RNA preservation protocols and integration of whole-genome sequencing from un-fixed cerebellar tissue. Finally, we discuss the community engagement strategies that have supported increasing donation rates in New Zealand.},
}
@article {pmid42577242,
year = {2026},
author = {Meera, B and Hiatt, M and Hays, A and Punshon, S and Christensen, JR and Fields, B},
title = {Implementation of Riding in the Moment™: the crucial role of implementer preparedness and satisfaction in an adaptive horseback riding program for older adults with dementia.},
journal = {Frontiers in health services},
volume = {6},
number = {},
pages = {1799552},
pmid = {42577242},
issn = {2813-0146},
abstract = {INTRODUCTION: Riding in the Moment™ (RM) is a community-based, standardized, evidence-informed equine-assisted service program designed to support individuals with Alzheimer's disease and related dementias and their caregivers through social connection, physical activity, and meaningful engagement. Delivered by trained non-clinical personnel, RM's long-term success depends on effective implementation and sustainability in real-world settings. This project explored implementation strategies used to deliver RM, focusing on staff and volunteer preparedness and satisfaction.<br><br>METHODS: A repeated measures survey design that included closed-ended items and open-ended questions, guided by the RE-AIM framework, was used to explore implementation strategies. Pre-and post-implementation surveys assessed training satisfaction, perceived preparedness, and delivery experience among RM staff and volunteers. Quantitative data were analyzed using descriptive statistics, while qualitative feedback was organized into key categories. Implementation and fidelity checklists were also completed.<br><br>RESULTS: Majority of the participants (95%; n&#x2009;=&#x2009;21) reported overall satisfaction with training and felt prepared to deliver RM. All fidelity checklist items were met, indicating strong adherence to program protocols. Post-implementation, majority of the participants (74%; n&#x2009;=&#x2009;11) were extremely satisfied with RM, and 100% (n&#x2009;=&#x2009;15) stated they would recommend the program. Qualitative feedback emphasized the emotional impact of the experience, value of structured training, and opportunities to improve volunteer engagement and communication.<br><br>DISCUSSION: This program evaluation project contributes to understanding early-stage implementation considerations for community-based dementia-specific programs in real-world settings. Continued evaluation is needed to determine how these factors influence long-term implementation, program sustainability, and scalability across broader settings.},
}
@article {pmid42577281,
year = {2026},
author = {Dhapola, R and Sharma, P and Kumari, S and Vellingiri, B and HariKrishnaReddy, D},
title = {Neuroprotective effect of normal and modified mesenchymal stem cell-derived exosomes by mitigating Alzheimer's-related oxidative and inflammatory damage via Nrf2/HO-1 in SH-SY5Y cells.},
journal = {Ibrain},
volume = {},
number = {},
pages = {},
pmid = {42577281},
issn = {2769-2795},
abstract = {Exosome therapy is emerging as a promising neuroprotective strategy for Alzheimer's disease (AD). We evaluated and compared whether normal exosomes (NE) and modified exosomes (ME) derived from AD rat brain extract-treated rat bone marrow mesenchymal stem cells possess the potential to protect SH-SY5Y cells against streptozotocin (STZ) induced toxicity. The effect of exosomes on oxidative stress, inflammation and neuronal survival was evaluated. Further, antioxidant mechanism of exosomes by nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) signaling was explored. Cells were exposed to 5 mM STZ and treated with NE and ME at an equivalent concentration of 50 µg/mL. Exosomes were characterized by specific exosomal markers, CD63 and CD9. Cell viability was assessed using the MTT assay. Neuronal growth and survival were evaluated by measuring brain-derived neurotrophic factor (BDNF) using ELISA and neuronal nuclei (NeuN) expression using immunocytochemistry. Intracellular reactive oxygen species (ROS) levels were determined using H2DCFDA, while inflammatory mediators, including interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were quantified by ELISA. Expression levels of Nrf2 and HO-1 were also determined. Exosome treatment improved cell viability, reduced ROS, and lowered IL-6 and TNF-α levels. Immunocytochemistry quantification showed increased nuclear Nrf2 and HO-1 expression in exosome-treated cells. Moreover, our data indicate that ME derived from AD rat brain extract-treated rat bone marrow mesenchymal stem cells are more potent in protecting SH-SY5Y cells from STZ-induced oxidative stress and inflammation, possibly via Nrf2/HO-1 signaling, as compared to NE. These in vitro results support further preclinical evaluation of exosome-based strategies for AD.},
}
@article {pmid42577341,
year = {2026},
author = {Chattopadhyay, T and Kush, R and Ankarath, RH and Senthilkumar, P and Gleave, EJ and Patterson, C and Owens-Walton, C and Thomopoulos, SI and Johnson, SC and Mormino, EC and Tosun, D and Hohman, TJ and Thompson, PM},
title = {Multi-modal deep learning and explainable AI for predicting multiple dementia-related neuropathologies from brain MRI, clinical, and genetic data.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1839071},
pmid = {42577341},
issn = {1664-2295},
abstract = {Alzheimer's disease and related dementias (ADRD) typically involve multiple, overlapping pathologies-such as amyloid-β (Aβ), tau, cerebral amyloid angiopathy (CAA), TDP-43, hippocampal sclerosis, and alpha-synuclein-that complicate diagnosis and treatment. While PET and CSF biomarkers can detect abnormal levels of Aβ and tau, they are invasive, expensive, and not widely available. By contrast, structural magnetic resonance imaging (MRI) offers a non-invasive and scalable alternative, one that is now showing promise for neuropathological prediction when combined with artificial intelligence methods. Prior efforts have largely focused on inferring single pathologies such as abnormal Aβ; however, there is a pressing need for models that can jointly predict multiple co-occurring pathologies. In this work, we develop and evaluate a hybrid deep learning framework that integrates 3D T1-weighted brain MRI with demographic, clinical, and genetic covariates to make inferences, in living individuals, regarding the presence of six ADRD pathologies. The models are trained and tested using autopsy-confirmed neuropathology from individuals who were scanned while they were alive. Based on their strong performance on related tasks, we evaluate two machine learning models: (1) a deep learning algorithm based on a 3D convolutional neural network, a widely used model in computer vision applications, and (2) AutoGluon, an automated machine learning framework that automatically selects an approach for the problem. Each method can use both imaging and non-imaging covariates as inputs. To improve model transparency, we incorporate explainable AI methods-including occlusion sensitivity analysis (OSA), Grad-CAM, and Integrated Gradients (IG)-to interpret the spatial contribution of brain regions to model predictions. Finally, we compare the resulting feature importance maps ('salience maps') with traditional voxel-based morphometry (VBM) analyses to assess their biological plausibility. Our findings show the promise of multimodal, interpretable AI approaches for comprehensive, non-invasive profiling of dementia-related pathologies.},
}
@article {pmid42577349,
year = {2026},
author = {Xu, Z and Li, H and Liu, W and Li, H},
title = {ScaleSpecter: a frequency-aware multi-scale patch framework for robust physiological classification under non-stationarity.},
journal = {Frontiers in human neuroscience},
volume = {20},
number = {},
pages = {1856803},
pmid = {42577349},
issn = {1662-5161},
abstract = {INTRODUCTION: Early detection and intervention for cognitive impairment associated with neurodegenerative diseases are important for slowing disease progression and improving quality of life. Electroencephalography provides high temporal resolution and sensitivity to neural oscillations, making it a promising tool for early disease identification. However, weak and transient pathological abnormalities are often obscured by diffuse, non-stationary low-frequency background rhythms, making robust feature extraction challenging.<br><br>METHODS: We propose ScaleSpecter, a frequency-aware multiscale patch framework for neurodegenerative disease-related EEG classification. ScaleSpecter first constructs temporal representations at multiple scales to jointly capture transient local abnormalities and long-term rhythmic variations. A lightweight cross-scale attention mechanism then enables interaction between fine-grained temporal tokens and coarse scale-level summaries. Finally, an amplitude-phase-aware spectral modulation module uses learnable complex-valued weights to recalibrate spectral responses and provide frequency-domain guidance for temporal feature aggregation.<br><br>RESULTS: Extensive experiments were conducted on three public EEG datasets: the Alzheimer's Disease and Frontotemporal Dementia (ADFTD) dataset, the Alzheimer's Patients' Relatives Association of Valladolid (APAVA) dataset, and the Two Decades-Brainclinics Research Archive for Insights in Neurophysiology (TDBRAIN) database. These datasets cover classification tasks related to Alzheimer's disease, frontotemporal dementia, and Parkinson's disease. ScaleSpecter achieved competitive and generally favorable performance on most key evaluation metrics. The ablation and visualization results further demonstrated the complementary contributions of multiscale temporal modeling, cross-scale interaction, and spectral modulation.<br><br>DISCUSSION: The results suggest that integrating frequency-domain guidance with multiscale temporal representations can improve the discriminative capability and robustness of EEG classification under non-stationary conditions. ScaleSpecter provides a potentially generalizable framework for neurodegenerative disease-related physiological signal analysis.},
}
@article {pmid42577352,
year = {2026},
author = {Lu, LC and Lan, SH and Lan, SJ and Hsieh, YP},
title = {Effectiveness of noninvasive brain stimulation techniques on cognitive function in individuals with Alzheimer's disease and MCI: a systematic review and meta-analysis.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1782521},
pmid = {42577352},
issn = {1663-4365},
abstract = {BACKGROUND: Noninvasive brain stimulation (NIBS) may alleviate cognitive impairments in individuals with Alzheimer's disease (AD). However, clinical findings remain inconsistent, highlighting the need for a systematic review and meta-analysis to clarify the efficacy of NIBS.<br><br>OBJECTIVE: To compare the effects of NIBS and sham stimulation on global cognition in individuals with AD.<br><br>METHODS: Randomized controlled trials were identified from PubMed, Web of Science, Scopus, and the Cochrane Central Register of Controlled Trials by using relevant search terms. Cognitive outcomes were assessed using objective scales, and pooled standardized mean differences with 95% confidence intervals (CIs) were calculated using a random-effects model.<br><br>RESULTS: NIBS was associated with significant improvements in global cognition in individuals with AD, as measured using the Mini-Mental State Examination (MMSE; standardized mean difference&#x202f;=&#x202f;0.58, 95% CI&#x202f;=&#x202f;0.32 to 0.84, p&#x202f;<&#x202f;0.001) and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog; standardized mean difference&#x202f;=&#x202f;-0.40, 95% CI&#x202f;=&#x202f;-0.68 to -0.13, p&#x202f;=&#x202f;0.004). The subgroup analysis revealed that treatment is efficacious when patients are stable medication users for 3&#x202f;months or less (MMSE scores), intervention is delivered for 6&#x202f;weeks, and NIBS is administered singularly. Longer duration of pharmacological treatment was associated with reduced NIBS efficacy on MMSE scores in both the meta-regression and subgroup analyses. Cognitive gains based on MMSE outcomes were maintained at 4 and 8&#x202f;weeks after treatment.<br><br>CONCLUSION: This meta-analysis provides evidence for the effects of NIBS on common cognitive outcomes in AD and explores potential moderators related to sample and intervention characteristics.<br><br>https://www.crd.york.ac.uk/PROSPERO/view/CRD420251065634.},
}
@article {pmid42577392,
year = {2026},
author = {Tan, NIYZ and Welton, T and Tan, YJ and Saffari, SE and Morgenroth, E and Foo, SJY and Kwok, ZR and Lim, YC and Chiew, HJ and Ng, KP and Ting, SKS and Kumar, S and Keong, N and Ng, ASL},
title = {Choroid plexus enlargement is negatively associated with cognitive performance in a DTI-ALPS-dependent manner.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1883244},
pmid = {42577392},
issn = {1663-4365},
abstract = {BACKGROUND: Disturbances in brain fluid homeostasis are increasingly implicated in neurodegeneration. Imaging measures of structural alterations of the choroid plexus (CP) and impaired glymphatic transport have each been associated with cognitive decline, yet their potential interaction in humans remains poorly understood.<br><br>METHODS: We investigated the relationship between CP volume, glymphatic diffusion, and cognitive performance in 100 memory clinic patients. Diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) was used as an imaging proxy of glymphatic diffusion, and CP volume and WMH volume were derived from structural MRI using FastSurfer segmentation. Multivariable linear regression models examined associations between CP volume, ALPS index, and global cognitive performance measured by the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE). Models were adjusted for age, sex, education, APOE &#x3b5;4 status, WMH burden and plasma phosphorylated tau (pTau217). Interaction terms tested whether CP structure and glymphatic diffusion jointly influenced cognition.<br><br>RESULTS: Larger CP volume was associated with lower ALPS index after adjustment for demographic and molecular covariates (&#x3b2;&#x202f;=&#x202f;-282.19, p&#x202f;=&#x202f;0.015). CP volume and ALPS index were not independently associated with MoCA scores; however, a significant interaction between CP volume and ALPS index was observed (&#x3b2;&#x202f;=&#x202f;-13,299.09, p&#x202f;=&#x202f;0.036). The association between CP volume and cognitive performance depended on DTI-ALPS, such that larger CP volumes were associated with poorer MoCA scores at higher ALPS values, whereas CP volume showed little association with cognition at lower ALPS values. This interaction improved model fit compared with main-effects models (R[2] &#x202f;=&#x202f;0.31). The findings remained significant after adjusting for CSF volume and were replicated using MMSE as the outcome. Plasma pTau217 levels were strongly associated with worse cognition but did not significantly modify the CP-ALPS interaction.<br><br>CONCLUSION: CP enlargement is associated with glymphatic diffusion, and its relationship with cognitive performance varies across DTI-ALPS index values. These findings suggest that interactions between CSF regulatory systems may correlate with cognitive performance in a state-dependent manner. Notably, higher ALPS values in individuals with enlarged CP may reflect compensatory or altered perivascular fluid dynamics rather than preserved glymphatic function, highlighting the complexity of interpreting diffusion-based markers of brain clearance.},
}
@article {pmid42577438,
year = {2026},
author = {Harris, GA and Barnhard, L and Brummet, J and Diaz, K},
title = {From clinical phenotypes to molecular precision: multimodal biomarkers for progressive supranuclear palsy.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1893149},
pmid = {42577438},
issn = {1662-4548},
abstract = {Progressive Supranuclear Palsy (PSP) is the most prevalent primary 4R-tauopathy, characterized by the pathogenic accumulation of misfolded tau protein within neurons and glial cells. Historically, clinical diagnosis relied upon the identification of Richardson's Syndrome, however, the recognition of diverse clinical phenotypes that overlap with Parkinson's disease, corticobasal syndrome, and frontotemporal dementia has complicated the diagnostic landscape and hindered the success of developing therapeutic interventions. As the field transitions toward a precision medicine paradigm, there is a growing need for validated biomarkers that can provide molecular specificity, facilitate early diagnosis, and accurately track disease progression. This paper reviews the recent advancements in neuroimaging and fluid-based biomarkers, assessing their potential to delineate PSP from similar neurodegenerative conditions and unlock the 4R-tau therapeutic pipeline. In the domain of neuroimaging, while structural magnetic resonance imaging (MRI) and the Magnetic Resonance Parkinsonism Index (MRPI) continue to provide measures of subcortical atrophy, the emergence of second-generation tau-selective positron emission tomography (PET) radioligands represents a transformative shift. New tau PET tracers offer the ability to visualize tau pathology in vivo, providing a more direct assessment of the underlying proteinopathy than traditional volumetric measures. These advancements are complemented by significant progress in fluid biomarkers. Plasma phosphorylated tau at residue 217 (p-tau217) has gained prominence as a robust marker for Alzheimer's disease, and its primary utility in PSP research currently serves as a critical negative signature to exclude amyloid-associated co-pathology. In contrast, novel assays targeting microtubule-binding region tau fragments show burgeoning potential for the specific identification of 4R-tau isoforms. Furthermore, neurofilament light chain (NfL) has been firmly established as a sensitive, albeit non-specific, indicator of neuroaxonal injury and clinical severity. Additional advancements with digital health approaches and electrophysiological assessments add to the opportunities for improved objective measures. This review concludes that the shift from clinical-only diagnostic criteria to a biomarker-enabled molecular framework is the necessary catalyst for developing effective disease-modifying therapies for PSP and related 4R-tauopathies. The synthesis of these multimodal biomarkers into a unified framework will be essential to improve participant stratification, enable the use of adaptive trial models, and provide supportive evidence of target engagement for future clinical trials.},
}
@article {pmid42577455,
year = {2026},
author = {Sabari Vasan, S and Jayalakshmi, P},
title = {TriFusion-ADFormer: a deep learning framework for early Alzheimer's disease detection using MRI and cognitive metrics.},
journal = {Frontiers in artificial intelligence},
volume = {9},
number = {},
pages = {1849315},
pmid = {42577455},
issn = {2624-8212},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with the gradual loss of cognitive functions and neuronal degeneration. Early and accurate diagnosis is essential for timely therapeutic intervention and improved patient management. However, effectively integrating complementary multimodal information for reliable AD classification remains a significant challenge.<br><br>METHODS: This study proposes TriFusion-ADFormer, a multimodal deep learning framework for multiclass classification of Alzheimer's disease (AD), mild cognitive impairment (MCI), and cognitively normal (CN) subjects. The framework extracts structural MRI features and MRI-derived clinical text summary based on volumetric measurements and cognitive assessment features such as MMSE, GDS, Global CDR, FAQ, and NPI-Q, then fuses them to classify the disease.<br><br>RESULTS: The proposed TriFusion-ADFormer achieved an overall classification accuracy of 86.0%, a Macro AUC of 0.93, and an F1-score of 86.0% for multiclass AD classification. Moreover, the MRI-based clinical summaries were also consistently consistent with structural abnormalities typically associated with AD, such as diffuse brain atrophy, which further supports the interpretability of the proposed framework.<br><br>DISCUSSION: The results show that the combination of multimodal information from structural MRI, semantic clinical summary generated from the MRI, and cognitive assessment scores enhances the accuracy and interpretability of Alzheimer's diagnosis. The results highlight the potential of incorporating complementary imaging, semantic, and cognitive features for better multiclass classification of AD, MCI, and CN in a transformer framework.},
}
@article {pmid42577511,
year = {2026},
author = {Tulupova, TV and Vedunova, MV and Mitroshina, EV},
title = {The prognostic potential of circulating BDNF levels and its polymorphisms in age-related cognitive impairment and neurodegeneration.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1901527},
pmid = {42577511},
issn = {1663-4365},
abstract = {Brain-derived neurotrophic factor (BDNF) is essential for neuronal survival, synaptic plasticity, and cognitive function. Age-related decline in BDNF signaling has been implicated in the pathogenesis of Alzheimer's disease, Parkinson's disease, and mild cognitive impairment. However, the prognostic value of circulating BDNF and its genetic variants remains controversial due to inconsistent findings across studies. This review synthesizes current evidence on peripheral BDNF levels and the Val66Met polymorphism as potential biomarkers of age-related cognitive decline and neurodegeneration. We critically analyze biological mechanisms linking BDNF to neurodegeneration, including its interaction with amyloid-beta and tau pathology. We further examine factors underlying discrepant results: demographic characteristics, comorbidities, lifestyle factors, pharmacological interventions, and methodological variability. Despite these challenges, BDNF remains a promising diagnostic factor. Nevertheless, standardizing preanalytical protocols and accounting for patient heterogeneity are essential to unlock its diagnostic potential.},
}
@article {pmid42577545,
year = {2026},
author = {Senapati, SG},
title = {Insulin resistance, aging biology, and non- communicable chronic diseases: a narrative review of bidirectional mechanisms and translational implications.},
journal = {Frontiers in endocrinology},
volume = {17},
number = {},
pages = {1891078},
pmid = {42577545},
issn = {1664-2392},
mesh = {Humans ; *Insulin Resistance/physiology ; *Aging/metabolism/physiology ; Animals ; *Noncommunicable Diseases/epidemiology ; Hyperinsulinism/metabolism ; Chronic Disease ; },
abstract = {BACKGROUND: Insulin resistance has been considered a metabolic disorder related to obesity, metabolic syndrome, and type 2 diabetes mellitus. Growing evidence points to possible interactions between insulin resistance and hyperinsulinemia and the biological aging process and age-related non-communicable diseases, like cardiovascular disease, neurodegenerative disorders, sarcopenia, frailty, adipose tissue dysfunction, chronic kidney disease, and liver disease. Most published associations lack causality, and some biological aging mechanisms may also independently increase the risk for both insulin resistance and chronic disease.<br><br>AIM: In this narrative review, we summarize bidirectional connections between insulin resistance, compensatory hyperinsulinemia, aging biology, and age-related non-communicable diseases and the quality of existing data.<br><br>METHODS: We performed a structured narrative literature review for mechanistic, translational, omics, epidemiologic, and intervention studies on the connection between insulin resistance and biological mechanisms of aging and chronic disease.<br><br>RESULTS: Mechanisms of age-related disease that may be affected by insulin resistance include insulin/IGF-1 signaling disruption, hyperinsulinemia, mitochondria dysfunction, oxidative stress, endothelial dysfunction, adipokine imbalance, chronic low-grade inflammation, cell senescence, ectopic lipids accumulation, AGE-RAGE signaling, and autophagy impairment. Aging mechanisms, such as cell senescence, mitochondria dysfunction, inflammaging, altered nutrient sensing, impaired proteostasis, adipose tissue remodeling, and physical inactivity may contribute to insulin resistance. Quality of evidence differs from strong to associative and exploratory depending on disease domain.<br><br>CONCLUSION: It is important to understand insulin resistance as an important mediator in reciprocal network of connections between metabolism, biological aging, and age-related chronic diseases, rather than one of the causes of aging.},
}
@article {pmid42577708,
year = {2026},
author = {Gelman, A and Nielsen, LK and Hansen, C},
title = {A Novel Plate Reader-Based Protocol for Measurement of DNAJB6 Dimerization Activity.},
journal = {Bio-protocol},
volume = {16},
number = {15},
pages = {e5776},
pmid = {42577708},
issn = {2331-8325},
abstract = {Progressive neurodegeneration linked to the accumulation of misfolded proteins is a hallmark of several neurodegenerative disorders, including Parkinson's disease, Huntington's disease, and Alzheimer's disease. Dysfunction in the protein homeostasis machinery correlates with pathology. The chaperone protein DNAJB6 is expressed in neurons and oligodendrocytes and has been shown to play a key role in preventing amyloid aggregation by binding to amyloidogenic proteins and facilitating their refolding or degradation, in cooperation with other chaperones. Here, we describe a simple and feasible assay that enables high-throughput screening for DNAJB6 activity in a plate reader format. We use genetically engineered HEK293 cells that stably express DNAJB6 fused to either CFP or YFP. These cells can be plated into multi-well plates, and the fluorescence resonance energy transfer (FRET) signal can be measured for analysis of DNAJB6 dimerization, which is linked to DNAJB6 activity. The protocol can be used for drug screening and to identify compounds that increase DNAJB6 dimerization, and can serve as a starting point for finding new medicines that act through modulating DNAJB6 activity. Key features • The protocol requires a plate reader capable of FRET analysis and bandwidth adjustment for CFP/YFP separation. It was developed using a CLARIOstar plate reader. • The protocol requires access to the authors' FRET DNAJB6 cell line or equivalent cells with stable expression of CFP/YFP-DNAJB6. • The assay measures DNAJB6 dimerization and can potentially be adapted to other proteins whose functional state is linked to dimerization activity. • The protocol is useful for compound screening purposes and requires pre-existing knowledge of basic cell culture.},
}
@article {pmid42578020,
year = {2026},
author = {Riccardi, C and Napolitano, E and Platella, C and Conte, A and Paladino, S and Musumeci, D and Montesarchio, D},
title = {Lipid-conjugated Ru(iii) complexes as inhibitors of pathological peptide aggregation in neurodegenerative disorders.},
journal = {RSC medicinal chemistry},
volume = {},
number = {},
pages = {},
pmid = {42578020},
issn = {2632-8682},
abstract = {Neurodegenerative diseases (NDs), characterized by the progressive loss of neuronal homeostasis and function, represent an increasing global health burden. Their severity and profound impact on quality of life highlight the urgent need for effective and targeted therapeutic strategies. Recent studies have drawn attention to the potential of certain Ru(iii) complexes, including NAMI-A and KP1019, as promising therapeutic candidates for NDs. Originally developed as anticancer agents, these compounds have demonstrated remarkable activity in inhibiting the aggregation of model misfolded proteins, which represent a common pathological feature of various neurological disorders. Herein, searching for Ru(iii) complexes which could be effective as anti-neurodegenerative agents, we selected AziRu - a NAMI-A-like compound - and some of its lipid-conjugated derivatives, previously explored as anticancer drug candidates, and tested them for their ability to interfere with the self-aggregation of selected model peptides involved in the pathogenesis of NDs, such as Alzheimer's disease (AD), Parkinson's disease (PD) and prion diseases. Among them, the Ru(iii) complexes we named MyriPyRu and PalmiPyRu, bearing myristic and palmitic acid-based tails, respectively, emerged as promising candidates. These complexes effectively modulated and inhibited the aggregation of amyloid peptides linked to AD pathogenesis with IC50 values in the low micromolar range (ca. 5 μM for both compounds). More detailed studies on their interaction with AD peptides revealed their capacity to be coordinated by histidine residues in the N-terminal region. Biological investigations on human neuroblastoma-derived cells indicated no relevant cytotoxicity at concentrations comparable to those that caused anti-aggregation effects. Overall, these findings are highly promising, as MyriPyRu or PalmiPyRu could be the starting compounds to evolve further modified derivatives functionalized with specific targeting moieties for amyloid peptides, potentially paving the way to a new generation of Ru(iii)-based anti-amyloid agents for the treatment of Alzheimer's disease.},
}
@article {pmid42578069,
year = {2026},
author = {Chen, HW},
title = {Active Craniospinal Tensioning (ACT) for Posture Correction and Spinal Decompression: Biomechanical Rationale for Glymphatic Clearance and Cerebral Venous Preconditioning (CVPC).},
journal = {Cureus},
volume = {18},
number = {7},
pages = {e112433},
pmid = {42578069},
issn = {2168-8184},
abstract = {For approximately two-thirds of each 24-hour period, the upright human spine bears a continuous gravitational load; yet no common movement or exercise naturally produces meaningful axial decompression of the entire spine. Active craniospinal tensioning (ACT) addresses this unmet need through a brief, self-administered squat maneuver against an overhead anchor, intended to generate reproducible axial spinal decompression without specialized equipment. This report, which extends a previously published series on axial spinal traction, presents ACT as a postural correction and spinal decompression intervention. Building on those findings, a second distinct hypothesis is advanced: that two transient physiological events occurring simultaneously during the maneuver may together acutely accelerate glymphatic clearance. The first is a cerebrospinal fluid (CSF) pressure gradient generated during traction and rapidly reversed upon release, as detailed in the previous technical reports; the second is suboccipital venous occlusion during the tensioning phase, followed by a rebound upon release. The second mechanism, suboccipital venous occlusion-rebound, is further proposed as a novel venous-side modality for cerebral venous preconditioning (CVPC), distinct from existing arterial-based ischemic preconditioning approaches, whether local or remote (e.g., remote ischemic preconditioning (RIPC)). Diffusion tensor image analysis along the perivascular space (DTI-ALPS) is proposed as the primary falsifiable endpoint for the glymphatic clearance hypothesis, which does not itself test the separately proposed CVPC effect of suboccipital venous occlusion-rebound. If confirmed, this endpoint would support glymphatic clearance as an additional mechanism of ACT, positioning ACT, alongside its proposed roles in posture correction, spinal decompression, and cerebral venous preconditioning (CVPC), as a brief, self-administered maneuver addressing multiple physiological targets through daily applications totaling less than one minute, without specialized equipment or clinical access.},
}
@article {pmid42578101,
year = {2026},
author = {Chandra, G and Rangasamy, SB and Pahan, K},
title = {Corrected Version: Neutralization of RANTES and Eotaxin Prevents the Loss of Dopaminergic Neurons in a Mouse Model of Parkinson's Disease.},
journal = {Journal of clinical &amp; experimental immunology},
volume = {11},
number = {3},
pages = {},
pmid = {42578101},
abstract = {Parkinson's disease (PD) is second only to Alzheimer's disease as the most common human neurodegenerative disorder. Despite intense investigation, no interdictive therapy is available for PD. Recent studies indicate that both innate and adaptive immune processes are active in PD. Accordingly, we found rapid increase in RANTES (regulated on activation, normal T cell expressed and secreted) and eotaxin, chemokines that are involved in T cell trafficking, in vivo in the substantia nigra pars compacta (SNpc) and the serum of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mice. RANTES and eotaxin were also upregulated in the SNpc of postmortem PD brains as compared to age-matched controls. Therefore, we investigated whether neutralization of RANTES and eotaxin could protect against nigrostriatal degeneration in MPTP-intoxicated mice. Interestingly, after peripheral administration, functional blocking antibodies against RANTES and eotaxin reduced the infiltration of CD4+ and CD8+ T cells into the nigra, attenuated nigral expression of proinflammatory molecules, and suppressed nigral activation of glial cells. These findings paralleled dopaminergic neuronal protection, normalized striatal neurotransmitters, and improved motor functions in MPTP-intoxicated mice. Therefore, we conclude that attenuation of chemokine-dependent adaptive immune response may be of therapeutic benefit for PD patients.},
}
@article {pmid42578165,
year = {2026},
author = {Kachhadia, MP and Puri, P and Topiwala, U and Shaikh, JD and Gill, G and Gupta, S and Byrus, M and Sanghvi, HA},
title = {Retinal Artery Occlusion and Incident Dementia in the All of Us Research Program: Detection Bias Calibration with Prespecified Negative-Control Outcomes.},
journal = {Journal of clinical medicine research},
volume = {18},
number = {7},
pages = {489-495},
pmid = {42578165},
issn = {1918-3003},
abstract = {BACKGROUND: Retinal artery occlusion (RAO) shares vascular pathophysiology with cerebrovascular disease, and its relationship to incident dementia remains unsettled. Reported associations may reflect shared vascular pathology, differential ascertainment along the intensive workup pathways that RAO patients enter, or both. No prior study has calibrated RAO-dementia estimates against prespecified negative-control outcomes spanning distinct ascertainment pathways.<br><br>METHODS: Among 129,279 All of Us participants aged 50 years or older and free of prevalent dementia (controlled-tier release R2024Q3R9, OMOP common data model), strict RAO was defined by seven verified SNOMED concept identifiers (n = 339). Incident dementia required two or more codes at least 30 days apart (Wilkinson algorithm), with prespecified vascular and Alzheimer subtypes. Cox models used age as timescale with left truncation and time-varying exposure; 1:5 propensity-score matching was the primary confounder-adjusted analysis. Cataract, benign paroxysmal positional vertigo (BPPV), and inguinal hernia were prespecified negative controls for ophthalmology, neurology, and general-contact pathways.<br><br>RESULTS: There were 1,506 incident dementia events. RAO was not associated with all-cause dementia (unmatched hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.40-1.64; matched HR 1.33, 95% CI 0.72-2.47; 10 exposed events). The vascular dementia estimate remained elevated but imprecise (unmatched HR 1.93, 95% CI 1.02-3.66; matched HR 1.81, 95% CI 0.66-4.94; 3 exposed events). Cataract was elevated (HR 1.87, 95% CI 1.45-2.42), whereas BPPV (HR 1.27, 95% CI 0.90-1.79) and hernia (HR 1.10, 95% CI 0.68-1.78) were not.<br><br>CONCLUSIONS: We found no evidence that RAO is independently associated with incident dementia, replicating a large European null finding in a diverse United States cohort. The cohort was underpowered to exclude clinically meaningful effects, particularly for vascular dementia. Detection bias in this dataset was demonstrably pathway-specific, but same-pathway calibration accounts for only part of the residual vascular dementia estimate.},
}
@article {pmid42578315,
year = {2026},
author = {Chib, S and Shukla, S and Sharma, K and Singh, R},
title = {Luteolin and neurodegenerative disease modulation: linking molecular mechanisms, neurotransmission, and pharmacokinetics.},
journal = {Nutritional neuroscience},
volume = {},
number = {},
pages = {1-18},
doi = {10.1080/1028415X.2026.2700760},
pmid = {42578315},
issn = {1476-8305},
abstract = {Neurodegenerative disorders arise from the convergence of oxidative stress, neuroinflammation, synaptic dysfunction, mitochondrial failure, and dysregulated cell death, highlighting the need for therapeutic agents capable of coordinated, multi-target modulation. Luteolin (3',4',5,7-tetrahydroxyflavone), a dietary flavonoid widely present in edible and medicinal plants, has emerged as a promising neuroactive compound with pleiotropic biological actions. Rather than focusing on isolated outcomes, this review presents an integrated summary of how luteolin orchestrates interconnected signaling networks, with receptor-level neuromodulation and neuroimmune regulation to preserve neuronal integrity. Particular emphasis is placed on pathway convergence, cross-talk, and system-level neuroprotection across models of Alzheimer's disease, Parkinson's disease, and related disorders. In parallel, pharmacokinetic behavior, metabolite activity, and emerging delivery strategies are examined in relation to mechanistic efficacy. By linking molecular signaling, neurotransmission and therapeutic feasibility within a unified framework, this review offers a refined perspective on role of luteolin in neurodegenerative disease modulation.},
}
@article {pmid42578516,
year = {2026},
author = {Seo, SH and Lee, JE and Cho, EJ and Shin, EH},
title = {Attenuation of Tau Hyperphosphorylation by Chronic Toxoplasma gondii Infection in a Mouse Model of Alzheimer's Disease.},
journal = {Parasite immunology},
volume = {48},
number = {8},
pages = {e70096},
doi = {10.1111/pim.70096},
pmid = {42578516},
issn = {1365-3024},
support = {RS-2025-00516274//NKorea Government (MSIT)/ ; RS-2025-00559259//NKorea Government (MSIT)/ ; },
mesh = {Animals ; *tau Proteins/metabolism/genetics ; *Alzheimer Disease/pathology/parasitology/metabolism ; Disease Models, Animal ; Phosphorylation ; Mice ; Brain/pathology/parasitology/metabolism ; Amyloid beta-Peptides/metabolism ; *Toxoplasma/immunology ; *Toxoplasmosis/metabolism ; Female ; Chronic Disease ; Mice, Transgenic ; },
abstract = {Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) peptide accumulation and tau protein-mediated neurodegeneration, and neuroinflammation is increasingly recognized as a major process associated with tau pathology. Chronic Toxoplasma gondii infection reduces amyloid accumulation in AD models through immune modulation, but its stage-specific associations with tau-related pathology remain unclear. Here, we investigated how chronic T. gondii infection is associated with tau-related molecular and neuropathological changes in the 5XFAD AD mouse model. At 40 weeks post-infection, we profiled transcriptomic changes and evaluated Aβ-associated (21 genes), Aβ/tau-shared (22 genes), and tau-associated (21 genes) pathological programs together with p-tau immunoreactivity in brain sections. Chronic infection was associated with selective modulation of molecular networks linked to neuroimmune signalling and tau-related pathways rather than broad suppression of AD-related gene expression. Among tau-related pathological stages, the neuroinflammation-related amplification module linking Aβ and tau exhibited the most prominent transcriptomic change in T. gondii-infected AD mice, whereas upstream kinase-related initiation pathways and downstream toxin conversion or accumulation-related processes changed relatively minimally. These transcriptomic changes were accompanied by a marked reduction in phosphorylated tau load at the tissue level. Collectively, these findings suggest that chronic T. gondii infection is associated with selective modulation of tau-related pathogenic programs and reduced p-tau burden in the 5XFAD brain.},
}
@article {pmid42578598,
year = {2026},
author = {Gameiro, GR and Hoover, A and Schor, P and Jiang, H and Wang, J},
title = {Reduced Retinal Perfusion With Preserved Microvascular Network Density in Early Alzheimer's Disease: A Multimodal Imaging Study.},
journal = {Translational vision science &amp; technology},
volume = {15},
number = {8},
pages = {7},
doi = {10.1167/tvst.15.8.7},
pmid = {42578598},
issn = {2164-2591},
mesh = {Humans ; *Alzheimer Disease/physiopathology/diagnostic imaging ; Female ; *Retinal Vessels/physiopathology/diagnostic imaging ; Male ; Tomography, Optical Coherence/methods ; Aged ; *Multimodal Imaging/methods ; Regional Blood Flow/physiology ; Cognitive Dysfunction/physiopathology/diagnostic imaging ; *Microvessels/diagnostic imaging ; *Microvascular Density/physiology ; Aged, 80 and over ; *Retina/diagnostic imaging/physiopathology ; },
abstract = {PURPOSE: To characterize retinal neurovascular alterations in Alzheimer's disease (AD) and mild cognitive impairment (MCI) and examine structure-function relationships.<br><br>METHODS: Eighty-two participants (28 with AD, 21 with MCI, and 33 cognitively normal controls) underwent retinal imaging. Retinal blood flow (RBF) was measured using a function imager. Retinal vessel density (RVD), retinal vessel length density (RVLD), vessel width, and capillary perfusion density (CPD) were quantified with optical coherence tomography (OCT) angiography and retinal tissue volume (RTV) with ultra-high-resolution OCT. Derived metrics included retinal tissue perfusion (RTP), retinal capillary flow index (RCF), and volumetric vessel density. Group comparisons and age-adjusted correlations were performed.<br><br>RESULTS: Compared with controls, the combined AD + MCI group had significantly lower RBF (3.18 &#xb1; 1.02 vs. 4.22 &#xb1; 0.79 nL/s; P < 0.001), RCF (0.21 &#xb1; 0.07 vs. 0.26 &#xb1; 0.04 nL/s/mm; P < 0.001), and RTP (2.89 &#xb1; 0.94 vs. 3.86 &#xb1; 0.77 nL/s/mm3; P < 0.001). Morphometric indices of the perfused capillary network and retinal tissue volume (RVD, RVLD, CPD, vessel width, RTV) did not differ (all P > 0.05). In AD + MCI, RBF was not associated with structural or morphometric microvascular metrics, whereas controls exhibited age-adjusted correlations between RBF and vessel density and length density.<br><br>CONCLUSIONS: AD and MCI are characterized by reduced retinal perfusion and capillary flow index despite preserved network density and retinal tissue volume, suggesting altered retinal hemodynamic-morphometric relationships.<br><br>TRANSLATIONAL RELEVANCE: Hemodynamic retinal imaging detects early perfusion impairment in AD and MCI before changes in microvascular network density or retinal tissue volume, offering a noninvasive biomarker for detection and therapeutic monitoring.},
}
@article {pmid42578810,
year = {2026},
author = {Welty, S and Bagnell, M and Ma, F and Herrup, K and Levine, AS},
title = {Effects of damaged astrocytes on DNA damage and repair in human neurons: Implications for Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261476036},
doi = {10.1177/13872877261476036},
pmid = {42578810},
issn = {1875-8908},
abstract = {BackgroundStudies suggest a strong association between astrocytes, neuronal DNA damage, elevated amyloid-β, and brain degeneration in Alzheimer's disease (AD).ObjectiveThis study aimed to show whether astrocytes with damaged DNA affect human neuronal progenitor cells (NPCs) or differentiated neurons in close proximity, dependent on astrocytic APOE allele expression.MethodsImmortalized human astrocytes (hTERT) expressing APOE were treated with etoposide to induce DNA damage and co-cultured in a transwell system with human NPCs or differentiated neurons. We used western blotting and immunostaining to evaluate the DNA damage response of the NPCs and neurons.ResultsUndamaged NPCs showed increased DNA damage when co-cultured with damaged astrocytes. The astrocytic APOE genotype had little to no effect on the transcellular damage response. NPCs overexpressing the amyloid-β protein precursor responded more robustly when co-cultured with damaged astrocytes. Differentiated neurons showed no significant changes in their DNA damage response to damaged astrocytes.ConclusionsThis study is the first to demonstrate that astrocytic DNA damage may contribute to early stages of neuronal pathology in AD by inducing a DNA damage response in vulnerable neuronal populations.},
}
@article {pmid42570809,
year = {2026},
author = {Wang, J and Liu, Y and Jiang, C and Wang, D and Wang, J and Feng, G and Zhong, B},
title = {Transferrin receptor upregulation mediates homocysteine-induced cytotoxicity in cerebral endothelial cells.},
journal = {Brain research},
volume = {},
number = {},
pages = {150486},
doi = {10.1016/j.brainres.2026.150486},
pmid = {42570809},
issn = {1872-6240},
abstract = {Hyperhomocysteinemia (HHcy) is a recognized risk factor for cognitive impairment, including Alzheimer's disease, but the mechanisms linking homocysteine (Hcy) accumulation to cerebral dysfunction remain unclear. Brain microvascular endothelial cells (BMECs) are an important cellular component of the blood-brain barrier (BBB) and play a key role in maintaining central nervous system homeostasis. However, how Hcy affects BMECs remains incompletely understood. In this study, we used the human brain microvascular endothelial cell line hCMEC/D3 to determine the half-maximal inhibitory concentration (IC50) of Hcy by CCK-8 assay, and then performed transcriptomic analysis to identify Hcy-regulated genes associated with endothelial cell injury. Hcy reduced hCMEC/D3 cell viability in a dose-dependent manner, with an IC50 of approximately 12.25 mM; therefore, 10 mM Hcy was selected for subsequent experiments. Transcriptomic sequencing revealed significant upregulation of the transferrin receptor (Tfrc) gene, which we confirmed by quantitative real-time PCR and Western blot analysis. Functionally, TFRC overexpression mimicked the Hcy-induced reduction in cell viability, whereas TFRC knockdown partially rescued cells from Hcy-induced cytotoxicity. TFRC overexpression reduced hCMEC/D3 cell viability, whereas TFRC knockdown partially alleviated Hcy-induced cytotoxicity. These results suggest that TFRC is involved in Hcy-induced injury of brain microvascular endothelial cells. Taken together, our in vitro findings provide a possible clue for future in vivo studies on HHcy-associated BBB dysfunction.},
}
@article {pmid42570992,
year = {2026},
author = {Cai, W and Pan, X and Qian, T and Yu, S and Zhao, R and Zhu, C and Sang, S and Zhong, C},
title = {An ApoE-Associated Low-Inflammatory Microglial State Emerges After Inflammatory Challenge in Alzheimer's Disease Mice.},
journal = {Neuroscience bulletin},
volume = {},
number = {},
pages = {},
pmid = {42570992},
issn = {1995-8218},
abstract = {Patients with Alzheimer's disease (AD) frequently experience inflammatory insults; however, the mechanisms by which microglia respond to these challenges remain unclear. Although AD microglia have been proposed to be primed for exaggerated inflammatory responses, single-cell evidence remains limited. To investigate microglial responses to inflammation in AD, we challenged AD mouse models with intraperitoneal lipopolysaccharide (LPS) and used single-cell RNA sequencing to characterize microglial states, along with in vivo immunostaining and in vitro models to define their features and underlying mechanisms. We found that, in response to an inflammatory challenge, microglia adopted a low-inflammatory state accompanied by elevated expression of mitochondrial respiratory chain genes. This state was associated with the phagocytosis of dystrophic neurites and was recapitulated in vitro using an efferocytosis-based model, with apolipoprotein E implicated in its underlying mechanism. In summary, we identified a distinct microglial state that provides new insights into the dynamic role of microglia in AD.},
}
@article {pmid42571023,
year = {2026},
author = {Frings, L and Brumberg, J and Meyer, PT},
title = {Semantic fluency predicts survival of memory clinic patients.},
journal = {Alzheimer's research &amp; therapy},
volume = {18},
number = {1},
pages = {},
pmid = {42571023},
issn = {1758-9193},
mesh = {Humans ; Female ; Male ; Aged ; Positron-Emission Tomography ; Neuropsychological Tests ; *Alzheimer Disease/mortality/diagnostic imaging ; Fluorodeoxyglucose F18 ; Aged, 80 and over ; *Semantics ; Predictive Value of Tests ; Registries ; Brain/diagnostic imaging/metabolism ; *Memory Disorders/mortality/diagnostic imaging ; },
abstract = {BACKGROUND: Semantic fluency is commonly assessed in the diagnostic work-up of individuals with suspected cognitive impairment due to neurodegenerative disease. Semantic fluency has a predictive value for survival in clinical AD and in healthy elderly individuals, but it is unknown if this also applies to biomarker-confirmed AD and non-AD memory clinic patients. Potential associations with and added value of imaging biomarkers of amyloid pathology and neurodegeneration have yet to be explored.<br><br>METHODS: From our clinical registry, we included patients who were assessed at a memory clinic with the neuropsychological assessment battery of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD-NAB) and whose vital status could be retrieved in 07/2024. We tested the association of semantic fluency performance at first assessment and over time (and, for comparison, further CERAD-NAB subtest scores) with mortality risk using age-adjusted single-predictor Cox proportional hazard models. Amyloid status (positive vs negative on clinical PET reads) and global cognitive impairment (MMSE) were included as covariates. In addition, we explored associations between semantic fluency performance and both regional cortical glucose metabolism (FDG PET) and global amyloid load (centiloids; PiB PET). Finally, the predictive value of global amyloid load and glucose metabolism in comparison to and in combination with semantic fluency performance was assessed.<br><br>RESULTS: 583 patients were included (age 68.9&#x2009;&#xb1;&#x2009;8.7, 45% female). 280 patients (48%) had died and 303 (52%) were alive after a median of 8.0&#xa0;years [95% C.I. 7.7-8.4]. Better semantic fluency (age-, sex- and education adjusted Z score, based on normative data) was significantly associated with lower mortality risk (HR&#x2009;=&#x2009;0.71 [0.63 - 0.80], Bonferroni-corrected p&#x2009;<&#x2009;0.001). Its predictive value was higher than that of all other CERAD-NAB subscores (e.g., memory, visuospatial abilities). Semantic fluency remained a significant predictor when amyloid status and global cognitive impairment were accounted for (HR&#x2009;=&#x2009;0.75 [0.61 - 0.91], p&#x2009;=&#x2009;0.0035). In patients with more than one assessment (N&#x2009;=&#x2009;163), longitudinal change of semantic fluency (derived from a linear mixed effects model) was also a significant predictor (HR&#x2009;=&#x2009;0.66 [0.53-0.83], p&#x2009;<&#x2009;0.001). In 218/583 patients who had received amyloid and FDG PET, worse semantic fluency was associated with decreased FDG uptake of left inferior and middle temporal, dorsolateral frontal, and posterior parietal cortical regions (Bonferroni-corrected p&#x2009;<&#x2009;0.05), but not with amyloid load. FDG uptake of the left IFG (pars opercularis) was itself a predictor of survival (HR&#x2009;=&#x2009;0.68 [0.55 - 0.84], Bonferroni-corrected p&#x2009;<&#x2009;0.05), but to a lesser degree than semantic fluency (and MMSE, naming and figure drawing). Predictive accuracy of semantic fluency was further improved by including FDG uptake of the right anterior cingulate (Bonferroni-corrected p&#x2009;=&#x2009;0.078). Global amyloid load was not associated with survival.<br><br>CONCLUSIONS: Survival of memory clinic patients can be predicted by semantic fluency, independently from amyloid status and global cognitive impairment. Anterior cortical glucose metabolism is itself a significant predictor of survival and slightly improves prediction by semantic fluency.},
}
@article {pmid42571045,
year = {2026},
author = {Marvanova, M},
title = {Comment on "Review of Donanemab and Lecanemab in Mild Dementia Stage of Alzheimer's Disease: Progress and Challenges".},
journal = {The Senior care pharmacist},
volume = {41},
number = {5},
pages = {157-158},
doi = {10.4140/TCP.n.2026.157},
pmid = {42571045},
issn = {2639-9636},
}
@article {pmid42571047,
year = {2026},
author = {Qudoos, MA and Elliott, DP},
title = {Response to Comment on "Review of Donanemab and Lecanemab in Mild Dementia Stage of Alzheimer's Disease: Progress and Challenges".},
journal = {The Senior care pharmacist},
volume = {41},
number = {5},
pages = {159-160},
doi = {10.4140/TCP.n.2026.159},
pmid = {42571047},
issn = {2639-9636},
}
@article {pmid42571168,
year = {2026},
author = {Oxenkrug, G and Comai, S},
title = {Up-Regulation of Anthranilic Acid Formation and Pro-Cognitive Effect of Indoleamine 2,3-Dioxygenase Inhibition.},
journal = {International journal of tryptophan research : IJTR},
volume = {19},
number = {},
pages = {11786469261472317},
pmid = {42571168},
issn = {1178-6469},
abstract = {Inhibition of indoleamine 2,3-dioxygenase (IDO) is a promising therapeutic strategy for cognitive impairment in Alzheimer's disease (AD). The pro-cognitive effect is often attributed to restoring glycolysis by preventing tryptophan (Trp) conversion to kynurenine (Kyn). However, this overlooks the metabolic fate of Trp when IDO is blocked. Since IDO and tryptophan 2,3-dioxygenase (TDO) compete for the same substrate, inhibiting IDO may shunt Trp toward TDO, potentially increasing Kyn and its downstream catabolites. This commentary explores the hypothesis that the upregulation of anthranilic acid (AA), a Kyn catabolite, contributes to the cognitive benefits of IDO inhibition. Recent evidence shows elevated AA in animal models of AD and individuals with mild cognitive impairment and preclinical AD, where it may serve as an early biomarker. Notably, these elevations and the pro-cognitive effects of AA-modulating compounds like sodium benzoate exhibit sex-specificity, being more prominent in females. The mechanism may involve AA's dual action on G-protein coupled receptors: antagonism of GPR17 promotes myelination, while agonism of GPR109A may protect myelin from degradation. Preserving myelin integrity is critical, as demyelination is an early event in AD pathogenesis. We propose that AA upregulation is not merely a biomarker but part of a compensatory defense mechanism. Therefore, the pro-cognitive effect of IDO inhibition may be partly mediated by the subsequent shunting of Trp toward TDO and production of the myelin-preserving metabolite, AA. This reframes the therapeutic goal from reducing neurotoxic kynurenines to leveraging the protective potential of the entire pathway.},
}
@article {pmid42571320,
year = {2026},
author = {Pinnelli, SP and T, SB and Ca, J and Pinnelli, VB and Harikrishna, GV and Mudamanchu, VK and Sam, KT and Ms, D and Bhupathiraju, P and Sucharitha, AS and Kandi, V},
title = {Artificial Intelligence for the Diagnosis and Management of Neurodegenerative Diseases: A Comprehensive Review With an Emphasis on Parkinson's and Alzheimer's Diseases.},
journal = {Cureus},
volume = {18},
number = {7},
pages = {e112325},
pmid = {42571320},
issn = {2168-8184},
abstract = {Artificial intelligence (AI) is rapidly transforming research in neurodegenerative diseases, yet its clinical translation remains limited. We conducted a structured literature search across Google Scholar, PubMed, Scopus, and Web of Science, screening studies published between 2015 and April 2026 that applied machine learning (ML), deep learning (DL), and multimodal data integration to neuroimaging, biomarkers, and digital phenotyping. Our analysis revealed that AI models demonstrate strong potential for differentiating disease subtypes, predicting progression, and enhancing diagnostic accuracy, with notable advances in neuroimaging interpretation, fluid biomarker analysis, and wearable sensor data. In Parkinson's disease (PD), digital phenotyping through gait, speech, and handwriting analysis has enabled sensitive monitoring, while in Alzheimer's disease (AD), AI applied to imaging and plasma biomarkers has improved risk stratification. Despite these advances, barriers such as dataset heterogeneity, label noise, lack of external validation, and ethical concerns regarding bias, transparency, and patient trust persist. We conclude that while AI holds promise to revolutionize the care of PD and AD, real-world adoption requires multicenter validation, standardized reporting frameworks, regulatory guidance, and interdisciplinary collaboration, alongside prospective trials that embed AI tools into clinical workflows to ensure safety, equity, and effectiveness.},
}
@article {pmid42571323,
year = {2026},
author = {Jiménez-Mausbach, M and Tijms, BM and Paterson, C and Refsgaard, JC},
title = {Semaglutide attenuates a proteomics-based dementia risk signature in older adults with overweight or obesity and cardiovascular disease without diabetes: A post hoc analysis of the SELECT phase 3 trial.},
journal = {Alzheimer's &amp; dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70432},
pmid = {42571323},
issn = {2352-8729},
abstract = {INTRODUCTION: Plasma proteomics detect multi-pathway biological changes preceding dementia onset. The Dementia SomaSignal Test (dSST) is a validated 25-protein score predicting 5- and 20-year all-cause dementia risk. Preclinical and clinical data suggest glucagon-like peptide-1 receptor agonists may have neuroprotective effects.<br><br>METHODS: In a post hoc analysis of the Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity (SELECT) trial, adults &#x2265; 65 years with overweight/obesity and cardiovascular disease without diabetes (n&#xa0;=&#xa0;2970) were randomized to semaglutide 2.4&#xa0;mg or placebo. Non-fasted serum samples at baseline and week 104 were analyzed using the dSST.<br><br>RESULTS: Semaglutide reduced increases in predicted dementia risk versus placebo: 2.5-fold less increase in 5-year risk (26.0% lower predicted event rate; odds ratio [OR] 0.74, 95% confidence interval [CI] 0.65-0.85) and 1.67-fold less increase in 20-year risk (8.8% lower; OR 0.91, 95% CI 0.88-0.94). It also reduced odds of higher dementia risk classification by 36% (&#x3b2; -0.44; P&#xa0;<&#xa0;0.001).<br><br>DISCUSSION: Semaglutide slowed progression of a validated proteomics-based dementia risk signature.},
}
@article {pmid42571406,
year = {2026},
author = {Urso, D and Nichols, E and Giannoni-Luza, S and Brayne, C and Ray, N and Logroscino, G},
title = {Burden of Dementia in Europe, 1990-2023: a systematic analysis from the Global Burden of Disease Study 2023.},
journal = {The Lancet regional health. Europe},
volume = {68},
number = {},
pages = {101796},
pmid = {42571406},
issn = {2666-7762},
abstract = {BACKGROUND: Dementia is a leading cause of disability and mortality in Europe, yet no recent harmonised assessment has described its impact across the European Union (EU-27) and the WHO European Region.<br><br>METHODS: We used data from the Global Burden of Disease Study 2023 (GBD 2023) to estimate prevalence, mortality, and disability-adjusted life years (DALYs) for dementia from 1990 to 2023. Estimates were produced for the EU-27 and the WHO European Region, by age and sex. Non-fatal outcomes were modelled using DisMod-MR 2.1, and dementia-attributable mortality was estimated using an excess-mortality framework. We also quantified DALYs attributable to six modifiable risk factors.<br><br>FINDINGS: In 2023, 7.76 million people (95% UI 6.69-8.72) were living with dementia in the EU-27 and 12.28 million (10.44-13.90) in the WHO European Region, representing &#x223c;90% increases since 1990 despite modest declines in age-standardised prevalence. Prevalence was nearly twice as high in women as in men. Dementia rose from the eighth to the third leading cause of death in the EU-27. Dementia accounted for 5.49 million DALYs (2.44-11.41) in the EU-27. An estimated 41% (24.4-57.4) of dementia DALYs in the EU-27 were attributable to modifiable risk factors, particularly ambient particulate matter pollution, high fasting plasma glucose, and high body-mass index, which are disproportionately concentrated in socioeconomically disadvantaged populations.<br><br>INTERPRETATION: Despite modest declines in age-standardised rates, the absolute burden of dementia in Europe continues to rise, driven by population ageing. The substantial contribution of modifiable risk factors highlights major opportunities for prevention. Robust, country-specific estimates are essential to guide integrated strategies combining prevention and care planning.<br><br>FUNDING: Regione Puglia and CNR for Tecnopolo per la Medicina di Precisione; Regione Puglia for the national "Fund for Alzheimer's and Dementia 2021-2023" (Piano Regionale Demenze 2021/2023).},
}
@article {pmid42571433,
year = {2026},
author = {Kloosterman, M and Vongpromek, R and Friesema, ECH and Bramer, W and Verhoeven, AJM and Mulder, MT},
title = {LR11/SorLA and its role in cardiovascular disease.},
journal = {International journal of cardiology. Heart &amp; vasculature},
volume = {66},
number = {},
pages = {101982},
pmid = {42571433},
issn = {2352-9067},
abstract = {Cardiovascular diseases account for the highest morbidity worldwide. LR11 (also called SorLA), an LDL receptor family member characterized as a sorting receptor, was initially identified in the brain and has a causative role in the development of Alzheimer's disease. However, LR11, and its circulating shed isoform, sLR11, are also associated to cardiovascular diseases and risk factors for atherosclerosis, such as obesity and diabetes. In the current narrative review, we discuss that elevation of plasma sLR11 levels can result from different forms of vascular injury, but also plays a role in subsequent vascular remodeling. We provide an overview of the mechanisms whereby LR11 promotes vascular remodeling and thereby atherosclerosis and how it could be involved in obesity and diabetes. Furthermore, we discuss the possibilities of (s)LR11 as a biomarker and therapeutic target for cardiovascular diseases.},
}
@article {pmid42571539,
year = {2026},
author = {Nguyen, HD and Siddiqui, S and Bohannon, DG and Blair, RV and Deng, HW and Prat, A and Kim, WK},
title = {Single-cell transcriptomic analysis reveals age-related remodeling of brain endothelial cells.},
journal = {Aging brain},
volume = {10},
number = {},
pages = {100164},
pmid = {42571539},
issn = {2589-9589},
abstract = {Blood-brain barrier (BBB) integrity naturally declines with age. Brain endothelial cells (ECs) and pericytes (PCs) form the BBB, and aging impairs tight junctions, likely via altered PC-to-EC signaling. However, the molecular mechanisms underlying this impairment remain unclear. Using single-cell RNA sequencing, we profiled 68,316 brain ECs expressing 15,564 genes from young and old mice. Unsupervised clustering and annotation revealed five distinct EC subtypes-Capillary EC1, Capillary EC2, Arterial EC, Venous EC1, and Venous EC2-defined by marker genes Mfsd2a, Plvap, Bmx, Nr2f2, and Vcam1, respectively. Aging shifted EC subtype distribution, with reduced Capillary EC1 (45% vs. 57%) and increased Arterial (33% vs. 16%) and Venous ECs (12% vs. 2%) compared with young mice. Mio analysis further showed that Capillary EC1 and Venous EC2 neighborhoods were less abundant in aged brains. Biotin metabolism was decreased in old vs. young mice, particularly within Capillary EC1, Capillary EC2, and Arterial EC. Although widespread gene downregulation was observed across EC subsets, overall expression trends were largely consistent among clusters. Key genes-Ramp2, Hbb-bs, Ly6c1, Calm1-were less abundant, whereas Rasgrf2 was uniquely enriched in aged mice. Immunohistochemistry confirmed reduced LY6C and RAMP2 and elevated RASGRF2 in aged mouse and human brains. Cell-cell interaction analyses revealed age-associated remodeling of ligand-receptor signaling. Enrichment analyses implicated pathways involved in neurovascular integrity, inflammation, amyloid processing, and vascular remodeling. Collectively, these findings show that aging reprograms EC subtype composition, gene expression, and metabolism, thereby contributing to BBB disruption and neurovascular dysfunction.},
}
@article {pmid42571702,
year = {2026},
author = {Dávila-Cervantes, CA and Agudelo-Botero, M},
title = {Uneven progress in Alzheimer's disease and other dementias across Mexico, 1990-2023: updated estimates from the Global Burden of Disease Study.},
journal = {Aging &amp; mental health},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/13607863.2026.2710256},
pmid = {42571702},
issn = {1364-6915},
abstract = {OBJECTIVES: To quantify the magnitude and trends the national and subnational burden of Alzheimer's disease and other dementias (ADOD) in Mexico from 1990 to 2023, analyzing patterns by sex and age and exploring their association with the Socio-Demographic Index (SDI) and the Healthcare Access and Quality Index (HAQI).<br><br>METHOD: A secondary ecological study was conducted using updated estimates from the Global Burden of Disease and Risk Factors Study (GBD) 2023. Prevalence, incidence, mortality, and disability-adjusted life years (DALYs) were examined. Temporal trends were assessed using joinpoint regression. Pearson correlation and linear regression were used to evaluate associations between DALYs rates and SDI and HAQI.<br><br>RESULTS: Between 1990 and 2023, ADOD prevalence and incidence increased, despite significant declines in age-standardized prevalence and incidence rates. Females consistently experienced higher mortality and disability, with age-standardized DALYs rates 1.28 times those of males. The ADOD burden increased sharply with age, peaking among those aged 85&#x2009;years and older, with premature mortality accounting for 63.0% of total DALYs. A significant increase in DALYs rates occurred during 2020-2023 after previous periods of gradual decline. DALYs rates were negatively correlated with both SDI and HAQI.<br><br>CONCLUSION: ADOD disproportionately affect women, while higher modeled burden was observed in several states with lower socioeconomic development and weaker health system performance. The post-2020 increase represents an epidemiological signal warranting further investigation into excess mortality among people with dementia, healthcare disruption, social isolation, and changes in long-term care during the COVID-19 period. Strengthening early diagnosis, long-term care, and management of modifiable risk factors is essential to reduce the future burden and persistent regional and sex-based inequalities in ageing populations.},
}
@article {pmid42571730,
year = {2026},
author = {Li, Q and Li, M and Huang, X and Cao, C and Hu, Y},
title = {Integrative multi-omics analysis identifies AIF1 as an immune-associated factor linked to monocyte-centered inflammatory networks in Alzheimer's disease.},
journal = {Immunobiology},
volume = {231},
number = {5},
pages = {153229},
doi = {10.1016/j.imbio.2026.153229},
pmid = {42571730},
issn = {1878-3279},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder in which immune dysregulation has emerged as an important component of disease pathogenesis; however, the contribution of circulating proteins and their cellular context remains incompletely understood. Here, we performed an integrative multi-omics analysis combining Mendelian randomization (MR), bulk transcriptomics, single-cell RNA sequencing, and peripheral blood validation to systematically identify plasma proteins associated with AD. Proteome-wide MR analysis identified multiple circulating proteins associated with AD risk. Integration with transcriptomic data identified AIF1 (allograft inflammatory factor 1) as a shared candidate supported by both genetic prioritization and differential expression analysis. Although bulk transcriptomic data showed reduced AIF1 expression in AD, single-cell analysis revealed distinct cell type-specific expression patterns, with predominant enrichment in monocytes and other innate immune populations. PBMC-based qPCR further confirmed an overall reduction in AIF1 expression in AD. Further analyses suggested that AIF1-associated immune alterations were linked to changes in inflammatory signaling pathways, including STAT, IRF, and NF-κB-related activity, as well as differences in intercellular communication involving MIF, GALECTIN, ANNEXIN, and CypA-related signaling. Peripheral immune cell composition analysis indicated differences between AD and control samples, characterized by relative changes in innate immune cell proportions. Collectively, these findings identify AIF1 as an immune-associated factor linked to genetic and transcriptional alterations in AD and suggest its association with monocyte-related immune states and altered immune signaling patterns. This study provides a multi-layered framework for investigating peripheral immune involvement in AD and highlights potential directions for understanding immune-related alterations and biomarker discovery.},
}
@article {pmid42571753,
year = {2026},
author = {Rani, S and Mahesh, KV and Sandhir, R and Prabhakar, N},
title = {AuNP decorated-Ni-MOF nanosheet based cDNA sensor for detection of miRNA-128 in Alzheimer's disease.},
journal = {Talanta},
volume = {312},
number = {Pt A},
pages = {130405},
doi = {10.1016/j.talanta.2026.130405},
pmid = {42571753},
issn = {1873-3573},
abstract = {A cDNA sensor based on gold nanoparticles (Au) supported on nickel metal-organic framework nanosheets (MOF-NS) modified fluorine-tin oxide (FTO) glass electrode for the ultrasensitive and selective detection of miRNA-128 biomarker associated with the progression of Alzheimer's disease (AD) has been reported. The MOF-NS and Au nanoparticles were electrodeposited onto FTO electrode using chronoamperometry to immobilize 5'-biotinylated DNA (btn-cDNA) complementary to miRNA-128 by streptavidin-biotin interaction, generating the modified electrode (btn-cDNA/SV/Au/MOF-NS/FTO). The fabricated electrode was characterized using various surface characterization techniques, including FESEM, XPS, FTIR, and electrochemical methods. The fabricated electrode was then utilized for the selective detection of miRNA-128 using electrochemical impedance spectroscopy. The results indicated a linear response range of 1.0 × 10[-1] fM-1.0 × 10[2] nM with limit of detection of 0.017 fM, and sensitivity of 180.11 Ω fM[-1]cm[-2]. Moreover, the cDNA sensor showed satisfactory performance with real serum samples from AD patients and healthy individuals, as validated by real time-PCR technique with area under curve of 0.93 and a sensitivity of 90%, respectively, demonstrating the potential of present cDNA sensing approach in the biomedical field.},
}
@article {pmid42571787,
year = {2026},
author = {Bhakta-Guha, D and Guha, G},
title = {Alzheimer's disease as a disorder of time-gated clearance: Circadian regulation of Glymphatic function in neurodegeneration.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115959},
doi = {10.1016/j.expneurol.2026.115959},
pmid = {42571787},
issn = {1090-2430},
abstract = {Alzheimer's disease (AD) is traditionally defined by amyloid-β (Aβ) accumulation, tau pathology, synaptic dysfunction, and progressive neurodegeneration. However, increasing evidence suggests that impaired brain waste clearance represents an additional and clinically relevant dimension of disease pathogenesis. The glymphatic system, a perivascular cerebrospinal fluid-interstitial fluid exchange network, facilitates removal of soluble metabolites including Aβ and tau, and functions most efficiently during sleep. Recent studies indicate that glymphatic influx, meningeal lymphatic drainage, and blood-brain barrier (BBB) efflux transport are temporally regulated by circadian mechanisms, creating time-restricted windows of maximal clearance capacity. In AD, sleep fragmentation, suprachiasmatic nucleus degeneration, clock gene disruption, vascular stiffening, BBB tight junction failure, aquaporin-4 depolarization, and neuroinflammation may converge to impair this coordinated clearance network. We propose a time-gated clearance framework in which temporally misaligned or insufficient waste removal contributes to protein accumulation and disease progression. We also evaluate major controversies, including relative roles of advection and diffusion in parenchymal transport, predominance of rodent-derived data, and current limitations of human imaging biomarkers. Finally, we discuss therapeutic implications of circadian re-entrainment, sleep optimization, BBB restoration, vascular protection, and enhancement of glymphatic-lymphatic flow. This systems-level perspective complements established amyloid/tau models and identifies potentially modifiable targets for AD intervention.},
}
@article {pmid42571855,
year = {2026},
author = {Guo, X and Wu, S and Sun, Z and Jia, T and Ouyang, Y and Zhang, M and Kou, C and Bai, W},
title = {Peripheral GDF15 as an early biomarker for brain disorders: A large prospective cohort study.},
journal = {Progress in neuro-psychopharmacology &amp; biological psychiatry},
volume = {},
number = {},
pages = {111886},
doi = {10.1016/j.pnpbp.2026.111886},
pmid = {42571855},
issn = {1878-4216},
abstract = {BACKGROUND: Growth differentiation factor 15 (GDF15) is a stress-responsive cytokine involved in metabolic and inflammatory pathways. We examined the associations of plasma GDF15 with incident brain disorders and explored potential mediating pathways and causality.<br><br>METHODS: UK Biobank participants were followed for a median of 14&#x202f;years. Plasma GDF15 was measured at baseline. Cox proportional hazards models assessed associations with incident brain disorders, including all-cause dementia (ACD), Alzheimer's disease (AD), Parkinson's disease (PD), anxiety, depression, sleep disorders, stroke, and epilepsy. Mediation analyses evaluated biochemical and hematological pathways, and one-sample Mendelian randomization (MR) was used to assess potential causal effects.<br><br>RESULTS: Higher GDF15 levels were associated with increased risks of overall brain disorders and all examined subtypes. In continuous analyses (per 1-unit increase in log2-transformed GDF15), hazard ratios (95% CIs) were 1.54 (1.48-1.60) for overall brain disorders, 1.98 (1.80-2.17) for ACD, 1.84 (1.60-2.10) for AD, 1.37 (1.18-1.59) for PD, 1.26 (1.16-1.37) for anxiety, 1.38 (1.29-1.49) for depression, 1.40 (1.26-1.55) for sleep disorders, 1.92 (1.81-2.05) for stroke, and 1.71 (1.46-2.01) for epilepsy (all P&#x202f;<&#x202f;0.001). Lipid- and inflammation-related markers appeared to partially mediate these associations. High-density lipoprotein cholesterol (HDL-C) accounted for an estimated 7.51% of the association with depression and 11.47% with sleep disorders, while neutrophil count showed relatively larger mediation estimates across multiple outcomes. MR analyses did not support a direct causal effect of GDF15.<br><br>CONCLUSION: Plasma GDF15 is associated with a broad range of incident brain disorders and may act partly through lipid- and inflammation-related pathways, particularly HDL-C and neutrophil count.},
}
@article {pmid42571862,
year = {2026},
author = {Ding, F and Yang, L and Qiao, S and Lam, TKY and Su, Z and He, Y and Chen, Z and Cui, X and Chan, Y and Zhang, W and Xu, J and Cai, Z and Lyu, A and Li, F},
title = {Targeting transthyretin tetramer with a novel blood-brain barrier-penetrating small-molecule stabilizer for the treatment of Alzheimer's disease.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {153998},
doi = {10.1016/j.ijbiomac.2026.153998},
pmid = {42571862},
issn = {1879-0003},
abstract = {The stability of the transthyretin (TTR) tetramer is critical for regulating cerebral amyloid-β (Aβ) homeostasis in Alzheimer's disease (AD). Stable TTR tetramer can directly bind Aβ and promote its clearance from the brain. However, current TTR tetramer stabilizers lack blood-brain barrier (BBB) penetration, limiting their clinical translation. Therefore, to fully realize the therapeutic potential of TTR in AD, novel TTR tetramer stabilizers with superior BBB penetration must be discovered. Here, we aim to identify TTR tetramer stabilizers with BBB penetration via a multidimensional virtual screening workflow, and perform preliminary validation of their biological activities. Finally, Z1097086893 was identified as the lead compound. In vitro, the compound exhibited significant BBB penetration and robust TTR tetramer stabilization activity. In vivo, Z1097086893 also crossed the BBB. MSI showed localization to the choroid plexus within the ventricular system, the principal site of TTR synthesis and secretion in the brain. In the 5xFAD mouse model, the compound significantly reduced hippocampal Aβ plaque burden, alleviated neuronal injury, and rescued spatial learning and recognition memory deficits. Safety assessments confirmed that Z1097086893 was well tolerated at therapeutic doses, with no detectable drug-induced organ toxicity or abnormalities in liver and kidney function. Our findings validate cerebral TTR tetramer stabilization as a promising therapeutic strategy for AD, and provide a lead compound for further clinical translation. Furthermore, the BBB-first screening workflow established in this work offers a generalizable technical framework for the development of brain-targeted therapeutics for AD.},
}
@article {pmid42571934,
year = {2026},
author = {Lee, SH and Kim, K and Bae, J and Choi, K and Jung, DH and Park, EJ and Ju, HC and Kang, WS and Moon, C},
title = {A Novel Methodology for Temporal Analysis of Consumer Wearable Sleep Data: Feasibility and Application to Early Cognitive Impairment.},
journal = {Experimental neurobiology},
volume = {},
number = {},
pages = {},
doi = {10.5607/en26014},
pmid = {42571934},
issn = {1226-2560},
abstract = {While sleep disturbances are recognized as early markers of Alzheimer's disease (AD), the practical application of gold-standard polysomnography (PSG) for long-term monitoring is limited. This study aims to establish a novel methodological framework for the time-series analysis of sleep data collected via consumer-grade wearables and to explore whether this approach can detect differentiated signals across various stages of cognitive impairment. Daily sleep patterns of thirteen participants (5 healthy controls, 4 with aMCI, and 4 with mild AD) were monitored over three months using the Fitbit Charge 2. Rather than relying on aggregate nightly averages, we implemented a time-resolved analysis across 10-minute intervals to examine the temporal dynamics of sleep architecture. The proposed analysis revealed distinct, group-dependent temporal signatures. Specifically, the aMCI and AD groups exhibited shorter deep sleep during the early phase of the night, reduced REM sleep approximately three hours after sleep onset, and consistently elevated levels of light sleep and wake after sleep onset (WASO). These findings demonstrate that time-series analysis of wearable sleep data presents the potential to identify candidate digital phenotypes associated with cognitive decline. This study supports the feasibility of using longitudinal, dynamic sleep monitoring as an exploratory analytical framework warranting further validation for the detection of pathophysiological changes in older adults, shifting the focus from simple detection to the identification of candidate temporal sleep features. All reported findings are exploratory in nature and require replication in larger, independent cohorts.},
}
@article {pmid42572052,
year = {2026},
author = {Pradhan, S},
title = {Letter to the Editor "Therapeutic Time Window of Disease-Modifying Therapy for Early Alzheimer's Disease in Japanese Individuals: Analysis Based on J-ADNI Study".},
journal = {Geriatrics &amp; gerontology international},
volume = {26},
number = {8},
pages = {e70784},
doi = {10.1111/ggi.70784},
pmid = {42572052},
issn = {1447-0594},
}
@article {pmid42572115,
year = {2026},
author = {Rodrigues, JFR and Rodrigues, LP and Teshima, T and Yang, S and Wu, Y and Hu, X and Abarca, GIF and da Cruz, KCT and Rodriguez, MFS and Rubatino, FVM and Yamakawa, M and de Godoy, MF and de Araújo Filho, GM},
title = {Replay Letter to: 'Loneliness as an Interface Between Alzheimer's Disease and Suicidal Behaviour: A Methodological Concern'.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {26},
number = {5},
pages = {e70203},
doi = {10.1111/psyg.70203},
pmid = {42572115},
issn = {1479-8301},
}
@article {pmid42572118,
year = {2026},
author = {Indumathi, J and Arulappan, A and Ramasamy, S},
title = {Comment on "Executive and General Cognitive Domain as a Relevant Factor of Specific Neuropsychiatric Symptoms in Alzheimer's Disease".},
journal = {Geriatrics &amp; gerontology international},
volume = {26},
number = {8},
pages = {e70763},
doi = {10.1111/ggi.70763},
pmid = {42572118},
issn = {1447-0594},
}
@article {pmid42572565,
year = {2026},
author = {Song, Z and Xie, Y and Zhu, H and Li, J and Yang, C and Guo, Y and Nong, X and Zhu, Z and Chen, Z and Wang, Z},
title = {Evaluating the cognitive efficacy of marine-derived drugs in Alzheimer's disease: A systematic review and Bayesian network meta-analysis.},
journal = {Therapeutic advances in neurological disorders},
volume = {19},
number = {},
pages = {17562864261476868},
pmid = {42572565},
issn = {1756-2856},
abstract = {BACKGROUND: In recent years, marine-derived drugs for Alzheimer's disease (AD) have attracted growing attention, but their comparative cognitive efficacy and safety remain uncertain because of inconsistent findings across studies.<br><br>OBJECTIVES: To compare the efficacy and safety of marine-derived interventions for Alzheimer's disease.<br><br>DESIGN: Systematic review and Bayesian network meta-analysis of randomized controlled trials conducted in accordance with PRISMA 2020.<br><br>DATA SOURCES AND METHODS: We systematically searched PubMed and the Cochrane Library for randomized controlled trials (RCT) of marine-derived drugs in patients with AD. Continuous outcomes were synthesized as mean differences (MD) in change-from-baseline, and dichotomous outcomes were synthesized as odds ratios (OR), each with 95% credible intervals (CI).<br><br>RESULTS: A total of 16 eligible RCTs involving 4,158 patients were included. For the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), GV-971 (vs placebo; MD -1.85, 95% CI -2.89 to -0.82) and tramiprosate (vs placebo; MD -0.83, 95% CI -1.63 to -0.02) significantly improved cognitive function. For the Mini-Mental State Examination (MMSE), rifampicin (vs placebo; MD 1.90, 95% CI 0.25 to 3.56) was associated with greater improvement in MMSE scores, whereas tramiprosate (vs placebo; MD -2.40, 95% CI -4.67 to -0.09) was associated with poorer cognitive performance. No statistically significant differences among drugs were observed for the Clinical Dementia Rating-Sum of Boxes (CDR-SB) or for the incidence of adverse events. Overall, treatment effects were outcome-dependent, with significant benefits observed mainly in ADAS-Cog and MMSE, whereas no intervention demonstrated consistent superiority across all cognitive outcomes.<br><br>CONCLUSION: Marine-derived drugs showed generally acceptable safety and potential cognitive benefits in selected outcomes. GV-971 and tramiprosate improved ADAS-Cog scores, while rifampicin therapy showed a possible MMSE benefit. However, no intervention was consistently superior across cognitive outcomes, and the antibiotic finding was based on a single small trial. Current evidence is therefore insufficient to identify the optimal marine-derived therapy for AD, highlighting the need for larger, adequately powered RCTs.},
}
@article {pmid42573021,
year = {2026},
author = {Alsfouk, AA and El-Shiekh, RA and Kariuki, BM and Sabry, E and Abouelenein, MG and Saleh, A and Saleh, MGA and Srour, AM},
title = {Design, Synthesis, X-Ray Crystallographic Characterization, Anticholinesterase and Antioxidant Evaluation, and Molecular Modeling of Novel Dispiroindene-Pyrrolidine Derivatives as Multifunctional Anti-Alzheimer Agents.},
journal = {Drug development research},
volume = {87},
number = {5},
pages = {e70361},
doi = {10.1002/ddr.70361},
pmid = {42573021},
issn = {1098-2299},
support = {PNURSP2026R116//Princess Nourah Bint Abdulrahman University/ ; NBU-FFR-2026-145-02//Northern Border University/ ; },
mesh = {*Cholinesterase Inhibitors/chemistry/pharmacology/chemical synthesis ; *Antioxidants/pharmacology/chemistry/chemical synthesis ; *Pyrrolidines/chemistry/pharmacology/chemical synthesis ; Drug Design ; Crystallography, X-Ray ; Acetylcholinesterase/metabolism/chemistry ; Butyrylcholinesterase/metabolism/chemistry ; *Alzheimer Disease/drug therapy ; Animals ; Models, Molecular ; Structure-Activity Relationship ; Humans ; Molecular Docking Simulation ; },
abstract = {A novel series of 5-chloro-N-alkyl-1',1″-dimethyl-4'-aryldispiro[indene-2,3'-pyrrolidine-2',3″-indoline]-1,2″(3H)-diones (4a-r) was rationally designed and synthesized via a one-pot multicomponent reaction of N-alkylated 5-chloroisatin derivatives, 2-(arylmethylidene)-2,3-dihydro-1H-inden-1-ones (2a-i), and sarcosine (3). To assess their potential therapeutic efficacy, the entire library of synthesized compounds was screened for its inhibitory profiles against both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), where most derivatives exhibited moderate to potent cholinesterase inhibitory activity. Notably, derivatives 4b, 4f, and 4o emerged as the most effective dual inhibitors, displaying strong potent activity against AChE (IC50 = 0.91 ± 0.02, 0.89 ± 0.01, and 0.74 ± 0.01 µM, respectively; donepezil IC50 = 0.68 ± 0.005 µM) alongside significant BChE inhibition (IC50 = 10.19 ± 0.16, 9.59 ± 0.08, and 9.11 ± 0.01 µM, respectively; donepezil IC50 = 2.97 ± 0.01 µM). The structure of the most active derivatives (4b, 4f, and 4o) was further confirmed by X-ray crystallographic analysis. In addition, antioxidant evaluation of compounds 4b, 4f, and 4o demonstrated that derivative 4f possessed the most superior radical scavenging profile (IC50 = 23.18 ± 0.33 µM), representing approximately a 5.5-fold enhancement in potency relative to ascorbic acid (IC50 = 128.20 ± 0.82 µM). Molecular docking studies revealed favorable binding interactions of the lead derivatives within the catalytic binding pockets of both AChE and BChE, with docking scores comparable to those of the standard inhibitor. Furthermore, in silico ADME profiling demonstrated promising pharmacokinetic behavior, characterized by robust gastrointestinal absorption and excellent predicted blood-brain barrier penetration, supporting the potential of these derivatives as promising multifunctional candidates for the development of anti-Alzheimer agents.},
}
@article {pmid42573081,
year = {2026},
author = {Saffour, S and Gul, TS and Gul, HI},
title = {Rational drug design for Alzheimer's disease: from approved therapies to next-generation clinical candidates and AI-guided innovation.},
journal = {Future medicinal chemistry},
volume = {},
number = {},
pages = {1-19},
doi = {10.1080/17568919.2026.2714022},
pmid = {42573081},
issn = {1756-8927},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by multifactorial pathology, including amyloid-β (Aβ) aggregation, tau hyperphosphorylation, oxidative stress, neuroinflammation, and synaptic dysfunction. Despite extensive research, currently approved treatment provides only symptomatic relief, while recently approved disease-modifying monoclonal antibodies have shown limited benefits. Ongoing clinical investigations have shifted toward multi-target directed ligands (MTDLs), RNA-based therapies, immunotherapies, and vaccines. Some approved drugs that have established safety profiles are being repurposed to address the disease's neuropsychiatric symptoms or modulate AD pathological changes. Integrating diverse pharmacophores, such as curcumin, resveratrol, chromone, and indole, within a single skeleton is anticipated to exert multi-modal modifying properties. In parallel, optimization of ADME properties, particularly blood-brain barrier (BBB) permeation and efflux modulation, remains a major obstacle in AD drug design. The incorporation of artificial intelligence (AI) and machine learning (ML) is expected to enhance the prediction of pharmacokinetic, pharmacodynamic, and toxicity parameters.},
}
@article {pmid42573117,
year = {2026},
author = {Abul, MS and Parvizi, J and Skowronek, P and Erdogan, F and Tuncay, &#x130; and Hirschmann, MT and Kayaalp, ME},
title = {Osteoarthritis management through medical reversal: Glucosamine, Alzheimer's disease risk, and long-term outcomes after arthroscopic partial meniscectomy.},
journal = {Knee surgery, sports traumatology, arthroscopy : official journal of the ESSKA},
volume = {},
number = {},
pages = {},
doi = {10.1002/ksa.70578},
pmid = {42573117},
issn = {1433-7347},
abstract = {The adoption of interventions in osteoarthritis and musculoskeletal care frequently precedes the availability of robust long-term evidence, creating the conditions for subsequent medical reversal. Recent findings raising concern about possible adverse neurocognitive associations with glucosamine use challenge the assumption that widely used supplements are necessarily biologically inert, although their causal significance and direct relevance to routine osteoarthritis management remain uncertain. In contrast, 10-year follow-up evidence after arthroscopic partial meniscectomy for degenerative meniscal tears provides a more established example of medical reversal, demonstrating no sustained clinical benefit over sham surgery and raising concern regarding structural harm. Evidence concerning repeated intra-articular corticosteroid injections similarly illustrates the limitations of relying on biological plausibility or short-term symptomatic outcomes. These examples, while differing in evidentiary maturity, support a common principle: orthopaedic interventions should be evaluated according to rigorous comparative evidence and durable patient-centred outcomes. Clinicians should communicate uncertainty, avoid treating structural abnormalities or mechanistic rationale as sufficient indications for intervention, and remain willing to revise established practices when stronger evidence emerges.},
}
@article {pmid42573418,
year = {2026},
author = {Norevik, CS and Huuha, AM and Kobro-Flatmoen, A and Lydersen, S and Røsbjørgen, RN and Bækkerud, FH and Scrimgeour, N and Tari, AR},
title = {Effects of Intravenously Administered Plasma from Exercise-Trained Donors on Mitochondrial Respiration in a Rat Model of Alzheimer's Disease.},
journal = {Medicine and science in sports and exercise},
volume = {58},
number = {9},
pages = {1901-1913},
doi = {10.1249/MSS.0000000000004018},
pmid = {42573418},
issn = {1530-0315},
mesh = {Animals ; *Alzheimer Disease/therapy/metabolism ; Male ; *Mitochondria/metabolism ; Disease Models, Animal ; *Physical Conditioning, Animal/physiology ; Oxidative Phosphorylation ; Rats ; Hippocampus/metabolism ; Rats, Transgenic ; *Plasma ; Proteomics ; Blood Donation ; Cell Respiration ; },
abstract = {PURPOSE: Dysfunction of mitochondria is observed early in Alzheimer's disease (AD), possibly driving the pathogenesis of the disease. This study aims to assess whether plasma from exercise-trained donors can enhance mitochondrial function in a transgenic AD model and to gain insight into the proteomic profile of the donor plasma.<br><br>METHODS: Male McGill-R-Thy1-APP rats (n = 3 per treatment group) were treated at either an early preplaque stage (2.2 months) or a later stage (5.2 months) with plasma from exercise-trained donors (ExPlas), sedentary donors (SedPlas), or saline. The rats received 14 transfusions over 6&#x2009;wk. Mitochondrial respiration was assessed in cornu ammonis (CA), dentate gyrus (DG), gastrocnemius, and left ventricle using high-resolution respirometry. Proteomic analyses were performed in donor blood using mass spectrometry.<br><br>RESULTS: In early-stage AD rats, ExPlas improved hippocampal mitochondrial respiration. Compared with saline, CA oxidative phosphorylation (OXPHOS) capacity for complex I increased by +30.8 pmol O2&#xb7;s-1&#xb7;mg-1 (P < 0.001) and CI+II by +37.8 pmol O2&#xb7;s-1&#xb7;mg-1 (P < 0.001). Compared with SedPlas, CA OXPHOS for CI increased by +16.9 pmol O2&#xb7;s-1&#xb7;mg-1 (P = 0.01) and CI+II by +23.8 pmol O2&#xb7;s-1&#xb7;mg-1 (P = 0.007). In DG, similar improvements were only seen compared with saline. In CA, but not DG, of later-stage rats, ExPlas produced smaller but significant increases in CI and CI+II OXPHOS compared with saline, but no significant differences compared with SedPlas. No changes were observed in muscle or heart. Proteomics revealed enrichment of complement and platelet-related pathways in ExPlas.<br><br>CONCLUSIONS: This proof-of-concept study shows that exercise-trained donor plasma enhances hippocampal mitochondrial respiration in early-stage AD rats and, to a lesser extent, in later-stage AD rats. The proteomic profile of the exercise-trained donor plasma indicates a role of altered complement and platelet functions.},
}
@article {pmid42573479,
year = {2026},
author = {Kang, S and Goodridge, HS},
title = {Metabolic Reprogramming of Brain Microglia: Implications for Aging and Aging-Associated Neurodegenerative Diseases.},
journal = {Aging cell},
volume = {25},
number = {8},
pages = {e70660},
doi = {10.1111/acel.70660},
pmid = {42573479},
issn = {1474-9726},
support = {ABA-25-1372697/ALZ/Alzheimer's Association/United States ; },
mesh = {Humans ; *Microglia/metabolism ; *Aging/metabolism ; *Neurodegenerative Diseases/metabolism/pathology ; *Brain/metabolism/pathology ; Animals ; Metabolic Reprogramming ; },
abstract = {Microglia, the resident macrophages of the central nervous system (CNS), are key players in maintaining brain and spinal cord homeostasis and protecting the CNS from damage and disease. During aging, the brain undergoes profound changes-including chronic low-grade inflammation, synaptic dysfunction, and increased vulnerability to neurodegenerative diseases-all of which are closely related to alterations in microglial function. One emerging theme is that microglial metabolism is a crucial determinant of their immune and homeostatic activity. In this mini-review, we explore how metabolic programs shape brain microglial behavior and how these processes change during aging and in neurodegenerative diseases. We first highlight the link between specific metabolic pathways and key microglial functions, including phagocytosis, cytokine production, and the oxidative stress response. We then discuss how microglial metabolism is reprogrammed during healthy aging and in Alzheimer's disease and Parkinson's disease, including sex-specific differences. Finally, we examine regulators that influence microglial metabolic states and discuss how these pathways contribute to disease susceptibility and progression. Collectively, recent findings highlight the central role of metabolic reprogramming in shaping microglial responses during aging and in neurodegenerative diseases. We emphasize the need for integrative studies that consider microglial subsets, sex differences, disease context, and upstream molecular regulators to better understand how microglial metabolism contributes to brain health and pathology. A deeper understanding of these pathways may offer new opportunities for therapeutic strategies aimed at restoring microglial homeostasis and mitigating harmful neuroinflammatory processes.},
}
@article {pmid42573507,
year = {2026},
author = {Zhu, X and Wang, L and Tang, R and Huang, ZA and Huang, YA and Tan, F and Hu, L and You, Z and Hu, P},
title = {Spatial-Spectral Fusion Enables Drug Repositioning by Capturing Indirect and Long-Range Associations in Biological Networks.},
journal = {Bioinformatics (Oxford, England)},
volume = {},
number = {},
pages = {},
doi = {10.1093/bioinformatics/btag553},
pmid = {42573507},
issn = {1367-4811},
abstract = {MOTIVATION: Drug repositioning accelerates clinical translation by identifying new therapeutic indications for approved drugs. However, therapeutic associations in biomolecular networks often exist indirectly, through transitive chains and long-range mechanisms, rather than as directly observed links. Shallow methods are confined to direct similarity and miss such indirect associations, whereas deep graph neural networks suffer from over-smoothing and lose discriminative power in highly connected networks.<br><br>RESULTS: We propose a spatial-spectral collaborative framework. In the spatial domain, a wave-evolution process propagates similarity from local to global, capturing multi-hop transitive associations while preserving discriminative representations. In the spectral domain, network-specific spectral transforms model global connectivity for long-range dependencies over homogeneous similarity and heterogeneous drug-protein-disease networks, with the two views aligned by contrastive learning. On three benchmarks the method outperforms state-of-the-art baselines on most evaluation metrics; case studies on Alzheimer's and Parkinson's disease and molecular docking confirm its ability to recover non-explicit therapeutic associations.<br><br>AVAILABILITY: The source code and data are available at https://github.com/Juniper-cola/BIO_SSF.<br><br>SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.},
}
@article {pmid42573665,
year = {2026},
author = {Mukim, RD and Xu, Y and Evola, V and Parmar, MS},
title = {Semaglutide as a potential neuroprotective agent for neurological and neurodegenerative disorders: Mechanisms, preclinical evidence, and translational challenges and opportunities.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42573665},
issn = {1573-4978},
mesh = {Semaglutide ; Humans ; *Glucagon-Like Peptides/pharmacology/therapeutic use/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; Biomarkers/metabolism ; Oxidative Stress/drug effects ; *Nervous System Diseases/drug therapy/metabolism ; },
abstract = {Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are established treatments for metabolic disease, with growing evidence suggesting neuroprotective potential in central nervous system (CNS) disorders. In preclinical models of Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and stroke, semaglutide has been reported to reduce neuroinflammatory and oxidative stress markers and improve selected pathological or behavioral outcomes, although the specific effects vary by model and indication. However, significant translational challenges remain. The Phase 3 EVOKE and EVOKE+ trials in early symptomatic AD failed to meet primary cognitive endpoints, although biological target engagement was reported, with improvements in selected AD-related biomarkers including p-tau181, p-tau217, neurogranin, YKL-40, and plasma hsCRP. This dissociation between biomarker changes and clinical benefit may reflect treatment timing, advanced neurodegeneration, limited CNS exposure, endpoint sensitivity, or other factors. In contrast, observational studies suggest an association between semaglutide or GLP-1 RA exposure and lower dementia-related risk in at-risk populations, although preservation of cognitive reserve has not been directly demonstrated and causality has not been established. This review evaluates the current mechanistic, preclinical, and emerging clinical evidence for semaglutide across neurodegenerative and neuroinflammatory disorders, with emphasis on distinguishing semaglutide-specific findings from broader GLP-1 RA class effects and identifying key translational limitations. Collectively, current evidence supports continued investigation of semaglutide as a potential neuroprotective strategy, while highlighting the need for earlier intervention studies, improved understanding of CNS target engagement, and further clinical validation.},
}
@article {pmid42573807,
year = {2026},
author = {Maman, D and Steinfield, Y and Berkovich, Y},
title = {Factors associated with selection of total hip arthroplasty versus hemiarthroplasty for femoral neck fracture in older adults: a nationwide analysis of 99,084 cases.},
journal = {Archives of orthopaedic and trauma surgery},
volume = {146},
number = {1},
pages = {},
pmid = {42573807},
issn = {1434-3916},
mesh = {Humans ; *Femoral Neck Fractures/surgery ; *Hemiarthroplasty/statistics &amp; numerical data ; *Arthroplasty, Replacement, Hip/statistics &amp; numerical data ; Aged ; Male ; Female ; Retrospective Studies ; Aged, 80 and over ; United States ; *Patient Selection ; Comorbidity ; Proximal Femoral Fractures ; },
abstract = {BACKGROUND: Surgical management of displaced femoral neck fractures in older adults typically involves hemiarthroplasty or total hip arthroplasty (THA). Although clinical guidelines suggest that THA may be considered in selected healthier and cognitively intact patients, real-world procedure selection varies widely. This study evaluated patient factors associated with selection of THA versus hemiarthroplasty in a contemporary U.S.<br><br>METHODS: A retrospective cohort study was conducted using the 2022 Nationwide Readmissions Database (NRD). Patients&#x2009;&#x2265;&#x2009;65 years hospitalized with femoral neck fracture were identified using ICD-10-CM codes. Those treated with internal fixation or non-arthroplasty procedures were excluded. Weighted analyses characterized demographics, comorbidities, and hospital utilization between THA and hemiarthroplasty groups. A multivariable logistic regression model identified factors independently associated with receiving THA. All analyses accounted for NRD survey design.<br><br>RESULTS: Among 142,013 operative cases, 99,084 met inclusion criteria (81.8% hemiarthroplasty; 18.2% THA). Patients receiving THA were younger (76.6 vs. 81.9 years), had shorter length of stay (6.06 vs. 7.24 days), and were more frequently discharged home (17.5% vs. 6.2%). Metabolic conditions were associated with increased odds of THA, including obesity (OR 1.17) and sleep apnea (OR 1.12). Frailty-related conditions were associated with markedly reduced THA likelihood, including Alzheimer's disease (OR 0.48), Parkinson disease (OR 0.55), chronic kidney disease (OR 0.78), chronic lung disease (OR 0.72), and congestive heart failure (OR 0.77). Each additional year of age decreased the odds of THA by approximately 9%.<br><br>CONCLUSION: In this nationwide cohort, selection of THA rather than hemiarthroplasty was associated with younger age and lower prevalence of frailty- and cognition-related comorbidities, while several metabolic comorbidities showed modest positive associations with THA use. These findings describe contemporary national selection patterns but do not establish treatment appropriateness, clinical benefit, or guideline concordance, as key factors such as pre-fracture mobility, functional independence, and living situation were not available in the dataset.<br><br>LEVEL OF EVIDENCE: Level III.},
}
@article {pmid42573852,
year = {2026},
author = {Nguyen, HM and Nguyen, LDT},
title = {Towards Structural Restoration: Epigenetic Reprogramming and Direct Astrocyte-to-Neuron Lineage Conversion as Next-Generation Regenerative Neurotherapeutics.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42573852},
issn = {1559-1182},
mesh = {Humans ; *Astrocytes/metabolism/cytology ; Animals ; *Neurons/metabolism/cytology ; *Epigenesis, Genetic ; *Cellular Reprogramming/genetics ; *Cell Lineage ; *Nerve Regeneration ; },
abstract = {While the recent clinical approval of amyloid-targeting monoclonal antibodies represents a landmark in Alzheimer's disease (AD) management, these immunotherapies fundamentally function as agents of mitigation rather than restoration, failing to reconstitute decimated neural circuitry. Direct in situ astrocyte-to-neuron reprogramming offers a compelling regenerative alternative by leveraging the abundant endogenous glial reservoir. However, translating this cellular plasticity in vivo is severely bottlenecked by the hostile pathological microenvironment and the deeply entrenched epigenetic memory of reactive astrocytes. In this review, we delineate a tripartite neuroregenerative framework. First, we evaluate the prerequisite use of senotherapeutics to engineer a permissive parenchymal niche for nascent neuronal survival. Second, we explore epigenomic editing strategies-including CRISPR-dCas9 platforms and targeted pharmacological modulators-required to dismantle repressive heterochromatin and unlock sequestered neurogenic loci. Third, we dissect the molecular execution of reprogramming via pioneer transcription factors (TFs), emphasizing the obligatory metabolic rewiring from astrocytic glycolysis to neuronal oxidative phosphorylation (OXPHOS). Finally, to overcome formidable translational hurdles, we highlight the convergence of AI-optimized lipid nanoparticles (LNPs) for non-viral blood-brain barrier (BBB) transcytosis alongside Neurological Digital Twins (NDTs) to computationally predict the optimal presymptomatic intervention window. By harmonizing microenvironmental conditioning, epigenetic rejuvenation, and precision delivery, this systems-level blueprint provides a promising rationale for transitioning AD therapeutics from passive deceleration to active structural restoration.},
}
@article {pmid42573994,
year = {2026},
author = {Di Molfetta, G and Brum, WS and Pola, I and Tan, K and Benedet, AL and Sauer, M and Montoliu-Gaya, L and Janelidze, S and Mattsson-Carlgren, N and Rahmouni, N and Chan, T and Denkinger, MN and Proitsi, P and Zetterberg, H and Hansson, O and Rosa-Neto, P and Ashton, NJ},
title = {Plasma Biomarkers for Neocortical Tau Burden.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2026.2650},
pmid = {42573994},
issn = {2168-6157},
abstract = {IMPORTANCE: Phosphorylated tau-217 (p-tau217) is now an established plasma biomarker for assessing amyloid-β pathology in individuals at risk of Alzheimer disease. However, its performance in identifying advanced neocortical neurofibrillary tangle burden remains suboptimal. Precise assessment of tau pathology is increasingly critical for the rational implementation of anti-amyloid therapies and developing anti-tau interventions. Improved biofluid biomarker-based tau staging could enhance patient stratification and optimize participant selection for clinical care and therapeutic trials.<br><br>OBJECTIVE: To develop and validate a multiprotein plasma panel to improve identification of neocortical tau pathology beyond p-tau217 alone.<br><br>This multicenter cohort study included 2 independent observational cohorts, Swedish BioFINDER study and Translational Biomarkers in Aging and Dementia (TRIAD). Cross-sectional clinical data and blood samples were collected between 2017 and 2024. Participants included 560 individuals spanning the clinical spectrum from cognitively unimpaired to dementia. These data were analyzed from January 2025 to May 2026.<br><br>EXPOSURES: Plasma concentrations of 125 proteins measured using Nucleic Linked Immuno-Sandwich Assay central nervous system panel.<br><br>MAIN OUTCOME AND MEASURE: Advanced tau pathology defined as tau positron emission tomography (PET) uptake within Braak stage V and VI regions. Predictive performance of biomarker models was evaluated using area under the receiver operating characteristic curve (AUC).<br><br>RESULTS: The study included 560 amyloid-positive participants (BioFINDER: n&#x2009;=&#x2009;431; mean [SD] age, 73.6 [7.0] years; 212 female [49.2%] and 219 male [51.8%]; TRIAD: n&#x2009;=&#x2009;129; mean [SD] age, 70.4 [8.3] years; 76 female [58.9%] and 53 male [41.1%]). Using multivariable logistic regression approaches, a 7-protein panel was found in BioFINDER to identify tau PET uptake within Braak stage V and VI regions. When compared with p-tau217 (AUC, 0.86-0.88; 95% CI, 0.82-0.94), this multiprotein panel was associated with improved identification in both discovery and validation cohorts (AUC, 0.92-0.94; 95% CI, 0.89-0.98; DeLong P&#x2009;<&#x2009;.001). This reduced the proportion of individuals classified within the intermediate-risk range (between paired sensitivity and specificity thresholds) in the validation cohort by 14.7% to 21.0%.<br><br>CONCLUSIONS AND RELEVANCE: This multicohort study demonstrated how including additional plasma proteins significantly enhanced the performance of p-tau217 in predicting advanced tau pathology among amyloid-positive individuals. This suggests a multiprotein approach may offer a viable and scalable alternative to tau PET staging in clinical or research settings.},
}
@article {pmid42574041,
year = {2026},
author = {Sarathkumar, E and Sasi, R and Menon, RN and Jayasree, RS},
title = {Electrochemical profiling of plasma pTau-181 levels associated with mild cognitive impairment and Alzheimer's disease using an MXene-gold nanorod interface.},
journal = {Journal of materials chemistry. B},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6tb00880a},
pmid = {42574041},
issn = {2050-7518},
abstract = {Early diagnosis of Alzheimer's disease (AD) remains a major clinical challenge, particularly during the mild cognitive impairment (MCI) stage, where subtle cognitive changes overlap with normal ageing and reliable diagnostic indicators are limited. Plasma phosphorylated tau at threonine-181 (pTau-181) has emerged as a disease-specific biomarker associated with tau pathology and early neurodegenerative progression, with increasing evidence supporting its relevance for identifying individuals at risk of AD during the prodromal phase. However, accurate quantification of plasma pTau-181 is hindered by its extremely low concentration and the complex biochemical environment of blood. In this study, a label-free electrochemical impedance biosensor was developed for sensitive detection of plasma pTau-181 using a self-assembled two-dimensional MXene-gold nanorod (MXene-GNR) hybrid interface. Modification of a glassy carbon electrode with the MXene-GNR nanocomposite enhanced interfacial charge-transfer behaviour and increased the electroactive surface area by approximately 37%, enabling improved anti-pTau-181 immobilization and signal transduction. The biosensor exhibited a concentration-dependent impedance response toward pTau-181 over a wide dynamic range and achieved an ultrasensitive limit of detection of 12.561 fg mL[-1] in 10% plasma spiked samples while maintaining high analytical selectivity. Clinical plasma analysis demonstrated statistically significant differentiation of AD and MCI groups from healthy controls (p < 0.001), supporting the relevance of plasma pTau-181 measurement for assessing disease-associated cognitive impairment. These findings demonstrate the potential of the MXene-GNR electrochemical platform as a minimally invasive approach for plasma biomarker evaluation toward early AD diagnosis and monitoring.},
}
@article {pmid42574303,
year = {2026},
author = {Mena, D and Vincze, A and Shultz, A and Rauch, JN},
title = {A Split-Luciferase Complementation Assay for Temporally Resolved Measurement of Tau Clearance in Microglia.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {233},
pages = {},
doi = {10.3791/71870},
pmid = {42574303},
issn = {1940-087X},
mesh = {*tau Proteins/metabolism/analysis ; *Microglia/metabolism/cytology/chemistry ; Humans ; Induced Pluripotent Stem Cells/metabolism/cytology ; *Luciferases/chemistry/metabolism/genetics ; *Luminescent Measurements/methods ; },
abstract = {As the resident immune cells of the central nervous system, microglia are central regulators of brain homeostasis and key mediators of neurodegenerative disease. These cells continuously survey the neural environment and play a critical role in the recognition, internalization, and degradation of extracellular substrates, including misfolded and aggregated proteins such as pathological tau. Despite growing evidence implicating microglia in tau clearance, existing approaches to measure tau uptake and degradation lack the temporal resolution and sensitivity needed to fully capture these dynamic processes. Here, we developed a luminescence-based assay to quantitatively monitor tau clearance in human induced pluripotent stem cell (iPSC)-derived microglia. This platform leverages a split-luciferase-based complementation system to enable highly sensitive, real-time detection of tau in live cells, allowing for precise tracking of its intracellular processing. This assay is scalable and adaptable across multiple cell types, providing a versatile tool to interrogate endolysosomal pathways and cellular mechanisms governing tau handling in neurodegenerative diseases, including Alzheimer's disease.},
}
@article {pmid42574385,
year = {2026},
author = {Flores, R and Musenda, K and Barbosa, DB and Cheng, KH and Sikazwe, D},
title = {Bis-hydrophobic 5-(1,2-dithiolan-3-yl)pentanamide budding leads targeting brain sigma-1 receptors.},
journal = {PloS one},
volume = {21},
number = {8},
pages = {e0352906},
doi = {10.1371/journal.pone.0352906},
pmid = {42574385},
issn = {1932-6203},
mesh = {*Receptors, sigma/metabolism/antagonists &amp; inhibitors/chemistry ; Sigma-1 Receptor ; Hydrophobic and Hydrophilic Interactions ; *Amides/chemistry/pharmacology/chemical synthesis ; *Brain/metabolism/drug effects ; Animals ; Ligands ; Humans ; Thioctic Acid/chemistry ; Molecular Docking Simulation ; Pharmacophore ; Protein Binding ; },
abstract = {Multi-mechanistic sigma-1 (σ1) receptors are implicated in several neurodegenerative pathologies including Alzheimer's disease (AD). As part of an ongoing effort to create a collection of diverse, readily synthesizable, σ1 acting small molecules for anti-neurodegenerative applications, we opted to try lipoic acid (LA) derived amides. These amides are designated as "5-(1,2 dithiolan-3-yl)pentanamides" throughout this publication. Our design approach was σ1 pharmacophore based - that is, ligands possessing three key functionalities (a hydrophobic dithiolane group, a flexible amide H-bonding linker, a hydrophobic alkyl/aryl group). Twenty-one dithiolane pentanamides were therefore designed, docked, synthesized, and pharmacologically assessed for σ1/σ2 binding affinities. Compounds 2, 6, 17 possessed promising selective σ1 binding affinities (with respective Ki values of 256, 133 and 32 nM) versus the standard ligand PD144418 (Ki = 0.08 nM). The three compounds will be used as leads in follow-up structure activity optimizations.},
}
@article {pmid42569895,
year = {2026},
author = {Qi, X and Belloy, ME and Gu, J and Liu, X and Tang, H and He, Z},
title = {Robust Inference With Ghostknockoffs in Genome-Wide Association Studies With Sample Relatedness.},
journal = {Genetic epidemiology},
volume = {50},
number = {6},
pages = {e70051},
pmid = {42569895},
issn = {1098-2272},
support = {AG066206/NH/NIH HHS/United States ; GM127063/NH/NIH HHS/United States ; AG066515/NH/NIH HHS/United States ; },
mesh = {*Genome-Wide Association Study/methods ; Humans ; *Models, Genetic ; Alzheimer Disease/genetics ; Polymorphism, Single Nucleotide ; Computer Simulation ; Phenotype ; UK Biobank ; },
abstract = {Genome-wide association studies (GWASs) have been extensively adopted to depict the underlying genetic architecture of complex traits. Recent studies show that knockoff-based methods can identify variants with unique, potentially causal effects on phenotypes. However, their statistical validity and effectiveness in studies with related individuals, such as the UK Biobank, remain unexplored. In this paper, we extensively evaluate a simple and effective analytical strategy that integrates GhostKnockoffs and state-of-the-art marginal association tests. We show that this approach is robust to arbitrary relatedness structure as long as the input Z-scores are derived from valid generalized linear mixed models. This robustness also extends GhostKnockoffs to other GWASs settings, including meta-analysis of studies with sample overlap when the input score test Z-scores are properly calibrated, and association test statistics beyond score tests in independent sample settings. We demonstrate the method's validity and practical utility using simulation studies and a meta-analysis of nine European ancestral genome-wide association studies and whole exome/genome sequencing studies for the Alzheimer's disease.},
}
@article {pmid42570063,
year = {2026},
author = {Paelaong, N and Sripha, K and Boondam, Y},
title = {Discovery of Anti-Neuroinflammatory Compounds in Alzheimer's Disease: Current Trends and Future Perspectives.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42570063},
issn = {1559-1182},
mesh = {*Alzheimer Disease/drug therapy ; Humans ; Animals ; *Drug Discovery/trends/methods ; *Anti-Inflammatory Agents/therapeutic use/chemistry/pharmacology ; *Neuroinflammatory Diseases/drug therapy ; Inflammation/drug therapy ; },
abstract = {Chronic neuroinflammation in response to abnormal protein aggregates has been implicated as a critical mechanism in several neurodegenerative diseases, and the modulation of signaling pathways associated with inflammation is being explored as a potential strategy for new therapeutics. In Alzheimer's disease (AD), the neuroinflammation hypothesis also starts to influence the landscape of drug discovery in place of the previously regarded amyloid hypothesis. As such, the objective of this review is to compile recent advanced in the discovery of anti-neuroinflammatory compounds developed through chemical synthesis and structural modification, providing an overview of current trends in drug discovery strategies and scaffold redesign for the development of the next-generation of anti-neuroinflammatory therapeutics. It was found that the compounds described in the publications could be categorized into four groups: modification of natural compounds, rational drug design, drug screening approaches, and drug repurposing. While the categorization seems to be similar to drug discoveries in other fields, with the modification of natural compounds accounting for most publications, specific observations could still be made. Namely, the growing interest in the multitarget-directed ligand approach reflects the increasing recognition of AD as a multifactorial disease. Despite this, further research is required to identify additional effective activities or the appropriate combinations besides anti-neuroinflammatory activity. Lastly, this review also gives brief overview regarding physicochemical properties of central nervous system-active agents, of which anti-neuroinflammatory compounds are parts of, and suggests the adoption of in silico prediction models as screening tools before the use of in vitro or in vivo models.},
}
@article {pmid42570085,
year = {2026},
author = {Bu, Y and Fan, Z and Li, L},
title = {Bacterial outer membrane vesicles in oral diseases: from pathogenic mediators to theranostic platforms.},
journal = {Critical reviews in microbiology},
volume = {},
number = {},
pages = {1-19},
doi = {10.1080/1040841X.2026.2713518},
pmid = {42570085},
issn = {1549-7828},
abstract = {Bacterial outer membrane vesicles (bOMVs) are nanoscale structures derived from Gram-negative (G[-]) bacteria that play an important role in oral diseases. As key mediators of host-microbe interactions, bOMVs contribute to the pathogenesis of periodontitis, oral squamous cell carcinoma (OSCC), and oral lichen planus (OLP) by disrupting immune homeostasis and promoting tissue destruction. Beyond the oral cavity, bOMVs serve as critical vectors in the oral-systemic axis, disseminating virulence factors to distant organs and contributing to atherosclerotic cardiovascular diseases (ACVDs), Alzheimer's disease (AD), and gastrointestinal (GI) disorders. Concurrently, their inherent properties, including cargo-loading capacity, immunogenicity, and biofilm penetration, position them as promising platforms for noninvasive diagnostics and targeted therapeutics. This review systematically integrates current knowledge on bOMVs biogenesis, pathogenic mechanisms in oral and systemic diseases, and emerging applications in diagnosis and treatment. We also highlight key challenges and future directions for translating bOMVs-based strategies into clinical practice, emphasizing their potential as next-generation theranostic tools (combining therapeutic and diagnostic functions) for oral diseases.},
}
@article {pmid42570239,
year = {2026},
author = {Cruz-Sese, J and Mirón-Alcala, M and Alfonso-Triguero, M and Olalde, J and Ruiz, L and Galbis-Gramage, N and Cortes, L and Escobar, L and Preman, P and Snellinx, A and Saito, T and Saido, TC and Saiz-Aúz, L and Rábano-Gutiérrez, A and Aransay, AM and Diez, I and Tcw, J and Goate, A and De Strooper, B and Alberdi, E and Arranz, AM},
title = {APOE3 and APOE4 human astrocytes differentially modulate Alzheimer's disease pathology and microglial responses in chimeric mice.},
journal = {Cell reports},
volume = {45},
number = {8},
pages = {117803},
doi = {10.1016/j.celrep.2026.117803},
pmid = {42570239},
issn = {2211-1247},
abstract = {Astrocytes and APOE are strongly implicated in Alzheimer's disease (AD), yet the impact of astrocytes carrying different APOE variants on AD hallmarks remains incompletely understood. Here, we generate a chimeric model of AD by transplanting isogenic APOE3 or APOE4 human induced pluripotent stem cell-derived astrocyte progenitors into neonatal AD mice. Donor cells differentiate into human astrocytes that integrate into the cortex and display morphologies consistent with interlaminar-like astrocytes. APOE3 and APOE4 astrocytes differ in expression of APOE, which associates differentially with Aβ plaques. Notably, APOE3 astrocytes are associated with reduced Aβ burden, Tau pathology, and neuritic dystrophy, whereas APOE4 astrocytes exacerbate these processes. They also induce distinct microglial responses: APOE4 astrocytes enhance microglial clustering around Aβ plaques and promote a disease-associated microglia-like state, whereas APOE3 astrocytes reduce clustering and support a more homeostatic profile. These findings highlight a role for human astrocytes and APOE-dependent astrocyte functions in modulating AD-related pathology.},
}
@article {pmid42570244,
year = {2026},
author = {Sun, GG and Wang, C and Mazzarino, RC and Perez-Corredor, PA and Davtyan, H and Blurton-Jones, M and Lopera, F and Arboleda-Velasquez, JF and Shi, Y},
title = {Microglial APOE3 Christchurch protects neurons from Tau pathology in a human iPSC-based model of Alzheimer's disease.},
journal = {Cell reports},
volume = {45},
number = {8},
pages = {117853},
doi = {10.1016/j.celrep.2026.117853},
pmid = {42570244},
issn = {2211-1247},
}
@article {pmid42570275,
year = {2026},
author = {Van Houwelingen, AS and Vernooij, MW and Vermeiren, MR and Ossenkoppele, R and Van De Giessen, E and Seelaar, H and Neitzel, J},
title = {Concordance between plasma biomarkers of phosphorylated tau and tau-PET: A narrative review.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261468708},
doi = {10.1177/13872877261468708},
pmid = {42570275},
issn = {1875-8908},
abstract = {Plasma phosphorylated tau (p-tau) and tau positron emission tomography (PET) are key biomarkers for detecting tau pathology in Alzheimer's disease (AD), offering both diagnostic and prognostic value. However, the concordance between plasma p-tau (p-tau217/p-tau181/p-tau231) positivity and tau-PET positivity remains incompletely understood. In this narrative review, we show that concordance varies by clinical disease stage, the plasma p-tau biomarker assessed, the definition of tau-PET positivity, and the presence of comorbidities and other risk factors. We also present evidence for a temporal sequence of plasma p-tau changes, with plasma p-tau231 positivity preceding p-tau181 positivity, followed by plasma p-tau217 reflecting more advanced stages of tau pathology. We highlight the relevance of these temporal dynamics for the potential development of a stage-specific trajectory framework for plasma p-tau and discuss how such a framework may support improved integration of plasma p-tau and tau-PET, thereby enhancing screening efficiency. Finally, we outline methodological challenges, highlight current efforts such as the development of tau-PET harmonization strategies, and identify priorities for future research. Taken together, this review provides a comprehensive overview of the factors influencing concordance between plasma p-tau positivity and tau-PET positivity. Careful consideration of these factors will be essential for the optimal integration of these biomarkers across the AD spectrum, with the potential to improve both diagnostic and therapeutic strategies.},
}
@article {pmid42570276,
year = {2026},
author = {Kurniadi, NE and Steele, JS and Mattek, N and Guevara, JE and Duff, K},
title = {Predicting progression from mild cognitive impairment to dementia with baseline neuropsychological test scores.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261469182},
doi = {10.1177/13872877261469182},
pmid = {42570276},
issn = {1875-8908},
abstract = {BackgroundAlthough neuropsychological scores have predicted progression from mild cognitive impairment (MCI) to dementia, past work has limitations, including small samples, limited batteries, and research cohorts.ObjectiveThis study sought to identify which baseline cognitive scores predicted progression in clinical patients with MCI followed over 1.5 years.Methods243 individuals clinically diagnosed with MCI at a baseline visit completed neuropsychological testing at baseline and were followed approximately 1.5 years later. Using follow-up diagnoses from neurologists, they were grouped as "MCI-Stable" (i.e., MCI at baseline and follow-up, n = 131) or "MCI-Progressors" (i.e., MCI at baseline but dementia at follow-up, n = 112). Stepwise logistic regression examined follow-up group status predicted from demographics, baseline cognitive scores, and self-reported depressive symptoms.ResultsNeither baseline demographic variables nor depressive symptoms significantly predicted group status at follow-up. Conversely, worse baseline performance on tests of visuospatial construction and semantic fluency were significant predictors of progression from MCI to dementia. Longer follow-up interval also significantly predicted conversion.ConclusionsAlthough many individuals progress from MCI to dementia, there is considerable variability in the timing and cognitive performance among those who convert to dementia versus those who remain stable over time. The current findings identified multiple baseline neuropsychological test scores that predicted that progression over approximately 1.5 years. Such results have implications for clinical care (e.g., providing more services and closer monitoring of at-risk individuals) and research (e.g., enriching clinical trials with those more likely to progress).},
}
@article {pmid42570281,
year = {2026},
author = {Amemiya, S and Takao, H and Matsumoto, S and Umeda-Kameyama, Y and Niimi, Y and Kakumoto, T and Satake, W and Mitsui, J and Ogawa, S and Abe, O},
title = {Subthreshold early white-matter hyperintensity increase predicts accelerated hippocampal and whole-brain atrophy in anti-amyloid-β immunotherapy.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261475336},
doi = {10.1177/13872877261475336},
pmid = {42570281},
issn = {1875-8908},
abstract = {BackgroundAnti-amyloid-β (anti-Aβ) therapy slows cognitive decline but paradoxically accelerates whole-brain gray matter atrophy, complicating outcome prediction.ObjectiveTo identify early imaging markers that predict long-term prognoses.MethodsThis longitudinal cohort study prospectively enrolled participants with early Alzheimer's disease, initiating anti-Aβ therapy. We performed automated T1-weighted MRI volumetric analysis of the whole-brain gray matter, hippocampus, and white matter hyperintensities (WMH). Temporal dynamics were characterized using piecewise linear regression, and predictive utility was assessed using multivariate linear regression analyses.ResultsTwenty-two participants (74 ± 11 years; 14 women) were followed for 376 ± 146 days. Significant volume changes occurred in all regions (p < 0.01). No overt amyloid-related edema was detected, and hemorrhagic events were mild to moderate. Piecewise regression revealed an initial WMH surge that decelerated after 60 days (β=-0.19 [95%CI: -0.33, -0.042], p = 0.01), whereas gray matter regions showed linear volume decline. Early subthreshold WMH expansion predicted long-term atrophy independent of baseline covariates (age, sex, amyloid burden, mini-mental state examination score, drug, and hemorrhagic events) in the hippocampus (β=-0.058 [95%CI: -0.092, -0.025], p = 0.003), and whole-brain gray matter (β=-0.033 [95%CI: -0.065, -0.002], p = 0.04). Early whole-brain gray matter atrophy correlated with the WMH surge (β=-0.53 [95%CI: -0.69, -0.38], p < 0.001) and predicted long-term hippocampal atrophy (β=0.098 [95%CI: 0.038, 0.16], p = 0.004).ConclusionsA transient WMH surge within the first 60 days of therapy mirrors the known time course of amyloid-related imaging abnormalities. Along with concurrent early whole-brain volume loss, this surge independently predicts accelerated long-term hippocampal and whole-brain atrophy, highlighting its potential as an early prognostic imaging marker.},
}
@article {pmid42570282,
year = {2026},
author = {Fatima, SUK and Jabber, A and Khanam, MH and Khan, J and Talukder, MM and Hasnat, MA},
title = {Integrative machine learning reveals telomere-associated gene modules reflecting neuronal dysregulation in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261476085},
doi = {10.1177/13872877261476085},
pmid = {42570282},
issn = {1875-8908},
abstract = {BackgroundTelomere dysfunction contributes to cellular aging and genome instability, but telomere-associated transcription in Alzheimer's disease (AD) is poorly characterized. Telomere genes are commonly tested gene by gene, leaving it uncertain whether they organize into reproducible, disease-linked co-expression programs across cohorts.ObjectiveTo identify AD linked telomere gene modules and evaluate their diagnostic and biological relevance.MethodsWe curated 157 telomere maintenance genes and analyzed two GPL570-platform GEO Series datasets: GSE5281 (n = 161; AD = 87, control = 74) and GSE48350 (n = 253; AD = 80, control = 173). In GSE5281 hippocampus, RMA + age-adjusted limma identified 38 AD-associated telomere genes (FDR<0.05). Ward clustering (silhouette) defined two modules, summarized as eigengenes (module PC1). Eigengenes were evaluated across seven classifiers with nested stratified 5 × 5 cross-validation; Youden's J thresholds from out-of-fold predictions were fixed and applied to GSE48350 using frozen z-scoring (GSE5281 μ/σ) and fixed cutoffs. Robustness used 500-bootstrap stability; hub genes from the dominant module were interpreted with BRETIGEA and Reactome/GO enrichment.ResultsPCA and t-SNE showed AD-associated structure in telomere-gene expression. With only two module features, models achieved ROC-AUC 0.722-0.780 internally and 0.689-0.695 externally. Bootstrap resampling converged on one dominant axis: Cluster 2 was consistently the strongest feature and was reduced in AD (Cohen's d = -1.07; Welch p = 8.13 × 10[-10]). Hub genes (TSPYL5, TUBB3, PLCL2, NHP2) were downregulated, tracked neuronal signatures positively, varied inversely with microglial/astrocytic signatures, and mapped to telomere/chromosome maintenance, DNA repair, and cell-cycle regulation.ConclusionsAD features a reproducible, resampling-stable telomere genome-maintenance module that provides an interpretable systems-level disease axis for mechanistic follow-up and integrative biomarker development.},
}
@article {pmid42570289,
year = {2026},
author = {Tian, Y and Qing, H and Quan, Z},
title = {A working feedback-based framework for goal-directed spatial memory deficits in Alzheimer's disease: Feedforward and feedback interactions along the RSC-MEC-CA1-RSC axis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261473933},
doi = {10.1177/13872877261473933},
pmid = {42570289},
issn = {1875-8908},
abstract = {Spatial navigation deficits are among the earliest and most clinically significant cognitive impairments in Alzheimer's disease (AD), particularly when navigation depends on goal-directed spatial memory. This review defines goal-directed spatial memory as a task-oriented construct and proposes a network-level framework for interpreting early AD navigation deficits. We synthesize anatomical, physiological, behavioral, and disease-related evidence concerning the retrosplenial cortex (RSC), medial entorhinal cortex (MEC), hippocampal CA1, and CA1-RSC feedback interactions. We propose the RSC-MEC-CA1-RSC axis as a testable working framework based on coordinated feedforward and feedback interactions. Within this system, the RSC integrates behaviorally relevant external cues and supports reference-frame transformation. The MEC contributes to path integration and self-goal relational coding, and CA1 consolidates these signals into functional goal-location representations. These representations can be retrieved, stabilized, and then transmitted back to cortical networks to guide continuous behavioral updating. Notably, we define the CA1-RSC pathway as a functional feedback route that supports iterative information updating, route correction and strategic adjustment. We argue that AD navigation deficits stem from the progressive breakdown of feedforward and feedback interactions across this axis, rather than from isolated dysfunction of single brain regions. The RSC-MEC-CA1-RSC framework offers a circuit-level mechanistic account for spatial disorientation in early AD. As a working model instead of a fully validated canonical circuit, it puts forward a series of testable hypotheses for future research, including cross-regional electrophysiological recordings, projection-specific circuit manipulation, imaging assessments, and differentiated navigation paradigms to examine cue use, path integration, goal retrieval and feedback-dependent updating.},
}
@article {pmid42570292,
year = {2026},
author = {Labbad, I and Youssef, LA and Rustom, M and Agha, MS},
title = {APOE ε4 and late-onset Alzheimer's disease in Syria: A case-control study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261475340},
doi = {10.1177/13872877261475340},
pmid = {42570292},
issn = {1875-8908},
abstract = {BackgroundThe apolipoprotein E (APOE) ε4 allele is the strongest known genetic risk factor for late-onset Alzheimer's disease (AD), but its prevalence and impact vary substantially across populations. No previous study has characterized APOE allele distribution among Syrian patients with AD.ObjectiveThis investigation aimed to assess the association between APOE genotypes and AD risk in a Syrian cohort.MethodsIn this case-control study, genomic DNA was extracted from 52 clinically diagnosed AD patients and 38 cognitively healthy controls. The APOE genotype was determined by direct sequencing of the rs429358 and rs7412 polymorphisms defining the ε2, ε3, and ε4 alleles. Genotypic and allelic frequencies were compared using Fisher's exact test, and Hardy-Weinberg equilibrium was assessed in the controls.ResultsThe ε3/ε3 genotype was predominant in both groups (73.1% of cases, 94.7% of controls). The ε3/ε4 genotype appeared in 23.1% of AD patients but was absent among controls (Corrected OR = 12.37, 95% CI = 0.65-233.7, p < 0.01). The overall ε4 allele frequency in patients (0.117) was significantly higher than in controls (0.000) (Corrected OR = 10.76, 95% CI = 0.59-195.7, p < 0.01). The ε2/2, ε4/4, and ε2/4 genotypes were not detected in any participants.ConclusionsThis study is the first to investigate the prevalence of the APOE ε4 allele in Syrian patients with Alzheimer's disease. These results underscore the importance of investigating genetic architectures when assessing AD risk and call for larger, multi-center studies across the Middle East to elucidate the interplay between APOE variants and metabolic determinants of cognitive decline.},
}
@article {pmid42570437,
year = {2026},
author = {Yan, Y and Tian, D and Yang, F and Zhao, R and Deng, L and Wang, Q and Xie, M},
title = {A brain-targeted biomimetic iron-porphyrin covalent organic framework nanoplatform for Alzheimer's disease: synergistic intervention via antioxidant, Aβ-regulating and immunomodulatory effects.},
journal = {Journal of colloid and interface science},
volume = {724},
number = {Pt 3},
pages = {141264},
doi = {10.1016/j.jcis.2026.141264},
pmid = {42570437},
issn = {1095-7103},
abstract = {The pathological progression of Alzheimer's disease (AD) involves multiple interconnected pathways, including β-amyloid (Aβ) deposition, oxidative stress, and microglial dysfunction, which together form a self-reinforcing vicious cycle. This complexity poses a major challenge to conventional single-target therapeutic strategies. To address this limitation, we developed a biomimetic nanoplatform integrating active brain targeting, multiple therapeutic bioactivities, and immunomodulatory function. The core of this platform was an iron-porphyrin-based covalent organic framework (COF) that possesses enzyme-mimetic antioxidant activity, metal-ion-chelating capability, and Aβ-modulating properties. The COF core was cloaked with a BV2 microglial membrane (BM) to enhance biocompatibility and further functionalized with Angiopep-2 peptide to enable efficient blood brain barrier (BBB) penetration. In vitro studies demonstrated that the platform effectively scavenged various reactive oxygen species, achieved a copper-ion chelation rate of 41.78%, inhibited Aβ aggregation, and depolymerized pre-formed fibrils. At the cellular level, the nanoplatform not only protected neurons from β-amyloid-induced toxicity but also improved the redox status and mitochondrial function of microglia. Furthermore, it promoted the polarization of microglia from the pro-inflammatory M1 phenotype toward the neuroprotective M2 phenotype, which was correlated with enhanced β-amyloid phagocytic capacity. In APP/PS1 (APPswe/PSEN1dE9) transgenic mice, treatment with this nanoplatform markedly reduced cerebral Aβ plaque deposition, attenuated neuroinflammation and oxidative stress, and improved BBB integrity, ultimately leading to the remarkable recovery of spatial learning, memory, and spontaneous exploration abilities in mice. In summary, this integrated nano-strategy, which combines delivery, clearance, and modulation, represents an effective multi-target approach for intervening in the complex pathological network of AD.},
}
@article {pmid42570467,
year = {2026},
author = {Lin, CH and Hung, PH and Chung, MC and Wu, LY and Chung, CJ},
title = {Risk of Dementia after initiation of GLP-1 RA versus long-acting insulin in patients with type 2 Diabetes mellitus.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {9},
pages = {100645},
doi = {10.1016/j.tjpad.2026.100645},
pmid = {42570467},
issn = {2426-0266},
abstract = {BACKGROUND: Recent studies suggest a decreased risk of dementia in patients treated with glucagon-like peptide-1 receptor agonist (GLP-1 RA). In this study, we compare the risk of dementia associated with GLP-1 RA versus long-acting insulin in adults aged over 50 years with type 2 diabetes (T2DM) using real-world administrative data from a large Taiwan cohort DESIGN: A population-based retrospective cohort study SETTING: We analyzed 10,783 propensity score-matched pairs of adults with T2DM who initiated either GLP-1 RA or long-acting insulin from Taiwan's National Health Insurance Research Database (2011-2021).<br><br>MEASUREMENTS: Primary outcome was new-onset dementia; secondary outcomes included dementia requiring treatment and specific dementia subtypes (Alzheimer's disease, vascular dementia, and unspecified dementia). Hazard ratios (HRs) were estimated using Cox models.<br><br>RESULTS: Analysis of matched pairs identified 375 cases of newly diagnosed dementia. The incidence rate was 4.86 per 1,000 person-years in GLP-1 RA users versus 7.56 in insulin users. GLP-1 RA use was associated with significantly lower risk of overall dementia (HR 0.64, 95% CI 0.46-0.89, P=0.0072) and unspecified dementia (HR 0.41, 95% CI 0.24-0.68, P=0.0006), but not for Alzheimer's disease (HR 1.48, 95% CI 0.61-3.63, P=0.3867) or vascular dementia (HR 1.66, 95% CI 0.21-13.03, P=0.6324). Among GLP-1 RAs, both liraglutide (HR 0.40, 95% CI 0.20-0.80, P=0.0091) and dulaglutide (HR 0.42, 95% CI 0.19-0.92, P=0.0311) showed significant protective effects against unspecified dementia.<br><br>CONCLUSIONS: GLP-1 RA use was associated with lower dementia risk versus long-acting insulin in T2DM patients, especially with liraglutide and dulaglutide. As observational, causality requires confirmation from randomized controlled trials.},
}
@article {pmid42570468,
year = {2026},
author = {Hüppi, RM and Langer, N and Hebling Vieira, B and , },
title = {Quantifying generalization error in machine learning prediction of cognitive decline.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {9},
pages = {100646},
doi = {10.1016/j.tjpad.2026.100646},
pmid = {42570468},
issn = {2426-0266},
abstract = {BACKGROUND: Predicting cognitive decline as a continuum, from healthy age-related decline to mild cognitive impairment and dementia, enables more precise individual-level predictions. However, the practical value of such models for early intervention and prevention depends on their ability to generalize to independent cohorts, a property that is often not evaluated.<br><br>OBJECTIVES: This study investigated whether adding structural magnetic resonance imaging (MRI) to non-brain data improved machine learning predictions of continuous cognitive decline and analyzed the models' generalizability.<br><br>DESIGN: Multi-target random forest regression models predicted annual decline in the Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) and Mini-Mental State Examination (MMSE) using non-brain data, structural MRI data, or their combination from the Alzheimer's Disease Neuroimaging Initiative (ADNI; N = 1237) and Open Access Series of Imaging Studies (OASIS-3; N = 662) datasets. Cross-site generalizability was evaluated.<br><br>SETTING: Data from ADNI and OASIS-3 were used for this study.<br><br>PARTICIPANTS: A total of 1899 participants who had demographic, clinical, and brain imaging data from a baseline session and clinical data from at least 2 follow-up sessions were included.<br><br>MEASUREMENTS: Baseline non-brain (demographics, clinical and neuropsychological scores, information on APOE genotype, cognitive diagnosis, health, and number of sessions before baseline) and/or structural MRI data were used to predict the yearly rate of change in CDR-SOB and MMSE scores.<br><br>RESULTS: Including structural MRI data improved prediction of CDR-SOB and MMSE change, reaching respective R[2] values of .41 and .33 in ADNI and .42 and .33 in OASIS-3. Model performance for across-dataset predictions was reduced (R[2] between .18 and .35), unexplained by distributional shifts of target variables. Models using only top predictive features performed similarly to full models when tested externally (R[2] between .18 and .34), suggesting predictor redundancy.<br><br>CONCLUSIONS: Incorporating structural MRI data enhances within-dataset prediction of continuous cognitive decline, allowing for more precise individual-level prediction and advancing towards precision medicine. Even though external validation remains limited, quantifying the generalizability gap is a crucial step towards the responsible use of ML models in clinical intervention and prevention.},
}
@article {pmid42570561,
year = {2026},
author = {Kristiansen, S and Eriksen, S and Treviño, CS and Välimäki, T and Atladóttir, H and Gudmundsdottir, G and Engedal, K and Snædal, J and Rokstad, AMM and Konradsen, H},
title = {Patients' experiences of living with the risk of Alzheimer's disease - a multicentre qualitative study.},
journal = {Geriatric nursing (New York, N.Y.)},
volume = {73},
number = {},
pages = {104209},
doi = {10.1016/j.gerinurse.2026.104209},
pmid = {42570561},
issn = {1528-3984},
abstract = {AIMS AND OBJECTIVES: To explore the experiences of receiving and living with a diagnosis of prodromal Alzheimer's disease.<br><br>BACKGROUND: Alzheimer's disease is a progressive dementia disorder, with pathology potentially developing years before clinical symptoms. Evidence concerning patients' perspectives on living with a prodromal Alzheimer's disease diagnosis remains scarce.<br><br>DESIGN AND METHODS: A qualitative, descriptive design was employed. Semi-structured interviews were conducted with 16 participants diagnosed with prodromal Alzheimer's disease in memory clinics in Denmark, Norway and Iceland. The data were analysed using thematic analysis.<br><br>FINDINGS: Four main themes emerged: 1) what led to the assessment, 2) receiving the diagnosis of prodromal Alzheimer's disease, 3) everyday life after the diagnosis and 4) planning for the future. The participants experienced diverse trajectories to diagnosis, with some being alerted by others to symptoms and some recognising the symptoms themselves. The diagnostic process was often perceived as intimidating, and person-centred care was valued. After the diagnosis, the participants focused on managing daily life, experienced changes in relationships and harboured mixed emotions about the future.<br><br>CONCLUSION: Receiving a prodromal Alzheimer's disease diagnosis impacts patients' perceptions of their abilities, relationships and future. There is a need for interventions targeting both patients and their families to maintain a close bond between them and support hope. Clear communication about the distinction between prodromal Alzheimer's disease and Alzheimer's dementia is crucial.<br><br>No Patient or Public Contribution.},
}
@article {pmid42570638,
year = {2026},
author = {Zou, Y and Ou, Y and Zhao, H and Chen, G and Chen, Z and Li, Y and Jiang, J},
title = {Microglial immunometabolism in Alzheimer's disease: A stage-resolved trajectory from adaptive remodeling to the metabolic paradox.},
journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie},
volume = {202},
number = {},
pages = {119841},
doi = {10.1016/j.biopha.2026.119841},
pmid = {42570638},
issn = {1950-6007},
abstract = {Microglia are central regulators of the cellular phase of Alzheimer's disease (AD). Under chronic exposure to amyloid-β, pathological tau, and aging-associated bioenergetic decline, these cells undergo immunometabolic remodeling that may initially be adaptive. As stress persists, this remodeling can become maladaptive, marked by disordered glycolysis, disturbed lipid handling, mitochondrial dysfunction, and compensatory failure. In this review, we organize these changes as a stage-dependent trajectory from adaptive remodeling to functional decompensation. We introduce the "metabolic paradox" as an operational descriptor: a concurrent, same-cell mismatch between increased substrate uptake or inflammatory activation and declining bioenergetic efficiency and homeostatic function. Along this trajectory we examine neurovascular energy bottlenecks, substrate redistribution, triggering receptor expressed on myeloid cells 2 (TREM2)/apolipoprotein E (APOE)-dependent lipid homeostasis, mitochondrial and proteostatic collapse, and their links to persistent neuroinflammation, defective phagocytosis, aberrant synaptic pruning, and senescence-like dysfunction. We synthesize prior primary findings and stratify each major claim by evidentiary strength, avoiding the overinterpretation of model-specific results as patient-level mechanisms. Finally, we frame immunoprevention as mechanism-based, early-stage metabolic intervention to preserve homeostatic microglial function, a strategy whose clinical benefit remains a hypothesis requiring prospective testing.},
}
@article {pmid42570705,
year = {2026},
author = {Li, N and Wu, Y and Feng, H and Jian, X and Yang, Z and Wang, X and Li, X and Yin, Y and Long, Y},
title = {Metabolic Reprogramming-Driven Neuroimmunoregulation: Key Mechanisms and Therapeutic Opportunities and Challenges in Central Nervous System Disorders.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103291},
doi = {10.1016/j.arr.2026.103291},
pmid = {42570705},
issn = {1872-9649},
abstract = {Central nervous system (CNS) disorders are fundamentally linked to metabolic dysregulation within immune and glial cells. This review provides a systematic synthesis of immunometabolic reprogramming-encompassing glucose, lipid, and amino acid metabolism, and oxidative phosphorylation-in CNS-resident microglia, immunomodulatory astrocytes, and peripherally infiltrating immune cells (T cells, B cells, and neutrophils) across Alzheimer's disease, Parkinson's disease, multiple sclerosis, and ischemic stroke. Critically, rather than presenting all reported metabolic alterations as equivalently established, we introduce an evidence-transparency framework that systematically distinguishes the nature of supporting data-ranging from direct metabolic flux measurements (Seahorse, isotope tracing, lipidomics) and molecular correlates, to genetic/pharmacological perturbations, human tissue validation, and model-specific observations-enabling readers to independently assess the strength of each major conclusion. We further delineate aging as an active analytical dimension, demonstrating how age-related changes in mitochondrial quality control, lipid handling, redox buffering, and glial-immune crosstalk establish a permissive baseline that modifies disease-specific reprogramming trajectories. By integrating analyses of intercellular crosstalk, neuroinflammation, blood-brain barrier integrity, and oxidative stress, we illustrate both convergent and divergent metabolic mechanisms across diseases. Finally, we critically assess therapeutic strategies targeting immunometabolism, emphasizing shared translational obstacles including target selectivity, blood-brain barrier penetration, stage-dependent efficacy, and the inherent challenge of pathway pleiotropy. This review provides a conceptually grounded framework for interpreting immunometabolic evidence, navigating the gap between correlative findings and causal mechanisms, and guiding future hypothesis-driven therapeutic design for CNS disorders.},
}
@article {pmid42570712,
year = {2026},
author = {Shokr, MM and Fawzy, MN},
title = {The gut-brain-mitophagy axis: Urolithin A as a transcriptional activator of Parkin in Alzheimer's and Parkinson's diseases.},
journal = {Molecular and cellular neurosciences},
volume = {},
number = {},
pages = {104112},
doi = {10.1016/j.mcn.2026.104112},
pmid = {42570712},
issn = {1095-9327},
abstract = {Mitochondrial dysfunction is a cardinal, causative, and convergent hallmark in both Alzheimer's disease (AD) and Parkinson's disease (PD). However, therapeutics that target the process of mitophagy, the selective removal of damaged mitochondria, are relatively undeveloped. Prior work has largely centered around post-translational modifications of the PINK1-Parkin signaling pathway while ignoring the key need for sustained protein synthesis of Parkin. In this review, we explore an innovative transcriptional circuit involving the gut microbiome, AMP-activated protein kinase (AMPK), sirtuin 1 (SIRT1), and mitophagy: gut-derived metabolites, such as Urolithin A (UA), activate AMPK and SIRT1, both of which converge to deacetylate and phosphorylate peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). The transcription of the mitophagy protein, Parkin, is then driven by activation of PGC-1α. This UA/AMPK/SIRT1/PGC-1α/Parkin/mitophagy pathway is disrupted in multiple layers in AD and PD; this includes impaired gut function, lowering the level of UA produced in the body, proteinopathy leading to reduced PGC-1α activity, and decreased transcription of Parkin. Therapeutic targets of these various nodes include UA, PGC-1α activator ZLN005, and SIRT1 activators, such as resveratrol or nicotinamide riboside. By shifting the paradigm from post-translational activation to transcriptional restoration of Parkin, this gut-brain metabolic axis offers a unifying, testable, and therapeutically tractable framework for mitigating mitophagy failure in AD and PD.},
}
@article {pmid42565262,
year = {2026},
author = {Collins, EC and Lu, M and Beck, R and Hendrix, J and Hodsdon, ME and Hansson, O},
title = {Plasma P-tau217 for detecting amyloid clearance after donanemab in Alzheimer's disease.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71740},
pmid = {42565262},
issn = {1552-5279},
support = {//Eli Lilly and Company/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/blood/diagnostic imaging ; *tau Proteins/blood ; Positron-Emission Tomography ; Biomarkers/blood ; Phosphorylation ; Female ; Male ; Aged ; *Amyloid beta-Peptides/metabolism ; *Amyloid/metabolism ; ROC Curve ; Antibodies, Monoclonal, Humanized ; },
abstract = {INTRODUCTION: This analysis of the phase 3 TRAILBLAZER-ALZ 2 trial examined whether plasma tau protein phosphorylated at threonine 217 (p-tau217) level can reliably monitor treatment-related amyloid clearance (TRAC) after donanemab treatment in early symptomatic Alzheimer's disease (AD).<br><br>METHODS: Amyloid positron emission tomography (PET) and plasma p-tau217 levels were assessed at baseline and longitudinally during study treatment. The diagnostic performance of p-tau217 in detecting post-treatment TRAC (<&#xa0;24.1 Centiloids [CL]) was evaluated by receiver operating characteristic (ROC) analysis.<br><br>RESULTS: Plasma p-tau217 showed suboptimal performance in detecting TRAC by PET in donanemab-treated participants (N&#xa0;=&#xa0;830), with an area under the ROC curve of 0.61 at 52&#xa0;weeks.<br><br>DISCUSSION: Despite reductions in plasma p-tau217 with donanemab treatment, this biomarker cannot currently be used to accurately detect TRAC by PET (<&#xa0;24.1 CL) in individuals with early symptomatic AD.},
}
@article {pmid42565396,
year = {2026},
author = {Alpidovskaya, OV and Tikhonov, BV},
title = {[Clusterin as a biomarker for Alzheimer's disease].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {126},
number = {7},
pages = {22-28},
doi = {10.17116/jnevro202612607122},
pmid = {42565396},
issn = {1997-7298},
mesh = {Humans ; *Clusterin/blood/metabolism ; *Alzheimer Disease/diagnosis/blood/metabolism ; Biomarkers/blood ; Oxidative Stress ; },
abstract = {OBJECTIVE: To examine and systematically review the existing literature regarding clusterin (CLU) as a potential biomarker for Alzheimer's disease.<br><br>MATERIAL AND METHODS: A comprehensive analysis of data, including generalization, comparison, and systematization, was conducted to review findings from both Russian and international publications. The study included a thorough search of the PubMed (MEDLINE) database and other scientific information sources over the last decade. The collected data underwent analytical scrutiny to elucidate the potential significance of CLU in AD pathogenesis.<br><br>RESULTS: This article presents evidence indicating that clusterin (CLU) may play a significant role in AD pathogenesis through various mechanisms, including regulation of inflammation, modulation of cellular apoptosis, facilitation of clearance of pathological proteins, and affecting oxidative stress and the aggregation and folding of extracellular proteins. CLU plays a vital role in promoting cell survival under stressful conditions. It offers protection against oxidative stress, ensuring both immediate resistance to damage and prolonged cellular viability. A loss of soluble clusterin (sCLU) protective function in response to ROS-induced damage may render neurons more susceptible to additional insults, such as A&#x3b2;, which generates H2O2 and other reactive oxygen species. Furthermore, CLU can activate the PI3K/Akt signaling pathway, which functions as an effector of mTOR and NF-&#x3ba;B. Inhibition of mTOR has been associated with a slowing of AD progression. Notably, elevated plasma levels of CLU in healthy older adults may precede significant A&#x3b2; deposition in the brain by as much as ten years, suggesting an early elevation of CLU within the pathogenesis of AD and its potential pathological implications.<br><br>CONCLUSIONS: Clusterin should be considered a significant biomarker for Alzheimer's disease, supporting the use of enzyme-linked immunosorbent assays to measure plasma CLU concentrations. This approach may serve as an additional tool for early screening and therapeutic interventions in Alzheimer's disease.},
}
@article {pmid42565414,
year = {2026},
author = {Ramirez-Contreras, LA and Camargo-Hernández, G and Sanchez-Enriquez, S and Silva-Jara, JM and Hernández Estrada, S and Hernández Villaseñor, LA and Anaya Esparza, LM},
title = {Bioinformatic Tools to Explore the Mechanisms and the Multitarget Recognition of Huperzine A in Alzheimer's and Parkinson's Diseases.},
journal = {Current drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113894501499352260714060149},
pmid = {42565414},
issn = {1873-5592},
abstract = {INTRODUCTION: Considering the shared physiological mechanisms between Alzheimer's disease (AD) and Parkinson's disease (PD), it is plausible that certain compounds may exert therapeutic effects on both neurological disorders. This study aimed to employ in silico techniques to investigate the pharmacological mechanisms of huperzine A (HA) as an alternative treatment for PD and AD.<br><br>METHODS: Molecular targets of HA and genes associated with AD and PD were identified from public databases. Gene Ontology analysis, metabolic pathway analysis, and protein-protein interaction (PPI) network construction were performed to identify shared molecular targets. Molecular docking was performed to assess HA affinity for hub proteins and to compare it with that of drugs used to treat AD and PD.<br><br>RESULTS: The results suggested that HA interacts with 77 molecular targets common to both diseases. Enrichment analysis revealed that proteins from these targets were involved in biological functions, such as serotonin and amine binding. Hub proteins (SRC, TP53, AKT1, and CASP3) were identified from the PPI network. Furthermore, molecular docking simulations showed favorable binding of HA to the hub proteins and adequate binding to the targets of standard drugs (MAOB and ACHE). On the other hand, molecular dynamics analyses were performed to compare the binding characteristics of HA with those of the control targets.<br><br>DISCUSSION: HA may modulate SRC, CASP3, and AKT1, suggesting a pleiotropic mechanism underlying the association between AD and PD. These computational findings provide a rational basis for experimental validation by modulating signaling pathways implicated in inflammatory processes and inhibiting enzymes involved in neurotransmitter degradation.<br><br>CONCLUSION: This study contributes to the understanding of the neuroprotective activity of HA in AD and PD. However, further in vitro and in vivo investigations are required to confirm the dual therapeutic potential of HA in the treatment of AD and PD.},
}
@article {pmid42565788,
year = {2026},
author = {Keller, JL and Pennartz, KJ and Sprick, JD and Hein, EJ and Irving, BA and Vann, CG and Butlig, ER and Al-Masri, S and Nelson, AR},
title = {A peripheral perspective on brain health: vascular and skeletal muscle contributions.},
journal = {American journal of physiology. Heart and circulatory physiology},
volume = {},
number = {},
pages = {},
doi = {10.1152/ajpheart.00462.2026},
pmid = {42565788},
issn = {1522-1539},
support = {AG079454//HHS | NIH | National Institute on Aging (NIA)/ ; NS135147//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; //Coins for Alzheimer's Research Trust (CART)/ ; AG070146//HHS | NIH | National Institute on Aging (NIA)/ ; AG054840//HHS | NIH | National Institute on Aging (NIA)/ ; AG000029//HHS | NIH | National Institute on Aging (NIA)/ ; HL153497//HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; },
abstract = {Age- and disease-related declines in brain health contribute to impairments in physical function, yet effective approaches to lessen these declines remain limited. Overall health is governed by a network of interdependent organ systems, such that dysfunction in one system can propagate across others. Although the brain has been viewed as a top-down regulator of vital functions, evidence indicates that cognition is affected by signals from peripheral organs. This interorgan communication likely explains the coexistence of Alzheimer's disease and related dementias with cardiovascular and metabolic disorders characterized by overlapping pathophysiology. Skeletal muscle and the peripheral vasculature are key contributors to this and represent modifiable systems that can alter brain structure and function. Skeletal muscle regulates myokine release through motor neuron function, contractile activity, and metabolic perturbations, thereby influencing neuroplasticity, mitochondrial function, and inflammatory signaling, and may affect measures of peripheral vascular function, like reactive hyperemia. Other properties of the vasculature, including arterial stiffness, directly affect cerebral perfusion and blood-brain barrier permeability. These systems form a muscle-vascular-brain axis that contributes to brain health and impacts the risk of cognitive impairment. Therefore, our aim was to synthesize the current understanding of interactions among skeletal muscle, the peripheral vasculature, and the brain, and their collective role in maintaining cognitive health. We also highlight recent clinical trials and emerging strategies affecting interorgan crosstalk. These conclusions support a model in which lifestyle interventions targeting peripheral systems, such as resistance training, may preserve brain health across all populations, offering scalable approaches applicable across the lifespan.},
}
@article {pmid42565943,
year = {2026},
author = {Liu, Z and Nie, JF and Liu, H and Liu, Z and Pang, Y and Fu, H and Zhang, Y},
title = {Integrating Metabolomics Data, Network Pharmacology, and Molecular Docking to Investigate the Effect of Aging Times on the Functional Activity of Liupao Tea.},
journal = {Plant foods for human nutrition (Dordrecht, Netherlands)},
volume = {81},
number = {3},
pages = {},
pmid = {42565943},
issn = {1573-9104},
support = {No. GuikeLT2600640006//Guangxi Science and Technology Innovation Platform Project/ ; No. GuikeAA23023006//Guangxi Science and Technology Major Project/ ; No. Guirencaiban202401//Guangxi Bagui Youth Talent Project/ ; Nos. 22464008 and 21765007//National Natural Science Foundation of China/ ; },
mesh = {Molecular Docking Simulation ; Metabolomics ; Oxidative Stress/drug effects ; *Antioxidants/analysis/pharmacology ; Network Pharmacology ; Humans ; *Tea/chemistry ; *Camellia sinensis/chemistry ; Time Factors ; },
abstract = {Liupao tea (LPT) undergoes significant bioactive changes during aging, while the link between these chemical shifts and the regulation of oxidative stress pathologies remains unclear. Therefore, this study integrated metabolomics, network pharmacology, and molecular docking to analyze Maosheng (MS) and Tianyu (TY) LPT samples aged 0-15 and 0-10 years, respectively, and elucidated the potential mechanisms of LPT in five oxidative stress - related diseases, including depression, obesity, Alzheimer's disease, diabetes, and hypertension. Metabolomics identified 42 and 13 core antioxidant metabolites in MS and TY samples, respectively. Among them, core metabolites in MS peaked at 5 years, while TY sustained high abundance levels from 3 to 8 years. Network pharmacology revealed synergistic regulation of all five pathologies by both LPTs, and eight key components were screened from MS, and nine from TY based on degree values. Interestingly, the highest node density was shown in depression, and Sankey connectivity confirmed its strongest modulatory effect. Besides, the core depression‑related components and targets were subjected to molecular docking simulations, and binding energies ranged from - 5.37 to -8.88 kcal/mol for MS components, as well as from - 4.11 to -8.39 kcal/mol for TY components. Importantly, oleaside A and CCRIS 7793 showed the strongest affinities for GAPDH and AKT1, respectively. In general, these results laid a practical foundation for developing an LPT product aimed at relieving oxidative stress-related health issues.},
}
@article {pmid42566020,
year = {2026},
author = {Lövdal, S and Meles, SK and Carli, G and Dortmond, A and Kogan, RV and Goldstein, O and Gana-Weisz, M and Orad, RI and Alcalay, RN and Bregman, N and Leenders, KL and Shiner, T},
title = {Effect of genetic factors on [[18]F]FDG PET metabolic phenotypes in dementia with Lewy bodies.},
journal = {European journal of nuclear medicine and molecular imaging},
volume = {},
number = {},
pages = {},
pmid = {42566020},
issn = {1619-7089},
abstract = {BACKGROUND: Neuroimaging with [[18]F]FDG PET can support the diagnosis of Dementia with Lewy Bodies (DLB), but it remains unclear how genetic factors influence metabolic phenotypes.<br><br>OBJECTIVES: To determine whether GBA1 and APOE &#x3b5;4 status are associated with diverging [[18]F]FDG PET metabolic patterns in DLB.<br><br>METHODS: We analyzed [[18]F]FDG PET scans from 43 patients with DLB stratified by GBA1 and APOE &#x3b5;4 status, and 35 from healthy subjects. Analyses included the cingulate island sign (CIS), regions of interest, SSM/PCA disease patterns, and a machine learning multi-class model. We evaluated the similarity of the DLB patient scans in our cohort with respect to typical DLB, Alzheimer's disease (AD) and Parkinson's disease (PD)-like patterns.<br><br>RESULTS: APOE &#x3b5;4 status mainly influenced the CIS, with APOE &#x3b5;4-negative patients showing greater preservation of the DLB-typical CIS pattern (p&#x2009;=&#x2009;0.03) compared to APOE &#x3b5;4 carriers. In contrast, GBA1 status influenced global metabolic phenotype. GBA1 carriers showed a more homogeneous PD/DLB-like metabolic pattern in the machine learning model (p&#x2009;=&#x2009;0.003) compared to GBA1 non-carriers, whereas the latter group demonstrated greater heterogeneity and higher expression of the AD-related metabolic pattern (p&#x2009;=&#x2009;0.004). These effects were observed along a metabolic spectrum rather than as distinct clusters.<br><br>CONCLUSIONS: APOE &#x3b5;4 and GBA1 modulate distinct aspects of the metabolic phenotype in DLB. GBA1 non-carriers and APOE &#x3b5;4 carriers showed a higher rate of atypical metabolic signatures, which may contribute to biological heterogeneity and increase the risk of diagnostic misclassification.},
}
@article {pmid42566137,
year = {2026},
author = {Barbosa, KA and Ribeiro, HM and Benevenuto, LGD and Maiorka, PC and Cominetti, MR and Amorim, RM and Cagnini, DQ},
title = {Advances in biomarker discovery for canine cognitive dysfunction: a comprehensive structured narrative review and future perspectives.},
journal = {Veterinary research communications},
volume = {50},
number = {5},
pages = {},
pmid = {42566137},
issn = {1573-7446},
mesh = {Animals ; Dogs ; *Biomarkers/cerebrospinal fluid/blood ; *Dog Diseases/diagnosis/cerebrospinal fluid/blood ; *Cognitive Dysfunction/diagnosis/cerebrospinal fluid/blood ; Amyloid beta-Peptides/cerebrospinal fluid/blood ; Glial Fibrillary Acidic Protein/cerebrospinal fluid/blood ; tau Proteins/cerebrospinal fluid/blood ; },
abstract = {Canine Cognitive Dysfunction (CCD) is a naturally occurring neurodegenerative syndrome in aging dogs that shares clinical and neuropathological parallels with Alzheimer's disease (AD). As the demand for objective diagnostic tools grows, identifying reliable biofluid biomarkers is essential for clinical staging and therapeutic monitoring. This review synthesizes evidence on cerebrospinal fluid (CSF) and blood-based biomarkers (BBM) of CCD, focusing on amyloid-β (Aβ), neurofilament light chain (NfL), tau, and glial fibrillary acidic protein (GFAP). Evidence shows that Aβ42 and Aβ42/Aβ40 ratios exhibit stage-dependent, non-linear alterations resembling early compensatory phases in human AD. In contrast, tau pathology in CCD consists mainly of pre-tangle synaptic hyperphosphorylation rather than abundant neurofibrillary tangles, limiting its current diagnostic utility. GFAP, a marker of astroglial activation, shows inconsistent associations with cognitive decline and remains exploratory. Conversely, NfL has emerged as the most robust biomarker; CSF and plasma NfL levels consistently increase with age, correlate with cognitive impairment, and reflect central axonal pathology, making it the leading candidate for staging and monitoring disease progression. Overall, the CCD biomarker landscape supports a multimodal approach integrating Aβ dysregulation, axonal injury, and glial activation. Advancing this field requires harmonized diagnostic criteria, standardized sampling, and longitudinal studies. Such efforts will strengthen the translational value of CCD as a model for human dementia, accelerating discovery and therapeutic development across species.},
}
@article {pmid42566636,
year = {2026},
author = {Chen, Y and Chen, X},
title = {Genetic evidence for a causal role of depression in late-onset Alzheimer disease: A Mendelian randomization study.},
journal = {Medicine},
volume = {105},
number = {32},
pages = {e50116},
doi = {10.1097/MD.0000000000050116},
pmid = {42566636},
issn = {1536-5964},
mesh = {*Alzheimer Disease/genetics/epidemiology ; Humans ; *Mendelian Randomization Analysis ; Polymorphism, Single Nucleotide ; *Depression/genetics/complications ; Genetic Predisposition to Disease ; Age of Onset ; },
abstract = {Observational studies link psychiatric disorders to Alzheimer disease (AD), but whether these associations are causal remains unclear due to confounding and reverse causality. We aimed to dissect these relationships using genetic evidence. We performed a two-sample Mendelian randomization (MR) study to assess the causal effects of 7 psychiatric and neurodevelopmental disorders on AD and its subtypes. The primary analysis utilized the inverse-variance weighted (IVW) method, supported by comprehensive sensitivity analyses (MR Steiger test, MR-Egger, and MR-PRESSO) and a supplementary analysis excluding single nucleotide polymorphisms (SNPs) associated with potential confounders. Depression showed a significant causal association with late-onset AD (odds ratio [OR] = 1.0736, 95% confidence interval [CI]: 1.0084-1.1431, P = .0264). No significant causal associations were found for other psychiatric disorders (all P > .05). A directionality test conducted by MR Steiger confirmed our estimation of potential causal direction (P < .001). Sensitivity analyses excluding pleiotropic SNPs yielded consistent results. The causal association for depression and late-onset AD remained significant after excluding pleiotropic SNPs linked to confounders (OR = 1.0726, 95% CI: 1.0069-1.1425, P = .03). Our study provides genetic evidence supporting a causal role for depression in the etiology of late-onset AD, a link not observed for other major psychiatric disorders tested. These findings highlight the specific importance of managing depression as a potential strategy for mitigating AD risk and suggest distinct etiological pathways between different mental health conditions and neurodegeneration.},
}
@article {pmid42566883,
year = {2026},
author = {Zhao, H and Gao, R and Zhang, B and Gao, J and Xue, B and Zhang, Y},
title = {Advances in dopamine transporter inhibitors: Design strategies, structural features, and pharmacological insights.},
journal = {European journal of medicinal chemistry},
volume = {318},
number = {},
pages = {119189},
doi = {10.1016/j.ejmech.2026.119189},
pmid = {42566883},
issn = {1768-3254},
abstract = {Dopamine transporter (DAT) plays a pivotal role in regulating synaptic dopamine homeostasis and is critically involved in various neuropsychiatric disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), and substance use disorders. This review highlights cutting-edge advances in the development of DAT inhibitors, offering new insights into their structure-activity relationships, pharmacological mechanisms, and therapeutic potential. The core findings emphasize the significance of conformational selectivity in overcoming addiction-related limitations of typical inhibitors and uncover novel strategies for engineering atypical and allosteric inhibitors with improved efficacy and safety profiles. Furthermore, a comprehensive analysis of clinical trials reveals the main challenges in DAT inhibitor development, such as off-target toxicity and multitarget-related adverse effects, providing a foundation for addressing these issues. By distilling critical design strategies and lessons learned, this review provides a theoretical framework and actionable guidance for the future development of safe, selective, and effective DAT-targeting therapies.},
}
@article {pmid42566983,
year = {2026},
author = {Aaltonen, A and Palviainen, T and Heikkinen, S and Herukka, SK and Hiltunen, M and Kokkola, T and Kärkkäinen, S and Palotie, A and Runz, H and Julkunen, V and Kaprio, J and Saari, TT and Vuoksimaa, E and , },
title = {Genetic architecture of Alzheimer's disease-related plasma biomarkers.},
journal = {Neurobiology of aging},
volume = {168},
number = {},
pages = {123-131},
doi = {10.1016/j.neurobiolaging.2026.07.010},
pmid = {42566983},
issn = {1558-1497},
abstract = {Alzheimer's disease-related plasma biomarker interrelationships and factors underlying these associations remain poorly understood. To address this, we studied the heritability of plasma biomarkers and their associations with cognition. This study included 696 twins, aged 65-85, without a diagnosis of Alzheimer's disease or related dementias. Plasma amyloid beta 42 and 40, phosphorylated tau (p-tau) 181 and 217, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) were quantified with Simoa HD-X, and cognition was assessed with cCOG. Heritability of plasma biomarkers was assessed with multivariate twin models and associations with cognition with linear mixed effect models. Phenotypic associations varied from 0.22 between p-tau181 and GFAP to 0.73 between p-tau181 and p-tau217, and the heritability estimates ranged from 0.39 (p-tau181) to 0.66 (GFAP). Genetic and environmental correlations were 0.32-0.67 and 0.06-0.78, with the strongest correlations observed between p-tau181 and p-tau217. P-tau181 and p-tau217 were associated with cognition (β = -0.12; 95% CI: -0.19--0.04 and β = -0.19; 95% CI: -0.26--0.12, respectively). The observed phenotypic and genetic associations highlight shared underlying mechanisms among plasma biomarkers. Despite p-tau181 and p-tau217 having the strongest genetic and environmental correlations, neither approached unity, implying unique genetic and environmental factors. Our results offer insight into the genetic architecture of diagnostic and progression markers of Alzheimer's disease and inform their use in future gene-finding studies.},
}
@article {pmid42567320,
year = {2026},
author = {Chen, H and Wu, Z and Ge, T and Wu, M and Ye, J and Shan, S and Gao, C and Yang, Y and Yuan, C},
title = {Low-carbohydrate and low-fat diets, genetic susceptibility, and long-term risk of dementia: A prospective cohort study.},
journal = {The American journal of clinical nutrition},
volume = {},
number = {},
pages = {101463},
doi = {10.1016/j.ajcnut.2026.101463},
pmid = {42567320},
issn = {1938-3207},
abstract = {BACKGROUND: Low-carbohydrate and low-fat diets (LCDs and LFDs) are promoted for cardiometabolic prevention.<br><br>OBJECTIVE: This study examined associations of LCDs and LFDs with incident dementia and evaluated modification by genetic susceptibility.<br><br>METHODS: We included 5301 dementia-free adults aged &#x2265;55 years from the Health and Retirement Study. Overall LCD and LFD indices were constructed based on macronutrient composition rankings assessed using a food frequency questionnaire in 2013-2014. Plant-based, animal-based, healthy, and unhealthy sub-scores were derived to characterize macronutrient sources and quality. Incident dementia was defined using the Langa-Weir algorithm through 2022. Genetic susceptibility was assessed using APOE genotype and Alzheimer disease polygenic risk score (AD-PRS). Cox models estimated hazard ratios (HRs).<br><br>RESULTS: During the 9-year follow-up, 506 participants developed dementia. Greater LCD score was associated with lower dementia risk (HR per SD increment 0.90, 95% CI, 0.82, 0.99), whereas an overall LFD was not (1.05, 95% CI, 0.96, 1.15). Plant-based and healthy LCDs showed stronger inverse associations (0.85, 95% CI, 0.78, 0.94 and 0.82, 95% CI, 0.74, 0.90), while higher animal-based (1.10; 95% CI, 1.00, 1.20) and unhealthy LFDs (1.13; 95% CI, 1.04, 1.24) were linked to higher dementia risk. Associations were consistent across APOE genotype and AD-PRS strata. Higher plant-based and healthy LCDs were also associated with better global and domain-specific cognitive performance.<br><br>CONCLUSION: Adherence to LCDs, particularly plant-based and higher-quality LCDs, was associated with lower dementia risk, consistently across genetic susceptibility strata. These findings underscored the importance of macronutrient quality, in addition to quantity, in promoting cognitive health.},
}
@article {pmid42567350,
year = {2026},
author = {Yang, ZL and Zhang, C and Tang, S and Zhang, XY and Huang, LY and Tan, L and , and , },
title = {Valine modulates Alzheimer's disease risk in APOE ε4 carriers: evidence from two cohorts.},
journal = {Journal of advanced research},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jare.2026.08.014},
pmid = {42567350},
issn = {2090-1224},
abstract = {INTRODUCTION: The apolipoprotein E ε4 (APOE ε4) allele confers the greatest genetic risk for sporadic Alzheimer's disease (AD).<br><br>OBJECTIVES: To identify APOE &#x3b5;4-associated metabolic factors related to AD risk and to provide preliminary insights into their biological and nutritional context.<br><br>METHODS: We leveraged multi-omics analyses across two independent cohorts to characterize biomarkers associated with AD. The effects of metabolite&#x202f;&#xd7;&#x202f;APOE &#x3b5;4 interactions were tested on incident AD and the &#x3b5;4-specific metabolic signatures were pinpointed. Multimodal analyses were used to test the underlying mechanisms, including neuroimaging, cerebrospinal fluid (CSF), and PET biomarkers within the A/T/N framework, as well as plasma proteomics combined with bioinformatics enrichment analyses.<br><br>RESULTS: Across both cohorts, valine emerged as the only metabolite associated with a reduced risk of incident AD specifically among APOE &#x3b5;4 carriers (P&#x202f;<&#x202f;0.005). Significant interaction effects between valine and APOE &#x3b5;4 were detected in both cohorts (P for meta-analyses&#x202f;<&#x202f;0.005). Higher levels of valine were associated with greater total white matter and posterior cingulate cortex volumes, as well as with lower levels of CSF tau proteins. Higher valine levels also predicted a slower decline in FDG-PET metabolism. No association was found between valine and A&#x3b2;. Mediation analyses of plasma proteomic data suggested statistically significant mediation effects involving GFAP, NEFL, and APOE (P&#x202f;<&#x202f;2&#x202f;&#xd7;&#x202f;10[-16]).<br><br>CONCLUSION: Valine is a metabolite associated with lower AD risk in APOE &#x3b5;4 carriers, with potential associations with tau pathology, neurodegeneration, and neuroinflammation-related processes. As this was an observational study, causality cannot be inferred.},
}
@article {pmid42567367,
year = {2026},
author = {Riffo-Lepe, N and Gonzalez-Sanmiguel, J and Meza, I and Saavedra-Sieyes, P and Armijo-Weingart, L and Zambrano, H and Riquelme, A and Salinas, A and Martín, LS and Aguayo, LG},
title = {Selective impairment of long-term depression in accumbal D1R+ MSNs involves calcium-permeable AMPARs in early Alzheimer's disease.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107568},
doi = {10.1016/j.nbd.2026.107568},
pmid = {42567367},
issn = {1095-953X},
abstract = {Alzheimer's disease (AD) is increasingly associated with early circuit dysfunction preceding cognitive decline, including neuronal hyperactivity and neuropsychiatric symptoms linked to mesolimbic pathways. The nucleus accumbens (NAc), a central regulator of reward and motivational processing, exhibits early alterations in excitation/inhibition balance in patients and experimental models, yet the synaptic mechanisms underlying its vulnerability remain unclear. Using a double transgenic APP/PS1 mice crossed with a Drd1a-tdTomato reporter line, we combined cell-type-specific electrophysiology, immunohistochemistry, ex vivo photometry, and behavioral assays. At a pre-plaque stage, intraneuronal Aβ accumulated in both dopamine D1 receptor-positive (D1R+) and D1R-negative medium spiny neurons (MSNs). Despite comparable Aβ levels, both high-frequency stimulation-induced long-term depression (LTD) and mGluR1/5-dependent LTD were selectively impaired in D1R+ MSNs. This vulnerability was accompanied by an increased contribution of calcium-permeable AMPA receptors (CP-AMPARs). Subsequent CP-AMPAR blockade reduced the residual evoked excitatory postsynaptic current that persisted after mGluR1/5 activation in APP/PS1 D1R+ MSNs. Because paired-pulse ratios remained unchanged, this residual response was consistent with a predominantly postsynaptic mechanism. These synaptic changes were accompanied by reduced evoked dopamine signaling, increased chocolate consumption, and altered baseline context preference, whereas standard pellet consumption, conditioned place preference, anxiety-like behavior, and social behavior were unchanged. These findings define a pre-plaque, cell-type-specific synaptic phenotype in male APP/PS1 mice in which impaired mGluR1/5-dependent plasticity and persistent CP-AMPAR signaling in D1R+ MSNs coincide with selective reward-related alterations.},
}
@article {pmid42567407,
year = {2026},
author = {Rabinovich, M and Lacham-Hartman, S and Papo, N},
title = {Modulating amyloid-β 42 aggregation and neurotoxicity by Kunitz domains and their derived peptides.},
journal = {New biotechnology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.nbt.2026.08.001},
pmid = {42567407},
issn = {1876-4347},
abstract = {Alzheimer's disease is associated with the aggregation of amyloid-β42 (Aβ42) into species of varying sizes, with intermediate oligomers being the most neurotoxic. We recently reported that amyloid precursor protein inhibitor (APPI), a Kunitz-type protein, and a cyclic peptide derived from its β-domain reduced Aβ42-mediated neurotoxicity, the former by reducing Aβ42 aggregation and formation of toxic Aβ42 oligomers, and the latter by promoting Aβ42 aggregation to form fibrils rather than the neurotoxic Aβ42 oligomers. To address the question of whether these two inhibition mechanisms are controlled by the structure or the amino acid sequence of the protein/peptide, we exploited three Kunitz-type proteins, bikunin, bovine pancreatic trypsin inhibitor (BPTI) and tissue factor pathway inhibitor (TFPI) - chosen for their similar β-strand-rich structures but different sequences to one another and to APPI - and also short peptides that mimic their β-domains, in either cyclic or linear conformation. In-vitro studies showed that the formation of Aβ42 aggregates was reduced by the three Kunitz-type proteins and by their derived cyclic peptides, but not by the linear counterparts of the cyclic peptides. In SH-SY5Y neuroblastoma cells, the Kunitz-type proteins and the cyclic (but not the linear) peptides reduced the intracellular and extracellular accumulation of Aβ42 aggregates, respectively. Both the Kunitz-type proteins and the cyclic peptides inhibited Aβ42-induced mitochondrial membrane depolarization and reduced Aβ42-mediated apoptosis and cell death. Overall, this study thus reveals the potential of the β-hairpin structure, whether as a segment within the Kunitz-type proteins or isolated as a cyclic peptide, to interact with Aβ42, thereby reducing Aβ42 aggregation and hence its neurotoxicity.},
}
@article {pmid42567574,
year = {2026},
author = {Chen, Y and Zhang, B and Yang, S and Wang, P and Wang, X and He, H},
title = {Ultrasensitive detection of blood-based p-tau217 for Alzheimer's disease integrated antibody-oligonucleotide conjugates and RCA/Cas12a system.},
journal = {Analytica chimica acta},
volume = {1418},
number = {},
pages = {345836},
doi = {10.1016/j.aca.2026.345836},
pmid = {42567574},
issn = {1873-4324},
mesh = {*Alzheimer Disease/blood/diagnosis ; Humans ; *tau Proteins/blood/immunology ; *Oligonucleotides/chemistry ; Immunoassay/methods ; Limit of Detection ; Phosphorylation ; },
abstract = {Tau phosphorylated at threonine 217 (p-tau217) is interesting increasingly as "star biomarker" in the field of Alzheimer's disease (AD) diagnosis due to the highest accuracy in detecting AD pathology and predicting future cognitive decline. Here, we developed an ultra-trace blood-based diagnostic platform for p-tau217, termed magnetic-particle-based Immunol Rolling-circle-amplification/Cas12a Assay (MPIRCA). In this approach, the operational process included two main stages: the preparation of All@MP (encompassing immobilization, capture, and binding) and the subsequent one-pot RCA/Cas12a reaction. Through the Ab-DNA, immunoassay was successfully converted into DNA-based molecular diagnostic technology (one-pot RCA/Cas12a reaction) to achieve ultra-high sensitivity with 1 fg/mL limitation of detection. The optimized assay exhibited excellent linearity across a range from 1 fg/mL to 1 ng/mL. The study presents a high feasible diagnostic strategy that combines one-pot operation, high sensitivity and selectivity, offering considerable potential for blood-based diagnosis and management of Alzheimer's disease (AD).},
}
@article {pmid42567782,
year = {2026},
author = {Risby-Jones, G and Lee, JD and Fung, JN},
title = {Interleukin-6 trans-signalling as a selectively targetable driver of neurodegeneration.},
journal = {Trends in neurosciences},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tins.2026.07.002},
pmid = {42567782},
issn = {1878-108X},
abstract = {Interleukin-6 (IL-6) exerts protective and pathogenic effects in the central nervous system through distinct receptor-signalling modes. Classical signalling via membrane-bound IL-6 receptor (IL-6R) is often associated with homeostatic and reparative functions, whereas trans-signalling, mediated by soluble IL-6R, expands IL-6 responsiveness to gp130-expressing cells and may promote chronic inflammation. Emerging evidence implicates dysregulated IL-6 trans-signalling in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis. Here, we review mechanisms linking IL-6 trans-signalling to immune, glial, neuronal, and vascular dysfunction in neurodegeneration. We highlight key knowledge gaps and discuss whether selective targeting of trans-signalling can limit inflammatory pathology while preserving beneficial classical IL-6 functions.},
}
@article {pmid42567789,
year = {2026},
author = {Hotta, M and Tabira, T and Murata, M and Yoshiura, K and Ishikawa, T and Tanaka, H and Nagata, Y and Hashimoto, M and Ikeda, M},
title = {Patterns of ADL and IADL independence across MMSE score ranges in Alzheimer's disease, dementia with Lewy bodies, and frontotemporal dementia: A cross-sectional analysis of a memory-clinic cohort.},
journal = {International psychogeriatrics},
volume = {},
number = {},
pages = {100250},
doi = {10.1016/j.inpsyc.2026.100250},
pmid = {42567789},
issn = {1741-203X},
abstract = {BACKGROUND: Domain-level ADL and IADL independence across MMSE score ranges has been less well described in Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD). This study described the observed proportions of basic ADL and IADL independence across MMSE score ranges in these three neurodegenerative dementias.<br><br>METHODS: In a cohort of 650 patients (524 AD, 90 DLB, 36 FTD), cognitive function was assessed with the Mini-Mental State Examination (MMSE), and daily function was evaluated using the Physical Self-Maintenance Scale and the Lawton IADL scale. Patients were grouped into MMSE score ranges. For each diagnosis and MMSE score range, we calculated the observed proportion of participants rated as independent in each ADL/IADL domain and Wilson score 95% confidence intervals. Because the FTD sample was small (n&#x202f;=&#x202f;36), with only 1-11 participants in individual five-point MMSE score ranges, and several MMSE-specific subgroup counts were sparse, the analyses were descriptive.<br><br>RESULTS: Observed independence proportions varied across ADL/IADL domains, MMSE score ranges, and diagnostic groups. In AD and DLB, shopping, food preparation, and medication management had low observed independence proportions even in higher MMSE ranges. In the MMSE 21-30 stratum, selected absolute numerical contrasts between DLB and AD ranged from 7.2 percentage points for feeding to 18.4 percentage points for bathing. Estimates for FTD, which were based on only 1-11 participants per five-point MMSE score range, and for DLB in the MMSE 0-10 stratum were based on small denominators and were therefore imprecise.<br><br>CONCLUSIONS: This study provides descriptive estimates of domain-level ADL and IADL independence across MMSE score strata in AD, DLB, and FTD. The results may contribute to domain-specific assessment and support planning for people living at home with MCI or dementia. These findings should be regarded as hypothesis-generating for future studies.},
}
@article {pmid42567790,
year = {2026},
author = {Xu, D and Zhang, H and Piao, Z and He, Y and Li, H and Zhang, N},
title = {Functional heterogeneity across structural MRI-based atrophy subtypes in Alzheimer's disease.},
journal = {International psychogeriatrics},
volume = {},
number = {},
pages = {100255},
doi = {10.1016/j.inpsyc.2026.100255},
pmid = {42567790},
issn = {1741-203X},
abstract = {OBJECTIVES: This study explored whether distinct Alzheimer's disease (AD) structural atrophy subtypes exhibit divergent functional profiles.<br><br>DESIGN: A cross-sectional multimodal neuroimaging and electrophysiological study.<br><br>SETTING: Department of Neurology, Tianjin Medical University General Hospital, Tianjin, China.<br><br>PARTICIPANTS: A total of 116 patients with AD and 74 cognitively unimpaired controls underwent structural MRI. Patients with AD were stratified into three MRI-derived atrophy-pattern groups corresponding to hippocampal-sparing (HpSp-MRI), typical (tAD-MRI), and limbic-predominant (LP-MRI) subtypes.<br><br>MEASUREMENTS: Resting-state functional MRI was used to assess intra- and internetwork functional connectivity, and EEG was used to evaluate spectral power and microstate dynamics.<br><br>RESULTS: The HpSp-MRI subtype showed lower intranetwork connectivity than both the LP-MRI and tAD-MRI subtypes in the visual, somatomotor, and dorsal attention networks. The LP-MRI and tAD-MRI subtypes differed in ventral attention network connectivity. Moreover, the LP-MRI subtype exhibited stronger internetwork connectivity in specific network pairs compared with the other subtypes. EEG analysis suggested a possible difference in the microstate 3-to-1 transition between the LP-MRI and tAD-MRI groups.<br><br>CONCLUSIONS: MRI-derived atrophy-pattern subtypes showed different resting-state functional connectivity profiles, providing a potential basis for personalized brain network-targeted interventions in AD.},
}
@article {pmid42567919,
year = {2026},
author = {Mogavero, F and Galluzzi, G and Dolce, E and Malangone, D and Raimo, S and Di Vita, A and Galosi, E and Bruno, G and Sepe Monti, M and Talarico, G and D'Antonio, F and Palermo, L},
title = {Inside and outside the body space: a study on environmental knowledge, interoceptive and functional body representations in the prodromal stage of dementia.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {9},
pages = {},
pmid = {42567919},
issn = {1590-3478},
mesh = {Humans ; Female ; Male ; Aged ; Cross-Sectional Studies ; *Cognitive Dysfunction/physiopathology/psychology ; *Spatial Navigation/physiology ; *Prodromal Symptoms ; *Interoception/physiology ; *Body Image/psychology ; Neuropsychological Tests ; Middle Aged ; Space Perception/physiology ; *Dementia/psychology/physiopathology ; },
abstract = {BACKGROUND: There is increasing interest in identifying sensitive cognitive markers for the early detection of Alzheimer's disease (AD). Spatial navigation has emerged as a promising marker, as impairments in both egocentric and allocentric navigation have been reported in preclinical AD and mild cognitive impairment (MCI). However, findings regarding the relative involvement of these navigational representations remain inconsistent. Moreover, little is known about how MCI affects other forms of spatial representation beyond navigation.<br><br>OBJECTIVE: The present study aims to investigate navigational, inner, and outer bodily representations in individuals with MCI to provide a broader characterization of the cognitive changes associated with this condition across different bodily and navigational space representations.<br><br>METHODS: We conducted a cross-sectional comparative study involving 28 healthy controls (HC) and 25 participants diagnosed with MCI (PtwMCI). All participants completed tasks and questionnaires probing: (a) different interoceptive dimensions (interoceptive accuracy [IAcc], awareness [IAw], and sensibility [ISe]); (b) action-oriented (aBR) and nonaction-oriented (NaBR) body representations; (c) landmark, route, and survey knowledge of a virtual environment.<br><br>RESULTS: PtwMCI showed reduced IAcc and ISe and performed less accurately in landmark and route tasks compared to HC.<br><br>CONCLUSIONS: Our findings indicate early impairments in interoceptive (inner body) and navigational processing, even in the initial stages of cognitive decline. These difficulties may thus represent an early marker of neurodegeneration. The observed co-occurrence of alterations across these domains highlights the need for future studies to clarify the relationship between body-related cognitive processes and broader cognitive functions in the Alzheimer's disease continuum.},
}
@article {pmid42568007,
year = {2026},
author = {Wang, Z and Chen, J},
title = {ARG128-associated recognition of nobiletin by BACE1 revealed by triplicate molecular dynamics, MM-GBSA, and residue-level decomposition.},
journal = {Molecular diversity},
volume = {},
number = {},
pages = {},
pmid = {42568007},
issn = {1573-501X},
abstract = {Alzheimer's disease (AD) remains the leading cause of dementia worldwide, and beta-secretase 1 (BACE1) remains a high-priority target for reducing amyloid-beta production. Nobiletin, a polymethoxylated flavonoid from citrus peel, has reported neuroprotective and amyloid-lowering effects in AD models, and previous enzymatic work suggested weak BACE1 inhibition; however, its replica-level binding stability and residue-level energetic determinants remain unresolved. Here, we analyzed the nobiletin-BACE1 complex using ChEMBL-based chemical-space contextualization, qualitative QSAR uncertainty assessment, molecular docking, triplicate 200-ns all-atom molecular dynamics simulations, molecular mechanics generalized Born surface area (MM-GBSA) end-point scoring, residue-level decomposition, ProLIF interaction fingerprints, electrostatic surface analysis, and a same-protocol OM99-2 structural control. The ligand remained locally accommodated within the BACE1 cleft across the sampled trajectories, with a mean internal MM-GBSA score (DeltaG_bind) of - 15.71 +/- 0.76 kcal/mol (n = 3: - 14.20, - 16.35, and - 16.57 kcal/mol). Residue-level decomposition identified ARG128 as the dominant computed hotspot (total mean = - 11.13 +/- 0.38 kcal/mol), with favorable van der Waals (VDW mean = - 6.88 +/- 0.21 kcal/mol) and Coulombic (Coulomb mean = - 4.25 +/- 0.53 kcal/mol) components. Additional hydrophobic/aromatic packing involved VAL69, TYR71, PRO70, PHE38, and PRO129, while ASP32/ASP228 were positioned outside the dominant nobiletin contact pattern. Together, these results support a putative ARG128-associated, non-dyad-dominant catalytic-cleft recognition model that should be interpreted as a hypothesis-generating computational framework for future biochemical testing and scaffold optimization.},
}
@article {pmid42568064,
year = {2026},
author = {Yang, J and Zhao, X and Liu, Y and Cai, Y and Fan, Y and , },
title = {Interactive Effects of Plasma Alzheimer Disease Biomarkers and White Matter Hyperintensities on Cognitive Decline and Clinical Progression in Nondemented Adults.},
journal = {Journal of the American Heart Association},
volume = {},
number = {},
pages = {e050676},
doi = {10.1161/JAHA.126.050676},
pmid = {42568064},
issn = {2047-9980},
abstract = {BACKGROUND: Alzheimer disease pathology and cerebral small-vessel disease frequently coexist in older adults, yet how their interaction influences early clinical progression remains poorly understood, particularly in individuals without dementia. We aimed to investigate how plasma Alzheimer disease biomarkers and white matter hyperintensities (WMHs) interact to influence cognitive trajectories and the risk of progression to cognitive impairment and dementia.<br><br>METHODS: We studied 463 nondemented participants from the ADNI (Alzheimer's Disease Neuroimaging Initiative). Linear mixed-effects models assessed interactions between plasma biomarkers and WMHs on cognitive trajectories. Cox models examined incident cognitive impairment and dementia. Moderated mediation analyses explored potential biological pathways.<br><br>RESULTS: Among 463 participants, plasma phosphorylated tau 217 to &#x3b2;-amyloid 42 ratio was the only biomarker that consistently interacted with WMHs across multiple stages of disease progression, including cognitive decline (Mini-Mental State Examination: &#x3b2;=-0.05 [95% CI, -0.06 to -0.03]; executive function: &#x3b2;=-0.02 [95% CI, -0.03 to -0.01]; memory: &#x3b2;=-0.03 [95% CI, -0.04 to -0.02]; language: &#x3b2;=-0.03 [95% CI, -0.04 to -0.02]; visuospatial function: &#x3b2;=-0.02 [95% CI, -0.04 to -0.01]) and increased clinical risk (cognitive impairment: &#x3c7;[2]=15.67, P=0.047; dementia: &#x3c7;[2]=15.88, P=0.044). These interactive associations were most pronounced in cognitively normal individuals and men. Moderated mediation analyses indicated that plasma glial fibrillary acidic protein partially mediated the interaction between phosphorylated tau 217 to &#x3b2;-amyloid 42 ratio and WMHs for executive function and language performance.<br><br>CONCLUSIONS: These findings indicate that phosphorylated tau 217 to &#x3b2;-amyloid 42 ratio and WMHs jointly contribute to clinical progression in nondemented individuals, with astrocytic activation potentially involved in this process.},
}
@article {pmid42568124,
year = {2026},
author = {Blujus, JK and Oh, H and , },
title = {The Impact of Denoising Approaches on the Relationship Between Alzheimer's Disease Diagnostic Status and Network Topology Measures.},
journal = {Human brain mapping},
volume = {47},
number = {11},
pages = {e70622},
doi = {10.1002/hbm.70622},
pmid = {42568124},
issn = {1097-0193},
support = {R01AG068990/NH/NIH HHS/United States ; R01AG069265/NH/NIH HHS/United States ; S10OD025181/NH/NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/physiopathology ; *Magnetic Resonance Imaging/methods/standards ; Female ; *Cognitive Dysfunction/diagnostic imaging/physiopathology ; Male ; *Brain/diagnostic imaging/physiopathology ; Aged ; *Nerve Net/diagnostic imaging/physiopathology ; *Image Processing, Computer-Assisted/methods/standards ; Aged, 80 and over ; Artifacts ; *Connectome/methods/standards ; },
abstract = {Graph theory provides a promising technique to investigate Alzheimer's disease (AD)-related alterations in brain network properties. However, there are discrepancies in the reported disruptions that occur to network topology across the AD continuum. In this study, we examined whether diagnostic group differences in graph metrics are attributed to differences in denoising approach used in fMRI processing. Resting state data from 60 cognitively normal (CN), 55 Mild Cognitive Impairment (MCI), and 38 AD participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database were denoised using 11 pipelines including combinations of confound regression (head motion parameters, white matter [WM], cerebrospinal fluid [CSF], global signal), volume censoring (scrubbing, spike regression), and component-based noise removal (Independent Component Analysis-based Automatic Removal of Motion Artifacts [ICA-AROMA], anatomical and temporal component correction). Graph metrics representing network segregation (clustering coefficient, modularity, local efficiency), network integration (largest connected component, path length, global efficiency), and small-worldness were calculated. The results revealed that diagnostic group differences in modularity and local efficiency were dependent on denoising approach, especially in high-parameter regression models in combination with censoring methods (36 parameters and spike regressor or volume censoring). Independent of denoising approach, CN exhibited more segregated (clustering coefficient) but less integrated (largest component, path length, global efficiency) networks than MCI and AD. Independent of diagnosis, denoising strategy significantly affected the magnitude of all metrics, particularly models including global signal regression. Collectively, these results suggest that the directionality of the diagnostic differences in network topology, particularly in global metrics of network segregation, can vary based upon the denoising approach employed, although the effect size is small. Transparent reporting of preprocessing decisions is critical for the accurate interpretation of graph theoretical findings in the context of AD and a better understanding of the mechanisms underlying pathological aging.},
}
@article {pmid42568171,
year = {2026},
author = {Lv, J and Cai, X and Yang, Z and Li, B and Zhou, Y and Li, F and Fu, H},
title = {A comprehensive assessment of cholinesterase inhibitors for the treatment of Alzheimer's disease based on drug selection recommendations for Chinese Medical Institutions.},
journal = {Expert review of pharmacoeconomics &amp; outcomes research},
volume = {},
number = {},
pages = {},
doi = {10.1080/14737167.2026.2715983},
pmid = {42568171},
issn = {1744-8379},
abstract = {BACKGROUND: Cholinesterase inhibitors (ChEIs) are widely used to treat Alzheimer's disease (AD), yet the optimal choice remains unclear.<br><br>RESEARCH DESIGN AND METHODS: This study aimed to comprehensively evaluate the overall clinical value of seven ChEI formulations (donepezil tablets, rivastigmine capsules, rivastigmine patches, galantamine tablets, galantamine orally disintegrating tablets, and two huperzine A formulations) to provide evidence-based guidance for rational AD pharmacotherapy selection. The evaluation framework used in this study was derived from the Rapid Guide for Drug Evaluation and Selection in Chinese Medical Institutions (Second Edition). This framework integrates mini-health technology assessment (mini-HTA) with the System of Objectified Judgment Analysis (SOJA). Seven formulations were assessed across five weighted dimensions: pharmacological properties (28 points), efficacy (27 points), safety (25 points), economy (10 points), and other attributes (10 points). A systematic literature search was performed using PubMed, CNKI, Wanfang, and official regulatory databases.<br><br>RESULTS: Within this assessment framework, donepezil tablets achieved the highest score (74.86), followed by rivastigmine patches (73.50) and rivastigmine capsules (72.28). These three formulations are recommended as priority options for inclusion in Chinese hospital formularies. The remaining four drugs may be prescribed according to individual patient conditions and institutional available resources.<br><br>CONCLUSIONS: This evaluation provides evidence-based guidance for clinical and institutional decision-making in AD management and delivers a generalizable assessment framework adaptable to local real-world data for healthcare institutions globally.},
}
@article {pmid42568185,
year = {2026},
author = {Larimi, MG and Thurber, KR and Tycko, R},
title = {Polymorphic structures of rapidly twisting 40-residue amyloid-β fibrils.},
journal = {Biophysical journal},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.bpj.2026.08.003},
pmid = {42568185},
issn = {1542-0086},
abstract = {Fibrils formed by 40- and 42-residue amyloid-β peptides (Aβ40 and Aβ42) are polymorphic, containing molecular structures that vary with growth conditions in ways that are not fully understood. Here we use cryogenic electron microscopy to characterize the structure of rapidly twisting Aβ40 fibrils, for which the distance between apparent width minima in electron microscope images ("cross-over distances") is approximately 25 nm. From samples grown under a single set of growth conditions, we obtain high-resolution structures for three different rapidly twisting polymorphs. Although their cross-over distances are similar, the three rapidly twisting polymorphs differ in twist handedness, symmetry, molecular conformations, and intermolecular contacts. Two of the rapidly twisting polymorphs resemble Aβ40 polymorphs with longer cross-over distances that have been described previously, including polymorphs extracted from brain tissue of Alzheimer's disease patients or created by seeded growth from amyloid in brain tissue, but have shorter conformationally ordered segments and other specific conformational differences. These results contribute to our understanding of amyloid polymorphism, connections between morphology and molecular structure, and relationships between brain-derived and in vitro-grown fibrils.},
}
@article {pmid42568190,
year = {2026},
author = {Kim, B and Belza, B and Johnson, S and Waddington, E and Moczygemba, W and Fazio, S and Prophater, L},
title = {Evaluating a Coaching Intervention for Dementia Care Practice Recommendations in Care Communities: A Cluster Randomized Controlled Trial.},
journal = {The Gerontologist},
volume = {},
number = {},
pages = {},
doi = {10.1093/geront/gnag183},
pmid = {42568190},
issn = {1758-5341},
abstract = {BACKGROUND AND OBJECTIVES: Within care communities, including nursing home and assisted living settings, person-centered dementia care, outlined by the 2018 Alzheimer's Association Dementia Care Practice Recommendations (DCPR), is foundational to quality care and improving staff outcomes. This study evaluates the effectiveness of a six-month Care Community Coaching Program in enhancing person-centered dementia care and staff outcomes in alignment with the DCPR.<br><br>RESEARCH DESIGN AND METHODS: A cluster randomized controlled trial was conducted with 77 care communities and 434 staff members-227 from 38 intervention communities and 207 from 39 control communities. Outcomes included employee satisfaction (areas: job satisfaction, team building and communication, scheduling and staffing, training, and management and leadership), person-centered care practices (areas: workplace practices, individualized care and services, caregiver-resident relationships), and dementia care confidence, measured pre- and post-intervention and at three-month follow-up. A generalized Estimating Equations (GEE) model was used to estimate intervention effects.<br><br>RESULTS: Care communities assigned to the coaching intervention showed statistically significant improvements in employee satisfaction and staff perceptions of workplace practices and individualized care. No statistically significant effects on staff perceptions of caregiver-resident relationships or on dementia care confidence were noted.<br><br>DISCUSSION AND IMPLICATIONS: Findings provide direction for future research and intervention development, including examining coaching's impact on resident quality outcomes, and incorporating skills training into future models. Collectively, findings provide evidence of the effectiveness of a Care Community Coaching Program in improving staff outcomes and person-centered practices, offering a practical path towards improving the lived experience of residents and staff in care communities.},
}
@article {pmid42568211,
year = {2026},
author = {Uruk, G and Youssef, H and Gatto, RG and Hossain, N and Whitwell, JL and Reichard, RR and Josephs, KA},
title = {Artificial intelligence-based 3D segmentation of tangle-associated TDP-43 in neurodegeneration.},
journal = {Brain pathology (Zurich, Switzerland)},
volume = {},
number = {},
pages = {e70131},
doi = {10.1111/bpa.70131},
pmid = {42568211},
issn = {1750-3639},
support = {R01-AG37491/NH/NIH HHS/United States ; },
abstract = {TAR DNA-binding protein 43 (TDP-43) inclusions are often associated with hyperphosphorylated tau, thus neurofibrillary tangles as the hallmark of Alzheimer's disease (AD) and primary age-related tauopathy (PART). TDP-43 in AD is associated with cognitive impairment, and while staging is known, the localization, cellular and inclusion characteristics of TDP-43 are yet to be elucidated. We investigate relationships between TDP-43 inclusions and the tangle maturation continuum in AD, PART, and co-pathologies by multiplex immunostaining combined with artificial intelligence (AI)-based segmentation via object recognition, reconstruction, and quantification. We performed anti-phosphorylated TDP-43 immunofluorescence with phosphorylated tau labeling different stages and modifications of tangles (AT8, pS396, TauC3, MN423, GT38) in three controls, three cases with PART and TDP-43 (PART-TDP), five cases with high likelihood AD and TDP-43 (AD-TDP), and four cases of high likelihood AD with TDP-43 and Lewy Body disease (AD-TDP-LBD). Confocal imaging was taken from eight regions: amygdala (amygdala-BL and amygdala-CM) and hippocampus (Cornu Ammonis (CA)-1, CA2/3, CA4, dentate gyrus (DG), subiculum (SUB)), and entorhinal cortex (ERC) and quantified with AI segmentation to identify 3D spatial relations, thus the maturity of neurofibrillary tangle associated TDP-43 (TAT) inclusions. TATs, which were either identified by pTDP-43 and AT8 or pTDP-43 and pS396 double positivity, were also investigated by Thioflavin S (ThioS) histochemistry. We found pS396 labeled mature TATs predominated in PART and AD in every region. Basolateral and centromedial amygdala displayed overall greatest number of pre-TATs and mature TATs. Mature TATs were homogenously distributed among hippocampal subfields whereas CA4 and DG had the greatest mature TAT composition. ERC revealed closer numbers of pre-TATs and mature TATs yet mature TATs predominated all groups. Unbiased AI-based object identification, reconstruction, and TAT maturation analysis pipeline in conjunction with TDP-43, tau, and ThioS multiplex immunostaining demonstrated unique aggregation and maturation patterns, highlighting region-specific dynamics in the neurodegenerative processes of PART and AD.},
}
@article {pmid42568438,
year = {2026},
author = {Sun, C and Zhang, T and Fan, B and Zhang, X and Zhao, N},
title = {Aerobic exercise combined with FK866 ameliorates Alzheimer's disease-like pathology in APP/PS1 mice with NAMPT abnormality.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1876444},
pmid = {42568438},
issn = {1664-3224},
mesh = {Animals ; *Nicotinamide Phosphoribosyltransferase/metabolism ; *Alzheimer Disease/therapy/pathology/metabolism ; *Piperidines/pharmacology ; Mice ; Amyloid beta-Protein Precursor/genetics ; *Acrylamides/pharmacology ; Mice, Transgenic ; *Physical Conditioning, Animal ; Disease Models, Animal ; *Cytokines/metabolism ; Presenilin-1/genetics ; NAD/metabolism ; Mitochondria/metabolism ; Amyloid beta-Peptides/metabolism ; Male ; Brain/metabolism/pathology ; Humans ; },
abstract = {Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD[+] salvage pathway, has emerged as an important regulatory node linking metabolic homeostasis to neuroinflammatory responses. However, although pharmacological inhibition of NAMPT may attenuate inflammatory activation, it may also reduce intracellular NAD[+] availability, thereby exacerbating mitochondrial dysfunction and disturbances in energy metabolism. Here, we found that 6-month-old APP/PS1 mice exhibited an abnormal, cell type-specific distribution of NAMPT in the brain, characterized by reduced neuronal NAMPT and increased microglial NAMPT. This abnormality was accompanied by disrupted NAD[+] homeostasis, marked neuroinflammatory activation, mitochondrial structural and functional impairment, increased β-amyloid (Aβ) burden, and impaired learning and memory ability. FK866 (1 mg/kg per injection, once every other day for 12 weeks) alone exerted limited effects and was insufficient to ameliorate the overall pathological phenotype. By comparison, a 12-week aerobic treadmill exercise program markedly ameliorated cognitive impairment, attenuated Aβ pathology, suppressed neuroinflammation, and improved mitochondrial integrity and bioenergetic function in APP/PS1 mice. More importantly, under NAMPT-inhibited conditions, exercise still preserved hippocampal NAD[+] homeostasis and maintained significant neuroprotective effects. Compared with exercise alone, the combined intervention with exercise and FK866 further improved selected indices related to Aβ pathology, neuroinflammation, oxidative stress, and mitochondrial damage. These additional effects may be associated with increased NAD[+] biosynthesis through the NMNAT3 pathway, as well as reduced NAD[+] consumption and neuroinflammatory activation through the suppression of CD38 and PARP1 expression.},
}
@article {pmid42568451,
year = {2026},
author = {Guo, J and Li, J and Gao, B and Liu, K and Sun, X and Ye, D and Mao, Y},
title = {Independent and combined associations of diabetes and thyroid disorders with risks of incident dementia.},
journal = {Frontiers in endocrinology},
volume = {17},
number = {},
pages = {1874555},
pmid = {42568451},
issn = {1664-2392},
mesh = {Humans ; *Thyroid Diseases/complications/epidemiology ; Female ; *Dementia/epidemiology/etiology ; Male ; Risk Factors ; *Diabetes Mellitus/epidemiology ; Incidence ; Aged ; United Kingdom/epidemiology ; Middle Aged ; },
abstract = {BACKGROUND: Diabetes and thyroid disorders are modifiable risk factors for cognitive impairment. However, no studies have been conducted to comprehensively examine associations of different types of the two diseases, as well as their combinations, with dementia risks.<br><br>METHODS: Based on the data from UK Biobank study, patients with different types of diabetes and thyroid disorders were identified with the hospital inpatient record. Status of dementia was assessed with multi-source information. Independent and combined associations of diabetes and thyroid disorders with dementia were estimated with Cox regression models.<br><br>RESULTS: Among 284,081 participants, 8,236 incident cases of all-cause dementia (ACD) [3,755 Alzheimer's disease (AD) cases, 1,893 vascular dementia (VD) cases] were identified over a mean [standard deviation (SD)] follow-up of 13.03 (2.29) years. Four types of diabetes and two types of thyroid disorders were significantly associated with increased risks of dementia. Compared with participants without diabetes and thyroid disorders, those with only thyroid disorders [hazard ratio (HR) = 1.33, 95% confidence interval (CI) = 1.21 to 1.47, P&#xa0;<&#xa0;0.001], only diabetes (HR&#xa0;=&#xa0;1.76, 95% CI&#xa0;=&#xa0;1.64 to 1.89, P&#xa0;<&#xa0;0.001), and both (HR&#xa0;=&#xa0;2.16, 95% CI&#xa0;=&#xa0;1.84 to 2.53, P&#xa0;<&#xa0;0.001) had elevated risks of ACD (P trend < 0.001), as well as higher risks of AD and VD. Combined associations of hypothyroid and diabetes and of hyperthyroid and diabetes were also significantly positive (all P values < 0.05). Moreover, cumulative years of diabetes and thyroid were related to higher risks of dementia.<br><br>CONCLUSIONS: Diabetes, thyroid disorders, and their combinations were associated with increased risks of dementia in adults aged 55 years and older.},
}
@article {pmid42568502,
year = {2026},
author = {Han, D and Yang, C},
title = {Infection-driven gut dysbiosis and epigenetic programming of microglia: toward a systems level framework linking microbial metabolites, neuroinflammation, synaptic dysfunction, and probiotic modulation.},
journal = {Frontiers in cellular and infection microbiology},
volume = {16},
number = {},
pages = {1815265},
pmid = {42568502},
issn = {2235-2988},
mesh = {*Microglia/metabolism/immunology ; Humans ; *Epigenesis, Genetic ; *Dysbiosis/microbiology ; *Probiotics ; Animals ; *Neuroinflammatory Diseases ; *Gastrointestinal Microbiome ; Inflammation ; Neurodegenerative Diseases ; Synapses ; },
abstract = {Neurodegenerative disorders such as Alzheimer's and Parkinson's diseases are increasingly viewed as conditions influenced by systemic immune and metabolic disturbances beyond the central nervous system (CNS). Emerging evidence suggests that infection-driven intestinal dysbiosis may function as an upstream contributor to systemic inflammation through disruption of gut barrier integrity. Increased permeability can facilitate the translocation of microbial components and metabolites into circulation, potentially influencing host immune programming via epigenetic mechanisms. Among CNS immune cells, microglia appear particularly susceptible to such peripheral cues due to their longevity and capacity for stimulus-dependent transcriptional adaptation. Experimental studies indicate that transient systemic immune challenges may induce persistent chromatin-level alterations within microglial regulatory regions, thereby reshaping their responsiveness to subsequent inflammatory stimuli or age-related stressors, including oxidative stress, chronic low-grade inflammation (inflammaging), and age-associated decline in cellular homeostatic and repair mechanisms. This phenomenon, often described as innate immune memory, may contribute to sustained neuroinflammatory activity and impaired synaptic function across the lifespan. Microbiota-derived metabolites, including short-chain fatty acids and tryptophan catabolites, have been implicated in modulating host transcriptional pathways through histone deacetylase inhibition and receptor-mediated signaling.},
}
@article {pmid42568632,
year = {2026},
author = {Liu, J and Chen, W},
title = {Identification and validation of mitophagy and astrocyte-related molecular signature in the pathogenesis of Alzheimer's disease: evidence from ensemble learning-driven multi-omics and clinical validation.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1910621},
pmid = {42568632},
issn = {1662-4548},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited diagnostic tools and therapeutic options. Dysregulated mitophagy in astrocytes plays a pivotal role in AD pathogenesis. This study aims to identify a mitophagy and astrocyte (MA)-associated molecular signature for AD diagnosis and therapeutic targeting.<br><br>METHODS: Limma, WGCNA, xCell, PPI network and integrated machine learning pipeline coupled with SHAP were deployed on AD patient hippocampal bulk profiles (GSE28146, GSE36980, GSE29378, GSE48350) for identification of MA-associated predictive model and hub gene. Next, astrocyte patten and MA-associated hub gene molecular performance were estimated in hippocampal single-cell profile of AD patients (GSE163577) via advanced analytical frameworks. In addition, active learning framework and molecular docking was deployed in GSE29378 for identification of therapeutic candidate for AD patients by targeting MA-associated hub gene. Furthermore, AD hippocampal tissues were collected, and then MA-associated hub gene expression was estimated.<br><br>RESULTS: A core 8-gene MA signature (ITSN1, VLDLR, CYP7A1, SREBF2, RASL12, TPMT, CYP4X1, ARHGEF) was identified, which can guide the molecular subgroup identification and predictive model construction for AD patients. ITSN1 can be considered as the MA-associated hub gene in AD pathogenesis, which was up-regulated and predominantly expressed in astrocytes. Drug repositioning identified BRD-K10008415 as the potential compound predicted to reverse the AD signature by targeting ITSN1.<br><br>CONCLUSIONS: This study identified ITSN1 as a MA-associated critical hub potential connecting mitophagy dysregulation and astrocyte dysfunction in AD. We also identified MA-associated molecular signatures that can potentially elaborate predictive effects on AD pathogenesis. BRD-K10008415 can be considered as potential candidate for AD treatment by targeting ITSN1.},
}
@article {pmid42569056,
year = {2026},
author = {Dowjat, WK and Hwang, YW},
title = {Overexpression of DYRK1A in down syndrome: Analysis of kinase activity.},
journal = {Biochemistry and biophysics reports},
volume = {47},
number = {},
pages = {102722},
pmid = {42569056},
issn = {2405-5808},
abstract = {DYRK1A (dual-specificity tyrosine phosphorylation regulated kinase 1A) is known to play critical roles in regulating numerous cellular functions like cell cycle, neuronal development, and immune homeostasis. Altered expression DYRK1A is implicated in Alzheimer's Disease and various features of Down Syndrome (DS). The DYRK1A gene is located on chromosome 21 and due to trisomy of this chromosome in DS, the level of DYRK1A is elevated in the gene-dosage dependent manner. Nevertheless, how an increase in DYRK1A protein level would affect its activity in DS remains to be determined. The question was examined by performing side by side comparison of protein levels and the activity of DYRK1A extracted from control and DS samples. We show that DYRK1A activity elevation in DS is in parallel to that of DYRK1A protein level regardless of the status of kinase phosphorylation. This suggests that DYRK1A catalytic activity in DS is mainly regulated by protein level.},
}
@article {pmid42569203,
year = {2026},
author = {Wu, HY and Hou, JH and Huang, LY and Tan, L and Xu, W},
title = {APOE Genotypes Modulate the Relationship of Hypertension With Alzheimer's Disease: Associations and Clues of Peripheral Mechanisms.},
journal = {Biological psychiatry global open science},
volume = {6},
number = {5},
pages = {100773},
doi = {10.1016/j.bpsgos.2026.100773},
pmid = {42569203},
issn = {2667-1743},
abstract = {BACKGROUND: Gene-environment interplay contributes to the heterogeneous etiology of Alzheimer's disease (AD). Hypertension (HTN) is a major modifiable vascular risk factor, but whether its association with AD differs across APOE genotypes remains unclear. We examined the interaction between HTN and APOE genotypes in relation to incident AD and explored plasma proteomic correlates as potential biological clues.<br><br>METHODS: Longitudinal data from 318,923 UK Biobank participants without dementia were analyzed; participants had a mean age of 56.24 years, an APOE &#x3b5;4 frequency of 28.29%, and a median follow-up period of 13 years. Cox proportional hazards models with competing-risk adjustment for death were used to assess additive and multiplicative interactions between HTN and APOE genotypes. Plasma proteomic data from 34,141 participants, covering 2790 proteins, were further analyzed using mediation and bioinformatics approaches.<br><br>RESULTS: HTN showed a significant multiplicative interaction with APOE &#x3b5;4 status for incident AD (p < .001). The association between HTN and AD risk was strongest among APOE &#x3b5;2 carriers, followed by &#x3b5;33 carriers and &#x3b5;4 carriers, with hazard ratios of 1.570, 1.213, and 1.129, respectively. Among APOE &#x3b5;2 carriers, prosaposin and ganglioside GM2 activator significantly mediated the HTN-AD association, with mediation proportions of 10.46% and 3.37%, respectively. These proteins were enriched in sphingolipid metabolism and lysosomal function.<br><br>CONCLUSIONS: The association between HTN and incident AD varies across APOE genotype strata, with the strongest relative association observed among APOE &#x3b5;2 carriers. These findings suggest genotype-dependent heterogeneity in vascular contributions to AD risk. Proteomic results should be interpreted as exploratory biological clues and require further validation.},
}
@article {pmid42569234,
year = {2026},
author = {Rizvi, B and Adams, JN and Bamford, A and Kim, S and Sathishkumar, M and Tustison, NJ and Taylor, L and Tuteja, N and McMillan, L and Nan, B and Cai, H and Escalante, YY and Meza, NJ and Harris, AL and Malhas, R and Brickman, AM and Mapstone, M and Thomas, EA and Yassa, MA},
title = {Parallel neuroinflammatory pathways to cerebrovascular burden and amyloid beta in Alzheimer's disease.},
journal = {Alzheimer's &amp; dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70415},
doi = {10.1002/dad2.70415},
pmid = {42569234},
issn = {2352-8729},
abstract = {INTRODUCTION: Upstream neuroinflammation plays an important role in Alzheimer's disease (AD) but remains poorly understood. We tested whether two distinct neuroinflammatory markers are associated with cerebrovascular burden and amyloid beta (Aβ), and downstream, with plasma phosphorylated tau (p-tau217), medial temporal lobe (MTL) cortical and hippocampal atrophy, and memory deficits.<br><br>METHODS: Cognitively unimpaired older adults without dementia or mild cognitive impairment were recruited from a community sample (Biomarker Exploration in Aging, Cognition, and Neurodegeneration; [BEACoN]; N&#xa0;=&#xa0;126). We used structural equation modeling to test whether plasma chitinase-3-like protein 1 (YKL-40) and glial fibrillary acidic protein (GFAP) contribute to distinct pathways.<br><br>RESULTS: Higher plasma YKL-40 was associated with greater white matter hyperintensity (WMH), whereas higher plasma GFAP was related to increased 18F-florbetapir (FBP) standardized uptake value ratio (SUVR). Higher plasma GFAP, WMH, and FBP SUVR were independently associated with increased p-tau217. Plasma p-tau217 was associated with reduced MTL cortical thickness and hippocampal volume. Reduced hippocampal volume was related to worse memory.<br><br>DISCUSSION: Future work can further investigate these neuroinflammatory pathways as potential therapeutic targets for AD.},
}
@article {pmid42569297,
year = {2026},
author = {Ortuño-Sahagún, D and Carrera-Quintanar, L},
title = {Editorial: Nutrients and bioactive compounds: preventing and treating neurodegenerative diseases and disorders.},
journal = {Frontiers in nutrition},
volume = {13},
number = {},
pages = {1908638},
doi = {10.3389/fnut.2026.1908638},
pmid = {42569297},
issn = {2296-861X},
}
@article {pmid42569462,
year = {2026},
author = {Alruwais, N and Althobaiti, GA and Alaql, YB and Almutairi, SAH and Alshareef, WM and Mahrous, FA and Aloqaybi, SAS and Lasloom, RAA and Aljasser, AA},
title = {Retinal Microvascular Biomarkers Measured by Optical Coherence Tomography Angiography in Neurodegenerative and Neurovascular Disorders: A Systematic Review and Meta-Analysis.},
journal = {Clinical ophthalmology (Auckland, N.Z.)},
volume = {20},
number = {},
pages = {609387},
doi = {10.2147/OPTH.S609387},
pmid = {42569462},
issn = {1177-5467},
abstract = {PURPOSE: Neurodegenerative and neurovascular disorders are increasingly recognized as major causes of disability worldwide and require accessible biomarkers for early detection and monitoring. Given the close anatomical and microvascular relationship between the retina and the central nervous system, optical coherence tomography angiography (OCTA) has emerged as a promising non-invasive technique for assessing retinal microvascular alterations associated with neurological disease. This systematic review and meta-analysis evaluated OCTA-derived retinal microvascular parameters as potential biomarkers of neurovascular dysfunction.<br><br>METHODS: This systematic review and meta-analysis was conducted in accordance with PRISMA guidelines and registered in PROSPERO (CRD420261305354). PubMed, Embase, Scopus, Web of Science, and the Cochrane Central Register of Controlled Trials were searched from January 2015 to December 2025. Studies comparing OCTA-derived retinal vascular parameters between patients with neurodegenerative or neurovascular disorders and healthy controls were included. Primary outcomes were superficial capillary plexus vessel density (SCP-VD), deep capillary plexus vessel density (DCP-VD), and foveal avascular zone (FAZ) area. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were pooled using random-effects models.<br><br>RESULTS: Thirteen studies were included in the quantitative synthesis. Compared with healthy controls, patients with neurodegenerative or neurovascular disorders demonstrated significantly reduced SCP vessel density (SMD -0.60, 95% CI -0.78 to -0.43; I[2] = 43%) and DCP vessel density (SMD -0.84, 95% CI -1.15 to -0.53; I[2] = 78%). FAZ area was significantly enlarged in disease groups (SMD 0.62, 95% CI 0.29 to 0.94; I[2] = 83%). Disease-specific subgroup analyses demonstrated generally consistent trends across the included disorders.<br><br>CONCLUSION: OCTA-derived retinal microvascular alterations were consistently associated with neurodegenerative and neurovascular disorders. Reduced retinal vessel density, particularly within the deep capillary plexus, and enlargement of the FAZ may reflect underlying neurovascular dysfunction. While these findings support the potential role of OCTA as a non-invasive biomarker of neurological disease, the available evidence remains limited by methodological heterogeneity and predominantly observational study designs. Further longitudinal studies using standardized OCTA protocols are needed to establish the diagnostic and prognostic utility of these biomarkers.},
}
@article {pmid42569517,
year = {2026},
author = {Chen, M and Cao, C and Chen, T and Alhamad, D and Liu, T and Su, L and Zhu, D},
title = {Fine-scale individualized gyral folding-based cortical similarity networks reveal distinct organizational patterns in Alzheimer's disease and Lewy body dementia.},
journal = {Imaging neuroscience (Cambridge, Mass.)},
volume = {4},
number = {},
pages = {},
doi = {10.1162/IMAG.a.1322},
pmid = {42569517},
issn = {2837-6056},
abstract = {Alzheimer's disease (AD) and Lewy body dementia (LBD) are common neurodegenerative dementias with overlapping clinical presentations, making differential diagnosis challenging. While structural magnetic resonance imaging (MRI) has revealed characteristic regional atrophy patterns, regional morphometric measures alone may not fully capture distributed cortical alterations. Morphometric similarity networks (MSNs) offer a systems-level framework to characterize coordinated structural organization, but existing approaches typically rely on atlas-based parcellations that may obscure individual-specific cortical folding geometry. Here, we propose a fine-scale, folding-informed cortical similarity network framework based on automatically detected three-hinge gyral (3HG) landmarks. Using a thickness-constrained arealization strategy in native surface space, we define individualized cortical regions and construct subject-specific MSNs without cross-subject registration. We then investigate how network topology relates to landmark-defined node count and how these properties differ between AD and LBD. We find that several graph theoretical metrics, particularly global efficiency and characteristic path length, exhibit clear associations with the number of detected landmarks, indicating that topology in individualized networks is partly shaped by node availability. When accounting for landmark count, several apparent group differences in global topology are attenuated, whereas multiple heterogeneity-related metrics remain significant, indicating that node-count scaling substantially influences the interpretation of individualized network topology. Nevertheless, multivariate topological patterns remain informative for AD/LBD classification after residualizing for node count, and landmark count itself provides modest diagnostic information. These findings highlight node-count scaling as a key methodological consideration in individualized structural networks and suggest that folding-based MSNs capture disease-related variation in cortical network organization between AD and LBD.},
}
@article {pmid42569620,
year = {2026},
author = {Ip, J and Heindel, WC and Ott, BR and Festa, EK},
title = {Distinct theta and alpha electrophysiological dynamics during audiovisual semantic processing in healthy aging and mild cognitive impairment.},
journal = {Aging brain},
volume = {10},
number = {},
pages = {100163},
doi = {10.1016/j.nbas.2026.100163},
pmid = {42569620},
issn = {2589-9589},
abstract = {Semantic memory decline is increasingly recognized as an early feature of Alzheimer's disease (AD) and amnestic mild cognitive impairment (MCI), yet the neural dynamics supporting automatic and controlled semantic retrieval in healthy aging remain poorly defined. This study examined task-evoked oscillatory activity during audiovisual object recognition in young adults (YA; N = 27), healthy older adults (OA; N = 33), and individuals with amnestic MCI (N = 21). Participants judged object orientation while viewing living and nonliving images paired with congruent or incongruent characteristic sounds, allowing semantic relationships to be manipulated under implicit retrieval demands. Accuracy was high across groups, although participants with MCI showed reduced performance under the more perceptually challenging inverted conditions. Reaction times were slower in OA than YA and further slowed in MCI, with group differences varying by object animacy and semantic congruency. Event-related spectral perturbation analyses revealed distinct group-related patterns. Healthy older adults showed reduced early and increased late theta activity in frontocentral and parieto-occipital regions, consistent with delayed recruitment of control-related and perceptual-attentional processes. In contrast, MCI participants showed elevated and less condition-sensitive posterior alpha power, together with task- and condition-specific differences in frontocentral theta. The principal pattern of delayed theta recruitment in healthy aging and elevated posterior alpha in MCI was also observed in a supplementary task requiring explicit audiovisual semantic judgments. These findings provide preliminary evidence that healthy aging and amnestic MCI are associated with partly distinct patterns of task-evoked oscillatory activity during audiovisual semantic processing.},
}
@article {pmid42569823,
year = {2026},
author = {Oblak, AL and Sasner, M and Carter, GW and Howell, GR and Sukoff Rizzo, SJ and Leal, K and Territo, PR and Lamb, BT},
title = {The past, the present, and the future of preclinical mouse models for Alzheimer's disease and related dementias.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71741},
doi = {10.1002/alz.71741},
pmid = {42569823},
issn = {1552-5279},
support = {U54AG054345/NH/NIH HHS/United States ; },
mesh = {Animals ; *Disease Models, Animal ; *Alzheimer Disease/genetics/pathology ; Humans ; Mice ; },
abstract = {Over the past decade, the Model Organism Development and Evaluation for Late-Onset Alzheimer's Disease (MODEL-AD) consortium has transformed preclinical Alzheimer's disease (AD) research by addressing critical limitations in traditional mouse models that failed to translate to human disease. By leveraging human genetic discoveries, MODEL-AD has developed > 70 genetically informed mouse models, standardized phenotyping pipelines, and an open-access data infrastructure aligned with late-onset AD biology. These models incorporate human risk variants, environmental factors, and aging to better capture disease complexity, including emerging recognition of mixed pathologies such as vascular contributions, Lewy body disease, and TDP-43 proteinopathy. Despite substantial progress, key challenges remain, including modeling multimorbidity, integrating aging, and improving translational predictability. Here, we outline a strategic roadmap spanning short-, intermediate-, and long-term approaches to refine disease modeling, enhance preclinical testing rigor, and support precision medicine. Continued investment in MODEL-AD will be essential to accelerate therapeutic discovery and establish a scalable framework for studying complex neurodegenerative diseases.},
}
@article {pmid42569825,
year = {2026},
author = {Zhu, X and Haure-Mirande, JV and Bicak, M and Dong, P and Kruglikov, I and Li, A and Al-Subaie, A and Fossati, V and Noggle, S and Gandy, S and Ehrlich, ME},
title = {miR155, triplicated in Down syndrome, regulates the development of neural stem cells and GABAergic interneurons in Alzheimer's disease mouse and human iPSC models.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71684},
doi = {10.1002/alz.71684},
pmid = {42569825},
issn = {1552-5279},
support = {RF1AG058469/NH/NIH HHS/United States ; },
mesh = {Animals ; *MicroRNAs/genetics/metabolism ; Humans ; *Down Syndrome/genetics/metabolism ; *Alzheimer Disease/genetics/metabolism/pathology ; *Induced Pluripotent Stem Cells/metabolism ; *Interneurons/metabolism ; *Neural Stem Cells/metabolism ; Disease Models, Animal ; Mice ; *GABAergic Neurons/metabolism ; Amyloid beta-Protein Precursor/genetics/metabolism ; Mice, Transgenic ; Mice, Knockout ; },
abstract = {INTRODUCTION: Dysfunctional microRNAs and GABAergic interneurons are features of Alzheimer's disease (AD). The role of neuronal microRNA155 (miR155), elevated in both AD and Down syndrome (DS), remains unknown.<br><br>METHODS: We utilized in silico analyses of published databases, MIR155-deleted and -overexpressing human induced pluripotent stem cell (hiPSC)-derived cells, cortical organoids, and amyloid beta precursor protein (APP)/PS1-miR155 knockout mouse.<br><br>RESULTS: MIR155HG (miR155 host gene) colocalizes with APP in a neuron-specific, topologically associated domain (TAD) in chromosome 21. In human neural stem cells (NSCs), neurons, and cortical organoids, MIR155 deletion enhanced NSC proliferation and GABAergic interneuron generation. MIR155 overexpression inhibited NSC marker expression and GABAergic interneuron generation. In APP/PS1 mice, miR155 deletion induced the expansion of hippocampal NSCs and increased hippocampal GABAergic interneurons.<br><br>DISCUSSION: Our findings, alongside the extensive studies of the role of microglial miR155 in neuroinflammation, reveal previously unrecognized miR155 roles in hippocampal NSC dynamics and GABAergic interneuron development, highlighting miR155 as a therapeutic target.},
}
@article {pmid42569826,
year = {2026},
author = {Groeneveld, J and Perlaza, D and Olivé, C and Grangeon, L and Tesi, N and Nicolas, A and Jiang, C and de Rojas, I and Wallon, D and Rousseau, S and Rovira, M and de Asúa, DR and Moldenhauer, F and Mu, R and Cassinari, K and Zarea, A and Escabias, JA and Lambert, JC and Pijnenburg, YAL and Hulsman, M and Vijverberg, EGB and Levin, J and Jucker, M and McDade, E and Fortea, J and Holstege, H and Duits, FH and Vermunt, L and Patel, M and Johnson, M and Renton, AE and Goate, AM and Cruchaga, C and Pottier, C and Fernandez, MV and Belbin, O and Nicolas, G and Dols-Icardo, O and van der Lee, SJ and , },
title = {APOE and genetic risk variants influence Alzheimer's disease onset in carriers of an extra copy of APP, with and without Down syndrome.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71738},
doi = {10.1002/alz.71738},
pmid = {42569826},
issn = {1552-5279},
support = {1051003212000/ZONMW_/ZonMw/Netherlands ; #73305095007/ZONMW_/ZonMw/Netherlands ; //Stichting Alzheimer Nederland and Stichting Steun Alzheimercentrum&#xa0;Amsterdam/ ; //Stichting Dioraphte/ ; #LSHM20106//Health&#x223c;Holland, Topsector Life Sciences &amp; Health/ ; //SURF Cooperative/ ; 15318/NWO_/Dutch Research Council/Netherlands ; 17232/NWO_/Dutch Research Council/Netherlands ; PI21/01395//Institute of Health Carlos III/ ; PI24/01087//Institute of Health Carlos III/ ; FI20/00215//Institute of Health Carlos III/ ; PI19/01301//Institute of Health Carlos III/ ; PI19/01240//Institute of Health Carlos III/ ; P22/I01403//Institute of Health Carlos III/ ; FI24/00029//Institute of Health Carlos III/ ; INT21/00073//Institute of Health Carlos III/ ; PI20/01473//Institute of Health Carlos III/ ; PI23/01786//Institute of Health Carlos III/ ; //Fondo Europeo de Desarrollo Regional, Uni&#xf3;n Europea, "Una manera de hacer Europa./ ; PDC-2023-51//Jerome Lejeune Foundation/ ; AARF-22-924456/ALZ/Alzheimer's Association/United States ; SG-20-690363-DIAN/ALZ/Alzheimer's Association/United States ; //Fundaci&#xf3;n bancaria "La Caixa," Fundaci&#xf3;n ADEY, Fundaci&#xf3;n Echevarne and Gr&#xed;fols SA (GR@ACE project)/ ; //Ace Alzheimer Center Barcelona is one of the participating centers of the Dementia Genetics Spanish Consortium (DEGESCO)/ ; AC19/00097//PREADAPT Joint Program for Neurodegenerative Diseases (JPND)/ ; //German Research Foundation/ ; //Fondo de Investigaciones Sanitario/ ; CB06/05/2004//Centro de Investigaci&#xf3;n Biom&#xe9;dica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII)/ ; CB18/05/00010//Centro de Investigaci&#xf3;n Biom&#xe9;dica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII)/ ; //Fondo Europeo de Desarrollo Regional, Uni&#xf3;n Europea, Una manera de hacer Europa/ ; 1R01AG056850-01A1//National Institutes of Health grants/ ; R21AG056974//National Institutes of Health grants/ ; R01AG061566//National Institutes of Health grants/ ; 1R01AG081394-01//National Institutes of Health grants/ ; 1R61AG066543-01//National Institutes of Health grants/ ; SLT006/17/00119//Department de Salut de la Generalitat de Catalunya/ ; IIBSP-DOW-2020151//Fundaci&#xf3;n Tatiana P&#xe9;rez de Guzm&#xe1;n el Bueno/ ; H2020-SC1-BHC-2018-2020//Horizon2020-Research and Innovation Framework Programme from the European Union/ ; U19AG032438//Institute on Aging/ ; //German Center for Neurodegenerative Diseases/ ; //Raul Carrea Institute for Neurological Research (FLENI)/ ; //Research and&#xa0;Development/ ; //Research and Development Grants for Dementia from Japan Agency for Medical Research and Development (AMED)/ ; //Korea Health Industry Development Institute (KHIDI), Korea Dementia Research Center (KDRC)/ ; RS-2024-00344521//Ministry of Health &amp; Welfare and Ministry of Science and ICT, Republic of Korea/ ; #733050512//Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ ; 2023-1334//Pascual Maragall Researchers Program/ ; },
mesh = {Humans ; *Down Syndrome/genetics/complications ; *Alzheimer Disease/genetics/epidemiology/complications ; *Amyloid beta-Protein Precursor/genetics ; Female ; Age of Onset ; Male ; Middle Aged ; *Genetic Predisposition to Disease ; *Apolipoproteins E/genetics ; Heterozygote ; Genetic Risk Score ; Risk Factors ; Apolipoprotein E4/genetics ; },
abstract = {INTRODUCTION: An extra copy of the amyloid precursor protein (APP) gene causes autosomal dominant Alzheimer's disease (AD) and AD in Down syndrome (DS), but the factors underlying variability in age at onset (AAO) remain unclear. We investigated whether sporadic AD risk variants modify AAO.<br><br>METHODS: We analyzed clinical and genetic data from 100 APP duplication (APPdup) carriers and 957 individuals with DS. Cox models assessed associations of apolipoprotein E (APOE) &#x3b5;2 and &#x3b5;4 and the AD genetic risk score (AD-GRS; excluding APOE and chromosome 21 variants) with AAO.<br><br>RESULTS: Mean AAO was earlier in APPdup than DS (51&#xa0;&#xb1;&#xa0;7&#xa0;vs. 53&#xa0;&#xb1;&#xa0;6 years; P&#xa0;=&#xa0;0.0005). APOE &#x3b5;2 delayed onset (hazard ratio [HR]&#xa0;=&#xa0;0.47, P&#xa0;<&#xa0;0.0001), whereas APOE &#x3b5;4 (HR&#xa0;=&#xa0;1.5, P&#xa0;=&#xa0;0.0003) and higher AD-GRS (HR&#xa0;=&#xa0;1.3 per standard deviation, P&#xa0;<&#xa0;0.0001) accelerated onset. Predicted median AAO differed by 10 years between lowest and highest genetic risk.<br><br>DISCUSSION: Sporadic AD genetic risk factors are important modifiers of AAO in APPdup and DS, explaining part of the marked variability in onset.},
}
@article {pmid42569829,
year = {2026},
author = {Ehrenberg, AJ and Falgàs, N and Jacobs, HIL and Grinberg, LT and , },
title = {Neuromodulatory subcortical systems in Alzheimer's disease.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71747},
doi = {10.1002/alz.71747},
pmid = {42569829},
issn = {1552-5279},
}
@article {pmid42471758,
year = {2026},
author = {Zhang, T and Dai, L and Ma, Y and Xu, S and Liu, X and Zhao, M and Li, W and Wang, J and Liu, Y},
title = {Conformational bifurcation of tau R3-R4 oligomers underlies fibril polymorphism.},
journal = {Biophysical journal},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.bpj.2026.07.020},
pmid = {42471758},
issn = {1542-0086},
abstract = {Tau aggregation into amyloid fibrils is a central pathological feature of multiple neurodegenerative diseases, yet identical tau sequences can adopt structurally distinct fibril conformations associated with different disorders. How such disease-specific folds emerge from the same sequence remains poorly understood. Here, we use metadynamics and all-atom molecular dynamics simulations to elucidate the folding mechanisms of tau trimers comprising the R3-R4 region, the minimal aggregation nucleus of tau fibrils. By constructing the folding free-energy landscape within a pre-organized fibril-like scaffold, we identify a shared, partially folded intermediate from which two energetically comparable minimum free-energy pathways diverge, leading to either a compact Alzheimer's disease-like or a more open chronic traumatic encephalopathy-like C-shaped conformation. Structural analysis reveals that the β4-β6 triangular region acts as the central determinant of this bifurcation. Hydrophobic-core rearrangements within this region provide the primary energetic driving force for compaction, whereas the conformational flexibility of the 332PGGG335 hinge modulates whether this tendency can be structurally realized. Additional simulations show that stable formation of the triangular region requires cooperative multichain interactions; reducing oligomer size destabilizes this scaffold and abolishes ordered folding. Together, our results establish a mechanistic framework in which identical tau sequences access alternative folding routes through a common intermediate, explaining the emergence of disease-specific fibril polymorphism at the oligomeric level and highlighting early folding intermediates as potential targets for therapeutic intervention.},
}
@article {pmid42560015,
year = {2026},
author = {Mandal, T and Sinharoy, U and Biswas, K and Sarkar, P and Biswas, A},
title = {Association of Serum Homocysteine and Vitamin B12 with Different Grades of Cognitive Impairment in Alzheimer's Disease Patients.},
journal = {Annals of African medicine},
volume = {},
number = {},
pages = {},
doi = {10.4103/aam.aam_592_26},
pmid = {42560015},
issn = {0975-5764},
abstract = {BACKGROUND: Studies have shown a relation between Vitamin B12 (B12) and cognitive impairment in Alzheimer's disease (AD). However, B12 levels do not indicate the severity of the disease. High homocysteine-induced neuroinflammation has been related to the pathogenesis of AD.<br><br>AIM: This study aimed to determine the correlation of Vitamin B12 and serum homocysteine with the cognitive status of AD patients.<br><br>MATERIALS AND METHODS: AD patients (n = 25) and healthy controls (n = 25) were recruited for this study. The revised criteria for diagnosis and staging of AD were used for the diagnosis of AD. Clinical history, laboratory investigations (B12, homocysteine, lipid profile, C-reactive protein, and serum creatinine), and Mini-Mental Status Examination (MMSE) were done. Based on MMSE score, AD patients were subdivided into four groups. All statistical analyses were done on IBM SPSSv26.<br><br>RESULTS: In AD patients, B12 was lower (221.3 &#xb1; 54.5 vs. 396.6 &#xb1; 88.4 pg/ml, P = 0.00), serum homocysteine was higher (15.2 &#xb1; 4.6 vs. 11.7 &#xb1; 2.3 &#xb5;mol/L, P = 0.00), and C-reactive protein was higher (0.95 &#xb1; &#xb1; 0.39 vs. 0.69 &#xb1; 0.12 mg/dl, P = 0.00). Among the four AD groups, we observed a gradual increase in the serum homocysteine levels with a decline in the cognitive status (lower MMSE score) (F = 13.32, P = 0.00). MMSE score had a statistically significant correlation with homocysteine (&#x3c1; = -0.85, P = 0.00), unlike B12 (&#x3c1; =0.33, P = 0.11).<br><br>CONCLUSION: Serum homocysteine is a better diagnostic indicator of cognitive impairment than B12. In resource-limited settings, screening with the Mini-Cog test and timely supplementation with B complex vitamins (B6, B12, and folic acid) can slow the progress of dementia in AD patients.},
}
@article {pmid42560134,
year = {2026},
author = {Papelian, S},
title = {Mechanisms, Biomarkers and Therapeutic Implications of Neuroinflammation in Alzheimer's Disease.},
journal = {International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience},
volume = {86},
number = {5},
pages = {e70168},
pmid = {42560134},
issn = {1873-474X},
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology/therapy/complications/immunology ; *Biomarkers/metabolism ; *Neuroinflammatory Diseases/metabolism/therapy/pathology ; Animals ; Blood-Brain Barrier/metabolism ; Microglia/metabolism/pathology ; },
abstract = {Alzheimer's disease (AD) represents the most prevalent neurodegenerative disorder worldwide, affecting millions of individuals and imposing substantial socioeconomic burdens. While traditional research has focused on amyloid-β (Aβ) plaques and neurofibrillary tangles as primary pathological hallmarks, mounting evidence implicates neuroinflammation as a critical third pillar in AD pathogenesis. This review critically evaluates current understanding of neuroinflammatory mechanisms in AD, examining the complex interplay between cellular mediators, molecular pathways and environmental triggers across a temporal disease-stage framework. We explore the dual and stage-dependent roles of microglia and astrocytes, expand discussion of blood-brain barrier (BBB) dysfunction and peripheral immune infiltration as underappreciated pathogenic contributors, and integrate emerging evidence linking neuroinflammation specifically to tau pathology and its stereotyped propagation through the brain. Diagnostic biomarkers, including translocator protein-positron emission tomography (TSPO-PET) and plasma glial fibrillary acidic protein (GFAP), are evaluated with explicit attention to clinical utility, technical limitations, and their relationship to established AD biomarkers. Therapeutic strategies are critically assessed with careful distinction between preclinical proof-of-concept data and available clinical evidence, and key translational challenges are highlighted throughout. The review emphasizes the need for stage-appropriate intervention windows, patient stratification by neuroinflammatory endotype, and biologically rational combination strategies. Understanding neuroinflammation's temporal and spatial dynamics offers promising but as yet insufficiently realized avenues for early intervention and disease modification in AD.},
}
@article {pmid42560407,
year = {2026},
author = {Feng, X and Yu, W and Guo, S and Ji, Y and Li, J and Wang, L and Zhong, G and Li, S and Niu, L and Zhu, D and Zhou, K and Du, Y},
title = {Aurantio-Obtusin Attenuates Aβ-Induced Cognitive Impairment and Synaptic Dysfunction by Suppressing Neuroinflammation in Mice.},
journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology},
volume = {21},
number = {1},
pages = {},
pmid = {42560407},
issn = {1557-1904},
support = {82371194//the National Natural Science Foundation of China/ ; CSTB2024NSCQ-QCXMX0004//the Natural Science Foundation of Chongqing Municipality/ ; },
mesh = {Animals ; Male ; Mice ; *Amyloid beta-Peptides/toxicity ; Mice, Inbred C57BL ; *Neuroinflammatory Diseases/drug therapy/chemically induced/metabolism ; *Synapses/drug effects/metabolism ; *Anthraquinones/pharmacology/therapeutic use ; *Peptide Fragments/toxicity ; *Cognitive Dysfunction/chemically induced/drug therapy/metabolism ; Maze Learning/drug effects ; },
abstract = {Alzheimer's disease (AD) features Aβ-driven neuroinflammation and synaptic dysfunction that converge on cognitive decline, underscoring the potential value of multi-target interventions. Aurantio-obtusin (AO), a bioactive anthraquinone from Cassia obtusifolia L., exhibits reported anti-inflammatory and antioxidant activities; however, whether AO counteracts Aβ-associated behavioral impairment through coordinated modulation of inflammatory and synaptic alterations remains unclear. Here, we investigated whether AO alleviates Aβ1-42-induced cognitive deficits and examined synapse- and inflammation-related molecular correlates. Male C57BL/6 mice received intracerebroventricular Aβ1-42 to establish an acute AD-like model and were treated with AO (10 mg/kg/day, oral gavage) for consecutive weeks. The results showed that AO improved spatial learning and memory in the Morris water maze, recognition memory in the novel object recognition test, and working memory in the Y-maze, without affecting spontaneous locomotor activity. Furthermore, AO alleviated synaptic dysfunction by restoring synaptophysin expression and upregulating GAD65, and mitigated neuroinflammation by elevating anti-inflammatory factors (IL-4, IL-10, ARG1) and reducing TNF-α. In vitro experiments confirmed that AO was non-cytotoxic to N2A[APP] cells across 0-80 μM, mildly downregulated BACE1 expression, and suppressed the Aβ-induced upregulation of pro-inflammatory mediators (IL-6, iNOS) in BV2 microglial cells. Overall, AO attenuated Aβ1-42-driven behavioral impairment in parallel with improvements in synapse-associated markers and inflammatory readouts. These findings support further evaluation of AO as a natural compound associated with modulation of Aβ-related neuroinflammatory and synapse-associated alterations.},
}
@article {pmid42560467,
year = {2026},
author = {Brimson, S and Thitilertdecha, P and Kumaree, KK and Brimson, JM},
title = {Sigma-1 Receptor Ligand Blarcamesine (ANAVEX 2-73) for Alzheimer's Disease: A Systematic Review.},
journal = {CNS drugs},
volume = {},
number = {},
pages = {},
pmid = {42560467},
issn = {1179-1934},
abstract = {BACKGROUND AND OBJECTIVES: Alzheimer's disease (AD) remains a major cause of dementia, and currently available therapies provide only modest clinical benefit or are limited by intravenous administration and treatment-related adverse effects. Blarcamesine (ANAVEX 2-73) is an orally administered sigma-1 receptor (S1R) agonist that has demonstrated neuroprotective effects in preclinical studies and has progressed through Phase I, Phase II and Phase IIb/III clinical trials. This systematic review evaluated the current clinical evidence for the efficacy and safety of blarcamesine in early-stage and mild-to-moderate AD.<br><br>METHODS: A systematic literature search was conducted in PubMed (including MEDLINE), Scopus, and Google Scholar, together with clinical trial registries, with the final search performed in September 2025. Reference sections of manuscripts were searched, and authors were contacted for additional data. Studies investigating only blarcamesine in participants with mild-to-moderate AD were included. Blarcamesine for other diseases or severe AD were excluded. Data were summarised descriptively in accordance with PRISMA guidelines. The risk of bias was assessed using version 2 of the Cochrane Risk of Bias tool (RoB2) for randomised, placebo-controlled trials, and an adapted version of RoB2 for cross-over trials.<br><br>RESULTS: One Phase I first-in-human study in healthy volunteers and ten reports describing two randomised clinical trials (NCT02244541, a randomised open-label study, and NCT03790709, a randomized placebo-controlled study) and their associated open-label extension studies (NCT02756858 and NCT04314934) were identified, including two peer-reviewed manuscripts, two preprints, and six conference abstracts. Thirty-two participants were enrolled in the Phase IIa open-label dose-finding study, where outcome measures were compared to baseline (NCT02244541). In the extended open-label study exploring the cognitive effect for another 52 weeks, 21 of 32 remained in the study (NCT02756858). The randomised placebo-controlled trial (NCT03790709) enrolled 509 participants and randomised them into three groups: 167 treated with 30 mg blarcamesine, 168 treated with 50 mg blarcamesine and 168 treated with placebo (for 30 mg blarcamesine, 112 completed the study; for 50 mg blarcamesine, 90 completed the study; and for placebo, 136 completed the study). Subsequently, 300 of 509 participants remained in the open-label extension (NCT04314934). Across these two studies, blarcamesine was generally well tolerated, with adverse events that were predominantly mild, transient, and dose-related. Treatment was associated with slower cognitive and functional decline, improvements in multiple clinical outcome measures, and reduced brain atrophy in genetically defined subgroups. Participants carrying the SIGMAR1 and COL24A1 wild-type genotypes were associated with greater therapeutic benefit, supporting the potential value of pharmacogenomic patient stratification.<br><br>CONCLUSIONS: Current clinical evidence suggests that blarcamesine is a promising orally administered therapeutic candidate for early-stage AD with an acceptable safety profile and encouraging efficacy, particularly in genetically defined populations. However, the available evidence is derived from a limited number of clinical studies, including secondary analyses and conference reports. Additional independent randomised clinical trials are required to confirm these findings and further define the role of blarcamesine in the treatment of AD.<br><br>PROSPERO REGISTRATION: CRD420251142826.},
}
@article {pmid42560687,
year = {2026},
author = {Joyce, NR and Balog, S and Gaither, R and Pfeiffer, MR and Bhondoekhan, F and Ott, BR and Margolis, SA and Curry, AE and Zullo, AR},
title = {A Motor Vehicle Crash as an Early Signal of Alzheimer's Disease and Related Dementias.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70630},
pmid = {42560687},
issn = {1532-5415},
support = {R01HD096221//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; R01AG065722/AG/NIA NIH HHS/United States ; R01AG065722-S1/AG/NIA NIH HHS/United States ; R01AG079295/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: People with Alzheimer's disease and related dementias (ADRD) are at increased risk of motor vehicle crash (MVC) due to cognitive decline, which often begins years before diagnosis. MVC could serve as an indicator of ADRD-related cognitive impairment and facilitate earlier diagnosis.<br><br>METHODS: We conducted a matched cohort study of Medicare beneficiaries in New Jersey aged &#x2265;&#x2009;69&#x2009;years with incident ADRD diagnoses from 2010 to 2017 compared to individuals without ADRD and with four other medical conditions: acute myocardial infarction (AMI), asthma, chronic obstructive pulmonary disease (COPD), and diabetes. Comparison groups were sampled with replacement and matched on sex, age, and calendar quarter of diagnosis or claim (for the non-ADRD group). Crash prevalence at 6&#x2009;months and 1, 2, and 3&#x2009;years before diagnosis was compared using chi-square tests, and the monthly prevalence was plotted to examine longitudinal trends in crashes.<br><br>RESULTS: We identified 43,115 eligible individuals with incident ADRD diagnosis from 2010 to 2017. MVC crash prevalence was higher in the ADRD group than in non-ADRD and negative control groups at all measured pre-diagnosis time points: 6&#x2009;months (2.99% vs. 2.31%-2.53%), 1&#x2009;year (5.26% vs. 4.18%-4.65%), 2&#x2009;years (9.52% vs. 7.88%-8.67%), and 3&#x2009;years (13.64% vs. 11.29%-12.37%). The ADRD group was more likely to have multiple crashes in the pre-diagnosis period, but multiple events were rare overall (<&#x2009;3%). Differences were statistically significant but represented small changes in prevalence. Crash prevalence did not reveal a clear signal of cognitive decline in the years leading up to the index diagnosis.<br><br>CONCLUSIONS: Older adults with ADRD had slightly higher prevalence of MVC in the 3&#x2009;years before diagnosis than matched comparison groups, but absolute differences were small and recurrent crashes were rare. MVC alone is too rare to serve as a signal of incipient ADRD, highlighting the need for more sensitive measures.},
}
@article {pmid42560912,
year = {2026},
author = {Zhao, BW and Zhao, HF and Huang, YA and Hu, PW and You, ZH and Hu, L},
title = {A Novel Graph Transformer Framework for Predicting Drug-Disease Associations with Structural Awareness.},
journal = {IEEE transactions on computational biology and bioinformatics},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/TCBBIO.2026.3721658},
pmid = {42560912},
issn = {2998-4165},
abstract = {Accurately predicting drug-disease associations (DDAs) is essential for accelerating the discovery of novel therapeutics. Graph representation learning-based computational models have become increasingly popular for this task due to their efficiency and cost-effectiveness. However, existing approaches often suffer from structural inductive biases and a limited ability to capture the rich heterogeneous context of biomedical molecules, which constrains their capacity to learn expressive drug and disease representations. To address this issue, we propose SGTL-DDA, a novel graph transformer framework designed to incorporate structural information and domain-specific knowledge from heterogeneous biological information networks (HBINs). SGTL-DDA integrates a meta-path-guided sampling strategy with a multi-level attention mechanism, enabling the model to jointly learn from both structural dependencies and attribute semantics in an end-to-end manner. Extensive experiments on two benchmark datasets demonstrate that SGTL-DDA consistently outperforms state-of-the-art methods in terms of Accuracy, F1-score, and AUC under a ten-fold cross-validation scheme. Furthermore, case studies on Alzheimer's disease and breast cancer confirm the predictive capability of SGTL-DDA, as it successfully identifies both known therapeutics and novel repositioning candidates, supported by molecular docking results and literature evidence.},
}
@article {pmid42560982,
year = {2026},
author = {Takeoka, C and Yada, T and Yamazaki, T and Kuroiwa, Y and Hirai, T and Fujino, K and Mizusawa, H and Takao, M and Terao, Y and Yamada, M},
title = {Classification of sporadic Creutzfeldt-Jakob disease based on resting state scalp-recorded electroencephalogram-derived indices.},
journal = {PloS one},
volume = {21},
number = {8},
pages = {e0355367},
pmid = {42560982},
issn = {1932-6203},
mesh = {Humans ; *Creutzfeldt-Jakob Syndrome/classification/diagnosis/physiopathology ; *Electroencephalography/methods ; Aged ; Female ; Male ; *Scalp/physiopathology ; Alzheimer Disease/physiopathology/diagnosis ; Middle Aged ; Rest ; },
abstract = {Prion disease is a general term for a disease that causes cognitive disorders due to the accumulation of abnormal prion protein in the brain. Creutzfeldt-Jakob disease (CJD) is the most common case of prion disease, and sporadic Creutzfeldt-Jakob disease (sCJD) accounts for more than 70% of CJD cases. Early and accurate diagnosis of sCJD remains challenging. The aim of this study is to classify 6 sCJD patients from 10 healthy older adults and 23 Alzheimer's disease (AD) patients using resting-state scalp-recorded electroencephalogram (EEG)-derived indices. Power spectrum, SL values by Synchronization Likelihood (SL), and graph metrics by SL values were calculated for 5 frequency bands as EEG-derived indices. In addition, power spectrum and SL values were standardized and exponentially transformed for each subject and each frequency band. Graph metrics were calculated by these SL values. These indices were used as features for classification. Classifiers were constructed by features selected by Recursive Feature Elimination (RFE). The highest classification accuracy was 97.44% using a 12-dimensional feature. This accuracy was confirmed by indices after standardization and exponential transformation. Additional validation analyses were performed to assess the reliability of the selected classifier. Accuracy of nested LOOCV was 84.62%, supporting meaningful classification ability under a leakage-controlled validation framework. An analysis of robustness removing a group of subjects with high similarity with many others showed that the selected classifier maintained a micro-F1 score of 90.32%. Permutation test indicated that the observed performance was significantly higher than chance level, and repeated stratified 10-fold cross-validation showed relatively stable performance across different data partitions. These findings suggest that resting-state EEG-derived indices may provide useful candidate features for classification of sCJD, AD, and healthy older adults. However, further validation using larger independent cohorts is required to establish the generalizability and clinical reliability of the proposed classifier.},
}
@article {pmid42561097,
year = {2026},
author = {Paladugu, L and Gharaibeh, A and Kolli, N and Learman, C and Hall, TC and Li, L and Rossignol, J and Maiti, P and Dunbar, GL},
title = {RETRACTED: Paladugu et al. Liraglutide Has Anti-Inflammatory and Anti-Amyloid Properties in Streptozotocin-Induced and 5xFAD Mouse Models of Alzheimer's Disease. Int. J. Mol. Sci. 2021, 22, 860.},
journal = {International journal of molecular sciences},
volume = {27},
number = {15},
pages = {},
pmid = {42561097},
issn = {1422-0067},
abstract = {The journal retracts the article entitled "Liraglutide Has Anti-Inflammatory and Anti-Amyloid Properties in Streptozotocin-Induced and 5xFAD Mouse Models of Alzheimer's Disease" [...].},
}
@article {pmid42561134,
year = {2026},
author = {Ehn, E and Thonberg, H and Nennesmo, I and Lindstrand, A and Kvarnung, M and Graff, C},
title = {Clinical genome sequencing in neurodegenerative diseases-outcome in the first 500 patients.},
journal = {Human molecular genetics},
volume = {35},
number = {16},
pages = {},
doi = {10.1093/hmg/ddag072},
pmid = {42561134},
issn = {1460-2083},
mesh = {Humans ; *Whole Genome Sequencing/methods ; *Neurodegenerative Diseases/genetics/diagnosis ; Amyotrophic Lateral Sclerosis/genetics/diagnosis ; Female ; C9orf72 Protein/genetics ; DNA Copy Number Variations/genetics ; Male ; Middle Aged ; Alzheimer Disease/genetics/diagnosis ; Genetic Predisposition to Disease ; Frontotemporal Dementia/genetics/diagnosis ; Aged ; DNA Repeat Expansion/genetics ; Adult ; Polymorphism, Single Nucleotide ; Phenotype ; },
abstract = {Neurodegenerative diseases (NDDs) are clinically and genetically heterogeneous, requiring neuropathology or molecular testing for a definitive diagnosis. Clinical whole genome sequencing (WGS) enables comprehensive variant calling across flexible gene lists that can be tailored to the clinical presentation. By allowing simultaneous detection of single-nucleotide variants, copy-number variants, structural variants, and repeat expansions, WGS has the potential to improve diagnostic yield, facilitate genetic counseling and support clinical trial inclusion. This study assesses the diagnostic performance of WGS in individuals with NDD. WGS in 500 individuals representing a wide spectrum of NDDs identified a disease-causing variant in 61 cases, resulting in a diagnostic yield of 12%. These variants were found in 16 different genes, with C9orf72 being the most prevalent. Repeat expansions represented the largest variant class, accounting for 35 of 61 LP/P cases (57%); most of which were C9orf72 expansions (31/35). In the largest phenotype groups, frontotemporal dementia (FTD) had the highest diagnostic yield (19%) followed by amyotrophic lateral sclerosis (ALS, 13%), whereas an underlying monogenic cause was expectedly low in Alzheimer disease (AD, 4%). A positive family history was present in the majority (74%) of FTD, ALS, combined ALS-FTD and AD cases with an LP/P finding. Clinical WGS provides a clear diagnostic advantage in NDDs marked by substantial clinical and genetic overlap. WGS enables comprehensive variant detection and mapping of genotype-phenotype relationships across the disease continuum. In FTD and ALS, these results support universal access to genetic testing independent of age at onset or family history.},
}
@article {pmid42561290,
year = {2026},
author = {Frota, LS and Barbosa, SICG and Prado, JCS and Ishiki, HM and Fontenelle, ROS and Morais, SM},
title = {Evaluation of bioactive compounds from Libidibia ferrea (Mart. Ex Tul) LP Queiroz: Antioxidant and antifungal activities, acetylcholinesterase inhibition, and implications in Alzheimer's disease.},
journal = {Anais da Academia Brasileira de Ciencias},
volume = {98},
number = {2},
pages = {e20250618},
doi = {10.1590/0001-3765202620250618},
pmid = {42561290},
issn = {1678-2690},
mesh = {*Cholinesterase Inhibitors/pharmacology/isolation &amp; purification ; *Antifungal Agents/pharmacology/isolation &amp; purification ; *Antioxidants/pharmacology/isolation &amp; purification ; *Plant Extracts/pharmacology/chemistry ; Microbial Sensitivity Tests ; Alzheimer Disease/drug therapy ; *Candida albicans/drug effects ; Molecular Docking Simulation ; *Burseraceae/chemistry ; Plant Leaves/chemistry ; },
abstract = {Fungal infections caused by Candida albicans represent a global health concern, with increasing antifungal resistance and potential links to neurodegenerative diseases such as Alzheimer's. In this context, this study evaluated the antifungal, antioxidant and acetylcholinesterase inhibitory activities of the hydroethanolic leaf extract of Libidibia ferrea, a species used in traditional medicine. The antioxidant potential was determined using DPPH and ABTS assays, while acetylcholinesterase inhibition was assessed by an in vitro enzymatic assay. Antifungal activity was assessed against Candida albicans strains by broth microdilution and molecular docking was employed to predict the interactions of the main phenolic compounds with acetylcholinesterase and sterol 14-α-demethylase. The extract showed potent antioxidant activity (CI50 = 9.68 ± 0.51 μg/mL for DPPH) and high inhibition of acetylcholinesterase (CI50 = 15.02 ± 0.16 μg/mL). It also showed fungistatic and fungicidal effects, with MIC values ranging from 0.118 to 0.469 mg/mL. In silico analyses highlighted rutin, catechin and ellagic acid as compounds with strong binding affinities to both enzymes, suggesting dual antifungal and neuroprotective effects. These results corroborate Libidibia ferrea as a promising source of bioactive compounds with potential therapeutic applications for fungal infections and neurodegenerative diseases, such as Alzheimer's.},
}
@article {pmid42561582,
year = {2026},
author = {Kumari, P and Lipton, RB and Aschenbrenner, AJ and Sperling, R and Donohue, MC and Grober, E},
title = {Stages of objective memory impairment (SOMI) as a predictor of clinical progression in the A4 study.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {8},
pages = {100641},
doi = {10.1016/j.tjpad.2026.100641},
pmid = {42561582},
issn = {2426-0266},
abstract = {BACKGROUND: About one third of amyloid positive, cognitively normal individuals develop mild cognitive impairment or clinical Alzheimer dementia (AD) over 5 years of follow-up. Sensitive cognitive measures, in addition to biomarkers of amyloid pathology, add to the efficiency of secondary prevention trials by identifying cognitively normal individuals at greatest risk of clinical progression. The Stages of Objective Memory Impairment (SOMI) system, based on the picture version of the Free and Cued Selective Reminding Test with immediate recall (pFCSRT+IR), predicted clinical progression in two observational studies.<br><br>OBJECTIVE: Our objective was to extend SOMI's findings to clinical trials using participants from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's(A4) study.<br><br>METHODS: Eligible participants were cognitively normal, had a Clinical Dementia Rating (CDR) =0, an elevated amyloid level, the pFCSRT+IR, pTau217, and longitudinal data on the CDR. Cox proportional hazards model was used to assess the association of baseline SOMI stage for clinical progression defined by time to the first of 2 consecutive CDRs > 0 or CDR>0 at last assessment. The sample was censored at 4.5 years of follow-up.<br><br>RESULTS: Of the 911 eligible participants, mean age was 72 years, 59% were female, 62% were APOE &#x3b5;4 carriers, and 37% progressed over 4.5 years. Hazard ratios (HR) for progression were estimated with follow-up time as the timescale and the SOMI 0 group as the reference. The HRs for progression across SOMI stage increased from 1.48(1.15-1.92 p=.003) for SOMI-1, to 1.83 (1.32-2.54, p &#x2264; 0.001) for SOMI-2, and to 3.04 (1.97-4.68, p &#x2264; 0.001) for SOMI 3/4. SOMI remained an independent and significant predictor when pTau217 was added to the model.<br><br>CONCLUSION: SOMI's risk profile in A4 was similar to prior findings in observational cohorts. SOMI provides a low-cost, non-invasive enrichment tool for identifying individuals at risk for early cognitive decline in secondary prevention trials.},
}
@article {pmid42561602,
year = {2026},
author = {Hajeforoosh, P and Moghaddam, AH and Jelodar, SK},
title = {Insulin resistance as a driver of neuroinflammation and oxidative stress in Alzheimer's disease: Mechanistic links and therapeutic approaches.},
journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie},
volume = {202},
number = {},
pages = {119760},
doi = {10.1016/j.biopha.2026.119760},
pmid = {42561602},
issn = {1950-6007},
abstract = {Alzheimer's disease (AD) is a complex, multifactorial neurodegenerative disorder characterized by the accumulation of amyloid-β plaques and hyperphosphorylated tau protein aggregates, leading to progressive cognitive decline. Growing evidence suggests that AD may also be considered a metabolic disorder closely associated with insulin resistance (IR). Impaired insulin signaling disrupts the PI3K/Akt and GSK3-β pathways, resulting in synaptic dysfunction, neuronal loss, and aberrant protein phosphorylation. Moreover, IR contributes to mitochondrial dysfunction, oxidative stress, and chronic neuroinflammation within the central nervous system (CNS). These metabolic alterations, together with impaired energy homeostasis, dysregulate intracellular signaling cascades and exacerbate amyloid and tau pathology. This narrative review examines the mechanistic interplay among insulin resistance, oxidative stress, and neuroinflammation in AD, with particular emphasis on the shared cellular pathways that underlie disease progression. In addition, it summarizes emerging therapeutic strategies targeting insulin signaling, including pharmacological insulin-sensitizing agents, incretin-based therapies, lifestyle interventions, and bioactive natural compounds. The review also highlights advances in intranasal delivery strategies, which have emerged as a promising approach for enhancing brain targeting and improving therapeutic efficacy. Despite substantial progress, the precise mechanisms linking insulin resistance to neurodegeneration remain incompletely understood. Further mechanistic and translational studies are urgently required to elucidate these interactions and advance the development of effective therapeutic interventions.},
}
@article {pmid42561665,
year = {2026},
author = {Tyagi, P and Kumari, S and Sharma, P and Dhapola, R and Paidlewar, M and Medhi, B and HariKrishnaReddy, D},
title = {HMGB1 signalling in Alzheimer's disease: pathogenic roles and therapeutic prospects.},
journal = {International immunopharmacology},
volume = {187},
number = {},
pages = {117204},
doi = {10.1016/j.intimp.2026.117204},
pmid = {42561665},
issn = {1878-1705},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative condition marked by the gradual loss of neurons, especially in the hippocampus and cerebral cortex. This neuronal loss results in cognitive decline, memory problems, and changes in behaviour. It accounts for roughly 90% of all cases, making it the most common reason for dementia worldwide, with a marked rise in its occurrence as one ages. AD is pathologically marked by the presence of intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein and the formation of extracellular amyloid-β plaques. Along with these defining characteristics, oxidative stress and chronic neuroinflammation, which are triggered by prolonged astrocyte and microglia activation and excessive reactive oxygen species production, play crucial roles in the development of the illness. The majority of cases of AD are sporadic late-onset illness, but the less common familial variant is linked to mutations in the APP, PSEN1, and PSEN2 genes that cause aberrant amyloid-β formation. High mobility group box 1 (HMGB1) is a crucial modulator of neuroinflammation in AD, according to new research. By activating the receptor for advanced glycation end products (RAGE) and Toll-like receptor 4 (TLR4), HMGB1, especially in its pro-inflammatory disulfide state, hinders memory and learning. RAGE/CaMKKβ-AMPK, ERK1/2, GSK-3β, NF-κB, MAPKs, and NLRP3 inflammasome cascades are among the overlapping downstream signalling pathways that these receptors initiate. Together, these pathways induce tau hyperphosphorylation, amyloid-β buildup, and persistent inflammatory responses. Therefore, a viable treatment approach for reducing neuroinflammation and associated pathologies with AD. is to target HMGB1-mediated signalling networks.},
}
@article {pmid42561776,
year = {2026},
author = {Chen, W and Zhan, K and Xu, C and Sun, S and Yang, X and Lei, H},
title = {Structure-based identification of novel indole-fused polycyclic derivatives as potent acetylcholinesterase inhibitors.},
journal = {Bioorganic &amp; medicinal chemistry},
volume = {142},
number = {},
pages = {118765},
doi = {10.1016/j.bmc.2026.118765},
pmid = {42561776},
issn = {1464-3391},
abstract = {The pathogenesis of Alzheimer's disease (AD) is closely associated with cholinergic neuronal impairment, which is induced by excessive degradation of acetylcholine (ACh) mediated by acetylcholinesterase (AChE). In this study, a series of novel indole-fused polycyclic derivatives (1-28) were designed, synthesized, and assessed for their AChE inhibitory activities. The biological evaluation results demonstrated that most of the compounds exhibited moderate to excellent AChE inhibitory activities. Among them, compounds 8, 9, 21, and 26 showed leading AChE inhibitory activity with IC50 values of 0.29 μM, 1.5 μM, 1.2 μM, and 1 μM, respectively, which were superior to the positive control galantamine (IC50 = 2.2 μM). Furthermore, favorable drug-likeness profiles and optimal pharmacokinetic properties were confirmed for compound 8 through ADME analysis. Stable binding interactions between compound 8 and AChE were validated by the results of 100 ns molecular dynamics simulations. Overall, compound 8 was characterized as a potent and well-qualified AChE inhibitor, and further systematic investigations are warranted for its application in the treatment of AD-related diseases.},
}
@article {pmid42561934,
year = {2026},
author = {Li, W and Rimal, S and Bhurtel, S and Yeung, L and Lu, BG and Grinberg, LT and Spina, S and Sillero, MIC and Seeley, WW and Guo, S and Lu, B},
title = {Tau-induced mitochondrial reverse electron transport drives neurodegeneration.},
journal = {Neuron},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuron.2026.07.012},
pmid = {42561934},
issn = {1097-4199},
abstract = {Hyperphosphorylation and aggregation of tau are pathological hallmarks of tauopathies. Mitochondrial dysfunction is also a common feature of tauopathies. The mechanistic link between tau abnormalities and mitochondrial dysfunction and its relationship to the physiological function of tau, however, is unclear. Here, we demonstrate that tau regulates mitochondrial reverse electron transport (RET), which produces excess reactive oxygen species (ROS), reduces the NAD[+]/NADH ratio, and is activated by aging or stress. In flies, mice, and human induced pluripotent stem cell (hiPSC)-derived neurons, tau depletion eliminates stress-induced RET and confers resilience. Mechanistically, tau enters mitochondria and directly interacts with the complex I subunit NDUFS3 to promote RET in a phosphorylation-dependent manner. Elevated RET further drives tau hyperphosphorylation, establishing a self-perpetuating pathological loop. Inhibition of RET ameliorates tau toxicity across species. RET regulation thus represents a previously unrecognized normal function of tau that becomes pathological in disease, providing a therapeutic target for various conditions characterized by tau abnormalities and mitochondrial dysfunction.},
}
@article {pmid42562307,
year = {2026},
author = {Yadav, A and Verma, H and Kumari, S and Gangwar, P and Rao, R and Yadav, B and Kaur, S and Dhiman, M and Mantha, AK},
title = {The emerging role of NADPH oxidases (NOX) in Alzheimer's disease pathogenesis.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.08.004},
pmid = {42562307},
issn = {1873-7544},
abstract = {Alzheimer's disease (AD) is a slow-progressing neurodegenerative disease, mainly characterized by the accumulation of amyloid beta (Aβ) plaques and intracellular hyperphosphorylated Tau protein, along with the generation of free radicals. In normal physiology free radicals play a promising role. However, the imbalance in the formation and clearance of the free radicals or reactive oxygen species/reactive nitrogen species (ROS/RNS) disrupts redox homeostasis, resulting in oxidative stress. Cellular disruption through the oxidation of lipids, proteins, and nucleic acids along with the disruption of the blood-brain barrier (BBB) integrity, and neuroinflammation are linked with AD pathogenesis. Albeit there are various ROS-generating sources, notably mitochondria, endoplasmic reticulum (ER), peroxisomes, NADPH oxidase (NOX), and several other oxidases, but out of all, the second most well-studied ROS-generating component after mitochondria is thought to be NOX. It is a multi-subunit enzyme family, activated by the phosphorylation of its cytosolic subunit, culminating in the production of superoxide (O2[•-]) anions. It comprises seven different isoforms, where NOX2 is the most studied isoform found to be the major source of ROS production in the brain. Therefore, inhibiting NOX-induced oxidative stress in the brain might be a promising therapeutic approach for AD. Thus, the current review enlightens the role of NOX in neurodegenerative AD progression, Aβ pathology and focusing on the therapeutic interventions by employing different phytochemicals as natural inhibitors and the synthetic inhibitors to combat the pathogenicity associated with NOX in the case of AD.},
}
@article {pmid42562385,
year = {2026},
author = {Gauch, M and Ablinger, I and Corsten, S and Dörr, F and Flöel, A and Grewe, T and Foede, J and Heinrich, I and Knels, C and Köb, AL and Meinzer, M and Rosenkranz, A and Schmischke, A and Unger, N and Volkmer, A and Wuttke, T and Rysop, AU},
title = {Mapping PPA Care: Results of a Survey Study on Speech and Language Therapy for People With Primary Progressive Aphasia Across Germany.},
journal = {Dementia (London, England)},
volume = {},
number = {},
pages = {14713012261473983},
doi = {10.1177/14713012261473983},
pmid = {42562385},
issn = {1741-2684},
abstract = {Background: Primary Progressive Aphasia (PPA) is a rare condition characterised by a gradual loss of language due to neurodegenerative processes including frontotemporal lobar degeneration and Alzheimer's disease. Speech and language therapy is one of the main treatment options for people with PPA (PwPPA). International survey studies among speech and language therapists (SLTs) have revealed considerable shortcomings in treatment options for this patient group. To date, there has been no survey on speech and language therapy for PwPPA in Germany. Methods: We translated a survey that was originally developed to describe speech and language therapy for PPA in the UK into German and adapted it to the German healthcare system. The final 32-item survey covering demographics of SLTs and PwPPA, referral patterns, as well as diagnostic and therapeutic procedures, was distributed online. Results: Data from 46 SLTs, from 10 of Germany's 16 federal states with experience in treating PwPPA were included. These 46 SLTs had treated 158 PwPPA in the last 24 months and reported working with PwPPA for >20 sessions on average. PwPPA were most frequently referred to speech and language therapy 2-3 years after symptom onset with word finding difficulties. Qualitative content analysis revealed barriers on multiple levels to access speech and language therapy. Informal assessments, including analysis of spontaneous speech, interviews with PwPPA and/or carers and screening of language and communication skills were reported as most frequently used. SLTs rated life story work, activity and participation-focused therapy and symptom-focused therapy. for language disorders as the most commonly used for PwPPA. Discussion: This study provides an overview of the current state of speech and language therapy for PwPPA in Germany. It shows that there is currently no clear pathway for PPA care that covers all levels of the International Classification of Functioning Disability and Health and encompasses both assessment and treatment approaches. A comparison of the results obtained from this survey study with those from other similar studies in the UK, Turkey and Italy revealed both similarities and differences. Our findings underscore the need for further research, the development of standardized, evidence-based assessment and intervention tools, and targeted professional training.},
}
@article {pmid42562450,
year = {2026},
author = {Mendes Ferreira, V and Viana-Baptista, M},
title = {Family history of cognitive impairment as a diagnostic clue in Fragile X-associated tremor/ataxia syndrome.},
journal = {BMJ case reports},
volume = {19},
number = {8},
pages = {},
doi = {10.1136/bcr-2026-273818},
pmid = {42562450},
issn = {1757-790X},
mesh = {Humans ; Male ; *Fragile X Syndrome/diagnosis/genetics/complications ; *Tremor/genetics/diagnosis ; *Ataxia/genetics/diagnosis/complications ; Fragile X Messenger Ribonucleoprotein 1/genetics ; *Cognitive Dysfunction/genetics/diagnosis/etiology ; Magnetic Resonance Imaging ; Diagnosis, Differential ; Middle Aged ; },
abstract = {Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by premutation alleles (55-200 CGG repeats) in the FMR1 gene, typically presenting in later adulthood with intention tremor, cerebellar ataxia and cognitive impairment. We report a male patient in his 5th decade presenting with progressive bilateral action tremor initially suggestive of essential tremor. Neurological examination revealed postural and intention tremor with mild dysdiadochokinesia. A family history of early-onset cognitive decline in a first-degree relative prompted brain MRI, which demonstrated bilateral T2 hyperintensities of the middle cerebellar peduncles, suggestive of FXTAS. Subsequent genetic testing confirmed an FMR1 premutation with 115 CGG repeats, establishing the diagnosis of FXTAS. Review of the brother's records revealed progressive cognitive impairment previously attributed to Alzheimer's disease, raising the possibility of unrecognised FXTAS. This case highlights the importance of family history and neuroimaging in distinguishing FXTAS from more common tremor disorders and dementia syndromes.},
}
@article {pmid42562606,
year = {2026},
author = {Karagianni, S and Moscoso, A and Raghavan, S and van Essen, M and Mainta, I and Camacho, V and Rodríguez-Fonseca, O and Silva-Rodríguez, J and Perissinotti, A and Gu, Y and Yun, J and Franzmeier, N and Grothe, MJ and Seo, SW and Frisoni, GB and Garibotto, V and Schwarz, CG and Petersen, RC and Jack, CR and Vemuri, P and Schöll, M},
title = {Concordance Between [[18]F]Flortaucipir PET Visual Reads and CenTauR-Based Quantification.},
journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine},
volume = {},
number = {},
pages = {},
doi = {10.2967/jnumed.126.272722},
pmid = {42562606},
issn = {1535-5667},
abstract = {Tau PET imaging with [[18]F]flortaucipir allows for the visualization and mapping of aggregated tau deposits, a key neuropathologic feature of Alzheimer disease (AD). A visual interpretation method for [[18]F]flortaucipir was approved by the Food and Drug Administration and European Medicines Agency and has been implemented for a standardized, clinically usable definition of tau PET positivity. The CenTauRz method, on the other hand, offers the possibility to harmonize the definition of tau PET positivity across different radiotracers using quantitative metrics, but its concordance with clinically relevant [[18]F]flortaucipir visual reads remains unclear. Methods: A convenience sample of 3991 participants, including cognitively unimpaired (CU) and cognitively impaired (CI) individuals (i.e., those with mild cognitive impairment or AD dementia), underwent [[18]F]flortaucipir PET imaging. Each [[18]F]flortaucipir scan was assessed by 3 trained readers using the approved visual interpretation method and quantified using the CenTauRz quantification pipeline in different regions of interest (ROIs). Concordance between positive visual reads and CenTauRz-defined positivity (i.e., >2 on the CenTauRz scale) was assessed using Cohen κ. Receiver-operating-characteristic (ROC) analysis evaluated the discriminative power of continuous CenTauRz values in distinguishing between negative and positive visual reads. Generalized additive models examined clinical progression on the basis of visual and CenTauRz-based assessments of tau PET positivity. Results: Concordance between visual reads and CenTauRz-based assessments of tau PET positivity was moderate, particularly in CU individuals (κ = 0.23-0.55 for CU participants, κ = 0.57-0.82 for CI participants, depending on the ROI). ROC analysis revealed that the agreement remained moderate, independent of the CenTauRz cut point used (area under the ROC curve, 0.72-0.87 vs. 0.87-0.97 for CU and CI individuals, respectively). Among discordant cases, participants with visually positive/CenTauRz-negative tau PET scans were more frequently amyloid-positive and exhibited faster clinical progression compared with visually negative/CenTauRz-positive individuals. Conclusion: Our findings highlight the relatively limited agreement between the visual assessment of [[18]F]flortaucipir PET images and CenTauRz-based quantification, particularly in CU individuals. Participants with visually positive/CenTauRz-negative tau PET scans showed a high frequency of amyloid positivity and faster clinical progression, suggesting that visual reads are more sensitive to heterogeneous, clinically relevant tau accumulation patterns not captured by ROI-based methods. These findings underscore the need for new quantification approaches to better capture the complex patterns of tau deposition, important for early AD detection and monitoring.},
}
@article {pmid42562773,
year = {2026},
author = {Zheng, X and Zhang, N and Wang, L and Zhao, H and Liu, C and Wang, J and Zhao, W and Zhao, J and Yang, P and Robinson, L and Hunt, L and Lokken, A and Lin, L and Nelson, PT and Kofler, J and Xie, H and Xia, H and Mao, Q},
title = {A phosphorylation‑independent monoclonal antibody improves detection of TDP‑43 pathology across frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and limbic predominant age related TDP‑43 encephalopathy neuropathological change.},
journal = {Journal of neuropathology and experimental neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/jnen/nlag085},
pmid = {42562773},
issn = {1554-6578},
support = {GC-202008-2020689//Alzheimer's Drug Discovery Foundation/ ; R21AG080502/AG/NIA NIH HHS/United States ; R21AG088509/AG/NIA NIH HHS/United States ; R01AG097508/AG/NIA NIH HHS/United States ; },
abstract = {TDP-43 proteinopathies encompass frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), amyotrophic lateral sclerosis (ALS-TDP), and limbic predominant age related TDP-43 encephalopathy neuropathological change (LATE-NC). These proteinopathies exhibit subtype-specific aggregate architectures that may constrain epitope accessibility in situ. We compared a phosphorylation-independent monoclonal antibody targeting a C-terminal epitope (MAb No. 9) with the phospho-specific pSer409/410 antibody to determine whether its signal relates to regional neurodegeneration in a multicenter autopsy cohort spanning FTLD-TDP types A-C, ALS-TDP, and Alzheimer disease neuropathologic change (ADNC) with or without LATE-NC. Immunolabeling with MAb No. 9 detected pathological TDP-43 across all diagnostic groups with enhanced labeling of dystrophic neurites and thread/dot-like pathology in FTLD-TDP types A/B and in ALS-TDP. MAb No. 9 performance was equivalent to p409/410 in FTLD-TDP type C. In ADNC with stage 3 LATE-NC, MAb No. 9 revealed a greater limbic burden and labeled both α type and β type inclusions. Dual label immunofluorescence demonstrated strong spatial overlap with p409/410 but additionally highlighted fine punctate pathology. MAb No. 9 burden in FTLD-TDP type A correlated strongly with cortical neurodegeneration but showed weaker and variable associations, particularly in severely atrophic cortex. These findings indicate that filament architecture governs C-terminal epitope accessibility and that MAb No. 9 may be a complementary tool for subtype refinement, clinicopathologic correlation and translational biomarker development in TDP-43 proteinopathies.},
}
@article {pmid42562777,
year = {2026},
author = {Shao, R and Li, W and Su, H and Zhou, S and Lan, M and Li, D},
title = {Impact of Narrative Nursing and Cognitive Behavioral Rehabilitation on Cognitive Function and Anxiety in Patients With Alzheimer's Disease.},
journal = {Geriatrics &amp; gerontology international},
volume = {26},
number = {8},
pages = {e70719},
doi = {10.1111/ggi.70719},
pmid = {42562777},
issn = {1447-0594},
mesh = {Humans ; Male ; Female ; *Alzheimer Disease/psychology/rehabilitation ; *Cognitive Behavioral Therapy/methods ; Aged ; *Quality of Life ; *Cognition/physiology ; *Anxiety/etiology ; Activities of Daily Living ; Treatment Outcome ; *Narrative Therapy/methods ; Middle Aged ; },
abstract = {OBJECTIVE: Alzheimer's disease (AD) progressively impairs cognitive function and quality of life (QoL). Patients frequently experience anxiety, which may accelerate cognitive decline. This study aimed to investigate the effects of narrative nursing combined with cognitive behavioral rehabilitation on cognitive function and anxiety in AD patients.<br><br>METHODS: In this randomized controlled trial, 172 AD patients were assigned to a control group (conventional care, n&#x2009;=&#x2009;86) or an observation group (additional 6-month narrative nursing and cognitive behavioral rehabilitation, n&#x2009;=&#x2009;86). Outcomes were assessed at baseline and after the 6-month intervention using validated Chinese versions of the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Generalised Anxiety Disorder-7 (GAD-7), Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL), and Quality of Life in Alzheimer's Disease (QoL-AD) scales.<br><br>RESULTS: Baseline characteristics, including age (mean: 68.5&#x2009;&#xb1;&#x2009;10.2&#x2009;years), sex distribution (57.6% men), body mass index (22.95&#x2009;&#xb1;&#x2009;3.44&#x2009;kg/m[2]), disease duration (5.32&#x2009;&#xb1;&#x2009;0.79&#x2009;years), and baseline cognitive scores (MMSE: 19.25&#x2009;&#xb1;&#x2009;2.88; MoCA: 17.00&#x2009;&#xb1;&#x2009;2.55), did not differ significantly between groups. After 6&#x2009;months of intervention, the observation group demonstrated greater improvement in cognitive function (MMSE: F&#x2009;=&#x2009;4.461, p&#x2009;=&#x2009;0.039; MoCA: F&#x2009;=&#x2009;5.441, p&#x2009;=&#x2009;0.040), anxiety (GAD-7: F&#x2009;=&#x2009;14.937, p&#x2009;<&#x2009;0.001), ADL (ADCS-ADL: F&#x2009;=&#x2009;11.967, p&#x2009;<&#x2009;0.001), and QoL (QoL-AD: F&#x2009;=&#x2009;7.307, p&#x2009;<&#x2009;0.001) than the control group. Adherence was high (92%), with no significant group differences. Missed sessions were primarily attributable to acute illness, transportation difficulties, or family commitments. Medication regimens (cholinesterase inhibitors, memantine, and antidepressants) remained stable between groups, with no significant interaction with the intervention.<br><br>CONCLUSION: Narrative nursing combined with cognitive behavioral rehabilitation can effectively increase cognitive function, reduce anxiety, and improve the ADL and QoL of patients with AD.<br><br>TRIAL REGISTRATION: ISRCTN10742199.},
}
@article {pmid42562893,
year = {2026},
author = {Khaki, PSS and Guillen-Poza, PA and Wong, C and Kan, C and Sharma, R and Sugimura, R and Robinson, AC and Valbuena, A and Ng, RC and Yang, Y and Hervas, R},
title = {Distinct amyloid-β filament fold in individuals with APP Flemish mutation.},
journal = {Nature structural &amp; molecular biology},
volume = {},
number = {},
pages = {},
pmid = {42562893},
issn = {1545-9985},
abstract = {The dominantly inherited Flemish mutation-an A692G substitution in the amyloid precursor protein, corresponding to an A21G change in amyloid-β (Aβ)-causes a rare, early-onset form of Alzheimer disease characterized by pronounced cerebral amyloid angiopathy and unusually large senile plaque cores. Here, we report cryo-electron microscopy structures of amyloid filaments extracted from the postmortem parietal lobes of two individuals representing the only two known Flemish pedigrees worldwide. Although tau paired helical filaments were present, the predominant filaments comprise Aβ40-A21G, assembled as two identical protofilaments (D1-V40) packed with two-start helical symmetry. Aβ40-A21G and wild-type Aβ42 filaments share a substructure preceding the substitution site (Y10-F19); however, loss of the methyl group at residue 21 gives rise to a distinct arrangement, termed the 'Flemish fold', which differs from all previously characterized Aβ folds and is defined by a unique hydrophobic interface. Using a cell-based assay, we find that this distinctive fold is associated with the vascular tropism characteristic of the Flemish variant. Together, our structural and cellular data define a familial Alzheimer-disease-associated amyloid fold and provide insight into the molecular basis of Flemish-type dementia and cerebral hemorrhage.},
}
@article {pmid42562894,
year = {2026},
author = {},
title = {Alzheimer's disease-linked Flemish APP mutation defines a distinct amyloid-β fold.},
journal = {Nature structural &amp; molecular biology},
volume = {},
number = {},
pages = {},
pmid = {42562894},
issn = {1545-9985},
}
@article {pmid42563066,
year = {2026},
author = {Almirón, RS and Tettamanti, C and Martinez, S and Antonino, M and Marmo, P and Debiagge, &#xc1; and Toselli, D and Moro, L and Allemandi, D and Lorenzo, A and Quinteros, DA and Bignante, EA},
title = {Gallein-Loaded Albumin Nanoparticles Prevent Amyloid-β-Induced Amyloidogenic APP Processing, Synaptic Loss, and Dendritic Pathology.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42563066},
issn = {1559-1182},
support = {ANPCyT PICT 2021-GRF-TI-00561//Agencia Nacional de Promoci&#xf3;n de la Investigaci&#xf3;n, el Desarrollo Tecnol&#xf3;gico y la Innovaci&#xf3;n/ ; ANPCyT PICT 2019-282//Agencia Nacional de Promoci&#xf3;n de la Investigaci&#xf3;n, el Desarrollo Tecnol&#xf3;gico y la Innovaci&#xf3;n/ ; PIDTA-SECYT 2023-2027//Secretaria de Ciencia y Tecnolog&#xed;a - Universidad Nacional de C&#xf3;rdoba/ ; PIP 2022-2024//Consejo Nacional de Investigaciones Cient&#xed;ficas y T&#xe9;cnicas/ ; PIP 2020-2022//Consejo Nacional de Investigaciones Cient&#xed;ficas y T&#xe9;cnicas/ ; AARGD-22-926476/ALZ/Alzheimer's Association/United States ; },
mesh = {Animals ; *Nanoparticles/chemistry ; *Amyloid beta-Peptides/toxicity/metabolism ; Humans ; *Synapses/pathology/drug effects/metabolism ; *Dendrites/pathology/drug effects/metabolism ; *Amyloid beta-Protein Precursor/metabolism ; Mice ; Rats ; *Albumins ; Neurons/metabolism/drug effects/pathology ; Cell Line, Tumor ; },
abstract = {Alzheimer's disease (AD) is a multifactorial and highly debilitating disorder with a long clinical course. The development of new therapeutic strategies capable of mitigating or delaying disease progression remains a major challenge. We previously identified the amyloid precursor protein (APP) as a receptor for aggregated amyloid-β (Aβ) species that signals through a Go/Gβγ-dependent pathway, thereby promoting amyloidogenesis and neurotoxicity. In this context, gallein (GAL), a selective inhibitor of Gβγ signaling, has demonstrated robust neuroprotective effects in preclinical AD models. However, GAL exhibits poor stability and limited aqueous solubility, which may restrict brain bioavailability. To overcome these limitations, a nanotechnology-based formulation strategy was implemented. Here, we report the design and generation of human serum albumin-based nanoparticles (HSA NPs) loaded with GAL (NP-GAL) using a green desolvation method followed by thermal stabilization. Using murine neuroblastoma cells, primary rat cortical neurons, and human iPSC-derived neurons, we demonstrate that NP-GAL effectively prevents Aβ-induced amyloidogenic APP processing, dendritic dystrophy, and presynaptic loss. In addition, both empty NPs and NP-GAL exhibit association with Aβ aggregates, suggesting an additional benefit, as these nanoparticles mitigate amyloid-associated toxicity. Notably, the nanoparticles themselves exert beneficial effects on dendritic morphology and provide protection against neurotoxic insults beyond amyloid pathology, including those induced by rotenone, a widely used experimental model of Parkinson's disease. Together, these in vitro findings suggest that HSA-based nanoparticles hold potential as a platform to stabilize GAL and exert intrinsic neuroprotective effects. These results provide a proof-of-concept for exploring nanoparticle-mediated Gβγ inhibition to counteract Aβ-induced neuronal dysfunction and synaptic pathology.},
}
@article {pmid42563554,
year = {2026},
author = {Asghariahmadabad, M and Metanat, P and Thomas, M and Bonham, LW and Lam, T and Kurt, M and Nguyen, H and Ellingson, T and Zucchelli, M and Casagranda, S and Lu, Q and Rauschecker, AM and Sugrue, L and Savastano, LE and Hess, CP and Ranasinghe, K and Josephson, SA and Miller, BL and Yokoyama, JS and Rabinovici, GD and Ljubenkov, PA and VandeVrede, L and Nael, K},
title = {Arterial Spin-Labeling MRI at the Cortical-CSF Interface: A Novel Biomarker in Alzheimer Disease.},
journal = {Annals of clinical and translational neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/acn3.70498},
pmid = {42563554},
issn = {2328-9503},
abstract = {BACKGROUND/OBJECTIVE: Arterial spin-labeling (ASL) MRI can measure perfusion signal adjacent to CSF spaces and may provide information regarding CSF-adjacent water transport physiology. We developed an automated pipeline to extract cortical-CSF interface (IF) perfusion for comparison between Alzheimer disease (AD) and cognitively normal controls.<br><br>METHODS: In this retrospective study, participants with AD and cognitively normal controls with ASL and 3D T1-weighted MRI were included. Parenchymal cerebral blood flow (CBF) was evaluated globally (whole brain, gray matter, white matter) and across 12 brain regions. IF-perfusion values were quantified using an automated pipeline with tissue segmentation, registration, partial-volume-aware masking, and arterial-signal exclusion. Multivariable sensitivity analysis was performed, adjusting for age, sex, scanner vendor, and acquisition site. Predictive modeling was performed using LASSO-regularized logistic regression with nested repeated stratified cross-validation, and feature contributions were summarized using SHAP.<br><br>RESULTS: A total of 51 patients with AD, age (median: 73&#x2009;years) and 53 cognitively normal subjects (median age: 69) were included. Global CBF did not differ between groups. However, IF-perfusion values were significantly lower in AD (median 4.4, IQR 3.2-4.8) than in controls (median 5.2, IQR 4.5-6.3; p&#x2009;<&#x2009;0.001). In multivariable analysis, AD remained independently associated with lower IF-perfusion after adjustment for age, sex, scanner vendor, and acquisition site (&#x3b2;&#x2009;=&#x2009;-1.88, 95% CI: -3.52 to -0.25; p&#x2009;=&#x2009;0.025). In LASSO-regularized logistic regression model, only IF-perfusion and cuneus-CBF remained as significant contributing features for the prediction of AD&#xa0;probability with the highest contribution from IF. The final model showed mean ROC-AUC 0.81 in the training and AUC of 0.78 in the testing dataset.<br><br>CONCLUSION: ASL-derived IF-perfusion is reduced in AD and may represent a promising imaging marker of altered CSF-adjacent water transport physiology. Further validation against established biomarkers of CSF dynamics and clearance pathways is warranted.},
}
@article {pmid42563724,
year = {2025},
author = {Yun, JE and Choi, S},
title = {Expanding the health belief model on dementia knowledge, fear, and preventive behaviors among older adults in Korea: a cross-sectional descriptive study.},
journal = {Journal of Korean biological nursing science},
volume = {27},
number = {1},
pages = {60-71},
pmid = {42563724},
issn = {2383-6423},
abstract = {PURPOSE: This study aimed to expand the health belief model by incorporating dementia knowledge and fear and to assess the effects of these variables on dementia prevention behaviors among older adults.<br><br>METHODS: In total, 199 elderly individuals from 10 senior centers in Korea completed a structured questionnaire assessing characteristics, dementia knowledge, fear, health beliefs, and prevention behaviors. Measures included the Alzheimer's Disease Knowledge Scale, the Korean version of the Fear of Alzheimer's Disease Scale, and the Korean version of the Motivation to Change Lifestyle and Health Behavior for Dementia. Hierarchical polynomial regression was conducted to examine the impact of integrating dementia knowledge and fear into the health belief model.<br><br>RESULTS: Hierarchical polynomial regression across four models revealed significant effects of various factors on dementia prevention behaviors, explaining 12%-36% of the variance. Perceived barriers significantly decreased dementia prevention behaviors, while higher levels of self-efficacy and cues to action had a positive influence. Additionally, a nonlinear relationship was identified between dementia knowledge and prevention behaviors, with the positive impacts of increased knowledge potentially diminishing beyond a certain point.<br><br>CONCLUSION: Our findings underscore the necessity of modifying the health belief model to integrate dementia knowledge and fear, which play critical roles in shaping preventive behaviors among older adults. Future investigations should examine the optimal level of dementia knowledge to promote these behaviors and elucidate the intricate relationship between knowledge and actions.},
}
@article {pmid42563959,
year = {2026},
author = {Liu, Y and Yi, M and Tang, C and Wang, T and Li, X},
title = {MEOX2: a homeobox transcription factor with multifaceted biological functions and broad disease associations.},
journal = {Frontiers in cell and developmental biology},
volume = {14},
number = {},
pages = {1895187},
pmid = {42563959},
issn = {2296-634X},
abstract = {The mesenchymal homeobox transcription factor MEOX2 is recognized for its roles in development and homeostasis, but the full landscape of its complex and often contradictory functions in human diseases, along with its potential unifying regulatory logic, remains to be systematically elucidated. This Review synthesizes current evidence to provide a comprehensive overview of MEOX2's widespread roles in both neoplastic and non-neoplastic diseases. MEOX2 is remarkably context-dependent: it acts as an oncogene in glioblastoma and lung cancer, but as a tumour suppressor in breast cancer, hepatocellular carcinoma and other tumour types. Its dysregulation is also linked to neurovascular deficits in Alzheimer disease (AD), cardiovascular disorders, metabolic fibrosis and developmental malformations. This functional versatility stems from MEOX2's role as a key signalling integrator, subject to fine-tuned regulation by epigenetic mechanisms, non-coding RNA networks and core pathways including PI3K/AKT, ERK and Hedgehog (Hh). Given the strong association between MEOX2 expression and clinical outcomes, it has emerged as a potential diagnostic and prognostic biomarker for several diseases. Intervention strategies targeting MEOX2 and its regulatory networks show translational promise. This Review proposes a conceptual framework placing MEOX2 as a 'cross-disease core regulatory node', systematically delineates its complex disease associations and molecular mechanisms, and charts a course for the future development of precision medicine strategies targeting MEOX2.},
}
@article {pmid42564156,
year = {2026},
author = {Ali, N and Chakbazof, N and Ghasem Pour, S and Contreras, L and Estrada, J and Alexander, GE and Raichlen, DA and Yassine, HN},
title = {APOE ε4, physical activity, and the brain: a review of systematic reviews.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1798639},
pmid = {42564156},
issn = {1663-4365},
abstract = {BACKGROUND: Physical activity (PA) is often proposed as a modifiable strategy to reduce cognitive decline and dementia risk, particularly among individuals at elevated genetic risk for Alzheimer's disease (AD). However, it remains unclear whether the existing literature tests PA at the disease stage and in the populations most likely to show benefit.<br><br>OBJECTIVE: This umbrella review evaluated whether associations between PA and cognitive, fluid biomarker, neuroimaging, and vascular/metabolic outcomes differ by apolipoprotein E &#x3b5;4 (APOE &#x3b5;4) genotype across stages of cognitive aging, with particular attention to how study design and baseline cognitive status shape interpretation of the evidence.<br><br>METHODS: Systematic reviews and meta-analyses were screened for primary studies examining PA in adults classified by baseline cognitive status as cognitively unimpaired, mild cognitive impairment (MCI), or dementia. Primary studies reporting APOE &#x3b5;4-stratified outcomes were extracted and qualitatively synthesized by outcome domain, cognitive stage, and study design.<br><br>RESULTS: Of 2,100 records identified, seven systematic reviews met inclusion criteria, yielding 68 unique primary studies. Favorable associations between PA and cognitive, biomarker, neuroimaging, and vascular/metabolic outcomes were most often reported in observational studies of younger or cognitively unimpaired adults. Several studies suggested stronger associations among APOE &#x3b5;4 carriers, including midlife cognitive associations, neuroimaging markers, and vascular/metabolic outcomes such as lipid profiles. In contrast, randomized controlled trials were few, generally enrolled older adults with MCI or dementia, included small APOE &#x3b5;4 subgroups, and reported largely null or mixed genotype-specific effects.<br><br>CONCLUSION: The current evidence does not establish a definitive APOE &#x3b5;4-specific preventive effect of PA. Future studies may be most informative if they target earlier-stage, low-active, or metabolically at-risk APOE &#x3b5;4 carriers using objective PA measures and proximal vascular, metabolic, imaging, or blood-based biomarker outcomes.},
}
@article {pmid42564234,
year = {2026},
author = {Macías, M and Escriche, E and Molina, M and Esnaola, I and Jiménez, A and Razquin-Sola, S and Roldan, M and Urdánoz-Casado, A and Sobrino, N and Fernández, C and Rubio, I and Aspra, D and Jáuregui, C and Muñoz, R and Herrera, M and Mendioroz, M},
title = {Association of acute-phase plasma pTau217 levels with long-term post-stroke cognitive impairment.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1839662},
pmid = {42564234},
issn = {1663-4365},
abstract = {BACKGROUND: Post-stroke cognitive impairment (PSCI) is a common complication affecting stroke survivors, yet early biomarkers for risk stratification remain scarce. Plasma pTau217 has emerged as a specific biomarker for Alzheimer's disease pathology. This study explores whether acute-phase pTau217 levels are associated with PSCI.<br><br>METHODS: We conducted a nested case-control study including 48 patients who developed PSCI within 5 years and 48 age and sex-matched patients as controls without cognitive decline. Plasma pTau217 was measured within 24 h after stroke onset using SIMOA. Statistical analysis included multivariable logistic regression, dose-response assessment via quartile stratification, and ROC curves.<br><br>RESULTS: Plasma pTau217 levels were significantly higher in PSCI cases than controls [0.313 (0.196-0.562) vs. 0.203 (0.126-0.343) pg/mL; p-value < 0.01]. Notably, pTau217 levels were not correlated with stroke severity (NIHSS at baseline) or atrial fibrillation, suggesting that pTau217 may reflect baseline neurobiological vulnerability. In multivariable models, ln-pTau217 levels were independently associated with PSCI risk (OR = 2.28; 95%CI = 1.19-4.37; p-value < 0.05). A significant linear dose-response relationship was observed, with PSCI risk increasing from 29.2% in the lowest quartile to 64.0% in the highest (p-value for trend < 0.05). The biomarker alone showed a significant discriminative capacity for clinically documented PSCI (AUC = 0.660; 95%CI = 0.552-0.768; p-value < 0.01). Furthermore, sex-stratified analysis revealed that the association was primarily driven by females.<br><br>CONCLUSION: Higher acute-phase pTau217 levels were associated with an increased likelihood of clinically documented cognitive impairment during follow-up. These exploratory findings suggest that acute-phase pTau217 may be associated with long-term cognitive outcomes after stroke, although larger prospective studies, integrating additional biomarkers with standardized neuropsychological assessment are needed.},
}
@article {pmid42564239,
year = {2026},
author = {Cretin, B and Philippi, N and Bousiges, O and Dibitonto, L and Blanc, F},
title = {The impact of long-term antiseizure treatment on cognitive decline in late-onset epileptic prodromal Alzheimer's disease: an exploratory study.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1786247},
pmid = {42564239},
issn = {1663-4365},
abstract = {BACKGROUND: The well-documented bidirectional relationship between Alzheimer's disease (AD) and epilepsy suggests that seizures are not merely a complication of AD but may also contribute to disease progression. Emerging evidence indicates that antiseizure medications (ASMs) could potentially slow the disease course and act as disease-modifying agents if initiated early.<br><br>OBJECTIVES: We investigated the long-term cognitive and functional effects of ASMs when introduced at the prodromal stage of AD.<br><br>METHODS: Twenty-two sporadic epileptic prodromal AD patients (epADs) and 21 matched subjects without epilepsy (nepADs) were followed for a median of 7&#x202f;years. Baseline cognition, daily functioning, clinical/paraclinical features, and pharmacological profiles were compared. Annual assessments included cognition, pharmacological burden, and functional impairment.<br><br>RESULTS: At the final follow-up, epADs evidenced more preserved cognition than nepADs, reflecting a significantly slower annual rate of cognitive decline (-1.2&#x202f;&#xb1;&#x202f;0.9 vs. -2.7&#x202f;&#xb1;&#x202f;2.4 points/year on the MMSE score, respectively; p =&#x202f;0.01). They were also less likely to require neuroleptics (9.1% vs. 47.6%, p&#x202f;<&#x202f;0.01) or memantine (0% vs. 28.6%, p&#x202f;<&#x202f;0.01). However, epADs and nepADs had the same proportion of Alzheimer's dementia at the final follow-up visit (90.9% vs. 90.5%, p&#x202f;=&#x202f;0.96). Despite being significant, these results had low statistical power due to our small sample size and should be considered exploratory.<br><br>CONCLUSION: Our findings support the idea that early ASM treatment may attenuate cognitive decline in sporadic prodromal AD patients with comorbid epilepsy. However, these benefits were not accompanied by a lower dementia rate at the final follow-up visit, suggesting that ASMs alone are insufficient for sustained disease modification. Combinatorial therapeutic strategies may be needed to achieve long-term neuroprotection in AD.},
}
@article {pmid42564294,
year = {2026},
author = {Zhao, M and Sui, X and Li, J and Wang, Q and Sun, Y and Zheng, H and Li, B},
title = {Ferroptosis-related biomarkers for diagnosis and mechanistic insights into Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1857642},
pmid = {42564294},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's disease (AD) lacks reliable early diagnostic biomarkers and effective disease-modifying therapies. Ferroptosis has been increasingly implicated in AD pathogenesis; however, ferroptosis-related genes with diagnostic and mechanistic relevance remain insufficiently characterized.<br><br>METHODS: Transcriptomic datasets were obtained from the GEO database and analyzed using differential expression analysis and WGCNA, followed by integration with ferroptosis-related gene sets. Key targets were identified through PPI networks and machine learning approaches, including LASSO regression and random forest. A diagnostic model was constructed and its discriminative performance was assessed across independent datasets by cohort-specific refitting. Functional roles were explored using GSEA, and experimental validation was conducted by qPCR in A&#x3b2;-treated PC12 cells. Potential therapeutic compounds were predicted using the CMAP database.<br><br>RESULTS: A total of 52 ferroptosis-related candidate genes were identified. Among these, three genes, NFKBIA, ATP6V1E1, and SUB1, were consistently selected as core features by machine learning algorithms. A diagnostic model based on these genes demonstrated strong performance in the training cohort (AUC&#x202f;>&#x202f;0.8) and reproducible discriminative ability across external datasets, albeit with cohort-dependent variability. Functional analysis suggested that these genes are involved in pathways related to neuroinflammation, lysosomal activity, and oxidative stress, indicating a potential link between ferroptosis and key pathological processes in AD. qPCR validation confirmed the differential expression trends of these genes. In addition, several candidate compounds, including etomoxir and tubastatin A, were predicted to potentially modulate these pathways.<br><br>CONCLUSION: Three ferroptosis-related genes, NFKBIA, ATP6V1E1, and SUB1, were identified in Alzheimer's disease and showed consistent discriminative ability across multiple cohorts, with links to neuroinflammation, lysosomal function, and oxidative stress. These findings highlight their potential as candidate biomarkers warranting further investigation, although prospective validation in independent cohorts is required to confirm their diagnostic utility.},
}
@article {pmid42564336,
year = {2026},
author = {Chi, M and Zhao, A and Zhang, Y and Fan, L and Wang, Q and Tang, B and Tao, M},
title = {Electroencephalography for early Alzheimer's disease diagnosis: from advanced feature engineering to interpretable ai and clinical translation.},
journal = {Frontiers in psychiatry},
volume = {17},
number = {},
pages = {1819726},
pmid = {42564336},
issn = {1664-0640},
abstract = {OBJECTIVE: This review aims to comprehensively review the methodologies and advancements in using electroencephalography (EEG) for the early diagnosis of Alzheimer's disease (AD), addressing the limitations of traditional diagnostic tools.<br><br>METHODS: We conducted a comprehensive analysis of current research, encompassing the complete EEG analysis pipeline from signal acquisition and preprocessing to feature extraction-including time-frequency and brain network metrics-and the application of machine learning and deep learning algorithms.<br><br>RESULTS: Characteristic EEG alterations, such as spectral slowing and reduced signal complexity, are associated with early AD. Advanced feature extraction combined with intelligent algorithms significantly enhances diagnostic performance, with some studies reporting classification accuracies exceeding 95%. Integration of EEG with multimodal data (e.g., MRI, genetic markers) further improves diagnostic robustness.<br><br>CONCLUSIONS: EEG is a promising, non-invasive, and cost-effective tool for early AD detection in appropriate clinical and research settings. The integration of advanced signal processing with intelligent algorithms can significantly improves diagnostic precision, though clinical translation requires standardized protocols and validation on larger, diverse cohorts.<br><br>SIGNIFICANCE: This work highlights the potential of EEG to facilitate accessible, early-stage AD screening, which is crucial for timely intervention and may contribute to reducing the disease's future socioeconomic burden.},
}
@article {pmid42564343,
year = {2026},
author = {Liu, H and Liu, X and Chen, Y and Pan, M and Fu, Y and Ma, C and Ge, W},
title = {Serum elemental profile-based machine learning models for Alzheimer's disease identification and cognitive score prediction.},
journal = {Neuroprotection (Chichester, England)},
volume = {},
number = {},
pages = {},
pmid = {42564343},
issn = {2770-730X},
abstract = {BACKGROUND: Current diagnostic approaches for Alzheimer's disease (AD) largely rely on cerebrospinal fluid biomarkers and neuroimaging, which may be invasive, costly, and not readily accessible in routine clinical settings. We investigated whether serum elemental profiling combined with machine learning could provide complementary information for AD identification and exploratory cognitive score prediction.<br><br>METHODS: This retrospective cross-sectional study included 874 participants enrolled between 2017 and 2023 from the Brain Aging National Cohort-Peking Union Medical College cohort, comprising 427 cognitively normal controls (NCs) and 447 patients with clinically defined AD. Serum concentrations of 20 elements were quantified by inductively coupled plasma mass spectrometry. Associations between serum element concentrations and AD status were evaluated using age- and sex-adjusted logistic regression models with false discovery rate (FDR) correction. Associations with Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) scores were assessed using linear regression models with FDR correction. Machine learning classification models were developed for AD identification, whereas regression models were developed for exploratory MMSE and MoCA score prediction. Model performance was evaluated in an internal hold-out test set.<br><br>RESULTS: Age did not differ significantly between NC and AD participants (66.4&#x2009;&#xb1;&#x2009;9.9 vs. 67.1&#x2009;&#xb1;&#x2009;9.0 years; t(872)&#x2009;=&#x2009;-1.13, p&#x2009;=&#x2009;0.260), whereas the proportion of women was higher in the AD group than in the NC group (255/447 [57.0%] vs. 211/427 [49.4%]; &#x3c7; [2](1)&#x2009;=&#x2009;5.11, p&#x2009;=&#x2009;0.024). MMSE scores were significantly lower in patients with AD than in NC participants (AD: n&#x2009;=&#x2009;277, median [interquartile range (IQR)]&#x2009;=&#x2009;24 [19-27]; NC: n&#x2009;=&#x2009;427, median [IQR]&#x2009;=&#x2009;30 [30-30]; Mann-Whitney U&#x2009;=&#x2009;3043.5, p&#x2009;<&#x2009;0.001), as were MoCA scores (AD: n&#x2009;=&#x2009;240, median [IQR] = 18.00 [14.00-20.25]; NC: n&#x2009;=&#x2009;427, median [IQR]&#x2009;=&#x2009;30 [30.00-30.00]; Mann-Whitney U&#x2009;=&#x2009;13.5, p&#x2009;<&#x2009;0.001). After adjustment for age and sex, higher serum lead (Pb) and tin (Sn) levels were associated with increased odds of AD (Pb: odds ratio [OR]&#x2009;=&#x2009;4.95, 95% confidence interval [CI]: 3.42-7.37; Sn: OR&#x2009;=&#x2009;1.45, 95% CI: 1.20-1.78), whereas higher serum antimony, nickel, manganese, cobalt, selenium, and calcium levels were associated with lower odds of AD (OR range: 0.50-0.81; all FDR-adjusted p-values&#x2009;<&#x2009;0.05). Among the eight classification models evaluated in the internal hold-out test set, the random forest model showed the highest apparent performance for distinguishing AD from NC, achieving an accuracy of 88% and an area under the receiver operating (AUC) (acharacteristic curv of 0.94. Among the three regression models evaluated, the random forest regression showed the highest apparent performance for cognitive score prediction, yielding the strongest correlations between predicted and observed scores for both MMSE (r&#x2009;=&#x2009;0.48, p&#x2009;<&#x2009;0.001) and MoCA (r&#x2009;=&#x2009;0.62, p&#x2009;<&#x2009;0.001).<br><br>CONCLUSION: Serum elemental profiles combined with machine learning may provide a minimally invasive and accessible complementary approach for AD identification and cognitive assessment.},
}
@article {pmid42564398,
year = {2026},
author = {Shi, P and Wang, S and Zang, Z and Wang, D and Yang, C and Tao, J and Liu, J and Sun, J and Shen, W and Wang, R and Sun, M},
title = {Barrier-to-Autointegration Factor 1: a key regulator of nuclear envelope integrity, genome stability, and disease progression.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1870828},
pmid = {42564398},
issn = {1664-3224},
mesh = {Humans ; *Genomic Instability ; *DNA-Binding Proteins/genetics/metabolism ; Animals ; *Nuclear Envelope/metabolism/genetics ; *Nuclear Proteins/genetics/metabolism ; Disease Progression ; Neoplasms/genetics/pathology/metabolism ; DNA Repair ; Neurodegenerative Diseases/genetics/metabolism ; cGAS-STING Signaling Pathway ; },
abstract = {Barrier-to-Autointegration Factor 1 (BANF1) is a self-associating protein encoded within the q13.1 locus of chromosome 11. It is integral to multiple cellular processes, including cell cycle regulation, chromatin organization, gene expression modulation, nuclear envelope (NE) repair, DNA damage repair (DDR), innate immune function, and viral infection control. While prior investigations have provided preliminary phenotypic and bioinformatic characterizations of BANF1 across various disease states, comprehensive analyses detailing its functional roles and mechanistic underpinnings in diverse pathological contexts remain scarce. In cancer, BANF1 is frequently upregulated, with cancer cells leveraging its functions to preserve NE integrity, inhibit activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) immune pathway, and facilitate epithelial-mesenchymal transition (EMT). These activities contribute to enhanced genomic stability and promote tumor cell proliferation and migration, thereby conferring oncogenic properties. In neurodegenerative diseases, BANF1 is implicated in disease pathogenesis, exemplified by its mediation of glutamate-induced oxidative stress and apoptosis in neuronal cells, as observed in Alzheimer's disease (AD). Additionally, rare mutations in BANF1 are associated with hereditary conditions: the recessive Ala12Thr (A12T) variant causes Néstor-Guillermo progeria syndrome (NGPS), whereas the dominant Gly16Arg (G16R) mutation results in dominant motor neuronopathy. This review further synthesizes recent progress in exploring BANF1 as a therapeutic target, encompassing the development of small-molecule inhibitors, immunomodulatory approaches, and its potential applications in cancer treatment. Overall, this article provides a comprehensive overview of BANF1's structural features, cellular functions, and involvement in disease initiation and progression, with particular emphasis on its expression profiles in malignancies and the therapeutic promise of BANF1-directed interventions.},
}
@article {pmid42564476,
year = {2026},
author = {Allaham, SMI},
title = {Diagnostic Accuracy of MRI-Based Artificial Intelligence Models for Distinguishing Alzheimer's Disease and Mild Cognitive Impairment From Cognitively Normal Controls: A Systematic Review and Meta-Analysis.},
journal = {Dementia and neurocognitive disorders},
volume = {25},
number = {3},
pages = {141-151},
pmid = {42564476},
issn = {2384-0757},
abstract = {Magnetic resonance imaging (MRI)-based artificial intelligence (AI) models are increasingly applied to brain MRI for diagnosing Alzheimer's disease (AD) and mild cognitive impairment (MCI), but their overall diagnostic performance remains unclear. We systematically searched PubMed/MEDLINE, Embase, Web of Science, Scopus, and IEEE Xplore until February 15, 2026, for diagnostic accuracy studies of machine-learning or deep-learning models using structural brain MRI to distinguish AD vs. cognitively normal (CN) controls and MCI or late mild cognitive impairment (LMCI) vs. CN controls. Seven studies met inclusion criteria, contributing five AD vs. CN and two MCI/LMCI vs. CN tasks, predominantly using deep-learning architectures applied to Alzheimer's Disease Neuroimaging Initiative cohorts. For AD vs. CN (five studies), pooled sensitivity was 0.96 (95% confidence interval [CI], 0.93-0.97) and pooled specificity was 0.95 (95% CI, 0.92-0.97), indicating excellent discrimination. For MCI/LMCI vs. CN (two studies), sensitivity was consistently high (0.91-0.93), whereas specificity varied widely (0.54-0.98), limiting the interpretability of pooled estimates. MRI-based AI models therefore show strong performance for established AD but heterogeneous specificity for MCI, underscoring the need for larger, externally validated studies in diverse populations.},
}
@article {pmid42564518,
year = {2026},
author = {Park, J},
title = {Druggable Pathophysiologic Targets in Alzheimer Disease: From Amyloid and Tau to Biomarker-Guided Multimodal Therapy.},
journal = {Dementia and neurocognitive disorders},
volume = {25},
number = {3},
pages = {152-163},
pmid = {42564518},
issn = {2384-0757},
abstract = {Alzheimer disease (AD) is no longer viewed only as a clinical syndrome of memory impairment but as a biological disease continuum driven by interacting amyloid-β, tau, glial, vascular, metabolic, and synaptic mechanisms. This shift has practical therapeutic consequences. Symptomatic agents such as cholinesterase inhibitors and memantine remain useful for selected patients, but they do not directly modify the core neurodegenerative process. In contrast, amyloid-β monoclonal antibodies have provided proof that biomarker-confirmed early AD can be slowed, although the magnitude of clinical benefit is modest, treatment is restricted to carefully selected patients, and amyloid-related imaging abnormalities require structured monitoring. Tau pathology, neuroinflammation, blood-brain barrier dysfunction, mitochondrial and oxidative stress, and impaired proteostasis are therefore increasingly important druggable axes rather than secondary background phenomena. A staged, biomarker-guided druggability framework can evaluate each target by biological proximity to clinical decline, biomarker measurability, therapeutic modifiability, implementation feasibility, and suitability for sequencing or combination therapy. Validated and emerging targets are summarized with emphasis on how biomarkers reshape patient selection and outcome assessment and how anti-amyloid therapy can be integrated with stage-specific interventions targeting tau propagation, glial activation, vascular injury, clearance failure, and metabolic vulnerability. The central conclusion is that AD drug development should move from a single-target rescue model toward biomarker-guided, mechanism-matched, and combination-ready strategies that can be tested earlier in the disease course while maintaining realistic safety and implementation standards.},
}
@article {pmid42564648,
year = {2026},
author = {Lee, S and Woo, SH and Nam, KC and Moon, C and Lee, K and Kim, KK and Kim, HR and Suh, J},
title = {Gait Analysis Using Wearable Sensors in Patients With Alzheimer's Dementia: A Preliminary Report.},
journal = {Dementia and neurocognitive disorders},
volume = {25},
number = {3},
pages = {178-190},
pmid = {42564648},
issn = {2384-0757},
abstract = {BACKGROUND AND PURPOSE: Gait dysfunctions have been frequently observed in patients with Alzheimer's disease (AD). Previous studies have used various methods to assess the gait impairment in AD. Here, we developed a wearable gait sensor, a Smart-insole, which is embedded in shoe insoles. We evaluated whether gait parameters measured using the Smart-insole were associated with cognitive performance in patients with AD.<br><br>METHODS: Participants aged 45-90 years, who were either cognitively unimpaired (CU) or had Alzheimer's disease dementia (ADD) were recruited from a hospital-based outpatient clinic, between January and December 2023. Participants performed three gait tasks (walk straight and turn test, timed up and go test, and ramp and stair test) while wearing the Smart-insole. The association of gait parameters with individual's cognitive status (CU vs. ADD) and cognitive test scores (Mini-Mental State Examination [MMSE] and various domain-specific cognitive tests from the Seoul Neuropsychological Screening Battery, 2[nd] Edition) was assessed.<br><br>RESULTS: Patients with ADD demonstrated decreased gait pace, rhythm, and stability as evidenced by longer task, cycle, and stance times, a higher number of steps, greater variability in swing time, and lower cadence during the gait task. Furthermore, gait parameters showed nominal associations with individual's MMSE score and each cognitive domain score (fronto-executive, memory, and language function).<br><br>CONCLUSIONS: Smart-insole wearable sensors showed exploratory gait-related alterations in patients with ADD. These hypothesis-generating findings suggest that wearable insole-based gait assessment may provide complementary information for characterizing gait and cognitive dysfunction in ADD.},
}
@article {pmid42564689,
year = {2026},
author = {Chen, L and Zhou, X and Zhang, B and Hou, Y and Sun, Y and Peng, D and , },
title = {Thalamic volume alterations mediate glymphatic function and cognitive dysfunction in Alzheimer's disease.},
journal = {Alzheimer's &amp; dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70304},
pmid = {42564689},
issn = {2352-8737},
abstract = {INTRODUCTION: Glymphatic dysfunction is implicated in Alzheimer's disease (AD), but its mechanism remains unclear. This study investigated the associations of the analysis along the perivascular space (ALPS) index, brain reserve, and cognitive outcomes across the AD continuum.<br><br>METHODS: This study enrolled two cohorts from the local hospital (n = 95) and the Alzheimer's Disease Neuroimaging Initiative (ADNI; n = 178). We calculated the diffusion tensor image ALPS to assess the whole-brain glymphatic function and evaluated its associations with cognition and brain structure.<br><br>RESULTS: A higher ALPS index was positively associated with better executive, memory, and language abilities (p < 0.05). A lower ALPS index correlated with thalamic atrophy, involving the anterior, lateral, ventral, and midline thalamic nuclei. Thalamic atrophy mediated the link between glymphatic dysfunction and worse cognition via structural association of full or part mediation.<br><br>CONCLUSIONS: Glymphatic system deterioration correlates with cognitive decline, potentially mediated by thalamic atrophy. The thalamic nuclei may be critical in this pathway.},
}
@article {pmid42564853,
year = {2026},
author = {Zelek, MC and Walker, JQ and Sabbagh, MN},
title = {Management of multimorbidity in the midst of cognitive decline through clinical decision-support software.},
journal = {Alzheimer's &amp; dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70395},
pmid = {42564853},
issn = {2352-8729},
abstract = {INTRODUCTION: Multimorbidity - the coexistence of multiple chronic conditions - is common among older adults with cognitive impairment but is rarely addressed in an integrated manner.<br><br>METHODS: We analyzed 17,915 adults aged 55 to 84 years (8997 receiving uMETHOD clinical decision-support care plans and 8918 from the National Health and Nutrition Examination Survey). The mean age was 69.0 years (SD 7.65; 95% CI: 68.86 to 69.1). Multimorbidity was quantified from diagnoses, labs, medications, vitals, and platform-inferred conditions. Associations with cognitive impairment were modeled using age- and sex-adjusted logistic regression.<br><br>RESULTS: Cognitive impairment was reported in 25.91% of participants (97.5% with &#x2265;2 conditions); each additional condition was associated with higher odds (odds ratio: 1.069; 95% CI: 1.061 to 1.077; p&#xa0;<&#xa0;0.0001). Prominent clusters included vascular-metabolic disorders and micronutrient deficiencies.<br><br>DISCUSSION: Cognitive vulnerability rises stepwise with disease burden. Precision, multimorbidity-aware decision support that integrates multidomain data can align cognitive and systemic care in real-world practice.},
}
@article {pmid42564867,
year = {2026},
author = {Mancy, AS},
title = {SIRT6 signaling as an underexplored mechanistic node in nanoformulation-based neuroinflammation therapy for Alzheimer's disease.},
journal = {Alzheimer's &amp; dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70305},
pmid = {42564867},
issn = {2352-8737},
abstract = {Chronic microglial neuroinflammation is a core driver of Alzheimer's disease (AD). Wei et al. recently reported a blood-brain barrier (BBB)-penetrating, microglia-targeting nanomodulator (Res@TcMNP/ASO) that simultaneously suppressed NF-κB signaling and enhanced NRF2-dependent antioxidant defense in chronically activated microglia, yet the molecular node coupling these two opposing circuits was not identified. In this perspective, drawing on primary literature spanning microglial inflammation, neuronal genome maintenance, tau regulation, and oncology, I propose that sirtuin 6 (SIRT6) is a plausible upstream candidate for this coordinated effect. SIRT6, a NAD[+]-dependent chromatin deacetylase, restrains NF-κB through H3K9 deacetylation at RELA target promoters and, in parallel, deacetylates and stabilizes NRF2 to amplify antioxidant transcription; its decline in the aging and AD brain promotes DNA damage and GSK3-driven tau hyperphosphorylation. Because a microglia-restricted carrier confines pathway modulation to the relevant cell population, this delivery strategy is well matched to a SIRT6-centered mechanism, while the context-dependent, potentially oncogenic nature of systemic SIRT6 activation reinforces the rationale for such restricted delivery. I outline specific loss- and gain-of-function experiments to test whether microglial SIRT6 mediates the dual-pathway effects of Res@TcMNP/ASO, offering a falsifiable hypothesis to guide future mechanistic and therapeutic work.},
}
@article {pmid42564896,
year = {2026},
author = {Kadaba Sridhar, S and Eastman, A and Wilson, P and Mishra, S and Broadbent, C and Truwit, C and Kuang, R and Samadani, U},
title = {Automatic coarse-to-fine AC-PC localization on CT using registration-guided 3D-UNets.},
journal = {Frontiers in neuroinformatics},
volume = {20},
number = {},
pages = {1853412},
pmid = {42564896},
issn = {1662-5196},
abstract = {INTRODUCTION: Automatically localizing the Anterior Commissure (AC) and Posterior Commissure (PC) is foundational for CT-based algorithmic disease screening, yet robust computational methods for this on CT remain lacking. We developed a registration-guided 3D-UNet framework for CT-based AC-PC localization, demonstrating its utility in computing ventriculomegaly features for Normal Pressure Hydrocephalus (NPH) detection.<br><br>METHODS: Framework development and evaluation were on an internal cohort of scans from patients with NPH, Alzheimer's disease, post-traumatic volume loss, and headache (Veterans Affairs [VA]-Cohort, n&#x202f;=&#x202f;427). External validation was on separate datasets (VA-ExtCohort, University of California, Santa Barbara [UCSB]-ExtCohort). AC-PC reference standard definition, model development, and evaluation were on 1 mm[3]-resampled scans.<br><br>RESULTS: On 1-mm[3] resampled scans, test-set AC-PC mean radial errors (MREs) were 1.64/1.49 mm on the VA-Cohort, 2.42/1.79 mm on the VA-ExtCohort (n&#x202f;=&#x202f;40), and 2.31/1.93 mm on the UCSB-ExtCohort (n&#x202f;=&#x202f;43). Notably, the upper limits of the 95% confidence intervals (CIs) for localization errors across all cohorts were well below 3.2 mm; we empirically determined this to be a clinically relevant threshold beyond which the discriminative power of AC-PC-referenced ventriculomegaly features degrades. Ventriculomegaly features assessed using our framework's predictions successfully distinguished NPH from Alzheimer's disease, post-traumatic volume loss, and headache on a chart-verified VA-Cohort subset (n&#x202f;=&#x202f;238) with a test-set Area Under the Receiver Operating Characteristic Curve (AUC) of 0.95, closely matching the performance of features assessed using manual AC-PC localization.<br><br>CONCLUSION: The proposed registration-guided 3D-UNet framework accurately and automatically localizes the AC-PC on CT despite varied structural degeneration, enabling standardized radiological feature computation. This approach can augment neurodegenerative disease screening on CT, the primary modality for elderly patients evaluated for falls and altered mentation.},
}
@article {pmid42564946,
year = {2026},
author = {Gardener, SL and Al Shamsi, HSS and Rainey-Smith, SR and Sohrabi, HR and Taddei, K and Masters, CL and Martins, RN and Binosha Fernando, WMAD and , },
title = {The moderating effect of dietary fiber and protein on the relationship between symptoms of depression and anxiety and cognitive decline.},
journal = {Alzheimer's &amp; dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70292},
pmid = {42564946},
issn = {2352-8737},
abstract = {INTRODUCTION: Depression and anxiety often co-occur with Alzheimer's disease, exacerbating the associated cognitive impairment. This study examined moderating effects of dietary protein and fiber intake on relationships between depressive and anxiety symptoms, and cognitive decline.<br><br>METHODS: Cognitively unimpaired (n = 553; 39.4% male, 70.6 &#xb1; 9.6 years) provided baseline fiber and protein intake, and had repeated cognitive testing and symptoms of depression/anxiety measured (baseline and up to eight follow-ups over 144 months). Moderation and simple slope analyses were employed in the cohort as a whole and following stratification by sex.<br><br>RESULTS: Fiber intake moderated the relationship between change in depressive symptoms and decline in language (&#x3b2; = -0.005, p < 0.001) and Preclinical Alzheimer Cognitive Composite (PACC); scores (&#x3b2; = -0.003, p = 0.010). In males, fiber intake moderated the relationship between change in anxiety symptoms and executive function decline (&#x3b2; = -0.003, p = 0.018), with protein intake moderating change in depressive symptoms and decline in attention (&#x3b2; = 0.006, p = 0.011).<br><br>DISCUSSION: Adequate dietary fiber and protein intake moderated association between depressive and anxiety symptoms and cognitive decline, supporting their potential role within multidomain strategies aimed at maintaining cognitive health in older adults.},
}
@article {pmid42565151,
year = {2026},
author = {Ramireddy, VVS and Shaikh, RG and Pednekar, AR and Tripathi, D and Munde, CT and Wagh, K},
title = {A Systematic Literature Review of Emerging Advances in Neurological Disorders: Diagnostic Innovations, Therapeutic Strategies, and Future Directions.},
journal = {Cureus},
volume = {18},
number = {7},
pages = {e112202},
pmid = {42565151},
issn = {2168-8184},
abstract = {Neurological disorders remain a major clinical burden because they affect cognition, movement, vascular function, behavior, psychological health, and long-term independence. Recent advances in imaging, biomarkers, artificial intelligence, regenerative therapy, immunotherapy, and targeted pharmacology have expanded diagnostic and therapeutic possibilities, yet the evidence remains dispersed across different neurological conditions and study designs. This review aimed to synthesize emerging advances in neurological disorders, focusing on diagnostic innovations, therapeutic strategies, and future clinical directions. A systematic literature review approach was applied using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-based screening principles. Eleven studies were included, covering ischemic stroke, glioblastoma, Alzheimer's disease, multiple sclerosis, Parkinson's disease, motor neuron disease, episodic migraine, transient ischemic attack, and postoperative delirium. Data were extracted on study design, condition, intervention or diagnostic method, comparator, outcomes, and key findings. Risk of bias was assessed using the Risk of Bias 2 (RoB 2) tool for randomized trials, the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) for nonrandomized, uncontrolled, post hoc, feasibility, and biomarker-monitoring studies, and the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) for diagnostic and radiomics studies. Findings showed increasing use of radiomics, circulating tumor DNA, rhythm monitoring, vascular imaging, inflammatory markers, biologics, cell therapy, psychological intervention, and lipid-lowering therapy. Several studies reported promising clinical or biomarker signals, while others clarified treatment limitations in specific disease subtypes. Overall, the findings suggest an emerging shift toward precision-oriented neurology, but larger controlled trials, prospective biomarker validation, standardized outcomes, and longer follow-up are required before routine implementation.},
}
@article {pmid42565245,
year = {2026},
author = {Lynch, SY and Wang, Y and Wang, D and Bachhav, SS and Xiong, H and Boiser, J and Stage, E and Bannon, AW and Graff, O and Florian, H},
title = {A randomized phase 1b/2 trial of ABBV-916 in adults with early Alzheimer's disease.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71715},
doi = {10.1002/alz.71715},
pmid = {42565245},
issn = {1552-5279},
support = {//AbbVie Inc./ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnostic imaging ; Female ; Male ; Double-Blind Method ; Aged ; Amyloid beta-Peptides ; Positron-Emission Tomography ; Dose-Response Relationship, Drug ; Middle Aged ; Aged, 80 and over ; *Antibodies, Monoclonal, Humanized/therapeutic use/pharmacokinetics ; Treatment Outcome ; Biomarkers/blood ; },
abstract = {INTRODUCTION: ABBV-916, an anti-amyloid immunotherapy, was evaluated in patients with early Alzheimer's disease (AD).<br><br>METHODS: This phase 1b/2, double-blind, placebo-controlled study consisted of two stages: multiple ascending dose (Stage A) and dose expansion (Stage B). In Stage A, patients were randomized to one of six planned cohorts to receive intravenous ABBV-916 (10&#xa0;mg to 3000&#xa0;mg) or placebo monthly through week 24. Assessments included amyloid PET, blood-based biomarkers, pharmacokinetics (PK), and safety. Dose selection for Stage B was to be based on results from Stage A.<br><br>RESULTS: One hundred six patients were randomized to ABBV-916 or placebo. The 3000&#xa0;mg dose was reduced to 2000&#xa0;mg and subsequently to 900&#xa0;mg after safety review. Dose-proportional PK were observed, and amyloid reduction was observed over 24&#xa0;weeks at doses &#x2265;300&#xa0;mg. Most adverse events were non-serious amyloid-related imaging abnormalities. The program ended before dose expansion due to business considerations.<br><br>DISCUSSION: Amyloid clearance rate and safety of ABBV-916 were generally comparable to approved anti-amyloid AD therapies.<br><br>NCT05291234.},
}
@article {pmid42565246,
year = {2026},
author = {Kolling, LJ and Wang, R and Gaudencio, GS and Fishbeyn, JS and James, TD and Mason, SM and McCoy, RO and Song, Z and McConnell, IP and Ziemke, K and Janik, KM and Xu, Y and Bierlein-De La Rosa, G and Ismail, S and Marcinkiewcz, CA},
title = {Dorsal raphe tau pathology disrupts sleep-wake orchestration and sleep architecture in a sex-specific manner.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71687},
doi = {10.1002/alz.71687},
pmid = {42565246},
issn = {1552-5279},
support = {//Alzheimer's Association and the Michael J. Fox Foundation for Parkinson's Research: 26BFDN-1576146A/ ; //Iowa Neuroscience Institute Research Program of Excellence (RPOE)/ ; R01 AG070841/AG/NIA NIH HHS/United States ; F32AG084196-01/AG/NIA NIH HHS/United States ; //Pappajohn Biomedical Institute/ ; //University of Iowa/ ; },
mesh = {Animals ; Male ; Female ; *Dorsal Raphe Nucleus/pathology/metabolism ; *tau Proteins/metabolism ; Mice ; Electroencephalography ; *Sleep/physiology ; *Sleep Wake Disorders/pathology/physiopathology/etiology ; *Sex Characteristics ; Serotonin/metabolism ; Alzheimer Disease ; *Tauopathies/pathology ; Wakefulness/physiology ; },
abstract = {INTRODUCTION: Sleep disturbances are frequent symptoms of Alzheimer's disease (AD), mirrored by early pathology in the dorsal raphe nucleus (DRN). Whether early DRN pathology can drive sleep disturbances, and the relative contributions of serotonin (5-HT) and sex, has not been directly tested.<br><br>METHODS: We isolate tau pathology to whole DRN (DRN[Tau]), serotonin neurons of the DRN (5-HT[Tau]), or non-serotonergic neurons of the DRN (non5HT[Tau]). We use longitudinal EEG recordings, in male and female mice, to determine the contributions of DRN neuronal subtypes to sleep disruption within the context of prodromal AD.<br><br>RESULTS: DRN[Tau], 5-HT[Tau], and non5HT[Tau] disrupt sleep architecture. 5-HT[Tau] and non5HT[Tau] further disrupt sleep-wake orchestration and exhibit sex-dependent alterations that coincide with changes in delta wave power.<br><br>DISCUSSION: Tau-mediated sleep dysfunction may be driven by various cellular subtypes of the DRN, are primarily sexually divergent, and may resultant in changes in 5-HT activity and relative spectral brain wave contributions.},
}
@article {pmid42565249,
year = {2026},
author = {Kim, YM and Colcord, K and Sajjadi, SA and Andrews, EJ and Schneider, JA and Kawas, CH and Corrada, MM},
title = {Hormone replacement therapy and its association with LATE-NC in older adults.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71730},
doi = {10.1002/alz.71730},
pmid = {42565249},
issn = {1552-5279},
support = {P30AG072975/NH/NIH HHS/United States ; R01AG17917/NH/NIH HHS/United States ; R01AG067482/NH/NIH HHS/United States ; R01AG042210/NH/NIH HHS/United States ; UCI MIND/WAM 01-2024//Women's Alzheimer's Movement (WAM)/ ; },
mesh = {Humans ; Female ; *Hormone Replacement Therapy ; Male ; Aged, 80 and over ; Aged ; Aging ; Dementia ; TDP-43 Proteinopathies ; },
abstract = {INTRODUCTION: Limbic-predominant age-related transactive response DNA-binding protein 43 (TDP-43) encephalopathy neuropathological change (LATE-NC) is a cause of dementia resembling Alzheimer's disease (AD). The 90+ Study found women using hormone replacement therapy (HRT) two to three decades before death had lower odds of LATE-NC. We attempted to replicate this finding in a different cohort.<br><br>METHODS: Participants (n&#xa0;=&#xa0;2056) included males (n&#xa0;=&#xa0;640) and females (n&#xa0;=&#xa0;1416) aged &#x2265;65 from the Religious Orders Study and Memory and Aging Project with HRT and neuropathology data. We examined the association between HRT and LATE-NC in males and females and between HRT-related and reproductive variables in relation to LATE-NC in females using logistic regression.<br><br>RESULTS: HRT use within 5 years before or after menopause (odds ratio [OR]&#xa0;=&#xa0;0.70, 95% confidence interval [CI]&#xa0;=&#xa0;0.50 to 0.98, p&#xa0;=&#xa0;0.03) or for 8 to 16 years (OR&#xa0;=&#xa0;0.44, 95% CI&#xa0;=&#xa0;0.24 to 0.79, p&#xa0;=&#xa0;0.006) was associated with lower odds of LATE-NC.<br><br>DISCUSSION: This finding identifies a potential factor related to LATE risk and highlights the importance of HRT timing and duration for its potential neuroprotective effects.},
}
@article {pmid37496245,
year = {2024},
author = {Singh, M and Panda, SP},
title = {The Role of Monosodium Glutamate (MSG) in Epilepsy and other Neurodegenerative Diseases: Phytochemical-based Therapeutic Approa-ches and Mechanisms.},
journal = {Current pharmaceutical biotechnology},
volume = {25},
number = {2},
pages = {213-229},
doi = {10.2174/1389201024666230726161314},
pmid = {37496245},
issn = {1873-4316},
mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/chemically induced/metabolism ; *Sodium Glutamate/adverse effects ; Animals ; *Epilepsy/drug therapy/chemically induced/metabolism ; *Phytochemicals/therapeutic use/pharmacology ; Glutamic Acid/metabolism ; },
abstract = {Epilepsy is a common neurological disease affecting 50 million individuals worldwide, and some forms of epilepsy do not respond to available treatments. Overactivation of the glutamate pathway and excessive entrance of calcium ions into neurons are proposed as the biochemical mechanisms behind epileptic seizures. However, the overactivation of neurons has also been associated with other neurodegenerative diseases (NDDs), such as Alzheimer's, Parkinson's, Huntington's, and multiple sclerosis. The most widely used food ingredient, monosodium glutamate (MSG), increases the level of free glutamate in the brain, putting humans at risk for NDDs and epilepsy. Glutamate is a key neurotransmitter that activates nerve cells. MSG acts on glutamate receptors, specifically NMDA and AMPA receptors, leading to an imbalance between excitatory glutamate and inhibitory GABA neurotransmission. This imbalance can cause hyperexcitability of neurons and lead to epileptic seizures. Overuse of MSG causes neuronal cells to become overexcited, which in turn leads to an increase in the flow of Ca[2+] and Na[+] ions, mutations, and upregulation in the enzymes superoxide dismutase 1 (SOD-1) and TDP43, all of which contribute to the development of NDDs. While TDP43 and SOD-1 protect cells from damage, a mutation in their genes makes the proteins unprotective and cause neurodegeneration. Yet to what extent mutant SOD1 and TDP43 aggregates contribute to neurotoxicity is generally unknown. This study is focused on neuroprotective herbal medications that can pass the blood-brain barrier and cure MSGinduced NDDs and the factors that influence MSG-induced glutaminergic, astrocyte, and GABAergic neuron abnormalities causing neurodegeneration.},
}
@article {pmid37537932,
year = {2024},
author = {Semwal, BC and Singh, B and Murti, Y and Singh, S},
title = {Therapeutic Potential of Ascorbic Acid in the Management of Alzheimer's Disease: An Update.},
journal = {Current pharmaceutical biotechnology},
volume = {25},
number = {2},
pages = {196-212},
doi = {10.2174/1389201024666230804102617},
pmid = {37537932},
issn = {1873-4316},
mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Ascorbic Acid/therapeutic use/pharmacology ; Humans ; Animals ; *Antioxidants/therapeutic use/pharmacology ; Oxidative Stress/drug effects ; },
abstract = {BACKGROUND: Ascorbic acid is a potent natural antioxidant that protects against oxidative stress and performs various bodily functions. It is commonly found in fruits and vegetables.<br><br>OBJECTIVE: The manuscript has been written to provide valuable insights into ascorbic acid in managing Alzheimer's disease.<br><br>METHODS: The data has been gathered from web sources, including PubMed, Science Direct, Publons, Web of Science, and Scopus from 2000-2022 using AA, ascorbic acid, Alzheimer's diseases, memory, dementia, and antioxidant keywords.<br><br>RESULTS: In the present manuscript, we have summarized the impact of ascorbic acid and its possible mechanism in Alzheimer's disease by, outlining the information currently available on the behavioral and biochemical effects of ascorbic acid in animal models of Alzheimer's disease as well as its usage as a therapeutic agent to slow down the progression of Alzheimer disease in human beings. Oxidative stress plays a significant role in the advancement of AD. AA is a wellknown antioxidant that primarily reduces oxidative stress and produces protein aggregates, which may help decrease cognitive deficits in Alzheimer's disease. The current paper analyses of ascorbic acid revealed that deficiency of ascorbic acid adversely affects the central nervous system and leads to cognitive defects. However, the results of clinical studies are conflicting, but some of the studies suggested that supplementation of ascorbic acid improved cognitive deficits and decreased disease progression.<br><br>CONCLUSION: Based on clinical and preclinical studies, it is observed that ascorbic acid supplementation improves cognitive deficits and protects the neurons from oxidative stress injury.},
}
@article {pmid42554796,
year = {2026},
author = {Ray, A and Agarwal, K and Jha, S and Singh, AM and Majumder, S and Lodh, E and Chowdhury, T and , },
title = {miRNA-mRNA Interaction Network Analysis in Alzheimer's Disease for Biomarker Discovery.},
journal = {Journal of molecular neuroscience : MN},
volume = {76},
number = {3},
pages = {},
pmid = {42554796},
issn = {1559-1166},
mesh = {*Alzheimer Disease/genetics/metabolism ; *MicroRNAs/genetics/metabolism ; Humans ; *RNA, Messenger/genetics/metabolism ; *Gene Regulatory Networks ; Biomarkers/metabolism ; Transcriptome ; },
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by widespread dysregulation of gene expression and regulatory pathways. MicroRNAs (miRNAs) act as key post-transcriptional regulators by modulating messenger RNAs (mRNAs), and their disruption can influence synaptic function, neuroinflammation, and neuronal survival. In this study, we present a transcriptomic-driven framework in which differentially expressed genes (DEGs) are identified from gene expression data and integrated with curated miRNA-target interaction databases to infer putative AD-associated miRNA-mRNA regulatory signatures and potential candidate biomarkers. Transcriptomic and clinical data were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI), and the GEO dataset GSE48552 was used as supplementary support to assess the consistency of observed transcriptomic patterns. Using an exploratory differential expression threshold with Welch's t-test and FDR correction, 123 candidate dysregulated genes (34 up-regulated, 89 down-regulated) were identified between AD and cognitively normal controls. To further assess robustness, threshold-sensitivity and cross-method concordance analyses were conducted, supporting the presence of a reproducible core transcriptional signal within the broader discovery-level DEG set. Experimentally validated and predicted miRNA-target interactions were integrated using miRTarBase, yielding 1,669,089 miRNA-gene interactions involving 3,055 unique miRNAs, with strong enrichment toward down-regulated gene targeting. Functional enrichment analysis revealed convergence of miRNA-regulated genes on synaptic signaling, neuronal communication, intracellular transport, apoptosis, oxidative stress, and PI3K-Akt/MAPK-related pathways. A bipartite putative miRNA-mRNA regulatory network (2,207 nodes connected by 11,437 edges, including 2,104 miRNAs and 103 significant genes) was constructed and analyzed using centrality metrics, prioritizing candidate hub genes, including PBX1 and KREMEN1, which were subsequently interpreted in the context of neuronal transcriptional regulation, Wnt-related signalling, synaptic vulnerability, and AD-associated pathway enrichment. Finally, supervised machine learning models trained on selected molecular features showed discriminative performance in the held-out test set, with Random Forest, Gradient Boosting, and LightGBM achieving the highest ROC-AUC values, indicating strong capability in distinguishing AD from control samples. Overall, the framework provides a biologically interpretable strategy for biomarker discovery, prioritizing AD-associated candidate biomarkers and putative regulatory interactions while highlighting targets for future experimental and clinical validation.},
}
@article {pmid42554848,
year = {2026},
author = {Neha, and Aran, KR},
title = {Epitranscriptomic imprints on glial cell polarization: METTL3/IGF2BP2 axis as a driver of neurodegeneration in Alzheimer's disease.},
journal = {Psychopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42554848},
issn = {1432-2072},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder involving synapse dysfunction, neuronal death and disorientation of cognitive processes that are caused by the accumulation of amyloid-β (Aβ) along with aberrant phosphorylation of tau. Aberrant proteolytic processing of amyloid precursor protein (APP) promotes Aβ production, which is pro-oxidant, activates microglia, and promotes chronic neuroinflammation. In parallel, neurofibrillary tangle formation, microtubule destabilisation, and impaired axonal transport are the consequences of pathological tau phosphorylation, which together are associated with accelerated neuronal degeneration. Recent findings implicate epitranscriptomic Dysregulation as an important, but understudied, component of AD pathobiology. In particular, emerging evidence suggests that the expression and activity of METTL3 are dynamically regulated throughout the course of AD, with up- or down-regulation at different disease stages, in specific brain regions, and across cell types, indicating that METTL3 signalling is dysregulated rather than uniformly increased or decreased in AD pathogenesis. Therefore, the changes in m6A deposition mediated by METTL3 could be different in various pathological contexts and cell types, with different downstream consequences in terms of neuronal survival, glial activation and inflammatory signalling. Context-dependent dysregulation of this regulatory axis drives a pronounced elevation in important pro-inflammatory mediators and promotes pyroptosis, including NLRP3, IL-1β, and STAT3, thereby enhancing glial activation, inflammasome assembly and caspase-dependent neuronal death. Integrating the Ab-mediated pathology, tau-mediated cytoskeletal dysfunction and chronic neuroinflammation, the METTL3/IGF2BP2 pathway defines a convergence point that helps break down neuronal homeostasis and plasticity. This review compiles new mechanistic truths of how m[6]A-dependent RNA regulation contributes to the progression of AD and discusses therapeutic opportunities of METTL3/IGF2BP2 axis targeting for novel RNA-based therapies for neurodegenerative disease.},
}
@article {pmid42554889,
year = {2026},
author = {Shi, C and Liu, Y and Zhu, Y},
title = {DNA Sensing Pathways in Innate Immunity: Implications for Alzheimer's Disease Progression and Therapy.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42554889},
issn = {1559-1182},
mesh = {Humans ; *Alzheimer Disease/immunology/therapy/pathology ; *Immunity, Innate/immunology ; Animals ; *Disease Progression ; *Signal Transduction ; Innate Immunity Recognition ; *DNA/metabolism/immunology ; cGAS-STING Signaling Pathway ; Toll-Like Receptor 9/metabolism ; Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase ; },
abstract = {DNA sensors are emerging regulators of innate immune activation in Alzheimer's disease (AD). In addition to detecting microbial DNA, these pattern-recognition receptors can respond to cytosolic or endosomal self-DNA generated by DNA damage, mitochondrial dysfunction, impaired DNA repair, cellular stress, or neuronal injury. Aberrant activation of DNA-sensing pathways may amplify neuroinflammation through type I interferon (IFN-I) signaling, inflammasome activation, pyroptosis, and microglial dysfunction, thereby contributing to amyloid pathology, tau-related inflammation, synaptic loss, and cognitive decline. In this review, we summarize current evidence linking major DNA sensors, including cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING), absent in melanoma 2 (AIM2), toll-like receptor 9 (TLR9) to AD pathogenesis. We emphasize the strongest available evidence for cGAS-STING and AIM2, discuss the context-dependent roles of TLR9, and highlight less-established sensors requiring further validation. Finally, we evaluate therapeutic strategies targeting DNA-sensing pathways, including pathway inhibition and controlled immune activation, and discuss translational challenges such as blood-brain barrier penetration, off-target effects, dose dependency, and disease-stage-specific modulation.},
}
@article {pmid42554922,
year = {2026},
author = {Fang, Y and Zhou, R},
title = {Two-stage deep learning framework for the restoration of incomplete-ring PET images.},
journal = {Medical &amp; biological engineering &amp; computing},
volume = {},
number = {},
pages = {},
pmid = {42554922},
issn = {1741-0444},
support = {12175212//Innovative Research Group Project of the National Natural Science Foundation of China/ ; },
abstract = {Positron Emission Tomography (PET) is an important molecular imaging tool widely used in medicine. Traditional PET systems rely on complete detector rings for full angular coverage and reliable data collection. However, incomplete-ring PET scanners have emerged due to hardware failures, cost constraints, or specific clinical needs. Standard reconstruction algorithms often suffer from performance degradation with these systems because of reduced data completeness and geometric inconsistencies. We present a two-stage deep-learning framework that, without incorporating any time-of-flight (TOF) information, restores high-quality images from data with about 50% missing coincidences-double the loss levels previously addressed by CNN-based methods. The pipeline operates in two stages: a projection-domain Attention U-Net first predicts the missing sections of the sinogram by leveraging spatial context from neighbouring slices, after which the completed data are reconstructed with OSEM algorithm and passed to a cascaded U-Net &amp; warm-start diffusion model for image refinement. This module starts the reverse diffusion process from the U-Net coarse prediction rather than pure Gaussian noise. Using 613 simulated brain volumes from real scans (196 healthy brain samples, 217 Alzheimer's disease samples, and 200 Mild Cognitive Impairment samples), the results show that our model successfully preserves most anatomical structures and tracer distribution features with PSNR of 38.18 to 38.59 dB and SSIM of 0.9904 to 0.9925. Our two-stage deep-learning framework effectively restores high-quality PET images from over 50 % incomplete-ring data, achieving near-complete anatomical fidelity and robust performance without requiring TOF information.},
}
@article {pmid42554925,
year = {2026},
author = {Lin, K and Sachdev, PS and Jiang, J and , },
title = {The Associations of cerebral blood flow and white matter hyperintensities with tau and amyloid-beta across the Alzheimer's disease spectrum.},
journal = {Brain imaging and behavior},
volume = {20},
number = {4},
pages = {},
pmid = {42554925},
issn = {1931-7565},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/physiopathology/metabolism/pathology ; *tau Proteins/metabolism ; *Amyloid beta-Peptides/metabolism/blood ; *White Matter/diagnostic imaging/pathology/metabolism ; Female ; *Cerebrovascular Circulation/physiology ; Male ; Cross-Sectional Studies ; Positron-Emission Tomography ; Aged ; Magnetic Resonance Imaging ; Brain/diagnostic imaging/pathology/metabolism ; Longitudinal Studies ; Aged, 80 and over ; Perfusion Magnetic Resonance Imaging ; Biomarkers/blood ; },
abstract = {Although the associations between cerebrovascular dysfunctions and Alzheimer's disease are increasingly appreciated, the relationship of cerebral blood flow and white matter hyperintensities with tau and amyloid-β pathology remains unclear, particularly in the longitudinal context. This study investigated cross-sectional and longitudinal associations of cerebral blood flow and white matter hyperintensities with tau and amyloid-β pathology using multimodal imaging and blood biomarkers in 179 participants from the ADNI3 cohort. Participants underwent structural (T1-weighted, T2-weighted FLAIR) and arterial spin labelling perfusion MRI, tau and amyloid-β PET, and plasma assay tests for amyloid-β 42, amyloid-β 40, and phosphorylated tau-217. Tau from PET was negatively associated with cerebral blood flow both cross-sectionally and longitudinally in the posterior brain, independent of amyloid-β quantified from PET. Higher white matter hyperintensities volumes were associated with higher levels of tau and amyloid-β at baseline, but the associations were significantly attenuated after further adjusting for amyloid-β and tau, respectively. Plasma amyloid-β 42/40 ratio was negatively associated with white matter hyperintensity volumes both cross-sectionally and longitudinally. In conclusion, tau pathology showed spatially specific associations with cerebral hypoperfusion, independent of amyloid-β, particularly in posterior regions. The attenuation of associations of white matter hyperintensities with amyloid-β and tau after adjustment may reflect shared disease-related variance rather than distinct independent effects.},
}
@article {pmid42554945,
year = {2026},
author = {Yang, S and Li, Y and Guo, Y and Li, Y and Li, M and Li, H and Zhang, Y},
title = {GPR146 Deficiency Enhances Microglial Phagocytosis and Blood-Brain Barrier-Associated Markers in an Acute Amyloid-β Model.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42554945},
issn = {1559-1182},
mesh = {Animals ; *Blood-Brain Barrier/metabolism/pathology ; *Amyloid beta-Peptides/metabolism/toxicity ; *Receptors, G-Protein-Coupled/deficiency/metabolism ; *Microglia/metabolism/pathology ; *Phagocytosis/drug effects ; *Biomarkers/metabolism ; Disease Models, Animal ; Mice, Knockout ; Mice, Inbred C57BL ; Male ; Signal Transduction ; },
abstract = {Dysregulation of brain cholesterol homeostasis is increasingly recognized as a critical driver of Alzheimer's disease (AD) pathogenesis. G protein-coupled receptor 146 (GPR146) has emerged as a pivotal regulator of systemic cholesterol metabolism; however, its role in the central nervous system and AD remains elusive. Here, we report that GPR146 deficiency in mice modulates ERK/PKA signaling without affecting baseline physiology or general behavior. Following intracerebroventricular (i.c.v.) injection of amyloid-β (Aβ)42 oligomers, GPR146 was associated with altered Aβ42-evoked ERK/PKA/Akt signaling both in vivo and in vitro. Mechanistically, Gpr146 ablation potentiated microglial Aβ phagocytosis, which correlated with the transcriptional upregulation of phagocytic receptors, including TREM2, GPR34, P2Y6, and CR3, alongside increased expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6). Moreover, GPR146 deficiency was linked to elevated levels of blood-brain barrier (BBB)-associated markers Cldn-5 and Glut-1 protein levels, while attenuating Aβ‑induced inflammatory responses in brain endothelial cells. At the metabolic level, GPR146 knockout modulated the expression of key enzymes governing glucose (GLUT1, GLUT3, G6PD, PFK, HK) and lipid (HMGCS1, ACACA, FASN, SCD1) metabolism and markedly reduced Aβ‑elicited lipid droplet accumulation in the cortex and hippocampus. Collectively, our findings establish GPR146 as a novel neurometabolic regulator whose deficiency correlates with enhanced Aβ phagocytosis, maintenance of BBB-associated proteins, and altered cerebral metabolism, thereby presenting a potential therapeutic axis for early AD intervention.},
}
@article {pmid42554959,
year = {2026},
author = {Welsh, TJ and Chen, Y and Kennelly, SP and Quinn, TJ and Religa, D and Shenkin, SD and Soysal, P and Roitto, HM},
title = {From memory clinics to Brain Health Services: implications for older adults and the future of cognitive care in Europe.},
journal = {European geriatric medicine},
volume = {},
number = {},
pages = {},
pmid = {42554959},
issn = {1878-7649},
abstract = {AIM: To explore the implications of transitioning from traditional memory clinics to Brain Health Services (BHS) for older adults, and to advocate for a geriatric-informed, equitable, and function-oriented approach to brain health care.<br><br>METHODS: This perspective article draws on discussions within the EuGMS Brain Health and Dementia Specialist Interest Group and relevant literature to examine the implications of emerging Brain Health Services for older adults.<br><br>RESULTS: The emergence of Brain Health Services represents a significant shift in cognitive healthcare, moving beyond traditional memory clinic models focussed primarily on dementia diagnosis and management towards prevention, risk reduction, and maintenance of cognitive function. Potential benefits include earlier engagement with cognitive care, multidomain lifestyle interventions, reduction of stigma surrounding dementia, and facilitation of access to emerging disease-modifying therapies. However, substantial challenges remain. Biomarker-driven approaches may overemphasise Alzheimer's disease-centric frameworks despite the high prevalence of mixed pathologies and complex comorbidity in older adults. Ethical concerns surrounding risk disclosure, inequitable access, and resource allocation are also considerable, particularly if services disproportionately benefit younger, healthier, or socioeconomically advantaged populations.<br><br>CONCLUSIONS: Brain Health Services should be reframed through a gerontologically informed lens that prioritises function, independence, quality of life, and equitable access alongside prevention. Integration with comprehensive geriatric assessment and existing older persons' care pathways is essential. Future research should focus on pragmatic real-world evaluation, inclusive outcome measures, and personalised approaches that account for heterogeneity in ageing. Ultimately, the success of BHS will depend on their ability to support healthy ageing while remaining responsive to the lived realities and priorities of older adults.},
}
@article {pmid42554972,
year = {2026},
author = {Wang, X and Tao, Y and Li, Q and Yang, J and Liu, Q and Xu, A},
title = {The Therapeutic Efficacy of Gold Needle "Regulating Spirit" Acupuncture for Amnestic Mild Cognitive Impairment: Protocol for a Randomized Controlled Trial.},
journal = {JMIR research protocols},
volume = {15},
number = {},
pages = {e96326},
pmid = {42554972},
issn = {1929-0748},
mesh = {Humans ; *Cognitive Dysfunction/therapy ; *Acupuncture Therapy/methods/instrumentation ; *Needles ; *Gold/therapeutic use ; Aged ; Female ; Male ; Middle Aged ; Treatment Outcome ; Biomarkers/blood ; },
abstract = {BACKGROUND: Amnestic mild cognitive impairment (aMCI), the predominant subtype of mild cognitive impairment, carries the highest risk of progression to Alzheimer disease among all mild cognitive impairment subtypes. Currently, clinical practice lacks an established, authoritative treatment method for this condition. Prior clinical evidence indicates acupuncture may enhance cognitive function in individuals with mild cognitive impairment. Further clinical evidence suggests Gold Needle therapy demonstrates significant therapeutic effects for challenging and refractory conditions; however, a critical gap exists: no clinical trials currently ascertain whether Gold Needle therapy surpasses conventional acupuncture in treating aMCI. This trial aims to rigorously evaluate the therapeutic efficacy and safety of the Gold Needle "Regulating Spirit" method for clinical symptoms in patients with aMCI, alongside investigating its underlying imaging and biochemical mechanisms.<br><br>OBJECTIVE: This proposed study aims to identify imaging and laboratory biomarkers for the early diagnosis of aMCI, thereby providing a theoretical foundation for clinical practice.<br><br>METHODS: This randomized controlled trial will recruit 90 patients diagnosed with aMCI from the Beijing Hospital of Traditional Chinese Medicine, affiliated with Capital Medical University, alongside 20 healthy volunteers. The 90 patients with aMCI will be randomly allocated to 1 of 3 groups: the Gold Needle "Regulating Spirit" group uses gold-based needles, the general acupuncture "Regulating Spirit" group, or a sham acupuncture control group. The Gold Needle "Regulate Spirit" group uses gold-based needles, the general acupuncture "Regulate Spirit" group uses standard needles, and the sham acupuncture group administers Park needles. Participants will undergo 3 sessions per week of their assigned acupuncture or placebo treatment over a continuous 12-week period.<br><br>RESULTS: This study was initiated on September 1, 2023. As of October 30, 2025, 110 eligible participants had been enrolled, and data collection had been completed in full. Data analysis is currently underway, and the preliminary results are expected to be available by June 2025. We hypothesize that, compared with the filiform needle-based mind-regulating acupuncture group, the golden needle-based mind-regulating acupuncture group will demonstrate superior efficacy in improving cognitive impairment. This superiority will be reflected in multiple key outcome measures, including Montreal Cognitive Assessment and Mini-Mental State Examination scores, plasma biomarkers, and functional magnetic resonance imaging findings.<br><br>CONCLUSIONS: We anticipate that by the end of the trial, we will be able to definitively ascertain whether the gold acupuncture needle technique for "regulating spirit" offers a significant advantage in treating aMCI, and further investigate the nature of this therapeutic benefit, to offer a more efficacious intervention for the clinical management of aMCI and the prevention of Alzheimer disease.},
}
@article {pmid42554979,
year = {2026},
author = {Fang, JR and Vogel, AP and Velakoulis, D and Yuan, Y and Nayler, D and Loi, SM and Joubert, L},
title = {Interventions for caregivers of persons with young-onset dementia in hospital environments: A systematic scoping review.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261469822},
doi = {10.1177/13872877261469822},
pmid = {42554979},
issn = {1875-8908},
abstract = {BackgroundCaregivers of patients with young-onset dementia (YOD), most commonly Alzheimer's disease and frontotemporal dementia, face unique challenges balancing employment, childcare, finances, and complex care responsibilities. Tailored interventions delivered in hospital environments may provide timely support and optimize caregiver preparedness, but evidence regarding these interventions remains limited.ObjectiveTo map and synthesize evidence on interventions supporting caregivers of individuals with YOD within hospital environments offering diagnostic services, multidisciplinary care, and opportunities for caregiver engagement. Intervention types, delivery modes, outcomes, and evidence gaps will be highlighted.MethodsA systematic scoping review adhering to PRISMA-ScR guidelines was conducted. Medline, Embase, PsycINFO, EBM Reviews, SocINDEX, CINAHL, and Scopus were searched for studies published up to 2025. Peer-reviewed studies in English describing or evaluating interventions for YOD caregivers were included. Data on study characteristics, intervention type, delivery, outcomes, and key findings were extracted and synthesized narratively.ResultsEight studies met the inclusion criteria. Interventions were largely focused on psychoeducation and support groups. Most studies targeted spouses with few including other caregiver types. Interventions addressed caregiver functions such as task management, safety, information, and caregiver needs related to emotional support and burden reduction, but rarely were both comprehensively addressed. Quantitative outcomes were mixed while qualitative findings consistently reported improved preparedness, support, and coping.ConclusionsEvidence on caregiver interventions in hospital environments is limited and largely exploratory. Future work should embed supports within diagnostic pathways, incorporate structured assessment, tailor interventions by subtype and caregiver role, and use outcome measures sensitive to early, meaningful changes.},
}
@article {pmid42554980,
year = {2026},
author = {Goldstein, FC and Hales, CM and Parker, MW and Trammell, AR and Manzanares, CM and Heldenberg, SC and Hanfelt, JJ and Levey, AI and Lah, JJ},
title = {Performance of the participant self-rating version of the Quick Dementia Rating System in a racially diverse cohort of non-demented older adults.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261471427},
doi = {10.1177/13872877261471427},
pmid = {42554980},
issn = {1875-8908},
abstract = {BackgroundEarly detection of clinical Alzheimer's disease and related dementias is a public health priority. The Clinical Dementia Rating is used for staging but is time intensive. The Quick Dementia Rating System (QDRS) is a brief, self-administered alternative, although studies have focused on informant rather than patient ratings.ObjectiveThis study evaluated the clinical utility of the QDRS Participant Self-Rating version for classifying cognitive status of White and Black/African Americans.MethodsParticipants (79 White, 95 Black/African American) enrolled in the Goizueta Alzheimer's Disease Research Center with Clinical Dementia Rating (CDR) Global scores of 0.0 or 0.5 completed the QDRS. Concordance rates and associations with the Montreal Cognitive Assessment (MoCA) were examined.ResultsAgreement between QDRS and CDR Global scores was 69% (κ = 0.36), and comparable between racial groups. QDRS Sum of Boxes demonstrated moderate correlations with CDR Sum of Boxes for the full sample and each group. Participants classified as impaired on the QDRS had lower MoCA Total and Memory Index scores, with similar effect sizes between racial groups. ROC analyses demonstrated good discrimination of CDR 0.0 versus 0.5 for the overall sample (AUC = 0.789, SE = 0.040, 95% CI = 0.711-0.866) and for White (AUC = 0.792, SE = 0.055, 95% CI = 0.683-0.900) and Black/African American participants (AUC = 0.777, SE = 0.058, 95% CI = 0.663-0.891). Positive predictive value of the QDRS Global score was 50%, and negative predictive value was 85%.ConclusionsThe QDRS Participant Self-Rating version is a clinically useful prescreening tool to rule out cognitive impairment in both White and Black/African American persons with early cognitive impairment.},
}
@article {pmid42554985,
year = {2026},
author = {Sánchez-Juan, P and García-Arcelay, E and Almagro, M and Balasa, M and Piñol-Ripoll, G and Boada, M and Landete, L and Abellan, I and Berbel, A and Espejo, B and Baquero, M and Marin, J and Franco-Macias, E and Villarejo-Galende, A and Viñuela Fernández, F and Feria Vilar, I and Perez-Vieitez, C and Rodríguez-Espinosa, N and Puig-Pijoan, A and Bargay Pizarro, E and Rodríguez-Rodríguez, E and Rodrigo, J and Maurino, J and Manzano, S},
title = {Burden, perception of stigma, and gender differences among informal care partners of individuals with mild cognitive impairment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261474135},
doi = {10.1177/13872877261474135},
pmid = {42554985},
issn = {1875-8908},
abstract = {BackgroundCaring for individuals with mild cognitive impairment (MCI) is increasingly recognized as a significant clinical challenge. However, the latent burden, driven by perceived stigma and gender-specific vulnerabilities, remains poorly characterized during these early stages of cognitive decline.ObjectiveThis study aimed to evaluate the prevalence of care partner strain and affiliate stigma, and to identify independent correlates of psychological distress and protective factors among informal care partners of individuals with MCI.MethodsWe conducted a multicenter, observational, cross-sectional study across 19 memory clinics in Spain. Care partners (n = 196) were evaluated using the Zarit Burden Interview, Affiliate Stigma Scale, and validated instruments assessing resilience, relationship quality, coping strategies, and psychological distress. Multivariate logistic regression models identified independent predictors of burden and stigma.ResultsSignificant care partner strain affected 59.7% of the cohort, while 39.3% perceived themselves as stigmatized. Multivariate analysis revealed that high burden was independently associated with anxiety symptoms (OR = 1.13, p = 0.017) and perceived stigma (OR = 1.07, p = 0.007). High resilience served as the primary determinant protecting the 60.7% of partners who did not report significant stigma (OR = 1.05, p < 0.001). Compared to their male counterparts, female care partners were significantly younger and reported higher levels of burden, anxiety, and stigma.ConclusionsCare partner strain and affiliate stigma are correlated phenomena that emerge long before formal patient dependency. These findings underscore the need for gender-sensitive clinical frameworks and specific interventions that actively strengthen resilience immediately upon MCI diagnosis to mitigate early psychological deterioration.},
}
@article {pmid42554989,
year = {2026},
author = {Qiu, J and Zhang, Y and Shang, Y and Shang, Q and Li, L and Chen, Y and Dai, S and Ai, M and Xi, X and Huang, W and Zhang, J and Liu, X},
title = {Impact of SARS-CoV-2 infection on the progression of Alzheimer's disease: A prospective cohort study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261469118},
doi = {10.1177/13872877261469118},
pmid = {42554989},
issn = {1875-8908},
abstract = {BackgroundSARS-CoV-2 infection is associated with neurological sequelae and may accelerate Alzheimer's disease (AD) progression through neuroinflammation and protein aggregation. However, longitudinal evidence regarding the cognitive impact of COVID-19 in patients with AD remains scarce, and this interaction requires further clarification.ObjectiveTo explore whether COVID-19 accelerates cognitive decline in patients with AD.MethodsA total of 120 participants were enrolled, including 63 in the COVID-19 group and 57 in the non-COVID-19 group. The primary outcomes were disease decline and disease deterioration over three months, assessed using CDR-SB. Disease deterioration indicated clinically meaningful worsening, whereas disease decline captured subtler progression. Multivariable logistic regression adjusted for demographic, clinical, lifestyle, genetic, and disease severity factors. Overlap-Weighted Propensity Score Matching was additionally performed to reduce confounding during the 3-month follow-up.ResultsCOVID-19 significantly increased the risk of disease decline (OR = 10.39, 95% CI:3.87 to 27.87, p < 0.001) and disease deterioration (OR = 10.37, 95% CI: 2.71 to 39.65, p = 0.001). APOE ε4 carrier status was associated with a higher risk of deterioration (OR = 1.72), while those with unknown APOE status exhibited an even greater risk (OR = 5.20, 95% CI:1.32 to 20.53, p = 0.019). Secondary analyses confirmed that COVID-19 patients experienced significantly greater increases in CDR-SB scores compared to non-COVID-19 patients.ConclusionsSARS-CoV-2 infection was associated with greater short-term cognitive worsening over a three-month period in patients with AD, underscoring its potential public health relevance and the need for early surveillance to guide timely clinical management.},
}
@article {pmid42554990,
year = {2026},
author = {Baird, KT},
title = {Thermodynamic impedance mismatch in neurodegeneration: A biophysical framework for the prediction of amyloid-related imaging abnormalities.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261474112},
doi = {10.1177/13872877261474112},
pmid = {42554990},
issn = {1875-8908},
abstract = {Amyloid-related imaging abnormalities (ARIA) represent a significant iatrogenic complication of anti-amyloid monoclonal antibody therapies. To address this, we propose the Impedance Mismatch Theory as a theoretical framework and hypothesis, reframing neurodegeneration as a network-level thermodynamic failure characterized by localized thermal runaway (Neural Physiological Load Index (NLI) greater than or equal to 1.0). Within this framework, amyloid-β (Aβ) is modeled not only in its established biological context, but as a potential thermodynamic heat sink and bio-conductive electrical shunt deployed to protect hyper-metabolic neural hubs. Utilizing the Pennes bioheat equation, we formalize the NLI and map its theoretical values to absolute [1]H-magnetic resonance spectroscopy thermometry signatures. Our model suggests that clearing Aβ in the setting of unresolved energetic mismatch could contribute to localized mechanical and thermal instability. We hypothesize that these upstream physical dynamics precipitate the downstream inflammatory cascades clinically observed as ARIA. If validated, these theoretical considerations suggest that effective disease modification may require thermodynamic normalization as a prerequisite to, or in parallel with, plaque clearance.},
}
@article {pmid42554993,
year = {2026},
author = {Palmer, AM and Francis, PT and Sims, NR},
title = {Fifty years of the cholinergic hypothesis: David Bowen's legacy in Alzheimer's disease.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag261},
pmid = {42554993},
issn = {1460-2156},
}
@article {pmid42555084,
year = {2026},
author = {Knox, S and Dooley, M and Cutty, M and Simpson, KN},
title = {Beyond binary classification: A tiered claims-based algorithm for Alzheimer's disease and related dementias in Medicare.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261471874},
doi = {10.1177/13872877261471874},
pmid = {42555084},
issn = {1875-8908},
abstract = {BackgroundAdministrative data is widely used to identify Alzheimer's disease and related dementias (ADRD), yet commonly applied algorithms (e.g., the Chronic Conditions Warehouse [CCW] algorithm) rely on binary classification that may obscure heterogeneity in likelihood and care needs.ObjectiveTo examine whether a tiered ADRD classification algorithm using Medicare home health data yields cohorts with more clearly distinguishable clinical and sociodemographic characteristics compared with the CCW-27 algorithm.MethodsWe conducted a retrospective cohort study of 2,252,040 Medicare Fee-for-Service beneficiaries with home health encounters. The novel algorithm applied episode-level and individual-level criteria to classify individuals into one of three mutually exclusive groups (ADRD-highly likely, ADRD-possible, ADRD-unlikely). Using descriptive statistics, we compared socio-demographic characteristics and OASIS-based cognitive and functional measures across groups defined by the novel algorithm and the CCW-27 algorithm.ResultsThe CCW-27 algorithm classified 34.3% of individuals as ADRD-positive, whereas the novel algorithm classified 7.6% as ADRD-highly likely, 29.3% as ADRD-possible, and 63.1% as ADRD-unlikely. The ADRD-highly likely group demonstrated greater cognitive and functional impairment than the CCW-27 ADRD-positive group. Discordant classifications revealed important sociodemographic differences: individuals classified as ADRD-highly likely by the novel algorithm but ADRD-negative by the CCW-27 algorithm were more frequently Medicare/Medicaid dual-eligible (52.9%) and non-White (39.5%) than concordant and alternative discordant groups.ConclusionsA tiered claims-based ADRD classification provides greater resolution than binary approaches and reveals clinically and sociodemographically distinct groups within the Medicare home health population. Such approaches may support more nuanced characterization of ADRD when clinical gold standards are unavailable.},
}
@article {pmid42555228,
year = {2026},
author = {Kaur, G and Goyal, B},
title = {Leveraging molecular dynamics to unravel the inhibition mechanism of potential β-secretase (BACE1) inhibitors.},
journal = {Physical chemistry chemical physics : PCCP},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6cp01160h},
pmid = {42555228},
issn = {1463-9084},
abstract = {Alzheimer's disease (AD) remains a formidable global health challenge, driving the urgent need for potent and selective therapeutics targeting β-site amyloid precursor protein cleaving enzyme 1 (BACE1), a key enzyme involved in the generation of amyloid-β (Aβ) peptide and a promising target for disease-modifying interventions. In this work, approximately 16 million small molecules from diverse databases were subjected to ligand-based virtual screening (LBVS), using LY3202626 as a reference compound, to identify new potent inhibitors of BACE1. LY3202626 is a highly potent, central nervous system (CNS) penetrant BACE1 inhibitor (IC50 = 0.615 nM) that has progressed to clinical trials, demonstrating efficacy at low doses against BACE1 activity. The lead candidates identified using ensemble molecular docking displayed stronger binding affinities (-11.2 to -9.6 kcal mol[-1]) to BACE1 as compared to LY3202626. Notably, molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) analysis revealed high-affinity binding of ChEMBL3667410 (C1), ChEMBL3667414 (C2), and ChEMBL3976114 (C5) with binding affinities of -32.9 ± 0.8, -33.6 ± 1.8, and -36.1 ± 1.7 kcal mol[-1], respectively, to BACE1 as compared to LY3202626 (-29.9 ± 1.8 kcal mol[-1]). Furthermore, MD simulations demonstrated enhanced structural stability and reduced residual fluctuations in BACE1 on the incorporation of C1, C2, and C5, as compared to apo-BACE1 and BACE1-LY3202626. Interestingly, the conformational snapshots, flap distances, and free energy landscape (FEL) analyses highlighted a closed flap, Val67-Glu77 (non-active) conformation in BACE1-C5 in comparison to an open flap (active) conformation in apo-BACE1, and partial restriction in the access to the active site of BACE1 due to the flap movement noticed in the presence of LY3202626, C1, and C2. Notably, conformational microstate analysis revealed key hydrogen bond interactions of C5 with the 10s loop (Gly11, Gly13), flap residues (Trp76), the catalytic residue (Asp228), Gly230, and Thr231 of BACE1, depicting its high-affinity binding to key residues of BACE1 and its potential as an effective inhibitor of BACE1 activity. The comprehensive in silico methodology in this work illuminated the inhibitory mechanism of LY3202626 and top hit compounds against BACE1 activity for the first time, which, in turn, will be highly valuable in further optimization and structural refinement using various functional group modifications to yield more potent next-generation therapeutic candidates against BACE1 in AD.},
}
@article {pmid42555262,
year = {2026},
author = {Prokopiou, PC and Van Egroo, M and Riphagen, JM and Baillet, M and Ashton, NJ and Janelidze, S and Sperling, RA and Johnson, KA and Blennow, K and Hansson, O and Zetterberg, H and Jacobs, HIL},
title = {Astrocyte reactivity modifies the effects of locus coeruleus norepinephrine-related dysfunction on tau and its impact on cognition.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71703},
pmid = {42555262},
issn = {1552-5279},
support = {WE.03-2019-02//Alzheimer Nederland/ ; R01AG062559/NH/NIH HHS/United States ; R01AG068062/NH/NIH HHS/United States ; R01AG082006/NH/NIH HHS/United States ; R21AG074220/NH/NIH HHS/United States ; R21AG081681/NH/NIH HHS/United States ; R01AG068398/NH/NIH HHS/United States ; A20211016F//BrightFocus Foundation/ ; 101109451//Marie Sk&#x142;odowska Curie Actions/ ; AARF-23-1145963/ALZ/Alzheimer's Association/United States ; ZEN-21-848495/ALZ/Alzheimer's Association/United States ; 2023-00356//Swedish Research Council/ ; 2022-01018//Swedish Research Council/ ; 2019-02397//Swedish Research Council/ ; 2017-00915//Swedish Research Council/ ; 101053962//European Union's Horizon Europe Research and Innovation Program/ ; ALFGBG-71320//Swedish State/ ; ALFGBG-715986//Swedish State/ ; ALFGBG-965240//Swedish State/ ; 201809-2016862//Alzheimer Drug Discovery Foundation (ADDF)/ ; RDAPB-201809-2016615//Alzheimer Drug Discovery Foundation (ADDF)/ ; JPND2021-00694//European Union Joint Programme-Neurodegenerative Disease Research/ ; JPND2019-466-236//European Union Joint Programme-Neurodegenerative Disease Research/ ; //National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre/ ; AF-930351//Swedish Alzheimer Foundation/ ; AF-939721//Swedish Alzheimer Foundation/ ; AF-968270//Swedish Alzheimer Foundation/ ; FO2022-0270//Hj&#xe4;rnfonden, Sweden/ ; 860197//Hj&#xe4;rnfonden, Sweden/ ; FO2017-0243//Hj&#xe4;rnfonden, Sweden/ ; ALZ2022-0006//Hj&#xe4;rnfonden, Sweden/ ; ADSF-21-831376-C//AD Strategic Fund/ ; ADSF-21-831381-C//AD Strategic Fund/ ; ADSF-21-831377-C//AD Strategic Fund/ ; ADSF-24-1284328-C//AD Strategic Fund/ ; //Bluefield Project/ ; //Cure Alzheimer's Fund/ ; UKDRI-1003//UK Dementia Research Institute at UCL/ ; //Olav Thon Foundation/ ; //Erling-Persson Family Foundation/ ; //Stiftelsen f&#xf6;r Gamla Tj&#xe4;narinnor/ ; 860197//European Union's Horizon 2020 Research and Innovation Programme/ ; },
mesh = {*Locus Coeruleus/metabolism/physiopathology/diagnostic imaging ; Humans ; *Astrocytes/metabolism/physiology ; *tau Proteins/blood/metabolism ; Male ; Glial Fibrillary Acidic Protein/blood ; *Norepinephrine/metabolism ; Female ; *Cognition/physiology ; Aged ; *Cognitive Dysfunction/metabolism/physiopathology ; Magnetic Resonance Imaging ; Biomarkers/blood ; },
abstract = {INTRODUCTION: Animal models demonstrated that pharmacologically-induced lesioning of the locus coeruleus (LC), the brain's primary source of norepinephrine, triggered astrocyte reactivity, exacerbating Alzheimer's disease (AD) pathology and cognitive deficits. We examined whether astrocyte reactivity modulates the relationship between LC dysfunction, tau pathology, and cognitive decline in humans.<br><br>METHODS: We combined ultra-high-field LC functional imaging during an affective task with plasma biomarkers of glial fibrillary acidic protein (GFAP) and hyperphosphorylated tau (p-tau), and longitudinal cognitive data from 78 asymptomatic individuals. Associations between LC activity and norepinephrine transporter-enriched LC functional connectivity (LCFC) with p-tau, GFAP, and cognitive decline were examined.<br><br>RESULTS: Lower LC activity and LCFC were related to elevated plasma p-tau217, particularly at elevated GFAP. Lower LC FC was also associated with cognitive decline in individuals with elevated plasma p-tau217 and GFAP.<br><br>DISCUSSION: LC-norepinephrine system dysfunction may contribute to emerging tau pathology and cognitive decline, with astrocytes playing a critical gating role.},
}
@article {pmid42555275,
year = {2026},
author = {Qi, X and Liu, R and Belsky, DW and Tian, Q and Luo, H and Liu, Y and Xu, Z and Langa, KM and Wu, B},
title = {Edentulism, blood-based neurodegenerative biomarkers, and 10-year dementia risk: A mediation analysis in a nationally representative United States cohort.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71731},
pmid = {42555275},
issn = {1552-5279},
support = {R01AG089856/NH/NIH HHS/United States ; //Intramural Research Program of the National Institute on Aging/ ; },
mesh = {Humans ; *Dementia/blood/epidemiology ; Biomarkers/blood ; United States/epidemiology ; Female ; Male ; Glial Fibrillary Acidic Protein/blood ; Amyloid beta-Peptides/blood ; Aged ; *Mouth, Edentulous/epidemiology/blood ; tau Proteins/blood ; Cohort Studies ; Cognitive Dysfunction/blood/epidemiology ; Risk Factors ; Neurofilament Proteins ; },
abstract = {INTRODUCTION: Tooth loss is associated with dementia risk, but mechanisms remain unclear. We examined whether blood-based neurodegenerative biomarkers mediate the edentulism-cognition association.<br><br>METHODS: Among 4238 Health and Retirement Study participants aged 50+, we linked edentulism (2012), biomarkers (neurofilament light chain [NfL], glial fibrillary acidic protein [GFAP], phosphorylated tau-181, and amyloid-&#x3b2; [A&#x3b2;] 42/40; 2016), and 10-year cognitive outcomes (2012-2022).<br><br>RESULTS: Edentulism was associated with higher NfL (&#x3b2;&#xa0;=&#xa0;4.21) and GFAP (&#x3b2;&#xa0;=&#xa0;8.06), but not pTau-181 or A&#x3b2;42/40, and predicted cognitive impairment (hazard ratio [HR] 1.49) and dementia (HR 1.28). GFAP mediated 9.8% and 12.0% of the cognitive impairment and dementia associations, respectively; NfL mediated 9.8% of the dementia association but not cognitive impairment.<br><br>CONCLUSION: In this observational cohort, elevated NfL and GFAP were associated with, and accounted for a small proportion of, the edentulism-cognition association. These associative findings support further study of oral health in dementia prevention but do not establish a causal effect.},
}
@article {pmid42555875,
year = {2026},
author = {Prodan, CI and Yabluchanskiy, A},
title = {The Challenge of Atypical Alzheimer Disease Phenotypes.},
journal = {Neurology},
volume = {107},
number = {5},
pages = {e218533},
doi = {10.1212/WNL.0000000000218533},
pmid = {42555875},
issn = {1526-632X},
}
@article {pmid42555876,
year = {2026},
author = {Shir, D and Corriveau-Lecavalier, N and Jones, DT and Ramanan, VK and Lachner, C and Knopman, DS and Petersen, RC and Josephs, KA and Day, GS and Graff-Radford, J and Graff-Radford, NR},
title = {Eligibility for Anti-Amyloid Therapies in Patients With Biomarker-Confirmed Atypical Alzheimer Disease Phenotypes.},
journal = {Neurology},
volume = {107},
number = {5},
pages = {e218347},
doi = {10.1212/WNL.0000000000218347},
pmid = {42555876},
issn = {1526-632X},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; Female ; Phenotype ; Aged ; Male ; Retrospective Studies ; Biomarkers ; Aged, 80 and over ; *Patient Selection ; Middle Aged ; *Eligibility Determination ; },
abstract = {BACKGROUND AND OBJECTIVES: Clinical trials of anti-amyloid therapies (AATs) for Alzheimer disease (AD) primarily enrolled patients with mildly symptomatic, amnestic predominant presentations. The applicability of eligibility criteria to atypical AD phenotypes, including posterior cortical atrophy (PCA), logopenic variant primary progressive aphasia (lvPPA), dysexecutive AD (dAD), and corticobasal syndrome because of AD (CBS-AD), is unknown.<br><br>METHODS: We conducted a retrospective eligibility analysis of patients with atypical AD evaluated at Mayo Clinic. Theoretical eligibility for AAT was assessed at initial clinical evaluation by applying inclusion and exclusion criteria from landmark clinical trials (Study to Confirm Safety and Efficacy of Lecanemab in Participants With Early Alzheimer's Disease [CLARITY-AD] and the Study of LY3002813 (Donanemab) in Participants With Early Symptomatic Alzheimer's Disease [TRAILBLAZER-ALZ2]) and appropriate use criteria for lecanemab and donanemab. Eligibility percentages and reasons for exclusion were compared across phenotypes.<br><br>RESULTS: The cohort included 184 patients (61.4% female) with biomarker-confirmed atypical AD: PCA (n = 98, 53.3%), lvPPA (n = 42, 22.8%), dAD (n = 37, 20.1%), and CBS-AD (n = 7, 3.8%). Age at onset (p = 0.039) and presentation (p < 0.001) differed, with patients with lvPPA oldest (median age at onset, presentation: 63.1, 66.9 years) and patients with dAD youngest (onset, presentation: 55.1, 57.3). Functional impairment differed by phenotype (p = 0.005), with lvPPA more often diagnosed at the mild cognitive impairment/very mild stage (Clinical Dementia Rating [CDR] 0.5; 71.4%), whereas PCA and dAD more frequently presented with mild dementia, although time from symptom onset to diagnosis did not differ (p = 0.634). Mini-Mental State Examination (MMSE) scores differed (p = 0.036), with lower scores in PCA and lvPPA (median 21 and 21, respectively) compared with CBS-AD (median 27). Depending on the eligibility framework applied, 70%-85% of patients would not meet treatment criteria. Bedside cognitive thresholds were the primary drivers of ineligibility (50%-67% of exclusions), despite most patients having early symptomatic disease (global CDR 0.5-1; 82%). Imaging-based exclusions (22%-27%) and severity thresholds (moderate or severe dementia, 19%-23%) were also frequent. Reasons for ineligibility were similar across phenotypes.<br><br>DISCUSSION: Most patients with atypical AD would not meet eligibility criteria for AAT, typically because of MMSE-based exclusion rather than measures of cognitive function. Eligibility rates are broadly similar across atypical phenotypes. These findings highlight the need for phenotype-sensitive staging and patient selection for treatment in atypical AD.},
}
@article {pmid42555976,
year = {2026},
author = {Xu, T and Zhang, C and Yang, Y and Shen, Z and Zhong, Z},
title = {Esketamine alleviates neuroinflammation and cognitive impairment in male 3xTg-AD mice by regulating the TAOK1/IL-17 axis.},
journal = {Canadian journal of physiology and pharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1139/cjpp-2025-0340},
pmid = {42555976},
issn = {1205-7541},
abstract = {Beyond its antidepressant effects, esketamine (ESK) has the potential to enhance neuroplasticity, facilitating the reconnection with emotional and cognitive processes, improving social cognition, and promoting resilience. However, not much is known about its role in Alzheimer's disease (AD). This study aims to explore the potential mechanism of ESK in AD treatment. The potential targets of ESK were predicted by bioinformatics analysis, and 3xTg-AD male mice were subjected to adeno-associated virus and ESK treatment. Cognitive ability, neuronal damage, and proinflammatory factors in 3xTg-AD mice were evaluated. An inflammatory model was established by inducing mouse cortical neurons with mouse IL-17A protein. Neuronal viability was assessed after treatment with different concentrations of ESK. TAOK1 knockdown or IL-17RA knockdown was performed on 3xTg-AD mice and neurons. TAOK1 was highly expressed in the cerebral cortex of ESK-treated 3xTg-AD mice. ESK improved IL-17-induced neuronal inflammation and DNA damage in a TAOK1-dependent manner. TAOK1 interacted with IL-17RA. IL-17RA knockdown improved DNA damage and inflammatory responses in cells and alleviated cognitive impairment and neuroinflammation in AD mice. Overall, ESK protects against DNA damage-mediated neuroinflammation by promoting TAOK1 and inhibiting IL-17 signaling, thereby improving cognitive dysfunction in 3xTg-AD mice.},
}
@article {pmid42556030,
year = {2026},
author = {Rodriguez, A and Judge, B and Shelley, N and Mehta, V and Friedrichsen, K and Strain, J and Benzinger, TL and Schindler, SE and Holtzman, DM and Cross, AH and Brier, MR},
title = {Clinical features of older MS patients with and without Alzheimer disease biomarkers.},
journal = {Multiple sclerosis and related disorders},
volume = {114},
number = {},
pages = {107406},
doi = {10.1016/j.msard.2026.107406},
pmid = {42556030},
issn = {2211-0356},
abstract = {Multiple sclerosis (MS) is a neurodegenerative disease characterized by inflammatory demyelination and axonal injury. Magnetic resonance imaging (MRI) plays a central role in MS diagnosis. Recent work suggests that biomarkers indicative of Alzheimer's disease (AD) are markedly reduced in people with MS. Whether differences in AD biomarkers are related to different features of MS, including MRI characteristics or treatment history, is unclear. In this study, 100 MS patients from Washington University in St. Louis underwent review of their most recent MRI as well as their prior and present MS disease-modifying treatment (DMT) exposures. We then ascertained the relation of MRI features and DMT to plasma AD biomarker measurements, with only a small subset (N=7) demonstrating APS2+ biomarker evidence of AD. Lesion distribution across MS topographies and total white matter lesion (WML) burden were both similar across MS patients with and without biomarker evidence of AD. Central vein sign (CVS), a recently integrated imaging biomarker of MS, was highly prevalent across the MS cohort and did not differ by AD biomarker status or MS clinical typicality at diagnosis, supporting the MS diagnoses even for people with atypical initial presentations. DMT exposure history showed associations with AD biomarkers: longer exposure to B cell-depleting anti-CD20 monoclonal antibody therapies (BCDT) corresponded to lower levels of amyloid pathology as measured by plasma biomarkers, and longer exposure to interferon-beta corresponded to a less pathological Aβ42/40 ratio. These findings indicate that structural MRI features do not explain differences in AD biomarker profiles in MS, whereas treatment-related immunologic effects may contribute to variation in AD pathology risk in MS patients.},
}
@article {pmid42556278,
year = {2026},
author = {Shi, Z and Cheng, X and Zhang, C and Hu, J and He, X and Chen, S and Wu, H and Tian, M and Yan, C and He, L},
title = {Vorinostat ameliorates cognitive impairment and Tau pathology in an AAV-P301L-Tau-induced tauopathy mouse model: insights into neuroinflammation and PI3K/AKT/GSK3β signaling.},
journal = {International immunopharmacology},
volume = {187},
number = {},
pages = {117216},
doi = {10.1016/j.intimp.2026.117216},
pmid = {42556278},
issn = {1878-1705},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder with significant sex-related differences, exhibiting a higher incidence rate in elderly women. Tau pathology has been implicated in sex-associated differences in AD susceptibility and disease progression, contributing to differential pathological burden between males and females. Vorinostat (SAHA), a histone deacetylase inhibitor (HDACi) used in cancer treatment, has shown potential therapeutic effects in various neurological and psychiatric disorders; however, the mechanisms underlying its regulation of tau-associated pathology remain poorly understood, with limited evidence regarding its effects in tau-related neurodegenerative conditions. In this study, we investigated the effects of SAHA treatment on an AAV-P301L-Tau-induced tauopathy model. In vivo, we observed that SAHA administration significantly improved p-Tau levels in the hippocampus and cortex of mice, reduced microglial activation and neuronal damage, and alleviated tauopathy-associated cognitive impairments. Our findings revealed sex-associated differences in Tau-related pathological alterations, with female mice exhibiting greater pathological changes and differential responses to SAHA treatment in several molecular and histological indicators. Further combined in vivo and in vitro experiments revealed that SAHA was associated with modulation of the PI3K/AKT/GSK3β signaling pathway, suppression of NF-κB activation, and attenuation of neuroinflammatory responses, including reductions in experimentally measured inflammatory markers such as interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-α). These molecular alterations may represent important regulatory components contributing to the neuroprotective effects of SAHA, rather than acting as the sole determinants of its therapeutic efficacy. In summary, these results indicate that SAHA can improve Tau-associated pathological alterations in an AAV-P301L-Tau-induced tauopathy model. The potential mechanisms may involve coordinated regulation of multiple pathological processes, including modulation of Tau phosphorylation, neuroinflammatory responses, and aging-associated signaling pathways. The observed sex-dependent responses to SAHA provide additional insights into the potential influence of biological sex on HDACi-based therapeutic strategies, although the molecular mechanisms underlying these differences require further investigation.},
}
@article {pmid42556319,
year = {2026},
author = {Koldamova, R and Fitz, NF and Lefterov, I},
title = {When less is more and when it isn't: Microglial Spi1 and the limits of what we know.},
journal = {Neuron},
volume = {114},
number = {15},
pages = {2669-2671},
doi = {10.1016/j.neuron.2026.06.017},
pmid = {42556319},
issn = {1097-4199},
mesh = {Animals ; *Microglia/metabolism ; Proto-Oncogene Protein Spi-1 ; *Trans-Activators/genetics/metabolism ; *Proto-Oncogene Proteins/metabolism/genetics ; Mice ; *Alzheimer Disease/metabolism/pathology ; Humans ; Amyloid beta-Peptides/metabolism ; },
abstract = {Microglia are key players in Alzheimer's disease, but the transcriptional control of their phagocytic function remains unclear. Kim et al. show that mouse microglial Spi1 deletion worsens amyloid pathology by impairing Aβ clearance through Syk, Lyn, and Fcgr1, providing new insight into PU.1-dependent regulatory networks and microglial functions in neurodegeneration.},
}
@article {pmid42556344,
year = {2026},
author = {Villareal, JAB and Bathe, T and Rosa, A and Sharma, RV and Hernández Gómez, EO and Ryan, AM and Hawkinson, TR and Tuzzolo, AM and Medina-Parrilla, E and Phillips, JL and Tsering, W and Iturbe, AA and Giasson, BI and Sun, RC and Gentry, MS and Prokop, S},
title = {Corpora amylacea profiling reveals disease stage and brain region-specific alterations in glycogen metabolism in Alzheimer's disease patient brains.},
journal = {Cell reports. Medicine},
volume = {},
number = {},
pages = {102968},
doi = {10.1016/j.xcrm.2026.102968},
pmid = {42556344},
issn = {2666-3791},
abstract = {Increasing evidence indicates that shifts in brain polysaccharide metabolism can influence the progression of multiple neurodegenerative diseases. Here, we profile corpora amylacea (CA) in 230 postmortem human brains, revealing significantly higher densities in Alzheimer's disease (AD) patients when compared with patients with other or no neurodegenerative diseases and a tight correlation of CA density with neurofibrillary tangle (NFT) pathology. Immunohistochemical profiling using an anti-glycogen antibody confirms the polysaccharide nature of CA and reveals plaque-like glycogen patches (GPs) and densely aggregated intraneuronal glycogen in AD patient brains correlated with the emergence of NFT pathology. matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) orthogonally verifies the polysaccharide identity of these structures and that GPs can be consistently observed at early neuropathological disease stages. GPs are also observed in murine models of AD-like pathology, correlating with tau pathology. The identification of these AD-associated glycogen pathologies in the human brain implies that alterations in glycogen metabolism are tightly associated with AD pathogenesis.},
}
@article {pmid42556454,
year = {2026},
author = {Xue, M and Pan, H and He, Y and Li, H and Zhou, H and Cheng, K and Xiao, C and Zhao, J and Jia, X and Li, Y and Liu, D and Yan, K},
title = {An accessible digital single-molecule sensing platform for plasma P-tau217 quantification in Alzheimer's disease screening.},
journal = {Clinica chimica acta; international journal of clinical chemistry},
volume = {593},
number = {},
pages = {121255},
doi = {10.1016/j.cca.2026.121255},
pmid = {42556454},
issn = {1873-3492},
abstract = {BACKGROUND: Early detection of Alzheimer's disease (AD) necessitates affordable and accessible blood biomarkers. Plasma phosphorylated tau 217 (P-tau217) is promising, but low-cost platforms for large-scale screening remain limited.<br><br>METHODS: We validated a Digital Single-Molecule Sensing (DiSMS) platform for plasma P-tau217 quantification. A reference interval was established in Cohort I (discovery, n&#xa0;=&#xa0;325, comprising 143 cognitively unimpaired controls, 80&#xa0;CE, 34 frontotemporal dementia [FTD], and 68 subcortical ischemic vascular dementia [SIVD] patients). Diagnostic performance was validated in Cohort II (n&#xa0;=&#xa0;242; 77&#xa0;CE, 165 controls). Cross-platform concordance was assessed against the Simoa HD-X in 137 paired samples.<br><br>RESULTS: The healthy reference interval was 0.09-0.51&#xa0;pg/mL. In Cohort II, P-tau217 strongly distinguished AD from controls (accuracy 93.4% [95% CI: 90.3%-96.5%], sensitivity 92.2% [95% CI: 83.2%-96.8%], specificity 93.9% [95% CI: 88.8%-96.9%]). A two-cutoff approach (< 0.40, 0.40-0.50, > 0.50&#xa0;pg/mL) yielded 94.1% accuracy and 95.9% sensitivity, leaving 8.4% of cases in the intermediate zone. DiSMS exhibited strong concordance with the Simoa (concordance rate&#xa0;=&#xa0;94.9%; Spearman r&#xa0;=&#xa0;0.94, P&#xa0;<&#xa0;0.001). Plasma P-tau217 was significantly higher in AD than FTD (median 0.25&#xa0;pg/mL) and SIVD (median 0.36&#xa0;pg/mL) (both P&#xa0;<&#xa0;0.001). Age-adjusted AUC was moderate for AD versus SIVD (0.777) but limited for AD versus FTD (0.665; sensitivity/specificity below 65%).<br><br>CONCLUSIONS: The DiSMS platform enables accurate, cost-accessible plasma P-tau217 quantification for AD screening, meeting consensus guidelines (&#x2265;90%). The limited P-tau217 performance for differentiating AD from FTD (AUC&#xa0;=&#xa0;0.665) highlights the need for integration with complementary biomarkers or clinical assessments.},
}
@article {pmid42556482,
year = {2026},
author = {Lu, QX and Guan, W},
title = {A role for apolipoprotein E4 (ApoE4) in the pathogenesis of depressive symptoms and Alzheimer's disease.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {118316},
doi = {10.1016/j.bcp.2026.118316},
pmid = {42556482},
issn = {1873-2968},
abstract = {Depression is a chronic mental disorder that is often difficult to diagnose and mostly left untreated. Apolipoprotein E (ApoE) is a lipid transport protein that plays a central role in the metabolism of plasma lipoproteins and the transport of lipids within tissues. Among its three major isoforms, only ApoE4 has a unique structural variant that confers significant neurotoxicity not present in the other two subtypes. ApoE4 not only disrupts lipid metabolism but also interferes with neuroimmune regulation and mitochondrial dynamics, thereby impairing synaptic integrity. It is a major genetic risk factor for Alzheimer's disease (AD) and accelerates its age of onset. Although developing depression in midlife may be a risk factor for AD, the underlying mechanisms by which ApoE4 influences depression or depression-related behaviors associated with AD remain fragmented, and systematic integrative reviews on this topic are scarce. We integrate existing evidence to elucidate the role of ApoE4 in depression or AD-associated prodromal depressive-like behaviors, with a focus on how its dysfunction disrupts cellular lipid homeostasis, impairs synaptic plasticity, and damages mitochondrial function. We also explored specific therapeutic strategies targeting the pathological defects of ApoE4 that enhance synaptic resilience, and utilizing conformational modulating small molecules such as EZ-482 and ALZ-801 to treat depressive symptoms in early AD. Thus, these findings indicate that ApoE4 may influence the progression of depressive phenotypes through multiple pathological pathways, making it a promising therapeutic target for treating depression comorbid with early AD.},
}
@article {pmid42556648,
year = {2026},
author = {Huang, W and Huang, J and Kuang, N and Wu, J and Feng, F and Luo, Y and Huang, N},
title = {Mitochondrial homeostasis dysregulation: Potential mechanisms of Alzheimer's disease mediated by TDP-43.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103290},
doi = {10.1016/j.arr.2026.103290},
pmid = {42556648},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD) exhibits substantial clinical and pathological heterogeneity that is not fully explained by amyloid-β and tau pathology alone. TAR DNA-binding protein 43 (TDP-43) is increasingly recognized as a frequent copathology in AD, particularly in limbic regions, where its presence is associated with accelerated cognitive decline. Disruption of mitochondrial homeostasis is also an early and consistent feature of AD and contributes to neuronal vulnerability. In this review, we summarize current evidence linking TDP-43 pathology to impaired mitochondrial homeostasis in AD. We outline key features of mitochondrial homeostasis in neurons, review neuropathological and clinical data supporting the relevance of TDP-43 in AD, and synthesize emerging mechanisms by which TDP-43 may perturb mitochondrial homeostasis, including effects on expression, aggregation and localization, quality control, organelle dynamics, and endoplasmic reticulum-mitochondria communication.},
}
@article {pmid42556890,
year = {2026},
author = {Giuliani, C and Schmidlin, PR and Fakheran, O},
title = {THE ROLE OF PERIODONTITIS IN THE INITIATION AND PROGRESSION OF COGNITIVE DISORDERS: AN UMBRELLA REVIEW.},
journal = {The journal of evidence-based dental practice},
volume = {26},
number = {3},
pages = {102307},
doi = {10.1016/j.jebdp.2026.102307},
pmid = {42556890},
issn = {1532-3390},
mesh = {Humans ; *Periodontitis/complications ; Disease Progression ; *Cognition Disorders/etiology ; Risk Factors ; Alzheimer Disease/etiology ; Systematic Reviews as Topic ; },
abstract = {BACKGROUND: Cognitive disorders are a major cause of morbidity worldwide, and accumulating evidence indicates that chronic systemic inflammation may play a key role in their initiation and progression. Periodontitis, a prevalent chronic inflammatory oral disease, has been increasingly recognized as a potential risk factor for cognitive disorders.<br><br>OBJECTIVE: This umbrella review synthesized evidence from systematic reviews and meta-analyses investigating the association between periodontitis and cognitive disorders, including Alzheimer's disease (AD), dementia and cognitive impairment.<br><br>METHODS: Following JBI methodological guidance for umbrella reviews, a comprehensive search was conducted across seven databases (Medline, Embase, Cochrane Library, CINAHL, PsycINFO, Web of Science, Scopus) from inception to April 2025 to identify systematic reviews and meta-analyses on the association between periodontitis and cognitive disorders in humans. Two reviewers independently performed study selection, data extraction, and quality appraisal using the JBI Critical Appraisal Tool. Due to heterogeneity, findings were synthesized narratively.<br><br>RESULTS: Twenty systematic reviews and meta-analyses comprising 333 primary studies were included. Most reviews reported a significant association between periodontitis and AD or dementia. Meta-analyses consistently found increased risk estimates, with the strongest associations for severe periodontitis. Biological plausibility was supported by shared inflammatory pathways and detection of periodontal pathogens in brain tissue. However, evidence was predominantly observational, with substantial heterogeneity in diagnostic criteria.<br><br>CONCLUSION: Evidence suggests a potential link between periodontitis and cognitive disorders, though results are inconsistent and causality remains unproven. Inflammatory and microbial mechanisms are proposed, but well-designed longitudinal and interventional studies with standardized criteria are needed.},
}
@article {pmid42557116,
year = {2026},
author = {Wei, M and Zhang, J and Shi, J and Li, T and Yao, L and Li, F and Xiao, W and Ni, J and Tian, J},
title = {Temporal order of clinical symptoms in Alzheimer's disease.},
journal = {International psychogeriatrics},
volume = {},
number = {},
pages = {100253},
doi = {10.1016/j.inpsyc.2026.100253},
pmid = {42557116},
issn = {1741-203X},
abstract = {BACKGROUND: Understanding the temporal order of clinical symptoms is critical for improving disease progression assessment in biomarker-defined Alzheimer's disease (AD). However, the sequential emergence of cognitive, neuropsychiatric, and functional manifestations remains incompletely characterized. The purpose of this study is to characterize the population-level sequence in which Alzheimer's disease symptoms appear, to help understand how the disease is progressing.<br><br>METHODS: We analyzed 932 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI), including 546 amyloid-positive individuals across the AD continuum and 386 amyloid-negative individuals in the comparison group. Longitudinal cumulative incidence was analyzed to estimate the temporal emergence of major clinical symptoms. Any symptom onset was defined using a >&#x202f;50% cumulative incidence threshold. Cross-sectional relationships between the sequence of clinical symptoms and Mini-Mental State Examination (MMSE) scores were analyzed using locally estimated scatterplot smoothing (LOESS). The concordance between the clinical symptom sequence and PET-derived Braak staging was assessed using weighted kappa statistics.<br><br>RESULTS: A reproducible temporal ordering of clinical symptoms was observed across longitudinal and cross-sectional analyses. Memory impairment emerged earliest, affecting 63.75% of participants at baseline, followed by behavioral and affective symptoms. At intermediate stages, executive dysfunction and instrumental activities of daily living (IADL) impairment affected 52.44% and 54.85% of participants, respectively. Language and visuospatial impairments appeared later, affecting 51.25% and 51.54% of participants, respectively, followed by psychotic symptoms and severe functional decline in basic activities of daily living (BADL), which suggests the disease has reached its late stage. The order in which different symptom groups appear-from memory to executive function and instrumental abilities, then language and visuospatial skills, and finally psychotic symptoms and basic abilities-shows moderate consistency respectively with CDR staging (&#x3ba; = 0.596, 95%CI: 0.524-0.668), and the PET-derived Braak staging (&#x3ba; = 0.517, 95%CI: 0.436-0.598).<br><br>CONCLUSION: Clinical symptoms in AD tend to emerge in a temporal sequence. This finding may help to better characterize disease progression clinically, serving as a symptom-staging framework for symptomatic AD and providing interpretable turning points for clinical assessment and individualized management.},
}
@article {pmid42557118,
year = {2026},
author = {Xu, S and Yang, Z and Zhi, Y and Yu, S and Zhang, T and Jiang, J and Tang, J and He, H and Lu, M and Wang, X and Wu, Q and Zhao, X},
title = {Retraction notice to "The effects of antimony on Alzheimer's disease-like pathological changes in mice brain" [Sci. Total Environ. 760 (2021) 143235].},
journal = {The Science of the total environment},
volume = {},
number = {},
pages = {182162},
doi = {10.1016/j.scitotenv.2026.182162},
pmid = {42557118},
issn = {1879-1026},
}
@article {pmid42557399,
year = {2026},
author = {Zhang, Y},
title = {Exercise-Mediated Modulation of the NLRP3 Inflammasome in Aging and Neurodegenerative Diseases: Mechanisms, Microglial Crosstalk, and Translational Perspectives.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42557399},
issn = {1559-1182},
mesh = {*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Microglia/metabolism/pathology ; *Aging/metabolism/pathology ; Animals ; *Neurodegenerative Diseases/metabolism/pathology ; Humans ; *Inflammasomes/metabolism ; *Exercise/physiology ; },
abstract = {Regular engagement in physical exercise has been recognized as a formidable non-pharmacological intervention aimed at mitigating age-associated neuroinflammation and neurodegenerative phenomena. A fundamental mechanism that underpins these advantageous effects pertains to the modulation of the NLRP3 inflammasome, which serves as a pivotal regulator of innate immune responses within microglial cells. The aging process is marked by a state of chronic low-grade inflammation, commonly referred to as "inflammaging," which is instigated by mitochondrial dysfunction, oxidative stress, and metabolic disturbances; these factors collectively facilitate the activation of NLRP3 and the subsequent secretion of pro-inflammatory cytokines, notably IL-1β. Contemporary research findings suggest that physical exercise diminishes NLRP3 inflammasome activation through various interrelated pathways. These pathways encompass the reduction of reactive oxygen species production, the inhibition of TXNIP-mediated assembly of the inflammasome, and the modulation of metabolites derived from the gut, such as trimethylamine N-oxide. In addition, factors circulating as a result of exercise, which include irisin and meteorin-like protein, play a significant role in promoting systemic and central anti-inflammatory responses, thereby impacting the functional dynamics of microglia. In experimental paradigms investigating the phenomena of aging and neurodegenerative disorders (NDDs), notably Alzheimer's and Parkinson's diseases, physical activity has been shown to diminish amyloid accumulation, tau pathology, and microglial activation, primarily through the attenuation of NLRP3 signaling pathways. Collectively, these observations underscore the role of exercise as a pivotal regulator of neuroimmune equilibrium, thereby providing mechanistic elucidation of its potential therapeutic efficacy in alleviating inflammaging and decelerating the progression of NDDs.},
}
@article {pmid42557842,
year = {2026},
author = {Rubtsova, K},
title = {Age-Associated B Cells: Origins, Regulation, and Tissue-Specific Pathogenic Contributions in Autoimmune, Metabolic, and Neurological Diseases.},
journal = {Immunological reviews},
volume = {341},
number = {1},
pages = {e70144},
doi = {10.1111/imr.70144},
pmid = {42557842},
issn = {1600-065X},
mesh = {Humans ; Animals ; *Autoimmune Diseases/immunology/metabolism ; *B-Lymphocytes/immunology/metabolism ; *Aging/immunology ; *Nervous System Diseases/immunology/metabolism ; Cell Differentiation ; Organ Specificity ; Autoimmunity ; Signal Transduction ; },
abstract = {Age-associated B cells (ABCs) are a distinct B cell population characterized by coexpression of T-bet and CD11c. First described in aged female mice and autoimmune-prone strains, ABCs are now recognized to be associated with multiple human autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis, where their frequency correlates with disease activity. Their differentiation requires toll-like receptor (TLR) signaling, IFN-γ, IL-21, BCR engagement, with ZEB2 emerging as the nonredundant transcriptional master regulator of ABC identity. Here we review requirements for ABC differentiation, their defining phenotypic and functional features, and their tissue-specific distribution and pathogenic contributions in diverse inflammatory settings. A central theme is that ABCs are tissue-homing cells whose contribution extends beyond blood and lymphoid organs. In kidney, inflamed synovium, salivary glands, and adipose tissue, ABCs drive pathology through locally differentiated autoantibody-secreting cells, stromal activation, antigen presentation, and cytokine production. We further discuss roles for ABCs in neurological diseases, including their enrichment in the cerebrospinal fluid in multiple sclerosis (MS) and their contribution to neuroinflammation in Alzheimer's disease, and highlight the EBV-ABC axis as a mechanism linking viral infection to autoimmunity. In summary, ABCs are multi-functional, tissue-adaptable pathogenic effectors whose contributions to human disease extend beyond classical autoimmunity into metabolic dysfunction and neurodegeneration.},
}
@article {pmid42557858,
year = {2026},
author = {Li, X and Yang, F and Jiang, Y and Zhao, F and Liu, F},
title = {HNRNPC Succinylation Influences the Neurodegeneration of Alzheimer's Disease Through YME1L1-Mediated Mitochondrial Metabolism.},
journal = {Aging cell},
volume = {25},
number = {8},
pages = {e70646},
doi = {10.1111/acel.70646},
pmid = {42557858},
issn = {1474-9726},
support = {Z2023168//National Key Clinical Specialty Scientific Research Project/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/genetics ; *Mitochondria/metabolism ; Mice ; Mice, Transgenic ; Sirtuins/metabolism ; Humans ; Disease Models, Animal ; *Mitochondrial Proteins/metabolism ; Metalloendopeptidases ; },
abstract = {Mitochondrial dysfunction and abnormal energy metabolism are important pathological features of Alzheimer's disease (AD). This study investigates how mitochondrial protease YME1L1 affects mitochondrial function and its upstream regulation in the pathogenesis of AD. The AD model was established by using APP/PS1 transgenic mice, primary neurons treated with Aβ1-42, and HT22 cells. The silencing of YME1L1 was achieved to evaluate its effects on mitochondrial function and OPA1 protein hydrolysis. RIP-qPCR and RNA pull-down test were used to evaluate the interaction between HNRNPC and YME1L1 mRNA. The protein succinylation level was detected by proteomic analysis of succinylation, and co-immunoprecipitation (Co-IP) was used to verify the succinylation of HNRNPC. Cognitive ability was tested by behavioral tests, including the Morris water maze, Y-maze, object recognition test, and olfactory test. Finally, the therapeutic potential of SIRT5 was studied by an overexpression experiment in an AD model. YME1L1 was significantly upregulated in the AD model, which promoted mitochondrial dysfunction and neuronal damage through OPA1 hydrolysis. HNRNPC enhances the stability of YME1L1 mRNA through an m6A-dependent mechanism, while its own K50 succinylation enhances the stability of HNRNPC by competitively inhibiting TRIM25-mediated ubiquitination, further amplifying the expression of YME1L1. SIRT5 downregulation in AD elevated HNRNPC succinylation levels. SIRT5 overexpression promoted HNRNPC desuccinylation, reduced YME1L1 expression, restored mitochondrial function, and ameliorated Aβ deposition and cognitive deficits in AD mice. The SIRT5-HNRNPC-YME1L1 axis contributes to AD pathogenesis by disrupting OPA1 proteolysis and mitochondrial dynamics. Targeting HNRNPC succinylation represents a promising therapeutic strategy for AD.},
}
@article {pmid42557872,
year = {2026},
author = {Vaughan, DP and Jensen, MT and Real, R and Fumi, RG and Wu, L and Lux, D and Hodgson, M and Jones, PS and Holland, N and Scotton, WJ and Serrano-Assensio, O and Quattrone, A and Heslegrave, AJ and Veleva, E and Swann, O and Zetterberg, H and Lynch, T and Mir, P and Stamelou, M and Seppi, K and Vandenberghe, R and Warner, TT and Lees, A and Bhatia, KP and Church, A and Kobylecki, C and Leigh, PN and Hu, MT and Taba, P and Matsalu, T and Pavese, N and Ghosh, BCP and Picillo, M and Wallin, J and Svenningson, P and Sánchez-Gómez, A and Fernández, M and Cámara, A and Planellas, L and Compta, Y and , and Quaegebeur, A and Jaunmuktane, Z and Revesz, T and Jabbari, E and Rohrer, JD and Rowe, JB and Morris, HR},
title = {Defining the underlying pathology of corticobasal syndrome using clinical features and biomarkers.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag257},
pmid = {42557872},
issn = {1460-2156},
abstract = {Corticobasal degeneration (CBD) is a late onset progressive neurodegenerative condition of the 4-repeat-tauopathy-type, classically presenting with asymmetrical rigidity, dystonia and myoclonus. In the most recent diagnostic criteria, Armstrong and colleagues (2013) described four clinical phenotypes associated with this pathology, including corticobasal syndrome (CBS), through a large retrospective analysis of published cases and confirmed brain bank cases of CBD. However, predicting CBD pathology remains challenging. With the advent of disease-modifying therapies, it has become particularly important to distinguish Alzheimer's disease pathology from other underlying pathologies. We therefore combined two prospectively recruited cohorts of patients with CBS and analysed their key demographic, clinical and biomarker features. We included a separate cohort from UK brain banks who were diagnosed with CBS in life. We divided patients into three groups: CBS-Alzheimer's (CBS-AD), CBS-non-Alzheimer's (CBS-non-AD) and CBS-indeterminate (CBS-IDT) based on biomarkers and pathology, comparing clinical features, regional volumetric MRI measures and Nucleic Acid-Linked Immuno-Sandwich Assay with detection by next generation sequencing (NULISAseq) blood protein levels between groups. We performed additional analyses of pathologically verified cases. We included 397 participants, of which 57.7% were female. The mean age at symptom onset was 65.9 years. AD biomarkers and pathology permitted classifying 47 (11.8%) of the cases as CBS-AD, 134 (33.8%) as CBS-non-AD and 216 (54.4%) as CBS-IDT. Patients with CBS-AD had a younger age at onset (61.8 years vs 66.1 years, P < 0.01 and less severe motor deficits (non-significantly lower scores on MDS-UPDRS and PSPRS) and more severe cognitive impairment (non-significantly lower scores on MoCA). Patients with CBS-AD had higher rates of cortical sensory impairment (P = 0.087) and lower rates of limb dystonia (P < 0.01) and falls (P < 0.01) compared to the CBS-non-AD group. Volumetric MRI analysis revealed smaller parietal lobe volumes in CBS-AD (P = 0.01). The most common pathological diagnoses were PSP, CBD and AD. Limb dystonia was more common in people with CBD and PSP pathology (P = 0.077). Falls, impaired verbal fluency and impaired vertical saccades were confirmed as more common in PSP (P = 0.046, P = 0.040, P = 0.012, respectively). In summary, younger onset, less parkinsonism and more cognitive and cortical sensory impairment, along with reduced MRI parietal volumes point to CBS-AD, while limb dystonia, falls and worse verbal fluency relate to CBS-non-AD. Clinical, imaging and blood-biomarkers in can augment the Armstrong criteria in predicting the underlying pathology of corticobasal syndromes.},
}
@article {pmid42557882,
year = {2026},
author = {Pini, L and Imbimbo, BP and Corbetta, M},
title = {Reply: The disconnectome as target in Alzheimer disease: a promising framework or a premature end-point?.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag263},
pmid = {42557882},
issn = {1460-2156},
}
@article {pmid42557932,
year = {2026},
author = {Wu, H and Chen, Q and Fang, M and Tang, H and Liu, H and Liu, J and Zhang, J and Chi, L and Liu, S and Xin, J and Leng, L and Wang, P and Chi, S and Li, Y and Chen, J and Zhang, L and Zhang, J and Ma, Q and Wang, X and Meng, X and Nao, J and Li, X and Lv, Y and Jia, Y and Zhao, Q and Liu, C and Gan, J and Zhu, J and Song, Y and Li, H and Fei, M and Guo, X and Liu, J and Peng, G and Chen, X and Ji, Y},
title = {Lecanemab use in Chinese patients with Alzheimer's disease: a 12-month multicenter real-world study.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71702},
doi = {10.1002/alz.71702},
pmid = {42557932},
issn = {1552-5279},
support = {TJYXZDXK-3-014B//Tianjin Key Medical Discipline Construction Project/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/blood/diagnostic imaging ; Female ; Biomarkers/blood ; Male ; Aged ; China ; Treatment Outcome ; Aged, 80 and over ; Amyloid beta-Peptides ; East Asian People ; },
abstract = {INTRODUCTION: We evaluated lecanemab's safety and cognitive outcomes in Chinese patients with Alzheimer's disease (AD) and the utility of blood-based biomarkers (BBMs) for treatment guidance.<br><br>METHODS: A multicenter, real-world cohort enrolled 1042 patients receiving lecanemab, with 453, 359, 97 patients followed up at 3, 6, 12 months, respectively. Safety outcomes included amyloid-related imaging abnormalities (ARIA) and infusion-related reactions (IRRs), and the main clinical outcome was Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) score change.<br><br>RESULTS: Of 1,042 patients, ARIA occurred in 7.87%, and IRRs in 16.12%. Discontinuation was 16.51%, mainly due to financial burden. CDR-SB did not change at 12 months overall or in any subgroup. High-accuracy BBMs were the sole AD biomarker assay in 5.28%, with comparable outcomes.<br><br>DISCUSSION: Lecanemab exhibited favorable 12-month safety, with no clear evidence of cognitive decline, and BBMs hold potential for treatment guidance. Further studies using a control group are now warranted.},
}
@article {pmid42557952,
year = {2026},
author = {Acharya, A and Thurman, M and Sutar, D and Olasunkanmi, OI and Malik, JR and Dyavar, SR and Végvári, &#xc1; and Byrareddy, SN},
title = {In-Vitro Evaluation of HIV/SARS-CoV-2 Co-Infection Mediated Proteomic Changes in Astrocytes and Pericytes Reveals Altered Signaling Pathways Associated With Neurodegenerative Disorders.},
journal = {Journal of medical virology},
volume = {98},
number = {8},
pages = {e71086},
doi = {10.1002/jmv.71086},
pmid = {42557952},
issn = {1096-9071},
support = {R01DA05284/NH/NIH HHS/United States ; R01DA061678/NH/NIH HHS/United States ; },
mesh = {*Pericytes/virology/metabolism ; *Astrocytes/virology/metabolism ; Humans ; *Signal Transduction ; *HIV Infections/metabolism/complications/virology ; *SARS-CoV-2/physiology ; *Coinfection/virology/metabolism ; *Neurodegenerative Diseases/metabolism/virology ; *COVID-19/metabolism/complications/virology ; Proteomics ; Microglia/virology/metabolism ; Post-Acute COVID-19 Syndrome ; Virus Replication ; Proteome ; },
abstract = {Coronavirus disease 2019 (COVID-19) survivors frequently experience a wide range of symptoms known as post-acute sequelae of SARS-CoV-2 (PASC) or long COVID. Importantly, complications arising from microvascular dysfunction, blood-brain barrier (BBB) disruption, and chronic neuroinflammation have been implicated in driving PASC within the central nervous system (CNS), known as neuro-PASC. Notably, people with HIV (PWH), who suffer from chronic neuroinflammation, BBB impairment, and glial cell dysfunction, collectively known as neuro-HIV, are generally at higher risk of neuro-PASC. The overlap between neuro-PASC and neuro-HIV raises concerns that HIV and SARS-CoV-2 co-infection may exacerbate neurological dysfunctions among PWH. In this study, using an in-vitro cell culture model, we examine the effects of HIV and SARS-CoV-2 mono- and co-infection in microglia, astrocytes, and pericytes. Our results demonstrated that majority of brain cell types support SARS-CoV-2 replication, in the presence and absence of HIV infection. Furthermore, in both mono- and co-infected cells, there were varying degree of up- and downregulation of SARS-CoV-2 host cell entry factors, such as ACE2, TMPRSS2, NRP1, and TRIM28, and inflammatory cytokines including IL-6, TNF-α, and IL-1β. Moreover, conditioned media collected from HIV, SARS-CoV-2, and HIV/SARS-CoV-2 co-infected astrocytes and pericytes were shown to be neurotoxic. Additionally, proteomic analysis has revealed a unique set of proteins significantly up/down regulated in HIV/SARS-CoV-2 co-infected astrocytes and pericytes. The gene set enrichment analysis of these proteins indicates dysregulation of lipid, energy, and immune metabolism pathways linked to neurodegenerative disorders like Alzheimer's, Parkinson's, Huntington's disease, and amyotrophic lateral sclerosis. These in-vitro findings indicate that astrocytes and pericytes from HIV/SARS-CoV-2 co-infection exhibit altered protein expression profiles, implicating dysregulated signaling pathways associated with neurodegenerative dysfunction.},
}
@article {pmid42557955,
year = {2026},
author = {Trudel, L and Therriault, J and Macedo, AC and Aumont, E and Hosseini, SA and Benedet, AL and Hazrati, LN and Gauthier, S and Zetterberg, H and Vitali, P and Ashton, NJ and Rosa-Neto, P and , },
title = {Predicting continuous amyloid PET levels with CSF and plasma brain-derived p-tau217.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71723},
doi = {10.1002/alz.71723},
pmid = {42557955},
issn = {1552-5279},
support = {//Weston Brain Institute/ ; MOP-11-51-31//Canadian Institutes of Health Research (CIHR)/ ; RFN 152985 159815 162303//Canadian Institutes of Health Research (CIHR)/ ; MOP-11-51-31 -team 1//Canadian Consortium of Neurodegeneration and Aging (CCNA)/ ; NIRG-12-92090 NIRP-12-259245//the Alzheimer's Association/ ; 34874//the Alzheimer's Association/ ; 33397//the Alzheimer's Association/ ; 2020-VICO-279314//the Fonds de Recherche du Qu&#xe9;bec - Sant&#xe9; (FRQS); Chercheur Boursier/ ; 2024-VICO-356138//the Fonds de Recherche du Qu&#xe9;bec - Sant&#xe9; (FRQS); Chercheur Boursier/ ; //the Swedish Research Council/ ; 101053962//European Union's Horizon Europe research and innovation programme/ ; #ALFGBG-71320//Swedish State Support for Clinical Research/ ; U01 AG024904//Alzheimer's Disease Neuroimaging Initiative (ADNI); National Institutes of Health/ ; //the Fonds de Recherche du Qu&#xe9;bec - Sant&#xe9;/ ; //Fondation Brain Canada/ ; /ALZ/Alzheimer's Association/United States ; //Consortium canadien en neurod&#xe9;g&#xe9;n&#xe9;rescence associ&#xe9;e au vieillissement/ ; },
mesh = {Humans ; *tau Proteins/cerebrospinal fluid/blood/metabolism ; *Positron-Emission Tomography ; Biomarkers/cerebrospinal fluid/blood ; Female ; *Alzheimer Disease/diagnostic imaging/metabolism/cerebrospinal fluid/blood ; *Amyloid beta-Peptides/metabolism/cerebrospinal fluid ; *Brain/metabolism/diagnostic imaging ; Male ; Aged ; Phosphorylation ; },
abstract = {BACKGROUND: Staging amyloid beta (Aβ) burden along a continuous spectrum provides clinically relevant information. Conventional phosphorylated tau (p-tau)217 reliably identifies amyloid positron emission tomography (PET) positivity, but its ability to capture the full Aβ continuum is limited. Recently developed brain-derived (BD) p-tau217 assays enrich for central nervous system tau species and may improve specificity.<br><br>METHODS: We tested how closely BD p-tau217 reflected continuous A&#x3b2; and how accurately it could classify participants as A&#x3b2; positive or negative across different Centiloid (CL) thresholds in 924 participants from the Alzheimer's Disease Neuroimaging Initiative. Conventional and BD cerebrospinal fluid (CSF) and plasma p-tau217 biomarkers were quantified using the Alamar NULISAseq panel.<br><br>RESULTS: Across the full cohort, plasma BD p-tau217 demonstrated the strongest continuous association with PET CL (R[2]&#xa0;=&#xa0;0.63), and the best prediction across the CL spectrum (root mean square error =&#xa0;=&#xa0;24.5). Prediction was precise in cognitively unimpaired participants at low CL and reasonably accurate in cognitively impaired participants across intermediate-to-high CL.<br><br>CONCLUSIONS: Plasma BD p-tau217 best captured the amyloid PET continuum, with BD processing improving discrimination in plasma but not CSF.},
}
@article {pmid42557961,
year = {2026},
author = {Carrigan, M and Birkenbihl, C and Klinger, HM and Langford, O and Coughlan, GT and Seto, M and Brown, JA and Li, A and Cuppels, M and Properzi, M and Chhatwal, J and Price, J and Schultz, A and Rentz, D and Amariglio, R and Krugers, HJ and Ossenkoppele, R and Johnson, K and Sperling, R and Hohman, TJ and Donohue, M and Buckley, RF},
title = {Sex specificity of resistance to caTAUstrophe.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71716},
doi = {10.1002/alz.71716},
pmid = {42557961},
issn = {1552-5279},
support = {WE.08-2024-06//Alzheimer Nederland/ ; WE.03-2021-03//Alzheimer Nederland/ ; K99 AG083063/AG/NIA NIH HHS/United States ; R01AG079142/AG/NIA NIH HHS/United States ; DP2AG082342/AG/NIA NIH HHS/United States ; R01AG073439/AG/NIA NIH HHS/United States ; 949570/ERC_/European Research Council/International ; U24AG074855/AG/NIA NIH HHS/United States ; U01AG082350/AG/NIA NIH HHS/United States ; },
mesh = {Female ; Humans ; *Amyloid beta-Peptides/metabolism ; *tau Proteins/metabolism ; Male ; Aged ; *Sex Characteristics ; *Alzheimer Disease/metabolism/pathology ; Aged, 80 and over ; Magnetic Resonance Imaging ; },
abstract = {INTRODUCTION: As amyloid beta (Aβ) accumulates, tau pathology spreads beyond medial temporal lobe (MTL) into neocortical (NEO) regions, though some older adults resist this progression, or what we call here "caTAUstrophe." Given previous evidence of higher tau levels in women, we tested how tau resistance presented in men and women separately.<br><br>METHODS: Employing data from 872 A&#x3b2;+ older adults across three cohorts, we trained sex-specific penalized linear regression models in individuals experiencing caTAUstrophe (females: NTrain&#xa0;=&#xa0;172; males: NTrain&#xa0;=&#xa0;121) to predict the expected NEO tau levels. We estimate resistance as lower-than-expected NEO tau levels in training-independent individuals (NTest&#xa0;=&#xa0;579) to assess sex-specific resistance associates.<br><br>RESULTS: Relative feature importance in sex-specific expectation models differed in 97.7% of variables (false discovery rate-adjusted p value <&#xa0;0.001). Age and A&#x3b2; burden associated with male resistance, while Clinical Dementia Rating, latent Preclinical Alzheimer's Cognitive Composite, and adjusted hippocampal volume were associates in both sexes.<br><br>DISCUSSION: Our study highlights sex-specific biological and clinical factors in the prediction of NEO tau and associates of resistance. Understanding sex-specific resistance pathways informs targeted Alzheimer's interventions.},
}
@article {pmid42557982,
year = {2026},
author = {Olayinka, O and Farrell, JJ and Zhu, C and Khurshid, Z and , and Martin, ER and Bush, WS and Pericak-Vance, MA and Wang, LS and Schellenberg, GD and Haines, JL and Lunetta, KL and Zhang, X and Farrer, LA},
title = {Stratification by a polygenic risk score of common variation aids in Alzheimer's disease rare variant discovery.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71710},
doi = {10.1002/alz.71710},
pmid = {42557982},
issn = {1552-5279},
support = {U01 AG024904/NH/NIH HHS/United States ; RF1AG054080/NH/NIH HHS/United States ; U01-AG058654/NH/NIH HHS/United States ; U54-AG052427/NH/NIH HHS/United States ; U19-AG068753/NH/NIH HHS/United States ; U01-AG062602/NH/NIH HHS/United States ; U01-AG 081230/NH/NIH HHS/United States ; U01-AG082665/NH/NIH HHS/United States ; P30-AG072978/NH/NIH HHS/United States ; P01AG03991/NH/NIH HHS/United States ; P01AG026276/NH/NIH HHS/United States ; P30AG066462/NH/NIH HHS/United States ; R01AG064614/NH/NIH HHS/United States ; U01AG052410/NH/NIH HHS/United States ; //Alzheimer's Disease Sequencing Project/ ; //Alzheimer's Disease Genetics Consortium/ ; AG033193/AG/NIA NIH HHS/United States ; AG049607/AG/NIA NIH HHS/United States ; AG033040/AG/NIA NIH HHS/United States ; U24 AG074855/AG/NIA NIH HHS/United States ; R01AG041797/AG/NIA NIH HHS/United States ; R01AG023629/AG/NIA NIH HHS/United States ; R01AG15928/AG/NIA NIH HHS/United States ; R01AG20098/AG/NIA NIH HHS/United States ; U01 AG068057/AG/NIA NIH HHS/United States ; R01 AG059716/AG/NIA NIH HHS/United States ; AI4AD//NIA/ ; //Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE)/ ; U01AG057659//Follow Up Study/ ; U01AG062943//Follow Up Study/ ; U54AG052427//Follow Up Study/ ; U01AG058589//Follow Up Study/ ; U01AG058654//Follow Up Study/ ; U01AG058635//Follow Up Study/ ; RF1AG058066//Follow Up Study/ ; RF1AG057519//Follow Up Study/ ; R01AG048927//Follow Up Study/ ; RF1AG054074//Follow Up Study/ ; U01 AG006781//Adult Changes in Thought (ACT)/ ; U19 AG066567//Adult Changes in Thought (ACT)/ ; P30 AG062429//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG066468//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG062421//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG066509//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG066514//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG066530//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG066507//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG066444//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG066518//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG066512//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG066462//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG072979//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG072972//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG072976//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG072975//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG072978//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG072977//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG066519//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG062677//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG079280//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG062422//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG066511//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG072946//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG062715//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG072973//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG066506//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG066508//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG066515//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG072947//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG072931//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG066546//Alzheimer's Disease Research Centers (ADRC)/ ; P20 AG068024//Alzheimer's Disease Research Centers (ADRC)/ ; P20 AG068053//Alzheimer's Disease Research Centers (ADRC)/ ; P20 AG068077//Alzheimer's Disease Research Centers (ADRC)/ ; P20 AG068082//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG072958//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG072959//Alzheimer's Disease Research Centers (ADRC)/ ; R01 AG11101//Alzheimer's Disease Research Centers (ADRC)/ ; RC4 AG039085//Alzheimer's Disease Research Centers (ADRC)/ ; K23 AG030944//Alzheimer's Disease Research Centers (ADRC)/ ; R01 AG019771//Indiana Memory and Aging Study (IMAS)/ ; R01 AG009956//Indiana Memory and Aging Study (IMAS)/ ; P30 AG010133//Indiana Memory and Aging Study (IMAS)/ ; R01 AG032990//Mayo Clinic (MAYO)/ ; U01 AG046139//Mayo Clinic (MAYO)/ ; R01 NS080820//Mayo Clinic (MAYO)/ ; RF1 AG051504//Mayo Clinic (MAYO)/ ; P50 AG016574//Mayo Clinic (MAYO)/ ; NS039764//Mayo Clinic (MAYO)/ ; NS071674//Mayo Clinic (MAYO)/ ; 5RC2HG005605//Mayo Clinic (MAYO)/ ; R01 AG027944//Mayo Clinic (MAYO)/ ; R01 AG028786//Mayo Clinic (MAYO)/ ; R01 AG019085//Mayo Clinic (MAYO)/ ; IIRG09133827//Mayo Clinic (MAYO)/ ; A2011048//Mayo Clinic (MAYO)/ ; R01 AG09029//Multi-Institutional Research in Alzheimer's Genetic Epidemiology Study (MIRAGE)/ ; R01 AG025259//Multi-Institutional Research in Alzheimer's Genetic Epidemiology Study (MIRAGE)/ ; U24 AG021886//National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD)/ ; U24 AG056270//National Institute on Aging Late Onset Alzheimer's Disease Family Study (NIA- LOAD)/ ; //Texas Alzheimer's Research and Care Consortium (TARCC)/ ; //Darrell K Royal Texas Alzheimer's Initiative/ ; R01 AG019757//Vanderbilt University/Case Western Reserve University (VAN/CWRU)/ ; R01 AG021547//Vanderbilt University/Case Western Reserve University (VAN/CWRU)/ ; R01 AG027944//Vanderbilt University/Case Western Reserve University (VAN/CWRU)/ ; R01 AG028786//Vanderbilt University/Case Western Reserve University (VAN/CWRU)/ ; P01 NS026630//Vanderbilt University/Case Western Reserve University (VAN/CWRU)/ ; /ALZ/Alzheimer's Association/United States ; RF1 AG054023//Washington Heights-Inwood Columbia Aging Project (WHICAP)/ ; //University of Washington Families/ ; RF1 AG015473//Columbia University Hispanic Estudio Familiar de Influencia Genetica de Alzheimer (EFIGA)/ ; //University of Toronto (UT)/ ; /WT_/Wellcome Trust/United Kingdom ; /MRC_/Medical Research Council/United Kingdom ; /CAPMC/CIHR/Canada ; R01 AG007584//Genetic Differences (GD)/ ; HL105756//National Heart, Lung, and Blood Institute (NHLBI)/ ; RC2HL102419//National Heart, Lung, and Blood Institute (NHLBI)/ ; //CHARGE/ ; //Austrian Stroke Prevention Study (ASPS)/ ; //Prospective Dementia Registry-Austria (ASPS/PRODEM-Aus)/ ; //Atherosclerosis Risk in Communities (ARIC)/ ; //Cardiovascular Health Study (CHS)/ ; //Erasmus Rucphen Family Study (ERF)/ ; //Framingham Heart Study (FHS)/ ; //Rotterdam Study (RS)/ ; //ASPS/ ; P20545-P05//Austrian Science Fond (FWF)/ ; P13180//Austrian Science Fond (FWF)/ ; //Medical University of Graz/ ; //ASPS-Fam/ ; //Austrian Science Fund (FWF)/ ; //Joint Programme - Neurodegenerative Disease Research (JPND)/ ; //BRIDGET/ ; //Austrian Research Promotion agency (FFG)/ ; //Austrian National Bank/ ; N01-HC-25195/HL/NHLBI NIH HHS/United States ; HHSN268201100006C/HL/NHLBI NIH HHS/United States ; HHSN268201100007C/HL/NHLBI NIH HHS/United States ; HHSN268201100008C/HL/NHLBI NIH HHS/United States ; HHSN268201100009C/HL/NHLBI NIH HHS/United States ; HHSN268201100010C/HL/NHLBI NIH HHS/United States ; HHSN268201100011C/HL/NHLBI NIH HHS/United States ; HHSN268201100012C/HL/NHLBI NIH HHS/United States ; U01 2U01HL096812//ARIC/ ; 2U01HL096814//ARIC/ ; 2U01HL096899//ARIC/ ; 2U01HL096902//ARIC/ ; 2U01HL096917//ARIC/ ; R01-HL70825//MRI/ ; HHSN268201200036C//CHS/ ; HHSN268200800007C//CHS/ ; N01HC55222//CHS/ ; N01HC85079//CHS/ ; N01HC85080//CHS/ ; N01HC85081//CHS/ ; N01HC85082//CHS/ ; N01HC85083//CHS/ ; N01HC85086//CHS/ ; U01HL080295//CHS/ ; U01HL130114//CHS/ ; 018947//EUROSPAN (European Special Populations Research Network)/ ; LSHG-CT-2006-01947//EUROSPAN (European Special Populations Research Network)/ ; //European Community's Seventh Framework Programme/ ; //European Commission under the programme/ ; //Erasmus Medical Center and Erasmus University/ ; //Rotterdam, the Netherlands Organization for Health Research and Development/ ; //Research Institute for Diseases in the Elderly (RIDE)/ ; //Ministry of Education, Culture and Science/ ; //Ministry for Health/ ; //Welfare and Sports/ ; //European Commission (DG XII)/ ; //Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO)/ ; //Netherlands Consortium for Healthy Aging (NCHA)/ ; R01AG11380//Cache County Study/ ; R01AG031272//Cache County Study/ ; R01AG21136//Cache County Study/ ; RF1AG054052//Cache County Study/ ; P50AG008012//Case Western Reserve University Brain Bank (CWRUBB)/ ; RF1AG058267//Case Western Reserve University Rapid Decline (CWRURD)/ ; NU38CK000480//Case Western Reserve University Rapid Decline (CWRURD)/ ; 3U01AG052410//Cuban American Alzheimer's Disease Initiative (CuAADI)/ ; 5R37AG015473//Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA)/ ; RF1AG015473//Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA)/ ; R56AG051876//Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA)/ ; 2R01AG09029//Genetic and Environmental Risk Factors for Alzheimer Disease Among African Americans Study (GenerAAtions)/ ; R01AG025259//Genetic and Environmental Risk Factors for Alzheimer Disease Among African Americans Study (GenerAAtions)/ ; 2R01AG048927//Genetic and Environmental Risk Factors for Alzheimer Disease Among African Americans Study (GenerAAtions)/ ; U01AG062602//Gwangju Alzheimer and Related Dementias Study (GARD)/ ; 2014-A-004-NET//Gwangju Alzheimer and Related Dementias Study (GARD)/ ; R01AG032289//Gwangju Alzheimer and Related Dementias Study (GARD)/ ; R01AG048234//Gwangju Alzheimer and Related Dementias Study (GARD)/ ; R01AG027944//Hussman Institute for Human Genomics Brain Bank (HIHGBB)/ ; 5R01AG009956//Ibadan Study of Aging (IBADAN)/ ; //Longevity Genes Project (LGP)/ ; R01AG042188//LonGenity/ ; R01AG044829//LonGenity/ ; R01AG046949//LonGenity/ ; R01AG057909//LonGenity/ ; R01AG061155//LonGenity/ ; P30AG038072//LonGenity/ ; R01AG018016//Mexican Health and Aging Study (MHAS)/ ; 2R01AG09029//Multi-Institutional Research in Alzheimer's Genetic Epidemiology (MIRAGE)/ ; R01AG025259//Multi-Institutional Research in Alzheimer's Genetic Epidemiology (MIRAGE)/ ; 2R01AG048927//Multi-Institutional Research in Alzheimer's Genetic Epidemiology (MIRAGE)/ ; R01NS29993//Northern Manhattan Study (NOMAS)/ ; RF1AG054074//Peru Alzheimer's Disease Initiative (PeADI)/ ; GR066133/GR080002//Peru Alzheimer's Disease Initiative (PeADI)/ ; 340755/ERC_/European Research Council/International ; RF1AG054074//Puerto Rican Alzheimer Disease Initiative (PRADI)/ ; U01NS041588//Reasons for Geographic and Racial Differences in Stroke (REGARDS)/ ; U01AG052410//Research in African American Alzheimer Disease Initiative (REAAADI)/ ; P30 AG10161//Religious Orders Study (ROS)/ ; R01 AG15819//Religious Orders Study (ROS)/ ; P30 AG72975//Religious Orders Study (ROS)/ ; R01 AG42210//Religious Orders Study (ROS)/ ; R01 AG017917//RUSH Memory and Aging Project (MAP)/ ; R01 AG060747//RUSH Memory and Aging Project (MAP)/ ; //Miami Brain Endowment Bank (MBB)/ ; U01AG052410//University of Miami/Case Western/North Carolina A&amp;T African American (UM/CASE/NCAT)/ ; R01AG028786//University of Miami/Case Western/North Carolina A&amp;T African American (UM/CASE/NCAT)/ ; R01AG027161//Wisconsin Registry for Alzheimer's Prevention (WRAP)/ ; R01AG054047//Wisconsin Registry for Alzheimer's Prevention (WRAP)/ ; R01AG069013//Mexico-Southern California Autosomal Dominant Alzheimer's Disease Consortium/ ; R01AG047649//Center for Cognitive Neuroscience and Aging/ ; R01AG063689//A4 Study/ ; U19AG010483//A4 Study/ ; U24AG057437//A4 Study/ ; //LSACs/ ; U54 HG003273//Human Genome Sequencing Center at the Baylor College of Medicine/ ; U54HG003067//Broad Institute Genome Center/ ; U01AG057659//American Genome Center at the Uniformed Services University of the Health Sciences/ ; U54HG003079//Washington University Genome Institute/ ; //ADSP FUS/ ; //Hussman Institute for Human Genomics (HIHG)/ ; //Center for Genome Technology (CGT)/ ; //National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site/ ; U24AG041689//NIAGADS/ ; /LM/NLM NIH HHS/United States ; //Phenotype Harmonization Consortium/ ; U19AG024904//Alzheimer's Disease Neuroimaging Initiative (ADNI)/ ; RF1AG058066//Alzheimer's Disease Neuroimaging Initiative (ADNI)/ ; W81XWH-12-2-0012//Department of Defense/ ; //AbbVie/ ; //Araclon Biotech/ ; //BioClinica, Inc./ ; //Biogen/ ; //Bristol-Myers Squibb Company/ ; //CereSpir/ ; //Cogstate/ ; //Eisai Inc./ ; //Elan Pharmaceuticals, Inc./ ; //Eli Lilly and Company/ ; //EuroImmun/ ; //F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc./ ; //NIH/ ; U24AG072122//NACC/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics ; Genetic Risk Score ; Genome-Wide Association Study ; *Genetic Predisposition to Disease/genetics ; *Genetic Variation/genetics ; *Multifactorial Inheritance/genetics ; Polymorphism, Single Nucleotide ; Female ; European People ; White People/genetics ; Male ; },
abstract = {INTRODUCTION: We utilized an Alzheimer's disease (AD) polygenic risk score (PRS) to discover associations with novel rare variants (RVs).<br><br>METHODS: PRSs for European ancestry (EA) participants of the Alzheimer's Disease Sequencing Project were calculated using summary statistics from a large genome-wide association study. Participants were classified into high (n&#xa0;=&#xa0;5738) and low (n&#xa0;=&#xa0;5324) PRS groups based on the median PRS and on the lower and upper 35% of the PRS distribution.<br><br>RESULTS: Risk variants were disproportionately enriched in the low-PRS group, while protective ones were disproportionately enriched in the high-PRS group. Genome-wide significant (GWS) associations for increased AD risk were identified with RVs spanning a 3.5-Mb region on chromosome 14. GWS protective variants in ALDH9A1, BICC1, and PAN3 were identified in the upper 35% PRS group.<br><br>CONCLUSION: Our findings provide unique opportunities to study RVs whose effects are opposite to the risk conferred by the genetic background.},
}
@article {pmid42558527,
year = {2026},
author = {Li, S and Cao, T and Zhang, Q},
title = {Oxidative stress as a driver of organelle cascade damage in neurological diseases.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1892923},
pmid = {42558527},
issn = {1663-4365},
abstract = {As a core driver in the pathological progression of neurological diseases, oxidative stress contributes to the onset and development of multiple disorders, including traumatic brain injury (TBI), Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), by inducing interconnected and bidirectional damage among mitochondria, endoplasmic reticulum, lysosomes, and the nucleus. This review systematically summarizes the oxidative stress-mediated inter-organelle crosstalk network: Mitochondria act as one of the earliest and central hubs, and their dysfunction (e.g., reactive oxygen species burst, calcium overload, and respiratory chain impairment) induces endoplasmic reticulum stress via ROS diffusion and calcium signaling disturbance. The disruption of endoplasmic reticulum calcium homeostasis further exacerbates mitochondrial damage, forming a vicious cycle. Lysosomes exhibit reduced membrane stability and impaired autophagic flux under oxidative stress, failing to clear damaged organelles and aggravating oxidative stress accumulation. Ultimately, oxidative stress signals are transmitted to the nucleus, resulting in DNA damage, aberrant epigenetic modifications, and activation of pro-inflammatory/pro-apoptotic genes, thereby accelerating disease progression. Notably, this organelle injury transmission is not a rigid unidirectional linear cascade; primary lysosomal or MAM defects can independently initiate the full organelle damage loop without preceding mitochondrial dysfunction. This review integrates current studies, clarifies context-dependent and disease-specific characteristics of organelle interactions, and discusses potential therapeutic strategies with critical consideration of translational challenges and limitations, providing a theoretical foundation for mechanistic research and clinical intervention of neurological diseases.},
}
@article {pmid42558626,
year = {2026},
author = {Chen, J and Zhang, Z},
title = {Advancements in non-pharmaceutical interventions for Alzheimer's disease management: an update review.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1855269},
pmid = {42558626},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD) is a chronic, progressive neurodegenerative condition that is characterized by an increasing incidence rate due to global population aging, resulting in a significant social and economic burden. Current pharmacological interventions offer only limited relief and are unable to halt neuronal loss and cognitive decline. Therefore, safe and effective non-pharmacological interventions (NPIs) are needed for the management of AD. This review systematically synthesizes literature from the PubMed and Web of Science databases (2020-2025) to evaluate the comparative efficacy of physical activity, dietary interventions, and cognitive stimulation therapy (CST), aiming to establish an evidence-based framework for optimized clinical implementation. Specifically, physical activity (e.g. aerobic exercise and strength training) has been shown to improve cognitive and physical function. Dietary interventions (e.g. the Mediterranean diet, Dietary Approaches to Stop Hypertension and The Mediterranean-DASH diet intervention for neurodegenerative delay diet) have been demonstrated to delay cognitive decline by modulating inflammation, but evidence regarding supplements is weak. Furthermore, CST has been evidenced to enhance patients' cognitive abilities and quality of life. The present review not only summarizes existing literature on the subject, but also explores future research directions, including mechanisms and personalized approaches of these interventions to improve the prognosis of AD patients.},
}
@article {pmid42558652,
year = {2026},
author = {Del Giudice, L and Guida, M and Aletta, MR and Pontieri, P},
title = {Targeting mitochondrial ribosomal proteins: a functional and translational framework for neurodegenerative disease research.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1882474},
pmid = {42558652},
issn = {1664-2295},
abstract = {Mitochondrial dysfunction is a central feature of neurodegenerative diseases, yet the molecular mechanisms governing mitochondrial protein synthesis remain insufficiently understood. Mitochondrial ribosomal proteins (MRPs), essential for the translation of mitochondrial-encoded components of the oxidative phosphorylation system, are emerging as critical regulators of neuronal homeostasis and survival. In this mini-review, we examine current knowledge on mitochondrial ribosomes with a focused analysis of three mitochondrial ribosomal proteins-MRPL44, NAM9, and GEP3-highlighting their structural and functional roles in maintaining mitochondrial integrity. We discuss evidence linking alterations in these proteins to key pathogenic processes relevant to neurodegeneration, including impaired oxidative phosphorylation, increased oxidative stress, and defective mitochondrial quality control. Importantly, we propose an integrative research perspective that positions these MRPs as potential modulators of tissue-specific vulnerability in neurodegenerative disorders. By synthesizing available data and identifying critical knowledge gaps, we outline future directions aimed at elucidating their contribution to neuronal dysfunction and disease progression. This work underscores mitochondrial ribosomal proteins as underexplored determinants of neurodegenerative pathology and suggests that their systematic investigation may reveal novel mechanistic insights and therapeutic opportunities.},
}
@article {pmid42558846,
year = {2026},
author = {Bhattacharya, A and Manjithaya, R and Chickabasaviah, Y and Alladi, PA},
title = {Locus Coeruleus as a Master Regulator of Diverse Functions in the Central Nervous System: Its Relevance in Ageing and Neurodegenerative Disorders.},
journal = {Annals of neurosciences},
volume = {},
number = {},
pages = {09727531261462296},
pmid = {42558846},
issn = {0972-7531},
abstract = {BACKGROUND: The brainstem nucleus locus coeruleus (LC) is a rod-shaped, cylindrical, deeply pigmented neuromelanin (NM)-rich cluster of noradrenergic cells placed bilaterally in the dorsolateral tegmentum of the pons. The main neurotransmitter synthesised by these neurons is norepinephrine (NE), which polymerises to NM. Collectively, it regulates a plethora of activities, including vigilance, synaptic plasticity, memory processing, pain, stress responses, selective attention, cognition, sleep, emotion, capillary wall permeability and cerebral blood flow, thereby holding a 'master key' to several processes. Despite being small in dimensions, it is of enormous significance in diverse functions. Degeneration of the LC occurs early and progressively in both Alzheimer's disease (AD) and Parkinson's disease (PD), with diverse impacts, and is linked to neuropsychiatric entities such as depression, anxiety, cognitive impairment, schizophrenia and rapid eye movement sleep disorders, thereby raising considerable interest in normal physiology as well as in disease.<br><br>SUMMARY: This review is to better understand the neuroanatomical connections of human LC (master regulator of the central nervous system), pigmentation, cellular types, neurotransmitters/co-transmitters, and its role in ageing and neurodegenerative diseases. Recent and relevant classical research and review articles were referred to from PubMed to prepare a short review of the structure of LC, its projections, NM pigment and neuroprotection. We further examined the details of its cell types, neurotransmitters, co-transmitter functions and its effects in ageing, AD and PD, with emphasis on human studies.<br><br>KEY MESSAGE: LC is a vital region that offers neuroprotection, assists in the maintenance of cognitive reserve and enhances resilience and neuronal survival, despite the presence of AD and PD pathology for several decades. Further, it synthesises NE and co-transmitters that regulate attention, sleep-wake cycle, mood, cognition and so on. Maintaining its integrity and function promises potential scope to promote its health with normal ageing and improve clinical strategies in patients with neurodegeneration.},
}
@article {pmid42558896,
year = {2026},
author = {Neal, V and Faria, AV and Zhang, W and Hillis, AE and Stockbridge, MD},
title = {Right hemisphere atrophy rate associates with naming recovery after left hemisphere ischaemic stroke.},
journal = {Brain communications},
volume = {8},
number = {4},
pages = {fcag291},
pmid = {42558896},
issn = {2632-1297},
abstract = {Numerous large-scale epidemiological studies investigating the trajectory of brain function after ischaemic stroke have presented data suggesting, on average, a persistent, accelerated decline in cognitive domains, including language, after accounting for the immediate impact of the stroke. We sought to further examine this trend, speculating that the average persistent decline may be a reflection of two subgroups with vastly different prognoses: (i) a minority experiencing decline secondary to neurodegenerative processes such as vascular dementia and Alzheimer's disease and (ii) a majority without marked progressive brain atrophy who typically see improvement. Our team thus investigated atrophy's association with language recovery, hypothesizing that declining naming performance in the year after left hemisphere ischaemic stroke would be correlated to atrophy of the contralesional hemisphere. We postulated that volume loss within the lesioned hemisphere would be less informative due to separate confounding processes related to the stroke itself, such as Wallerian degeneration and encephalomalacia. Participants [n = 72; M (SD) age = 60 (11)] in a longitudinal cohort study of language following left hemisphere ischaemic stroke were included if they completed an MRI both acutely and chronically (either 6 or 12 months post-stroke). Naming performance was assessed using the Boston Naming Test; stroke volumes were extracted from acute imaging; and atrophy was measured as the monthly per cent change in hemispheric volume from baseline to chronic scan for each individual. Pearson's correlations were calculated to determine the relationship between lesion volume and atrophy along with atrophy and change in Boston Naming Test score. Lesion volume negatively correlated with the monthly per cent change in volume of the left (ipsilesional) hemisphere (r = -0.48; P < 0.0001) but did not correlate with rate of right (contralesional) hemisphere volume loss. While there was no clear relationship between atrophy of the left hemisphere and language recovery, we found that volume changes of greater negative magnitude within the right hemisphere (increased atrophy) were associated with worse functional recovery of language (r = 0.38; P = 0.0025). By showing that atrophy of the right hemisphere was not significantly impacted by left hemisphere lesion size, we suggest that accelerated volume loss in the non-lesioned hemisphere after stroke may be indicative of a separate pathology. We then support this claim with behavioural data showing that greater rates of volume loss within the non-lesioned hemisphere were associated with poorer naming recovery. Together, these findings imply that contralesional atrophy after stroke may have negative implications for recovery and could serve as a useful imaging signature for separate neurodegenerative processes.},
}
@article {pmid42558962,
year = {2026},
author = {Corley, DA and Alavi, M and Fireman, BH and Finch, T and Prausnitz, S and Rouillard, S and Lee, K and Hamilton, L and Ansari, M},
title = {Associations of multiple evidence-based care strategies with disease mortality, life expectancy, and disparities in the United States.},
journal = {Health affairs scholar},
volume = {4},
number = {8},
pages = {qxag184},
pmid = {42558962},
issn = {2976-5390},
abstract = {INTRODUCTION: Limited data exist regarding the potential cumulative effects of multiple, integrated, system-level strategies on population-level outcomes and disparities.<br><br>METHODS: We evaluated associations between membership within a multi-disease, integrated population health management model with disease-specific mortality, life expectancy, and demographic disparities and relevant comparators. Bias was minimized through use of a large, representative, multicenter community-based setting, multiple comparators (including similar insured status, same-state, comparable comorbidity distributions, and national), demographic adjustments, and causality criteria.<br><br>RESULTS: Among 3 944 173 persons demographics-adjusted mortality was significantly lower for 9 of 10 leading causes of death, including the 5 leading preventable conditions (age-, sex-, race-adjusted risk ratios and 95% CIs Kaiser Permanente, Northern California vs United States [US, all])-cancer (0.85; 0.83-0.88), heart disease (0.69; 0.67-0.71), stroke (0.86; 0.82, 0.91), injury (majority overdoses and falls; 0.45; 0.42-0.48), and respiratory disease (0.59; 0.55-0.63)-but not unmodifiable causes (eg, Alzheimer's disease (1.58; 1.51-1.66). Most life-years gained occurred during ages most impacted by disease-management programs: 50-72 years (>0.075 life-year/year). Life expectancy exceeded comparators and was 4.9 years higher than the US average (83.3 vs 78.4 years, 2023). Findings were robust to index years, multiple other comparator populations, and adjusted analyses. Demographic disparities were smaller across major benchmarks.<br><br>CONCLUSION: These findings suggest that high uptake of multiple, existing, evidence-based population health strategies may be cumulatively associated with substantially reduced disease-specific mortality, decreased disparities, and increased life expectancy, comparable to values in comparator countries.},
}
@article {pmid42559122,
year = {2026},
author = {, and Boquet-Pujadas, A and Anagnostakis, F and Yang, Z and Tian, YE and Duggan, MR and Erus, G and Srinivasan, D and Joynes, CM and Bai, W and Patel, PJ and Walker, KA and Zalesky, A and Davatzikos, C and Wen, J},
title = {Multi-organ AI endophenotypes chart the heterogeneity of brain, eye and heart pan-disease.},
journal = {Nature. Mental health},
volume = {4},
number = {2},
pages = {203-230},
pmid = {42559122},
issn = {2731-6076},
abstract = {Disease heterogeneity and commonality pose significant challenges to precision medicine, as traditional approaches frequently focus on single disease entities and overlook shared mechanisms across conditions. Inspired by pan-cancer and multi-organ research, we introduce the concept of "pan-disease" to investigate the heterogeneity and shared etiology in brain, eye, and heart diseases. Leveraging individual-level data from 129,340 participants, as well as summary-level data, curated from the MULTI consortium, we applied a weakly-supervised deep learning model (Surreal-GAN) to multi-organ imaging, genetic, proteomic, and RNA-seq data, identifying 11 AI-derived biomarkers, called Multi-organ AI Endophenotypes (MAEs), for the brain (Brain 1-6), eye (Eye 1-3), and heart (Heart 1-2), respectively. We found Brain 3 to be a risk factor for Alzheimer's disease (AD) progression and mortality, whereas Brain 5 was protective against AD progression. Crucially, in data from an anti-amyloid AD drug (solanezumab), heterogeneity in cognitive decline trajectories was observed across treatment groups. At week 240, patients with lower brain 1-3 expression had slower cognitive decline, whereas patients with higher expression had faster cognitive decline. A multi-layer causal pathway pinpointed Brain 1 as a mediational endophenotype linking the FLRT2 protein to migraine, exemplifying novel therapeutic targets and pathways. Additionally, genes associated with Eye 1 and Eye 3 were enriched in cancer drug-related gene sets with causal links to specific cancer types and proteins. Finally, Heart 1 and Heart 2 had the highest mortality risk and unique medication history profiles, with Heart 1 showing favorable responses to antihypertensive medications and Heart 2 to digoxin treatment. The 11 MAEs provide novel AI dimensional representations for precision medicine and highlight the potential of AI-driven patient stratification for disease risk monitoring, clinical trials, and drug discovery.},
}
@article {pmid42559376,
year = {2026},
author = {Niu, S and Liu, X and Xu, R and Zhu, A and Zhu, S and Hu, F and Ding, K and Li, S and Zhu, B and Liang, P and Zhang, S and Xiao, A and Fan, K and Zhang, Z},
title = {Multifunctional nanozyme platforms in central nervous system therapies: from rational design to translational medicine.},
journal = {Theranostics},
volume = {16},
number = {14},
pages = {8385-8426},
pmid = {42559376},
issn = {1838-7640},
mesh = {Humans ; *Central Nervous System Diseases/drug therapy/therapy ; Animals ; *Nanostructures/chemistry/therapeutic use ; Translational Research, Biomedical/methods ; Drug Delivery Systems/methods ; Neuroprotective Agents ; *Enzymes ; },
abstract = {Central nervous system (CNS) disorders-including ischemic stroke, traumatic brain/spinal cord injury, Parkinson's disease, and Alzheimer's disease-have long faced limitations in achieving functional recovery and disease-modifying therapies because of their complex pathophysiological mechanisms. Traditional therapies are often constrained by poor penetration across CNS barriers, limited participation in multiple pathological cascades, and insufficient persistence of therapeutic effects. Nanozymes are a class of nanomaterials with enzyme-like catalytic activity and tunable physicochemical properties. Not only do these nanozymes continuously scavenge reactive oxygen and nitrogen species in pathological environments through stable multi-enzyme synergistic effects by leveraging their abundant active sites, but also serve as multimodal therapeutic delivery platforms to achieve efficient drug delivery, opening up new avenues for neuroprotection and regenerative medicine. This review systematically examines the fundamental characteristics, classification systems, and functional design approaches of nanozymes, along with their potential for combined therapeutic strategies, including synergistic applications with drugs, hydrogels, genes, or cells. Additionally, it summarizes the latest advancements in neuroprotection and repair associated with CNS disorders. The review further analyzes current limitations and challenges related to clinical translation and offers insights into future research directions to enhance scientific knowledge and clinical applications in this significant field.},
}
@article {pmid42559503,
year = {2026},
author = {Acevedo-Nieto, J and Martínez, K and Amaya, C},
title = {The Role of Slow Gait Speed in Cognitive Decline among Aging Women: A Systematic Review.},
journal = {HSOA journal of gerontology &amp; geriatric medicine},
volume = {12},
number = {1},
pages = {},
pmid = {42559503},
issn = {2381-8662},
abstract = {UNLABELLED: The prevalence of Alzheimer's disease and related dementias are increasing at an alarming rate, with projections estimating that by 2060, approximately 13.8 million adults aged 65 years and older in the U.S. will be affected by one or both. Among the many symptoms associated with cognitive decline, gait impairment is one that significantly affects functional independence and mobility.<br><br>METHODS: A systematic review was conducted to analyze 49 peer-reviewed studies using the Covidence systematic review software and adhering to PRISMA guidelines. The selected articles examined variables related to gait speed, and cognition. Participants were assessed through validated neurocognitive and mobility measures, including the MoCA and Dynamic Gait Index.<br><br>RESULTS: A significant negative correlation was identified between usual walking speed and age. This trend was particularly pronounced in women, in whom a significant negative association between MoCA scores and age (P = -0.019) was observed, suggesting an increased susceptibility to cognitive deterioration with advancing age.<br><br>CONCLUSION: These findings underline the sex-specific nature of the relationship between gait speed and cognitive function, highlighting increased vulnerability in aging women. The decline in mobility and cognition observed in this population underscores the urgency of developing targeted interventions that integrate physical and cognitive rehabilitation strategies.},
}
@article {pmid42559518,
year = {2026},
author = {Uppalapati, A and Vishnubhotla, A and Pahan, K},
title = {Prospect of Muscle-Building Supplement HMB in Alzheimer's Disease.},
journal = {Journal of clinical &amp; experimental immunology},
volume = {11},
number = {3},
pages = {},
pmid = {42559518},
abstract = {Alzheimer's disease (AD) is the most common progressive and irreversible neurodegenerative disorder in humans that affects memory, thinking and behavior. Impairment in synaptic plasticity is one of the hallmarks in AD, with most of the impairment occurring in the hippocampal region, a key part of the brain for memory and learning. Therefore, the upregulation of hippocampal plasticity is critical to remediate the progression of AD and preserve memory formation and cognitive functions. Recent studies have described β-hydroxy-β-methylbutyrate (HMB), a body building supplement commonly used by athletes, as a candidate molecule for improving hippocampal plasticity. Clinically, AD is characterized by the abnormal accumulation of beta amyloid (Aβ) plaques, coupled with intracellular aggregates of hyperphosphorylated tau protein. In addition to enhancing hippocampal plasticity, HMB has been also demonstrated to lower amyloid plaques in a mouse model of AD. Although liver is rich in peroxisome proliferator-activated receptor alpha (PPARα), recent findings have established the presence of PPARα in hippocampus and other parts of the brain. Interestingly, HMB has been shown to utilize PPARα for lowering plaques and increasing hippocampal plasticity. Here, we discuss these newly described features of HMB with possible implications for the use of HMB supplement in patients with dementia and AD.},
}
@article {pmid42559821,
year = {2026},
author = {Moradi, K and Hadidchi, R and Majbri, A and Hughes, TM and Lu, H and Zhu, Y and Mohammadi, S and Momtazmanesh, S and Mukherjee, P and Abdullah, M and Simonsick, E and Schrack, JA and Goncalves, MD and Coresh, J and Albert, M and Demehri, S},
title = {Temporalis muscle biomarkers from routine brain MRI and risk of dementia in two independent cohorts.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71622},
doi = {10.1002/alz.71622},
pmid = {42559821},
issn = {1552-5279},
support = {//National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)/ ; R01AR079620//National Institutes of Health (NIH)/ ; W81XWH-12-2-0012//DOD ADNI/ ; U01HL096812//ARIC Neurocognitive Study/ ; U01HL096814//ARIC Neurocognitive Study/ ; U01HL096899//ARIC Neurocognitive Study/ ; U01HL096902//ARIC Neurocognitive Study/ ; U01HL096917//ARIC Neurocognitive Study/ ; U01AG024904/AG/NIA NIH HHS/United States ; R01AR079620/AR/NIAMS NIH HHS/United States ; },
mesh = {Humans ; *Magnetic Resonance Imaging ; Female ; *Dementia/diagnostic imaging ; Male ; *Brain/diagnostic imaging ; Biomarkers ; Aged ; Cohort Studies ; *Muscle, Skeletal/diagnostic imaging/pathology ; Neuroimaging ; Alzheimer Disease/diagnostic imaging ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Skeletal muscle loss is associated with cognitive decline, but whether neuroimaging-derived muscle characteristics predict incident dementia remains unclear.<br><br>METHODS: We evaluated associations of deep learning-derived temporalis muscle (TM) cross-sectional area (CSA) and radiomic texture features from baseline T1-weighted magnetic resonance imaging (MRI) with incident dementia in dementia-free participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) (n&#xa0;=&#xa0;750) and the Atherosclerosis Risk in Communities (ARIC) study (n&#xa0;=&#xa0;532). TM was segmented using a convolutional neural network trained in ADNI and externally validated in ARIC. Radiomic features were reduced using least absolute shrinkage and selection operator-penalized Cox models to generate a composite score. Multivariable Cox regression adjusted for demographics, apolipoprotein&#xa0;E &#x3b5;4, baseline cognition, body mass index, and physical performance.<br><br>RESULTS: Higher TM radiomic scores were associated with increased dementia risk in ADNI (hazard ratio per SD, 1.32) and ARIC (1.64). Smaller TM CSA predicted dementia in ADNI but not ARIC.<br><br>DISCUSSION: TM texture patterns from routine brain MRI are associated with dementia risk, supporting TM phenotyping as a scalable marker of systemic biological vulnerability.},
}
@article {pmid42560011,
year = {2026},
author = {Abrar, F and Martin, DDO},
title = {Molecular switches of SQSTM1: the impact of post-translational modifications on autophagy and neurodegeneration.},
journal = {Autophagy},
volume = {},
number = {},
pages = {1-17},
doi = {10.1080/15548627.2026.2711593},
pmid = {42560011},
issn = {1554-8635},
abstract = {SQSTM1/p62 (sequestosome 1) is an important receptor protein involved in many cellular signaling processes, including macroautophagy/autophagy. It is a molecular hub for cellular homeostasis and cellular responses. Within autophagy, SQSTM1 targets ubiquitinated cargo for degradation, maintaining cellular proteostasis. Structurally, SQSTM1 consists of several domains that facilitate its binding to ubiquitinated cargo, the formation of SQSTM1 aggregate inclusions, interactions with MAP1LC3/LC3, and the mediation of clearance via the autophagy pathway. Beyond its structure, post-translational modifications of SQSTM1 dynamically regulate its function within a cell. Post-translational modifications - such as phosphorylation, ubiquitination, acetylation, S-acylation, and S-nitrosylation - are crucial for regulating SQSTM1 function, localization, and interaction with autophagic components, thereby influencing SQSTM1's role in the autophagy pathway. Understanding the role of these protein modifications in modulating autophagy may provide better insight into developing therapeutic strategies for diseases with dysregulated autophagy, such as neurodegenerative diseases. This review will discuss the role of these post-translational modifications in controlling SQSTM1's localization and function in autophagy.Abbreviations: ABHD = α/β-hydrolase domain; AD = Alzheimer Disease; ALS = amyotrophic lateral sclerosis; ATG = autophagy related ; CSNK2/CK2 = casein kinase 2; HD = Huntington Disease; HDAC/KDAC = histone deacetylase/lysine deacetylase; HTT = huntingtin; KAT = lysine acetyltransferase; KEAP1 = kelch like ECH associated protein 1; KIR = KEAP1-interacting region; LIR = LC3-interacting region; LYPLA/APT = lysophospholipase/acyl-protein thioesterase; MAP1LC3/LC3 = microtubule associated protein 1 light chain 3; MEF = mouse embryonic fibroblast; mHTT = mutant huntingtin; MTORC1 = MTOR complex 1; NBR1 = NBR1 autophagy cargo receptor; NEDD4 = NEDD4 E3 ubiquitin protein ligase ; NO = nitric oxide; NFE2L2/Nrf2 = nuclear factor erythroid 2-factor 2; PAT = palmitoyl acyltransferase; PB1 = Phox-BEM1 domain; PE = phosphatidylethanolamine; PLEKHM1 = pleckstrin homology and RUN domain containing M1; PLK2 = polo like kinase 2; PRKA/PKA = protein kinase cAMP-activated; PPT1 = palmitoyl-protein thioesterase 1; RB1CC1 = RB1 inducible coiled-coil 1; SNCA/α-synuclein = synuclein alpha; SNO = S-nitrosothiol; SOD1 = superoxide dismutase 1; SQSTM1 = sequestosome 1; TARDBP/TDP-43 = TAR DNA binding protein ; TBK1 = TANK binding kinase 1; TAX1BP1 = Tax1 binding protein 1; TRIM = tripartite motif containing ; UBA = ubiquitin-associated domain; UBE = ubiquitin-conjugating enzyme; ULK1 = unc-51 like autophagy activating kinase 1; UPS =ubiquitin-proteasome system; USP8 = ubiquitin specific peptidase 8; ZDHHC = zDHHC palmitoyltransferase.},
}
@article {pmid37259937,
year = {2024},
author = {De, SK},
title = {Novel Pyrimidin-4-yl-3-amino-pyrrolo[3,4-c]pyrazoles as Protein Kinase C Inhibitors for Treating Diseases.},
journal = {Current medicinal chemistry},
volume = {31},
number = {8},
pages = {1036-1039},
doi = {10.2174/0929867330666230531164754},
pmid = {37259937},
issn = {1875-533X},
mesh = {Humans ; *Protein Kinase Inhibitors/chemistry/therapeutic use/pharmacology ; *Pyrazoles/chemistry/therapeutic use/pharmacology ; *Protein Kinase C/antagonists &amp; inhibitors/metabolism ; Animals ; Neoplasms/drug therapy ; Cardiovascular Diseases/drug therapy ; *Pyrimidines/chemistry/therapeutic use/pharmacology ; Central Nervous System Diseases/drug therapy ; Inflammation/drug therapy ; },
abstract = {This patent describes the series of compounds and their pharmaceutically acceptable salts, such as compound K7 (as a representative potent compound). These protein kinase C selective inhibitors are useful for treating diabetes mellitus and its complications, cancer, ischemia, inflammation, central nervous system disorders, cardiovascular disease, Alzheimer's disease, dermatological disease, virus diseases, inflammatory disorders, or diseases in which the liver is a target organ.},
}
@article {pmid42551536,
year = {2026},
author = {Lei, Y and Liu, L and Tang, Y},
title = {How do energy metabolism disorders and neuroinflammation collectively contribute to the pathogenesis of Alzheimer's disease?.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103287},
doi = {10.1016/j.arr.2026.103287},
pmid = {42551536},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD), as the leading cause of dementia, poses an increasingly severe socioeconomic burden in the context of global ageing. Traditionally defined by amyloid-β and tau pathology, it's increasingly recognized as a systems disorder in which impaired glucose metabolism, mitochondrial dysfunction, and neuroinflammation interact across neural cell types and disease stages. However, the interaction among these three mechanisms, their role in promoting the classical pathology of AD, and their verification in major neural cell types remains unclear. This review summarizes the alterations in glucose metabolism and mitochondrial metabolism in neurons, astrocytes and microglia in AD and their relationship with neuroinflammation, while also discussing some unaddressed questions, outlining therapeutic strategies, and future promising directions. Biomarkers that reflect disease stage and pathological status, multitarget therapeutic strategies, individualized precision medicine, and the integration of pharmacological with non-pharmacological interventions represent particularly promising directions for the future.},
}
@article {pmid42551552,
year = {2026},
author = {Kumar, V and Arulsamy, S and Sharma, S and Kumar, S and Kakoty, V},
title = {Covalent small-molecule RNA targeting in Alzheimer's disease: computational strategies, challenges and opportunities.},
journal = {Drug discovery today},
volume = {},
number = {},
pages = {104758},
doi = {10.1016/j.drudis.2026.104758},
pmid = {42551552},
issn = {1878-5832},
abstract = {RNA dysfunction is increasingly recognized as an upstream driver of Alzheimer's disease pathology, and covalent small molecules that engage pathogenic RNA structures are emerging as a therapeutic strategy. In addition to its role as a template, RNA governs amyloid-β production, the tau isoform balance and neuroinflammation through aberrant splicing, noncoding RNA activity and epitranscriptomic modification. The irreversible engagement of these structures enables modulation with sustained target occupancy. This analysis examines how covalent docking, molecular dynamics and AI-enabled screening can be combined to identify electrophilic RNA binders, using the microtubule-associated protein tau exon 10 splicing regulatory element and the amyloid precursor protein 5'-UTR as concrete reference points. It assesses the determinants of nucleophilic reactivity in folded RNA, the electrophilic modules with demonstrated RNA reactivity and the barriers of selectivity, brain delivery and translational validation.},
}
@article {pmid42551683,
year = {2026},
author = {Gao, J and Xu, Y and Jiang, W and Wang, Z and Wang, L and Zhang, H},
title = {Adenosine monophosphate-activated protein kinase: A golden mediator of exercise in metabolic dysfunction-associated diseases (review).},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {153885},
doi = {10.1016/j.ijbiomac.2026.153885},
pmid = {42551683},
issn = {1879-0003},
abstract = {Metabolic diseases represent a major threat to human health and are largely associated with excessive energy intake and insufficient energy expenditure. Increasing evidence indicates that obesity, diabetes, metabolic dysfunction-associated fatty liver disease, sarcopenia, Alzheimer's disease, and cancer are closely associated with metabolic dysfunction. Extensive clinical studies and therapeutic strategies have been developed for the prevention and treatment of these disorders. Among these approaches, targeted regulation of cellular energy homeostasis has emerged as a widely recognized strategy, with adenosine monophosphate-activated protein kinase (AMPK) identified as an important therapeutic target for metabolic disease intervention. With the growing development of sports medicine, exercise has become a preferred non-pharmacological approach for the prevention and management of metabolic dysfunction-related diseases, with its beneficial effects largely mediated through AMPK activation. However, the mechanisms by which exercise modulates AMPK and its subtypes in different tissues and diseases remain incompletely understood. Therefore, this narrative review retrieved English-language literature published up to May 2026 from the PubMed, Web of Science, and Scopus databases. A search strategy was constructed using the terms "AMPK", "exercise", "obesity", "diabetes", "NAFLD/MASLD", "sarcopenia", and "Alzheimer's disease" and the corresponding tissues associated with these metabolic diseases. A comprehensive analysis was conducted focusing on AMPK and its subtypes. In this narrative review, we synthesize current research on how exercise modulates AMPK in different tissues and subtype-specific functions, summarizing and analyzing existing evidence that may provide a theoretical basis for subtype-targeted therapeutic strategies (including exercise therapy and pharmacological therapy) for metabolic dysfunction-related diseases.},
}
@article {pmid42551762,
year = {2026},
author = {Lin, S and Xue, M and Xu, C and Sheng, C and Wang, T and Sun, J and Chen, Y and Lian, J and Zhang, T and Wang, W},
title = {White and gray matter microstructural alterations in subjective cognitive decline: an exploratory study using TBSS and GBSS.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {112070},
doi = {10.1016/j.brainresbull.2026.112070},
pmid = {42551762},
issn = {1873-2747},
abstract = {OBJECTIVE: Subjective cognitive decline (SCD), which may represent the preclinical stage of Alzheimer's disease (AD) in a subset of individuals, lacks objective biomarkers, thus hindering the implementation of early intervention for AD. This study tentatively explored the potential value of neurite orientation dispersion and density imaging (NODDI) in assessing the microstructural integrity of gray matter (GM) and white matter (WM) in SCD.<br><br>METHODS: We enrolled 47 SCD subjects and 30 healthy controls (HCs). Through the TBSS and GBSS analysis based on NODDI, the neurite density index (NDI) and orientation dispersion index (ODI) were used to evaluate the microstructural integrity of GM and WM. NODDI parameters were extracted from multiple brain regions to assess their diagnostic utility in distinguishing SCD from HCs.<br><br>RESULTS: In WM microstructure, NDI of the genu of corpus callosum was decreased, and the ODI of the left posterior thalamic radiation and posterior corona radiata were decreased. In GM microstructure, the NDI of the left hippocampus, amygdala and parahippocampal gyrus were decreased, whereas the ODI of the rolandic operculum, opercular part of inferior frontal gyrus, and precentral gyrus were increased. Logistic regression analysis results showed that the NDI value of GM, the ODI value of GM and the ODI value of WM were independent predictors and the combination of the three parameters had the best classification effect.<br><br>CONCLUSION: This exploratory study suggests that NODDI may detect microstructural differences in GM and WM associated with SCD. These preliminary findings provide hypothesis-generating clues for future research into potential imaging markers for identifying SCD individuals. Additional studies are necessary to confirm these preliminary results.},
}
@article {pmid42551772,
year = {2026},
author = {Muedano-Sosa, A and Trujillo-Pineda, M and Ruiz-Pérez, S and Cervera, A and González-Barrios, R and Arias, C and Flores-León, M},
title = {In silico analysis of transcriptomic datasets reveals nonlinear gene expression trajectories in aging microglia and Alzheimer's disease.},
journal = {Experimental gerontology},
volume = {},
number = {},
pages = {113263},
doi = {10.1016/j.exger.2026.113263},
pmid = {42551772},
issn = {1873-6815},
abstract = {BACKGROUND: Neuroinflammation, a key factor in aging and neurodegeneration, is characterized by the increased activation of microglia, the brain's resident immune cells. Microglia play a central role in maintaining brain homeostasis, and their dysregulation during aging is increasingly implicated in the onset and progression of Alzheimer's disease (AD). However, the molecular mechanisms underlying microglial state transitions across physiological and pathological aging remain poorly understood.<br><br>METHODS: To address this gap, we conducted an in silico comparative transcriptomic study using publicly available datasets from two murine bulk RNA-seq including wild-type (WT) and APP/PS1 transgenic (Tg) mice at multiple ages, one human scRNA-seq dataset with multiple ages, and data obtained from SCAD-Brain.<br><br>RESULT: Our analyses revealed that physiological microglial aging is characterized by dynamic, non-linear gene expression trajectories, whereby genes involved in mitochondrial function, lysosomal degradation, and immune response follow a mirror-like pattern across aging. This mirror-like behavior was conserved in human microglial data across ages. In contrast, this adaptive pattern was disrupted at late-stage pathological aging in Tg mice, where sustained alterations in inflammatory, mitochondrial, and lysosomal pathways became more pronounced. Consistent with these findings, genes dysregulated in Tg mice showed similar expression trends in AD patients in the SCAD-Brain database.<br><br>CONCLUSION: These results suggest that middle age may represent a critical transition stage preceding neuroinflammation and neurodegeneration, making it an attractive window to identify preventive or therapeutic targets in early AD. Collectively, this study identifies candidate pathways and genes that warrant further experimental validation in the context of AD and age-related neurodegeneration.},
}
@article {pmid42551778,
year = {2026},
author = {Jaiswal, V and Deb, N and Latif, F and Shrestha, AB and Garimella, V and Shama, N and Jitta, SR and Naz, S and Kumar, T and Khan, S and Perone, F and Mattumpuram, J and Ang, SP},
title = {Association between PCSK9 targeted therapy and the risk of stroke and dementia: A Meta-Analysis of Randomized Controlled Trials.},
journal = {The American journal of medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.amjmed.2026.06.034},
pmid = {42551778},
issn = {1555-7162},
abstract = {BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) targeted therapies have been shown to reduce low-density lipoprotein cholesterol (LDL-C) levels and circulating PCSK9. However, its effect on cerebrovascular outcomes, especially stroke and dementia, has not been well established to date.<br><br>METHODS: We conducted a systematic literature search of electronic databases for relevant randomized controlled trials (RCTs) from inception through January 2025. Odds ratios (OR) and 95% confidence intervals (CI) were pooled using a random-effect model, and a p-value of <0.05 was considered statistically significant.<br><br>RESULTS: A total of 22 RCTs with 64,116 patients were included in the study. Pooled analysis showed that PCSK9-targeted therapy significantly reduced the risk of all-cause stroke (OR, 0.78 (95% CI: 0.68-0.90), P < 0.001) and ischemic stroke (OR, 0.77 (95% CI: 0.63-0.94), P=0.01). However, no significant association was observed for the risk of hemorrhagic stroke (OR, 1.16 (95%CI: 0.70-1.93), P=0.56), transient ischemic attack (OR, 0.98 (95%CI: 0.48-2.06), P= 0.95), dementia (OR, 0.77 (95%CI: 0.14-4.28), P=0.76), dementia of Alzheimer's type (OR, 0.81 (95%CI: 0.14-4.70), P=0.82), and Parkinson's disease (OR, 0.82 (95%CI: 0.11-6.37), P=0.85).<br><br>CONCLUSION: PCSK9 targeted therapies appear to reduce the risk of stroke; however, no significant association was observed for the risk of dementia and Parkinson's disease.},
}
@article {pmid42551844,
year = {2026},
author = {Xie, Q and Zhang, J and Wang, Y and Huang, J and Lin, F and Weng, RL and He, H and Chen, Q and Xu, H},
title = {CiteSure: retrieval-augmented large language models for faithful biomedical citation recommendation.},
journal = {Journal of the American Medical Informatics Association : JAMIA},
volume = {},
number = {},
pages = {},
doi = {10.1093/jamia/ocag122},
pmid = {42551844},
issn = {1527-974X},
support = {R01AG073435/NH/NIH HHS/United States ; R01LM013519/NH/NIH HHS/United States ; R01AG080429/NH/NIH HHS/United States ; 1K99LM01402/NH/NIH HHS/United States ; 1K99LM014614-01/NH/NIH HHS/United States ; },
abstract = {OBJECTIVES: Accurate citation of relevant publications is essential for scientific integrity in biomedical research. Large language models (LLMs) excel at text generation but often hallucinate fabricated or inaccurate citations. Retrieval-augmented generation (RAG) can mitigate these errors, yet current approaches lack semantic precision in evidence retrieval. This study aims to develop a domain-specific RAG system for reliable, context-specific biomedical citation recommendations.<br><br>MATERIALS AND METHODS: We introduce CiteSure, a sentence-level citation recommendation tool designed to deliver reliable, evidence-based, and context-specific references using LLMs. CiteSure utilizes a 2-stage retrieval-augmented generation (RAG) framework, combining a domain-specific dense retriever (BioLLM2Vec) and reranker (BioRankLLaMA), adapted from LLaMA3-8B-Instruct using biomedical-specific training data. CiteSure leverages the complementary strengths of retrieval and generative LLM models, ensuring factual precision and contextual alignment. We evaluated CiteSure on a curated Alzheimer's disease dataset, comparing it to standalone LLMs and traditional retrieval-based methods.<br><br>RESULTS: CiteSure achieved 100% factual accuracy and the highest relevance score of 77.50%, outperforming all baselines. BioLLM2Vec retrieved relevant articles with over 80% accuracy in the top 100 candidates. BioRankLLaMA consistently outperformed baseline rerankers across MAP, MRR, and Precision@5 metrics, confirming the benefit of domain-specific adaptation and contrastive fine-tuning.<br><br>DISCUSSION AND CONCLUSION: Our results demonstrate that CiteSure, built on a 2-stage retrieval-augmented generation framework, effectively integrates domain-specific retrieval with LLM-based generation to achieve substantial improvements over baseline approaches. Our work underscores the importance of domain-specific adaptation in biomedical citation recommendation and provides publicly available datasets, models, and code for support future research.},
}
@article {pmid42552038,
year = {2026},
author = {Peter L, IR and Chatterjee, D and Chrishone, AF and Francis, D},
title = {Metabolic therapeutic targets in Alzheimer's disease.},
journal = {International review of neurobiology},
volume = {188},
number = {},
pages = {1-32},
doi = {10.1016/bs.irn.2026.05.010},
pmid = {42552038},
issn = {2162-5514},
mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy ; Animals ; *Energy Metabolism/physiology/drug effects ; *Brain/metabolism ; *Mitochondria/metabolism ; Glucose/metabolism ; },
abstract = {Alzheimer's disease (AD) is increasingly recognized as a disorder marked not only by amyloid-β and tau pathology, but also by profound disturbances in brain energy metabolism that arise early in disease progression. Accumulating evidence indicates that impairments in glucose utilization, insulin signaling, and mitochondrial function precede neurodegeneration and contribute directly to synaptic failure and cognitive decline. This chapter presents a comprehensive overview of Alzheimer's disease through the lens of metabolic dysfunction, highlighting disrupted neuronal bioenergetics as a central and unifying feature of pathogenesis. We examine key metabolic pathways implicated in AD, including cerebral glucose hypometabolism, brain insulin resistance, impaired glycolysis, mitochondrial oxidative phosphorylation deficits, oxidative stress, and altered mitochondrial dynamics. The chapter further discusses therapeutic strategies aimed at restoring metabolic homeostasis, such as insulin sensitization, enhancement of glucose transport, activation of mitochondrial biogenesis, modulation of the electron transport chain, and the use of mitochondria-targeted antioxidants. In parallel, alternative energy approaches-including ketone metabolism, fatty acid oxidation, and pentose phosphate pathway activation-are explored as promising avenues to bypass glucose-dependent energy deficits and reinforce neuronal resilience. Emerging directions in metabolic therapeutics are also highlighted, including combination treatment strategies, NAD[+]-sirtuin and AMPK signaling, and the expanding role of the gut microbiome-brain metabolism axis. By integrating insights from experimental models, neuroimaging studies, and clinical trials, this chapter underscores the potential of metabolic interventions to enable early, disease-modifying strategies for Alzheimer's disease.},
}
@article {pmid42552040,
year = {2026},
author = {Chaurasia, V and Das Modak, S and Singh, GK and Modi, G},
title = {A comprehensive review on therapeutics and diagnostic agents targeting acetyl and butyryl cholinesterases for AD.},
journal = {International review of neurobiology},
volume = {188},
number = {},
pages = {145-198},
doi = {10.1016/bs.irn.2026.05.017},
pmid = {42552040},
issn = {2162-5514},
mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnosis/enzymology/metabolism ; *Butyrylcholinesterase/metabolism/drug effects ; *Cholinesterase Inhibitors/pharmacology/therapeutic use ; Animals ; *Acetylcholinesterase/metabolism/drug effects ; },
abstract = {Alzheimer's disease (AD) is a progressive, irreversible, and multifaceted neurodegenerative disorder characterized by cognitive decline, memory loss, and behavioral impairment, posing a major global health challenge. Its multifactorial pathology includes cholinergic dysfunction, amyloid-β deposition, tau hyperphosphorylation, oxidative stress, and neuroinflammation. Among these, impairment of the cholinergic system, characterized by reduced acetylcholine levels, plays a crucial role in cognitive deficits. The enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), which hydrolyze acetylcholine, are closely involved in disease progression and serve as important therapeutic and diagnostic targets in AD. This book chapter provides a comprehensive overview of therapeutic and diagnostic agents targeting AChE and BChE in AD, and discusses small-molecule inhibitors, multifunctional ligands, and emerging strategies to modulate cholinesterase activity and restore cholinergic neurotransmission, alleviating disease symptoms. In addition, the chapter highlights advances in diagnostic approaches using fluorescent probes, particularly near-infrared (NIR) probes, for selective detection and imaging of AChE and BChE, including their molecular design, photophysical properties, enzyme selectivity, and mechanisms of action, all of which are critically examined. Targeting AChE and BChE offers a dual advantage in AD by enabling both symptomatic treatment and early-stage diagnosis. This chapter aims to present a clear and comprehensive overview of recent advances in therapeutic and diagnostic approaches, offering meaningful insights for researchers in developing effective strategies for the treatment and monitoring of AD.},
}
@article {pmid42552041,
year = {2026},
author = {Khodve, G and Raval, S and Banerjee, S},
title = {Intestinal microbiota in neurodegeneration and ageing: Mechanisms, pathways, and therapeutic interventions.},
journal = {International review of neurobiology},
volume = {188},
number = {},
pages = {199-229},
doi = {10.1016/bs.irn.2026.05.015},
pmid = {42552041},
issn = {2162-5514},
mesh = {Humans ; *Neurodegenerative Diseases/microbiology/metabolism/immunology/diet therapy/therapy ; *Aging/metabolism/immunology ; *Gastrointestinal Microbiome/physiology ; Animals ; *Dysbiosis/metabolism/immunology ; *Brain-Gut Axis/physiology ; Probiotics ; Brain/metabolism ; },
abstract = {The human gut microbiota represents a complex ecosystem of trillions of microorganisms with profound implications for neurological health. Emerging evidence demonstrates that dysbiosis, an imbalance in microbial composition and function, plays a crucial role in the pathogenesis of neurodegenerative diseases and age-related cognitive decline. This chapter summarizes current knowledge of the microbiota-gut-brain axis (MGBA) and elucidates how intestinal microbes and their metabolites communicate with the central nervous system via neural, immune, endocrine, and metabolic pathways. We examine the mechanistic links between gut dysbiosis and specific neurodegenerative conditions, including Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and Multiple sclerosis (MS). Furthermore, we explore age-related changes in the microbiota and their contributions to neuroinflammation, immunosenescence, and cognitive decline. Finally, we evaluate therapeutic interventions targeting the microbiota, including probiotics, prebiotics, synbiotics, and dietary modulation as promising strategies to prevent and ameliorate neurodegenerative pathology. The chapter provides a comprehensive summary of how microbiota-targeted approaches may delay ageing and neurodegeneration.},
}
@article {pmid42552042,
year = {2026},
author = {Milmile, M and Singh, S and Pandey, A and Pawar, G and Petkar, P and Chander, Y and Mishra, R and Chawla, R},
title = {Brain energy crisis in Alzheimer's and Parkinson's disease: Nanotechnology as a therapeutic strategy.},
journal = {International review of neurobiology},
volume = {188},
number = {},
pages = {231-271},
doi = {10.1016/bs.irn.2026.05.016},
pmid = {42552042},
issn = {2162-5514},
mesh = {Humans ; *Parkinson Disease/metabolism/drug therapy/therapy ; *Energy Metabolism/physiology/drug effects ; *Alzheimer Disease/metabolism/drug therapy/therapy ; Animals ; *Brain/metabolism/drug effects ; *Nanotechnology/methods ; Mitochondria/metabolism ; Nanoparticles ; Oxidative Stress ; Drug Delivery Systems/methods ; },
abstract = {Alzheimer's disease and Parkinson's disease are increasingly recognized as disorders marked not only by protein aggregation but by a sustained failure of brain energy metabolism. Years before overt cognitive or motor symptoms emerge, neurons begin to experience impaired glucose utilization, mitochondrial dysfunction, and declining ATP production. Because the brain is highly energy-dependent, even subtle metabolic disturbances can disrupt synaptic function, impair neuronal signaling, and trigger oxidative stress. As mitochondrial efficiency declines, reactive oxygen species accumulate, inflammatory pathways become chronically activated, and damaged cellular components are insufficiently cleared, creating a vicious cycle that accelerates neurodegeneration. Conventional metabolic therapies, including antioxidants and mitochondrial cofactors, have produced limited clinical success, largely due to poor penetration across the blood-brain barrier and lack of specificity for vulnerable neuronal populations and intracellular targets such as mitochondria. Nanotechnology introduces a more precise therapeutic strategy by enabling targeted delivery of metabolic modulators directly to the brain. Engineered nanocarriers can be designed to cross biological barriers, enhance drug stability, and release therapeutic agents in a controlled or stimuli-responsive manner within diseased regions. Advanced systems including polymeric nanoparticles, lipid-based carriers, intranasal nano formulations, biomimetic vesicles, and catalytic nanozymes offer the ability to simultaneously modulate oxidative stress, restore mitochondrial function, and regulate neuroinflammation. By integrating delivery precision with metabolic intervention, neuro-nanomedicine shifts the therapeutic focus from symptomatic management toward addressing the underlying bioenergetic crisis. Although challenges remain in safety validation, scalability, and clinical translation, targeted nanotherapeutic strategies hold significant promise for transforming the treatment landscape of these debilitating neurodegenerative disorders.},
}
@article {pmid42552043,
year = {2026},
author = {Jain, V and Bharti, S},
title = {The potential of HDAC inhibitors for Alzheimer's disease.},
journal = {International review of neurobiology},
volume = {188},
number = {},
pages = {273-298},
doi = {10.1016/bs.irn.2026.01.005},
pmid = {42552043},
issn = {2162-5514},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Histone Deacetylase Inhibitors/pharmacology/therapeutic use ; Animals ; *Histone Deacetylases/metabolism ; Epigenesis, Genetic/drug effects ; *Neuroprotective Agents/pharmacology ; },
abstract = {Alzheimer's disease is a progressive neurodegenerative condition characterized by cognitive deterioration, memory loss, and persistent neuroinflammation. Notwithstanding considerable scientific advancements, current therapy strategies predominantly address symptoms and are ineffective in arresting illness progression. Recent studies have demonstrated the crucial role of epigenetic changes, especially histone modifications, in the pathophysiology of Alzheimer's disease. Removal of the acetyl group from histones and non-histone proteins by histone deacetylases (HDACs) plays a pivotal role in the regulation of gene expression, synaptic plasticity, and neuronal survival. Such changes lead to dysregulated HDAC activity, which is further associated with significant clinical characteristics of Alzheimer's disease, including amyloid-beta accumulation, tau hyperphosphorylation, oxidative stress, and neuroinflammation. In Alzheimer's disease and other neurodegenerative diseases, the histone acetylation equilibrium is markedly disrupted, resulting in a shift towards hypoacetylation, which further inhibits the production of neuroprotective genes. Pharmacological inhibition of HDACs can reinstate hyperacetylation, therefore facilitating neuroprotective effects. This chapter explores the therapeutic potential of HDAC inhibitors in relation to Alzheimer's disease. This chapter also focuses on various HDAC isoforms associated with disease progression and explores the detailed mechanism by which HDAC inhibitors affect the epigenetic regulation and neuronal function. Preclinical investigations focusing on the role of HDAC inhibitors in mitigating neuroinflammation and Alzheimer's diseases, with a special focus on HDAC inhibitors in clinical trials, present intriguing opportunities for therapeutic advancement. The chapter further explores various challenges such as off-target effects, restricted isoform specificity, and inadequate blood-brain barrier permeability. To address these constraints, various strategies such as isoform-selective inhibitors, targeted delivery methods, and combination treatments are also explored. Thus, the chapter provides in-depth information on the role of HDAC inhibitors, which hold significant potential as disease-modifying agents in the treatment of Alzheimer's disease.},
}
@article {pmid42552044,
year = {2026},
author = {Singh, AK and M R, S and P S, A and Krishnamoorthi, S and Iyaswamy, A and Durairajan, SSK},
title = {The Tau-mitochondria connection and its impact on cellular energy metabolism in Alzheimer's disease.},
journal = {International review of neurobiology},
volume = {188},
number = {},
pages = {299-361},
doi = {10.1016/bs.irn.2026.06.002},
pmid = {42552044},
issn = {2162-5514},
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; *Energy Metabolism/physiology ; *Mitochondria/metabolism ; *tau Proteins/metabolism ; Animals ; },
abstract = {Alzheimer's disease (AD) is a complex multifactorial neurodegenerative disease process resulting in progressive cognitive deterioration and synaptic dysfunction. The primary research approach in AD has traditionally focused on amyloid- pathology however an increasingly evidence suggests that tau protein is a key mediator of neuronal damage via a direct action on mitochondrial bioenergetics. In this chapter we look at the nature of the tau-mitochondrial interface, and propose a paradigm of tau-induced energy failure in AD. Physiologically tau provides stability to the microtubules and is involved in transport mechanisms within cells. In AD, tau is excessively post-translationally modified hyperphosphorylated and truncated tau species form toxic oligomers that incorrectly translocate to mitochondria, interacting pathologically with critical proteins such as voltage-dependent anion channel 1 (VDAC1) and adenine nucleotide translocase (ANT), impeding the mitochondrial ATP/ADP exchange and reducing oxidative phosphorylation efficiency. Tau also further damages mitochondria by excessive fission, inhibition of axonal transport and Inhibition of mitophagy by interrupting PINK1-Parkin signaling. In turn, the build-up of dysfunctional mitochondria leads to ROS production, mtDNA damage and calcium imbalance creating a vicious cycle toward oxidative stress and tau pathology. At the cellular level they cause an energy depletion of the synapse and at the systems level cause glucose hypometabolism and activation of neuroinflammation. The chapter additionally discusses novel therapeutic approaches that target both tau and mitochondrial abnormalities, namely antisense oligonucleotides (ASO), mitochondria targeted compounds and mitophagy modifiers, stressing that it would be more effective to utilize a cocktail of these inhibitors. As a whole, in the context of decreased bioenergetics, the tau-mitochondria axis is an important factor to consider in the successful treatment of AD.},
}
@article {pmid42552045,
year = {2026},
author = {Khodadadi, S and Rezaeimanesh, N and Ariyae Motahar, A and Yousefi, F and Avateffazeli, M and Montazeri-Shatouri, R and Hosseini, E and Sahab Negah, S and Naser Moghadasi, A},
title = {Brain energy metabolism changes and neuropsychological impairment in Parkinson disease vs Alzheimer disease.},
journal = {International review of neurobiology},
volume = {188},
number = {},
pages = {33-66},
doi = {10.1016/bs.irn.2026.06.001},
pmid = {42552045},
issn = {2162-5514},
mesh = {Humans ; *Parkinson Disease/metabolism/complications ; *Energy Metabolism/physiology ; *Alzheimer Disease/metabolism/complications ; *Brain/metabolism ; Animals ; *Cognitive Dysfunction/metabolism/etiology ; },
abstract = {Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative disorders, posing a significant public health risk. Although they are separate diseases, they have similar neuropsychological characteristics. Despite making up only a small portion of total body mass, the brain requires a disproportionately large amount of energy to maintain neuronal activity, synapse function, and cellular homeostasis. Disruption of energy metabolism is thus a major contributor to neurodegeneration. Energy metabolism has a wide-ranging impact on brain function, including cognitive and psychological processes, and gets increasingly compromised in neurodegenerative disorders. This chapter aims to offer a thorough overview of the link between altered brain energy metabolism and neuropsychological impairment in AD and PD.},
}
@article {pmid42552046,
year = {2026},
author = {Yadav, N and Banerjee, J and Tiwari, M and Dixit, A},
title = {Brain lipid dysregulation as a driver of energy metabolism failure in Alzheimer's disease.},
journal = {International review of neurobiology},
volume = {188},
number = {},
pages = {363-396},
doi = {10.1016/bs.irn.2026.02.004},
pmid = {42552046},
issn = {2162-5514},
mesh = {Humans ; *Alzheimer Disease/metabolism ; *Energy Metabolism/physiology ; Animals ; *Lipid Metabolism/physiology ; *Brain/metabolism ; Mitochondria/metabolism ; },
abstract = {Alzheimer's Disease (AD) is becoming more widely recognized as a condition of brain energy metabolism, wherein lipid dysregulation plays a crucial, although unrecognized, role. In addition to functioning as structural elements of neuronal membranes, lipids such as phospholipids, sphingolipids, and cholesterol play a crucial role in regulating mitochondrial bioenergetics, synaptic activity, and membrane-associated signaling pathways. In AD, modifications in lipid composition, distribution, and turnover compromise membrane fluidity, disturb mitochondrial dynamics, and obstruct lipid-mediated transport of energy substrates. These alterations intensify oxidative stress, impair glucose and ketone utilization, and stimulate neuroinflammatory pathways that further diminish metabolic capacity. Progress in lipidomics has uncovered disease-specific lipid signatures, providing a fresh understanding of the relationship between lipid homeostasis and neuronal energy loss. Despite extensive focus on amyloid and tau, lipid-mediated bioenergetic failure remains underrepresented in integrative AD models; this chapter addresses this gap and consolidates existing information connecting lipid modifications to metabolic dysfunction in AD, emphasizing molecular pathways and prospective treatment strategies aimed at lipid metabolism to re-establish bioenergetic equilibrium.},
}
@article {pmid42552047,
year = {2026},
author = {Mittal, R and Priya, and Banerjee, J and Dixit, A},
title = {Metabolic dysregulation in Alzheimer's disease: Mechanisms, markers, and therapeutic prospects.},
journal = {International review of neurobiology},
volume = {188},
number = {},
pages = {397-434},
doi = {10.1016/bs.irn.2026.05.011},
pmid = {42552047},
issn = {2162-5514},
mesh = {Humans ; *Alzheimer Disease/metabolism/therapy ; Biomarkers/metabolism ; Animals ; Amyloid beta-Peptides/metabolism ; Glucose/metabolism ; *Brain/metabolism ; },
abstract = {Metabolic dysregulation has emerged as a crucial pathogenic factor that contributes in progression of Alzheimer's disease (AD), and is often found to precede classical AD's pathologies, the amyloid-β accumulation and hyperphosphorylated tau proteinopathies. The key metabolic underpinnings associated with Alzheimer's disease (AD) includes cerebral glucose hypometabolism, insulin resistance, mitochondrial dysfunction, altered lipid metabolism, vascular and systemic metabolic impairments, disrupted amino acid and nitrogen metabolism driving secondary metabolic disturbances. The chapter outlines the current evidences on dysregulated metabolic processes, and highlights emerging metabolic biomarkers that are identified through advanced neuroimaging modalities, plasma/cerebrospinal fluid (CSF) profiles, lipidomic signatures and markers of mitochondrial impairment, underscoring their diagnostic and prognostic potential. Furthermore, the chapter discusses about the therapeutic prospects targeting metabolic pathways, addressing current challenges in development of therapeutic strategies, reinforcing the need for integrative and precision-based interventions for early diagnosis and disease modifying therapeutic strategies in AD.},
}
@article {pmid42552048,
year = {2026},
author = {Baskar, G and Kandasamy, M},
title = {Energetic crisis, mitochondrial vulnerability and disruption of lactate shuttle in Alzheimer's disease.},
journal = {International review of neurobiology},
volume = {188},
number = {},
pages = {67-89},
doi = {10.1016/bs.irn.2026.05.012},
pmid = {42552048},
issn = {2162-5514},
mesh = {Humans ; *Alzheimer Disease/metabolism ; Animals ; *Energy Metabolism/physiology ; *Mitochondria/metabolism/pathology ; *Lactic Acid/metabolism ; *Neurons/metabolism ; Astrocytes/metabolism ; *Brain/metabolism ; },
abstract = {Alzheimer's disease (AD) has traditionally been characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles. Emerging evidence reveals that metabolic dysfunction represents a key pathological feature central to disease progression. Mitochondrial dysfunction in AD leads to impaired electron transport chain activity and reduced level of adenosine triphosphate (ATP) synthesis, preceding neurodegeneration and structural abnormalities in cognitive centres of the brain. Early glucose hypometabolism and lactate deprivation or interference with their utilization represent a primary bioenergetic failure driving mitochondrial dysfunction and neuroinflammation prior to the clinical manifestation of AD. While the brain relies on lactate as a prominent energy substrate, astrocytic metabolic defects lead to impaired neuronal energy homeostasis, thereby promoting neurodegeneration. In turn, this metabolic uncoupling could also be associated with defects in regenerative mechanisms by impairing adult neurogenesis in the hippocampus due to energy deprivation, accounting for memory deficits. This chapter discusses the evidence for the energetic crisis in AD, focusing on the disruption of the astrocyte-neuron lactate shuttle (ANLS), hypometabolism of glucose, and mitochondrial vulnerability, as interconnected pathogenic mechanisms. We emphasise cerebral bioenergetic metabolic failure as a central driver of cognitive decline, arising from irreversible reactive gliosis and neuroblastosis mechanisms and highlight various therapeutic options, including restoration of ANLS to mitigate the pathogenesis and memory loss in AD.},
}
@article {pmid42552066,
year = {2025},
author = {Liu, Y and Poon, CH and Tse, LSR and Roy, J and So, CT and Tong, BC and Yao, KM and Tipoe, GL and Steinbusch, H and Aquili, L and Kalueff, A and Cheung, KH and Fung, ML and Lim, LW},
title = {Homeostatic DNMT3a Activity Is Required to Restore Cognition and Hippocampal DNA Methylation in the 5xFAD Model of Alzheimer's Disease.},
journal = {Aging and disease},
volume = {17},
number = {5},
pages = {2710-2739},
doi = {10.14336/AD.2025.0283},
pmid = {42552066},
issn = {2152-5250},
mesh = {Animals ; *Alzheimer Disease/genetics/metabolism/drug therapy ; DNA Methyltransferase 3A ; *Hippocampus/metabolism ; *DNA Methylation/drug effects ; Disease Models, Animal ; Mice ; *DNA (Cytosine-5-)-Methyltransferases/metabolism/genetics ; *Cognition/drug effects/physiology ; Mice, Transgenic ; Methionine/pharmacology ; Spatial Memory/drug effects ; Homeostasis ; Male ; Neuronal Plasticity/drug effects ; },
abstract = {Dysregulation of DNA methylation has been implicated in Alzheimer's disease (AD), making the manipulation of DNA methylation processes a promising therapeutic strategy. DNA methyltransferase 3a (DNMT3a), one of the two de novo DNMTs, is involved in learning and memory. However, it remains elusive whether and how alterations in DNMT3a expression contributes to AD pathogenesis. In this study, we investigated the consequences of DNA methylation dysregulations in the hippocampus of 5xFAD mouse model of AD and explored the use of L-methionine (MET) supplement to restore DNA methylation dysregulations. The 5xFAD model exhibited spatial memory impairments accompanied by global DNA hypomethylation and dysregulated hippocampal expression of DNA methyltransferases (DNMT) and demethylases. Prolonged treatment with MET rescued memory deficits, reduced amyloid-β load, decreased neuroinflammation, restored the expression of plasticity-regulating genes and proteins, and enhanced serotonergic neurotransmission. DNMT3a knockdown diminished the pro-cognitive effects of MET and independently impaired spatial memory and hippocampal neuroplasticity in both wildtype and 5xFAD mice. Interestingly, DNMT3a overexpression also had detrimental effects on spatial memory and hippocampal neuroplasticity in both genotypes. Our findings demonstrate that methyl supplementation can be a promising therapeutic strategy for AD patients with brain DNA hypomethylation and that maintaining DNMT3a homeostasis is crucial for normal cognitive functions and the pro-cognitive effects of MET.},
}
@article {pmid42552207,
year = {2026},
author = {Chen, R and Pan, C and Mao, X and Zhang, Y and Chen, G and Xu, M and Nivar, J and Tao, Y and Cao, H and JunLi, },
title = {Retraction notice to "Chloride intracellular channel 4 blockade improves cognition in mice with Alzheimer's disease: CLIC4 protein expression and tau protein hyperphosphorylation" [Int. J. Biol. Macromol. 278 (2024) 134972].},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {153849},
doi = {10.1016/j.ijbiomac.2026.153849},
pmid = {42552207},
issn = {1879-0003},
}
@article {pmid42552272,
year = {2026},
author = {Turrisi, R and Cammarasana, S and Paccini, M and Patanè, G and , },
title = {Super-Resolution of Through-Plane Undersampled MRIs in Alzheimer's Disease Diagnosis.},
journal = {Journal of imaging informatics in medicine},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10278-026-02159-9},
pmid = {42552272},
issn = {2948-2933},
support = {ECS00000035//Ministero dell'Universit&#xe0; e della Ricerca/ ; 2022WK7NHC//Ministero dell'Universit&#xe0; e della Ricerca/ ; },
abstract = {Alzheimer's disease is a complex neurodegenerative disorder and the leading cause of dementia worldwide. Learning-based techniques applied to magnetic resonance imaging (MRI) have recently shown strong potential for automated diagnosis. Accurate classification typically relies on high-resolution (HR) 3D MRI acquired with thin axial slices to reduce partial-volume artefacts, capture fine anatomical details, and improve diagnostic performance. However, acquiring such data is time-consuming, costly, and prone to motion artefacts and patient discomfort. Super-resolution methods offer a promising alternative by reconstructing HR 3D images from lower-resolution scans and enabling shorter acquisition times. In this study, we propose a novel pipeline that applies super-resolution to through-plane undersampled 3D magnetic resonance images and demonstrates that the resulting volumes preserve Alzheimer's disease diagnostic accuracy comparable to that achieved using fully sampled HR scans. We compare different state-of-the-art super-resolution methods from distinct methodological families, with the best-performing method achieving an F1 score of 65.6, close to the HR reference of 65.7 and substantially higher than the low-resolution baseline of 55.9. Furthermore, we investigate whether standard image quality metrics (e.g. pixel-based metrics) are sufficient to assess the contribution of super-resolution to the clinical evaluation of Alzheimer's disease. To this end, we compare them with machine learning-based measures, such as maximum mean discrepancy, and surface-based metrics derived from segmented anatomical structures, highlighting their limitations in clinically oriented evaluations.},
}
@article {pmid42552337,
year = {2026},
author = {Ma, N and Stieler, J and Hilbrich, I and Vogel, T and Hilgeroth, A and Briel, D and Schaefer, M and Holzer, M and Metelmann, M},
title = {NanoBiT screening identifies the azaoxafluorene VT11 as potent tau interaction inhibitor.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {42552337},
issn = {2045-2322},
mesh = {*tau Proteins/metabolism/antagonists &amp; inhibitors/chemistry ; Humans ; Protein Binding/drug effects ; Tauopathies/drug therapy/metabolism ; Biosensing Techniques ; },
abstract = {Tauopathies are neurodegenerative disorders characterized by accumulating misfolded, insoluble tau protein aggregates in neurons or glial cells. In this study, we screened the Spectrum Collection and other compound libraries for inhibitors of tau self-interaction using a structural complementation reporter system (NanoLuciferase Binary Technology). Resulting candidates were tested in dose-response assays and evaluated for cell toxicity and microtubule destabilization. Further, a seed-induced tau interaction biosensor assay and a cell-free tau Real-Time Quaking-Induced Conversion assay have been established to study their effects on the kinetics of tau interaction and aggregation, respectively. The substances ritanserin, 3-methoxycatechol, gambogic amide, azaoxafluorenes VT11, and NS 185 and thieno[2,3-d][1.3]oxazine B6/55 showed a concentration-dependent tau self-interaction inhibition without relevant cell toxicity or microtubule destabilization. Ritanserin, VT11, NS 185 and B6/55 blocked tau interaction in the seed-induced tau interaction biosensor assay. Finally, the cell-free tau RT-QuIC assay displayed highest inhibitory potential for VT11. Thus, the azaoxafluorene VT11 seems to be a promising candidate for further investigations as tau interaction inhibitor to address a pivotal pathological process in Alzheimer's disease and other tauopathies.},
}
@article {pmid42552384,
year = {2026},
author = {Klimmt, J and Cardoso Gonçalves, C and Montgomery, JV and Müller, SA and Bublitz, M and Filser, S and Paeger, L and Nuscher, B and Dannert, A and Roeber, S and Pravata, V and Schifferer, M and Shrouder, JJ and Schulz, N and González-Gallego, J and Cappello, S and Misgeld, T and Plesnila, N and Beltrán, E and Herms, J and De Domenico, E and Beyer, MD and Schultze, JL and Haass, C and Lichtenthaler, SF and Carraro, C and Paquet, D},
title = {A reproducible three-dimensional model of human brain tissue to investigate physiological and disease-associated microglia phenotypes.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {42552384},
issn = {1546-1726},
support = {ADR AD2019604S//BrightFocus Foundation (BrightFocus)/ ; 16LW047//Bundesministerium f&#xfc;r Bildung und Forschung (Federal Ministry of Education and Research)/ ; },
abstract = {Stem-cell-based in vitro models offer promising potential to elucidate human brain cell functions and interactions, but limitations in reproducibility, maturation and cell-type diversity persist. Especially, prolonged incorporation of mature microglia and studies of neuroinflammation have proven challenging. Here, we developed a human induced pluripotent stem cell-based three-dimensional cortical brain tissue model (3BTM) containing neurons, astrocytes and microglia with high reproducibility, maturity and viability. 3BTMs show morphological, functional and proteomic maturation of all cell types, leading to high similarity to their in vivo counterparts. Incorporated microglia survive for over 6 months and display mature morphology, functions and gene expression. Importantly, when engineered to model Alzheimer's disease pathology, 3BTMs recapitulate key disease hallmarks, including amyloid deposition, increased phospho-tau levels and neuroinflammation, with microglia shifting their transcriptional landscape to disease-relevant signatures. Treatment of Alzheimer's disease 3BTMs with anti-Aβ immunotherapy cleared deposits and largely reversed disease signatures in glia. Together, our microglia-containing model provides a platform for studying physiological and pathological states of human brain tissue.},
}
@article {pmid42552390,
year = {2026},
author = {Lucey, BP and Howell, MJ},
title = {Losing sleep over glia: new mechanisms for Alzheimer-related sleep disruption.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {42552390},
issn = {1759-4766},
}
@article {pmid42552421,
year = {2026},
author = {Liao, K and Xie, M and Ibáñez, CF},
title = {p75 neurotrophin receptor signaling through the RhoA/ROCK pathway contributes to Tau-mediated neurodegeneration.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42552421},
issn = {1476-5578},
support = {X2026t/77//Royal Swedish Academy of Sciences (Kungl. Vetenskapsakademien)/ ; },
abstract = {Therapeutic development in Alzheimer's Disease (AD) has for the most part been focused on reducing β-amyloid load. Nevertheless, neurofibrillary tangles (NFTs), produced by aggregation of hyper-phosphorylated Tau protein, correlate with neurodegeneration and cognitive impairment significantly better than amyloid accumulation in AD patients. Here we report that P301S mice, a model of Tau-mediated neurodegeneration, carrying mutant variants of the p75 neurotrophin receptor (p75[NTR]) deficient in RhoA/ROCK signaling are protected from neurodegeneration and cognitive impairment. Both p75[∆DD], lacking the death domain, and triple mutant p75[KKEA], unable to interact with RhoGDI, decreased insoluble Tau species, reduced gliosis, neurodegeneration and synapse loss, and improved spatial learning and memory in P301S mice. Intriguingly, p75[C259A], a variant unresponsive to neurotrophins but still competent for RhoA signaling induced by myelin-derived ligands, did not afford any neuroprotection. P301S neurons expressing p75[∆DD] or p75[KKEA], but not p75[C259A], showed reduced phospho-Tau and ROCK and GSK3β activity, the two main kinases responsible for Tau phosphorylation. In line with this, treatment with myelin-associated glycoprotein (MAG) enhanced Tau phosphorylation and ROCK activity in P301S neurons expressing wild type p75[NTR] or p75[C259A], but not p75[∆DD] or p75[KKEA]. Together, these results indicate that p75[NTR] contributes to AD Tauopathy by enhancing the activity of the RhoA-ROCK pathway.},
}
@article {pmid42552687,
year = {2026},
author = {Koychev, I and Rowe, JB and Amin, J and Arsland, D and Archer, H and Barber, R and Burns, A and Coulthard, E and Deasy, C and Dunne, R and Fox, N and Humphrey, SH and Jenkinson, J and Jones, D and Kennelly, S and Khan, F and Krishnan, MSP and Malhotra, P and McFarlane, B and McGuinness, B and Mummery, C and Pennington, C and Perry, JR and Raczek, G and Rasmussen, J and Ritchie, C and Taylor, JP and Underwood, BR and Venkataraman, AV and Raymont, V},
title = {Interpreting evolving evidence in Alzheimer's disease: implications for dementia clinicians.},
journal = {The British journal of psychiatry : the journal of mental science},
volume = {},
number = {},
pages = {1-2},
doi = {10.1192/bjp.2026.10750},
pmid = {42552687},
issn = {1472-1465},
}
@article {pmid42552722,
year = {2026},
author = {Kotah, JM and Lima, MT and Dragt, EC and Voulgaroglou, A and Brouwer, N and Holtman, IR and Kooistra, SM and Eggen, BJL},
title = {Predicting Relevant Microglia-Associated Cell-Cell Communication Pathways in Alzheimer's Disease: A Role for SPP1.},
journal = {Glia},
volume = {74},
number = {10},
pages = {e70210},
doi = {10.1002/glia.70210},
pmid = {42552722},
issn = {1098-1136},
support = {WE.03-2025-06//Alzheimer Nederland/ ; WE.03-2020-03//Alzheimer Nederland/ ; //Stichting De Cock-Hadders/ ; MODEM 10510032120006/ZONMW_/ZonMw/Netherlands ; },
mesh = {*Microglia/metabolism/pathology ; *Alzheimer Disease/metabolism/pathology ; Humans ; *Cell Communication/physiology ; *Brain/metabolism/pathology ; *Osteopontin/metabolism/genetics ; Signal Transduction/physiology ; Male ; Female ; Aged ; Plaque, Amyloid/pathology/metabolism ; Aged, 80 and over ; },
abstract = {Microglia play a key role in the pathophysiology of Alzheimer's Disease (AD) and their increased heterogeneity likely affects disease progression. We previously identified distinct microglial signatures that were enriched in AD donors and associated with amyloid and tau, respectively. Here we generated a snRNAseq dataset from postmortem control and AD cases and analyzed alterations in cell-cell communication pathways that might be relevant to AD pathophysiology. One signaling pathway perturbed in AD cases involved SPP1, and while this pathway was also present in control samples, microglia-microglia SPP1 signaling was restricted to AD donors. Further analyses within microglia-microglia signaling predict AD-specific induction of GAS6-AXL signaling (from inflammatory and ribosomal microglia), and SPP1-ITGAV/ITGB5 signaling (from disease-associated and inflammatory microglia, among others). Together, these findings might in part explain the increased microglia phagocytic profile described in AD. RNAscope confirmed enrichment of SPP1 expressing microglia near amyloid plaques in AD brain tissue samples. These data indicate altered cellular communications between microglia in the AD brain.},
}
@article {pmid42552749,
year = {2026},
author = {Boustani, M and Klein, EG and Zimmer, JA and Wang, H and Engle, SE and Phipps, A and Japha, M and Schilling, T and Hartry, A and , },
title = {Further data to address the Alzheimer's coverage with evidence development questions.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71724},
doi = {10.1002/alz.71724},
pmid = {42552749},
issn = {1552-5279},
support = {//Eli Lilly and Company/ ; },
mesh = {*Alzheimer Disease/drug therapy ; Humans ; United States ; *Medicare ; *Antibodies, Monoclonal, Humanized/therapeutic use ; },
abstract = {INTRODUCTION: Medicare patients currently access amyloid-targeting therapies for Alzheimer's disease through the class-based National Coverage Determination (NCD) with coverage with evidence development (CED) established in 2022. Evidence addressing the stated CED questions was previously published in a 2024 review; however, the original 2022 NCD remains unchanged.<br><br>METHODS: Update the previously published review responding to the CED questions by summarizing recently published donanemab and lecanemab extension data and new safety-related data.<br><br>RESULTS: New evidence addresses each of the three CED questions. Extension data show that the benefit of amyloid-targeting therapy continues to accrue with no new safety signals observed. Safety analyses identified baseline risk factors for amyloid-related imaging abnormalities (ARIA). Further, a more gradual donanemab titration regimen decreased risk of ARIA-edema/effusions.<br><br>DISCUSSION: With CED questions addressed, reconsideration of the class-based NCD is scientifically justified.<br><br>CLINICAL TRIAL REGISTRATION: NCT04437511, NCT05738486, NCT03887455.},
}
@article {pmid42552750,
year = {2026},
author = {Fernández-Lebrero, A and Jiménez-Balado, J and García-Escobar, G and Contador, J and Estraguès-Gázquez, I and Peraferrer-Montesinos, L and Manero-Borràs, RM and Gramegna, LL and Viles, M and Campello, AR and Ortiz-Romero, P and de Diego, M and Del Campo, M and Torres-Torronteras, J and Jiménez-Moyano, E and Blasco-Forniés, H and Suárez-Calvet, M and Ois, A and Puig-Pijoan, A and Navalpotro-Gómez, I},
title = {Plasma p-tau217 detects Alzheimer's disease co-pathology in cerebral amyloid angiopathy: Comparison to CSF biomarkers in the ANGMAR cohort.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71709},
doi = {10.1002/alz.71709},
pmid = {42552750},
issn = {1552-5279},
support = {PI21/00194//the Fondo de Investigaci&#xf3;n Sanitaria (FIS)/ ; ERA-CVD_JTC2020-015//the European Research Area Network on Cardiovascular Diseases/ ; AC20/00001//the European Research Area Network on Cardiovascular Diseases/ ; CP25/00015//Miguel Servet program/ ; 948677//the European Research Council (ERC)/ ; PI22/00456//Instituto de Salud Carlos III (ISCIII)/ ; 847648 (LCF/BQ/PR21/11840004)//"la Caixa" Foundation/ ; },
mesh = {Humans ; *tau Proteins/blood/cerebrospinal fluid ; *Cerebral Amyloid Angiopathy/blood/pathology/complications/cerebrospinal fluid/diagnostic imaging ; *Alzheimer Disease/blood/cerebrospinal fluid/pathology/complications/diagnostic imaging/diagnosis ; Female ; Biomarkers/blood/cerebrospinal fluid ; Male ; Aged ; Magnetic Resonance Imaging ; Cohort Studies ; Phosphorylation ; Aged, 80 and over ; Middle Aged ; Brain/pathology ; },
abstract = {INTRODUCTION: Cerebral amyloid angiopathy (CAA) frequently co-occurs with Alzheimer's disease (AD), generating mixed vascular-neurodegenerative phenotypes. Plasma phosphorylated tau (p-tau)217 is a robust biomarker of AD, but its performance in CAA remains unclear.<br><br>METHODS: We studied 231 participants, including 50 patients with CAA (Boston v2.0), 154 with AD, and 27 cognitively unimpaired controls. Plasma p-tau217 was measured on an automated platform and compared to cerebrospinal fluid (CSF)-defined AD status. Associations with magnetic resonance imaging (MRI) markers of CAA burden were evaluated.<br><br>RESULTS: Among CAA participants, 29 met CSF criteria for AD co-pathology. Plasma p-tau217 discriminated CAA patients with and without AD co-pathology (area under the curve&#xa0;=&#xa0;0.920) and showed no association with MRI markers of CAA burden. Predefined cut-offs (&#x2265; 0.27 pg/mL and &#x2265; 0.34 pg/mL) yielded high accuracy for identifying AD co-pathology within CAA.<br><br>CONCLUSIONS: Plasma p-tau217 shows high diagnostic accuracy for identifying AD co-pathology in CAA and is not associated with MRI markers of CAA burden, supporting its specificity for AD-related pathology.},
}
@article {pmid42552753,
year = {2026},
author = {Hutten, CG and Beck, T and Evans, D and Rajan, KB},
title = {The role of polygenic risk in Alzheimer's disease prediction for African Americans.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71712},
doi = {10.1002/alz.71712},
pmid = {42552753},
issn = {1552-5279},
support = {R01AG073627/AG/NIA NIH HHS/United States ; R01AG058679/AG/NIA NIH HHS/United States ; UH2AG083289/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/genetics/ethnology ; *Black or African American/genetics ; Genetic Risk Score ; Female ; Male ; *Genetic Predisposition to Disease ; Aged ; White People/genetics ; *Multifactorial Inheritance/genetics ; Risk Factors ; Aged, 80 and over ; Apolipoprotein E4/genetics ; European People ; },
abstract = {INTRODUCTION: African Americans (AAs) face a higher risk of Alzheimer's disease and related dementias (ADRD) than European Americans (EUs), yet the utility of polygenic risk scores (PRS) in AAs remains underexplored.<br><br>METHODS: A standardized dementia PRS was evaluated in the Chicago Health and Aging Project (n&#xa0;=&#xa0;4336; 61% AA) for associations with ADRD and cognitive trajectories over 8.4 years.<br><br>RESULTS: PRS predicted ADRD more strongly in EUs (c-index 0.86) than AAs (0.77); however, it conferred higher risk in AAs (hazard ratio [HR]&#xa0;=&#xa0;1.36, 95% confidence interval [CI]: 1.04-1.78) compared to EU (HR&#xa0;=&#xa0;1.13, 95% CI: 0.88-1.44). The PRS remained predictive among AAs after apolipoprotein E (APOE) &#x3b5;4 adjustment (HR&#xa0;=&#xa0;1.53, 95% CI: 1.03-2.27). Higher PRS associated with lower baseline cognition and faster decline (p&#xa0;<&#xa0;0.05).<br><br>DISCUSSION: PRS conferred greater ADRD risk in AAs and comparable rates of cognitive decline, despite stronger discrimination in EUs, adding to the limited knowledge of genetic contributions to ADRD risk among AAs beyond APOE &#x3b5;4 alleles.},
}
@article {pmid42552789,
year = {2026},
author = {Piras, F and Serra, L and Caltagirone, C and Giove, F},
title = {The disconnectome as target in Alzheimer disease: a promising framework or a premature end-point?.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag262},
pmid = {42552789},
issn = {1460-2156},
}
@article {pmid42552845,
year = {2026},
author = {Wang, X and Li, Y and Ye, J and Lian, H and Li, T and Wang, J},
title = {Lymphedema and Alzheimer's Disease: Connecting Through the "Peripheral-Central Lymphatic System".},
journal = {Lymphatic research and biology},
volume = {},
number = {},
pages = {15578585261471251},
doi = {10.1177/15578585261471251},
pmid = {42552845},
issn = {1557-8585},
abstract = {The connection between the peripheral lymphatic system (PLS) and the central lymphatic system (CLS) plays a crucial role for the overall circulatory system. Notably, there are several similarities between lymphedema and Alzheimer's disease (AD). Accumulating evidence suggests that lymphedema might be associated with AD, potentially influencing its progression through mechanisms related to the peripheral-central lymphatic circulation. This review summarizes the lymphatic system's structure, function, and drainage pathways, emphasizing how aging and blockage of the CLS can exacerbate the progression of AD. Additionally, we discuss the relationship between lymphedema and AD, highlighting the significance of the PLS-CLS and exploring lymphaticovenous anastomosis as a promising treatment for both lymphedema and AD.},
}
@article {pmid42553105,
year = {2026},
author = {Rubinshtein, R and Obied, B and Salti, T and König, AI and Zahavi, A and Goldenberg-Cohen, N},
title = {Longitudinal assessment of intraocular pressure in the 5xFAD mouse model of Alzheimer's disease.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1858031},
pmid = {42553105},
issn = {1664-2295},
abstract = {OBJECTIVES: Glaucoma and Alzheimer's disease (AD) are major neurodegenerative disorders with increasing evidence of shared pathogenic pathways. Glaucoma involves progressive optic nerve degeneration and irreversible vision loss, often associated with elevated intraocular pressure (IOP) but also occurring independently of it. AD, the leading cause of dementia, results in progressive cognitive and functional decline, with vision disturbances including visual field defects. Epidemiological studies report higher co-prevalence of glaucoma and AD in older adults. This study longitudinally assessed IOP in a transgenic AD mouse model to determine whether AD-related amyloid pathology inherently drives alterations in ocular pressure.<br><br>METHODS: Ten young (25 weeks old; 9 males, 1 female) and fifteen aged 5xFAD (57-60 weeks old; 5 males and 10 females) transgenic mice, a well-established amyloidogenic model of AD, were examined. Age-matched control groups included ten young wild type (WT) mice (9 males and 1 female) and fourteen aged WT mice (7 males and 7 females). IOP was measured repeatedly without anesthesia using a rebound tonometer (Icare Tonolab) calibrated for mice. Four IOP measurement sessions were performed at days 1, 36, 55, and 77, with all measurements conducted during midday hours (11:00-14:00) to minimize circadian variability.<br><br>RESULTS: IOP remained stable across most groups and time points. Aged 5xFAD mice exhibited transient, statistically significant fluctuations, characterized by an initial decrease at day 36 followed by a return to baseline levels. Age-matched WT mice showed no significant longitudinal changes. When comparing between groups, the only significant difference was observed at day 36, where aged 5xFAD mice demonstrated significantly lower IOP than aged WT controls.<br><br>CONCLUSIONS: 5xFAD mice did not exhibit sustained IOP elevation compared with WT controls, with aged animals displaying only transient fluctuations that likely reflect physiological or measurement variability. These results suggest that amyloid-driven pathology in this model is not accompanied by chronic ocular hypertension. Consequently, our findings support the hypothesis that visual dysfunction in AD models may occur independently of elevated intraocular pressure, though the specific overlapping mechanisms between AD and glaucoma warrant cautious interpretation and further investigation.},
}
@article {pmid42553297,
year = {2026},
author = {Li, Q and You, M},
title = {Targeting mitochondria for the treatment of neurodegenerative diseases.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1835506},
pmid = {42553297},
issn = {1662-4548},
abstract = {Mitochondria are central regulators of cellular metabolism, redox balance, calcium signaling, and cell survival, making them essential for neuronal function. Because neurons rely heavily on mitochondrial oxidative phosphorylation to meet their high energetic demands, mitochondrial dysfunction has emerged as a key pathogenic driver in major neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Defects in mitochondrial bioenergetics, excessive reactive oxygen species production, impaired mitochondrial dynamics, disrupted mitophagy, and dysregulated calcium handling collectively contribute to neuronal damage, synaptic dysfunction, and neuroinflammation. These insights have prompted growing interest in therapeutic strategies that directly target mitochondria to restore organelle homeostasis. Recent advances in chemical biology and nanomedicine have enabled the development of mitochondria-targeted ligands, peptide-based targeting systems, and carrier or nanotechnology-enabled delivery platforms designed to overcome biological barriers and selectively deliver therapeutic cargos to mitochondria within the central nervous system. In this Review, we summarize mitochondrial pathological mechanisms in neurodegenerative diseases and discuss emerging mitochondria-targeted therapeutic strategies, highlighting delivery technologies, therapeutic modalities, and translational challenges. Although most strategies remain at the preclinical or proof-of-principle stage, these advances are beginning to shape a conceptual framework for precision mitochondrial medicine, with the longer-term goal of developing disease-modifying interventions for neurodegenerative disorders.},
}
@article {pmid42553403,
year = {2026},
author = {Fan, JD and Fu, Y and Li, QY and Zhang, ZQ and Zhao, YL and Hao, Q and Tan, L and Tan, MS and , },
title = {Association of cerebrospinal fluid amphiphysin-1 levels with cognition and Alzheimer's disease pathology biomarkers.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1875646},
pmid = {42553403},
issn = {1663-4365},
abstract = {INTRODUCTION: Amphiphysin-1 (AMPH), an accessory component of the clathrin-mediated endocytosis (CME) machinery, plays a critical role in synaptic vesicle recycling and membrane dynamics and has been implicated in Alzheimer's disease (AD) risk. However, its relationship with core AD biomarkers and disease progression remains unclear.<br><br>METHODS: In this study, we examined the associations between cerebrospinal fluid (CSF) AMPH and core AD biomarkers (CSF amyloid-&#x3b2;42 [A&#x3b2;42], phosphorylated tau [P-tau], and total tau [T-tau]), cognitive performance, neurodegeneration, and clinical progression in 723 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Participants were categorized according to the AT(N) framework into stage 0, stage 1, stage 2, and suspected non-AD pathophysiology (SNAP).<br><br>RESULTS: AMPH exhibited stage-dependent alterations across the AD continuum, characterized by lower levels in stage 1, and elevated levels in stage 2 and SNAP. Cross-sectionally, CSF AMPH was positively associated with core CSF biomarkers. Longitudinal analyses showed that, among amyloid-negative individuals, higher baseline AMPH was associated with faster decreases in CSF A&#x3b2;42 and increases in P-tau and T-tau. In the overall cohort, higher baseline AMPH was associated with accelerated hippocampal atrophy and cognitive decline, and with an increased risk of clinical progression (HR = 1.21, 95% CI: 1.05-1.37).<br><br>DISCUSSION: In ADNI, CSF AMPH was associated with biological changes across the AD continuum, cognitive decline, hippocampal atrophy, and clinical progression. These findings may provide complementary information for understanding disease progression.},
}
@article {pmid42553595,
year = {2026},
author = {Tamvaka, N and Scotton, W and Lilley, MT and Shoai, M and Gavrielatos, M and Heckman, MG and Soto-Beasley, AI and Roemer, SF and Baker, MC and Rademakers, R and Murray, ME and Dickson, DW and Hardy, JA and Cook, CN and Rohrer, JD and Ross, OA and , and , },
title = {Evaluating MAPT p.A152T as a risk factor for the 3R tauopathy Pick's disease.},
journal = {Brain communications},
volume = {8},
number = {4},
pages = {fcag266},
pmid = {42553595},
issn = {2632-1297},
abstract = {Genetic studies have significantly advanced our understanding of tauopathies, yet the genetic aetiology of Pick's disease, a rare 3-Repeat tauopathy, remains unclear. The MAPT p.A152T variant has been identified as a risk factor for Alzheimer's disease and progressive supranuclear palsy, but its role in Pick's disease is unknown. In this study, we examined the prevalence of MAPT p.A152T in the largest series of neuropathologically confirmed Pick's disease cases to date (n = 401). Through genotyping, we identified a single mutation carrier in the Pick's disease cohort (minor allele frequency = 0.12%). We previously reported MAPT p.A152T at a 0.20% frequency in healthy controls (n = 2456), suggesting that it does not associate with 3-Repeat tauopathy risk. To further investigate the effect of the variant on MAPT transcript expression, we used bulk RNA sequencing in Alzheimer's disease and progressive supranuclear palsy A152T mutation carriers. We did not detect significant differences in 4-Repeat tau levels, though preliminary trends may indicate more nuanced effects that need to be examined with long-read sequencing in a larger series. Overall, our study suggests that MAPT p.A152T does not increase Pick's disease risk and may instead be linked to 4-Repeat or mixed tau pathologies, warranting further functional investigation.},
}
@article {pmid42553702,
year = {2026},
author = {Morgan, J and Aarons, T and Mukhopadhyay, A and Lace, G},
title = {Distinct brain extracellular vesicle microRNA profiles differ in frontotemporal dementia and Alzheimer's disease.},
journal = {Brain communications},
volume = {8},
number = {4},
pages = {fcag277},
pmid = {42553702},
issn = {2632-1297},
abstract = {Dementia is a syndrome caused by various diseases including Alzheimer's disease (AD) and frontotemporal dementia (FTD) with an estimated global prevalence of 60 million individuals. Recently, therapeutic development in the dementia field has accelerated, with the introduction of monoclonal antibody therapeutics such as Lecanemab and Donanemab. However, AD and FTD patients are still either diagnosed too late to benefit from available therapies or are misdiagnosed due to the clinical overlap between dementia subgroups making therapeutic intervention challenging. This highlights a real need to improve early diagnostic tools of neurodegenerative disease (ND) biomarkers. A potential source of such biomarkers come from small extracellular vesicles (sEVs), groups of cell-derived, lipid-bound assemblies with the capability to cross the blood-brain barrier (BBB) and known to carry pathogenic proteins associated with AD and FTD. A known cargo of sEVs is microRNA (miRNA), regulatory molecules that post-transcriptionally silence gene expression including transcripts of autophagic systems, processes which dysfunction in dementia-causing diseases leading to toxic aggregate build-up, causing neurodegeneration. The targeting of functional machineries in macroautophagy (MA) and chaperone-mediated autophagy (CMA) by different miRNA may vary between AD and FTD mutations, leading to potential biomarkers of disease being highlighted. Through isolating sEVs from the frontal cortex of post-mortem brain tissue of AD, FTD-MAPT, FTD-C9orf72, FTD-GRN and no-disease control patients (Manchester Brain Bank), miRNA cargoes were analysed and compared using real-time quantitative PCR (RT-qPCR). Seven autophagy-associated miRNA candidates (MA: miR-124-3p, miR-30a-5p, miR-128-3p; and CMA: miR-224-5p, miR-373-5p, miR-106a-3p and miR-26b-5p) were tested to identify dementia sub-group variations, used alongside small RNA-sequencing to explore broader miRNA variation within sEV populations. Of the miRNA tested miR-224-5p (P = 1.76 × 10[-5]) and miR-106a-3p (P = 0.033) showed significant group differences, and further significant pairwise comparison differences [miR-224-5p: AD fold change (FC) = 4.29, MAPT FC = 7.62; miR-106a-5p: AD FC = 5.59] when compared with no disease controls and other dementia subgroups, potentially showing initial diagnostic and differentiating potential. Small RNA-sequencing results revealed 8 AD, 2 FTD-GRN, 52 FTD-MAPT and 12 FTD-C9orf72 differentially expressed sEV-miRNAs when compared with no disease controls. Further direct comparisons between AD versus FTD mutation-derived sEV cargoes, and even FTD mutation versus FTD mutation-derived sEV cargoes, identified additional miRNA with differentiating capabilities. These findings demonstrate sEV-derived miRNA signatures vary across dementia sub-types and suggest potential roles of sEV cargoes in both disease diagnostics and identifying drivers of ND, such as autophagic impairments and signalling pathways.},
}
@article {pmid42553791,
year = {2026},
author = {Mehdi, MR and Al-Qassab, ZMS and Sabuni, O and Rai, M and Patel, T and Patel, R and Iftikhar, L},
title = {Exploring the Link Between Obstructive Sleep Apnea and Neuropsychiatric Disorders: Role of Neuroinflammatory Mechanisms.},
journal = {Cureus},
volume = {18},
number = {7},
pages = {e112096},
pmid = {42553791},
issn = {2168-8184},
abstract = {Obstructive sleep apnea syndrome (OSAS) is a prevalent sleep-related breathing disorder characterized by recurrent episodes of upper airway obstruction during sleep, resulting in intermittent reductions or complete cessation of airflow. These interruptions reduce oxygen saturation and disrupt normal sleep architecture, frequently resulting in daytime fatigue and adverse health outcomes. Recent research has provided increasing evidence that OSAS may be associated with neuroinflammation, defined as inflammation within the brain and nervous system. Such neuroinflammation may contribute to the development of conditions including depression, anxiety, Alzheimer's disease, and Parkinson's disease. This narrative review examines the association between OSAS and neuroinflammation and outlines the potential biological mechanisms involved. Intermittent hypoxemia and recurrent sleep fragmentation are thought to promote oxidative stress, neuroinflammation, and neuronal injury, ultimately contributing to impaired memory, executive function, emotional regulation, and overall neurological function. Over time, these processes can impair memory, executive function, emotional regulation, and overall neurological function. The review also highlights key risk factors and clinical manifestations and emphasizes the importance of early diagnosis and intervention for OSAS. Evidence from both experimental animal studies and human clinical studies is discussed to highlight current understanding while distinguishing established findings from emerging hypotheses. In summary, this review indicates that neuroinflammation may represent an important mechanistic pathway linking OSAS with depression, anxiety, cognitive impairment, and neurodegenerative disorders. However, much of the available evidence remains associative, and further longitudinal and biomarker-driven studies are required to clarify causal relationships and determine the long-term impact of interventions such as continuous positive airway pressure (CPAP) therapy. Improved understanding of these mechanisms may facilitate earlier diagnosis, risk stratification, and the development of targeted therapeutic strategies for individuals with OSAS.},
}
@article {pmid42553843,
year = {2026},
author = {Sharma, S and Sharma, S and Raghuvanshi, V and Kumari, S and Singh, S and Butcher, RJ and Srikrishna, S and Katiyar, D},
title = {Design, synthesis, and evaluation of pyrano[3,2-c]coumarin derivatives for simultaneous targeting of amyloid-β42 and acetylcholinesterase in transgenic AD model of Drosophila.},
journal = {RSC advances},
volume = {},
number = {},
pages = {},
pmid = {42553843},
issn = {2046-2069},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder involving amyloid-β (Aβ) aggregation, cholinergic dysfunction, oxidative stress, mitochondrial impairment, and progressive neuronal loss. Consequently, the development of multi-target-directed ligands (MTDLs) capable of modulating multiple pathological pathways simultaneously has emerged as a promising therapeutic strategy. In this context, the present study describes the design, synthesis, and biological evaluation of a novel series of pyrano[3,2-c]coumarin derivatives 4a-n as dual Aβ42 and acetylcholinesterase (AChE) targeting anti-AD agents. Compounds 4a-n showed significant protection by inhibiting tissue specific Aβ42 aggregation in a transgenic AD model of Drosophila. In particular, compounds 4g and 4i were identified as potential lead compounds for targeting AD. These compounds inhibited endogenous Aβ42 aggregation and exhibited a significant rescue of eye phenotypes at respective effective concentrations (ECs) (4g, 46% rescue at EC = 250 µM and 4i, 65% rescue at EC = 50 µM). Furthermore, compounds 4g and 4i effectively reduced lipid-peroxidation, which was determined by assessing thiobarbituric acid reactive substances (TBARS) levels, at 25 and 50 µM, respectively, and reactive oxygen species (ROS). Compounds 4g and 4i also exhibited AChE inhibitory activity, with IC50 values of 0.02652 and 0.0268 µM, respectively. In silico molecular docking studies of 4i with Aβ42 (PDB ID: 1IYT) and AChE (PDB ID: 4EY4) also corroborated their anti-AD activity. Therefore, the present study indicated these compounds, especially 4i, could be promising lead candidates for AD drug development.},
}
@article {pmid42554173,
year = {2026},
author = {Yıldırım, N and Güven Aksu, NM and Perk, B&#xd6; and Can Eke, B},
title = {Plasma Concentrations of Amyloid-β Peptides, BACE-1, and Tau Proteins in Alzheimer's Disease.},
journal = {Turkish journal of pharmaceutical sciences},
volume = {},
number = {},
pages = {},
doi = {10.4274/tjps.galenos.2026.68256},
pmid = {42554173},
issn = {2148-6247},
abstract = {OBJECTIVES: The aim of this study was to compare, using ELISA, plasma levels of amyloid beta (Aβ)40, Aβ42, beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1), total tau (t-tau), and phosphorylated tau (p-tau), as well as the Aβ42/Aβ40 ratio, between patients with Alzheimer's disease (AD) and healthy controls, and to evaluate their diagnostic performance in relation to demographic and lifestyle factors.<br><br>MATERIALS AND METHODS: This study is a single-center, cross-sectional, case-control study. Twenty-four individuals diagnosed with AD and 37 healthy volunteers included in the study. Alongside the analysis of plasma samples obtained from the participants, demographic data were analyzed to assess the potential influence of lifestyle and environmental factors on disease development.<br><br>RESULTS: Analysis of the case data showed that increasing age was a risk factor for AD, higher education level was associated with an increased risk of AD, and tea consumption was inversely associated with AD. While age is a well-known risk factor, both the increased risk of AD associated with higher education and the relatively protective effect of tea consumption against AD are supported by the literature. Evaluation of the levels of A&#x3b2;40, A&#x3b2;42, BACE-1, t-tau, and p-tau and of the A&#x3b2;42/A&#x3b2;40 ratio revealed no significant differences between the patient and control groups. Additionally, A&#x3b2;40, A&#x3b2;42, BACE-1 showed correlations in both the control and Alzheimer's groups, whereas t-tau did not.<br><br>CONCLUSION: None of the investigated plasma biomarkers (A&#x3b2;40, A&#x3b2;42, BACE-1, t-tau, p-tau, and the A&#x3b2;42/A&#x3b2;40 ratio) discriminated Alzheimer's patients from healthy controls, with all receiver operating characteristic area under the curve values below 0.62. These findings indicate that in this cohort, plasma levels of these individual markers did not provide diagnostic value; larger longitudinal studies including cerebrospinal fluid comparisons and multi-marker panels are needed.},
}
@article {pmid42554188,
year = {2026},
author = {Zhang, H and Zhang, Y and Cheng, Y and Liu, Q and Meng, X and Wang, D and Li, M},
title = {Docosahexaenoic acid improves cognitive function and reduces neuronal apoptosis in an Alzheimer's disease mouse model: association with reduced oxidative stress and telomere attrition.},
journal = {Nutritional neuroscience},
volume = {},
number = {},
pages = {1-19},
doi = {10.1080/1028415X.2026.2700765},
pmid = {42554188},
issn = {1476-8305},
abstract = {OBJECTIVE: Given the global aging intensification, age-related chronic diseases like Alzheimer's disease (AD) severely harm the elderly's health, with unclear pathogenesis and no effective drugs. Thus, this study intervened in APP/PS1 mice with docosahexaenoic acid (DHA) feeds of different doses to explore DHA's effects on the mice's cognitive function and nerve cell apoptosis, aiming to find the ways to prevent or delay the elderly's cognitive decline.<br><br>METHODS: Six-month-old APP/PS1 mice were divided into 4 groups: wild control (WT), model control (Con), low-dose DHA (DHA-L), and high-dose DHA (DHA-H). After intervention, the study evaluated mice's cognitive function, determined brain AD-related protein and free fatty acid levels, assessed neuronal degeneration and apoptosis, measured telomere oxidative damage, telomere length, and brain oxidative stress levels.<br><br>RESULTS: (1) DHA shortened water maze escape latency, increased platform crossings and target quadrant residence time, and reduced the expression of AD-related proteins (APP, A&#x3b2;, etc.) (P&#x2009;<&#x2009;0.05); (2) It improved brain neuronal degeneration and apoptosis (P&#x2009;<&#x2009;0.05); (3) It enhanced brain antioxidant capacity, regulated SOD, LPO, and MDA levels, and reduced DNA and telomere oxidative damage (P&#x2009;<&#x2009;0.05); (4) It prolonged brain telomere length (P&#x2009;<&#x2009;0.05).<br><br>CONCLUSION: DHA supplementation can improve cognitive decline in AD model mice, and the mechanism may be that DHA supplementation alleviates oxidative stress-mediated telomere wear in brain tissue, thereby inhibiting apoptosis of neuronal cells. These conditions provide a scientific basis for the elderly and people with cognitive impairment to prevent or alleviate cognitive impairment with reasonable intake of DHA.},
}
@article {pmid42554237,
year = {2026},
author = {Maestre, GE and Patel, NK and Pirela, RV and Hilsabeck, RC and Stine, K and Epps, FR and Garcia, N and Santiago-Mejias, S and Reyes, R and Satizabal, CL and Mejia-Arango, S and Sullivan, AC and Oropeza, O and Gireud-Goss, M and Rodriguez, H and Trevino, H and Ramirez, A and Young, VM and Alliey-Rodriguez, N and LaRoche, A and Martinez-Menendez, CJ and Tanner, JA and Otto, L and Garza-Parker, C and Garza, N and Flores, M and Casas, N and Robles, S and Davila, A and Maestre, CA and Shipp, E and Melgarejo, JD and de Erausquin, GA and Williams-Blangero, S and Seshadri, S},
title = {Engagement of understudied populations as community change: The South Texas ADRC model.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71695},
doi = {10.1002/alz.71695},
pmid = {42554237},
issn = {1552-5279},
support = {P30AG066546/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; Texas ; *Alzheimer Disease ; Hispanic or Latino ; *Patient Selection ; Community-Institutional Relations ; Focus Groups ; Rural Population ; Registries ; },
abstract = {Many populations experiencing the highest burdens of Alzheimer's disease and related dementias remain understudied, in part because traditional recruitment and retention models are insufficient to support sustained engagement. The Outreach, Recruitment, and Engagement Core (OREC) of the South Texas Alzheimer's Disease Research Center reconceptualized participant recruitment as a long-term system change in a Hispanic-majority, urban-rural region. OREC institutionalizes shared power through community advisory governance, aligns research protocols with local lived realities (through patient navigators, community health workers/promotores, and decentralized access points), and employs a data-driven feedback loop for continuous improvement. In 1 year, 46 outreach events touched 10,134 individuals (71% Hispanic) and generated 172 new registry enrollments. Qualitative engagement (focus groups/key-informant interviews) progressed to high-sensitivity topics (e.g., brain donation), signaling maturation of trust. This shift from outreach to reciprocity infrastructure reflects a systems-level change, one that lowers barriers, builds trust, and enables research participation to become routine rather than exceptional.},
}
@article {pmid42554250,
year = {2026},
author = {Song, W and Liu, X and Yu, T and Xiang, Y and Fu, P and Wu, M and Yin, X and Zhang, X and Chen, Z},
title = {Early identification of vascular cognitive impairment from a multimodal perspective: a combined diagnosis from targeted cognitive assessments, imaging biomarkers, and molecular fluid biomarkers to ecological behavioral characteristics.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71667},
doi = {10.1002/alz.71667},
pmid = {42554250},
issn = {1552-5279},
support = {81960221//National Natural Science Foundation of China/ ; 82260249//National Natural Science Foundation of China/ ; 202311506//Jiangxi Provincial Health Commission Science and Technology Plan project/ ; 2022A322//Jiangxi Provincial Administration of Traditional Chinese Medicine science and technology plan project/ ; 20224BAB216045//Youth Foundation of Natural Science Foundation of Jiangxi Province/ ; JXJG-24-17-20//Research and Reform Project on Education and Teaching in Ordinary Colleges/ ; JXJG-24-17-2//Research and Reform Project on Education and Teaching in Ordinary Colleges/ ; JXYJG-2024-140//Research and Reform Project on Education and Teaching in Ordinary Colleges/ ; },
mesh = {Humans ; *Biomarkers/cerebrospinal fluid ; Early Diagnosis ; *Cognitive Dysfunction/diagnosis ; Neuroimaging ; Machine Learning ; *Dementia, Vascular/diagnosis ; Neuropsychological Tests ; },
abstract = {Vascular cognitive impairment (VCI), the second leading cause of dementia, is characterized by heterogeneous pathophysiology and a potentially reversible early phase, underscoring the need for timely identification. This review synthesizes advances across four complementary domains - targeted cognitive assessments, imaging biomarkers, molecular fluid biomarkers, and ecological behavioral characteristics - conceptualized as the TIME framework. Emerging markers, including the peak width of skeletonized mean diffusivity (PSMD), oxygen extraction fraction, brain-derived extracellular vesicles, and digital gait metrics, enable the detection of microvascular injury before overt cognitive decline. Given the limitations of single modalities, we advocate for multimodal integration via machine learning to capture the disease continuum from vascular insult to clinical impairment. Establishing a standardized, pathophysiologically anchored classification system, analogous to the AT(N) framework in Alzheimer's disease, is essential to advance precision risk stratification and early intervention in VCI.},
}
@article {pmid42554263,
year = {2026},
author = {Kim, BH and Lee, H and Kim, J and Seo, SW and Nho, K and , },
title = {Epigenetic aging in Alzheimer's disease: Relation to proteome.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71732},
doi = {10.1002/alz.71732},
pmid = {42554263},
issn = {1552-5279},
support = {P30AG010133/NH/NIH HHS/United States ; P30AG072976/NH/NIH HHS/United States ; R01AG081951/NH/NIH HHS/United States ; R01LM012535/NH/NIH HHS/United States ; U01AG06857/NH/NIH HHS/United States ; U01AG24904/NH/NIH HHS/United States ; U01AG072177/NH/NIH HHS/United States ; U19AG074879/NH/NIH HHS/United States ; RS-2020-KH106434//Korea Dementia Research Center (KDRC)/ ; RS-2025-02223212//Korea Health Industry Development Institute (KHIDI)/ ; 2024-ER1003-02//Korea National Institute of Health/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/cerebrospinal fluid ; *Epigenesis, Genetic ; *Aging/genetics ; *Proteome ; DNA Methylation ; Proteomics ; Biomarkers/cerebrospinal fluid ; Female ; Male ; Aged ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) arises from heterogeneous biological processes, and long-term environmental exposures may become biologically embedded, as reflected in epigenetic clocks.<br><br>METHODS: We calculated blood DNA methylation-based epigenetic clocks and constructed protein co-abundance networks of cerebrospinal fluid (CSF) proteomics data. We performed association analysis of epigenetic age acceleration with network modules, followed by functional and cell-type enrichment analyses, association analyses of hub proteins with AD endophenotypes, and pseudotime trajectory analysis.<br><br>RESULTS: Six network modules were significantly associated with epigenetic age acceleration and were enriched in pathways related to neuronal connectivity, proteostasis, immune activation and remodeling, immune signaling, and immunoepigenetic regulation. Hub proteins demonstrated significant associations with baseline amyloid/tau/neurodegeneration biomarkers and longitudinal cognitive changes. Pseudotime analysis revealed continuous, non-linear variation in epigenetic age acceleration along the inferred trajectory.<br><br>DISCUSSION: Our CSF proteomics study identified neuronal, proteostatic, and immune-related molecular signatures associated with epigenetic age acceleration in AD.},
}
@article {pmid42554285,
year = {2026},
author = {Benussi, A and Bracca, V and Premi, E and Cantoni, V and Palacino, F and Saccavini, A and Cotelli, MS and Binetti, G and Manenti, R and Alberici, A and Gasparotti, R and Ashton, NJ and Zetterberg, H and Blennow, K and Ghidoni, R and Borroni, B},
title = {Temporal order of clinical, imaging, and biomarker changes in frontotemporal lobar degeneration-associated syndromes.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71722},
doi = {10.1002/alz.71722},
pmid = {42554285},
issn = {1552-5279},
support = {//University of Brescia, Italy/ ; //Italian Ministry of Health (Ricerca Corrente)/ ; },
mesh = {Humans ; Female ; *Biomarkers/blood ; Male ; Magnetic Resonance Imaging ; *Frontotemporal Lobar Degeneration/pathology/diagnostic imaging/blood ; Aged ; Middle Aged ; Neurofilament Proteins/blood ; Disease Progression ; Glial Fibrillary Acidic Protein/blood ; Atrophy/pathology ; Brain/pathology/diagnostic imaging ; Neuropsychological Tests ; Supranuclear Palsy, Progressive/pathology ; },
abstract = {BACKGROUND: The temporal sequence of clinical, imaging, and biological changes in sporadic frontotemporal lobar degeneration (FTLD)-associated syndromes remains poorly characterized, and a comprehensive biomarker cascade model is lacking.<br><br>METHODS: We developed a data-driven biomarker cascade model in 489 patients across the FTLD spectrum (211 behaviorial variant frontotemporal dementia [bvFTD], 129 primary progressive aphasia [PPA], 71 corticobasal syndrome [CBS], 66 progressive supranuclear palsy [PSP], and 12 FTD associated with amyotrophic lateral sclerosis [FTD-ALS]; 1904 patient-visit observations). Plasma, magnetic resonance imaging (MRI), and clinical biomarkers were modeled using sigmoid trajectories fitted to covariate-adjusted longitudinal data.<br><br>RESULTS: Plasma glial fibrillary acidic protein departed from normality earliest, followed by Trail Making Test Part B (TMT-B), white matter lesion volume, and neurofilament light chain. Insular atrophy showed the steepest transition among MRI measures; clinical dementia rating dementia staging instrument plus National Alzheimer's Coordinating Center behavior and language domains sum of boxes declined most steeply overall. TMT-B inflected earliest in bvFTD, whereas insula atrophy dominated in PPA.<br><br>CONCLUSIONS: This first data-driven temporal cascade of multimodal biomarkers in sporadic FTLD-associated syndromes offers a framework for disease staging and stage-specific clinical trial design.},
}
@article {pmid42554607,
year = {2026},
author = {Wang, J and Xie, W and Yang, L and Wang, Z and Huang, Y and Huang, P and Liu, Y and Hu, J},
title = {Systematic Multi-Level Analyses Decode the Arthritis-Neurodegeneration Axis With In Vivo Validation.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e76930},
doi = {10.1002/advs.76930},
pmid = {42554607},
issn = {2198-3844},
support = {82272544//National Natural Science Foundation of China/ ; 81672218//National Natural Science Foundation of China/ ; BK20251945//Natural Science Foundation of Jiangsu Province/ ; },
abstract = {Arthritis may influence neurodegenerative risk, but directionality and mediators remain unclear. This study integrates population survival analysis, Mendelian randomization, transcriptomic mapping, and mouse perturbation to map osteoarthritis (OA)/rheumatoid arthritis (RA) links with five neurodegenerative outcomes and prioritize mediators. In 310 162 European-ancestry UK Biobank participants, Cox models associate OA with higher risks of Alzheimer's disease (AD; hazard ratio: 1.13, 95% confidence interval: 1.04-1.22), Parkinson's disease (PD; 1.10, 1.00-1.21), and disorders of autonomic nervous system (DANS; 1.36, 1.06-1.74), and RA with higher AD risk (1.37, 1.13-1.67) (all p < 0.05), but not incident PD. Mendelian randomization prioritizes a modest protective genetic effect of RA on PD (odds ratio: 0.93, 0.88-0.99; p = 0.015), without reverse causation. Transcriptome-wide association and colocalization analyses identify shared RA-PD genes and prioritize Ring Finger Protein 40 (RNF40). In a collagen-induced arthritis (CIA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model, CIA attenuates dopaminergic injury, whereas systemic Rnf40 knockdown alleviates arthritis but exacerbates Parkinsonian pathology. Endogenous RNF40 is induced in arthritic joints but remains stable in midbrain. These cross-layer data define arthritis-neurodegeneration connections and nominate RNF40 as a context-dependent joint-brain candidate linking inflammatory arthritis with dopaminergic vulnerability.},
}
@article {pmid42492825,
year = {2026},
author = {Bunch, TJ and May, HT and Muhlestein, JB and Anderson, JL and Le, V and Woller, SC and Cutler, MJ and Mahajan, R and Targueta, GP and Gurol, ME and Knowlton, K},
title = {Concussion AF trial: Longitudinal assessment of brain injury biomarkers and cognitive decline in elderly patients with atrial fibrillation.},
journal = {Heart rhythm},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.hrthm.2026.07.019},
pmid = {42492825},
issn = {1556-3871},
abstract = {BACKGROUND: Atrial fibrillation (AF) is associated with cognitive impairment. Serum biomarkers to detect subclinical brain injury or predict dementia in patients with anticoagulated AF are understudied.<br><br>OBJECTIVE: This study aimed to quantify neural injury biomarkers and assess their ability to predict incident dementia or moderate cognitive decline in patients with AF.<br><br>METHODS: Prospective longitudinal study of 120 patients with AF (mean age 71.1 &#xb1; 10.7 years; 62.5% male) without baseline dementia. Assessments at baseline and at 6, 12, and 24 months (60% completed all visits). Cognitive and functional measures included the Mini-Mental State Examination (MMSE), the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog11), the Disability Assessment for Dementia, and quality-of-life measures. Serum biomarkers measured were glial fibrillary acidic protein, neuron-specific enolase (NSE), tau, S100 calcium-binding protein B (S100B), and spectrin N-terminal fragment (SNT145). The primary endpoint was incident dementia (MMSE score <24 with memory-related quality-of-life impact). The secondary endpoint was moderate cognitive decline defined as >30% worsening in ADAS-cog11 or >30% decline in the Disability Assessment for Dementia.<br><br>RESULTS: Comorbidities were common: hypertension 64.2%, heart failure 23%, diabetes 16%, and sleep apnea 30.8%; 2 had previous stroke. No participants met the criteria for incident dementia; 3 had an MMSE score of <24 without quality-of-life impact. At 24 months, 9 of 72 (12.5%) exhibited moderate cognitive decline by ADAS-cog11. Biomarkers indicated chronic subclinical stress rather than acute injury: S100B was persistently elevated (baseline 0.18 &#xb1; 0.23; 24 months 0.18 &#xb1; 0.19 pg/mL). SNT145 was elevated (baseline 2.85 &#xb1; 3.73; 24 months 2.36 &#xb1; 1.86 ng/mL). NSE and tau remained within normal ranges; inflammatory markers were persistently elevated. Changes in biomarker levels did not correlate with cognitive decline.<br><br>CONCLUSION: Over 2 years, dementia incidence was low but 12.5% experienced moderate cognitive decline. Persistent elevations of S100B and SNT145 suggest ongoing subclinical brain injury in patients with anticoagulated AF without acute spikes in traditional stroke markers such as NSE.},
}
@article {pmid42545796,
year = {2026},
author = {St-Amant, A and St-Georges, MA and Marier, A and Montembeault, M},
title = {Associations between clinician-observed test anxiety and neuropsychological performance in older adults.},
journal = {Applied neuropsychology. Adult},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/23279095.2026.2704635},
pmid = {42545796},
issn = {2327-9109},
abstract = {OBJECTIVE: As dementia diagnoses rise with population aging, understanding factors that influence neuropsychological performance become increasingly important. While research has established links between test anxiety and poorer test results in younger populations, its effects in older adults remain unclear.<br><br>METHOD: A total of 342 cognitively unimpaired older adults from the National Alzheimer's Coordinating Center were included. Participants were categorized according to clinician-observed test anxiety using the Social Behavioral Observer Checklist into Anxious versus Non-anxious groups and Self-conscious versus Non-self-conscious groups. Measures of episodic memory, executive functions, language, and visuospatial abilities were administered. Analyses of covariance tested performance differences, adjusting for sex, education, and age.<br><br>RESULTS: Anxious and self-conscious participants performed significantly worse than their counterparts on episodic memory (delayed recall), although effect sizes were small (&#x3b7;[2] &#x2248; .02-.04). No significant group differences were observed on other cognitive measures. The association between being Self-conscious during testing and lower episodic memory remained significant when controlled for everyday anxiety and depression symptoms, whereas the association for being Anxious did not.<br><br>CONCLUSIONS: Findings suggest that clinician-observed test anxiety may have minimal impact on cognitive results in aging. Nonetheless, the specific association between test anxiety and episodic memory performance underscores the need to minimize anxiety during assessments to support accurate diagnosis.},
}
@article {pmid42545807,
year = {2026},
author = {Ghahremani, M and Smith, EE and Ismail, Z},
title = {Reply to Comments on "Persistent Functional Impairment as an Early Indicator of Alzheimer's Disease Pathology and Progression".},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70615},
pmid = {42545807},
issn = {1532-5415},
support = {//NIHR Exeter Biomedical Research Centre/ ; //Gordie Howe CARES/ ; BCA527734/CAPMC/CIHR/Canada ; },
}
@article {pmid42545971,
year = {2026},
author = {Salas-Venegas, V and Ramírez-Carreto, RJ and Chavarría, A},
title = {Senescence Associated With Neurodegeneration: Simultaneous Assessment of β-gal Activity And Nissl Stain In Histological Sections of Rodent Brain.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {233},
pages = {},
doi = {10.3791/70676},
pmid = {42545971},
issn = {1940-087X},
mesh = {Animals ; *beta-Galactosidase/metabolism/analysis ; *Cellular Senescence/physiology ; *Neurodegenerative Diseases/pathology/enzymology ; *Brain/pathology/enzymology/metabolism ; Rats ; Staining and Labeling/methods ; Neurons/pathology/enzymology ; Mice ; },
abstract = {Cellular senescence is a physiological process characterized by irreversible cell cycle arrest that impairs tissue regeneration and function. This phenomenon has emerged as a key driver of neurodegeneration, fueled by the accumulation of senescent cells within the central nervous system (CNS). Senescent cells acquire a pro-inflammatory senescence-associated secretory phenotype (SASP) that sustains chronic neuroinflammation and disrupts the neuronal microenvironment. Consequently, essential processes such as neurogenesis, synaptic plasticity, and neuronal survival are compromised. An extensive body of literature associates cellular senescence with several neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease, or multiple sclerosis, and acute neuronal-related damage, such as cerebral ischemia or traumatic brain injury. The combined assessment of senescence-associated β-galactosidase (SA-β-gal) activity and Nissl staining in histological sections provides a comprehensive approach to evaluate cellular senescence and neuronal integrity simultaneously within the same tissue context. This strategy enables precise spatial correlation between the accumulation of senescent cells in specific vulnerable regions (e.g., the hippocampus or cortex) and neuronal loss or tissue damage. By integrating a functional marker of senescence with a classical indicator of neuronal morphology and density, this approach strengthens the interpretative robustness of the analysis. Moreover, it enables a more accurate characterization of the relationship between senescent burden and neurodegenerative changes, maximizing the information yield from limited tissue samples. Moreover, this protocol can determine how senescent cell accumulation occurs in response to interventions (pharmacological, genetic manipulation, etc.) in rodent models of neurodegenerative diseases, thereby providing a powerful tool to analyze this contribution to their pathophysiology.},
}
@article {pmid42546187,
year = {2026},
author = {Chaudhari, NN and Vega Huerta, OM and Bhattacharya, S and Chowdhury, NF and Irimia, A and , },
title = {Deep learning maps local brain aging in relation to cognition across human adulthood.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {123},
number = {32},
pages = {e2532233123},
doi = {10.1073/pnas.2532233123},
pmid = {42546187},
issn = {1091-6490},
support = {R01 AG 079957//HHS | NIH | National Institute on Aging (NIA)/ ; },
mesh = {Humans ; *Deep Learning ; *Aging/physiology/pathology ; Female ; Aged ; *Cognition/physiology ; Magnetic Resonance Imaging/methods ; *Brain/diagnostic imaging/physiology/pathology ; Male ; Alzheimer Disease/diagnostic imaging/physiopathology/pathology ; Cognitive Dysfunction/diagnostic imaging/physiopathology/pathology ; Middle Aged ; Brain Mapping/methods ; Adult ; Aged, 80 and over ; },
abstract = {Brain aging, the strongest risk factor for Alzheimer's disease (AD), varies across cortical regions. Global brain age (GBA), an imaging-derived measure of neuroanatomic decline, reduces structural aging to a single summary value. This can potentially obscure regional patterns of cognitive vulnerability preceding AD. This study introduces a deep-learning architecture trained on the [Formula: see text]-weighted MRIs of 14,748 cognitively normal (CN) participants from multiple sites to estimate local brain age (LBA) at voxel level. By mapping spatial variations in brain aging, the model reveals relatively advanced aging in frontal and temporal lobes compared to parietal and occipital regions. Beyond aging in CN aging adults ([Formula: see text]), findings reveal a pattern of progressively advanced frontotemporal aging as a function of neurodegeneration stage, ranging from mild cognitive impairment (MCI, [Formula: see text]) to AD ([Formula: see text]). Compared to CN adults, key cortical and subcortical structures known to manifest early AD pathology exhibit significantly older LBAs in both early MCI and AD ([Formula: see text]). Deviations from normative regional aging are significantly associated with cognitive performance supported by neural processes linked to those regions ([Formula: see text]), thereby relating anatomic aging to functional outcomes. By quantifying regional variations in brain aging, this framework extends GBA models to provide anatomically interpretable measures that can improve characterization of typical and pathological aging.},
}
@article {pmid42546216,
year = {2026},
author = {Thangavel, M and Masurkar, AV},
title = {Nuclear garbage disposal: An unexpected role for amyloid precursor protein in Alzheimer's disease.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {123},
number = {32},
pages = {e2619791123},
doi = {10.1073/pnas.2619791123},
pmid = {42546216},
issn = {1091-6490},
}
@article {pmid42546232,
year = {2026},
author = {Kropp, E and Varkanitsa, M and Stein, TD and Turk, K and Alosco, ML and Tripodis, Y and Romero, JR and Kiran, S and Budson, AE and , and Charidimou, A},
title = {Diagnostic Accuracy of the Boston Criteria v2.0 in Memory Clinic Patients: An MRI-Neuropathology Validation Study.},
journal = {Neurology},
volume = {107},
number = {4},
pages = {e218314},
doi = {10.1212/WNL.0000000000218314},
pmid = {42546232},
issn = {1526-632X},
mesh = {Humans ; Female ; *Magnetic Resonance Imaging ; Male ; Aged ; Retrospective Studies ; *Cerebral Amyloid Angiopathy/diagnostic imaging/diagnosis/pathology/complications ; Aged, 80 and over ; Sensitivity and Specificity ; *Brain/pathology/diagnostic imaging ; *Memory Disorders/diagnostic imaging/etiology ; Alzheimer Disease ; },
abstract = {BACKGROUND AND OBJECTIVES: Cerebral amyloid angiopathy (CAA) is common in older adults and frequently contributes to cognitive impairment and dementia. Existing in vivo diagnostic criteria for CAA (Boston Criteria) were developed primarily in patients with intracerebral hemorrhage, and their performance in memory clinic populations remains uncertain. The updated Boston Criteria v2.0 incorporate nonhemorrhagic MRI markers intended to improve case detection. We evaluated the diagnostic accuracy of the Boston Criteria v1.5 and v2.0 against neuropathologically confirmed CAA in memory clinic patients.<br><br>METHODS: We performed a retrospective diagnostic accuracy study of participants from the Alzheimer's Disease Neuroimaging Initiative and National Alzheimer's Coordinating Center, selected based on availability of required brain MRI and autopsy-based neuropathology data. Patients were classified as no, possible, or probable CAA according to the Boston Criteria v1.5 and v2.0. The primary reference standard was moderate-to-severe neuropathologic CAA; analyses using any neuropathologic CAA were secondary/exploratory. Diagnostic performance was assessed using sensitivity, specificity, predictive values, likelihood ratios, F1 scores, accuracy, and area under the (receiver-operating characteristic) curve (AUC), with formal comparisons between criteria versions.<br><br>RESULTS: Eighty patients were included (mean age: 81 years, interquartile range 74-86 years; 36.2% female, &#x223c;80% with dementia and Alzheimer disease). Using moderate-to-severe CAA as the neuropathologic reference standard, probable CAA by Boston Criteria v1.5 had a sensitivity of 32% (95% CI 15%-50%), specificity 87% (77%-95%), and AUC 0.59 (0.49-0.69). Using the Boston Criteria v2.0, the corresponding values were 43% (25%-62%), 83% (72%-92%), and 0.63 (0.52-0.74), respectively. No overall performance measures were significantly different between the criteria versions. Secondary analyses using any neuropathologic CAA showed similar patterns.<br><br>DISCUSSION: In memory clinic patients, both Boston Criteria versions showed only modest overall diagnostic performance against neuropathology. Compared with v1.5, Boston Criteria v2.0 showed a numerical shift toward greater sensitivity at the expense of specificity but no clear overall gain in accuracy. These findings support cautious, context-dependent interpretation of MRI-based CAA criteria in memory clinic settings and highlight the need for additional biomarkers to improve in vivo diagnosis in nonhemorrhagic populations.<br><br>CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, in memory clinic populations, Boston Criteria v2.0 show a trade-off between sensitivity and specificity for probable CAA diagnosis, with only modest overall diagnostic accuracy for identifying moderate-to-severe neuropathologically defined CAA.},
}
@article {pmid42546668,
year = {2026},
author = {Wuensche, TE and Stotz, S and Battisti, UM and Herth, MM},
title = {Pretargeted imaging beyond the blood-brain barrier: From concept to reality.},
journal = {Nuclear medicine and biology},
volume = {158-159},
number = {},
pages = {109653},
doi = {10.1016/j.nucmedbio.2026.109653},
pmid = {42546668},
issn = {1872-9614},
abstract = {Pretargeted positron emission tomography (PET) is emerging as a transformative approach for imaging biologics in the brain, overcoming the limitations of direct radiolabeling. Conventional methods with long-lived radionuclides suffer from high radiation exposure, off-target accumulation, and suboptimal imaging properties. Pretargeting separates the targeting from the imaging step, enabling the use of short-lived radionuclides such as fluorine-18, the clinical gold standard, and thereby allowing high-contrast, low-dose imaging. Realizing this strategy in the brain remains challenging due to the restrictive blood-brain barrier, pharmacokinetic constraints, and the requirement for efficient in vivo click chemistry. Recent progress spanning in silico design, in vitro validation, and in vivo studies has now demonstrated successful pretargeting with BBB-shuttled antibodies and antisense oligonucleotides in rodents, non-human primates, and Alzheimer's disease models. Together, these studies demonstrate that what was once considered utopian has now become reality.},
}
@article {pmid42546694,
year = {2026},
author = {Balak, CD and Schlachetzki, JCM and Lana, AJ and West, E and Hong, C and DuGal, J and Zhou, Y and Li, B and Spann, NJ and Saisan, P and Sarsani, V and Kleemann, KL and Zhang, X and Pasillas, MP and O'Brien, S and Bokor, JA and Gordts, PLSM and Butovsky, O and Stevens, B and Kamme, F and Glass, CK},
title = {Lysosomal dysfunction drives a transcriptional and epigenetic signature found in disease-associated microglia in neurodegenerative diseases.},
journal = {Immunity},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.immuni.2026.07.008},
pmid = {42546694},
issn = {1097-4180},
abstract = {Lysosomal dysfunction is causally linked to neurodegeneration in many lysosomal storage disorders and is associated with various age-related neurodegenerative diseases. Here, we investigated the question of underlying mechanisms using a mouse model of mucopolysaccharidosis type IIIA caused by deficiency of the lysosomal hydrolase SGSH. Systematic imaging and transcriptomic and epigenetic studies revealed microglia to be the most profoundly impacted cell type in brains of Sgsh-deficient mice. Further investigation identified dominant and context-dependent roles of members of the MITF/TFE family as major drivers of microglia-specific epigenetic and transcriptional changes resulting from lysosomal stress that are dependent on collaborative interactions with AP-1/ATF, C/EBP, and PU.1/ETS transcription factors. Features of the transcriptomic and epigenetic alterations observed in murine Sgsh deficiency were also observed in microglia derived from mouse models of age-related neurodegeneration and in human Alzheimer's disease patients. These findings reveal common and disease-specific transcriptional mechanisms associated with disease-associated microglia phenotypes.},
}
@article {pmid42546822,
year = {2026},
author = {Ghaderi, S and Mohammadi, S and Iturria-Medina, Y},
title = {Quantitative susceptibility mapping in neurodegenerative diseases: An umbrella review of iron-related biomarkers and mechanisms.},
journal = {Magnetic resonance imaging},
volume = {},
number = {},
pages = {110765},
doi = {10.1016/j.mri.2026.110765},
pmid = {42546822},
issn = {1873-5894},
abstract = {Pathological iron accumulation is a common pathophysiological hallmark across multiple neurodegenerative diseases (NDDs), motivating the need for accurate, non-invasive quantification methods. Quantitative susceptibility mapping (QSM) is an advanced magnetic resonance imaging (MRI) technique that enables in vivo measurement of tissue magnetic susceptibility (χ), providing a sensitive proxy for iron content. This umbrella review systematically evaluates the diagnostic accuracy, clinical correlations, and distinct iron distribution patterns of QSM in major NDDs, such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and atypical Parkinsonism. We included 15 (13/15 were rated Low or Critically Low on AMSTAR 2) systematic reviews and meta-analyses (through July 15, 2026); however, the findings should be interpreted cautiously because of heterogeneity and the low methodological quality. A Corrected Covered Area (CCA) analysis demonstrated only slight overlap of primary studies across the included reviews (CCA = 5.42%). Collectively, the evidence indicates that QSM provides comparable or higher diagnostic sensitivity and reliability than conventional R2* and SWI techniques, particularly for deep gray matter structures. The findings support significant iron overload in the substantia nigra, particularly in the pars compacta, as a robust biomarker for PD that correlates with motor severity and disease duration. Furthermore, regional iron profiling in the basal ganglia is critical for differential diagnosis; specifically, elevated χ in the putamen and globus pallidus effectively distinguishes multiple system atrophy and progressive supranuclear palsy from idiopathic PD. Distinctively, AD and ALS exhibit specific χ alterations in the thalamus, motor cortex, and hippocampus, reflecting divergent iron-related pathophysiological mechanisms, which correlate with cognitive impairment and upper motor neuron signs. Overall, QSM shows diagnostic promise and offers mechanistic insights into iron-related neurodegenerative processes.},
}
@article {pmid42546862,
year = {2026},
author = {Zahran, A and Bdair, M and Milhem, F and Jallad, H and Awartani, A and Khaled, A and Salah, Q and Jamaleddin, R and Thouqan, L and Aldarak, S},
title = {Neurocognitive Outcomes and Survival with High- vs Low-Intensity Statins in Stroke Survivors: A Propensity Score-Matched Cohort (2010-2025).},
journal = {Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association},
volume = {},
number = {},
pages = {108721},
doi = {10.1016/j.jstrokecerebrovasdis.2026.108721},
pmid = {42546862},
issn = {1532-8511},
abstract = {BACKGROUND: Stroke survivors face elevated risks of cognitive decline and dementia. Whether initiating high-intensity versus low/moderate-intensity statins after stroke confers additional neurocognitive benefit-beyond vascular risk reduction-remains uncertain.<br><br>METHODS: Retrospective propensity-matched cohort in TriNetX Research (104 U.S. healthcare organizations). Adults &#x2265;18 years with stroke (ICD-10-CM I60/I61/I63) who received a statin within 7 days were included.<br><br>EXPOSURE: high-intensity versus low/moderate intensity. One-to-one matching on 24 covariates.<br><br>PRIMARY OUTCOME: time to first diagnosis of any dementia within 5 years from day 30. Secondary: Alzheimer's disease, vascular dementia, and all-cause mortality. Hazard ratios with 95% CIs were estimated.<br><br>RESULTS: Of 254,711 eligible patients (148,198 high-intensity; 106,513 low/moderate), matching yielded 206,416 patients (103,208 per group) with good balance (all SMDs <0.10). Over 5 years, incident dementia occurred in 6.6% of the high-intensity group (6,816/103,208) vs 6.9% of the low/moderate group (7,104/103,208) (HR 0.954, 95% CI 0.923-0.986; P=0.005). High-intensity therapy was associated with lower risk of AD (HR 0.882, 95% CI 0.826-0.943; P<0.001) and lower all-cause mortality (HR 0.945, 95% CI 0.926-0.965; P<0.001). There was no significant difference for vascular dementia (HR 1.047, 95% CI 0.996-1.100; P=0.072).<br><br>CONCLUSION: Initiation of high-intensity statins within 7 days of stroke was associated with modestly lower 5-year dementia and mortality; randomized trials are needed to confirm causality and define agent- and subtype-specific effects.},
}
@article {pmid42546867,
year = {2026},
author = {Wong, MS and Wang, J and Lin, YH and Wu, CW and Chen, HY and Lu, KC},
title = {Glaucoma and Neurodegenerative Disease Risk: A 10-Year Assessment of Real-World Global Data.},
journal = {American journal of ophthalmology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ajo.2026.07.051},
pmid = {42546867},
issn = {1879-1891},
abstract = {PURPOSE: To evaluate 10-year risk trajectories of newly diagnosed neurodegenerative diseases among glaucoma patients across age-stratified cohorts and clinical subtypes.<br><br>DESIGN: Retrospective cohort study.<br><br>METHODS: Using TriNetX data (2005-2025), glaucoma patients were propensity-matched 1:1 to controls based on baseline demographics, comorbidities, medications, and laboratory metrics. Outcomes were defined using International Classification of Diseases, Tenth Revision codes. Risks for mild cognitive impairment (MCI), Alzheimer's disease (AD), vascular dementia (VD), unspecified dementias, and Parkinson's disease (PD) were assessed. Cohorts were stratified by age (<45 vs >65 years) and subtype (primary open-angle [POAG], primary angle-closure [PACG], and normal-tension [NTG] glaucoma).<br><br>MAIN OUTCOME MEASURES: 1-, 3-, 5-, and 10-year hazard ratios (HRs) and 95% confidence intervals (CIs).<br><br>RESULTS: Among 384,256 matched pairs, glaucoma correlated with elevated 10-year risks for AD (HR&#x202f;=&#x202f;1.485; 95% CI,1.427-1.546; P < .001), VD (HR&#x202f;=&#x202f;1.213; 95%CI, 1.159-1.27; P < .001), and a delayed PD risk peaking at 10 years (HR&#x202f;=&#x202f;1.115; 95%CI, 1.066-1.167; P < .001). AD and VD risks emerged early in late-onset glaucoma but showed delayed emergence in early-onset patients, where AD risk peaked at 10 years (HR&#x202f;=&#x202f;2.320; P&#x202f;=&#x202f;.03). Subtype analysis revealed no significant AD associations for POAG (HR&#x202f;=&#x202f;1.044; P&#x202f;=&#x202f;.10), PACG (HR&#x202f;=&#x202f;1.096; P&#x202f;=&#x202f;.13), or NTG (HR&#x202f;=&#x202f;1.097; P&#x202f;=&#x202f;.19). However, VD risk was elevated in POAG (HR&#x202f;=&#x202f;1.203; 95% CI, 1.129-1.281; P < .001) and PACG (HR&#x202f;=&#x202f;1.224; 95% CI, 1.056-1.419; P&#x202f;=&#x202f;.007), but not NTG (P&#x202f;=&#x202f;.08). MCI risk increased in POAG (HR&#x202f;=&#x202f;1.201; 95% CI, 1.120-1.288; P < .001) and NTG (HR&#x202f;=&#x202f;1.235; 95% CI, 1.089-1.401; P&#x202f;=&#x202f;.001). NTG demonstrated the only significant PD association (HR&#x202f;=&#x202f;1.283; 95% CI, 1.043-1.577; P&#x202f;=&#x202f;.018), while POAG (P&#x202f;=&#x202f;.05) and PACG (P&#x202f;=&#x202f;.58) showed no correlation. All 3 subtypes maintained significant associations with unspecified dementia (all P < .05).<br><br>CONCLUSIONS: Glaucoma is observationally associated with subsequent neurodegenerative diagnoses, with statistical trajectories varying by onset age and clinical subtype. These findings indicate population-level correlations rather than causal mechanistic linkages.},
}
@article {pmid42546888,
year = {2026},
author = {Aggarwal, P and Sarkar, S},
title = {Neuron-specific suppression of aberrantly active Toll-NFκB signalling mitigates pathogenic tau hyperphosphorylation via Gsk-3β in Drosophila.},
journal = {Biochimica et biophysica acta. Molecular basis of disease},
volume = {},
number = {},
pages = {168393},
doi = {10.1016/j.bbadis.2026.168393},
pmid = {42546888},
issn = {1879-260X},
abstract = {Chronic brain ailments like Alzheimer's disease and Frontotemporal dementia, together referred to as tauopathies, are strongly influenced by neuroinflammation, an age-associated functional anomaly. Neuroinflammation arising from a dysfunctional innate immune response, such as Toll-NFκB signalling, is implicated in modulating tau pathophysiology, with limited understanding of the molecular mechanisms. Pathogenic hyperphosphorylation of tau and its aggregation into neurotoxic species is considered as a central trigger of tau pathology; however, the mechanistic association between these pathogenic events and the Toll signalling remains largely unexplored. We examined the status of the Toll signalling in Drosophila tauopathy models and evaluated whether its modulation modifies disease severity. We present compelling evidence that neuronal expression of pathogenic human tau causes aberrant activation of the Toll signalling. In line, its additional upregulation further aggravates disease severity, while genetic downregulation of Toll components remarkably alleviates both structural and functional deficits. We subsequently noted that knockdown of the Toll pathway attenuates pathogenic tau hyperphosphorylation in a site-specific manner, largely coinciding with restoration of physiological activity of Gsk-3β/Akt/PP2Ac signalling, a relatively less explored molecular axis in neurons. Our study posits a potential contribution of neuron-intrinsic altered Toll signalling cascade in tau pathogenesis, warranting further exploration of this evolutionarily conserved pathway as a therapeutic target.},
}
@article {pmid42546917,
year = {2026},
author = {Liang, Y and Zhi, T and Fan, B and Wu, Y and Wu, L and Xie, Z and Yang, Y and Mu, R and Wu, X},
title = {Activation and increased hippocampal GPR55 prevents cognitive deficits in male APP/PS1 mice.},
journal = {Neuropharmacology},
volume = {},
number = {},
pages = {111129},
doi = {10.1016/j.neuropharm.2026.111129},
pmid = {42546917},
issn = {1873-7064},
abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by progressive memory loss and cognitive decline. G protein-coupled receptor 55 (GPR55) has been linked to cognitive regulation, yet its precise role in AD pathogenesis remains unclear.<br><br>OBJECTIVES: Here, we investigated the role of GPR55 in AD and its molecular mechanism.<br><br>METHODS: This study utilized APP/PS1 and GPR55 knockout (GPR55KO) mice to investigate the role and possible mechanism of GPR55 in AD.<br><br>RESULTS: We observed progressive reduction of GPR55 levels in the hippocampus of aging APP/PS1 mice. Conversely, hippocampal GPR55 overexpression rescued cognitive deficits, neuroinflammation, and impairment of synaptic plasticity in APP/PS1 mice. Moreover, GPR55 activation reduced neuronal death and memory impairments in APP/PS1 mice. In addition, aged GPR55KO mice showed cognitive deficits, but hippocampal GPR55 reexpression improved cognition. We also demonstrated that GPR55 activation mitigates A&#x3b2;1-42-induced synaptic damage and apoptosis in HT22 cells. Further studies revealed that in both animal and cell models, the activation levels of P-AKT/AKT and P-GSK3&#x3b2;/GSK3&#x3b2; were significantly decreased, and the activation level of P-ERK/ERK was markedly increased, while upregulation of GPR55 reversed this trend.<br><br>CONCLUSIONS: These results indicate that hippocampal GPR55 may improve cognitive dysfunction by regulating the AKT/GSK3&#x3b2; and ERK signaling pathways, highlighting its crucial role in AD.},
}
@article {pmid42546981,
year = {2026},
author = {Jaganathan, R and Vijayakumar, S and Chen, Y and Ye, J and Bakthavatchalam, P and Wankar, D and Yang, C and Iyaswamy, A and Li, M},
title = {New insights on microglial lysosomal acidification: A therapeutic target of neurodegenerative diseases.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107555},
doi = {10.1016/j.nbd.2026.107555},
pmid = {42546981},
issn = {1095-953X},
abstract = {BACKGROUND: Microglia, the resident immune cells of the central nervous system (CNS), maintain brain homeostasis and respond to pathological insults. Microglial dysfunction has been implicated in the pathogenesis of several neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Impaired lysosomal function, particularly defective lysosomal acidification, leads to the accumulation of undegraded material, thereby promoting neuroinflammation and neuronal damage.<br><br>PURPOSE: This review examines the mechanisms governing lysosomal acidification in microglia and evaluates its potential as both a therapeutic target and a prognostic biomarker in neurodegenerative diseases.<br><br>METHODS: The literature on microglial lysosomal acidification, lysosomal pH regulation, autophagy, and neurodegeneration was searched in PubMed, Scopus, and Web of Science. Relevant mechanistic, preclinical, and translational studies were critically appraised and synthesized.<br><br>RESULTS: Lysosomal acidification is increasingly recognized as a key regulator of microglial function and homeostasis. Defective acidification, driven by dysregulation of the vacuolar H+-ATPase (V-ATPase) proton pump, TFEB/TFE3 signaling pathways, and lysosomal ion channels such as TRPML1 and TMEM175, impairs autophagic flux and substrate degradation, facilitating the accumulation of neurotoxic aggregates including amyloid-&#x3b2; and &#x3b1;-synuclein. Emerging evidence suggests that the degree of microglial lysosomal acidification may serve as a prognostic biomarker for disease progression and therapeutic response. Restoration or enhancement of lysosomal acidification through pharmacological modulation of lysosomal pH, activation of autophagy, or targeting of key regulatory pathways has been shown to re-establish microglial homeostasis, attenuate neuroinflammation, and confer neuroprotection in preclinical models.<br><br>CONCLUSION: Restoration of microglial lysosomal acidification represents a promising therapeutic strategy for neurodegenerative diseases. A deeper understanding of the molecular mechanisms regulating lysosomal acidification in microglia may facilitate the identification of novel biomarkers and therapeutic targets, ultimately contributing to the development of innovative interventions for neurodegenerative disorders.},
}
@article {pmid42547074,
year = {2025},
author = {Mimenza-Alvarado, AJ and Vazquez-Guajardo, M and Martínez-Bravo, LE and Aguilar Navarro, SG},
title = {The state of Alzheimer's disease in Mexico: current challenges and directions for diagnosis and treatment.},
journal = {Gaceta medica de Mexico},
volume = {161},
number = {6},
pages = {558-568},
doi = {10.24875/GMM.25000128},
pmid = {42547074},
issn = {0016-3813},
mesh = {Humans ; *Alzheimer Disease/diagnosis/therapy/epidemiology ; Mexico/epidemiology ; Biomarkers/blood ; tau Proteins ; Disease Progression ; },
abstract = {Alzheimer's disease (AD) is a major public health challenge in Mexico, with cases expected to rise significantly by 2050. For years, AD lacked major medical advances, but the emergence of plasma biomarkers and disease-modifying therapies has shifted the paradigm from symptomatic treatment to altering disease progression. While these advances are promising, they present substantial challenges for developing countries such as Mexico. The availability and interpretation of new biomarkers must be carefully managed, ensuring their use only in individuals with cognitive impairment rather than for asymptomatic screening. Furthermore, the presence of core biomarkers such as phosphorylated tau 217 in asymptomatic individuals should be considered, indicating "at-risk" status rather than biological AD. Although plasma biomarkers offer new opportunities, cerebrospinal fluid remains the only validated tool in Mexico for confirming amyloid pathology. In addition, two disease-modifying therapies are now approved in Mexico, but defining appropriate candidates, balancing potential benefits against risks, and monitoring treatment response remain significant challenges, especially in the absence of amyloid positron emission tomography imaging. Addressing these issues is critical to ensuring that new diagnostic and therapeutic strategies are effectively and equitably integrated into Mexico's healthcare system. Accordingly, there is an urgent need for the development of public policies and diagnostic infrastructure to ensure the safe, affordable, and sustainable implementation of these advances in countries such as Mexico.},
}
@article {pmid42547271,
year = {2026},
author = {Kim, B and Miller, C and Dhingra, S and Al-Ghezi, M and Wilson, E and Bhatt, NK},
title = {Vocal Fold Atrophy in Patients With Alzheimer's Disease and Related Dementias.},
journal = {The Laryngoscope},
volume = {},
number = {},
pages = {},
doi = {10.1002/lary.70761},
pmid = {42547271},
issn = {1531-4995},
support = {K08AG090629//National Institute on Aging of the National Institutes of Health/ ; },
abstract = {OBJECTIVES: Alzheimer's disease and related dementias (AD/ADRD) can lead to deterioration in voice and swallowing. Vocal fold atrophy (VFA), seen with aging and neurodegenerative disease, results in thin/bowed vocal folds with incomplete glottic closure during voicing and swallowing, leading to breathy voice from air leakage. Magnitude of VFA in AD/ADRD has not been previously studied. This study compared endoscopic measures of VFA in AD/ADRD patients with age-matched controls.<br><br>METHODS: Thirteen patients with a diagnosis of AD (n&#x2009;=&#x2009;3), Lewy body dementia (n&#x2009;=&#x2009;3), vascular dementia (n&#x2009;=&#x2009;1), or multiple-etiology dementias (n&#x2009;=&#x2009;6) presenting to a tertiary laryngology practice were included in this cross-sectional study. Demographics, Consensus Auditory-Perceptual Evaluation of Voice (CAPE-V), Voice Handicap Index-10, and stroboscopic still images were obtained. Images were analyzed for bowing index (BI), normalized glottal gap area (NGGA), and normalized mucosal wave amplitude (NMWA). Two age-matched controls were selected for each patient, yielding 13 AD/ADRD patients and 26 controls (1:2 ratio).<br><br>RESULTS: Mean age for patients was 80&#x2009;&#xb1;&#x2009;10&#x2009;years. AD/ADRD patients demonstrated higher BI scores compared with controls (4.51; 95% CI [1.39, 7.63]; p&#x2009;=&#x2009;0.008). AD/ADRD patients displayed significantly lower NMWA values (-8.2; 95% CI [-9.8, -6.6]; p&#x2009;<&#x2009;0.0001). No significant difference seen in NGGA between groups (0.26; 95% CI [-1.69, 2.43]; p&#x2009;=&#x2009;0.7).<br><br>CONCLUSION: This is the first study to quantify VFA in AD/ADRD patients. Endoscopic measures revealed significant atrophic differences compared with age-matched controls. These measures may serve as potential laryngeal indicators of neurodegenerative involvement in ADRD, though larger studies are needed to establish clinical utility.},
}
@article {pmid42547528,
year = {2026},
author = {Carlsson, A and Axell, E and Wallerstein, J and Thacker, D and Olsson, U and Linse, S},
title = {Human chaperone DNAJB6b suppresses tau fibril formation through co-aggregation.},
journal = {Communications chemistry},
volume = {9},
number = {1},
pages = {},
pmid = {42547528},
issn = {2399-3669},
abstract = {The aggregation of the tau protein into intraneuronal fibrillar tangles is closely associated with the pathology of Alzheimer's disease. The endogenous defense system against this process includes molecular chaperones, among which DNAJB6b has emerged as a key component. Using a tau model system comprising the tau fragment 304-380C322S, which spans the amyloidogenic core of ex vivo Alzheimer's disease fibrils, we investigated the impact of DNAJB6b on tau fibril formation. Here, we show that DNAJB6b potently delays tau aggregation by co-assembling with small tau aggregates and by binding to mature fibrils, thereby reducing their ability to catalyze further fibril growth. This interplay between tau and the chaperone results in greatly reduced fibril formation rate and a lower final fibril mass, which we interpret as increased tau solubility. Moreover, solution-state NMR spectroscopy confirms that DNAJB6b does not interact with tau monomers.},
}
@article {pmid42547581,
year = {2026},
author = {Behrangi, N and Stadler, MS and Reinbach, C and Burkert, L and Hawlitschka, A and Kaddatz, H and Wenzel, L and Llovera, G and Wree, A and Hoornaert, C and Ponsaerts, P and Splietker, U and Brandenburg, LO and Amor, S and Tauber, SC and Bohn, A and Schmitz, C and Kipp, M and Hochstrasser, T},
title = {CD44 as a Conserved Biomarker and Functional Modulator of Neuroinflammation in Multiple Sclerosis and Beyond.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42547581},
issn = {1559-1182},
mesh = {Animals ; *Multiple Sclerosis/metabolism/pathology ; *Hyaluronan Receptors/metabolism ; Humans ; Encephalomyelitis, Autoimmune, Experimental/metabolism/pathology ; *Biomarkers/metabolism ; Mice, Inbred C57BL ; *Neuroinflammatory Diseases/metabolism/pathology ; Female ; Cuprizone ; Mice ; },
abstract = {Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by demyelination, blood-brain barrier disruption, and leukocyte infiltration. The transmembrane glycoprotein cluster of differentiation 44 (CD44) has been implicated in neuroinflammation, but its functional role remains unclear. Here, we examined CD44 expression and function across both non-immune-mediated and immune-mediated MS animal models, including cuprizone-induced demyelination, experimental autoimmune encephalomyelitis (EAE), and combined cuprizone/EAE (Cup/EAE), as well as in human MS tissue and cerebrospinal fluid (CSF), using immunohistochemistry, flow cytometry and enzyme-linked immunosorbent assay. CD44 expression increased in parallel with demyelination and was most pronounced in the forebrain of Cup/EAE mice, where it localized to perivascular cuffs and lesion-associated parenchyma. CD44 expression co-localized to IBA1[+] microglia/monocytes and CD3[+] T cells. Flow cytometry analyses revealed high CD44 expression on myeloid-derived suppressor cells and regulatory T cells, which further increased upon immune activation. On the functional level, Cd44-deficient mice exhibited exacerbated disease severity in EAE, accompanied by increased immune cell infiltration and tissue damage. In human MS samples, CD44 expression and soluble CD44 levels in CSF were significantly elevated. Notably, CD44 upregulation was also observed in other neurological disease models, including ischemic stroke and APPswe/PS1dE9 mice, a model of Alzheimer's disease. Together, these findings identify CD44 as a conserved marker of neuroinflammatory activity and a context-dependent regulator of neuroinflammation with partially protective functions, rather than an exclusively pro-inflammatory molecule, highlighting its potential relevance in MS and related neurological disorders.},
}
@article {pmid42547584,
year = {2026},
author = {Phénix, J and Sarty, I and Katz, MS and Vázquez Cobá, A and Marure Rojano, AE and Nie, H and Kerksiek, A and Jerry, I and Berger, CS and Kiss, RS and Lütjohann, D and Pastor, WA and Poirier, J and Munter, LM and , },
title = {Reducing CETP activity prevents memory decline in an Alzheimer's disease mouse model.},
journal = {EMBO molecular medicine},
volume = {},
number = {},
pages = {},
pmid = {42547584},
issn = {1757-4684},
support = {PJT-162302//Canadian Institutes of Health Research (CIHR)/ ; PJT-175306//Canadian Institutes of Health Research (CIHR)/ ; PJT-186080//Canadian Institutes of Health Research (CIHR)/ ; PJT 153287//Canadian Institutes of Health Research (CIHR)/ ; PJT-178210//Canadian Institutes of Health Research (CIHR)/ ; RR172187//WFF | Weston Brain Institute (WBI)/ ; 32565//Canada Foundation for Innovation (CFI)/ ; 17-02//ASC | Alzheimer Society Research Program (ASRP)/ ; RGPIN-2015-04645//Natural Sciences and Engineering Research Council of Canada (NSERC)/ ; 356162//FRQ | Sant&#xe9; (FRQS)/ ; 1017734//Secretar&#xed;a de Ciencia, Humanidades, Tecnolog&#xed;a e Innovaci&#xf3;n (Secihti, Conacyt), Ciudad de M&#xe9;xico, M&#xe9;xico/ ; },
abstract = {Epidemiological studies have shown that lower activity of the cholesteryl ester transfer protein (CETP) correlates with reduced Alzheimer's disease (AD) risk. While small-molecule CETP inhibitors like evacetrapib have previously been assessed for cardiovascular diseases, their involvement in AD has not been investigated. Here, we establish CETP as a novel pharmacological target for AD treatment. Using CETP transgenic mice crossed to a mouse model of amyloidosis and administering evacetrapib, we provide evidence that CETP inhibition maintained memory independent of classic AD markers, likely through maintained vascular health, while increasing hippocampal cholesterol and altering plasma lipoproteins. Using proteomic data of cerebrospinal fluid (CSF) from cognitively unimpaired individuals at risk for AD in the PResymptomatic EValuation of Experimental or Novel Treatments for AD (PREVENT-AD) cohort, we confirm that our mouse model reflects physiological changes in pre-symptomatic human subjects. We propose the repurposing of CETP inhibitors as an effective therapeutic strategy to delay or prevent cognitive impairment in AD.},
}
@article {pmid42547702,
year = {2026},
author = {Alsubaie, MG and Luo, S and Shaukat, K and Zhang, W},
title = {Biomarker-Conditioned Vision Transformers with Deformable Biomarker Attention for Alzheimer's Disease Classification.},
journal = {Journal of imaging informatics in medicine},
volume = {},
number = {},
pages = {},
pmid = {42547702},
issn = {2948-2933},
abstract = {Alzheimer's disease (AD) classification from structural magnetic resonance imaging (MRI) remains challenging, particularly when distinguishing mild cognitive impairment (MCI) from both cognitively normal (CN) ageing and established AD. Multimodal approaches that combine imaging with clinical information are promising, but most confine the influence of clinical variables to the classifier head, so biomarkers cannot shape spatial feature extraction inside the imaging encoder. We propose a bimodal deep learning framework operating on two input sources: 3D T1-weighted structural MRI and tabular clinical assessment scores. A biomarker encoder maps the clinical scores into a conditioning representation that modulates vision transformer patch tokens through spatial rescaling and cross-attention throughout feature extraction. Within selected transformer layers, deformable biomarker attention (DBA) acts as an internal cross-modal modulation pathway rather than a third input modality, enabling sparse biomarker-guided spatial sampling from the 3D MRI feature grid. The framework was evaluated on ADNI data under strict subject-wise train, validation and test splits, so that repeated scans from the same individual never crossed partitions. On the held-out test set, the model achieved 95.68% accuracy, 95.39% macroprecision, 94.65% macrorecall and 95.01% macro F1 score, exceeding all comparison methods reproduced under the same protocol. Prediction uncertainty was higher for misclassified cases, and rejecting the most uncertain cases raised retained set accuracy to 98.31% at 85.03% coverage. Performance degraded gradually rather than catastrophically when clinical scores were with-held, falling to 93.20% accuracy with all five biomarkers imputed. These results indicate that within-encoder biomarker conditioning improves AD classification and yields uncertainty-aware predictions that may support decision-making in clinical research settings.},
}
@article {pmid42547799,
year = {2026},
author = {Kubota, M and Kurose, S and Tagai, K and Momota, Y and Ichihashi, M and Endo, H and Seki, C and Moriguchi, S and Yamamoto, Y and Kataoka, Y and Goto, R and Tamura, T and Shiwaku, H and Matsuoka, K and Suzuki, H and Onaya, M and Tokuda, T and Uchida, H and Takahashi, H and Kawamura, K and Zhang, MR and Higuchi, M and Takahata, K},
title = {High prevalence of tau pathologies in late-onset psychosis: A PET study.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42547799},
issn = {1476-5578},
support = {22H02998//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 19H03583, 24K02379//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 24K02374//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; JPMJMS2024//MEXT | Japan Science and Technology Agency (JST)/ ; JP24wm0625001, JP24zf0127012, JP24wm0625304//Japan Agency for Medical Research and Development (AMED)/ ; },
abstract = {Late-onset psychosis (LOP) exhibits distinct clinical features compared with younger-onset psychosis. Although postmortem and epidemiological studies have suggested an association between LOP and neurodegenerative processes, particularly tauopathies, in vivo evidence remains limited. This study aimed to investigate the involvement of Alzheimer's disease (AD) and non-AD tauopathies in LOP using amyloid PET and tau PET with florzolotau (18F) ([18]F-florzolotau; also known as [18]F-APN-1607 or [18]F-PM-PBB3), a tracer capable of detecting a broad range of tau pathologies. Thirty-seven patients with LOP and 47 age-matched controls underwent PET scans with [11]C-PiB and [18]F-florzolotau to assess group differences in amyloid beta (Aβ) and tau accumulation. Diagnostic effects on regional [18]F-florzolotau standardized uptake value ratios (SUVRs) were assessed. Associations between regional SUVRs and cognitive and clinical features were examined separately in Aβ-positive and Aβ-negative subgroups. Patients exhibited significantly higher positivity rates for both Aβ (13 of 37 patients, 35.1%) and tau (24 patients, 64.9%) than controls (one of 47 controls, 2.1% for Aβ and seven controls, 14.9% for tau). A significant diagnostic effect was observed on regional [18]F-florzolotau SUVRs (P = 0.004), with post-hoc analyses revealing increased tracer retention in the parietal cortex. This diagnostic effect remained robust when the analysis was restricted to Aβ-negative participants (P = 0.002). Among Aβ-positive patients, greater parietal tau burden was associated with lower Frontal Assessment Battery scores. In conclusion, this in vivo PET study demonstrated a high prevalence of AD-like and non-AD-like tau accumulation patterns in LOP, suggesting that LOP may be associated with heterogeneous tau-related neurodegenerative processes.},
}
@article {pmid42547900,
year = {2026},
author = {Xiang, M and Cao, SY and Sun, XH and Hu, JW and Lv, MZ and Li, JY and Li, W},
title = {Brain insulin resistance as a driver of proteinopathy in neurodegeneration: from cell-type-specific mechanisms to targeted therapeutics.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {42547900},
issn = {2047-9158},
support = {LJKMZ20221207//Department of Education of Liaoning Province/ ; 2023-02216//the Swedish Research Council/ ; 1494/2023, 1663/2025//Parkinsonfonden/ ; FO2023-0397, FO2025-0296//The Brain Foundation/ ; 82371273, 82361138574, 31800898, 81430025, and U1801681//National Natural Science Foundation of China/ ; 2024JH6/100800008//department of Science and Technology of Liaoning Province/ ; },
mesh = {Humans ; *Brain/metabolism/pathology ; Animals ; *Insulin Resistance/physiology ; *Neurodegenerative Diseases/metabolism/pathology ; alpha-Synuclein/metabolism ; Amyloid beta-Peptides/metabolism ; },
abstract = {Neurodegenerative diseases are increasingly linked to systemic metabolic dysfunction, with brain insulin resistance (BIR) positioned as a central mediator. Yet translating this insight into effective therapies has proven remarkably difficult. This review argues that BIR-driven neurodegeneration should be interpreted at two distinct but interconnected levels: cell-type-specific disruption of brain homeostasis by BIR, and the direct, mechanistic role of BIR in driving the proteinopathies that define Alzheimer's and Parkinson's diseases. We first show how BIR produces distinct functional deficits across neurons, astrocytes, microglia, and oligodendrocytes, impairing synaptic plasticity, metabolic coupling, immunometabolic homeostasis, and myelination, resulting in a cellular milieu that favors proteinopathy. We then map molecular pathways through which BIR directly distrubs the metabolism of amyloid-β, tau, and α-synuclein. We further examine how islet amyloid polypeptide cross-seeds cerebral amyloid pathology, suggesting a direct molecular interaction between the peripheral drivers of BIR and protein aggregation. In this framework, BIR functions not as a passive risk factor, but as an active, upstream driver of proteostatic collapse. Cellular dysfunction combined with proteostatic failure, defines the therapeutic target space. We evaluate interventions accordingly, distinguishing those that primarily restore cellular function from those that enhance protein clearance, and those that achieve both. For each strategy, we assess the translational evidence, critically appraising the barriers that have limited their clinical success, including patient heterogeneity, narrow therapeutic windows, and inadequate central nervous system delivery. By integrating cell-type-specific biology with proteostatic mechanisms and a clinically oriented therapeutic framework, this review aims to provide a foundation for multi-target strategies that address the BIR-neurodegeneration axis at its mechanistic roots.},
}
@article {pmid42548036,
year = {2026},
author = {Peña-Tauber, A and Hernández Arriaza, R and Reil, D and Muntaner, M and Park, J and Grenier-Boley, B and Hulsman, M and Amouyel, P and Bellenguez, C and Charbonnier, C and Deleuze, JF and Dols-Icardo, O and Hardy, J and Holstege, H and Nicolas, G and Mead, S and Wagner, M and Ramirez, A and Sims, R and van Swieten, J and Willams, J and Lambert, JC and Khosla, C and Le Guen, Y and Greicius, MD},
title = {Genetic Modifiers of ABCA1 Activity Interact with APOE Isoforms to Mediate Alzheimer's Disease Risk.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78303},
pmid = {42548036},
issn = {1531-8249},
abstract = {OBJECTIVE: ATP-binding cassette transporter A1 (ABCA1) has been associated with Alzheimer's disease (AD), but the mechanisms by which it impacts disease risk are unknown. ABCA1 is known to bind apolipoprotein E (ApoE) and catalyze apolipoprotein lipidation. We explored whether genetic variants altering ABCA1 function interact with APOE isoforms to modify AD risk.<br><br>METHODS: Using data from the Alzheimer's Disease Sequencing Project (ADSP), UK Biobank, and the Alzheimer Disease European Sequencing consortium, we assessed the impact of ABCA1 variants on AD risk in APOE subgroups and tested for statistical interactions with APOE &#x3b5;2 and &#x3b5;4 in an all-APOE cohort. We first examined damaging nonsynonymous ABCA1 variants previously associated with AD. We then constructed a measure of predicted ABCA1 activity based on HDL-associated variants and tested its association with AD risk. Finally, we explored potential pathogenic mechanisms of missense variants of interest.<br><br>RESULTS: Damaging nonsynonymous ABCA1 variants had differential AD risk effects between APOE genotype groups and exhibited interaction effects with APOE &#x3b5;2 and &#x3b5;4. Predicted ABCA1 activity based on HDL-associated variants was associated with reduced AD risk and interacted with APOE &#x3b5;4. Replication analyses suggested similar differences in effect size of ABCA1 variants between APOE groups and had concordant effect directions, although not statistically significant, in the APOE interaction model. ABCA1 missense variants N1800H and E1172D were strongly associated with plasma HDL and interacted with APOE in AD risk. In cell-based assays, ABCA1-N1800H showed plasma membrane localization defects potentially driven by misfolding.<br><br>INTERPRETATION: Genetic modifiers of ABCA1 activity interact with APOE isoforms to alter AD risk. ANN NEUROL 2026.},
}
@article {pmid42548078,
year = {2026},
author = {Vöglein, J and Levin, J and Brendel, M},
title = {Amyloid-Related Imaging Abnormalities (ARIA) in Alzheimer's Disease.},
journal = {Deutsches Arzteblatt international},
volume = {123},
number = {13},
pages = {366},
doi = {10.3238/arztebl.m2025.0204},
pmid = {42548078},
issn = {1866-0452},
}
@article {pmid42548576,
year = {2026},
author = {Suffian, M and Mammone, N and Ieracitano, C and Tripodi, GG and Pascarella, A and Ferlazzo, E and Morabito, FC},
title = {EEGDecoder-x: an explainable deep learning framework for cross-subject EEG-based detection of Alzheimer's and Creutzfeldt-Jakob disease.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1851752},
pmid = {42548576},
issn = {1664-2295},
abstract = {Early detection of neurodegenerative diseases is critical. Distinguishing early-stage Creutzfeldt-Jakob disease (CJD) from "mimics" like Alzheimer's disease (AD) remains a major challenge; while EEG is valuable in advanced CJD, early-stage abnormalities are often non-specific and overlap with other rapidly progressive dementias. Deep learning offers promising EEG-based diagnostic solutions, but clinical adoption requires transparent decision-making, the interpretability of the features learned by deep learning models is equally important. In this context, careful model design and explainability are essential. In this paper, we propose a novel interpretable framework, EEGDecoder-x, for decoding EEG signals from subjects with Alzheimer's disease, Creutzfeldt-Jakob disease, and healthy controls, while providing insight into the model's learned characteristics. The EEGDecoder-x framework comprises two main components: a hybrid attention network for disease decoding (EEGDecoder-Net) and an explainability module (EEGDecoder-XAI). EEGDecoder-Net combines a convolutional neural network with a dual attention mechanism, followed by a classification layer, enabling efficient spatio-temporal feature extraction. EEGDecoder-XAI provides a comprehensive local and global explanations of the network's learning process for spatio-temporal dimensions. We validate the proposed framework using a Leave-One-Subject-Out evaluation paradigm, achieving 97.22% classification accuracy on a dataset of 36 subjects (12 with AD, 12 with CJD, and 12 healthy controls), and outperforming the baseline models, demonstrating both the effectiveness and interpretability of EEGDecoder-x.},
}
@article {pmid42548677,
year = {2026},
author = {Zhao, J and Zhang, M and Vidano, C and Takarabe, C and Bonakdarpour, B},
title = {Musical Museum: an integrative approach to emotional, intellectual and social stimulation for individuals with Alzheimer's disease and related disorders and their caregivers.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1849901},
pmid = {42548677},
issn = {1664-2295},
abstract = {INTRODUCTION: Musical Museum is a concert series that features live music and short music appreciation lectures in a socially safe setting designed for individuals with neurocognitive disorders (NcDs) and their caregivers. This program was created to provide emotional well-being, intellectual stimulation and social interaction. In this manuscript, we present our viable methodology, satisfaction ratings, implementation practicality, exploratory outcomes, and plans for future quantitative research on this program.<br><br>METHODS: Participants, which included individuals with NcDs, their caregivers and other program supporters, experienced hourlong sessions with diverse music (both familiar and unfamiliar), enhanced by verbal introductions providing historical and musical context. Post-concert receptions encouraged social interaction. Anonymous surveys assessed satisfaction, pleasure, intellectual stimulation, likelihood to recommend and change in mood. Participants also provided open-ended feedback to evaluate logistics to determine practicality.<br><br>PRELIMINARY RESULTS: Musical Museum sessions require operational, logistical, and artistic components including venue setup, audiovisual support, communications, printed materials, staffing, and performance planning. Attendance data and expenses were tabulated to assess practicality and acceptability. In surveys, participants reported high satisfaction, pleasure, intellectual stimulation and likelihood to recommend. Participants' perceived mood significantly improved post-session, and they showed appreciation of the social benefits of the program in open-ended questions.<br><br>DISCUSSION: Over 11 completed sessions, implementation of Musical Museum proved to be practical in terms of operational, logistical, and artistic components. Largely positive survey feedback and consistent interest and attendance suggested acceptability to individuals with NcDs and their caregivers. Future directions include a controlled quantitative trial integrating psychosocial and neurophysiologic measures to examine efficacy and underlying mechanisms beyond participant-reported acceptability as well as assessment of the program's longitudinal impact on participant well-being.},
}
@article {pmid42548715,
year = {2026},
author = {Su, TS and Su, KP and Hsueh, PR and Lai, ZL and Chen, CM and Lai, YC and Chen, CS and Nian, X and Chang, YW and Tsai, ST},
title = {Memory training through Chinese classics recitation for individuals with subjective cognitive decline: study protocol for a pilot study.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1830299},
pmid = {42548715},
issn = {1663-4365},
abstract = {BACKGROUND: Subjective cognitive decline (SCD) is a preclinical condition associated with an increased risk of dementia and Alzheimer's disease, with no consensus regarding effective therapeutic interventions to date. As the global burden of aging-related neurodegenerative diseases continues to rise, early intervention has become increasingly critical. Cognitive training has been proposed as a promising behavioral intervention; however, few studies have integrated multimodal assessments to elucidate its underlying neurobiological and psychological mechanisms, particularly within the educational system that shapes cognitive reserve and learning strategies across the lifespan. This pilot study aims to estimate effect sizes for future definitive trials, assess the feasibility and acceptability of the intervention and multimodal evaluations, and generate hypotheses regarding the relationship between recitation practice and clinical biomarkers.<br><br>METHODS: A total of 60 individuals with subjective cognitive decline will be enrolled in a randomized, assessor-blinded, controlled pilot study. Participants will be randomly assigned to either an intervention group or a non-active control group prior to baseline assessment. The intervention group will undergo a six-month structured recitation training program. Both groups will undergo short-term follow-up after the intervention, and long-term follow-up annually post-intervention. Multimodal assessments will include neuropsychological testing, functional magnetic resonance imaging (fMRI), electroencephalography (EEG), blood biomarker profiling, gut microbiota analysis, and fecal metabolomics.<br><br>DISCUSSION: This study protocol outlines a randomized, assessor-blinded, controlled pilot study designed to advance understanding of the feasibility of Chinese Classics recitation training on both physiological and psychological outcomes in individuals with subjective cognitive decline. The findings are expected to provide mechanistic insights into non-pharmacological interventions and to address the current underrepresentation of Asian populations in neuroscience research.<br><br>CLINICAL TRIAL REGISTRATION: We registered this randomized controlled trial on ClinicalTrials.gov on March 11, 2026, under the identifier NCT07463391.},
}
@article {pmid42548797,
year = {2026},
author = {Pan, Z and Shen, Y and Peng, D and Tang, L and Ran, T and Liu, Y and Zeng, X and Liu, H},
title = {Caenorhabditis elegans in neuroscience: from neural communication to neurodegenerative disease modeling.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1865186},
pmid = {42548797},
issn = {1663-4365},
abstract = {Consistent with humans and other metazoans, the nematode Caenorhabditis elegans (C. elegans) undergoes progressive structural and functional decline during aging. Possessing highly conserved genetic pathways that share extensive homology with human genes, and characterized by a streamlined, fully mapped connectome, C. elegans has emerged as a robust model for dissecting the mechanisms underlying neuronal aging and degeneration. In this review, we summarize the intrinsic advantages of C. elegans as a model organism, highlighting its readily quantifiable behavioral phenotypes, short lifespan, and genetic tractability. We elaborate on its foundational neural communication architecture and its unique utility in constructing molecular models of neurodegenerative diseases. Additionally, we explore the integration of this model system with high-throughput pharmacological screening, environmental toxicology evaluations, and advanced genomic sequencing technologies. Ultimately, this synthesis aims to provide a comprehensive framework for investigating neurodegenerative mechanisms and facilitating clinical translation under specific stress conditions, particularly hypoxia.},
}
@article {pmid42548880,
year = {2026},
author = {Alhowail, AH},
title = {Dapagliflozin and cognitive impairment: pharmacological mechanisms, translational evidence, and future directions.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1895764},
pmid = {42548880},
issn = {1663-9812},
abstract = {Cognitive impairment increasingly emerges at the intersection of type 2 diabetes mellitus, vascular brain injury, chronic kidney disease, heart failure, and neurodegeneration, prompting interest in therapies that modify shared metabolic and inflammatory drivers of brain vulnerability. Dapagliflozin, a sodium-glucose cotransporter 2 inhibitor widely used in type 2 diabetes and cardiorenal disease, has attracted attention as a candidate modulator of cognitive decline because its established peripheral pharmacology extends beyond glucose lowering to include natriuresis, blood pressure reduction, weight loss, improved insulin resistance, reduced oxidative and inflammatory stress, and favorable cardiorenal effects. In this review, we examine the pharmacological basis by which these systemic actions could influence the neurovascular unit, mitochondrial homeostasis, glial activation, autophagy-related signaling, and synaptic plasticity pathways implicated in cognitive impairment. We summarize preclinical evidence suggesting that dapagliflozin can improve cognitive performance and modulate pathways such as AMPK-mTOR, Wnt/β-catenin, CREB/BDNF, oxidative stress responses, and neuroinflammatory signaling in experimental models, while also critically evaluating the limitations of these models. We then assess the current human evidence, distinguishing observational studies that suggest lower dementia risk from randomized clinical evidence that has not yet established a definitive cognition-related benefit. We argue that dapagliflozin should currently be viewed not as a proven cognitive therapeutic, but as a mechanistically plausible metabolic-neurovascular intervention whose relevance may be greatest in metabolically vulnerable phenotypes. Finally, we outline key translational challenges, including uncertainty regarding direct central target engagement, the need for biomarker-enriched trial designs, and the importance of integrating pharmacological, vascular, and neurodegenerative frameworks in future studies.},
}
@article {pmid42548982,
year = {2026},
author = {Piccarducci, R and Mainardi, M and Marchetti, L},
title = {Editorial: New horizons in Alzheimer's disease research: combining cell, gene, and emerging therapies.},
journal = {Frontiers in medicine},
volume = {13},
number = {},
pages = {1919555},
pmid = {42548982},
issn = {2296-858X},
}
@article {pmid42549172,
year = {2026},
author = {Liu, BB and Wang, HC and He, YL and Zhang, LJ and Meng, DL and Fu, Y and Wang, MY and Zhang, W},
title = {Inhibition of amyloid β aggregation by venetoclax: a computational and in vitro experimental approach.},
journal = {RSC advances},
volume = {},
number = {},
pages = {},
pmid = {42549172},
issn = {2046-2069},
abstract = {The aggregation of amyloid β-protein (Aβ) plays a key role in the pathological progression of Alzheimer's disease (AD). Given the current absence of effective therapeutic strategies, the drug repurposing approach provides novel insights into the treatment of AD. Venetoclax, a B-cell lymphoma 2 (BCL-2) inhibitor, has demonstrated remarkable efficacy in the treatment of hematological malignancies, characterized by well-defined pharmacokinetic properties and a favorable safety profile. However, its effects and molecular mechanisms in the treatment of AD remain unexplored. Here, we investigated the potential of venetoclax in the inhibition of Aβ aggregation and elucidated its underlying mechanism. The inhibitory effect of venetoclax on Aβ aggregation was assessed using thioflavin T (ThT) fluorescence assays, transmission electron microscopy (TEM), and circular dichroism (CD) spectroscopy. Cellular assays were performed to evaluate the neuroprotective effects of venetoclax against Aβ42-induced neurotoxicity and oxidative stress. Molecular dynamics (MD) simulations were conducted to explore the molecular interactions between venetoclax and Aβ42 peptides. Venetoclax significantly inhibited Aβ aggregation, reduced fibril formation, and decreased β-sheet content at molar ratios of 2 : 1 and 1 : 1 (Aβ : venetoclax). Cellular assays showed that venetoclax attenuated Aβ42-induced neurotoxicity and oxidative stress. MD simulations revealed that venetoclax stabilized Aβ peptides via hydrogen-bonding networks, increasing solvent accessibility and reducing hydrophobic interactions. Venetoclax inhibited Aβ aggregation and mitigated Aβ-induced neurotoxicity by stabilizing Aβ peptide dynamics. These findings support the potential of venetoclax as a repurposed therapeutic candidate for AD.},
}
@article {pmid42549443,
year = {2026},
author = {Kamiya, M and Osawa, A and Kagaya, H and Kondo, I},
title = {The effects of tabletop gaming on patients with mild cognitive impairment and Alzheimer's disease: A feasibility study.},
journal = {Fujita medical journal},
volume = {12},
number = {3},
pages = {215-221},
pmid = {42549443},
issn = {2189-7255},
abstract = {OBJECTIVES: This study examined the feasibility of patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD) performing gaming tasks.<br><br>METHODS: Ten patients with MCI and nine patients with AD participated. Gaming and tabletop tasks were the two types of interventions designed for this study. Following a randomized crossover design, the two interventions were conducted at a rate of 1 hour per week for 4 weeks. The Genki! Ha&#x2022;tsu&#x2022;ra&#x2022;tsu Trepachi-table (TOYOMARU INDUSTRY CO., LTD., Aichi, Japan) device was used for the gaming intervention. Using this table-shaped gaming device with cognitive training components, one to four players can compete in various gaming challenges on a touchscreen mounted on the top of the table. For the tabletop task intervention, patients completed arithmetic and spot-the-difference exercises as cognitive training activities. A visual analog scale was used to quantify mood before and after each intervention session, and a reaction scale measuring the "autonomy" and "degree of participation" of patients was completed after each intervention.<br><br>RESULTS: The gaming intervention significantly increased the visual analog scale score of the AD group (p=0.031). The MCI group had significantly higher autonomy reaction scale scores during the gaming intervention than the AD group (p=0.007).<br><br>CONCLUSIONS: Activities using gaming technology may enhance the willingness and mood of senior citizens with diminished cognitive capabilities and could potentially support ongoing brain training.},
}
@article {pmid42549510,
year = {2026},
author = {Silva, A and Silva, S and Macedo, J and Moreira, P and Baptista, D and Bicker, J and Fortuna, A and Liberal, J and Rodrigues, B and Resende, R and Vitorino, I and Santos, AE and Neves, BM and Pereira, C and Cruz, MT},
title = {Intranasal Administration of Isoeugenol Improves Memory Deficits in APP/PS1 Old Mice-A Role Beyond Nrf2 Activation?.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {40},
number = {15},
pages = {e72186},
doi = {10.1096/fj.202601575R},
pmid = {42549510},
issn = {1530-6860},
support = {LA/P/0058/2020//MEC | Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e a Tecnologia (FCT)/ ; UID/04539/2025//MEC | Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e a Tecnologia (FCT)/ ; UID/PRR/4539/2025//MEC | Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e a Tecnologia (FCT)/ ; },
mesh = {Animals ; *NF-E2-Related Factor 2/metabolism ; *Eugenol/analogs &amp; derivatives/administration &amp; dosage/pharmacology ; Mice ; Administration, Intranasal ; *Memory Disorders/drug therapy/metabolism ; *Alzheimer Disease/drug therapy/metabolism ; Humans ; Mice, Transgenic ; *Amyloid beta-Protein Precursor/genetics/metabolism ; *Presenilin-1/genetics/metabolism ; Male ; Disease Models, Animal ; Microglia/metabolism/drug effects ; },
abstract = {Alzheimer's disease (AD), a neurodegenerative disorder and the most common cause of dementia, has no cure or effective treatment; thus, identification of disease-modifying therapeutics is crucial. Nrf2 is a master controller of homeostatic functions whose activity is compromised in AD. Most pharmacological Nrf2 activators are electrophilic molecules that covalently modify cysteine residues in the thiol-rich Keap1, and many are Michael acceptors, such as low-molecular-weight (LMW) skin allergens. However, LMW allergens-induced Nrf2 activation in a pharmacological setting has only recently attracted attention, exemplified by the clinical success of Dimethyl Fumarate. Hence, we investigated, for the first time, the potential of the skin allergen Isoeugenol to activate Nrf2 and reverse selected AD hallmarks, both in vitro and in vivo, in AD-specific models. In vitro studies were performed using microglia cells exposed to LPS and neuronal cells overexpressing human APP with Swedish mutation, to evaluate Isoeugenol's potential in decreasing neuroinflammation and activating the Nrf2 pathway, respectively. In vivo studies were conducted in 10-month-old AD double-transgenic mice (APP/PS1), which were intranasally administered Isougenol. Isoeugenol's pharmacokinetic and pharmacodynamic profile, and its effect on mice cognition were evaluated. The results showed that Isoeugenol (1) activated Nrf2 in AD neuronal cells (likely involving AKT signaling); (2) exhibited antioxidant and Nrf2-dependent anti-inflammatory activity, which was abolished after Nrf2 silencing; (3) exhibited good pharmacokinetic and pharmacodynamic profiles; (4) reduced the levels of Aβ peptides in vitro and in vivo; (5) reduced triglyceride and LDL cholesterol levels in treated mice; and (6) improved the memory deficits in old mice. This is the first study reporting Isoeugenol's intranasal administration, and on specific AD mice models. Overall, the results reinforce Isoeugenol as a pleiotropic molecule, with great potential for AD treatment.},
}
@article {pmid42549671,
year = {2026},
author = {Du, X and Yi, G and Ren, Y and Zhang, Z and Mi, H},
title = {Generalized Multilevel Multisource Functional Regression With an Application to Alzheimer's Disease.},
journal = {Statistics in medicine},
volume = {45},
number = {18-19},
pages = {e70688},
doi = {10.1002/sim.70688},
pmid = {42549671},
issn = {1097-0258},
support = {21BTJ044//National Social Science Fund of China/ ; 12371267//National Natural Science Foundation of China/ ; ZK-2026-fw-18//College of Advanced Interdisciplinary Studies, National University of Defense Technology/ ; },
mesh = {*Alzheimer Disease/diagnostic imaging ; Humans ; Bayes Theorem ; *Principal Component Analysis ; Computer Simulation ; Regression Analysis ; Longitudinal Studies ; Models, Statistical ; Disease Progression ; Neuroimaging ; },
abstract = {With population aging, Alzheimer's disease has gained increasing attention. Advances in medical technology and longitudinal studies such as the Alzheimer's Disease Neuroimaging Initiative (ADNI) have generated diverse follow-up data, which can be viewed as multilevel multisource functional data for understanding disease progression. In this paper, we propose a new estimation method for the multilevel multisource functional principal components. This method first applies the multilevel functional principal component analysis on the univariate multilevel functional data, then obtains the estimation of the principal components of the multilevel multisource functional principal component model based on the relationship between the univariate and the multisource principal component models, thus realizing the multisource-component-based two-stage estimation of the generalized multilevel multisource functional regression model. We also further consider Bayesian estimation based on the two-stage estimation. Numerical simulations and empirical analyses show that both the proposed multisource-component-based two-stage estimation and Bayesian estimation methods work well. Compared to the multisource-component-based two-stage estimation methods, the classification performance of Bayesian estimation is significantly improved.},
}
@article {pmid42549715,
year = {2026},
author = {Manabe, Y},
title = {A Diagnostic Pitfall in the Era of Amyloid-Targeting Therapy: Creutzfeldt-Jakob Disease Masquerading as Biologically Defined Alzheimer's Disease.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {26},
number = {5},
pages = {e70202},
doi = {10.1111/psyg.70202},
pmid = {42549715},
issn = {1479-8301},
}
@article {pmid42549923,
year = {2026},
author = {Takahashi, M and Abe, T and Fujii, M},
title = {Targeting Ubiquitinated Protein Aggregates in Neurodegenerative Diseases: current Status and Future Directions.},
journal = {Molecular and cellular biology},
volume = {},
number = {},
pages = {1-19},
doi = {10.1080/10985549.2026.2705871},
pmid = {42549923},
issn = {1098-5549},
abstract = {Various cellular stressors inhibit translation initiation and promote ribosome disassembly, thereby transiently inducing stress granules (SGs), dynamic ribonucleoprotein condensates that contain mRNAs and RNA-binding proteins. Although SG assembly is usually reversible, dysregulated SG dynamics can trigger the formation of persistent ubiquitin-positive protein inclusions. There is increasing evidence that this conversion of SGs into insoluble aggregates represents a central pathogenic mechanism in neurodegenerative proteinopathies, such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD). TAR DNA-binding protein 43 (TDP-43) and Tau are causative factors in ALS and AD, respectively, and both localize to SGs under stress conditions. During disease progression, TDP-43 or Tau within SGs undergoes pathological changes that promote the formation of neurotoxic inclusions, which propagate neuronal dysfunction and death. This review summarizes recent advances in understanding the molecular factors that regulate SG assembly and disassembly, as well as the pathological processes that drive the conversion of SGs into aggregates associated with neurodegenerative diseases. Particular emphasis is placed on the role of the ubiquitin-specific protease 10 (USP10), which modulates SG dynamics and has been mechanistically implicated in both ALS and AD. Finally, we discuss the therapeutic potential of targeting these pathways to mitigate neurodegenerative disease progression.},
}
@article {pmid42550250,
year = {2026},
author = {Li, G and Li, Y},
title = {Psychological and neurological benefits of physical activity: impact on mental health, Parkinson's disease, and Alzheimer's disease.},
journal = {Brain structure &amp; function},
volume = {231},
number = {7},
pages = {},
pmid = {42550250},
issn = {1863-2661},
mesh = {Humans ; *Alzheimer Disease/psychology/physiopathology/metabolism ; *Parkinson Disease/psychology/physiopathology/therapy ; *Mental Health ; *Exercise/psychology/physiology ; *Brain/physiopathology/metabolism ; Animals ; Exercise Therapy ; },
abstract = {This review synthesizes current evidence on the psychological and neurological benefits of physical activity, with emphasis on mental health, Parkinson's disease (PD), and Alzheimer's disease (AD). Physical inactivity is increasingly recognized as a modifiable risk factor that may exacerbate neuroinflammatory and metabolic dysfunctions associated with these conditions. Structured exercise has been shown to activate muscle-brain signaling pathways, including neurotrophic factors (BDNF, IGF-1, VEGF), immune modulation (IL-6, IL-10), metabolic regulators (PGC-1α, SIRT1), and peripheral mediators such as myokines and gut-brain axis components. For mental health, exercise is associated with reductions in depressive, anxiety, and stress-related symptoms, potentially through HPA-axis recalibration, neurotransmitter remodeling (serotonin, dopamine), and enhanced endocannabinoid signaling. These changes are supported by fMRI and EEG studies showing improved prefrontal-limbic connectivity and cognitive resilience. In PD, exercise interventions are linked to improvements in motor control, balance, and mood, likely mediated by dopaminergic integrity, neurotrophic support, and anti-inflammatory effects, with multimodal programs (aerobic, resistance, and dance-based) often demonstrating superior outcomes. In AD, mid-life physical activity has been associated with reduced dementia risk in epidemiological studies; proposed mechanisms include enhanced amyloid/tau clearance, glymphatic function, and synaptic adaptation, with some RCTs reporting hippocampal volume preservation and improved network connectivity. Shared mechanisms across conditions include neurotrophic upregulation and anti-inflammatory effects, whereas distinct pathways involve dopaminergic circuit remodeling in PD and glymphatic facilitation in AD. Clinical translation through FITT principles (frequency, intensity, time, type) requires personalized prescriptions, strong adherence strategies, and multidisciplinary integration. Despite methodological heterogeneity and limitations in the existing trials, structured physical activity emerges as a scalable, non-pharmacological intervention with potential for prevention, symptom management, and neuroprotection. Larger, well-designed studies are needed to optimize its application and clarify long-term disease-modifying effects.},
}
@article {pmid42550339,
year = {2026},
author = {Yu, H and Liu, X and Liu, J and Tang, D},
title = {Kaempferol-Conjugated Manganese Oxide Nanocomposites Mitigate Aluminium Chloride-Induced Neurobehavioral Impairments in a Rat Model of Alzheimer's disease.},
journal = {Journal of molecular neuroscience : MN},
volume = {76},
number = {3},
pages = {},
pmid = {42550339},
issn = {1559-1166},
mesh = {Animals ; *Oxides/chemistry/therapeutic use/pharmacology/administration &amp; dosage ; *Manganese Compounds/chemistry/therapeutic use/administration &amp; dosage/pharmacology ; *Alzheimer Disease/drug therapy ; Humans ; Rats ; Aluminum Chloride/toxicity ; *Antioxidants/therapeutic use/pharmacology/chemistry ; *Kaempferols/chemistry/therapeutic use/pharmacology/administration &amp; dosage ; *Nanocomposites/therapeutic use/chemistry/administration &amp; dosage ; *Neuroprotective Agents/therapeutic use/chemistry/pharmacology/administration &amp; dosage ; Male ; Chlorides/toxicity ; Cell Line, Tumor ; Blood-Brain Barrier/metabolism ; },
abstract = {The neurodegenerative illness Alzheimer's disease (AD) causes cognitive decline. The production of oxidative stress in neurons is thought to play a role in the emergence of AD. The antioxidants, including kaempferol, reduce the course of AD; however, their use is limited by poor bioavailability. Kaempferol-conjugated manganese oxide nanocomposites (KMF@PEG-MnO2 NCs) exhibit enhanced protective effects against AD compared to free kaempferol. In this study, the potential of KMF@PEG-MnO2 NCs as an anti-Alzheimer's disease (AD) agent was explored through in silico and experimental approaches. The effective preparation of KMF@PEG-MnO2 NCs was validated by FT-IR, XRD, DLS, and SEM-EDX characterization techniques. The influence of KMF@PEG-MnO2 NCs on antioxidant capacity using the DPPH assay, reactive oxygen species (ROS) quantification with the SH-SY5Y cell line, and determining the amyloid β disaggregation was determined. Additionally, blood-brain barrier permeability was assessed with brain endothelial cells, and an anticholinesterase study was performed to explore its potential for treating Alzheimer's disease. Surface characterization revealed a spherical shape of the nanoparticle. DPPH and FR assay showed a substantial rise in antioxidant defence for KMF@PEG-MnO2 NCs compared to KMF. Anti-aggregation studies demonstrated the nanoparticle's ability to inhibit Aβ fibrils. Additionally, the BBB permeability assay indicated that the nanoparticle can permeate the BBB. Furthermore, in vivo studies demonstrated that KMF@PEG-MnO2 NCs protected against cognitive and synaptic deficits in AlCl3-induced AD rats (AlCl3-AD). KMF@PEG-MnO2 NCs significantly reduced AChE activity. Furthermore, it markedly reduced the brain's levels of nitric oxide (NO) while increasing the function of superoxide dismutase (SOD) and catalase (CAT) activities. Overall, the findings suggest that KMF@PEG-MnO2 NCs may serve as a promising therapeutic candidate for AD management.},
}
@article {pmid42550363,
year = {2026},
author = {Sood, A},
title = {A Review on Structural Insights into NLRP3 and NEK7: Domain Architecture, Subcellular Localization, and Their Interaction in Inflammasome Assembly and Signaling.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42550363},
issn = {1559-1182},
mesh = {*NIMA-Related Kinases/metabolism/chemistry ; Humans ; *Inflammasomes/metabolism/chemistry ; Animals ; *Signal Transduction/physiology ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/chemistry ; Protein Domains ; },
abstract = {The NLRP3 inflammasome plays an important role in the innate immune system that mediates caspase-1 activation and the subsequent secretion of the pro inflammatory cytokines IL-1β and IL-18 in response to microbial infections and cellular stress. Aberrant activation of the NLRP3 inflammasome has been implicated in a range of inflammatory and metabolic disorders, including cryopyrin-associated periodic syndromes (CAPS), Alzheimer's disease, type 2 diabetes, and atherosclerosis. NLRP3 activation can be triggered by diverse stimuli and involves multiple cellular events, such as ionic flux, mitochondrial dysfunction, reactive oxygen species (ROS) generation, and lysosomal damage. A critical regulator of NLRP3 activation is NEK7, a serine/threonine kinase also known for its role in mitotic spindle formation and cytokinesis. Structurally, NEK7 exhibits a partially assembled regulatory spine (R-spine), consistent with an inactive kinase state. However, a mutant form of NEK7 engineered to stabilize the R-spine retains catalytic activity and has been crystallized in complex with compound 51- an ATP-competitive, small-molecule chemical inhibitor that targets both NEK2 and NEK7. Interestingly, wild-type NEK7 crystallized in both apo form and with compound 51 showed variable R-spine conformations, while NEK7 displayed a uniform, partially stacked R-spine configuration. Despite the structural similarity in compound 51 binding between NEK2 and NEK7, subtle differences in ligand orientation reveal potential avenues for designing isoform-selective inhibitors. In this review, we comprehensively examine the structural domains and subcellular localizations of NLRP3 and NEK7, and highlight how their interaction promotes inflammasome assembly. I also discuss recent insights from cryo-electron microscopy (cryo-EM), X-ray crystallography, and molecular modeling studies that illuminate the conformational dynamics of the NLRP3-NEK7 complex. Additionally, we explore the crosstalk between the STING pathway and inflammasome signaling, and address key unanswered questions that may guide future research into therapeutic modulation of these essential protein-protein interactions.},
}
@article {pmid42550365,
year = {2026},
author = {Talebi Taheri, A and Motamedzadeh, A and Zahedi, E and Farasat, A and Dadgostar, E and Aschner, M and Khanifar, H and Rahmati-Dehkordi, F and Tamtaji, OR},
title = {Therapeutic potential of spirulina and its bioactive compound phycocyanin in neuropsychiatric disorders.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42550365},
issn = {1573-4978},
mesh = {*Spirulina/chemistry/metabolism ; *Phycocyanin/therapeutic use/pharmacology ; Humans ; Animals ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Mental Disorders/drug therapy/metabolism ; Oxidative Stress/drug effects ; },
abstract = {Neuropsychiatric disorders are of great health concerns, and despite the availability of drugs, effective therapies are poor, emphasizing the need for novel therapeutics. Among the natural substances screened for neuromodulation properties, Spirulina platensis, a cyanobacterium, and its main bioactive compound (phycocyanin) have attracted great attention. Substantial evidence demonstrates that spirulina and phycocyanin possess neuroprotective properties by targeting multiple interconnected cellular and molecular pathways, including apoptosis, oxidative stress, neuroinflammation, and regulators of synaptic plasticity. Consequently, these compounds have shown therapeutic potential in experimental models of Alzheimer's disease, Parkinson's disease, multiple sclerosis, cerebral ischemia, epilepsy, schizophrenia, depression, and autism spectrum disorder. Herein, we summarize various cellular and molecular pathways which are affected by spirulina and phycocyanin in neuropsychiatric disorders.},
}
@article {pmid42550584,
year = {2026},
author = {Huchegowda, R and Harbishettar, V and Sinha, P and Das, S and Pt, S and John, JP},
title = {Vitamin B12, Homocysteine, and Cognitive Function in the Older Adults Attending a Tertiary Geriatric Psychiatry Center: A Retrospective Case Notes-Based Study.},
journal = {Journal of nutrition in gerontology and geriatrics},
volume = {},
number = {},
pages = {1-16},
doi = {10.1080/21551197.2026.2713421},
pmid = {42550584},
issn = {2155-1200},
abstract = {BACKGROUND: Cognitive impairment in older adults has been linked to low serum Vitamin B12 (B12) and elevated homocysteine (HCY) levels, but evidence remains inconclusive. This study examined their relationship with cognitive impairment among older adults in India.<br><br>METHODS: This retrospective case note-based study included 96 subjects: cognitively normal (n&#x2009;=&#x2009;21), Alzheimer's disease (AD; n&#x2009;=&#x2009;42), and other cognitive disorders (n&#x2009;=&#x2009;33). The mean age was 70.1 (&#xb1; 8.9) years, with 58% males. Cognitive function was assessed using the Hindi Mental Status Examination (HMSE). Serum B12 (pg/ml) and HCY (micromol/L) levels were measured. Pearson's correlation, multiple linear regression, and bootstrapped mediation analyses were performed.<br><br>RESULTS: Elevated HCY (>15 micromol/L) was seen in 72%, and low B12 (<200&#x2009;pg/mL) in 33%. The mean HMSE score was 16.9 (&#xb1; 8.5). No significant correlation was found between HMSE scores and HCY (r&#x2009;=&#x2009;-0.006, p&#x2009;=&#x2009;0.95) or B12 (r&#x2009;=&#x2009;0.12, p&#x2009;=&#x2009;0.23). HCY levels were higher in cognitively impaired groups than controls, but not significantly. Regression analysis showed gender as a significant predictor, while B12, HCY, and age were not.<br><br>CONCLUSION: B12 and HCY levels were not independently associated with cognitive performance. No significant moderation effect between B12 and HCY on HMSE scores was observed.},
}
@article {pmid42550597,
year = {2026},
author = {Cruz-Gonzalez, S and Okpala, O and Gu, E and Gomez, L and Mews, M and Vance, JM and Cuccaro, ML and Cornejo-Olivas, MR and Feliciano-Astacio, BE and Byrd, GS and Haines, J and Pericak-Vance, MA and Griswold, AJ and Bush, WS and Capra, JA},
title = {Methylation clocks fail to generalize across genetically admixed individuals.},
journal = {eLife},
volume = {14},
number = {},
pages = {},
doi = {10.7554/eLife.105343},
pmid = {42550597},
issn = {2050-084X},
support = {F31AG090006/AG/NIA NIH HHS/United States ; R35GM127087/GM/NIGMS NIH HHS/United States ; R01AG070935/AG/NIA NIH HHS/United States ; U01AG076482/AG/NIA NIH HHS/United States ; U01AG072579/AG/NIA NIH HHS/United States ; R01AG070864/AG/NIA NIH HHS/United States ; R01AG072547/AG/NIA NIH HHS/United States ; U19AG074865/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *DNA Methylation ; *Epigenesis, Genetic ; *Alzheimer Disease/genetics ; *Aging/genetics ; White People/genetics ; Female ; CpG Islands ; Black or African American/genetics ; European People ; Quantitative Trait Loci ; },
abstract = {Epigenetic aging clocks based on DNA methylation patterns across the genome have emerged as a potential biomarker for risk of age-related diseases, like Alzheimer's disease (AD), and environmental and social stressors. However, methylation clocks have not been comprehensively validated in genetically diverse individuals. Here, we evaluate a set of first-, second-, and third-generation methylation clocks in 621 AD patients and matched controls from African American, Hispanic, and White cohorts. The clocks are less accurate at predicting age in genetically admixed cohorts compared to the White cohort, especially for those with substantial African ancestry. This decreased accuracy holds in >2500 individuals of European and African ancestry from three additional datasets. The clocks also fail to consistently identify age acceleration in admixed AD cases compared to controls. To explore potential causes for the lack of generalization of the clocks, we intersected clock CpGs with methylation, germline genetic variants, and methylation QTL (meQTL) data from global populations. We find differential methylation between African and European ancestry individuals is common for clock CpGs. Genetic variants rarely disrupt clock CpGs between populations, but a substantial fraction of clock CpGs have meQTL with significantly higher frequencies in African genetic ancestries. Our results demonstrate that methylation clocks often fail to predict age and AD risk when applied across populations and suggest avenues for improving their portability by considering differences in genetic and epigenetic patterns across human populations.},
}
@article {pmid42550766,
year = {2026},
author = {Tuokkola, T and Parkkola, R and Koikkalainen, J and Vahlberg, T and Kaprio, J and Lötjönen, J and Eero, V and Rinne, J},
title = {A magnetic resonance imaging analysis of cognitively discordant monozygotic and dizygotic twins: a comparative study of visual rating method and tensor-based morphometry.},
journal = {Acta radiologica (Stockholm, Sweden : 1987)},
volume = {},
number = {},
pages = {2841851261438991},
doi = {10.1177/02841851261438991},
pmid = {42550766},
issn = {1600-0455},
abstract = {BackgroundAtrophy of the medial temporal lobes and deep gray matter, along with ventricular enlargement, are typical structural magnetic resonance imaging (MRI) findings in the brains of patients with Alzheimer's disease (AD). However, there are few twin studies on this subject.PurposeTo determine whether the visual rating method (VRM) and tensor-based morphometry (TBM) can detect the structural brain changes in monozygotic and dizygotic twin pairs discordant for memory performance.Material and MethodsA total of 12 monozygotic and 24 same-sex dizygotic twin pairs discordant for memory performance and 44 cognitively healthy non-twin volunteers were studied.ResultsSignificant within-twin pair differences in brain atrophy were detected in the medial temporal lobes and ventricular areas (both with VRM and TBM), and in deep gray matter structures (TBM only). When monozygotic and dizygotic twin pairs were analyzed separately, the differences were not statistically significant.ConclusionOur study yielded promising TBM results in distinguishing memory-discordant co-twins in temporal and deep gray matter atrophy. In addition, the findings confirm the assumption that AD affects twins in the same way, independent of genes. Studies with larger twin cohorts would better reveal possible differences between monozygotic and dizygotic twin pairs.},
}
@article {pmid42550855,
year = {2026},
author = {López-Dequidt, I and Leira, Y and Cinza-Sanjurjo, S and Rey-Aldana, D and Jiménez, I and Campos, F and Sobrino, T and Castillo, J and Rodríguez-Yáñez, M},
title = {Circulating MMP-7 is associated with cognitive decline in individuals with vascular risk factors.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261474103},
doi = {10.1177/13872877261474103},
pmid = {42550855},
issn = {1875-8908},
abstract = {BackgroundVascular risk factors contribute substantially to late-life cognitive impairment and interact with neurodegenerative processes underlying dementia. Blood-brain barrier (BBB) dysfunction has emerged as a key mechanism linking vascular pathology to cognitive decline; however, circulating biomarkers reflecting BBB remodeling remain incompletely characterized.ObjectiveTo explore the association between circulating markers of BBB remodeling, amyloid-β (Aβ)1-40 and longitudinal cognitive decline in individuals with vascular risk factors.MethodsIn this prospective cohort study, 101 individuals (mean age 71 ± 5 years; 59.4% women) with long-standing hypertension and/or type 2 diabetes mellitus underwent serial assessment of serum BBB-related biomarkers (matrix metalloproteinases [MMPs], TIMP-1 and soluble tumor necrosis factor-like weak inducer of apoptosis [sTWEAK]), Aβ1-40, brain MRI, and standardized cognitive testing (Mini-Mental State Examination and Addenbrooke's Cognitive Examination Version V) over a mean follow-up of 24 ± 4.9 months. Cognitive decline was defined as a clinically meaningful reduction in global cognitive scores.ResultsTwelve participants (11.9%) developed cognitive decline. Higher serum MMP-7 levels at 12 months were independently associated with subsequent cognitive decline after adjustment for age, sex and baseline cognition (adjusted OR 2.13; 95% CI 1.09-4.13; p = 0.026). Baseline levels of Aβ1-40, MMP-9, and sTWEAK were associated with lower cognitive performance.ConclusionsElevated circulating MMP-7 at 12 months was associated with cognitive decline suggesting a potential role for BBB remodeling in vascular contributions to cognitive impairment. These findings should be considered exploratory and require validation in larger studies.},
}
@article {pmid42550989,
year = {2026},
author = {Casarini, A and Ballerini, A and Maramotti, R and Tondelli, M and Carbone, C and Chiari, A and Vinceti, G and Bedin, R and Urbano, T and Malagoli, M and Genovese, M and Scolastico, S and Giovannini, G and Pugnaghi, M and Orlandi, N and Molinari, MA and Meletti, S and Zamboni, G and Vaudano, AE},
title = {Cognitive and Biomarker Signatures of Late-Onset Temporal Lobe Epilepsy: Toward Non-Alzheimer Neurodegenerative Mechanisms.},
journal = {Neurology},
volume = {107},
number = {4},
pages = {e218356},
doi = {10.1212/WNL.0000000000218356},
pmid = {42550989},
issn = {1526-632X},
mesh = {Humans ; Female ; *Epilepsy, Temporal Lobe/cerebrospinal fluid/diagnostic imaging/psychology/complications/pathology ; Male ; Biomarkers/cerebrospinal fluid ; Cross-Sectional Studies ; tau Proteins/cerebrospinal fluid ; *Alzheimer Disease/cerebrospinal fluid/diagnostic imaging ; Magnetic Resonance Imaging ; *Cognitive Dysfunction/cerebrospinal fluid/diagnostic imaging ; Amyloid beta-Peptides/cerebrospinal fluid ; Aged ; Middle Aged ; Neurofilament Proteins/cerebrospinal fluid ; Neuropsychological Tests ; *Cognition ; Cohort Studies ; Age of Onset ; },
abstract = {BACKGROUND AND OBJECTIVES: Late-onset unexplained epilepsy (LOUE) represents a substantial proportion of epilepsies with onset after 50 years and often manifests as temporal lobe epilepsy (LO-TLE). Although a link with Alzheimer disease (AD) has been suggested, only a subset of LO-TLE shows AD-related biomarkers, indicating biological heterogeneity. This study aims to characterize the cognitive and CSF phenotype of LO-TLE and compare it with healthy controls (HCs) and patients with mild cognitive impairment due to AD (MCI-AD).<br><br>METHODS: This Italian cross-sectional cohort study included LO-TLE patients with normal CSF &#x3b2;-amyloid (A&#x3b2;) biomarkers, MCI-AD, and age-matched and sex-matched HC. Participants underwent structural MRI, neuropsychological assessment, and CSF biomarkers assay, including neurofilament light chain (NfL) and the phosphorylated-to-total tau ratio (p/t-tau). Cortical thickness and subcortical volumes were quantified from structural MRI. Cognitive performance was summarized using principal component analyses. Group differences in imaging, cognition, and CSF biomarkers were assessed, and associations between CSF markers and cognition were examined within groups.<br><br>RESULTS: The study included 18 LO-TLE, 24 MCI-AD, and 17 HC. LO-TLE showed preserved cortical thickness and subcortical volumes comparable with HC, whereas MCI-AD exhibited widespread cortical thinning and medial temporal atrophy. Despite normal imaging, LO-TLE showed lower performance compared with HC in episodic memory (t(53) = -7.79, pFDR < 0.001), short-term memory (t(53) = -2.94, pFDR = 0.007), language (t(53) = 4.12, pFDR < 0.001), and executive functions (t(53) = -3.76, pFDR < 0.001), while attention was preserved. Global cognitive performance further distinguished LO-TLE from MCI-AD, with the former group performing better (t(53) = 4.21, pFDR < 0.001). LO-TLE CSF profiles were characterized by low NfL levels and a p/t-tau ratio below the proposed cutoff of 0.17, whereas MCI-AD showed pathologic A&#x3b2; and tau alterations, elevated NfL, and p/t-tau ratio above 0.17. In LO-TLE, a higher p/t-tau ratio was associated with better performance on global cognition (rs = 0.585, pFDR = 0.032) and short-term memory (rs = 0.588, pFDR = 0.032), whereas no associations emerged in MCI-AD.<br><br>DISCUSSION: LO-TLE with normal CSF AD biomarkers is characterized by distinct cognitive and biological features compared with MCI-AD, suggesting a disease process independent of AD. The low p/t-tau ratio may reflect alternative pathophysiologic mechanisms and warrants further investigation in larger longitudinal studies to clarify the underlying pathology and clinical trajectories.},
}
@article {pmid42551144,
year = {2026},
author = {Li, J and Gao, Y and Guan, Z and Cheng, T and Wu, R and Yu, H and Yang, A and Xu, M and Wang, Y and Yang, P and Wang, T and Ma, G and Lei, B},
title = {Deep Cross-Branch Multi-Modal Fusion Network for early Alzheimer's diagnosis.},
journal = {Artificial intelligence in medicine},
volume = {181},
number = {},
pages = {103497},
doi = {10.1016/j.artmed.2026.103497},
pmid = {42551144},
issn = {1873-2860},
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder where early diagnosis is pivotal for effective intervention, yet it is hindered by subtle pathological feature differences among AD subtypes and severe class imbalance in medical imaging datasets. Existing structural magnetic resonance imaging (sMRI) and resting-state functional MRI (rs-fMRI) multimodal fusion methods for AD diagnosis mostly adopt simple concatenation or summation without fine-grained cross-modal alignment and interaction. To address these issues, we propose a Deep Cross-Branch Multi-Modal Fusion Network (DCMFNet) for early AD diagnosis. We first preprocess sMRI and rs-fMRI to extract ROI-based features, then perform dimension unification and normalization to realize cross-modal feature alignment. A novel Deep Cross-branch Multi-modal Feature Fusion (DCMF) module with three parallel branches and a dual-pathway cross-modal branch is designed to fully mine complementary and correlated cross-modal information, and the fused features are input into a Transformer encoder for classification. Moreover, we introduce the Logit Adjustment Cross-Entropy (LACE) loss to mitigate class imbalance by correcting decision boundaries based on class prior probabilities, enhancing the recognition of minor classes. The model is evaluated on a private clinical dataset. Experimental results show that DCMFNet outperforms traditional machine learning methods and state-of-the-art deep learning models in six binary AD subtype classification tasks, with the LACE loss and DCMF module effectively alleviating class imbalance and improving cross-modal feature representation. This work provides a reliable multimodal fusion framework for early AD diagnosis and reduces the diagnostic burden on healthcare professionals.},
}
@article {pmid42551412,
year = {2026},
author = {Furtado, J and Schneeberger, M},
title = {When lactate speaks: Rewiring astrocyte-neuron metabolism in Alzheimer's disease.},
journal = {Cell metabolism},
volume = {38},
number = {8},
pages = {1527-1528},
doi = {10.1016/j.cmet.2026.05.007},
pmid = {42551412},
issn = {1932-7420},
mesh = {*Astrocytes/metabolism ; *Alzheimer Disease/metabolism/pathology ; Humans ; *Neurons/metabolism ; Animals ; *Lactic Acid/metabolism ; Glycolysis ; Glucagon-Like Peptide-1 Receptor/metabolism ; },
abstract = {Metabolic dysfunction is a defining but poorly understood feature of Alzheimer's disease. Du et al. show that a brain-penetrant GLP-1 receptor agonist rewires astrocyte-neuron metabolic coupling through lactate-driven histone lactylation, linking astrocytic glycolysis to neuronal lipid homeostasis and positioning metabolite signaling as a therapeutic axis in neurodegeneration.},
}
@article {pmid42541636,
year = {2026},
author = {Yang, F and Gao, W and Wang, J and Li, H},
title = {The Glial Autophagy-Lysosomal-Inflammation Axis in Alzheimer's Disease: a Unifying Mechanistic Framework.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42541636},
issn = {1559-1182},
mesh = {Humans ; *Alzheimer Disease/pathology/metabolism ; *Autophagy/physiology ; *Neuroglia/pathology/metabolism ; Animals ; *Lysosomes/metabolism/pathology ; *Inflammation/pathology/metabolism ; Signal Transduction ; },
abstract = {Recent studies suggest that impairment of the glial autophagy-lysosomal pathway (ALP) critically contributes to the sustained neuroinflammatory response and neurodegenerative processes in Alzheimer's disease (AD). Glial cells, comprising microglia, astrocytes, oligodendrocytes, and ependymal cells, serve as key immune regulators in the central nervous system, where they are essential for maintaining ALP homeostasis, promoting proteostasis, and modulating neuroinflammatory responses. Here, we systematically review the regulatory roles of glial ALP in AD pathology, emphasizing its involvement in amyloid accumulation, tau hyperphosphorylation, synaptic impairment, white matter damage, and mitochondrial as well as other organelle dysfunction, and provide an in-depth analysis of key signaling pathways including TFEB, mTOR, and NLRP3. Furthermore, we outline therapeutic strategies aimed at restoring lysosomal function, regulating autophagic flux, and suppressing inflammation, along with a discussion of the multi-target regulatory potential of acupuncture and natural bioactive agents. We also highlight emerging ALP-associated biomarkers and their potential utility in early diagnosis and treatment response assessment. The objective of this review is to uncover the mechanistic interplay between glial ALP dysregulation and the pathological cascade of AD, offering a conceptual framework for the development of novel therapeutics that integrate neuroprotection with immune modulation.},
}
@article {pmid42541645,
year = {2026},
author = {Chu, M and Tan, M and Gan, X and Cui, S and Shi, L},
title = {Targeting Mitochondrial Dysfunction in Microglia: A New Frontier for Treating Neurodegenerative Diseases.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42541645},
issn = {1559-1182},
mesh = {*Microglia/metabolism/pathology/drug effects ; Humans ; *Neurodegenerative Diseases/metabolism/pathology/therapy/drug therapy ; *Mitochondria/metabolism/pathology/drug effects ; Animals ; },
abstract = {Neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) pose an urgent global health challenge. Growing evidence establishes microglia-driven neuroinflammation as a key driver of disease onset and progression, with mitochondrial dysfunction emerging as an early trigger of microglial activation. This review comprehensively summarizes current progress on how mitochondrial alterations regulate microglial activation across AD, PD, and ALS. We identify conserved mechanisms including metabolic reprogramming, impaired mitophagy, and inflammatory signaling, though Aβ, α-synuclein, and TDP-43 engage these pathways through disease-specific molecular routes. Therapeutic strategies targeting microglial mitochondria, including cGAS-STING and NLRP3 inhibitors, TREM2 agonists, and mitochondrial transplantation, remain largely preclinical. Emerging targets such as OLFML3 and GPNMB require functional validation in microglia. Collectively, this review underscores that preserving microglial mitochondrial health represents a promising therapeutic frontier and identifies key priorities for translating these strategies toward clinical application.},
}
@article {pmid42541674,
year = {2026},
author = {Kewal, A and Rajput, MS and Shah, J and Gandhi, D},
title = {Valorization of 2-aminoethoxydiphenyl borate as a neurotherapeutic agent: modulation of calcineurin, TRPC1 and MARK2/GSK-3β signaling in scopolamine-triggered tauopathy.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42541674},
issn = {1568-5608},
support = {(IP/2023-24/68)//Nirma University Funded Minor Research Project Scheme. Directorate of Research, Nirma University, Ahmedabad, India/ ; },
abstract = {In Alzheimer's disease (AD), amyloid beta (Aβ) plaques and hyperphosphorylated tau tangles drive neurodegeneration and cognitive decline. Disrupted calcium homeostasis-particularly via transient receptor potential canonical-1 (TRPC1) channels-contributes to tauopathy and disease progression. This study investigated the therapeutic potential of 2-aminoethoxydiphenyl borate (2-APB), a modulator of TRP channels, in a scopolamine-induced rat model of AD. Adult Wistar rats were assigned to six groups: normal control, disease control (scopolamine 2.5 mg/kg), three 2-APB treatment groups (2.5, 5.0 and 10.0 mg/kg) and a donepezil group (5.0 mg/kg), each with six animals. Treatments lasted three weeks. Cognitive performance was assessed using the Morris water maze, memory consolidation and open field tests. Biochemical assays measured acetylcholinesterase (AChE), calcineurin, oxidative stress markers (GSH, MDA) and inflammatory cytokines (TNF-α, IL-6, IL-1β). Protein and gene expression analyses (Western blot, qRT-PCR) evaluated tau, GSK-3β, TRPC1, MARK2, and calcineurin A/PPP3CA, alongside histopathological and immunohistochemical studies. 2-APB treatment significantly reduced pro-inflammatory cytokines, alleviated neuroinflammation, and decreased oxidative stress. Cognitive function improved, correlating with normalized AChE activity and preserved neuronal structure. At the molecular level, 2-APB reduced tau hyperphosphorylation at Ser396 and Thr231, likely through suppression of TRPC1-associated calcium entry and consequent modulation of calcium-dependent kinases (MARK2) and phosphatases (calcineurin), as well as the GSK-3β pathway. However, given that 2-APB is a broad-spectrum calcium signaling modulator - known to act on IP3 receptors, SOCE/ORAI pathways, and multiple TRPC subtypes in addition to TRPC1-the present findings provide supportive evidence linking TRPC1 modulation to the observed neuroprotective effects. Although, the involvement of additional interconnected signaling mechanisms cannot be excluded and these findings should be interpreted within the context of 2-APB's pleiotropic pharmacological profile. Downregulation of TRPC1 and calcineurin A/PPP3CA gene expression supported 2-APB's role in restoring calcium balance and mitigating tau pathology. These results highlight 2-APB's potential in addressing key AD features-tauopathy, oxidative stress, neuroinflammation and cognitive impairment-warranting further preclinical and clinical research as a potential therapeutic for AD and related tauopathies.},
}
@article {pmid42541877,
year = {2026},
author = {Salama, RS and Hulshizer, CA and Crowson, CS and Lennon, RJ and Rocca, WA and George, RJ and Frechette, N and Allen, M and Myasoedova, E},
title = {Menopause status and its role in incident Alzheimer's disease and related dementias, rheumatoid arthritis (RA) disease severity, and overall mortality in women with RA.},
journal = {Seminars in arthritis and rheumatism},
volume = {80},
number = {},
pages = {153051},
doi = {10.1016/j.semarthrit.2026.153051},
pmid = {42541877},
issn = {1532-866X},
abstract = {INTRODUCTION/OBJECTIVES: We aimed to investigate associations between menopausal characteristics, including age at menopause and cause (natural vs. artificial), with long-term outcomes in women with rheumatoid arthritis (RA), incident Alzheimer's disease and related dementias (ADRD), RA severity, and overall mortality. We hypothesized that atypical menopausal characteristics increase ADRD risk and disease severity.<br><br>METHODS: Women with incident RA in 1980-2014 who were &#x2265;50 years of age at RA incidence were included. Menopause cause and age at menopause (categorized as <45, 45-54, &#x2265;55 years) were abstracted from medical records. Associations between menopausal characteristics and ADRD, extra-articular manifestations (ExRA), erosions, cardiovascular events, and mortality were evaluated using Cox models. Associations with clinic visits for flares and remissions were assessed using mixed-effects models. Data were collected using the Rochester Epidemiology Project medical records-linkage system.<br><br>RESULTS: Both early/premature and late menopause were associated with nonsignificant near two-fold increases in ADRD risk. In addition, early/premature (HR 2.40; 95% CI 1.15-5.01) and late menopause (HR 2.17; 95% CI 1.01-4.66) significantly increased severe ExRA risk. Menopausal characteristics were not associated with presence of erosions or mortality. Artificial menopause was associated with fewer cardiovascular events and fewer visits for RA remission. Early/premature menopause was associated with fewer remission visits (OR 0.50; 95% CI 0.29-0.87).<br><br>CONCLUSION: Women with early/premature and late menopause had nonsignificant, increased risk of incident ADRD. Menopausal characteristics had significant associations with RA severity and cardiovascular events, and may be relevant contextual factors in long-term risk assessment for women with RA.},
}
@article {pmid42541965,
year = {2026},
author = {Vanderlip, CR and Lingad, JN and Treadwell, Z and Loritsch, JM and Illeck, CL and Ubele, MF and Boaz, K and Mefford, JL and Jones, ED and Perpich, JA and McCarty, K and Meacham, B and Bembenek Bailey, SA and Puskás, LG and Bresch, F and Powell, DK and Norris, CM and Head, E and Stark, CEL},
title = {Amyloid-associated cognitive trajectories in aging dogs mirror early changes in humans.},
journal = {Neurobiology of aging},
volume = {168},
number = {},
pages = {99-108},
doi = {10.1016/j.neurobiolaging.2026.07.009},
pmid = {42541965},
issn = {1558-1497},
abstract = {Amyloid-β (Aβ) accumulation begins many years before the onset of clinical symptoms in Alzheimer's disease (AD). Studies in humans suggest that unimpaired individuals with elevated Aβ exhibit subtle changes in cognitive trajectories over time, particularly in memory. Identifying animal models that recapitulate these early changes is critical for translational research on preclinical AD. Here, we hypothesized that aging dogs, which naturally accumulate Aβ, show similar patterns to those observed in humans. Forty-three beagles underwent longitudinal cognitive testing on tasks assessing spatial memory, landmark discrimination, and reversal learning, while Aβ burden was measured using cerebrospinal fluid Aβ42/40. Parallel analyses were conducted in cognitively unimpaired older adults from the Harvard Aging Brain Study (n = 287) using Aβ PET imaging and neuropsychological assessments. Despite no baseline differences, dogs with lower CSF Aβ42/40 showed worse longitudinal trajectories on a spatial memory task. No comparable effects were observed for landmark discrimination or reversal learning. Using a data-driven approach, Low CSF Aβ42/40 dogs were more likely to be classified in the Lower trajectory group than High CSF Aβ42/40 dogs. A similar pattern emerged in humans: Aβ+ individuals showed lower memory trajectories compared to Aβ- individuals. Across species, memory deficits were characterized by reduced benefits of practice effects rather than abrupt decline. Together, these findings suggest that aging dogs show Aβ-associated memory trajectories that parallel patterns observed in cognitively unimpaired older adults and support the canine model as a valuable translational platform for studying the earliest stages of AD.},
}
@article {pmid42542073,
year = {2026},
author = {Oriquat, G and Rizaev, J and Abdulqader, AF and Kadhim, AA and Jamuna, KV and Singhal, D and Bainsal, N and Mansurova, N},
title = {Gut microbiota and brain health: Disease-specific pathways and emerging therapeutic strategies.},
journal = {Multiple sclerosis and related disorders},
volume = {113},
number = {},
pages = {107407},
doi = {10.1016/j.msard.2026.107407},
pmid = {42542073},
issn = {2211-0356},
abstract = {The microbiota-gut-brain axis (MGBA) has emerged as a dynamic, bidirectional communication system linking the gastrointestinal tract and the central nervous system (CNS) through neural, immune, endocrine, and metabolic mechanisms. Increasing evidence indicates that alterations in gut microbial communities are associated with a wide range of neurological disorders; however, the strength of this association varies across diseases, and many mechanistic observations still rely predominantly on experimental models rather than human studies. This review provides an overview of current evidence regarding the role of the gut microbiota in maintaining CNS homeostasis, with particular emphasis on intestinal barrier function, immune modulation, vagal and enteric communication, and the generation of biologically active microbial metabolites, including short-chain fatty acids, bile acids, and neurotransmitter-related compounds. Studies in both clinical and experimental settings have reported disease-specific microbial signatures in conditions such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, autism spectrum disorders, and amyotrophic lateral sclerosis. In parallel, microbiota-directed interventions-including probiotics, prebiotics, dietary approaches, fecal microbiota transplantation, and strategies targeting microbial metabolites-have produced encouraging findings in preclinical studies and early-stage clinical investigations. Nevertheless, considerable heterogeneity in study populations, experimental methodologies, and therapeutic protocols continues to limit the translation of these findings into routine clinical practice. Collectively, current evidence supports the MGBA as a valuable framework for understanding neurological diseases while underscoring the need for rigorously designed longitudinal studies and well-controlled clinical trials to define its therapeutic relevance better.},
}
@article {pmid42542107,
year = {2026},
author = {Sui, JZ and Yin, WW and Yu, HH and Hu, H and Wei, LL and Zhang, JS and Wang, FY and Tan, L and Xue, M and Zhao, B and , },
title = {Trajectories of sleep disturbance in older adults and their associations with clinical and pathological outcomes in AD: A longitudinal study.},
journal = {Sleep medicine},
volume = {147},
number = {},
pages = {109168},
doi = {10.1016/j.sleep.2026.109168},
pmid = {42542107},
issn = {1878-5506},
abstract = {BACKGROUND: Sleep disturbance is a core feature of affective and neurodegenerative disorders. This study tracks long-term sleep disturbance trajectories and their links to incident Alzheimer's disease (AD) and longitudinal clinical and pathological changes.<br><br>METHODS: A total of 774 non-demented participants from the ADNI cohort were included. Sleep disturbance (NPI sleep item) trajectories over 8 years were identified via group-based trajectory modeling. Cox proportional hazards regression was used to estimate the risk of incident AD. Linear mixed-effects models were used to assess longitudinal changes in cognition, structural magnetic resonance imaging, amyloid-&#x3b2; positron emission tomography (A&#x3b2;-PET), fluorodeoxyglucose (FDG)-PET, and cerebrospinal fluid (CSF) biomarkers.<br><br>RESULTS: Three trajectories emerged: "Low-stable" (37.2%), "High-peaked" (21.0%), and "Moderate-increasing" (41.8%). Compared to those without sleep disturbance, a significantly elevated risk of incident AD was associated with "High-peaked" (hazard ratio [HR]&#x202f;=&#x202f;3.28; 95% confidence interval [CI] = 1.89-5.70; p&#x202f;<&#x202f;0.001) and "Moderate-increasing" trajectories (HR&#x202f;=&#x202f;2.13; 95% CI = 1.28-3.53; p&#x202f;=&#x202f;0.003) but not with the "Low-stable" trajectory (p&#x202f;=&#x202f;0.888). Participants with "High-peaked" trajectory exhibited faster declines in cognition (MMSE, memory, executive function) (p&#x202f;<&#x202f;0.050) and a steeper reduction in CSF A&#x3b2;1-42 levels (p&#x202f;=&#x202f;0.038) than those with non-sleep disturbance. However, there were no significant differences between groups in the rates of hippocampal, entorhinal, or middle temporal atrophy, global A&#x3b2;-PET burden, or FDG-PET changes (p&#x202f;>&#x202f;0.050).<br><br>CONCLUSIONS: "High-peaked" and "Moderate-increasing" sleep trajectories predict higher AD risk, faster cognitive decline, and faster A&#x3b2;1-42 reduction. Long-term monitoring of sleep behaviors is essential for identifying and stratifying individuals at high risk for AD.},
}
@article {pmid42542170,
year = {2026},
author = {Xu, X and Li, H and Zhu, Y and Fu, X and Hu, Q and Dong, X},
title = {The critical role of ceramide in mental health and psychiatric diseases.},
journal = {Pharmacology &amp; therapeutics},
volume = {},
number = {},
pages = {109093},
doi = {10.1016/j.pharmthera.2026.109093},
pmid = {42542170},
issn = {1879-016X},
abstract = {Ceramides (Cer) are lipid signaling molecules regulating cell proliferation, differentiation, senescence and apoptosis, whose metabolic disturbance disrupts organismal homeostasis. Accumulating evidence links ceramide imbalance to psychiatric and neurodegenerative diseases, yet few systematic reviews summarize subtype-specific ceramide functions. This review outlines ceramide anabolic and catabolic pathways, compares functional distinctions among ceramides with distinct acyl chain lengths, describes substrate preferences of ceramide metabolic enzymes, and introduces ceramide detection techniques. On this basis, we discuss regulatory roles and underlying molecular mechanisms of ceramides in schizophrenia, Alzheimer's disease, epilepsy, depression, bipolar disorder and anxiety disorders, identify disease-specific effects of distinct ceramide subtypes, and provide theoretical evidence for lipid-targeted pharmacological research on psychiatric disorders.},
}
@article {pmid42542289,
year = {2026},
author = {Rodrigues, ES and Gomes, J and Neto, AAC and Arena, RVP and Meus, SS and Evangelista, HC and Luzardo, BFS and Ávila, DS and Rosa, SG and Pinton, S},
title = {Differential effects of Lactobacillus casei in probiotic and paraprobiotic forms on behavioral performance, oxidative stress, neuroinflammation, and cholinergic dysfunction in a streptozotocin-induced model of sporadic Alzheimer's disease.},
journal = {Progress in neuro-psychopharmacology &amp; biological psychiatry},
volume = {},
number = {},
pages = {111865},
doi = {10.1016/j.pnpbp.2026.111865},
pmid = {42542289},
issn = {1878-4216},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, oxidative stress, neuroinflammation, and cholinergic dysfunction. Increasing evidence suggests that gut microbiota disturbances contribute to AD progression, encouraging the investigation of microbiota-modulating approaches such as probiotics and paraprobiotics. This study evaluated the effects of Lactobacillus casei probiotic and its thermally inactivated paraprobiotic on cognitive, behavioral, oxidative, cholinergic, and inflammatory alterations in a sporadic AD model induced by intracerebroventricular streptozotocin (STZ-ICV; 3 mg/3 μL/site) in female rats. From day 4, animals received daily oral treatment with probiotic L. casei (1 × 10[9] CFU), paraprobiotic (100 mg/kg), or saline for 14 days. Behavioral assessments of memory and exploratory activity were performed alongside biochemical analyses of oxidative stress markers, antioxidant defenses, acetylcholinesterase (AChE) activity, and neuroinflammatory parameters in central and peripheral tissues. STZ-ICV administration induced impairments in working and long-term memory, increased oxidative stress and neuroinflammation, elevated AChE activity, and promoted intestinal and behavioral alterations. Both probiotic and paraprobiotic treatments attenuated memory deficits, reduced lipid peroxidation, inhibited AChE activity, and decreased inflammatory markers. However, their effects differed in magnitude and tissue specificity. The probiotic mainly improved peripheral antioxidant defenses, whereas the paraprobiotic exerted broader neuroprotective effects, reducing cerebral oxidative stress, restoring non-enzymatic antioxidant levels in the hippocampus and colon, improving jejunal catalase activity, and attenuating hippocampal astrogliosis. These findings demonstrate that modulation of the gut-brain axis through L. casei-based interventions mitigates key pathological features of sporadic AD, with paraprobiotics emerging as a promising and stable alternative with enhanced neuroprotective potential independent of bacterial viability.},
}
@article {pmid42542356,
year = {2026},
author = {Suciu, S and Jolly, P and Toumert, S},
title = {[Emergency care for patients with MA: the key role of IPA].},
journal = {Soins. Gerontologie},
volume = {31},
number = {180},
pages = {23-25},
doi = {10.1016/j.sger.2026.06.006},
pmid = {42542356},
issn = {1268-6034},
mesh = {Humans ; *Alzheimer Disease/nursing ; *Advanced Practice Nursing ; Aged ; *Nurse's Role ; Nurse-Patient Relations ; },
abstract = {The importance of advanced practice nurses (APNs) in improving emergency care for patients with Alzheimer's disease is a reality. APNs play a crucial role by providing advanced clinical skills and an approach centered on Naomi Feil's Validation®, a non-pharmacological therapy. This method involves empathetic acknowledgment and affirmation of patients' emotions and experiences, which helps build a relationship of trust and address their specific needs. By collaborating with other healthcare professionals, APNs ensure high-quality care tailored to the emergency situations faced by vulnerable patients.},
}
@article {pmid42542440,
year = {2026},
author = {Wang, J and Huang, L and Li, B and Guo, Q and Xie, F},
title = {Advancing Alzheimer's disease research in China: insights, innovations, and future directions from the chinese preclinical Alzheimer's disease study (CPAS).},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42542440},
issn = {1476-5578},
abstract = {This review delves into the advancements in Alzheimer's Disease (AD) research in China, focusing on insights, innovations, and future directions derived from the Chinese Preclinical Alzheimer's Disease Study (CPAS). With an aging population, AD prevalence has risen, increasing societal and economic burdens. CPAS, initiated in 2019, aims to identify early Alzheimer's pathology using plasma biomarkers and PET imaging. The study includes participants across the cognitive spectrum, including cognitively unimpaired individuals, patients with mild cognitive impairment (MCI), and patients with dementia, undergoing comprehensive assessments. Key findings include the impact of Aβ-PET on diagnosis and management, risk factors for amyloid pathology, and the expansion of biomarkers to include synaptic and other PET imaging markers. Future directions involve exploring disease-modifying therapies and applying multi-omics approaches to enhance the understanding and treatment of AD. These efforts are crucial for advancing personalized medicine and improving therapeutic outcomes in China and globally.},
}
@article {pmid42542447,
year = {2026},
author = {Thierry, M and Leitner, D and Balcomb, K and Kavanagh, T and Tang, L and Kanshin, E and William, C and Oakley, D and Hyman, B and Ueberheide, B and Drummond, E and Wisniewski, T},
title = {Proteomic comparison of hippocampal neurofibrillary tangles in PART, intermediate Alzheimer's disease and advanced Alzheimer's disease.},
journal = {Acta neuropathologica},
volume = {152},
number = {1},
pages = {},
pmid = {42542447},
issn = {1432-0533},
support = {P30AG062421/NH/NIH HHS/United States ; P30AG066512 and U24NS141774/NH/NIH HHS/United States ; },
mesh = {Humans ; *Neurofibrillary Tangles/pathology/metabolism ; *Alzheimer Disease/pathology/metabolism ; *Hippocampus/pathology/metabolism ; Proteomics/methods ; Aged, 80 and over ; Female ; tau Proteins/metabolism ; Male ; Aged ; Amyloid beta-Peptides/metabolism ; Laser Capture Microdissection ; },
abstract = {Alzheimer's disease (AD) is characterised by the intraneuronal aggregation of phosphorylated Tau (pTau) into neurofibrillary tangles and by the extracellular deposition of β-amyloid (Aβ). Tau pathology restricted to the hippocampal formation is frequently observed in the elderly brain in the absence of any Aβ deposition and considered as "primary age-related tauopathy" (PART). Here, we applied an unbiased proteomic approach to determine how concomitant Aβ pathology modifies the neurofibrillary tangle proteome. Neurofibrillary tangles were isolated by dissecting Tau pSer202/pThr205 "AT8" immunopositive neuronal profiles, combining chromogenic immunohistochemistry with laser capture microdissection, from hippocampal sections of 17 post-mortem brains spanning three groups: PART (n = 5; A0, B1-2, C0 scores), intermediate AD (n = 6; A1-2, B2-3, C1-2 scores) and advanced AD (n = 6; A3, B3, C3 scores). A label-free quantitative liquid chromatography-mass spectrometry based proteomic analysis, using data independent acquisition (DIA) on a Bruker timsTOF, was performed. A conserved core of 63 proteins was identified as enriched in tangles across all groups, mostly associated with "RNA binding" and "regulation of mRNA metabolic process", based on the Gene Ontology database. Group-specific signatures were also observed: 33 proteins were significantly enriched only in tangles collected from PART cases and were predominantly linked to "structural molecule activity", whereas Aβ-positive cases showed specific enrichment of "RNA binding" and "cytoplasmic translation" pathways-with intermediate AD cases displaying a transitional profile. Our findings are consistent with PART having distinct tangle proteomic features; however, the majority of its proteomic signature is in common with tangles within the AD continuum. By addressing how Aβ accumulation alters the tangle proteome, this study provides mechanistic insights into the expansion of Tau pathology, paving the way towards the identification of biomarkers and therapeutic strategies that would allow for stabilisation of Tau pathology in the elderly.},
}
@article {pmid42542553,
year = {2026},
author = {Linhares, MT and de Sousa, IV and de Castro Eloy, LR and de Oliveira Neto, JM and Quillas, LJA and Ubiali, DG and Carvalho, LRRA and Lucena, RB},
title = {Hepatic encephalopathy associated with extensive hepatic diaphragmatic herniation in an adult horse.},
journal = {BMC veterinary research},
volume = {22},
number = {1},
pages = {},
pmid = {42542553},
issn = {1746-6148},
mesh = {Animals ; Horses ; *Horse Diseases/pathology/diagnosis ; Male ; *Hepatic Encephalopathy/veterinary/pathology/etiology/complications ; *Hernia, Diaphragmatic/veterinary/complications/pathology ; Fatal Outcome ; },
abstract = {BACKGROUND: Diaphragmatic hernia in horses is a rare condition, most commonly presenting with signs of colic and, less frequently, respiratory compromise. Hepatic herniation through a diaphragmatic defect with secondary hepatic failure and encephalopathy has rarely been documented in horses.<br><br>CASE PRESENTATION: A 5-year-old Mangalarga Marchador stallion was evaluated for progressive neurological deterioration, including obtundation, head pressing, ataxia, and circling. Serum biochemistry revealed severe hepatobiliary dysfunction, characterised by increased gamma-glutamyl transferase and alkaline phosphatase activities, hyperbilirubinaemia and hypertriglyceridaemia. The horse died within 12&#xa0;h of admission. Post-mortem examination revealed a chronic pleuroperitoneal diaphragmatic defect with herniation of the left lateral, left medial, and quadrate hepatic lobes into the thoracic cavity. The herniated portion showed severe atrophy, haemorrhagic necrosis, cholestasis, and ductular proliferation, while the non-herniated hepatic mass exhibited bridging fibrosis and nodular regenerative remodelling. Histopathological examination of the brain confirmed the presence of Alzheimer type II astrocytes in the cerebral cortical grey matter, consistent with hepatic encephalopathy.<br><br>CONCLUSIONS: This case documents an unusual manifestation of equine diaphragmatic hernia in which extensive chronic hepatic incarceration resulted in severe hepatobiliary dysfunction and hepatic encephalopathy. The findings suggest that diaphragmatic hernia with hepatic involvement should be considered in the differential diagnosis of horses presenting with severe hepatopathy and neurological signs compatible with hepatic encephalopathy, particularly when classical signs of colic are absent.},
}
@article {pmid42542663,
year = {2026},
author = {Choudhary, G and Rajput, H and Kulkarni, R and Siddiqui, H and Prakash, A and Medhi, B},
title = {Computational drug repurposing identifies flavoxate as a novel NLRP3 inflammasome inhibitor for Alzheimer's disease therapy.},
journal = {In silico pharmacology},
volume = {14},
number = {2},
pages = {200},
pmid = {42542663},
issn = {2193-9616},
abstract = {UNLABELLED: Alzheimer's disease (AD) remains a debilitating neurodegenerative disorder with limited therapeutic options, necessitating novel approaches to target its underlying mechanisms. The NLRP3 inflammasome has emerged as a critical player in AD pathogenesis, driving neuroinflammation and amyloid-beta aggregation, yet existing inhibitors face challenges such as hepatotoxicity and poor blood-brain barrier (BBB) penetration. We conducted a computational drug repurposing study to identify FDA-approved drugs with NLRP3 inhibitory potential and favourable BBB permeability. Using molecular docking we screened a library of 2600 FDA approved compounds against the NLRP3 structure (PDB ID:8WSM), followed by molecular dynamics (MD) simulations and binding free energy calculations to validate top hits. Our results identified Flavoxates as the most promising candidate, exhibiting a high docking score (- 10.241 kcal/mol) and stable binding affinity (- 52 kcal/mol via MMPGBSA). MD simulations confirmed its robust interaction with NLRP3, demonstrating low RMSD (0.168 +/- 0.019 nm) and RMSF (0.088 +/- 0.035 nm) values over 100 ns. Moreover, Flavoxate showed optimal pharmacokinetic properties, including BBB permeability and low toxicity, as predicted by SwissADME and ProTox 3.0 The study highlights the efficacy of in silico methods in accelerating drug repurposing, bypassing the need fo de novo drug development. By repurposing Flavoxate, we propose a clinically translatable strategy to mitigate NLRP3-mediated neuroinflammation in AD, offering a potential disease modifying therapy with an established safety profile. This work underscores the significance of computational approaches in bridging the gap between preclinical discovery and therapeutic application for neurodegenerative diseases.<br><br>SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-026-00696-3.},
}
@article {pmid42542938,
year = {2026},
author = {Shea, YF and Wong, YL and Wong, TK and Chan, PL and Yam, KK and Wong, FCK and Chan, KPF and Cheung, YWE and Mak, HKF and Ip, SMM and Chiu, PKC and Lam, CW},
title = {Diagnosis and analysis of plasma phosphorylated tau 217 in a memory clinic cohort: limitations of Generative Pre-trained Transformer-5.},
journal = {Singapore medical journal},
volume = {},
number = {},
pages = {},
doi = {10.4103/singaporemedj.SMJ-2025-289},
pmid = {42542938},
issn = {2737-5935},
abstract = {INTRODUCTION: No published studies have evaluated the application of Generative Pre-trained Transformer-5 (GPT-5) in the analysis of memory clinic patient clinical notes or the interpretation of plasma phosphorylated tau (P-tau) 217 values. We compared Alzheimer's disease (AD) probability estimates generated by GPT-5 before and after incorporating plasma P-tau 217 with pre- and posttest probabilities.<br><br>METHODS: This was a retrospective study comprising 74 patients from a memory clinic in Queen Mary Hospital, Hong Kong. Final diagnoses were made by physicians, supported by medical history, physical examination, neuroimaging and amyloid positron emission tomography. Extracted clinical data included cognitive, functional and neuropsychiatric assessments. Pretest AD probabilities were derived from a published meta-analysis, while posttest probabilities were calculated using a Bayesian approach. These values were compared with those estimated by GPT-5. The diagnostic performance of GPT-5 and physicians was assessed using accuracy and Kappa coefficient, with final diagnosis as reference.<br><br>RESULTS: There were 40 amyloid-positive (A+) and 34 amyloid-negative (A-) patients. In A+ patients, Bayesian posttest probabilities were higher than GPT-5 estimates (median 97.0% vs. 80.0%, P = 0.003), while those of A- patients were lower than GPT-5 estimates (median 3.0% vs. 27.5%, P < 0.001). With application of plasma P-tau 217, physicians achieved higher diagnostic accuracy than GPT-5 (81.1% vs. 45.9%, P < 0.001), while GPT-5 suggested mixed aetiologies more frequently (23.0% vs. 8.1%, P = 0.04) and inappropriate anti-amyloid therapy in 31% (11/36) of scenarios.<br><br>CONCLUSION: Our findings show that GPT-5 has limitations in analysing clinical information of real-life memory clinic patients.},
}
@article {pmid42543113,
year = {2026},
author = {Calon, F and Otaegui, L and Bouali, ML and Hébert, SS},
title = {Are mouse models of Alzheimer's disease truly flawed, or are we misusing them?.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.07.069},
pmid = {42543113},
issn = {1873-7544},
abstract = {The first transgenic mouse models of Alzheimer's disease (AD) developed in the 1990 s were hailed as a major breakthrough. As newer generations of models have emerged over the decades after, they still face growing criticism for translating poorly into clinical outcomes, even if the effects of newer therapeutic compounds, including monoclonal antibodies, align well with those seen in mice. Like any disease model, AD mice have substantial limitations. The real issue is that they are often treated as miniature humans with AD, which they are not. Overreliance on specific pathogen-free (SPF) housing may also blunt immune-related endpoints and compromise translational relevance. The impact of biological sex and ambient temperature may also differ between animal models and humans. In this review, we argue that despite these limitations, they remain highly useful for specific scientific questions and preclinical development. They are far better suited for pharmacokinetic and biodistribution studies, and for testing target engagement in vivo on well-defined neuropathological processes. Thus, while criticisms of these models are justified, researchers have often used them with misaligned objectives. As discussed herein, these models should not be discarded, but used more thoughtfully, in ways that align with their true strengths.},
}
@article {pmid42543118,
year = {2026},
author = {Du, L and Yan, J},
title = {Lineage-calibrated peripheral monocyte-derived myeloid states in neurodegenerative disease: Recruitment, lesion decoding, and state persistence.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107556},
doi = {10.1016/j.nbd.2026.107556},
pmid = {42543118},
issn = {1095-953X},
abstract = {Peripheral monocytes and monocyte-derived macrophages are increasingly implicated in neurodegenerative disease, yet interpretation remains limited by phenotypic convergence with resident microglia, inconsistent lineage attribution, and strong dependence on experimental model and disease stage. We present a structured, lineage-calibrated framework that separates three linked processes: a recruitment gate controlling access to CNS borders and lesions; a lesion-decoding hub through which aggregate, lipid, cytokine, complement, antigenic, hypoxic, and danger-associated inputs are interpreted; and a state-persistence layer in which metabolic and epigenetic reinforcement stabilizes inflammatory, repair-supportive, or hybrid repair-restrictive programs. To make the framework operational, we first provide a cross-disease synthesis and then map representative models of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis to their specific recruitment routes, lesion cues, lineage confidence, and functional outcomes. We also distinguish what single-cell or spatial data can infer from what only origin-resolving approaches can establish, and propose practical terminology for studies that cannot perform fate mapping or parabiosis. A worked therapeutic example illustrates why the same recruitment pathway may be harmful during lesion expansion but useful during debris clearance and recovery. The central question is therefore not whether monocytes are present, but which model, compartment, time point, evidentiary tier, and stabilized state justify a disease-modifying claim. This framework links mechanistic evidence to biomarkers, patient stratification, and stage-aware intervention while reducing over-attribution of peripheral origin.},
}
@article {pmid42543121,
year = {2026},
author = {Shenzhi, L and Nan, Z and Rongqiang, Z},
title = {Conditional neuroprotection: Blood selenium attenuates the cognitive toxicity of DEHP metabolites in older adults.},
journal = {Neurotoxicology},
volume = {},
number = {},
pages = {103537},
doi = {10.1016/j.neuro.2026.103537},
pmid = {42543121},
issn = {1872-9711},
abstract = {BACKGROUND: Phthalates, particularly di(2-ethylhexyl) phthalate (DEHP), are ubiquitous environmental contaminants with well-documented neurotoxic potential. Selenium, an essential antioxidant trace element, may mitigate oxidative stress-induced neuronal damage. However, whether selenium modifies the cognitive effects of phthalate exposure remains unclear in human populations.<br><br>METHODS: We analyzed cross-sectional data from adults aged &#x2265;60 years in the National Health and Nutrition Examination Survey (NHANES) 2011-2014. Urinary phthalate metabolites and blood metals (lead, cadmium, mercury, manganese) were quantified. Survey-weighted linear regression with interaction terms tested whether blood selenium modified the associations between these exposures and global cognitive Z-scores. Effect modification was further evaluated using restricted cubic splines, simple slope analysis, and joint Wald tests. Oxidative stress biomarkers (alkaline phosphatase, total bilirubin, serum iron) were assessed as potential mediators. To contextualize the main NHANES findings, we performed two supplementary analyses: (i) bidirectional two-sample Mendelian randomization (MR) to test whether selenium has an independent causal effect on Alzheimer's disease (AD), and (ii) an exploratory ecological analysis using Global Burden of Disease (GBD) 2021 data to illustrate the risk of ecological fallacy when environmental co-exposures are unaccounted for. These ancillary analyses do not constitute formal triangulation, as they address selenium's main effects rather than its interaction with phthalates.<br><br>RESULTS: Among 573 participants (mean age 69.5 years, 52.2% female), blood selenium significantly modified the associations of four DEHP metabolites with cognitive function, with the strongest interaction observed for MEHP (&#x3b2; = 0.00103, 95% CI: 0.00081-0.00124, P < 0.001). In individuals with low selenium, higher MEHP was associated with lower cognitive scores; this association was reversed in those with high selenium. In contrast, no significant interactions were found for any heavy metal (all P > 0.05). Joint Wald tests confirmed effect modification for phthalates (F = 13.34, P = 0.003) but not for metals (F = 1.03, P = 0.43). Oxidative stress biomarkers did not mediate the observed interactions. Bidirectional MR found no causal effect of selenium on AD (IVW &#x3b2; = -0.008, P = 0.87), ruling out reverse causation as an explanation. An exploratory ecological analysis using GBD data found a counterintuitive inverse association between dietary selenium inadequacy and dementia burden (&#x3b2; = -0.325, P = 0.037). This paradoxical pattern remained consistent in sensitivity analyses and likely reflects ecological confounding. It underscores that population-level nutrient-disease links can be strongly distorted by differences in diagnostic practices and unmeasured co-exposures, such as phthalates.<br><br>CONCLUSIONS: Selenium reduces the cognitive harm of DEHP metabolites in older adults, with clearer and more consistent evidence for phthalates than for heavy metals. Null MR results rule out an independent causal effect of selenium on Alzheimer's disease, reinforcing that selenium's role is conditional rather than universal. A paradoxical ecological pattern, presented as a cautionary example, highlights the risk of ecological fallacy when co-exposures are unaccounted for. Together, these findings suggest that selenium's neuroprotection is context-dependent-it appears to act mainly under specific toxicant exposure rather than offering universal benefits. These findings caution against indiscriminate selenium supplementation and suggest that further longitudinal studies are needed before targeted interventions can be recommended.},
}
@article {pmid42543123,
year = {2026},
author = {Suk, K},
title = {Brain aging clocks: From methodological advances to cellular mechanisms.},
journal = {Experimental gerontology},
volume = {},
number = {},
pages = {113260},
doi = {10.1016/j.exger.2026.113260},
pmid = {42543123},
issn = {1873-6815},
abstract = {Brain aging represents a critical risk factor for neurodegenerative diseases and cognitive decline, yet the measurement of biological brain age remains challenging. Brain aging clocks, which quantify the discrepancy between predicted brain age and chronological age, have emerged as powerful tools for assessing brain health and predicting disease outcomes. Recent advances have transformed these clocks from simple global metrics to sophisticated, multi-modal approaches that capture regional heterogeneity, measure the pace of aging, and achieve cellular resolution. This review examines the methodological evolution of brain aging clocks, including the development of regional brain age gradients, pace-of-aging measurements, and multi-modal integration strategies. We then explore the cellular and molecular mechanisms underlying accelerated brain aging, with particular emphasis on cellular senescence, cell-type-specific aging patterns, vascular dysfunction and blood-brain barrier breakdown, mitochondrial decline, proteostasis failure, synaptic loss, and the accumulation of senescent cells in neurodegenerative conditions. Epigenetic clocks and emerging plasma biomarkers (neurofilament light, GFAP, phosphorylated tau), particularly DNA methylation-based approaches, are discussed in the context of their relationship with neuroimaging markers and cognitive outcomes. Clinical applications are reviewed, including the prediction of neurodegenerative disease, the impact of socioeconomic and geographic disparities on brain aging, and emerging senotherapeutic interventions. Finally, we address current challenges in biomarker standardization, the need for longitudinal validation, and future directions toward precision aging medicine. Together, these advances position brain aging clocks as essential tools for understanding neural aging mechanisms and developing targeted interventions to promote healthy brain aging. SIGNIFICANCE STATEMENT: As populations age globally, predicting who will develop dementia or cognitive decline before symptoms appear has become a critical medical challenge. Brain aging clocks - tools that measure whether a person's brain appears biologically older or younger than their chronological age - offer a promising solution. This review explains how these tools have advanced from simple brain scans to sophisticated methods that detect aging at the level of individual cell types, and how "zombie cells" called senescent cells drive accelerated brain aging. We also show that brain aging may be slowed through lifestyle changes and emerging drugs, though robust human efficacy trials are ongoing. These insights open new paths toward earlier diagnosis and personalized treatments for Alzheimer's disease and other brain disorders.},
}
@article {pmid42543199,
year = {2026},
author = {Sakurai, R and Montero-Odasso, M},
title = {Gait Impairment and Alzheimer's Disease Pathology: A Narrative Review on Mechanistic Links.},
journal = {Geriatrics &amp; gerontology international},
volume = {26},
number = {8},
pages = {e70675},
doi = {10.1111/ggi.70675},
pmid = {42543199},
issn = {1447-0594},
support = {MOP 211220//Canadian Institute of Health Research/ ; PJT 153100//Canadian Institute of Health Research/ ; BH210118//Weston Family Foundation/ ; FRN CNA 137794//Canadian Consortium on Neurodegeneration in Aging/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/physiopathology/complications ; *Gait Disorders, Neurologic/etiology/physiopathology ; Amyloid beta-Peptides/metabolism ; Aged ; Aging/physiology ; *Gait/physiology ; Brain/pathology ; },
abstract = {In older adults, gait has emerged as an important indicator of overall health and a strong predictor of adverse outcomes, including dementia. This association has been corroborated by findings from Alzheimer's disease (AD) research. In AD, amyloid-β brain accumulation is succeeded by tau pathology and neurodegeneration, commencing within the medial temporal lobe. Older adults exhibiting slower gait speed or reduced gait adaptability display greater amyloid and tau brain deposition, as well as more pronounced hippocampal atrophy, suggesting that gait impairment may serve as an early clinical marker of AD-related neurodegeneration. Despite accumulating evidence linking gait impairment to AD-related pathology, the underlying mechanisms remain inadequately understood. Traditional explanations have focused on shared neural substrates, including frontal-subcortical and motor control networks, which decline with aging and result in parallel deterioration of gait and executive function. Although this framework aligns with cognitive reserve theory, it fails to fully explain the potential pathways linking gait disturbances to AD-related and mixed brain pathology. In this review, we explore interacting mechanisms suggesting that gait impairment and AD-related changes may arise from common vulnerabilities and mutually reinforcing processes. By synthesizing the current evidence, we aim to advance the understanding of gait decline as a prodromal symptom of dementia, advocate for early screening of gait performance, and highlight the importance of maintaining gait function across the lifespan as part of healthy aging strategies that may help delay the onset of dementia. The conclusion underscores a life-course perspective on health, rather than one that focuses solely on functional decline in old age.},
}
@article {pmid42543274,
year = {2026},
author = {DU, YZ and Wang, Z and Ma, DC and Liu, T and Ma, LL and Zhou, YM and Li, XL and Dou, FY and Lyu, RL and Chai, MN and Zhang, YG and Li, YF},
title = {[Research progress on active ingredients of Astragali Radix and Acori Tatarinowii Rhizoma and mechanism of their herb pair against Alzheimer's disease].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {51},
number = {11},
pages = {3152-3159},
doi = {10.19540/j.cnki.cjcmm.20260209.501},
pmid = {42543274},
issn = {1001-5302},
mesh = {*Alzheimer Disease/drug therapy/metabolism/genetics ; *Drugs, Chinese Herbal/chemistry/administration &amp; dosage ; Humans ; Animals ; *Acorus/chemistry ; *Astragalus Plant/chemistry ; Rhizome/chemistry ; },
abstract = {Alzheimer's disease(AD) is a highly prevalent neurodegenerative disorder with complex pathogenesis. Currently available mainstream drugs offer limited efficacy and often cause significant side effects. The herb pair of Astragali Radix and Acori Tatarinowii Rhizoma, known for its Qi-tonifying and orifice-opening properties in TCM, has demonstrated advantages in multi-target and holistic regulation in anti-AD research. This review systematically summarizes the synergistic mechanisms of active ingredients such as astragaloside Ⅳ, calycosin, and β-asarone against AD through multiple pathways, including peroxisome proliferator-activated receptor γ(PPARγ)/brain-derived neurotrophic factor(BDNF) pathway, phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt) pathway, and gut-brain axis. It also points out that current studies remain largely confined to in vitro and animal experiments, with insufficient evidence for clinical translation. Building on this, the review further proposes innovative research directions, such as constructing astragaloside Ⅳ-β-asarone co-delivery nanosystems, optimizing the compatibility ratio of the herb pair, and combining with fecal microbiota transplantation to validate causal mechanisms via microbiota-gut-brain axis. These proposals aim to provide a systematic theoretical framework and experimental pathway for the in-depth development and clinical translation of the herb pair of Astragali Radix and Acori Tatarinowii Rhizoma.},
}
@article {pmid42543712,
year = {2026},
author = {Karan, KR and Hackett, NR and Crystal, RG},
title = {Adeno-Associated Virus-Mediated Central Nervous System Gene Transfer to Suppress Alzheimer's Disease High-Risk APOE4 Variant and Replace with Protective APOE2.},
journal = {Human gene therapy},
volume = {},
number = {},
pages = {10430342261473427},
doi = {10.1177/10430342261473427},
pmid = {42543712},
issn = {1557-7422},
abstract = {Common genetic variants of APOE are major risk factors for sporadic late-onset Alzheimer's disease (AD). APOE has three common variants: APOE3, APOE4, and APOE2. Epidemiological, clinical, and experimental evidence demonstrate that APOE3 is associated with an average risk for AD, APOE4 is pathogenic and conveys a high risk, and APOE2 is protective and reduces risk. In prior mouse studies, we have demonstrated that (1) adeno-associated virus (AAV)-mediated central nervous system (CNS) gene transfer of APOE2 is highly protective against the toxic effects of APOE4 and (2) AAV-mediated CNS transfer of anti-APOE4 microRNA (miRNA) significantly suppresses the expression of APOE4. The ideal therapy for APOE4 homozygotes would both reduce CNS levels of APOE4 and substitute APOE4 with the addition of APOE2. We have developed a "silence-and-replace" therapy, where suppression of CNS APOE4 is achieved through AAV-mediated expression of miRNAs designed to silence the endogenous human APOE4 messenger RNA (mRNA), together with simultaneous replacement by an APOE2 coding sequence [APOE2(R)] resistant to those miRNAs. AAV vectors expressing APOE2(R) with and without the miRNAs were administered to the hippocampus of human APOE4 mice, and APOE levels at the mRNA and protein levels were the same for both vectors. Dideoxy Sanger sequencing and allele-specific real-time quantitative PCR were used to assess the CNS APOE2 to APOE4 ratio. As expected, both vectors with APOE2(R) increased the E2/E4 ratio relative to controls by 3.5 ± 0.6-fold for APOE2(R) and 6.3 ± 0.4-fold for APOE2(R) + miRNAs. We conclude that a single AAV vector can deliver a cassette with dual functionality: suppression of the toxic APOE4 variant and simultaneous delivery of the protective APOE2. This dual approach may provide a more potent gene therapy for APOE4-dependent AD than either strategy.},
}
@article {pmid42543724,
year = {2026},
author = {Rouanet, A and Philipps, V and Taddé, BO and Pérès, K and Proust-Lima, C},
title = {Modeling Temporal Relationships Between Multivariate Repeated Markers Along With Clinical Endpoints: Application to Alzheimer's Disease and Related Dementias.},
journal = {Biometrical journal. Biometrische Zeitschrift},
volume = {68},
number = {4},
pages = {e70157},
doi = {10.1002/bimj.70157},
pmid = {42543724},
issn = {1521-4036},
support = {ANR-18-CE36-0004-01//French National Research Agency/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/diagnosis ; Biomarkers/metabolism ; *Models, Statistical ; Multivariate Analysis ; *Biometry/methods ; *Dementia/metabolism/diagnosis ; Disease Progression ; Time Factors ; *Endpoint Determination ; },
abstract = {Diseases often involve multiple dimensions of interrelated impairments. Although significant advances have been made in joint models to simultaneously assess these processes in relation to clinical endpoints, they often fail to evaluate how these dimensions influence each other. We propose an original joint modeling framework to describe the temporal relationships between the processes involved in Alzheimer's disease and related dementias (ADRD) progression, and assess their association with ADRD diagnosis and death. The longitudinal submodel is a dynamic model that combines a structural multivariate mixed model based on differential equations to explain the instantaneous change over time of each latent dimension according to the others, and observation models that can accommodate ordinal, binary, and continuous (whether Gaussian or non-Gaussian) biomarkers. The association of the biomarkers with ADRD diagnosis and death are described via a shared random-effect joint modeling approach. The estimation procedure, carried out within the maximum likelihood framework is made available in the DynNet R package. The methodology is validated in a simulation study and is applied in a population-based French cohort study to disentangle the temporal relationships between three major drivers of ADRD natural history, depression, cognition, and functional dependency in link with the two major clinical events in ADRD progression: ADRD diagnosis and death. The methodology and application are designed to help understand the complex interplay between biomarkers over time.},
}
@article {pmid42544033,
year = {2026},
author = {Lou, Y and Monin, JK and Fowler, NR},
title = {How Does Receipt of Dementia Screening Impact Depressive Symptoms Among Patients and Their Family Members?.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70603},
pmid = {42544033},
issn = {1532-5415},
support = {1R24AG089064-01/AG/NIA NIH HHS/United States ; R01AG056325/AG/NIA NIH HHS/United States ; U54AG063546/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: The impact of dementia screening on the mental health of older adults and their family members remains insufficiently understood, particularly in light of the bidirectional dynamics within the older adult-family dyad. This study aims to examine how dementia screening affects older adults and their family members over time, and whether these effects occur independently or simultaneously within the dyad.<br><br>PARTICIPANTS AND SETTING: One thousand eight hundred five older adults (&#x2265;&#x2009;65&#x2009;years old) and their family member dyads participated in the multi-site Caregiver Outcomes of Alzheimer's Disease Screening (COADS) trial were randomized into three study arms: screening only, screening plus referral for diagnostic assessment, and no-screening control.<br><br>METHODS: Depressive symptoms measured by Patient Health Questionnaire-9 (PHQ-9) were collected in both older adults and their family members at baseline, 6&#x2009;months, and 12&#x2009;months post-intervention. A cross-lagged panel model was used to examine longitudinal and dyadic associations in depressive symptoms between members of the dyad. Intervention status (0&#x2009;=&#x2009;no-screening control, 1&#x2009;=&#x2009;combined screening group who received negative results, 2&#x2009;=&#x2009;combined screening group who received positive results) was included as a predictor of depressive symptoms at 6&#x2009;months.<br><br>RESULTS: Compared with controls, dyads in the combined screening groups who received negative (&#x3b2;&#x2009;=&#x2009;-0.53, p&#x2009;=&#x2009;0) and positive (&#x3b2;&#x2009;=&#x2009;-0.84, p&#x2009;=&#x2009;0.058) results showed lower depressive symptoms among older adults at 6 months. Improvements in older adults' depressive symptoms subsequently influenced family members' mental health through a dyadic pathway, resulting in reduced depressive symptoms among family members at 12&#x2009;months (&#x3b2;&#x2009;=&#x2009;0.05, p&#x2009;=&#x2009;0.016).<br><br>CONCLUSIONS: The findings suggest that screening for dementia in older adults has a spillover effect to family members. Dementia screening may have a double benefit in families. Further clinical trials should include measures of both dyad members to understand how to best target the mental health of families more efficiently.},
}
@article {pmid42544645,
year = {2026},
author = {Luth, EA and Brennan, C and Hurley, S and Sheldon, KG and Zhang, Y},
title = {Hospice Care in the Era of AI: Hospices' Views on Data-Driven Tools to Support Live Discharge Decisions.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70621},
pmid = {42544645},
issn = {1532-5415},
support = {R56 AG085541/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: Live discharge occurs for 20% of hospice enrollees, resulting in loss of support and disruptive care transitions, with higher risk for patients with Alzheimer's disease and related dementias (ADRD). Little is understood about how data-driven clinical decision support tools (e.g., predictive algorithms) might support decision making regarding live discharge. As hospices adopt value-based care, identifying opportunities and challenges for data-driven tools to predict and support live discharge holds great potential to support hospice patients and their caregivers.<br><br>METHODS: Semi-structured interviews were conducted with 20 hospice leaders in clinical care, quality, and data science at seven non-profit United States hospices. Four-step rapid analysis and deductive approaches were used to summarize interview content in response to research questions and identify cross-organizational themes.<br><br>RESULTS: Participants identified multilevel-individual and family, organizational, community, and system-challenges and facilitators to support patients following live discharge. Families dealing with ADRD face a heavier care burden but also access ADRD-specific programs. Participants expressed strong interest in using predictive tools to identify patients at increased risk for live discharge and either support them to remain in hospice or facilitate robust discharge planning. Participants emphasized the importance of tool specification and clinical workflow integration to make predictive tools useful and impactful.<br><br>CONCLUSIONS: Hospices face barriers to support hospice patients and caregivers experiencing burden and suboptimal outcomes following live discharge. Predictive modeling could be a potentially powerful tool to facilitate support for patients discharged alive, provided they are accurately specified and thoughtfully integrated into clinical workflows.},
}
@article {pmid42544873,
year = {2026},
author = {Wang, DW and Liu, MM and Zhao, YC and Li, JY and Li, W and Yu, X},
title = {Targeting Hippocampal PTEN Suppresses Ferroptosis and Rescues Cognitive Decline in Alzheimer's Disease via Dual AKT/GSK3β/Nrf2 and AKT/STAT3 Axes.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e76989},
doi = {10.1002/advs.76989},
pmid = {42544873},
issn = {2198-3844},
support = {81901116//National Natural Sciences Foundation of China/ ; 2024JH6/100800008//Department of Science and Technology of Liaoning Province/ ; LJKMZ20221207//Department of Education of Liaoning Province/ ; },
abstract = {Elevated phosphatase and tensin homolog (PTEN) expression is observed in Alzheimer's disease (AD) brain, yet the precise mechanism through which PTEN contributes to AD progression remains undefined. This study provides the direct evidence that PTEN promotes neurodegeneration by driving neuronal ferroptosis. Using APP/PS1 transgenic mice with hippocampal-specific PTEN knockdown mediated by adeno-associated virus (AAV), we demonstrated that downregulation of PTEN substantially ameliorates cognitive dysfunction and neuronal loss. Mechanistically, PTEN silencing upregulated glutathione peroxidase 4 (GPX4), inhibiting lipid peroxidation and ferroptosis. We identified a dual-signaling framework through which PTEN regulates GPX4 expression. PTEN reduction activates the PI3K/AKT axis, which drives GSK3β phosphorylation and facilitates nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2). Concurrently, PTEN knockdown induces phosphorylation and nuclear translocation of signal transducer and activator of transcription 3 (STAT3). Both Nrf2 and STAT3 act as transcriptional activators of GPX4, establishing two convergent axes: PTEN/AKT/GSK3β/Nrf2/GPX4 and PTEN/AKT/STAT3/GPX4. These pathways cooperatively upregulate GPX4 expression, thereby attenuating lipid peroxidation and inhibiting ferroptosis. Importantly, PTEN knockdown restored redox homeostasis by bolstering cellular antioxidant defenses. Our findings reveal a novel PTEN-regulated ferroptotic pathway in AD pathogenesis and highlight PTEN as a promising therapeutic target for AD.},
}
@article {pmid42544975,
year = {2026},
author = {Branson, CO},
title = {Sleep and Neurodegeneration.},
journal = {Continuum (Minneapolis, Minn.)},
volume = {32},
number = {4},
pages = {1142-1160},
doi = {10.1212/cont.0000000000001734},
pmid = {42544975},
issn = {1538-6899},
mesh = {Humans ; *Neurodegenerative Diseases/complications/diagnosis ; *Sleep Wake Disorders/complications ; *Sleep/physiology ; Female ; Male ; },
abstract = {OBJECTIVE: This article discusses the relationship between sleep and neurodegenerative disorders.<br><br>LATEST DEVELOPMENTS: Sleep disorders disrupt neurotransmitters, facilitating the progression of neurodegenerative changes. Sleep impairment promotes amyloid-&#x3b2; aggregation, propagating memory impairment in neurodegenerative disorders. The use of biomarkers for early diagnosis of neurodegenerative disorders may include sleep features. Sleep apnea is associated with an increased risk of Parkinson disease.<br><br>ESSENTIAL POINTS: Sleep disorders, such as obstructive sleep apnea, are five times more likely in people with Alzheimer disease. Notably, individuals with genetic factors, including carriers of APOE4, are found to have decreased overall regulation of regions within the brain that control sleep. External factors that increase the risk of dementia include long-term use of antihistamines. The risk of mild cognitive impairment is reduced with the intake of 200 mg/d of caffeine, which aligns the circadian activity of suprachiasmatic nucleus cells. People diagnosed with idiopathic rapid eye movement (REM) sleep behavior disorders have more than a 90% risk of developing an &#x3b1;-synucleinopathy at 14 years follow-up.},
}
@article {pmid42545032,
year = {2026},
author = {Brik, SB},
title = {The systemic Ben Brik score, MAROC 22: A mechanism-anchored bedside instrument for the surveillance of reversible cognitive burden in octogenarians-A single-center pilot.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261474889},
doi = {10.1177/13872877261474889},
pmid = {42545032},
issn = {1875-8908},
abstract = {BackgroundCognitive decline in octogenarians is routinely attributed to irreversible neurodegeneration, yet a substantial fraction is driven by partly reversible physiological mechanisms. Oxidative and mitochondrial damage are among the earliest events in Alzheimer's disease pathology, upstream of amyloid deposition, and this framework has not been operationalized into a bedside instrument for the oldest-old.ObjectiveTo present the SBG-MAROC 22-a 310-point, 22-parameter, seven-pillar bedside matrix whose item weights are anchored to published hazard ratios for incident dementia-and to report preliminary single-center data on its feasibility and capacity to flag reversible contributors and acute decompensation.MethodsSingle-center, single-author, retrospective pilot. Forty-seven consecutive patients aged ≥ 80 years [mean age 83.7 ± 2.9 years; 55.3% female; baseline Montreal Cognitive Assessment (MoCA) 16.2 ± 4.1] were assessed with the SBG-MAROC 22 alongside the MoCA. A subgroup (n = 11) received the PD-GOLD protocol with MoCA reassessment at ∼45 days. No power calculation or concurrent control group; reporting followed STROBE.ResultsThe score showed a preliminary association with concurrent MoCA (r≈0.78), within-pilot inter-rater agreement (κ≈0.85), and at least one reversible contributor in 89.4% of patients. The treated subgroup gained a mean +6.0 MoCA points at 45 days (95% CI +3.0 to +9.0; prediction interval -3.1 to +15.1, crossing zero). An exploratory FXTAS-versus-Alzheimer's area under the curve was 0.92. All values are internal, uncontrolled pilot estimates, not validation.ConclusionsThe SBG-MAROC 22 is a clinically feasible, MRI-independent bedside instrument whose hypothesis-generating profile warrants independent, blinded, prospective multicenter validation before any clinical use. Claims of validated discrimination or therapeutic efficacy are not made.},
}
@article {pmid42545253,
year = {2026},
author = {Li, L and Kenner, E and Wan, L and Yan, Z and Feng, J},
title = {Reduced expression of Brain Expressed X-linked genes in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261471446},
doi = {10.1177/13872877261471446},
pmid = {42545253},
issn = {1875-8908},
abstract = {BackgroundAltered expression of Brain Expressed X-linked (BEX) genes has been implicated in Alzheimer's disease (AD) with inconsistencies and a lack of experimental confirmation.ObjectiveThis study aims to characterize BEX expression patterns, examine the association of their expression with AD pathology, and investigate cellular changes induced by altered BEX expression.MethodsWe integrated bulk and single-cell transcriptomics datasets to characterize cortical BEX expression changes in 5xFAD mice and AD patients, which were validated by RT-qPCR in postmortem AD cortical tissue. We manipulated the expression of BEX genes in SH-SY5Y cells and examined changes in oxidative stress.ResultsCortical expression of BEX genes was reduced in AD. With the dysregulation being more pronounced at a later stage of the disease, the reduction was closely related to the impairment of synaptic transmission and oxidative phosphorylation in excitatory neurons. Consistent with these, BEX3 knockdown increased oxidative stress.ConclusionsOur findings suggest that reduced BEX expression in neurons appears to be a contributing factor to AD pathogenesis and BEX depletion may increase oxidative stress.},
}
@article {pmid42545429,
year = {2026},
author = {Bjørklund, G and Gurgas, L and Hangan, T},
title = {Nicotine in Neurodegenerative and Neuropsychiatric Disorders: Mechanisms and Clinical Evidence.},
journal = {Neurochemical research},
volume = {51},
number = {4},
pages = {},
pmid = {42545429},
issn = {1573-6903},
mesh = {Humans ; *Nicotine/therapeutic use/pharmacology ; Animals ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Mental Disorders/drug therapy/metabolism ; Receptors, Nicotinic/metabolism ; *Nicotinic Agonists/therapeutic use/pharmacology ; },
abstract = {Nicotine, a psychoactive compound primarily known for its role in tobacco addiction, has attracted increasing interest for its neuromodulatory and neuroprotective properties. Acting predominantly through nicotinic acetylcholine receptors, nicotine influences multiple neurotransmitter systems, modulates neuroinflammation, and supports synaptic plasticity. These mechanisms may be therapeutically relevant in disorders characterized by neurodegeneration or disrupted neurocircuitry, including Parkinson's disease, Alzheimer's disease, schizophrenia, attention-deficit/hyperactivity disorder, depression, and post-traumatic stress disorder. This review critically examines the current state of preclinical and clinical evidence, with particular attention to receptor subtype activity, cognitive and emotional modulation, and human trial data. Although nicotine's addictive potential and receptor desensitization remain concerns, advances in selective ligands offer new therapeutic avenues. By consolidating mechanistic insights and disease-specific data, this review highlights both the promise and challenges of developing nicotinic-based therapeutics for brain disorders.},
}
@article {pmid42545504,
year = {2026},
author = {Hooshmandi, S and Rahimi Jaberi, K and Kamalov, F and Nami, M},
title = {Adaptive cascading artificial intelligence for Alzheimer's disease assessment: a clinically oriented narrative review and implementation framework.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {8},
pages = {},
pmid = {42545504},
issn = {1590-3478},
support = {2024CANAD-KAM-060//Dubai Future Foundation/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnosis ; *Artificial Intelligence ; Biomarkers/blood ; },
abstract = {Artificial intelligence (AI) has achieved remarkable success in the diagnosis of Alzheimer's disease (AD) in the literature, where many of the models use multi-modal methods including neuroimaging, cerebrospinal fluid, genetics, and cognitive assessment. But clinical adoption of these systems is still limited since most systems are developed in an idealized setting, as cost-effective and specialized diagnostic studies are not universally accessible. We discuss the translation of benchmark performance of AI to real-world dementia care pathways. A practical framework that would be useful for scalable, equitable, and clinically deployable AI-assisted dementia care. In fact, recent advancements in blood-based biomarkers such as plasma phosphorylated tau, glial fibrillary acidic protein, and neurofilament light chain are providing new opportunities for a flexible and minimally invasive diagnosis method. Based on these advances, we propose a clinically grounded AI-assisted cascading model which mirrors real-world workflows via progressive screening, biomarker-guided assessment, selective imaging escalation, and longitudinal prognostic monitoring. We further discuss enabling methods such as sequential decision-making, reinforcement learning, cost-sensitive learning, missing-modality robustness, and explainable AI. Finally, we outline the challenges for data design, for future validation and integration into healthcare systems, and ethical use.},
}
@article {pmid42545654,
year = {2026},
author = {Wu, J and Wang, P and Wang, D and Yao, H and Zhou, B and Lu, J and Zhang, X and Han, Y and Zhao, Y and Zhang, Y and Zhao, K and Liu, Y},
title = {A Neuroimaging Biomarker for Hippocampal Network Dysfunction in Alzheimer's Disease.},
journal = {Neuroscience bulletin},
volume = {},
number = {},
pages = {},
pmid = {42545654},
issn = {1995-8218},
}
@article {pmid42545731,
year = {2026},
author = {Maiese, K},
title = {Oxidative stress, aging, metabolism, SIRT1, and the gut microbiota: the neurocardiac basis of cognitive loss.},
journal = {Medical gas research},
volume = {},
number = {},
pages = {},
pmid = {42545731},
issn = {2045-9912},
abstract = {FactsCardiovascular disease, Alzheimer's disease, and multiple sclerosis share a neurocardiac basis linked by cellular metabolism and diabetes, indicating the presence of common pathological pathways.Current care remains symptomatic and prevention focused, and interventions targeting shared pathways such as oxidative stress, senescence, and autophagy are lacking.Apolipoprotein E (APOE), glucagon-like peptide-1 (GLP-1) agonism, silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), mitochondrial dynamics, and the gut microbiome are key modulators of the neurocardiac axis and are highly interdependent.Understanding the interactions among ferroptosis, pyroptosis, and apoptosis under comorbid conditions is essential for clinical translation.Open questionsIs oxidative stress a primary driver or a consequence of autophagy dysregulation that links cardiac dysfunction to cognitive decline?Are GLP-1 receptor agonists neuroprotective independent of glycemic control, and what is the optimal timing and disease stage?Which microbial metabolites influence mitochondrial dynamics and senescence, and can microbiome targeting improve both cardiac and cognitive outcomes?Is combined inhibition of ferroptosis and pyroptosis superior to single-pathway blockade, and how can strategies for different comorbidity profiles be chosen?How can APOE genotypes and individual metabolic states guide personalized therapies that simultaneously reduce cardiovascular risk and neurodegeneration? Cardiovascular disease and cognitive loss have a neurocardiac basis. Poor vascular perfusion can impair cognitive function in both Alzheimer's disease and multiple sclerosis. However, a treatment gap exists because current approaches do not adequately address the shared underlying cellular mechanisms responsible for cognitive dysfunction in these conditions. Current treatments for cognitive impairment in diseases such as cardiovascular disease, Alzheimer's disease, multiple sclerosis, and diabetes often fail to fully address the shared underlying cellular mechanisms. Consequently, the prevailing precision treatment strategy, which focuses on managing symptoms and preventing disease progression, is insufficient. This highlights the urgent need for innovative approaches capable of targeting these common cellular pathways across these diverse conditions. Novel investigations into oxidative stress, cellular senescence, programmed cell death with apoptosis, ferroptosis, pyroptosis, and autophagy, cellular metabolism with apolipoprotein E and glucagon-like peptide-1 receptor agonism, silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae), mitochondrial dynamics, and the gut microbiome offer the potential to address the risk factors and clinical treatments for cardiovascular disease and cognitive loss. These pathways are exquisitely dependent upon one another and require in-depth knowledge of the modulatory cellular mechanisms for effective translation to clinical care.},
}
@article {pmid42541117,
year = {2026},
author = {McNamara, E and Smith, C and Postlethwaite, N and Wozencraft, A},
title = {Privacy-Enhancing Technologies: Unlocking Responsible Cross-Border Data Research.},
journal = {International journal of population data science},
volume = {11},
number = {5},
pages = {3615},
doi = {10.23889/ijpds.v11i5.3615},
pmid = {42541117},
issn = {2399-4908},
mesh = {Humans ; *Information Dissemination/legislation &amp; jurisprudence ; *Privacy/legislation &amp; jurisprudence ; *Confidentiality/legislation &amp; jurisprudence ; *International Cooperation ; *Computer Security/legislation &amp; jurisprudence ; },
abstract = {International data transfer rules, designed to protect individuals, often create barriers to collaborative research by imposing constraints misaligned with modern data ecosystems. Frameworks like GDPR and UK GDPR can unintentionally hinder scientific progress by failing to recognise the safeguards provided by emerging technologies. More nuanced legal approaches are needed to preserve privacy while enabling responsible international research. We will examine how privacy-enhancing technologies (PETs) can help address these challenges. Informed by insights from pilot projects under the Alzheimer's Disease Data Initiative which seek to address critical dementia questions, while expanding dataset access. With dementia cases projected to rise globally from 57 million to 153 million by 2050, this work demonstrates the urgent need for cross-border data sharing in brain health research. Specifically, we will explore how PETs offer pathways through regulatory barriers, and how Trusted Research Environments (TREs), aligned with the Five Safes Framework, provide strong safeguards to prevent identifiable data disclosure. We will demonstrate how remote querying techniques enable international analysis without data transfers, as researchers receive only aggregate results. The presentation will address persistent challenges: under European Data Protection Board guidance, even viewing data across borders constitutes a transfer, meaning TRE access may trigger complex compliance requirements despite technical safeguards. We will explore the rapidly evolving landscape through new UK legislation, the European Health Data Space, and emerging case law. Finally, we will discuss whether PETs can bridge the gap between privacy protection and scientific progress, and what regulatory adaptations are required to recognise the protections they provide.},
}
@article {pmid42541418,
year = {2026},
author = {Zhang, J and Wang, C and Liang, C and Peng, T and Chang, K and Bu, J and Wang, Z and Wang, X and Hua, Q and Tan, Y},
title = {Neurolymphatic formula restores meningeal and peripheral lymphatic function via VEGFR3 activation: Mechanistic validation of coptisine as a key anti-Alzheimer's compound.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261470114},
doi = {10.1177/13872877261470114},
pmid = {42541418},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is characterized by amyloid-β (Aβ) accumulation with impaired lymphatic clearance, yet therapies targeting lymphatic dysfunction remain underexplored. The Neurolymphatic Formula (NLF), a traditional Chinese medicine, demonstrates lymphatic modulation potential, but its mechanistic role in AD remains unknown.ObjectiveThis study aimed to elucidate NLF's therapeutic efficacy in AD and investigate whether it enhances central and peripheral lymphangiogenesis via VEGF receptor 3 (VEGFR3) activation.MethodsWe evaluated NLF's pharmacological effects on behavior and AD pathology in APP/PS1 mice, including sunitinib-induced lymphatic impairment models. Underlying mechanisms were explored using network pharmacology, molecular docking, and in vitro assays on human lymphatic endothelial cells (HLECs).ResultsIn APP/PS1 mice, 4-week NLF treatment reduced Aβ plaque burden by 43% (p < 0.01) and improved spatial memory latency by 35% (p < 0.05). NLF restored meningeal and mesenteric lymphatic density in sunitinib-treated mice to 82% and 133% of baseline, respectively (p < 0.01), while upregulating serum VEGFR3 2.3-fold (p < 0.01). To validate NLF's molecular basis, coptisine was identified as a representative VEGFR3 ligand (-7.1 Kcal/mol). In vitro, coptisine (25 μM) enhanced HLEC viability by 60%, accelerated wound closure 2.5-fold, and increased tube junctions by 75% (all p < 0.01) alongside VEGFR3 upregulation.ConclusionsNLF alleviates AD pathology by promoting Aβ clearance through VEGFR3-mediated dual modulation of central and peripheral lymphatic systems. The in vitro efficacy of its constituent, coptisine, mechanistically validates this pro-lymphangiogenic pathway, highlighting NLF's therapeutic potential as a holistic lymphatic-targeted AD treatment.},
}
@article {pmid42541419,
year = {2026},
author = {Clément, G and Hansmannel, F and Hopes, L and Bossenmeyer-Pourié, C and Renaud, M},
title = {Alzheimer's disease and nutrition: Focus on the impact of hyperhomocysteinemia.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261471813},
doi = {10.1177/13872877261471813},
pmid = {42541419},
issn = {1875-8908},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disease. Despite advances in the understanding of the genetics of AD, environmental risk factors are still under investigation, and the etiology is still not completely understood. The environmental component of AD, which we explore in the first part of this review, takes on greater importance with more advanced disease onset. Moreover, genetics does not explain all of AD. Environmental risk factors are divided into modifiable and nonmodifiable risk factors. Among the modifiable risk factors, nutrition seems to play a predominant role. One-carbon metabolism (OCM) is involved in this food-related component, notably through B vitamins. Homocysteine, a sulfur-containing amino acid, is at the crossroads of OCM. Abnormal increases in homocysteine levels (hyperhomocysteinemia) are associated with deleterious effects on cognition. Various mechanisms can lead to hyperhomocysteinemia, including genetic factors associated with different polymorphisms, dietary deficiencies targeting vitamins B9 and B12, and renal insufficiency. The second part of the review details OCM and the role of homocysteine. Finally, part 3 highlights the numerous studies in the literature describing the association between hyperhomocysteinemia and cognitive decline. However, the mechanistic links between hyperhomocysteinemia and cognitive decline in AD are poorly understood. Several hypotheses have been proposed in the literature. The toxic effects of homocysteine could be mediated by N-homocysteinylation, a nonenzymatic reaction leading to the irreversible accumulation of N-homocysteinylated proteins. Finally, we detail some therapeutic trials targeting one-carbon metabolism in AD, notably vitamin B9 and B12 supplementation.},
}
@article {pmid42541423,
year = {2026},
author = {Sanz Simon, S and Gal, M and Lee, S and Walker, MD and Schnaider Beeri, M and Bachmann, G and Lauriola, V and Sloan, R and Stern, Y and Gazes, Y},
title = {Can menopausal status moderate the effects of aerobic exercise on executive functions? evidence from a randomized controlled trial.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261471900},
doi = {10.1177/13872877261471900},
pmid = {42541423},
issn = {1875-8908},
abstract = {BackgroundPhysical exercise is widely recognized for its cognitive benefits; however, the effect of menopausal status in modulating the cognitive effects of exercise is not definitively established.ObjectiveTo examine the cognitive benefits of two 6-month physical exercise programs in cognitively healthy older women across adulthood, and whether menopause status moderates these benefits.MethodsIn a post hoc analysis of a randomized controlled trial, 93 cognitively healthy women (aged 20-67; 43% at post-menopause) were assigned to either aerobic exercise (AE) or stretching/toning (ST) 4 days a week for six months. Neuropsychological assessment, cardiorespiratory exercise test, and blood draw were performed at baseline, 3-months, and 6-months. Linear mixed-effects regression models assessed whether menopausal status moderated the impact of exercise on executive functions and processing speed.ResultsSeventy-six participants (81.7%) completed the intervention. A time-by-group-by-menopause interaction emerged after 3 months (β = -0.89; p = 0.001) and 6 months (β = -0.67, p = 0.016). Post-menopausal women in the AE group showed greater improvement in executive functions compared to the ST group and pre-menopausal women. Models controlled for age, education, and baseline cognitive performance.ConclusionsOur results provide novel evidence that AE improves cognition with pronounced executive functions benefits in post-menopausal women, a population at higher risk for dementia. Since women are at a higher risk of developing Alzheimer's disease compared to men, these findings support AE as a relevant strategy to promote women's brain health. Although this is a secondary analysis, it may inform future exercise trials targeting women.},
}
@article {pmid42541425,
year = {2026},
author = {Jodlowska-Siewert, E and Liu, L and Yang, K and Ostroushko, D and Lutsey, PL and Chekouo, T and Safo, SE and , },
title = {A score based on MRI imaging variables can predict time to moderate progression in mild cognitive impairment: Multimodal data integration study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261469162},
doi = {10.1177/13872877261469162},
pmid = {42541425},
issn = {1875-8908},
abstract = {BackgroundMild cognitive impairment (MCI) is an intermediate stage between normal aging and Alzheimer's disease (AD). Because there is no treatment for AD, it is vital to establish which patients are at a higher risk of disease progression, and might benefit from early intervention.ObjectiveThis study investigates whether a score based on clusters of MRI and lipidomic variables can predict the time to moderate progression in MCI.MethodsWe analyzed MRI and lipidomics data from 480 individuals with MCI (mean age 72.14 years, range 55-90 years). Moderate progression was defined as a ≥ 2.5-point increase in the Clinical Dementia Rating Scale Sum of Boxes (baseline mean CDR-SB of 1.2, range 0-10 points). Multi-source data integration and clustering methods were used to derive predictive scores.ResultsThe MRI-based score outperformed the lipidomics score (c-index: 0.754 versus 0.666). A 1-unit increase in the MRI score was linked to a 13% higher risk of moderate progression. Individuals in the top 25% of MRI scores had a 3-fold greater risk of decline.ConclusionsAn MRI-based score offers a simple, effective tool to predict moderate MCI progression and identify high-risk individuals for AD.},
}
@article {pmid42541427,
year = {2026},
author = {Luna-Viramontes, NI and Méndez-Llaca, RE and Morlett Paredes, A and Ordoñez-Lozano, I and Acra-Despradel, C and Guillen-Sarita, J and Pacheco-Herrero, M and Gonzalez-Chavez, VE and Perry, G and Jaramillo-Loranca, BE and Vargas-Hernández, G and Garcés-Ramírez, L and de la Cruz-López, F and Villanueva-Fierro, I and Hernandes-Alejandro, M and Montiel-Sosa, JF and Rojas-Pérez, FJ and Pérez-Pérez, EG and Ocampo-Barba, N and Cenobio-García, FJ and Luna-Muñoz, J},
title = {Experience, challenges, and regional integration of the National Dementia Biobank (Mexico) and the National Brain Bank-UNPHU (Dominican Republic).},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261474026},
doi = {10.1177/13872877261474026},
pmid = {42541427},
issn = {1875-8908},
abstract = {Neurobiobanks focused on the study of major cognitive impairment constitute a strategic infrastructure for translational research and personalized medicine in the neurosciences. In Mexico and the Dominican Republic, the National Dementia Biobank (BND) at the Universidad Politécnica de Pachuca and the National Brain Bank at the Universidad Nacional Pedro Henríquez Ureña (BNC-UNPHU) have developed integrated mechanisms for the collection, processing, and preservation of human brain tissue, as well as other tissues such as kidney, liver, intestine, pancreas, and skin, intended exclusively for biomedical research. Both institutions share research lines centered on the molecular pathological study of the tau protein and the amyloid-β peptide, key markers of Alzheimer's disease and other dementias. Protocols for immunohistochemistry, silver staining, single and multiple immunofluorescences, as well as staining with fluorochromes such as thiazine red and thioflavin-S, have been standardized for the precise detection of neuropathological lesions. Transgenic animal models, including the triple transgenic mouse with mutations in presenilin-1, amyloid-β protein precursor, and tau, have served as complementary tools to dissect the temporal sequence of protein aggregation. In parallel, both institutions have implemented sustained scientific outreach programs, including a traveling museum of neurodegenerative diseases, Brain Awareness Week, Alzheimer's fairs, and media campaigns, aimed at reducing stigma, promoting altruistic tissue donation, and building public trust. Collectively, these neurobiobanks represent an emerging model of research contextualized within Latin American populations, with the potential to integrate into regional and international networks that contribute to reducing knowledge gaps in neurodegeneration.},
}
@article {pmid42541545,
year = {2026},
author = {Hirschmüller, KCE and Prieto, E and Guillén, EF and Echeveste, B and Mínguez, F and Romera, M and Pareja, F and Fahmi, R and Riverol, M and Arbizu, J},
title = {From image reconstruction to clinical prognosis: A comprehensive analysis of centiloid-based amyloid PET assessment.},
journal = {European journal of nuclear medicine and molecular imaging},
volume = {},
number = {},
pages = {},
pmid = {42541545},
issn = {1619-7089},
abstract = {PURPOSE: To investigate the sources of variability in Centiloid (CL) calculations, particularly the influence of image reconstruction and reference region selection, and to examine the relationship between baseline CL scores, visual interpretation and subsequent disease progression.<br><br>METHODS: 162 aMCI patients who underwent amyloid PET at a single center were retrospectively analyzed. Visual assessment was performed by two nuclear medicine physicians and Centiloid scoring was determined using syngo.MI Neurology Cortical Analysis, using different reference regions (RR) and image reconstruction settings. The CL values were compared against visual interpretation, using a ROC analysis. The value of CL in predicting the onset of Alzheimer's dementia was assessed.<br><br>RESULTS: The use of the whole cerebellum as RR provided the most robust and consistent CL values across reconstruction methods. The RR was critical in the case of flutemetamol, as CL varied in more than 20 units between pons and whole cerebellum. Visual classifications and CL values showed strong concordance (area under the ROC curve: 0.9786) and the CL cut-off value that maximized agreement with visual reading was 28 CL. During follow-up, 49% of patients progressed to AD dementia and CL-based amyloid positivity was a significant predictor of progression.<br><br>CONCLUSION: Standardized CL quantification using the whole cerebellum as RR enhances the reliability of amyloid PET interpretation across tracers and reconstruction settings. CL values strongly correlate with visual assessment and are predictive of clinical progression. These findings suggest the potential utility of CL quantification in both clinical and research settings.},
}
@article {pmid42541586,
year = {2026},
author = {Du, X and Shen, Z and Xu, Y and Song, W and Guo, Y and Kou, J and Gong, S and Ren, Q},
title = {Research progress of traditional Chinese medicine interventions for aging-related nervous system diseases.},
journal = {Biogerontology},
volume = {27},
number = {4},
pages = {},
pmid = {42541586},
issn = {1573-6768},
support = {82574744//National Natural Science Foundation of China/ ; JSTJ-2025-490//The Youth Science and Technology Talent Support Program of Jiangsu Association for Science and Technology/ ; YJQN2025005//Research Project Funding from Affiliated Jiangning Hospital of Chinese Medicine, China Pharmaceutical University/ ; },
mesh = {Humans ; *Medicine, Chinese Traditional/methods ; *Aging/drug effects ; Animals ; *Nervous System Diseases/drug therapy ; *Drugs, Chinese Herbal/therapeutic use ; Oxidative Stress/drug effects ; },
abstract = {Aging-related neurological disorders, including stroke, Alzheimer's disease (AD), Parkinson's disease (PD), epilepsy, and various neuroinflammatory conditions, affect over three billion individuals worldwide and constitute leading causes of morbidity, disability, and socioeconomic burdens. Aging contributes not only to the increased incidence of these disorders but also to their progression through interconnected mechanisms, including endothelial dysfunction, oxidative stress, chronic inflammation, mitochondrial dysfunction, cellular senescence, metabolic imbalance, and gut microbiota dysbiosis. These processes collectively impair neuronal survival, synaptic plasticity, and cognitive and motor functions. Traditional Chinese medicine (TCM), with its characteristic multi-component and multi-target therapeutic strategies, has emerged as a promising approach to counteract age-associated neurological decline. Accumulating preclinical studies suggest that TCM interventions may exert neuroprotective, anti-inflammatory, and antioxidant effects, modulate autophagy, restore metabolic homeostasis, and potentially delay cellular senescence. However, high-quality clinical evidence on safety and efficacy remains limited. This review summarizes current insights into the molecular interplay between aging and neurological disorders and highlights the therapeutic potential of TCM in targeting hallmarks of aging, providing perspectives for integrative prevention and treatment strategies for neurodegenerative and neurovascular diseases.},
}
@article {pmid42535277,
year = {2026},
author = {Kang, SH and Park, YJ and Lee, S and Kang, J and Lee, S and Lee, ES and Jung, HN and Ryoo, I and Hwang, H and Choi, K and Eo, JS and Suh, SI and Oh, K and Koh, SB},
title = {Heterogeneity in plasma p-tau217 response and its association with cognitive trajectories under lecanemab treatment.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71705},
pmid = {42535277},
issn = {1552-5279},
support = {RS-2025-16066879//National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT)/ ; K2615351//Korea University Guro Hospital (Korea Research-Driven Hospital) and grant funded by Korea University Medicine/ ; RS-2023-00273685//Starting Growth Technological R&amp;D Program (TIPS Program) funded by the Ministry of SMEs and Startups, Korea/ ; BT240027//Seoul R&amp;BD Program through the Seoul Business Agency funded by the Seoul Metropolitan Government/ ; },
mesh = {Humans ; *tau Proteins/blood ; *Alzheimer Disease/drug therapy/blood ; Female ; Biomarkers/blood ; Male ; Aged ; Disease Progression ; Phosphorylation ; Prospective Studies ; Longitudinal Studies ; Treatment Effect Heterogeneity ; Aged, 80 and over ; *Cognition/drug effects ; },
abstract = {INTRODUCTION: Plasma phosphorylated tau 217 (p-tau217) is a promising biomarker for monitoring treatment response in Alzheimer's disease (AD), but its longitudinal dynamics and clinical relevance remain unclear.<br><br>METHODS: In this prospective real-world study, 153 patients with early AD receiving lecanemab were analyzed. Longitudinal changes in plasma p-tau217 were assessed, and trajectory patterns were identified using clustering and slope-based approaches. Associations with baseline factors and cognitive outcomes were evaluated.<br><br>RESULTS: Plasma p-tau217 levels decreased significantly from 3 months, with the greatest decline between 3 and 6 months, followed by a plateau. Two distinct trajectory groups were identified. Patients in the greater reduction group showed more favorable cognitive trajectories, particularly slower progression in Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores. Hypertension was associated with a diminished biomarker response.<br><br>DISCUSSION: These findings support plasma p-tau217 as an early pharmacodynamic biomarker and highlight its potential role in guiding individualized treatment strategies in routine clinical practice.},
}
@article {pmid42535660,
year = {2026},
author = {Duncan-Cross, I and Miles, E and Hicks, B},
title = {Coping Styles Predict Timing of Dementia Diagnosis: Evidence From DETERMIND.},
journal = {International journal of geriatric psychiatry},
volume = {41},
number = {8},
pages = {e70246},
pmid = {42535660},
issn = {1099-1166},
support = {ES/S010351/1//Economic and Social Research Council/ ; },
mesh = {Humans ; *Adaptation, Psychological ; *Dementia/diagnosis/psychology ; Female ; *Coping Skills ; Male ; Aged ; Caregivers/psychology ; Aged, 80 and over ; *Delayed Diagnosis/psychology ; Early Diagnosis ; Middle Aged ; Treatment Delay ; },
abstract = {OBJECTIVES: Early diagnosis underpins global policy directives aimed at supporting people to live well with dementia. While people encounter numerous barriers when seeking early dementia diagnosis, previous research has primarily focussed on non-modifiable, socio-demographic determinants of diagnostic timing. This study examined whether individuals' coping style could provide further insight into diagnostic delay.<br><br>METHODS: Coping was assessed via the dispositional Brief COPE in 935 individuals recently diagnosed with dementia and 697 carers from the DETERMIND cohort. Through principal component analysis, we identified three distinct coping styles. Hierarchical regression assessed the association of participant demographics and coping factors with diagnostic timing, operationalised via symptom severity and time between first symptoms and diagnosis.<br><br>RESULTS: Coping predicted diagnostic timing in terms of both symptom severity and temporal delay. Increased symptom severity at diagnosis was predicted by individuals with dementia using more avoidant coping and less approach coping. Longer temporal delays were associated with individuals with dementia using less support seeking coping and carers using less avoidant coping.<br><br>CONCLUSIONS: Our findings suggest diagnostic timing is related to the coping strategies employed by individuals with dementia and their carers, over and above demographic influences. These results identify coping as a modifiable factor that could help understand who is most at risk and inform interventions to promote early diagnosis, aligning with global policy directives.},
}
@article {pmid42535671,
year = {2026},
author = {Mortazavi, N and Vandewalle, G and Talwar, P},
title = {Response to "On the Directionality of Predictor-Outcome Assignment When Modeling Polygenic Risk for Alzheimer's Disease Alongside Sleep Arousal Phenotypes".},
journal = {Sleep},
volume = {},
number = {},
pages = {},
doi = {10.1093/sleep/zsag211},
pmid = {42535671},
issn = {1550-9109},
}
@article {pmid42535759,
year = {2026},
author = {Yang, D and Wu, X and Luo, X and Teng, Y and Duan, X and Kang, T and Wu, W},
title = {Stable Isotope-Resolved Metabolomics in Elucidating Mitochondrial Metabolic Reprogramming and Therapeutic Targets.},
journal = {Biomedical chromatography : BMC},
volume = {40},
number = {9},
pages = {e70560},
pmid = {42535759},
issn = {1099-0801},
support = {25ZC-36//the Natural Science Funding Program of Yibin Vocational and Technical College/ ; },
mesh = {Humans ; *Metabolomics/methods ; *Mitochondria/metabolism ; Metabolic Reprogramming ; Animals ; Isotope Labeling/methods ; Neoplasms/metabolism ; },
abstract = {Stable isotope-resolved metabolomics (SIRM) has emerged as a pivotal methodology for dissecting mitochondrial metabolic reprogramming and its connection to therapeutic targets. By combining isotopically labeled substrates with metabolic flux analysis (MFA), SIRM enables dynamic, quantitative tracking of carbon flux through mitochondrial pathways. This review focuses on three disease contexts where SIRM has provided transformative insights: cancer, neurodegenerative disorders (Alzheimer's and Parkinson's diseases), and metabolic syndrome (type 2 diabetes and non-alcoholic fatty liver disease). Recent applications have delineated reprogramming signatures, identified metabolic dependencies, and elucidated drug mechanisms. SIRM also facilitates therapeutic monitoring and resistance assessment, offering quantitative biomarkers for patient stratification. We summarize recent advances, technical challenges, AI-powered innovations, and future directions, providing a foundation for optimizing metabolism-targeted therapies.},
}
@article {pmid42535978,
year = {2026},
author = {Gholami, M and Ahmadi, AA and Niaki, MAA and Asouri, M and Saeedi, S and Amoli, MM and Larijani, B},
title = {New Genetic Associations Between Alzheimer's Disease and Its Key Risk Factors.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {26},
number = {5},
pages = {e70198},
pmid = {42535978},
issn = {1479-8301},
support = {1403-2-221-73223//Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics ; Risk Factors ; Mitochondrial Precursor Protein Import Complex Proteins ; *Apolipoproteins E/genetics ; *Genetic Predisposition to Disease/genetics ; Membrane Transport Proteins/genetics ; ATP Binding Cassette Transporter 1/genetics ; Genome-Wide Association Study ; Female ; Polymorphism, Single Nucleotide ; Metabolic Syndrome/genetics ; Linkage Disequilibrium ; Male ; Haplotypes ; Aged ; Waist-Hip Ratio ; Diabetes Mellitus/genetics ; },
abstract = {INTRODUCTION: This study aimed to explore shared genetic architectures underlying Alzheimer's disease (AD) and its known risk factors.<br><br>METHODS: Significant common variants between AD and its risk factors were identified using GWAS data. The 1000 Genomes Project genotyping data enabled the detection of linkage disequilibrium (LD) blocks and haplotype structures. Functional impact assessments, protein-protein interaction analyses, pathway mapping and enrichment studies were performed.<br><br>RESULTS: Sixteen significant variants across nine genes were associated with AD and at least one risk factor (p&#x2009;&#x2264;&#x2009;5&#x2009;&#xd7;&#x2009;10[-8]). Genes APOE, ABCA1 and TOMM40 showed strong associations with AD (adjusted p&#x2009;=&#x2009;9.75&#x2009;&#xd7;&#x2009;10[-9]). High-confidence interactions were identified among these genes, as well as APP and LRP1, within the AD pathway. Variant rs429358 (p&#x2009;&#x2264;&#x2009;3&#x2009;&#xd7;&#x2009;10[-15]) on the APOE gene was linked to AD, metabolic syndrome (MetS), diabetes, waist-to-hip ratio (WHR) and ageing. Variant rs2075650 (p&#x2009;&#x2264;&#x2009;6&#x2009;&#xd7;&#x2009;10[-9]) on TOMM40 correlated AD risk with MetS, WHR and body mass index (BMI). Variants rs483082 (p&#x2009;&#x2264;&#x2009;2&#x2009;&#xd7;&#x2009;10[-32]) and rs71352238 (p&#x2009;&#x2264;&#x2009;1&#x2009;&#xd7;&#x2009;10[-11]) on APOC1 and TOMM40 were associated with AD and MetS. Variants rs4420638 (p&#x2009;&#x2264;&#x2009;2&#x2009;&#xd7;&#x2009;10[-34]) and rs1800978 (p&#x2009;&#x2264;&#x2009;2&#x2009;&#xd7;&#x2009;10[-9]) on APOC1 and ABCA genes were associated with AD and WHR. The rs13237518 (p&#x2009;&#x2264;&#x2009;5&#x2009;&#xd7;&#x2009;10[-11]) was associated with AD risk in diabetic patients. Furthermore, the rs4277405 (p&#x2009;&#x2264;&#x2009;9&#x2009;&#xd7;&#x2009;10[-20]) associated AD with cardiovascular disease (CVD). Haplotypic structures were also identified for all these variants (D' and r[2]&#x2009;&#x2265;&#x2009;0.8).<br><br>DISCUSSION: This study identifies genetic variants and LD blocks on APOE, ABCA1, TOMM40 and APOC1 genes shared between AD and its risk factors, revealing common genetic links and potential shared susceptibility pathways.},
}
@article {pmid42536015,
year = {2026},
author = {Li, S and Jin, J and Liu, Y and Yuan, J and Dong, Y and Wang, Z and Li, L and Zhang, Y},
title = {Microglial immunometabolic reprogramming in Alzheimer's disease: From mitochondrial dysfunction and redox imbalance to NLRP3 inflammasome-driven neuroinflammation.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261469862},
doi = {10.1177/13872877261469862},
pmid = {42536015},
issn = {1875-8908},
abstract = {Alzheimer's disease (AD) is increasingly recognized as a disorder in which amyloid-β deposition and tau pathology interact with neuroinflammation and metabolic dysregulation. Although mitochondrial dysfunction, redox imbalance, and NLRP3 inflammasome activation have each been implicated in AD pathogenesis, their mechanistic continuity within microglial immunometabolic reprogramming remains insufficiently defined. This narrative review integrates mechanistic, preclinical, and human-relevant evidence to propose a stage-dependent mitochondrial dysfunction-redox imbalance-NLRP3 inflammasome axis. We discuss how AD-related stimuli shift microglia toward a pro-inflammatory metabolic phenotype; how impaired mitochondrial quality control promotes reactive oxygen species generation and oxidized mitochondrial DNA release; and how these signals facilitate NLRP3 inflammasome activation and sustained inflammatory amplification. We further summarize therapeutic strategies targeting upstream mitochondrial homeostasis, intermediate metabolic-redox coupling, and downstream NLRP3 signaling, while emphasizing the translational limitations and biomarker needs. We conclude that this proposed axis provides a testable stage-dependent framework for interpreting chronic, self-amplifying neuroinflammation in AD and may inform biomarker-guided, combinatorial therapeutic strategies.},
}
@article {pmid42536022,
year = {2026},
author = {Rehman, MU and Masip, D},
title = {Artificial intelligence in retinal imaging for early Alzheimer's disease detection: A review.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261473304},
doi = {10.1177/13872877261473304},
pmid = {42536022},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disorder that necessitates early, accessible, and non-invasive diagnostic methods.ObjectiveThis review examines the potential of artificial intelligence (AI)-based retinal imaging as a transformative and scalable tool for early AD detection across the full diagnostic continuum, including the preclinical stage.MethodsFollowing PRISMA guidelines, 63 primary studies were selected from an initial pool of 240 articles retrieved from PubMed, IEEE Xplore, Scopus, Web of Science, and Google Scholar (2017-mid-2025). Advancements in optical coherence tomography (OCT), retinal fundus imaging, and OCT angiography are examined for their capacity to capture structural and vascular biomarkers, including retinal nerve fiber layer thinning and microvascular alterations. AI architectures, including convolutional neural networks, vision transformers, and hybrid models, are evaluated for their accuracy in retinal biomarker analysis. Benchmark datasets, including public and private ones, are assessed for their role in supporting AI-based AD research.ResultsKey challenges are identified, including data heterogeneity arising from variability in acquisition protocols and demographic representation, as well as computational complexity and limited model interpretability. Emerging approaches-notably multimodal data integration and federated learning-offer promising avenues for enhancing diagnostic accuracy while preserving patient privacy.ConclusionsThe socioeconomic implications of integrating AI-based retinal imaging into clinical workflows are discussed. By synthesizing recent advancements, unresolved challenges, and future directions, this review underscores the transformative potential of AI-driven oculomics in facilitating early AD diagnosis and improving patient outcomes.},
}
@article {pmid42536222,
year = {2026},
author = {Serna, MF and Mosquera, M and García-Perdomo, HA},
title = {Motor performance and its association with Alzheimer's-related biomarkers: a systematic review.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {8},
pages = {},
pmid = {42536222},
issn = {1590-3478},
mesh = {Humans ; *Alzheimer Disease/cerebrospinal fluid/physiopathology/diagnosis ; Biomarkers/cerebrospinal fluid ; Amyloid beta-Peptides/cerebrospinal fluid ; *Cognitive Dysfunction/physiopathology/cerebrospinal fluid ; tau Proteins/cerebrospinal fluid ; Peptide Fragments/cerebrospinal fluid ; Neurofilament Proteins/cerebrospinal fluid ; },
abstract = {PURPOSE: To examine associations between neurodegenerative and inflammatory biomarkers and motor function in adults with Alzheimer's disease (AD), mild cognitive impairment (MCI), or at risk of AD.<br><br>METHODS: A systematic review was conducted using MEDLINE, Web of Science, Scopus, LILACS, and CENTRAL.<br><br>RESULTS: Seventeen studies (2018-2026) were included. CSF A&#x3b2;42 levels were associated with gait speed, balance, and mobility outcomes, while p-tau, p-tau181, p-tau217, and t-tau correlated with mobility impairments, dual-task performance, and reduced physical function. Higher neurofilament light chain (NfL) levels were linked to poorer Short Physical Performance Battery (SPPB) performance, slower gait speed, and lower grip strength. One study found serum IL-8 associated with mobility outcomes.<br><br>CONCLUSIONS: AD-related biomarkers, particularly A&#x3b2;42, p-tau, p-tau181, p-tau217, t-tau, and NfL, show consistent associations with gait disturbances, mobility decline, and reduced physical function. Motor changes may precede cognitive decline, supporting their potential as early indicators of neurodegeneration.},
}
@article {pmid42536296,
year = {2026},
author = {Li, YQ and Chen, DX and Zhu, XT and Li, W and Wu, JL and Fang, LM and Li, MQ},
title = {Therapeutic Potential of Jiedu Yizhi Formula for Alzheimer's Disease: A Randomized Controlled Trial.},
journal = {Chinese journal of integrative medicine},
volume = {},
number = {},
pages = {},
pmid = {42536296},
issn = {1993-0402},
abstract = {OBJECTIVE: To observe the clinical effect and safety of Jiedu Yizhi Formula (JYF) in Alzheimer's disease (AD) patients.<br><br>METHODS: Eligible patients with mild to moderate AD and Chinese medicine (CM) syndrome of Pi (Spleen)-Shen (Kidney) deficiency with phlegm-turbidity obscuring orifices were collected from the Third Affiliated Hospital of Changchun University of Chinese Medicine between December 2022 and December 2023. Patients were randomly assigned to JYF and donepezil groups at a 1:1 ratio by using a random number table and received a total of 24 weeks of continuous treatment. Both groups were given AD cognitive behavior training and health education at the same time. The Mini Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), AD Assessment Scale-Cognitive (ADAS-cog), Activity of Daily Living (ADL), and Hamilton Depression (HAMD) scale scores were measured before treatment, 12 and 24 weeks after treatment. The cognitive domain scores and the total effective rates were also compared between groups. During the study period, any adverse reactions were recorded and compared between groups.<br><br>RESULTS: Totally 62 participants completed the study, with 31 in each group. The MMSE, MoCA, ADAS-cog, ADL, and HAMD scores significantly improved after 12 and 24 weeks of treatment in both groups (P<0.05 or P<0.01). Moreover, significant improvements in the ADL and HAMD scores were observed in the JYF group at 12 or 24 weeks than in the donepezil group (P<0.05 or P<0.01). Meanwhile, the cognitive domain scores of orientational and abstraction abilities and the total effective rate (64.52% vs. 45.16%) in the JYF group were significantly higher (P<0.05). No significant difference was found in the incidence of adverse reactions between groups (9.68% vs. 6.45%, P>0.05).<br><br>CONCLUSION: JYF can improve the cognitive dysfunction of mild to moderate AD patients with CM syndrome of Pi-Shen deficiency with phlegm-turbidity obscuring orifices, and its safety is good. (Trial registration No. NCT06393413).},
}
@article {pmid42536368,
year = {2026},
author = {Chiotis, S and Giannopoulos, G and Zagalioti, SC and Konstantinidou, SE and Mountourli, MI and Zgouridou, A and Anastasiou, A and Bakogiannis, K and Evaggeliou, A and Sapouridis, G and Toumpourleka, M and Triantafyllou, C and Poptsi, E and Symeonidis, A and Tsolaki, M and Vassilikos, V},
title = {Global and Domain-Specific Cognitive Outcomes After Catheter Ablation for Atrial Fibrillation.},
journal = {JAMA network open},
volume = {9},
number = {7},
pages = {e2626642},
doi = {10.1001/jamanetworkopen.2026.26642},
pmid = {42536368},
issn = {2574-3805},
mesh = {Humans ; *Atrial Fibrillation/surgery/complications ; *Catheter Ablation/adverse effects/methods ; Female ; Prospective Studies ; Male ; Middle Aged ; *Cognition ; *Cognitive Dysfunction/etiology ; Greece ; Magnetic Resonance Imaging ; Aged ; Treatment Outcome ; },
abstract = {IMPORTANCE: Atrial fibrillation (AF) is associated with cognitive impairment, but the cognitive effects of catheter ablation (CA) using contemporary techniques remain uncertain.<br><br>OBJECTIVE: To evaluate changes in global and domain-specific cognitive function after CA for AF.<br><br>This prospective cohort study included consecutive patients undergoing CA for AF and a nonablation AF control group at a tertiary university hospital in Greece between January 2022 and June 2024. Cognitive assessments were performed at baseline and at 6-month follow-up.<br><br>EXPOSURES: CA using cryoballoon or pulsed field ablation (PFA).<br><br>MAIN OUTCOMES AND MEASURES: Changes from baseline to 6 months in Montreal Cognitive Assessment (MoCA) scores and the novel REMEDES for Alzheimer (R4Alz) total and subdomain scores. Brain magnetic resonance imaging was performed before and within 48 hours after ablation to detect new cerebral infarcts.<br><br>RESULTS: Among 75 patients (40 [53.3%] female) undergoing ablation (mean [SD] age, 61.9 [10.4] years; 54 cryoballoon, 21 PFA) and 40 in a nonablation control group (26 [65.0%] female; mean [SD] age,61.4 [9.2] years), baseline cognitive scores were similar between groups. No new cerebral infarcts were detected after ablation. At 6 months, MoCA scores in the ablation group did not change significantly (mean change, 0.27; 95% CI, -0.08 to 0.62), whereas R4Alz total scores increased (mean change, 2.81; 95% CI, 1.55 to 4.07), mainly associated with gains in short-term working memory and perceptual inhibition. No significant changes were observed in the control group. Compared with the control group, the ablation cohort demonstrated significantly greater improvements in both MoCA (mean difference in change, 0.74; 95% CI, 0.17 to 1.31; P&#x2009;=&#x2009;.01) and R4Alz total score (mean difference in change score, 3.18; 95% CI, 0.87 to 5.49; P&#x2009;=&#x2009;.007). In adjusted analyses accounting for baseline cognitive score and clinical covariates, ablation was independently associated with higher follow-up MoCA (&#x3b2;&#x2009;=&#x2009;0.88; 95% CI, 0.31 to 1.44) and R4Alz scores (&#x3b2;&#x2009;=&#x2009;3.80; 95% CI, 1.70 to 5.90).<br><br>CONCLUSIONS AND RELEVANCE: In this prospective observational cohort study of 75 patients undergoing CA for AF, ablation was not associated with cognitive decline and was instead associated with modest short-term improvements in selected cognitive domains. Domain-specific assessment detected changes not captured by global cognitive screening, suggesting that modern ablation techniques may be associated with early subtle cognitive gains.},
}
@article {pmid42536379,
year = {2026},
author = {Rubin, R},
title = {Soccer Players' Brains, P-Tau217 Blood Tests, Lifestyle and Dementia Risk, and More From AAIC 2026.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2026.14334},
pmid = {42536379},
issn = {1538-3598},
}
@article {pmid42536688,
year = {2026},
author = {Xie, Y and Lim, CT and Lam, XJ and Cheah, PS and Ling, KH and Huang, T},
title = {Integrative network pharmacology, transcriptomics, and molecular docking identify candidate Centella asiatica constituents and targets in neurodegenerative diseases.},
journal = {PloS one},
volume = {21},
number = {7},
pages = {e0354882},
pmid = {42536688},
issn = {1932-6203},
mesh = {*Molecular Docking Simulation ; *Neurodegenerative Diseases/drug therapy/genetics/metabolism ; *Centella/chemistry ; Humans ; *Network Pharmacology/methods ; *Triterpenes/chemistry/pharmacology ; *Transcriptome/drug effects ; Gene Expression Profiling ; },
abstract = {BACKGROUND: Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), are progressive disorders with limited therapeutic options. Centella asiatica (C. asiatica), a medicinal and edible plant, has been reported to exert neuroprotective and anti-neuroinflammatory properties. Yet, the mechanisms underlying its effects against neurodegenerative diseases remain largely unclear.<br><br>METHODS: We employed an integrative strategy combining network pharmacology, transcriptomic analyses, machine learning and molecular docking to prioritize disease-associated molecular networks and candidate compound-target relationships in AD, PD and HD.<br><br>RESULTS: Sixteen candidate constituents of C. asiatica met the predefined drug-likeness, gastrointestinal absorption and blood-brain barrier permeability criteria, yielding 370 unique predicted targets. Disease-gene mining identified 983 AD-associated genes, 1,103 PD-associated genes, and 3,316 HD-associated genes. Integration of compound targets, disease-associated genes, and transcriptomic profiles prioritized five hub genes in PD (CCKAR, MAPK8, PSEN2, SLC6A3, and TH), four in AD (APP, PGK1, PIK3CA, and TTR), and four in HD (CHRND, HSP90AA1, PRKCQ, and TH). Enrichment analyses highlighted disease-relevant processes involving neurotransmitter signalling, cAMP and calcium pathways, MAPK-related responses and inflammatory regulation. ROC analyses provided additional support for the discriminatory performance of the prioritized genes in independent datasets, whereas molecular docking identified favourable predicted Vina docking scores and structurally plausible interactions between selected compounds and hub targets.<br><br>CONCLUSION: This integrative computational analysis prioritizes candidate C. asiatica constituents, putative disease-associated targets, and molecular pathways in AD, PD, and HD. The findings provide a foundation for subsequent biochemical, cellular, and in vivo validation.},
}
@article {pmid42536712,
year = {2026},
author = {},
title = {Retraction: Detection of Peri-Synaptic Amyloid-β Pyroglutamate Aggregates in Early Stages of Alzheimer's Disease and in AβPP Transgenic Mice Using a Novel Monoclonal Antibody.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261474572},
doi = {10.1177/13872877261474572},
pmid = {42536712},
issn = {1875-8908},
}
@article {pmid42537247,
year = {2026},
author = {Du, X and Bao, M and Li, Y and Ding, J and Zhang, Z and Chen, H and Liu, Y},
title = {Neuroprotective mechanism of Ribisin A on Aβ25-35-induced PC12 cell damage model.},
journal = {Tissue &amp; cell},
volume = {104},
number = {Pt 1},
pages = {103825},
doi = {10.1016/j.tice.2026.103825},
pmid = {42537247},
issn = {1532-3072},
abstract = {Amyloid-β (Aβ) is a neurotoxic substance, and studies have found that its excessive deposition in the brain, forming senile plaques, is a major pathological feature of Alzheimer's disease (AD). In previous studies, Ribisin A, a benzofuran compound, was purified from Phellinus ribis and found to have neuroprotective effects. This study aims to elucidate the neuroprotective mechanism of Ribisin A in an Aβ25-35-damaged PC12 cell model. This study established an in vitro AD model using PC12 cells damaged by Aβ25-35. We applied methyl tetrazolium (MTT), enzyme-linked immunosorbent assay (ELISA) kits, flow cytometry, and western blotting techniques to study the effects of Ribisin A on the Aβ25-35 injury model and the relationship with the ERK pathway from the aspects of cell injury degree, cytokine content, Calcium ion (Ca[2 +]) concentration, mitochondrial membrane potential (MMP), and the ERK pathway-related protein expression. Results indicate that Ribisin A reduced lactate dehydrogenase (LDH), reactive oxygen species (ROS), tumour necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) levels in the Aβ25-35-induced cellular injury model while increasing superoxide dismutase (SOD) levels. Furthermore, it inhibited Aβ25-35-induced increases in Ca[2+] concentration and decreases in MMP, leading to upregulation of ERK pathway-related proteins TrkB, p-ERK1/2, and p-CREB, with significant elevations in p-ERK/ERK and p-CREB/CREB ratios (P < 0.01). Ribisin A can reduce oxidative damage, inhibit inflammation, restore mitochondrial function, and reduce apoptosis. The neuroprotective mechanism of Ribisin A may involve regulation of the TrkB-mediated ERK/CREB signaling cascade. Our study provides evidence for the neuroprotective mechanism of Ribisin A in an Aβ25-35-induced cellular injury model.},
}
@article {pmid42537334,
year = {2026},
author = {Larico-Ramirez, LP and Paco-Chipana, M and Herrera, MI and Goyzueta-Mamani, D and Chavez-Fumagalli, M and Barazorda-Ccahuana, HL},
title = {Integrative computational discovery of a lichen-derived acetylcholinesterase inhibitor candidate for Alzheimer's disease.},
journal = {Computational biology and chemistry},
volume = {125},
number = {},
pages = {109275},
doi = {10.1016/j.compbiolchem.2026.109275},
pmid = {42537334},
issn = {1476-928X},
abstract = {Alzheimer's disease (AD), the leading cause of dementia worldwide, is a progressive neurodegenerative disorder for which current pharmacological treatments provide only limited symptomatic relief. Human acetylcholinesterase (hAChE) remains one of the most extensively validated therapeutic targets because its inhibition enhances cholinergic neurotransmission and temporarily improves cognitive function. Motivated by the remarkable structural diversity of lichen secondary metabolites, we investigated their potential as novel hAChE inhibitors using an integrated multiscale computational strategy that combined structure-based virtual screening, ADME/Tox profiling, density functional theory (DFT) calculations, molecular dynamics (MD) simulations, and MM/GBSA binding free-energy analysis, with donepezil employed as the reference inhibitor. Among the screened compounds, calycin emerged as the most promising candidate. It displayed high predicted binding affinity together with favorable pharmacokinetic characteristics, including high gastrointestinal absorption and blood-brain barrier permeability. Electronic structure analysis revealed greater chemical reactivity and electronic adaptability than donepezil, indicating an enhanced ability to establish stabilizing interactions within the hAChE active site. Molecular electrostatic potential and local reactivity descriptors further identified chemically active regions responsible for favorable non-covalent interactions along the active-site gorge. Long-timescale MD simulations confirmed the structural stability of the hAChE-calycin complex, while MM/GBSA calculations demonstrated a thermodynamically favorable binding process predominantly driven by van der Waals and hydrophobic interactions with key aromatic residues. Collectively, these findings identify calycin as a promising lead scaffold for the development of next-generation hAChE inhibitors and demonstrate the potential of lichen-derived natural products as an underexplored source of chemically diverse candidates for Alzheimer's disease drug discovery.},
}
@article {pmid42537728,
year = {2026},
author = {Zhang, Y and Ge, P and Mao, J and Wang, T and Yuan, H},
title = {Role of auricular vagus nerve stimulation in alleviating neuronal apoptosis and cognitive dysfunction in male rats with vascular dementia.},
journal = {Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association},
volume = {},
number = {},
pages = {108716},
doi = {10.1016/j.jstrokecerebrovasdis.2026.108716},
pmid = {42537728},
issn = {1532-8511},
abstract = {BACKGROUND AND PURPOSE: Vascular dementia (VD) is characterized by cognitive impairment resulting from cerebrovascular damage. Prior studies have shown that vagus nerve stimulation improves learning and memory in patients with Alzheimer's disease. This study, therefore, investigated whether auricular vagus nerve stimulation (aVNS) ameliorates cognitive dysfunction in a rat model of VD through activation of the adenosine A2A receptor (A2AR) and nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathways.<br><br>METHODS: Fifty male rats were randomly assigned to five groups by a computer-generated sequence: control (A), sham-operated (B), VD model (C), aVNS-treated (D), and aVNS combined with the A2AR antagonist SCH 58261 (E). Rats in the aVNS group received stimulation (0.6 mA, 40 Hz, 0.5 ms square pulses) for 4 weeks. Spatial learning and memory were evaluated using the Morris water maze test. Rat brain microvascular endothelial cells were cultured and treated with an A2AR agonist and/or a protein kinase A (PKA) inhibitor to verify the involvement of the A2AR-Nrf2/HO-1 pathway. Expression levels of inflammatory cytokines (IL-1&#x3b2; and IL-6), key signaling proteins (A2AR, p-PKA, p-Nrf2, and HO-1), and phosphorylated tau (p-tau) were measured using western blot or enzyme-linked immunosorbent assays.<br><br>RESULTS: Compared with Groups C and E, Group D exhibited improved spatial learning and memory. aVNS markedly increased the p-PKA and p-Nrf2/HO-1 levels while reducing p-tau and proinflammatory cytokine levels. In vitro experiments showed that A2AR agonist treatment upregulated p-PKA and p-Nrf2/HO-1 expression; however, this effect was abolished by PKA inhibition.<br><br>CONCLUSION: aVNS ameliorates cognitive impairments in VD rats and attenuates neuronal apoptosis, p-tau accumulation, and neuroinflammation, and these effects are associated with activation of the A&#x2082;AR/PKA/Nrf2/HO-1 signaling pathway. These findings suggest that aVNS may represent a promising therapeutic strategy for cognitive impairment associated with VD.},
}
@article {pmid42537760,
year = {2026},
author = {Misrani, A and Wang, J and Xu, Y and Liu, F},
title = {IL-17A levels in Alzheimer's Disease brains are mediated by X chromosome dosage.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {112065},
doi = {10.1016/j.brainresbull.2026.112065},
pmid = {42537760},
issn = {1873-2747},
abstract = {Among inflammatory mediators, interleukin-17A (IL-17A) has emerged as a potential contributor to AD pathogenesis, although its role remains incompletely defined. Notably, sex differences are evident in AD, with males exhibiting earlier mortality and greater cognitive deficits during aging and preclinical stages compared to females. While hormonal influences have been widely studied, the contribution of sex chromosome complement was suggested critical and remains poorly understood. Here, we investigated the impact of sex chromosome on cognitive function and neuroinflammation using amyloid and tau mouse models. Female Tg2576 and PS19 mice were crossed with XY* males to generate XX, XO, XY, and XXY genotypes, enabling separation of X from Y chromosomal effect. Behavioral assessments, including fear conditioning, novel object recognition, and Barnes maze, revealed that XY mice exhibited significantly greater cognitive impairment compared to XX and XXY counterparts. The same pattern was seen in IL-17A levels, indicating an effect of X chromosome instead of Y. Amyloid-β and phosphorylated tau pathology by immunohistochemistry and Elisa confirmed robust disease-associated accumulation in Tg2576 and PS19 mice, but showed no differences across sex chromosome complements. Collectively, our study identifies X chromosome dosage as a key modulator of cognitive resilience and IL-17A-linked neuroinflammation in AD models. Future studies focused on understanding how X-linked factors regulate IL17 mediated neuroinflammatory pathways could reveal novel therapeutic targets for AD.},
}
@article {pmid42537824,
year = {2026},
author = {Abouali, O and Mokabber, A and Naderpour, S and Vojoudi, E and Sefat, F and Saeinasab, M and Rahimzadegan, M and Nosrati, R},
title = {Chitosan-based hydrogel for intranasal drug delivery; current advances in the brain diseases treatment.},
journal = {International journal of pharmaceutics},
volume = {},
number = {},
pages = {127259},
doi = {10.1016/j.ijpharm.2026.127259},
pmid = {42537824},
issn = {1873-3476},
abstract = {Neurodegenerative diseases represent a growing health concern that is projected to become more prevalent and affect more people in the upcoming decades. One of the most complicated components of recent neurodegenerative disease therapies is the penetration and delivery of therapeutics to the central nervous system (CNS), which are hindered via the blood-brain barrier (BBB). In response, innovative treatment approaches leveraging noninvasive techniques including nanosized drug delivery systems and intranasal (IN) administration with higher treatment efficacy and patient satisfaction are developing as potential options. IN administration delivers medications directly to the brain through both the olfactory and trigeminal pathways, with the olfactory pathway representing the primary route for nose-to-brain transport. Among various IN platforms, chitosan (CS)-based hydrogels have attracted considerable attention because of their excellent biocompatibility, biodegradability, mucoadhesive properties, and ability to enhance drug permeation by prolonging nasal residence time and transiently modulating epithelial tight junctions. This review critically summarizes recent advances in CS-based hydrogels for IN drug delivery for the treatment of brain diseases including Alzheimer's disease (AD), Parkinson's disease (PD), depressive manifestations, ischemia,brain tumors,epilepsy, seizures, and schizophrenia. In addition, the review discusses the relationships between hydrogel design and therapeutic performance, highlights current translational challenges, and outlines future perspectives for the clinical development of CS-based IN hydrogel systems.},
}
@article {pmid42537957,
year = {2026},
author = {Chen, K and Xuan, ZY and Sun, BY and Zhong, GN and Sun, XL and Yan, J},
title = {The critical role of microglia in the stress response.},
journal = {Neuroscience and biobehavioral reviews},
volume = {189},
number = {},
pages = {106894},
doi = {10.1016/j.neubiorev.2026.106894},
pmid = {42537957},
issn = {1873-7528},
abstract = {Microglia are the principal resident innate immune cells of the central nervous system (CNS). Beyond maintaining brain homeostasis via cytokine secretion and phagocytic clearance, they fulfill essential roles in synaptic pruning, oligodendrocyte maturation, and higher-order functions including learning and memory. In response to stress exposure, microglia undergo robust activation, characterized by morphological remodeling, altered phagocytic activity, and dysregulated inflammatory signaling, positioning them as active mediators of the integrated systemic stress response. This review systematically synthesizes preclinical and clinical evidence regarding the multifaceted contributions of microglia to stress processing, their mechanistic involvement in the pathogenesis of major stress-related disorders-including post-traumatic stress disorder (PTSD), major depressive disorder (MDD), Alzheimer's disease (AD), and Parkinson's disease (PD)-and summarizes emerging microglia-targeted therapeutic strategies. We underscore the substantial mechanistic and translational value of microglial research for advancing our understanding of stress adaptation and associated brain pathologies.},
}
@article {pmid42538506,
year = {2026},
author = {Zhang, M and Ho, FK and Pell, JP and Celis-Morales, C and Bailey, MES and Strawbridge, RJ and Lyall, DM},
title = {Heterogeneity in the association between APOE ε4 carrier status and dementia risk by modifiable and non-modifiable risk factors.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42538506},
issn = {2509-2723},
abstract = {Dementia is a major public health challenge, and Apolipoprotein E (APOE) ε4 is strongly associated with all-cause dementia, particularly Alzheimer's disease (AD). We aim to quantify the overall contribution of modifiable lifestyle, adiposity, socioeconomic status (SES), and health conditions occurring before dementia, to the association between ε4 genotype and the development of all-cause dementia, with AD examined as a major subtype. A population cohort study of 181,006 white UK Biobank participants aged ≥ 55 years at baseline was conducted, to examine the associations between APOE ε4 and all-cause dementia, and specifically AD, including modification and mediation role of lifestyle factors, adiposity, SES, and health conditions occurring before dementia. All risk factors, except for high alcohol intake, low diet quality, and phenotypic obesity, were associated with higher risk of all-cause dementia. The interaction contributions of lifestyle, adiposity, SES, and health conditions occurring before dementia varied by sex and dementia type. Low educational attainment had the strongest interaction effects with the association of APOE ε4 carriers and AD/all-cause dementia (up to 32.1%). In women, high deprivation level, abnormal sleep duration, anxiety, and depression showed interaction effects with APOE genotype (5-11.6%) as well. Phenotypic adiposity was associated with an increased risk of dementia among APOE ε4 non-carriers, but with a reduced risk among APOE ε4 carriers. Educational attainment explained a meaningful proportion of the APOE ε4 association with dementia. The strength of the association between APOE ε4 and dementia differed by risk factors and sex.},
}
@article {pmid42538752,
year = {2026},
author = {Van Langenhove, T and Van Mossevelde, S and Miatton, M and De Lepeleire, J and Bruffaerts, R and Bier, JC and Segers, K and Verschraegen, J and Petrovic, M and Ventura, M and Jedidi, H and Beyer, I and Mormont, E and Vandenberghe, R and Delva, A and Gilles, C and Van Weehaeghe, D and Picard, G and De Deyn, P and Strauss, M and Thiery, E and Salmon, E and Cypers, G and Vlaemynck, J and Gillis, K and Versijpt, J and Bjerke, M and Sieben, A and Hanseeuw, B and Engelborghs, S and Deryck, O and , },
title = {Biomarker-Based Diagnosis and Care Pathways for Alzheimer's Disease in the Era of Disease-Modifying Treatments: A Consensus Statement by Belgian Experts.},
journal = {European journal of neurology},
volume = {33},
number = {8},
pages = {e70668},
doi = {10.1111/ene.70668},
pmid = {42538752},
issn = {1468-1331},
mesh = {Humans ; *Alzheimer Disease/diagnosis/therapy ; *Biomarkers/cerebrospinal fluid/blood ; Belgium ; },
abstract = {BACKGROUND: The recent approval of disease-modifying therapies (DMTs) for early Alzheimer's disease (AD) marks a major shift in clinical practice. Biomarker confirmation of amyloid pathology is now required alongside clinical assessment, and blood-based tests are improving accessibility. This creates increased demand for timely and accurate diagnosis while avoiding overdiagnosis in low-probability cases. This Belgian consensus aims to guide biomarker-based diagnosis of AD in the era of DMTs and to highlight the system adaptations required for safe and equitable implementation. Belgium, with universal healthcare but regionally organised dementia care, provides a relevant case to illustrate both opportunities and challenges.<br><br>METHODS: This consensus was developed by 31 experts in cognitive neurology, geriatrics, neuropsychology, neuroimaging, neurochemistry, and primary care, coordinated by the Belgian Dementia Council (BeDeCo). Recommendations were based on multidisciplinary discussion, current evidence, and the organisation of dementia care in Belgium.<br><br>RESULTS: The consensus outlines a stepwise diagnostic approach that integrates clinical assessment with biomarker confirmation using cerebrospinal fluid, amyloid-PET, and emerging blood-based tests. We review the strengths and limitations of each modality and provide guidance for use across clinical scenarios. Using Belgium as a case example, we illustrate challenges that are shared across European healthcare systems, such as limited reimbursement, unequal access to expertise, and insufficient diagnostic capacity, and formulate pragmatic recommendations to address these issues.<br><br>CONCLUSIONS: This consensus offers practical guidance for embedding biomarker-based diagnostic strategies into clinical care. By outlining structured pathways and system-level priorities, it facilitates safe, feasible, and equitable implementation of DMTs for AD.},
}
@article {pmid42538765,
year = {2026},
author = {Sun, H and Huang, D and Yang, F and Zhang, P and Yang, D and Zeng, C},
title = {Metabolomic Discoveries for Traditional Chinese Medicine Efficacy in Alzheimer's Disease.},
journal = {BioMed research international},
volume = {2026},
number = {1},
pages = {e2455800},
pmid = {42538765},
issn = {2314-6141},
support = {2023008//Scientific Research Projects of Medical and Health Institutions of Longhua District, Shenzhen/ ; 82270940//The National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy ; *Medicine, Chinese Traditional/methods ; *Metabolomics/methods ; *Drugs, Chinese Herbal/therapeutic use ; Animals ; Brain/metabolism ; Metabolic Networks and Pathways/drug effects ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory impairment, and behavioral alterations. However, the complex etiology and pathogenesis of AD have thus far precluded the development of satisfactory therapeutic agents. Traditional Chinese medicine (TCM) has garnered increasing recognition for its potential in AD management due to its multicomponent, multitarget therapeutic strategy. Metabolomics, an advanced analytical methodology for investigating metabolic alterations in biological systems, has yielded significant insights into both the therapeutic efficacy and mechanistic underpinnings of TCM interventions for AD. This review synthesizes recent metabolomic findings associated with TCM approaches to AD treatment, identifying key metabolic pathways across diverse biological specimens, including brain tissue, blood, urine, and feces. Through systematic elucidation of these metabolic networks, metabolomics offers substantial potential to facilitate the advancement of TCM-derived therapeutics for AD, potentially enhancing global patient outcomes.},
}
@article {pmid42538866,
year = {2026},
author = {Jiang, Y and Yang, T},
title = {In APP/PS-1 Transgenic Mice and Aβ-Induced P12 Cell Models, ADCYAP1 Inhibits Neuronal Apoptosis and Autophagy, Thereby Alleviating The Pathology of Alzheimer's Disease.},
journal = {Cell journal},
volume = {28},
number = {1},
pages = {1-13},
doi = {10.22074/cellj.2026.2045830.1718},
pmid = {42538866},
issn = {2228-5814},
abstract = {OBJECTIVE: Alzheimer's disease (AD) is a common neurodegenerative disease in the elderly. ADCYAP1 encodes pituitary adenylate cyclase activating polypeptide (PACAP), which can exert neuroprotective effects in neurodegenerative diseases. This study aims to probe the specific function of ADCYAP1 in AD.<br><br>MATERIALS AND METHODS: In this experimental study, brain tissue samples from AD patients and healthy controls were collected to assess ADCYAP1 expression. APP/PS-1 transgenic mice were utilised as an AD mouse model along with amyloid beta (A&#x3b2;)-induced PC12 cells as an AD cell model. ADCYAP1 expression in the AD mice was determined by real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot. An IF assay was employed to test A&#x3b2; deposition and microtubule-associated protein 2 (MAP2) expression (a neuron marker). Behavioural tests, including the Morris water maze (MWM) and footprint tests, were performed to evaluate cognitive impairment and motor ability. Cell apoptosis was determined using the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-nick end labelling (TUNEL) assay. Western blot was utilised to test the expression of autophagy-related genes, including LC3 and beclin1. The expressions of transcription factors involved in neuronal differentiation was assessed by RTqPCR.<br><br>RESULTS: ADCYAP1 expression was significantly downregulated in the brain tissues of AD patients and mice. ADCYAP1 overexpression reduced A&#x3b2; deposition and enhanced MAP2 expression in the AD mice. ADCYAP1 overexpression effectively improved cognitive impairment and mobility decline in the AD mice. ADCYAP1 upregulation inhibited neuronal apoptosis and autophagy both in vivo and in vitro. ADCYAP1 upregulated the expression of neuronal differentiationrelated factors [transforming growth factor &#x3b2; (TGF&#x3b2;), early growth response 1 (Egr1), brain-derived neurotrophic factor (BDNF), fibroblast growth factor 21 (FGF21), and insulin-like growth factor 1 (Igf1)] in the AD models.<br><br>CONCLUSION: ADCYAP1 inhibits neuronal apoptosis and autophagy to improve AD progression in APP/PS-1 mice and A&#x3b2;-induced P12 cells.},
}
@article {pmid42538916,
year = {2026},
author = {Villalba-Moreno, JL and El-Amri, Y and Kim, KY and Villalba-Moreno, ND and Shafiq, M and Ortiz-Cordero, C and Wang, S and Ossa, JA and Suarez-Uribe, I and Cardona-Madrigal, D and Villegas, A and Glatzel, M and Krasemann, S and Posada-Duque, R and Kiessling, LL and Lopera, F and Arboleda-Velasquez, J and Kalaria, R and Ellisman, M and Sepulveda-Falla, D},
title = {Astrocyte-driven small vessel disease is an early, amyloid-independent feature of PSEN1 E280A familial Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.17.739026},
pmid = {42538916},
issn = {2692-8205},
abstract = {Cerebral Small vessel disease (cSVD) is a prevalent feature of Alzheimer's disease (AD) pathology. Whether this pathology is a late consequence of amyloid and tau accumulation or an early, direct effect of PSEN1 dysfunction has remained unresolved. We found that it is more severe in familial AD (FAD) caused by E280A mutation in presenilin 1 (PSEN1). These cases present with a distinctive proteomic signature, associated with pathological features, more dysregulated in the occipital cortex (OC) compared to the frontal cortex (FC), and characterized by multiple dysregulated proteins involved in extracellular matrix (ECM) and RNA-associated processes. This proteomic fingerprint was associated with abnormal collagen build up, ECM disorganization, and signatures of aberrant angiogenesis. Six months old transgenic knock-in mice homozygous for Psen1 E280A mutation (PSEN1Ki) also showed a similar phenotype with microvascular tortuosity and proteomic changes. Critically, these mice develop neither Aβ plaques nor tau tangles, indicating that the shared microvascular and RNA-associated changes are direct consequences of PSEN1 dysfunction rather than downstream effects of amyloid pathology. Remarkably, dysregulated RNA-associated protein networks overlapped between FAD and PSEN1Ki mice. Cerebral microvessels microstructure in PSEN1Ki mice at two months and six months showed abnormal astrocytic end-feet with lamellar deposits implicating blood-brain barrier damage. Finally, single nuclei transcriptomic analysis of AD patients and controls showed similar abnormal astrocytes in both sporadic and familial variants, but FAD astrocytes expressed dysregulated genes identified in the proteomic analyses, such as GLUL, APOE, and CLU. Our findings suggest that cSVD is an early pathological event in PSEN1 FAD and that is driven by abnormal RNA-associated processes and astrocytic dysfunction.},
}
@article {pmid42538997,
year = {2026},
author = {Krunic, A and Umesh Ganesh, N and Coskun, U and Brennan, W and Patel, C and Joshi, O and Lee, J and Gu, TS and Caruso, J and O'Connell, A and Lisboa, C and Crossland, N and Kurkela, M and Julia, T and Fowler, A and Tay, TL and Fischer, A and Delalle, I and Blusztajn, JK and Mellott, TJ},
title = {MicroRNA-223 Enhances Microglia-Dependent Clearance of Amyloid Beta Plaques and Ameliorates Behavioral Deficits in a Mouse Model of Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.20.738977},
pmid = {42538997},
issn = {2692-8205},
abstract = {The Alzheimer's disease (AD) brain is characterized by dysregulated expression of multiple microRNAs (miRNA), positioning them as promising diagnostic and therapeutic targets. The levels of glia-enriched miR-223 are abnormal in the brains and plasma of AD patients and miR-223 is neuroprotective in models of stroke. However, whether miR-223 can be beneficial in AD is not known. Here, we report that intracerebroventricular (ICV) injection of miR-223 oligonucleotide mimic alleviated cognitive impairment, reduced amyloid beta (Aβ) pathology, and ameliorated the defects in synaptic marker expression in App [NL-G-F] AD model mice. Mechanistically, miR-223 induced microglial clustering around Aβ plaques with a concomitant upregulation of microglial phagocytic receptors AXL, TREM2 and CD11c, while pharmacological microglial depletion abolished the plaque-clearance phenotype. Moreover, in human iPSC-derived microglia miR-223 directly targeted multiple genes in the endo-lysosomal pathway, including AD risk gene SPPL2A , indicating that it acts as a major regulator of microglial phenotype. Lastly, long-term AAV-mediated overexpression of miR-223 recapitulates its beneficial effects on cognition, pathology, and synaptic marker expression. Our study demonstrates a novel approach for the treatment of AD using miR-223 and highlights the potential of RNAi-based therapeutics in neurodegenerative disease.},
}
@article {pmid42539005,
year = {2026},
author = {DeLong, LN and Salimi, Y and Balabin, H and Galdi, P and Fleuriot, JD and Brennan, P and , },
title = {Encoding Discordance in the Alzheimer's Disease A/T/N Framework.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.19.26358425},
pmid = {42539005},
abstract = {INTRODUCTION: The biomarker-based amyloid/ tau/ neurodegeneration (A/T/N) framework has become a popular staging method for Alzheimer's disease (AD) research. Previous studies use the framework either as a rule-based or data-driven approach but typically sacrifice either adaptivity or interpretability.<br><br>METHODS: We present an interpretable, hybrid method, called Neurosymodal Data Fusion, for predicting incident AD in the ADNI dataset. Specifically, we encode the A/T/N framework as a logic program, where the input biomarker features are extracted by one or more neural networks.<br><br>RESULTS: Our pipeline predicted four-year incident AD with a sensitivity of up to 0.84. Additionally, our models learned scores for each A/T/N profile, denoting relative importances to model predictions. These scores also indicated that empirically-derived cut-off values for the A and T criteria might be uninformative for the ADNI data.<br><br>DISCUSSION: Our pipeline provides a novel way to use the A/T/N framework that could potentially improve early AD screening years before clinical manifestations.},
}
@article {pmid42539013,
year = {2026},
author = {Stark, D and Shin, H and Münster, N and Federmann, L and Ritter, K and , },
title = {What Do Persistent Misclassifications Tell Us About Alzheimer's Disease Detection using Structural MRI?.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.17.26358326},
pmid = {42539013},
abstract = {Deep learning classifiers applied to structural MRI (sMRI) have achieved high performance in detecting Alzheimer's Disease (AD), yet systematic investigation of their failure modes remains limited. In this study, we trained two deep learning architectures to classify AD from cognitively normal (CN) participants using sMRI data from the ADNI dataset, and examined whether misclassifications persist across models and training configurations. We identified a subgroup of subjects who were persistently misclassified across 100 model instances, and found that these subjects exhibited a markedly different atrophy subtype distribution compared to correctly classified AD cases, with substantial enrichment of hippocampal-sparing and minimal atrophy subtypes. To disentangle whether persistent false negatives (FN) reflect earlier disease stage or atypically presenting disease, we analyzed longitudinal follow-up scans and tested whether model predictions changed as neurodegeneration progressed. A change in prediction (from FN to true positive (TP)) was observed in only a subgroup of subjects and required intervals of up to five years, suggesting that persistent misclassification may not always be explained by disease staging alone. Although the sample size is small, these findings underscore the importance of accounting for disease heterogeneity in the development and evaluation of clinical AI models for AD detection.},
}
@article {pmid42539024,
year = {2026},
author = {Yang, C and Cook, N and Zeng, Y and Fu, T and Budde, J and Cruchaga, C and Belloy, ME},
title = {LocusBlend: Flexible multi-index regional visualization of genomic association signals.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
pmid = {42539024},
abstract = {SUMMARY: It has become standard practice to visualize regional signals from genome-wide association studies (GWAS) using LocusZoom plots. Similarly, GWAS signals are compared to regionally matched quantitative trait loci (QTLs), i.e. variant-to-gene regulation data, using LocusCompare plots to aid assessment of candidate trait-related genes. Despite broad usage, these tools annotate variants by linkage disequilibrium (LD) to a single lead or index variant. This single-index representation has limitations for visualizing complex loci that contain multiple independent signals. We present LocusBlend, an interactive web application for multi-index LD-blended visualization of genomic loci. LocusBlend supports one or two genomic association summary-statistic datasets and one to three index variants, multi-index LocusZoom color-blended plots, and matching LocusCompare visualizations. Applications to Alzheimer's disease GWAS and QTL signals illustrate LocusBlend enables visualization and separation of independent signals despite shared LD and high genomic complexity. Overall, LocusBlend is aimed at supporting researchers handle the continuously expanding complexity of human genomics findings.<br><br>LocusBlend is freely available at https://locusblend.wustl.edu . Publication ready plots are generated in <1min. Source code, documentation, example datasets, input templates, and reproducibility instructions are available at https://github.com/Belloy-Lab/LocusBlend . LocusBlend is implemented in Python using Streamlit, Plotly, and PLINK.<br><br>SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.},
}
@article {pmid42539043,
year = {2026},
author = {Krogsaeter, EK and McKetney, J and Li, L and Liu, I and Richards, AL and Subramanyam, V and Yin, K and Gordon, M and Belio Mairal, P and Stevenson, EJ and Qian, H and Huang, Y and Goodarzi, H and Krogan, NJ and Swaney, DL},
title = {APOE4 disrupts the central dogma by arresting neuronal proteome dynamics.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.15.738801},
pmid = {42539043},
issn = {2692-8205},
abstract = {Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer's disease and promotes neuronal dysfunction through incompletely understood mechanisms. Here, we integrated transcriptomic, translatomic, and proteomic profiling of isogenic APOE3 and APOE4 human iPSC-derived neurons and found that APOE4 fundamentally impairs neuronal proteome renewal. Although transcriptional changes were modest, APOE4 disrupted ribosome occupancy, altered translational dynamics, and uncoupled protein abundance from transcript levels. Proteome-wide turnover measurements revealed a global extension of protein half-lives and widespread accumulation of long-lived proteins. Functional proteomic analyses demonstrated concurrent lysosomal and proteasomal impairments associated with reduced proteasome activity and increased association of APOE with neuronal proteasomes. Longitudinal proteomics further showed that protein accumulation emerges during neuronal maturation and precedes a senescence-like cellular stress state. Together, these findings identify impaired proteome renewal as a central mechanism underlying neuronal vulnerability to APOE4 and establish defective proteostasis as an early pathogenic event in Alzheimer's disease.},
}
@article {pmid42539046,
year = {2026},
author = {Wang, H and Matei, E and Dou, J and Morgan, RK and Colacino, J and Bakulski, KM},
title = {Cell composition, transcriptomic, and functional pathway changes in the hippocampus in Alzheimer's disease and overlap with lead (Pb) exposure signatures.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.21.26358590},
pmid = {42539046},
abstract = {BACKGROUND: Lead (Pb) is associated with Alzheimer's disease (AD); however, the relationships between Pb and AD hippocampal transcription remains unclear. We evaluated overlap between Pb-response signatures and cell-type-independent AD transcriptomic signatures.<br><br>METHOD: Three toxicology studies (two neuronal cell lines, one mouse hippocampus) provided Pb-response genes. Five human postmortem hippocampal AD case-control transcriptional datasets (n=90 AD, n=106 normal cognition) were cell type deconvoluted and tested with beta regression. Differential gene expression, adjusted for age, sex, and estimated cell-types, were meta-analyzed. Overlapping Pb and AD genes and biological pathways were identified (p adj <0.05).<br><br>RESULTS: Consistent Pb response was observed at 25 genes (INPP5F , KIF20B , KIFC1) and 47 pathways (ensheathment of neurons, glial cell differentiation, regulation of nervous system processes). Relative to controls, AD samples had fewer neurons (-2.46%), greater microglia (0.42%), astrocytes (0.31%), oligodendrocytes (0.46%), and endothelial cells (0.95%), and 1,455 differentially expressed genes, which were enriched for cellular energy production and metabolism pathways. Six genes (EHD3 , LAP3 , NRXN3 , PPP1R16B , RPL29 , THRA) and four pathways (synaptic vesicle maturation, vesicle docking) overlapped between Pb and AD.<br><br>CONCLUSION: We identified overlapping Pb and AD transcriptomic signatures and pathways, providing molecular context for epidemiologic associations.},
}
@article {pmid42539058,
year = {2026},
author = {Bos, L and van Nederpelt, DR and Cole, JH and Jasperse, B and Meije Wink, A and Tranfa, M and Strijbis, E and Killestein, J and Uitdehaag, BMJ and Barkhof, F and Vrenken, H and Schoonheim, MM and Pontillo, G},
title = {The value of brain age as a transdiagnostic biomarker of neurodegeneration.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.21.26358569},
pmid = {42539058},
abstract = {Progressive structural brain changes are a hallmark of neurodegenerative conditions like Alzheimer's disease (AD), frontotemporal dementia (FTD), multiple sclerosis (MS), and Parkinson's disease (PD). The brain-predicted age difference (brain-PAD) has emerged as a promising biomarker to quantify these alterations, yet its unique clinical contribution relative to conventional measures of global brain atrophy such as the brain parenchymal fraction (BPF) remains underexplored. In this transdiagnostic study across AD, FTD, MS, and PD, we systematically evaluated brain-PAD's capacity to distinguish patients from controls, its cross-sectional and longitudinal associations with cognition, and its voxel-wise structural correlates. We benchmarked brain-PAD against BPF to determine its added explanatory value. Brain-PAD successfully distinguished patients from controls, adding to BPF alone, in AD, FTD, and MS, but not PD. Across disorders, higher brain-PAD correlated with worse cognition, showing clear added value beyond BPF particularly in AD and MS. Baseline brain-PAD also independently predicted subsequent cognitive changes in AD, FTD, and MS, over and above BPF. Voxel-wise analyses revealed spatial features underlying brain-PAD including, beyond global tissue loss, specific regional atrophy matching each disease's characteristic pattern. Collectively, these findings demonstrate that brain-PAD is a clinically meaningful, transdiagnostic biomarker of neurodegeneration that complements conventional volumetric measures like the BPF.},
}
@article {pmid42539062,
year = {2026},
author = {Ambaw, Y and Nana, A and Li, Z and Singh, S and Monetti, M and Miller, B and Spina, S and Grinberg, L and Seeley, W and Walther, T and Farese, R},
title = {Shared lipidome and proteome signatures of frontotemporal lobar degeneration and Alzheimer's disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10305293/v1},
pmid = {42539062},
issn = {2693-5015},
abstract = {Frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD) differ in their clinical features and genetic etiologies but share progressive cognitive decline. Emerging evidence implicates lipid dysregulation in neurodegeneration, but its extent across FTLD subtypes and how it compares to AD are unclear. Here, we performed integrated lipidomic and proteomic analyses of matched frontal (disease-vulnerable) and occipital (relatively spared) post-mortem cortices from individuals with genetic and sporadic FTLD-TDP, FTLD-tau (Pick's disease, PiD), AD, and controls. FTLD and AD exhibited convergent lipid alterations, including reduced levels of cardiolipins and phosphatidylethanolamines, alongside increased gangliosides, diacylglycerols, cholesterol esters, acylcarnitines, and coenzyme Q, with generally greater changes in FTLD frontal cortex. FTLD displayed additional alterations, including reductions in bis(monoacylglycerol)phosphate, ceramides, phosphatidylserines, phosphatidylinositols, and sulfatides. These lipid changes were accompanied by proteomic alterations involving lysosomal proteins, phospholipases, phospholipid remodeling enzymes, and fatty acid oxidation pathways. Although lipidomic and proteomic signatures were broadly shared across FTLD subtypes, GRN associated FTLD-TDP and PiD showed the most extensive alterations. Triglycerides were selectively reduced in PiD in association with decreased DGAT1 expression, whereas cholesterol esters were elevated across all subtypes except C9orf72 associated FTLD-TDP. These findings identify shared disruptions in lipid homeostasis and lysosomal lipid metabolism across FTLD and AD, highlighting convergent metabolic pathways underlying neurodegeneration.},
}
@article {pmid42539070,
year = {2026},
author = {Doherty, LK and Dechiario, I and Sherif, H and Bowers, A and Martinez, D and Sanchez, DL and Febres, GJ and Carmichael, O and Shah, V and Nadkarni, NK and Goldberg, TE and Noble, J and Luchsinger, JA and Temprosa, M and , },
title = {Implementing the National Alzheimer's Coordinating Center Uniform Data Set (v3) within the Diabetes Prevention Program Outcomes Study.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.17.26357765},
pmid = {42539070},
abstract = {INTRODUCTION: The Diabetes Prevention Program (DPP) was a randomized clinical trial designed to prevent type 2 diabetes (T2D) in adults with prediabetes. The DPP Outcomes Study (DPPOS) is the 30-year follow-up of this cohort, focusing on T2D, prediabetes, and related complications. Cognitive assessments began in 2009 and expanded in 2022 to examine cognitive impairment, including Alzheimer's disease (AD) and AD related dementias (ADRD), in the surviving cohort. To support these aims, the National Alzheimer's Coordinating Center Uniform Data Set version 3 (NACC-UDSv3), the standardized framework used by Alzheimer's Disease Research Centers, was implemented in DPPOS in 2022 to enable data sharing with NACC. These forms were complemented by cognitive tests administered in DPPOS. We aimed to integrate the NACC-UDSv3 into the existing longitudinal DPPOS framework while maintaining fidelity to its structure and developing automated reports to streamline cognitive outcomes adjudication.<br><br>METHODS: Items from the 16 NACC-UDSv3 data forms were compared with those already collected within DPPOS to integrate overlapping similar items, add missing NACC-UDSv3 items, and create a dataset harmonized with NACC-UDSv3. Forms were adapted for electronic data capture (EDC) using the MIDAS (Multimodal Integrated Data Acquisition System, George Washington University). Automated reports integrated current and prior neuropsychological scores to support adjudications. In the first wave of the DPPOS-AD/ADRD study, 1561 cognitive adjudications were successfully completed using the harmonized DPPOS and NACC-UDSv3 data implemented into MIDAS.<br><br>DISCUSSION: The DPPOS-AD/ADRD project demonstrated that NACC-UDSv3 can be successfully integrated into a long-standing longitudinal cohort not originally designed for AD/ADRD research. The harmonization, electronic capture, and automated adjudication processes may provide a practical framework for other cohorts seeking to incorporate NACC-UDSv3 to align with national AD/ADRD research standards.},
}
@article {pmid42539099,
year = {2026},
author = {Rabin, J and Alexander, MW and Nyman, A and Casaletto, K and Saloner, R and Vandeloo, K and Splinter, T and Swardfager, W and Ottoy, J and Masellis, M and Galea, L and Black, S and Einstein, G and Denkinger, M and Ashton, N and Caldwell, J and Johnson, S and Arvanitakis, Z},
title = {Age at menopause, APOE-ε4, and Alzheimer's disease risk.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10121551/v1},
pmid = {42539099},
issn = {2693-5015},
abstract = {Importance: APOE-ε4 is an established risk factor for Alzheimer's disease (AD) and confers greater risk in women than in men. Earlier age at menopause also increases AD risk in women. Yet whether menopause timing influences APOE-ε4 -related AD risk remains unclear. Objective: To examine whether age at menopause modifies the association of APOE-ε4 with AD risk. Design, setting and participants: Data were analyzed from postmenopausal women free from known dementia at study entry in two longitudinal datasets: (1) the harmonized data from the Religious Orders Study, Rush Memory and Aging Project, and Minority Aging Research Study (ROS/MAP/MARS), and (2) the Wisconsin Registry for Alzheimer's Prevention (WRAP). Data were collected between 1994-2025. Main outcomes and measures: In both datasets, neuropsychological tests assessed longitudinal memory performance, and MRI quantified cortical thickness and brain volume in AD vulnerable regions. In WRAP, which included in vivo AD biomarkers, AD pathology was assessed using longitudinal plasma p-tau217 and cross-sectional beta-amyloid (Aβ) PET. Menopause history was self-reported, and APOE status was classified as ε4 carrier vs. non-carrier. Linear mixed-effects or linear regression models were used, as appropriate, to test interactions between APOE-ε4 carrier status and age at menopause on memory decline, brain atrophy, p-tau217 accumulation, and Aβ-PET burden, adjusting for relevant covariates. Results: The study included 2,625 women in ROS/MAP/MARS (mean [ SD ] age=77.4 [7.77], mean [SD] age at menopause=47.9 [7.10]) and 512 women in WRAP (mean [SD] age=60.2 [5.57], mean [SD] age at menopause=50.1 [6.29]). In both datasets, earlier age at menopause strengthened associations of APOE-ε4 with memory decline (ROS/MAP/MARS: β=0.068, p =.02; WRAP: β=0.092, p =.03) and MRI measures of brain atrophy (ROS/MAP/MARS: β=0.071, p =.05; WRAP: β=0.256, p =.03). In WRAP, earlier menopause also amplified associations of APOE-ε4 with p-tau217 accumulation (β=-0.029, p =.05) and global Aβ-PET burden (β=-0.146, p =.01). Conclusions and relevance: Earlier menopause strengthened the associations between APOE -ε4 and key AD outcomes. These findings suggest that menopause timing may influence APOE -ε4-related susceptibility to AD, highlighting midlife endocrine processes as potential targets for prevention in women.},
}
@article {pmid42539115,
year = {2026},
author = {Tewolde, S and Rosellini, AJ and Michals, A and Skotko, BG and Fortea, J and Khor, B and Handelman, S and Rubenstein, E},
title = {Death in People with Down syndrome: Mortality statistics and novel predictors in US Medicaid and Medicare enrolled adults.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.17.26358090},
pmid = {42539115},
abstract = {People with Down syndrome have higher age-specific mortality rates compared to the general population as well as peers with other intellectual and developmental disabilities. While a large proportion of mortality is attributable to Alzheimer's disease, many die prior to Alzheimer's diagnosis and some live to old ages, dying without Alzheimer's. Our objectives were to use 11 years of Medicaid and Medicare data to describe characteristics and factors related to death in adults with Down syndrome and use machine learning to identify which conditions most strongly predict death in the full population and stratified by age. We identified death using Center for Medicare and Medicaid Systems reported date of death health conditions using ICD 9 and 10 codes. We used a case-control design with risk set sampling to have that controls to mimic the distribution of times of incident Alzheimer's disease. We trained gradient boosted trees to identify strongest predictors. Our cohort included 137,293 adults with Down syndrome. Among those, 30,894 (22.5%) died during the study period. Mean age at death among those who died was 55 years (SD=10). Mean age of death in those with Alzheimer's disease was 59 (SD=7) and those without was 52 (SD=12). The most influential predictors of mortality were any claim for dementia, any claim for pneumonia, re-occurring claim for cardiovascular disease three years before index death, and any claim for heart failure and epilepsy. Our results align with previous clinical work and highlight intervenable areas to reduce mortality in the Down syndrome population.},
}
@article {pmid42539145,
year = {2026},
author = {Brown, K and Storey, B and Williams, J and Simet, D and Umar, MB and Madsen, E and Shan, Z and Bi, L},
title = {Spatial MALDI-MSI Reveals a Coordinated Vicious Cycle of Oxidative Membrane Damage and Ceramide-Driven Sphingolipid Dysregulation in the Chronically Neuroinflamed Brain.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.14.738110},
pmid = {42539145},
issn = {2692-8205},
abstract = {BACKGROUND: Chronic neuroinflammation is a major driver of cognitive decline, vascular cognitive impairment, and Alzheimer's disease. However, the spatial lipidomic alterations underlying neuroinflammatory brain injury remain poorly defined. Oxidative stress and sphingolipid dysregulation have been implicated, but their regional distribution and interplay in the brain are not well characterized.<br><br>METHODS: We performed positive-ion mode matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) on coronal brain sections from middle-aged spontaneously hypertensive rats (SHR), a model of chronic neuroinflammation, and normotensive Wistar-Kyoto (WKY) controls. Spatial distributions and relative abundances of multiple lipid classes, including phosphatidylcholines (PCs), sphingomyelins (SMs), hexosylceramides (HexCers), ceramides, phosphatidylserines (PSs), phosphatidylinositols (PIs), phosphatidylethanolamines (PEs), phosphatidic acids (PAs), and sulfatides, were mapped and compared between genotypes. Region-of-interest analysis was used to quantify changes across cortex, hippocampus, and white-matter tracts.<br><br>RESULTS: SHR brains exhibited a coordinated lipidomic signature characterized by pronounced oxidative stress and membrane remodeling. Oxidized and short-chain PCs were markedly upregulated (up to 11.6-fold), while major structural diacyl PCs were broadly downregulated. Concurrently, sphingolipids were significantly altered, with robust upregulation of SM(d36:1) (7.5-fold) and multiple HexCer species (1.5-1.9-fold), accompanied by accumulation of ceramides. These changes were accompanied by heterogeneous redistribution of PS, PI, and PE species, particularly within the hippocampus. Sulfatide patterns in white-matter tracts were also altered, suggesting myelin remodeling. Region-of-interest analysis confirmed that the most pronounced lipid alterations were concentrated in the hippocampus and white-matter regions.<br><br>CONCLUSIONS: Chronic neuroinflammation induces a spatially organized, multi-class lipid remodeling response in the brain, driven by advanced oxidative membrane damage and a shift toward a pro-apoptotic sphingolipid profile. The convergence of these pathways creates a vicious cycle of membrane injury, mitochondrial dysfunction, and sustained neuroinflammation that is especially prominent in the hippocampus and white matter. These spatially resolved findings provide direct evidence that oxidative stress and sphingolipid dysregulation are central, interrelated mechanisms contributing to neurovascular injury and increased risk of cognitive impairment. The study highlights the power of MALDI-MSI to uncover region-specific lipid pathology and identifies potential lipid-based targets for therapeutic intervention in neuroinflammatory brain disease.},
}
@article {pmid42539244,
year = {2026},
author = {Wagle, MM and Wang, Y and Samanta, S and Liu, Z and Patrick, E and Yang, P and Kellis, M},
title = {Deep interpretable learning of sample representations for characterizing disease states in single-cell transcriptomics.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.21.738207},
pmid = {42539244},
issn = {2692-8205},
abstract = {Single-cell transcriptomics technology offers unprecedented insights into molecular heterogeneity. However, capturing sample-level representations that reflect both systemic and cellular states remains challenging, especially when disease annotations are mostly available as coarse sample-level labels. Here, we introduce Phenoverse, an interpretable deep learning framework that learns sample-level disease state representations through cell type-aware residual encoding, prototype learning, and Perceiver-based aggregation. Applied to independent single-cell transcriptomic cohorts of COVID-19, Alzheimer's disease, and systemic lupus erythematosus, totaling over 5 million cells, we demonstrate that learned sample representations enable disease state prediction and encode a continuous spectrum of disease severity on unseen data that correlate with multiple clinical and pathological measures, despite being trained solely on binary phenotype labels. Further, we demonstrate that trajectory-derived genes reveal cross-cohort molecular programs and show consistently higher reproducibility than traditional case-control comparisons. Finally, prototype learning provides intrinsic model interpretability and enables the characterization of cell type-specific disease states. Taken together, Phenoverse offers an interpretable disease-phenotyping approach to dissecting sample heterogeneity, and our results highlight its utility in translating complex single-cell transcriptomic data into patient-level biological insights.},
}
@article {pmid42539274,
year = {2026},
author = {Javid, S and Nir, TM and Zhu, AH and Bhatt, RR and Aksman, LM and Jahanshad, N and , },
title = {FastEBM: Fast, Scalable, and Uncertainty-Aware Event-Based Disease Progression Modeling.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.18.739221},
pmid = {42539274},
issn = {2692-8205},
abstract = {Event-based models (EBMs) are used to infer ordering of biomarker alteration patterns with respect to disease progression. However, EBM approaches rely on computationally expensive permutation-based inference, assumptions of feature independence, and likelihood optimization that can limit scalability and stability in high-dimensional settings. Here, we introduce Fast Event-Based Model (FastEBM), a scalable, uncertainty aware, Markov- chain-based framework that reformulates disease progression inference as a subject-ordering problem on a data-driven diffusion manifold. The progression uncertainty, used to derive positional variance diagrams, is quantified using first-passage-time variability derived directly from the inferred Markov process. Using synthetic experiments varying feature dimensionality, cohort size, noise level, and feature-correlation structure, we compared FastEBM with established methods, including Gaussian mixture model EBM (GMM-EBM), kernel density estimation EBM (KDE-EBM), and discriminative EBM (DEBM). FastEBM achieved the best accuracy and runtime. In low-subject/high-dimensional stress tests, FastEBM retained event-order recovery. FastEBM remained robust in simulations containing correlated and redundant features after decorrelation and feature-group handling. We applied FastEBM to real-world data to characterize biomarker progression in Alzheimer's disease. First, we evaluated a low-dimensional multi- modal dataset from The Alzheimer's Disease Prediction Of Longitudinal Evolution (TAD- POLE) challenge. Second, to demonstrate high-dimensional disease progression mapping, we applied FastEBM to regional cortical tau-PET data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). In both cases, FastEBM recovered progression patterns broadly consistent with the literature, also revealing lateralized progression trends. These results show that diffusion-based Markov geometry provides a scalable and robust alternative to conventional event-based modeling. FastEBM is available at: https://github.com/sjusc07/FastEBM .},
}
@article {pmid42539283,
year = {2026},
author = {Chattopadhyay, T and Shelar, K and Thomopoulos, S and Thompson, PM},
title = {When does more data help? Spectral Geometry and Scaling Laws in MRI Transformers.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.14.738571},
pmid = {42539283},
issn = {2692-8205},
abstract = {Scaling laws describe how model performance improves as the amount of training data increases, and recent theories such as the zeta law suggest that scaling behavior is influenced by the eigenspectrum of the model's latent representation. Here, we evaluated whether the distribution of discriminative signals across spectral modes predicts the future scaling behavior, for MRI transformers trained for disease classification. We trained three supervised 3D vision transformers (ViT3D, MINiT, and NIT) for Alzheimer's disease classification using 2,822 training scans from the Alzheimer's Disease Neuroimaging Initiative (ADNI); we compared their encoder spectra with that of a frozen self-supervised DINO ViT-B/16 encoder adapted to 3D MRI. The supervised models learned highly concentrated representations, with 90-96% of CLS-token variance captured by a single principal component, whereas DINO distributed signal across many latent directions. Via spectral expansion of the Mahalanobis signal, we found that supervised training concentrated disease information into a single dominant mode, while self-supervised training produced a richer spectral geometry with higher effective rank and discoverability. This led to different scaling behavior: supervised models exhibited flatter AUC(N) curves, yet DINO continued to improve as sample size increased, gaining 11.0 percentage points from N=50 to N=2,822. Overall, the spectral distribution of the discriminative signal, for these different encoder types, influenced how much performance remained discoverable as sample size increased. Distributed representations may retain signal across many latent modes and continue to improve with additional data, whereas concentrated representations tend to exhaust most of the discoverable signal at much lower sample sizes.},
}
@article {pmid42539361,
year = {2026},
author = {Srikanth, M and Jiang, S and Wellman, SM and Sarkar, S and Lorman, DE and Lantin, T and Runyan, AM and Kumar, M and Sydney, E and Figueroa, HY and Yang, M and Wang, Q and Myeku, N},
title = {Immunoproteasome Deficiency Impairs Microglial Clearance and Worsens Tau and Amyloid Pathology.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.14.738427},
pmid = {42539361},
issn = {2692-8205},
abstract = {Immunoproteasome induction is prominent in Alzheimer's disease (AD), but whether it protects proteostasis or amplifies neuroinflammation remains unresolved. Here, we generated immunoproteasome-deficient PS19 tauopathy and APP/human tau double-knock-in mice by crossing each disease model with L7M1 mice lacking two immunoproteasome catalytic subunits. Immunoproteasome deficiency increased phospho-tau burden, exacerbated amyloid-β pathology and heightened microglial reactivity without suppressing constitutive 26S proteasome activity. In primary microglia and longitudinal two-photon imaging, immunoproteasome-deficient microglia engaged and engulfed tau aggregate-bearing material but failed to resolve internalized cargo, revealing a post-engulfment degradative checkpoint. Single-nucleus transcriptomics identified a remodeled P2ry12 [low] /Trem2 [high] microglial state with impaired phagolysosomal and mitochondrial programs. Reanalysis of human single-nucleus transcriptomic datasets showed that reduced microglial immunoproteasome expression was associated with cargo-processing gene-program changes similar to those observed in immunoproteasome-deficient mouse microglia. Together, these findings identify immunoproteasome biogenesis as a protective glial stress response that supports microglial aggregate clearance in AD.},
}
@article {pmid42539398,
year = {2026},
author = {Liu, L and Chen, X and Zeng, Q and Zhou, S and Zhang, X},
title = {An edge-aware salient context fusion and refinement network for hippocampal segmentation in MR images and its diagnostic value for mild cognitive impairment.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1899123},
doi = {10.3389/fneur.2026.1899123},
pmid = {42539398},
issn = {1664-2295},
abstract = {BACKGROUND: Accurate assessment of hippocampal volume is of significant clinical value for the early diagnosis and disease monitoring of Alzheimer's disease (AD). However, automatic segmentation of the hippocampus in MR images remains challenging due to its elongated and irregular morphology, blurred boundaries, low contrast with surrounding tissues, and substantial inter-individual anatomical variability.<br><br>METHODS: We propose an Edge-aware Salient Context Fusion Refinement Network (ESCFR-Net). Built upon a classic U-shaped encoder-decoder architecture, the proposed network employs a Salient Feature Enhancer to suppress background interference and enhance weak feature responses of the hippocampus. A Global Channel Context Attention (GCCA) module is introduced to model long-range spatial dependencies, while a Multi-scale Context Fusion Refinement Module (MCFRM) improves the utilization of multi-scale features. Furthermore, an Edge-Guided Refinement Attention (EGRA) module synergistically enhances edge and semantic features to precisely delineate weak boundaries.<br><br>RESULTS: Experimental results on a self-constructed dataset comprising 225 3D-T1 MRI scans demonstrate that ESCFR-Net achieves a Dice coefficient of 0.9004, outperforming state-of-the-art methods such as SwinUNETR and PMFS-Net. Clinical association analysis, conducted on 91 healthy controls (HCs) and 91 patients with mild cognitive impairment (MCI), reveals that bilateral hippocampal volumes in MCI group are significantly smaller than those in HCs (p&#x202f;<&#x202f;0.001). Additionally, the total hippocampal volume achieves an area under the curve (AUC) of 0.927 in distinguishing HCs from patients with MCI, with sensitivity and specificity reaching 90.11 and 83.52%, respectively.<br><br>CONCLUSION: This study provides a highly accurate and robust automated hippocampal segmentation tool for early diagnosis, disease monitoring, and clinical decision-making in Alzheimer's disease.},
}
@article {pmid42539584,
year = {2026},
author = {Lo, H and Li, S and Chen, J and Zhou, Q and Qiu, Y and Ma, S and Yu, B and Gu, T and Nie, L},
title = {Multispectral photoacoustic microscopy and NIR-II fluorescence imaging of TREM2-positive microglia in Aβ-driven Alzheimer's pathogenesis.},
journal = {Fundamental research},
volume = {6},
number = {4},
pages = {2235-2249},
doi = {10.1016/j.fmre.2026.04.016},
pmid = {42539584},
issn = {2667-3258},
abstract = {Monitoring microglial activation mediators remains challenging in neurodegeneration. Few imaging studies track amyloid-β (Aβ)-linked microglial dynamics across a wide field of view with high spatiotemporal resolution. Leveraging the triggering receptor expressed on myeloid cells 2 (TREM2), a pivotal Alzheimer's disease (AD) biomarker that enhances Aβ clearance while suppressing neuroinflammation, we developed a dual-modal probe, TREM2-ICG, by conjugating a TREM2-specific antibody with indocyanine green (ICG), an FDA-approved dye, for robust in vivo photoacoustic and near-infrared-II (NIR-II) fluorescence imaging. Multi-wavelength photoacoustic microscopy imaged AD pathology at 532 nm (hemoglobin, vasculature), 559 nm (Aβ probe AOI987), and 780 nm (TREM2-ICG for peri‑plaque microglia). Time-resolved NIR-II imaging (30 frames/sec) tracked Aβ-oligomer-induced microglial displacement at ∼50 µm resolution, showing a rapid chemotaxis phenomenon. Immunofluorescence-verified TREM2-microglia plaque engagement demonstrates AD pathogenesis. Overall, our multiscale photoacoustic-fluorescence imaging resolved cortex-wide Aβ-microglial interactions, combining wide-field, high-speed, and deep-penetration to overcome confocal depth and two-photon field of view limits. This enabled in vivo tracking of microglial responses to Aβ, revealing potential for investigating AD-specific mechanisms.},
}
@article {pmid42539597,
year = {2026},
author = {Varrasi, S and Pulvirenti, A and Catania, V and Palesi, M and Spampinato, C and Patti, D and Tomarchio, O and Micale, G and Simone, A and Passarello, L and Proietto Salanitri, F and Patanè, G and Ravidà, S and Chisari, CG and Zappalà, G and D'Amico, E and Avolio, C and Felicetti, F and Gasperini, C and Rossi, S and Manganotti, P and Busan, P and Rodolico, C and Laudani, R and Marino, R and Villari, M and Patti, F and , and , },
title = {AI-based predictive biomarkers for chronic neurological diseases: the rAIdD prospective, multicenter, observational study protocol.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1885919},
doi = {10.3389/fneur.2026.1885919},
pmid = {42539597},
issn = {1664-2295},
abstract = {BACKGROUND: Chronic neurological disorders such as Multiple Sclerosis (MS), Parkinson's disease (PD), and Alzheimer's Disease (AD) represent a major global health burden characterized by progressive neurodegeneration, functional disability, and cognitive decline. Despite differences in etiology and clinical presentation, these conditions share multifactorial pathophysiological mechanisms influenced by genetic, environmental, and lifestyle-related factors. Advances in artificial intelligence (AI), wearable technologies, and multimodal clinical data integration offer new opportunities for identifying predictive digital biomarkers and improving personalized disease management. The rAIdD project ("eHealth Network: AI and new ICT technology equipment for digital diagnosis") aims to develop an interoperable digital infrastructure to support early diagnosis, monitoring, and risk stratification in chronic neurological diseases. This study protocol describes the neurological component of the rAIdD network focusing on MS, PD, and AD.<br><br>METHODS AND ANALYSIS: This prospective, multicenter, observational study involves six Italian academic and clinical centers and will enroll 780 participants: 300 MS, 150 PD, 150 AD, and 180 healthy controls. Participants will be followed for 18 months within a 48-month study period. Standardized clinical, neuropsychological, neuroimaging, and digital assessments will be performed at baseline and at 6-, 12-, and 18-month follow-ups. Clinical evaluation includes disease-specific disability and functional scales, mood and quality-of-life assessments, and lifestyle and environmental risk factor profiling. Continuous digital monitoring will be conducted using wearable sensors to collect biometric and behavioral data, including physical activity, sleep patterns, and cardiovascular parameters. Structural neuroimaging will be acquired longitudinally and integrated with clinical and digital data through a centralized web-based electronic data capture platform. Machine learning approaches will be applied to identify multimodal predictive biomarkers and model disease progression patterns across disorders.<br><br>ETHICS AND DISSEMINATION: The study has been approved by the Ethics Committee of the coordinating center and by local ethics committees of all participating institutions. Written informed consent is obtained from all participants in accordance with the Declaration of Helsinki and the General Data Protection Regulation (GDPR 2016/679). Results will be disseminated through peer-reviewed publications, scientific conferences, and digital communication platforms to support knowledge translation and implementation of precision neurology approaches.},
}
@article {pmid42539626,
year = {2026},
author = {Han, J and Zhao, W and Deng, R and Wang, Y and Gong, W and Wang, Z and Sun, G and Liu, H and Geng, M and Zhang, Y},
title = {Sodium oligomannate reduces cerebral infarction and improves neurological function through microbiota remodeling in MCAO/R rats.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1880590},
doi = {10.3389/fphar.2026.1880590},
pmid = {42539626},
issn = {1663-9812},
abstract = {BACKGROUND: Ischemic stroke is the second leading cause of death worldwide, characterized by high mortality and a narrow therapeutic window for thrombolysis. Gut microbiota dysbiosis and gliosis following ischemic stroke are key drivers of post-stroke neurological impairment. Sodium oligomannate (GV-971) is a low-molecular-weight acidic oligosaccharide that targets the gut-brain axis. It alleviates gliosis and improves cognitive dysfunction by remodeling gut microbiota in Alzheimer's disease. However, it is still unknown whether GV-971 has pharmacological activity against ischemic stroke.<br><br>METHODS: Here, we explore the efficacy of GV-971 on infarct volume, gliosis, blood-brain barrier integrity, gut microbiota composition, and post-stroke cognitive impairment (PSCI) using a middle cerebral artery occlusion/reperfusion (MCAO/R) model in male Sprague-Dawley rats.<br><br>RESULTS: Administer medication before surgery for 4 consecutive days and once after surgery, after stroke 24-hour triphenyltetrazolium chloride (TTC) staining revealed that 0.3 mg/kg GV-971 significantly reduced infarct volume in ischemic brain tissue from 37.81&#xb1;2.391% to 13.30&#xb1;4.801% and neurological impairment score of GV-971 treatment significantly decreased from 11.50&#xb1;0.54 to 7.29&#xb1;1.47. After stroke 24-hour immunofluorescence analysis of glial activation confirmed that GV-971 significantly reduced central inflammatory responses. Western blot combined with Evans blue staining collectively demonstrated that after stroke 24-hour, GV-971 exerts a significant protective effect on the blood-brain barrier. In the gut, GV-971 reversed microbial dysbiosis, as revealed by shotgun metagenomics, enhanced intestinal barrier integrity, and suppressed colonic inflammation. Antibiotic depletion abolished GV-971's neuroprotective effect, while fecal microbiota transplantation from GV-971-treated donors restored protection, supporting a microbiota-dependent contribution. Furthermore, GV-971-treated rats subjected to MCAO/R exhibited significant improvements in motor and cognitive function. For example, on day 35, Y-maze test results indicated that GV-971 administered either before MCAO/R (pre-treatment) or during the perioperative period (co-treatment) increased spontaneous alternation rate from 60.95&#xb1;4.91% to 85.60&#xb1;6.32% and 85.64&#xb1;5.027%. On day 32, novel object recognition assay results indicated that GV-971 treatment increased new-object exploration from 0.2039&#xb1;0.03752 to 0.3991&#xb1;0.1122 (pre-treatment) and 0.5066&#xb1;0.06982 (co-treatment). On day 42, Barnes maze test results indicated that GV-971 treatment reduced the time required to locate the target hole from 76.45&#xb1;17.41s to 31.03&#xb1;20.75&#x2009;s and 33.37&#xb1;19.30&#x2009;s for pre- and co-treatment, respectively.<br><br>CONCLUSION: Taken together, GV-971 demonstrated neuroprotective potential in experimental ischemic stroke.},
}
@article {pmid42539875,
year = {2026},
author = {Luo, Y and Yu, H and Ye, K},
title = {Distinct factors drive the progression of tau pathology in Alzheimer's disease.},
journal = {Fundamental research},
volume = {6},
number = {4},
pages = {2289-2298},
doi = {10.1016/j.fmre.2025.04.001},
pmid = {42539875},
issn = {2667-3258},
abstract = {Alzheimer's disease (AD) is the most common cause of dementia worldwide. The primary histopathological markers for AD diagnosis are extracellular amyloid plaques and intracellular neurofibrillary tangles (NFTs), featured by aggregation of hyperphosphorylated and truncated tau proteins. Emerging evidence shows that tau pathology, rather than amyloid-β deposition, exhibits a stronger correlation with brain atrophy and cognitive decline in AD, emphasizing its pivotal role in disease progression. However, the molecular mechanisms of tau propagation in the brain are incompletely understood, and there is no effective therapy to halt tau pathology propagation in AD. In this review, we summarize current knowledge on the multifactorial triggers of tau pathology in AD in the aspects of (1) physiological or pathological driving factors, (2) different types of brain cells and (3) key regulatory proteins that steer tau aggregation and spread. Based on these findings, we also critically evaluate the current and potential therapeutic strategies against tau pathology in AD. Together, this review provides a comprehensive understanding of tau pathology regulation and highlights promising strategies for therapeutic intervention.},
}
@article {pmid42539876,
year = {2026},
author = {Singh, R and Asthana, S and Arya, A and Kaushik, M and Khan, M},
title = {The Oral-Brain Axis: Mechanistic Insights Linking Periodontitis With Alzheimer's and Parkinson's Diseases.},
journal = {Cureus},
volume = {18},
number = {6},
pages = {e111856},
doi = {10.7759/cureus.111856},
pmid = {42539876},
issn = {2168-8184},
abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), are major causes of disability and mortality worldwide. Emerging evidence suggests that chronic peripheral inflammation and microbial dysbiosis may contribute to neurodegenerative processes. The oral-brain axis has recently gained attention as a biological framework linking oral microbial communities, systemic inflammatory responses, immune regulation, and central nervous system function. Within this context, periodontitis, a prevalent chronic inflammatory disease driven by oral dysbiosis, has been proposed as a potential modifiable risk factor for neurodegeneration. This narrative review examines current evidence supporting the oral-brain axis and its role in the relationship between periodontitis and neurodegenerative disorders. Key mechanisms include systemic dissemination of periodontal pathogens and their virulence factors, persistent inflammatory signaling, blood-brain barrier dysfunction, neuroimmune activation, oxidative stress, and protein aggregation. Particular attention is given to the contribution of Porphyromonas gingivalis and associated virulence factors to neuroinflammation, amyloidogenesis, and neuronal injury. Epidemiological, clinical, and experimental studies linking periodontal disease with cognitive decline, Alzheimer's disease, and Parkinson's disease are also discussed. Current evidence supports a biologically plausible association between periodontal disease and neurodegeneration through interconnected microbial, inflammatory, and vascular pathways. Although causality remains to be established, the oral-brain axis provides valuable insight into potential mechanisms underlying this relationship. Improved understanding of these interactions may facilitate the development of preventive and therapeutic strategies that integrate oral healthcare with approaches aimed at preserving neurological health and reducing the burden of neurodegenerative diseases.},
}
@article {pmid42540036,
year = {2026},
author = {Chan, AM and Ng, R and Inderjeeth, C and Nossent, J},
title = {Temporal incidence and impact of dementia in rheumatoid arthritis: a cohort study.},
journal = {EULAR rheumatology open},
volume = {2},
number = {2},
pages = {100159},
doi = {10.1016/j.ero.2026.03.007},
pmid = {42540036},
issn = {3050-7081},
abstract = {OBJECTIVES: The objective of this study is to address conflicting evidence that chronic inflammation may increase the risk of dementia in patients with rheumatoid arthritis (RA).<br><br>METHODS: Retrospective population-based study using longitudinally linked administrative health data over a 30-year period for ever hospitalised patients with RA (n = 14,041, age 64 years, 67.2% female) and controls (n = 33,785, age 65 years, 65.6% female). Dementia was defined by the International Classification of Diseases codes for Alzheimer's disease (AD), vascular dementia, and nonspecific dementia subtypes. Dementia incidence rate (IR) and mortality rate (MR) per 1000 person-years and comorbidities are reported.<br><br>RESULTS: During 9.6 years of follow-up, 1463 (10.4%) of patients with RA and 3701 (11%) of controls were diagnosed with dementia at respective age of 83 vs 84 years (P = .01). The IR was 12.07 (95% CI: 11.15-12.71) in patients with RA and 11.59 (95% CI: 11.22-11.97) in controls corresponding to an IR ratio of 1.04 (95% CI: 0.98-1.11, P = .21), which did not change significantly over 3 decades. Traditional risk factors for dementia were equal in both groups, but patients with RA with dementia were less likely to be classified as AD (odds ratio = 0.59, 95% CI: 0.48-0.73, P < .001). Hospitalisation rates after dementia diagnosis were higher for patients with RA, and the crude MR (overall 91.8 vs 90.4, P = .64) remained similar before or after 2000 for both groups.<br><br>CONCLUSIONS: There was no difference in temporal incidence and MRs for dementia between patients with RA and matched controls. These data suggest that there is minimal impact of RA on the frequency and outcome of dementia.},
}
@article {pmid42540093,
year = {2026},
author = {Floden, AM and Manocha, GD and Frolov, NI and Lerick, AE and Combs, CK},
title = {Comparison of amyloid and tau pathology in the small and large intestines of individuals with Alzheimer's disease, Parkinson's disease, and Dementia with Lewy bodies.},
journal = {microPublication biology},
volume = {2026},
number = {},
pages = {},
doi = {10.17912/micropub.biology.002056},
pmid = {42540093},
issn = {2578-9430},
abstract = {Alzheimer's disease (AD) brains are characterized by accumulations of neurofibrillary tangles and amyloid β (Aβ) plaques. Since enteric neurons express tau and the amyloid precursor protein (APP), we asked whether neurofibrillary tangles and Aβ aggregates were present in AD intestines compared to healthy controls and individuals with Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB). Neuron-like APP and Aβ immunoreactivities were observed in all groups with no observable plaques. No tangle-like structures were observed in any group although p-Ser 396/404 tau immunoreactivity was seen. The enteric nervous system appears to be protected from developing tangle and plaque pathology in AD.},
}
@article {pmid42540265,
year = {2026},
author = {Taşci, H and Avcı, A and Özenver, N and Sağlık Özkan, BN and Tozkoparan, B and Kelekçi, NG},
title = {Benzoxazolinone-Based Propionyl Thiosemicarbazides as Multi-Target-Directed Ligands for Alzheimer's Disease: Cholinesterase and MAO Inhibition, Docking, and Molecular Dynamics.},
journal = {ACS omega},
volume = {11},
number = {29},
pages = {43129-43156},
doi = {10.1021/acsomega.5c12925},
pmid = {42540265},
issn = {2470-1343},
abstract = {Alzheimer's disease (AD) benefits from multitarget-directed ligands (MTDLs) that can enhance cholinergic transmission while attenuating monoamine-oxidase-linked oxidative stress. Here, we report a benzoxazolinone-based propionyl thiosemicarbazide series, synthesized and fully characterized by infrared (IR) spectroscopy, [1]H nuclear magnetic resonance (NMR), and high-resolution mass spectra (HRMS). The compounds showed consistent submicromolar inhibitory activity across AChE, BChE, MAO-A, and MAO-B in vitro. Several AChE potencies approached the reference donepezil, and selected BChE activities were within an order of magnitude of tacrine. Notably, 4bk' (5-Me/benzyl) inhibited three targets (IC50: 0.029 ± 0.001 μM for AChE, IC50: 0.071 ± 0.003 μM for BChE, IC50: 0.048 ± 0.002 μM for MAO-B), and 4af' (5-Cl/phenyl) showed a balanced profile (IC50: 0.025 ± 0.001 μM for AChE, IC50: 0.056 ± 0.002 μM for BChE, IC50: 0.095 ± 0.003 μM for MAO-A), 4ac' (5-Cl/propyl) combined potent AChE and MAO-B inhibition (IC50: 0.035 ± 0.001 μM for AChE, IC50: 0.045 ± 0.002 μM for MAO-B), whereas 4ag' (5-Cl/4'-Cl-phenyl) was strongly MAO-B-selective (IC50: 0.041 ± 0.001 μM for MAO-B). Antioxidant capacity was pronounced for para-substituted analogues. The efficient compounds 4bk', 4af', 4ac', and 4ag' presented quite low toxicity on healthy cells (cell survival % was above %70 for 4bk', 4af', and 4ac', while it was around 64% for 4ag') even when they were applied at 100 times higher concentrations than their IC50 values, which indicates that they are safe at effective doses. Moreover, assessment of the compounds at a concentration of 10 μM demonstrated no cytotoxic effects on either healthy BV-2 microglial cells or H9c2 rat myoblastoma cells. Docking and 100 ns molecular dynamics (MD) simulations (AChE: 4EY7; MAO-B: 2V5Z) supported stable binding for dual-active representatives (RMSD ∼1.5-2.8 Å). In silico ADME (QikProp) indicated compliance with Lipinski's Rule of Five and Jorgensen's Rule of Three. Collectively, this scaffold is tunable from MAO-B-selective to balanced MTDL profiles suitable for further AD-relevant optimization.},
}
@article {pmid42540280,
year = {2026},
author = {Chu, AL and Chu, BSL and Qiang, W},
title = {Molecular Dynamics Simulations of Aβ42 Dimers with Solid-State NMR Restraints Capture the Key Structural Motifs in Aβ42 Fibrillation Pathways.},
journal = {ACS omega},
volume = {11},
number = {29},
pages = {44425-44433},
doi = {10.1021/acsomega.6c05189},
pmid = {42540280},
issn = {2470-1343},
abstract = {Formation of the β-amyloid (Aβ) plaques is a pathological hallmark of Alzheimer's disease (AD) and is believed to be a primary cause of dementia in elderly individuals. In the present work, we performed molecular dynamics (MD) simulations on the conformational evolution of Aβ42 dimers in solution and in a membrane-like environment to explore the folding of Aβ42 during fibrillation. Particularly, the MD simulation was steered by experimental internuclear distance restraints obtained using solid-state nuclear magnetic resonance (ssNMR) spectroscopy. Our results revealed that several hydrophobic and polar motifs within the Aβ42 sequence played key roles in the early-stage nucleation process of fibrillation, and these motifs are also the stabilizing agents in the mature fibrils, as judged by the energy contribution. Our results also indicated that the membrane-binding of small Aβ oligomers could modulate their structural evolution pathways toward fibrillation. These findings contributed to a better understanding of the molecular-level structural polymorphisms inherent to Aβ42 fibrils. Further, the current work demonstrated that the combination of MD simulations with ssNMR-based experimental restraints provided a reliable method for studying structural changes of Aβ.},
}
@article {pmid42540298,
year = {2026},
author = {McFall-Boegeman, H and Talbot, C and Montalbano, M and Puangmalai, N and Wang, KW and Kannan, M and Shi, J and Linning-Duffy, K and Nick, S and Yan, L and Kuo, MH and Kayed, R and Huang, X},
title = {A Virus-Like-Particle-Based Conjugate Vaccine Targeting the Microtubule Binding Region of Tau Protein.},
journal = {ACS omega},
volume = {11},
number = {29},
pages = {43242-43254},
doi = {10.1021/acsomega.6c00852},
pmid = {42540298},
issn = {2470-1343},
abstract = {There is a pressing need to develop novel strategies to ameliorate symptoms and slow the progression of Alzheimer's disease. One of the hallmarks of Alzheimer's disease is the high levels of tau protein, which can form toxic oligomers and characteristic neurofibrillary tangles in the brain. Antitau antibodies can potentially bind tau protein and reduce tau pathology. In order to elicit a powerful antitau antibody response, virus-like-particle bacteriophage Qβ-based conjugate vaccines were developed targeting the microtubule binding region of tau protein. The Qβ-tau vaccines were able to produce a strong antitau antibody response in not only wild-type mice but also in human tau transgenic mice and a llama. The levels of antibody induced were superior to those generated by a corresponding keyhole limpet hemocyanin-based tau conjugate mimicking the one vaccine that successfully completed phase 1/2 human clinical trials. The Qβ-tau vaccine significantly improved the cognitive functions of the immunized mice and reduced the levels of inflammatory cytokines and tau in the brains, suggesting its translational potential.},
}
@article {pmid42540333,
year = {2026},
author = {Gabb, VG and Neary, C and Mair, D and Kendrick, A and Russell, G and Clayton, J and Begum, S and Huckstepp, RTR and Turner, N and Coulthard, E},
title = {Sleep Apnoea and Memory (SAM): protocol for a prospective study of prevalence and symptoms of sleep apnoea in memory clinics.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1862599},
doi = {10.3389/fnagi.2026.1862599},
pmid = {42540333},
issn = {1663-4365},
abstract = {INTRODUCTION: Sleep apnoea is common in older adults and a risk factor for cognitive decline and dementia but is rarely assessed in memory clinics. The Sleep Apnoea and Memory (SAM) study will assess the prevalence of sleep apnoea and identify optimal screening for sleep apnoea in memory clinics.<br><br>METHODS: SAM is a prospective observational multi-site study recruiting adults attending NHS memory clinics. Participants will undergo a single night of polygraphy using a home sleep apnoea test (WatchPAT[&#xae;] 300) and complete questionnaires based on NICE guidance for sleep apnoea assessment. The primary outcome will be the prevalence of sleep apnoea. Secondary outcomes include determining sleep apnoea prevalence across different cognitive diagnoses, identifying which symptoms and risk factors which best predict sleep apnoea, and assessing feasibility of remote sleep apnoea screening.<br><br>DISCUSSION: The SAM study will improve understanding of the extent of sleep apnoea in people attending memory clinics and inform design of an interventional trial for treating sleep apnoea in patients with cognitive impairment. Treating sleep apnoea in memory clinics may help to improve symptoms and/or prognosis for people experiencing memory problems.},
}
@article {pmid42540517,
year = {2026},
author = {Otenaike, TA and Farodoye, OM and Olaniyan, H and Teibo, JO and Faleke, HO and Akinola, IA and Molik, ZA and Aschner, M and Abolaji, AO},
title = {Neurotoxicity of heavy metals across the lifespan: The beneficial role of nutrition from fetus to the elderly.},
journal = {Advances in neurotoxicology},
volume = {16},
number = {1},
pages = {307-349},
doi = {10.1016/bs.ant.2026.03.003},
pmid = {42540517},
issn = {2468-7480},
abstract = {Heavy metals pose a profound threat to neurological health across all stages of human life, from prenatal development to old age. Heavy metals such as lead, mercury, cadmium, and arsenic are pervasive environmental pollutants that disrupt neural function through mechanisms including oxidative stress, inflammation, mitochondrial dysfunction, and neurotransmitter system imbalances. During critical developmental windows such as fetal growth and early childhood, exposure can impair neurogenesis, synaptic plasticity, and myelination, leading to lifelong cognitive deficits, behavioral disorders, and increased vulnerability to neurodegenerative diseases in later life. Even in adulthood and aging, chronic exposure exacerbates neurodegeneration, accelerating conditions like Alzheimer's and Parkinson's diseases through persistent oxidative damage and inflammatory cascades. This chapter underscores the dual role of nutrition as both a shield and a therapeutic tool against heavy metal neurotoxicity. Key nutrients, such as polyphenols, vitamins, and essential minerals, counteract heavy metal-induced damage by scavenging free radicals, enhancing antioxidant defenses, modulating inflammation, and promoting neuronal repair. By integrating evidence from epidemiological, preclinical, and clinical studies, this chapter emphasizes actionable strategies, such as fortified infant formulas, plant-based proteins, and micronutrient supplementation to reduce heavy metal bioavailability and bolster neurological resilience. Public health initiatives targeting vulnerable populations, alongside policies regulating environmental pollutants, are critical to curbing this silent epidemic. This chapter advocates for a proactive, nutrition-centered approach to safeguarding brain health, demonstrating that dietary interventions are not merely complementary but foundational in combating the pervasive threat of heavy metal neurotoxicity across generations.},
}
@article {pmid42540519,
year = {2026},
author = {Rajabpour-Sanati, A and Nasiri, H and Khosravi, F and Ghahrieh, F and Asemanrafat, A and Bahaqiqat, AK and Saberian, P and Bakhshi, R and Rastegari, F and Ahangar-Sirous, R and Shahidzadehasadi, A and Seif, H and Ghahremani, M and Gandomi-Nasrabadi, F and Azizan, Z and Mayeli, M and , },
title = {Diagnostic Performance of the AlzoSure Predict Assay and Its Association With Alzheimer's Disease Biomarkers and Imaging Findings.},
journal = {Health science reports},
volume = {9},
number = {8},
pages = {e72914},
doi = {10.1002/hsr2.72914},
pmid = {42540519},
issn = {2398-8835},
abstract = {BACKGROUND: Early diagnosis of Alzheimer's disease (AD) is critical for improving patient outcomes. The laboratory-developed blood test of AlzoSure measures the unfolded conformational variant of p53 (U-p53AZ) in plasma and has shown promise as a screening tool for AD risk. We aimed to evaluate the association between U-p53AZ with established cerebrospinal fluid (CSF) and neuroimaging measures, and to determine its diagnostic performance in distinguishing cognitively normal (CN) individuals from those with mild cognitive impairment (MCI).<br><br>METHODS: Participants included CN and MCI individuals aged 55-90 years with complete baseline and 24-month follow-up assessments. Associations between U-p53AZ, CSF biomarkers, standardized uptake value ratio (SUVR) of glucose measured by fluorodeoxyglucose positron emission tomography (FDG-PET), and cognition were examined with multivariable regression models adjusted for age, sex, and APOE &#x3b5;4 status. Diagnostic performance was assessed with receiver operating characteristic (ROC) analysis.<br><br>RESULTS: At baseline, no significant group differences were observed in plasma U-p53AZ, FDG SUVR, or CSF biomarkers between CN and MCI. Longitudinally, FDG SUVR significantly declined in MCI (p&#x2009;=&#x2009;0.040), while CSF t-tau and p-tau181 increased in both groups (all p&#x2009;<&#x2009;0.05). Higher U-p53AZ levels were independently associated with elevated CSF t-tau (&#x3b2;&#x2009;=&#x2009;0.38; p&#x2009;=&#x2009;0.033) and p-tau181 (&#x3b2;&#x2009;=&#x2009;0.37; p&#x2009;=&#x2009;0.033) at baseline, and these associations persisted at follow-up (&#x3b2; range 0.43-0.48; all p&#x2009;<&#x2009;0.02). No significant associations were found with FDG SUVR or cognitive scores. The discriminative ability of U-p53AZ to distinguish CN from MCI was modest (AUC&#x2009;=&#x2009;0.617, 95% CI 0.518-0.716).<br><br>CONCLUSION: AlzoSure measurements are significantly associated with CSF tau values but demonstrate limited utility in differentiating CN from MCI. Although promising as a marker of tau-related neurodegeneration, AlzoSure has a modest diagnostic performance as a stand-alone assessment.},
}
@article {pmid42540536,
year = {2026},
author = {Wang, S and Lin, Y and Che, Y and Zhao, J and Xu, L and He, W and Zhang, W},
title = {Genetically inferred effects of brain structure and gene expression on neurodegenerative diseases: a Mendelian randomization study.},
journal = {Archives of medical science : AMS},
volume = {22},
number = {3},
pages = {1663-1677},
doi = {10.5114/aoms/219499},
pmid = {42540536},
issn = {1734-1922},
abstract = {INTRODUCTION: Against the backdrop of accelerating population aging, the risk of neurodegenerative diseases (NDDs) has risen significantly. While brain structure plays a critical role in NDDs, the interplay between them remains unclear. This study employed Mendelian randomization (MR) to investigate potential causal relationships between brain structure, region-specific gene expression, and four NDDs - Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS) - providing new directions and genetically informed hypotheses for disease research.<br><br>MATERIAL AND METHODS: MR analyses were conducted using inverse-variance weighted (IVW), MR-Egger, weighted median, weighted mode, and Wald ratio methods. Summary-data-based MR (SMR) was applied to identify brain genes influencing NDDs. We calculated F-statistics, 95% confidence intervals (CIs), odds ratios, and p-values. Sensitivity analyses included the heterogeneity I[2] statistic, Cochran's Q test, Egger intercept test, MR-PRESSO, and leave-one-out validation.<br><br>RESULTS: Data from 512 unsupervised deep-learning imaging phenotypes (UDIPs) were analyzed. Thirty-four UDIPs showed associations consistent with a potential causal role in AD, 56 in PD, 22 in ALS, and 92 in MS. After false discovery rate (FDR) correction, 4 remained significant for AD and PD, 3 for ALS, and 28 for MS (p < 0.05). Brain regions (excluding the cervical spinal cord C-1) exhibited shared causal genetic features across all four NDDs, primarily involving HLA-class genes.<br><br>CONCLUSIONS: This study provides genetic evidence suggestive of potential causal associations between UDIPs, brain gene expression, and NDDs. These findings offer genetically predicted evidence that may generate hypotheses and inform future mechanistic research into NDD pathogenesis.},
}
@article {pmid42540688,
year = {2026},
author = {Paonessa, F and Bizzini, BD and Campbell, T and Coode, E and Lam, J and Solanki, R and Butler, R and Smith, J and Davidson, CM and Larrieu, D and Brand, AH and Livesey, FJ},
title = {NAT10 inhibition corrects nuclear defects in tau mutant human neurons and extends lifespan in a Drosophila tauopathy model.},
journal = {iScience},
volume = {29},
number = {8},
pages = {116861},
doi = {10.1016/j.isci.2026.116861},
pmid = {42540688},
issn = {2589-0042},
abstract = {Mutations in the gene encoding the microtubule-associated protein tau (MAPT) that are causal for frontotemporal dementia result in nuclear envelope deformation and disrupted nucleocytoplasmic transport when expressed in human neurons. A small-molecule inhibitor of the acetyltransferase NAT10 has been shown to correct similar nuclear membrane defects in Hutchinson-Gilford progeria syndrome, primarily by modulating microtubule dynamics. We report here that NAT10 inhibition and loss of function correct nuclear membrane abnormalities in human MAPT-mutant neurons. Similarly, NAT10 inhibition and haploinsufficiency correct neuronal nuclear shape defects and extend lifespan in vivo in a Drosophila model of tauopathy. NAT10 inhibition changes microtubule dynamics and corrects aberrant nucleocytoplasmic transport, and NAT10 directly interacts with regulators of microtubule dynamics in human MAPT-mutant neurons. We conclude that NAT10 mediates neuronal pathologies in tauopathies and is a potential therapeutic target in these diseases.},
}
@article {pmid42540732,
year = {2026},
author = {Saloner, R and Paolillo, EW and VandeBunte, AM and Cadwallader, CJ and Chen, C and Steffen, BT and Bennett, DA and Boeve, BF and Rosen, HJ and Boxer, AL and Kramer, JH and Casaletto, KB},
title = {Plasma proteomics reveals molecular overlap between physical activity and dementia risk.},
journal = {Brain communications},
volume = {8},
number = {4},
pages = {fcag287},
doi = {10.1093/braincomms/fcag287},
pmid = {42540732},
issn = {2632-1297},
abstract = {Physical activity (PA) is a modifiable lifestyle behaviour associated with lower dementia risk; however, molecular pathways bridging PA-related dementia prevention are poorly understood. We leveraged large-scale plasma proteomics to identify biological signatures of objectively monitored PA and cognitive ageing in functionally intact older adults, cross-validated these signatures in independent exercise cohorts and tested associations with both symptomatic and presymptomatic stages of neurodegeneration across multiple Alzheimer's disease and related dementias (ADRD) cohorts. We analysed large-scale plasma proteomics data (SomaScan 7k) across three cohorts including naturalistic, objective PA monitoring (University of California, San Francisco Brain Aging Network for Cognitive Health cohort, n = 65), self-reported PA (Atherosclerosis Risk In Communities study, n = 10 644) and PA intervention (Health Risk Factors, Exercise Training and Genetics study, n = 654). Differential regression models examined individual protein correlates of PA, adjusting for age and sex. Weighted gene co-expression network analysis assembled proteins into unbiased modules of protein co-expression, which were annotated for gene ontology and cell-type enrichment. To test clinical relevance to ADRD, we examined PA-related protein levels across-cohorts of symptomatic Alzheimer's disease and Parkinson's disease (Stanford Alzheimer's Disease Research Center), as well as frontotemporal dementia-spectrum disorders (ARTFL/LEFFTDS Longitudinal Frontotemporal Lobar Degeneration consortium). PA-related plasma proteins were also tested as predictors of antemortem cognitive change and post-mortem brain tissue mass spectrometry proteomic signatures in brain donors from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP) cohort. Differential regression and network analyses identified PA plasma proteomic signatures linked to cell adhesion/extracellular matrix (ECM), immune response and lipid metabolism. Protein co-expression module M12 ECM/neurodevelopment harboured growth factor, cell adhesion and vascular remodelling proteins that (i) were positively associated with PA across exercise cohorts, (ii) positively associated with cognitive function and (iii) negatively associated with Alzheimer's disease, Parkinson's disease and frontotemporal dementia. Furthermore, M12 was enriched for proteins from Alzheimer's disease risk genes and antemortem plasma abundance of anthrax toxin receptor cell adhesion molecule 2 (ANTXR2), an M12 'hub' protein and top PA hit across-cohorts, forecasted longitudinal global cognitive decline and post-mortem brain tissue signatures of synaptic function and proteolysis in ROSMAP. Collectively, our integrated systems biology analysis of six independent plasma proteomic datasets facilitated discovery and validation of blood-detectable molecular signatures of PA and neurodegenerative disease, including PA-related proteins with clinical and biological relevance to early stages of disease. Circulating levels of PA-related proteins reflecting ECM biology (e.g. ANTXR2) may represent key molecular targets for dementia prevention.},
}
@article {pmid42541080,
year = {2026},
author = {Espinosa, PS and Li, S and Preisler, J and Hennekens, CH},
title = {Donanemab Infusion and Recurrent Seizures in a Patient With Alzheimer's Disease and Epilepsy in the Absence of Amyloid-Related Imaging Abnormalities (ARIA).},
journal = {Cureus},
volume = {18},
number = {7},
pages = {e111911},
doi = {10.7759/cureus.111911},
pmid = {42541080},
issn = {2168-8184},
abstract = {Donanemab is an immunoglobulin G1 (IgG1) monoclonal antibody that was recently approved by the United States Food and Drug Administration for the treatment of early symptomatic Alzheimer's disease (AD). The drug was approved with boxed warnings for amyloid-related imaging abnormalities (ARIA). While seizures are recognized adverse events, they are predominantly characterized in the context of ARIA and accompanied by edema (ARIA-E) or hemosiderin deposition (ARIA-H). The precise epileptogenic mechanisms of anti-amyloid immunotherapies independent of macroscopic ARIA remain poorly understood. We report the case of a 90-year-old man with mild cognitive impairment due to AD and a history of well-controlled focal epilepsy on levetiracetam, who experienced two generalized tonic-clonic seizures. Each paroxysmal event occurred within two hours of completing his fifth and sixth monthly donanemab (1,400 mg intravenous) infusions. Inter-ictal magnetic resonance imaging (MRI), including fluid-attenuated inversion recovery (FLAIR) and susceptibility-weighted imaging (SWI) sequences, demonstrated no evidence of ARIA-E or ARIA-H. Routine electroencephalography (EEG) revealed no interictal epileptiform discharges. Seizure recurrence necessitated an escalation of his levetiracetam dosage to 750 mg twice daily and the immediate discontinuation of donanemab therapy, after which he remained seizure-free. The temporal proximity of the seizures to the infusions, the positive rechallenge, and the absence of identifiable structural, metabolic, or infectious precipitants raise the possibility of an association with donanemab. However, causality cannot be established from a single case report. Several biologically plausible mechanisms may explain this temporal association, including rapid amyloid-beta (Aβ) clearance, microglial activation, neuroinflammatory responses, and transient blood-brain barrier dysfunction, which may lower the seizure threshold in a patient with pre-existing epileptogenic networks. However, these mechanisms remain hypothetical and were not directly demonstrated in this patient. Clinicians should maintain a high index of suspicion for acute post-infusion seizures in patients receiving donanemab, particularly those with a history of epilepsy, even in the absence of radiographically detectable ARIA. Clinicians should be aware of this potential safety signal in patients with pre-existing epilepsy. Additional studies are needed before specific monitoring or treatment recommendations can be established.},
}
@article {pmid42531044,
year = {2026},
author = {Li, Y and Wang, S and Xie, K and Qian, S and Ma, M and Zhang, H},
title = {Burden trends of Alzheimer's disease and other dementias in China, 1990-2023: Sex, age, and risk-attributable patterns.},
journal = {Annals of the Academy of Medicine, Singapore},
volume = {},
number = {},
pages = {},
doi = {10.47102/annals-acadmedsg.2026146},
pmid = {42531044},
issn = {2972-4066},
abstract = {INTRODUCTION: China's population has aged rapidly in recent decades, accompanied by a steady rise in Alzheimer's disease and other dementias (ADOD). Understanding long-term national trends is important for anticipating future healthcare needs.<br><br>METHOD: The authors analysed Global Burden of Disease (GBD) 2023 estimates for China from 1990 to 2023, following the Guidelines for Accurate and Transparent Health Estimates Reporting, with STROBE used as a secondary reporting reference. Deaths, disability-adjusted life years (DALYs), incidence, and prevalence were examined together with crude rates, age-standardised rates (ASRs), and average annual percentage changes. Results were evaluated and stratified by sex and broad age group. Modelled risk-attributable burden was assessed for selected GBD risk factors-ambient particulate matter pollution, high fasting plasma glucose, smoking, and household air pollution from solid fuels.<br><br>RESULTS: Over the study period, the number of people affected increased markedly. Deaths rose from 122,411 in 1990 to 586,002 in 2023, while DALYs and prevalent cases more than tripled. In contrast, ASR showed only modest upward changes. Women had higher ASRs in 2023, although mortality- and DALY-related rates increased more quickly among men. The burden remained concentrated in those aged 75 years and older. Among the selected exposures, ambient particulate matter pollution accounted for the largest attributable share in 2023, whereas household air pollution declined over time.<br><br>CONCLUSION: The marked increase in absolute ADOD burden, together with smaller changes in ASR, is consistent with demographic ageing being an important contributor to rising dementia-related service needs in China. The risk-attributable estimates suggest changing population-level patterns for selected environmental and metabolic exposures, but they should not be interpreted as individual-level causal effects.},
}
@article {pmid42531071,
year = {2026},
author = {Le Bars, S and Soudy, M and Glaab, E},
title = {XYomics: detecting sex-dependent molecular mechanisms in omics data.},
journal = {Nucleic acids research},
volume = {54},
number = {14},
pages = {},
pmid = {42531071},
issn = {1362-4962},
support = {//Luxembourg Fondation Wivine/ ; INTER/JPND23/17999421/AD-PLCG2//Luxembourg National Research Fund/ ; INTER/22/17104370/RECAST//Luxembourg National Research Fund/ ; INTER/EJP RD22/17027921/PreDYT//Luxembourg National Research Fund/ ; C24/BM/18865990/AsynIntact//Luxembourg National Research Fund/ ; },
mesh = {Humans ; *Software ; Male ; *Sex Characteristics ; *Alzheimer Disease/genetics/metabolism ; Female ; *Computational Biology/methods ; Genomics/methods ; Single-Cell Analysis ; },
abstract = {Understanding sex-dependent differences in disease risk, manifestation, and treatment response is essential for precision medicine. While funding agencies now mandate consideration of Sex as a Biological Variable (SABV), existing bioinformatics tools lack systematic approaches to characterize sex-related molecular mechanisms. Current practices frequently treat sex as a confounding variable, which may obscure important biological differences such as sex-specific alterations, sex-dimorphic changes (opposite effects between sexes), and sex-modulated changes (different effect magnitudes). We present XYomics, an open-source R package for systematic analysis of sex-dependent alterations in biomedical omics data. The software identifies sex-specific, sex-dimorphic, and sex-modulated changes at both individual feature and systems levels. XYomics implements dual analytical modes: sex-disease interaction term modeling for adequately powered datasets and sex-stratified analysis with robust non-significance filtering for smaller sample sizes. Using single-cell RNA sequencing data from Alzheimer's disease patients, we demonstrate how XYomics identifies sex-dimorphic genes largely undetected by standard sex-averaged analyses. By integrating statistical categorization with pathway enrichment and network analysis using a curated hormone signaling interactome, the software facilitates discovery of sex-specific biomarkers and disease mechanisms frequently obscured in sex-aggregated analyses.},
}
@article {pmid42531136,
year = {2026},
author = {Shen, D and Jin, H and Feng, H and Gao, R and Sun, R and Xiao, Y and Wan, W and Ma, C and Liu, Y},
title = {Neutral Borate Buffer Activates Diazo for Rapid Protein Labeling.},
journal = {Angewandte Chemie (International ed. in English)},
volume = {},
number = {},
pages = {e1990347},
doi = {10.1002/anie.1990347},
pmid = {42531136},
issn = {1521-3773},
support = {22374148//National Natural Science Foundation of China/ ; 2024JH3/50100009//Liaoning Province Science Foundation for Distinguished Young Scholars/ ; 2022RJ04//Dalian Science Foundation for Distinguished Young Scholars/ ; 028GJHZ2023079FN//International Partnership Program of Chinese Academy of Sciences for Future Network/ ; 2023JJ12WZ037//Dalian Science and Technology Innovation Foundation/ ; 2024-MSBA-59//Natural Science Foundation of Liaoning Province/ ; DICP I202458//Innovation Program of Science and Research from the DICP, CAS/ ; DICP I202310//Innovation Program of Science and Research from the DICP, CAS/ ; DICP I202529//Innovation Program of Science and Research from the DICP, CAS/ ; },
abstract = {Diazo, a carbene precursor, offers an effective chemistry for bioorthogonal labeling upon activation by acids, metals, and/or photo-illumination. Here, we report neutral borate buffer can trigger diazo compounds into carbene for protein labeling without the need for acid, metal, or light. We show that such boron-diazo-mediated covalent modification rapidly occurs within seconds under physiological conditions and preferentially targets carboxylate-containing amino acid residues. Towards applications of such boron-diazo protein chemistry, we exemplify the design of an affinity-based covalent inhibitor for dihydrofolate reductase by installing diazo on the non-covalent trimethoprim drug. When extended to stressed cells, we also capture cellular aggresomes using a diazo-Thioflavin T probe that selectively labels aggregated proteins. Finally, in Alzheimer's disease brain tissue, we employ this boron-diazo chemistry to label, enrich, and profile amyloid plaques, identifying proteins related to pathological deposition. Together, the boron-diazo chemistry reported herein provides a rapid and facile protein modification strategy under mild conditions.},
}
@article {pmid42531512,
year = {2026},
author = {Khawar, M and Nasir, MF and Qadeer, A and Khawar, MMH and Malik, MA and Mubarika, M and Iftikhar, Q and Shahid, A and Zahid, A and Awais, M and Dalil, L and Khaliq, M and Ali, SZ},
title = {Diagnosed oral cavity and salivary gland disorders and the risk of incident Parkinson disease, Alzheimer disease, dementia and all-cause mortality: a retrospective cohort study.},
journal = {Internal medicine journal},
volume = {},
number = {},
pages = {},
doi = {10.1111/imj.70577},
pmid = {42531512},
issn = {1445-5994},
abstract = {BACKGROUND: Oral diseases encompass a heterogeneous group of conditions affecting the oral cavity and associated structures. Certain chronic inflammatory oral diseases, particularly periodontitis, have been linked to systemic inflammation and may contribute to neurodegenerative processes. However, long-term evidence on their association with Parkinson's disease (PD), Alzheimer's disease (AD), dementia and mortality remains inconsistent. This study aims to investigate whether diagnosed oral cavity and salivary gland disorders are associated with long‑term risk of PD, AD, dementia and all-cause mortality in older adults.<br><br>AIMS: To investigate whether diagnosed oral cavity and salivary gland disorders are associated with long-term risk of Parkinson disease, Alzheimer disease, dementia, and all-cause mortality in older adults.<br><br>METHODS: This retrospective propensity score-matched cohort study utilised the TriNetX US Collaborative Network. Patients aged &#x2265;60&#x2009;years with a documented diagnosis of diseases of the oral cavity and salivary glands (ICD-10-CM K00-K14) were 1:1 matched with patients without oral diseases on demographics, comorbidities and medication use (n =&#x2009;232&#x2009;809 per group after matching). The index date was the first documented oral disease diagnosis (exposure cohort) or equivalent healthcare encounter (control cohort). New-onset PD, AD, any-type dementia and all-cause mortality were assessed at 5- and 13-year follow-up using risk ratios (RRs), hazard ratios (HRs) and Kaplan-Meier survival analysis.<br><br>RESULTS: At 5&#x2009;years, diagnosis of oral cavity and salivary gland diseases was associated with significantly increased risk of new-onset PD (HR 1.212, 95% confidence interval (CI) 1.133-1.296), any dementia (HR 1.132, 95% CI 1.098-1.167) and all-cause mortality (HR 1.117, 95% CI 1.101-1.134). AD risk was modestly elevated (HR 1.100, 95% CI 1.033-1.171). At 13&#x2009;years, the increased risk persisted for PD (HR 1.146), dementia (HR 1.060) and mortality (HR 1.113), but the association with AD was no longer significant (HR 0.998, 95% CI 0.959-1.038).<br><br>CONCLUSIONS: Diagnosed oral cavity and salivary gland diseases are independently associated with sustained long-term risk of PD, dementia and all-cause mortality, but the association with AD appears time-limited. These findings highlight oral health as a potentially modifiable factor in neurodegenerative disease prevention and support multidisciplinary approaches to oral care in older adults.},
}
@article {pmid42531527,
year = {2026},
author = {Kuran, &#x130; and Eşme, M},
title = {Comments on "Persistent Functional Impairment as an Early Indicator of Alzheimer Disease Pathology and Progression".},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70614},
pmid = {42531527},
issn = {1532-5415},
}
@article {pmid42531533,
year = {2026},
author = {Mohamed, MI and Sameh, R and Farghaly, D and Ashraf, B and Kamel, B and Mahmoud, NH and Abdelall, NA and Nada, MAF},
title = {Autoimmune Neurologic Disorders and the Risk of Alzheimer, Vascular, and Other Dementias: A Comprehensive Systematic Review and Meta-Analysis (P2-13.006).},
journal = {Neurology},
volume = {107},
number = {5},
pages = {e218536},
doi = {10.1212/WNL.0000000000218536},
pmid = {42531533},
issn = {1526-632X},
}
@article {pmid42531538,
year = {2026},
author = {Lin, YR and Lee, WJ and Lee, PL and Lin, CP and Wang, PN and Chen, LK and Chung, CP},
title = {Validation of the VasCog-2-WSO VCID Criteria in a Dementia-Free and Stroke-Free Community Cohort: Cardiovascular Risk and Mortality.},
journal = {Neurology},
volume = {107},
number = {4},
pages = {e218311},
doi = {10.1212/WNL.0000000000218311},
pmid = {42531538},
issn = {1526-632X},
mesh = {Humans ; Female ; Male ; Aged ; *Dementia, Vascular/mortality/diagnosis/diagnostic imaging ; *Cardiovascular Diseases/mortality/epidemiology ; Middle Aged ; Longitudinal Studies ; *Cognitive Dysfunction/diagnosis/mortality ; Magnetic Resonance Imaging ; Neuropsychological Tests ; Cohort Studies ; },
abstract = {BACKGROUND AND OBJECTIVES: Vascular cognitive impairment and dementia (VCID), a major contributor of dementia, remains underrecognized, owing to the absence of universally accepted diagnostic criteria. The VasCog Society and WSO recently released updated criteria (VasCog-2-WSO); however, their applicability is unknown yet. We aimed to evaluate these criteria in a dementia-free and stroke-free community cohort and determine their associations with vascular burden and long-term mortality.<br><br>METHODS: We conducted a community-based cohort study using data from the I-Lan Longitudinal Aging Study. Adults aged 50 years or older without prior stroke or dementia underwent standardized brain MRI and comprehensive neuropsychological assessment. VCID was classified according to the VasCog-2-WSO criteria using a neuroimaging-first approach. Participants were categorized as non-VCID, preclinical VCID (with or without objective cognitive impairment), or vascular mild cognitive impairment (vaMCI). Baseline 10-year Framingham cardiovascular disease risk was assessed. The primary outcome was all-cause mortality over a mean follow-up of 9.4 years, analyzed using multivariable Cox proportional hazards and Poisson regression models.<br><br>RESULTS: A total of 1,236 participants (62.7 &#xb1; 8.8 years; 52.9% female) were included. Neuroimaging evidence of cerebrovascular disease was present in 19.6% of participants; 19.2% met criteria for preclinical VCID and 0.4% for vaMCI. Compared with non-VCID participants, neuroimaging-positive groups had worse cognitive performance and higher 10-year cardiovascular risk. Mortality increased across the VCID spectrum (7.4 [95% CI 5.7-9.4], 24.9 [16.0-37.1], 27.4 [18.2-39.6], and 137.9 [37.6-353.2] per 1,000 person-years). In adjusted Cox models, preclinical VCID was associated with a 1.5-1.7-fold higher mortality risk, and vaMCI with a hazard ratio of 7.2 (95% CI 2.4-21.1), with a significant graded association across the spectrum (p for trend <0.001).<br><br>DISCUSSION: The VasCog-2-WSO criteria identify a spectrum of MRI-defined vascular cognitive vulnerability associated with increased cardiovascular risk and mortality, with excess mortality risk detectable at a neuroimaging-defined preclinical stage before overt cognitive impairment. These findings support their utility for early detection and risk stratification in community settings. A key limitation is the inability to assess mixed etiologies due to the absence of genetic data and Alzheimer disease biomarkers, which limits the ability to thoroughly evaluate the VasCog-2-WSO VCID diagnostic framework.},
}
@article {pmid42531673,
year = {2026},
author = {Leuci, R and Paparella, M and Cerini, M and Simic, S and Chaves, S and Carrieri, A and Tortorella, P and Loiodice, F and Laghezza, A and Santos, MA and Wackerlig-Damle, J and Piemontese, L},
title = {Lead optimization of rivastigmine-like hybrids: Impact of nitro group and halogen substitution on multi-target anti-Alzheimer's activity.},
journal = {Bioorganic &amp; medicinal chemistry},
volume = {141},
number = {},
pages = {118760},
doi = {10.1016/j.bmc.2026.118760},
pmid = {42531673},
issn = {1464-3391},
abstract = {The multifactorial profile of Alzheimer's disease has led researchers to adopt a multi-target strategy for the design of new small molecules. In this context, starting from the structure of ROS151, a novel series of seventeen rivastigmine-like hybrids was developed. Structural modification involved the aryloxy-methylene portion, with the substitution of the nitro group with other groups and the variation of type and position of the halogen atom. The nitro group was confirmed to be essential for high anti-ChE activity, with compound 3 showing the most balanced profile, superior to that of the lead compound (IC50 = 0.827 ± 0.012 μM and 4.58 ± 0.01 μM against hAChE and eqBChE, respectively). Hybrid 2 showed inhibitory activity against hAChE close to that of donepezil (IC50 = 0.029 ± 0.005 μM), while 7 had better activity against eqBChE than the parent drug rivastigmine (IC50 = 0.45 ± 0.02 μM). In silico experiments were performed to corroborate these results. When the nitro group was reduced to amine, as for compound 10, relevant antioxidant activity (ABTS, IC50 = 25.2 ± 1.2 μM) and remarkable chelating properties toward Fe[3+] (pM = 15.6) and Cu[2+] (pM = 11.4), with a good selectivity over Zn[2+] (pM = 6.0) were observed. Inhibition of fatty acid amide hydrolase (hFAAH) resulted less relevant but still appreciable. Cyano-derivative 8 appears to be the only compound with preserved multi-enzymatic inhibitory potential, even without nitro-group in its structure and can be used as starting point for further series. Finally, many hybrids demonstrated interesting experimental pharmacokinetic properties, evaluated using bioanalytical methods.},
}
@article {pmid42531948,
year = {2026},
author = {Chang, CH and Chien, SC and Wang, CC and Chuang, CC and Chen, JC},
title = {Alzheimer's disease-related β-amyloid deposition prediction based on plasma biomarkers, ApoE4, and CDR with a machine learning approach.},
journal = {Computer methods and programs in biomedicine},
volume = {286},
number = {},
pages = {109567},
doi = {10.1016/j.cmpb.2026.109567},
pmid = {42531948},
issn = {1872-7565},
abstract = {BACKGROUND: Alzheimer's disease (AD) is an irreversible, incurable neurodegenerative disorder that imposes a substantial economic and social burden. As current therapies can only slow disease progression, early detection is of critical importance. Among existing diagnostic tools, amyloid positron emission tomography (PET) remains the most accurate non-invasive method for detecting β-amyloid deposition; however, its high cost significantly limits its applicability for early screening. To address this challenge, this study investigates the use of plasma biomarkers as a low-cost alternative for predicting cerebral β-amyloid burden.<br><br>METHODS: The predictive performance of three machine learning models-Classification and Regression Trees (CART), Support Vector Machines (SVM), and Logistic Regression (LR)-was systematically compared under varying feature subsets and thresholding strategies. Data were obtained from 276 participants in the ADNI database. The qualitative status of cerebral amyloid deposition, defined using threshold-based classification of Centiloid values, was set as the prediction target. Plasma biomarkers and other AD-related risk factors were employed as model features.<br><br>RESULTS: Cross-domain data integration enabled effective prediction of amyloid deposition status. The SVM model, combined with feature subset selection (FSS) and a threshold value of 25, achieved the best performance, yielding an area under the curve (AUC) of 0.80.<br><br>CONCLUSION: By applying the Centiloid quantification framework for amyloid-PET and employing plasma biomarkers along with established AD-related risk factors, this study demonstrates the feasibility of machine learning models as a low-risk, cost-effective approach for predicting amyloid-PET imaging outcomes. These findings highlight the potential to support clinical decision-making and reduce reliance on costly imaging techniques for early AD detection.},
}
@article {pmid42532103,
year = {2026},
author = {Pfuhlmann, K and Koch, AK and Langhorst, J},
title = {Ginkgo biloba Leaf Extracts in Global Dementia and Mild Cognitive Impairment Guidelines. A Review.},
journal = {Planta medica},
volume = {},
number = {},
pages = {},
doi = {10.1055/a-2895-5345},
pmid = {42532103},
issn = {1439-0221},
abstract = {Age-related diseases like dementia are increasing globally, with limited treatments. Extracts of Ginkgo biloba are often used alongside synthetic drugs. The aim of this article was to identify clinical guidelines from countries around the world to assess recommendations on the use of Ginkgo biloba in dementia, mild cognitive impairment, and prevention. PubMed was systematically searched for guidelines on dementia and mild cognitive impairment on the 25th of April 2023. A search update was conducted on the 3rd of March 2026. Additional guidelines were identified via citation searching and organisations. Seventy-seven guideline documents were included: 47 on dementia (subtype not further defined), 25 on Alzheimer's disease, 19 on vascular dementia, 18 on mild cognitive impairment, and seven on prevention, with some guidelines including multiple mentions. The guidelines come from four continents and 28 countries, plus seven international guidelines. Regarding Ginkgo biloba, 52 give positive, 18 negative, and 26 neutral recommendations (double mentions possible); 27 do not mention it. Ginkgo biloba is referred to in guidelines worldwide, usually without reference to specific preparations. Preparation standardisation would be beneficial.},
}
@article {pmid42532278,
year = {2026},
author = {Haut, MW and Vieira Ligo Teixeira, C and Ranjan, M and Carpenter, J and Mehta, RI and Worhunsky, P and D'Haese, PF and Arsiwala, T and Everson, K and Suffridge, J and Keith, C and Phelps, HE and Ebbert, M and Finomore, V and Rezai, A},
title = {Neuromodulation in Alzheimer's disease: a review with illustrative pilot data using focused ultrasound.},
journal = {Biological psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.biopsych.2026.07.019},
pmid = {42532278},
issn = {1873-2402},
abstract = {Alzheimer's disease (AD) is increasingly characterized as a disorder of large-scale brain networks driven by synaptic dysfunction, excitation-inhibition imbalance, and progressive breakdown of hippocampal-cortical communication. While recently developed disease-modifying therapies target molecular pathology, their clinical benefits remain modest, underscoring the need for interventions that target dysfunctional circuits. Neuromodulatory techniques such as transcranial magnetic stimulation, transcranial electrical stimulation, and deep brain stimulation demonstrate safety and act at network/system levels to engage target sites yet are limited by their ability to modulate deep anatomic structures and/or their invasiveness. Focused ultrasound (FUS) offers the distinct capability of modulating cortical and deep subcortical networks noninvasively and with anatomic precision. Preclinical studies demonstrate that FUS neuromodulation can influence mechanosensitive ion channels, synaptic plasticity, neurotrophic signaling, and oscillatory dynamics, with downstream effects on distributed memory networks. Early human investigations similarly suggest FUS neuromodulation can alter functional connectivity within default mode, frontoparietal, and limbic networks. Together, these findings support a framework in which FUS may help reshape pathological network states that emerge prior to irreversible neurodegeneration. Here, we present a narrative review of evidence across neuromodulation approaches to define principles of circuit engagement in AD and discuss a network-based rationale for ultrasound interventions. As an illustration of this framework, we also report preliminary findings from a Phase I pilot study of FUS neuromodulation in amyloid-positive mild cognitive impairment demonstrating safety, tolerability, and measurable modulation of hippocampal connectivity. We conclude mechanistic biomarkers of network response may accelerate translational development and guide future controlled trials.},
}
@article {pmid42532327,
year = {2026},
author = {Tan, C},
title = {Depression and amyloid-β across CSF, PET, and plasma biomarkers: a systematic review and meta-analysis.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.07.065},
pmid = {42532327},
issn = {1873-7544},
abstract = {Alzheimer's disease is increasingly defined by biomarker evidence of amyloid-β and tau pathology, sharpening questions about whether late-life depression contributes to, or instead reflects, this pathology. We conducted a systematic review and meta-analysis of studies published between 2000 and 2025 that compared amyloid-β biomarkers in adults with and without depression, with depression defined by validated clinical diagnoses or symptom rating scales. Twenty-four studies were included, spanning three biomarker sources: cerebrospinal fluid, positron emission tomography imaging, and plasma. Across all sources, the pooled difference in amyloid-β burden between depressed and non-depressed individuals was small and clustered near zero, indicating only a weak, statistically non-significant tendency toward higher amyloid in depression. When the three sources were examined separately, each yielded a similar near-null result, although between-study heterogeneity was considerable for cerebrospinal fluid and plasma and moderate for imaging. Importantly, a prespecified subgroup analysis showed that imaging results diverged by quantification method: studies using the simpler standardized uptake value ratio clustered around zero, whereas the smaller group of studies using kinetic distribution volume ratio modelling showed a significant positive association, suggesting that methodological choices critically influence the observed relationship. Taken together, these findings indicate that depression is not consistently accompanied by greater amyloid-β burden across widely used biomarker platforms. The distribution volume ratio signal nonetheless raises the possibility of subtle associations that cruder methods may obscure, and suggests that depression may shape Alzheimer's disease trajectories more by modifying the clinical impact of amyloid than by altering its amount.},
}
@article {pmid42532345,
year = {2026},
author = {Di Domenico, F and Barone, E and Perluigi, M},
title = {BACH1/HO-1 axis dysregulation links Down syndrome to Alzheimer-like neurodegeneration.},
journal = {Neurochemistry international},
volume = {199},
number = {},
pages = {106232},
doi = {10.1016/j.neuint.2026.106232},
pmid = {42532345},
issn = {1872-9754},
abstract = {Down syndrome (DS), caused by trisomy of chromosome 21, is characterized by early-onset oxidative stress, impaired neuronal development, and an increased risk of Alzheimer's disease (AD)-like neuropathology. Among chromosome 21 genes, the transcription factor BTB and CNC homology 1 (BACH1) has emerged as a critical regulator of redox homeostasis. Under physiological conditions, the balance between BACH1 and nuclear factor erythroid 2-related factor 2 (NRF2) warrants tight control of antioxidant defenses and heme metabolism. However, in DS, BACH1 overexpression disrupts this balance, impairing the induction of heme oxygenase-1 (HO-1) and of other cytoprotective pathways, thereby contributing to chronic oxidative stress, neuronal vulnerability, and pathological processes. The present review summarizes the molecular mechanisms that regulate the BACH1/HO-1 axis in the central nervous system. We recapitulate data from studies showing how dysregulation of this axis affects antioxidant defenses, iron homeostasis, ferroptosis, neuroinflammation, and mitochondrial function. We further provide evidence from the aging and AD literature, highlighting BACH1 as a convergent molecular node linking genetic and age-related neurodegeneration. Remarkably, we explore BACH1's contribution to the transition of DS to AD-like pathology. Finally, we evaluate emerging therapeutic strategies employing BACH1 inhibitors, NRF2 activators, and upstream signaling pathway modulators, and assess their applicability to the AD-like dementia context, concluding that targeting BACH1-dependent regulation of HO-1 represents a promising and unifying strategy to mitigate neurodegeneration in both DS and AD.},
}
@article {pmid42532353,
year = {2026},
author = {Li, T and Chang, Y and Tang, S and Chen, Y and Li, X and Wang, Y},
title = {The Microbiota-Gut-Brain Axis in Neuropsychiatric Disorders: Mechanisms, Advances, and Clinical Applications.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {112062},
doi = {10.1016/j.brainresbull.2026.112062},
pmid = {42532353},
issn = {1873-2747},
abstract = {Neuropsychiatric disorders are increasingly recognized as systemic conditions arising from dynamic interactions within the gut-brain-immune network. The Microbiota-Gut-Brain Axis (MGBA) serves as a central regulatory system orchestrating neurodevelopment, neural homeostasis, and immune-metabolic balance. This review summarizes evidence across seven major neuropsychiatric disorders, Depression, Autism Spectrum Disorder, Attention-Deficit/Hyperactivity Disorder, Alzheimer's disease, Schizophrenia, Anxiety and Obsessive Compulsive Disorder, demonstrating that dysregulation of the MGBA constitutes a shared pathological mechanism. On this common basis, we delineate disorder specific neurochemical and immunological features and highlight the clinical potential of microbiota-targeted interventions. Moreover, psychotropic medications profoundly alter microbial physiology, influencing bacterial growth and metabolism, thereby complicating interpretation of MGBA-disease relationships. Future research should define strain-specific therapeutic actions and integrate multi-omics approaches to unravel causal pathways, ultimately enabling precision microbiome modulation in neuropsychiatric medicine.},
}
@article {pmid42532399,
year = {2026},
author = {Yildirim, C and Bekerecioglu, S and Akyıldız, S and Bingol, B and Ulusal, H and Yilmaz, SG and Bal, R},
title = {Naringin preserved cognitive function through modulation of cholinergic dysfunction, oxidative stress, and synaptic proteins in scopolamine-induced cognitive impairment.},
journal = {Progress in neuro-psychopharmacology &amp; biological psychiatry},
volume = {},
number = {},
pages = {111868},
doi = {10.1016/j.pnpbp.2026.111868},
pmid = {42532399},
issn = {1878-4216},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory loss and cognitive decline. The cholinergic hypothesis remains central to its framework, suggesting that the degeneration of cholinergic neurons and resulting neurotransmission disruption play a major role in cognitive impairment. Naringin, a potent polyphenolic compound abundant in citrus fruits, has gained attention for its antioxidant, anti-inflammatory, and neuroprotective properties. This study aims to investigate naringin's neuroprotective potential in a scopolamine-induced amnesia model, focusing on the BDNF/GAP-43 signaling pathway and markers of synaptic plasticity.<br><br>MATERIALS AND METHODS: A total of 42 male Wistar albino rats were divided into six groups: Saline, Scopolamine (Sco; 1&#x202f;mg/kg/day), Sco&#x202f;+&#x202f;Naringin (50, 100, and 200&#x202f;mg/kg), and Sco&#x202f;+&#x202f;Donepezil (3&#x202f;mg/kg). Following a 21-day treatment period, cognitive and emotional behaviors were assessed using the Morris Water Maze (MWM) and Elevated Plus Maze (EPM) tests. Hippocampal tissues were analyzed for acetylcholinesterase (AChE) activity and oxidative/nitrosative stress markers (MDA, Peroxynitrite, NO, NOS). BDNF and GDNF mRNA expression was quantified by RT-qPCR, and the protein levels of BDNF, GAP-43, PSD-95, SYP, GFAP, SIRT1, KEAP1, Nrf2, and HO-1 were evaluated by Western blot. PSD-95, SYP, GFAP, and NeuN were further examined by confocal imaging.<br><br>RESULTS: Scopolamine administration induced significant impairments in spatial learning and memory, alongside anxiogenic-like behaviors. Biochemical analyses revealed a marked increase in AChE activity and oxidative/nitrosative stress in the Sco group. Additionally, scopolamine caused a profound reduction in BDNF, GDNF, GAP-43, PSD-95, and SYP levels, while increasing GFAP expression. Naringin treatment effectively attenuated these deficits by lowering AChE activity, reducing oxidative damage, and suppressing neuroinflammation. Notably, naringin preserved the expression of synaptic proteins, in association with upregulation of the BDNF/GAP-43 pathway and maintaining pre- and post-synaptic protein levels (SYP and PSD-95).<br><br>CONCLUSION: These findings demonstrate that naringin exerts significant neuroprotective effects against scopolamine-induced cholinergic amnesia. These findings are consistent with the possibility that naringin preserves synaptic plasticity, enhances neurotrophic support, and mitigates inflammatory responses, suggesting that it may represent a promising natural therapeutic candidate for Alzheimer-like neurodegeneration.},
}
@article {pmid42532494,
year = {2026},
author = {Alfaqih, MA and Haessner, P and LeLaurin, JH and Guo, J and Hammer, NC and Ike-Okpe, O and Pappa, MJ and He, X and Salloum, RG and Bian, J and Gregory, ME},
title = {Co-designing an Outpatient Clinical Decision Support Prototype for Managing Social Risks in Patients Living with Dementia.},
journal = {Applied clinical informatics},
volume = {17},
number = {3},
pages = {659-667},
doi = {10.1055/a-2917-6503},
pmid = {42532494},
issn = {1869-0327},
support = {R01AG089445/NH/NIH HHS/United States ; },
mesh = {Humans ; *Dementia ; *Decision Support Systems, Clinical ; *Outpatients ; Female ; *Risk Management ; },
abstract = {BACKGROUND: Patients living with dementia (PLWD) require attention to social determinants of health (SDoH), but social information is often unavailable or incomplete during care encounters, and clinicians report uncertainty about how to act on this information.<br><br>OBJECTIVE: This study aimed to co-design the Intelligent Social Risk Management in Alzheimer's Disease and Alzheimer's Disease-Related Dementias Patients (iSMART) clinical decision support (CDS) prototype, which integrates an AI-driven individualized polysocial risk score (iPsRS) to identify PLWD at high social risk for hospitalization.<br><br>METHODS: We conducted a qualitative user-centered design study with nine outpatient providers and clinical staff who care for PLWD at a large academic health system. Participants completed semi-structured interviews to explore perceived social risks in dementia care, gather feedback on the iSMART prototype and its features, and identify implementation considerations. Interview transcripts were coded and analyzed via rapid qualitative and thematic analysis.<br><br>RESULTS: Nine participants (six providers, two nurses, and one social worker) were interviewed. Lack of caregiver or family support was identified as the most important social factor to consider for PLWD, followed by financial strain and transportation issues. Participants described the iSMART prototype as helpful for identifying social risks among PLWD, summarizing and prioritizing factors contributing to hospitalization risk, and connecting patients to relevant social resources. Participants suggested primary care providers and social workers should be the primary users. Recommended improvements included auto-populated (as opposed to manual entry) but editable SDoH fields for model input, incorporating caregiver presence as a model input, and providing clearer visual representations of risk.<br><br>CONCLUSION: Outpatient providers and staff viewed the iSMART prototype as a promising approach to support social risk screening, resource connection, and referral support in dementia care. These findings inform practical strategies for integrating iPsRS-informed CDS tools into routine workflows in dementia clinics.},
}
@article {pmid42532804,
year = {2026},
author = {Ptomey, LT and Aschenbrenner, AJ and Helsel, B and Bodde, A and Clina, JG and Danon, JC and Lepping, R and Martin, LE and Brucks, M and Sherman, JR and Forsha, DE and Washburn, RA and Donnelly, JE},
title = {The impact of a 12-month randomized exercise intervention on cognitive function and brain volume in adults with down syndrome.},
journal = {Disability and health journal},
volume = {},
number = {},
pages = {102134},
doi = {10.1016/j.dhjo.2026.102134},
pmid = {42532804},
issn = {1876-7583},
abstract = {BACKGROUND: Adults with Down syndrome (DS) have a high risk for Alzheimer's disease (AD). While exercise improves cognition and brain health in the general population, few long-term studies have evaluated its effects in DS.<br><br>OBJECTIVE: We examined the impact of a 12-month remotely delivered exercise program on cognitive function and brain volume in adults with DS.<br><br>METHODS: 81 adults with DS (mean age&#x202f;=&#x202f;27 years) were randomized to high-frequency remote exercise (3 sessions/week, RH), low-frequency remote exercise (1 session/week, RL), or a support and education control (SE). Cognitive function was assessed using the DS-adapted Cambridge Neuropsychological Test Automated Battery (CANTAB), and brain volumes were measured via MRI at baseline and 12 months.<br><br>RESULTS: There were no significant changes in any group in executive function or episodic memory (all p&#x202f;>&#x202f;0.05), but the RH arm significantly improved processing speed across the 12-month intervention (EMM change: 0.17; p&#x202f;=&#x202f;0.04). No between-group differences were observed for changes in overall cognitive scores. The RL group showed a decrease in total grey matter volume (EMM change -0.82; p&#x202f;=&#x202f;0.02) and the RH group had no change (EMM change: 0.08; p&#x202f;=&#x202f;0.72), yielding a significant group effect across time (EMM: 0.90; p&#x202f;=&#x202f;0.04). Additionally, the RH arm had an increase in right hippocampal volume over 12 months (EMM change: 0.004; p&#x202f;=&#x202f;0.04).<br><br>CONCLUSION: The improvements in reaction time, right hippocampal volume, and grey matter preservation suggest that structured exercise may influence cognition and brain health in adults with DS.<br><br>CLINICAL TRIALS REGISTRATION: NCT04048759.},
}
@article {pmid42533036,
year = {2026},
author = {Yu, R and Suraev, A and Vidal, V and Kong, S and Zachariae, R and Piccio, L and Heneka, MT and Naismith, SL and Michaelian, JC},
title = {Neuroinflammatory markers sTREM2 and YKL-40 in association with Alzheimer's disease pathology: a systematic review and meta-analysis.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42533036},
issn = {1476-5578},
abstract = {BACKGROUND/OBJECTIVES: Neuroinflammation is increasingly recognised as a key feature of Alzheimer's Disease (AD) pathophysiology. Markers of glial reactivity, sTREM2 and YKL-40, are elevated in mild cognitive impairment (MCI) and AD, but their associations with core pathology across these stages have not yet been systematically investigated. This systematic review and meta-analysis examined their cross-sectional and longitudinal associations with core pathological biomarkers of AD, and examine how these relationships may evolve dynamically across the disease continuum.<br><br>METHODS: A systematic literature search conducted across Medline, Embase, PsycINFO, PubMed and Scopus (PROSPERO: CRD420250653864) identified 42 studies for sTREM2 and 44 for YKL-40 that were included in this study.<br><br>RESULTS: Meta-analyses revealed that both markers showed robust positive associations with pTau181, tTau and NfL (pooled r&#x2009;=&#x2009;0.31-0.55), including in covariate-adjusted correlations. In contrast, associations with A&#x3b2; pathology (CSF A&#x3b2;42/40, A&#x3b2;-PET) were weaker and not significant in covariate-adjusted estimates. Meta-regression analyses revealed that glial-tau associations were strongest in cognitively unimpaired (CU) individuals, and progressively weakened in MCI and AD, independent of age effects. Longitudinal data were limited and summarised descriptively; glial reactivity predicts increases in soluble CSF hyperphosphorylated tau pathology, yet is concurrently associated with slower accumulation of insoluble PET-detectable amyloid and tau aggregates.<br><br>CONCLUSIONS: Our findings indicate that sTREM2 and YKL-40 preferentially associate with tauopathy and neurodegeneration over pathological A&#x3b2; accumulation. The progressive attenuation of glial-pathology coupling may reflect glial saturation or "exhaustion" with disease progression, offering new insights into how impaired glial responses may be involved in AD pathophysiology.},
}
@article {pmid42533108,
year = {2026},
author = {Breithaupt, AG and Weiner, M and Tang, A and Possin, KL and Sirota, M and Lah, J and Levey, AI and Van Hentenryck, P and Zandehshahvar, R and Gorno-Tempini, ML and Giorgio, J and Wang, J and Rauschecker, AM and Rosen, HJ and Nosheny, RL and Miller, BL and Pinheiro-Chagas, P},
title = {Agentic AI for scaling diagnosis and care in neurodegenerative disease.},
journal = {Nature aging},
volume = {},
number = {},
pages = {},
pmid = {42533108},
issn = {2662-8465},
support = {NA/ALZ/Alzheimer's Association/United States ; NA//Eisai/ ; NA//American Brain Foundation (ABF)/ ; 2112533//National Science Foundation (NSF)/ ; 2112533//National Science Foundation (NSF)/ ; },
abstract = {US healthcare systems are struggling to meet the growing demand for neurological care, particularly in Alzheimer's disease and related dementias. Generative artificial intelligence (AI) built on large language models now enables agentic AI systems that can streamline clinical workflows, integrate multimodal data and learn from practicing specialists. We envision an agentic AI system that scales specialist-level care to nonspecialist clinical settings through a continuously learning healthcare system. We describe this destination and outline a phased roadmap for responsible design and integration into care of Alzheimer's disease and related dementias: (1) high-quality standardized data collection across modalities; (2) decision support; (3) clinical integration enhancing workflows; (4) rigorous validation and monitoring protocols; (5) continuous learning through clinical feedback; and (6) robust ethics and risk management frameworks. This human-centered approach optimizes clinicians' capabilities in comprehensive data collection, interpretation of complex clinical information and timely application of relevant medical knowledge while prioritizing patient safety, healthcare equity and transparency.},
}
@article {pmid42533130,
year = {2026},
author = {Cao, T and Pang, JC and Gajwani, M and Segal, A and Holmes, A and Wiley, JF and Chopra, S and Zhou, JH and Chen, CLH and Ji, F and Harrison, BJ and Davey, CG and Constable, T and Tiego, J and Hartshorn, B and Kwee, J and Bellgrove, MA and Fornito, A},
title = {The cross-site reproducibility of MRI morphometric phenotypes in psychiatric disorders.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {42533130},
issn = {1546-1726},
support = {2034000//Department of Health | National Health and Medical Research Council (NHMRC)/ ; 2033976//Department of Health | National Health and Medical Research Council (NHMRC)/ ; 1146292, 1197431//Department of Health | National Health and Medical Research Council (NHMRC)/ ; DP200103509, FL220100184//Department of Education and Training | Australian Research Council (ARC)/ ; },
abstract = {Decades of structural magnetic resonance imaging (MRI) studies have documented alterations of gray matter morphometry in psychiatric disorders, but the field has failed to identify any consensus disease phenotypes. Here we examine whether current approaches will ever converge on such phenotypes by evaluating the consistency of brain-wide maps of gray matter volume and cortical thickness differences obtained for each of 59 study sites of five psychiatric disorders (schizophrenia, schizoaffective disorder, autism spectrum disorder, major depressive disorder and bipolar disorder), totaling 2,437 patients and 2,065 controls. We find that cross-site consistency is low (median r ≤ 0.16); markedly reduced compared to Alzheimer's disease (r = 0.54); unexplained by demographic, clinical or scanner differences; and robust to analytic choices. Using bootstrapping, we observe that consistency may improve for sample sizes ≥200 per group for schizophrenia but that other disorders may require much larger samples. Our findings indicate that current widespread practices in structural MRI are unlikely to identify robust morphometric phenotypes for psychiatric disorders.},
}
@article {pmid42533301,
year = {2026},
author = {Singh, AK and Dunde, V and Maurya, MH and Vora, N and Maheta, D and Frishman, WH and Aronow, WS},
title = {Protecting the Aging Brain in Diabetes: Mechanism, Biomarkers, and Emerging Therapeutic Frontiers in Cognitive Impairment-A Comprehensive Review.},
journal = {Cardiology in review},
volume = {},
number = {},
pages = {},
doi = {10.1097/CRD.0000000000001405},
pmid = {42533301},
issn = {1538-4683},
abstract = {Diabetes, which impacts over 500 million individuals globally, has been identified as a significant risk factor for accelerated cognitive aging, mild cognitive impairment, and various forms of dementia, including Alzheimer's disease and vascular dementia. Despite its clinical relevance, cognitive decline remains an underrecognized complication within diabetes management. This comprehensive review aims to synthesize evidence across the mechanisms, biomarkers, and therapeutic approaches pertinent to diabetes-associated cognitive impairment, with a particular emphasis on the aging brain. The primary literature search was conducted across the decade 2015-2025; however, earlier landmark studies and foundational scientific contributions have been selectively included where necessary to contextualize contemporary findings within the broader historical trajectory of the field. A systematic literature search was executed across PubMed, MEDLINE, Embase, and PsycINFO utilizing MeSH terms such as "type 2 diabetes mellitus," "cognitive decline," "dementia," "insulin resistance," "neuroinflammation," and "neuroprotection." Diabetes contributes to accelerated brain aging via several convergent pathways, including insulin resistance, chronic neuroinflammation, oxidative stress, blood-brain barrier dysfunction, and cerebrovascular damage. These mechanisms facilitate amyloid-beta accumulation and tau hyperphosphorylation, thereby linking diabetes to the Alzheimer's disease spectrum. Promising biomarkers for early detection include plasma p-tau 217, neurofilament light chain, and various neuroimaging markers.},
}
@article {pmid42533535,
year = {2026},
author = {Qiya, Z and Mandic, M and Waterboer, T and Ruijie, X and Brenner, H and Schöttker, B},
title = {Associations of Inherited Chromosomally-Integrated Human Herpesvirus 6 With Dementia Incidence, Inflammation, and Other Dementia Risk Factors in the UK Biobank.},
journal = {Journal of medical virology},
volume = {98},
number = {8},
pages = {e71085},
doi = {10.1002/jmv.71085},
pmid = {42533535},
issn = {1096-9071},
support = {//China Scholarship Council/ ; /WT_/Wellcome Trust/United Kingdom ; /MRC_/Medical Research Council/United Kingdom ; //Department of Health, Scottish government/ ; //Northwest Regional Development Agency/ ; //Welsh Assembly Government/ ; //British Heart Foundation./ ; },
mesh = {Humans ; *Herpesvirus 6, Human/genetics/immunology ; Female ; Male ; Risk Factors ; United Kingdom/epidemiology ; Aged ; *Inflammation/epidemiology/virology ; *Dementia/epidemiology/virology ; Incidence ; Middle Aged ; *Roseolovirus Infections/epidemiology/virology/complications ; Antibodies, Viral/blood ; Biological Specimen Banks ; Aged, 80 and over ; UK Biobank ; Alzheimer Disease/epidemiology/virology ; Biomarkers/blood ; },
abstract = {The infection theory of dementia states that viral infections and chronic inflammation play a role in its pathogenesis. We aimed to test whether testing positive for inherited chromosomally-integrated human herpesvirus 6 (iciHHV-6) is associated with an increased dementia incidence, inflammation, and other dementia risk factors. We included n = 247,731 participants of the UK Biobank in the analysis, of whom n = 3388 (1.4%) tested positive for iciHHV-6. Linear and logistic regression models were performed to assess the associations between iciHHV-6 with HHV-6 antigens, blood-based biomarkers of inflammation, and other dementia risk factors. Cox proportional hazards regression models were applied to assess the associations of iciHHV-6 with all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VD). Subjects with iciHHV-6 exhibited statistically significantly higher antibody responses to the HHV-6 antigens IE1A (p = 0.002) and IE1B (p < 0.001). IciHHV-6 positivity was significantly more frequent among subjects with European or Chinese ethnicity, with lower education, higher alcohol consumption, current smoking, and longer telomere length. Interestingly, iciHHV-6 positive subjects had lower C-reactive protein (CRP) levels (p = 0.029). All other inflammatory biomarkers did not differ according to iciHHV-6 status. Overall, 6615 participants were diagnosed with all-cause dementia during a median of 13.6 years, including 3340 with AD and 1708 with VD. There was no significant association between iciHHV-6 positivity and the risk of any dementia outcome. IciHHV-6 positivity was not a risk factor for dementia outcomes or increased inflammation in this large study, but was associated with higher antibody responses against HHV-6 antigens, ethnicity, telomere length, and lifestyle factors.},
}
@article {pmid42533583,
year = {2026},
author = {Chen, X and Qian, FY and Zhao, N and Liu, XT and Wang, YJ and Geng, F and Zhu, MM and Zhang, ZJ and Ren, QG},
title = {DNAJB6a deficiency induces tau pathology through IRE1α-Xbp1-induced mitochondria dysfunction.},
journal = {Zoological research},
volume = {47},
number = {4},
pages = {1319-1331},
doi = {10.24272/j.issn.2095-8137.2025.348},
pmid = {42533583},
issn = {2095-8137},
mesh = {Animals ; *HSP40 Heat-Shock Proteins/genetics/metabolism/deficiency ; *Protein Serine-Threonine Kinases/metabolism/genetics ; *Mitochondria/metabolism ; Humans ; *tau Proteins/metabolism/genetics ; *X-Box Binding Protein 1/metabolism/genetics ; *Alzheimer Disease/genetics/metabolism/pathology ; *Molecular Chaperones/genetics/metabolism ; *Endoribonucleases/metabolism/genetics ; Mice ; *Nerve Tissue Proteins/genetics/metabolism ; Gene Expression Regulation ; Brain/metabolism ; Mice, Knockout ; },
abstract = {Endoplasmic reticulum (ER) stress and mitophagy have been indicated in the early stage of Alzheimer's disease (AD), in which tau hyperphosphorylation is one major pathological alteration. However, the precise mechanism remains unclear. Herein, the study identifies a crucial protein, the DnaJ (Hsp40) homolog, subfamily B, member 6a (DNAJB6a), and elucidates its potential pathogenic role in AD. The DNAJB6 gene is systematically screened using bioinformatics methods, confirming its decreased expression in AD patients' brains. And decreased DNAJB6a was found in the brains of the APP/PS1 mice compared to the control mice. DNAJB6a [-/-] mice exhibited cognitive impairment, synaptic loss and the pathological phenotypes of AD. Depletion of DNAJB6a led to activated ER stress depending on the downregulation of heat shock 70kDa protein 5 (HSPA5). Furthermore, DNAJB6a deficiency induced and accelerated AD-like phenotypes through activating IRE1α-XBP1 induced mitochondria dysfunction. These findings highlight DNAJB6a as a potential key target for preventing AD pathology.},
}
@article {pmid42533677,
year = {2026},
author = {Lin, YC and Chiu, SC and Massey, R and Fang, YD and , },
title = {Classification of tau status with machine learning models in amyloid-positive cohorts.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71683},
doi = {10.1002/alz.71683},
pmid = {42533677},
issn = {1552-5279},
support = {P30AG086401/NH/NIH HHS/United States ; },
mesh = {Humans ; *Machine Learning ; *tau Proteins/metabolism ; Positron-Emission Tomography ; *Alzheimer Disease/diagnostic imaging/pathology/metabolism ; Magnetic Resonance Imaging ; Female ; Aged ; Cognitive Dysfunction/diagnostic imaging/pathology ; Predictive Learning Models ; Classification Algorithms ; Brain/diagnostic imaging/pathology ; Aged, 80 and over ; Neuroimaging ; },
abstract = {INTRODUCTION: Although tau positron emission tomography (PET) imaging is effective for staging tau pathology, it is limited clinically by cost and availability. Machine learning models based on magnetic resonance imaging (MRI)- and amyloid PET-derived features may serve as useful screening tools for tau pathology.<br><br>METHODS: Multiple machine learning models were developed to classify tau positivity in the Braak III/IV region using structural MRI, amyloid PET, and demographic features. Alzheimer's Disease Neuroimaging Initiative (ADNI) (n&#xa0;=&#xa0;410) data were used for model training. Open Access Series of Imaging Studies (OASIS-3; n&#xa0;=&#xa0;143) and the Standardized Centralized Alzheimer's Disease Neuroimaging (SCAN; n&#xa0;=&#xa0;154) data were used for external validation.<br><br>RESULTS: Logistic regression achieved the best performance with areas under the curve (AUCs) of 0.92 for both internal and external validation. Combined external validation yielded accuracy/sensitivity/specificity of 85%/83%/85%. Subjects with mild cognitive impairment and predicted tau positivity progressed to AD at a significantly faster pace (p&#xa0;<&#xa0;10[-6]).<br><br>DISCUSSION: Our model demonstrates the feasibility of classifying tau burden in amyloid-positive cohorts with MRI- and amyloid PET-derived features and may serve as a surrogate biomarker.},
}
@article {pmid42533763,
year = {2026},
author = {Nakashima, S and Sato, K and Niimi, Y and Ihara, R and Suzuki, K and Iwata, A and Satake, W and Iwatsubo, T and , },
title = {Therapeutic Time Window of Disease-Modifying Therapy for Early Alzheimer's Disease in Japanese Individuals: Analysis Based on J-ADNI Study.},
journal = {Geriatrics &amp; gerontology international},
volume = {26},
number = {8},
pages = {e70698},
doi = {10.1111/ggi.70698},
pmid = {42533763},
issn = {1447-0594},
support = {24dk0207068//Japan Agency for Medical Research and Development/ ; 25dk0207075//Japan Agency for Medical Research and Development/ ; JP24K10653//Japan Society for the Promotion of Science/ ; JP25K19014//Japan Society for the Promotion of Science/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnosis ; Female ; Japan/epidemiology ; Retrospective Studies ; Male ; Aged ; Time Factors ; Aged, 80 and over ; Mental Status and Dementia Tests ; *Antibodies, Monoclonal, Humanized/therapeutic use ; East Asian People ; },
abstract = {BACKGROUND: Lecanemab and donanemab are recently approved disease-modifying therapies (DMTs) for early Alzheimer's disease (AD), indicating amyloid positivity, with Mini-Mental State Examination (MMSE) requirements. Prior analyses using North American population data suggested that baseline Clinical Dementia Rating-Global Score (CDR-GS) and MMSE may define the "therapeutic time window," but generalizability to Asian populations remains uncertain.<br><br>OBJECTIVE: To investigate the duration and predictors of the therapeutic time window, defined as the period until patients with early AD no longer meet eligibility criteria in Japanese patients.<br><br>METHODS: We retrospectively analyzed amyloid-positive participants from Japanese Alzheimer's Disease Neuroimaging Initiative, classified as lecanemab-eligible (MMSE 22-30, n&#x2009;=&#x2009;129) or donanemab-eligible (MMSE 20-28, n&#x2009;=&#x2009;143). Kaplan-Meier survival was estimated over 24&#x2009;months, and Cox proportional-hazards models included age, sex, MMSE, CDR-GS, and baseline diagnosis. Education years, apolipoprotein-E &#x3b5;4 (APOE-&#x3b5;4), and CDR-Sum of Boxes (CDR-SB) were tested individually.<br><br>RESULTS: At 12 and 24&#x2009;months, survival probabilities for remaining eligible were 82% and 69% (MCI) versus 51% and 38% (AD) in the lecanemab group, and 92% and 81% (MCI) versus 69% and 52% (AD) in the donanemab group. Baseline CDR-GS of 1 versus 0.5 predicted shorter eligibility for donanemab (HR&#x2009;=&#x2009;2.50, 95% CI: 1.20-5.21), but not for lecanemab (HR&#x2009;=&#x2009;0.48, 95% CI: 0.18-1.29). Each one-point increase in MMSE above threshold was protective (HR&#x2009;=&#x2009;0.67-0.68).<br><br>CONCLUSIONS: Baseline CDR-GS and MMSE strongly predict the therapeutic time window in Japanese patients, supporting cross-population generalizability and contributing to the management of AD DMTs under resource constraints.},
}
@article {pmid42534606,
year = {2026},
author = {Wen, J and Zhao, M and Xiao, Y and Li, S and Hu, W},
title = {Correction: OATP1A2 mediates Aβ1-42 transport and may be a novel target for the treatment of Alzheimer's disease.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1903977},
doi = {10.3389/fphar.2026.1903977},
pmid = {42534606},
issn = {1663-9812},
abstract = {[This corrects the article DOI: 10.3389/fphar.2024.1443789.].},
}
@article {pmid42534730,
year = {2026},
author = {Liu, L and Xiao, H and Zhou, J and Zhang, M and Duan, J},
title = {Polyphenols and microglial dynamics in neurodegenerative diseases: mechanistic advances and therapeutic perspectives.},
journal = {PeerJ},
volume = {14},
number = {},
pages = {e21359},
pmid = {42534730},
issn = {2167-8359},
mesh = {*Polyphenols/pharmacology/therapeutic use ; *Microglia/drug effects/metabolism ; Humans ; *Neurodegenerative Diseases/drug therapy ; Animals ; *Neuroprotective Agents/pharmacology/therapeutic use ; Blood-Brain Barrier/metabolism ; Neuroinflammatory Diseases/drug therapy ; },
abstract = {Neuroinflammation plays a central role in multiple neurological and neurodegenerative disorders, including ischemic brain injury, Alzheimer's disease (AD), and Parkinson's disease (PD). Microglia, the principal immune cells with in the central nervous system (CNS) are pivotal mediators of neuroinflammatory responses via their dynamic transition across a spectrum of polarization states, broadly delineated by pro-inflammatory M1-like and anti-inflammatory M2-like phenotypic profiles. A pathological skew towards pro-inflammatory microglial activation drives and exacerbates disease progression, thereby rendering the modulation of microglial polarization states a promising therapeutic target for neuroprotective intervention. Natural polyphenols have garnered increasing interest owing to their capacity to traverse the blood-brain barrier (BBB), confer neuroprotective effects, and mitigate neuroinflammation. Despite challenges in clinical translation stemming from poor bioavailability and rapid in vivo metabolism, innovative delivery systems are being developed to address these limitations. This review consolidates current evidence regarding the mechanisms by which polyphenols modulate microglial phenotypic balance and polarization states and examines advanced delivery strategies designed to enhance their therapeutic efficacy in neuroinflammatory disorders. By synthesizing these perspectives, we offer novel insights into the potential application of polyphenols in neuroprotective therapies targeting pathological neuroinflammation.},
}
@article {pmid42534796,
year = {2026},
author = {Manchester, M and Boughrum, A and Helmly, V and Olupitan, O and Arias, J},
title = {A 10-state investigation of AD/ADRD-capable assisted living regulations using a comprehensive dementia care model.},
journal = {Frontiers in dementia},
volume = {5},
number = {},
pages = {1789887},
pmid = {42534796},
issn = {2813-3919},
abstract = {INTRODUCTION: State regulation is central in shaping dementia care practices in assisted living facilities. Yet, there is limited systematic evidence examining how regulatory requirements vary and affect residents across states. Additionally, regulatory frameworks governing the training requirements and staff presence of ALFs play a vital role in shaping ALFs' dementia care capacity.<br><br>METHODS: This article reports the results of a legal mapping study that evaluated the variation of assisted living facility (ALF) memory care regulations across 10 states. We compared the regulations of these 10 selected states to the "gold standard" Dementia Care Practice Recommendations, a comprehensive memory care model compiled by the Alzheimer's Association (Fazio et al., 2018).<br><br>RESULTS: Of the care model's nine recommendations, regulations aligned most to the following: 1. Supportive and Therapeutic Environment (84% average alignment across 10 states), 2. Information Education and Support (74% average), and 3. Ongoing Care (70% average). States with regulation in highest alignment to the care model included California, Missouri, and Minnesota. Regulations were least aligned with the following recommendations: 7. Person-Centered Care (55% average), 8. Detection and Diagnosis (51% average), and 9. Medical Management (50%). States with regulation in lowest alignment to the care model included Texas, Georgia, and Connecticut.<br><br>DISCUSSION: Overall, inconsistencies in state alignment to the Care Model also underscore the absence of a standardized enforcement mechanism across assisted living systems. Additional evidence is needed to link regulatory standards to actual measured changes in state-level care coordination practice in the ALF setting. Target areas for regulation change may also exist outside of mechanisms that govern the staff and services directly provided by ALFs. Methods of this study are building blocks from which researchers may systematically collect and analyze regulations data for future across-state LTSS studies.},
}
@article {pmid42534839,
year = {2026},
author = {Li, Z and Ming, Q and Fu, L and Yang, J and Lv, Y and Chen, B and Qiu, X and Lu, Z},
title = {Anemia, iron deficiency, and blood biomarkers for Alzheimer disease: clinical interpretation and dementia risk stratification.},
journal = {Frontiers in nutrition},
volume = {13},
number = {},
pages = {1897378},
pmid = {42534839},
issn = {2296-861X},
abstract = {Anemia and iron deficiency are common in older adults, yet their relevance to blood biomarkers for Alzheimer disease (AD) remains underappreciated. As these biomarkers move into clinical pathways, their interpretation depends not only on assay performance but also on comorbidity, kidney function, inflammation, and nutritional status. Against this backdrop, anemia, absolute iron deficiency, and functional iron deficiency are better viewed as distinct hematopoietic nutritional phenotypes than as background covariates, with important implications for interpreting the amyloid-β42/40 ratio, phosphorylated tau 217 (p-tau217), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). Current human data link anemia and iron-restricted states to higher dementia risk and to variation in plasma p-tau217, GFAP, and NfL; kidney function, body mass index (BMI), inflammation, and multimorbidity further shift biomarker distributions and cutoff interpretation. Among available analytes, p-tau217 is closest to routine clinical use within validated intended-use diagnostic pathways; however, its interpretation remains assay- and cutoff-specific and depends on pretest probability, gray-zone handling, kidney function, BMI, hemoglobin, ferritin, and transferrin saturation. Mechanistic work supports plausible links involving impaired oxygen delivery, disrupted iron-mitochondrial bioenergetics, hepcidin-mediated functional iron restriction, and glial, myelin, and blood-brain barrier vulnerability, although a complete human causal chain has not been established. Current evidence therefore favors phenotype-aware interpretation over hemoglobin-only screening or biomarker-only reading. In memory clinics and geriatric practice, complete blood count and iron studies may provide useful interpretive context in selected patients, particularly when multimorbidity, chronic kidney disease (CKD), inflammation, nutritional vulnerability, fatigue, or low or low-normal hemoglobin could affect biomarker interpretation or downstream decisions. Future studies should test whether, and in whom, correcting iron-related phenotypes changes biomarker-guided risk stratification, biomarker trajectories, or clinical decisions.},
}
@article {pmid42534861,
year = {2026},
author = {Wu, X and Yu, T and Hu, S and Zhang, T},
title = {Global research trends and hotspots of short-chain fatty acids in cognitive impairment: a bibliometric analysis based on two databases.},
journal = {Frontiers in medicine},
volume = {13},
number = {},
pages = {1857769},
pmid = {42534861},
issn = {2296-858X},
abstract = {OBJECTIVE: Short-chain fatty acids (SCFAs) have been widely investigated in research related to cognitive impairment, yet systematic bibliometric analyses focusing on their correlation remain relatively scarce. This study employed bibliometric analysis to objectively review relevant literature, identify key research contributors, and uncover emerging frontiers in the field.<br><br>METHODS: Relevant literature published from 2009 to 2025 was retrieved from the Web of Science Core Collection (WoSCC) and Scopus databases. Bibliometric analyses were performed using the Bibliometrix R package, VOSviewer, and CiteSpace software to evaluate research outputs and generate visualizations.<br><br>RESULTS: A total of 425 eligible articles from WoSCC and 514 from Scopus were included. Annual publications on SCFAs and cognitive impairment showed a continuous upward trend from 2009 to 2025. China contributed the largest number of publications in this field, and an international collaboration network has been established, with Wenzhou Medical University (China) serving as the core collaboration hub. International Journal of Molecular Sciences was identified as a major publication platform, and Zhang, Xin was recognized as a core author in SCFA-cognitive impairment research. High-frequency keywords included "gut microbiota," "Alzheimer's disease," "neuroinflammation," and "gut-brain axis." In addition, recent research frontiers encompassed "drug therapy," "microbiology," and "chemistry," revealing the core themes and trends of SCFA and cognitive impairment studies.<br><br>CONCLUSION: This study conducted a comprehensive bibliometric analysis of the association between SCFAs and cognitive impairment, clarified the evolutionary trajectory of research themes, and identified potential future research directions. It revealed a developmental pattern whereby research in this field has gradually advanced from exploring basic correlations between diet and gut microbiota to in-depth investigations of pathological mechanisms, precise targeted interventions, and clinical translational applications. By systematically depicting the current research landscape, this study aims to provide guidance for subsequent investigations and fill critical knowledge gaps.},
}
@article {pmid42534986,
year = {2026},
author = {Xavier, C and Correia, AP and Lopes, J and Fernandes, J and Laranjinha, I and Pinto, N},
title = {Mapping Alzheimer's disease heterogeneity through exploratory unsupervised learning.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1869804},
pmid = {42534986},
issn = {1663-4365},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is becoming one of the most pressing health challenges of the century, affecting circa 55 million people worldwide and expected to triple this number by 2050. Besides the growing prevalence, AD remains difficult to diagnose due to its long preclinical phase and substantial symptomatic heterogeneity. Despite the existence of international guidelines for AD diagnosis emphasizing the use of biomarkers (such as neuroimaging and cerebrospinal molecular biomarkers), most research studies are still using data disregarding their diagnostic quality, blurring the overall statistical outcomes. Aiming to circumvent this effect, biomarker confirmed samples from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were used, which integrate genetic and neuroimaging data for all participants.<br><br>METHODS: Unsupervised machine learning clustering methods were tested to explore whether curated genetic markers can reveal underlying substructure within sporadic AD (sAD). Here two specific sets of single nucleotide polymorphisms (SNPs) were selected: (i) candidate SNPs highlighted in previous studies that identified the existence of different subtypes in sAD and (ii) SNPs found associated with sAD in genome wide association studies (GWAS) that used at least 50% of samples with biomarker-confirmed diagnosis.<br><br>RESULTS: This strategy minimized background noise and enabled the construction of high quality SNP sets for analysis. Different clustering algorithms were evaluated with agglomerative hierarchical clustering consistently yielding the most robust performance. Across SNP sets, most trials revealed a reproducible binary structure within sAD samples, suggesting the presence of genetically distinguishable subgroups.<br><br>DISCUSSION: These findings align with emerging multimodal evidence supporting biological heterogeneity in AD. Overall, this work demonstrates that curated SNP panels combined with unsupervised learning can uncover meaningful substructure in sAD, reinforcing the value of integrating high quality genetic data into subtype research.},
}
@article {pmid42535261,
year = {2026},
author = {Saef, B and Petersen, KK and Volluz, K and Li, Y and Tosun, D and Mila-Aloma, M and Shaw, LM and Zetterberg, H and Dage, JL and Rubel, CE and Ferber, K and Du-Cuny, L and Coomaraswamy, J and Baratta, M and Mordashova, Y and Saad, ZS and Triana-Baltzer, G and Ashton, NJ and Meyers, EA and Rosenbaugh, EG and Sabandal, JM and Bannon, AW and Potter, WZ and , and , and Schindler, SE},
title = {Exploring longitudinal relationships among Alzheimer's disease biomarkers.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71711},
doi = {10.1002/alz.71711},
pmid = {42535261},
issn = {1552-5279},
support = {//the Foundation for the National Institutes of Health (FNIH)/ ; R01AG070941 (S.E.S.)/AG/NIA NIH HHS/United States ; //AbbVie Inc., Alzheimer's Association, Diagnostics Accelerator at the Alzheimer's Drug Discovery Foundation, Biogen, Janssen Research &amp; Development, LLC, and Takeda Pharmaceutical Company Limited/ ; //Foundation for the National Institutes of Health/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/blood/pathology ; *Biomarkers/blood ; Positron-Emission Tomography ; *tau Proteins/blood ; *Amyloid beta-Peptides/blood ; Longitudinal Studies ; Female ; Male ; Aged ; Peptide Fragments/blood ; Brain/diagnostic imaging/pathology ; },
abstract = {INTRODUCTION: While most studies of Alzheimer's disease (AD) examine cross-sectional relationships among biomarkers, longitudinal relationships are also highly relevant.<br><br>METHODS: This study in the Alzheimer's Disease Neuroimaging Initiative cohort (n&#xa0;=&#xa0;373)&#xa0;used non-parametric Spearman correlations to explore the relationships of baseline values and rates of change in plasma biomarkers and rates of change in key AD outcomes.<br><br>RESULTS: Compared to rates of change of plasma biomarkers, baseline values of plasma biomarkers were more strongly associated with rates of change in key AD outcomes. Change in amyloid positron emission tomography (PET) was most strongly associated with baseline values of amyloid beta (A&#x3b2;)42/A&#x3b2;40 and phosphorylated tau (p-tau)217, especially in amyloid PET--negative individuals. Changes in cortical thickness and measures of cognition were most strongly associated with baseline p-tau217, especially in amyloid PET-positive individuals.<br><br>DISCUSSION: Baseline p-tau217 is associated with rates of change of amyloid pathology and cognition. Visualization tools were developed to enable researchers to explore AD biomarker relationships.},
}
@article {pmid42535268,
year = {2026},
author = {Hampel, H and Nakamura, Y and Bell, J and Hendrix, S and Derchansky, M and Montezano, BB and Stoeckel, LE and Teipel, S and Willis, DR and Cummings, JL and Cobb, BR},
title = {Evaluating digital cognitive tests for clinical use in Alzheimer's disease: A novel framework and scoping review.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71559},
doi = {10.1002/alz.71559},
pmid = {42535268},
issn = {1552-5279},
support = {//Eisai Incorporated/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnosis ; *Cognitive Dysfunction/diagnosis ; Digital Health ; *Neuropsychological Tests ; Early Diagnosis ; Prodromal Symptoms ; Digital Media ; },
abstract = {Mild cognitive impairment (MCI), a prodromal stage of Alzheimer's disease (AD), remains undiagnosed in > 90% of individuals, delaying access to timely evaluation and interventions. Self-administered digital cognitive assessments (SA-DCAs) offer scalable approaches for early detection, yet their real-world validation and clinical readiness remain uncertain. We developed a use-case-specific framework to evaluate SA-DCAs intended for community and primary-care MCI screening and applied it to a comprehensive scoping review of published evidence (2012-2025). Among 79 identified SA-DCAs, only four tools met predefined framework criteria across nine eligible studies. Common limitations included restricted population representativeness, inconsistent diagnostic performance reporting, limited biomarker anchoring, and reliance on prefiltered cohorts. Overall, the current evidence base is methodologically heterogeneous and incomplete for clinical deployment. The proposed framework characterizes requirements including anchoring strength, prevalence-adjusted performance reporting, and representative sampling establishing a foundation for advancing robust real-world evidence needed to translate SA-DCAs from research to clinical practice.},
}
@article {pmid42525250,
year = {2026},
author = {Sitdikova, K and Tsoy, A and Chaprov, KD and de Munter, J and Svirin, E and Torosyan, H and Yenkoyan, K and Askarova, S and Steinbusch, HW and Anthony, DC and Strekalova, T},
title = {Large amyloid plaques associate with early behavioral alterations in 6-month-old APPswe/PS1dE9 mice.},
journal = {Journal of neuropathology and experimental neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/jnen/nlag078},
pmid = {42525250},
issn = {1554-6578},
support = {AP23485236//Ministry of Science and Higher Education of the Republic of Kazakhstan/ ; //COBRAIN Center/ ; 21T-3A327//the Higher Education and Science Committee of the Republic of Armenia/ ; 26YSMU-CON-S-3A//the Higher Education and Science Committee of the Republic of Armenia/ ; 101007642//the Higher Education and Science Committee of the Republic of Armenia/ ; 101086453//Aqua-Synapse/ ; EP/Y000420/1//Aqua-Synapse/ ; //EU frameworks/ ; //European Union's HORIZON 2020/ ; //European Commission/ ; },
abstract = {Understanding the earliest pathological changes in Alzheimer disease (AD) is critical for improving early intervention strategies. However, the relationship between amyloid plaque characteristics and early behavioral and molecular alterations remains unclear. We used 6-month-old female APPswe/PS1dE9 mice, a model of early amyloid-dominant pathology, to assess cognition and emotionality across a battery of behavioral tests. Amyloid plaques were quantified using Congo red staining; RT-qPCR and GFAP immunoreactivity were used to assess molecular and glial changes. APPswe/PS1dE9 mice exhibited increased anxiety-like behavior without significant changes in overall locomotor activity. Small plaques (<100 μm2) predominated across all regions; however, behavioral measures of hyperactivity and anxiety correlated specifically with the density and size of large (>200 μm2) plaques. Gene expression changes, including altered SYP, IGF1, TNF, and IL6 expression, were observed primarily in the midbrain and did not correlate with amyloid plaque characteristics. These findings demonstrate that large amyloid plaques, rather than total plaque burden, are selectively associated with early behavioral alterations in APPswe/PS1dE9 mice. Moreover, the midbrain emerges as an early site of molecular dysregulation despite limited plaque deposition. Together, these results support the use of 6-month-old APPswe/PS1dE9 mice as a model of early, amyloid-dominant stages of AD.},
}
@article {pmid42525347,
year = {2026},
author = {Kumari, A and Aran, KR},
title = {KLF4 in Parkinson's Disease: Decoding the Molecular Puzzle of Neuroinflammation, Oxidative Stress, and Emerging Therapies.},
journal = {Current medical science},
volume = {},
number = {},
pages = {},
pmid = {42525347},
issn = {2523-899X},
abstract = {Parkinson's disease (PD) is the most prevalent neurodegenerative movement condition. Tremors, stiffness, bradykinesia/akinesia, and postural instability are its primary motor symptoms; nevertheless, the clinical features also include non-motor and additional motor symptoms. Krüppel-like factor 4 (KLF4), a zinc finger transcription factor, is present in several human tissues and performs a range of cell-dependent regulatory actions. Various neurological diseases, such as PD, Alzheimer's disease (AD), and Huntington's disease (HD), have been linked to KLF4, which regulates some neurophysiological and neuropathological processes in the brain. Recent data indicate that KLF4 plays a crucial regulatory role in the neurophysiological and neuropathological processes underlying PD, suggesting that it might be a viable therapeutic target for neurodegenerative diseases. This review focuses on the potential molecular mechanism underlying KLF4-mediated neuroinflammation, oxidative stress, mitochondrial dysfunction, and apoptosis. KLF4-mediated pathways are clarified by the information gathered here, and targeting them appears to be a viable therapeutic strategy for treating PD. Nevertheless, there is insufficient information on this subject, and more investigations are needed to fully understand the translational significance of the KLF4-oriented therapeutic strategy in PD.},
}
@article {pmid42525357,
year = {2026},
author = {Sklinda, K and Bocianski, J and Budlewski, T and Kobylecka, M and Dorobek, M and Gorecki, A and Mruk, B and Błaszczak, M and Walecki, J},
title = {Perfusion as a biomarker of brain dysfunction in dementia (AD, DLB, FTD/PPA, PDD): comparison of CT, MRI (ASL/DSC/DCE), SPECT, and PET with interpretive pitfalls - a narrative review.},
journal = {Acta neurologica Belgica},
volume = {},
number = {},
pages = {},
pmid = {42525357},
issn = {2240-2993},
abstract = {The term 'brain perfusion' is applied in clinical practice to a family of neuroimaging techniques that measure, in reality, quite different physiological quantities in the brain circulation. CT perfusion (CTP) and DSC-MRI track a contrast bolus to derive semi-quantitative haemodynamic parameters. ASL-MRI estimates cerebral blood flow (CBF) without contrast, but the result is sensitive to arterial transit time, haematocrit, and the patient's haemodynamic state on the day of the scan. DCE-MRI quantifies blood-brain barrier (BBB) permeability, a property of the neurovascular unit rather than a flow measurement. Perfusion SPECT provides a relative, normalisation-dependent CBF map that is distorted by cortical atrophy. [[18]F]FDG-PET reflects synaptic glucose metabolism, but not blood flow. Because these techniques answer different physiological questions, their results are not interchangeable, and applying a threshold or pattern derived from one modality to interpret another is methodologically unsound - yet this conflation occurs with regularity in clinical practice. This narrative review synthesises the clinical applications, diagnostic performance, and interpretive pitfalls of each technique in Alzheimer's disease (AD)/mild cognitive impairment (MCI-AD), dementia with Lewy bodies (DLB)/Parkinson's disease dementia (PDD), frontotemporal dementia (FTD)/primary progressive aphasia (PPA), and mixed dementia with vascular pathology. Recognised limitations include the narrative study design and the small number of head-to-head multi-modal studies in pathologically confirmed cohorts. A comparative table and practical minimum reporting elements are provided.},
}
@article {pmid42525901,
year = {2026},
author = {Zheng, J and Lip, GYH and Zhang, Z and Lee, SWR},
title = {Association of Sugar Restriction in Utero Through Age 2 Years on Dementia Risk Later in Life.},
journal = {Neurology},
volume = {107},
number = {4},
pages = {e218313},
doi = {10.1212/WNL.0000000000218313},
pmid = {42525901},
issn = {1526-632X},
mesh = {Humans ; Female ; *Dementia/epidemiology/etiology/diagnostic imaging ; *Prenatal Exposure Delayed Effects/epidemiology ; Pregnancy ; Male ; Middle Aged ; United Kingdom/epidemiology ; Developmental Origins of Health and Disease ; Risk Factors ; Dementia, Vascular/epidemiology ; Magnetic Resonance Imaging ; Alzheimer Disease/epidemiology ; Brain/diagnostic imaging ; Aged ; Adult ; Infant ; },
abstract = {BACKGROUND AND OBJECTIVES: Excess sugar intake in early life may affect long-term brain health, but evidence for dementia is limited. We used the abrupt end of UK sugar rationing in September 1953 as a natural experiment to test whether exposure to sugar rationing during different windows within the first 1,000 days from conception was associated with adult risk of all-cause dementia, Alzheimer disease (AD), and vascular dementia (VaD).<br><br>METHODS: We analyzed UK Biobank participants born around the end of UK sugar rationing. Exposure was classified as rationing in utero only, in utero plus the first year of life, in utero plus 1-2 years of life, or no exposure. Incident dementia was identified from linked ICD-10 records. MRI of the brain and cognitive function were assessed in the imaging subcohort. Adjusted Cox and Gompertz models estimated HRs and 95% CIs, Fine-Gray models accounted for competing risk, and mediation analyses evaluated type 2 diabetes and hypertension.<br><br>RESULTS: Among 64,737 participants included in the analysis, the mean age at recruitment was 54.6 years, and 56.4% were women; 40,963 were exposed to sugar rationing during fetal and/or early-childhood life, and 23,774 were unexposed. Compared with unexposed individuals, sugar rationing in utero plus the first year of life was associated with lower hazards of all-cause dementia (HR, 0.79; 95% CI 0.66-0.94) and AD (HR, 0.77; 95% CI 0.59-1.00). Similar or slightly stronger associations were observed for exposure in utero plus 1-2 years (all-cause dementia: HR, 0.77; 95% CI 0.63-0.95; AD: HR, 0.72; 95% CI 0.53-0.98). Exposure in utero plus 1-2 years was associated with delayed onset of all-cause dementia by 2.55 years, AD by 2.87 years, and VaD by 2.49 years. Early-life sugar rationing was also associated with higher total gray matter volume (&#x3b2;, 3.27; 95% CI 0.46-6.07), lower white matter hyperintensity volume (&#x3b2;, -0.64; 95% CI -0.97 to -0.31), and better performance in processing speed and reasoning. Incident type 2 diabetes and hypertension jointly mediated 25.5% of the association.<br><br>DISCUSSION: Sugar restriction in the first 1,000 days was associated with lower dementia hazards, delayed onset, and more favorable brain-health profiles. These results support early-life sugar reduction as a potential strategy for dementia prevention.},
}
@article {pmid42526376,
year = {2026},
author = {Hu, H},
title = {Interpreting plasma p-tau217 discordance in real-world memory clinics.},
journal = {Journal of the neurological sciences},
volume = {489},
number = {},
pages = {126117},
doi = {10.1016/j.jns.2026.126117},
pmid = {42526376},
issn = {1878-5883},
}
@article {pmid42526554,
year = {2026},
author = {Peng, B and Zou, S and Shi, Y and Zhu, X and Liu, M and Li, H and Zhang, Y},
title = {Fluorescence imaging-based investigation of tau-mediated promotion of U1 small nuclear ribonucleoprotein 70 kDa co-phase separation.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {153818},
doi = {10.1016/j.ijbiomac.2026.153818},
pmid = {42526554},
issn = {1879-0003},
abstract = {Neurofibrillary tangles formed by Tau protein are a core pathological hallmark of Alzheimer's disease (AD). Although liquid-liquid phase separation (LLPS) of Tau is thought to induce its aggregation, and the basic-acidic dipeptide (BAD) domain-containing protein U1 small nuclear ribonucleoprotein 70 kDa (U1-70K) abnormally co-localizes with Tau tangles in AD brains, the molecular mechanism underlying their co-aggregation remains unclear. In this study, we found that Tau co-phase separates with two low-complexity domains (LC1/LC2). Both LC1 and LC2 promote the gelation of Tau droplets and the formation of pathological Tau aggregates under the conditions tested. Furthermore, under cellular stress, Tau and U1-70K exhibit aberrant cytoplasmic co-localization, suggesting a functional link between them under pathological conditions and providing new insights into the molecular basis of Tau pathology in AD.},
}
@article {pmid42526715,
year = {2026},
author = {Bang, KY and Walenga, R and Chopski, S and Luke, MC and Blinova, K and Zhao, L and Guo, S},
title = {Intranasal drug delivery to the brain for neurodegenerative diseases: Current efforts and challenges in delivery platforms and modeling.},
journal = {Advanced drug delivery reviews},
volume = {},
number = {},
pages = {115938},
doi = {10.1016/j.addr.2026.115938},
pmid = {42526715},
issn = {1872-8294},
abstract = {Neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease (AD), globally pose a significant challenge with an aging population. Despite the presence of various therapeutic agents, AD and PD treatments with small molecules currently only address the symptoms; certain biologic agents for AD have been approved for their disease-modifying effects, but the risk of intracerebral hemorrhage severely limits their use. Moreover, the bioavailability of orally administered agents in the brain is challenged by the blood-brain barrier, complicating brain-targeted drug development. Extensive efforts are currently underway to develop intranasal platforms with nanoparticles for direct nose-to-brain drug delivery. Additionally, various in vitro designs involving brain organoids, and in vivo models, such as rodents and zebrafish, have been explored to improve the efficiency and accuracy of preclinical models. Efforts to develop sophisticated computational modeling of intranasal drug delivery, including computational fluid dynamics (CFD) deposition and physiologically based pharmacokinetics (PBPK) modeling, also continue to advance the intranasal drug delivery research and potentially improve the feasibility of developing clinically relevant intranasal platforms for neurodegenerative disease.},
}
@article {pmid42527124,
year = {2026},
author = {Li, J and Wang, Y and Shi, L and Zheng, Z and Wu, Y and Jiang, N},
title = {Global Perspectives on Social Relationships and Cognitive Decline in Older Adults: Insights From Cohort Studies in the U.S., Mexico, England, and China.},
journal = {Journal of applied gerontology : the official journal of the Southern Gerontological Society},
volume = {},
number = {},
pages = {7334648261470866},
doi = {10.1177/07334648261470866},
pmid = {42527124},
issn = {1552-4523},
abstract = {BackgroundThis research aimed to explore associations between social relationships and annual cognitive decline in older adults globally.MethodsHarmonized data from 4 longitudinal aging cohorts across the U.S., Mexico, England, and China were included. Participants (aged ≥55) with social relationship data and repeated cognitive assessments were analyzed, excluding dementia cases. Linear mixed models assessed associations between social relationship markers and annual rate of cognitive decline, with effects pooled via two-stage random-effects meta-analysis.ResultsAmong 29,805 participants, living with others was associated with slower decline in episodic memory (b = 0.086, 95%CI: 0.013 to 0.158) and global cognition (b = 0.025, 95%CI: 0.013 to 0.038). Felt loneliness was associated with faster decline in episodic memory (b = -0.087, 95%CI: -0.140 to -0.034) and global cognition (b = -0.023, 95%CI: -0.040 to -0.006).ConclusionsGood social relationships were associated with slower cognitive decline, while poor social relationships with faster decline.},
}
@article {pmid42527215,
year = {2026},
author = {Ahmad, M and Irshad, A and Ahmed, MA and Ahmed, FK and Noor, S and Irshad, H},
title = {Demographic, gender and ethnic disparities in COPD associated mortality trends among older adults (&gt;55 years) with Alzheimer's disease in the United States, 1999-2020: a 20 year retrospective analysis using CDC WONDER database.},
journal = {Journal of the National Medical Association},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jnma.2026.06.021},
pmid = {42527215},
issn = {1943-4693},
abstract = {BACKGROUND: Alzheimer's disease (AD) is the 3rd leading cause of global deaths. COPD and AD have a bi-directional positive relationship, increasing the interrelated mortality.<br><br>OBJECTIVES: To analyze the mortality trends associated with COPD in Alzheimer's disease among older adults (>55 years of age) in the United States, using CDC WONDER data from 1999 to 2020.<br><br>METHODS: A retrospective analysis using the CDC WONDER database was conducted to analyse the mortality trends due to COPD in Alzheimer's disease patients, stratified by sex, race/ethnicity, census region, states and urbanization status.<br><br>RESULTS: A total of 58,495 deaths due to COPD-associated Alzheimer's disease occurred among older adults (aged >55 years). Overall mortality increased from an AAMR of 2.04 per 100,000 in 1999 to 5.19 per 100,000 in 2020 (AAPC=4.31%, p&#x202f;<&#x202f;0.05). Men exhibited higher mortality than women (AAMR 4.00&#x202f;vs. 3.58 per 100,000). Non-Hispanic Whites had the highest mortality (AAMR 4.04), followed by Hispanics (AAMR; 2.58) and Non-Hispanic Blacks (AAMR; 2.39). The mortality was highest in the Western region (AAMR; 4.3), followed by Southern region (AAMR; 4.14), Midwestern region (AAMR; 3.94) and least in Northeastern region (AAMR; 2.26). Non-Metropolitan areas exhibit higher AAMR (4.62) than Metropolitan areas (AAMR; 3.52). Tennessee, Kentucky, and Washington were the top 3 states with the highest mortality. Significant increases in mortality were observed across most demographic groups (p&#x202f;<&#x202f;0.05).<br><br>CONCLUSION: These findings highlight the increasing COPD-related mortality among Alzheimer's patients and reveal significant disparities by sex, race, and urbanization status. Systemic inflammation, oxidative stress, and COPD-induced hypoxia may contribute to cognitive impairment and dementia. These results underscore the urgent need for targeted healthcare strategies and further research to address these disparities.},
}
@article {pmid42527300,
year = {2026},
author = {Luppi, JJ and Koomen, AP and Stam, CJ and Scheltens, P and de Haan, W},
title = {Connectome-guided personalization of optimal tDCS intervention selection in Alzheimer's disease: A modeling study.},
journal = {eNeuro},
volume = {},
number = {},
pages = {},
doi = {10.1523/ENEURO.0407-25.2026},
pmid = {42527300},
issn = {2373-2822},
abstract = {Transcranial direct current stimulation (tDCS) could reduce the neurophysiological effects in Alzheimer's disease (AD), but progress is hampered by variable outcomes across studies, likely related to both methodological and individual differences. We recently described a virtual brain network simulation method for optimizing tDCS interventions and now propose a method for further personalizing this approach. We now personalized the model for 6 female and 4 male biomarker-confirmed AD patients based on their brain structure and functional connectivity, by using individual structural magnetic resonance imaging (MRI) data and amplitude envelope correlation (AEC)-based connectivity matrices extracted from magnetoencephalography (MEG) scans, respectively. We then assessed a set of previously established stimulation strategies based on their ability to improve relevant neurophysiological outcome parameters in each personalized model, while undergoing AD damage. Personalized tDCS strategies were able to delay neurophysiological deterioration, but while the general model favored posterior anodal stimulation targeting the precuneus region, the personalized models favored frontal anodal stimulation targeting the dorsolateral prefrontal cortex (dlPFC) region in 90% of the cases. This may be explained by higher connectivity levels of frontal regions in the personalized connectivity matrices, as anodal stimulation of highly connected regions produced more beneficial effects. In this methodological study we propose several ways to improve personalized computational tDCS stimulation prediction modeling. We conclude that connectome-guided personalization of tDCS effects lead to different strategies with potentially better intervention outcomes. For external validation of this model-guided tDCS approach, model predictions are being tested in an ongoing clinical tDCS-MEG trial in AD patients.Significance statement Our aim is to improve the efficacy of transcranial direct current stimulation (tDCS) in Alzheimer's disease (AD) through the use of a personalized modeling approach. This is beneficial since results of tDCS remain variable across groups, and therefore a systematic approach to choosing the stimulation parameters such as placement of electrodes is required. Modeling of tDCS allows us to do this while assessing multiple possible approaches without necessitating a considerable burden on patients across multiple trials. Furthermore, personalizing the model can enable more accurate selection of target regions for stimulation, for example by locating highly connected brain regions without too much damage in each patient, thus increasing the potential for recovery.},
}
@article {pmid42527361,
year = {2026},
author = {Persson, J and Geffre, G},
title = {Mind Matters: South Dakota's Public Health Response to Dementia.},
journal = {South Dakota medicine : the journal of the South Dakota State Medical Association},
volume = {79},
number = {6},
pages = {262-264},
pmid = {42527361},
issn = {0038-3317},
mesh = {Humans ; South Dakota/epidemiology ; *Dementia/diagnosis/therapy/epidemiology ; *Public Health ; Caregivers ; },
abstract = {Alzheimer's disease and related dementias pose a growing health and societal challenge in South Dakota, where dementia ranks as the fourth leading cause of death. The burden extends beyond patients to families and caregivers, many of whom report significant emotional, financial, and physical strain. In response, the South Dakota Department of Health introduced the South Dakota Healthy Brain Initiative. This statewide effort aims to improve brain health across the lifespan, promote earlier detection, strengthen caregiver support, and prepare the state's workforce to better respond to the needs of people living with dementia. The initiative promotes routine cognitive assessment, distributes clinical toolkits to assist with diagnosis and care planning, and expands access to community-based services. A core focus of the initiative is health equity, particularly for rural, tribal, and underserved communities that face significant barriers to care. Through strengthened partnerships among public health, healthcare systems, and aging services, the Healthy Brain Initiative seeks to reduce disparities, support caregivers, and improve outcomes for individuals and families affected by dementia across South Dakota.},
}
@article {pmid42527385,
year = {2026},
author = {Postuma, RB},
title = {Amyloid Co-Pathology and Clinical Heterogeneity of Parkinson's Disease.},
journal = {Movement disorders : official journal of the Movement Disorder Society},
volume = {},
number = {},
pages = {},
doi = {10.1002/mds.70459},
pmid = {42527385},
issn = {1531-8257},
}
@article {pmid42527552,
year = {2026},
author = {Dan, X and Croteau, DL and Liu, W and Chu, X and McDevitt, RA and Robbins, PD and Bohr, VA},
title = {Mitochondrial accumulation and lysosomal dysfunction result in mitochondrial plaques in Alzheimer's disease.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {42527552},
issn = {1546-1726},
support = {U19 AG056278 and U54 AG079754//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
abstract = {Dysfunctional mitophagy is proposed as a key component of Alzheimer's disease (AD) pathology, yet direct in vivo evidence and mechanistic insights are still lacking. Here we show that AD model mice expressing a mitophagy reporter (APP/PSEN1/mt-Keima) develop large accumulation of acidic and neutral mitochondria within neuronal processes that form a previously unrecognized pathological structure termed mitochondrial plaques (MPs). The development of MPs is driven by abnormal mitochondrial buildup and lysosomal recruitment occurs as a delayed response to promote mitochondrial degradation. However, degradation through mitophagy is incomplete due to impaired lysosomal functions, resulting in accumulation of both neutral and acidic mitochondria. MPs frequently codevelop with amyloid to form mixed plaques but can also emerge independently at early stages of disease. Notably, MPs were also identified in the 5xFAD AD mouse model and postmortem human AD brains. These findings establish MPs as a new pathological entity in AD.},
}
@article {pmid42527710,
year = {2026},
author = {Le Bras, A},
title = {Metabolomics atlas of Alzheimer's disease models.},
journal = {Lab animal},
volume = {55},
number = {8},
pages = {283},
doi = {10.1038/s41684-026-01782-x},
pmid = {42527710},
issn = {1548-4475},
}
@article {pmid42527713,
year = {2026},
author = {Jiang, M and Lin, Y and Wang, L and Ou, K},
title = {LncRNA DLX6-AS1 Regulates the Pathological Process Related to Alzheimer's Disease via miR-204-5p.},
journal = {Neuromolecular medicine},
volume = {28},
number = {1},
pages = {},
pmid = {42527713},
issn = {1559-1174},
mesh = {Humans ; *Alzheimer Disease/pathology/genetics/blood/metabolism ; *MicroRNAs/physiology/genetics/biosynthesis/blood ; tau Proteins/metabolism ; Female ; Male ; Amyloid beta-Peptides/pharmacology/toxicity ; Phosphorylation ; *RNA, Long Noncoding/physiology/blood/genetics ; Cell Line, Tumor ; Aged ; Animals ; *Homeodomain Proteins/physiology/genetics ; Peptide Fragments/pharmacology/toxicity ; Aged, 80 and over ; Mice ; Brain/pathology ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder causing progressive neuronal damage. Incidence rises with age, and early diagnosis is difficult. This study examined DLX6-AS1 clinical relevance and regulatory mechanism in AD, and its interaction with miR-204-5p in AD pathology. It offers new insights into early diagnosis and treatment. A total of 133 AD patients and 105 healthy controls were selected. Their serum levels of DLX6-AS1 and miR-204-5p were analyzed using quantitative polymerase chain reaction. β-amyloid (Aβ)1-42-induced SH-SY5Y neuronal injury and okadaic acid (OA)-induced Neuro-2a tau abnormal phosphorylation models were constructed. The role/function of DLX6-AS1/miR-204-5p axis was then investigated using cell counting kit-8, flow cytometry, western blotting, enzyme-linked immunosorbent assay and a dual-luciferase reporter gene assay. AD patients had higher serum DLX6-AS1 and lower miR-204-5p levels. DLX6-AS1 showed an AUC of 0.838 for AD diagnosis. DLX6-AS1 levels were negatively associated with cognitive function, brain structural integrity, and benign pathology-and positively associated with disease severity, functional impairment, and pathological markers. In AD cell models, DLX6-AS1 was upregulated. Silencing it promoted cell proliferation, reduced apoptosis and oxidative stress, improved mitochondrial and synaptic function, decreased tau phosphorylation, and enhanced microtubule stability and axonal transport. Dual-luciferase assays confirmed direct binding between DLX6-AS1 and miR-204-5p. Co-inhibition reversed the protective effects of DLX6-AS1 silencing. Serum DLX6-AS1 is a potential biomarker for early diagnosis and assessment of AD. It regulates Aβ-induced neuronal damage and tau phosphorylation by targeting miR-204-5p, offering a new mechanism target for AD molecular therapy.},
}
@article {pmid42527781,
year = {2026},
author = {Salvador, GLO and Park, JW and Schmidt, TS and Park, Y and Jeon, K and You, SC and Nagy, P and Dewey, B and , },
title = {Advancing the FAIRness of Multimodal Imaging Research Through the OMOP MI-CDM Framework: A Case Replication Study in Alzheimer's Disease.},
journal = {Journal of imaging informatics in medicine},
volume = {},
number = {},
pages = {},
pmid = {42527781},
issn = {2948-2933},
abstract = {The objective of this study is to demonstrate an end-to-end approach for operationalizing the Findable, Accessible, Interoperable, and Reusable (FAIR) principles in multimodal medical imaging research using standardized data models and reproducible computational workflows, illustrated by reproducing the design and directional findings of a published Alzheimer's disease (AD) imaging study. Clinical and imaging data from the Alzheimer's Disease Neuroimaging Initiative (ADNI-4) were harmonized within the Observational Medical Outcomes Partnership Common Data Model and its Medical Imaging extension (OMOP MI-CDM). MRI acquisition metadata (DICOM) were extracted and mapped to standardized concepts, while clinical variables were integrated via reproducible extract-transform-load processes. Interoperable phenotypes were defined using OHDSI tools. Hippocampal volumes were derived from T1-weighted MRI using a fully automated machine learning segmentation pipeline (OpenMap-T1). Imaging attributes and derived measurements were stored as structured, provenance-preserving records in OMOP MI-CDM. We replicated a reference study evaluating hippocampal volume differences across AD, mild cognitive impairment (MCI), and cognitively normal controls, stratified by age and sex. We included 289 participants and 545 MRI studies. Across age- and sex-stratified cohorts, mean hippocampal volumes showed consistent directional reductions in AD compared with controls, with intermediate values in MCI, matching trends reported in the replication study. FAIR principles can be operationalized across the full imaging research pipeline using OMOP MI-CDM and automated analysis workflows. This framework enables transparent cohort definition, reproducible image processing, and interoperable reuse of machine learning-derived imaging features to support scalable validation and reproducible multimodal imaging research.},
}
@article {pmid42527810,
year = {2026},
author = {Marois, B and Leger, P and Petit, Y and Le Vot, R and Le Naveaux, F and Benoit, D and Aumeras, R and Wagnac, E},
title = {A Novel Video-Based Method to Estimate American Football Helmet Pad Deformation During Impact Testing.},
journal = {Annals of biomedical engineering},
volume = {},
number = {},
pages = {},
pmid = {42527810},
issn = {1573-9686},
support = {ETS-124//Axelys/ ; },
abstract = {PURPOSE: American football is among the sports with the highest incidence of mild traumatic brain injuries (mTBI), associated with long-term neurological consequences including cognitive impairment, chronic traumatic encephalopathy, and Alzheimer's disease. Despite recent rule changes and stricter National Football League (NFL) safety guidelines, mTBI remains common, underscoring the need for improved helmet design and evaluation. Current helmet testing protocols, such as the NFL's, measure head kinematics to derive performance scores but do not characterize helmet component behavior during impact. This study proposes a novel approach through the Pad Deformation Index (PDI)-a quantitative metric estimating compressive deformation of helmet pads during impact.<br><br>METHODS: Standard helmet impact tests were conducted at the Side Upper location, at three velocities (5.5, 7.4, and 9.3&#xa0;m/s). Complementary mechanical tests on isolated pads using a drop tower at equivalent velocities linked helmet-level outcomes with localized pad response. High-speed videos enabled frame-by-frame reconstruction of the headform-impactor interaction and calculation of the minimum distance between the two rigid bodies, from which PDI was derived.<br><br>RESULTS: Higher PDI values generally coincided with reduced peak linear acceleration (PLA), Head Injury Criterion (HIC), DAMAGE, HARM, and partial Helmet Performance Score (HPS), supporting the use of PDI as an indicator connecting impact performance metric to pad deformation. Furthermore, pads exhibiting later densification within high-PDI range produced the lowest performance scores, underscoring the critical role of delayed densification.<br><br>CONCLUSION: PDI offers a practical tool for identifying absorption mechanisms and guiding helmet design.},
}
@article {pmid42527889,
year = {2026},
author = {Li, W and Suarez-Farinas, M and Shuster, A and Mednick, S and Figueiro, MG},
title = {Home-Based Tailored Light Therapy for Sleep, Mood, and Cognitive Outcomes in Mild Cognitive Impairment: A Randomized Trial.},
journal = {Journal of applied gerontology : the official journal of the Southern Gerontological Society},
volume = {},
number = {},
pages = {7334648261474211},
doi = {10.1177/07334648261474211},
pmid = {42527889},
issn = {1552-4523},
abstract = {BackgroundLight offers a promising approach to sleep and circadian disturbances in mild cognitive impairment (MCI).ObjectiveTest a home-based lighting intervention in people living with MCI.MethodsIn a randomized, placebo-controlled trial, 61 participants received active or placebo light for 24 weeks, with assessments for cognition, sleep, depression, and quality of life at baseline, week 13, 25, and, post-intervention, at week 37. Light exposure was measured as area under the curve (AUC) for morning circadian stimulus (CS).ResultsActive light participants (mean age 69.7 years; 52% male; mean MoCA 21.4) showed greater improvement in ADAS-Cog memory scores than placebo (p = 0.035), higher morning CS AUC by week 25 (0.021 vs -0.030; p = 0.025), and better sleep percent (-0.21 vs -1.29; p = 0.042), wake percent (-0.10 vs 1.19; p = 0.023), and wake after sleep onset (2.19 vs 8.23 min; p = 0.031).},
}
@article {pmid42527927,
year = {2026},
author = {Hu, X and Yu, Y and Luo, H and Li, J and Zhang, X and Wang, G and Li, J and Li, J and Chen, H and Qiu, Y},
title = {Transaldolase 1 contributes to pentose phosphate pathway disruption and synaptic dysfunction in Alzheimer's disease.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {42527927},
issn = {2047-9158},
support = {82373844//National Natural Science Foundation of China/ ; ZXY25001//Shanghai Jiao Tong University School of Medicine High level Local University Construction of Integrated Traditional Chinese and Western Medicine Research Platform Construction Project/ ; },
mesh = {*Alzheimer Disease/metabolism/pathology ; *Pentose Phosphate Pathway/physiology ; Animals ; Humans ; Mice ; *Transaldolase/metabolism/genetics ; Male ; *Synapses/metabolism/pathology ; Glucose/metabolism ; Neurons/metabolism ; Female ; Proteomics ; Mice, Transgenic ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and synaptic dysfunction. Increasing evidence suggests that impaired glucose utilization is a major contributor to AD pathogenesis. Neurons preferentially use glucose through the pentose phosphate pathway (PPP). In AD, the flux through the PPP is significantly reduced; however, the underlying mechanism is still elusive. This study was aimed to elucidate how PPP was affected in AD and its contribution to the AD pathogenesis.<br><br>METHODS: Proteomic analyses of temporal cortex synaptosomes from AD patients and controls were conducted to identify dysregulated pathways and significantly affected proteins. Functional analysis was performed by knockdown or restoration of protein expression in primary cultured neurons, as well as in wild-type and 5&#x2009;&#xd7;&#x2009;FAD mice. Pseudotargeted metabolomics and biochemical, molecular, electrophysiological and behavioral assessments were performed to evaluate metabolic characteristics, redox status, mitochondrial function, synaptic plasticity and cognition.<br><br>RESULTS: Proteomic analysis of synaptic compartments identified glucose metabolism as the most significantly dysregulated functional network in AD. Further, transaldolase 1 (TALDO1), a rate-limiting enzyme in the PPP, was identified as a key enzyme affected in AD. TALDO1 was markedly downregulated at the early stage of AD. Downregulation of TALDO1 reduced glucose metabolism by inhibiting the PPP, TCA cycle and oxidative phosphorylation, causing broad metabolic collapse. Further, downregulation of TALDO1 depleted the nicotinamide adenine dinucleotide phosphate and glutathione pools, weakening antioxidant defense, thus resulting in mitochondria impairment and reduced energy supply. These collectively drive synaptic dysfunction and cognitive decline. Conversely, restoring TALDO1 expression in 5&#x2009;&#xd7;&#x2009;FAD mice improved glucose uptake, mitigated oxidative stress, restored metabolic homeostasis, and rescued neuronal and cognitive functions.<br><br>CONCLUSION: These findings identify TALDO1 as a key regulator of the impaired PPP in AD and may represent a promising therapeutic target for restoring neuronal metabolic homeostasis and function.},
}
@article {pmid42528450,
year = {2026},
author = {Dewhurst, HE and Jorda, L and Aranda, A and Chunduri, B and Lopez, OL and Patira, R and Gogniat, MA},
title = {Multi-case review of posterior cortical atrophy in a neuropsychology clinic.},
journal = {Neurocase},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/13554794.2026.2710636},
pmid = {42528450},
issn = {1465-3656},
abstract = {Posterior Cortical Atrophy (PCA) is a neurodegenerative syndrome defined by occipital atrophy that results in visuospatial deficits, often caused by Alzheimer's disease (AD) pathology. Patients with PCA are younger than typical AD patients and can present with anxiety. A rare and atypical variant of AD, the variable presentation of PCA has left it understudied, misdiagnosed, and with few in-depth examinations of cognitive profiles. This project reviews three patients referred for neuropsychological evaluation who were determined to have probable PCA. A comprehensive neuropsychological battery examined learning and memory, executive function, language, attention and processing speed, and visuospatial ability. Cases were examined based on cognitive complaints, daily functioning based on informant report, neuropsychological test performance, and neurodiagnostic work-up. Striking visuospatial deficits were observed in visuospatial construction tests (all patients scored < 1 percentile), and performance was impaired on most tests with visual components. Memory scores were impaired on some tests, but scores were slightly better on a contextualized verbal task compared to a word list. Patients had trouble functioning related to vision (e.g. object finding, reading) and tested positive for AD biomarkers. These cases highlight key aspects of the neuropsychological work-up for suspected PCA, including visuospatial deficits, AD biomarkers, and cognitive complaints.},
}
@article {pmid42528496,
year = {2026},
author = {Boeriu, AI and Andrews, SJ and Hoang, T and Bae, S and Yaffe, K},
title = {Epigenetic Clock Trajectories and Brain Health in Midlife.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.16.26358251},
pmid = {42528496},
abstract = {BACKGROUND: Accelerated biological aging can be assessed with DNA methylation (DNAm)-based epigenetic clocks. Research suggests that greater DNAm is associated with faster cognitive decline and risk of Alzheimer disease (AD) and other dementias. However, most studies have relied on single-time-point measurements of clocks, rather than evaluating dynamic changes over time. We examined the association between 15-year epigenetic aging trajectories and brain health outcomes in midlife.<br><br>METHODS: We analyzed 2,833 middle-aged adults (mean baseline age 40 years, 59% female and 44% Black) with &#x2265; 3 DunedinPACE (a recently developed epigenetic clock) measurements, collected over 15 years. Using mixed-effects modeling, we derived individual-specific slopes of epigenetic aging trajectories and categorized participants as Fast Agers (slopes > 1 SD above the mean), Slow Agers (slopes < 1 SD below the mean), or Typical Agers (within &#xb1;1 SD of the mean). We examined associations between trajectory group and cognition on five cognitive domains as well as on plasma AD biomarkers (NfL, p-tau217, A&#x3b2;42/A&#x3b2;40), all assessed 15-20 years post-baseline. Models were adjusted for demographics, education, physical activity and APOE *&#x3b5;4 carrier status (with additional adjustments for eGFRcr for biomarker outcomes).<br><br>RESULTS: Epigenetic aging trajectories were associated with multiple domains of cognition and AD biomarkers (Figure 1). Compared to Typical Agers, Fast Agers showed worse processing speed, memory, executive function, and global cognition (all p<0.05), with no difference in verbal fluency. Slow Agers had better performance on memory and global cognition (both p < 0.05). Fast Agers also exhibited significantly lower A&#x3b2;42/A&#x3b2;40 levels (p = 0.011) compared to Typical agers; no significant associations with p-tau217 or NfL were observed in either group.<br><br>CONCLUSION: Middle-aged adults with faster 15-year epigenetic aging trajectories demonstrated worse cognitive performance, whereas those with slower biological aging trajectories exhibited cognitive resilience and more favorable AD biomarker profiles. By examining long-term trajectories rather than single timepoints, these findings identify individuals at differential risk for brain health outcomes.},
}
@article {pmid42528498,
year = {2026},
author = {Moradi, E and Dahnke, R and Gaser, C and Rikkonen, T and Kröger, H and Väänänen, S and Solomon, A and Sund, R and Tohka, J and , },
title = {Elevated BrainAGE precedes cognitive impairment and improves prediction of future cognitive decline.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
pmid = {42528498},
abstract = {Magnetic Resonance Imaging (MRI) derived brain age varies substantially between individuals, but it remains unclear whether early deviations from normal brain ageing precede future cognitive decline and whether they provide predictive value beyond conventional MRI measures. Here, we investigated whether MRI-derived brain age gap estimation (BrainAGE) identifies early structural brain ageing differences among cognitively normal individuals who later develop mild cognitive impairment (MCI) or dementia. We analysed longitudinal structural MRI data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and replicated the main findings in the population-based Kuopio Osteoporosis Risk Factor and Prevention Study (OSTPRE). Individuals who later converted to MCI or dementia had higher BrainAGE values several years before diagnosis and, in ADNI, showed steeper longitudinal increases than stable individuals. Elevated BrainAGE values were also associated with increased risk of future conversion to MCI in cognitively healthy individuals and faster subsequent memory decline. Cross-sectional differences and the association between BrainAGE and risk of future conversion were replicated in OSTPRE. Importantly, adding BrainAGE to models including demographic, APOE4, cognitive, and MRI-derived measures consistently improved prediction of future cognitive outcomes, with the greatest benefit observed for individuals who converted after longer follow-up. These findings show that structural brain ageing begins to diverge years before the onset of MCI. BrainAGE captures this early divergence, providing complementary information beyond conventional structural MRI measures that may improve the early identification of cognitively normal individuals at increased risk of future cognitive decline when integrated with other biomarkers.},
}
@article {pmid42528526,
year = {2026},
author = {Noble, JM and Nadkarni, NK and Martinez, D and Temprosa, M and Bowers, A and Carmichael, O and Doherty, L and Febres, GJ and Sanchez, D and Goldberg, TE and Sherif, H and Shah, V and Luchsinger, JA and , },
title = {Implementation of a standardized Video-based Asynchronous Neurological Examination (VANE) in a multi-center observational study of Alzheimer's disease (AD) and AD related dementias.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
pmid = {42528526},
abstract = {INTRODUCTION: The Diabetes Prevention Program Outcomes Study (DPPOS) is an established cohort of aging persons with pre-diabetes and type 2 diabetes with 25 years of median follow-up. In 2022 DPPOS added Alzheimer's disease (AD), and AD related dementias (ADRD) phenotyping using the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDSv3), which included a standardized neurological examination across 25 clinical sites, administered by clinical staff and interpreted centrally by clinicians.<br><br>METHODS: A DPPOS video-based asynchronous neurological examination (DPPOS-VANE) was developed iteratively through consensus from research clinicians and staff feedback to harmonize with UDSv3 to identify common neurological diagnoses aside from dementia including diabetic cranial neuropathies, stroke and parkinsonism. DPPOS-VANE was designed to be conducted without direct participant contact by the examiner, reproducible, and independent of clinical skills of PCs. An iPad&#x2122; camera recorded the video exam, comprised of assessments of extraocular and facial movements, visual fields, speech, gross motor strength, pronator drift, praxis and parkinsonism. A 10-minute training video demonstrated the examination step-by-step with scripts and instructions in English and Spanish. Site-specific performance review, feedback, and staff certification preceded central reading of video recordings by physicians.After two years of implementation, 1286 DPPOS-VANEs led to 1284 examination reviews. Of these, 1204 (93%) were completed by having the examiner follow the standard script. Overall, 1237 examinations (96%) were delivered as planned, 41 (3%) had minor errors but were still usable, and 6 (0.4%) had major deviations in exam technique; two additional recorded evaluations were not usable as recorded videos were inaccessible due to technical errors. Each examination was completed within 10-15 minutes. Each site on average completed 51.4 examinations (range 14-92).<br><br>DISCUSSION: Engaging 55 research staff across 25 sites and 3 physician-reviewers, this study is the first to demonstrate feasibility of a VANE as an efficient neurological examination model enabled by commonly used devices. Such a multisite standardized VANE represents a novel paradigm for large epidemiological studies.},
}
@article {pmid42528531,
year = {2026},
author = {Okorie, M and Jiang, X and Tolosa-Tort, P and Sharma, RU and Clark, AL and Yaffe, K and Yokoyama, JS and Andrews, S and , },
title = {Orthogonal Contributions of Genetic, Clinical, and Social Determinants of Health Risk Burdens on Alzheimer's Disease Pathophysiology.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.07.26357509},
pmid = {42528531},
abstract = {IMPORTANCE: Alzheimer's disease (AD) arises from complex interactions among genetic, clinical, and social determinants of health (SDoH) risk factors, yet their independent contributions to underlying AD pathophysiology remain elusive.<br><br>OBJECTIVE: To quantify the effects of risk factors across amyloid (A&#x3b2;)/tau, neurodegeneration, and cognition.<br><br>DESIGN: Cross-sectional analysis using structural equation modeling (SEM).<br><br>SETTING: Health and Aging Brain Study-Health Disparities (HABS-HD), a community-based cohort study.<br><br>PARTICIPANTS: A total of 2,276 participants with demographics, genetic, clinical, and biomarker data from the baseline visit.<br><br>EXPOSURES: APOE &#x3b5;4 carrier status, AD polygenic risk score (AD-PRS), clinical risk score (CogDRisk), and a social determinants of health (SDoH) latent score derived using factor analysis.<br><br>MAIN OUTCOMES AND MEASURES: Latent variables representing A&#x3b2;/tau pathology (plasma pTau 181 , plasma pTau 217 /A&#x3b2; 42 , amyloid PET positivity, and global standardized uptake value ratio), neurodegeneration (plasma neurofilament light, cortical thickness, hippocampal volume), and cognition (memory, executive, and language tests) were modeled and regressed on AD latent variables using SEM adjusted for age, sex, genetic principal components, and spoken language.<br><br>RESULTS: The total analytic sample included 2,276 participants (mean age: 65.3 &#xb1; 8.7; non-Hispanic White: 43.0%, non-Hispanic Black: 16.2%, and Latinx/Hispanic adults: 40.8%). APOE &#x3b5;4 was strongly associated with worse A&#x3b2;/tau latent variable (&#x3b2;=0.31; p<0.001), with smaller but significant associations with neurodegeneration (&#x3b2;=0.085; p<0.001) and cognition (&#x3b2;=0.083; p<0.001). Higher AD-PRS was modestly associated with worse A&#x3b2;/tau (&#x3b2;=0.075; p<0.01) but was not associated with neurodegeneration or cognition. A higher clinical risk score was significantly associated with worse neurodegeneration (&#x3b2;=0.16; p<0.001) but not with A&#x3b2;/tau or cognition. Adverse SDoH was associated with worse neurodegeneration (&#x3b2;=0.071; p<0.05) and strongly associated with worse cognition (&#x3b2;=0.22; p<0.001), with no associations with A&#x3b2;/tau.<br><br>CONCLUSION AND RELEVANCE: Genetic risks were primarily associated with A&#x3b2; and tau pathology, clinical risks with neurodegeneration, and SDoH risks with cognition, suggesting that risk factors exert differential effects on AD pathophysiology. Future studies investigating additional risk factors and their longitudinal associations with AD pathophysiological changes are warranted.<br><br>KEY POINTS: Questions: Do Alzheimer's disease (AD) risk factors differentially influence underlying AD pathophysiological processes, and do these associations vary across demographic subgroups?Findings: Genetic and genomic risk burdens demonstrated the strongest associations with amyloid and tau pathology; clinical risk burden with neurodegeneration; and adverse social determinants of health with cognition.Meaning: Because of the differential effects of risk factors on the underlying AD pathophysiology, a one-size-fits-all approach to AD risk prediction and prevention is insufficient. AD risk assessment should leverage multidomain frameworks incorporating genomic, clinical, and social determinants of health information to better inform disease development and progression.},
}
@article {pmid42528554,
year = {2026},
author = {De Carli, D and Sudati, A and Dercole, F},
title = {Explainable Machine Learning Models for Alzheimer's Diagnosis Using Routine and Low-Cost Clinical Data.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.10.26357720},
pmid = {42528554},
abstract = {Emerging as a significant global health challenge, Alzheimer's Disease (AD) is a progressive neurodegenerative disorder that causes memory loss and cognitive decline. Despite the ever-increasing waiting time for a specialist diagnosis, the need for a cost-effective and fast diagnostic technique is evident. This study explores the development of an explainable deep learning model to diagnose AD using only routine and low-cost clinical data, including demographic information, patient history, and results of neuropsychological tests (limited to those that can be automatically acquired). The analysis was carried out using a dataset provided by the National Alzheimer's Coordinating Center, comprising 167,364 observations and 1,024 features. The findings demonstrate diagnostic performance comparable, and slightly superior, to that of clinicians when evaluated under similar informative constraints. This study introduces two classification models to discriminate whether the presumptive etiological cause of cognitive impairment is Alzheimer's disease. The deep neural network achieved an accuracy of 90% with an area under the receiver operating characteristic curve (ROC-AUC) of 0.96, whereas the Light Gradient Boosting Machine reached the same accuracy with a ROC-AUC of 0.97.},
}
@article {pmid42528566,
year = {2026},
author = {Lopez, FV and Gillis, M and Lee, S and Sakamoto, MS and Zhang, R and , and Sherva, R and Logue, MW and Merritt, VC},
title = {Curation of Mini Mental State Examination (MMSE) Scores in the VA Million Veteran Program (MVP): Applications for Cognitive Aging Research.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.14.26358064},
pmid = {42528566},
abstract = {BACKGROUND: Electronic health record (EHR)-linked biorepositories provide opportunities to advance epidemiological research in Alzheimer's disease (AD) and related dementias.<br><br>OBJECTIVE: Evaluate the extraction, curation, and associative validity of Mini Mental State Examination (MMSE) scores from the VA EHR for participants in the VA Million Veteran Program (MVP).<br><br>METHODS: The sample (N = 49,555; 7.4% women) included a multiethnic cohort (European [68.3%], African [20.4%], Hispanic [9.0%]) with EHR-extracted MMSE scores; 30.7% were apolipoprotein E (APOE) &#x3b5;4 carriers, and 25.8% had multiple scores. Linear regressions examined cross-sectional associations between &#x3b5;4 dosage (0, 1, 2) and first and lowest MMSE scores. MMSE scores were also evaluated against MVP dementia diagnostic algorithms in participants aged &#x2265;65 years.<br><br>RESULTS: Among participants of European ancestry, there was a significant &#x3b5;4 dose-response relationship (p s < .001) with MMSE scores. Homozygote carriers scored lower than heterozygote carriers (M diff : first = -0.5; lowest = -0.9), who scored lower than non-carriers (M diff : first = -0.4; lowest = -0.6). Among Veterans of African and Hispanic ancestry, no dose-response relationship was observed, although &#x3b5;4 carriers had lower scores than non-carriers (p s &#x2264; .04). MMSE scores corresponded strongly with dementia case/control status across phenotypes: mild impairment on the MMSE was strongly associated with AD (odds ratio [OR] = 11.48), with more severe MMSE impairment showing stronger associations (moderate OR = 17.95; severe OR = 27.83).<br><br>CONCLUSION: This study demonstrated MMSE scores can be systematically extracted and curated from the VA EHR. Findings offer a scalable framework for future studies on risk stratification, highlighting the potential for harnessing MVP to explore genetic and clinical factors contributing to cognitive and dementia outcomes in diverse samples.},
}
@article {pmid42528609,
year = {2026},
author = {Ayubcha, C and Dennis, E and Bhattacharyya, U and John, J and Lam, M and Lencz, T and Ge, T and Chen, CY},
title = {Characterizing the impact of plasma protein levels on human brain structure and disorders leveraging integrative multi-omics analysis.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.13.26358006},
pmid = {42528609},
abstract = {With recent advances in high-throughput proteomic technologies, population-scale plasma proteomics datasets, often linked to extensive genetic and phenotypic information, have become increasingly accessible. Yet the relationships between circulating protein levels, brain imaging phenotypes, and risk for neurological and psychiatric disorders remain largely unexplored. Proteome-wide association studies offer a promising approach for elucidating biological mechanisms that connect genetic variation to complex brain-related traits and diseases. In this study, we integrated protein quantitative trait loci (pQTLs) from the two largest plasma proteomic resources (the UK Biobank Pharma Proteomics Project [UKB-PPP] and Ferkingstad et al. [deCODE]) with genome-wide association studies of brain imaging-derived phenotypes in UK Biobank using Mendelian randomization and colocalization analyses. We identified 120 cis and 20 trans associations between plasma proteins and imaging phenotypes and validated these findings using brain tissue-derived proteomic and transcriptomic datasets. Multivariable Mendelian randomization revealed eleven plasma proteins (coding genes APOE, ARL3, MICB, NSF, RHOC, RSPO3, ENPP2, BTN2A1, EIF2AK3, MRVI1, and OPLAH) with significant direct effects on the risk of Alzheimer's disease, Parkinson's disease, multiple sclerosis, bipolar disorder, and schizophrenia. Single-cell expression and pathway enrichment analyses further revealed cell-type-specific effects and distinct biological processes underlying these protein- disease associations. Together, these findings demonstrate robust links between plasma protein variation and brain structure, delineate protein-disease pathways, and highlight the cellular and molecular mechanisms that contribute to neurobiological diversity and pathology.},
}
@article {pmid42528719,
year = {2026},
author = {Yang, M and Gao, Z and Zhao, Z and Niu, X and Xue, F and Zhang, J and Sun, H and Shen, Y and Liu, G},
title = {The dual pathological roles and targeted therapy of PGE2: from receptor signaling networks to disease microenvironment modulation.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1810417},
pmid = {42528719},
issn = {1663-9812},
abstract = {Prostaglandin E2 (PGE2) is a pleiotropic lipid mediator that exerts context-dependent effects via four G protein-coupled receptors (EP1-EP4), playing a pivotal role in the pathogenesis of diverse disorders, including neurodegenerative, cardiovascular, neoplastic, and chronic inflammatory diseases. In this review, we systematically delineate the dualistic functions and mechanisms of PGE2 across these diseases. In neurodegenerative conditions such as Alzheimer's and Parkinson's diseases, PGE2 exacerbates neuroinflammation and neuronal injury in part through EP1 and EP2 in specific cell types, whereas EP4 signaling can confer neuroprotection in certain disease-stage and cellular contexts. Within the tumor microenvironment, PGE2 can drive immunosuppression, angiogenesis, and tumor progression via the EP2/EP4 axis, particularly in colorectal carcinoma, lung adenocarcinoma, and melanoma where this axis is best characterized. In cardiovascular and metabolic diseases, PGE2 exhibits both protective (EP4-mediated) and detrimental (EP3-mediated) effects. Building on this mechanistic framework, we highlight emerging therapeutic strategies designed to overcome the limitations of conventional non-steroidal anti-inflammatory drugs (NSAIDs). These include modulating key enzymes involved in PGE2 synthesis and degradation, developing subtype-selective EP receptor modulators for context-specific intervention, and synergistically targeting downstream pathogenic signaling pathways (e.g., PI3K/Akt/mTOR). By integrating mechanistic and translational perspectives, this review aims to advance next-generation therapies targeting the PGE2 signaling network.},
}
@article {pmid42528726,
year = {2026},
author = {Kelley, AR and Sackinger, E and Frischman, M and Thomas, N and Kim, K and Scuderi, G and Labut, EM and MacMurchy, D and Ikea-Mario, T and Rauenhorst, J and Neitzel, E and Vu, T and Liko, L and Hoff, A and Hoff, A and Wallace, O and Harry, WKE and Hagen, B and Bihun, AZ and Abou-Seada, IA and Lee, K and Butler, J and Nigussie, F and Ebrahimi, A and Lee, PY and Marney, LC and Maier, CS and Magnusson, KR and Hagen, TM},
title = {Pre-plaque glutamatergic hyperexcitability, mitochondrial dysfunction, and dendritic remodeling in the hippocampus of one-month-old 5xFAD mice.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1804332},
pmid = {42528726},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD) is characterized by progressive cognitive decline and stereotyped neuropathology, yet the earliest cellular events that precede overt plaque burden and measurable behavioral impairment remain incompletely defined. Here, we tested the hypothesis that synaptic hyperexcitability and subcellular metabolic dysfunction emerge early in the 5xFAD mouse model and contribute to region-specific neuronal vulnerability before substantial amyloid plaque deposition. Using the 5xFAD heterozygous mouse, we first established the onset of transgene expression and the timing of plaque accumulation. Robust transgene expression was detected by postnatal day 15 and statistically significant plaque accumulation in the CA1 stratum radiatum by 4 months of age. Hippocampal slice electrophysiology revealed an early hyperexcitable phenotype at 1 month of age, including both increased AMPA receptor-mediated transmission and N-methyl-D-aspartate receptor signaling associated with the GluN2B subunit. Given the tight coupling between glutamatergic hyperactivity, oxidative stress, calcium dysregulation, and mitochondrial health, we assessed mitochondrial structure and function at this pre-plaque stage. Mitochondrial abnormalities consistent with impaired bioenergetic homeostasis were evident within hippocampal synaptic processes. Morphological analyses demonstrated that these early changes were associated with altered dendritic architecture in the CA1 and dentate gyrus regions, revealing hippocampal subregional susceptibility. Finally, spatial transcriptomics identified regionally enriched molecular signatures consistent with differential vulnerability. The CA1 subregion exhibited pronounced downregulation of mitochondria-related transcripts, and single-cell deconvolution resolved this transcriptomic suppression specifically to CA1 pyramidal neurons (CA1.ProS); CA3 and dentate gyrus did not show equivalent mitochondrial pathway suppression. Together, these findings define a pre-plaque window in 5xFAD mice marked by GluN2B-linked glutamatergic hyperexcitability, early mitochondrial disruption, and selective dendritic and transcriptional vulnerability. Mitochondrial transcriptomic suppression was anatomically restricted to CA1 pyramidal neurons, establishing a cell-type-specific bioenergetic signature at 1 month of age, well before overt amyloid pathology. While the observations herein are descriptive in nature and detailed mechanisms have yet to be established, nevertheless, the integrated timeline suggests that synaptic and metabolic dysfunctions arise before substantial plaque deposition and may represent tractable early targets for intervention in AD.},
}
@article {pmid42528828,
year = {2026},
author = {Serra, L and Bonarota, S and Caruso, G and Mancini, M and Sperati, S and Di Domenico, C and Tamigi, FM and Di Lorenzo, F and Ricci, F and Caltagirone, C and Koch, G and Giove, F and Bozzali, M and Petrosini, L},
title = {Stage-dependent effects of cognitive reserve on memory and brain structural integrity across the spectrum from healthy aging to Alzheimer's disease.},
journal = {Frontiers in human neuroscience},
volume = {20},
number = {},
pages = {1830181},
pmid = {42528828},
issn = {1662-5161},
abstract = {INTRODUCTION: Cognitive reserve (CR) has been proposed as a key factor explaining inter-individual variability in cognitive performance despite comparable neuropathology. However, its role across the Alzheimer's disease (AD) continuum remains unclear. This study investigates stage-dependent effects of CR on the relationship between memory performance and brain structural network integrity across healthy subjects (HS), individuals with subjective cognitive decline (SCD), and patients with amnestic mild cognitive impairment (a-MCI), and AD dementia.<br><br>MATERIALS AND METHODS: A total of 209 participants underwent a comprehensive neuropsychological assessment and 3T MRI. Source-based morphometry identified three grey matter structural covariance networks, involving orbitofrontal-temporal-insular regions (OTIN), precuneus-posterior cingulate cortex (PreCiN), and cingulate-hippocampal regions (CHiN). A composite memory score was derived using factor analysis. Regression and moderation models examined the predictive and moderating effects of CR (operationalized as years of education) and network integrity on cognitive performance within each group.<br><br>RESULTS: OTIN and PreCiN showed progressive structural vulnerability along the AD continuum, whereas CHiN showed no significant between-group differences. Across the sample, OTIN and PreCiN integrity significantly predicted cognitive performance. In HS, CR was positively associated with memory performance independently of structural network integrity, suggesting an additive protective role of cognitive reserve in healthy aging. In the SCD group, CR was not directly associated with memory, and only limited effects emerged, indicating early alterations in reserve-related processes. In a-MCI patients, the significant interaction between CR and OTIN integrity suggested patterns consistent with compensatory mechanisms, with higher reserve supporting memory despite structural decline. In AD patients, CR and its interaction with structural networks no longer predicted cognitive outcomes, suggesting a possible exhaustion of reserve capacity.<br><br>CONCLUSION: These findings support a stage-dependent model of CR, characterized by an additive protective role in healthy aging, patterns consistent with compensatory recruitment in early cognitive decline, and a possible loss of reserve effectiveness beyond a critical neuropathological threshold. Distinct network vulnerabilities and stage-specific CR effects highlight potential windows for reserve-enhancing interventions across the AD continuum.},
}
@article {pmid42528992,
year = {2026},
author = {Ren, C and Zhu, J and Huang, L and Hu, T and Guan, Y and Xie, F and Jin, J and Guo, Q},
title = {Dual decline in gait and cognition as a high-risk clinical phenotype: differential associations with cerebral amyloid-β deposition and the apolipoprotein E ε4 allele and implications for integrated assessment.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1845747},
pmid = {42528992},
issn = {1663-4365},
abstract = {BACKGROUND: Gait slowing and cognitive impairment often coexist in older adults, yet their relationship with core Alzheimer's disease (AD) biomarkers remains incompletely understood.<br><br>OBJECTIVE: To investigate the associations of isolated and combined slow gait (SG) and cognitive impairment subtypes with cerebral amyloid-&#x3b2; (A&#x3b2;) deposition and the apolipoprotein E &#x3b5;4 (APOE &#x3b5;4) allele in Chinese older adults.<br><br>METHODS: This cross-sectional study included 1,753 participants (mean age 65.9&#x202f;years). Based on gait speed and cognitive status, participants were classified into six groups: normal, slow gait alone (SG-A), subjective cognitive decline alone (SCD-A), mild cognitive impairment alone (MCI-A), SCD with slow gait (SCD-SG), and MCI with slow gait (MCI-SG). 687 individuals underwent 18F-florbetapir positron emission tomography (PET) scans, 654 participants were examined for Apolipoprotein E (APOE) genotyping, and 618 participants had all relevant information recorded.<br><br>RESULTS: The MCI-SG group exhibited the most pronounced physical decline (slowest gait speed and weakest handgrip strength) and the highest burden of AD pathology, with a significantly higher prevalence of A&#x3b2; positivity (38%) and APOE &#x3b5;4 carriage (32%) compared with other groups. While overall A&#x3b2; positivity rates across the six groups were not significantly different, logistic regression analyses revealed specific, strong associations. A&#x3b2; positivity was significantly associated with both SCD-SG (OR&#x202f;=&#x202f;1.78, 95% CI: 1.03-3.08) and MCI-SG (OR&#x202f;=&#x202f;1.85, 95% CI: 1.07-3.21) compared with the normal group. In contrast, APOE &#x3b5;4 carriage was specifically and more strongly linked to MCI-SG (OR&#x202f;=&#x202f;3.21, 95% CI: 1.41-7.31) compared with the SCD-A group. These combined gait-cognitive impairment phenotypes showed consistently stronger associations with AD biomarkers than isolated impairments across multiple reference groups. The risk was greatest for MCI-SG in individuals who were both A&#x3b2; positive and APOE &#x3b5;4 carriers (OR&#x202f;=&#x202f;2.27, 95% CI: 1.19-5.15).<br><br>CONCLUSION: The co-occurrence of slow gait and mild cognitive impairment (MCI-SG) represents a distinct high-risk clinical phenotype strongly linked to AD pathology. A&#x3b2; and APOE &#x3b5;4 show differential associations across the gait-cognitive spectrum. Integrated assessment of gait and cognition improves risk stratification in older adults and may guide early intervention strategies.},
}
@article {pmid42529009,
year = {2026},
author = {Zhou, H and Jiang, N and Bernheim, S and Paik, P and Zhou, Q and Kurabayashi, K and Ray, K},
title = {Wearable monitoring during music-based interventions in dementia: physiological and behavioral observations from a pilot study.},
journal = {Frontiers in human neuroscience},
volume = {20},
number = {},
pages = {1854021},
pmid = {42529009},
issn = {1662-5161},
abstract = {INTRODUCTION: Music-based interventions (MBIs) are widely used in dementia care, but objective methods for characterizing participant responses during intervention sessions remain limited. Synchronized datasets combining wearable physiological signals and behavioral observations are particularly scarce.<br><br>METHODS: We conducted a pilot feasibility study involving five individuals with Alzheimer's disease and related dementias (ADRD) who participated in 13 formal MBI sessions. Physiological signals, including photoplethysmography (PPG), electrodermal activity (EDA), skin temperature (TEMP), and accelerometry (ACC), were collected using a wrist-worn wearable sensor and synchronized with intervention playlists and time-stamped behavioral observations. Exploratory analyses examined physiological responses across intervention phases, participant-specific response patterns, time-of-day effects, and music-preference effects.<br><br>RESULTS: The dataset contains 13 intervention sessions, 99 music segments, and 248 behavioral observations. PPG, ACC, TEMP, and behavioral observations were available for all sessions, while EDA quality varied because of sensor-contact challenges. Behavioral responses were highly heterogeneous across participants, with engagement and calm behaviors observed most frequently. Physiological responses also showed substantial inter-individual variability, and case studies demonstrated that physiological and behavioral responses were not always concordant.<br><br>CONCLUSION: This study demonstrates the feasibility of collecting synchronized physiological, behavioral, and intervention-context data during MBIs in people living with dementia. The resulting publicly available multimodal dataset provides a foundation for future investigations of participant-specific responses and adaptive music-based interventions.},
}
@article {pmid42529064,
year = {2026},
author = {Swann, P and Malpetti, M and Chouliaras, L and White, SR and Mak, E and Surendranathan, A and Jones, PS and Su, L and Savulich, G and Kigar, S and McKeever, A and Fryer, T and Hong, YT and Aigbirhio, FI and Rowe, JB and O'Brien, JT},
title = {Peripheral and central inflammation associated with progressive cognitive decline in dementia with Lewy bodies.},
journal = {Brain communications},
volume = {8},
number = {4},
pages = {fcag274},
pmid = {42529064},
issn = {2632-1297},
abstract = {Dementia with Lewy bodies (DLB) is the second most common cause of neurodegenerative dementia, pathologically defined by the presence of Lewy bodies. Peripheral and central inflammation are increasingly recognized in DLB in clinical, post-mortem and animal studies. Finding clinically relevant biomarkers of inflammation in DLB will support the identification of novel pathways for disease-modifying therapies or use in clinical trials of immunomodulatory agents. Whilst there are cross-sectional studies of inflammation markers in DLB, there is limited evidence on the association between these markers and cognitive decline over time. Twenty participants with DLB underwent blood sampling for serum inflammatory markers, paired with PET imaging of the translocator protein (TSPO) and up to 4 years of longitudinal cognitive testing. Thirty participants with Alzheimer's disease-comprising both Alzheimer's dementia and/or mild cognitive impairment with biomarker evidence of amyloid pathology (AD/MCI+)-and 28 controls were also recruited for group comparisons. Data from 42 baseline cytokine immunoassays and TSPO PET were used as predictors of longitudinal cognitive scores in linear mixed-effects models. Partial least squares regression was used to test the association between peripheral and central inflammation. Using peripheral inflammatory markers as single predictors, we identified 14 associated with either a slower or faster rate of cognitive decline in DLB, whilst no single marker was predictive of decline in AD/MCI+. As many inflammatory markers were highly correlated, we used principal component analysis to identify a cytokine component associated with reduced cognitive decline in both DLB and AD/MCI+, that overlapped with the single markers identified in the previous analysis. A separate component was associated with cognitive decline in AD/MCI+ or DLB with Alzheimer's dementia co-pathology (ascertained by amyloid PET). Widespread TSPO binding was associated with reduced cognitive decline in DLB, whilst a fronto-temporal pattern was associated with more rapid cognitive decline in both DLB and AD/MCI+. There were associations between peripheral cytokines and TSPO PET in AD/MCI+, but these were not significant in DLB. Overall, peripheral and central inflammation predicted cognitive decline in DLB. Specific patterns associated with both faster and slower rates of decline were identified. These profiles had both overlapping and contrasting associations when compared to AD/MCI+. Collectively, these data add to a body of evidence suggesting clinically relevant levels of inflammation in DLB. Future studies in larger, multi-site cohorts with multiple biomarker sampling points are required to understand the impact and dynamics of inflammation across all stages of the disease.},
}
@article {pmid42529168,
year = {2026},
author = {McCool, S and Jain, A and Smith, JC and Van Hook, MJ},
title = {Plaque-associated microglial polarization in visual brain regions of the 5xFAD mouse model.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1824891},
pmid = {42529168},
issn = {1663-4365},
abstract = {INTRODUCTION: Alzheimer's disease (AD), a neurodegenerative disorder associated with amyloid beta (Aβ) plaque deposition, leads to cognitive decline in affected individuals. Vision changes are among the reported symptoms in AD with studies showing both decline in functions performed by the visual system as well as associations between vision loss and cognitive impairment in AD patients. Due to the increasing number of individuals diagnosed with AD and its early impact on vision, we sought to provide an in-depth analysis of how Aβ, a primary pathology typically preceding many other AD-associated pathologies, affects visual regions of the brain and how microglia, key immune regulators of the brain's environment, respond to this AD-like pathology.<br><br>METHODS: Amyloid pathology was examined in histological sections containing the dorsolateral geniculate nucleus (dLGN), and the primary visual cortex (V1), suprachiasmatic nucleus (SCN), and superior colliculus (SC) of 5xFAD mice using thioflavin-S and anti-amyloid staining. Microglia morphology was analyzed in Iba1 antibody-stained sections and phagocytic activity was evaluated with CD68 co-staining.<br><br>RESULTS: We found that in the pathway for image-forming vision, including the dLGN and V1, there was significant A&#x3b2; pathology, shifts in microglial morphology to an amoeboid state, localization of microglia around plaques, and increased Iba1/CD68 co-labeling. However, in non-image-forming visual brain regions such as the SC and SCN, there was minimal A&#x3b2; pathology, ramified microglial morphology, and minimal phagocytic activity.<br><br>CONCLUSION: Overall, A&#x3b2; plaque deposition was related to brain-region-specific differences in microglial responses, indicating that visual brain regions are differentially affected by AD pathology in the 5xFAD mouse model of amyloidosis.},
}
@article {pmid42529199,
year = {2026},
author = {Lin, Y and Cheng, L and Zhang, Z and Cui, L and Li, W and Guo, Q and Miao, Y},
title = {Blood transcriptomic signatures link β-amyloid deposition to molecular pathways across SCD, MCI, and dementia.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1816733},
pmid = {42529199},
issn = {1663-4365},
abstract = {INTRODUCTION: Brain β-amyloid (Aβ) accumulation is a hallmark of Alzheimer's disease, but noninvasive detection remains challenging. Blood transcriptomics may provide accessible biomarkers associated with Aβ pathology.<br><br>METHODS: We integrated peripheral blood transcriptomic profiling and MRI-derived structural metrics from 48 individuals across the cognitive continuum, including subjective cognitive decline (SCD), mild cognitive impairment (MCI), and dementia, stratified by A&#x3b2;-PET status. Predictive models were constructed using leave-one-out cross-validation (LOOCV), and selected genes were validated by qRT-PCR.<br><br>RESULTS: Cross-stage analysis identified RUNX1T1 and COL14A1 as consistently downregulated in A&#x3b2;-positive individuals regardless of clinical stage. A predictive model incorporating these two genes demonstrated moderate discrimination of A&#x3b2;-PET status in internal leave-one-out cross-validation (LOOCV) evaluation (AUC&#x202f;=&#x202f;0.81). In addition, COL14A1 expression was associated with cortical thickness and hippocampal volume, whereas RUNX1T1 was primarily associated with hippocampal structure. Among individuals with MCI or dementia, HCN1 and NRG3 were upregulated, whereas KCNMB2 was downregulated in A&#x3b2;-positive subjects. A three-gene model based on these markers achieved an LOOCV AUC of 0.79.<br><br>DISCUSSION: These findings indicate that peripheral blood transcriptomic alterations are associated with A&#x3b2; pathology across clinical groups. RUNX1T1 and COL14A1 represent candidate peripheral biomarkers associated with A&#x3b2; pathology, while the observed molecular signatures and their associations with brain structural measures provide a basis for further validation in larger, longitudinal cohorts and mechanistic studies.},
}
@article {pmid42529446,
year = {2026},
author = {Hakhverdyan, S and Hansson, S and Kadej, P and Orlovsky, SB and Hladkou, S and Viirman, B and Nilsson, A and Lord, M and Cologna, SM and Mohr, JT and Syvänen, S and Andrén, PE and Michno, W},
title = {Spatially Resolved Free Fatty Acid Profiling Reveals Region- and Age-Dependent Remodeling of Alzheimer's Disease Plaques.},
journal = {JACS Au},
volume = {6},
number = {7},
pages = {4153-4165},
pmid = {42529446},
issn = {2691-3704},
abstract = {Free fatty acids (FFAs) are bioactive mediators of inflammation, energy metabolism, and membrane remodeling, yet their spatial organization within the Alzheimer's disease (AD) brain and at individual amyloid-β (Aβ) plaques has remained inaccessible. We developed a novel, chemically tailored MALDI workflow that enables simultaneous, spatially resolved detection of nearly 30 FFAs alongside over 100 complex lipid species within the same tissue section. Applying this approach to a transgenic AD mouse model across brain regions and disease stages, and combining it with single-plaque microenvironment analysis (SPMA) that treats each plaque as an individual analytical object, we uncover two previously inaccessible dimensions of plaque-associated lipid biology. FFA distributions form highly structured spatial compartments reflecting regional cytoarchitecture, with distinct enrichment of saturated, monounsaturated, and polyunsaturated species across cortical layers. Within Aβ plaques, nearly 75% of detected FFAs are significantly remodeled, with reciprocal enrichment of short saturated and highly unsaturated species alongside depletion of long-chain monounsaturated FFAs. This pattern is consistent with concurrent disruption of ELOVL-mediated elongation and FADS-mediated desaturation, including opposing enrichment of pro-inflammatory arachidonic acid and pro-resolving docosahexaenoic acid. Machine learning of single-plaque profiles reveals that FFA composition alone classifies plaque age with high accuracy, demonstrating that lipid remodeling continues after Aβ peptide composition has stabilized. Together, these findings establish spatial FFA profiling as a new analytical dimension in neurodegeneration research, revealing that Aβ plaques are dynamic lipid-metabolic microenvironments that continue to remodel long after Aβ deposition has stabilized.},
}
@article {pmid42529466,
year = {2026},
author = {Shi, B and Wang, Z and Lian, J and Yang, Z and Zuo, X},
title = {APLG-Net: an anatomy-guided local-global hybrid network with progression-aware supervision for structural MRI-based NC/MCI/AD classification.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1885491},
pmid = {42529466},
issn = {1664-2295},
abstract = {INTRODUCTION: Structural MRI-based Alzheimer's disease classification remains challenging due to subtle anatomical variations and the intermediate nature of mild cognitive impairment (MCI).<br><br>METHODS: We propose APLG-Net, an anatomy-guided local-global hybrid network with progression-aware supervision for NC/MCI/AD classification. The model integrates a global whole-brain encoder and a local ROI-based encoder, followed by cross-attention fusion and vector-gated integration. An ordinal supervision strategy is introduced to model disease progression.<br><br>RESULTS: On the ADNI dataset, APLG-Net achieves 87.1% accuracy, 86.4% balanced accuracy, 86.8% Macro-F1, and 85.6% MCI F1, outperforming CNN-based, Transformer-based, and hybrid baselines.<br><br>DISCUSSION: The results demonstrate that incorporating anatomical priors, local-global feature interaction, and ordinal supervision significantly improves MCI discrimination and overall classification robustness.},
}
@article {pmid42529533,
year = {2026},
author = {Kummer, N and Cihova, M and Nirmalraj, PN},
title = {Antiamyloid Antibody Effects on Aβ-42 Protein Aggregates Profiled Using Nanospectroscopy.},
journal = {Chemical &amp; biomedical imaging},
volume = {4},
number = {7},
pages = {1379-1389},
pmid = {42529533},
issn = {2832-3637},
abstract = {Anti-amyloid-β (Aβ) monoclonal antibodies are designed to selectively target protein biomarkers and promote amyloid clearance in Alzheimer's disease. Yet the effects of antibodies on individual Aβ protein aggregates remain to be fully clarified. The work presented here employs nanospectroscopy (atomic force microscopy combined with infrared spectroscopy) to resolve morphological and secondary structural changes in Aβ-42 protein aggregates upon treatment with aducanumab and lecanemab antibodies (biosimilars). The treatment of Aβ-42 peptides with aducanumab resulted in reduction of oligomer prevalence and formation of larger-diameter fibril bundles confirmed from the AFM height maps and infrared spectral readouts recorded at nanometer-scale spatial resolution. Conversely, lecanemab treatment of Aβ-42 peptides did not suppress oligomer generation but was observed to preferentially bind along the full length of the nodular-shaped protofibril surface. Importantly, neither aducanumab nor lecanemab was observed to induce any surface adsorption-driven disassembly of Aβ-42 protofibrils or elongated mature fibrils. Thus, nanospectroscopy enables direct characterization of antibody-amyloid interfacial interactions and provides insights into the distinct modes of action of emerging anti-Aβ therapeutics through label-free chemical imaging.},
}
@article {pmid42529812,
year = {2026},
author = {Harkess-Murphy, E and Macrae, R and Brown, M and Hall, J},
title = {Trauma-Informed Support in a Dementia Helpline: Retrospective Mixed Methods Study.},
journal = {JMIR formative research},
volume = {10},
number = {},
pages = {e71746},
doi = {10.2196/71746},
pmid = {42529812},
issn = {2561-326X},
mesh = {Humans ; *Dementia/psychology ; Retrospective Studies ; *Hotlines/statistics &amp; numerical data ; *Caregivers/psychology ; Male ; Female ; *COVID-19/psychology/epidemiology ; United Kingdom ; Qualitative Research ; Aged ; },
abstract = {BACKGROUND: People with dementia and their caregivers experience significant psychological distress, which may increase their vulnerability to trauma across the dementia diagnostic and caregiving trajectory. Specialist dementia helplines offer immediate emotional support, information, and signposting; however, little empirical evidence exists about how call handlers account for potential trauma in their responses.<br><br>OBJECTIVE: This study aimed to examine the extent to which call handlers' responses on the United Kingdom's only 24-hour dementia helpline reflected trauma-informed (TI) principles of safety, trust, choice, collaboration, and empowerment and to describe caller characteristics and reasons for contact during the COVID-19 pandemic.<br><br>METHODS: No participants were actively recruited. Instead, the study analyzed 198 anonymized, routinely collected helpline call logs (out of 200 randomly selected) drawn from 7357 calls received by Alzheimer Scotland's 24-hour helpline between April 2020 and April 2021. A retrospective deductive framework analysis mapped narrative summaries to 5 TI principles (safety, trustworthiness and transparency, choice, collaboration, and empowerment). Double&#x2011;coding and calibration were undertaken in line with established guidance on intercoder reliability for qualitative research. Descriptive statistics summarized caller characteristics and theme frequencies; no inferential testing was conducted due to the exploratory nature of the analysis, sample properties, and the subjective nature of theme ratings.<br><br>RESULTS: Most calls were made during daytime hours (159/198, 79.5%) and were made by carers, family members, or friends (n=179, 89.5%). Emotional support was the most frequently recorded reason for contact (91 instances), followed by carer stress (66 instances) and information on caring (51 instances). Across call handlers' responses, collaboration (126/179, 70.4%) and empowerment (108/179, 60.3%) were the most frequently observed TI principles, followed by safety (105/179, 58.7%), choice (66/179, 37.4%), and trust (56/179, 31.3%). Safety-focused responses were more prevalent in nighttime calls than daytime calls (76.9% vs 56%). Illustrative call log excerpts demonstrated empathetic listening, validation, shared problem-solving, and signposting practices aligned with TI principles.<br><br>CONCLUSIONS: In this exploratory retrospective evaluation, responses from a national dementia helpline commonly reflected TI principles, despite call handlers receiving primarily awareness-level TI content within their wider role preparation. Findings should be interpreted as descriptive and hypothesis-generating because they are based on call log summaries rather than recorded interactions and were obtained within the unique context of the COVID-19 pandemic. The results suggest that TI principles may be feasible and relevant in dementia helpline services and highlight the potential value of more structured approaches to TI workforce development. Future prospective research incorporating richer data sources such as recorded calls and call-reported outcomes is warranted to support service development and evaluation.},
}
@article {pmid42529883,
year = {2026},
author = {Li, X and Chen, H and Wang, X and Hu, Y and Yang, Z and Wei, M},
title = {Advances in biomarkers for Parkinson's disease: from molecular pathology to precision diagnostics.},
journal = {Journal of Zhejiang University. Science. B},
volume = {27},
number = {7},
pages = {736-760},
doi = {10.1631/jzus.B2500789},
pmid = {42529883},
issn = {1862-1783},
support = {82101513//the National Basic Research Program of China/ ; 2019-ZD-0943//the Natural Science Foundation of Liaoning Province/ ; },
mesh = {Humans ; *Parkinson Disease/diagnosis/pathology/genetics ; *Biomarkers/analysis ; alpha-Synuclein ; *Precision Medicine ; Pathology, Molecular ; },
abstract = {Parkinson's disease (PD) is the second most common neurodegenerative disorder, and continues to present significant challenges in early diagnosis, precise subtyping, and prognosis assessment. In recent years, the field of biomarker research has undergone a profound paradigm shift from static concentration measurements to functional activity detection. The most revolutionary breakthrough is the α-synuclein seed amplification assay (α-Syn-SAA), which enables ultrasensitive and specific detection of pathological α-Syn in both clinical and prodromal stages, thus providing an unprecedented window for early intervention. Substantial progress has also been made in the development of biomarkers such as neurofilament light chain (NfL), Alzheimer's disease-related biomarkers, and genetic biomarkers, as well as in detection technologies based on peripheral samples. The integrated application of cutting-edge technologies, such as real-time quaking-induced conversion (RT-QuIC), high-resolution mass spectrometry, and high-field magnetic resonance imaging (MRI), is advancing the field into a new stage characterized by a focus on pathological activity, multi-omics integration, and non- or minimally invasive approaches. In this review, we explore recent advances in PD biomarkers, focusing on core pathophysiological markers. We examine the potential of multi-omics and artificial intelligence (AI) to enhance diagnostic, subtyping, and prognostic accuracy, while also outlining the pivotal role and future directions of biomarkers in advancing precision medicine for PD.},
}
@article {pmid42530031,
year = {2026},
author = {Benbaji, M and Raveh, B and Bassal, L and Elias, U and Gazit, L and Allali, G and Marshall, GA and Arzy, S},
title = {Alzheimer disease in the computational era: from a deterministic disease to a multifaceted disorder.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag248},
pmid = {42530031},
issn = {1460-2156},
abstract = {The definition of Alzheimer disease (AD) keeps changing over the years, which is critical for studying it, understanding it, and developing treatments. Here we first review the different definitions proposed for AD from its original characterization by Kraepelin in 1908, to the recent Alzheimer's Association revised criteria in 2024. We describe these definitions in parallel to the new knowledge gained, demonstrating how they vacillate between restricted and circumscribed clinicopathological characterizations and wider clinical and pathological ones. Then, we describe AD multifaceted clinical presentations, including very early subtle cognitive and behavioural changes, alongside its pathological multifactorial variability of core-pathologies, co-pathologies and risk factors, encompassing changes in various cortical and subcortical brain regions, and its genetic complex landscape. We suggest that all potential factors among the different levels should be considered to provide a patient-tailored clinical profile. To address the richness and complexity of the data, we outline a metamodeling-based computational framework that allows diverse sources of evidence to be integrated without forcing them into a single monolithic model. Specifically, different data subsets are first used to construct partial models, each addressing selected domains and factors; these models are then converted into probabilistic surrogate models with shared variables and parameters; finally, the latent variables inferred from the surrogate models are related via a probabilistic coupling layer to create predictions of individual patients' trajectories and intervention effects, staging, clinical stratification and attribution maps. Taken together, the computational and data revolutions may enable us to expose the complexity of AD through large-scale patients' data, computational metamodeling, and hypothesis-free analyses, leading to reconceptualization of AD from a monolithic diagnostic category into a stratified, mechanistically interpretable nosology, with practical implications at the individual patient level.},
}
@article {pmid42530037,
year = {2026},
author = {Skondra, M and Papadopoulos, L and Kougioumtzoglou, T and Kandilakis, CL and Konidari, E and Papalexiou, V and Marouli, I and Malagkoniari, LM and Kostakiotis, A and Veskoukis, T and Peritogiannis, V and Economou, P and Felemegkas, P and Alexopoulos, P},
title = {Anticholinergic Burden and Cognitive Function, Depressive Symptoms, and Functional Performance in Individuals With Neurocognitive Disorders: Real-World Evidence.},
journal = {Journal of integrative neuroscience},
volume = {25},
number = {7},
pages = {51135},
doi = {10.31083/JIN51135},
pmid = {42530037},
issn = {0219-6352},
mesh = {Humans ; Female ; Male ; Aged ; *Depression/chemically induced/physiopathology ; Aged, 80 and over ; *Activities of Daily Living ; *Cholinergic Antagonists/adverse effects ; *Neurocognitive Disorders/physiopathology ; *Cognition/drug effects ; *Cognitive Dysfunction/physiopathology/chemically induced ; *Functional Status ; },
abstract = {BACKGROUND: Despite their negative effects on cognitive function and cognitive decline risk, drugs with anticholinergic properties are commonly prescribed, particularly in older individuals. In this observational study we aimed to shed light on the relationships between anticholinergic burden (ACB) and depressive symptoms and cognitive and functional performance in a real-world clinical setting.<br><br>METHODS: The study included individuals seeking care at the old-age psychiatry outpatient clinic of Patras University Mental Health Services. Depressive symptoms were assessed using the 15-item Geriatric Depression Scale; cognitive function was tapped using the Cognitive Telephone Screening Instrument, the Montreal Cognitive Assessment, and the Mini-Mental State Examination; and functional performance was assessed using the Bristol Activities of Daily Living Scale. Differences in demographic and clinical variables across the four diagnostic groups were analyzed. Regression analyses were performed to examine the associations between ACB, cognitive and non-cognitive symptoms, and demographic variables. In addition, clustering analyses were conducted to identify distinct, naturally occurring examinee subgroups and to assess if ACB differed across them.<br><br>RESULTS: The study sample consisted of individuals without cognitive impairment (N = 301), people with mild neurocognitive disorder (MiND, N = 264), major neurocognitive disorder caused by Alzheimer's disease (ADMaND, N = 114), or other diseases (nonADMaND, N = 63). Significant associations were detected between ACB and depressive symptoms (0.72, p < 0.001), short-term memory (-0.11, p = 0.017), long-term memory (-0.24, p < 0.001), working memory (-0.24, p = 0.001), attention/concentration (-0.13, p = 0.004), verbal fluency (-0.57, p = 0.003), inductive reasoning (-0.17, p = 0.002), basic activities of daily living (0.29, p = 0.001), and instrumental activities of daily living (0.58, p < 0.001). The clustering analyses indicated that in the cluster including individuals with more advanced cognitive decline, poorer functional status, and more severe depressive symptoms, ACB was higher compared with the second group identified by the analyses (p < 0.001).<br><br>CONCLUSIONS: ACB is related to different aspects of the clinical phenotype of cognitive decline. Despite the lack of solid evidence regarding causal relationships and need for further research, minimizing ACB in clinical settings may embody a potential pragmatic strategy in managing cognitive decline in ageing.},
}
@article {pmid42530040,
year = {2026},
author = {Shi, Q and Pradhan, AK and Dong, S and Rammes, G and Wang, X},
title = {Sevoflurane and Aβ1-42 Oligomers Synergistically Induce Morphological Changes of Astrocytes in the Hippocampus of Male Mice.},
journal = {Journal of integrative neuroscience},
volume = {25},
number = {7},
pages = {50442},
doi = {10.31083/JIN50442},
pmid = {42530040},
issn = {0219-6352},
support = {2024MZFS003//Open Fund Program of the Key Laboratory of Anesthesiology and Resuscitation, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China/ ; },
mesh = {Animals ; *Amyloid beta-Peptides/pharmacology ; *Sevoflurane/pharmacology ; *Peptide Fragments/pharmacology/administration &amp; dosage ; *Astrocytes/drug effects/pathology/metabolism ; Male ; *Hippocampus/drug effects/pathology/metabolism ; Glial Fibrillary Acidic Protein/metabolism/drug effects ; *Anesthetics, Inhalation/pharmacology/administration &amp; dosage ; Mice ; },
abstract = {BACKGROUND: Reactive gliosis serves as a characteristic feature of the pathophysiology of Alzheimer's disease (AD). Nevertheless, the influence of anesthetics on the morphological dynamics of astrocytes remains ambiguous.<br><br>METHODS: Employing ex vivo hippocampal slices, in this study, we explored the impacts of sevoflurane and Amyloid-&#x3b2; peptide 1-42 (A&#x3b2;1-42) oligomers on astrocytic morphology. The primary outcomes encompassed the fluorescence intensity of glial fibrillary acidic protein (GFAP), the levels of a 38-kDa GFAP breakdown product (a marker of astroglial injury), and quantitative morphometric analyses (cell volume, surface area, branch complexity, and Sholl intersections).<br><br>RESULTS: Co-exposure to sevoflurane and A&#x3b2;1-42 led to an elevation of the 38-kDa GFAP breakdown product and a significant reduction in the mean fluorescence intensity of GFAP. Moreover, it resulted in a decrease in astrocytic volume, surface area, branch complexity, and Sholl intersections. These synergistic alterations were not observed when either treatment was administered alone.<br><br>CONCLUSIONS: These findings imply that sevoflurane aggravates A&#x3b2;1-42-induced astrocytic dysfunction, which has implications for perioperative management in patients with AD or those at risk of developing AD.},
}
@article {pmid42530050,
year = {2026},
author = {Sheng, J and Lin, J and Zhang, Q and Gong, Z and Zhang, R and Wu, M and Cheng, Y and Zhu, X and Sun, Z},
title = {A Multi-Frequency Self-Supervised Fusion Model for EEG-Based Dementia Classification.},
journal = {Journal of integrative neuroscience},
volume = {25},
number = {7},
pages = {50737},
doi = {10.31083/JIN50737},
pmid = {42530050},
issn = {0219-6352},
support = {LZ24F010007//Key Program of Natural Science Foundation of Zhejiang Province/ ; 62271177//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Alzheimer Disease/physiopathology/diagnosis/classification ; *Electroencephalography/methods ; *Frontotemporal Dementia/diagnosis/physiopathology/classification ; *Supervised Machine Learning ; *Brain Waves/physiology ; Classification Algorithms ; },
abstract = {BACKGROUND: Brain source localization technology enables precise characterization of the spatial distribution of neural activity, serving as a crucial tool for exploring the pathological mechanisms underlying dementia. However, effectively integrating complementary diagnostic information from source localization features across multiple frequency bands remains a major challenge to enhancing classification performance and model interpretability.<br><br>METHODS: An attention-based multi-frequency self-supervised fusion model (AM-SSF) is proposed to address this issue. Independent contrastive self-supervised encoders are trained for the &#x3b8; (4-8 Hz), &#x3b1; (8-13 Hz), &#x3b2; (13-30 Hz), and &#x3b3; (30-48 Hz) frequency bands to learn band-specific latent representations. Then, an attention-guided adaptive fusion module is introduced to dynamically allocate band weights through cross-entropy-based supervised optimization, thereby achieving effective cross-band information integration. Finally, a random forest classifier is employed to evaluate the model's performance in distinguishing Alzheimer's disease (AD) from frontotemporal dementia (FTD).<br><br>RESULTS: Experimental results show that the proposed framework achieves a classification accuracy of 93.1% under five-fold cross-validation, significantly outperforming baseline methods such as single-band self-supervised learning (SSL) and average pooling fusion. Further analysis of the attention weight distributions revealed that the &#x3b8; and &#x3b2; bands contributed most to model decision-making, providing interpretability regarding frequency-specific effects.<br><br>CONCLUSIONS: In summary, the proposed AM-SSF model enhances AD and FTD classification performance while offering valuable insights into the discriminative roles of frequency band features.},
}
@article {pmid42530052,
year = {2026},
author = {Shcheblykina, OV and Kostina, DA and Pokrovskii, MV and Korokin, MV},
title = {Neurotrophic Factors in Stroke, Traumatic Brain Injury, and Neurodegeneration: A Convergent Pathophysiological and Translational Perspective.},
journal = {Journal of integrative neuroscience},
volume = {25},
number = {7},
pages = {51543},
doi = {10.31083/JIN51543},
pmid = {42530052},
issn = {0219-6352},
support = {FZWG-2026-0003//Ministry of Science and Higher Education of the Russian Federation/ ; },
mesh = {Humans ; *Brain Injuries, Traumatic/metabolism/therapy/physiopathology ; Animals ; *Stroke/metabolism/therapy/physiopathology ; *Nerve Growth Factors/metabolism ; *Neurodegenerative Diseases/metabolism/therapy/physiopathology ; },
abstract = {Neurotrophic factors (NTFs), including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), glial cell line-derived neurotrophic factor (GDNF), ciliary neurotrophic factor (CNTF), and vascular endothelial growth factor (VEGF), play a central role in neuronal survival, plasticity, and regeneration. Despite their distinct etiologies and temporal profiles, stroke (both ischemic and hemorrhagic), traumatic brain injury (TBI), and neurodegenerative diseases (NDDs), including Alzheimer's disease (AD) and Parkinson's disease (PD), converge on a common pathophysiological phenotype characterized by excitotoxicity, oxidative stress, mitochondrial dysfunction, neuroinflammation, blood-brain barrier (BBB) disruption, and neuronal apoptosis. Neurotrophic factors modulate these pathological cascades through tropomyosin receptor kinase (Trk) receptors, p75 neurotrophin receptor (p75NTR), and related signaling pathways, thereby supporting neuroprotection, neurogenesis, and synaptogenesis. Experimental evidence from preclinical models demonstrates robust beneficial effects of neurotrophin-based interventions in stroke, TBI, AD, and PD across protein, gene, and cell-based strategies. However, clinical translation remains severely limited. Early-phase clinical trials of adeno-associated virus (AAV)-mediated GDNF and neurturin gene therapy for PD, ex vivo NGF gene therapy for AD, and BDNF gene therapy for AD have confirmed acceptable safety profiles but yielded modest or inconsistent efficacy, largely due to constraints in brain delivery, the need for invasive neurosurgical procedures, restricted target coverage, suboptimal control of expression, and marked patient heterogeneity. Consequently, the principal barrier to clinical success is not biological validity, but the lack of safe, effective and scalable delivery platforms capable of bypassing or functionally modulating the BBB. In this review we synthesize shared pathophysiological mechanisms linking stroke, TBI and NDDs; examine the biology, receptor systems, and signaling pathways of key neurotrophic factors; summarize preclinical evidence for their therapeutic potential; and critically evaluate current delivery strategies, including viral vectors, lipid nanoparticles, exosomes, cell-based therapies, small-molecule mimetics, and intranasal administration. We conclude that overcoming delivery barriers through development of improved viral and non-viral platforms, minimally invasive administration routes, controllable expression systems, and rational patient stratification based on disease stage and biomarkers will be essential to fully realize the neuroprotective and neuroregenerative potential of neurotrophin-based therapies for acute and chronic brain disorders.},
}
@article {pmid42530076,
year = {2026},
author = {Li, Y and Gong, J and Yang, L and Jin, L and Peng, R and Wang, F and Wang, L},
title = {Investigating the Therapeutic Mechanism of Ginkgo Biloba Extract in Alzheimer's Disease via Integrated Network Pharmacology and Molecular Docking.},
journal = {Die Pharmazie},
volume = {81},
number = {7},
pages = {51748},
doi = {10.31083/Pharmazie51748},
pmid = {42530076},
issn = {3053-691X},
support = {232102311152//Scientific and Technological Project in Henan Province/ ; },
mesh = {Animals ; Molecular Docking Simulation ; *Ginkgolides/pharmacology ; *Ginkgo biloba/chemistry ; *Alzheimer Disease/drug therapy/genetics ; *Plant Extracts/pharmacology/chemistry ; Mice ; Ginkgo Extract ; Molecular Dynamics Simulation ; Network Pharmacology ; Humans ; Amyloid beta-Peptides ; Protein Interaction Maps/drug effects ; Cell Line ; Disease Models, Animal ; },
abstract = {OBJECTIVE: This study aimed to investigate the mechanisms through which ginkgolides in Ginkgo biloba extract (GBE) may protect against Alzheimer's disease (AD).<br><br>METHODS: Candidate ginkgolide constituents and their putative targets were identified using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and SwissTargetPrediction. AD-associated genes were retrieved from OMIM and GeneCards. Overlapping targets were used to construct component-target-disease and protein-protein interaction (PPI) networks for hub target screening. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using DAVID. AutoDock Vina was used for molecular docking, and molecular dynamics simulations were conducted to evaluate ligand-target stability. The predicted mechanisms were further examined in APP/PS1 mice and A&#x3b2;1-42-treated HT22 cells.<br><br>RESULTS: A total of 27 active ginkgolide-related constituents and 336 intersecting targets were identified. Ginkgolides B and M were identified as the major active compounds, whereas MAPK3, HIF-1&#x3b1;, and AKT1 emerged as important targets. Enrichment analysis indicated a close association with the PI3K-Akt pathway. Docking analysis showed that ginkgolides B and M bound strongly to MAPK3 and HIF-1&#x3b1; with binding energies ranging from -9.34 to -8.41 kcal/mol. Molecular dynamics simulations supported the stable formation of these complexes. In vivo and in vitro experiments showed that ginkgolides B and M alleviated synaptic protein damage, decreased HIF-1&#x3b1; expression, and improved cognitive deficits.<br><br>CONCLUSIONS: Ginkgolides B and M may contribute to anti-AD effects in experimental models, partly through modulation of HIF-1&#x3b1;-related stress responses and PI3K-Akt-associated survival pathways.},
}
@article {pmid42530129,
year = {2026},
author = {Monge-García, V and Lorenzo-García, S and Bernal-Soriano, MC and Torrella-Esteban, P and Monge-García, S and Sánchez-Payá, J and Monge-Argilés, JA},
title = {Validation of Plasma p-tau217 as a Biomarker of Prodromal Alzheimer's Disease.},
journal = {Revista de neurologia},
volume = {81},
number = {7},
pages = {50619},
doi = {10.31083/RN50619},
pmid = {42530129},
issn = {1576-6578},
mesh = {Humans ; *Alzheimer Disease/blood/diagnosis/cerebrospinal fluid ; *tau Proteins/blood/cerebrospinal fluid ; Biomarkers/blood/cerebrospinal fluid ; Female ; Male ; Aged ; Cognitive Dysfunction/blood/cerebrospinal fluid/diagnosis ; Reproducibility of Results ; Prodromal Symptoms ; Middle Aged ; Sensitivity and Specificity ; },
abstract = {BACKGROUND: Plasma phosphorylated tau 217 protein (p-tau217p) has recently been proposed as a useful biomarker for the early diagnosis of Alzheimer's disease (AD). However, local validation is recommended because of the potential influence of clinical, analytical, and preanalytical factors on assay performance.<br><br>METHODS: Between 2021 and 2024, we evaluated patients with amnestic mild cognitive impairment (aMCI) through clinical history, neurological and neuropsychological examination, blood sampling for biobanking, brain imaging, and lumbar puncture, among other diagnostic tests. In September 2025, p-tau217p levels were measured simultaneously using the LUMIPULSE immunoassay (Fujirebio). The diagnostic validity, reproducibility, receiver operating characteristic (ROC) curve performance, correlation with cerebrospinal fluid (CSF) biomarkers, and influence of clinical and analytical variables were evaluated in this study.<br><br>RESULTS: Among the 108 aMCI patients included, 66 met the criteria for clinic-biological AD, while the remainder had alternative clinical diagnoses. Using a two-threshold approach, p-tau217p levels &#x2265;0.19 yielded a sensitivity of 88% and a positive predictive value of 83% for identifying AD. Levels &#x2265;0.39 showed a specificity of 91% and a positive predictive value of 90% for the same purpose. Intermediate values (0.20-0.38) achieved a specificity of 83%. The intraclass correlation coefficient for the assay reproducibility was 0.97. The ROC curve for p-tau217p demonstrated an area under the curve of 0.86 for diagnosing AD. P-tau217p correlated more strongly with CSF p-tau181 (&#x3c1; = 0.63; p < 0.01) than with CSF A&#x3b2;1-42 (&#x3c1; = -0.40; p < 0.01). Finally, a reduced glomerular filtration rate was associated with a significant increase in p-tau217p levels (p < 0.006).<br><br>CONCLUSIONS: In our setting, p-tau217p measurement showed a high validity for the diagnosis of prodromal AD, which is consistent with the recent neurological literature. The assay showed high reproducibility, although results may be influenced by renal function. P-tau217p correlated more strongly with CSF p-tau181 than with CSF A&#x3b2;1-42.},
}
@article {pmid42530130,
year = {2026},
author = {Li, P and Wang, Y},
title = {AI-Enabled Modeling for Alzheimer's Disease Risk Prediction and Validation.},
journal = {Revista de neurologia},
volume = {81},
number = {7},
pages = {49220},
doi = {10.31083/RN49220},
pmid = {42530130},
issn = {1576-6578},
mesh = {Humans ; *Alzheimer Disease/diagnosis/genetics/cerebrospinal fluid ; Female ; Retrospective Studies ; Risk Assessment/methods ; Male ; Aged ; Random Forest ; Boosting Machine Learning Algorithms ; Predictive Learning Models ; Risk Factors ; Prediction Algorithms ; *Artificial Intelligence ; Amyloid beta-Peptides/cerebrospinal fluid ; Apolipoprotein E4/genetics ; Biomarkers/cerebrospinal fluid ; },
abstract = {BACKGROUND: To investigate the multimodal clinical influencing factors of Alzheimer's disease (AD) onset, and to establish and test a risk prediction tool derived from these determinants and additional clinical measures, thus facilitating early intervention and risk classification in individuals at high risk for AD.<br><br>METHODS: A retrospective cohort of 502 high-risk individuals for AD (exhibiting cognitive decline or family history) who visited our hospital was included. A total of 502 participants were randomly split into a training cohort (n = 350) and a validation cohort (n = 152) in a 7:3 proportion. Demographic characteristics, clinical indicators, biomarkers, and genetic markers were collected. In the training set, univariate analysis and least absolute shrinkage and selection operator (LASSO) regression were first applied for variable screening, followed by multivariate logistic regression to pinpoint independent influencing factors. Random forest (RF), XGBoost, and deep learning models were constructed using Python, with performance evaluated using area under the curve (AUC). The optimal model was selected, and feature importance was analyzed.<br><br>RESULTS: Between the training and validation sets, no statistically significant baseline characteristic differences were found (p > 0.05). Multivariate logistic regression identified the apolipoprotein E epsilon 4 allele (APOE &#x3b5;4) genotype, cerebrospinal fluid (CSF) p-tau181/amyloid-beta 42 (A&#x3b2;42) ratio, and diabetes as independent risk factors for AD (p < 0.05), while serum folate levels, Mini-Mental State Examination (MMSE) scores, and Montreal Cognitive Assessment (MoCA) scores served as independent protective factors (p < 0.05). In the validation set, the RF model achieved the highest AUC (0.879), followed by XGBoost (0.869) and deep learning (0.844), with the CSF p-tau181/A&#x3b2;42 ratio identified as the most predictive feature.<br><br>CONCLUSION: The RF model, based on integrated multimodal clinical influencing factors and clinical indicators, demonstrates potential for AD risk stratification in high-risk populations when evaluated on a validation cohort.},
}
@article {pmid42530254,
year = {2026},
author = {Stepenko, Y and Shcheblykina, O and Zhunusov, N and Shmigerova, V and Kozin, S and Mitkevich, V and Radchenko, A and Kuzubova, E and Khalzov, L and Korokin, M},
title = {Peripheral Administration of isoD7-Aβ Exacerbates Motor Deficits and Tau Pathology in P301S Mice.},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {31},
number = {7},
pages = {53279},
doi = {10.31083/FBL53279},
pmid = {42530254},
issn = {2768-6698},
support = {FZWG-2026-0003//Program of Fundamental Research in the Russian Federation/ ; 124031800075-1//Program of Fundamental Research in the Russian Federation/ ; },
mesh = {Animals ; *tau Proteins/metabolism/genetics ; Mice ; *Amyloid beta-Peptides/administration &amp; dosage ; Mice, Transgenic ; Male ; *Alzheimer Disease/pathology/metabolism ; Brain/metabolism/pathology ; Proto-Oncogene Proteins c-akt/metabolism ; Mice, Inbred C57BL ; Signal Transduction ; Disease Models, Animal ; Glycogen Synthase Kinase 3 beta/metabolism ; Apoptosis ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder leading to dementia, disability, and premature death. Beta-amyloid (Aβ) and tau pathology are considered key components of its pathogenesis; however, the role of peripheral amyloid load in modulating pre-existing tau pathology remains understudied. We hypothesized that peripheral amyloid load could exacerbate tau pathology through mechanisms potentially linked to the disruption of the Akt/glycogen synthase kinase-3β-associated signaling pathway, which could lead to increased behavioral deficits and progression of neurodegenerative changes.<br><br>OBJECTIVE: To evaluate the effect of double peripheral (retro-orbital) administration of the A&#x3b2; isoform D7 on the behavioral phenotype, morphological signs of tau pathology, and the expression of genes related to Akt/GSK-3&#x3b2;-associated signaling, neuroinflammation, and apoptosis in the brains of P301S transgenic mice.<br><br>MATERIALS AND METHODS: The study included 12-week-old male P301S transgenic mice (Tg(Thy1-MAPT*P301S)2541Godt) (n = 20, biological duplication) and wild-type C57Black6/J mice (n = 10). P301S mice received two retro-orbital injections of isoD7-A&#x3b2; into the venous sinus at a dose of 100 &#xb5;g (n = 10) with a 1-month interval; control P301S mice received an equivalent volume of water for injection (n = 10). Behavioral testing ("open field", "novel object recognition", "vertical pole", "inverted screen") was performed at 16 and 20 weeks of age. Tau pathology was assessed immunohistochemically using AT-8 (pSer202/pThr205) antibodies in the frontal cortex and brainstem, and amyloid deposits were assessed histologically using Congo red staining in the entorhinal cortex and hippocampus. The expression of Akt1, Gfap, Mapt, Cdk5, Casp3, Bax, and Bcl2 genes in brain tissue was analyzed by quantitative real-time PCR.<br><br>RESULTS: Two peripheral administrations of isoD7-A&#x3b2; were not associated with further deterioration of performance in the "open field" and "novel object recognition" tests compared to the control P301S group, which likely reflects the already established deficit characteristic of this transgenic line. In contrast, in motor coordination tests ("vertical pole", "inverted screen"), motor impairments in the P301S+A&#x3b2; group emerged by week 16, whereas in P301S mice without amyloid load, they appeared only by week 20. Immunohistochemical analysis revealed an increase in AT-8-positive staining in the brainstem, whereas no statistically significant differences were found between groups in the frontal cortex. Histological analysis did not reveal amyloid plaques in the entorhinal cortex and hippocampus of P301S+A&#x3b2; mice and control P301S mice. At the molecular level, the P301S+A&#x3b2; group showed decreased Akt1 expression, increased Gfap and Bax expression, and decreased Bcl2 expression, with no significant changes in Mapt, Casp3, and Cdk5. This pattern is consistent with dysregulation of Akt/GSK-3&#x3b2;-associated signaling, enhanced glial activation, and a pro-apoptotic shift.<br><br>CONCLUSIONS: Two peripheral administrations of isoD7-A&#x3b2; to P301S mice were associated with earlier development of motor impairments, increased tau protein phosphorylation, and changes in gene expression consistent with a disrupted Akt/GSK-3&#x3b2;-associated signaling pathway. These findings support the hypothesis that peripheral amyloid load can exacerbate tauopathy manifestations, and the observed transcriptional changes are consistent with the possible involvement of the Akt/GSK-3&#x3b2;-associated signaling pathway, which may represent a potential therapeutic target in AD.},
}
@article {pmid42530260,
year = {2026},
author = {Kravtsov, A and Kozin, S and Kondratenko, R and Lyasota, O and Dorohova, A and Leontyeva, O and Hernandez-Caceres, JL and Dzhimak, S},
title = {Neuroprotective Properties and Molecular Mechanisms of Action of 4H-Pyran-Based Acids.},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {31},
number = {7},
pages = {48552},
doi = {10.31083/FBL48552},
pmid = {42530260},
issn = {2768-6698},
support = {075-15-2025-283//Ministry of Science and Higher Education of the Russian Federation/ ; },
mesh = {Humans ; *Neuroprotective Agents/pharmacology/chemistry ; Animals ; Signal Transduction/drug effects ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Pyrans/pharmacology/chemistry ; Pyrones/pharmacology/chemistry ; Antioxidants/pharmacology ; },
abstract = {The development of effective neuroprotective agents remains one of the most urgent and complex challenges in modern medical and biological research, given the increasing prevalence of neurodegenerative diseases and the limited efficacy of existing therapeutic options. In recent years, compounds belonging to the 4H-pyran chemical class have attracted significant attention due to their pronounced antioxidant, anti-inflammatory, and cytoprotective properties. These molecules exhibit structural versatility, enabling modulation of multiple molecular targets involved in neuronal survival, redox homeostasis, and mitochondrial function. This review provides a comprehensive analysis of the pharmacological activity and molecular mechanisms of action of five 4H-pyran-based compounds-maltol, kojic acid, chelidonic acid, comenic acid, and meconic acid. Special attention is paid to their effects on signaling pathways that play a central role in maintaining neuronal integrity and resistance to stress factors. In particular, the review examines how these compounds regulate key intracellular cascades such as nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1)/antioxidant response element (ARE), Nrf2/PTEN-induced putative kinase 1 (PINK1)/Parkin, nuclear factor-kappa B (NF-κB), and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR), which are critically involved in controlling oxidative stress, mitochondrial autophagy, inflammation, and neuronal plasticity. The integrated evaluation of these mechanisms demonstrates that 4H-pyran-based acids can act as multitarget neuroprotective agents capable of influencing both primary metabolic processes and secondary signaling responses to neurotoxic stimuli. Their pleiotropic action highlights the promise of these compounds as molecular scaffolds for the development of novel drugs aimed at preventing or delaying the progression of neurodegenerative disorders such as Alzheimer's and Parkinson's diseases.},
}
@article {pmid42530543,
year = {2026},
author = {Pan, Y and Cho, B and Stallings-Smith, S},
title = {Sex and racial/ethnic patterns in subjective cognitive concerns-related functional difficulties among middle-aged and older adults: A multi-year cross-sectional analysis of a population-based U.S. adult sample in 2015-2022.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261472887},
doi = {10.1177/13872877261472887},
pmid = {42530543},
issn = {1875-8908},
abstract = {BackgroundExperiencing subjective cognitive concerns (SCC) marks a potential risk stage for Alzheimer's disease.ObjectiveThis study examined sex and racial/ethnic patterns in the prevalence of functional difficulties among U.S. adults with SCC.MethodsData for 32,105 adults aged ≥45 years who experienced SCC in the past year were sourced from the Behavioral Risk Factor Surveillance System in 2015-2022. Individuals reporting SCC-related functional difficulties in daily or social life activities always/usually/sometimes (versus rarely/never) in the past year were considered having each of the functional difficulties. Weighted binomial logistic regression analyses were conducted to examine the association of sex (male or female) and race/ethnicity (non-Hispanic White [NHW], non-Hispanic Black [NHB], Hispanic, or non-Hispanic Other [NHO]) with SCC-related daily and social life difficulties, adjusting for all covariates.ResultsOverall, a decreasing trend in SCC-related functional difficulties was observed in both sexes, while female adults had higher prevalence. Trends in these functional difficulties varied by race/ethnicity, with NHW adults exhibiting the most stable and lowest prevalence. Female adults had significantly higher odds of experiencing SCC-related daily life (adjusted odds ratio [AOR] = 1.28, 95% confidence interval [CI] = 1.15, 1.41) and social life difficulties (AOR = 1.12, 95% CI = 1.01, 1.24) than male adults. NHB, Hispanic, and NHO groups had higher odds of experiencing SCC-related daily and social life difficulties compared to NHW participants.ConclusionsFemale and racial/ethnic minority individuals experienced higher levels of SCC-related functional difficulties. Public health interventions are warranted to alleviate such challenges for vulnerable populations.},
}
@article {pmid42530559,
year = {2026},
author = {Manzine, PR and Carrasco, M and Antonia Alves Fernandes, T and Santos Alves, S and Guzman, L and Driouech, L and Millet, M and Garcia Cairasco, N and Olloquequi, J and Juan, ME and Ettcheto, M and Cominetti, MR and Camins, A},
title = {Cognitive-enhancing drugs in Phase II clinical trials for Alzheimer's disease: emerging therapeutic candidates.},
journal = {Expert opinion on investigational drugs},
volume = {},
number = {},
pages = {},
doi = {10.1080/13543784.2026.2710112},
pmid = {42530559},
issn = {1744-7658},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is biologically defined by amyloid-β (Aβ) and tau pathology but clinically manifests as progressive synaptic dysfunction and cognitive decline. Although anti-amyloid and anti-tau therapies modestly slow disease progression, they do not directly restore cognition or synaptic function.<br><br>AREAS COVERED: Phase II trials of cognition&#x2011;enhancing therapies in AD and prodromal AD were reviewed to identify factors behind success or failure. Trials from ClinicalTrials.gov and the EU Clinical Trials Register with cognitive endpoints were assessed by mechanism, design, population, and outcomes. Strategies included synaptic, inflammatory, metabolic, vascular, and regenerative approaches.Most therapies showed limited or inconsistent cognitive effects, and many trials did not demonstrate clear efficacy.<br><br>EXPERT OPINION: Phase II cognition&#x2011;enhancing trials in AD show biological plausibility but remain methodologically limited. Cognitive signal detection depends on the fit between mechanism, disease stage, and trial design, and on the statistical approach used to capture subtle change. Outcome variability highlights the need for sensitive cognitive measures and adequate power. Progress will require precision&#x2011;enriched designs, with biomarker&#x2011;defined populations, cognitive&#x2011;trajectory modeling, and integrated cognitive and functional endpoints.},
}
@article {pmid42530714,
year = {2026},
author = {Asgari, M and Mousavi, SE and Zaeifi, D and Ehsani, E},
title = {Maternal Traumatic Brain Injury Increases Fetal Brain Cis p-tau Levels: Evidence for Potential Transplacental Effects in a Murine Model.},
journal = {Journal of molecular neuroscience : MN},
volume = {76},
number = {3},
pages = {},
pmid = {42530714},
issn = {1559-1166},
support = {1402-2-209-67616//Experimental Medicine Research Center, Tehran University of Medical Sciences/ ; },
mesh = {Animals ; Female ; Pregnancy ; *tau Proteins/metabolism/genetics ; *Brain Injuries, Traumatic/metabolism ; Mice ; *Brain/metabolism/embryology ; Mice, Inbred BALB C ; *Maternal-Fetal Exchange ; },
abstract = {Traumatic brain injury (TBI) is a well-established risk factor for Alzheimer's disease-related tauopathy. However, whether maternal TBI can lead to transgenerational transmission of pathogenic tau to offspring remains unknown. This study examines whether maternal Traumatic brain injury (TBI) induces pathogenic tau transfer to offspring, impairing fetal brain development. TBI was induced in pregnant Balb/C mice prior to pregnancy using a weight-drop model, while the sham group underwent anesthesia without injury, and the fetal brains were analyzed for cis p-tau using immunofluorescence (IF) and Western blotting (WB). Maternal anxiety post-TBI was assessed via the Elevated Plus Maze (EPM). Compared with the sham group, maternal TBI resulted in 4.25 and 5.81-fold increase in cis p-tau aggregation in embryonic and fetal brains, respectively (F(2,12) = 68.45, p < 0.001; F(2,12) = 102.34, p < 0.0001), and protein levels showed 3.13- and 6.79-fold increases (F(2,12) = 45.12, p < 0.001; F(2,12) = 89.67, p < 0.0001). This was accompanied by a significant increase in apparent transfer efficiency of p-tau to fetal brains (t(8) = 12.50, p < 0.0001). EPM assessment revealed that TBI-induced dams spent significantly more time in the open arms compared with sham (t(8) = 2.65, p = 0.029), suggesting reduced anxiety-like behavior or increased risk-taking. Maternal serum p-tau181 and fetal cis p-tau showed a positive but non-significant correlation (r(3) = 0.78, p = 0.120). These changes were associated with IL-6 and TNF increased by 2.8-fold (t(8) = 4.22, p = 0.003) and 1.8-fold (t(8) = 2.45, p = 0.040), respectively. These findings demonstrate a significant increase in apparent p-tau transfer efficiency from maternal serum to fetal brain following maternal TBI, although the correlation between maternal serum p-tau181 and fetal brain cis p-tau did not reach statistical significance.},
}
@article {pmid42530851,
year = {2026},
author = {},
title = {RETRACTION: The Preventive Effects of Edible Folic Acid on Cardiomyocyte Apoptosis and Survival in Early Onset Triple-transgenic Alzheimer's Disease Model Mice.},
journal = {Environmental toxicology},
volume = {},
number = {},
pages = {},
doi = {10.1002/tox.70167},
pmid = {42530851},
issn = {1522-7278},
abstract = {K. Lin, C. Chiu, W. Kuo, D. Ju, C. Shen, R. Chen, C. Lin, V. P. Viswanadha, J. Liu, R. S. Huang, and C. Huang, "The Preventive Effects of Edible Folic Acid on Cardiomyocyte Apoptosis and Survival in Early Onset Triple-transgenic Alzheimer's Disease Model Mice," Environmental Toxicology 33, no. 1 (2017): 83-92, https://doi.org/10.1002/tox.22498. The above article, published online on 25 October 2017 in Wiley Online Library (https://wileyonlinelibrary.com), has been retracted by agreement between the journal's Editor-in-Chief, April Rodd, and Wiley Periodicals LLC. A third party reported on PubPeer [1] that bands in Figures 2, 3, and 4 appeared to have been duplicated in other articles and preprints [Chiang et al. 2016 (https://doi.org/10.3402/fnr.v60.31417); Bai et al. 2019 (https://doi.org/10.1101/823088); and Asokan et al. 2019 (https://doi.org/10.1186/s12906-019-2700-8)]. Each article describes these bands as different samples and many show additional blots that were not included in this article. Additionally, the GAPDH control bands in Figures 2 and 3 in this article also appear to have been duplicated. The retraction has been agreed to because the evidence of data duplication and manipulation fundamentally compromises the editors' confidence in the results presented in this article. The authors were informed of the retraction. Reference [1] René Aquarius, Comments on "The preventive effects of edible folic acid on cardiomyocyte apoptosis and survival in early onset triple-transgenic Alzheimer's disease model mice," PubPeer, April 2026. https://pubpeer.com/publications/76A62C91CAA2ABA60C4A9E31783C55.},
}
@article {pmid42530901,
year = {2026},
author = {Li, TY and Yu, ZM},
title = {Opposing effects of uric acid and triglycerides on cognitive decline cancel within a metabolic oxidative composite: Longitudinal evidence from CHARLS and cross-sectional replication in NHANES.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261471903},
doi = {10.1177/13872877261471903},
pmid = {42530901},
issn = {1875-8908},
abstract = {BackgroundComposite metabolic-oxidative scores have shown inconsistent associations with cognitive outcomes, yet whether their components move in the same direction remains unexamined.ObjectiveTo test whether Metabolic Oxidative Risk Score (MORS) tracks cognitive change, and to decompose MORS to assess whether component effects on cognitive slope are concordant or opposing.MethodsWe constructed a four-component MORS (uric acid, triglycerides, fasting glucose, reverse-scored HDL; range 4-20) and examined its association with cognitive change across four waves (2011-2018) in CHARLS (N = 7,300, age ≥ 45 years) using linear mixed models. Equivalence testing distinguished null findings from insufficient power. Components were decomposed individually and simultaneously. Cross-sectional triangulation used NHANES 2011-2014 (N = 1,340, age ≥ 60 years).ResultsThe adjusted MORS × time interaction was β = -0.00046 SD/year (95% CI -0.00185 to 0.00093; p = 0.516); equivalence testing rejected any clinically meaningful effect (p = 0.0002). Component decomposition revealed opposing effects: higher uric acid predicted steeper decline (β = -0.0055; p = 0.003) while higher triglycerides predicted attenuated decline (β = + 0.0042; p = 0.045), with near-perfect cancellation at the composite level. In NHANES, the MORS-cognition association reversed sign after socioeconomic adjustment and showed a significant non-linear association (p = 6 × 10[-4]); leave-one-out analysis identified uric acid as the dominant signal carrier.ConclusionsAn equal-weight metabolic-oxidative composite does not track cognitive decline because its components exert opposing effects that cancel. Uric acid emerges as an independent, potentially modifiable risk factor with implications for Alzheimer's disease prevention research.},
}
@article {pmid42530906,
year = {2026},
author = {Novotný, JS and Thatcher, A and Shatti, D and Mofardin, S and Rakuša, M and Kolenc, M and Zupan, M and Frol, S and Popović, K&#x160; and Oblak, JP and Bossert, I and Kuruvilla, T and Lyburn, I and Trifiro, G and Stokin, GB},
title = {Evaluation of the Addenbrooke's Cognitive Examination-Revised in a routine cognitive outpatient clinic.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261471428},
doi = {10.1177/13872877261471428},
pmid = {42530906},
issn = {1875-8908},
abstract = {BackgroundThe Addenbrooke's Cognitive Examination-Revised (ACE-R) is a widely used multidomain cognitive screening instrument. However, its performance in routine cognitive outpatient clinics with heterogeneous, diagnostically unselected populations remains insufficiently characterized.ObjectiveTo evaluate the diagnostic accuracy and clinical utility of ACE-R across the spectrum of cognitive impairment in a real-world cognitive outpatient setting.MethodsThis retrospective observational study included 348 consecutive patients attending a cognitive outpatient clinic. Diagnostic accuracy was assessed using binary and multiclass classification, and longitudinal cognitive trajectories were analysed using multilevel modelling.ResultsACE-R reliably differentiated dementia from non-dementia and distinguished Alzheimer's disease from mild cognitive impairment. Discrimination between subjective cognitive impairment and normal cognition was limited, consistent with the absence of objective cognitive deficits in subjective cognitive impairment. The instrument demonstrated greater sensitivity for cortical dementias than for subcortical conditions. Longitudinal analyses showed significant cognitive decline in Alzheimer's disease.ConclusionsACE-R is a practical and clinically useful screening tool for routine outpatient settings, particularly for dementia detection. However, limited sensitivity in early-stage impairment and restricted ability to differentiate dementia subtypes support its use within a multimodal diagnostic framework rather than as a standalone instrument.},
}
@article {pmid42530934,
year = {2026},
author = {Calderón-Garcidueñas, L and Stommel, EW and Hernández-Luna, J and Clouston, SAP and Muñoz, MJ and Loera-Barba, BA and Torres-Jardón, R and Nalbantoglu, OU},
title = {Abnormal eye movements reflect early cortical and volumetric brain changes in apparently healthy, PM2.5-exposed urban youth.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261471048},
doi = {10.1177/13872877261471048},
pmid = {42530934},
issn = {1875-8908},
abstract = {BackgroundEye movement dysfunction plays an important role in understanding the pathology of neurodegenerative disorders. Fine particulate matter (PM2.5) exposures are associated with hallmark proteins diagnostic of Alzheimer's and Parkinson's diseases in Metropolitan Mexico City (MMC) ≤ 40-year-old residents.ObjectiveTo assess oculomotor function with neuroanatomical correlates using magnetic resonance imaging (MRI) region of interest analysis in young urbanites.MethodsVideo-based eye-tracking was used to explore oculomotor dysfunction and structural brain MRI changes in two highly exposed PM2.5 cohorts. We assessed fixation stability, smooth pursuit, pro-saccades, and anti-saccades using the Eyelink 1000-plus eye-tracker, in 80 volunteers' age 33 ± 11 years from MMC and Cuernavaca. Forty-five MMC subjects age 31.2 ± 14.7 years with oculomotor assessment had brain MRIs. Measurements of saccadic accuracy, latency, and smooth pursuit gain and square wave jerk frequency were collected.ResultsOculomotor variables did not reach statistically significant differences in MMC versusCuernavaca. Abnormal antisaccades, low gain pursuit, and square wave jerks were documented more often in MMC residents. Correlational analysis between oculomotor function and structural MRI data revealed statistical cortical and subcortical changes at frontal-temporal-parietal regions, hippocampus, thalamus, caudate, amygdala, habenula, nucleus accumbens, and cerebellum. Involved regions potentially reveal the location and severity of neurodegeneration processes via altered saccade parameters.ConclusionsOur findings suggest that simple oculomotor test batteries may provide a useful tool to monitor and/or measure the impact of pollution on neurodevelopment and early neurodegeneration. The integration of ocular movement parameters into the Continuum model of neurodegeneration offers a promising approach for neuroprotection decision-making and rigorous emissions control in polluted settings.},
}
@article {pmid42530937,
year = {2026},
author = {Tanaka, K and Ogawa, S and Suzuki, H and Fujiwara, Y and Nobuhara, T and Kato, H and Kawamoto, R and Kimura, E and Miyake, Y},
title = {Association between number of teeth and functional tooth units and prevalence of mild cognitive impairment in Japan: Baseline data from the Aidai Cohort Study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261470790},
doi = {10.1177/13872877261470790},
pmid = {42530937},
issn = {1875-8908},
abstract = {BackgroundEpidemiological studies have suggested a possible association between tooth loss and dementia, yet evidence regarding mild cognitive impairment (MCI) remains limited.ObjectiveWe examined the association between the number of remaining teeth and functional tooth units (FTUs) and the prevalence of MCI.MethodsA total of 8697 adults aged 20-95 years (3786 men and 4911 women) were included. Dental status was assessed visually, excluding third molars. MCI was defined as a score of less than 26 on the Japanese version of the Montreal Cognitive Assessment. Participants were categorized into five groups based on the FTUs of natural teeth (n-FTUs) and total FTUs: n-FTUs ≥10; n-FTUs 6-9 and total FTUs ≥10; n-FTUs 6-9 and total FTUs <10; n-FTUs <6 and total FTUs ≥10; and n-FTUs <6 and total FTUs <10.ResultsThe prevalence of MCI was 35.5%. A reduced number of teeth was significantly associated with the higher prevalence of MCI (p for trend <0.0001). Compared with having n-FTUs ≥10, having n-FTUs <6 and total FTUs ≥10, and having n-FTUs <6 and total FTUs <10 were independently associated with a higher prevalence of MCI. There was no association between having 6-9 n-FTUs, regardless of total FTUs, and the prevalence of MCI.ConclusionsEven when occlusal function is maintained through prosthodontic restorations, a reduced number of natural teeth is independently associated with MCI, underscoring the importance of preserving natural dentition for maintaining cognitive health.},
}
@article {pmid42520314,
year = {2026},
author = {Thompson, J and Johnson, PK},
title = {Clinical, genetic, and neuropathologic correlates of limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC): A systematic review and meta-analysis.},
journal = {Journal of neuropathology and experimental neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/jnen/nlag079},
pmid = {42520314},
issn = {1554-6578},
abstract = {Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) has emerged as a major contributor to cognitive decline in older adults; however, the constellation of factors associated with its presence remains poorly defined. To date, no analysis has comprehensively evaluated correlates of LATE-NC. This analysis was conducted to quantify associations between LATE-NC and an array of potential links, including neurocognitive disorders, neurodegenerative neuropathologic change (NC), cerebrovascular NC, demographic factors, clinical comorbidities, and genetic factors. A comprehensive literature search through December 2025 identified 40 eligible studies. Meta-analyses demonstrated significant associations between LATE-NC and neurocognitive disorders including all-cause dementia, Alzheimer disease (AD), and mild cognitive impairment. Significant neurodegenerative NC associations included ADNC, higher amyloid-β and tau burden, hippocampal sclerosis, and aging-related tau astrogliopathy. Significant cerebrovascular NC associations included cerebral amyloid angiopathy and arteriosclerosis. Increasing age at death was the only significant demographic correlate. Most clinical comorbidities were not significantly associated. Significant genetic associations included APOE ε4 and GRN. This first-of-its-kind meta-analysis outlines a distinct pattern of correlates associated with LATE-NC, emphasizing its strong linkage to AD-related and multimorbid neuropathologic processes, and underscoring the need for refined diagnostic frameworks and future mechanistic studies to differentiate LATE-NC from coexisting neuropathologies.},
}
@article {pmid42520518,
year = {2026},
author = {Han, M and Liao, Q and He, S and Guo, L and Lu, Z and Wang, X and Sun, W and Duan, Y and Lyu, W and Li, Q},
title = {Regulation of different kinases for Alzheimer's disease therapy: progresses and perspectives.},
journal = {Bioorganic chemistry},
volume = {181},
number = {},
pages = {110300},
doi = {10.1016/j.bioorg.2026.110300},
pmid = {42520518},
issn = {1090-2120},
abstract = {Alzheimer's disease (AD) is clinically characterized by extracellular amyloid plaques caused by β-amyloid (Aβ) aggregation and intracellular neurofibrillary tangles (NFTs) formed by hyperphosphorylation of tau protein. Plaques and tangles attract microglia to their periphery, causing them to adopt the proinflammatory M1 type. In the central nervous system (CNS), activated microglia are a major source of inflammatory molecules, which trigger a positive feedback mechanism that activates more microglia, which further aggravates the neuroinflammatory response. In this procedure, many kinases are involved in the main signaling pathways of microglia activation. Kinases phosphorylate different substrate proteins, thereby regulating various processes of AD occurrence and development. Therefore, many researchers have developed kinase modulators to reduce the phosphorylation process of downstream substrates, in order to achieve the effect of AD treatment.},
}
@article {pmid42520619,
year = {2026},
author = {Zhao, H and Zhang, T and Liu, L and Zhang, S and Ma, W},
title = {The management of daily topics in conversations with individuals with Alzheimer's disease in Chinese residential care.},
journal = {Social science &amp; medicine (1982)},
volume = {406},
number = {},
pages = {119617},
doi = {10.1016/j.socscimed.2026.119617},
pmid = {42520619},
issn = {1873-5347},
abstract = {BACKGROUND: Individuals with Alzheimer's Disease (AD) often experience difficulties managing topics in daily interactions, which can hinder their participation in interactions and affect their social engagement. There is a gap in exploring the interactional dynamics and the maintenance of personhood when interacting with individuals with AD in asymmetric institutional settings.<br><br>OBJECTIVES: This study aims to examine the interactional competence of individuals with AD and how their vulnerabilities are managed in daily-topic interactions within institutional healthcare settings.<br><br>METHODS: This study adopts Conversation Analysis (CA) to examine video-recorded conversations between a trained researcher and individuals with mild cognitive impairment due to AD residing in two residential care facilities in China.<br><br>FINDINGS: Individuals with mild AD demonstrate agency within asymmetric interactions by reshaping conversational frames, preserving face, and situating themselves within relational contexts to maintain their personhood. This agency emerges only when interlocutors actively engage, providing validation and recognition while accommodating temporary incoherence. These findings underscore the collaborative nature of sustaining identity in dementia care and highlight the particular significance of such interactional practices within the Chinese cultural context.<br><br>IMPLICATIONS: Conversation partners can support agency in individuals with AD by ratifying frame reconfigurations, sustaining topics, acknowledging repetitions, and responding flexibly to disengagement. Care facilities are also expected to create more opportunities for residents to engage in casual conversation.},
}
@article {pmid42520739,
year = {2026},
author = {Jafari, M and Tang, Z and Acharya, UR and Li, Y},
title = {Applications of quantum AI in brain disorder diagnosis: A systematic review.},
journal = {Computer methods and programs in biomedicine},
volume = {286},
number = {},
pages = {109565},
doi = {10.1016/j.cmpb.2026.109565},
pmid = {42520739},
issn = {1872-7565},
abstract = {BACKGROUND AND OBJECTIVE: Brain disorder diagnosis and prediction remain challenging because neuroimaging, electrophysiological, behavioral, and multimodal data are high-dimensional, noisy, heterogeneous, and limited by small clinical cohorts. This systematic review synthesised applications of quantum artificial intelligence (QAI) for brain disorder diagnosis, prediction, detection, and monitoring.<br><br>METHODS: Following PRISMA guidelines, studies published from 2016 to 13 January 2026 were retrieved from Scopus, Web of Science, and IEEE Xplore. After screening, 36 studies met the eligibility criteria and were qualitatively analysed according to disorder category, data modality, QAI method, implementation setting, validation strategy, and performance.<br><br>RESULTS: At the broader disease-group level, neurodegenerative disorders were the most frequently investigated, followed by mental health and psychiatric disorders. At the individual level, Parkinson's disease and schizophrenia were the leading applications, followed by depression, anxiety, Alzheimer's disease, and stress-related tasks. MRI-based modalities were the most frequently used data source, followed by multimodal data and EEG. Methodologically, primary QAI approaches were dominated by quantum neural and QDL architectures, followed by quantum-inspired optimization or feature-selection methods and quantum-kernel/conventional QML classifiers. Qiskit/IBM Quantum and PennyLane were the most frequently reported quantum software frameworks. However, most studies relied on simulators, classical quantum-inspired implementations, or unclear implementation settings, with limited real-hardware evaluation.<br><br>CONCLUSIONS: QAI shows emerging potential for brain disorder analysis, particularly through hybrid quantum-classical learning, quantum neural architectures, quantum-kernel methods, and quantum-inspired optimization. Nevertheless, current evidence remains preliminary and requires larger datasets, subject-level and external validation, fair classical benchmarking, noise-resilient circuits, real quantum hardware evaluation, explainability, and clinical validation.},
}
@article {pmid42520782,
year = {2026},
author = {Persson, J and Voss, G},
title = {Anti-Amyloid Therapies for Early Alzheimer's Disease: Evidence-Based Recommendations.},
journal = {South Dakota medicine : the journal of the South Dakota State Medical Association},
volume = {79},
number = {1},
pages = {35-39},
pmid = {42520782},
issn = {0038-3317},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Antibodies, Monoclonal/therapeutic use ; Evidence-Based Medicine ; Cognitive Dysfunction/drug therapy ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia in older adults and represents a growing public health burden. Traditional therapies offer only symptomatic relief without modifying disease progression. Recently approved anti-amyloid monoclonal antibodies, donanemab and lecanemab, represent a shift toward disease-modifying treatment in patients with mild cognitive impairment (MCI) or mild AD with confirmed amyloid pathology.<br><br>METHODS: This review synthesizes current evidence from key clinical trials, real-world safety considerations, and expert-driven appropriate use recommendations (AURs) to guide the safe and effective use of donanemab and lecanemab.<br><br>RESULTS: Both agents demonstrate statistically significant and clinically meaningful slowing of cognitive and functional decline in early symptomatic AD. Key differences exist in their mechanisms of action, dosing schedules, and treatment duration. Safety monitoring, particularly for amyloid-related imaging abnormalities (ARIA) and apolipoprotein E (APOE) &#x3b5;4 genotyping, is an essential component of care.<br><br>CONCLUSION: Anti-amyloid therapies offer a meaningful step forward in AD management, but their use requires careful patient selection, biomarker confirmation, and adherence to safety protocols. As long-term outcomes and comparative effectiveness remain uncertain, continued surveillance, patient education, and equitable access will be important in optimizing the clinical impact of anti-amyloid therapies.},
}
@article {pmid42520805,
year = {2026},
author = {Savignac, C and St-Onge, F and Villeneuve, S and Badhwar, A and Gagliano Taliun, SA and Farhan, S and Geddes, M and Iturria Medina, Y and Poirier, J and Spreng, RN and Bzdok, D and , },
title = {Parent-of-origin effects in Alzheimer's liability dissociate neurocognitive and cardiovascular traits in at-risk individuals.},
journal = {Cell reports. Medicine},
volume = {},
number = {},
pages = {102943},
doi = {10.1016/j.xcrm.2026.102943},
pmid = {42520805},
issn = {2666-3791},
abstract = {Alzheimer's disease (AD) has a higher prevalence in women than men and is more frequently inherited from mothers than fathers. Yet, while neuroimaging and biomarker studies link maternal family history to stronger AD-related alterations, epidemiological studies suggest that paternal history confers comparable or even greater risk. Here, we leverage the deeply profiled PREVENT-AD cohort to derive three intermediate phenotypes of AD susceptibility. Drawing on nearly 1,000 individual study visits, we quantify how these intermediate phenotypes vary as a function of maternal versus paternal AD lineage. We show that lineage-specific differentiation, including both maternal and paternal biases, is reflected in the brain structure and phenome of adult children of AD patients. Cognitive and cardiovascular risk markers, together with associated genetic variants, show the strongest differentiation along the parental-lineage spectrum of disease susceptibility relative to other correlates of AD burden. Our cross-generational analysis ultimately delineates multidimensional parent-of-origin effects in AD genealogy.},
}
@article {pmid42520915,
year = {2026},
author = {Xing, S and Ren, P and Chen, Z and Fu, Y},
title = {Non-transgenic rodent models associated with Alzheimer's disease: applications, evaluation, and perspectives.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.07.063},
pmid = {42520915},
issn = {1873-7544},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Familial AD accounts for less than 1% of cases, while sporadic AD (SAD) accounts for over 95%. Mild cognitive impairment (MCI) is the critical transition phase from normal aging to AD dementia. Understanding the pathological progression from MCI to AD and the mechanisms underlying SAD is essential. Rodent models, including transgenic and non-transgenic models, are vital tools for developing effective AD therapies. However, transgenic models primarily mimic familial AD and poorly replicate MCI and the complex pathological features of SAD. Non-transgenic models address these limitations by incorporating genetic, environmental, and aging factors, thereby better simulating SAD complexity. In addition, non-transgenic models are valuable for studying the compensatory mechanisms within neural networks that preserve cognitive function despite early pathology during MCI. In this review, we provide a comprehensive summary of non-transgenic rodent models used in AD and MCI research. First, we detail modeling strategies, including agents, administration routes, and dosages. Next, we discuss evaluation methods, such as behavioral and molecular assessments. We emphasize the importance of electrophysiological data, such as long-term potentiation, for evaluating cognition. Finally, we discuss the advantages and limitations of these non-transgenic models. This review may serve as a reference for selecting models to study the progression from MCI to AD and to develop related therapeutics. Combining non-transgenic and transgenic models more accurately replicates the complex, multifactorial pathology of the disease.},
}
@article {pmid42521027,
year = {2026},
author = {de Sevilla, LP and Majumdar, S and Recio, B},
title = {The Human Retina in Alzheimer's Disease: Pathology, Mechanisms, and Biomarkers.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103275},
doi = {10.1016/j.arr.2026.103275},
pmid = {42521027},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD) is characterized by progressive neurodegeneration and synaptic dysfunction that begins decades before clinical symptoms emerge. While AD research has traditionally focused on the brain, increasing evidence suggests that the retina undergoes pathological remodeling that shares features with cerebral changes. Advances in retinal imaging, including optical coherence tomography (OCT), OCT angiography, and hyperspectral approaches, have identified structural, vascular, and functional abnormalities in individuals with mild cognitive impairment (MCI) and early-stage AD. This supports the potential utility of the retina as a non-invasive biomarker for detecting neurodegenerative processes. Furthermore, postmortem studies have demonstrated accumulation of amyloid-β and phosphorylated tau, increased vulnerability of retinal ganglion cells (RGC), synaptic alterations in the inner plexiform layer (IPL), and significant activation of glial cells and complement-mediated inflammatory pathways. Melanopsin RGCs appear to be selectively affected, suggesting a mechanistic link between retinal pathology and the circadian or sleep disturbances commonly observed in AD. This review synthesizes human clinical data from imaging, histopathological, and proteomic studies supporting retinal involvement in AD, with emphasis on convergent mechanisms, including mitochondrial dysfunction, oxidative stress, microglial activation, and synaptic degeneration. Key limitations and sources of variation in current retinal biomarker studies, including cohort heterogeneity, comorbid ocular disease, and methodological variability, are discussed, and future directions are outlined to strengthen retinal diagnostics and therapeutic monitoring of visual system dysfunction in AD.},
}
@article {pmid42521029,
year = {2026},
author = {Virlley, M and Spooner, RK and Wilson, TW and Pruitt, T and Davenport, EM and Maldjian, JA and Proskovec, AL},
title = {Gating of Somatosensory Neural Oscillations Across the Lifespan: A Narrative Review.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103276},
doi = {10.1016/j.arr.2026.103276},
pmid = {42521029},
issn = {1872-9649},
abstract = {Healthy and pathological aging are associated with progressive changes in cortical inhibition, yet the underlying neural mechanisms remain incompletely understood. Somatosensory gating (SG), the brain's suppression of redundant tactile input, provides a pre-attentive marker of inhibitory function. Paired-pulse paradigms concurrent with noninvasive magnetoencephalography (MEG) provide a millisecond portrayal of the neural dynamics underlying somatosensory processing and the gating of such responses with excellent spatial resolution. This narrative review synthesizes SG research focusing on neural oscillations, with a particular emphasis on gamma-band activity which is linked to GABAergic inhibitory processes. SG oscillatory metrics are sensitive to both healthy chronological aging and biological stressors such as allostatic load and epigenetic aging and offer insight beyond neural evoked responses. We also examine aberrant presentations of SG oscillatory metrics in age-related neuropathologies, including Alzheimer's disease and HIV-associated neurocognitive disorder, sensorimotor pathologies, and psychiatric conditions. Finally, we outline methodological considerations and propose future directions to refine SG oscillatory metrics as markers of inhibitory decline or potential compensatory mechanisms, situating the existing findings within prominent theories of neurocognitive aging. Collectively, this review underscores how an oscillatory perspective to brain function reveals frequency-specific somatosensory and inhibitory mechanisms, highlighting their differential sensitivity to healthy aging and pathology.},
}
@article {pmid42521030,
year = {2026},
author = {Kechko, OI and Moskalev, AA and Franceschi, C and Mitkevich, VA and Makarov, AA},
title = {Is amyloid beta peptide a driver of inflammaging?.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103280},
doi = {10.1016/j.arr.2026.103280},
pmid = {42521030},
issn = {1872-9649},
abstract = {Inflammaging, the chronic subclinical systemic inflammation accompanying aging, represents a critical pathogenetic mechanism underlying age-related neurodegenerative diseases. While amyloid beta (Aβ) peptides are established contributors to neuroinflammation in Alzheimer's disease, their role in aging-related subclinical inflammation remains insufficiently elucidated. In humans, Aβ exhibits dual functions: it supports neuronal activity, survival, and protection against neurotrauma, while also promoting inflammation and central nervous system dysfunction. This review highlights the beneficial effects of Aβ, including its antioxidant and antipathogenic properties, and synthesizes current knowledge of the molecular mechanisms driving Aβ-associated inflammaging. We structure this analysis across distinct brain cell types - microglia, astrocytes, oligodendrocytes, neurons, pericytes, and endothelial cells - and consider additional factors influencing Aβ-related neuroinflammation. Finally, we examine strategies to counteract the detrimental effects of Aβ, focusing on Aβ physiological clearance via the blood-brain barrier and glymphatic system, as well as therapeutic interventions. Understanding Aβ-driven inflammaging mechanisms offers new therapeutic avenues for early intervention in age-related neurodegenerative diseases, particularly in genetically susceptible populations. Targeting Aβ-associated inflammaging reframes Aβ not solely as a pathological marker but also as a context-dependent contributor to inflammatory processes during brain aging.},
}
@article {pmid42521309,
year = {2026},
author = {Moncion, K and Rodrigues, L and Bon, A and Sutoski, A and Sikorska, K and Allison, EY and Abreu, J and Golchi, S and Arbour, N and Gauthier, C and Paquette, C and Rosa-Neto, P and Leppert, I and Rowley, C and Tardiff, CL and Thiel, A and Al-Khazraji, B and Tang, A and Roig, M},
title = {Protecting the brain from post-stroke cognitive impairment and dementia with multimodal exercise training: study protocol for a Bayesian adaptive trial (PROTECT).},
journal = {BMJ open},
volume = {16},
number = {7},
pages = {e123336},
doi = {10.1136/bmjopen-2026-123336},
pmid = {42521309},
issn = {2044-6055},
mesh = {Humans ; *Stroke/complications ; *Stroke Rehabilitation/methods ; *Cognitive Dysfunction/prevention &amp; control/etiology ; *Dementia/prevention &amp; control/etiology ; Bayes Theorem ; *Exercise Therapy/methods ; Randomized Controlled Trials as Topic ; Clinical Trials, Phase III as Topic ; Resistance Training/methods ; Brain ; Multicenter Studies as Topic ; Biomarkers/blood ; Cognition ; Neuroimaging ; },
abstract = {INTRODUCTION: Stroke triggers acute vascular and inflammatory mechanisms that predispose the brain to rapid neurodegeneration. Up to 52% of stroke survivors develop cognitive impairment within 6 months and 20% receive a clinical diagnosis of dementia within 5 years. The subacute phase (<6 months) represents a critical window in which the brain may be most responsive to neuroprotective interventions. Multimodal aerobic and resistance training improves cognition in chronic stroke, but whether it improves cognition, neuroimaging markers and blood biomarkers of dementia risk when delivered during this early window remains unknown. The PROTECT trial will compare the effects of 12 weeks of multimodal exercise (moderate-to-high-intensity resistance and aerobic training) versus a low-intensity exercise comparator on cognition, neuroimaging outcomes, blood biomarkers of cognitive decline and dementia risk in people with subacute stroke.<br><br>METHODS AND ANALYSIS: The PROTECT trial is a 12-week, Phase 3, assessor-blinded, multisite Bayesian adaptive randomised controlled trial (RCT) following a two-arm parallel group sequential design with 6-month and 12-month follow-up (NCT07445841). Participants will be randomised to multimodal training or the comparator using concealed allocation with permuted blocks of varying sizes. The primary outcome is cognition, measured using the 13-item Alzheimer's Disease Assessment Scale-Cognitive assessment (ADAS-Cog-13). Secondary outcomes include ADAS-Cog-Plus, structural and perfusion neuroimaging and blood biomarkers of inflammation and neurodegeneration. Tertiary outcomes include cardiorespiratory fitness, functional mobility, muscle strength, body composition, neuropsychological status, patient-reported cognition, quality of life, fatigue and healthcare utilisation. Outcomes will be assessed at baseline, post-intervention (primary endpoint) and at 6-month and 12-month follow-up. Sample size was estimated via 20&#x2009;000 Monte Carlo simulations using an ADAS-Cog effect size of Cohen's d=0.63 from a previous exercise RCT. The target was &#x2265;80% power to detect this treatment effect at a one-sided type I error rate of 2.5%, using a weakly informative prior centred at zero with a variance of 100. The minimum required was 45 completers per arm (N=90) and accounting for 25% attrition, up to 120 participants (60 per arm) will be enrolled. Pre-planned adaptive features include: (1) two interim analyses at 50% and 75% of completers; (2) early stopping for efficacy and futility; and (3) sample size re-estimation.<br><br>ETHICS AND DISSEMINATION: Ethical approval to conduct this study has been granted by the Centre de recherche interdisciplinaire en r&#xe9;adaptation du Montr&#xe9;al m&#xe9;tropolitain (CRIR MP-50-2025-2294) and Hamilton Integrated Research Board (HIREB 19222). Any protocol amendments will be submitted to the appropriate ethics boards. Written informed consent to participate in this study will be obtained from all participants by study coordinators or assistants. Study results will be published and reported in peer-reviewed journal following Adaptive Designs Consolidated Standards of Reporting Trials extension guidelines.<br><br>TRIAL REGISTRATION NUMBER: NCT07445841.},
}
@article {pmid42521490,
year = {2026},
author = {Jung, WH and Oh, ST and Choe, MS and Kwon, YJ and Kim, SJ and Jeon, YS and Baek, KM and Chang, W and Lim, KS and Kim, JS and Yun, SP and Lee, MY},
title = {A Cerebral Organoid Model of Familial Alzheimer's Disease Using Amyloid Precursor Protein Mutation, Val669Leu (APP[Seoul]).},
journal = {International journal of stem cells},
volume = {},
number = {},
pages = {},
doi = {10.15283/ijsc25044},
pmid = {42521490},
issn = {2005-3606},
abstract = {Various animal and cellular Alzheimer's disease (AD) models harboring familial AD (fAD) mutations have been developed and widely used for AD research. In this study, we established an AD cerebral organoid (CO) model using a novel Val669Leu (APP[Seoul]) mutation in the APP gene. We generated a human embryonic stem cell (hESC) line overexpressing APP[Seoul], referred to as the fAD-S hESC line. Using this line, we produced COs and confirmed robust AD-associated pathologies, including amyloid-β (Aβ) accumulation and tau phosphorylation. In addition, increased expression of β-secretase was observed in this model. Based on these findings, we investigated the effects of BACE1 inhibitor IV, a β-secretase inhibitor, in the CO model. Treatment with BACE1 inhibitor IV significantly reduced Aβ levels and tau phosphorylation. Furthermore, we differentiated the fAD-S hESC line into cortical neurons (fAD-S neurons) to establish a 2D cellular AD model. Consistent with the CO results, fAD-S neurons exhibited elevated levels of Aβ and phosphorylated tau, which were also significantly attenuated by BACE1 inhibitor IV treatment. Collectively, these results demonstrate the successful establishment of hESC-derived 2D and 3D AD models based on the APP[Seoul] fAD mutation.},
}
@article {pmid42521537,
year = {2026},
author = {da Silva, AMP and Haddad-Santos, D and de Siqueira Lima, DV and Cardoso, LJC and Moura, CB and Høilund-Carlsen, PF and Perry, G and Kishi, T and Barbosa, BJAP and Anghinah, R},
title = {Bayesian Reanalysis of a Pilot Randomized Clinical Trial of Low-Dose Lithium in Mild Cognitive Impairment: A Probabilistic Re-Expression of the LATTICE Trial.},
journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jagp.2026.06.014},
pmid = {42521537},
issn = {1545-7214},
abstract = {OBJECTIVE: The LATTICE pilot randomized clinical trial found no statistically significant effect of low-dose lithium on 6 coprimary outcomes in mild cognitive impairment (MCI). We aimed to re-express these results in Bayesian terms and estimate the probability of benefit, negligible difference, or harm across cognitive, neuroimaging, biomarker, and safety outcomes.<br><br>METHODS: We conducted a Bayesian reanalysis of published aggregate data from LATTICE, a single-site, randomized, double-blind, placebo-controlled 2-year trial of low-dose lithium carbonate versus placebo. The trial randomized 83 older adults with MCI, of whom 80 initiated treatment. Outcomes included verbal and visuospatial delayed recall, Preclinical Alzheimer Cognitive Composite, hippocampal and cortical volume measures, brain-derived neurotrophic factor, and serious adverse events. Posterior means, 95% credible intervals (CrI), and posterior probabilities were estimated using weakly informative priors.<br><br>RESULTS: Lithium was associated with a posterior mean standardized effect of 0.38 SD for CVLT-II delayed recall (95% CrI, -0.03 to 0.80), corresponding to a 96.5% probability of benefit and an 80.6% probability of exceeding 0.20 SD. The raw between-group difference was 1.47 points (95% CrI, 0.18-2.75). Bayesian re-expression of the intention-to-treat model showed an annualized CVLT-II treatment-by-time effect of 0.69 points per year (95% CrI, 0.02-1.35). BVMT-R remained near null. Hippocampal outcomes were directionally favorable but imprecise. Other cognitive, biomarker, imaging, and safety outcomes showed no robust signal.<br><br>CONCLUSIONS: This Bayesian reanalysis supports an inconclusive interpretation of LATTICE, while identifying a probabilistic signal for verbal delayed recall-not seen in the other outcomes-that warrants testing in adequately powered trials.},
}
@article {pmid42521539,
year = {2026},
author = {Bassiouni, W and Ye, E and Colson, TL and Ferguson, SSG and Abd-Elrahman, KS},
title = {M1 muscarinic receptor modulation drives sex-specific alterations of Alzheimer's pathophysiology in APPswe/PSEN1ΔE9 mice.},
journal = {The Journal of pharmacology and experimental therapeutics},
volume = {},
number = {},
pages = {104980},
doi = {10.1016/j.jpet.2026.104980},
pmid = {42521539},
issn = {1521-0103},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder marked by cognitive decline, where females account for 60% of diagnosed cases. AD is featured by β-amyloid deposition, which influences the activity of M1 muscarinic acetylcholine receptors (M1 mAChRs) that are essential for memory and learning. We previously demonstrated that VU0486846, a M1 mAChR positive allosteric modulator, improves cognitive function in AD mice by ameliorating β-amyloid pathology. However, it remains unclear how changes in M1 mAChR signaling and subcellular localization in AD brain influences its mechanism and how this differs between sexes. Nine-month-old male and female APPswe/PSEN1ΔE9 (APP/PS1) and wild-type mice were treated with VU0486846 (10 mg/kg/day) or vehicle via drinking water for 8 weeks. Elevated extracellular signal-regulated kinase 1/2 signaling, a plausible driver for β-amyloid pathology, was observed in female but not male APP/PS1 mice cortices, whereas VU0486846 mitigated this change. Additionally, VU0486846 enhanced the phosphorylation of the neuronal transcription factor cAMP response element-binding protein and increased the level of c-Fos, which regulate neuronal survival, in female wild-type and APP/PS1 mice only. In contrast, only male APP/PS1 mice exhibited increased levels of p62/SQSTM1 and decreased glycogen synthase kinase-3β activity, indicative of impaired autophagic flux, a change that was ameliorated by VU0486846 treatment. In subcellular fractions obtained from mice cortices, VU0486846 only increased cytosolic M1 mAChR level in female wild-type and APP/PS1 mice but not in males. Our findings indicate that M1 mAChR signaling is disrupted in APP/PS1 mice in a sex-dependent manner. VU0486846 enhances prosurvival signaling in females, potentially by increasing the cytosolic pool of M1 mAChRs, while modulating autophagy pathways in males, highlighting a sex-specific mechanism of action and underscoring its therapeutic potential. SIGNIFICANCE STATEMENT: The study highlights the sex-specific role of M1 muscarinic acetylcholine receptor (M1 mAChR) in Alzheimer's disease (AD) pathophysiology, providing evidence that the ability of M1 mAChR positive allosteric modulation to alleviate β-amyloid pathology occurs through distinct mechanisms. It rescues neuronal activity in females, which could be linked to enhanced cytosolic receptor pooling, while restoring autophagic flux in males. The study also reinforces the therapeutic potential of M1 mAChR positive allosteric modulators and supports the development of sex-tailored interventions for AD.},
}
@article {pmid42521649,
year = {2026},
author = {Na, HK and Sun, Y and Park, CW and Lee, JH and Choi, YY and Vo, QP and Chung, SJ and Yoo, HS and Lyoo, CH and Sohn, YH and Hong, JY and Lee, PH},
title = {Greater Motor and Nonmotor Burden at Diagnosis Is Associated With Amyloid Copathology in Parkinson's Disease.},
journal = {Movement disorders : official journal of the Movement Disorder Society},
volume = {},
number = {},
pages = {},
doi = {10.1002/mds.70446},
pmid = {42521649},
issn = {1531-8257},
support = {2024ER100200//Korean National Institute of Health/ ; RS-2026-25498013//National Research Foundation of Korea/ ; },
abstract = {BACKGROUND: Concurrent Alzheimer's disease pathology is increasingly recognized as a poor prognostic factor in Parkinson's disease (PD), yet reliable clinical indicators for early identification of AD copathology remain poorly established.<br><br>OBJECTIVE: To investigate baseline motor and nonmotor symptom profiles associated with amyloid-&#x3b2; (A&#x3b2;) copathology in newly diagnosed PD.<br><br>METHODS: Among patients with PD who underwent A&#x3b2; imaging, we retrospectively identified 152 patients who completed the Cross-Cultural Smell Identification Test (CC-SIT), autonomic function tests, neuropsychological assessment, and Neuropsychiatric Inventory Questionnaire (NPI-Q) at drug-naive state. Predictors of A&#x3b2; positivity were identified using stepwise multivariable logistic regression and validated with Random Forest classifiers employing Boruta feature selection.<br><br>RESULTS: Compared with A&#x3b2;-negative counterparts (n&#x2009;=&#x2009;93), A&#x3b2;-positive (A&#x3b2;&#x2009;+&#x2009;PD, n&#x2009;=&#x2009;59) patients demonstrated greater olfactory dysfunction (CC-SIT, P&#x2009;=&#x2009;0.002), dysautonomia (Composite Autonomic Severity Scale [CASS], P&#x2009;<&#x2009;0.001), and mood disturbance (NPI-Q-mood, P&#x2009;<&#x2009;0.001) and higher prevalence of probable rapid eye movement sleep behavior disorder (P&#x2009;=&#x2009;0.009) and neurogenic orthostatic hypotension (P&#x2009;=&#x2009;0.006). A&#x3b2;&#x2009;+&#x2009;PD patients showed greater motor disability (Unified Parkinson's Disease Rating Scale Part III [UPDRS-III], P&#x2009;<&#x2009;0.001) despite comparable striatal dopamine transporter uptake. Logistic regression identified lower CC-SIT scores (odds ratio [OR]&#x2009;=&#x2009;0.821, 95% confidence interval [CI95%]: 0.703-0.959), higher CASS scores (OR&#x2009;=&#x2009;1.380, CI95%: 1.144-1.666), higher NPI-Q-mood scores (OR&#x2009;=&#x2009;1.057, CI95%: 1.005-1.111), higher UPDRS-III (OR&#x2009;=&#x2009;1.080, CI95%: 1.030-1.132), and APOE &#x3b5;4 carrier status (OR&#x2009;=&#x2009;3.643, CI95%: 1.479-8.969) as independent predictors of A&#x3b2; positivity, which were also confirmed as important variables by Boruta feature selection.<br><br>CONCLUSIONS: Our findings suggest that greater motor and nonmotor symptom burden at diagnosis, characterized by olfactory/autonomic dysfunction, mood disturbance, and motor deficits disproportionate to dopaminergic denervation, was associated with A&#x3b2; positivity in PD. &#xa9; 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.},
}
@article {pmid42521874,
year = {2026},
author = {Vanderlip, CR and Stark, CEL},
title = {Modernizing cognitive assessment in Alzheimer's disease.},
journal = {Nature aging},
volume = {},
number = {},
pages = {},
pmid = {42521874},
issn = {2662-8465},
support = {T32AG00096//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01 AG066683/AG/NIA NIH HHS/United States ; P30 AG066519/AG/NIA NIH HHS/United States ; },
}
@article {pmid42521895,
year = {2026},
author = {Abidar, S and Nhiri, M and Bianchi, V},
title = {Suicide in neurodegenerative diseases: a systematic review.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {8},
pages = {},
pmid = {42521895},
issn = {1590-3478},
mesh = {Humans ; *Neurodegenerative Diseases/psychology ; *Suicide/psychology/statistics &amp; numerical data ; Amyotrophic Lateral Sclerosis/psychology ; Multiple Sclerosis/psychology ; },
abstract = {BACKGROUND AND OBJECTIVE: Suicide is a public health issue, which differs from suicidality, the continuum from suicidal ideation to the suicidal act, including suicide attempts and completed suicide. The main goal of the present study is to determine the relationship between Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS) with suicidality.<br><br>METHODS: This is a systematic review aiming to determine the relationship between AD, PD, ALS, and MS with suicidality following PRISMA 2020 guidelines by collecting cross-sectional, case-control, and cohort studies; case series; case reports; and retrospective and prospective studies from Google Scholar, PubMed, and Cochrane Library. The protocol of this systematic review was registered on PROSPERO; the registration number is CRD420261422354.<br><br>RESULTS: From 2247 records identified from electronic databases, only 24 articles were included: three studies focusing on AD, nine on PD, and six studies focusing on ALS and MS, respectively. These studies exhibited moderate to low risk of bias. Despite the broad differences regarding the neurochemistry, pathophysiology, diagnosis, symptoms, and treatments of the selected diseases, patients are at a higher risk of suicidality. Depression and low social connectivity are the most prevalent risk factors. Suicidality is mainly detected during the first years post-diagnosis in PD, ALS, and MS patients, while the results in AD are confusing.<br><br>CONCLUSIONS: Data about this topic is scarce and largely varying. Further research is required to elucidate this paradigmatic realm, fostering awareness, enhancing therapies, and providing explanations and interpretations of the mechanisms involved.},
}
@article {pmid42522048,
year = {2026},
author = {Wang, QQ and Sun, QQ and Guo, YS and Yin, S and Zhou, JW},
title = {Neuroinflammation in Alzheimer's and Parkinson's diseases: pathogenic mechanisms and therapeutic strategies.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {42522048},
issn = {2047-9158},
support = {82301629//National Natural Science Foundation of China/ ; ZR2024MH129//Natural Science Foundation of Shandong Province/ ; 2021ZD0200900//STI2030-Major Projects/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/therapy/metabolism/immunology ; *Parkinson Disease/pathology/therapy/metabolism/immunology ; *Neuroinflammatory Diseases/pathology/therapy/metabolism ; Animals ; Inflammation/pathology ; Amyloid beta-Peptides/metabolism ; },
abstract = {Neuroinflammation is increasingly recognized as a key contributor and amplifier associated with the pathogenesis of Alzheimer's disease (AD) and Parkinson's disease (PD). Neuroinflammation occurs throughout various stages of these diseases with expanding complexity. Currently, no effective therapies exist that specifically target neuroinflammatory processes in these disorders. In this review, we synthesize current understanding of central and peripheral inflammatory mechanisms implicated in both diseases. We illustrate how endogenous pathological triggers, such as amyloid-β (Aβ) peptide, hyperphosphorylated tau, and α-synuclein, activate glial cells, contributing to chronic neuroinflammation that exacerbates neurodegeneration. Additionally, peripheral factors, including systemic inflammation, environmental exposures, and gut-brain axis interactions, are discussed for their roles in modulating neuroinflammatory responses. Notably, the underappreciated roles of oligodendrocyte precursor cells and oligodendrocytes in neuroimmune crosstalk are also highlighted. Advanced methodologies, including glial cell imaging, single-cell transcriptomics, and human induced pluripotent stem cell-derived organoid models, are providing unprecedented insights into the molecular and cellular mechanisms underlying neuroinflammation. Finally, we evaluate emerging therapeutic strategies and ongoing clinical trials targeting neuroinflammatory pathways and analyze the potential of immunomodulatory approaches to slow disease progression. This comprehensive review emphasizes that precise targeting of neuroinflammation represents a tractable strategy for developing effective disease‑modifying treatments for AD and PD.},
}
@article {pmid42522051,
year = {2026},
author = {Souza, MR and Alvarenga, TA and Mazaro-Costa, R and Tufik, S and Andersen, ML},
title = {Reproductive neuroendocrine pathways as modulators of sleep-related sex differences in Alzheimer's disease.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71699},
doi = {10.1002/alz.71699},
pmid = {42522051},
issn = {1552-5279},
support = {2020/13467-8//Funda&#xe7;&#xe3;o de Amparo&#xa0;&#xe0; Pesquisa do Estado de S&#xe3;o Paulo/ ; //Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; //Associa&#xe7;&#xe3;o Fundo de Incentivo &#xe0; Pesquisa/ ; },
}
@article {pmid42522056,
year = {2026},
author = {Wear, D and Morrone, CD and Yu, WH},
title = {Refining our understanding of sleep impairment and connection to Alzheimer's disease in preclinical models.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71700},
doi = {10.1002/alz.71700},
pmid = {42522056},
issn = {1552-5279},
support = {A2022016F//BrightFocus Foundation/ ; //Ontario Ministry of Colleges and Universities/ ; 11020222023Q2412//Natural Sciences and Engineering Research Council of Canada/ ; AG080781//Foundation for the National Institutes of Health/ ; },
}
@article {pmid42522059,
year = {2026},
author = {Okorie, M and Jonson, C and Oddi, AP and Castruita, PA and Fulton-Howard, B and Yaffe, K and Yokoyama, JS and Udeh-Momoh, C and Andrews, SJ and , },
title = {Cross-ancestry polygenic risk scores enhance Alzheimer's disease risk prediction in multiethnic cohorts.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71529},
doi = {10.1002/alz.71529},
pmid = {42522059},
issn = {1552-5279},
support = {ZIAAG000534//NIH Intramural Center for Alzheimer's and Related Dementias (CARD)/ ; R01AG062588//NIH Intramural Center for Alzheimer's and Related Dementias (CARD)/ ; R01AG057234//NIH Intramural Center for Alzheimer's and Related Dementias (CARD)/ ; P30AG062422//NIH Intramural Center for Alzheimer's and Related Dementias (CARD)/ ; P01AG019724//NIH Intramural Center for Alzheimer's and Related Dementias (CARD)/ ; U19AG079774//NIH Intramural Center for Alzheimer's and Related Dementias (CARD)/ ; U24AG072122//National Alzheimer's Coordinating Center/ ; U54NS123985/NS/NINDS NIH HHS/United States ; U19AG079774/AG/NIA NIH HHS/United States ; //Rainwater Charitable Foundation/ ; //Bluefield Project to Cure Frontotemporal Dementia/ ; /ALZ/Alzheimer's Association/United States ; //Global Brain Health Institute/ ; //Genentech/ ; //French Foundation/ ; //Mary Oakley Foundation/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics ; Genetic Risk Score ; Genome-Wide Association Study ; *Genetic Predisposition to Disease ; Amyloid beta-Peptides/cerebrospinal fluid ; Bayes Theorem ; *Multifactorial Inheritance/genetics ; Female ; Cohort Studies ; tau Proteins/cerebrospinal fluid ; White People/genetics ; Male ; },
abstract = {INTRODUCTION: Genome-wide association studies (GWAS) have identified 80+ genetic loci associated with Alzheimer's disease (AD), enabling the development of polygenic risk scores (PRS). However, the predictive accuracy of PRS in diverse populations remains low. Here, we evaluated the predictive accuracy of single-, multi-, and cross-ancestry AD-PRS models across multi-ancestral populations.<br><br>METHODS: We used AD GWAS summary statistics from European, African, Admixed American, and East Asian populations to construct AD-PRS for each target population. Model performance was assessed by estimating odds ratios, R[2], and area under the curve.<br><br>RESULTS: The cross-ancestry Bayesian PRS model demonstrated the highest predictive performance in non-European populations. It was significantly associated with poorer cognitive function, lower A&#x3b2;42 cerebrospinal fluid levels, and the most severe category of A&#x3b2; and tau neuropathological burden.<br><br>DISCUSSION: Inclusive genetic datasets and cross-ancestry PRS models are needed to enhance the transportability of AD-PRS across multi-ancestral populations.},
}
@article {pmid42522069,
year = {2026},
author = {Okorie, M and Jiang, X and Yaffe, K and Yokoyama, JS and Andrews, SJ and , },
title = {Associations of dementia polyexposure scores to Alzheimer's disease endophenotypes in a diverse population.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71567},
doi = {10.1002/alz.71567},
pmid = {42522069},
issn = {1552-5279},
support = {U24AG072122//National Alzheimer's Coordinating Center/ ; //Mary Oakley Foundation/ ; //French Foundation/ ; //Genentech/ ; //Global Brain Health Institute/ ; /ALZ/Alzheimer's Association/United States ; //Rainwater Charitable Foundation/ ; U54NS123985/NS/NINDS NIH HHS/United States ; U19AG079774/AG/NIA NIH HHS/United States ; R01AG057234/AG/NIA NIH HHS/United States ; P30AG062422/AG/NIA NIH HHS/United States ; P01AG019724/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Endophenotypes ; *Alzheimer Disease/epidemiology/diagnosis/diagnostic imaging ; Amyloid beta-Peptides/metabolism ; Female ; Male ; Aged ; tau Proteins/metabolism ; *Dementia/epidemiology/diagnosis ; Risk Factors ; Positron-Emission Tomography ; Aged, 80 and over ; Peptide Fragments ; },
abstract = {INTRODUCTION: Dementia clinical risk scores (CRSs) provide accessible tools for identifying individuals at risk for Alzheimer's disease (AD) and related dementias, yet their performance across diverse populations and relationships to AD endophenotypes remains unclear.<br><br>METHODS: We evaluated four CRSs, modified Cardiovascular Risk Factors, Aging, and Incidence of Dementia (mCAIDE), Washington Heights-Inwood Columbia Aging Project (WHICAP), Lifestyle for Brain Health (LIBRA), and Cognitive Dementia Risk (CogDRisk), in relation to cognitive impairment (CI) and AD endophenotypes, including tau phosphorylated at threonine 217 (pTau217)/amyloid beta 42 (A&#x3b2;42) positivity defined using a Youden index-derived cutoff for amyloid positron emission tomography (PET) positivity. Logistic and linear regression models stratified by self-reported race/ethnicity were used to assess the associations of CRS with endophenotypes and CI and to evaluate predictive performance.<br><br>RESULTS: CogDRisk showed the strongest and most consistent performance across endophenotypes, pTau217/A&#x3b2;42 positivity, and CI, with mCAIDE performing the worst and lacking associations with plasma biomarkers. Higher CRS were consistently associated with increased odds of dementia across all races/ethnicities.<br><br>CONCLUSIONS: CRSs capture AD-related risk across diverse populations and modestly reflect underlying biological endophenotypes, supporting their utility in community-based risk assessment.},
}
@article {pmid42522110,
year = {2026},
author = {Quigley, DD and Walsh, S and Kassner, CT and Dhingra, L and Dick, AW},
title = {Private Equity Ownership in Hospice Care: A Systematic Review (2012-2026).},
journal = {The American journal of hospice &amp; palliative care},
volume = {},
number = {},
pages = {10499091261471107},
doi = {10.1177/10499091261471107},
pmid = {42522110},
issn = {1938-2715},
abstract = {Hospice care is associated with improved end-of-life outcomes. Recent shifts in hospice utilization highlight several key trends. Alzheimer's disease and related dementias (ADRD) (25%) have surpassed cancer (23%) as the leading primary diagnosis. Concurrently, industry ownership has transitioned from predominantly nonprofit to for-profit (70%) and private equity (PE) ownership has grown dramatically from 3% to 15%. To date, no study has synthesized evidence on PE ownership in hospice care. We conducted a systematic review of English-language, peer-reviewed studies published 2012-2026, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Of 630 screened articles, 114 underwent full-text review and 6 met inclusion criteria. All studies used national data; sample sizes ranged from 80 to 536 PE-owned hospices. Three studies examined PE prevalence and market trends; two assessed caregiver-reported care experiences, and one evaluated financial outcomes by PE ownership. The evidence regarding PE ownership of hospices remains limited. It highlights the increasing role of PE in hospice markets. It consistently found (across two studies) worse care experiences at PE-owned hospices vs nonprofit hospices, except for emotional and religious support which was similar across ownership type. The evidence suggests PE ownership is associated with complex, often worse patterns related to market structure, care experiences, and financial allocation. Additionally, it underscores the limited evidence base to inform policy development. Research is needed to examine associations between PE ownership and hospice care quality, both overall and among vulnerable populations. Research should clarify modifiable factors influencing hospice quality and better characterize evolving ownership structures.},
}
@article {pmid42522301,
year = {2026},
author = {Ishak, NI and Siran, R and Mohamad Zain, WNIW and Azme, N},
title = {Endothelial-to-mesenchymal Transition at the Blood-brain Barrier: Molecular Mechanisms and Pathological Roles Across Brain Diseases.},
journal = {CNS &amp; neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273485479260721072747},
pmid = {42522301},
issn = {1996-3181},
abstract = {Endothelial-to-Mesenchymal Transition (EndMT) is a significant contributor to Blood- Brain Barrier (BBB) dysfunction in various brain diseases. The majority of current therapies, aimed at reducing BBB dysfunction, focus on preventing inflammation or stabilizing tight junctions. In most cases, these therapies do not provide adequate or long-lasting vascular protection. Endothelial cells undergo phenotypic programming, losing their barrier-forming capacity and developing features of mesenchymal and extracellular matrix-producing cells as the disease progresses. The change leads to chronic vascular leakage, neuroinflammation, microvascular fibrosis, and dysfunctional neurovascular coupling. Several upstream stimuli, including inflammatory cytokines, TGF-β/BMP-Smad signaling, and oxidative damage, converge to drive EndMT within the distinctive, specialized environment of the brain endothelium. Ischemic stroke, multiple sclerosis, cerebral cavernous malformations, arteriovenous malformations, glioblastoma, brain metastasis, and Alzheimer's disease indicate that EndMT is not a rare or unique process but a shared and common pathologic process that may result in disease progression and eventual resistance to treatment. Recent single-cell and spatial transcriptomic data have shown that partial EndMT states exist and may be precursors to irreversible microvascular remodeling. It is necessary to identify therapeutic approaches that go beyond short-term stabilization of the BBB and target the molecular programs underlying the loss of endothelial identity. This review synthesizes mechanistic, disease-related, and therapeutic evidence indicating that EndMT is a leading cause of BBB failure and highlights therapeutic opportunities for targeting this endothelial plasticity in brain diseases.},
}
@article {pmid42522305,
year = {2026},
author = {Paliwal, D and Thakur, A},
title = {Exploring the Therapeutic Potential of Chalcones in Alzheimer's Disease: Mechanistic Insights and SAR Perspectives.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575457432260717112508},
pmid = {42522305},
issn = {1875-5607},
abstract = {Alzheimer's disease is a multifactorial neurodegenerative disorder characterized by amyloid- β aggregation, oxidative stress, neuroinflammation, tau hyperphosphorylation, and cholinergic dysfunction. The limited efficacy of current therapies has driven the development of multitargetdirected ligands (MTDLs). Chalcones represent a versatile scaffold for modulating multiple ADrelated targets. This review provides a concise analysis of the structure-activity relationship (SAR) of chalcone derivatives, highlighting the effects of hydroxylation, methoxylation, halogenation, and heterocyclic hybridization on biological activity. Electron-withdrawing substituents (e.g., halogens, -CF3) enhance enzyme inhibition and MAO-B selectivity, whereas electron-donating groups (e.g., hydroxyl and methoxy groups) contribute to antioxidant activity, metal chelation, and hydrogen bonding interactions. Scaffold hybridization and optimized linker design further improve multitarget engagement, including AChE/BuChE inhibition, MAO-B modulation, and anti-amyloid activity. However, despite promising in vitro and in silico findings, translational limitations remain due to insufficient in vivo validation and pharmacokinetic constraints. Overall, chalcone-based MTDLs provide a rational framework for the development of next-generation anti-Alzheimer agents.},
}
@article {pmid42522313,
year = {2026},
author = {Tian, J and Yao, R and Shen, L and Jiao, B and Luo, SL},
title = {PP2A: Decoding Its Structure, Regulation and Therapeutic Applications in Neurological Disorders.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X482496260716074148},
pmid = {42522313},
issn = {1875-6190},
abstract = {Protein phosphatase 2A (PP2A) is a highly conserved serine/threonine phosphatase that plays a pivotal role in maintaining cellular homeostasis by counterbalancing kinase activity. As a heterotrimeric enzyme composed of scaffolding, regulatory, and catalytic subunits, PP2A achieves extraordinary functional diversity through the dynamic assembly of more than 80 holoenzyme variants. This structural versatility allows PP2A to regulate a wide range of biological processes, including cell cycle progression, apoptosis, DNA damage response, and major signaling pathways such as MAPK and Wnt. Dysregulation of PP2A, through altered subunit expression, post-translational modification, or inhibition by endogenous suppressors like CIP2A and SET, has been implicated in diverse diseases, notably neurodegenerative disorders, cancers, and metabolic syndromes. In neurological disorders such as Alzheimer's and Parkinson's diseases, impaired PP2A activity contributes to pathogenic protein hyperphosphorylation, neurofibrillary tangle formation, and neuroinflammation. Recent advances have fundamentally reshaped our understanding of PP2A biology. High-resolution structural studies have revealed the molecular basis of holoenzyme assembly and substrate recruitment, while accumulating evidence suggests that PP2A activity is dynamically regulated across tissues and cell types, largely driven by differential expression of regulatory subunits and post-translational modifications. Despite these advances, current knowledge remains fragmented, and a comprehensive synthesis linking PP2A structural dynamics, regulatory mechanisms, and its roles in pathophysiology, particularly in the context of neurological disorders, is still lacking. This review deciphers the structural complexity and regulatory mechanisms of PP2A, elucidates its multifaceted roles in neural physiology and pathology, and examines current and emerging therapeutic strategies targeting PP2A modulation to intervene in neurological disease.},
}
@article {pmid42522580,
year = {2026},
author = {Park, CW and Choi, Y and Lee, HS and Jeong, SH and Lee, PH and Kim, YJ and Sohn, YH and Lee, J and Chung, SJ},
title = {Amyloid-linked trajectories of cerebral hypoperfusion and dopamine loss in dementia with Lewy bodies.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag264},
pmid = {42522580},
issn = {1460-2156},
abstract = {Dementia with Lewy bodies (DLB) is clinically heterogeneous, and the evolutionary trajectories of cortical dysfunction, nigrostriatal dopaminergic degeneration, and amyloid accumulation, as well as the interactions among them, remain poorly understood. This study enrolled 83 patients with DLB who underwent dual-phase 18F-FP-CIT PET and 18F-FBB PET scans at initial assessment. Fifteen standardised imaging biomarkers capturing cerebral perfusion (early-phase 18F-FP-CIT PET images), striatal dopamine depletion (late-phase 18F-FP-CIT PET images), and amyloid burden (18F-FBB PET images) were entered into a Subtype and Stage Inference (SuStaIn) model. The SuStaIn analysis delineated two subtypes of DLB with distinct evolutionary trajectories: Subtype 1 (n = 37) was characterized by early amyloid accumulation, followed by cerebral hypoperfusion progressing from the posterior cingulate cortex to other cortical and limbic regions, and later diffuse striatal dopamine depletion; Subtype 2 (n = 36) initially presented with selective dopamine loss in the putamen, with subsequent dopaminergic deficits in other striatal subregions, followed by amyloid accumulation and cerebral hypoperfusion progressing from the precuneus to other cortical and limbic regions. The remaining 10 patients with DLB did not have sufficiently abnormal imaging findings to be categorized into a defined subtype (Subtype 0). Subtype 1 exhibited more severe Alzheimer's disease (AD)-like cortical atrophy and lower cingulate island sign ratios on early-phase 18F-FP-CIT PET images. Patients in Subtype 2 had a higher prevalence of rapid eye movement sleep behavior disorder and visual hallucinations than those in Subtype 1. In conclusion, we delineate two distinct multimodal imaging progression patterns in DLB: an early nigrostriatal dopamine depletion-linked trajectory with more typical DLB characteristics and an early amyloid deposition-linked trajectory characterised by an inverse cingulate island sign and AD-like cortical atrophy. These findings highlight the clinical and biological heterogeneity within DLB.},
}
@article {pmid42522648,
year = {2026},
author = {Wei, Z and Qian, H and Dai, C and Wu, J and Li, Y and Yin, K and Li, M and Yang, H},
title = {Global Research Trends of Protein Post-translational Modifications in Alzheimer's Disease: A Bibliometric Analysis.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X457922260717112524},
pmid = {42522648},
issn = {1875-6190},
abstract = {BACKGROUND: In recent years, a considerable body of research has increasingly underscored the critical roles that protein Post-Translational Modifications (PTMs) play in the pathogenesis of Alzheimer's Disease (AD). However, a comprehensive bibliometric analysis of this field is still lacking. This study aims to systematically map research trends and hotspots and to identify promising directions for future work.<br><br>METHODS: The data in this study were extracted from the Web of Science Core Collection (WOSCC) and visualized using CiteSpace, VOSviewer, R-bibliometrix, and Microsoft Excel 2016 to analyze bibliometric indicators including countries, institutions, authors, journals, citations, production categories, and keywords.<br><br>RESULTS: A collection of 1,170 articles was retrieved, spanning the publication period from January 1, 1990, to December 31, 2024. The top three countries in terms of publications were the United States, China, and Germany. The most productive institution was the University of California System in the United States, contributing 57 articles. The leading authors identified were Mitkevich Vladimir, Perry George, and Makarov Alexander A. The Journal of Alzheimer's Disease was the top-ranked journal in terms of published papers. The most frequently cited article was "The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation," published in the International Journal of Molecular Sciences. Finally, the most prolific research category was neuroscience, with 432 papers published. High-frequency keywords included Alzheimer's disease, phosphorylation, tau, and neurodegeneration.<br><br>DISCUSSION: The study's findings suggest that PTM research in AD continues to revolve around the core pathological hallmarks represented by A&#x3b2; and tau protein. At the same time, some studies have reported aberrant modifications of &#x3b1;-synuclein and its potential role in AD. By systematically cataloging diverse PTM types and the molecular mechanisms involving A&#x3b2; and tau throughout AD progression, this analysis paves the way for a reassessment of AD pathogenesis from a "modification-function-pathology" perspective and provides a basis for identifying potential PTM-related targets and intervention strategies.<br><br>CONCLUSION: This bibliometric analysis highlights the growing scholarly attention devoted to the relationship between PTMs and AD. The significant contributions and emerging trends emphasize the pivotal role of PTMs in the pathogenesis of AD, which may guide future biomarker discovery.},
}
@article {pmid42522708,
year = {2026},
author = {Li, H and Khang, TF},
title = {SIEVEseq: Unified differential expression, variability, and skewness analyses using RNA-Seq data.},
journal = {DNA research : an international journal for rapid publication of reports on genes and genomes},
volume = {},
number = {},
pages = {},
doi = {10.1093/dnares/dsag012},
pmid = {42522708},
issn = {1756-1663},
abstract = {RNA-Seq data analysis is commonly biased towards detecting differentially expressed genes and insufficiently conveys the complexity of gene expression changes between biological conditions. This bias arises because discrete count models cannot fully and independently parameterize the mean, variance, and skewness of gene expression distributions. Therefore, a unified statistical framework that simultaneously tests differential expression, variability, and skewness is needed. We present SIEVEseq, a statistical methodology that provides such a framework. SIEVEseq embraces a compositional data analysis strategy to transform discrete RNA-Seq counts into continuous form with a distribution well-fitted by the skew-normal distribution. Both parametric and nonparametric simulations show that SIEVEseq better controls the false discovery rate and Type II error than existing differential expression methods. Analysis of the Mayo RNA-Seq dataset for Alzheimer's disease demonstrates that gene sets with significant differences in mean, variance, and skewness between control and disease groups strongly predict disease state. Furthermore, functional enrichment analysis indicates that relying solely on differentially expressed genes identifies only part of the biological spectrum, whereas incorporating genes with differential variability and skewness reveals additional disease-related aspects. Cross-data and cross-methodology validation suggest the detected biological signals are genuine. The SIEVEseq R package is available at https://cran.r-project.org/web/packages/SIEVEseq.},
}
@article {pmid42523103,
year = {2026},
author = {Dey, C and Pal, P and Khan, A and Dey, SG},
title = {Heme-copper-Aβ mediated dopamine oxidation through self-sustaining redox cycling.},
journal = {Chemical communications (Cambridge, England)},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6cc03615e},
pmid = {42523103},
issn = {1364-548X},
abstract = {Alzheimer's disease is characterized by progressive neurodegeneration, with Aβ peptides playing a critical role in disease pathology. Beyond their aggregation into plaques, Aβ peptides can interact with redox-active cofactors such as copper and heme, forming complexes capable of catalyzing ROS generation. While Cu-Aβ is known to oxidise catecholamines like dopamine through redox cycling, the functional implications of ternary heme-Cu-Aβ assemblies remain poorly understood. In this study, we demonstrate that the heme-Cu-Aβ complex catalyzes dopamine oxidation more efficiently than Cu-Aβ alone, driven by a self-sustaining cooperative redox cascade involving Cu-mediated H2O2 generation and subsequent heme-mediated peroxidase-like activity in the presence of the endogenously produced H2O2. Moreover, kinetic analysis and mutant studies reveal the critical contributions of Arg5 in modulating the redox behavior of the complex. These findings establish the heme-Cu-Aβ complex as a potent catalytic assembly capable of altering dopamine homeostasis under oxidative stress, offering new insights into Aβ-mediated neurotoxicity in Alzheimer's disease.},
}
@article {pmid42523146,
year = {2026},
author = {Vellone, D and Leon, R and Goodarzi, Z and Forkert, ND and Smith, EE and Ismail, Z},
title = {Mild behavioral impairment-apathy and Alzheimer's disease plasma phosphorylated tau biomarker levels.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261470257},
doi = {10.1177/13872877261470257},
pmid = {42523146},
issn = {1875-8908},
abstract = {BackgroundMild behavioral impairment (MBI), characterized by later-life emergence of persistent neuropsychiatric symptoms (NPS), is an early clinical indicator of dementia risk. Global MBI has been associated with Alzheimer's disease (AD) pathology; studies have also explored MBI domains. Prior work has linked MBI-apathy to AD cerebrospinal fluid (CSF) biomarkers, but whether associations are detectable using plasma-based biomarkers such as phosphorylated tau (p-tau) is unknown. Establishing such relationships is critical, as plasma biomarkers are more accessible than CSF.ObjectiveTo explore cross-sectional and longitudinal associations between MBI-apathy and plasma p-tau181 levels using Alzheimer's Disease Neuroimaging Initiative data.MethodsOlder adults with normal cognition or mild cognitive impairment were categorized as MBI-apathy (n = 69), non-MBI NPS (n = 112), and no-NPS (n = 215) based on Neuropsychiatric Inventory scores and symptom persistence over one year. Linear regression modelled cross-sectional associations between NPS group and plasma p-tau181, adjusting for age, sex, education, apolipoprotein E4 status, and Mini-Mental State Examination score. Hierarchical linear mixed-effects modelling assessed associations over two and three years, including time-by-NPS group interactions.ResultsMBI-apathy was associated with significantly higher plasma p-tau181 levels at baseline (24.05% [6.06-45.08%]; adjusted p = 0.014), and over two (26.46% [7.24-49.12%]; adjusted p = 0.012) and three years (29.28% [10.17-51.72%]; adjusted p = 0.004) compared to no-NPS. No significant associations were observed for non-MBI NPS. In sensitivity analyses, non-MBI apathy was not associated with plasma p-tau181 at baseline (-9.96% [-32.69-20.44%]; unadjusted p = 0.478).ConclusionsMBI-apathy is associated with elevated plasma p-tau181 cross-sectionally and longitudinally, supporting MBI-apathy as a potential proxy marker of tau pathology for early AD detection.},
}
@article {pmid42523149,
year = {2026},
author = {Mosquera-Heredia, MI and Vidal, OM and Barceló, E and Morales, LC and Silvera-Redondo, C and Bolívar, DA and Allegri, R and Arcos-Burgos, M and Garavito-Galofre, P and Vélez, JI},
title = {Novel blood lncRNA biomarkers associated with clinical severity and specific cognitive dimensions in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261470430},
doi = {10.1177/13872877261470430},
pmid = {42523149},
issn = {1875-8908},
abstract = {BackgroundDifferential expression of long non-coding RNAs (lncRNAs) in brain, serum, and blood show strong potential to distinguish Alzheimer's disease (AD) from healthy controls.ObjectiveTo explore whether lncRNA signatures delineate AD pathology and map to distinct, multidimensional cognitive domains, enhancing specificity in assessing AD severity and progression.MethodsWe profiled 29,603 lncRNAs transcripts in blood samples from 15 AD patients and 15 healthy controls, alongside comprehensive neuropsychological assessments. Generalized Linear Models and Predictive Power Score analyses, with statistical prioritization, identified lncRNAs associated to AD neuropsychological architecture.ResultsSeveral lncRNAs share strongly associated with cognitive performance and AD severity, mapping to genes involved in key AD-related molecular processes, including synaptic and neurotransmitter regulation (e.g., EPHB1, CHRNA4, TEAD1), protein homeostasis and Aβ pathology (e.g., FBXL2, FAM221A, APP), mitochondrial function and cellular stress (e.g., VDAC3, PPT2-EGFL8), neuroinflammation and immune regulation (e.g., TEAD1, EMX2OS, LY6E-DT), epigenetic and transcriptional control (e.g., PRDM2, DLEU1, FIRRE), neuronal excitability (e.g., KCNJ14), and neuroprotection and synaptic plasticity (e.g., SIL1). Novel associations included ferroptosis, DNA stability, microtubule dynamics, and dendritic orientation (e.g., BTB3, DICER1, GNG7, IBA57, NEAT1, POT1, SRD5A3).ConclusionsWe identify candidate lncRNA signatures that may serve as potential biomarkers and enhance our understanding of the molecular basis of the cognitive architecture in AD, opening new avenues for biomarker identification and targeted therapeutic strategies development. Validation in larger, diverse cohorts is essential to confirm their mechanistic contributions to AD.},
}
@article {pmid42523152,
year = {2026},
author = {Oliveira, MPB and Da Silva, SLA and Cezar, NOC and Lima-Truax, CR and Truax, BD and Brito-Costa, S and Takahashi, ACM and Serrão, PRMDS and Andrade, LP},
title = {Exploring the relationship between Alzheimer's disease and lower extremity isokinetic muscle strength in community-dwelling older adults: A cross-sectional observational study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261471888},
doi = {10.1177/13872877261471888},
pmid = {42523152},
issn = {1875-8908},
abstract = {BackgroundOlder adults diagnosed with Alzheimer's disease (AD) often experience diminished muscle strength, highlighting the continued importance of evaluating muscle function in this population.ObjectiveTo examine the relationship between AD and isokinetic lower limb muscle strength in older adults.MethodsA cross-sectional observational study was conducted to examine the association between AD and lower limb isokinetic muscle strength in community-dwelling older adults. AD diagnosis was the independent variable; dependent variables included peak torque, average peak torque, and total work. A standardized isokinetic protocol adapted for older adults with cognitive impairment was used to assess knee (flexion/extension at 60°/s and 180°/s) and ankle (dorsiflexion/plantar flexion at 30°/s) strength. Crude and adjusted linear regression models evaluated statistical associations, with significance set at p ≤ 0.05.ResultsA total of 80 older adults were included, 50% of whom had a diagnosis of AD. The crude model's analysis showed an association between AD and all knee and ankle isokinetic measurements. When the models were adjusted, the association was maintained only for ankle peak torque (β1 = -16.23; p < 0.048) and ankle average peak torque (β1 = -13.65; p < 0.049) at 30°/s (plantar flexion).ConclusionsAlzheimer's disease is associated with lower ankle plantar flexors isokinetic muscle strength in community-dwelling older adults. No significant associations between AD and knee (flexors and extensors) and ankle (dorsiflexors) isokinetic muscle strength were found.},
}
@article {pmid42523300,
year = {2026},
author = {Flores, S and Wilpitz, A and Ojeda-Juarez, D and Wang, J and Danque, G and Sumowski, P and Funk, G and Malik, A and Pizzo, D and Richards, E and Iliff, JJ and Sigurdson, CJ},
title = {Aquaporin-4 mislocalization from astrocyte endfeet prolongs survival in a prion-cerebral amyloid angiopathy model.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.13.732468},
pmid = {42523300},
issn = {2692-8205},
abstract = {Aquaporin 4 (AQP4) water channels are polarized to astrocytic endfeet at blood vessel interfaces, and lose polarity in vascular diseases, including stroke, chronic traumatic encephalopathy, and Alzheimer's disease. AQP4 modulates water influx and efflux in the interstitial fluid, yet how AQP4 localization impacts cerebral amyloid angiopathy (CAA) remains poorly understood. Here we show that astrocytic end feet and AQP4 are displaced from amyloid-bearing vessels in a prion-CAA mouse model that expresses GPI-anchorless PrP [C] . Displacing AQP4 genetically through deleting alpha-syntrophin (Snta1 [-/-]) led to a marked prolongation in survival, together with reduced microglial inflammation and C1q, in prion-CAA-affected mice. Additionally, synaptic structural proteins were better maintained. Finally, the level and distribution of prion aggregates were similar among the mice, indicating that prion conversion and spread was not affected. These results suggest that reducing AQP4 water channel function slows the decline in a vascular amyloid disease by reducing neuroinflammation.},
}
@article {pmid42523318,
year = {2026},
author = {Wisch, JK and Jiao, Z and Millar, PR and McKay, NS and Beric, A and Lin, W and Baker, B and Stauber, J and Preminger, S and Jucker, M and R Barthélemy, N and Chhatwal, J and Ryan, NS and Schindler, SE and Morris, JC and Cruchaga, C and Benzinger, TLS and Karch, CM and Bateman, RJ and McDade, E and Llibre-Guerra, J and , and , and Gordon, BA and Ances, BM and Ibanez, L},
title = {Biomarker Variability Limits Individualized Amyloid Time Estimation in Alzheimer Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.08.737258},
pmid = {42523318},
issn = {2692-8205},
abstract = {OBJECTIVE: Disease progression modeling (DPM) or "amyloid time" is increasingly used to stage Alzheimer disease (AD). DPM performance depends on within-individual heterogeneity in rates of pathological accumulation as well as test-retest reliability of the biomarker. The relative contributions of these variabilities have not been systematically assessed. This would be particularly relevant if extrapolations from DPM were to be used to make individual-level predictions for research, clinical trials, or potentially future clinical practice.<br><br>METHODS: We conducted simulation studies incorporating empirically-derived noise properties from amyloid biomarkers to assess the contributions of inter- and intra-individual variability. Findings generalized in an autosomal dominant AD cohort with amyloid positron emission tomography (PET), cerebrospinal fluid (CSF), and plasma biomarkers and in a sporadic AD cohort with both amyloid PET and plasma biomarkers. We assessed group level DPM performance via mean average error (MAE) and root mean squared error (RMSE). At the individual level, we evaluated distinctness of distributions of biomarker levels associated with specific disease timings.<br><br>RESULTS: Inter-individual variability was the dominant source of error in temporal estimates. Intra-individual variability reduced estimate stability. Optimal performance occurred in biomarkers with positive average accumulation rates where a subset of individuals had exceptionally high levels of accumulation. In research study data, amyloid PET outperformed CSF and plasma biomarkers.<br><br>INTERPRETATION: DPM is fundamentally constrained by dynamic range, variability, and test-retest reliability of the biomarker of interest. Current DPM approaches are more robust at the group level, particularly when applied to biomarkers with more than 10-15% variability like fluid biomarkers.<br><br>FUNDING: National Institute on Aging, Alzheimer's Association, German Center for Neurodegenerative Diseases, Raul Carrea Institute for Neurological Research, Japan Agency for Medical Research and Development, Korean Ministry of Health &amp; Welfare and Ministry of Science and ICT, Spanish Institute of Health.},
}
@article {pmid42523335,
year = {2026},
author = {Vrba, SM and Limkar, AR and Keil-Steitz, K and Nirschl, JJ and Laaker, CJ and Bansal, D and Ordonez, SFW and Brooks, EG and Helgager, J and Pehar, M and Sandor, M and Ricke, WA and Fabry, Z},
title = {Amyloid-beta is present in the spinal cord of APP/PS1 mice and may contribute to neuropathology manifesting as lower urinary tract dysfunction.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.09.737006},
pmid = {42523335},
issn = {2692-8205},
abstract = {Urinary incontinence (UI) is a common and debilitating comorbidity in Alzheimer's disease (AD), yet its underlying pathophysiology remains poorly defined. While UI in dementia has traditionally been attributed to functional impairment, emerging clinical and urodynamic data suggest that neurologic mechanisms may contribute to lower urinary tract dysfunction in this population. Here, we investigated urinary function and neuropathological changes in aged APP/PS1 mice (AD mice), a widely used model of amyloid pathology. Using functional voiding assays, we identified a pattern of urinary dysfunction characterized by increased urinary frequency, small-volume voiding, shortened void duration, and reduced bladder compliance in the absence of bladder outlet obstruction or gross changes in bladder or prostate morphology. These findings are most consistent with a storage-phase abnormality accompanied by impaired voiding coordination rather than classic detrusor overactivity or underactivity. We examined spinal cord and peripheral components involved in bladder innervation and identified amyloid-beta deposition throughout the thoracolumbar and lumbosacral spinal cord, dorsal root ganglia, ventral roots, cauda equina, and associated meningeal structures in AD mice. Importantly, amyloid deposition was accompanied by reduced expression of vesicular acetylcholine transporter and decreased neuronal activation in bladder-innervating pathways, without evidence of increased apoptosis. Taken together, these data demonstrate that AD mice develop a mixed lower urinary tract dysfunction phenotype associated with amyloid-beta deposition and altered neuronal signaling within the spinal cord and peripheral micturition pathways. These findings support a neurogenic contribution to urinary dysfunction in AD and highlight the spinal cord as a novel site of pathology that may influence urinary symptoms in Alzheimer's dementia.},
}
@article {pmid42523338,
year = {2026},
author = {Gutierrez-Kuri, E and Marie Garcia-Rogers, JL and Perez, J and Smith, S and Kenwood, MR and Archuleta, KS and Xiao, Y and Campos, G and Barannikov, S and Wang, H and Pardo, S and Romsdahl, TB and Miller, H and Stowe, AM and William, R and Goldberg, M and Han, X and Bieniek, KF and Weintraub, ST and Griffith, AV and Hopp, SC and Palavicini, JP},
title = {PLCγ2 deficiency compromises systemic immune tolerance and erodes myelin homeostasis while enhancing oxidative metabolism in the mouse brain.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.13.738356},
pmid = {42523338},
issn = {2692-8205},
abstract = {BACKGROUND: Phospholipase C gamma-2 (PLCγ2) catalyzes the hydrolysis of the membrane phosphatidylinositol-4,5-bisphosphate (PIP 2) to form diacylglycerol (DAG) and inositol trisphosphate (IP 3), feeding into diverse downstream signaling pathways. PLCG2 polymorphisms have been associated with reduced and/or increased risk of Alzheimer's disease (AD) and related dementias, longevity, autoinflammation, and immune disorders. In the brain, PLCγ2 is expressed in microglia, and other neuroimmune and vascular interface populations, yet its role in brain homeostasis remains incompletely defined.<br><br>METHODS: We analyzed the brains of three-month-old Plcg2 wild-type (WT), heterozygous (Het KO) and homozygous knockout (Homo KO) littermate mice modeling human PLCG2 loss-of-function risk alleles linked to AD risk using a multiomic approach that included lipidomics, metabolomics, proteomics, and transcriptomics, together with immunofluorescence, as well as flow-cytometric profiling of peripheral and brain-draining immune compartments.<br><br>RESULTS: Plcg2 deficiency substantially impaired early survival and produced splenomegaly without increasing total spleen cellularity, instead shifting spleen composition toward myeloid/innate-enriched cells and away from B cells, with expansion of age-associated B-cell (ABC-like) subsets and parallel reductions in CD4 and CD8 regulatory T cells in spleen and cervical lymph nodes. Brain lipidomics revealed selective depletion of PIP 2 , despite very low bulk PLC&#x3b3;2 protein abundance relative to other PLC family members. PLC&#x3b3;2 loss led to significant reductions in myelin-enriched lipid classes and myelin/paranode-associated proteins, accompanied by compensatory upregulation of oligodendrocyte/myelin genes, and modest shifts in microglial, lysosomal, complement, and oxidative metabolism pathways by NanoString and DIA-MS. Targeted acylcarnitine profiling demonstrated reprogramming of brain oxidative metabolism, with increased short-, medium-, and long-chain acylcarnitines and enrichment of mitochondrial matrix fatty-acid and amino-acid catabolic enzymes in Homo KO brains.<br><br>CONCLUSIONS: Loss of PLC&#x3b3;2 installs a coordinated program that compromises systemic immune tolerance and subtly erodes central myelin and phosphoinositide homeostasis while enhancing brain oxidative metabolism, effects that extend beyond microglial phagocytic signaling and may underlie increased vulnerability to AD pathology and aging, providing a mechanistic framework for how PLCG2 variation may link systemic immune regulation, white-matter integrity, and neurodegenerative risk.<br><br>LIMITATIONS: Because constitutive Plcg2 Homo KO mice display high early mortality and intestinal vascular abnormalities, observed phenotypes may reflect developmental compensation and may not fully recapitulate protective human PLCG2 variants.},
}
@article {pmid42523383,
year = {2026},
author = {Matsumoto, N and Choi, H and Freda, PJ and Hernandez, ME and Wang, ZP and Moore, JH},
title = {EcoXAI: Autonomous Agentic Ecosystem for Explainable Artificial Intelligence and Biomedical Discovery.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.08.737358},
pmid = {42523383},
issn = {2692-8205},
abstract = {MOTIVATION: As biomedical datasets and knowledge graphs continue to grow in size, complexity, and heterogeneity, navigating and extracting actionable insights from them presents a major bottleneck for researchers. There is a clear need for autonomous analytical solutions that can utilize recent advancements in agentic AI such as agent harnessing and loop engineering without introducing hallucination or workflow fragmentation. Researchers, regardless of technical expertise, need tools that streamline complex data analysis and deliver meaningful, actionable insights grounded in both data and established biomedical knowledge. EcoXAI addresses this by introducing a modular, customizable, containerized multi-agent system that structures analysis into explicit pipeline execution stages, lowering the computational barrier for clinical and translational researchers.<br><br>RESULT: EcoXAI replaces monolithic AI text interfaces with an autonomous execution-driven framework with specialized bioinformatics agents for delivering proactive, data-driven insights grounded in established biological knowledge. Unlike purely LLM-driven or less integrated AI solutions prone to hallucinations or biologically implausible outcomes, EcoXAI's multi-agent framework, which leverages modern agentic management and explicit knowledge graph integration, provides greater transparency and verifiability in its reasoning. In our use case in drug repurposing for Alzheimer's Disease, EcoXAI evaluated 103 drug candidates and identified 79 novel candidates whose predictive models exceeded a randomized baseline, including the CCR5 antagonist Maraviroc, whose generated hypothesis was subsequently supported by the literature. These results demonstrate the potential of knowledge graph-grounded AI agents to accelerate hypothesis-driven biomedical research.<br><br>EcoXAI is available on GitHub at: https://github.com/EpistasisLab/EcoXAI .<br><br>CONTACT: jason.moore@csmc.edu.},
}
@article {pmid42523480,
year = {2026},
author = {Goate, A and Romero-Molina, C and Gomez-Gutierrez, R and See, WY and Patel, T and Davtyan, H and Ma, J and Xu, Q and Sewell, M and Allton, K and McReynolds, M and Calderon, O and Lightfoot, Y and Bommer, G and Cruchaga, C and Blurton-Jones, M and Ray, W and Marcora, E},
title = {Reduced LACTB expression in myeloid cells is associated with elevated succinylcarnitine and reduced Alzheimer's disease risk.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10216155/v1},
pmid = {42523480},
issn = {2693-5015},
abstract = {Lactamase β (LACTB) is a serine β-lactamase-like mitochondrial enzyme genetically associated with obesity, kidney disease, and hyperlipidemia. LACTB is located in an Alzheimer's Disease (AD) risk locus and its expression in the brain has been genetically associated with AD susceptibility. The aim of this study was to investigate LACTB function and genetic link to AD in myeloid cells, due to their central role in modulating AD risk. Our Mendelian randomization analyses revealed that lower LACTB expression in myeloid cells is genetically associated with reduced disease susceptibility and increased succinylcarnitine, a metabolite independently associated with AD risk. We identified LACTB as a primary enzyme responsible for succinylcarnitine hydrolysis. In human macrophages and microglia, LACTB loss promoted enhanced oxidative phosphorylation, reduced protein synthesis and altered lipid homeostasis. LACTB expression was upregulated following interferon or TNF stimulation, and LACTB loss modified efferocytosis-related functions under inflammatory conditions. In vivo , xenotransplanted human LACTB knockout microglia showed enhanced association with amyloid plaques in the mouse brain. Together, these findings experimentally validated the genetic association between reduced LACTB expression and elevated succinylcarnitine and identified LACTB as an inflammation-responsive regulator of myeloid cell metabolism and function that may contribute to its protective genetic association with AD. Given its druggability and potential to use succinylcarnitine as a genetically-validated endophenotype and target engagement biomarker, LACTB represents a promising therapeutic target for AD.},
}
@article {pmid42523500,
year = {2026},
author = {Kim, Y and Heo, W and Park, SJ and Kim, Y and Cho, YE},
title = {Astrocytic lactate shuttle disruption and the energy-starved lysosome in Alzheimer's disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
pmid = {42523500},
issn = {2693-5015},
abstract = {Lysosomal dysfunction is central to Alzheimer's disease (AD), yet why structurally intact vacuolar H[+]-ATPase (V-ATPase) proton pumps fail to maintain lysosomal pH remains unresolved. Because V-ATPase activity depends on continuous ATP supply, we hypothesized that disruption of the astrocyte-neuron lactate shuttle imposes a cross-cellular energy deficit-an "energy-starved lysosome" (ESL) state. Integrating single-nucleus transcriptomics (SEA-AD; 1.3 million nuclei, 84 donors) with cerebrospinal fluid proteomics (ADNI Emory; n = 1,105), we found that astrocytic lactate-export genes, led by MCT4 (- 43%), declined far faster than V-ATPase, and that astrocytic MCT4 was coupled to neuronal V-ATPase independently of disease stage (donor-level partial r = + 0.466). At the protein level, V-ATPase V1A abundance was preserved across diagnostic groups-consistent with structural pump integrity-while, at the individual level, glycolytic capacity (hexokinase-1, HK1) tracked Tau pathology; this glycolysis-Tau coupling reproduced on an independent proteomic platform and against immunoassay Tau, whereas an apparent CSF V1A-Tau correlation did not survive distribution-robust analysis or validation against immunoassay Tau and is not interpreted as an individual-level marker. These findings position cross-cellular metabolic decoupling, rather than structural pump loss, as a candidate upstream constraint on lysosomal acidification, defining a candidate intervention window.},
}
@article {pmid42523505,
year = {2026},
author = {Salomón-Cruz, ID and Agudelo-Castrillon, SC and Barbosa-Carvajal, JP and Lozano-Trujillo, LA and Ríos, MH and Trujillo-Chacón, LM and Villegas, A and Osorio, E and Fernandez, GJ and Area-Gómez, E and Cardona-Gómez, GP},
title = {APOE3 Christchurch is associated with sphingolipids recycling and glial lipid remodeling in autosomal dominant Alzheimer's disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10297182/v1},
pmid = {42523505},
issn = {2693-5015},
abstract = {Alzheimer's disease is characterized by profound disturbances in brain lipid metabolism, which regulate membrane integrity, connectivity, immune response, and cell survival. However, the mechanisms by which the protective APOE3 Christchurch variant modulates lipid homeostasis in autosomal dominant AD remain poorly understood. Here, we investigated lipid changes in postmortem brains carriers of PSEN1-E280A mutation, including APOE3Ch variant. Using a multimodal approach integrating thin-layer chromatography lipid profiling, enzymatic activity assays, digital PCR, immunofluorescence, flow cytometry, and single-nucleus RNA sequencing, we characterized lipid composition and transcriptional expression in the cerebral cortex. Familial and sporadic AD brains exhibited extensive remodeling of lipid pathways, including depletion of structural phospholipids and marked alterations in sphingolipid metabolism. Notably, APOE3Ch carriers displayed reduced cholesterol and phospholipid content, preservation of ceramide pools, and enrichment of specific ganglioside fractions, accompanied by increased sphingomyelinase activity and coordinated downregulation of genes involved in sphingolipid biosynthesis and remodeling. Single-nucleus transcriptomic analyses further revealed cell-type-specific alterations across glial populations, including reduced pruning of differentiated oligodendrocytes and suppression of lipid metabolic process in astrocytes and microglia. Together, these findings suggest that APOE3Ch promotes a reduced de novo biosynthesis of cholesterol and a distinct sphingolipid metabolic state characterized by enhanced lipid recycling, potentially attenuating lipid-driven neuroinflammatory responses.},
}
@article {pmid42523517,
year = {2026},
author = {Diaz, CS and Baghirova, N and Vu, DT and Can, DC and Allali, G and Ryvlin, P and Chén, OY},
title = {Imputation-free transformer learning enables robust Alzheimer's disease prediction and calibrated uncertainty quantification across heterogeneous clinical cohorts.},
journal = {ArXiv},
volume = {},
number = {},
pages = {},
pmid = {42523517},
issn = {2331-8422},
abstract = {Accurate diagnostic classification and disease-severity prediction for Alzheimer's disease are hampered by the incompleteness and heterogeneity of real-world clinical data. Left unaddressed, these barriers prevent reliable disease modelling and hinder effective clinical evaluation. Conventional imputation strategies introduce systematic bias, distort inter-feature relationships, and yield overconfident predictions, limitations especially consequential in diagnostic settings. Here, we propose NITROGEN, an imputation-free transformer that jointly models within-patient feature dependencies and between-patient relational structure through masked and intersample attention, enabling robust multimodal learning directly from partially observed records. We trained NITROGEN on ADNI (N=7858 scans), and evaluated it on two independent cohorts: OASIS-3 (N=2675 scans) and AIBL (N=1286 scans). Across cohorts and diagnostic and cognitive score prediction tasks, NITROGEN showed robust calibration and uncertainty quantification advantages over tree-based ensemble methods, while maintaining competitive discriminative performance. Cross-cohort and cross-method analyses identified cortical thickness in the temporal pole, age, and APOE genotype as important, though not individually sufficient, features for AD classification. We further introduced a modality-aware uncertainty adjustment that augments predictive uncertainty proportionally to the importance of absent modalities, enabling calibrated confidence when diagnostic information is unavailable. Together, our results show that imputation-free attention learning preserved meaningful discrimination under cohort shift, revealing expected degradation on more distributionally different cohorts, and demonstrate that evaluating models along calibration, interpretability, and cross-cohort reliability, not accuracy alone, is essential for clinical deployment.},
}
@article {pmid42523519,
year = {2026},
author = {Chen, X and Munoz-Mayorga, D and Lyu, X and Jati, S and Zhang, J and Rossitto, LA and Tao, Y and Zhao, S and Hui, E and Kauffman, A and Zhu, B},
title = {A non-canonical androgen signaling pathway drives microglial activation and tau pathology in females.},
journal = {Research square},
volume = {},
number = {},
pages = {},
pmid = {42523519},
issn = {2693-5015},
abstract = {Alzheimer's disease (AD) disproportionately affects women, who exhibit greater vulnerability to Tau pathology and neuroinflammation. The precise mechanisms underlying this vulnerability remain elusive, although sex hormones are thought to play a pivotal role. Here, we report that supplementation with the non-aromatizable androgen dihydrotestosterone (DHT) exacerbates Tau pathology in female tauopathy models, with microglia as the main driver of this effect. DHT treatment upregulates proinflammatory gene expression in microglia and promotes the disease-associated microglia (DAM) phenotype in a Trem2-dependent manner. Surprisingly, these effects are independent of the canonical androgen receptor (AR) and instead depend on the orphan nuclear receptor TR4, which mediates DHT-driven effects by transcriptionally regulating Trem2 in microglia. Moreover, TR4 protein levels are elevated in postmortem brain tissue from Braak stage 6 female AD patients and correlate with p-Tau levels. Together, our findings uncover a non-canonical DHT-TR4- Trem2 signaling axis in microglia and identify TR4 as a key regulator of neuroinflammation in female neurodegeneration, providing mechanistic insight into female-specific vulnerability to AD.},
}
@article {pmid42523523,
year = {2026},
author = {Estrella, LD and Dasgupta, S and Gundavelli, A and Li, H and Yang, SH and Chancellor, S and Pastika, T and Abdourahman, A and Tamm, J and Yanamandra, K and Romanul, N and Liao, F and Zhao, K and Lin, G and Srinivasa, P and Wang, X and Martin, A and Asque, E and Doering, A and Ried, JS and Talanian, RV and Kwon, T and Woodbury, ME and Grinberg, YY and Agastra, E and Oakley, DH and Hyman, BT and Serrano-Pozo, A and Zwang, T and Das, S and Bennett, RE},
title = {Cerebrovascular Single-Nucleus RNA-Seq Reveals Heat Shock Activation and Vascular Remodeling in Alzheimer's Disease and Primary Tauopathies.},
journal = {Research square},
volume = {},
number = {},
pages = {},
pmid = {42523523},
issn = {2693-5015},
abstract = {Cerebrovascular alterations are widely observed in both Alzheimer's Disease (AD) and primary tauopathies. Here, we hypothesized that mechanisms of cerebrovascular alterations are shared between AD and primary tauopathies. We performed single-nucleus RNA sequencing of postmortem human inferior temporal gyrus to characterize transcriptomic changes across cerebrovascular cell types in AD and primary tauopathies (Corticobasal Degeneration, Pick's disease, and Progressive Supranuclear Palsy). Differential gene expression analyses revealed disease-specific transcriptional programs across vascular cell populations. However, genes involved in the heat-shock response were consistently upregulated across all diseases, suggesting a conserved cerebrovascular stress response during neurodegeneration. We further identified marked cerebrovascular remodeling in AD relative to primary tauopathies, along with dysregulation of genes mapping to AD risk loci in endothelial cells. Transcriptomic findings were validated using tissue clearing, light-sheet microscopy, and immunofluorescence quantification of vascular markers. These results define a conserved vascular stress program alongside AD-specific remodeling, highlighting the vasculature as a therapeutic target in neurodegeneration.},
}
@article {pmid42523541,
year = {2026},
author = {Ambekar, A and Zielinski, R and Eloyan, A},
title = {TRAECR: A Tool for Preprocessing Positron Emission Tomography Imaging for Statistical Modeling.},
journal = {ArXiv},
volume = {},
number = {},
pages = {},
pmid = {42523541},
issn = {2331-8422},
abstract = {Positron emission tomography (PET) imaging is widely used in a number of clinical applications, including cancer and Alzheimer's disease (AD) diagnosis, monitoring of disease development, and treatment effect evaluation. Statistical modeling of PET imaging is essential to address continually emerging scientific questions in these research fields, including hypotheses related to evaluation of effects of disease modifying treatments on amyloid reduction in AD and associations between amyloid reduction and cognitive function, among many others. In this paper, we provide background information and tools for statisticians interested in developing statistical models for PET imaging to pre-process and prepare data for analysis. We introduce our novel pre-processing and visualization tool TRAECR (Template registration, MRI-PET co-Registration, Anatomical brain Extraction and COMBAT/RAVEL harmonization) to facilitate data preparation for statistical analysis.},
}
@article {pmid42523631,
year = {2026},
author = {Ding, X and Hu, X and Xue, W and An, Y and Cheng, W and Zhang, S and Lei, A and Zhang, J},
title = {Anti-inflammatory CAR-microglia targeting Aβ for Alzheimer's disease therapy.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1820099},
pmid = {42523631},
issn = {1664-3224},
mesh = {*Alzheimer Disease/therapy/metabolism/immunology ; Animals ; *Microglia/metabolism/immunology/transplantation ; *Amyloid beta-Peptides/metabolism/immunology ; Humans ; Mice ; Axl Receptor Tyrosine Kinase ; Receptor Protein-Tyrosine Kinases/genetics/metabolism ; Disease Models, Animal ; *Induced Pluripotent Stem Cells/metabolism ; c-Mer Tyrosine Kinase/genetics/metabolism ; Efferocytosis ; Mice, Transgenic ; Proto-Oncogene Proteins/genetics/metabolism ; Phagocytosis ; Cytokines/metabolism ; Anti-Inflammatory Agents ; },
abstract = {Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ) plaques and chronic neuroinflammation, which together drive progressive neuronal loss and cognitive decline. In recent years, monoclonal antibodies targeting Aβ have demonstrated encouraging clinical benefits in Alzheimer's disease (AD). However, their therapeutic efficacy remains limited by insufficient and unsustained clearance of Aβ, as well as treatment-associated neuroinflammatory responses. These limitations highlight the need for alternative strategies that can achieve efficient Aβ elimination while maintaining immune homeostasis. To overcome these challenges, we developed a novel anti-inflammatory CAR-Microglia (CAR-Mic) incorporating a construct based on the TAM receptor family (TYRO3, AXL, and MERTK), which are key regulators of efferocytosis and anti-inflammatory responses. The resulting Aβ-targeted CAR-Mics showed enhanced Aβ engulfment and reduced proinflammatory cytokines release. Among the constructs tested, AXL-CAR demonstrated the most favorable overall performance and was therefore selected for the generation of human induced pluripotent stem cell (iPSC)-derived CAR microglia-like cells (CAR-iMGLs). In an AD mouse model, AXL-CAR-iMGLs exhibited enhanced Aβ clearance without evidence of severe adverse effects. Collectively, these findings establish TAM receptor-based CAR-iMGLs as a promising cell therapy model for AD and potentially other neurodegenerative disorders characterized by chronic neuroinflammation and defective pathological protein clearance.},
}
@article {pmid42523676,
year = {2026},
author = {Cai, H and Wang, Y and Che, S and Hou, Z},
title = {Transcranial low-intensity pulsed ultrasound in neurological disorders: mechanisms, therapeutic applications, and translational challenges.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1850924},
pmid = {42523676},
issn = {1664-2295},
abstract = {Transcranial low-intensity pulsed ultrasound (LIPUS) is an emerging non-invasive modality with high spatial precision, substantial tissue penetrability, and favorable biosafety. Acting predominantly through mechanical rather than thermal bioeffects, LIPUS modulates mechanosensitive ion channels, intracellular calcium signaling, synaptic transmission, glial activation, neurovascular coupling, and, in selected settings, blood-brain barrier permeability. These features support its growing application in neurological disorders. In this review, we summarize the mechanistic basis of transcranial LIPUS and discuss its therapeutic applications in Alzheimer's disease, Parkinson's disease, epilepsy, ischemic stroke, and major depressive disorder. Across these conditions, LIPUS has been associated with neuroprotection, enhanced synaptic plasticity, suppression of pathological neural activity, attenuation of neuroinflammation, promotion of vascular remodeling, and facilitation of targeted delivery through reversible blood-brain barrier opening. We further highlight the major barriers to clinical translation, including heterogeneity of stimulation parameters, incomplete mechanistic understanding, limited comparability across studies, and insufficient large-scale clinical validation. Current evidence supports transcranial LIPUS as a promising ultrasound-based platform for neuromodulation and brain repair, while emphasizing the need for standardized protocols and rigorous translational studies.},
}
@article {pmid42524115,
year = {2026},
author = {Raikes, AC and Bhattrai, A and Wang, T and Wiegand, JP and Brinton, RD},
title = {Humanized APOE mouse brain volume increases over age irrespective of sex and APOE genotype: implications for translational validity to the human.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1843319},
pmid = {42524115},
issn = {1662-4548},
abstract = {BACKGROUND: Humanized APOE mouse models are widely used to study late-onset Alzheimer's disease (LOAD) risk, yet it remains unclear whether they reproduce the macrostructural brain changes observed in human aging and disease.<br><br>METHODS: We performed ex vivo magnetic resonance imaging to quantify total and voxelwise brain volumes in male and female mice across APOE genotypes (&#x3b5;3/&#x3b5;3, &#x3b5;3/&#x3b5;4, &#x3b5;4/&#x3b5;4) and ages spanning 6-25 months.<br><br>RESULTS: Total brain volume increased with age (cross-sectional estimate: 2.12 mm[3]/month) and was greater in APOE-&#x3b5;4 carriers, with no effect of sex. Voxelwise analyses revealed regionally specific changes independent of total volume, characterized by cortical volume decreases and subcortical preservation or increases, as well as sex-dependent spatial patterns. No localized volumetric effects of APOE genotype were detected.<br><br>CONCLUSION: These findings indicate that, despite incorporating a major genetic risk factor for LOAD, this model does not reproduce the atrophy phenotype characteristic of human aging and Alzheimer's disease. Instead, the observed pattern is more consistent with non-pathological or vulnerable aging, suggesting that humanized APOE alone is insufficient to induce MRI-detectable macrostructural atrophy within this cross-sectional comparison, though this finding does not preclude other APOE-dependent pathological mechanisms.},
}
@article {pmid42524118,
year = {2026},
author = {Rafiey, M and Nosrati, R and Pourgholaminejad, A and Ahangaran, S and Babaei, P},
title = {Histone Deacetylase Inhibitor Combined with Rosiglitazone Improves Cognitive Function Via Microglial Polarization and Increased Mature/Pro-BDNF in Alzheimer's Disease.},
journal = {Advanced pharmaceutical bulletin},
volume = {16},
number = {1},
pages = {157-165},
pmid = {42524118},
issn = {2228-5881},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is characterized by diminished brain metabolism, cognitive impairments, neural loss, astrogliosis, and microgliosis. We hypothesized that co-administration of a peroxisome proliferator-activated receptor gamma (PPARγ) agonist and a histone deacetylase (HDAC) inhibitor would enhance cognitive function in an AD model of rats.<br><br>METHODS: Forty adult male Wistar rats were randomly assigned into five groups (n=8 per group): (1) Control group receiving saline, (2) AD model group (induced by i.c.v injection of Streptozocin), (3) AD+Rosiglitazone (ROSI) (4) AD+MS-275, and (5) AD+combined ROSI and MS-275 group. Cognitive functions were evaluated using the passive avoidance test and the Morris water maze (MWM). Microglial polarization was assessed by flow cytometry, and protein expression was analyzed by western blotting.<br><br>RESULTS: Data analyzed by one-way ANOVA and post hoc Tukey for (MWM) showed a significant decrease in latency to the target quadrant both in working and reference memories, and a significant increase in total time spent (TTS) in the target quadrant for reference memory in the group of STZ+ROSI+MS-275 (P<0.000). Kruskal-Wallis H test revealed a significant increase in the M2/M1 ratio for ROSI+MS-275+STZ group compared with the STZ+Saline group (P=0.001). Also an increased mature brain-derived neurotrophic factor (BDNF)/pro-BDNF ratio was found in treated groups compared with STZ+saline (P<0.001).<br><br>CONCLUSION: These findings suggest that co-administration of Rosiglitazone and MS-275 improves cognitive function in AD rats, potentially through shifting microglial polarization from the M1 to the M2 phenotype and enhancing synaptic strength via an increased mature BDNF/pro-BDNF ratio.},
}
@article {pmid42524288,
year = {2026},
author = {Yu, F and Salisbury, DL and Todd, M and Chow, LS and Porsteinsson, AP and Maxfield, M and Joseph, RP and LoVecchio, F and Heffner, KL and Lin, FV},
title = {Efficacy of sequential aerobic exercise and cognitive training in older adults with amnestic mild cognitive impairment.},
journal = {Aging and health research},
volume = {6},
number = {2},
pages = {},
pmid = {42524288},
issn = {2667-0321},
abstract = {BACKGROUND: Multi-component interventions may be critical for reducing Alzheimer's disease (AD) risk since AD pathogenesis is multi-factorial. Combined Aerobic exercise and Cognitive Training (ACT) may have synergistic effects, but studies are limited with mixed findings.<br><br>METHODS: A 3-site, single-blinded Stage II 2 &#xd7; 2 factorial trial aimed to test the effects of 6-month ACT on cognition in older adults with amnestic mild cognitive impairment in academic research facilities and gyms. Among 325 participants consented, 146 were enrolled and randomized equally to 6-month ACT, cycling only, speed of processing (SOP) cognitive training only, or control. Primary outcomes, executive function and episodic memory, were measured with alternating EXAMINER and Brief Visuospatial Memory Test-Revised (BVMT-R) forms at baseline, 3, 6, 12, and 18 months, and global cognition with the Montreal Cognitive Assessment (MoCA) and EXAMINER/BVMT-R composite.<br><br>RESULTS: Executive function improved significantly from baseline to 6 months (ds = 0.58-1.18, adjusted Ps < 0.001-0.026) in all groups except SOP. Global cognition composite increased in cycling only (d = 0.73; adjusted P = 0.012). MoCA decreased over 18 months (adjusted P = 0.030) in the control group only. Between-group comparison was significant between ACT and SOP groups at 6 months (adjusted P = 0.029), but sensitivity analyses showed ACT being superior to both cycling- and SOP-only groups (Ps = 0.030 and 0.002, respectively) among in-person interventions (48.6% of all sessions were delivered in person as designed due to COVID-19).<br><br>CONCLUSIONS: ACT's synergistic effects remain to be determined. All interventions are feasible for clinical practice.<br><br>TRIAL REGISTRATION: www.clinicaltrials.gov (NCT03313895; date of registration: 10/18/2017).},
}
@article {pmid42524328,
year = {2026},
author = {Miaja, P and Martinez-Baños, M and Martin-Bermejo, MJ and Moreno, I and Dominguez, M and Bovolenta, P},
title = {Pharmacodynamic and stage-dependent therapeutic efficacy of SFRP1 neutralization in a mouse model of Alzheimer's disease.},
journal = {Alzheimer's &amp; dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70301},
pmid = {42524328},
issn = {2352-8737},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is characterized by early synaptic dysfunction followed by progressive amyloid beta (Aβ) accumulation, neuroinflammation, and cognitive decline. We previously identified secreted frizzled-related protein 1 (SFRP1) as a multifactorial contributor to AD pathogenesis and provided initial evidence that its neutralization ameliorates pathological AD-like traits in mice. Here we evaluate the pharmacodynamics, biodistribution, and therapeutic window of an anti-SFRP1 monoclonal antibody (α-SFRP1) in double transgenic amyloid precursor protein (APP) and presenilin-1 (PS1) mice (APP/PS1).<br><br>METHODS: Pharmacokinetics and target engagement of &#x3b1;-SFRP1 were assessed in groups of both male and female APP/PS1 mice using biotinylated or Zirconium-89 labeled ([89]Zr) antibodies, with tissue distribution and &#x3b1;-SFRP1 levels quantified by in-house enzyme-linked immunosorbent assay (ELISA) or positron emission tomography/computed tomography (PET/CT). Therapeutic efficacy was evaluated by administering &#x3b1;-SFRP1 or the SFRP1 inhibitor WAY-316606 at different stages of disease progression via retro-orbital injection, followed by analysis of AD-like pathology using ELISA and quantitative immunofluorescence assays and statistical analysis.<br><br>RESULTS: Using [89]Zr-labeled antibodies, we show that intravenously administered &#x3b1;-SFRP1 engages its target systemically and reaches the brain, although at substantially lower levels and with a rapid 24-h clearance. Treatment with &#x3b1;-SFRP1 had no apparent systemic side effects or sex-dependent differences, but its therapeutic efficacy against AD-like brain pathology was strongly dependent on disease stage. Although early administration reduced amyloid pathology in previous studies, treatment initiated at intermediate or advanced stages showed minimal benefit at standard doses. Higher antibody doses reduced amyloid burden and dystrophic neurites but were associated with increased mortality. Pharmacological inhibition of SFRP1 using a small-molecule inhibitor similarly failed to ameliorate pathology at intermediate stages.<br><br>DISCUSSION: Together, these findings demonstrate that SFRP1 remains a relevant therapeutic target in AD, but its effective modulation is constrained by limited brain exposure and a narrow therapeutic window, underscoring the importance of early intervention and prompting the search for improved brain-targeted delivery strategies.},
}
@article {pmid42524462,
year = {2026},
author = {Sungted, S and Rangubpit, W and Phongphanphanee, S and Yoshida, N and Dias, CL and Wong-Ekkabut, J},
title = {Aggregation of Amyloid-like Peptides in Different Solvents.},
journal = {Journal of molecular liquids},
volume = {457},
number = {},
pages = {},
pmid = {42524462},
issn = {0167-7322},
abstract = {The aggregation of amphipathic peptides into β-sheet rich structures is a hallmark of several neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. At the molecular level, the toxic mechanism of these peptides involves an increase in the permeation of the cellular membrane, which starts with the partition of nonpolar and polar residues at the water-lipid interface that facilitates aggregation. Here, we study this process using all-atom molecular dynamics simulations in four model peptides composed of 4 phenylalanine (F), 2 lysine (K), and 2 glutamic acid (E) under three solvent conditions. In two sequences, nonpolar and charged amino acids alternate along the chain (FKFEFKFE and FFKKFFEE), and, in the other two sequences (FFFKFEKE and FFFFKKEE), they are segregated to the N- and C-terminals. Peptides are solvated in water and octane to study aggregation in hydrophilic and hydrophobic solvents, respectively. In all simulations, peptides aggregate promptly, adopting mostly random coil conformations; except for FKFEFKFE, which spontaneously forms β-sheet conformations in water that resemble the cross-beta structures found in amyloid diseases. Aggregation takes place with a lower free energy of dimerization in octane compared to water. Simulations are also performed in a water-octane to mimic the water-lipid interface where amyloid peptides aggregate before damaging cell membranes. All peptides are spontaneously attracted to this polar-nonpolar interface which corresponds to a minimum in the free energy profile. At the interface, peptides generally exhibit low backbone interaction energies with a high content of secondary structure. The types of secondary structure formed in the system depend on the sequence pattern. In addition, the arrangement of polar and nonpolar residues modulates the free energy profile of peptide transfer from water to octane, and monomers adsorb at the interface more preferentially than the β-sheet dimer. These findings provide insights into how sequence pattern and solvent environment influence peptide aggregation, secondary structure formation, and interfacial behavior.},
}
@article {pmid42524625,
year = {2025},
author = {Fernandez, F and Reyes-Reyes, E and Chinnasamy, D and Trial, M and Rodgers, KE},
title = {Aging shapes baseline immunity in sterile-housed female hAPOE mouse genotypes.},
journal = {Journal of cellular and molecular immunology},
volume = {4},
number = {1},
pages = {33-39},
pmid = {42524625},
issn = {2833-1141},
abstract = {The Apolipoprotein E ε4 allele (APOE4) is a major risk factor in the development of late-onset Alzheimer's Disease (LOAD; AD) and has been associated with altered immunological responses, particularly under inflammatory challenge. Whether APOE genotype shapes baseline peripheral immunity across aging remains unclear. Because experimental context can influence immune phenotypes, we focus here on baseline profiles under specific-pathogen-free barrier housing (sterile housing) and discuss their implications. To this end, we highlight the peripheral immune profile in female humanized APOE mice (APOE3/3, APOE3/4, APOE4/4) maintained under sterile housing at 6, 9, and 15 months of age. Immunophenotyping of blood and spleen revealed significant age-related changes in B and T cell subpopulations and cytokine levels. Significant increases in activated and effector CD4[+] and CD8[+] T cells, as well as plasma cells, were observed at 15 months of age, particularly in the spleen. These shifts were primarily driven by ageing rather than APOE genotype. The only genotype-related differences detected were an increase in plasma TNF-α and IL-1β levels at 15 months and 9 months, respectively, in APOE4 compared with APOE3. Overall, aging exerts a stronger influence than APOE genotype on baseline peripheral immunity in female hAPOE mice under sterile housing, establishing an age-stratified baseline and providing a context-dependent rationale for future challenge-based studies to define genotype-by-inflammation interactions relevant to LOAD.},
}
@article {pmid42524732,
year = {2026},
author = {Ruiz Piñero, M and Pérez Carmona, N and Piñol Ferrer, B and Pérez Sempere, &#xc1; and Abellán Miralles, I},
title = {Minor hallucinations as an early marker to differentiate dementia with Lewy bodies from Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261468798},
doi = {10.1177/13872877261468798},
pmid = {42524732},
issn = {1875-8908},
abstract = {BackgroundEarly differentiation between Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) remains clinically challenging, particularly in the initial stages, when cognitive profiles largely overlap. Accurate diagnosis is increasingly relevant given disease-specific therapeutic implications.ObjectiveTo compare clinical, neuropsychological, and perceptual features of early-stage AD and DLB, with a particular focus on minor hallucinations (MH), and to assess their diagnostic utility in differentiating both conditions.MethodsThis prospective, cross-sectional study included 121 patients with probable AD (n = 60) or DLB (n = 61), all in mild stages (GDS 3-4) and supported by disease-specific biomarkers. Participants underwent standardized clinical assessment, comprehensive neuropsychological evaluation, structured evaluation of psychotic symptoms, and perceptual testing, including the Pareidolia Test. Group comparisons and ROC analyses were performed to assess discriminative accuracy.ResultsGlobal cognition, attention, executive functions, language, and visuospatial abilities largely overlapped between groups. Episodic memory impairment was significantly more severe in AD across all recall measures. In contrast, DLB patients showed a higher prevalence of core clinical features and a markedly higher frequency of MH (54.1% versus 13.3% in AD). Pareidolic responses were significantly more frequent in DLB and showed the highest discriminative accuracy among perceptual measures. The presence of MH demonstrated a high positive predictive value for DLB.ConclusionsIn early disease stages, MH and susceptibility to perceptual distortions differentiate DLB from AD more effectively than standard cognitive testing. Systematic assessment of these phenomena may improve early diagnostic accuracy in routine clinical practice.},
}
@article {pmid42524837,
year = {2026},
author = {Li, J and Ma, H and Wang, G},
title = {Accelerated Biological Aging, Neurodegenerative Disease, and Mortality in Cardiovascular Disease Patients: Mediation and Modification Analysis.},
journal = {CNS neuroscience &amp; therapeutics},
volume = {32},
number = {8},
pages = {e71059},
doi = {10.1002/cns.71059},
pmid = {42524837},
issn = {1755-5949},
support = {2026-2G-20111//Capital's Funds for Health lmprovement and Research (CFH)/ ; QNPY202518//Scientific Research Project of Xuanwu Hospital, Capital Medical University/ ; },
mesh = {Humans ; *Cardiovascular Diseases/mortality/epidemiology ; Male ; Female ; *Aging ; Aged ; *Neurodegenerative Diseases/mortality/epidemiology ; Middle Aged ; Aged, 80 and over ; Nutrition Surveys ; Risk Factors ; },
abstract = {AIMS: Cardiovascular disease (CVD) patients exhibit increased neurodegenerative diseases and mortality risks, implying a shared heart-brain aging pathway. As a composite biological aging predictor, the association of Phenotypic age (PhenoAge) with mortality and the mediating role of brain health remain unclear in CVD patients.<br><br>METHODS: In 4104 CVD patients (57.3% male, mean age 67.3&#x2009;years) from the National Health and Nutrition Examination Survey (median follow-up of 7.2&#x2009;years), weighted regression models examined associations of PhenoAge and its acceleration with Alzheimer's disease (AD), Parkinson's disease (PD), and mortality. Mediation effects of the association between PhenoAge and mortality explained by AD and PD were quantified.<br><br>RESULTS: The mean PhenoAge was 69.9&#x2009;years, and AD and PD prevalences were 7.6% and 1.8%. Each 5-year increment of PhenoAge acceleration independently increased risks of AD (OR&#x2009;=&#x2009;1.24; 95% CI:1.13,1.36), PD (OR&#x2009;=&#x2009;1.22; 95% CI:1.02,1.46), and all-cause mortality (HR&#x2009;=&#x2009;1.30; 95% CI:1.24,1.36). AD and PD mediated 20.46%-33.18% of the association between PhenoAge and mortality. Early-onset CVD amplified biological aging-related mortality risk, while a healthier lifestyle attenuated the CVD mortality risk (Pinteraction <&#x2009;0.05).<br><br>CONCLUSION: Accelerated biological aging was associated with adverse brain health outcomes and mortality in CVD patients, with AD and PD as significant mediators. PhenoAge assessment may identify high-risk individuals for personalized heart-brain aging prevention.},
}
@article {pmid42524884,
year = {2026},
author = {Sa, Y and Yuan, H and Ma, J and Yang, Z and Wang, M and Wang, W and Yang, L and Ma, F and Zhang, W and Mening'oo, GW and Chen, G and Ma, X},
title = {Innovative Test Strip-Based Colorimetric Sensors Integrated With Affinity Chromatography: Acetylcholinesterase Inhibitor Screening Breakthrough in Lycium Barbarum Leaves.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e76863},
doi = {10.1002/advs.76863},
pmid = {42524884},
issn = {2198-3844},
support = {2023BEG02014//Key Research and Invention Program of Ningxia/ ; 82360684//National Natural Science Foundation of China/ ; 2024AAC02043//Natural Science Foundation of Ningxia/ ; 2026AAC030216//Natural Science Foundation of Ningxia/ ; XJKF240324,XJKF240330//Key Research Projects of Ningxia Medical University/ ; },
abstract = {Current Alzheimer's drugs exhibit limited effectiveness, highlighting the necessity for multi-target treatments. This study developed an innovative and efficient screening platform combining hydrogen peroxide test strip-based colorimetric sensing with affinity chromatography for rapid identification of acetylcholinesterase (AChE) inhibitors from complex herbal medicines. Applying this strategy, from Lycium barbarum leaves, we identified three potent inhibitors: chlorogenic acid, N-acetyl-N'-caffeoylputrescine (NANCP), and N-caffeoylputrescine (NCP), with IC50 ranging from 55.7 to 143.2 µm. Molecular analyses confirmed their stable binding to AChE. In a D-galactose and AlCl3-induced Alzheimer's disease (AD) mouse model, NCP treatment significantly rescued cognitive deficits in AD mice, with the spontaneous alternation rate in the Y-maze test improved by up to 50%. It markedly reduced cerebral Aβ levels (by 54%) and pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6, alleviated oxidative stress, and attenuated hippocampal neuronal damage. Mechanistically, NCP modulated glycerophospholipid metabolism, reshaped gut microbiota, and targeted the proteasome-autophagy pathway, revealing a multi-faceted synergistic mechanism. The research offers a new screening tool for AChE inhibitors and highlights a promising natural multi-target candidate, NCP, for AD therapy.},
}
@article {pmid42525141,
year = {2026},
author = {Zheng, M and Hou, B and Ma, R and Wang, K and Xia, J and Tan, Z},
title = {SOX9 knockdown alleviates Aβ1‑42‑induced neuroinflammation by regulating microglial polarization via inactivation of the ASK1/JNK signaling pathway.},
journal = {Journal of molecular histology},
volume = {57},
number = {4},
pages = {},
pmid = {42525141},
issn = {1567-2387},
mesh = {*Microglia/metabolism/pathology ; Humans ; *MAP Kinase Kinase Kinase 5/metabolism/genetics ; *SOX9 Transcription Factor/metabolism/genetics ; *Amyloid beta-Peptides/metabolism ; *Inflammation/metabolism/pathology ; Female ; Animals ; *MAP Kinase Signaling System ; Male ; Gene Knockdown Techniques ; Alzheimer Disease/metabolism/pathology/genetics ; *Peptide Fragments/metabolism ; Mice ; *Cell Polarity ; Aged ; Cell Line ; },
abstract = {Neuroinflammation driven by microglial polarization imbalance plays a key role in Aβ-induced neuronal injury, a core pathological feature of Alzheimer's disease (AD). The transcription factor SOX9 has been linked to AD progression, but its mechanism remains unclear. SOX9 expression was measured in peripheral blood mononuclear cells from 24 patients with AD and 24 age-matched healthy controls and correlated with Montreal Cognitive Assessment scores. An Aβ1-42-stimulated BV-2 cell model was used to investigate the effects of SOX9 and apoptosis signal-regulating kinase 1 (ASK1) on microglial polarization. Neuronal injury was evaluated in a BV-2/SH-SY5Y co-culture system. The transcriptional regulation of ASK1 by SOX9 was examined using dual-luciferase reporter and chromatin immunoprecipitation assays. ASK1 overexpression and the ASK1 inhibitor GS-4997 were used for mechanistic validation. SOX9 expression was increased in peripheral blood mononuclear cells from patients with AD and was negatively correlated with cognitive function. SOX9 was also upregulated in Aβ1-42-stimulated BV-2 cells. SOX9 overexpression enhanced M1-associated inflammatory markers and reduced M2-associated markers, whereas SOX9 knockdown produced the opposite effects. In the co-culture system, SOX9 knockdown increased SH-SY5Y cell viability, reduced LDH release and apoptosis, increased Bcl-2 expression, and decreased Bax and cleaved caspase-3 expression. SOX9 bound to the ASK1 promoter and promoted ASK1 transcription. SOX9 silencing suppressed ASK1, JNK, and p38 phosphorylation, while ASK1 overexpression reversed the effects of SOX9 knockdown on microglial polarization and neuronal injury. Consistently, GS-4997 blocked the pro-inflammatory and neurotoxic effects induced by SOX9 overexpression. SOX9 exacerbates AD neuroinflammation by promoting microglial M1 polarization via the ASK1/JNK signaling axis.},
}
@article {pmid42525165,
year = {2026},
author = {Tahir, MM and Liu, X and Yi, LS and Hou, XQ and Liao, Q and Yu, HL},
title = {From astrocyte cholesterol synthesis to synaptic dysfunction: mechanisms of neuron-glia lipid coupling.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42525165},
issn = {1573-4978},
support = {32371039//National Natural Science Foundation of China/ ; YDZJ202201ZYTS620//Project supported by Jilin Province and Central Government Guides Local Science and Technology Development Fund/ ; },
mesh = {*Astrocytes/metabolism ; *Cholesterol/metabolism/biosynthesis ; Humans ; *Neurons/metabolism ; Animals ; *Synapses/metabolism/pathology ; *Neuroglia/metabolism ; Apolipoproteins E/metabolism ; Sterol Regulatory Element Binding Proteins/metabolism ; Lipid Metabolism ; },
abstract = {BACKGROUND: The brain contains a large proportion of the body's cholesterol, highlighting its importance in central nervous system function. Cholesterol supports neuronal membrane structure, synapse formation, synaptic vesicle activity, receptor signaling, and myelin integrity. Because the blood-brain barrier limits the entry of peripheral lipoproteins, the brain relies mainly on local cholesterol synthesis, transport, recycling, and turnover.<br><br>OBJECTIVE: This review examines the mechanisms that regulate astrocyte-to-neuron cholesterol transfer and explains how defects in SREBP-dependent synthesis, ApoE lipidation, ABC transporter-mediated export, neuronal uptake, intracellular trafficking, and cholesterol turnover contribute to synaptic dysfunction and neurodegeneration.<br><br>MECHANISMS: In the adult brain, astrocytes are an important source of cholesterol for neurons. Astrocytic cholesterol synthesis is regulated by sterol regulatory element-binding proteins, which control the expression of key cholesterol-biosynthetic genes. Astrocytes release cholesterol in ApoE-containing lipoprotein particles through ATP-binding cassette transporters. Neurons acquire astrocyte-derived cholesterol through LDLR/LRP1, redistribute it via NPC1/NPC2, and eliminate excess cholesterol as 24 S-hydroxycholesterol through CYP46A1.<br><br>CONCLUSION: Disruption of this pathway impairs membrane organization, lipid raft signaling, synaptic function, and neuronal survival. These disturbances are associated with Alzheimer's disease, Huntington's disease, and multiple sclerosis.},
}
@article {pmid42525186,
year = {2026},
author = {Bao, YW and Ji, YQ and Wang, LN and Zhou, Y and Wang, F and Shen, DM and Pylypenko, D and Tong, Q and Mak, KF and Guo, LL},
title = {Topography of Juxtaventricular white matter hyperintensities and cognitive associations in Alzheimer's disease: a dual-cohort study.},
journal = {European radiology experimental},
volume = {10},
number = {1},
pages = {},
pmid = {42525186},
issn = {2509-9280},
support = {HABL202235//the special funds for the Science and Technology Programs of Huai'an/ ; NMUB20220204//Science and Technology Development Programs of Nanjing Medical University/ ; HAKY202400205//Northern Jiangsu Clinical Medicine Research Institute's 2024 Projects/ ; GQ202202//Start-up Grant for High-Level Talents of Huai'an No.1 People's Hospital/ ; BK20240307//Basic Research Program of Jiangsu/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/pathology ; *White Matter/diagnostic imaging/pathology ; *Magnetic Resonance Imaging/methods ; Cohort Studies ; Female ; Male ; Aged ; Positron-Emission Tomography ; *Cognition ; Amyloid beta-Peptides/metabolism ; Cognitive Dysfunction/diagnostic imaging ; Aged, 80 and over ; },
abstract = {OBJECTIVE: White matter hyperintensities (WMHs), a hallmark of cerebral small vessel disease, frequently coexist with Alzheimer's disease (AD) and facilitate cognitive deterioration. Juxtaventricular WMH (JVWMH) is hypothesized to reflect pathological processes at the cerebrospinal fluid (CSF)-parenchyma interface and hold particular clinical significance. Therefore, this study specifically investigated associations between JVWMH burden and cognitive performance, CSF volume (CSFV), and amyloid-β (Aβ) pathology.<br><br>MATERIALS AND METHODS: Automated WMH segmentation was applied in two cohorts: 295 from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study and 82 from a memory clinic. All participants underwent 3-T magnetic resonance imaging, amyloid-positron emission tomography, and cognitive assessment. Analyses evaluated JVWMH associations with A&#x3b2;, its discriminative value for cognitive impairment (CI) versus cognitively normal (CN), prediction of longitudinal decline, and mediation of CSFV-cognition relationships.<br><br>RESULTS: JVWMH volume significantly discriminated CI from CN participants in both cohorts and predicted cognitive decline in longitudinal AIBL data. JVWMH volume showed strong correlations with CSFV in both cohorts. Notably, JVWMH partially mediated the associations between CSFV and cognition in the AIBL cohort. Non-juxtaventricular WMHs and Fazekas scores demonstrated no significant diagnostic or predictive power.<br><br>CONCLUSION: JVWMH volume provides diagnostic and prognostic information beyond conventional WMH metrics in AD. Its correlation with CSFV implicates CSF-parenchyma interface processes, though causality remains unproven. These findings highlight the importance of incorporating spatially stratified WMH metrics in AD research to better capture disease-relevant white matter pathology.<br><br>KEY POINTS: Question: JVWMH volume provides diagnostic and prognostic value beyond conventional WMH metrics in AD.<br><br>FINDINGS: JVWMH volume discriminated CI from normal cognition, predicted longitudinal decline, correlated with CSF volume, and partially mediated CSF volume-cognition associations.<br><br>RELEVANCE STATEMENT: JVWMH volume provides diagnostic and prognostic information beyond conventional WMH metrics in AD, highlighting the value of spatially stratified WMH analysis in AD research to better capture disease-relevant white matter pathology.},
}
@article {pmid42525245,
year = {2026},
author = {Santiago, J and Pocevičiūtė, D and Sällberg, T and Önnerfjord, P and , and Vogel, JW and Wennström, M},
title = {Retinal proteome changes mirror brain pathology and reveal synaptic and cytoskeletal dysfunction in Alzheimer's disease.},
journal = {Acta neuropathologica},
volume = {152},
number = {1},
pages = {},
pmid = {42525245},
issn = {1432-0533},
support = {2025-337//Stiftelsen f&#xf6;r gamla tj&#xe4;narinnor/ ; KAW 2020.0239//SciLifeLab &amp; Wallenberg Data Driven Life Science Program/ ; 2024-03642//Swedish Research Council/ ; 2024-02875//Swedish Research Council/ ; FO2023-0113//Brain Foundation/ ; 20230519//Crafoord Foundation/ ; 243007//&#xc5;hl&#xe9;n Foundation/ ; },
mesh = {*Alzheimer Disease/pathology/metabolism ; Humans ; *Proteome/metabolism ; *Retina/metabolism/pathology ; Female ; *Synapses/pathology/metabolism ; *Cytoskeleton/pathology/metabolism ; Male ; *Hippocampus/pathology/metabolism ; Aged ; Aged, 80 and over ; *Brain/pathology/metabolism ; Proteomics ; },
abstract = {Visual dysfunction is increasingly recognized as an important feature of Alzheimer's disease, and substantial retinal changes have been documented across multiple studies. Yet the molecular changes underlying retinal neurodegeneration and which retinal protein signatures best track cerebral pathology remain incompletely defined. Here, we performed comprehensive mass spectrometry-based proteomics on paired retinal and hippocampal tissue from the same postmortem donors (8 AD, 8 non-demented controls) to identify disease-associated molecular signatures and assess their overlap between these tissues. Using a sequential dual-extraction protocol, we identified 372 differentially abundant retinal proteins in AD, including established APP-processing regulators (SORL1, BACE1) and synaptic proteins. Retinal proteomes clearly separated AD from controls in principal component analysis, indicating robust AD-related molecular differences in the retina. Notably, 87% of proteins were detected in both retina and hippocampus, with 64 differentially abundant proteins shared between tissues, some of which showed strong cross-tissue correlation. Several retinal proteins also correlated with neuropathological disease stage. Functional enrichment analysis revealed convergent alterations in synaptic organization, cytoskeletal dynamics, mitochondrial function, cell adhesion, and APP metabolism in both tissues. Cell-type mapping using single-cell retinal reference data indicated that most proteomic changes were broadly distributed across cell types, though some proteins showed enrichment in specific populations, such as SORL1 in microglia and EYS in photoreceptors. The molecular changes identified here offer a potential basis for the retinal alterations previously documented through in vivo imaging and histological studies. Their similarities with brain pathology further support the retina as a promising window for assessing cerebral disease.},
}
@article {pmid42508283,
year = {2026},
author = {Davis, RC and Wood, LE and Wilkes, L and Chandler, HL and Anderson, EL and Hiscox, LV},
title = {Impact of apolipoprotein Ε4 (APOE ε4) on neuroimaging outcomes in cognitively healthy midlife adults: A systematic review.},
journal = {NeuroImage. Clinical},
volume = {51},
number = {},
pages = {104035},
doi = {10.1016/j.nicl.2026.104035},
pmid = {42508283},
issn = {2213-1582},
abstract = {BACKGROUND: The apolipoprotein E ε4 (APOE ε4) allele is the strongest genetic risk factor for Alzheimer's disease (AD); however, its neurobiological impact assessed by neuroimaging outcomes during midlife, before the onset of cognitive impairment, has not been summarised. This systematic review synthesises evidence on neuroimaging differences associated with APOE ε4-carrier status in cognitively healthy midlife adults and evaluates whether AD-related risk can be detected across imaging modalities.<br><br>METHODS: A literature search was conducted up until November 2025 to identify studies reporting neuroimaging outcomes in healthy adults aged 30-60&#xa0;years with known APOE genotype. Eligible studies employed positron emission tomography (PET) and/or magnetic resonance imaging (MRI) and reported outcomes stratified by APOE &#x3b5;4-carrier status. Risk of bias was assessed using the ROBINS-E tool, and a narrative synthesis was performed.<br><br>RESULTS: Searches yielded 7786 articles, and 46 studies met the inclusion criteria. Nine studies used PET, forty used MRI, and three of these studies employed both modalities. Substantial heterogeneity in methods and outcome reporting meant that a meta-analysis was not feasible. PET evidence consistently identified greater amyloid deposition and lower glucose metabolism in midlife APOE &#x3b5;4-carriers compared with non-carriers, while MRI findings most reliably indicate higher cerebral blood flow. In contrast, other MRI-derived structural, microstructural, functional, and metabolic findings were mixed and largely inconclusive.<br><br>CONCLUSION: Cognitively healthy APOE &#x3b5;4-carriers demonstrate measurable neurobiological differences as early as midlife, consistent with a preclinical vulnerability associated with genetic risk for AD. These findings highlight the importance of characterising APOE-related mechanisms during midlife to inform early detection strategies and the development of preventative interventions for AD.},
}
@article {pmid42508295,
year = {2026},
author = {Lu, W and Caulfield, TR and Lee, E and Jeevaratnam, S and Wang, N and Bu, G and Kanekiyo, T and Li, Y},
title = {Discovery of a CI-994 derivative as a dual modulator of class I histone deacetylases and Wnt/β-catenin signaling for Alzheimer's disease therapy.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {23},
number = {5},
pages = {e00974},
doi = {10.1016/j.neurot.2026.e00974},
pmid = {42508295},
issn = {1878-7479},
abstract = {Alzheimer's disease (AD) is a multifactorial disease with mixed pathologies. Consequentially, drugs targeting multiple pathological processes may offer synergistic benefits. While histone deacetylase (HDAC) inhibitors have demonstrated efficacy in alleviating AD-related pathologies in animal models, the neuroprotective Wnt/β-catenin signaling pathway remains compromised in AD brain. CI-994 is a class I HDAC inhibitor containing N-(2-aminophenyl)-benzamide. Our recent studies indicate that CI-994 is also an activator of Wnt/β-catenin signaling by stabilizing Wnt co-receptor LRP6. We herein use CI-994 as a scaffold to develop novel potent dual modulators of class I HDACs and Wnt/β-catenin signaling for AD therapy. Our lead compound, W2A-28, selectively inhibits class I HDAC1, 2 and 3 with IC50 values of 0.51 μM, 0.68 μM and 0.22 μM, respectively, and shows no inhibitory activities on other HDACs. Furthermore, W2A-28 potently activates Wnt reporter activity with an EC50 value of 1.61 μM in Wnt-3A-expressing HEK293 cells. As expected, activation of Wnt/β-catenin signaling by W2A-28 is associated with elevated LRP6 protein level. Importantly, W2A-28 displays excellent microsomal stability in both mouse and human liver microsomal stability assays, alongside high permeability and a lack of active efflux in MDR1-MDCKII models. Critically, W2A-28 treatment significantly enhances histone acetylation, activates Wnt/β-catenin signaling, suppresses tau phosphorylation, and reduces Aβ levels in AD patient-specific cerebral organoids carrying APOE ε4/ε4 or APOE ε3/ε4 with PSEN1 M146V mutation. Our findings position W2A-28 as a promising multi-target drug candidate for AD therapy.},
}
@article {pmid42508312,
year = {2026},
author = {Peng, M and Shao, L and Zhai, J and Yao, Y and Mei, X and Zhu, S},
title = {Simultaneous and ultrasensitive detection of Alzheimer's disease blood biomarkers using magnetic SERS-encoded tags-based LFIA assay.},
journal = {Talanta},
volume = {312},
number = {Pt A},
pages = {130348},
doi = {10.1016/j.talanta.2026.130348},
pmid = {42508312},
issn = {1873-3573},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder requiring early diagnosis for effective intervention. The combination of blood Aβ42/Aβ40 ratio and p-tau-181 is recognized as a promising core biomarker panel for AD diagnosis. However, conventional detection methods suffer from limitations including time-consuming procedures, lack of multiplexing capability, and insufficient sensitivity. Herein, we developed a magnetic surface-enhanced Raman scattering (SERS)-encoded tags-based lateral flow immunoassay (LFIA) for simultaneous detection of Aβ42, Aβ40, and p-tau-181 on a single test line. Magnetic Fe3O4@Au nanoparticles were synthesized and modified with three distinct Raman reporters (DTNB for Aβ42, 4-MBA for Aβ40, and 2-MPY for p-tau-181) and corresponding detection antibodies. Under optimal conditions, the assay achieved rapid detection (∼28 min) and high sensitivity, with limits of detection of 93.33 fg/mL for Aβ42, 218.78 fg/mL for Aβ40, and 56.23 fg/mL for p-tau-181. The method exhibited excellent specificity against interfering substances (BSA, human IgG) and closely related species (Aβ38, p-tau-217), as well as good reproducibility (RSD <5%) and stability (≥4 weeks). In clinical plasma samples (n = 40), the combined score (p-tau-181/(Aβ42/Aβ40)) progressively increased with disease severity and correlated well with MMSE scores and MRI MTA grades, capturing both cognitive decline and hippocampal atrophy. This magnetic SERS-encoded LFIA platform offers a rapid, sensitive, user-friendly, and multiplex-capable approach for early AD diagnosis and progression monitoring, showing promise for future point-of-care applications.},
}
@article {pmid42508316,
year = {2026},
author = {Wang, D and Huang, W and Wang, X and Zhang, L and Tao, X and Qin, F and Guo, S and Han, G and Zhang, Z},
title = {Fluorescence lifetime imaging of G-quadruplex RNA dynamics in Alzheimer's disease using a novel nucleic acid-sensitive probe.},
journal = {Talanta},
volume = {312},
number = {Pt A},
pages = {130351},
doi = {10.1016/j.talanta.2026.130351},
pmid = {42508316},
issn = {1873-3573},
abstract = {Real-time monitoring of G-quadruplex (G4) RNA dynamics is vital for understanding their biological roles in the progression and treatment of Alzheimer's disease. However, this remains challenging due to two key difficulties. First, current fluorescent probes lack sufficient selectivity for G4 RNA over G4 DNA and other non-G4 secondary structures in live-cell competitive environments. Second, fluorescence intensity-based imaging cannot detect subtle changes in G4 RNA because of variations in fluorophore uptake and photobleaching. Herein, we report a novel thiazole orange derivative (TOGR) for fluorescence lifetime imaging of G4 RNA in living cells. Structural modifications of thiazole orange enhance RNA-binding affinity and G4 selectivity. TOGR exhibits a unique fluorescence lifetime when bound to G4 structures, enabling sensitive detection of G4 formation independent of local probe concentration via FLIM. FLIM imaging reveals that TOGR primarily colocalizes with RNA in the cytoplasm and nucleoli. Due to its preferential RNA-binding affinity in competitive cellular environments, TOGR enables selective monitoring of G4 RNA dynamics, facilitating the exploration of novel roles of G4 RNA in cells without interference from G4 DNA. Importantly, the dynamic behavior of G4 RNA during Alzheimer's disease pathology and the effects of glucocorticoids on G4 RNA dynamics were successfully revealed using this lifetime-sensitive and RNA-selective imaging probe. This research not only paves the way for advanced probe design for detailed G4 RNA imaging but also lays the foundation for exploring G4 RNA-related pathological mechanisms in Alzheimer's disease.},
}
@article {pmid42508318,
year = {2026},
author = {Christifano, DN and Kelly, E and Sands, SA and Honea, RA and Morris, JK and Burns, JM and Taylor, MK},
title = {Omega-3 fatty acids and Alzheimer's disease-related brain biomarkers in older adults enriched for preclinical Alzheimer's disease.},
journal = {Prostaglandins, leukotrienes, and essential fatty acids},
volume = {210},
number = {},
pages = {102762},
doi = {10.1016/j.plefa.2026.102762},
pmid = {42508318},
issn = {1532-2823},
abstract = {BACKGROUND: Preclinical and limited human data suggest long-chain omega-3 fatty acids, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), may be protective of brain volume and amyloid-beta (Aβ) accumulation, hallmarks of Alzheimer's disease (AD), which may be modulated by Apolipoprotein E ε4 (APOE4) carriage.<br><br>METHODS: This cross-sectional study was conducted using baseline data from a clinical trial at the University of Kansas Medical Center that included cognitively normal older adults, enriched for preclinical AD. We investigated serum DHA+EPA's (% total triacylglycerol fatty acids) relationship with MRI-derived gray matter volume and PET-derived A&#x3b2; burden (Florbetapir F18) overall and by APOE4 carriage status.<br><br>RESULTS: Among all participants (n = 104, 67.3% female, 69.2% preclinical AD, 44.2% APOE4), higher DHA+EPA was related to larger gray matter volume in a left precuneus/postcentral gyrus cluster, with similar relationships between APOE4 carriers and non-carriers. Higher DHA+EPA was also related to lower brain A&#x3b2; in the frontoparietal cortex, bilaterally. In APOE sensitivity analyses, higher DHA+EPA was related to lower global and AD-related regional brain A&#x3b2; among APOE4 carriers .<br><br>CONCLUSIONS: Higher DHA+EPA was associated with larger gray matter volume and lower A&#x3b2; in AD-susceptible regions, especially among APOE4 carriers. These findings are consistent with the hypothesis that omega-3 fatty acids influence brain volume and A&#x3b2;. Well-designed DHA+EPA supplementation RCTs are needed as DHA supplementation RCTs have inconsistently impacted brain volume and no RCTs investigating the impact of omega-3 on brain A&#x3b2; have been reported.<br><br>TRIAL REGISTRATION: NCT02000583 (https://clinicaltrials.gov/study/NCT02000583?term=NCT02000583&amp;viewType=Card&amp;rank=1) registered on November 26, 2013.},
}
@article {pmid42508388,
year = {2026},
author = {Gilson, KM and Higueras, AF and Walters, WM and Sanchez-Molano, J and Almeida, VW and Zeier, Z and Dietrich, WD and Bramlett, HM and Kerr, NA},
title = {Intestinal Organoids from Alzheimer's Disease Transgenic Mice Reveal Structural and Molecular Gut Pathology.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.0233},
pmid = {42508388},
issn = {2152-5250},
abstract = {Alzheimer's disease (AD) is the most common form of dementia, and early alterations in the gut may contribute to disease progression. The current study focused on generating intestinal organoids from 3xTg-AD transgenic and Wild Type (WT) mice to investigate the role of the gut-brain axis in AD. Intestinal organoid cultures were produced through isolation of leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5+) crypt cells from 4-5-month-old or 1-year-old intestinal tissue. Transmission electron microscopy (TEM) analysis of aged 3xTg organoids demonstrated evidence of impaired gut epithelial viability compared to WT controls. In aged 3xTg organoids, enlarged intercellular spaces, disrupted cell adhesions, diminished tight junction complexes, cellular debris, and amyloid-like fibrils were prominent findings. Immunostaining also demonstrated decreased E-Cadherin and ZO1 expression, along with increased cellular and luminal Aβ in aged 3xTg organoids compared to young 3xTg and WT organoids and p-tau protein accumulation in aged 3xTg organoids compared to all other experimental groups. In the aged 3xTg cohort, increased immunoreactivity of inflammasome components, including IL-1β, ASC, and GSDMD, implicated pyroptosis as a potential mechanism of cell death. These results support the hypothesis that familial AD pathology includes pronounced effects on gut organoid viability, junctional integrity, and abnormal protein accumulation within the intestinal epithelium. This study provides early evidence of gut organoid abnormalities occurring independently of alterations in the AD brain. These findings suggest that the gut epithelium may warrant further investigation as a potential target for future therapeutic strategies in AD.},
}
@article {pmid42508391,
year = {2026},
author = {Gao, W and Lee, HY and Min, KJ},
title = {Aging-Related Metaflammation and Mitochondrial Dysfunction in Neurodegenerative Diseases.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.0366},
pmid = {42508391},
issn = {2152-5250},
abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are increasingly recognized as manifestations of aging-associated systemic dysfunction, rather than isolated brain disorders. Central to this dysfunction is the interplay among metaflammation, mitochondrial breakdown, and chronic neuroinflammation. Metaflammation, driven by peripheral metabolic stress, may prime the brain's immune environment through cytokine signaling and blood-brain barrier compromise. This metabolic-inflammatory crosstalk is thought to impair mitochondrial integrity in neurons and glial cells, promoting oxidative stress and the release of pro-inflammatory mitochondrial components. These mitochondrial signals, in turn, may activate microglial and astrocytic innate immune responses, creating a potentially self-reinforcing cycle of neuroinflammation and energy failure that may contribute to neuronal loss. This review outlines a proposed framework linking metaflammation to neurodegeneration, emphasizing shared mechanisms across AD, PD, and ALS. We further examine preclinical and clinical advances in therapeutic strategies that target this axis including anti-inflammatory agents, caloric restriction, mitophagy enhancers, mitochondrial antioxidants, and senescence-targeted therapies. Together, these interventions reflect a shift from symptom management to systemic metabolic and immune modulation, offering a unified framework for understanding and potentially influencing age-related neurodegeneration.},
}
@article {pmid42508392,
year = {2026},
author = {Kumar, V and Jang, S and Choi, Y and Kim, S and Nam, Y and You, M and Moon, M},
title = {Targeting the Microbiota-Butyrate-BHB Axis As a Potential Metabolic Therapeutic Strategy for Alzheimer's Disease.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.0606},
pmid = {42508392},
issn = {2152-5250},
abstract = {Alzheimer's disease (AD) is increasingly linked to metabolic and microbial dysregulations, with butyrate and β-hydroxybutyrate (BHB) identified as key modulators. BHB is a ketone body primarily produced by the liver during periods of low glucose availability, and BHB levels are reduced in the AD brain and peripheral blood. Butyrate, a microbiota-derived short-chain fatty acid, is also reduced in the peripheral blood in association with gut microbiota dysbiosis. The reduction of butyrate and BHB, together with gut microbiota dysbiosis, is commonly observed in AD patients and correlates with cognitive decline and AD-related pathologies. Reduced levels of butyrate and BHB may impair energy metabolism, exacerbating amyloid-beta (Aβ) and tau pathologies. In contrast, preliminary evidence from interventional and ketogenic studies suggests that increasing butyrate and BHB levels may attenuate AD-related pathologies, such as Aβ and tau abnormalities, while improving cognitive function. Emerging evidence suggests that both butyrate and BHB can cross the blood-brain barrier (BBB), suppressing oxidative stress and pro-inflammatory cytokines and potentially mitigating Aβ aggregation and tau hyperphosphorylation. Accordingly, therapeutic strategies targeting the microbiota-butyrate-BHB axis represent a promising and biologically plausible approach that warrants further rigorous clinical investigation for the prevention and treatment of AD. This review comprehensively examines the roles of butyrate and BHB in ameliorating key AD-related pathologies, including Aβ aggregation, tau hyperphosphorylation, neuroinflammation, and neurodegeneration. Additionally, the review explores the bidirectional association between butyrate/BHB and gut dysbiosis in AD, including how dysbiosis reduces butyrate/BHB levels while elevating them may reverse dysbiosis and improve gut-brain axis function. Collectively, these findings suggest that butyrate and BHB emerge as promising candidates for potential novel adjunctive therapies for AD, although supporting human evidence remains preliminary and heterogeneous.},
}
@article {pmid42508514,
year = {2026},
author = {Shang, Y and Zhai, Z and Cong, L and Dong, X},
title = {Corrigendum to 'Targeting the APOE4-driven peripheral-central immune axis: A new frontier for Alzheimer's disease therapy' [Pharmacological Research (2026), YPHRS_108339].},
journal = {Pharmacological research},
volume = {},
number = {},
pages = {108355},
doi = {10.1016/j.phrs.2026.108355},
pmid = {42508514},
issn = {1096-1186},
}
@article {pmid42508529,
year = {2026},
author = {Chatterjee, A and Singh, TG and Singh, S and Kaur, A and Vishwas, S},
title = {Interplay between RNA m[6]A modification and transglutaminase 2 inhibitor effects on mitophagy dysfunction in Alzheimer's disease.},
journal = {Drug discovery today},
volume = {},
number = {},
pages = {104748},
doi = {10.1016/j.drudis.2026.104748},
pmid = {42508529},
issn = {1878-5832},
abstract = {Alzheimer's disease (AD) involves amyloid-β aggregation, tau hyperphosphorylation and mitochondrial dysfunction with defective mitophagy. Emerging evidence implicates RNA N6-methyladenosine (m[6]A) modification and transglutaminase 2 (TG2) as critical regulators of mitochondrial quality control in AD. Downregulation of METTL3/METTL14 and upregulation of fat mass and obesity-associated protein reduce m[6]A methylation, impair PTEN-induced putative kinase 1/Parkinson protein 2-mediated mitophagy and promote reactive oxygen species accumulation and synaptic loss. Conversely, TG2 overexpression exacerbates mitochondrial stress by crosslinking Aβ and tau, disturbing dynamin-related protein 1- and mitochondrial fission 1 protein-mediated dynamics and suppressing mitophagy. Crosstalk between TG2-induced oxidative stress and m[6]A dysregulation amplifies neuronal damage. Pharmacological modulation, using TG2 inhibitors (e.g. Z-DON) and m[6]A enhancers (e.g. METTL3 overexpression), restores mitophagic flux and mitigates pathology in preclinical models, suggesting dual m[6]A-TG2 targeting as a promising disease-modifying approach in AD.},
}
@article {pmid42508631,
year = {2026},
author = {Alanazi, SM and Al-Kuraishy, HM and Alexiou, A and Papadakis, M and Faheem, SA and Batiha, GE},
title = {Isoform-selective HSP90 inhibition as a precision therapeutic strategy for neurodegenerative and metabolic diseases.},
journal = {Progress in neuro-psychopharmacology &amp; biological psychiatry},
volume = {149},
number = {},
pages = {111834},
doi = {10.1016/j.pnpbp.2026.111834},
pmid = {42508631},
issn = {1878-4216},
abstract = {Heat shock protein 90 (HSP90) is a central regulator of cellular proteostasis, coordinating the folding, stabilization, and turnover of a wide range of client proteins in the cytosol, endoplasmic reticulum, and mitochondria. Accumulating evidence indicates that the four HSP90 paralogs HSP90α, HSP90β, GRP94, and TRAP1 have distinct pathological roles in neurodegenerative and metabolic diseases. In neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, aberrant HSP90 activity contributes to the persistence of toxic protein conformers, defective autophagy, mitochondrial dysfunction, and chronic neuroinflammation. In metabolic disorders such as obesity, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease, GRP94- and TRAP1-dependent signaling promotes endoplasmic reticulum stress, impaired mitochondrial metabolism, insulin resistance, and inflammatory remodeling. These mechanistic insights have accelerated the development of a new generation of HSP90 inhibitors with improved selectivity, tissue targeting, and brain penetration. Unlike earlier pan-HSP90 inhibitors, these compounds are designed to exploit paralog-specific vulnerabilities and may enable safer long-term modulation of disease-relevant chaperone networks. This review summarizes current advances in the biology and pharmacology of HSP90 paralogs and proposes isoform-selective HSP90 targeting as a promising therapeutic strategy at the intersection of neurodegeneration and metabolic dysfunction.},
}
@article {pmid42508695,
year = {2026},
author = {Azimzadeh, M and Azimzadeh, M},
title = {From Gut Microbiota to Synaptic Plasticity: Mechanisms Shaping Cognitive Function and Brain Disorders.},
journal = {Behavioural brain research},
volume = {},
number = {},
pages = {116404},
doi = {10.1016/j.bbr.2026.116404},
pmid = {42508695},
issn = {1872-7549},
abstract = {The gut microbiota has emerged as a key regulator of central nervous system development and function. Accumulating experimental and clinical evidence demonstrates that microbial signals influence brain activity through integrated neural, immune, neuroendocrine, and metabolic pathways. These pathways converge on core mechanisms of synaptic plasticity, including neurotrophic signaling, glutamatergic transmission, dendritic remodeling, and adult neurogenesis, thereby shaping learning, memory, executive function, and emotional regulation. Disruption of microbiota-brain communication is implicated in a range of neurodevelopmental and neurodegenerative disorders, including autism spectrum disorder (ASD), major depressive disorder (MDD), Alzheimer's disease (AD), and Parkinson's disease (PD), suggesting shared systems-level vulnerabilities across conditions and highlighting the translational potential of microbiota-targeted interventions such as probiotics, dietary modulation, postbiotics, and precision microbiome-based strategies. Overall, the gut microbiota functions as a dynamic regulator of brain plasticity and cognitive resilience across the lifespan. Future progress will require identification of causal mechanisms at the level of specific microbial metabolites, neural circuits, and developmental windows using integrated multi-omics and spatially resolved approaches, alongside translation into targeted therapeutic strategies.},
}
@article {pmid42508744,
year = {2026},
author = {Datta, D and Arnsten, A and Sukoff Rizzo, SJ and Silva, AC and Joyce, MK and Tripathy, SJ and Roberts, A and Lewis, DA},
title = {Dorsolateral prefrontal cortex circuitry at the intersection of cognition and disease.},
journal = {Biological psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.biopsych.2026.07.012},
pmid = {42508744},
issn = {1873-2402},
abstract = {Schizophrenia, major depressive disorder (MDD), and Alzheimer's disease (AD) involve dysfunction of distributed cortical-subcortical networks that support complex cognitive processes and emotion regulation. Convergent evidence identifies the dorsolateral prefrontal cortex (dlPFC) as a critical site of molecular, cellular, and circuitry alterations in these disorders. The primate dlPFC contains recurrent, excitatory microcircuits in layer III that sustain working memory and top-down control through specialized forms of neurotransmission and intracellular signaling. Specifically, NMDA receptor and cholinergic modulation, as well as tightly regulated calcium-cAMP signaling within dendritic spines, support task-specific firing of layer III pyramidal neurons, but may also increase vulnerability to genetic risk, stress, inflammation and aging. This review integrates findings from human postmortem studies, neuroimaging, and genetics to examine how dlPFC circuitry is altered in these disease states. In schizophrenia, layer III pyramidal neurons exhibit altered synaptic and cytoskeletal signaling, lower dendritic spine density, and compensatory shifts in inhibitory inputs that likely weaken recurrent excitation and network synchrony. In MDD, dysfunction of dlPFC pathways regulating subgenual cingulate cortex contributes to impaired top-down control of emotion and motivation. In AD and frontotemporal lobar degeneration, tau pathology and neurodegeneration target association cortices, including layer III dlPFC circuits, contributing to progressive cognitive decline and impaired executive function. The review also highlights how studies in rhesus macaques and genetically engineered marmosets have provided important insight into the organization, physiology, and disease vulnerability of primate dlPFC circuits. Together, these findings inform the development of emerging therapeutic strategies aimed at strengthening prefrontal network function.},
}
@article {pmid42508750,
year = {2026},
author = {Zhang, X and Zhuang, D and Lai, C and Zheng, C and Soh, ZD and Wagner, S and Cai, VY and Yang, Z and Wang, S and Geng, X and Wang, Z and Feng, S and Qu, Y and Wang, L and Tang, S and Mok, VCT and Cheung, C and Chen, C and Zhu, Z and Cheng, CY and Yu, H},
title = {Retinal Manifestations of Alzheimer's Disease: Insights from Animal Models, Clinical Detection, and Future Translation.},
journal = {Progress in retinal and eye research},
volume = {},
number = {},
pages = {101504},
doi = {10.1016/j.preteyeres.2026.101504},
pmid = {42508750},
issn = {1873-1635},
abstract = {The retina, as an extension of the central nervous system, shares a common embryological origin with the brain. In Alzheimer's disease (AD), studies of human tissue and animal models have revealed that hallmark AD pathologies, including amyloid-β (Aβ) deposits and pathological tau protein tangles, also appear in the retina. These findings, coupled with advances in high-resolution retinal imaging techniques, suggest the potential to detect and characterize AD-related molecular and structural changes in the retina. However, retinal findings across different AD mouse models have significant discrepancies and show limited concordance with human phenotypes, complicating the identification of AD-specific alterations and the selection of optimal models for translational research. Moreover, the temporal sequence and functional significance of retinal abnormalities across the AD continuum, from preclinical stages to mild cognitive impairment and overt dementia, remain poorly defined. Addressing these knowledge gaps is essential to establish the retina as a reliable, non-invasive screening and monitoring approach. This review synthesizes current evidence on the spectrum of retinal alterations in AD, including vascular dysfunction, neuroinflammation, impaired Aβ clearance, and neurodegeneration, as observed in diverse mouse models. We compare these manifestations across species and between different models, highlighting findings along the disease continuum to delineate convergent and divergent pathways. We further discuss how emerging technologies enable the identification of AD-specific retinal alterations, and advocate for a paradigm shift from non-specific morphological assessment ("seeing shapes") toward molecular-level interrogation ("seeing components"). Interdisciplinary efforts and technological integration are crucial to establish retina as a dynamic mirror of pathology in AD.},
}
@article {pmid42508872,
year = {2026},
author = {Zhou, K and Cohn, M and Novik, R and Batur, P and Just, C},
title = {Menopause and Brain Health: Neurobiological Changes, Cognitive Implications, and the Role of Estrogen.},
journal = {Obstetrics and gynecology clinics of North America},
volume = {53},
number = {3},
pages = {449-461},
doi = {10.1016/j.ogc.2026.04.001},
pmid = {42508872},
issn = {1558-0474},
abstract = {The menopausal transition is characterized by significant hormonal fluctuations, culminating in a decline in estrogen levels. This decline impacts synaptic plasticity, neurotransmitter regulation, the blood brain barrier, cerebral blood flow, and metabolism, leading to cognitive symptoms often described as brain fog. Menopause-related cognitive changes, often transient, differ from the progressive decline seen in Alzheimer's Disease (AD). Research continues to explore estrogen's role in AD risk, but current evidence does not support using exogenous estrogen solely for dementia prevention. Hormone therapy can help manage menopausal symptoms and should be personalized based on factors like age, timing, and overall brain health.},
}
@article {pmid42508906,
year = {2026},
author = {de Souza, ID and Queiroz, MEC and Pichon, V and Combès, A},
title = {Online aptamer-based solid-phase extraction coupled with high-performance liquid chromatography-mass spectrometry for the determination of Alzheimer's disease biomarkers.},
journal = {Analytica chimica acta},
volume = {1417},
number = {},
pages = {345809},
doi = {10.1016/j.aca.2026.345809},
pmid = {42508906},
issn = {1873-4324},
abstract = {BACKGROUND: Reliable quantification of amyloid-β (Aβ) peptides in biological fluids is of major clinical and research interest in Alzheimer disease context. Conventional offline extraction approaches often involve labor-intensive manual steps and high solvent consumption, limiting throughput routine applications, reproducibility, and sustainability. To address these limitations, this study reports the development of an online coupling between a monolithic oligosorbent (mOS) in capillary and high-performance liquid chromatography-mass spectrometry (HPLC-MS) method for selective Aβ peptide analysis.<br><br>RESULTS: A mOS was incorporated online in a set up including a C18 trap column coupled with an HPLC-MS analytical system. Systematic optimization of mOS loading/elution conditions, trapping column desalting/preconcentration, and chromatographic mobile phase composition enabled efficient retention, transfer, and separation of A&#x3b2;40 and A&#x3b2;42 in a fully automated method. This method achieved lower limits of quantification down to 0.03 ng mL[-1] with good precision and accuracy (CV ranging from 1.1 to 6.2% for A&#x3b2;40 and from 4.3 to 10.9% for A&#x3b2;42). Comparative evaluation of offline and online extraction using the same mOS capillary demonstrated improved reproducibility and enhanced sensitivity for the online configuration. The method's applicability to a controlled CSF-like matrix was demonstrated using artificial cerebrospinal fluid (aCSF) diluted 1:2 (v/v) in binding buffer (BB), yielding recoveries of 60% for A&#x3b2;40 and 34% for A&#x3b2;42.<br><br>SIGNIFICANCE: The online coupling of the mOS capillary with HPLC-MS also represents a strategic advance toward environmentally responsible bioanalysis. Indeed, the superior AGREEprep score (0.7) for the online configuration compared to offline mode (0.59), underscores its alignment with green analytical chemistry principles, reflecting reductions in solvent use, manual intervention, and overall environmental burden.},
}
@article {pmid42509195,
year = {2026},
author = {Reichert, L and Delparente, A and Hipfinger, IR and Reininger, L and Castro, AP and Hubin, DJ and Schibli, R and Fraley, AE and Mu, L},
title = {Identification of Pyrazolidine-3-One Derivatives as a Novel Structural Scaffold for ATP Synthase Inhibitors.},
journal = {ChemMedChem},
volume = {21},
number = {14},
pages = {e70399},
pmid = {42509195},
issn = {1860-7187},
support = {205321_192409/1//Swiss National Fundation/ ; #22A047//Novartis Stiftung f&#xfc;r Medizinisch-Biologische Forschung/ ; },
abstract = {In a recent study, the oxadiazin-5-one-based compound CJ1-34 was identified as a partial ATP synthase inhibitor, which was found to bind the F1 region of the ATP synthase. These findings were used as a starting point for the design and synthesis of smaller heterocycles, such as pyrazolidine-3-ones and pyrazol-3-ones, as novel structural scaffolds for potential ATP synthase inhibitors. Among the newly synthesized compounds, pyrazolidin-3-one derivatives 9a and 10a outperformed the lead compound CJ1-34 in vitro by inhibiting ATP hydrolytic activity and decreasing ATP levels in HT-22 cells. Subsequent dose-dependent studies identified compound 9a as the most promising ATP synthase inhibitor. Molecular docking revealed similar binding modes for all compounds in the F1-binding site and the calculated docking scores aligned with the measured IC50 values of the tested compounds. This study identified pyrazolidine-3-ones as promising structural scaffolds for ATP synthase inhibition, opening avenues for further biomedical applications in central nervous system diseases such as Alzheimer's and Parkinson's.},
}
@article {pmid42509403,
year = {2026},
author = {Anand, A and Sania, A and Singh, SK and Bajad, N},
title = {Targeting Histone Deacetylase 2 in Alzheimer's Disease: From Molecular Insights to Epigenetic Therapeutic Opportunities.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42509403},
issn = {1559-1182},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder that leads to cognitive impairment, memory loss, and nerve cell dysfunction. Despite substantial research efforts, effective AD therapies remain limited. Histone deacetylase 2 (HDAC2) is a principal epigenetic regulator that is essential for controlling gene expression and neuronal connectivity. Recently, HDAC2 has attracted significant attention as a potential therapeutic target in AD owing to its involvement in key disease hallmarks, including neuroinflammation, Aβ accumulation, and abnormal tau phosphorylation. We have outlined and discussed the molecular insights into HDAC2 in AD and its recently emerged inhibitors. Inhibiting HDAC2 has demonstrated potential in lowering neuroinflammatory signalling and reestablishing synaptic and neuroprotective gene expression patterns in preclinical AD models. Current preclinical evidence indicates that HDAC2 may play a significant role in AD development and may represent a target for therapeutic intervention. Recent progress in HDAC2 inhibitor development offers a rationale for this approach, although further mechanistic and clinical investigations are required. Resolving the precise roles of HDAC2 dysregulation in AD and determining the utility of combination strategies remain important priorities. Whether HDAC2-targeted inhibitors can yield disease-modifying benefits in AD remains to be demonstrated in clinical studies.},
}
@article {pmid42509523,
year = {2026},
author = {Neller, SA and Fernandez Cajavilca, M and Wong, B and Johnson, J and Ellington, L and Eaton, J},
title = {Identifying and Mapping Levels of Active Engagement Within an Arts-Based Intervention: A Qualitative Analysis and Conceptual Development.},
journal = {International journal of behavioral medicine},
volume = {},
number = {},
pages = {},
pmid = {42509523},
issn = {1532-7558},
abstract = {BACKGROUND: Active engagement is crucial in psychoeducational interventions for care partners of persons living with dementia, yet measurement is limited. This manuscript explores participant engagement in an arts-based intervention designed to increase engagement in addressing dementia-related behavioral symptoms. The intervention uses multisensory activities, including caregiver-informed vignettes, to foster engagement and process caregiving experiences.<br><br>METHODS: Care partners of persons living with dementia (n&#x2009;=&#x2009;9) participated in six focus groups. Focus group data were analyzed using process coding to define and map patterns of active engagement across 27 intervention activities. The findings informed development of a conceptual model of active engagement.<br><br>RESULTS: Four levels of engagement were identified-Participating, Clarifying, Contributing, and Applying-and explored across participants, time points, and activities. The conceptual model illustrates that (1) antecedents contribute to (2) levels of engagement, leading to (3) the intervention's hypothesized mechanisms of action, proximal outcomes (capacity to adapt, appraisal of caregiving demands), and distal outcomes (perceived stress, caregiver well-being).<br><br>CONCLUSION: This manuscript provides a clear framework for operationalizing and measuring active engagement and demonstrates how engagement patterns can be conceptually linked to the intervention's proposed mechanisms of action and outcomes. These findings provide transparency in reporting engagement patterns within an intervention, offering valuable insight into the components of active engagement and how these may be measured. The ability to track active engagement during intervention development and testing has the potential to improve our understanding of intervention dose and fidelity and how active engagement interacts with these to improve outcomes for participants.},
}
@article {pmid42509652,
year = {2026},
author = {Mielke, MM and Gaussoin, SA and Casanova, R and Latham, LA and Manson, JE and Mouton, CP and Ng, TKS and Rapp, SR and Resnick, SM and Sachs, BC and Saquib, N and Shadyab, AH and McEvoy, LK and LaCroix, AZ and Wallace, RB and Espeland, MA and Chen, JC and Hayden, KM},
title = {Alzheimer's blood-based biomarkers, incident dementia, and interactions with age, APOE status, and hormone therapy.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71704},
doi = {10.1002/alz.71704},
pmid = {42509652},
issn = {1552-5279},
support = {/AG/NIA NIH HHS/United States ; /HL/NHLBI NIH HHS/United States ; /NH/NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; 75N92021D00002/HL/NHLBI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; },
abstract = {INTRODUCTION: Cognitive impairment among older adults is often due to multiple pathologies and heterogenous risk factors. We assessed whether Alzheimer's blood-based biomarkers (BBMs) were associated with incident mild cognitive impairment (MCI)/probable dementia, and whether associations were modified by age, apolipoprotein E (APOE), and hormone therapy (HT).<br><br>METHODS: Analyses included 2467 Women's Health Initiative Memory Study women (&#x2265;65 years of age) randomized between 1995 and 1998 to 3-5-years of HT or placebo. Cox regression (mean 18-year follow-up) assessed associations between the z-scored BBMs and MCI/dementia.<br><br>RESULTS: Lower baseline amyloid beta (A&#x3b2;)42/40 ratio and higher phosphorylated tau 181 (p-tau181), glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) were associated with an increased risk of MCI and dementia; GFAP was most strongly associated. The p-tau181 and NfL associations were stronger among APOE &#x3b5;4 carriers; BBMs varied non-linearly by age. The associations of BBMs with the cognitive outcomes also varied inconsistently between HT groups.<br><br>DISCUSSION: BBMs for AD and related dementias (ADRD) are associated with incident MCI/dementia in older women. Interactions between the BBMs and HT were inconsistent and require further investigation.},
}
@article {pmid42509698,
year = {2026},
author = {Wang, X and Li, J and Wei, Z and Rong, C and Zhao, D and Wang, Y},
title = {Integrating Multi-Omics and Mendelian Randomization Reveals the Role of Epstein-Barr Virus Infection in Alzheimer's Disease and the Therapeutic Potential of Resveratrol.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050463115260708111634},
pmid = {42509698},
issn = {1875-5828},
abstract = {INTRODUCTION: The pathogenesis of Alzheimer's disease (AD) is complex, with immune system dysregulation playing a critical role. However, the specific molecular mechanisms linking peripheral immune responses to central pathologies in AD remain unclear. This study aims to systematically screen for reliable plasma biomarkers of AD by integrating transcriptomics, Mendelian randomization (MR) of plasma proteomics, and bioinformatics analyses, and to explore their potential pathogenic mechanisms and therapeutic drugs.<br><br>MATERIALS AND METHODS: Transcriptomic sequencing of plasma samples from three AD patients and three healthy controls was first performed to identify differentially expressed genes (DEGs) and perform functional enrichment analyses. The aim of this study is to provide a preliminary indication of gene expression changes based on real patient samples for subsequent MR and bioinformatics analyses, rather than serving as confirmatory evidence. Following this, two-sample MR was performed to explore the potential causal relationship between plasma proteins and AD in genetic prediction, and MR-positive results were intersected with transcriptome DEGs to identify highconfidence targets. After that, protein-protein interaction (PPI) analysis, functional enrichment (GO/KEGG), and transcription factor (TF) target network analysis were conducted. Based on the KEGG pathway analysis, the causal association between antibodies related to Epstein-Barr virus and AD in genetic prediction was further evaluated. In the end, the diagnostic power of core biomarkers was validated in the GEO dataset. Potential therapeutic drugs were screened in the CTD database, followed by verification through molecular docking and molecular dynamics simulation.<br><br>RESULT: Our transcriptomic enrichment analysis of DEGs indicates that AD is significantly correlated with viral infection and immune and inflammatory pathways. According to the results of MR analyses, 36 plasma proteins have a causal effect on AD in genetic prediction. Among these 36 targets, two pathways are identified as enriched: "EBV Infection" and "Efferocytosis". Seven core targets are CR2, ICAM1, TAPBP, TNFAIP3, THBS1, SCARF1, and SIRPG. Also, the concentration of antibodies against EBV EBNA-1 and VCA p18 was confirmed by MR analyses to be risk factors for AD. According to drug predictions, molecular docking, and molecular dynamics simulations, resveratrol can stabilize CR2.<br><br>DISCUSSION: This study systematically identifies major plasma immune biomarkers associated with AD and proposes a mechanism by which EBV infection regulates plasma proteins CR2, TNFAIP3, and THBS1, which may affect AD risk. Resveratrol is thought to have preventive and protective effects, as predicted computationally.<br><br>CONCLUSION: This study systematically identified key plasma markers associated with AD. Resveratrol is likely to become a potentially effective preventive and protective drug in the prevention and treatment of AD, providing new ideas and targets for immune intervention of AD.},
}
@article {pmid42509699,
year = {2026},
author = {Barczak, A and Krempa-Kowalewska, A and Golan, M},
title = {Cognitive Profiles in Early- and Late-Onset Alzheimer's Disease: The Role of Dementia Severity in Typical Amnestic Presentations Using the Addenbrooke's Cognitive Examination III.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050489392260702044957},
pmid = {42509699},
issn = {1875-5828},
abstract = {INTRODUCTION: Early-Onset (EOAD) and Late-Onset Alzheimer's Disease (LOAD) are often described as presenting distinct cognitive phenotypes. However, reported differences are inconsistent and may reflect demographic and severity-related confounding rather than stable etiological distinctions.<br><br>MATERIALS AND METHODS: A retrospective analysis was conducted in 776 patients with clinically diagnosed Alzheimer's disease (EOAD, n = 175; LOAD, n = 601). Cognitive performance was assessed using the Addenbrooke's Cognitive Examination III (ACE-III) and the Mini-Mental State Examination (MMSE). Dementia severity was staged using the Functional Assessment Staging Tool (FAST). Cognitive outcomes were analysed using age- and severity-adjusted ANCOVA models including a diagnosis &#xd7; age interaction. Severity-stratified and domain-level analyses were also performed.<br><br>RESULTS: Unadjusted analyses revealed limited EOAD-LOAD differences in the Attention and Visuospatial domains, with small effect sizes. After adjustment for demographic variables and dementia severity, no cognitive measure reliably differentiated EOAD from LOAD. Cognitive performance showed similar cross-sectional patterns across groups and was primarily determined by dementia severity.<br><br>DISCUSSION: Small, stage-dependent differences observed at mild and moderate stages did not persist in more advanced dementia and did not indicate stable cognitive dissociation between EOAD and LOAD.<br><br>CONCLUSIONS: After adjustment for demographic factors and dementia severity, EOAD and LOAD do not exhibit distinct cognitive profiles on ACE-III. Cognitive performance reflects disease stage rather than age at onset, supporting the use of ACE-III for staging cognitive impairment rather than for differentiating EOAD from LOAD in typical amnestic presentations.},
}
@article {pmid42509706,
year = {2026},
author = {Shen, Z and Cheng, J and Wang, L and Hou, Q},
title = {Molecular Mechanisms and Therapeutic Strategies in Parkinson's Disease: From Pathogenic Signaling to Drug Development.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X457429260706102249},
pmid = {42509706},
issn = {1875-6190},
abstract = {Parkinson's Disease (PD) is the second most common neurodegenerative disease after Alzheimer's Disease (AD), yet no effective disease-modifying therapy is currently available. Its pathogenesis is highly complex, involving multiple interacting pathological processes, which poses substantial challenges for therapeutic intervention. Moreover, PD often has a prolonged prodromal phase and lacks sufficiently sensitive and specific diagnostic methods for early-stage detection, further limiting timely identification and treatment. Current pharmacological therapies mainly provide symptomatic relief, but their long-term use is frequently associated with reduced efficacy and motor complications. Therefore, the development of novel therapeutic strategies and potential disease-modifying agents remains an urgent priority. This review systematically summarizes the molecular mechanisms and biomarkers associated with PD, outlines current symptomatic treatments, and discusses emerging therapeutic candidates in clinical development, with particular emphasis on disease-modifying strategies. By integrating pathogenic mechanisms, diagnostic advances, and therapeutic progress, this review aims to provide a comprehensive perspective to support the development of more effective interventions for PD.},
}
@article {pmid42509708,
year = {2026},
author = {Liu, Y and Zhang, Y and Zheng, W and Shi, X and Yao, W and Zhang, J and Bai, F},
title = {Cortico-white Matter Functional Coupling as a Biomarker of Alzheimer's Disease Progression and rTMS Therapeutic Efficacy.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X470892260706231913},
pmid = {42509708},
issn = {1875-6190},
abstract = {INTRODUCTION: Alzheimer's disease (AD) spectrum disorders are characterized by progressive cognitive decline, with white matter degeneration and disrupted cortico-cortical connectivity as early features. Cortico-white matter functional coupling integrates neuronal activity with axonal conduction, yet its natural trajectory across the AD spectrum and ability to be modulated by repetitive transcranial magnetic stimulation (rTMS) remain unclear.<br><br>METHODS: Longitudinal resting-state fMRI from the ADNI cohort (n = 160: 59 cognitively normal, CN; 65 mild cognitive impairment, MCI; 36 AD) was used to assess baseline and 1-year changes in mean Fisher's z-transformed coupling between 82 cortical seeds (AAL-90 atlas, excluding subcortical nuclei) and a probabilistic group white matter mask. Specifically, 54 patients with amnestic MCI (aMCI) from the rTMS cohort were allocated to active (n = 40) or sham (n = 14) groups and received four weeks of neuronavigated rTMS targeting the left angular gyrus. Cortico-white matter functional coupling was calculated identically in both cohorts. Changes in coupling strength and their associations with changes in neuropsychological performance were examined across all cortical seeds.<br><br>RESULTS: At baseline, mean cortico-white matter functional coupling followed a nonlinear pattern (MCI > AD and CN). One-year follow-up revealed that the CN group exhibited a slight decrease in coupling, and the MCI and AD groups showed a pathological increase. Compared with the sham group, active rTMS significantly attenuated this increase in coupling. After adjusting for covariates, coupling changes were strongly correlated with cognitive decline. The AD group demonstrated the most significant associations (n = 104), whereas the active rTMS group showed 71 associations, predominantly linked to objective memory improvement.<br><br>DISCUSSION: This abnormal overcoupling, leading to compensation and decompensation, is associated with the progression of Alzheimer's disease. rTMS effectively moderates this pathological surge by enhancing neural efficiency and stabilizing large-scale network integration. Our findings position cortico-white matter functional coupling as an effective indicator of disease intensity and a measurable link in the chain of rTMS effectiveness for early-stage AD.<br><br>CONCLUSION: Overall, cortico-white matter functional coupling may serve as a novel scan-based biomarker for tracking AD progression and evaluating rTMS treatment efficacy in patients with MCI.},
}
@article {pmid42509738,
year = {2026},
author = {Wali, Z and Neha, and Shahwan, M and Dinislam, K and Shamsi, A and Anwar, S},
title = {Network Biology of Alzheimer's Disease and Related Neurodegenerative Disorders: Molecular Mechanisms and Therapeutic Strategies.},
journal = {Biomolecules},
volume = {16},
number = {7},
pages = {},
doi = {10.3390/biom16070944},
pmid = {42509738},
issn = {2218-273X},
support = {NA//Ajman University/ ; },
abstract = {The most persistent biomedical challenges of the 21st century are neurodegenerative disorders (NDs), where molecular alterations lead to devastating clinical consequences and progressive neuronal loss. The prevalence of neurodegeneration is continuously rising and becoming the main contributor to chronic disability and mortality. Despite their clinical differences, many conditions share pathogenic processes, including oxidative stress, protein misfolding and aggregation, mitochondrial dysfunction, and neuroinflammation. Instead of functioning independently, these processes cooperate to form a self-reinforcing network that gradually weakens synapses and ultimately leads to neuronal death. This study redefines neurodegeneration as a disorder of system-level failure by emphasizing poor cellular stress integration. In addition to demonstrating how gut microbiome gene networks impact inflammation and amyloid production, new research highlights the relationships between mitochondrial-lysosomal interactions, endoplasmic reticulum stress responses, and transcriptionally driven synaptic vulnerability. A key molecular topic is the interaction and pathogenic convergence of the JAK/STAT, HIF-1α, and Notch signaling pathways. Under ongoing metabolic stress, prolonged stimulation of this triad increases inflammation, hinders the regenerative processes, and maintains pseudo-hypoxic conditions, explaining why single-target treatments have mostly been unsuccessful. This review also explores progress in fluid, digital, and imaging biomarkers that facilitate early diagnosis and patient stratification, and assesses new disease-modifying approaches such as antisense oligonucleotides, immunomodulators, gene therapies, and small-molecular agents. Artificial intelligence is emphasized as an essential tool for integrating multimodal data, drug discovery and predictive modeling.},
}
@article {pmid42509739,
year = {2026},
author = {Narita, A and Nakano-Doi, A and Nishiyama, R and Sawano, T and Fukushima, K and Matsuyama, T and Nakagomi, T},
title = {Mirtazapine Induces Lipocalin-Type Prostaglandin D Synthase Expression in Brain Pericytes.},
journal = {Biomolecules},
volume = {16},
number = {7},
pages = {},
doi = {10.3390/biom16070945},
pmid = {42509739},
issn = {2218-273X},
abstract = {The brain maintains homeostasis partially by scavenging waste products. Failure of this function is closely associated with the onset and pathogenesis of various brain diseases, such as Alzheimer's disease, sleep disorder, and the delay of the reparative process after brain injuries. We recently demonstrated that brain pericytes (BPCs) are sources of lipocalin-type prostaglandin D synthase (L-PGDS), a waste scavenger, in the brain. Based on the above, chemical compounds which promote L-PGDS production could have potential against brain diseases, such as dementia, sleep disorders, and brain injuries. However, the specific chemical compounds that may enhance L-PGDS production in BPCs have not yet been identified. In this study, we explored 158 chemical compounds from FDA-approved drug libraries with these activities. qPCR analysis showed that mirtazapine (MTZ), a noradrenergic and specific serotonergic antidepressant, can increase L-PGDS expression in BPCs as well as in mouse- (m-BPCs) and human-derived BPCs (h-BPCs) in a dose-dependent manner. Since L-PGDS is a secretory protein, m-BPCs and h-BPCs were treated with various MTZ doses and L-PGDS levels in the culture supernatant were investigated. Western blot analysis showed that L-PGDS levels were significantly increased in a dose-dependent manner in both cell types, indicating that MTZ promoted L-PGDS secretion from m-BPCs and h-BPCs. Thus, MTZ may have the potential to be applied as drug repositioning for various brain diseases other than depression by activating L-PGDS production in BPCs, highlighting the importance of BPCs as the source to maintain brain homeostasis.},
}
@article {pmid42509786,
year = {2026},
author = {Guo, L and Grimaldi, N and Wang, M and Ho, L and Shackleton, B and Neff, R and Wang, E and Tu, Z and Gandy, S and Haroutunian, V and Ehrlich, ME and Mobbs, C and Zhang, B},
title = {Molecular Networks and Key Regulators Underlying Resilience of the Human Brain to Aging and Dementia.},
journal = {Biomolecules},
volume = {16},
number = {7},
pages = {},
doi = {10.3390/biom16070992},
pmid = {42509786},
issn = {2218-273X},
support = {5R01AG057907-05/NH/NIH HHS/United States ; },
abstract = {Alzheimer's disease (AD) is an aging-related neurodegenerative disease characterized by an initial memory impairment that progresses to a widespread cerebrocortical failure, culminating in death. Understanding the molecular mechanisms that protect brain function during aging may help reveal novel targets for the development of effective treatments for the memory and cognitive deficits associated with AD. In this study, we analyzed a gene expression dataset generated from the prefrontal cortices of individuals showing no neurological or cognitive abnormalities. The gene expression profiles were used to identify candidate protective genes. We then compared the expression patterns of these genes in aging with their expression patterns in AD, thereby enabling us to pinpoint the genes that potentially contribute to brain resilience that delays or prevents aging-related dementia. We selected seven genes that are potentially protective for aging and AD, and have known homologues in Caenorhabditis elegans (C. elegans). Among these genes, SRPK2, AAK1, EFR3A and MAPK10 were previously implicated in attenuating AD-related cognitive decline. Our experiments demonstrated that all seven genes prioritized by our resilience model significantly extended the lifespan of C. elegans. Given the important relationship between neuronal functional integrity and lifespan (i.e., lifespan vs. brain health span), this work suggests the predicted AD resilience genes could serve as important candidate targets for therapeutic intervention.},
}
@article {pmid42509845,
year = {2026},
author = {De Oliveira, LF and Karunarathne, K and Zona, D and Muschol, M and Ullah, G},
title = {Shrinking of Extracellular Space During Metabolic Stress Accelerates Amyloid-β Aggregation.},
journal = {Biomolecules},
volume = {16},
number = {7},
pages = {},
doi = {10.3390/biom16071053},
pmid = {42509845},
issn = {2218-273X},
support = {R21AG087910/NH/NIH HHS/United States ; },
mesh = {*Amyloid beta-Peptides/metabolism/chemistry ; *Extracellular Space/metabolism ; *Stress, Physiological ; Humans ; Alzheimer Disease/metabolism/pathology ; Protein Aggregates ; Kinetics ; Neurons/metabolism ; Animals ; *Peptide Fragments/metabolism/chemistry ; *Protein Aggregation, Pathological/metabolism ; },
abstract = {Pathological states associated with metabolic stress, such as traumatic brain injury (TBI), hypoxia, ischemic stroke, and migraine, are considered elevated risk factors for developing Alzheimer's disease (AD). However, the mechanism underlying the effect of these conditions on the progression of AD remains largely unknown. Here, we determine how metabolic stress associated with spreading depolarization (SD)-a hallmark of stroke, hypoxia, TBI, and migraine-modulates amyloid β (Aβ42) aggregation kinetics through dynamic changes in extracellular space (ECS). To achieve this, we used ThT fluorescence to determine how the formation of different Aβ42 aggregate species depends on Aβ42 concentrations. Based on this input, we build a multiscale computational framework that integrates volume regulation, including its dependence on neuronal ion homeostasis, and Aβ42 aggregation kinetics. Our model predicts that neuronal swelling during SD accelerates aggregation, where the impact of metabolic stress is highly dependent on the timing relative to aggregation progression and the initial monomer concentration. At low monomer concentrations, early SD events promote off-pathway oligomer formation, while at higher concentrations they rapidly drive fibril formation to saturation. In the absence of mature fibrils, recurrent metabolic stress events further amplify oligomer accumulation, whereas pre-existing fibril nuclei suppress oligomer formation at the expense of fibril nucleation and growth. Increasing the intensity of metabolic stress prolongs ECS shrinkage and enhances oligomer formation. These findings reveal a mechanistic link between SD-induced microenvironmental changes and Aβ aggregation dynamics, providing a quantitative framework for understanding how acute brain injury and metabolic stress may contribute to early AD pathogenesis.},
}
@article {pmid42509854,
year = {2026},
author = {Alessio, M and Giulia, N and Annagrazia, A and Francesco, A and Raffaele, M and Massimo, C and Giacinto, B and Carlo, N and Romano, E and Rossella, R},
title = {Lithium as a Potential Neuroprotective Strategy in Glaucoma: Mechanisms and Therapeutic Perspectives.},
journal = {Biomolecules},
volume = {16},
number = {7},
pages = {},
doi = {10.3390/biom16071062},
pmid = {42509854},
issn = {2218-273X},
abstract = {Glaucoma is a major global health concern, identified as the foremost cause of irreversible blindness, affecting nearly 95 million individuals. It is characterized by the progressive degeneration of retinal ganglion cells (RGCs), leading to significant vision-related disabilities and an extensive socio-economic impact. The concept that glaucoma should be viewed not solely as an ocular condition but also as a neurodegenerative disorder, sharing pathophysiological features with diseases like Alzheimer's and Parkinson's, is now widely accepted. This review examines the convergence of molecular mechanisms, including the roles of amyloid precursor proteins and neuroinflammation, that contribute to RGC loss. Notably, lithium, traditionally used as a mood stabilizer, has emerged as a potential neuroprotective agent for the treatment of Alzheimer's disease. In light of the common neurodegenerative mechanisms linking glaucoma with central neurodegenerative diseases, here, we review the current evidence supporting lithium's therapeutic potential in glaucoma, emphasizing the need for further clinical studies to determine its effectiveness in preserving optic nerve health and improving patient outcomes.},
}
@article {pmid42510415,
year = {2026},
author = {Li, R and Wu, M},
title = {Multidimensional Prosodic and Semantic Coherence Modeling for Mandarin Mild Cognitive Impairment Detection.},
journal = {Bioengineering (Basel, Switzerland)},
volume = {13},
number = {7},
pages = {},
doi = {10.3390/bioengineering13070748},
pmid = {42510415},
issn = {2306-5354},
support = {2025J01001//Fujian Provincial Department of Science and Technology/ ; 32071057, 61673322, 31200769//National Natural Science Foundation of China/ ; Not applicable (Xiamen University Undergraduate Innovation and Entrepreneurship Training Program)//Undergraduate Innovation and Entrepreneurship Training Program of Xiamen University/ ; },
abstract = {Early detection of Alzheimer's disease (AD) and mild cognitive impairment (MCI) remains critically important, yet conventional neuroimaging and biomarker-based approaches are costly, invasive, and poorly scalable for population screening. Speech offers a non-invasive, cost-effective alternative cognitive biomarker, but existing systems rarely integrate its multiple linguistic dimensions. We present Multi-Spec MCI-Net, a multimodal framework for HC/MCI classification that jointly models three complementary speech representations: token-level semantics via dVAE and BERT operating on Mel spectrograms; temporal prosodic dynamics via a 1D-CNN with attention; and discourse-level semantic coherence via a graph convolutional network. A gated fusion mechanism adaptively weights these modalities, yielding clinically interpretable predictions tailored to individual phenotypic profiles. Evaluated on the Chinese NCMMSC2021_AD challenge dataset and the DementiaBank Mandarin subset, the model achieves 89.29% accuracy and 0.9584 ROC AUC on NCMMSC2021_AD, with 92.31% MCI recall-critical for minimizing false negatives in screening contexts. Evaluation on the combined NCMMSC2021_AD and DementiaBank Mandarin dataset attains 77.46% accuracy and 0.8280 AUC, demonstrating robustness across spontaneous dialog and picture description tasks. Ablation studies confirm that multimodal fusion outperforms the semantic-only baseline by 5.16 percentage points, with each branch contributing non-redundant diagnostic information. These results establish an effective, interpretable approach for scalable, speech-based early MCI screening.},
}
@article {pmid42510516,
year = {2026},
author = {Song, C and Deng, C and Zhang, T and Yao, W and Li, D and Wang, X},
title = {Rhodopseudomonas pseudopalustris Mitigates Alzheimer's Disease-Related Pathology in C. elegans Models by Enhancing Antioxidant Defense Capacity and Immune Activity.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {15},
number = {7},
pages = {},
doi = {10.3390/antiox15070785},
pmid = {42510516},
issn = {2076-3921},
support = {32571125//National Natural Science Foundation of China/ ; },
abstract = {Alzheimer's disease (AD) lacks effective disease-modifying therapeutics. Probiotics, promising neuroprotective candidates, exert benefits mainly by modulating gut-brain-axis (GBA) signaling. This study explored the anti-AD effects and mechanisms of Rhodopseudomonas pseudopalustris (R. pse). Using Caenorhabditis elegans (C. elegans) AD models, we evaluated AD-related phenotypes (learning deficits, paralysis) after R. pse administration, and performed genetic analysis and metabolomic profiling to clarify its regulatory pathways and metabolites. Mechanistically, R. pse significantly alleviated AD-related phenotype in C. elegans. It upregulated γ-glutamylcysteine synthetase (GCS-1) to enhance the glutathione (GSH)-dependent antioxidant defense. Knockout of the oxidation repair enzyme methionine sulfoxide reductase A-1 (MSRA-1) abolished the neuroprotective effects of R. pse, which was rescued by methionine. R. pse also activated activating transcription factor 7 (ATF-7)-mediated innate immunity and transforming growth factor β (TGF-β) signaling, with pantothenic acid as its functional metabolite. Collectively, R. pse is a potential anti-AD bacterium that mitigates AD model pathogenesis by enhancing the cellular antioxidant capacity, providing experimental evidence for bacteria-based AD interventions.},
}
@article {pmid42510529,
year = {2026},
author = {Vietri, M and Napolitano, E and Miranda, MR and Marino, C and Musella, S and Di Sarno, V and Ostacolo, C and Manfra, M and Campiglia, P and Tecce, MF and D'Ursi, AM and Moltedo, O and Bertamino, A and Ciaglia, T and Vestuto, V},
title = {Metabolic Reprogramming Associated with Ferroptosis Protection by an Indole-Based Antioxidant in Aβ(25-35)-Treated SH-SY5Y Cells.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {15},
number = {7},
pages = {},
doi = {10.3390/antiox15070798},
pmid = {42510529},
issn = {2076-3921},
support = {J97G22000400006//Ministero dell'universit&#xe0; e della ricerca/ ; },
abstract = {Ferroptosis has emerged as a critical mechanism linking iron dysregulation, oxidative stress, and neurodegeneration in amyloid-associated pathologies. Building on our previous work, which identified compound 20 as a promising antioxidant and neuroprotective agent, the present study investigates the molecular mechanisms underlying its protective activity against amyloid-induced ferroptosis in human neuroblastoma SH-SY5Y cells exposed to Aβ(25-35). Compound 20 (3-(((4-hydroxybenzyl)(methyl)amino)methyl)-1-methyl-N-(2-(piperazin-1-yl)ethyl)-1H-indole-5-carboxamide) markedly counteracted Aβ(25-35)-induced ferroptotic damage by restoring intracellular glutathione levels, depleting the labile iron pool, and suppressing lipid peroxidation. In parallel, the compound significantly rescued mitochondrial membrane potential and attenuated endoplasmic reticulum (ER) expansion associated with ER stress, thereby preserving cellular homeostasis under oxidative challenge. These protective effects were further corroborated by real-time PCR analysis, which revealed the modulation of key genes involved in the oxidative stress response, endoplasmic reticulum stress, and inflammatory pathways. To gain a systems-level insight into these mechanisms, untargeted [1]H-NMR metabolomic profiling was performed. This analysis confirmed the activation of antioxidant pathways and disclosed a significant modulation of energy metabolism and GABA-related pathways, both of which are closely linked to redox balance and neuronal resilience. Overall, these findings demonstrate that compound 20 drives metabolic reprogramming that orchestrates its multifactorial protective effect against Aβ(25-35)-induced ferroptosis by coordinating antioxidant defense, iron homeostasis, and ER stress mitigation.},
}
@article {pmid42510588,
year = {2026},
author = {Ciccone, L and Petrarolo, G and D'Agostino, I and Scianò, F and Bernardoni, BL and Leri, M and Ann, J and Nencetti, S and Lee, J and Bucciantini, M and La Motta, C},
title = {Polyphenolic Imidazopyridines as Multifunctional Modulators of Oxidative Stress, Metal Dyshomeostasis, and β1-42 Amyloid Aggregation in an In Vitro Model of Alzheimer's Disease.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {15},
number = {7},
pages = {},
doi = {10.3390/antiox15070857},
pmid = {42510588},
issn = {2076-3921},
abstract = {Alzheimer's disease (AD) involves oxidative stress, metal dyshomeostasis, and toxic oligomers of the amyloid-β peptide (Aβ1-42), calling for multifunctional agents. We investigated a panel of imidazo[1,2-a]pyridines bearing catechol or resorcinol motifs previously designed as SIRT1-activating agents. Their antioxidant profile was evaluated using in vitro DPPH and ABTS assays, which revealed promising radical scavenging activities, and TBARS assays on rat brain homogenates showing inhibition of lipid peroxidation, strictly dependent on the phenolic pattern. UV-Vis studies revealed metal-binding properties, particularly Cu[2+] and Fe[2+] interactions. In Aβ1-42 aggregation assays, the most active derivatives appeared to promote fibril maturation and the growth of large, ThT-low aggregates with distinct morphological features observed by TEM. Notably, Aβ1-42 aggregates generated in the presence of these compounds exhibited reduced cytotoxicity, preserved cell viability, and induced lower ROS levels in RA-differentiated SH-SY5Y cells compared to aggregates formed in their absence. Imaging and FRET analyses further indicated reduced formation of membrane-binding toxic species. Overall, our data suggest that polyphenolic imidazo[1,2-a]pyridines can remodel Aβ1-42 aggregation, redirecting it toward structurally distinct and less toxic assemblies, while also counteracting oxidative and metal-associated damage. These findings highlight their potential as multifunctional agents capable of addressing several pathological hallmarks of AD.},
}
@article {pmid42510665,
year = {2026},
author = {Mitroshina, EV and Strelkova, PL and Korokozova, MV and Vedunova, MV},
title = {HIF1 Stabilization by Roxadustat Improves Cognition and Prevents Neuron Loss in Alzheimer's Diseases In Vivo.},
journal = {Biology},
volume = {15},
number = {14},
pages = {},
doi = {10.3390/biology15141118},
pmid = {42510665},
issn = {2079-7737},
support = {22-15-00178-p//Russian Science Foundation/ ; },
abstract = {Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders worldwide and is characterized by progressive memory impairment, cognitive decline, and behavioral dysfunction. The brain's high energy demand makes it vulnerable to hypoxia, which can trigger AD pathology. Hypoxia-inducible factor (HIF) is a transcription factor that mediates cellular and tissue adaptation to low oxygen levels. HIF-1 plays a dual role in AD: on the one hand, it is considered a potential neuroprotective target; on the other hand, its activation may exacerbate disease pathogenesis by promoting amyloid plaque formation. Given this ambiguity, further studies are needed. This study investigated the HIF prolyl hydroxylase inhibitor Roxadustat in 6-month-old male 5xFAD mice. Stabilization of the HIF-1 complex exerted a positive effect on learning ability and the retention of long-term spatial memory in 6-month-old male 5xFAD mice. Four-week treatment with Roxadustat significantly reduced pathological morphological alterations in cells of the prefrontal cortex. In addition, animals treated with Roxadustat exhibited significantly increased expression of the brain-derived neurotrophic factor (BDNF) in the cerebral cortex. Our findings suggest that stabilization of the HIF-1 complex through inhibition of HIF prolyl hydroxylase may represent a promising strategy for neuroprotection in AD.},
}
@article {pmid42510722,
year = {2026},
author = {Avitabile, A and Rusciano, D and Amato, R and Cannizzaro, L and Gagliano, C},
title = {Sex-Dependent Brain Plasticity in Neurological Disease: From Biological Variability to Adaptive, Compensatory, and Maladaptive Trajectories.},
journal = {Biology},
volume = {15},
number = {14},
pages = {},
doi = {10.3390/biology15141176},
pmid = {42510722},
issn = {2079-7737},
abstract = {Brain plasticity is often described as the capacity of the nervous system to change in response to development, experience, injury, disease, or treatment. That definition is useful, but it can obscure two clinically important points: plasticity is biologically constrained, and change is not always beneficial. This narrative review examines sex-dependent brain plasticity as a context-sensitive process rather than as a simple male-female contrast. We distinguish four operational outcomes of plasticity: (i) reparative plasticity, which restores structure or function; (ii) compensatory plasticity, which preserves performance through alternative or more costly strategies; (iii) insufficient plasticity, in which reorganization is too weak or unstable to sustain function; and (iv) maladaptive plasticity, in which plastic change reinforces dysfunction, pain, excitability, rigidity, or decline. We also define adaptive reserve as the integrated capacity of neural, glial, vascular, immune, metabolic, endocrine, and gene-regulatory systems to support useful reorganization under stress. The review evaluates endocrine, synaptic, neuroimmune, mitochondrial, vascular, stress-related, and epigenetic mechanisms, indicating where evidence for sex-dependent effects is relatively strong and where it remains indirect, inconsistent, or context-dependent. Disease examples include autism spectrum disorder, attention-deficit/hyperactivity disorder, epilepsy, intellectual disability, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, traumatic and ischemic injury, multiple sclerosis, chronic pain, aging, and systemic metabolic or inflammatory disorders. Throughout, biological sex is separated from gender-related social, diagnostic, and health-care determinants. We conclude that therapeutic strategies should not aim simply to enhance plasticity, but to guide it by matching intervention, timing, dose, biological readiness, and monitoring to the patient's adaptive state.},
}
@article {pmid42510815,
year = {2026},
author = {Deng, K and Deng, X and Li, S and Fang, S and Wei, F},
title = {The Genetic and Transcriptomic Nexus of Age-Related Hearing Loss and Alzheimer's Disease.},
journal = {Genes},
volume = {17},
number = {7},
pages = {},
pmid = {42510815},
issn = {2073-4425},
support = {2023A1515012713//Guangdong Basic and Applied Basic Research Foundation/ ; },
abstract = {Introduction: Despite the recognized association between age-related hearing loss (ARHL) and Alzheimer's disease (AD), the genetic relationship and shared transcriptional mechanisms between them remain largely unexplored. Methods: We systematically investigated the ARHL-AD axis using a multi-layered genomic strategy, incorporating causal inference, cis-eQTL mediation, Bayesian colocalization, and independent replication cohort validation. Results: Genetically predicted ARHL was associated with a reduced risk of overall AD and its early/late-onset subtypes, with no evidence of reverse causality in reverse MR analyses. Among 36 identified mediating genes, CSK showed the most consistent mediation signals across discovery and replication cohorts, although the replication was statistically partial (Sobel p = 0.078). Pathway analyses revealed that these genetic links predominantly involve Wnt signaling and endoplasmic reticulum protein processing. Discussion: Our integrative multi-omics findings suggest a potential genetic association between ARHL liability and AD risk. More importantly, we identified a prioritized CSK-driven transcriptional network, providing novel mechanistic insights and highlighting a candidate gene for future functional investigation in neurodegeneration.},
}
@article {pmid42510931,
year = {2026},
author = {Schuck, PF and da Costa Ferreira, G and Freitas, HR},
title = {Astrocyte Subtype-Specific Expression of the Sodium-Coupled Citrate Transporter SLC13A5 and Citrate Metabolism Genes Across Alzheimer's Disease Pseudoprogression: A Single-Nucleus RNA Sequencing Analysis of the Human Middle Temporal Gyrus.},
journal = {Current issues in molecular biology},
volume = {48},
number = {7},
pages = {},
doi = {10.3390/cimb48070691},
pmid = {42510931},
issn = {1467-3045},
support = {307377/2023-7//National Council for Scientific and Technological Development/ ; 445305/2024-0//National Council for Scientific and Technological Development/ ; 312744/2025-0//National Council for Scientific and Technological Development/ ; E-26/200.256/2026//Funda&#xe7;&#xe3;o Carlos Chagas Filho de Amparo &#xe0; Pesquisa do Estado do Rio de Janeiro/ ; E-26/210.624/2025//Funda&#xe7;&#xe3;o Carlos Chagas Filho de Amparo &#xe0; Pesquisa do Estado do Rio de Janeiro/ ; U24NS133077//Allen Institute/ ; 2024/2025 Scholarship for Young Professors and Researchers from Latin American Universities//Coimbra Group/ ; Early-Career Investigator Research Grant (2022/2023)//Tess Research Foundation/ ; },
abstract = {The sodium-coupled citrate transporter NaCT (SLC13A5) imports extracellular citrate into cells. In the CNS, SLC13A5 is described to be expressed predominantly in neurons. Cytosolic citrate levels rely on citrate generated in mitochondria and imported from other CNS cells, regulating intermediary metabolism and supplying acetyl-CoA for lipid synthesis and histone acetylation. Despite evidence for NaCT's role in neurometabolic homeostasis, its transcriptional behavior across Alzheimer's disease (AD) progression and across astrocyte subtypes remains uncharacterized at single-cell resolution. We analyzed single-nucleus RNA sequencing data from 1,378,211 nuclei across 84 donors in the Seattle Alzheimer's Disease Brain Cell Atlas (SEA-AD) Middle Temporal Gyrus dataset to profile SLC13A5 and seven citrate metabolism genes across a continuous AD pseudoprogression score. SLC13A5 expression was restricted to astrocytes (~20% prevalence) and concentrated in the Astro 2 supertype (24.0%), a homeostatic subtype characterized by low C3 (1.6%) and CD44 (5.5%), which expanded with pseudoprogression (Spearman rho = +0.345, FDR < 0.001). The A1-reactive Astro 3 supertype, where SLC13A5 prevalence was 0.87%, declined concordantly (rho = -0.393). Opposing compositional and transcriptional forces produced apparent stability in overall SLC13A5 prevalence. SLC13A3 and ACO1 showed progressive donor-level declines correlating with Braak stage and Thal phase (rho range: -0.307 to -0.349, FDR < 0.01). APOE4 carriers exhibited lower SLC13A5 prevalence specifically within Astro 2 nuclei (median 17.6% vs. 25.9%; Wilcoxon p = 0.025), though this association did not survive multivariate regression. No difference in Astro 2 SLC13A5 expression was detected between cognitively resilient and expected-AD donors with equivalent high Braak burden (p = 0.888). Contrary to the prevailing description of NaCT as a neuronal transporter, SLC13A5 transcript in the SEA-AD MTG dataset was detected almost exclusively in astrocyte nuclei, concentrated in the homeostatic Astro 2 subtype, and maintained as this subtype expanded with advancing AD pathology. Because these are nuclear transcript measurements, they delimit where SLC13A5 mRNA is detectable rather than establishing the cellular site of NaCT protein or activity, which requires in situ validation.},
}
@article {pmid42510934,
year = {2026},
author = {Wang, TS and Tzeng, IS and Chen, YC and Chen, ML},
title = {Herbal Bioactives Targeting Rho GTPases: A Multi-Targeted Strategy for Mitigating Neuroinflammation in Alzheimer's and Parkinson's Diseases.},
journal = {Current issues in molecular biology},
volume = {48},
number = {7},
pages = {},
doi = {10.3390/cimb48070694},
pmid = {42510934},
issn = {1467-3045},
support = {TCRD-TPE-111-28 (1/3) -(3/3)//Taipei Tzu Chi Hospital/ ; },
abstract = {Neuroinflammation plays an essential role in the pathogenesis of several associated brain diseases, including neurodegenerative disorders (Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS)), and traumatic brain injury (TBI). In these diseases, persistent microglial and astrocyte aggregates, elevated proinflammatory cytokines, and oxidative stress drive neuronal injury and cognitive disability. Rho GTPases, in particular the Rho family members Ras homolog family member A (RhoA), Ras-related C3 botulinum toxin substrate 1 (Rac1), and cell division control protein 42 homolog (CDC42), regulate neuroinflammation, cytoskeletal dynamics, immune responses, and the maintenance of BBB integrity. These proteins are involved in many neuropathological diseases due to dysregulation, making them interesting therapeutic targets. Bioactives used in herbal care have attracted interest for their ability to influence neuroinflammation and even their anti-neurodegenerative activity. Studies show that flavonoids, alkaloids, polyphenols, and other botanical compounds alter Rho GTPase activity, which, in turn, leads to decreased inflammation. This review critically summarizes current evidence regarding phytochemical regulation of Rho GTPase signaling in neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD), with particular emphasis on the underlying molecular mechanisms, context-dependent signaling responses, and current translational challenges. Furthermore, existing knowledge gaps and future research priorities are discussed to facilitate the development of mechanism-based therapeutic strategies targeting Rho GTPases.},
}
@article {pmid42511444,
year = {2026},
author = {Suwansukho, B and Poempul, K and Samee, W and Tadtong, S},
title = {The Synergistic Neuroprotective Effect of Honokiol and Magnolol Against Amyloid-β and MPP[+]-Induced Neurotoxicity in SH-SY5Y Cells: An Antioxidant, Molecular Orbital, and ADMET Study.},
journal = {International journal of molecular sciences},
volume = {27},
number = {14},
pages = {},
pmid = {42511444},
issn = {1422-0067},
support = {Grant No. 634/2568//Srinakharinwirot University/ ; },
abstract = {Alzheimer's disease (AD) and Parkinson's disease (PD) are the two main neurodegenerative diseases and cause disability and death in patients worldwide. Neurodegeneration is characterized by a progressive loss of neuronal function and structure, causing enormous impairment in cognitive-motor function. Magnolol and honokiol are isomeric biphenyl neolignans and have exhibited neuroprotective activity in previous studies. Hence, we assessed and compared honokiol, magnolol, and mixtures of honokiol and magnolol in honokiol/magnolol molar ratios of 1:3, 1:1, and 3:1 in terms of their neurotoxicity, using the cell counting kit-8 (CCK-8) assay, and of their neuroprotective effect on intracellular reactive oxygen species (iROS) against amyloid-beta (Aβ)- and 1-methyl-4-phenylpyridinium ion (MPP[+])-induced neurotoxicity in SH-SY5Y cells, using the 2',7'-dichlorodihydrofluorescein diacetate (H2DCF-DA) assay. The results showed that honokiol (H) and magnolol (M) at 0.1 μM and the mixtures of honokiol and magnolol in H/M ratios of 1:3, 1:1, and 3:1 at 0.0001 μM exhibited a significant neuroprotective effect of reducing iROS in SH-SY5Y cells where neurotoxicity was induced by Aβ- and MPP[+] (p-value with respect to Aβ-treated cells < 0.005 and p-value with respect to MPP[+]-treated cells < 0.0001). Moreover, magnolol and honokiol possess antioxidant properties according to computational molecular analysis with Highest Occupied Molecular Orbital (HOMO)- Lowest Unoccupied Molecular Orbital (LUMO) prediction, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), 2,2-diphenyl-1-picrylhydrazyl (DPPH), and Ferric Reducing Antioxidant Power (FRAP) assays. The mixtures of honokiol and magnolol exerted synergistic neuroprotective ability at all ratios while showing better antioxidation ability than that of pure magnolol alone but comparable to that of pure honokiol alone. Drug-likeness, Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) prediction, and toxicity profiles showed that both compounds are promising neuroprotective agents and that one of the possible targeting mechanisms is the ROS-mediated oxidative stress pathway. Additional neuronal cell lines and in vivo models are required to determine similar effects or other protective mechanisms involving the neuroprotective ability of honokiol and magnolol.},
}
@article {pmid42511465,
year = {2026},
author = {Alshamari, AK and Magdy, N and Basiony, EA and Hassan, NA and Alshammari, OAO and Abdel-Rahman, AA and Alsaif, NOS and Alshammari, MZ and Elrashedy, AA and Hassan, AA},
title = {Synthesis, Biological Evaluation, Molecular Docking and Molecular Dynamics of Substituted Thieno[2,3-d]pyrimidine Derivatives as Potential Anti-Alzheimer Agents.},
journal = {International journal of molecular sciences},
volume = {27},
number = {14},
pages = {},
pmid = {42511465},
issn = {1422-0067},
support = {RG-23 108//University of Ha'il/ ; },
abstract = {Thienopyrimidine derivatives are emerging as potent scaffolds for cholinesterase inhibition in Alzheimer's disease therapy. In this work, a novel series of substituted thieno[2,3-d]pyrimidines was synthesized via Gewald's reaction, followed by cyclization and functionalization through nucleophilic substitution and hydrazone formation. Structural confirmation was achieved using spectroscopic techniques, and biological evaluation was performed against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with donepezil and rivastigmine as reference drugs. Compound 4 emerged as the most potent and selective AChE inhibitor (IC50 = 0.58 µM), while compound 7 also showed strong AChE inhibition (IC50 = 0.63 µM). Notably, compound 9 exhibited superior BChE inhibition (IC50 = 3.05 µM) compared to donepezil (IC50 = 8.41 µM). Dual inhibitory activity was observed for compounds 5, 6, and 11, highlighting their multitarget potential. Molecular dynamics simulations (200 ns) and MM/GBSA binding free energy calculations provided mechanistic insights. Compound 4 showed the most favorable binding energy (ΔGbind = -59.16 kcal/mol), driven by hydrogen bonds with Tyr121 and Glu199 and π-π stacking with Trp83. Residue-level decomposition identified Tyr121, Trp83, Glu199, and Tyr338 as critical contributors to binding stability. Structure-activity relationship analysis confirmed that nitrogen-containing substituents and cyclic amino moieties enhance potency, whereas bulky aromatic groups reduce activity. These findings establish thieno[2,3-d]pyrimidine derivatives as promising candidates for the development of next-generation anti-Alzheimer agents.},
}
@article {pmid42511496,
year = {2026},
author = {Cha, S and Kim, J and Kim, J and Kim, D and Song, H and Lim, KS and Chae, S},
title = {Spatial Transcriptomics for Dissecting Cellular and Molecular Heterogeneity in the Aging and Diseased Brain.},
journal = {International journal of molecular sciences},
volume = {27},
number = {14},
pages = {},
pmid = {42511496},
issn = {1422-0067},
support = {RS-2024-00441289//National Research Foundation of Korea/ ; RS-2025-00512586//National Research Foundation of Korea/ ; RS-2023-00301850//Ministry of Education/ ; },
abstract = {The brain is a spatially organized tissue where the molecular characteristics of each cell are closely linked to its anatomical location. However, conventional bulk and single-cell RNA sequencing lose this spatial context during the tissue separation process. Spatial transcriptomics (ST) overcomes these limitations by measuring gene expression while preserving the positional information of cells within intact tissues, making it a powerful approach for elucidating the cellular and molecular heterogeneity that defines brain structure and disease. This review summarizes the two main types of ST technology: next-generation sequencing (NGS)-based platforms (Visium, Stereo-Seq, Slide-Seq) and in situ platforms (MERFISH, seqFISH+, Xenium). NGS-based platforms provide unbiased whole-transcriptome profiling across extensive tissue regions, while in situ platforms offer subcellular resolution within individual cells. We aim to assist in platform selection by comparing the principles, advantages, and limitations of each platform. Next, we focus on how spatial sequencing (ST) has been utilized to analyze the spatial heterogeneity of aging and diseased brains, and examine region- and cell-type changes observed in brain aging, the lesion-related microenvironments of Alzheimer's and Parkinson's diseases, and the spatially isolated tumor cell states and immunosuppressive environments of glioblastoma. We also introduce the key brain ST data resources that underpin these studies. Collectively, ST is emerging as an essential tool for understanding the spatial logic of brain function and pathology, demonstrating increasingly greater potential in the field of precision medicine.},
}
@article {pmid42511504,
year = {2026},
author = {Post, WM and Widomska, J and Oosterwijk, E and De Witte, W and Tiemessen, DM and Klemann, CJHM and Ruisch, IH and Coenen, MJH and Janssen, DAW and Martens, F and Carnes, MU and Marks, JA and Page, GP and Richter, HE and Cartwright, R and Minassian, VA and Thomas, LF and Skogholt, AH and Stafne, SN and Hveem, K and Kluivers, KB and Poelmans, G},
title = {Amyloid Precursor Protein Processing Links Female Urgency Urinary Incontinence with Alzheimer's Disease: Implications for Treatment.},
journal = {International journal of molecular sciences},
volume = {27},
number = {14},
pages = {},
pmid = {42511504},
issn = {1422-0067},
support = {PROJ00787 (DIABIP)//European Fund for Regional Development (EFRD)/ ; },
abstract = {Urgency urinary incontinence (UUI) and Alzheimer's disease (AD) are highly comorbid conditions in women, but the underlying molecular mechanisms are largely unknown. Therefore, we used network enrichment analyses and an elaborate literature search to integrate the most significant genes from four genome-wide association studies (GWASs) and other genetic, expression and functional evidence into a molecular landscape of female UUI. This molecular landscape centers around local, i.e., bladder-based, processing of the AD-associated amyloid precursor protein (APP). To further elucidate how APP processing is implicated in the comorbidity between UUI and AD, we conducted polygenic risk score (PRS)-based analyses, which showed that genetic risk factors associated with AD and a decreased amyloid beta 42/40 blood level ratio (also) contribute to UUI susceptibility. In conclusion, APP processing constitutes a putative molecular link between UUI and AD, adding further weight to their clinical comorbidity and having implications for the treatment (and prevention) of both traits.},
}
@article {pmid42511534,
year = {2026},
author = {Naso, F and Gandaglia, A and Sturaro, G and Lepore, A and Arcaro, A and Gentile, F and Di Costanzo, A and Angiolillo, A},
title = {Anti-Alpha-Gal Antibodies Against Gangliosides: Preliminary Data on a New Autoimmune Target in Alzheimer's Disease Patients.},
journal = {International journal of molecular sciences},
volume = {27},
number = {14},
pages = {},
pmid = {42511534},
issn = {1422-0067},
support = {//Fondazione Anticorpi Antifosfolipidi Onlus/ ; //National Plan for NRRP Complementary Investments D&#x2227;3 4 Health/ ; },
abstract = {Human anti-αGal antibodies (Abs), known for their marked polyreactivity, have been detected bound to the gray matter of the brains of Alzheimer's disease (AD) patients, although their targets were unclear. Since αGal is a strictly xenogenic antigen absent in humans, this observation raised questions regarding the nature of the structures recognized by these antibodies. In this study, we investigated their potential interaction with gangliosides-glycan structures that are highly abundant in the central nervous system. Using a competitive inhibition ELISA, serum profiles of anti-αGal Abs isotypes and their indirect cross-reactivity with selected soluble gangliosides were analyzed in AD patients and healthy subjects (HSs). AD patients showed reduced levels of anti-αGal IgG and IgM, but increased IgA compared to HSs. Notably, pre-incubation with GM1, GM2, or GD1b did not reduce αGal-HSA binding in HS sera. In contrast, in AD sera, pre-incubation with GD1b reduced residual αGal-HSA binding for all antibody isotypes; additionally, GM1 inhibited IgM binding, and GM2 inhibited IgA binding. These results should therefore be interpreted as competitive inhibition patterns consistent with ganglioside-associated cross-reactivity rather than as direct evidence of antibody binding to immobilized gangliosides. Overall, the findings provide preliminary evidence that, in AD sera, a fraction of αGal-HSA-reactive antibodies can be competitively inhibited by selected gangliosides. This observation supports the presence of an altered humoral anti-carbohydrate signature in AD and identifies neuronal gangliosides as plausible candidate autologous targets that may help explain the previously reported binding of anti-αGal Abs to gray matter. However, given the indirect nature of the assay, these data should be considered hypothesis-generating and require confirmation by direct binding approaches.},
}
@article {pmid42511539,
year = {2026},
author = {Nguyen, LTH and Nguyen, HT and Nguyen, TU},
title = {Investigation of the Potential Neuroprotective Mechanisms of Acalypha indica Against Alzheimer's Disease by Integrated Bioinformatics Analysis.},
journal = {International journal of molecular sciences},
volume = {27},
number = {14},
pages = {},
pmid = {42511539},
issn = {1422-0067},
abstract = {Alzheimer's disease (AD) is one of the most common neurodegenerative disorders; however, available treatments majorly offer symptomatic relief without delaying disease progression and are associated with various adverse effects, highlighting the need for development of alternative therapies. Acalypha indica has previously showed neuroprotective effects in aging-related animal models, yet its mechanisms against AD were not fully understood. In this study, we employed an integrated bioinformatics approach combining network pharmacology, transcriptomic analysis, and molecular docking to investigate the anti-AD potential of this herb. A total of 282 overlapping targets between A. indica compounds and AD were identified. Network pharmacology analysis indicated chrysin, daidzein, galangin, kaempferol, and quercetin as the key bioactive components. Enrichment analyses suggested that targets of these compounds are mainly associated with phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) and mitogen-activated protein kinase (MAPK) signaling pathways. Protein-protein interaction (PPI) analysis identified AKT1, epidermal growth factor receptor (EGFR), interleukin 6 (IL6), tumor necrosis factor (TNF), and p53 protein (TP53) as crucial hub targets. These targets were significantly upregulated in AD brain samples and were closely associated with pathways related to neurodegeneration, inflammation, as well as alterations in immune cell infiltration. Among the compounds, quercetin exhibited the strongest binding affinity to these target proteins. Overall, these findings provide a strong foundation for the multi-target therapeutic potential of A. indica in AD.},
}
@article {pmid42511649,
year = {2026},
author = {Kiss, E and Kirsch, J and Kins, S and Kuhse, J},
title = {Synaptic vs. Non-Synaptic Glycine Receptors: Physiological Role and Implications in Alzheimer's Disease Pathology.},
journal = {International journal of molecular sciences},
volume = {27},
number = {14},
pages = {},
pmid = {42511649},
issn = {1422-0067},
support = {PN-III-P4-PCE-2021-1089//Ministry of Research and Innovation/ ; },
abstract = {Strychnine-sensitive glycine receptors (GlyRs) are pentameric ligand-gated chloride channels that mediate fast inhibitory neurotransmission in the central nervous system (CNS), with high expression in the spinal cord, brainstem, cerebellum, and retina. Beyond traditional postsynaptic phasic inhibition, emerging evidence highlights the importance of extrasynaptic GlyRs-expressed in both neuronal and non-neuronal cells-in mediating tonic inhibition by sensing ambient glycine levels, including in the forebrain. These non-synaptic receptors display high agonist affinity, unique subunit compositions, and distinct pharmacodynamics. Notably, recent studies have begun to implicate aberrant GlyR signaling in Alzheimer's disease (AD) pathology; however, its functional role in this specific neurodegenerative context remains only poorly understood. This review synthesizes the molecular properties and functional significance of these diverse GlyR populations, emphasizing their involvement in calcium signaling, inhibitory tone, and neural circuit modulation, while critically evaluating their emerging therapeutic potential in AD.},
}
@article {pmid42511671,
year = {2026},
author = {Khan, MS and Zafar, I and Bopassa, JC},
title = {Phytochemicals in Alzheimer's Disease Prevention and Management: Molecular Mechanisms, Therapeutic Potential, Translational Challenges, and Emerging Research Directions.},
journal = {International journal of molecular sciences},
volume = {27},
number = {14},
pages = {},
pmid = {42511671},
issn = {1422-0067},
abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disorder and a leading cause of dementia worldwide, characterized by progressive cognitive decline, memory impairment, and neuronal loss. The pathological hallmarks of AD include extracellular accumulation of amyloid-β (Aβ) plaques, intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein, chronic neuroinflammation, oxidative stress, mitochondrial dysfunction, and synaptic degeneration. Current symptomatic therapies provide modest clinical benefits, while recently approved amyloid-targeting monoclonal antibodies, such as lecanemab and donanemab, can slow decline in selected early-stage AD patients but do not cure the disease and are associated with safety, access, and cost concerns. This narrative review summarizes mechanistic evidence from in vitro and in vivo studies and distinguishes preclinical promise from validated clinical utility. Phytochemicals, including polyphenols, flavonoids, alkaloids, terpenoids, and carotenoids, demonstrate neuroprotective effects through antioxidant activity, anti-inflammatory modulation, inhibition of amyloid aggregation, regulation of tau phosphorylation, and support of mitochondria and synapses. Evidence from experimental models suggests that several phytochemicals may help slow AD pathology and improve cognitive function, but clinical translation remains limited due to poor bioavailability, inadequate blood-brain barrier (BBB) penetration, and a lack of large-scale clinical trials. This review highlights critical research gaps and emerging strategies to facilitate phytochemical-based preventive and therapeutic approaches in AD.},
}
@article {pmid42511680,
year = {2026},
author = {Podshivalova, ES and Kutsev, SI and Shestopalov, AV},
title = {The Kynurenine Pathway: Unraveling Its Role in Neurological Disorders via Mammalian Cellular Models.},
journal = {International journal of molecular sciences},
volume = {27},
number = {14},
pages = {},
pmid = {42511680},
issn = {1422-0067},
abstract = {The kynurenine pathway (KP) constitutes the primary route of tryptophan catabolism, generating a spectrum of neuroactive metabolites that profoundly influence central nervous system function. Dysregulation of the KP is increasingly recognized as a critical pathogenic mechanism underlying diverse neuropathological conditions. This review critically evaluates the most widely cited mammalian cellular models currently utilized to delineate the causal role of KP alterations in neurological disease. Specifically, this article examines primary cell cultures, immortalized and tumor-derived cell lines, stem cell-derived systems, and ex vivo organotypic brain slices and tissues, highlighting their distinct methodological advantages, translational limitations, and specific enzymatic profiles. Across the described cellular systems, a recurring mechanistic theme emerges: quinolinic acid-driven mitochondrial dysfunction, oxidative stress, and NAD+ depletion converge in neurodegenerative conditions such as Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Conversely, kynurenic acid exhibits disorder-dependent-and at times opposing-roles, attenuating dopaminergic neurotoxicity in Parkinson's disease models while contributing to synaptic pruning deficits in schizophrenia models. Furthermore, cellular models demonstrate that IDO1/TDO induction and downstream metabolite shifts are frequently cell type- and species-dependent, complicating direct extrapolation to human pathology. Because no single experimental system achieves complete physiological fidelity, elucidating the complex dynamics of the KP and identifying novel therapeutic targets requires the integration of data across complementary platforms.},
}
@article {pmid42511717,
year = {2026},
author = {Sümer, A and Şahin, S and Menteşe, A},
title = {Carbonic Anhydrase I and II as Biomarkers and Therapeutic Targets in Human Disease: From Physiology to Clinical Translation.},
journal = {International journal of molecular sciences},
volume = {27},
number = {14},
pages = {},
pmid = {42511717},
issn = {1422-0067},
abstract = {Carbonic anhydrases (CAs) are zinc-containing metalloenzymes that catalyze the reversible conversion of carbon dioxide and water into bicarbonate and protons, contributing to acid-base balance, pH regulation, and ion transport. Among human cytosolic isoforms, carbonic anhydrase I (CA I) and carbonic anhydrase II (CA II) are abundant and clinically relevant, yet their distinct roles are often obscured within broader discussions of the CA family. This narrative review evaluates CA I and CA II as biomarkers and therapeutic targets in glaucoma, atherosclerosis and vascular calcification, anemia, epilepsy, Alzheimer's disease, obstructive sleep apnea, obesity-related metabolic dysfunction, and selected cancers. CA II emerges as the more established pharmacological target, particularly in glaucoma, with acetazolamide and sultiame showing therapeutic potential in obstructive sleep apnea and possible contributions to epilepsy and neurodegeneration through pH regulation, bicarbonate-dependent signaling, and mitochondrial function. CA I instead appears more valuable as a disease-associated biomarker, especially in disorders involving erythrocyte turnover, inflammation, anemia, and malignancy, though circulating CA I may be confounded by hemolysis and altered erythrocyte dynamics. Clinical translation requires isoform-selective modulators, tissue-targeted delivery, standardized biomarker assays, and mechanistic models distinguishing primary CA involvement from secondary disease-related changes.},
}
@article {pmid42511728,
year = {2026},
author = {Malaplate, C and Oster, T},
title = {Special Issue "Molecular Insight into Alzheimer's Disease".},
journal = {International journal of molecular sciences},
volume = {27},
number = {14},
pages = {},
pmid = {42511728},
issn = {1422-0067},
abstract = {Alzheimer's disease (AD) remains one of the greatest biomedical challenges of our time, mostly because it appears to result from a complex interplay of several determinants [...].},
}
@article {pmid42511787,
year = {2026},
author = {Sun, D and Wang, S and Meng, Q and Wang, X and Amiri, M and Unnithan, RR and French, C},
title = {Large-Scale Neural Recording Technologies for Investigating Circuit Dysfunction and Functional Biomarker Discovery in Animal Models of Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {14},
pages = {},
pmid = {42511787},
issn = {1422-0067},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with amyloid beta accumulation, tau pathology, and neuronal loss. Increasing evidence suggests that AD is associated with disruptions in large-scale circuit activity across multiple disease animal models, even before clear cognitive decline. These findings highlight the need for functional biomarkers that capture dynamic changes in neuronal network activity, rather than relying solely on molecular or anatomical measures. Recent advances in neural recording technologies now allow AD-related network dysfunction to be examined with greater spatial and temporal resolution. This review summarises recent progress in large-scale neural recording technologies, including miniaturized fluorescence microscopy, voltage-sensitive optical recording, high-density probe electrophysiology, and high-density CMOS microelectrode array systems. These techniques provide improved characterization of large network-level abnormalities in AD animal models. Although they are unlikely to serve directly as routine clinical biomarkers, their translational value lies in clarifying circuit-level disease mechanisms, identifying functional features that may inform candidate clinical biomarkers, and supporting preclinical evaluation of therapeutic interventions.},
}
@article {pmid42511940,
year = {2026},
author = {Victoria-Martínez, J and Martín-Nieto, J},
title = {Exploring Alzheimer Disease from a Retinal and Ocular Perspective.},
journal = {Biomedicines},
volume = {14},
number = {7},
pages = {},
doi = {10.3390/biomedicines14071465},
pmid = {42511940},
issn = {2227-9059},
support = {Grants VIGROB24-237, UADIF24-81 and UAUSTI24-14, awarded to J.M.-N.//University of Alicante/ ; },
abstract = {Alzheimer disease (AD) is a neurodegenerative disorder currently recognized as the leading cause of dementia worldwide. It is characterized by a progressive cognitive decline, which can be studied and diagnosed through the use of various brain biomarkers. The retina, being part of the central nervous system, shares numerous structural and functional features with the brain. In this light, a wide range of alterations have been found in the retina with significant potential as biomarkers for AD diagnosis, even at early stages of its manifestation in the brain, and for monitoring disease progression within this organ. Furthermore, the detection of such alterations in the eye and retina is feasible through non-invasive, relatively simple and cost-effective techniques, such as optical coherence tomography, scanning laser ophthalmoscopy and electroretinography. Using these methods, numerous studies have identified molecular, morphological and functional changes associated with AD in the retina and other ocular elements, including the choroid, cornea, lens, intraocular humors and tear fluid. This review addresses the main anomalous changes identified to date in the retina and other eye structures in patients with AD, highlighting their potential utility as biomarkers for the diagnosis of this disease and their possible extrapolation to its prognosis in the brain.},
}
@article {pmid42511997,
year = {2026},
author = {Apostol, A and Kuzubova, E and Radchenko, A and Chaprov, K and Shcheblykina, O and Lebedev, P and Korokina, L and Pokrovskii, M and Sedinova, V and Khizeva, A and Ninkina, NN and Korokin, M},
title = {Traumatic Brain Injury Modulates Synuclein-Associated Transcription, Amyloid Plaque Morphology and Cognitive Performance in APPswe/PS1dE9/Blg Mice.},
journal = {Biomedicines},
volume = {14},
number = {7},
pages = {},
doi = {10.3390/biomedicines14071524},
pmid = {42511997},
issn = {2227-9059},
support = {This work was supported by the Ministry of Science and Higher Education of the Russian Federation, agreement No. 075-15-2025-558.//The Ministry of Education and Science of the Russian Federation/ ; The Federal Scientific-technical Programme for Genetic Technologies Development for 2019-2030, agreement N&#x25e6; 075-15-2025-558//The Ministry of Education and Science of the Russian Federation/ ; },
abstract = {Background/Goals: Traumatic brain injury (TBI) is increasingly recognised as an important risk factor for delayed neurodegeneration and has been implicated in the modulation of Alzheimer's disease (AD)-related amyloid pathology. However, experimental evidence remains equivocal, suggesting that the effects of TBI on amyloidogenesis are context-dependent and influenced by factors including disease stage, injury severity, and the pre-existing neurodegenerative background. This study aimed to comprehensively assess the effects of TBI on cognitive function, synuclein-family gene expression, neuroinflammatory gene expression and amyloid plaque morphology in APPswe/PS1dE9/Blg mice. Methods: Wild-type and APP/PS1 mice were assigned to four experimental groups: WT, WT-TBI, APP/PS1 and APP/PS1-TBI. TBI was induced at 6 months of age using a controlled cortical impact device (precision impactor). Behavioural assessments were conducted at two post-injury time points to evaluate locomotor activity, object recognition memory, short-term spatial memory and spatial learning. Cortex and hippocampus samples were analysed by qRT-PCR to evaluate synuclein-family gene expression and neuroinflammation-related markers. Amyloid plaque pathology was evaluated in Congo red-stained brain sections using QuPath-based image analysis. Results: TBI did not induce a consistent increase in amyloid plaque burden in APP/PS1 mice. Instead, TBI was associated with changes in plaque-size distribution, particularly at the later post-injury time point. Behavioural assessments revealed early trauma-associated cognitive impairmen; whereas, impairments observed at later stages appeared to be driven predominantly by progression of the APP/PS1 phenotype. Gene expression analysis revealed region- and genotype-dependent alterations in synuclein-family transcripts and inflammatory markers with the most pronounced changes observed in the cortex. Conclusions: These findings indicate that TBI does not uniformly accelerate β-amyloid deposition in APP/PS1 mice with established amyloid pathology. Rather, TBI appears to modify the temporal progression and morphological characteristics of amyloid pathology while interacting with genotype-dependent transcriptional responses involving synuclein-family genes and neuroinflammatory pathways. These results highlight the complex interplay between traumatic injury and pre-existing neurodegenerative processes and warrant further studies at the protein-level and over extended follow-up periods to elucidate the underlying mechanisms.},
}
@article {pmid42512037,
year = {2026},
author = {Bagda, V and Farooz, ZH and Knuckey, NW and South, SM and Gribble, SK and Tomar, M and Bharadwaj, P and Ariyath, A and Taddei, K and Martins, RN and Meloni, BP},
title = {The Poly-Arginine Peptide R18D Inhibits Amyloid-Beta (Aβ) Aggregation and Aβ-Induced Cytotoxicity, Reduces Intracellular Tau Aggregation, and Exhibits Oral Bioavailability.},
journal = {Biomedicines},
volume = {14},
number = {7},
pages = {},
doi = {10.3390/biomedicines14071564},
pmid = {42512037},
issn = {2227-9059},
support = {N/A//Perron Institute for Neurological and Translational Science/ ; N/A//Argenica Therapeutics/ ; },
abstract = {Background/Objectives: Effective disease-modifying therapies targeting pathogenic proteins associated with Alzheimer's disease (AD) remain limited. This study investigated the therapeutic potential of the neuroprotective, cationic arginine-rich peptide R18D to mitigate the pathogenic effects of amyloid-beta (Aβ) and tau associated with AD. Methods: R18D was examined for its ability to inhibit Aβ aggregation in a cell-free assay, attenuate Aβ-induced cytotoxicity in MC65 cells, and suppress intracellular tau aggregation in two neural cell models. Intracellular tau aggregation was quantified using a homogeneous time-resolved fluorescence assay. Additionally, a pilot pharmacokinetic study of R18D was conducted in mice following oral gavage administration. Results: In the cell-free assay, R18D inhibited Aβ aggregation by up to 65%. In human MC65 cells induced to overexpress APP-C99 and accumulate Aβ, treatment with R18D inhibited cellular toxicity by as much as 100%. Preformed tau seeds were applied to human SH-SY5Y cells and rat primary cortical neurons to induce intracellular tau aggregation, and tau levels were quantified after 48 h. Exposure to tau seeds induced robust tau aggregation in both cellular models, which was significantly attenuated by R18D treatment, reducing aggregation by 34.8% in SH-SY5Y cells and 49.9% in cortical neurons. Pharmacokinetic studies demonstrated that R18D was detectable in plasma at 30 and 60 min following oral administration in mice. Conclusions: Together, these results demonstrate that R18D can modulate both Aβ and tau pathologies in vitro and is orally bioavailable, supporting its further evaluation as a therapeutic candidate for AD and other tau-associated neurodegenerative disorders.},
}
@article {pmid42512081,
year = {2026},
author = {Che Mohd Nassir, CMN and Vishnumukkala, T and Kalerammana Gopalakrishna, P and Jagadeesan, S and Mohd Nor, NH and Mehat, MZ and Mohd Moklas, MA and Hein, ZM and Kamaruzzaman, MA},
title = {Rodent Models of Alzheimer's Disease: Bridging the Translational Gap Through Systems-Level Integration.},
journal = {Biomedicines},
volume = {14},
number = {7},
pages = {},
doi = {10.3390/biomedicines14071609},
pmid = {42512081},
issn = {2227-9059},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder and a leading cause of dementia worldwide, yet effective disease-modifying therapies remain elusive. Rodent models have been indispensable for elucidating key pathological mechanisms, including amyloid-beta (Aβ) deposition, tau pathology, neuroinflammation, and synaptic dysfunction. However, despite decades of preclinical success, the translation of therapeutic findings from rodent studies to clinical efficacy in humans has been largely unsuccessful, highlighting critical limitations in current modelling approaches. This narrative review provides a comprehensive and critical evaluation of rodent models of AD, encompassing transgenic, chemically induced, metabolic, inflammatory, and lesion-based paradigms. Rather than presenting these models in isolation, we propose a systems-level framework that categorizes them based on their ability to recapitulate distinct domains of AD pathology, including genetic, environmental, and systemic contributors. By synthesising existing research, highlighting critical gaps, and proposing a tiered minimum-criteria framework for the development of next-generation models, we offer a definitive operational roadmap instead of merely a list of deficiencies. We highlight that most existing models predominantly reflect familial and reductionist aspects of the disease, while failing to capture the complexity of sporadic AD, aging processes, vascular dysfunction, and whole-body interactions. Importantly, we emphasize emerging dimensions that are underrepresented in current rodent models, including glymphatic dysfunction, cerebral small vessel disease, and the microbiota-gut-brain axis, all of which play crucial roles in AD pathogenesis. We further discuss how integrating these factors into next-generation models may improve translational relevance and therapeutic predictability. By synthesizing current evidence and identifying key gaps, we provide a strategic roadmap for the development of more physiologically relevant and translationally robust rodent models. Advancing toward integrative, systems-based approaches will be essential for bridging the persistent gap between preclinical discoveries and clinical success in AD.},
}
@article {pmid42512434,
year = {2026},
author = {Yang, Y and Kwak, YT},
title = {Behavioral Complexity in Alzheimer's Disease: A Diversity-Based Analysis of Neuropsychiatric Symptoms.},
journal = {Brain sciences},
volume = {16},
number = {7},
pages = {},
doi = {10.3390/brainsci16070659},
pmid = {42512434},
issn = {2076-3425},
abstract = {Background and Objectives: To quantify behavioral complexity in probable Alzheimer's disease (AD), compare complexity phenotypes, and determine whether behavioral complexity provides clinically meaningful information beyond total neuropsychiatric burden. We also explored whether global amyloid extent and lobar amyloid topography added explanatory value. Methods: In this cross-sectional retrospective study, we analyzed 245 psychotropic drug-naïve patients with probable AD, positive [18]F-FC119S amyloid positron emission tomography (PET), and complete neuropsychiatric, cognitive, functional, and regional PET data. Behavioral complexity was derived from 12 Korean Neuropsychiatric Inventory domains using symptom count, normalized Shannon entropy of the frequency × severity profile, and a composite index. Patients were classified into tertiles. Multivariable regression and burden-stratified analyses examined associations with cognition, dementia severity, function, and amyloid measures. Results: Higher behavioral complexity was associated with lower Korean Mini-Mental State Examination (K-MMSE) scores and higher Clinical Dementia Rating (CDR) and Global Deterioration Scale (GDS) stages. In multivariable analysis, higher CDR, higher GDS, and lower Barthel Index independently predicted greater complexity, whereas amyloid extent did not. After adjustment for total neuropsychiatric burden, higher CDR remained independently associated with the composite complexity index and normalized entropy, while amyloid extent remained non-significant. Complexity-related clinical differences were most evident in the lowest burden stratum and attenuated at higher burden levels. Regional amyloid analyses yielded only selective signals. Conclusions: Behavioral complexity is a clinically meaningful neuropsychiatric phenotype in AD. Although strongly related to total neuropsychiatric burden, it is not fully reducible to it, with its clearest independent association seen for global dementia severity, particularly at lower overall burden.},
}
@article {pmid42512440,
year = {2026},
author = {Wang, B},
title = {WGTMM: WGAN with Transformer Feature Matching for Generating fMRI Data in MCI Patients.},
journal = {Brain sciences},
volume = {16},
number = {7},
pages = {},
doi = {10.3390/brainsci16070665},
pmid = {42512440},
issn = {2076-3425},
support = {62306268//National Natural Science Foundation of China/ ; },
abstract = {BACKGROUND: The emergence of generative adversarial networks has laid the groundwork for data augmentation, addressing challenges of missing training data in various research scenarios. However, simulating functional magnetic resonance imaging (fMRI) data remains particularly challenging, especially for populations with varying degrees of mild cognitive impairment (MCI). Effectively characterizing and capturing the mechanisms of brain function variations poses a critical issue in cognitive neuroscience. This study aims to simulate and analyze synthetic fMRI blood-oxygen-level-dependent (BOLD) signals across four cognitive stages: healthy control (HC), early MCI (EMCI), late MCI (LMCI), and Alzheimer's disease (AD).<br><br>METHODS: We propose WGTMM, an innovative method that integrates the Vision Transformer for fMRI (VTFF) into a generative adversarial network architecture. Crucially, WGTMM directly generates fMRI time-series data from pink noise rather than modeling in a latent space, thereby preserving rich temporal dynamics. The framework incorporates a Wasserstein GAN (WGAN) with feature matching to enhance generation quality and mitigate mode collapse.<br><br>RESULTS: demonstrate that WGTMM-generated fMRI data exhibit lower Kullback-Leibler (KL) divergence compared to traditional GAN and WGAN models, indicating a closer resemblance to real datasets from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Furthermore, when applied to data augmentation, the synthetic data substantially improve multi-class classification performance.<br><br>CONCLUSIONS: WGTMM not only enriches training datasets but also provides new insights into spatial biomarkers of cognitive decline. By leveraging VTFF to investigate class token attention patterns across 360 brain regions, this study reveals monotonic weight variations along disease stages in key cortical areas, including the rostral Area 6, the primary sensory cortex, and PFm near Wernicke's area, offering a fine-grained exploration of disease progression.},
}
@article {pmid42512442,
year = {2026},
author = {Crisci, V and Sagliano, L and Ferrara, A and Salzillo, A and Trojano, L and Panico, F},
title = {Qualitative Analysis of Constructional Errors in Neurodegenerative Conditions: A Systematic Review.},
journal = {Brain sciences},
volume = {16},
number = {7},
pages = {},
doi = {10.3390/brainsci16070667},
pmid = {42512442},
issn = {2076-3425},
abstract = {Background/Objectives: Constructional apraxia (CA) is an impairment in combining simple elements into coherent spatial configurations without basic motor deficits. Although common in neurodegenerative disorders, the qualitative features of visuo-constructional errors and their role in differentiating dementia types remain unclear. This systematic review aimed to synthesize patterns of visuo-constructional errors in dementia and mild cognitive impairment (MCI), exploring distinctive qualitative features associated with different neurodegenerative conditions. Methods: A systematic literature search was conducted in PubMed, Scopus, and Web of Science for studies published between January 1990 and January 2026, following PRISMA guidelines. Studies on adults with dementia or MCI assessing drawing/copying abilities through standardized tasks and qualitative error analysis were included. Reviews, meta-analyses, case reports, non-English articles, and studies not explicitly assessing constructional apraxia were excluded. The quality of evidence was assessed using an adapted version of the Newcastle-Ottawa Scale. Results: A total of 25 studies were included, showing heterogeneous and condition-specific visuo-constructional deficits. Spatial errors and simplifications were the most common across disorders, while perseverations, rotations, and closing-in phenomena were less frequent. Alzheimer's disease was mainly associated with spatial disorganization, omissions, and conceptual errors linked to temporo-parietal dysfunction; frontotemporal dementia with executive deficits such as perseverations and planning impairments; Lewy body and Parkinson's disease dementias with visuospatial and attentional alterations; and Huntington's disease with simplifications and executive dysfunction related to fronto-striatal involvement. Conclusions: No single error pattern was pathognomonic, but qualitative assessment of constructional errors may provide clinically useful information when integrated with the broader neuropsychological profile.},
}
@article {pmid42512450,
year = {2026},
author = {Yogi, S and Singh, A},
title = {Molecular Mechanisms of Neurodegenerative Diseases: Emerging Biomarkers and Therapeutic Targets.},
journal = {Brain sciences},
volume = {16},
number = {7},
pages = {},
doi = {10.3390/brainsci16070675},
pmid = {42512450},
issn = {2076-3425},
abstract = {Neurodegenerative diseases (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), involve the gradual loss of structure or function of neurons in the nervous system and are an increasing threat to the aging population worldwide. Although these disorders have different clinical features which affect cognition, movement and other vital body functions, they share key underlying molecular and cellular processes. This starts with protein misfolding and aggregation, mitochondrial dysfunction, oxidative stress, dysregulated protein homeostasis, neuroinflammation, and disrupted cell death pathways. Recent findings have added disease-specific processes, like amyloid-β and tau aggregates in AD, α-synuclein aggregation and mitophagy failure in PD's, TDP-43-related impaired RNA metabolism in ALS, and mutant huntingtin causing transcription aberrations in HD. Protein interactome network analysis showed mechanistic crosstalk between pathogenic proteins of AD and PD. New evidence highlights how lysosomal dysfunction, endoplasmic reticulum stress, and microglial activation, act as a common axis in neurodegeneration. Advancements in genomics and epigenomics have found shared genetic risk loci and regulatory processes that affect how diseases develop and progress. Simultaneously, new biomarkers like circulating microRNAs, exosome-related pathological proteins, neurofilament light chain, inflammatory cytokines, and microglial activation markers are powering early diagnosis tools and disease variations. New imaging techniques also allow for the identification of protein aggregations before symptoms appear. Overall, these findings are accelerating targeted treatments and personalized medicine aimed at disease progression. This review highlights current insights into the molecular mechanisms of NDs and discusses new biomarkers and treatment targets that help future diagnostic and treatment strategies.},
}
@article {pmid42512462,
year = {2026},
author = {Siarkos, K and Politis, AM and Politis, AA and Smyrnis, N and Papageorgiou, C and Prentakis, A and Gournellis, R and Katirtzoglou, E and Theleritis, C},
title = {Non-Pharmacological Interventions for Managing Apathy in Older Adults with Neurocognitive Disorders: A Systematic Review of Randomized Controlled Trials.},
journal = {Brain sciences},
volume = {16},
number = {7},
pages = {},
doi = {10.3390/brainsci16070687},
pmid = {42512462},
issn = {2076-3425},
abstract = {BACKGROUND/OBJECTIVES: Apathy is among the most common neuropsychiatric features of late-life neurocognitive disorders and predicts functional decline and greater caregiver burden. As no treatment is formally established, identifying effective interventions is a priority. We systematically reviewed non-pharmacological randomized controlled trials (RCTs) targeting apathy in older adults with neurocognitive disorders.<br><br>METHODS: We searched PubMed/MEDLINE, PsycInfo, the Cochrane Library, and Google Scholar (final search 23 March 2026). Eligible studies were non-pharmacological RCTs reporting an apathy outcome. Evidence levels were graded with OCEBM and quality with PEDro; two reviewers mapped PEDro items onto Cochrane risk-of-bias domains. Reporting followed PRISMA 2020.<br><br>RESULTS: Sixty-two RCTs were included. Physical exercise and music-based interventions showed the most consistent benefit, whereas technology-based and brain stimulation approaches remained experimental. Only 30 trials (48%) showed a significant between-group effect on apathy-most were null, within-group, or had apathy as a secondary outcome. Marked heterogeneity precluded meta-analysis. Most trials were of moderate to high quality, though near-universal performance bias arose from the inability to blind participants and providers.<br><br>CONCLUSIONS: Managing apathy in these populations remains challenging, and the certainty of the evidence is limited. Purpose-built, apathy-focused trials reporting effect sizes and durability are needed before disease-specific recommendations can be made.},
}
@article {pmid42512531,
year = {2026},
author = {Phutirat, A and Culevski, KA and Mach, H and Kwon, J and Tan, H and Koh, G and Marzban, C and Mourad, PD},
title = {Low-Intensity Focused Ultrasound Alters Alzheimer's Disease Pathology, In Vivo, as a Function of Ultrasound Dose and Age.},
journal = {Brain sciences},
volume = {16},
number = {7},
pages = {},
doi = {10.3390/brainsci16070757},
pmid = {42512531},
issn = {2076-3425},
support = {W81XWH-20-1-0479//Congressionally Directed Medical Research Programs/ ; },
abstract = {BACKGROUND/OBJECTIVES: Alzheimer's Disease (AD) and vascular dementia contribute up to ~75% of dementia cases, as determined via autopsy. AD arises in part due to the buildup of aberrant proteins (amyloid beta (Aβ) and Tau); vascular dementia is caused by reduced cerebral blood flow. Each dementia mechanisms damages brain. Bobola et al. found that their low-intensity focused ultrasound (FUS) protocol applied to the brains of the 5XFAD mouse model of AD reduced Aβ by 50% through activation of microglia. Eguchi et al. found that their own FUS protocol applied to the brains of the same mouse model reduced Aβ by 15% and increased cerebral blood flow by 50% through an increase in endothelial nitric oxide synthase (eNOS). Here, we sought to test a combined version of those two FUS protocols, expecting both a decrease in Aβ burden and an increase in eNOS.<br><br>METHODS: Using a diagnostic ultrasound probe, we applied our combined FUS protocol primarily to the left hippocampus of anesthetized 5XFAD mice, for an hour a day, for three days for younger mice and for five days for older mice. On day three or five, respectively, we harvested their brains and performed histological analysis to assess A&#x3b2; burden, microglial activation and their co-localization with A&#x3b2;, as well as the burden of eNOS within neuronal nuclei (here called intra-neuronal eNOS) and outside of neurons.<br><br>RESULTS: Relative to untreated mice, the treated younger mice had more activated microglia co-localized with A&#x3b2; and reduced A&#x3b2; burden for large plaques, as well as no change in each measure of eNOS. In contrast, the treated older AD mice had no change in activated microglia co-localized with A&#x3b2;, and no change in A&#x3b2; burden. However, relative to untreated older AD mice, FUS decreased total and extra-neuronal eNOS and increased intra-neuronal eNOS.<br><br>CONCLUSIONS: The ability of our FUS protocol to reduce A&#x3b2; burden and alter the eNOS distribution depends critically upon the age of the AD mice (more A&#x3b2; plaques for a comparable number of microglia for older mice relative to younger mice) and duration of the treatment. The observed decrease in extra-neuronal eNOS distribution in older AD mice caused by FUS raises the concern that our protocol may increase ischemia, while the increase in intra-neuronal eNOS may counteract that effect via protection of synaptic function. These findings also identify two candidate therapeutic windows for our FUS treatment protocol, each requiring more research before translation to humans. One window is early intervention to maximize A&#x3b2; plaque removal via activation of microglia. The second is later intervention to protect synaptic function if it is possible to mitigate the potential ischemic risk caused by the differential effects of FUS on eNOS.},
}
@article {pmid42512540,
year = {2026},
author = {Manzo, J and Hernández-Aguilar, ME},
title = {Autism and Neurodegeneration: Distinct Disorders or a Shared Biological Continuum?.},
journal = {Brain sciences},
volume = {16},
number = {7},
pages = {},
doi = {10.3390/brainsci16070766},
pmid = {42512540},
issn = {2076-3425},
abstract = {BACKGROUND/OBJECTIVES: Autism spectrum disorder (ASD) is traditionally classified as a neurodevelopmental condition, whereas neurodegenerative diseases are defined by progressive neuronal decline in later life. This separation has shaped research and clinical practice, yet emerging evidence suggests potential biological overlap. This review aims to evaluate whether ASD and neurodegenerative disorders represent distinct entities or are linked through shared mechanisms operating across the lifespan.<br><br>METHODS: This narrative review synthesizes findings from genetic, molecular, cellular, circuit-level, and epidemiological studies examining ASD and major neurodegenerative conditions, including Alzheimer's disease, Parkinson's disease, and Amyotrophic lateral sclerosis. Emphasis is placed on identifying convergent pathways and evaluating evidence within a lifespan-oriented framework.<br><br>RESULTS: Across multiple levels of analysis, ASD and neurodegenerative diseases share partially overlapping biological mechanisms, including mitochondrial dysfunction, impaired proteostasis, neuroimmune alterations, and network-level instability. Genetic and molecular data reveal pleiotropic pathways influencing both early neurodevelopment and later neuronal resilience. Circuit-level studies highlight shared principles of network vulnerability, including cerebellar involvement and excitation-inhibition imbalance. Epidemiological data further indicate increased risk of dementia and parkinsonian features in autistic adults. These convergences suggest that early neurodevelopmental alterations may establish latent vulnerabilities that, under specific conditions, intersect with neurodegenerative processes later in life.<br><br>CONCLUSIONS: ASD and neurodegenerative diseases are best understood as distinct clinical conditions that share partially overlapping biological substrates. Rather than implying a deterministic progression, the evidence supports a model of lifespan convergence in which timing, context, and individual susceptibility shape outcomes. This framework highlights the need for integrated research and clinical approaches that consider brain health as a continuous process from development through aging.},
}
@article {pmid42512898,
year = {2026},
author = {Kannenieks, D and Priede, Z and Millers, A and Velins, KK},
title = {Development and External Validation of a Machine Learning Model for Classification of Mild Cognitive Impairment and Dementia Using Clinical Data.},
journal = {Medicina (Kaunas, Lithuania)},
volume = {62},
number = {7},
pages = {},
doi = {10.3390/medicina62071356},
pmid = {42512898},
issn = {1648-9144},
abstract = {Background and Objectives: As society ages, the number of patients with cognitive impairment is increasing. Machine learning methods that use structured clinical and cognitive-assessment data during routine diagnostic work-up may support and monitor structured classifications of cognitive status. This kind of approach can improve early screening, reduce physicians' workload and develop greater support for personalized treatment. To develop an XGBoost-based machine learning model using the National Alzheimer's Coordinating Center (NACC) dataset and to evaluate the model's precision with clinician-assigned diagnosis in a Latvian retrospective cohort study. Materials and Methods: The research was designed as a retrospective external validation cohort study that used two data sources. Firstly, the National Alzheimer's Coordination Center (NACC) longitudinal dataset was used to train the ML model. Secondly, medical records gathered from Pauls Stradins Clinical University Hospital dating from 2020 to May 2025 were used to evaluate the algorithm's precision. Results: In the NACC study, the weighted four-class model achieved an overall accuracy of 84.0% and a balanced accuracy of 70.9%, but the SCD class remained poorly classified. After reframing the model to a three-class model the performance grew stronger for normal cognition, mild cognitive impairment (MCI) and dementia. Class distribution in the Latvian cohort consisted of dementia (n = 138); MCI (n = 13); and subjective cognitive decline (SCD) (n = 2). Dementia was identified most strongly-124/138 (sensitivity-89.9%). MCI was correct in 9/13 cases (sensitivity-69.2%). SCD cases were excluded. Overall, the model agreed with the neurologist-assigned diagnoses in 88.1% of the cases (133/151). Conclusions: The ML classification model has high precision when comparing with neurologist-assigned diagnoses, but it struggles to separate adjacent early-stage diagnoses, meaning that it did not reliably identify SCD. These findings support further methodological development and the implementation of prospective research. Nevertheless, this technology has high potential for being integrated in the future to aid triage and early screening, especially when advanced diagnostics are limited.},
}
@article {pmid42513102,
year = {2026},
author = {Zhu, BT},
title = {Cholesterol at the Center of Alzheimer's Disease: A Unifying Hypothesis on the Pathogenic Mechanism.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {14},
pages = {},
doi = {10.3390/molecules31142418},
pmid = {42513102},
issn = {1420-3049},
abstract = {It is hypothesized that in most cases of sporadic late-onset Alzheimer's disease (LOAD), the abnormally elevated cholesterol level in brain neurons represents a critical causative factor that drives the pathogenic processes of LOAD. Specifically, it is hypothesized that the abnormally elevated neuronal cholesterol will disrupt mitochondrial structure and metabolic activity, resulting in ATP deficiency as well as reduced formation of neuroactive metabolic intermediates (such as mevalonate and geranylgeraniol) along the cholesterol synthesis pathway in brain neurons. In addition, the abnormally elevated neuronal cholesterol will cause direct neuronal damage as well as other pathogenic changes in the brain, including increased formation and deposition of amyloid β (Aβ) plaques. It is speculated that Aβ accumulation and plaque formation in most LOAD cases only represent characteristic secondary pathological changes and are usually not the main force driving the pathogenesis of LOAD. As discussed in detail in this paper, abnormally elevated neuronal cholesterol in conjunction with ATP deficiency and lack of neuroactive metabolic intermediates will not only cause learning and memory impairment, but will also induce tauopathy and reduce the formation of cholinergic vesicles. It is expected that these pathogenic changes are more readily seen initially in ischemia-sensitive neurons in hippocampus and posterior parietal cortex, which are then followed by neurodegenerative and atrophic changes in other brain regions along with progressive cognitive decline. As explained in this paper, ApoE4 is a major risk factor in LOAD because it has a drastically reduced ability than ApoE2 and ApoE3 to efflux excess cholesterol out of neurons. Overall, there is a large body of direct, indirect and circumstantial clinical and experimental evidence which jointly offers strong support for the cholesterol-centered hypothesis on the etiology and pathogenesis of LOAD. Considerable efforts are made to apply the proposed hypothesis to offer a better mechanistic explanation for many of the poorly understood experimental and/or clinical observations related to AD (mostly LOAD).},
}
@article {pmid42513287,
year = {2026},
author = {Ben Ayed, I and Makni, E and Ammar, A and Brahim, MB and Elloumi, M},
title = {Criterion-Referenced Sex-Specific Six-Minute Walk Distance Cut-Offs for Staging Alzheimer's Disease.},
journal = {Journal of clinical medicine},
volume = {15},
number = {14},
pages = {},
pmid = {42513287},
issn = {2077-0383},
abstract = {Background: Functional decline emerges early in Alzheimer's disease (AD) and may support clinical staging. However, criterion-referenced thresholds for interpreting the six-minute walk distance (6MWD) across AD stages are lacking. This study aims to derive sex-specific 6MWD cut-off values to differentiate mild cognitive impairment (MCI) from moderate AD dementia. Methods: In this cross-sectional study, 233 community-dwelling adults (128 women) were consecutively recruited from a neurology department and classified using IWG-2 criteria (MCI: MMSE ≥ 26; moderate AD dementia: MMSE 10-19). All participants completed a standardized 6 min walk test (6MWT) following American Thoracic Society guidelines. Receiver operating characteristic (ROC) analyses were performed overall and by sex, optimal thresholds were selected using Youden's index, and diagnostic indices such as area under the curve (AUC), sensitivity, specificity, 95% confidence intervals (CI), likelihood ratios (LR) and odds ratio (OR) were computed. Results: Overall, participants with moderate AD dementia exhibited substantially lower 6MWD values than those with MCI (313.7 ± 46.5 m vs. 461.2 ± 60.1 m, p < 0.001). The optimal overall threshold was 390 m, yielding an AUC of 0.97, sensitivity of 98.0%, and specificity of 79.4%. Sex-specific thresholds were 389 m in men (AUC = 0.96, sensitivity = 96.4%, specificity = 79.3%) and 367 m in women (AUC = 0.98, sensitivity = 97.8%, specificity = 87.7%). Conclusions: The 6MWD demonstrates strong discriminatory ability between MCI and moderate AD dementia in this sample. Sex-specific thresholds may support functional staging and monitoring but require internal and external validation before clinical implementation.},
}
@article {pmid42513614,
year = {2026},
author = {Çetinkaya, K and Ünsal, Y},
title = {The Glymphatic System and Neurosurgery: A Comprehensive Narrative Review of Current Concepts and Future Directions.},
journal = {Journal of clinical medicine},
volume = {15},
number = {14},
pages = {},
pmid = {42513614},
issn = {2077-0383},
abstract = {The glymphatic system is a recently defined perivascular waste elimination pathway responsible for the efficient clearance of metabolic waste and neurotoxic proteins in the central nervous system. This system facilitates the entry of cerebrospinal fluid (CSF) into the brain parenchyma via arterial perivascular spaces and its interaction with interstitial fluid (ISF) via glial cell-associated aquaporin-4 (AQP4) channels. It functions particularly actively during sleep. Impairment of glymphatic flow contributes to nerve cell damage and neuroinflammation in various pathologies such as Alzheimer's disease, Parkinson's disease, traumatic brain injury, subarachnoid hemorrhage, and neurological tumors. In neurosurgical practice, surgical positioning, anesthesia regimen, and intracranial pressure changes play a decisive role in glymphatic function, and perioperative modulation of the system can affect postoperative recovery and cognitive outcomes. Today, non-invasive imaging techniques and molecular biological approaches are deepening our understanding of the functioning of the glymphatic system in humans, and this system is emerging as a potential target in the diagnosis and treatment of neurological diseases. This review comprehensively addresses the basic anatomical and physiological principles of the glymphatic system, its role in pathological processes, and its clinical significance in neurosurgical applications.},
}
@article {pmid42514123,
year = {2026},
author = {Malkov, A and Proshchina, A and Krivova, Y and Kharlamova, A and Godovalova, O and Gulimova, V and Saveliev, S},
title = {Neuroglia Alterations in the Olfactory Bulbs in Patients with Schizophrenia: An Exploratory Postmortem Study.},
journal = {Life (Basel, Switzerland)},
volume = {16},
number = {7},
pages = {},
doi = {10.3390/life16071053},
pmid = {42514123},
issn = {2075-1729},
support = {FURG-2025-0031//Russian Scientific Center of Surgery/ ; Charitable donation//Helicon Ltd./ ; },
abstract = {The human olfactory bulb is a promising structure for the investigation of central nervous system disorders, including dementias of various etiologies. In Alzheimer's disease, anosmia is among the earliest clinical manifestations. Although olfactory disturbances have also been reported in schizophrenia, alterations within the olfactory system remain insufficiently studied. The aim of this study was to identify changes in the olfactory bulbs of patients with schizophrenia. Olfactory bulbs obtained from patients with schizophrenia (n = 23) and individuals without identified nervous system pathology (n = 23) were examined. Patients with schizophrenia demonstrated a statistically significant decrease in the immunoreactive area of myelin basic protein and a significant increase in the immunoreactive area of glial fibrillary acidic protein compared with the control group. In addition, the thickness of the layer of incoming olfactory nerve fibers was significantly reduced in the schizophrenia group. Overall, our findings demonstrate neuroglial alterations in the human olfactory bulb in schizophrenia. Together with observations from other brain regions, these results may indicate that the identified changes are systemic rather than localized in nature.},
}
@article {pmid42514192,
year = {2026},
author = {Freij, KW and Akbar, A and Domoyeri, P and Polycarp, N and Higginbotham, DR and Arora, I and Aroke, EN},
title = {Epigenetic Regulation of Modulatory Neurotransmitter System Integrity in the Aging Brain: A Scoping Review Across the Lifespan.},
journal = {Life (Basel, Switzerland)},
volume = {16},
number = {7},
pages = {},
doi = {10.3390/life16071122},
pmid = {42514192},
issn = {2075-1729},
abstract = {Age-related changes in neurotransmitter systems contribute to declines in cognitive, emotional, and motor function, yet the biological mechanisms linking these changes to aging are not completely understood. Epigenetic regulation offers a promising framework to bridge this gap. DNA methylation-based biomarkers of biological aging (i.e., epigenetic clocks) capture cumulative and dynamic aspects of biological aging that may reflect vulnerability in neural systems beyond chronological age. However, whether these indices track with the integrity of neurotransmitter systems has not been systematically examined. This scoping review synthesizes evidence across human studies to evaluate how epigenetic aging processes influence neurotransmitter gene regulation and system function across the lifespan. We included 109 studies spanning 2005-2026. GABAergic genes (GAD1, GABRA2) showed the most consistent and reproducible age-related promoter hypermethylation across the cortex, inversely correlated with mRNA expression and corroborated by MRS evidence of cortical GABA decline. Dopaminergic and serotonergic evidence during normative aging was sparse; most epigenetic data in these systems came from disease cohorts. Histone modifications converged on neurotransmission and synaptic-plasticity loci, predominantly in Alzheimer's disease tissue. Subcortical and brainstem nuclei central to monoaminergic and cholinergic systems remain under-investigated for normative aging epigenetic processes. Environmental and social determinants, socioeconomic status, childhood adversity, and chronic stress, were consistently associated with accelerated peripheral epigenetic aging, but brain-specific data are scarce.},
}
@article {pmid42514209,
year = {2026},
author = {Rodríguez-Escobar, ML and Singh Raj, V and Martínez-Peinado, N and Fuentes, AF and Maldonado, C and Gabaldón-Figueira, JC and Alonso-Padilla, J and Bastida, J and Tallini, LR and Torras-Claveria, L},
title = {Phytochemical Characterization and Evaluation of the Anticholinesterase and Anti-Trypanosoma cruzi Potential of Andean Amaryllidaceae from Bolivia: (Pyrolirion boliviense and Stenomesson miniatum).},
journal = {Life (Basel, Switzerland)},
volume = {16},
number = {7},
pages = {},
doi = {10.3390/life16071139},
pmid = {42514209},
issn = {2075-1729},
abstract = {The Amaryllidaceae family is a rich source of structurally diverse alkaloids with recognized neuroactive and antiparasitic properties. This study provides the first phytochemical and biological characterization of Pyrolirion boliviense and wild Stenomesson miniatum from Bolivia. Alkaloid extracts from bulbs and leaves were analysed by GC-MS and evaluated for acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and Trypanosoma cruzi inhibitory activities. Thirty-two Amaryllidaceae alkaloids were identified, with P. boliviense exhibiting greater alkaloid diversity (25 compounds) and S. miniatum a higher total alkaloid content (227.86 vs. 138.92 μg Gal/100 mg DW). P. boliviense bulb extracts showed the strongest cholinesterase inhibition (AChE IC50 = 6.07 ± 0.47 μg·mL[-1]; BuChE IC50 = 30.93 ± 1.17 μg·mL[-1]), whereas S. miniatum extracts displayed weaker AChE inhibition and no detectable BuChE activity. In anti-T. cruzi assays, bulb extracts were the most active, with S. miniatum showing an IC50 of 0.90 ± 0.15 μg·mL[-1] (SI = 20.12) and selective anti-amastigote activity (IC50 = 1.42 ± 0.66 μg·mL[-1]; SI = 12.77). These findings identify Bolivian Andean Amaryllidaceae as promising sources of bioactive alkaloids with potential applications for Alzheimer's disease and Chagas disease drug discovery.},
}
@article {pmid42514272,
year = {2026},
author = {Lai, C and Xia, H and Zhang, Y and He, Y and Wu, X and Ye, B and Yang, H and Zhang, B},
title = {A Comprehensive Review on the Pharmacological Activities and Biosynthetic Strategies of Protocatechuic Acid.},
journal = {Life (Basel, Switzerland)},
volume = {16},
number = {7},
pages = {},
pmid = {42514272},
issn = {2075-1729},
support = {20252BAC220041//Jiangxi Provincial Department of Science and Technology/ ; 32360021//National Natural Science Foundation of China/ ; 32160016//National Natural Science Foundation of China/ ; },
abstract = {Protocatechuic acid (PCA) is a simple natural phenolic acid widely distributed in plants. It is recognized as an active constituent of numerous traditional herbal medicines and serves as an important metabolic intermediate of polyphenolic compounds such as anthocyanins and proanthocyanidins. At present, PCA production relies on plant extraction and microbial fermentation. Among these, microbial fermentation has emerged as an attractive approach for industrial development owing to its process controllability, environmentally benign nature, and potential for high productivity. This review systematically summarizes the major pharmacological properties of PCA, including its antioxidant, anti-inflammatory, antimicrobial, antiviral, anti-aging, neuroprotective, and hepatoprotective activities. It further highlights the therapeutic potential of PCA in the prevention and management of various chronic diseases, such as cancer, diabetes, Alzheimer's disease, and hypertension. Furthermore, this review summarizes the representative microbial biosynthetic pathways for PCA and discusses recent progress in metabolic engineering strategies aimed at enhancing its microbial production. These strategies include reinforcing precursor supply, redirecting metabolic flux toward the shikimate pathway, blocking PCA degradation routes, relieving intracellular feedback regulation, improving host tolerance, and optimizing fermentation processes to achieve higher PCA productivity and yield. Finally, the major bottlenecks limiting PCA biomanufacturing are discussed, and prospective directions for future research are proposed.},
}
@article {pmid42514407,
year = {2026},
author = {Gaffney, M and Ryan, M and Loetscher, T and Singh, B and Murphy, KJ},
title = {Modification of Visual Contrast in the Dining Environment and Its Impact on Dietary Intake in Older Adults-A Systematic Review.},
journal = {Nutrients},
volume = {18},
number = {14},
pages = {},
doi = {10.3390/nu18142338},
pmid = {42514407},
issn = {2072-6643},
abstract = {Background/Objectives: Malnutrition among older adults, particularly those in aged care, is a major contributor to morbidity and healthcare costs. Reduced visual contrast sensitivity, common with ageing and dementia, may impair the ability to distinguish food from tableware, potentially leading to decreased intake. This systematic review examined whether enhancing visual contrast in the dining environment improves dietary intake in older adults. Methods: Following PRISMA guidelines, five databases were searched from inception to March 2025. Studies were eligible if they involved adults aged ≥65 years and used visual contrast interventions (e.g., coloured tableware, lighting adjustments) aimed at improving food or fluid intake. A narrative synthesis was conducted, and study quality was assessed using the Mixed Methods Appraisal Tool. Results: Of 2901 records screened, four studies (five reports) met the inclusion criteria, involving a total of 64 participants. All studies implemented visual contrast enhancements, including high-contrast dishware and environmental modifications. Most reported increases in food or liquid intake, though statistical significance varied. Some studies also evaluated mealtime behaviours, functional abilities, and food waste, with mixed findings. Methodological limitations, including small sample sizes, short interventions, and inconsistent reporting limited the strength of evidence. Conclusions: Limited and low-quality evidence suggests a possible effect of modifying the dining environment to improve visual contrast for enhancing dietary intake in older adults, with visual contrast sensitivity, particularly those with dementia. However, the evidence gap is large and remains inconclusive. Future well-powered trials with standardised interventions and outcome measures are needed to determine whether these strategies can meaningfully reduce malnutrition in aged care settings.},
}
@article {pmid42514574,
year = {2026},
author = {Karageçili, H and Bingöl, Z and Yılmaz, MA and Fidan, M and Karaismailoğlu, MC and Akıncıoglu, H and Gulcin, &#x130;},
title = {Integrated Assessment of Bioactive Properties of Nine Thlaspi Species: Antioxidant Activity, Enzyme Inhibition and LC-MS/MS Polyphenolic Characterization.},
journal = {Plants (Basel, Switzerland)},
volume = {15},
number = {14},
pages = {},
doi = {10.3390/plants15142207},
pmid = {42514574},
issn = {2223-7747},
abstract = {Brassicaceae plants, among the most widely consumed vegetables worldwide, are recognized as rich sources of biologically active compounds. In this study, nine species belonging to the cruciferous genus Thlaspi were investigated, including T. alliaceum, T. arvense, T. violascens, T. aghricum, T. cataonicum, T. annuum, T. watsonii, T. cariense, and T. elegans. In the past, pennycress species were consumed to alleviate hunger and provide nutritional support during periods of food scarcity. To evaluate the antioxidant capacities of methanol and water extracts obtained from Thlaspi species, several complementary assays were employed, including 2,2'-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid radical (ABTS[•+]) scavenging, 1,1-diphenyl-2-picrylhydrazyl free radicals (DPPH[•]) scavenging, N,N-dimethylphenylenediamine radicals (DMPD[•+]) scavenging, Fe[3+]-2,4,6-tris(2-pyridyl)-s-triazine (TPTZ)-reducing, Fe[3+] ion-reducing, and Cu[2+] ion-reducing assays. The IC50 values of both methanol and water extracts from the aerial parts of Thlaspi species for ABTS[•+], DPPH[•], and DMPD[•+] scavenging activities were studied compared with antioxidant standards, including α-tocopherol, Trolox, butylated hydroxytoluene (BHA), and butylated hydroxyanisole (BHT). The total phenolic and flavonoid contents of the extracts ranged from 8.29 to 49.14 mg gallic acid equivalent (GAE)/g extract and from 2.33 to 74.66 mg quercetin equivalent (QE)/g extract, respectively. Furthermore, the inhibitory effects of water and methanol extracts of Thlaspi species against α-amylase, acetylcholinesterase (AChE), and carbonic anhydrase (CA II) enzymes were evaluated. The IC50 values were determined to range from 122.4 to 245.9 μg/mL for α-amylase, from 17.3 to 24.1 μg/mL for AChE, and from 41.9 to 256.5 μg/mL for CA II inhibition. In addition, the phenolic profiles of Thlaspi species were comprehensively characterized by LC-MS/MS analysis using 53 reference standards. The findings demonstrated that the aerial parts of Thlaspi species are rich in polyphenolic antioxidants and may serve as promising natural sources with potential applications in the management of diabetes, Alzheimer's disease (AD), glaucoma, epilepsy, and cancer.},
}
@article {pmid42514879,
year = {2026},
author = {Osmanlioglu Dag, SR and Alagoz, MA},
title = {Dual Targeting of AChE Inhibition and GPX4 Binding by Plant-Derived Compounds for the Treatment of Alzheimer's Disease: Insights from Molecular Docking and Molecular Dynamics Simulations.},
journal = {Pharmaceutics},
volume = {18},
number = {7},
pages = {},
doi = {10.3390/pharmaceutics18070798},
pmid = {42514879},
issn = {1999-4923},
support = {TSA-2025-4366.//Inonu University/ ; },
abstract = {Background/Objectives: Alzheimer's disease (AD) is primarily characterized by cholinergic dysfunction, for which acetylcholinesterase (AChE) inhibition remains the mainstay of symptomatic treatment. However, additional hypotheses such as ferroptosis-an iron-dependent form of regulated cell death-have gained prominence in explaining disease progression. Glutathione peroxidase 4 (GPX4), a critical antioxidant enzyme, plays a protective role by suppressing ferroptotic pathways. In this context, identifying phytochemicals capable of inhibiting AChE and exhibiting activator-like binding toward GPX4 may provide a dual therapeutic benefit. This study aimed to identify such dual-acting compounds through a structure-based virtual screening approach. Methods: A total of 3014 natural compounds were collected from three curated databases: NPACT, HIT, and HIM. Molecular docking was performed against GPX4 (7U4I) and AChE (7D9Q). Compounds demonstrating high affinity for both targets were shortlisted. Z-score normalization and statistical ranking were used to select the best two dual-target compounds. Results: Out of 3014 compounds, 68 showed dual-binding potential. Among these, NPACT00189 (docking scores: -6.720 kcal/mol for GPX4; -8.983 kcal/mol for AChE) and NPACT01210 (docking scores: -5.813 kcal/mol for GPX4; -9.640 kcal/mol for AChE) were identified as top candidates based on docking scores. Molecular dynamics (MD) simulations were conducted for both compounds for 250 ns on the AChE binding site and the allosteric site of GPX4. The results indicated that NPACT00189 maintained stable interactions throughout the simulation period at both targets, indicating its dual-targeting potential. Conclusions: NPACT00189 represents a promising dual-target candidate for further investigation in AD therapy. Its potential requires confirmation through comprehensive in vitro and in vivo studies.},
}
@article {pmid42514962,
year = {2026},
author = {Chen, C and Leung, C and Zhai, Z and Wang, G and Yang, R and Hu, Q and Yue, X and Yao, Z and Zhao, Z and Zhang, X},
title = {Feasibility Study of Nose-to-Brain Delivery of Galantamine for Alzheimer's Disease: Enhancing Olfactory-Region Deposition to Improve Therapeutic Efficacy.},
journal = {Pharmaceutics},
volume = {18},
number = {7},
pages = {},
doi = {10.3390/pharmaceutics18070885},
pmid = {42514962},
issn = {1999-4923},
support = {2025A1515010639//Natural Science Foundation of Guangdong Province/ ; },
abstract = {Background: Alzheimer's disease (AD) is the seventh leading cause of death worldwide, posing a substantial global health burden. Although galantamine (GNT) is a first-line clinical drug for AD treatment, its therapeutic efficacy is constrained by inefficient brain delivery across the blood-brain barrier (BBB). Nose-to-brain delivery represents a promising route to bypass the BBB. However, its efficiency remains limited by insufficient drug deposition in the anatomically restricted olfactory region. In this study, we developed a galantamine nasal spray (GNT-NS) with enhanced olfactory region deposition and evaluated its feasibility for nose-to-brain delivery in AD treatment. Methods: We optimized the formulation by systematically investigating the cascade relationship among formulation physicochemical properties, spray performance, and olfactory region deposition. Nasal deposition distribution was quantitatively evaluated using a physiologically realistic 3D-printed human nasal cavity model reconstructed from clinical magnetic resonance imaging (MRI) data. Further, the in vivo biodistribution and therapeutic efficacy of GNT-NS were evaluated in AD rats. Results: The optimized formulation P3 achieved an olfactory region fraction of 23.85%, markedly exceeding that of the unoptimized formulation P0. Subsequent in vivo biodistribution studies showed that P3 produced higher brain drug exposure than both intranasally administered P0 and the commercial oral formulation. Further pharmacodynamic studies demonstrated that GNT-NS significantly improved cognitive and behavioral deficits in AD rats, exhibiting superior therapeutic efficacy over commercially available oral galantamine tablets. Conclusions: Collectively, this study proposes a cascade regulation strategy linking formulation physicochemical properties, spray performance, and olfactory region deposition and demonstrates that optimizing nasal spray properties can enhance olfactory deposition, increase brain exposure and improve therapeutic efficacy. These findings provide a useful reference for the design of nose-to-brain delivery formulations for AD and other central nervous system diseases.},
}
@article {pmid42514986,
year = {2026},
author = {Ziaka, M},
title = {A Comprehensive Review of the Gut-Microbiota-Brain Axis in Alzheimer's Disease: From Pathophysiology to Potential Therapies.},
journal = {Pathogens (Basel, Switzerland)},
volume = {15},
number = {7},
pages = {},
doi = {10.3390/pathogens15070659},
pmid = {42514986},
issn = {2076-0817},
abstract = {The gut-microbiota-brain axis (GMBA), an intricate network connecting the gastrointestinal (GI) tract and the brain, plays a pivotal role in maintaining overall health and influencing disease processes. The human gut microbiota, comprising over 3000 bacterial species, regulates immune responses, hormonal signals, and metabolite production, maintaining homeostasis under normal conditions. Dysbiosis, or microbial imbalance, has been linked to various central nervous system (CNS) disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and autism spectrum disorder (ASD). Given the growing interest in this topic and the limited effectiveness of current therapeutic strategies for managing patients with AD, the purpose of the current narrative review is to analyze the pathophysiological role of the GMBA in the pathogenesis of AD and assess potential therapeutic strategies targeting the GMBA, particularly the microbiome and its metabolites. A comprehensive literature search was conducted using PubMed, Scopus, and Web of Science to identify clinical studies, experimental research, and review articles examining the GMBA in health and AD, as well as related therapeutic strategies. The search terms included "Alzheimer's disease", "neuroinflammation", "amyloid-beta", "tau", "gut-brain axis", "microbiome", "short-chain fatty acids", "probiotics", "prebiotics", and "fecal microbiota transplantation". In AD, altered gut microbiota composition is associated with neuroinflammation, neurodegeneration, and exacerbation of disease progression. Probiotics have shown potential in enhancing cognitive function and reducing neuroinflammation by modulating microbiota composition and influencing brain-derived neurotrophic factor (BDNF) levels. Prebiotics, through their impact on gut microbiota and metabolite production, also offer therapeutic promise by improving cognitive function and mitigating neuroinflammation. With its historical and modern applications, fecal microbiota transplantation (FMT) may represent a potential strategy for addressing dysbiosis and its neurological implications. This manuscript focuses on GMBA and its effects on neuroinflammation, neurodegeneration, and CNS health while emphasizing the need for further research into microbiome-based therapies and the gut-brain relationship in patients with AD.},
}
@article {pmid42515114,
year = {2026},
author = {Penalva-Olcina, R and Franco-Campos, F and Taroncher, M and Ruiz, MJ and Fernández-Franzón, M},
title = {Mechanistic Evidence Mapping Ochratoxin A Toxicity onto Alzheimer's Disease-Relevant Neurodegenerative Pathways: A Systematic Review of Experimental Models.},
journal = {Toxics},
volume = {14},
number = {7},
pages = {},
doi = {10.3390/toxics14070549},
pmid = {42515114},
issn = {2305-6304},
support = {PID2024-160527OB-I00//Ministry of Science and Information/ ; },
abstract = {Ochratoxin A (OTA) is a prevalent foodborne mycotoxin that has been increasingly recognized as a potential environmental contributor to neurodegenerative diseases. Despite extensive research, a systematic integration of how OTA replicates the specific pathological hallmarks of Alzheimer's Disease (AD) is currently lacking. This study provides a comprehensive systematic review of the mechanistic evidence linking OTA exposure to AD-related pathways, utilizing the Adverse Outcome Pathway (AOP) framework to categorize complex toxicological data into biological key events (KEs). A systematic literature search was conducted across PubMed, Scopus, and Web of Science. A total of 24 peer-reviewed articles were selected for synthesis, comprising 14 in vitro studies and 10 in vivo investigations. The integrated evidence demonstrates that OTA exposure triggers a robust toxicological cascade that replicates several key mechanistic pathways associated with AD in experimental models. Early molecular triggers involve significant redox imbalance and mitochondrial bioenergetic failure, which serve as catalysts for sustained neuroinflammation and microglial activation. In vivo data, from multiple animal models, consistently show that these cellular dysfunctions culminate in structural damage. This systematic integration provides a clearer roadmap for future risk assessment and emphasizes the urgent need for refined regulatory guidelines to protect neurological health from chronic mycotoxin exposure.},
}
@article {pmid42515635,
year = {2026},
author = {Lawal, AO and Jacob, IB and Karnik, V and Fan, H and Thangamani, S and Massa, PT and Wang, G},
title = {Neuroinflammation, Pericyte Dysfunction, and Alzheimer's Disease-Associated Gene Expression and Pathway Activation in the Brain of SARS-CoV-2-Infected Mice.},
journal = {Viruses},
volume = {18},
number = {7},
pages = {},
doi = {10.3390/v18070783},
pmid = {42515635},
issn = {1999-4915},
abstract = {SARS-CoV-2 infection leads to extrapulmonary complications in multiple organs, including the brain, both in the short-term and long-term. The neurological manifestation of SARS-CoV-2 infection ranges from benign signs like loss of smell and loss of taste to severe complications like encephalitis, stroke, and exacerbation of Alzheimer's disease (AD) progression. Pericytes are mural cells of the brain vasculature that help maintain the blood-brain barrier (BBB), regulate cerebral blood flow (CBF), modulate neuroinflammation, and clear toxic materials, including amyloid beta. Pericytes express ACE2, the receptor for SARS-CoV-2, and therefore may be targeted by either direct virus infection or virus-induced inflammatory cytokines induced by the virus in the brain. To further study the effects of SARS-CoV-2 on pericytes and BBB integrity, the long-term effects of SARS-CoV-2 infection on brain pericytes, inflammation, and other neuropathological complications were analyzed in mice. K18 (human ACE2 transgenic) mice were infected with 10[3] PFU of SARS-CoV-2 (delta strain), and the brains were analyzed at 6, 14, and 30 days post-infection (dpi). A significant reduction in the weight of infected mice was observed by 6 dpi. Viral nucleocapsid protein and infectious SARS-CoV-2 were observed in the brains of all mice by 6 dpi, and in some mice by 14 dpi, but not at 30 dpi. This observation suggests viral neurotropism with subsequent clearance at later timepoints. Despite virus clearance, the levels of inflammatory mediators, including TNF-α and IFN-γ were significantly elevated up to 30 dpi. We also observed a significant reduction in the level of brain pericytes by 14 dpi up to 30 dpi. Importantly, an increase was observed in the level of Friend Leukemia Integration 1 (FLI-1), a transcription factor known to promote pericyte cell death, from 14 dpi up to 30 dpi. The level of amyloid beta 1-42 was elevated in the brain of infected mice at 6 dpi, and this was maintained up to 30 dpi, and there was a decrease in neuronal density from 14 to 30 dpi. Furthermore, we observed an increased expression of Alzheimer's disease (AD)-associated genes like PSEN1, BACE1, and APP. Furthermore, there was increased activation of several neurodegenerative pathways, including "G alpha (z) signaling pathway", "Apelin muscle signaling pathway", and "G beta-gamma (Gβγ) signaling", in the brains of infected mice compared to control mice. Collectively, the observed neuropathology and unique molecular markers of neurodegenerative disease progression provide a novel mechanism by which COVID-19 may promote dementia/AD by contributing to pericyte loss and BBB dysfunction during infection.},
}
@article {pmid42515671,
year = {2026},
author = {Su, G and Wang, Y and Yao, L},
title = {Research Trends and Emerging Frontiers in Proteolysis Targeting Chimeras (PROTACs): A Bibliometric Analysis of 2630 Publications (2001-2025).},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {7},
pages = {},
doi = {10.3390/ph19070988},
pmid = {42515671},
issn = {1424-8247},
abstract = {Background/Objectives: Proteolysis Targeting Chimeras (PROTACs) are heterobifunctional small molecules that induce ubiquitin-proteasome-mediated degradation of target proteins and have matured from proof-of-concept chemistry to a clinically validated therapeutic modality, with the first Phase 3 readout reported in 2025. A systematic bibliometric analysis covering this pivotal-trial era, however, has been lacking. This study aimed to map the historical trajectory, current research front, and emerging frontiers of PROTAC research. Methods: We analyzed 2630 PROTAC-related publications indexed in the Web of Science Core Collection (WoSCC) from 2001 to 2025 using a combined toolkit of CiteSpace, HistCite, the Alluvial Generator, and R (ggplot2), covering co-occurrence networks, burst detection, keyword clustering, citation historiography, alluvial flow analysis, and reference co-citation timeline visualization. Results: China and the USA led global output, and the Chinese Academy of Sciences, China Pharmaceutical University, and Harvard University were the most productive institutions; the Journal of Medicinal Chemistry was the leading publishing venue, and Alessio Ciulli, Jian Jin, and Craig M. Crews anchored the author network. Keyword burst analysis showed that early research centred on E3 ubiquitin ligase recruitment and small-molecule PROTAC design, whereas the current hotspots, resolved through keyword clustering and co-citation timelines, included structural basis and ternary complex design, EGFR-directed degradation, oral bioavailability optimization, applications in multiple myeloma and Alzheimer's disease, tumour-targeted delivery, and computational/AI-driven design. Conclusions: This study extends the bibliometric record of PROTACs across 2001-2025 and identifies oral bioavailability, E3 ligase repertoire expansion, and CNS-penetrant degrader design as the emerging frontiers likely to shape the next phase of the field.},
}
@article {pmid42515707,
year = {2026},
author = {Mella, J and Vega-Muñoz, A and Soto, M and Moraga, D and Campanini-Salinas, J and Sandoval-Obando, E and Contreras-Barraza, N and Salazar-Sepúlveda, G and Salas-Guzmán, N and Carabantes-Silva, R and Mellado, M},
title = {Evolution of Multitarget Strategies for Alzheimer's Disease: From Cholinergic Inhibition to Network-Oriented Therapeutic Design (2006-2025).},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {7},
pages = {},
doi = {10.3390/ph19071024},
pmid = {42515707},
issn = {1424-8247},
support = {Puente de Investigaci&#xf3;n UCEN Convocatoria A&#xf1;o 2025 grant CIPPTE202505//Central University of Chile/ ; },
abstract = {Background: Alzheimer's disease (AD) is a complex neurodegenerative disorder and a major global health challenge. The traditional "one drug-one target" paradigm has shown limitations in addressing its multifactorial nature. Multitarget-directed ligands (MTDLs), designed to modulate multiple pathological pathways, have emerged as a promising therapeutic strategy. Objectives: To examine the structural, thematic, and temporal evolution of multitarget strategies for AD treatment between 2006 and 2025. Methods: A total of 1184 Web of Science-indexed articles were analyzed. Publication growth, h-index, author productivity, institutional and national contributions, and keyword co-occurrence networks were evaluated using VOSviewer. Bibliometric laws (Price, Bradford, Zipf, and Lotka) were applied to characterize productivity patterns and thematic organization. Results: Multitarget research shows exponential growth, suggesting a consolidation of the MTDL paradigm. China, India, the United States, Italy, and Spain were the most productive countries. Early studies focused on cholinesterase inhibition, particularly acetylcholinesterase-based hybrids. The field expanded to include β-amyloid aggregation, oxidative stress, metal chelation, and blood-brain barrier permeability. Recent trends emphasize integration of computational approaches, including molecular docking, molecular dynamics, virtual screening, and network pharmacology, alongside targets such as BACE1 and GSK-3β. Conclusions: Multitarget strategies have evolved toward a systems-oriented framework. Despite advances, challenges remain in reducing cholinesterase dependency and improving translational validation. This study provides a framework to interpret therapeutic evolution and guide future network-based drug design.},
}
@article {pmid42515735,
year = {2026},
author = {Rosiak, N and Stojceski, F and Maroni, G and Piontek, B and Cielecka-Piontek, J},
title = {Integrative Network Pharmacology and Molecular Docking Analysis Reveals the Multitarget Mechanisms of Pterostilbene in Neurodegenerative Diseases.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {7},
pages = {},
doi = {10.3390/ph19071053},
pmid = {42515735},
issn = {1424-8247},
support = {UMO-2020/37/B/NZ7/03975//National Science Centre/ ; },
abstract = {Background: Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), differ in etiology but share several convergent pathological mechanisms. Pterostilbene (PTR) is a natural stilbene with reported antioxidant, anti-inflammatory, and neuroprotective properties. This study aimed to prioritize putative PTR-associated targets and biological processes potentially relevant to shared neurodegenerative mechanisms. Methods: An integrative in silico workflow combining network pharmacology, protein-protein interaction (PPI) analysis, GO Biological Process (GO BP) enrichment, molecular docking, and molecular dynamics (MD) simulations was applied. GO BP terms were filtered, focused on neurodegeneration- and neuroprotection-related processes, and subjected to REVIGO-based redundancy reduction. Selected targets were further evaluated by docking and 500 ns MD simulations. Results: A total of 181, 165, 128, and 109 shared PTR-disease targets were identified for AD, PD, HD, and ALS, respectively. Redundancy-reduced GO BP analysis indicated associations with neuroinflammation, oxidative stress and reactive oxygen species-related responses, programmed cell death, MAPK/ERK- and PI3K/AKT-related signaling, ion and calcium transport, and lipid-, steroid-, or hormone-associated regulation. PPI topology prioritized SRC, ESR1, and HSP90AA1 as recurrent hub-bottleneck proteins, whereas MD-based structural interpretation focused on ESR1 and HSP90AA1. MD analyses indicated stable PTR interactions with both proteins, with ESR1 showing the most favorable predicted interaction profile. Conclusions: These findings suggest that PTR may interact with shared neurodegeneration-relevant molecular systems, particularly through ESR1- and HSP90AA1-associated mechanisms. However, the results are exclusively computational and should be interpreted as hypothesis-generating, requiring further experimental validation.},
}
@article {pmid42515744,
year = {2026},
author = {Takomthong, P and Waiwut, P and Kongkiatpaiboon, S and Phemphunananchai, K and Boonyarat, C},
title = {Multi-Targeted Anti-Alzheimer's Effects of Tri-Sannibat-Phol: Biological Evaluation, Behavioral Validation, and LC-MS/MS Phytochemical Profiling.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {7},
pages = {},
doi = {10.3390/ph19071063},
pmid = {42515744},
issn = {1424-8247},
support = {B13F680065//NSRF via the Program Management Unit for Human Resources &amp; Institutional Development, Research and Innovation, Thailand/ ; B38G670003//Program Management Unit for Human Resources &amp; Institutional Development, Research and Innovation, Thailand/ ; //Faculty of Pharmaceutical Sciences, Khon Kaen University/ ; //Ubon Ratchathani University/ ; //BCG Economy and Sustainable Development Network through Center of Excellence Consortium under the Reinventing University System (Khon Kaen University),Visiting Professor Program 2025, Thailand/ ; },
abstract = {Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by oxidative stress, cholinergic dysfunction, and amyloid-β (Aβ) aggregation. Tri-Sannibat-Phol (TSB), a classical Thai polyherbal formulation comprising Piper retrofractum fruit, Ocimum tenuiflorum root, and Piper nigrum root, has been traditionally used for its medicinal properties, yet its anti-AD potential has never been scientifically evaluated. Methods: The therapeutic potential of TSB was investigated through in vitro bioassays including antioxidant, acetylcholinesterase (AChE) inhibitory, and anti-Aβ aggregation assays, alongside neuroprotective evaluation in H2O2-induced SH-SY5Y neuroblastoma cells. Acute oral toxicity was assessed in male ICR mice in accordance with OECD Guideline 420. Cognitive-enhancing effects were evaluated using the modified Y-maze, Novel Object Recognition, and Morris Water Maze tests in a scopolamine-induced amnesic mouse model. LC-MS/MS analysis was performed for phytochemical characterization and chemical standardization of the formulation. Results: TSB demonstrated significant antioxidant activity, AChE inhibitory activity, and anti-Aβ aggregation effects, with P. nigrum and O. tenuiflorum identified as the primary contributing components. Neuroprotective effects were confirmed in H2O2-induced SH-SY5Y cells, where TSB significantly improved cell viability across concentrations of 1-100 µg/mL. Acute oral toxicity assessment revealed an LD50 exceeding 2000 mg/kg, indicating a favorable safety profile. In vivo behavioral studies demonstrated that TSB at medium-to-high doses significantly reversed scopolamine-induced cognitive deficits across all three behavioral tests. LC-MS/MS analysis identified thirteen piperidine alkaloids, with piperine as the dominant constituent at 17.61 ± 0.80% w/w, proposed as the primary bioactive driver and chemical marker for future quality standardization. Conclusions: These findings suggest that TSB exerts multi-targeted anti-AD effects through complementary mechanisms, supporting its potential as a traditional medicine-based therapeutic candidate for further preclinical and clinical investigation.},
}
@article {pmid42515760,
year = {2026},
author = {Yeysin, L and Akın, D and Çalışkan, S and Hasanoğlu Özkan, E and Hashem, H and Akocak, S and Bräse, S and Çete, S},
title = {Recent Advances in Pyrazole-Based Cholinesterase Inhibitors: Medicinal Chemistry Perspectives from 2020 to 2025.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {7},
pages = {},
doi = {10.3390/ph19071079},
pmid = {42515760},
issn = {1424-8247},
abstract = {Pyrazole derivatives have attracted considerable interest in medicinal chemistry as adaptable frameworks for developing cholinesterase inhibitors, owing to their advantageous physicochemical properties and structural flexibility. The heteroaromatic characteristics of the pyrazole core allow for various substitution patterns, promoting selective interactions with both the catalytically active site (CAS) and the peripheral anionic site (PAS) of cholinesterase enzymes. These attributes enable pyrazole-based drugs to be viable candidates for the therapy of cognitive disorders, especially Alzheimer's disease. This study aims to systematically describe medicinal chemistry studies on pyrazole-based cholinesterase inhibitors conducted from 2020 to 2025. The focus is on structural alterations of the pyrazole core and their impact on the inhibitory action against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) using structure-activity relationship (SAR) analysis. Recent advancements in in vitro enzymatic inhibition studies, molecular docking, kinetic analysis, ADME predictions, and multi-target-directed ligand (MTDL) techniques are rigorously evaluated to elucidate trends in potency, selectivity, and drug-like characteristics based on information retrieved from three search engines: Scopus, PubMed, and Google Scholar. This review addresses significant challenges in pharmacokinetics, blood-brain barrier permeability, and safety while delineating prospects for integrating rational design, computational modeling, and biological validation to expedite the development of clinically relevant pyrazole-based cholinesterase inhibitors for Alzheimer's disease.},
}
@article {pmid42515850,
year = {2026},
author = {Valletta, M and Vetrano, DL and Laukka, EJ and Kalpouzos, G and Oltra, J and Rizzuto, D and Canevelli, M and Fredolini, C and Qiu, C and Winblad, B and Fratiglioni, L and Grande, G},
title = {Blood Biomarkers of Alzheimer's Disease and Patterns of Structural Brain Changes in the Community.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78309},
pmid = {42515850},
issn = {1531-8249},
abstract = {OBJECTIVE: We aimed to investigate the associations between Alzheimer's disease (AD)-related blood biomarkers and changes in brain volumes and cerebrovascular burden in community-dwelling older adults.<br><br>METHODS: We included 361 dementia-free participants with a Mini-Mental State Examination (MMSE) score &#x2265;&#x2009;27 and without prior cerebrovascular events from a Swedish population-based study. Blood phosphorylated-tau217 (p-tau217), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were measured at baseline. Brain magnetic resonance imaging (MRI) was performed at baseline and after 3 and/or 6&#x2009;years. Linear mixed models were used to examine associations between AD-related blood biomarkers and changes in volumes of total brain tissue (TBTV), lateral ventricles, hippocampus, amygdala, and white matter hyperintensities (WMHs).<br><br>RESULTS: During the follow-up, higher p-tau217 was associated with faster volume loss in the hippocampus (&#x3b2;*year = -0.047, 95% confidence interval [CI] = -0.077 to -0.018) and in the amygdala (&#x3b2;*year = -0.064, 95% CI = -0.105 to -0.022). Elevated GFAP was linked to faster TBTV decline (&#x3b2;*year = -0.040, 95% CI = -0.059 to -0.021), ventricular enlargement (&#x3b2;*year&#x2009;=&#x2009;0.028, 95% CI&#x2009;=&#x2009;0.013 to 0.042), and hippocampal shrinkage (&#x3b2;*year = -0.038, 95% CI = -0.064 to -0.013). Participants with higher NfL showed steeper TBTV decline, ventricular enlargement, hippocampal and amygdala shrinkage, and faster WMH accumulation. Results remained largely consistent after excluding participants with mild cognitive impairment at baseline.<br><br>INTERPRETATION: In cognitively unimpaired older adults, elevated blood p-tau217 was linked to faster shrinkage in AD-specific brain regions, whereas NfL and GFAP were associated with more widespread atrophy, with NfL also associated with accelerated WMH accumulation. These findings suggest that AD-related blood biomarkers may capture different dementia-related structural brain changes already at early stages. ANN NEUROL 2026.},
}
@article {pmid42515851,
year = {2026},
author = {Luo, P and Yang, X and Gao, K and Le, J and Xian, S and Zheng, M and Cai, J and Wang, M and Liang, H and Xiao, Z and Cui, W and Sun, Q},
title = {Subacute Toxicological Evaluation of 9-Methylfascaplysin, a Marine-Derived Neuroprotective Compound, via an Integrated Multiomics Approach.},
journal = {Journal of applied toxicology : JAT},
volume = {},
number = {},
pages = {},
doi = {10.1002/jat.70364},
pmid = {42515851},
issn = {1099-1263},
support = {2023YFFO724802//National Key Research and Development Program of China/ ; 2026C02A1153//Zhejiang Provincial Applied Basic Research Program/ ; 82271443//National Natural Science Foundation of China/ ; LMS25H090007//Natural Science Foundation of Zhejiang Province/ ; 2024Z191//Ningbo Key Science and Technology Development Program/ ; 2025Z184//Ningbo Key Science and Technology Development Program/ ; 2025HY1010//Zhejiang Provincial Health Industry Science and Technology Plan/ ; //Li Dak Sum Yip Yio Chin Kenneth Li Marine Biopharmaceutical Development Fund/ ; //K. C. Wong Magna Fund in Ningbo University/ ; },
abstract = {9-Methylfascaplysin (9-MF) is a novel marine-derived neuroprotective compound with potential for the development as a therapeutic agent for Alzheimer's disease and ischemic stroke. However, its systematic toxicological profile remains to be fully characterized. In this study, the subacute toxicity of 9-MF was evaluated in male and female Sprague-Dawley rats following 14 consecutive days of intravenous administration. 9-MF at 1-5 mg/kg did not induce significant alterations in body weight, food consumption, motor function, or anxiety-like behavior. Sex-dependent sensitivity to 9-MF-induced hepatotoxicity was observed. Furthermore, 9-MF induced mild hepatic inflammation, red pulp hemorrhage in the spleen, inflammatory cell infiltration, and alveolar septal thickening in the lung, as well as mild neuronal degeneration and structural loosening in the dentate gyrus region of the brain. Integrated transcriptomic, proteomic, and metabolomic analyses further revealed that 5 mg/kg 9-MF regulated 6-pyruvoyltetrahydropterin synthase-centered biopterin metabolism, arachidonate 15-lipoxygenase-centered linoleate metabolism, and the mTOR pathway in the brain, as well as SMPD4/phytosphingosine-centered sphingolipid metabolism, PLA2G2A-centered arachidonic acid metabolism, and GMPR-centered porphyrin metabolism in the blood, contributing to the observed abnormalities. These findings not only provided a toxicological basis for the further drug development of 9-MF but also served as an example of a toxicological study integrating traditional assessments with multiomics strategies.},
}
@article {pmid42515874,
year = {2026},
author = {Ruankham, P and Thiankhaw, K and Chattipakorn, N and Chattipakorn, SC},
title = {Targeting the Adipose-Brain Axis: Adipokines as Key Modulators of Cognitive Dysfunction.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X483381260714095824},
pmid = {42515874},
issn = {1875-6190},
abstract = {INTRODUCTION: Adipose tissue is an active endocrine organ that secretes adipokines capable of modulating brain function through metabolic, inflammatory, vascular, and neurotrophic pathways. Emerging evidence suggests that dysregulated adipokine signaling contributes to cognitive decline and neurodegeneration by impairing neuronal energy metabolism, mitochondrial function, insulin signaling, and synaptic plasticity, while amplifying oxidative stress and neuroinflammation. Therefore, this review aimed to summarize and discuss the potential roles of adipokines in brain health, particularly cognitive function, based on findings from preclinical and clinical studies.<br><br>METHODS: The search strategy incorporated combinations of keywords and MeSH terms, including: "adipokine*", "leptin", "adiponectin", "resistin", "brain", "cognition", "cognitive decline", "dementia", "Alzheimer's disease", "aging", and "metabolic dysfunction".<br><br>RESULTS: Preclinical studies demonstrate the neuroprotective effects of adipokines such as leptin, adiponectin, and C1q/TNF-Related Protein-3 (CTRP3), which act through AMPK, PI3K/Akt, sirtuin, and anti-inflammatory signaling pathways to preserve neuronal survival and cognitive function. In contrast, adipokines including resistin, Dipeptidyl Peptidase-4 (DPP-4), Angiopoietin-like protein 4 (ANGPTL4), and visfatin may exacerbate neurodegeneration by promoting insulin resistance, amyloidogenic processing, mitochondrial dysfunction, oxidative stress, and chronic inflammation. However, clinical studies in aging populations have reported paradoxical associations between elevated circulating adipokine levels and worse cognitive outcomes, potentially reflecting compensatory upregulation, adipokine resistance, altered body composition, or age-related metabolic dysregulation.<br><br>CONCLUSION: This review highlights mechanistic and clinical evidence supporting adipokines as promising biomarkers and therapeutic targets for modulating the adipose-brain axis to prevent or slow cognitive decline.},
}
@article {pmid42515891,
year = {2026},
author = {Jia, J},
title = {Glycogen Synthase Kinase-3β in Alzheimer's Disease: Targets for Therapy and Imaging.},
journal = {Current topics in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115680266497019260720045602},
pmid = {42515891},
issn = {1873-4294},
abstract = {Glycogen synthase kinase-3β (GSK-3β) is a key regulator of the pathogenesis of Alzheimer's disease (AD), capable of simultaneously modulating core pathological processes such as amyloid-β (Aβ) deposition, tau protein hyperphosphorylation, synaptic damage, and neuroinflammation. Therefore, it has become one of the core druggable molecular nodes for AD intervention. This review is mainly divided into two parts. The first part focuses on the GSK-3β inhibitors that have been validated in AD-related cell and animal models. These inhibitors are specifically classified into four categories: metal ion-based compounds, adenosine triphosphate (ATP)-competitive inhibitors, non-ATP-competitive inhibitors, and multi-target inhibitors. The second part focuses on GSK-3β-specific positron emission tomography (PET) radioligands, which can non-invasively monitor GSK-3β enzyme activity in vivo, providing quantitative in vivo molecular imaging tracers for the study of AD pathogenesis and quantitative assessment of treatment effects. This review systematically summarizes GSK-3β-related inhibitors and PET radioligands in AD, thereby providing key references for the rational design of next-generation AD therapeutic drugs and diagnostic agents.},
}
@article {pmid42515906,
year = {2026},
author = {Mailavaram, RP and Chaudhari, Y and S Tarwani, R and Venugopala, KN and Ghosh, M and Maity, P and Deb, PK},
title = {A Comprehensive Review of Phosphodiesterases 4 (PDE4) Inhibitors in Clinical Trials.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128436242260714073027},
pmid = {42515906},
issn = {1873-4286},
abstract = {Phosphodiesterase 4 (PDE4) facilitates the enzymatic breakdown of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), through its four distinct isotypes, namely PDE4A to PDE4D, along with more than 25 splice variants. It plays a crucial role in cancer development, respiratory issues such as asthma and chronic obstructive pulmonary disease (COPD), autoimmune diseases like psoriasis, and neurological disorders such as Alzheimer's disease. Various methods are being developed to enhance clinical efficacy and reduce side effects. Some of these methods include drug delivery via inhalation and the development of non-emetic PDE4 inhibitors and mixed PDE inhibitors. These inhibitors offer several advantages over traditional formulations, including selectivity for specific inhibitors, targeted tissue distribution, and oral effectiveness. All these efforts have led to the emergence of novel PDE4 inhibitors, with some having progressed to clinical trial stages and others approved as medications. This review summarises PDE4 inhibitors currently in clinical trials, highlighting their therapeutic potential, limitations, and future prospects.},
}
@article {pmid42515913,
year = {2026},
author = {Liu, C and Liu, BP and Pan, F and Larbi, A and Ng, TP and Lu, Y},
title = {Depression and Risk of Alzheimer's Disease: A Mendelian Randomization Study.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050477354260714063740},
pmid = {42515913},
issn = {1875-5828},
abstract = {INTRODUCTION/BACKGROUND: Recent studies show that depression often occurs years before Alzheimer's disease onset in many older adults. However, it is unclear whether this link reflects a causal relationship.<br><br>MATERIALS AND METHODS: Summary statistics from Genome-Wide Association Studies (GWAS) of depression and Alzheimer's disease were utilized. Data associated with broad depression included up to 407,746 Europeans, and data associated with major depression disorder included up to 480,359 Europeans; the corresponding Alzheimer's disease associations from consortia included up to 488,285 European participants in the UK Biobank. Two-sample Mendelian randomization analyses served as our primary approach, with additional three-sample analyses performed to validate the findings.<br><br>RESULTS: In the sample of 407,746 participants, genetically predicted levels of broad depression showed no significant association with Alzheimer's disease risk (odds ratio, 1.00007; p = 0.908). As for the sample of 480,359 participants associated with major depressive disorder, the result was consistent (odds ratio, 0.99918, p = 0.138) with findings from broad depression. Secondary analyses present consistent results with primary findings. Statistically significant bias from pleiotropy or genetic confounding was not detected in sensitivity analyses.<br><br>DISCUSSION: The study's findings do not support a causal role of depression in AD and are more consistent with depression reflecting early disease processes or shared mechanisms.<br><br>CONCLUSION: This study's Mendelian randomization approach revealed no causal relationship between depression and Alzheimer's disease, consistent with depression reflecting early disease manifestations rather than a direct causal factor, and hinting at possible shared pathological processes in both conditions.},
}
@article {pmid42515916,
year = {2026},
author = {Saini, M and Hooda, T and Dar, MO and Kumar, S and Khatri, R and Lather, A},
title = {Network Pharmacology-guided Target Evaluation of Nefopam for Alzheimer's Disease: Insights from Docking and Molecular Dynamics Simulations.},
journal = {Current computer-aided drug design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115734099474093260712091739},
pmid = {42515916},
issn = {1875-6697},
abstract = {INTRODUCTION: Amyloid-β accumulation, aberrant tau protein, neuroinflammation, and oxidative stress are some of the main pathogenic characteristics of Alzheimer's disease (AD), a degenerative illness characterized by cognitive deterioration. The majority of current AD therapies provide symptomatic alleviation with significant adverse effects, highlighting the urgent need for novel therapeutic approaches.<br><br>OBJECTIVE: This study examines nefopam, a centrally acting analgesic with NMDA antagonist and monoaminergic properties, as a potential treatment for AD using in silico methods like Network Pharmacology, Docking, and Molecular Dynamics Simulation studies.<br><br>RESULTS: Using network pharmacology, 90 molecular targets shared by the AD and nefopam pathways were identified. Following the selection of important hub proteins for further analysis, eight proteins with accessible 3D structures were put through molecular docking and MMGBSA computations. Nefopam demonstrated significant binding affinities, especially to 5HTR2A, GRIN1, 5HTR2C, SLC6A4, SLC6A3, and MAOB, whereas OPRM1 displayed weaker interactions, consistent with its lower MM-GBSA value (-37.04 kcal/mol) and docking score (-2.963). Molecular dynamics simulations of particular complexes over 100 ns revealed stable contacts and minimal structural changes for SLC6A3, SLC6A4, and 5HTR2A, suggesting strong and long-lasting binding.<br><br>DISCUSSION: The findings suggest that nefopam exhibits significant multi-target interactions with several proteins involved in AD pathogenesis, particularly those associated with neurotransmission, neuroprotection, and neuroinflammatory pathways. Its stable binding behavior and favorable interaction profiles support its potential role in modulating disease progression beyond symptomatic management.<br><br>CONCLUSION: Overall, this computational analysis confirms that nefopam can target multiple proteins linked to AD. These results show that more experimental research is necessary to validate nefopam's therapeutic potential and provide positive support for its repositioning in AD treatment.},
}
@article {pmid42516019,
year = {2026},
author = {Tijms, BM and van Harten, AC and Carillo, MC and Scheltens, P and Vijverberg, EGB},
title = {Analytical framing of Amyloid beta monoclonal antibody trials in Alzheimer's disease can obscure clinical effects.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71646},
doi = {10.1002/alz.71646},
pmid = {42516019},
issn = {1552-5279},
support = {//ZonMW VIDI/ ; 101171721//HORIZON EUROPE European Research Council/ ; },
abstract = {Cochrane Reviews are widely regarded as the gold standard for evidence synthesis, yet analytical framing influences interpretation. A recent Cochrane review of amyloid beta-targeting monoclonal antibodies pools mechanistically and biologically heterogenous interventions. These antibodies differ in biological targets and clinical effects, making a class-level estimate difficult to interpret. Pooling effects across these studies risks obscuring meaningful differences between interventions and may produce conclusions that do not reflect the underlying data, with important consequences for the evaluation of disease-modifying therapies in Alzheimer's disease.},
}
@article {pmid42516031,
year = {2026},
author = {Snyder, HM and Tampi, MP and Aisen, PS and Allegri, R and Apostolova, LG and Atri, A and Aurora, S and Caramelli, P and Crivelli, L and Cummings, J and de Strooper, B and Fox, NC and Grinberg, LT and Hardy, J and Lamb, BT and Levey, A and Lopez, O and Mummery, C and Nitrini, R and Pahlke, S and Petersen, RC and Pike, KJ and Porsteinsson, AP and Rabinovici, GD and Rafii, M and Raman, R and Sabbagh, MN and Salloway, SP and Scheltens, P and Schott, JM and Selkoe, DJ and Sevlever, G and Sperling, R and Tansey, MG and van Dyck, C and Zetterberg, H and Carrillo, MC},
title = {Recent Cochrane review has serious flaws: A perspective of clinicians and researchers from around the world.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71696},
pmid = {42516031},
issn = {1552-5279},
abstract = {In response to a Cochrane review (published in April 2026) on the clinical trials of monoclonal antibodies targeting beta amyloid, this perspective outlines a number of critiques. The scientists, methodologists, subject-matter experts, and clinicians on this perspective strongly recommend that the Cochrane editorial board consider a call for editorial response, correction of press materials, or commissioned reply to this review for four overarching reasons: (1) decision to pool antibodies that do and do not clear beta amyloid, (2) decision to include studies from a time when biomarkers of Alzheimer's disease were not available, (3) analytical and methodological limitations of the approach used, (4) conflating the distinct roles and methodological processes of systematic review and guideline methodologies, (5) contextualizing the present critique within the existing evidence-synthesis literature, and (6) mechanistic inference beyond the scope of the presented analyses. Conclusions that may not accurately reflect treatment-specific effects could cause significant downstream clinical and psychosocial harm to those currently undergoing treatment and their family members as well as individuals considering participation in Alzheimer's clinical trials.},
}
@article {pmid42516127,
year = {2026},
author = {Vieira, GH and Braga, VHG and Mesquita, IM and Rodrigues, SS and Maia, SD and Araújo, GO and Sousa, IMS and de Moura, ALD},
title = {Matrix-assisted laser desorption/ionization mass spectrometry (MALDI) in Alzheimer's disease: a scoping review of proteomic alterations in neurological tissues.},
journal = {Dementia &amp; neuropsychologia},
volume = {20},
number = {},
pages = {e20250437},
pmid = {42516127},
issn = {1980-5764},
abstract = {Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) has become a valuable tool for molecular mapping in neurological disorders. This scoping review synthesized current evidence on its use in proteomic analysis of neural tissues in Alzheimer's disease (AD). From 1,419 screened records, 26 studies met the inclusion criteria. Findings highlight MALDI-MS's capacity to detect beta-amyloid (Aβ) proteoforms, and tau protein post-translational modifications linked to AD. Its high spatial resolution enables region-specific molecular profiling, enhancing understanding of AD pathophysiology and supporting early biomarker discovery. The review underscores the translational potential of MALDI-MS in advancing targeted therapeutic development.},
}
@article {pmid42516270,
year = {2026},
author = {Rodríguez-Millan, L and Angarita-Rodríguez, A and Vargas-López, V and Pinzón, A and Tarifeño-Saldivia, E and González, J},
title = {Comparative evaluation of reference-free transcriptomic deconvolution highlights the importance of biological validation in astrocytes across Alzheimer's disease.},
journal = {Frontiers in bioinformatics},
volume = {6},
number = {},
pages = {1858866},
pmid = {42516270},
issn = {2673-7647},
abstract = {INTRODUCTION: Astrocytes are central regulators of neuronal energy metabolism and redox homeostasis-processes that become progressively disrupted across the Alzheimer's disease (AD) continuum. However, bulk transcriptomic data obscure cell-type-specific signals, and existing reference-free deconvolution methods often prioritize either statistical robustness or quantitative accuracy without fully integrating both dimensions.<br><br>METHODS: Here, we present a comparative framework evaluating two complementary unsupervised approaches, CDSeq and DECODER, to reconstruct astrocyte-associated transcriptomic profiles from human hippocampal samples spanning control, mild cognitive impairment (incipient and moderate), and AD (severe) stages (GSE28146; n = 30). The inferred profiles were functionally contextualized through integration into a genome-scale metabolic model of human astrocytes, enabling the assessment of system-level metabolic alterations associated with disease progression.<br><br>RESULTS: Our results reveal consistent dysregulation of key astrocytic pathways, including impairment of the astrocyte-neuron lactate shuttle, disruption of glutamine metabolism, and reduced glutathione-mediated an oxidant capacity. Methodological benchmarking showed distinct yet complementary performance profiles: DECODER achieved higher accuracy in reconstructing global expression magnitudes, whereas CDSeq exhibited greater stability and preservation of gene-gene relationships. Crucially, external validation using independent single-nucleus RNA-seq astrocyte data demonstrated that CDSeq-derived profiles achieve moderate but robust concordance with reference signatures (r &#x2248; 0.43-0.44), substantially exceeding DECODER-derived concordance (r &#x2248; 0.19-0.23), with higher concordance with astrocyte-associated signatures, alongside preservation of canonical astrocyte markers and enrichment of astrocyte-specific pathways, indicating superior biological coherence.<br><br>DISCUSSION: Together, these findings demonstrate that technical accuracy does not necessarily translate into biological validity and highlight CDSeq as the method that more reliably captures astrocyte-specific transcriptional programs in this context. While DECODER remains valuable for detecting absolute expression changes, CDSeq provides a more consistent recovery of astrocyte-associated transcriptional patterns. More broadly, our results support the incorporation of biological validation alongside statistical benchmarking when selecting deconvolution methods for downstream systems biology and metabolic modeling applications. This framework establishes a reproducible strategy for evaluating deconvolution methods and their functional consequences, advancing the interpretation of bulk transcriptomic data in neurodegenerative disease.},
}
@article {pmid42516384,
year = {2026},
author = {Giacovazzo, G and Latina, V and Yurtsever, ZN and Piccolino, I and Iannuzzi, F and Bossù, P and Amadoro, G and Coccurello, R},
title = {Prenatal immune activation and adult Poly(I:C) re-challenge promote neuroimmune priming and AD-related behavioural, cellular and molecular alterations in wild-type mice.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1845312},
pmid = {42516384},
issn = {1664-3224},
abstract = {OBJECTIVE: Alzheimer's Disease (AD) is neurodegenerative disorder characterized by deposition of Aβ plaques, tau-positive neurofibrillary tangles, neuroinflammation and clinical dementia. Epidemiological and experimental evidence suggest that peripheral immune inflammation is a risk factor for age-related neurodegeneration but whether its sustained activation is sufficient to drive behavioural, molecular and cellular changes consistent with AD-associated neurodegenerative vulnerability remains unclear. Here we investigated whether prenatal immune stimulation followed by an adult systemic re-challenge with Polyinosinic-polycytidylic acid (Poly(I:C)) induces persistent cognitive/motivational/social deficits and hippocampal neurodegeneration in wild-type mice, consistent with long-lasting neuroimmune priming mechanism(s).<br><br>METHODS: Pregnant C57Bl/6J dams received intravenously Poly(I:C) at gestational day 17 and male offspring received intraperitoneal Poly(I:C) at 9 months (single- or double-hit design) and were analyzed at 12 months. Recognition memory, working memory, reward-related learning, and social interaction were assessed followed by hippocampal Western blotting and immunofluorescence.<br><br>RESULTS: Poly(I:C)-exposed mice exhibited impaired recognition and working memory, reduced palatable food-induced conditioned place preference, and blunted social investigation. These behavioral abnormalities were accompanied by increased amyloidogenic APP processing (BACE1/PSEN1 upregulation and &#x3b2;-CTF accumulation), tau dysregulation (AT8 hyperphosphorylation), microglial activation (Iba1/CD68 upregulation and process retraction), synaptic alterations (&#x3b1;-synuclein reduction), and bioenergetic impairment (reduced mitochondrial and glycolytic markers) in the hippocampus.<br><br>CONCLUSION: Overall, these findings indicate that repeated prenatal and postnatal peripheral activation of innate immunity may act as a contributing factor to neurodegenerative phenotype with features relevant to AD-related susceptibility, paving the way for the development of next-generation therapeutical interventions affecting systemic-to-brain inflammatory signaling.},
}
@article {pmid42516522,
year = {2026},
author = {Haye, S and Jacobson, M and Zissimopoulos, J},
title = {Heterogeneous responses to risk-adjustment reform: evidence from dementia diagnosis in Medicare Advantage.},
journal = {Health affairs scholar},
volume = {4},
number = {7},
pages = {qxag167},
pmid = {42516522},
issn = {2976-5390},
abstract = {INTRODUCTION: In 2020, Alzheimer's disease and related dementias (ADRD) diagnoses were reintroduced into the Medicare Advantage (MA) risk-adjustment model creating financial incentives that may increase diagnostic coding and plan payments. This effect may vary across plans depending on provider integration, administrative capacity, and geographic context, with implications for payments and potential "upcoding."<br><br>METHODS: Using 100% Medicare data from 2016-2021, we estimated event study and difference-in-differences models comparing adjusted trends in incident ADRD diagnoses in MA relative to traditional Medicare before and after the policy change.<br><br>RESULTS: Incident dementia diagnoses increased in MA relative to traditional Medicare, despite an overall downward trend in diagnosis rates. Increases were larger among enrollees in MA health maintenance organization plans (20.8%) than in preferred provider organization plans (7.6%) and varied across insurers, ranging from 7.2% (United Healthcare) to 21.6% (Kaiser Permanente). Increases were more pronounced in urban than in rural areas.<br><br>CONCLUSION: Reintroducing ADRD into the MA risk-adjustment model was associated with increased diagnostic coding, with substantial variation across plan types, insurers, and geographic contexts. Because ADRD diagnoses increase risk-adjusted payments, larger increases across some plans may reflect coding practices rather than true disease prevalence, highlighting the need for closer monitoring.},
}
@article {pmid42516540,
year = {2026},
author = {Passalacqua, E and Barberi, G and Amico, P and Di Martino, S and De Rosa, M},
title = {Peptide-drug conjugation: a strategy to address blood-brain barrier limitations in central nervous system diseases.},
journal = {RSC medicinal chemistry},
volume = {},
number = {},
pages = {},
pmid = {42516540},
issn = {2632-8682},
abstract = {Central nervous system diseases are among the most challenging to treat, mainly due to the blood-brain barrier, which restricts the entry of most therapeutics into the brain, preventing them from reaching pharmacological concentrations. Moreover, the multifactorial causes of these diseases require targeting diverse key processes. In this context, peptide-drug conjugates represent a promising strategy and offer a multitargeting regimen platform. In this work, we describe the latest developments of peptide-drug conjugates for glioma, Alzheimer's, and Parkinson's diseases, highlighting how conjugating payloads to specific peptides can offer several therapeutic advantages over conventional approaches. Particular emphasis was given to the chemical nature of the conjugation bonds and to the synthetic reactions to underscore the versatility of the methods used.},
}
@article {pmid42516760,
year = {2026},
author = {Lee, HW and Choi, Y and Lee, S and Kim, JE and Jeon, MT and Jo, M and Park, G and Park, JS and Kim, DG and Cheon, M and Kim, HJ},
title = {Identification of a robust multitarget protein panel for Parkinson's disease via absolute quantification and large-scale external replication.},
journal = {Brain communications},
volume = {8},
number = {4},
pages = {fcag282},
pmid = {42516760},
issn = {2632-1297},
abstract = {This study aimed to identify and validate a robust, generalizable panel of plasma protein biomarkers to improve diagnostic precision in Parkinson's disease. We analysed plasma samples from 12 patients with [[18]F]-FP-CIT PET-confirmed Parkinson's disease and 15 healthy controls using the Olink Target 96 Inflammation Panel to identify differentially expressed proteins. Candidate biomarkers were subsequently validated through absolute quantification using Luminex and Olink Flex platforms in an independent cohort of 46 patients with Parkinson's disease and 33 amyloid-negative and cognitively normal control participants. To assess generalizability, the findings were replicated across multiple heterogeneous populations using large-scale datasets from the UK Biobank and Global Neurodegeneration Proteomics Consortium (GNPC) cohorts. Markers of neurodegeneration [neurofilament light chain (NfL)] and Alzheimer's disease [phosphorylated tau (pTau181), amyloid β [Aβ]42, Aβ40] co-pathology were measured using the single molecule array platform. Our analyses revealed elevated levels of interleukin (IL)-10 and IL-17C and reduced levels of urokinase plasminogen activator (uPA) and neurotrophin-3 (NTF3) in patients with Parkinson's disease. These findings were confirmed in the validation cohort. Multitarget models demonstrated superior diagnostic performance over individual markers, with the combination of IL-17C and uPA achieving the highest discrimination (area under the curve = 0.780). External validation in the UK Biobank and GNPC datasets confirmed consistent directional changes of three candidates (IL-17C, NTF3 and uPA), reinforcing the biological relevance of these markers. Notably, while NfL levels were significantly elevated in Parkinson's disease, no significant differences were observed for pTau181 levels or Aβ42/Aβ40 ratios. These findings identify a specific plasma protein panel, particularly the combination of IL-17C and uPA, as a robust and generalizable diagnostic signature that captures fundamental pathophysiological aspects of Parkinson's disease and enhances diagnostic precision alongside established biomarkers.},
}
@article {pmid42516873,
year = {2026},
author = {Bago Rožanković, P and Šimić, G},
title = {Emerging biomarkers for Parkinson's disease in biological fluids.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1835751},
pmid = {42516873},
issn = {1663-4365},
abstract = {Early and accurate diagnosis of Parkinson's disease (PD) remains a challenge, hindering the efficient recruitment of patients into clinical trials aimed at disease modification. This underscores the urgent need for validated and clinically applicable biomarkers. Research continues to expand our knowledge of fluid biomarkers for detecting and monitoring PD progression. Cerebrospinal fluid α-synuclein (α-syn) seed amplification assays (SAA) have emerged as highly sensitive and specific biomarkers for the diagnosis of PD. The development of less invasive procedures using biological fluids such as serum or saliva would be more practical for routine clinical use. Recent data demonstrate the presence of pathogenic α-synuclein in the serum of PD patients compared with healthy controls, detected using real-time quaking-induced conversion (RT-QuIC) assays. Elevated ratios of pS129-α-syn and/or oligomeric α-syn to total α-syn have also been reported in PD. Future research should clarify differences in protein aggregate formation across various synucleinopathies. Promising advances toward a clinically useful blood-based diagnostic test for PD include the quantification of proteins released from neural-derived extracellular vesicles (NDEVs), such as oligomeric and phosphorylated α-syn, tau, and disease-associated microRNAs. Given the role of neuroinflammation in PD pathogenesis, inflammatory biomarkers, including interleukin (IL)-6, IL-10, tumor necrosis factor-α(TNF-α), glial fibrillary acidic protein (GFAP), chitinase-3-like protein 1 (YKL-40), and monocyte chemoattractant protein-1 (MCP-1), are under active investigation. Furthermore, fluid biomarkers associated with Alzheimer's disease pathology are being explored for their potential to predict motor and cognitive decline in PD and related synucleinopathies. Salivary EVs hold promise as a non-invasive source of PD biomarkers; however, robust validation in large, well-characterized cohorts is essential to improve the diagnostic and prognostic accuracy of PD.},
}
@article {pmid42516875,
year = {2026},
author = {Tropea, MR and Aceto, G and Trovato, RC and Nicitra, E and Santuccio, N and Intili, G and D'Ascenzo, M and Puzzo, D},
title = {Dopamine D3 receptor blockade restores hippocampal synaptic plasticity and rescues memory deficits in Alzheimer's disease mouse models.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1840697},
pmid = {42516875},
issn = {1663-4365},
abstract = {INTRODUCTION: Early synaptic failure is widely considered a primary driver of cognitive decline in Alzheimer's disease (AD), and previous studies have suggested that dopaminergic signaling may contribute to hippocampal synaptic dysfunction. Among dopaminergic receptors, dopamine D3 receptors (D3Rs) have emerged as important modulators of synaptic plasticity and cognitive processes, but their role in AD-related synaptic impairment remains unclear. The aim of this study was to determine whether pharmacological blockade of D3Rs could restore memory deficits and hippocampal synaptic dysfunction in preclinical models of AD.<br><br>METHODS: Behavioral studies, including novel object recognition (NOR), novel object location (NOL), and open-field tests, were performed to evaluate recognition memory, spatial memory, locomotor activity, and anxiety-related behavior in two mechanistically distinct mouse models of AD: triple-transgenic 3xTg-AD mice and &#x3b1;7 nicotinic acetylcholine receptor knockout (&#x3b1;7KO) mice. Electrophysiological recordings in hippocampal slices were used to assess AMPA/NMDA ratio, basal synaptic transmission, and long-term potentiation (LTP). qPCR and western blot analyses were performed to evaluate hippocampal D3R mRNA and protein expression, respectively. Pharmacological treatments included the selective D3R antagonist NGB-2904 and cariprazine, a clinically approved antipsychotic with high affinity for D3Rs.<br><br>RESULTS: Recognition and spatial memory deficits were rescued by NGB-2904 and cariprazine in both AD models, without affecting locomotor activity or anxiety-related behavior. No sex-dependent differences were observed in the behavioral response to treatment. Electrophysiological recordings revealed a reduced AMPA/NMDA ratio and impaired LTP in both models, while basal synaptic transmission was selectively reduced in 3xTg-AD mice. D3R-targeting compounds restored synaptic transmission and plasticity. Inhibition of PKA prevented the rescue of LTP induced by D3R blockade, suggesting the involvement of the cAMP/PKA signaling pathway. Both models displayed reduced hippocampal D3R mRNA expression and protein levels, suggesting that the residual population of D3Rs might represent a viable target.<br><br>CONCLUSION: Together, these findings demonstrate that D3R-targeting compounds rescue synaptic plasticity and memory deficits in two mechanistically distinct AD models. These results support a role for dopaminergic signaling in early synaptic dysfunction and highlights D3R modulation as a relevant pathway for further investigation in AD-related cognitive impairment.},
}
@article {pmid42516878,
year = {2026},
author = {Jalloh, MB and Fadlu Deen, G and Bah, O and Bah, I and Suma, AA and Abiri, OT and Thompson, MC and Tejan, E and Jalloh, F and Foray, FM and Faulkner, MMJ and Gaye, B},
title = {Rising burden of Alzheimer's disease and other dementias in Sierra Leone, 1990-2023: analysis of Global Burden of Disease 2023 estimates.},
journal = {BMJ neurology open},
volume = {8},
number = {2},
pages = {e001507},
pmid = {42516878},
issn = {2632-6140},
abstract = {BACKGROUND: Dementia is an increasing cause of disability and mortality worldwide. Primary dementia surveillance data remain limited in many low-income settings, including Sierra Leone.<br><br>OBJECTIVE: To describe trends in Burden of Disease (GBD) 2023 modelled estimates for Alzheimer's disease and other dementias in Sierra Leone from 1990 to 2023, and to decompose the change in estimated deaths into demographic and age-specific mortality components.<br><br>METHODS: We conducted a secondary analysis of GBD 2023 estimates for the cause category 'Alzheimer's disease and other dementias' in Sierra Leone. We analysed estimated counts and age-standardised rates for prevalence, deaths, years of life lost, years lived with disability and disability-adjusted life years (DALYs) stratified by age and sex. Temporal trends were described with log-linear regression to estimate annual per cent change, and a three-component decomposition attributed changes in deaths to population growth, ageing and age-specific mortality.<br><br>RESULTS: GCD 2023 estimated that dementia deaths in Sierra Leone increased from 188 in 1990 to 474 in 2023, an absolute increase of 286 estimated deaths (152% relative increase). Estimated DALYs increased from 3703 to 7440. The modelled age-standardised death rate rose 26.8% (16.3 to 20.7 per 100 000) and the age-standardised DALY rate 13.4% (293.7 to 333.2 per 100 000). Estimated prevalent cases increased from 5647 to 8887, while the modelled age-standardised prevalence rate declined from 430.7 to 404.0 per 100&#x2009;000 population. The log-linear annual percentage change was +1.02% for age-standardised death rates, +0.60% for DALY rates and -0.18% for prevalence rates. Decomposition attributed 62% of the increase in estimated deaths to changes in age-specific mortality, 30% to population growth and 8% to population ageing.<br><br>CONCLUSIONS: GBD 2023 estimates show a rising absolute burden of dementia in Sierra Leone, against a background of limited local surveillance and mortality ascertainment.},
}
@article {pmid42517390,
year = {2026},
author = {Guo, X and Jiang, T and Ma, W and Cao, D and Mao, X},
title = {Targeting Ferroptosis-associated Histone Acylation for Amelioration of Neurological Disease.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X479697260707073238},
pmid = {42517390},
issn = {1875-6190},
abstract = {Ferroptosis is an iron-dependent, lipid peroxidation-driven form of programmed cell death. There is substantial evidence supporting the critical role of ferroptosis in multiple neurological diseases, including stroke, Alzheimer's disease, Parkinson's disease, epilepsy, and traumatic brain injury. Histone acylation, an important epigenetic mechanism, effectively regulates ferroptosis. To date, the regulation of ferroptosis by histone acylation in neurological diseases has rarely been summarized. Therefore, this review discusses the key mechanisms by which histone acylation regulates ferroptosis, including iron metabolism, antioxidant defense, and lipid peroxidation. Additionally, we summarize the latest advances in understanding the role of histone acylation in ferroptosis and its relation to the emerging hallmarks of neurological diseases. Furthermore, we provide the prospect of targeting key regulatory factors of histone acylation, such as writers, erasers, and readers, for potential therapeutic strategies to ameliorate neurological diseases.},
}
@article {pmid42517391,
year = {2026},
author = {Wei, M and Sui, Y and Xia, X},
title = {Mechanisms and Applications of Transcranial Ultrasound Stimulation in Neurological Disorders and Psychiatric Conditions.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X495837260717044104},
pmid = {42517391},
issn = {1875-6190},
abstract = {Transcranial ultrasound stimulation (TUS) is an emerging non-invasive neuromodulation strategy with high spatial precision and the ability to target both cortical and deep brain regions. This review summarizes recent progress in low-intensity, non-thermal TUS in representative neurological and psychiatric disorders, including Parkinson's disease, Alzheimer's disease, epilepsy, ischemic stroke, depression, anxiety disorders, and schizophrenia. Current preclinical evidence suggests that TUS may alleviate disease-related pathological and functional abnormalities by regulating neurotransmitter release, enhancing neurotrophic factor expression, promoting synaptic plasticity, modulating neural oscillations and circuit connectivity, improving cerebral blood flow, suppressing neuroinflammation and oxidative stress, and facilitating blood-brain barrier opening when combined with microbubbles. These biological effects may act across molecular, cellular, synaptic, circuit, and system levels, ultimately contributing to improvements in motor, cognitive, and emotional dysfunction. This review also discusses the marked heterogeneity of acoustic parameters in preclinical and clinical studies, as well as current evidence on safety. With further standardization of stimulation parameters, deeper mechanistic understanding, and stronger clinical evidence, TUS may develop into a safe, precise, and clinically translatable neuromodulation strategy.},
}
@article {pmid42517395,
year = {2026},
author = {Chen, Y and Zhang, C and Yu, X and Ma, S and Zhai, Y and Zhao, C and Li, C and He, K and Shang, Y},
title = {Bioinformatics-Guided Mechanistic Insights into Scutellaria Barbata Flavonoids Improving CREB Signaling-Related Cognitive Dysfunction through ERK-RSK-CREB Cascade Modulation.},
journal = {Current medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0109298673429444260629063831},
pmid = {42517395},
issn = {1875-533X},
abstract = {INTRODUCTION: There is evidence showing that cognitive dysfunction is a typical characteristic in Alzheimer's Disease (AD) patients. CREB signaling-related neuronal dysfunction through ERK-RSK-CREB is a subtype of the pathological mechanism of AD. The present study aimed to investigate whether Scutellaria Barbata Flavonoids (SBFs) ameliorate the rats' cognitive impairment by targeting the ERK-RSK-CREB signaling pathway, utilizing the CREB indirect inhibition model by a specific ribosomal S6 kinase (RSK) inhibitor BI-D1870 application.<br><br>METHODS: Bioinformatics analysis was conducted to identify key pathways involved in AD. Based on this, an in vivo memory impairment model of related-AD was established in rats by indirect inhibition of CREB via intraperitoneal injection of the RSK inhibitor BI-D1870. Following successful memory impairment model of related-AD rats screening with the Morris water maze, the successful model rats were treated with SBFs (140 mg/kg) or the CREB activator Rolipram (0.5 mg/kg). Spatial and short-term memory were assessed using the Barnes maze and the Passive Avoidance Test, respectively. NeurN and Nissl body for neuronal integrity and the expression of ERK-RSK-CREB pathway-related molecules (p-CREB-Ser133/Ser142, RSK, CREB, EGR-1) were evaluated by histological staining, immunohistochemistry, and molecular biology techniques.<br><br>RESULTS: Bioinformatics analysis identified the MAPK signaling pathway as a key pathway for further investigation. Experimentally, SBFs administration significantly improved both spatial and short-term memory deficits induced by BI-D1870. This cognitive recovery was associated with the restoration of neuronal Nissl bodies and NeuN expression. Mechanistically, SBFs upregulated the phosphorylation of CREB at Ser133 and the expression of RSK, CREB, and EGR-1 mRNA and/or protein, while concurrently downregulating the elevated phosphorylation of CREB at Ser142, which demonstrated the bidirectional regulatory mechanism of SBFs on CREB phosphorylation of the ERK-RSK-CREB pathway.<br><br>DISCUSSION: This study demonstrates that BI-D1870 can cause the rats' memory deficits, and SBFs can mitigate BI-D1870-induced memory deficits by enhancing ERK-RSK-CREB signaling, similar to Rolipram. SBFs restored neuronal integrity (Nissl bodies, NeuN) and upregulated p- CREB-Ser133, RSK, CREB, and EGR-1, suggesting SBFs' neuroprotection. These findings highlight SBFs as a potential therapeutic agent for memory disorders via CREB pathway modulation. However, our research has some limitations. Bioinformatics identified the key signaling pathway involved in AD, but the BI-D1870 model merely estimates AD-related cognitive dysfunction; it does not recapitulate the full spectrum of AD pathology. Future studies should validate the efficacy, mechanisms, bioactive substances, and metabolized root of SBFs in more etiologically relevant transgenic AD models.<br><br>CONCLUSION: Our findings indicate that SBFs exert neuroprotective effects against CREB indirect inhibitor-induced cognitive dysfunction, likely through the modulation of the ERK-RSK-CREB pathway. This suggests SBFs as a potential candidate for mitigating memory deficits associated with CREB dysregulation.},
}
@article {pmid42517615,
year = {2026},
author = {Ya, J and Liu, M and Ji, Y and Tong, Z and Luo, B and Bai, J and Ren, J and Qu, X},
title = {Diazonium-Enabled Post-Synthetic Construction of Enantiomeric Single-Atom Nanoagents Used for Alzheimer's Disease Treatment.},
journal = {Small (Weinheim an der Bergstrasse, Germany)},
volume = {},
number = {},
pages = {e74610},
doi = {10.1002/smll.74610},
pmid = {42517615},
issn = {1613-6829},
support = {T2495262//National Natural Science Foundation of China/ ; 22437006//National Natural Science Foundation of China/ ; 22237006//National Natural Science Foundation of China/ ; 2025ZD0617100//National Science and Technology Major Project/ ; },
abstract = {Alzheimer's disease (AD) is driven by a self-amplifying interplay between oxidative stress and neuroinflammation, in which mitochondrial DNA (mtDNA) leakage-induced activation of the cGAS-STING pathway plays a central role. Strategies that solely eliminate reactive oxygen species (ROS) are insufficient to suppress downstream inflammatory cascades. Here, we report a pair of chiral dual-functional single-atom nanoagents that can simultaneously scavenge ROS and sequester leaked mtDNA. A diazonium-enabled post-synthetic modification strategy is employed to graft benzoic acid linkers onto a single-atom catalyst, enabling covalent conjugation of nona-arginine peptides with opposite chirality (L-/D-R9). The resulting constructs are further encapsulated by KLVFFAED peptides and tannic acid to yield L-/D-TKRM, conferring blood-brain barrier permeability and mitochondrial targeting. Both L- and D-TKRM effectively scavenge ROS and preserve mitochondrial function in Aβ-stimulated microglia, while D-TKRM exhibits enantioselectively prolonged mtDNA capture, more efficient suppression of cGAS-STING signaling, enhanced M2 microglial polarization, and superior neuroprotection. In vivo studies have demonstrated that these two nanoagents rescue cognitive function in 3 × Tg-AD mice, with D-TKRM showing better efficacy accompanied by reduced amyloid pathology, microglial activation, and neuronal loss. This work highlights diazonium chemistry as a new, versatile single-atom functionalization strategy and underscores that chirality is important for developing effective therapeutic agents for AD treatment.},
}
@article {pmid42517781,
year = {2026},
author = {Scerri, A and Scerri, K and Scerri, C},
title = {Global trends in Alzheimer's and dementia research (2019-2024): A machine learning-based bibliometric analysis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261471922},
doi = {10.1177/13872877261471922},
pmid = {42517781},
issn = {1875-8908},
abstract = {BackgroundDementia, including Alzheimer's disease, represents one of the fastest-growing global health challenges. To coordinate research priorities, the World Health Organization (WHO) introduced the Blueprint for Dementia Research in 2022. This framework outlines six research themes spanning disease mechanisms, diagnosis, treatment development, risk reduction, epidemiology and health economics, and care and support. However, empirical evidence assessing whether global research activity aligns with these priorities remains limited.ObjectiveTo analyse global trends in dementia and Alzheimer's disease research and examine how research output is distributed across the thematic priorities defined in the WHO Blueprint for Dementia Research.MethodsA total of 206,636 unique peer-reviewed primary care studies published between 2019 and 2024 were retrieved from databases on the EBSCOhost platform. A machine-learning-assisted natural language processing pipeline classified publications into the six WHO research themes. Temporal trends were assessed and differences in thematic distributions before and after publication of the WHO blueprint were evaluated.ResultsAnnual dementia research output increased from 27,248 publications in 2019 to 39,147 in 2024. Research activity was consistently dominated by studies on disease mechanisms and diagnosis. Risk reduction and drug development demonstrated the strongest growth. Research related to dementia care and support, epidemiology and health economics increased more slowly and declined following publication of the WHO blueprint.ConclusionsGlobal dementia research continues to expand but remains unevenly distributed across research priorities. While progress in biomedical discovery is substantial, comparatively limited growth in care-related research highlights the need for stronger investment in studies addressing implementation and real-world dementia care.},
}
@article {pmid42517794,
year = {2026},
author = {Lista, S and Minoretti, P and Emanuele, E and López-Ortiz, S and Hsiao, IT and Merino-País, M and Imbimbo, C and Cisale, GY and Garaci, F and Imbimbo, BP and Santos-Lozano, A and Yen, TC},
title = {[18F]-florzolotau PET imaging in Alzheimer's disease: Current evidence and future directions.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261469867},
doi = {10.1177/13872877261469867},
pmid = {42517794},
issn = {1875-8908},
abstract = {Tau positron emission tomography (PET) has become a central imaging modality for in vivo detection and quantification of tau pathology across the Alzheimer's disease (AD) clinical and biological continuum. [18F]-Florzolotau is a second-generation tau PET tracer developed to improve target-to-background contrast and mitigate off-target binding relative to first-generation ligands, thereby improving interpretability for translational research and clinical use. In this narrative review, we provide a critical appraisal of the available literature on [18F]-Florzolotau PET imaging in AD, with emphasis on diagnostic and differential-diagnostic performance, the spatiotemporal topography of tau deposition in relation to Braak staging and disease progression, and the clinical significance of tracer uptake with respect to cognitive measures, disease severity, and prognosis. Eligible studies were clinical investigations published between 2020 and 2025 that applied [18F]-Florzolotau PET in cohorts spanning cognitively unimpaired individuals through symptomatic AD stages. Across reports, [18F]-Florzolotau PET differentiated AD dementia from cognitively unimpaired comparators with high accuracy, with sensitivities ≥ 90% and specificities of 87-96%. Regional uptake patterns were broadly consistent with Braak-like propagation, progressing from medial temporal regions toward associative neocortex in parallel with increasing clinical severity. Quantitative tracer uptake also correlated with global cognition and key domains, including episodic memory and executive function. We conclude that [18F]-Florzolotau PET provides a robust in vivo measure of AD tau burden, motivating further evaluation for diagnostic and prognostic applications. Larger multicenter studies with harmonized acquisition/quantification and head-to-head comparisons versus other second-generation tracers remain priorities.},
}
@article {pmid42517796,
year = {2026},
author = {Kloppenburg-Lagendijk, M and Van Nyendaal, C and Verberk, IMW and Van Harten, AC and Ferket-Franken, W and Teunissen, CE and Hempenius, L and Verwey, NA},
title = {Agreement between clinical diagnosis and blood biomarkers of Alzheimer's disease in a real-world peripheral memory clinic.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261469893},
doi = {10.1177/13872877261469893},
pmid = {42517796},
issn = {1875-8908},
abstract = {BackgroundBlood-based biomarkers (BBM) are promising to help diagnose Alzheimer's disease (AD) and are on the verge of implementation in diagnostic dementia workups. However, evaluating BBM performance in peripheral memory clinics is essential to establish their real-world clinical utility.ObjectiveTo evaluate the diagnostic concordance of BBMs with clinically established diagnoses in an unselected peripheral memory clinic population using predefined, validated thresholds.MethodsIn a peripheral memory clinic, plasma levels of phosphorylated Tau217 (pTau217), amyloid-β 42/40 ratio (Aβ42/Aβ40), glial fibrillary acidic protein, and neurofilament light (NfL) were measured in patients (mean age 75.2 ± 8.8 years, 48.3% female) clinically diagnosed with subjective cognitive decline (SCD; n = 108), mild cognitive impairment (MCI; n = 55), AD dementia (n = 132), or non-AD dementia (non-AD; n = 28). BBM levels were compared across diagnostic groups and concordance between clinical diagnoses and BBM test results, based on thresholds developed in an academic memory clinic, were analyzed.ResultsThe levels of all four BBMs differed between SCD and AD dementia (p < 0.001). Between AD dementia and non-AD dementia, only PTau217 levels differed (p = 0.03). In SCD participants, 50% (pTau217) to 79% (NfL) showed abnormality in at least one BBM. In AD dementia patients, this ranged from 83% (pTau217) to 97% (NfL); all had at least one abnormal BBM, and 68% had abnormalities in all four BBMs.ConclusionsIn a peripheral real-world memory clinic setting the BBMs demonstrated high concordance with clinically diagnosed dementia due to AD. Our findings suggest utility of BBMs in peripheral memory clinic practice, in patients with suspected dementia.},
}
@article {pmid42517797,
year = {2026},
author = {Engedal, K and Benth, J&#x160; and Knapskog, AB and Wagle, J and Persson, K},
title = {Normative Norwegian scores on the clock drawing test using the Shulman version.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261471901},
doi = {10.1177/13872877261471901},
pmid = {42517797},
issn = {1875-8908},
abstract = {BackgroundStudies have shown that the performance on the Clock Drawing Test (CDT) is influenced by age and education. Thus, normative scores are needed.ObjectiveTo develop normative Norwegian scores for Shulman's version of CDT.MethodsPerformance on CDT of 2572 cognitively healthy people between age 25 and 95 years were included. Ordinal regression analysis was used to derive regression-based norms with sex, age and education as covariates.ResultsOf all, 76.4% scored five, 12.9% scored four, 8.1% scored three and 2.5% scored zero to two. Men scored higher than women. An interaction between age and education was found. The probability of higher CDT score is highest at younger ages and among those with highest education. It progressively declines with increasing age, while higher education delays, but does not prevent this decline. Participants scoring zero to two fell below the 5[th] percentile, except among women above 93 years and men above 85 years. By age 95, the probability of different scores converged. In the age range of 60 to 90 years a score of three corresponded to percentiles of 3.7-26.9 in men and 5.2-34.1 in women, while a score of four corresponded to percentiles of 9.7-50.4 in men and 13.2-59.0 in women.ConclusionsScores four and five are considered normal for any person aged 60-90 years. Whether a score of three is normal depends on the person's sex, age and educational level, whereas score zero to two should not be regarded as normal.},
}
@article {pmid42517799,
year = {2026},
author = {Jiang, X and Lv, G and Burroughs, A and Li, M and Yuan, J and Lu, ZK},
title = {Heterogeneity in the association between antihypertensive medications and Alzheimer's disease and related dementias risk: A multidimensional machine learning analysis to inform drug repurposing.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261469115},
doi = {10.1177/13872877261469115},
pmid = {42517799},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease and related dementias (ADRD) place an immense burden on patients, families, and health systems in the United States. Hypertension is highly prevalent in ADRD patients, and antihypertensive medications (AHMs) may confer neuroprotective benefits. However, evidence of association between AHM use and ADRD risk remains limited, especially by drug classes and across population subgroups.ObjectiveThis study aimed to evaluate the association between antihypertensive medications (AHMs) use and ADRD risk, and assess heterogeneity by drug classes and demographics.MethodsWe analyzed 2015-2019 Medicare Current Beneficiary Survey data linked with Medicare claims. ADRD was identified by International Classification of Diseases (ICD) codes, anti-dementia drug use, and survey responses. This study included AHMs from 8 classes. Double/debiased machine learning was employed, adjusting for factors from environmental, sociocultural, behavioral, and biological domains.ResultsAmong 144,788,079 weighted Medicare beneficiaries, 75.44% used AHMs. Overall, AHM use was associated with a 5% reduction in ADRD risk (Effect: 0.95; 95% CI: 0.94-0.95). Heterogeneity in protective effects was observed for most AHM classes, except vasodilators and centrally acting alpha-adrenergic agonists, which were linked to increased ADRD risk (p < 0.001). Disparities were found across age and sex groups, with greater effects in older adults, and were observed for all racial and ethnic groups (p < 0.05) except Hispanics.ConclusionsThis study found that AHM use was associated with reduced ADRD risk, with notable heterogeneity across subgroups, highlighting the importance of integrating hypertension care into cognitive health to develop equitable and personalized strategies.},
}
@article {pmid42517803,
year = {2026},
author = {Kiene, F and Becker, A and Betten, L and Roheger, M},
title = {Subtle visuo-cognitive deficits as a potential early marker of cognitive decline.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261469875},
doi = {10.1177/13872877261469875},
pmid = {42517803},
issn = {1875-8908},
abstract = {BackgroundIndividuals with subjective cognitive decline (SCD) report declining cognitive abilities but do not have an objective cognitive impairment at present. Research indicates that they are at an elevated risk of developing Alzheimer's disease (AD). Identifying or developing cognitive measures capable of detecting cognitive deficits that individuals with SCD may experience is crucial, as they may benefit from additional diagnostic procedures and interventions aimed at delaying further cognitive decline.ObjectiveTo investigate whether specific cognitive tasks selected for their relevance in detecting early changes possibly related to AD can predict group membership SCD and Non-SCD.MethodsNeuropsychological assessment data of 73 older adults (35 SCD, 38 Non-SCD) was analyzed. Logistic regression analyses, classification metrics, and receiver operating characteristic curves were used to evaluate the predictive power of a model including a verbal fluency, word list learning, and constructional praxis test.ResultsIndividuals with SCD were older and reported higher levels of depression. The logistic regression model demonstrated limited sensitivity (0.54) but high specificity (0.87). Constructional Praxis (visuo-spatial- and constructional abilities) emerged as a significant predictor (OR = 0.49, 95% CI: 0.26-0.86, p < 0.05), even in an additional model controlling for affective symptoms. Better performance in this task was associated with lower odds of belonging to the SCD group.ConclusionsExisting cognitive assessments appear to lack sensitivity in the context of SCD. Visuo-cognitive functioning may represent a promising domain for the development of more sensitive diagnostic tools to detect possible cognitive alterations that individuals with SCD may experience.},
}
@article {pmid42517806,
year = {2026},
author = {Topbaş, U and Alan, &#x15e; and Oğuzhan, G and Özge, A},
title = {"A light, A breath": A community-based temporary care model for enhancing quality of life in Alzheimer's disease patients and supporting caregivers.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261471873},
doi = {10.1177/13872877261471873},
pmid = {42517806},
issn = {1875-8908},
abstract = {BackgroundNon-pharmacological interventions may improve quality of life in patients with Alzheimer's disease and reduce caregiver burden.ObjectiveThis study aimed to compare the effects of a single-modal social (choir) and a multimodal intervention program on patient quality of life and caregiver burden in early-stage Alzheimer's disease.MethodsThis quasi-experimental study included 20 patients with early-stage Alzheimer's disease and their primary caregivers. Participants were allocated to either choir (control) group or multimodal (intervention) group. The former consisted of choir-based social stimulation, whereas the latter combined structured activities with supervised respite care. Both programs were delivered twice weekly for 6 months. Outcomes were assessed before and after the intervention using patient- and caregiver-rated Quality of Life in Alzheimer's Disease scores and Zarit Caregiver Burden Interview scores.ResultsPatient-rated quality of life scores improved in both groups, with a significantly greater increase in the multimodal group (F(1,18) = 17.78, p = 0.001, partial η[2] = 0.497). Difference-in-differences analysis confirmed a greater improvement in patient-rated quality of life in the multimodal group (β = 6.20, p = 0.001). Caregiver-rated quality of life scores also improved more prominently in the multimodal group (F(1,18) = 15.46, p = 0.001; β = 9.30, p < 0.001). Zarit caregiver burden scores decreased in both groups, with a significantly greater decrease in the multimodal group (F(1,18) = 7.09, p = 0.016, partial η[2] = 0.283).ConclusionsA multimodal community-based intervention incorporating respite care may offer greater benefits than a single-modal intervention alone.},
}
@article {pmid42517808,
year = {2026},
author = {Bekena, S and Singh, RK and Pal, S and Zhu, Y and Trani, JF and McClannahan, KS and Babulal, GM},
title = {Hearing in noise and cognitive status in older adults: Biomarker associations and bidirectional survival analyses.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261470816},
doi = {10.1177/13872877261470816},
pmid = {42517808},
issn = {1875-8908},
abstract = {BackgroundHearing impairment (HI) has been identified as a potentially modifiable risk factor for dementia, yet its relationship with Alzheimer's disease (AD) neuropathology and the temporal directionality remain unclear, particularly in late life.ObjectiveTo examine cross-sectional and longitudinal associations between HI, clinical cognitive status, and AD biomarkers in community-dwelling older adults.MethodsWe included 474 DRIVES Project participants (mean age 73.5 ± 5.2 years). Hearing was assessed using the NIH Toolbox Words-in-Noise (WIN) test. Clinical cognitive status was assessed using Clinical Dementia Rating (CDR). AD biomarkers included cerebrospinal fluid (CSF) Aβ42/Aβ40, t-tau/Aβ42, and p-tau/Aβ42 ratios and amyloid PET imaging. Multivariable linear, logistic, Cox proportional hazards, and Fine-Gray competing-risk models were used.ResultsHI was more prevalent among participants with mild cognitive impairment (MCI; defined as CDR = 0.5) than cognitively normal individuals (50% versus 24%, p < 0.001), and MCI status was independently associated with worse baseline WIN thresholds (β = 1.55 dB SNR; 95% CI 0.72-2.37). HI was not cross-sectionally associated with CSF amyloid or tau ratios or amyloid PET positivity. Longitudinally, baseline MCI was associated with a higher risk of incident HI (Cox HR = 2.63, 95% CI 1.48-4.67; Fine-Gray sHR = 2.79, 95% CI 1.06-7.40), whereas baseline HI was not associated with subsequent CDR progression.ConclusionsIn older adults, HI was associated with MCI but not core AD biomarkers or future CDR progression, suggesting that late-life HI may reflect cognitive vulnerability or broader brain aging rather than independently driving AD pathology.},
}
@article {pmid42517811,
year = {2026},
author = {Hadji, M and Moradi, E and Tohka, J},
title = {Predicting future brain atrophy based on longitudinal MRI.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261471049},
doi = {10.1177/13872877261471049},
pmid = {42517811},
issn = {1875-8908},
abstract = {BackgroundNeuron loss is a hallmark of neurodegenerative diseases and leads to brain atrophy detectable with magnetic resonance imaging (MRI). Accurate prediction of future atrophy is valuable for research in Alzheimer's disease (AD) and related dementias.ObjectiveThis study aimed to predict annualized percentage changes in hippocampal, ventricular, and total gray matter (TGM) volumes in individuals ranging from cognitively normal to dementia, and to evaluate whether longitudinal MRI-derived change measures improve prediction performance compared with single-time-point MRI information.MethodsUsing elastic net regression, we compared baseline models based on single-timepoint MRI information with longitudinal models incorporating prior MRI-derived change measures. Both approaches were evaluated as MRI-only and MRI + risk-factor variants, with risk factors including age, sex, APOE4, and diagnostic status.ResultsIn cross-validated analyses using the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort, the longitudinal MRI + risk-factor model performed best, yielding Pearson correlations of 0.62 for hippocampal atrophy, 0.51 for ventricular enlargement, and 0.41 for TGM atrophy. Longitudinal models consistently outperformed single time-point models, and adding risk factors improved predictive performance beyond MRI alone. External validation using the Australian Imaging, Biomarkers and Lifestyle cohort confirmed these findings. Predicted atrophy outperformed present-day regional volumes in identifying individuals progressing from normal cognition to MCI/dementia and from MCI to dementia.ConclusionsMRI-derived longitudinal features enhance atrophy prediction, and predicted atrophy rates provide sensitive markers of future cognitive decline. These findings support the potential utility of predicted atrophy for cohort enrichment and therapeutic trial design.},
}
@article {pmid42517812,
year = {2026},
author = {Zhang, S and Tao, K and Zhou, L and Wang, S and Gao, Z and Liu, X and Gao, L and Ruan, L and Xu, Y and Liu, X and Song, W and Tao, F and Liu, K},
title = {Dichotomous associations of circulating short-chain organic acids with cognitive impairment in older adults: An epidemiological and network analysis study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261471889},
doi = {10.1177/13872877261471889},
pmid = {42517812},
issn = {1875-8908},
abstract = {BackgroundShort-chain organic acids (SCOAs) may have paradoxical effects on neurocognition, acting as either neuroprotective bioenergetic substrates or potential neurotoxicants. However, the joint effects of SCOA mixtures on cognitive impairment and the mechanisms underlying their divergent associations remain unclear.ObjectiveTo investigate the joint effects of serum SCOAs mixtures on cognitive impairment and elucidate underlying mechanisms.MethodsSerum levels of 11 SCOAs were quantified in 4192 older adults. Logistic regression and Bayesian kernel machine regression (BKMR) were used to assess individual and mixture associations with cognitive impairment. Potential targets were screened from public databases, intersected with cognitive impairment-related genes, and mapped to protein-protein interaction networks. Core targets were validated using four machine learning algorithms. Functional enrichment and molecular docking analyses were performed to explore potential mechanisms.ResultsIn adjusted models, β-hydroxybutyric, butyric, and propionic acids were inversely associated with cognitive impairment, whereas isobutyric and crotonic acids were positively associated. BKMR revealed a non-linear joint effect, with the overall association shifting from positive to negative when the mixture quantile exceeded 0.5; butyric acid showed an inverted U-shaped relationship. Network analysis identified two functional groups: the inverse group centered on GAPDH, AKT1, CASP3, NFKB1, and STAT3 and was enriched in PI3K-Akt and insulin signaling, whereas the positive group centered on ribosomal proteins and HSP90AA1, implicating ribosomal stress and NOD-like receptor signaling.ConclusionsSerum SCOAs showed divergent associations with cognitive impairment. Bioenergetic metabolites were linked to putative neuroprotective signaling, whereas risk-associated metabolites were linked to ribosomal stress signatures.},
}
@article {pmid42517821,
year = {2026},
author = {Wen, B and Dang, Y and Zhang, Y and Long, Y and Tian, W},
title = {scReGAT: Leveraging Knowledge of Regulatory Interactions to Predict Long-range Gene Regulation at Single-cell Resolution.},
journal = {Genomics, proteomics &amp; bioinformatics},
volume = {},
number = {},
pages = {},
doi = {10.1093/gpbjnl/qzag072},
pmid = {42517821},
issn = {2210-3244},
abstract = {Understanding gene regulation at single-cell resolution is crucial for unraveling development, disease, and cellular identity. We introduce single-cell regulatory graph attention network (scReGAT), a deep learning framework that integrates prior knowledge of cis-regulatory element (cRE)-gene and transcription factor-gene interactions to reconstruct cell-specific regulatory networks. Central to scReGAT is a knowledge-guided regulatory graph (kRG), which combines experimentally validated regulatory interactions with cell-resolved chromatin accessibility profiles. These graphs serve as the foundation for training a Graph Attention Network (GAT) to predict gene expression and quantify the contribution of specific regulatory interactions using an interpretable regulatory score for each edge. In benchmarking across five single-cell multi-omics datasets, scReGAT successfully recapitulates known cell-type-specific cRE-gene interactions. In both neuroblastoma and osteogenic differentiation systems, it uncovers dynamic regulatory rewiring that predicts transcriptional transitions. Furthermore, by integrating genome-wide association studies loci from Alzheimer's disease, multiple sclerosis, and schizophrenia, scReGAT identifies disease-associated cell types and uncovers candidate regulatory mechanisms underlying complex trait associations. These results position scReGAT as a robust and generalizable framework for decoding long-range gene regulation at single-cell resolution. The source code of scReGAT can be accessed at https://github.com/TianLab-Bioinfo/scReGAT/ and https://ngdc.cncb.ac.cn/biocode/tool/BT008081.},
}
@article {pmid42518107,
year = {2026},
author = {Lopes, C and Araújo, N and Pereira, S and Lunet, N},
title = {Perceptions of cognitive functioning among 10-year breast cancer survivors: a qualitative study.},
journal = {Journal of cancer survivorship : research and practice},
volume = {},
number = {},
pages = {},
pmid = {42518107},
issn = {1932-2267},
abstract = {PURPOSE: To explore the context and experiences of breast cancer survivors living with perceived mild cognitive impairment (MCI) and the trajectory of these changes since diagnosis. Additionally, to explore the impact on psychosocial well-being, identity, functionality, and the strategies used to mitigate these difficulties. Lastly, to investigate the facilitators and barriers to the discussion of these concerns with the primary healthcare professionals.<br><br>METHODS: This qualitative study used an analytic approach, through semi-structured interviews with 11 breast cancer survivors (for&#x2009;&#x2265;&#x2009;10&#xa0;years) who had cognitive complaints during or after cancer treatments, without formal diagnosis of MCI.<br><br>RESULTS: The participants reported impairments in memory, attention, processing speed and temporal orientation, that began during treatments and remained stable after their completion. Feelings of anger, embarrassment, frustration, and not seeing themselves as capable as before emerged from these difficulties. The fear of developing neurocognitive disorders, such as Alzheimer's disease, was reported as an important concern. Social isolation and work difficulties are among the most relevant implications for these women. Coping strategies (e.g., memory aids and compensation methods) are employed by these women. Lack of validation of cognitive concerns by the primary healthcare professionals was reported as a constraint in getting the help they aimed for.<br><br>CONCLUSION: The study provides new in-depth data about perceived cognitive impairment, its multidomain impact, and strategies used to reduce its effects.<br><br>These findings contribute to a better understanding of cognitive symptoms to create frameworks and interventions to formally improve survivors' quality of life.},
}
@article {pmid42518151,
year = {2026},
author = {Alreshidi, NF and Abdullah Alghamdi, A and Almasoudi, KS and Mirza, IM and Abduljawad, S and Zakaria, SS and Alharbi, SS and , },
title = {Higher baseline CSF cortisol is associated with adverse 24-month tau-related, neuroimaging, and cognitive outcomes across the Alzheimer's disease continuum.},
journal = {European geriatric medicine},
volume = {},
number = {},
pages = {},
pmid = {42518151},
issn = {1878-7649},
support = {26UQU4350354GSSR02R//Umm Al-Qura University/ ; },
abstract = {PURPOSE: Cortisol dysregulation has been implicated in Alzheimer's disease (AD), but its associations with amyloid and tau-related outcomes remain unclear. This study examined whether baseline CSF cortisol was associated with cross-sectional and baseline-adjusted 24-month multimodal AD biomarkers and cognitive outcomes.<br><br>METHODS: A total of 764 participants were included, comprising cognitively normal (CN; n = 284), individuals with mild cognitive impairment (MCI; n = 356), and patients with AD dementia (n = 124). Associations between baseline CSF cortisol, multimodal AD biomarkers, and cognitive outcomes were assessed with FDR correction.<br><br>RESULTS: CSF cortisol increased modestly from CN to MCI and AD dementia, with a small but statistically significant overall group difference after FDR correction. Cross-sectionally, in the MCI group, higher CSF cortisol was associated with higher CSF total tau and p-tau181 and a lower A&#x3b2;42/total tau ratio. In baseline-adjusted 24-month analyses, in MCI groups, higher CSF was associated with higher CSF total tau and p-tau181, greater temporal tau-PET burden, lower hippocampal volume, greater ventricular volume, and poorer cognitive outcomes. In the full cohort and MCI group, CSF-defined amyloid positivity strengthened associations of higher baseline CSF cortisol with adverse 24-month tau-related outcomes. Exploratory analyses suggested that 24-month CSF total tau and hippocampal volume partly accounted for the association between higher baseline CSF cortisol and poorer 24-month cognition in MCI; however, these findings do not establish causal mediation.<br><br>CONCLUSION: Higher CSF cortisol may be linked to tau-related pathology and poorer cognition, supporting further evaluation of its prognostic value across the AD continuum.},
}
@article {pmid42518164,
year = {2026},
author = {Sattar, Z and Asili, J},
title = {Probiotics and Plant Extracts in the Gut-Brain Axis: Mechanisms, Interactions, and Clinical Perspectives.},
journal = {Probiotics and antimicrobial proteins},
volume = {},
number = {},
pages = {},
pmid = {42518164},
issn = {1867-1314},
abstract = {Growing evidence highlights the microbiota-Gut-Brain Axis (MGBA) as a critical pathway linking diet to neurological health. This review synthesizes current evidence on the complementary, additive, and potentially synergistic interactions between probiotics and plant-derived phytochemicals within the MGBA. While the individual benefits of these dietary components are well established, their combined synbiotic application offers expanded mechanistic breadth through coordinated modulation of microbial ecology, epithelial barrier integrity, immune inflammatory signaling, and neurochemical pathways. Probiotics and phytochemicals interact bidirectionally via microbial biotransformation, enhancing short-chain fatty acid production, reducing endotoxin translocation, and attenuating systemic and neuroinflammation. These effects are further linked to indirect modulation of neurotransmitter systems and neurotrophic signaling relevant to mood regulation, cognitive function, and neurodegenerative processes. Evidence from preclinical and emerging clinical studies supports the relevance of these mechanisms in conditions such as Alzheimer's disease, Parkinson's disease, mood disorders, and Autism Spectrum Disorder, although human data remain limited. Overall, this narrative review proposes a mechanistic framework describing how probiotics and plant-derived phytochemicals may interact through complementary microbial, immune, and neurochemical pathways within the Microbiota-Gut-Brain Axis. It also highlights current knowledge gaps and emphasizes the need for well-designed clinical studies to validate their combined therapeutic potential.},
}
@article {pmid42518233,
year = {2026},
author = {von Arnim, CAF and Sadlonova, M and Derad, C and Hohberg, M and Celano, CM and Günther, I and Titsch, T and Krasiuk, I and Packroß, K and Becker, MM and Rediske, AI and Süttmann, NP and Knopp, CM and Heinemann, S and Itting, PT and Kutschka, I and Morgado, B and Esselmann, H and Baraki, H and Asendorf, T and Hansen, N and Wiltfang, J and , },
title = {Plasma Amyloid-β 1-40 and Postoperative Delirium After Cardiac Surgery.},
journal = {JAMA network open},
volume = {9},
number = {7},
pages = {e2625730},
doi = {10.1001/jamanetworkopen.2026.25730},
pmid = {42518233},
issn = {2574-3805},
abstract = {IMPORTANCE: Postoperative delirium (POD) is a frequent and severe complication after cardiac surgery that is associated with increased risk of dementia and adverse outcomes. Early identification of high-risk patients remains challenging.<br><br>OBJECTIVE: To examine whether preoperative plasma Alzheimer disease biomarkers are associated with baseline cognition and can independently estimate POD in patients undergoing elective cardiac surgery.<br><br>This prospective, observational cohort study (FIND Delirium Risk Factors [FINDERI]) included patients 50 years or older undergoing elective cardiac surgery at a comprehensive cardiac surgery center in Germany between February 1, 2021, and October 31, 2022. Statistical analysis was performed from January to December 2025.<br><br>EXPOSURES: Preoperative plasma concentrations of amyloid-&#x3b2; 1-40 (A&#x3b2;1-40), amyloid-&#x3b2; 42 (A&#x3b2;1-42), phosphorylated tau 181 (pTau181), and phosphorylated tau 217 (pTau217) were measured using validated immunoassays between November 1, 2022, and July 31, 2024.<br><br>MAIN OUTCOMES AND MEASURES: The primary outcome was POD, assessed daily for 5 days postoperatively using the Confusion Assessment Method algorithm. Baseline cognitive function was assessed using the Montreal Cognitive Assessment (MoCA). Risk estimation accuracy was evaluated using receiver operating characteristic analysis and multivariate logistic regression, adjusting for relevant clinical covariates.<br><br>RESULTS: Of 504 enrolled patients, 491 completed POD assessment (mean [SD] age, 68.4&#x2009;[8.3] years; 385 [78.4%] male), of whom 106 (21.6%) developed POD. In multiple linear regression, pTau217 (&#x3b2; = -0.51; 95% CI, -0.89 to -0.12; P = .01) and age (&#x3b2; = -0.12; 95% CI, -0.16 to -0.08; P < .001) remained significant factors associated with lower MoCA scores. Patients who developed POD had higher preoperative A&#x3b2;1-40, A&#x3b2;1-42, pTau217, and A&#x3b2;1-40/A&#x3b2;1-42&#x2009;&#xd7;&#x2009;pTau217, and lower A&#x3b2;1-42/A&#x3b2;1-40. A&#x3b2;1-40 was the independent biomarker most strongly associated with POD (area under the receiver operating curve [AUC],&#x2009;0.65; 95% CI, 0.59-0.71; P&#x2009;<&#x2009;.001). Combining biomarkers with clinical factors improved risk estimation (AUC, 0.74; 95% CI, 0.69-0.79; P&#x2009;<&#x2009;.001) compared with clinical factors alone (AUC, 0.73; 95% CI, 0.67-0.78; P&#x2009;<&#x2009;.001). A combined model including MoCA achieved an AUC of 0.77 (95% CI, 0.72-0.82; P&#x2009;<&#x2009;.001), driven primarily by A&#x3b2;1-40.<br><br>CONCLUSIONS AND RELEVANCE: In this prospective cohort study, preoperative A&#x3b2;1-40 showed the strongest association with POD risk among the measured biomarkers. These findings suggest that preoperative plasma A&#x3b2;1-40 may contribute to POD risk stratification, but further research is needed to validate these findings and determine clinical utility.},
}
@article {pmid42518273,
year = {2026},
author = {Maloney, EK and Bleakley, A and Hull, S and Langbaum, J},
title = {Using Iterative Concept Testing to Identify Key Considerations for Increasing Research Participation Among Older Racial and Ethnic Minorities Through Social Media Advertising.},
journal = {Health communication},
volume = {},
number = {},
pages = {1-16},
doi = {10.1080/10410236.2026.2706529},
pmid = {42518273},
issn = {1532-7027},
abstract = {The US population is becoming older and more diverse, which puts people at higher risk for developing diseases that are the focus of ongoing research studies. These groups are under-represented in clinical research trials. This study is part of a larger project to expand and diversify older adult participation in Alzheimer's and dementia research studies using theory-based targeted messages. Analyses to identify the most important issues to address in health messaging for specific groups have been published broadly, but less has been written about turning this information into messages that are interpreted as intended by members of the target audience. This manuscript reports on the iterative concept testing approach used to create and refine targeted messages based on the reasoned action approach (RAA) to recruit White male, Black, and Hispanic older adults to sign up for an Alzheimer's and dementia-focused research registry using social media advertising. We conducted 20 focus groups with a total of 185 Hispanic (30.8%), Black (48.1%), and White (21.1%) adults between the ages of 50 and 80-years-old in the United States. Results highlighted key considerations for social media advertising recruitment of these target populations, including the importance of attributing the recruitment message to a reputable source to offset concerns about internet scams, and using racial and ethnically diverse images for targeted messaging was preferred over single race/ethnicity images. These results that extend beyond Alzheimer's and dementia-focused research registries can be generalized to recruitment of these target demographic groups across a variety of medical research contexts.},
}
@article {pmid42518409,
year = {2026},
author = {Van, DTT and Hoang, TLH and Din, NV and Nguyen, THC and Tran, TVT and Le, TH and Nguyen, THH and Le, LS and Vu Ho, XA and Tran, TM and Bich, TTN and Thuan, NTM and Nguyen, CC},
title = {Potential of Phenolic Metabolites from Gymnopetalum cochinchinense for Alzheimer's Disease Alleviation.},
journal = {ACS omega},
volume = {11},
number = {27},
pages = {39733-39742},
doi = {10.1021/acsomega.5c13219},
pmid = {42518409},
issn = {2470-1343},
abstract = {This study attempts to explore the neuroprotective potential of Gymnopetalum cochinchinense (Lour.) through the evaluation of antioxidant, anti-inflammatory, and acetylcholinesterase (AChE) inhibition activities. The achieved extract, containing a high total phenolic content (256.03 ± 1.50 mg GAE/g), exhibits potent radical-scavenging activity (IC50 = 22.45 ± 0.21 μg/mL for DPPH; 29.37 ± 0.72 μg/mL for ABTS), 97.04% inhibition of nitric oxide production, and over 40% inhibition of AChE activity at 100 μg/mL. LC-MS/MS profiling identifies rutin (278.39 ± 3.34 μg/g) and epigallocatechin gallate (205.63 ± 1.80 μg/g) as the major phenolic constituents. Molecular docking reveals that rutin, epigallocatechin gallate, and hesperidin exhibit strong binding affinities within the catalytic site of AChE, suggesting their contribution to the observed inhibitory activity. These findings provide the first comprehensive evidence that G. cochinchinense is a rich source of phenolic metabolites with significant AChE-inhibitory and antioxidant activities, supporting its potential as a natural resource for the development of nutraceuticals with neuroprotective benefits.},
}
@article {pmid42518426,
year = {2026},
author = {Gohar, N and Abbas, M and Masaud, SM and Zulfiqar, I and Jabeen, H and Malik, NS and Nadeem, H},
title = {"Behavioral and Neuroinflammatory Evaluation of a Novel Isoxazole-5-One Derivative in Animal Models of Alzheimer's Disease via TNF-α, COX-2, IL-6, and NF-κB Modulation".},
journal = {ACS omega},
volume = {11},
number = {27},
pages = {39910-39921},
doi = {10.1021/acsomega.6c01108},
pmid = {42518426},
issn = {2470-1343},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, cholinergic dysfunction, and neuroinflammation. Multitarget-directed ligands (MTDLs) are increasingly recognized as promising therapeutic approaches for such multifactorial pathological disorders. Isoxazole-5-one derivatives represent a novel scaffold with potential neuroprotective activity. In current study, the cognitive and anti-inflammatory properties of a newly synthesized isoxazole-5-one derivative, (E)-3-((benzylamino)-methyl)-4-(3,4,5-trimethoxybenzylidene) isoxazol-5-(4H)-one (M5), were evaluated using scopolamine-induced mice models of AD and biochemical analysis, respectively. Behavioral performance was assessed using the Morris Water Maze (MWM) and Y-maze paradigms. Scopolamine administration significantly impaired spatial learning, memory consolidation, and spontaneous alternation behavior, while treatment with M5 produced dose-dependent memory improvements. At the highest dose (10 mg/kg), M5 markedly reduced escape latency and enhanced target quadrant occupancy in the MWM, as well as restored alternation rates in the Y-maze (p < 0.001 vs scopolamine), with effects comparable to donepezil, a standard cholinesterase inhibitor. Biochemical analyses further demonstrated that M5 significantly reduced hippocampal levels of TNF-α and IL-6, while downregulating COX-2 and NF-κB expression, confirming its potent anti-inflammatory action. Taken together, these findings suggest that M5 ameliorates memory impairment potentially through its anti-inflammatory actions. Therefore, M5 may represent might be a promising multitarget-directed ligand for Alzheimer's disease.},
}
@article {pmid42518442,
year = {2026},
author = {Koca, &#x130; and Çapan, &#x130; and Mehtap Özden, E and Sert, Y and Demir, Y and Gülçin, &#x130;},
title = {Design and Synthesis of Novel Bioactive Squamolone Derivatives Targeting Carbonic Anhydrase and Acetylcholinesterase Enzymes.},
journal = {ACS omega},
volume = {11},
number = {27},
pages = {40043-40061},
doi = {10.1021/acsomega.6c01815},
pmid = {42518442},
issn = {2470-1343},
abstract = {A new series of squamolone-based γ-lactam derivatives (SQ1a-SQ1l) was rationally designed, synthesized, and structurally confirmed via FT-IR, NMR, and HRMS analyses. The synthesized compounds were evaluated for their inhibitory potential against human carbonic anhydrase isoforms I and II (hCA I and hCA II) and acetylcholinesterase (AChE), enzymes implicated in a range of pathological conditions including glaucoma, epilepsy, cancer, and Alzheimer's disease. Several derivatives demonstrated potent nanomolar inhibition, notably SQ1g against hCA I (K i = 17.99 ± 8.31 nM), SQ1c against hCA II (K i = 31.41 ± 10.26 nM), and SQ1b against AChE (K i = 0.35 ± 0.16 nM). Molecular docking studies corroborated the experimental findings, revealing key hydrogen bonding and hydrophobic interactions within the active sites of each enzyme. Furthermore, DFT-based HOMO-LUMO and molecular electrostatic potential (MEP) analyses provided insight into the compounds' electronic and reactive properties. In silico pharmacokinetic profiling using SwissADME tools showed that several compounds possessed favorable oral bioavailability, lipophilicity, and metabolic stability. Among them, SQ1g emerged as the most promising multitarget candidate due to its superior enzymatic activity, drug-like properties, and favorable docking profile. Collectively, these results highlight Squamolone as a versatile pharmacophore for the development of multifunctional enzyme inhibitors with therapeutic potential in neurodegenerative, oncological, and ophthalmological disorders, thereby supporting United Nations Sustainable Development Goal 3 (UN SDG3, Good Health and Well-being) through the advancement of innovative therapeutic agents for major human diseases.},
}
@article {pmid42518684,
year = {2026},
author = {Zhao, X and Sun, L and Zhang, X and Qi, X and Wu, G},
title = {Nanoparticles Navigating the Blood-Brain Barrier for Neurodegenerative Therapy.},
journal = {International journal of nanomedicine},
volume = {21},
number = {},
pages = {620793},
doi = {10.2147/IJN.S620793},
pmid = {42518684},
issn = {1178-2013},
abstract = {The blood-brain barrier (BBB) blocks most drugs from entering the brain. Over 98% of small-molecule drugs and nearly all biologics fail to cross this barrier. Nanoparticles (NPs) provide multiple ways to bypass the BBB. These include receptor-mediated transcytosis, adsorptive-mediated transport, and intranasal delivery. NPs can also modify disease-related pathways. For example, they promote amyloid-β clearance, reduce tau phosphorylation, and reprogram neuroimmune responses. Many preclinical studies have shown promising results in Alzheimer's, Parkinson's, and Huntington's diseases. However, no NP-based therapy has moved beyond early-stage clinical trials. Several issues remain unresolved. Direct comparisons between different NP platforms are lacking. The long-term toxicity of NPs in the brain is not well understood. Animal models also do not accurately reflect human disease. We suggest that future work should focus on standardized characterization, better predictive models, and clinical trial designs that address NP diversity. Researchers should also compare NP therapies with existing treatments in a rigorous manner.},
}
@article {pmid42518750,
year = {2026},
author = {Deenadayalan, T and Shantharajah, SP},
title = {PredatorNet: a clinically trustworthy deep learning framework for multi-class Alzheimer's disease classification using MRI.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1835340},
doi = {10.3389/fnagi.2026.1835340},
pmid = {42518750},
issn = {1663-4365},
abstract = {MRI-based staging of Alzheimer's Disease (AD) requires not only high classification accuracy but also clinically reliable probability estimates, transparent evidence for decisions, and robustness to shifts in data distribution. We propose PredatorNet, a multi-class AD classification framework with three key modules: (i) EagleAttention, which uses spatial self-attention to focus on diagnostically salient regions; (ii) RegionImportance, which produces an explicit spatial weighting map to support interpretability; and (iii) WolfPackFusion, which fuses complementary feature pathways to improve prediction stability. The training process requires us to use weighted random sampling because we need to handle class imbalance. We establish the Clinical Trust Score (CTS) as a metric that evaluates clinical effectiveness through the combination of seven performance benchmarks. The test set results show PredatorNet achieves 96.64% accuracy with macro Receiver Operating Characteristic Area Under the Curve of 0.9950 and mean sensitivity of 0.9803 and mean specificity of 0.9876 across 1,280 MRI scans. The model shows strong calibration (Calibration Reliability = 0.9912) and stable explanations (Regional Importance Stability Index = 1.0000). The evaluation method achieves an Out-Of-Distribution (OOD) stability score of 0.2810, which demonstrates its ability to handle distributional shifts. The CTS results show a value of 0.9491 without anatomical weighting and a value of 0.8652 under stricter anatomy-based validation. The Gradient-Weighted Class Activation Mapping visualizations establish a connection between learned importance patterns and neuro-anatomical regions relevant to clinical practice, which supports clinically oriented reporting.},
}
@article {pmid42518751,
year = {2026},
author = {Xu, Y and Zhang, G and Cui, X and Sun, L},
title = {Neuroinflammation in Alzheimer's disease-associated sensory dysfunction: mechanistic links, actionable targets and therapeutic strategies.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1838634},
doi = {10.3389/fnagi.2026.1838634},
pmid = {42518751},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD) is the most common cause of dementia and major public-health challenge in aging societies worldwide. Accumulating evidence suggests that olfactory and visual deficits can precede overt cognitive symptoms and are closely associated with amyloid-β deposition, pathological tau phosphorylation, and disease progression. Early sensory abnormalities in AD likely arise from converging pathological processes. Among these, chronic neuroinflammation marked by microglial and astrocytic reactivity, inflammasome activation and increased pro-inflammatory mediators might play a pivotal role linking sensory-circuit injury to neurodegeneration. A coherent synthesis of the inflammatory mechanisms underlying early olfactory and visual impairment in AD remains limited, and putative molecular pathways and interventions have not been fully integrated. We aimed to identify AD-related olfactory and visual or retinal abnormalities, combine core inflammatory pathways and their interactions with amyloid-β and tau pathology, and summarize actionable targets and candidate interventions along a "receptor-intracellular signaling-inflammasome-effector" axis, to inform earlier-stage detection and mechanism-guided intervention in AD.},
}
@article {pmid42518955,
year = {2026},
author = {Zhu, CW and Schneider, LS and Elder, GA and Soleimani, L and Neugroschl, J and Schimming, C and Sano, M},
title = {Neuropsychiatric symptom profile in neurocognitive disorders and their relationship with functional decline.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1805908},
doi = {10.3389/fneur.2026.1805908},
pmid = {42518955},
issn = {1664-2295},
abstract = {INTRODUCTION: Neuropsychiatric symptoms (NPS) are common in neurocognitive disorders (NCD) and are known to negatively impact patient's functional abilities. However, our understanding of the relationship between individual NPS and functional decline in patients with NCD across the spectrum of cognitive impairment is limited. Here we examine the relationship between specific NPS to characterize their effects on patient's function within and across different etiologies.<br><br>METHOD: Longitudinal observational study using the National Alzheimer's Coordinating Center Uniform Data Set (NACCUDS). We examined NPS as characterized by expert clinicians and report its impact on the outcome of functional decline, measured by the Functional Assessment Questionnaire (FAQ), a standardized assessment of activities of daily living, by dementia etiology (Alzheimer's disease (AD, N&#x202f;=&#x202f;11,044), Lewy Body Disease (LBD, N&#x202f;=&#x202f;921), and behavioral variant frontal temporal lobe dementia (bvFTD, N&#x202f;=&#x202f;933)).<br><br>RESULTS: We find apathy was the most commonly endorsed and the most persistent symptom across dementia types in all groups and was associated with more rapid functional decline in AD and bvFTD. On the contrary, depression, occurring in 40% or more of all groups, was not associated with worsening functional impairment in any group. We identified patterns that indicated higher rates of disinhibition and persistent disinhibition in bvFTD compared to AD and LBD. Psychosis had unique impact on functional decline in AD and LBD as did agitation in AD.<br><br>DISCUSSION: Differential impact of individual NPS across dementia etiologies and their impact on functional decline may have important consequences for clinical trial designs for the treatment of these symptoms.},
}
@article {pmid42518978,
year = {2026},
author = {Gazem, NA and Latif, S and Ghaban, W and Qasem, SN},
title = {Topology-aware hybrid graph-transformer network for Alzheimer's disease diagnosis from structural magnetic resonance imaging.},
journal = {Frontiers in computational neuroscience},
volume = {20},
number = {},
pages = {1834764},
doi = {10.3389/fncom.2026.1834764},
pmid = {42518978},
issn = {1662-5188},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by localized cortical atrophy and large-scale disruption of brain connectivity. Although deep learning (DL) methods have shown promise for neuroimaging-based diagnosis, many approaches fail to jointly capture localized structural changes and global network-level degeneration.<br><br>METHODS: We propose a topology-aware hybrid DL framework for AD classification from structural MRI. The model integrates (1) a 3D convolutional neural network (CNN) to extract volumetric morphometric features, (2) a dynamic graph attention network (GAT) to infer patient-specific structural connectivity without predefined atlases, and (3) a topology-biased Vision Transformer (Topo-ViT) that incorporates this connectivity into global attention. The framework is trained under strict subject-level data segregation and optimized using focal loss with an AUC-driven strategy.<br><br>RESULTS: Evaluated on a structural MRI dataset derived from the OASIS cohort, the proposed model achieved a test ROC-AUC of 0.857, with an overall accuracy of 85% and high sensitivity in detecting demented cases. Ablation studies show that topology-guided attention improves performance over CNN and hybrid baselines. Additional analyses reveal stable connectivity patterns and well-separated latent representations.<br><br>DISCUSSION: The results demonstrate that integrating topology-aware mechanisms enables more coherent modeling of AD as a network-level disorder. The proposed framework captures both local and global structural patterns, offering improved diagnostic reliability. Further validation on larger datasets is required for clinical deployment.},
}
@article {pmid42519007,
year = {2026},
author = {Zhao, Z and Zhao, F and Zhang, M and Sun, J and Wang, X and Lou, J and She, R and Kwok, LY and Sun, Z and Huangfu, W and Menghe, B},
title = {Multi-omics profiling reveals gut microbiome signatures associated with cognitive decline in Alzheimer's disease.},
journal = {iScience},
volume = {29},
number = {8},
pages = {116622},
doi = {10.1016/j.isci.2026.116622},
pmid = {42519007},
issn = {2589-0042},
abstract = {Alzheimer's disease (AD) is increasingly being linked to gut microbial dysbiosis via the gut-brain axis. We applied integrated metagenomics and metabolomics to characterize gut microecology in 28 patients with AD and 33 controls. Metagenomic analysis revealed distinct microbial community structures, with increased abundance of Akkermansia massiliensis, Alistipes onderdonkii, and Barnesiella intestinihominis in AD. Phageome analysis revealed increased richness and altered composition, with more Podoviridae and fewer Microviridae. Functional profiling identified shifts in microbial metabolic pathways involving tryptophan and short-chain fatty acid metabolism. Untargeted metabolomics revealed elevated fecal spermidine, taurocholate, and glycerophosphocholine levels in patients with AD. A random forest model combining metabolites, gut metabolic modules, and bacteriophages achieved good within-cohort classification (AUC = 0.83) but lacked external validation due to unavailable matched fecal metabolomic data. Overall, these findings link AD to coordinated disruptions across bacterial, viral, and metabolic gut layers, highlighting the need for external validation and mechanistic studies.},
}
@article {pmid42519233,
year = {2026},
author = {Irfan, Z and Prusty, SK and Giri, S and Nandi, A and Gouda, M},
title = {Functional Implications of Marine Biosurfactants and Their Therapeutic Potential Against Alzheimer's Disease.},
journal = {Food science &amp; nutrition},
volume = {14},
number = {7},
pages = {e72106},
doi = {10.1002/fsn3.72106},
pmid = {42519233},
issn = {2048-7177},
abstract = {Neuronal damage and cerebral impairment are defining characteristics of Alzheimer's disease (AD), a progressive neurodegenerative disorder associated with amyloid-β aggregation, oxidative stress, and neuroinflammation. Current treatments mainly provide symptomatic relief and do not effectively prevent disease progression, highlighting the need for novel disease-modifying strategies. Marine microorganisms produce amphiphilic substances called biosurfactants that exhibit diverse biological properties, including anti-inflammatory, antioxidant, and neuroprotective activities. Due to their amphiphilic nature, biosurfactants may interact with cellular membranes and modulate crucial pathological processes in AD, including inhibiting amyloid-β fibrillation, reducing oxidative stress, suppressing neuroinflammation via pathways such as NF-κB signaling, and enhancing drug delivery across the blood-brain barrier. Notably, various biosurfactant classes, such as lipopeptides, exhibit significant neuroprotective potential. This review explores the structural diversity and biological functions of marine biosurfactants, their potential as therapeutic candidates for managing AD, and the pathophysiology of AD. Overall, marine biosurfactants represent promising and sustainable therapeutic options for AD; however, extensive experimental and clinical research is necessary to confirm their effectiveness.},
}
@article {pmid42519311,
year = {2026},
author = {Wang, B and Yan, W and Zhang, Y},
title = {A multi-omics framework integrating gut microbiota, blood metabolites, and immune cells to elucidate the pathogenesis of Alzheimer's disease.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1842398},
doi = {10.3389/fimmu.2026.1842398},
pmid = {42519311},
issn = {1664-3224},
abstract = {BACKGROUND: Alzheimer's disease (AD) develops through complex interactions between the central nervous system and peripheral systems. The microbiota-metabolite-immune axis has emerged as an important focus of AD research. However, the coordinated mechanisms that regulate this axis remain poorly understood.<br><br>METHODS: We used a multi-stage, multi-omics strategy to systematically investigate peripheral-central interactions in AD. The analytical framework integrated Mendelian randomization (MR), summary-data-based Mendelian randomization (SMR), differential expression analysis, machine learning, single-cell and spatial transcriptomics, and quantitative real-time polymerase chain reaction (qPCR) trend confirmation.<br><br>RESULTS: Exploratory MR analyses identified multiple microbial taxa, metabolites, and immune cell phenotypes showing associations consistent with potential causal effects on AD. Integrating the SMR and MR findings with differential expression analysis led to the identification of 31 core genetically associated genes. A five-gene predictive model comprising ATF7IP2, TWSG1, PTPRN2, ASCC3 and IGF1R was then developed using machine learning. The diagnostic potential of the individual feature genes was further evaluated in an external validation dataset. Spatial transcriptomic analyses revealed clear cell type-specific expression patterns in brain tissue, with IGF1R, ASCC3and TWSG1 showing potential co-localization in oligodendrocytes. qPCR trend confirmation in pooled samples produced expression trends consistent with the directions inferred from eQTL-based MR.<br><br>CONCLUSIONS: This study mapped a regulatory network underlying the AD microbiota-metabolite-immune-brain axis and identified core genes with potential diagnostic and therapeutic value. The spatial transcriptomic findings, while primarily based on in situ co-localization analysis, highlight a biologically plausible but provisional working hypothesis regarding an active role for oligodendrocytes in AD pathology. Overall, this study supports a systems-level view of AD that may inform precision medicine strategies.},
}
@article {pmid42519433,
year = {2026},
author = {Chompalov, K and Spray, GJ and Georgieva, D},
title = {Preliminary validation of the Bulgarian SCCAN: initial reliability, validity, and screening accuracy across neurological populations.},
journal = {Frontiers in psychology},
volume = {17},
number = {},
pages = {1846359},
doi = {10.3389/fpsyg.2026.1846359},
pmid = {42519433},
issn = {1664-1078},
abstract = {PURPOSE: Bulgaria currently lacks standardized instruments for assessing cognitive-communicative abilities in adults with neurological disorders. This study reports preliminary validation evidence for the Bulgarian version of the Scales of Cognitive and Communicative Ability for Neurorehabilitation (SCCAN-B).<br><br>METHODS: Eighty-nine Bulgarian-speaking adults were assessed at a tertiary university hospital in Plovdiv, Bulgaria. The main analytic sample included four separate groups: neurotypical controls, individuals with mild cognitive impairment (MCI), Alzheimer's disease (AD) dementia, and ischemic stroke. All participants had previously received a formal diagnosis prior to being classified within one of these four groups. After informed consent was obtained, participants completed the SCCAN-B and the validated Bulgarian version of the Mini-Mental State Examination (MMSE-B). Analyses examined internal consistency, convergent validity with MMSE-B, known-groups differences, and preliminary screening classification using receiver operating characteristic analysis.<br><br>RESULTS: The SCCAN-B showed high internal consistency across the eight performance scales, &#x3b1; = 0.931. The SCCAN-B total score correlated strongly with MMSE-B scores, &#x3c1; = 0.84, p < 0.001. Significant group differences were observed for the SCCAN-B total score and all performance scales, with the largest impairments in the Alzheimer's disease group. ROC analysis distinguishing controls from the main clinical groups yielded an AUC of 0.850. A preliminary SCCAN-B total cut-off of 80 showed 70.7% sensitivity and 87.1% specificity.<br><br>CONCLUSION: Findings provide preliminary evidence that the SCCAN-B is a clinically promising screening instrument for identifying cognitive-communicative difficulties in Bulgarian-speaking neurological populations. However, the results should be interpreted cautiously because of the modest sample size, clinical heterogeneity, limited control of confounding variables, and the need for further normative and cross-cultural validation work.},
}
@article {pmid42519716,
year = {2026},
author = {Labounek, R and Matheson, MJ and Strong, CA and Petersen, A and Hill, A and Robertson, AJ and Hansen, A and Block, AD and Henderson, JN and Nestrasil, I and Lenglet, C and Mantyh, WG},
title = {Reduced Effect of APOE4 on White Matter Microstructure in an American Indian Community.},
journal = {Neurology. Genetics},
volume = {12},
number = {4},
pages = {e200418},
doi = {10.1212/NXG.0000000000200418},
pmid = {42519716},
issn = {2376-7839},
abstract = {BACKGROUND AND OBJECTIVES: Apolipoprotein E4 (APOE4) is central to Alzheimer disease (AD) personalized medicine, yet its link to AD is highly ancestry-dependent. Emerging evidence suggests an attenuated risk of APOE4 on brain health in American Indian (AI) participants. This study examines white matter microstructure, an early indicator of brain health deterioration, among tribal Elders carrying the APOE4 allele.<br><br>METHODS: We performed a cross-sectional, community-based study in partnership with the Bois Forte Band of Chippewa. Tribal Elders (>54 years of age) were evaluated at the Tribal Nation's health clinic or urban office and were recruited via radio, health fairs, social media, and flyers. We preselected 7 MRI white matter tracts that prior work has shown to be consistently associated with APOE4 status and AD in non-Hispanic white (NHW) participants. We compared microstructural integrity between AI and NHW APOE4 carriers vs noncarriers while controlling for age, sex, and hypertension status.<br><br>RESULTS: Sixty-two tribal Elders were included. The mean age was 65 years, and the mean Mini-Mental State Examination score was 29. Forty-nine (79%) participants were female, 33 (53%) had hypertension, and 10 (16%) were APOE4 heterozygotes. In contrast to NHW Alzheimer Disease Neuroimaging Initiative participants, tribal Elders had consistently attenuated associations of APOE4 on white matter microstructure.<br><br>DISCUSSION: Tribal elders have an attenuated effect of APOE4 on a neuroimaging measure of brain health. This finding parallels volumetric and neuropsychological findings in other AI populations. Caution is required when interpreting APOE4 for AI patients in clinical settings, where APOE4 status is increasingly used for prognostic, diagnostic, and treatment eligibility purposes.},
}
@article {pmid42520006,
year = {2026},
author = {Li, B and Yang, M and Luo, NA and Yi, Z},
title = {Combined Effects of Social Determinants of Health on Alzheimer's Disease: Insights from Bibliometric and NHANES Analyses.},
journal = {Neuroepidemiology},
volume = {},
number = {},
pages = {1},
doi = {10.1159/ned/adwag002},
pmid = {42520006},
issn = {1423-0208},
abstract = {BACKGROUND: Evidence on social determinants of health (SDoH) and Alzheimer's disease (AD) remains limited.<br><br>METHODS: This two-stage study combined bibliometric analysis (42 studies, 1997-2025) with NHANES data (n=14,420, age &#x2265;60). Survey-weighted logistic regression and weighted quantile sum (WQS) regression examined SDoH-AD associations. Bibliometric results showed heterogeneous, predominantly single-domain analyses.<br><br>RESULTS: Forty-two studies (1997-2025) indicated increasing but fragmented research dominated by single-domain analyses. In NHANES, employment, food security, marital status, and insurance type correlated with AD. WQS revealed a positive association between overall SDoH mixture and AD (OR 1.82, 95% CI 1.14-2.93), with marital status and poverty-income ratio contributing highest weights.<br><br>DISCUSSION: Multidimensional social disadvantage may be associated with AD, warranting integrated approaches.},
}
@article {pmid42520013,
year = {2026},
author = {Barczak, A},
title = {Functional staging of Alzheimer's disease dementia with Addenbrooke Cognitive Examination-III: evidence for subtype-specific cognitive thresholds.},
journal = {Dementia and geriatric cognitive disorders},
volume = {},
number = {},
pages = {1},
doi = {10.1159/dem/aciag001},
pmid = {42520013},
issn = {1421-9824},
abstract = {INTRODUCTION: Translating cognitive test results into clinically meaningful measures of dementia severity remains challenging in real-world settings, where biomarkers are limited and functional assessment may occasionally be confounded by non-cognitive factors. Although the Addenbrooke's Cognitive Examination III (ACE-III) is widely used for detecting Alzheimer's disease (AD), its role in severity staging is less established. This study evaluated the usefulness of ACE-III for functionally anchored staging and compared it with the Mini-Mental State Examination (MMSE).<br><br>METHODS: In a retrospective real-world cohort of 1,170 patients with AD dementia (late-onset, early-onset, and mixed), severity was classified using the Functional Assessment Staging Tool (FAST). Receiver operating characteristic analyses were used to derive cut-offs for differentiating adjacent stages (FAST 4 vs 5; FAST 5 vs 6). Domain-level and subtype-specific analyses were conducted.<br><br>RESULTS: ACE-III showed excellent discrimination between FAST 4 and 5 (AUC = 0.92; cut-off &#x2264;56) and moderate discrimination between FAST 5 and 6 (AUC = 0.77; cut-off &#x2264;42), outperforming MMSE in later stages (AUC = 0.63). Attention contributed most to earlier transitions, whereas later stages showed broader domain involvement. Cut-offs varied across AD subtypes.<br><br>CONCLUSION: ACE-III provides clinically meaningful estimates of dementia severity and may help overcome limitations of functional assessment in real-world settings, supporting its use for staging and monitoring in routine clinical practice.},
}
@article {pmid42520110,
year = {2026},
author = {Horiuchi, M and Yamanaka, J and Shigemori, H and Higashimura, Y and Sekiguchi, M},
title = {Four Undescribed Chromane-Type Meroterpenoids From Sargassum siliquastrum and Their Inhibitory Activity Against Amyloid-β42 Aggregation.},
journal = {Chemistry &amp; biodiversity},
volume = {23},
number = {7},
pages = {e71550},
doi = {10.1002/cbdv.71550},
pmid = {42520110},
issn = {1612-1880},
support = {//Mitani Foundation for Research and Development/ ; },
abstract = {Four undescribed chromane-type meroterpenoids, sargasilides H-K (1-4), were isolated from the brown alga Sargassum siliquastrum. Their structures were elucidated by comprehensive spectroscopic analyses, and their absolute configurations were partially established by electronic circular dichroism and the modified Mosher's method. The inhibitory effects of 1-4 against amyloid-β42 aggregation were evaluated using a thioflavin T fluorescence assay. Among them, sargasilide J (3) exhibited the strongest activity. Furthermore, compound 3 significantly delayed paralysis in a transgenic Caenorhabditis elegans model expressing amyloid-β42. These findings provide further insight into the structural features governing amyloid-β42 aggregation inhibition in chromane-type meroterpenoids.},
}
@article {pmid42520257,
year = {2026},
author = {Ko, J and Meyer, K and Wang, J},
title = {Care Partner Perspectives on Hypertension Management in Alzheimer Disease and Related Dementias in an Online Forum: Qualitative Thematic Analysis.},
journal = {JMIR nursing},
volume = {9},
number = {},
pages = {e85818},
doi = {10.2196/85818},
pmid = {42520257},
issn = {2562-7600},
abstract = {BACKGROUND: Family care partners manage care for individuals with Alzheimer disease and related dementias (ADRD), including hypertension management crucial for preventing cognitive decline. Nurses frequently interact with these caregiver-patient dyads but have limited evidence about caregivers' real-world experiences of managing this comorbidity. Understanding these experiences is essential for developing nurse-led interventions that support both patients and caregivers.<br><br>OBJECTIVE: This study aimed to explore ADRD care partners' perceptions, experiences, and challenges related to hypertension management. A qualitative thematic analysis of care partner posts from an online forum focused on ADRD was conducted.<br><br>METHODS: We analyzed 300 posts from ALZConnected, collected using the keywords "hypertension" and "blood pressure." Two independent researchers used reflexive thematic analysis, following the Braun and Clarke framework until data saturation was achieved.<br><br>RESULTS: Among posts from predominantly family care partners (10,427/11,092, 94%, mostly adult children), 7 themes emerged: Pharmacotherapy (155/300, 51.7%), addressing medication efficacy, polypharmacy, and side effects; Patient Health Care Implementation Strategies (n=125, 41.7%), encompassing care coordination and provider interactions; Comorbid Care Management (n=136, 45.3%), highlighting caregiving demands, behavioral symptoms of ADRD, and care coordination challenges as barriers to hypertension control; Hypertension Management and Outcomes (n=71, 23.7%), including hypertensive crises; Managing Behavioral Symptoms (n=38, 12.7%), particularly care resistance; Peer Medical Advice Exchange (n=9, 3%); and Caregiver Burden and Self-Care for Hypertension (n=25, 8.3%), revealing care partners' own hypertension attributed to caregiving stress.<br><br>CONCLUSIONS: Managing comorbid hypertension in ADRD presents challenges spanning medication management, behavioral symptoms, and health care coordination. Caregivers reported developing hypertension themselves, highlighting bidirectional health impacts. Health care providers should implement dyadic interventions addressing both patient hypertension management and caregiver health within the care partnership.},
}
@article {pmid42500978,
year = {2026},
author = {Jones, DT and Corriveau-Lecavalier, N},
title = {Reply: Interpreting early default mode network dysfunction across the Alzheimer's disease Spectrum.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag254},
pmid = {42500978},
issn = {1460-2156},
}
@article {pmid42500984,
year = {2026},
author = {Xia, L and Ren, K and Demetriou, I and Gurunandan, K and Meeker, KL and Vidal-Pineiro, D and Henson, R},
title = {Bilingualism and Cognitive Aging in Ethnically Diverse Older Adults: Cross-sectional and Longitudinal Evidence from HABS-HD.},
journal = {The journals of gerontology. Series B, Psychological sciences and social sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/geronb/gbag150},
pmid = {42500984},
issn = {1758-5368},
abstract = {OBJECTIVES: Identifying modifiable factors that shape cognitive aging trajectories is a central goal in aging research. This study examined whether bilingualism is associated with dementia status and longitudinal cognitive decline, and whether associations vary by ethnicity or gender.<br><br>METHODS: We analyzed Wave 7 data from the Health and Aging Brain Study-Health Disparities (HABS-HD), a longitudinal U.S. cohort of adults aged &#x2265;50 years. Bilingualism was defined by self-reported use of a second language. Cross-sectional analyses included 4,140 participants (1,013 bilinguals); longitudinal analyses included 1,760 participants (522 bilinguals) followed for up to four visits at approximately 2-year intervals. Outcomes were baseline dementia status and latent factor scores for executive function and episodic memory derived from 11 neuropsychological tests. Regression and linear mixed-effects models assessed associations, adjusting for age, education, gender, ethnicity, and practice effects.<br><br>RESULTS: Bilingualism was not associated with baseline dementia status or conversion to probable dementia. Cross-sectionally, associations varied by ethnicity: Hispanic bilinguals showed higher executive function and episodic memory scores. No advantage was observed in White participants; conversely, Black bilinguals had lower episodic memory scores. Longitudinally, bilingualism was associated with slower episodic memory decline independent of sociodemographic factors; no longitudinal association was observed for executive function.<br><br>DISCUSSION: These findings suggest that bilingualism may confer domain-specific benefits for memory trajectories in later life, while cross-sectional differences appear shaped by sociocultural context. The results underscore the importance of considering ethnic diversity and language history when evaluating experiential influences on cognitive aging.},
}
@article {pmid42501008,
year = {2026},
author = {Verma, B and Kumar, R and Sharma, A and Kumar, N and Khan, Z and Ashique, S and Rani, R and Parihar, VS and Antal, S and Mumtaz, and Anand, A},
title = {Targeting the microbiota-gut-brain axis in neurodegeneration: Zebrafish-based investigations.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-16},
doi = {10.1080/17582024.2026.2705869},
pmid = {42501008},
issn = {1758-2032},
abstract = {The microbiota-gut-brain axis (MGBA) is a bidirectional signaling pathway regulated by the gut microbiome and the central nervous system (CNS). Moreover, MGBA is crucial for normal growth, development, and physiology of the brain and gut of the host; dysfunction in MGBA has been closely linked with the development of neurological disorders. Gut dysbiosis and its metabolites modulate barrier permeability and cause gastrointestinal tract (GIT) inflammation, which is followed by an increase in pro-inflammatory cytokines, immune cell infiltration into the brain, and vagus nerve dysfunction, resulting in neuroinflammation and neuronal defects in the brain, as well as some other behavioral defects. In this review, we will discuss the molecular and neurobehavioral properties of Zebrafish as a research model to study MGBA, as well as current discoveries in humans, highlighting the vital role of MGBA in neuropathological conditions. Using Zebrafish as a genetic model in combination with in vivo imaging technology may suggest some novel mechanisms for the interaction between gut microbiota and CNS, particularly in the case of neurological disorders including Alzheimer's disease (AD), Parkinson's disease (PD) and autism spectrum disorder (ASD). A comprehensive literature search was conducted using electronic databases including PubMed, Scopus, Web of Science, and Google Scholar.},
}
@article {pmid42501010,
year = {2026},
author = {Chen, S and Huang, H and Xu, X and Wang, Q and Lu, Y and Zhuang, Z and Lin, W and Zeng, Q and Wang, D and Chen, S},
title = {Multi-Index Brain Function-Cognition Correlation in Amnestic Mild Cognitive Impairment: A Resting-State fMRI Study.},
journal = {American journal of Alzheimer's disease and other dementias},
volume = {41},
number = {},
pages = {15333175261460967},
pmid = {42501010},
issn = {1938-2731},
mesh = {Humans ; *Cognitive Dysfunction/physiopathology/diagnostic imaging ; Magnetic Resonance Imaging/methods ; Female ; Male ; Aged ; *Brain/physiopathology/diagnostic imaging ; *Amnesia/physiopathology/diagnostic imaging ; *Cognition/physiology ; Neuropsychological Tests ; Middle Aged ; Brain Mapping ; },
abstract = {BackgroundThis study aimed to investigate the correlation between multi-metric resting-state fMRI (rs-fMRI) changes and cognitive performance in amnestic mild cognitive impairment (aMCI), moving beyond single-metric analyses.MethodsForty aMCI patients and twenty healthy controls underwent 3.0T rs-fMRI and neurocognitive assessment (MoCA, DST). Multiple rs-fMRI metrics (ReHo, ALFF/fALFF, RSFC) were analyzed for their association with cognition.ResultsaMCI patients showed increased frontal ReHo, decreased ALFF in default mode network hubs, and reduced prefrontal-parietal-temporal RSFC. Frontal hyper-synchronization correlated negatively with cognitive scores, while DMN ALFF correlated positively.ConclusionsMulti-metric fMRI detects characteristic functional alterations in aMCI, indicating regional brain damage or compensatory changes linked to cognitive performance.},
}
@article {pmid42501667,
year = {2026},
author = {Kunwar, D and Kumar, J and Ali, SA and Namdeo, AG and Flora, SJS},
title = {Ceruloplasmin and neurodegeneration: A link between copper dysregulation, iron imbalance, and neuronal damage.},
journal = {Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)},
volume = {97},
number = {},
pages = {127929},
doi = {10.1016/j.jtemb.2026.127929},
pmid = {42501667},
issn = {1878-3252},
abstract = {Ceruloplasmin (Cp) is a multifunctional multicopper oxidase principally produced in the liver and, to a lesser extent, in the central nervous system. It regulates iron homeostasis and oxidative balance, Cp oxidizes ferrous iron (Fe[2+]) to ferric iron (Fe[3+]), thereby enabling its safe integration into transferrin and averting reactive oxygen species formation. Beyond its ferroxidase activity, Cp also serves as a major copper carrier in plasma and contributes to antioxidant defense mechanisms. Although, the imbalance of ceruloplasmin has been gradually recognized as a key marker in the pathogenesis of neurodegenerative disorders. It is associated with neurofibrillary tangles, amyloid plaques, tau hyperphosphorylation, oxidative stress, and mitochondrial dysfunction. In the past, Cp and neuropathology were first established when a decreased level of serum ceruloplasmin was reported as a diagnostic biomarker of Wilson's disease, a disorder characterized by copper build-up triggered by mutations in the ATP7B gene. Furthermore, some studies suggest the absence of Cp was known in aceruloplasminemia, a different neurodegenerative condition characterized by extensive deposition of iron in the brain and progressive neuronal loss. However, several studies have reported that Cp's function and expression undergo important modifications in Alzheimer's, Parkinson's, Wilson's disease, and other neurological conditions. These alterations in Cp are directly linked to disrupted metal homeostasis, alleviating oxidative stress and neuroinflammation. Thus, besides understanding the structural, metabolic, and biological roles of Cp, this review aims at explaining its possible effects on common neurological disorders. The review also focusses on the therapeutic opportunities targeting Cp-mediated pathways, primarily, focusing on how Cp dysfunction interrelates with copper metabolism, iron dysregulation, and neuroinflammatory signalling, as reported in various clinical and experimental studies. Understanding Cp mechanism may highlight novel strategies for overcoming these neurodegenerative diseases.},
}
@article {pmid42501808,
year = {2026},
author = {Yang, G and Xu, X and Xu, Y},
title = {Presenilin deficiency beyond amyloid: Lessons from presenilin 1/2 conditional double-knockout mice on synaptic failure, calcium dyshomeostasis, and inflammation-driven Alzheimer's disease.},
journal = {Brain research bulletin},
volume = {244},
number = {},
pages = {112057},
doi = {10.1016/j.brainresbull.2026.112057},
pmid = {42501808},
issn = {1873-2747},
abstract = {Presenilins are best known as the catalytic core of γ-secretase, where familial Alzheimer's disease (FAD) mutations shift amyloid-β (Aβ) trimming toward aggregation-prone species. Yet conditional and cell-type-specific genetic analyses in mice now place presenilin (PS) biology far beyond amyloidogenesis. In PS1/2 conditional double-knockout (PS cDKO) models, which combine germline PS2 deletion with postnatal PS1 inactivation in forebrain excitatory neurons, the earliest phenotype is a synaptopathy: presynaptic release probability and short-term plasticity collapse, N-methyl-D-aspartate receptor (NMDAR) function wanes, and cAMP response element-binding protein (CREB)/CREB-binding protein (CBP)-dependent transcriptional programs falter. Compensatory glial responses rapidly consolidate into a neuroinflammatory state, with inflammasome activation and cytokine surges that further erode synaptic signaling and promote tau hyperphosphorylation. Progressive cortical and callosal atrophy and ventriculomegaly follow, culminating in neuron loss, even as cortical Aβ is reduced, severing the mechanistic necessity of plaques for degeneration. Across interventions, anti-inflammatory, cholinergic, and metabolic manipulations rescue cognition and plasticity in PS cDKO mice without engaging amyloid, underscoring a disease axis that is Aβ-independent yet clinically salient. Here we synthesize lessons from PS cDKO studies, integrate them with contemporary presenilins/γ-secretase biology, and outline a translational agenda focused on presynaptic Ca[2 +] microdomains, RyR-coupled release, activity-dependent gene programs, and innate immune checkpoints. We conclude that PS integrate vesicular release machinery with trophic and inflammatory homeostasis; their loss initiates a multi-scale failure cascade that redefines early AD-related neurodegeneration beyond Aβ.},
}
@article {pmid42501950,
year = {2026},
author = {Lian, W and Zhou, F and Tong, Z and Xia, C and Yan, Y and He, J and Xu, J and Zhang, W},
title = {Targeting the NLRP3 Inflammasome in Alzheimer's Disease: Mechanistic Insights and Therapeutic Advances.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103273},
doi = {10.1016/j.arr.2026.103273},
pmid = {42501950},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD) is the leading cause of dementia, yet current therapies provide limited clinical benefit. Neuroinflammation, as an early and sustained driver of AD, places the NLRP3 inflammasome at the center of pathological and therapeutic focus. In this review, we synthesize recent advances in the structure, assembly, and activation of the NLRP3 inflammasome, and evaluate its contribution to AD using evidence from human brain tissues, cerebrospinal fluid, and diverse AD animal models. Available data consistently support aberrant NLRP3 activation in AD brain, where it is closely associated with amyloid-β (Aβ) deposition, tau pathology, glial reactivity, and cognitive decline. We further discuss the cell-type-specific roles of microglia and astrocytes, highlighting microglia as the principal effector cells in inflammasome-associated pathology. Mechanistically, Aβ and tau converge on NLRP3 activation through interconnected pathways involving K[+] efflux, lysosomal rupture, mitochondrial dysfunction, and impaired autophagy. Downstream IL-1β, IL-18, and gasdermin D amplify neuroinflammation and neuronal injury. We summarize emerging therapeutic strategies directly targeting its core components or downstream effectors, as well as anti-AD agents with indirect NLRP3 modulation including endogenous molecules, repurposed drugs, and natural products. Collectively, this review regards NLRP3 inflammasome as a critical inflammatory hub and a promising target for disease-modifying therapy in AD, and provide useful perspectives on AD pathogenesis and inform the development of more rational therapeutic strategies.},
}
@article {pmid42502037,
year = {2026},
author = {Montano, CB and Chumki, SR and Wang, D and Palma, AM and Zhang, Z and Porsteinsson, AP},
title = {Brexpiprazole With Antidepressants for Agitation in Alzheimer's Dementia: Post Hoc Analysis.},
journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jagp.2026.06.015},
pmid = {42502037},
issn = {1545-7214},
abstract = {OBJECTIVE: To analyze the efficacy and safety of brexpiprazole versus placebo on agitation symptoms in participants with Alzheimer's dementia, with and without concomitant antidepressants.<br><br>METHODS: Data were pooled from two Phase 3, 12-week, randomized, double-blind, placebo-controlled trials of brexpiprazole (ClinicalTrials.gov identifiers: NCT01862640, NCT03548584). Post hoc, participants were stratified by antidepressant use. Efficacy was assessed using the Cohen-Mansfield Agitation Inventory (CMAI) and safety using treatment-emergent adverse events (TEAEs).<br><br>RESULTS: Brexpiprazole 2 or 3 mg/day improved CMAI Total score versus placebo in participants with concomitant antidepressant (n = 97; least squares mean difference at Week 12, -12.1 [95% confidence interval, -19.1 to -5.05]; t(77) = -3.4, p = 0.001; Cohen's d = 0.72) and without concomitant antidepressant (n = 513; -2.93 [-5.49 to -0.37]; t(487) = -2.2, p = 0.025; Cohen's d = 0.20). Falls were the only TEAE reported for &#x2265;5% of participants with concomitant antidepressant (brexpiprazole, 6.5%; placebo, 5.7%).<br><br>CONCLUSION: In this exploratory post hoc analysis, brexpiprazole improved agitation symptoms and was generally well tolerated in participants with Alzheimer's dementia with and without concomitant antidepressants.},
}
@article {pmid42502106,
year = {2026},
author = {El-Mezayen, NS and Eesa, YA and Hassan, WA and Aly, DA and Saafan, YS and Khedr, EM and Sherief, A and Elkordy, EA},
title = {Vitamin a modulates neurogenesis-associated pathways and cholinergic signaling in Alzheimer's disease: potential role of reactive astrocytes via NGN2/SOX-11 and SIRT-1.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {42502106},
issn = {2045-2322},
mesh = {Animals ; *Astrocytes/metabolism/drug effects/pathology ; *Alzheimer Disease/metabolism/pathology/drug therapy ; *Sirtuin 1/metabolism ; *Vitamin A/pharmacology/metabolism ; *Neurogenesis/drug effects ; Rats ; Signal Transduction/drug effects ; *Basic Helix-Loop-Helix Proteins/metabolism ; *Nerve Tissue Proteins/metabolism ; Male ; Cholinergic Neurons/metabolism/drug effects ; Humans ; Disease Models, Animal ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder lacking effective disease-modifying therapies. A promising regenerative approach involves enhancing endogenous neurogenic capacity within the injured brain. Reactive astrocytes-stellate-like cells in the AD brain-may contribute to a pro-neurogenic environment through transcription factors (TFs) such as neurogenin 2 (NGN2) and SOX-11. This process is tightly regulated by epigenetic mechanisms, particularly SIRT-1, a neuroprotective histone deacetylase that modulates TF activity and neuronal fate. Vitamin A (VA), a key regulator of differentiation and epigenetic remodeling via its active metabolite retinoic acid, is stored in astrocytes and hepatic stellate cells (HSCs). We hypothesized that AD-related astrocyte activation depletes cerebral VA, mobilizes hepatic stores, contributes to liver fibrosis, and that VA supplementation may restore astrocytic function, activate endogenous TFs via SIRT-1, and drive cholinergic neuron regeneration. In a scopolamine (SCO)-induced AD rat model, VA biodistribution was traced using confocal microscopy. Brain and liver VA deficiency were confirmed via retinol-binding protein (RBP) and ALDH1A1 expressions. Rats received VA (1500, 3000, or 4500 IU/kg/day) or donepezil. Outcomes included neurogenesis (DCX), NGN2/SOX-11 expression, SIRT-1 activation, cholinergic regeneration, amyloid-β deposition, and serum tau. Liver fibrosis was assessed via TGF-β, hydroxyproline and histopathologically. AD induced systemic VA depletion and liver fibrosis. Medium-dose VA (VAMD) significantly enhanced neurogenesis, TF expression, SIRT-1 activation, cholinergic regeneration, and reversed liver fibrosis. VAMD demonstrated neuroregenerative and antifibrotic effects, indicating a possible therapeutic role in AD.},
}
@article {pmid42502242,
year = {2026},
author = {Luo, B and Kouznetsova, VL and Tsigelny, IF},
title = {Comparative Screening of Alzheimer's Disease, Lewy Body Dementia, and Frontotemporal Dementia Using miRNA and Machine Learning.},
journal = {International journal of neural systems},
volume = {},
number = {},
pages = {2750002},
doi = {10.1142/S012906572750002X},
pmid = {42502242},
issn = {1793-6462},
abstract = {Current dementia diagnostic methods can be costly, invasive, or limited in their ability to distinguish between disorders with overlapping clinical symptoms. Dysregulated microRNAs (miRNAs) have emerged as promising noninvasive biomarkers for neurodegenerative disease, but individual miRNA changes alone may not capture the complex molecular patterns needed for accurate disease classification. Machine learning provides a way to integrate multiple layers of miRNA-derived information and identify disease-specific biomarker signatures. In this study, we developed machine learning models to classify dysregulated miRNAs associated with Alzheimer's disease dementia (AD), Lewy body dementia (LBD), and frontotemporal dementia (FTD). Each miRNA was represented using sequence-derived descriptors, predicted gene targets, and KEGG pathway features. The highest-performing models trained on AD, LBD, and FTD achieved 10-fold cross-validation accuracies of 90.6%, 92.9%, and 100%, respectively. When evaluated on independent datasets, the AD, LBD, and FTD models achieved accuracies of 88.9%, 77.8%, and 90.9%, respectively. Cross-disease testing showed reduced performance when models were applied across dementia types, suggesting partially disease-specific miRNA patterns while also indicating overlap among the molecular signatures of AD, LBD, and FTD. These results suggest that machine learning-based integration of miRNA sequence, target-gene, and pathway information can improve the identification of dementia-associated biomarker signatures and may support the future development of noninvasive diagnostic tools for dementia.},
}
@article {pmid42502360,
year = {2026},
author = {Houmani, A and Parul, FNU and Saeed, M and Skowronek, R and Katkoori, V and Pikuleva, IA and Grant, MB and Busik, JV and Yavari, M and Abela, GS},
title = {Cholesterol crystal formation and embolism in the central nervous system and their potential role in Alzheimer's disease.},
journal = {American heart journal plus : cardiology research and practice},
volume = {69},
number = {},
pages = {100826},
pmid = {42502360},
issn = {2666-6022},
abstract = {The brain and nervous tissues are very rich in cholesterol with local sterol biosynthesis being the primary source. The production of cholesterol in the brain may also lead to cholesterol crystal formation that in turn can cause inflammation which potentially can contribute to Alzheimer's disease. In this review we provide examples of cholesterol crystals (CCs) in human brains of Alzheimer patients. Moreover, cholesterol in the arterial circulation is also a major contributor to brain pathology. Specifically, CCs embolization released during plaque rupture may lead to reduced cognitive function, transient ischemic attacks, and ischemic strokes. Ischemic strokes can be caused by either thrombotic emboli from atrial fibrillation or CC emboli and platelets from ruptured plaques in the carotid arteries and aortic arch. CC emboli can cause blood flow obstruction, localized inflammation, and vasospasm of the local arterial vasculature, all contributing to ischemia and brain injury. Prevention and treatment of CC emboli with statins and aspirin has been found to be effective. Moreover, previous studies have demonstrated that both statins and aspirin can dissolve CCs. Thus, preventing formation and/or dissolving CCs could potentially be effective in reducing end organ injury induced by both CCs formation and emboli. Although further investigation with human studies remain lacking, recent studies have demonstrated prevention of thrombus formation induced by CCs may also provide another approach to inhibiting end-organ ischemic injury.},
}
@article {pmid42502428,
year = {2026},
author = {Song, JY and Hunter, LE and Freudenberg-Hua, Y and Lubin, N and Hu, S and Ye, K and Lipton, RB and Engeland, CG and Lipton, ML},
title = {APOE genotype is associated with Ex vivo inflammatory responses in healthy individuals: Potential implications for Alzheimer's disease.},
journal = {Brain, behavior, &amp; immunity - health},
volume = {56},
number = {},
pages = {101307},
pmid = {42502428},
issn = {2666-3546},
abstract = {BACKGROUND: Apolipoprotein E (APOE) genotype and inflammation are each linked to Alzheimer's disease (AD) risk. The APOE-ε4 (APOE4) allele is associated with increased AD risk, while the APOE-ε2 (APOE2) allele is protective. The mechanisms behind these associations remain unclear, particularly regarding the role of inflammation. This study examined the association between APOE genotype and different measures of inflammation, including mitogen-stimulated cytokine production (ex vivo) which provides a stable measure of immune response traits.<br><br>METHODS: We examined basal and lipopolysaccharide (LPS)-stimulated cytokine levels (interleukin (IL)-1&#x3b2;, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor-alpha (TNF-&#x3b1;), granulocyte-macrophage colony-stimulating factor (GM-CSF)) and C-reactive protein (CRP) in blood samples from 91 healthy individuals (ages 18-51) of varying APOE genotypes.<br><br>RESULTS: APOE4 carriers exhibited higher LPS-stimulated inflammatory responses (IL-1&#x3b2;, TNF-&#x3b1;) in peripheral whole blood compared to non-carriers, while APOE2 carriers showed a hypo-inflammatory profile (lower stimulated IL-1&#x3b2;) compared to APOE3 individuals.<br><br>CONCLUSION: Distinct inflammatory phenotypes were associated with APOE genotypes, with APOE4 carriers exhibiting a hyper-inflammatory response and APOE2 carriers exhibiting a hypo-inflammatory response. These profiles may contribute to differential AD risk, highlighting the potential involvement of inflammation in APOE-associated AD susceptibility.},
}
@article {pmid42502675,
year = {2026},
author = {Yu, L and Alhoqail, WA and Mickymaray, S and Li, F},
title = {Cnicin Attenuates Aluminium Chloride-Induced Neurodegeneration Through Antioxidant and Anti-Inflammatory Mechanisms.},
journal = {Dose-response : a publication of International Hormesis Society},
volume = {24},
number = {3},
pages = {15593258261471150},
pmid = {42502675},
issn = {1559-3258},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited disease-modifying therapies. Aluminium chloride (AlCl3)-induced neurotoxicity mimics key pathological features of AD, including oxidative stress, neuroinflammation, and cholinergic dysfunction.<br><br>OBJECTIVE: This study aimed to evaluate the neuroprotective effect of cnicin in an AlCl3-induced rat model of Alzheimer-like neurodegeneration.<br><br>METHODS: Rats were divided into five groups: normal control, AlCl3 control (75 mg/kg/day, p.o.), AlCl3 with cnicin (20 and 40 mg/kg/day, p.o.), and AlCl3 with donepezil (5 mg/kg/day, p.o.) for 30 days. Behavioral performance was assessed using hanging wire and beam walking tests. Biochemical parameters, including acetylcholinesterase (AChE), antioxidant enzymes (SOD, CAT, GSH), malondialdehyde (MDA), and inflammatory cytokines (TNF-&#x3b1;, IL-1&#x3b2;) were analyzed, along with histopathology.<br><br>RESULTS: AlCl3 administration induced significant behavioral deficits, increased AChE activity, oxidative stress, neuroinflammation, and neuronal damage. Cnicin treatment dose-dependently improved motor function, reduced AChE activity, restored antioxidant levels, decreased lipid peroxidation, and suppressed inflammatory markers. Histological analysis confirmed preservation of neuronal architecture, comparable to that of donepezil.<br><br>CONCLUSION: Cnicin exhibits significant neuroprotective effects against AlCl3-induced neurodegeneration by modulating cholinergic activity, oxidative stress, and inflammation, suggesting its potential as a therapeutic agent for AD.},
}
@article {pmid42502987,
year = {2026},
author = {Zhu, XA and Lu, H and Liu, Y and Xue, X and Lin, L},
title = {Mechanistic and functional study of lncRNA SNHG3/miR-128-3p/UBR5 axis in neuroinflammation in Alzheimer's disease.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/gerona/glag187},
pmid = {42502987},
issn = {1758-535X},
abstract = {Neuroinflammation assumes a pivotal role in Alzheimer's disease (AD) pathogenesis. Long noncoding RNAs (lncRNAs) regulate neuroinflammation through a competitive endogenous RNA (ceRNA) mechanism. This study aimed to explore the mechanism of SNHG3/miR-128-3p/UBR5 axis in AD associated neuroinflammation. SNHG3, miR-128-3p, and UBR5 levels were recognized by reverse transcription - quantitative polymerase chain reaction (RT-qPCR). In vitro AD model was established by Aβ1-42 stimulation in human microglial cells HMC3 and neuronal cells SK‑N‑SH. Cell apoptosis was detected by flow cytometry. Enzyme - linked immunosorbent assay (ELISA) and oxidative stress indicators were used to evaluate the neuroinflammatory phenotype. Morris water maze (MWM) test assesses the spatial learning and memory abilities of amyloid precursor protein/presenilin 1 (APP/PS1) mice with AAV-si-SNHG3. Serum SNHG3 was clearly upregulated in AD patients, and negatively related to MMSE score (r = -0.691, P<0.001). SNHG3 had diagnostic potential for AD (AUC=0.847, 95% CI = 0.806-0.888, sensitivity=75.63%, specificity=76.88%). SNHG3 regulates UBR5 expression by sponges miR-128-3p. Silence of SNHG3 inhibited M1 polarization (reducing TNF-α, IL-6, and iNOS), promotes M2 polarization (increasing Arg1, IL-10, and TGF-β), inhibits IL-1β release, suppresses neuronal apoptosis, and mitigates oxidative stress damage (reducing MDA and increasing SOD) via miR-128-3p/UBR5 axis in Aβ-stimulated HMC3 cells. SNHG3 also contributes to Aβ‑induced neuronal apoptosis, inflammation, and oxidative stress in SK‑N‑SH cells. AAV-si-SNHG3 significantly enhances spatial learning and memory abilities of APP/PS1 mice, and inhibits neuroinflammation and oxidative stress in the hippocampus. This study is the first to elucidate that SNHG3 could regulate microglial polarization and neuroinflammation through the SNHG3/miR-128-3p/UBR5 axis.},
}
@article {pmid42503382,
year = {2026},
author = {Yang, IG and Heo, JY and Myung, JH and Jeong, MY and Park, JS and Kim, DE and Noh, SY and Jeong, MG and Kim, MJ and Kim, JY and Seo, DW and Choi, MK and Choi, YS and Kang, MJ},
title = {Donepezil nanocrystals-incorporated carboxymethyl cellulose nanopaste for high-payload transdermal delivery with improved skin compatibility.},
journal = {International journal of biological macromolecules},
volume = {377},
number = {},
pages = {153735},
doi = {10.1016/j.ijbiomac.2026.153735},
pmid = {42503382},
issn = {1879-0003},
abstract = {Donepezil (DPZ), an acetylcholinesterase inhibitor for Alzheimer's disease, suffers from skin irritation during transdermal delivery. Herein, a drug high-payload nanopaste (NP) system was designed employing carboxymethyl cellulose (CMC) to enhance transdermal delivery of DPZ while mitigating cutaneous irritation. DPZ NPs (10, 20, and 27.5% w/v) were fabricated via wet bead-milling with low-molecular-weight CMC (90 K) to obtain submicron particles, followed by incorporation into high-molecular-weight CMC (700 K) matrix. The drug nanocrystals were uniformly distributed in the CMC matrix, preserving crystal size (505.6-563.8 nm), zeta potential (-48.93 to -51.95 mV), and crystallinity. Fourier-transform infrared analysis revealed the electrostatic interaction between the anionic polymers and drug nanocrystals. Pharmacokinetic evaluations in rats revealed that while the 10% NP achieved systemic absorption comparable to the commercial patch, the 20% NP provided a 2.1-fold higher transdermal absorption. Level A IVIVC analysis established a robust correlation (R[2] > 0.96) between in vitro dissolution profile and in vivo absorption. Crucially, the CMC-based NPs showed markedly improved dermal tolerability, showing minimal hyperplasia and inflammation compared to acrylic-based commercial patches. Additionally, NPs were chemically stable under accelerated conditions without antioxidants. These findings suggest that CMC-based NP system of DPZ represents a biocompatible transdermal platform for long-term Alzheimer's therapy.},
}
@article {pmid42503498,
year = {2026},
author = {Lee, YS and Roh, S and Han, J and Moon, I and Stone, ST and Warne, DK},
title = {Alzheimer's Disease Knowledge Among American Indians: The Role of Social Determinants of Health.},
journal = {Dementia (London, England)},
volume = {},
number = {},
pages = {14713012261471592},
doi = {10.1177/14713012261471592},
pmid = {42503498},
issn = {1741-2684},
abstract = {American Indian populations experience a disproportionately high prevalence of risk factors for Alzheimer's disease and related dementias. This study assessed Alzheimer's disease knowledge across seven domains and identified factors associated with overall and domain-specific Alzheimer's disease knowledge among American Indian adults. Guided by the social determinants of health framework, we conducted a cross-sectional survey of American Indian adults residing in South Dakota. A total of 227 participants completed a self-administered survey questionnaire measuring Alzheimer's disease knowledge across seven domains. Multivariable regression analyses were performed to examine factors associated with overall Alzheimer's disease knowledge and each domain. Participants demonstrated 63.5% accuracy in overall Alzheimer's disease knowledge (M = 18.7, SD = 4.1), indicating a moderate level of knowledge. Knowledge varied across domains: participants were most knowledgeable about the life impact of Alzheimer's disease and least knowledgeable about risk factors and symptoms. Four domains were found to be statistically significant: disease course, treatment and management, risk factors, and caregiving. Higher educational attainment and employment status were significantly associated with greater overall Alzheimer's disease knowledge. Education was the most consistent factor associated with greater knowledge across all four domains, whereas other social determinants of health variables (e.g., social support from significant others, lower depressive symptoms, health status, exercise) showed domain-specific associations. Findings highlight the need for educational outreach and culturally tailored interventions grounded in the social determinants of health and responsive to American Indian community contexts. Notable gaps in knowledge-particularly regarding risk factors and symptoms-suggest priority areas for Alzheimer's disease prevention efforts. Health initiatives should address key social determinants, including education, employment, social support, health/mental health status, and health behaviors. Interventions must be developed in partnership with Indigenous leaders and health professionals to ensure culturally relevant, community-driven, and holistic approaches that improve Alzheimer's disease knowledge and support Alzheimer's disease prevention in American Indians.},
}
@article {pmid42503573,
year = {2026},
author = {Socher, KLR and Ferreira, NV and Paes, VR and Justo, AFO and Rodriguez, RD and Silva, CM and Leite, REP and Ururahy, RR and de Moraes, FOC and Padrão, IL and Ferriolli, E and Pasqualucci, CA and Nitrini, R and Grinberg, LT and Brucki, SMD and Suemoto, CK},
title = {Sex differences in dementia pathology and cognitive performance in a population-based, ethnically diverse Brazilian autopsy study.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71691},
doi = {10.1002/alz.71691},
pmid = {42503573},
issn = {1552-5279},
support = {24CBIDR-1185483 AARG-20-678884 AARGD-22-972378/ALZ/Alzheimer's Association/United States ; 2020/14339-3 2024/03917-7//S&#xe3;o Paulo Research Foundation/ ; },
mesh = {Humans ; Female ; Male ; Brazil ; Aged ; *Dementia/pathology ; Aged, 80 and over ; *Brain/pathology ; Autopsy ; *Sex Characteristics ; *Cognition/physiology ; },
abstract = {INTRODUCTION: Sex differences in dementia-related neuropathology are understudied in diverse populations.<br><br>METHODS: We analyzed sex differences in neuropathological and cognitive data from the Brazilian Biobank for Aging Studies. Cognitive performance was evaluated with the Clinical Dementia Rating-Sum of Boxes (CDR-SOB). Linear and logistic regression models were conducted, including interaction terms for age, race, and education.<br><br>RESULTS: In 2229 participants (50.7% female, mean age &#xb1; SD 75.4&#xa0;&#xb1;&#xa0;12.3 years, 62.1% White), female sex was associated with a higher odds of AD pathology (Braak: odds ratio [OR]&#xa0;=&#xa0;1.42, 95% confidence interval [CI] &#xa0;=&#xa0;1.17-1.72; Consortium to Establish a Registry for Alzheimer's Disease (CERAD): OR&#xa0;=&#xa0;1.58, 95% CI&#xa0;=&#xa0;1.27-1.98), and trans-activation response (TAR) DNA-binding protein 43 (TDP-43) (OR&#xa0;=&#xa0;1.77, IC 95%&#xa0;=&#xa0;1.22-2.59), and lower odds of Lewy body disease (OR&#xa0;=&#xa0;0.69, 95% CI&#xa0;=&#xa0;0.51-0.95). Female participant had worse cognitive performance (&#x3b2;&#xa0;=&#xa0;1.56, 95% CI&#xa0;=&#xa0;1.03-2.10). Sex modified associations of Braak, CERAD, TDP-43, and cerebral amyloid angiopathy with cognition. Age also interacted with sex and pathology on CDR-SOB.<br><br>DISCUSSION: Sex differences in the associations between sex and neuropathology suggest the need for sex-informed dementia research.},
}
@article {pmid42503576,
year = {2026},
author = {Mansour, RM and Alam-ElDein, KM and Abdel Mageed, SS and El-Sayyad, GS and Ghanem, A and Shaker, AAS and Mohammed, OA and Farag, DAA and Abdelnaby, M and Hathout, A and Adelaziz, RY and Ahmed, NE and Mohamed, MYA and Doghish, AS},
title = {Targeting the Microbiota-Gut-Brain Axis: Emerging Nanomedicine Approaches for Neurodegenerative Diseases.},
journal = {The European journal of neuroscience},
volume = {64},
number = {2},
pages = {e70606},
doi = {10.1111/ejn.70606},
pmid = {42503576},
issn = {1460-9568},
mesh = {Humans ; *Neurodegenerative Diseases/microbiology/therapy ; *Gastrointestinal Microbiome/physiology ; Animals ; *Dysbiosis/therapy/microbiology ; *Brain/metabolism ; *Nanomedicine/methods ; Fecal Microbiota Transplantation/methods ; *Brain-Gut Axis/physiology ; Probiotics/therapeutic use ; },
abstract = {The microbiota-gut-brain axis (MGBA) is a bidirectional relationship between the gut microbiota (GM) and the brain, where the GM affects the gastrointestinal tract (GIT) and the central nervous system (CNS), and vice versa. Microbiotas are important for several vital body processes, including metabolism, immunity, and homeostasis. The MGBA has three main pathways: the vagal nerve mechanism, the immune-related mechanism, and the neuroendocrine mechanism. GM imbalance, known as dysbiosis, affects the GIT, the brain, and the CNS. Furthermore, dysbiosis is linked to several neurological disorders such as Alzheimer's (AD), Parkinson's (PD), depression, autism spectrum disorder (ASD), and multiple sclerosis (MS). Studying MGBA gives researchers new therapeutic ideas using microbiota. Using special diets rich in fiber and probiotics, in addition to fecal microbiota transplantation (FMT), is being studied as a new therapy for MGBA. From the point of view that these therapeutic interventions maintain microbiota imbalance, which in turn will affect the brain and can relieve the neurological disorders caused by dysbiosis and MGBA.},
}
@article {pmid42503587,
year = {2026},
author = {Jiang, J and Larsen, EK and Levett, BA and Core, LB and Froud, SA and Della Monica, C and Hassanin, H and Atzori, G and Hardy, CJ and Busche, MA and Dijk, DJ and Revell, VL and Harris, SS and Eriksson, SH and Warren, JD},
title = {The Pittsburgh Sleep Quality Index and Epworth Sleepiness Scale in frontotemporal dementia and Alzheimer's disease.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71686},
doi = {10.1002/alz.71686},
pmid = {42503587},
issn = {1552-5279},
support = {//by Alzheimer's Research UK/ ; //Brain Research Trust,/ ; //The Wolfson Foundation/ ; //National Brain Appeal/ ; //UCL Research Excellence Scholarship/ ; //UK Medical Research Council/ ; UKDRI-1208 to M.A.B.//UK Dementia Research Institute/ ; UKDRI-7206 to D.J.D.//UK Dementia Research Institute/ ; AARF-23-1149637/ALZ/Alzheimer's Association/United States ; 25AARG-1376792/ALZ/Alzheimer's Association/United States ; A2019112S//BrightFocus Foundation/ ; //Cure Alzheimer's Fund/ ; Future Leaders Fellowship (MR/X011038/1)//UK Research and Innovation/ ; //University College London/ ; NIHR204280//National Institute for Health and Care Research/ ; NIHR306146//National Institute for Health and Care Research/ ; AS-PG-16-007/ALZS_/Alzheimer's Society/United Kingdom ; 627/ALZS_/Alzheimer's Society/United Kingdom ; //Wolfson Foundation/ ; G105 to J.D.W.//Royal National Institute for Deaf People/ ; },
mesh = {Humans ; *Frontotemporal Dementia/complications/psychology ; *Alzheimer Disease/complications/psychology ; Female ; Male ; Aged ; *Sleep Quality ; *Sleep Wake Disorders/diagnosis/etiology ; Neuropsychological Tests ; Middle Aged ; Aphasia, Primary Progressive/complications ; *Sleepiness ; Sleep Duration ; },
abstract = {INTRODUCTION: Sleep disturbance is common in dementia, impacting daytime function and care. Compared with Alzheimer's disease (AD), sleep in frontotemporal dementia (FTD) is poorly characterized.<br><br>METHODS: We assessed sleep using the Epworth Sleepiness Scale and Pittsburgh Sleep Quality Index in 58 people with primary progressive aphasia (PPA) and right temporal variant FTD, 32 with AD, and 36 cognitively healthy older volunteers. All participants had cognitive and behavioral assessments. Groups were compared using non-parametric statistics and correlations assessed sleep versus other indices.<br><br>RESULTS: Subjective sleep duration was increased in all syndromic groups. AD and semantic PPA were associated with increased daytime somnolence. Reported sleep quality varied between syndromes. Across the disease cohort, somnolence correlated with behavioral and empathy deficits; in AD, poorer sleep quality correlated additionally with self-monitoring deficits.<br><br>DISCUSSION: FTD and AD syndromes have distinct sleep phenotypes, and sleep alterations are associated with behavior. Standard sleep scales require careful interpretation in dementia.},
}
@article {pmid42503774,
year = {2026},
author = {Jagaselvan, E and Mondal, P and Zhang, C},
title = {Modulating Stress Granules via HDAC6 Inhibition: A Promising Strategy against Alzheimer's Disease.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00264},
pmid = {42503774},
issn = {1948-7193},
abstract = {Emerging evidence suggests that dysregulated cellular stress responses, particularly the formation and persistence of stress granules (SGs), may significantly contribute to Alzheimer's disease (AD) pathogenesis. SGs are dynamic, membrane-less ribonucleoprotein assemblies that sequester stalled translation preinitiation complexes during cellular stress. Under physiological conditions, SGs are transient and disassemble upon stress resolution, often facilitated by heat shock proteins (HSPs). However, under chronic stress, persistent or aberrant SGs can form, which may seed pathological protein aggregation and exacerbate proteostatic imbalance, neuroinflammation, and neurodegeneration. Despite the growing body of evidence linking HDAC6 to SG dynamics and AD pathology, the precise mechanistic relationship remains unresolved. This review highlights the current understanding of HDAC6-mediated SG regulation in AD, identifies critical knowledge gaps, and discusses the therapeutic potential of selective HDAC6 inhibition in modulating SG pathology and neuroinflammation.},
}
@article {pmid42503871,
year = {2026},
author = {Dong, H and Lv, X and Qian, Y and Chang, A and Cheng, M and Yang, X and Ding, J and Yang, Z and Zhou, Y and Zhang, Y and Li, Z and Xu, M},
title = {Dual-Mode Turn-On Fluorescent and Ratiometric Electrochemical Detection of Cu[2+] in Alzheimer's Disease Mouse Brains Based on a Single Resorufin-Picolinate Probe.},
journal = {Analytical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.analchem.6c03646},
pmid = {42503871},
issn = {1520-6882},
abstract = {Copper ions (Cu[2+]) are closely implicated in the pathogenesis of Alzheimer's disease (AD) by mediating oxidative stress and promoting β-amyloid (Aβ) aggregation. Accurate quantification of labile Cu[2+] in the brain extracellular microenvironment is critical for elucidating its pathological roles and developing AD diagnostic tools. Herein, we report a dual-mode sensing platform integrating "turn-on" fluorescence and ratiometric electrochemistry for sensitive and selective Cu[2+] quantification, based on a resorufin-picolinate conjugate (RP) probe and a carbon nanotube-modified carbon fiber microelectrode (CFME/CNT). Resorufin (Re) acts as both the fluorescent reporter and electrochemical redox center, while picolinate serves as the Cu[2+]-specific recognition moiety. Cu[2+] coordinates with picolinate to catalyze the ester hydrolysis of RP, releasing free Re that triggers a fluorescence enhancement at 594 nm and a ratiometric electrochemical response, corresponding to the oxidation currents of free Re and intact RP, respectively. The RP probe exhibits high selectivity for Cu[2+] over other metal ions, with limits of detection of 19 nM (fluorescence) and 7.2 nM (electrochemistry). The dual-mode platform was successfully applied to the accurate quantification of endogenous labile Cu[2+] in cerebral cortex dialysate from AD mice and age-matched wild-type (WT) mice, and noninvasive in vivo fluorescence imaging further confirmed the elevated Cu[2+] level in living AD mouse brains. Quantitative results revealed that the labile Cu[2+] concentration in AD mouse cerebral cortex dialysate was significantly higher than that in WT mice. The two detection modes yielded highly consistent results, validating the reliability of the dual-mode platform in complex biological matrices. This dual-mode strategy synergizes the merits of fluorescence and ratiometric electrochemistry, providing a robust and selective tool for investigating AD pathogenesis related to Cu[2+] dyshomeostasis and holds great potential for clinical translational applications in AD diagnosis.},
}
@article {pmid42504106,
year = {2026},
author = {Rius-Bonet, J and Gras-Font, J and Macip, S},
title = {Exploring ageing as a potential new therapeutic target for schizophrenia.},
journal = {The British journal of psychiatry : the journal of mental science},
volume = {},
number = {},
pages = {1-3},
doi = {10.1192/bjp.2026.10746},
pmid = {42504106},
issn = {1472-1465},
abstract = {Increased age-related biological changes have been causally linked to various pathologies in the brain, including Alzheimer's and Parkinson's diseases. There is also evidence that schizophrenia could be included in this group of brain disorders that may actually be manifestations of a broader multisystemic premature ageing phenotype.},
}
@article {pmid42504206,
year = {2026},
author = {Zhang, Y and Qin, G and Lian, Q and Sun, Y and Liu, Z and Chen, B and Li, Z and Li, N and Song, R and Wang, Y},
title = {Deciphering the Multi-Target Therapeutic Mechanisms of Traditional Chinese Medicine Against Alzheimer's Disease: A Network Pharmacology Perspective.},
journal = {Drug design, development and therapy},
volume = {20},
number = {},
pages = {597886},
pmid = {42504206},
issn = {1177-8881},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Medicine, Chinese Traditional ; *Network Pharmacology ; *Drugs, Chinese Herbal/therapeutic use/pharmacology/chemistry ; Signal Transduction/drug effects ; Animals ; },
abstract = {Alzheimer's disease (AD) poses a growing threat to global health, with no disease-modifying therapies currently available to cure or reverse its progression. Given its favorable safety profile and multi-target nature, Traditional Chinese Medicine (TCM) has attracted increasing attention as a potential strategy for AD prevention and treatment. In recent years, network pharmacology (NP) has emerged as a valuable predictive and analytical tool in TCM research, offering insights into the potential mechanisms underlying AD interventions. This review aims to systematically outline the methodology and commonly used databases in TCM NP, summarize the main TCM monomers and compounds studied for AD over the past decade, and identify five core signaling pathways, namely, the PI3K/Akt signaling pathway, the MAPK signaling pathway, the JAK-STAT signaling pathway, the AGE-RAGE signaling pathway, and the Nrf2 signaling pathway, implicated in pathogenesis and TCM action. To guide further exploration of TCM's role in AD management and to support subsequent research on its disease mechanisms and therapeutic strategies.},
}
@article {pmid42504602,
year = {2026},
author = {Eisen, A and Durham, HD and Pioro, E},
title = {The aging brain that doesn't fail: how neural resilience masks neurodegeneration.},
journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration},
volume = {},
number = {},
pages = {1-15},
doi = {10.1080/21678421.2026.2705693},
pmid = {42504602},
issn = {2167-9223},
abstract = {Neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease are usually framed as consequences of aging-related pathogenic processes, including impaired proteostasis with protein aggregation, mitochondrial dysfunction, oxidative stress, and neuroinflammation. Yet, most individuals, even into advanced age, do not develop clinically significant neurodegenerative disease. This discrepancy suggests that the nervous system possesses robust and redundant protective mechanisms that maintain neural integrity despite cumulative molecular and cellular stress. In this perspective, we propose that neurodegenerative diseases arise not simply from the presence of pathogenic processes, but when integrated resilience systems fail to maintain homeostasis or when reserve mechanisms no longer compensate for accumulated pathology. We have synthesized a threshold-based model of disease emergence based on evidence across proteostasis, mitochondrial function, neuroimmune regulation, glial biology, network-level compensation, and barrier integrity, while integrating genetic, environmental, developmental, and stochastic modifiers. We distinguish biological resilience, which actively limits or repairs pathology, from reserve, which permits function despite pathology. We further propose that clinical disease emerges only when age-related cumulative stress exceeds the combined capacity of resilience and reserve. Reframing neurodegeneration as a failure of preservation systems offers new directions for prevention and therapeutic development.},
}
@article {pmid42504619,
year = {2026},
author = {Hefny, AA and Karuturi, RC and Madhuranthakam, CMR and Rao, PPN},
title = {Design, Synthesis, and Evaluation of Novel Phenoselenazine Derivatives as Potent Modulators of Aβ42 Aggregation.},
journal = {Journal of medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jmedchem.6c01959},
pmid = {42504619},
issn = {1520-4804},
abstract = {A novel class of fused tricyclic phenoselenazine derivatives possessing a redox-active selenium atom were designed, synthesized, and evaluated as Aβ42 aggregation inhibitors with antioxidant activity. They exhibit remarkable inhibition of Aβ42 aggregation as confirmed by fluorescence aggregation kinetics study, electron microscopy, and cell-based studies in mouse hippocampal HT22 neuronal and BV2 microglial cells. Compounds 5i and 9g exhibited potent inhibition of Aβ42 aggregation with IC50 values of 350 and 317 nM, respectively, with compound 9g exhibiting exceptional ability to destabilize preformed Aβ42 fibrils (IC50 = 210 nM), surpassing those of the reference compounds resveratrol and methylene blue. Both 5i and 9g showed efficient blood-brain barrier permeability and provided significant neuroprotection toward Aβ42-induced cytotoxicity and demonstrated strong antioxidant properties by conferring protection toward hydrogen peroxide-induced cytotoxicity in mouse hippocampal HT22 cells. Collectively, our results demonstrate that these novel phenoselenazines represent a promising class of therapeutics to treat Alzheimer's disease.},
}
@article {pmid42504849,
year = {2026},
author = {Kumar, S and Burhan, AM and Colman, S and Chu, L and Davies, S and Derkach, P and Elmi, S and Gerretsen, P and Graff-Guerrero, A and Greenway, K and Hussain, M and Ismail, Z and Kim, D and Krisman, L and Ma, C and Moghabghab, R and Mulsant, BH and Pollock, BG and Rej, S and Rostas, A and Schoer, N and Streiner, DL and Van Bussel, L and Rajji, TK and , },
title = {Standardizing care for agitation in Alzheimer's disease, results from a randomized controlled trial of an integrated care pathway versus usual care - the StaN trial.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71610},
doi = {10.1002/alz.71610},
pmid = {42504849},
issn = {1552-5279},
support = {//Centre for Aging and Brain Health Innovation/ ; //Brain Canada Foundation through the Canada Brain Research Fund/ ; },
mesh = {Humans ; Female ; Male ; Double-Blind Method ; *Psychomotor Agitation/therapy/drug therapy/etiology ; *Alzheimer Disease/complications/therapy/drug therapy ; Aged ; Aged, 80 and over ; Polypharmacy ; Canada ; Treatment Outcome ; Long-Term Care ; Psychotropic Drugs/therapeutic use ; },
abstract = {BACKGROUND: Adherence to treatment guidelines for agitation in dementia is suboptimal and inconsistent. We designed and evaluated an Integrated Care Pathway (ICP) for the management of agitation in dementia.<br><br>METHODS: This was a double-blind randomized controlled trial at 12 inpatient units and long-term-care homes (LTCHs) across Canada. Participants were randomized 1:1 to the ICP or treatment-as-usual (TAU). Primary outcomes were Cohen Mansfield Agitation Inventory (CMAI) and psychotropic polypharmacy at 12 weeks.<br><br>RESULTS: We randomized 185 participants (93 inpatients, 92 in LTCHs). For CMAI, there were no significant time-by-treatment-group interactions among inpatients (F4, 299.3&#xa0;=&#xa0;1.7, p&#xa0;=&#xa0;0.14) or LTCH residents (F4, 296.0&#xa0;=&#xa0;0.87, p&#xa0;=&#xa0;0.48). For polypharmacy, there were significant time-by-treatmentgroup interactions among both inpatients (&#x3c7; 7 2 =&#xa0;15.3, p&#xa0;=&#xa0;0.032) and LTCH residents (&#x3c7; 7 2 =&#xa0;30.0, p&#xa0;<&#xa0;0.001), with lower rates of polypharmacy in the ICP group at certain time points, but not at week 12.<br><br>CONCLUSIONS: Standardizing care for agitation in dementia may result in lesser polypharmacy without affecting efficacy. Future studies should assess the ICP in the broader community and outpatients.},
}
@article {pmid42504877,
year = {2026},
author = {Mei, Y and Cao, Y and Mignani, S and Majoral, JP and Shen, M and Shi, X},
title = {Phosphorus Dendrimer-Mediated Protein Delivery.},
journal = {Biomacromolecules},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.biomac.6c01257},
pmid = {42504877},
issn = {1526-4602},
abstract = {Phosphorus dendrimers represent a next-generation nanoplatform that has garnered increasing attention for delivering diverse protein therapeutics. Compared with conventional organic and inorganic protein carriers, phosphorus dendrimers possess distinct advantages, including intrinsic bioactivity, well-defined molecular architecture, multimodal protein-loading mechanisms, considerable structural modifiability, reliable stability, and desired biocompatibility, realizing simple and mild protein complexation merely through physical interactions to construct phosphorus dendrimer-based protein nanomedicines. Recent studies have demonstrated the synergistic therapeutic enhancement against multiple diseases, such as osteoarthritis, cancer, ischemic stroke, Alzheimer's disease, and Parkinson's disease, based on these nanomedicines. In this Perspective, the primary synthesis routes of phosphorus dendrimers are systematically outlined at first, and their superiority as protein nanoplatforms over other carriers is comparatively analyzed. Then, the latest advances of the above nanomedicines in disease therapies are summarized in detail, and the current challenges hindering their applications from bench to bedside are also discussed.},
}
@article {pmid42504920,
year = {2026},
author = {Zheng, Y and Zheng, Y and Chen, P and Wang, X},
title = {Exercise, Demethylase FTO, Neurological Disorders, and Neuropathic Pain: Potential Molecular Mechanisms.},
journal = {CNS neuroscience &amp; therapeutics},
volume = {32},
number = {7},
pages = {e71051},
doi = {10.1002/cns.71051},
pmid = {42504920},
issn = {1755-5949},
support = {82372578//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Alpha-Ketoglutarate-Dependent Dioxygenase FTO/metabolism/genetics ; *Neuralgia/metabolism/genetics/therapy ; Animals ; *Nervous System Diseases/metabolism/genetics/therapy ; *Exercise/physiology ; },
abstract = {MAIN PROBLEM AND METHODS: This review aims to summarize the role of fat mass and obesity-associated protein (FTO) in neurological disorders and neuropathic pain (NP).<br><br>RESULTS: Key findings suggest that in neurological disorders such as Alzheimer's disease, Parkinson's disease, and depression, FTO-regulated m[6]A modification plays a critical role in the hippocampus and striatum. FTO-mediated m[6]A modification is involved in the pathological processes of NP. These findings suggest that FTO may serve as a potential therapeutic target for neurological disorders and NP. Common mechanisms may include the regulation of downstream mTOR and BDNF/TrkB signaling pathways, as well as modulation of neuronal excitability and synaptic plasticity. However, research on the relationship between exercise and m[6]A modification remains in its early stages. Emerging evidence suggests that exercise reduces FTO expression and increases m[6]A levels in the hippocampus and hypothalamus, indicating that exercise may serve as an effective intervention for modulating epigenetic modifications in the central nervous system.<br><br>CONCLUSIONS: This implies that exercise may serve as an effective intervention for modulating epigenetic modifications, potentially by downregulating the demethylase FTO, regulating m[6]A modification, enhancing synaptic plasticity, modulating neuronal excitability, and providing neuroprotection, thereby contributing to disease mitigation. We hypothesize that exercise may regulate neurological disorders and NP through FTO-mediated m[6]A modification, with FTO potentially serving as a biomarker.},
}
@article {pmid42505348,
year = {2026},
author = {Liu, B and Zhang, L and Lv, B and Xu, C and Han, L and Yan, Q and Wang, X},
title = {Copper Homeostasis and Cuproptosis in Neurodegenerative Diseases.},
journal = {Cells},
volume = {15},
number = {14},
pages = {},
doi = {10.3390/cells15141238},
pmid = {42505348},
issn = {2073-4409},
mesh = {Humans ; *Copper/metabolism ; *Cuproptosis ; *Homeostasis ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; Mitochondria/metabolism ; Proteotoxic Stress ; },
abstract = {Copper is an essential trace element required for numerous enzymatic processes in the brain, including mitochondrial metabolism, antioxidant defense, and gene expression regulation. Recent studies have further implicated copper in a newly defined form of regulated cell death termed cuproptosis, providing a mechanistic framework for copper-dependent cytotoxicity. Increasing evidence indicates that copper dyshomeostasis is a common feature of major neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), where it is associated with protein misfolding, redox imbalance, and neuronal vulnerability. Nevertheless, the mechanistic link between copper dysregulation and neuronal cell death remains incompletely defined. In this review, we systematically summarize the molecular mechanisms governing copper homeostasis and intracellular copper trafficking, while providing a timely, updated, and in-depth overview of the mechanistic basis and emerging biology of cuproptosis. We further comprehensively evaluate the current evidence linking copper dysregulation and cuproptosis-related pathways to neurodegenerative diseases, with particular emphasis on distinguishing mechanistic causation from pathological correlation. Importantly, we discuss current therapeutic strategies and emerging clinical efforts targeting copper metabolism, while highlighting the major challenges in defining the pathological significance and mechanistic contribution of cuproptosis in neurodegenerative diseases. Collectively, this review provides an updated framework for understanding the pathological significance and translational potential of cuproptosis in neurodegenerative diseases.},
}
@article {pmid42505375,
year = {2026},
author = {Yuan, NY and Richards, WD and Parham, KT and Clark, SG and Lebakken, CS},
title = {Stimulus-Based ApoE Alzheimer's Disease Induction Model Using Microglia-Containing Brain Organoids for Drug Discovery.},
journal = {Cells},
volume = {15},
number = {14},
pages = {},
doi = {10.3390/cells15141266},
pmid = {42505375},
issn = {2073-4409},
support = {R43NS139845/NS/NINDS NIH HHS/United States ; R43AG082625/AG/NIA NIH HHS/United States ; R44ES029898/ES/NIEHS NIH HHS/United States ; },
mesh = {*Alzheimer Disease/pathology/drug therapy/metabolism/genetics ; *Microglia/metabolism/pathology/drug effects ; *Organoids/pathology/metabolism/drug effects ; *Brain/pathology/metabolism ; Humans ; Animals ; *Apolipoproteins E/metabolism/genetics ; *Drug Discovery/methods ; Induced Pluripotent Stem Cells/metabolism ; Mice ; Models, Biological ; },
abstract = {Alzheimer's Disease (AD) is a multifaceted progressive neurodegenerative disease characterized by memory deficits and cognitive impairment. The disease is clinically diagnosed by the presence of β-amyloid (Aβ), hyperphosphorylated tau, and neurodegeneration. Animal models serve as an indispensable tool to understanding AD pathogenesis and evaluating potential therapeutic approaches. However, despite the development of more than 200 rodent models, species-specific differences limit the translational relevance. Brain organoids generated from induced pluripotent stem cells (iPSCs) have the potential to bridge the gap between transgenic mouse models and clinical trials in human patients. Herein, we describe a robust stimulus-based neuroimmune organoid model that demonstrates neuroinflammation, neurodegeneration, and lipid dysregulation with AD-relevant pathological markers. Using planar organoids containing neurons, astrocytes, microglia, and vascular cells, we performed in-depth characterization of the induced AD-like phenotype using supernatant proteomic analysis, immunofluorescence staining, NfL and GFAP release, scRNAseq, bulk RNAseq, and pathway analysis both acutely (24 h) and chronically (7 days). Furthermore, we show that the induced neuroinflammation, lipid dysregulation, and neurodegeneration can be ameliorated using small molecules. This defined inducible model system presents an opportunity for drug discovery and development using a complex multicellular brain microenvironment derived from human iPSCs.},
}
@article {pmid42505379,
year = {2026},
author = {Wang, L and Ma, X and Zeng, Q and Liu, M and Yue, Z and Hu, R},
title = {Molecular Basis of Glia-ECM Interplay in Central Nervous System Homeostasis and Plasticity.},
journal = {Cells},
volume = {15},
number = {14},
pages = {},
doi = {10.3390/cells15141268},
pmid = {42505379},
issn = {2073-4409},
support = {No. 82505780//The National Natural Science Foundation of China/ ; GZB20240217//the Postdoctoral Fellowship Program of CPSF under Grant Number/ ; },
mesh = {Humans ; *Extracellular Matrix/metabolism ; *Neuroglia/metabolism ; *Homeostasis ; *Central Nervous System/metabolism ; Animals ; *Neuronal Plasticity ; Mechanotransduction, Cellular ; },
abstract = {Interactions between glial cells and the central nervous system (CNS) extracellular matrix (ECM) maintain neural homeostasis and plasticity. In contrast to traditional reviews focusing on biochemistry, this work summarizes the structural and mechanical properties of major ECM subtypes, and illustrates how mechanical and biochemical signals jointly regulate glial activity via key mechanosensitive pathways. Glia in turn dynamically remodel ECM, forming a reciprocal regulatory network. This paper also analyzes characteristic mechanical disorders in Alzheimer's disease, multiple sclerosis and traumatic brain injury, and addresses targeted therapeutic strategies. Current research challenges and emerging interdisciplinary directions are also discussed. This review provides a valuable reference for exploring neurological disease mechanisms and developing new therapies.},
}
@article {pmid42505383,
year = {2026},
author = {Razmi, AH and Penny, JI},
title = {Interleukin-1β and Interleukin-6 Signaling Differentially Regulate ABC Transporter Activity and Amyloid-β Handling in Primary Porcine Brain Endothelial Cells.},
journal = {Cells},
volume = {15},
number = {14},
pages = {},
doi = {10.3390/cells15141273},
pmid = {42505383},
issn = {2073-4409},
support = {N/A//Majlis Amanah Rakyat/ ; },
mesh = {Animals ; *Amyloid beta-Peptides/metabolism ; *Interleukin-6/metabolism ; *Endothelial Cells/metabolism ; *Interleukin-1beta/metabolism ; *Signal Transduction ; *Brain/cytology/metabolism ; Swine ; *ATP-Binding Cassette Transporters/metabolism ; Blood-Brain Barrier/metabolism ; Cells, Cultured ; Receptors, Interleukin-6/metabolism ; Peptide Fragments ; },
abstract = {Impaired amyloid-β clearance at the blood-brain barrier (BBB) contributes to Alzheimer's disease (AD), yet the regulation of endothelial transport processes under neuroinflammatory conditions remains incompletely understood. Here, we investigated the time-dependent effects of interleukin-1β (IL-1β), interleukin-6 (IL-6) classical signaling directly via the membrane-bound IL-6 receptor, and IL-6 trans-signaling via the IL-6 /soluble IL-6 receptor complex (IL-6/sIL-6r) on ATP-binding cassette (ABC) transporter activity and expression in primary porcine brain endothelial cells (PBECs), and assessed intracellular accumulation of amyloid-β(1-42). Cytokine exposure did not affect PBEC viability. IL-1β induced a robust, time-dependent increase in ABCB1 activity and expression, whereas IL-6 produced a transient enhancement that was not sustained at 72 h. In contrast, IL-6 trans-signaling elicited a delayed but sustained increase in ABCB1 function and expression. IL-1β increased ABCG2 activity and expression at early time points, while IL-6 and IL-6/sIL-6r had minimal effects. Notably, IL-1β and IL-6 trans-signaling increased ABCC5 activity without detectable changes in protein expression. Cytokine-induced transporter modulation was associated with reduced intracellular amyloid-β accumulation. Pharmacological inhibition of ABC transporters increased intracellular amyloid-β levels, supporting a role for these transporters in endothelial amyloid-β handling. However, as transendothelial amyloid-β transport was not directly assessed, these findings should be interpreted as changes in intracellular amyloid-β accumulation rather than direct evidence of altered BBB clearance. These findings demonstrate signaling- and time-dependent regulation of BBB ABC transporters and reveal distinct effects of IL-6 classical signaling and IL-6 trans-signaling on endothelial transporter regulation. Collectively, these results highlight signaling context as an important determinant of BBB transport responses under neuroinflammatory conditions.},
}
@article {pmid42505394,
year = {2026},
author = {Lu, Y and Xu, C and Fu, P and Gong, L},
title = {Role of Exercise in Cardiovascular Disease and Alzheimer's Disease Comorbidity: A Blood Biomarker Perspective.},
journal = {Cells},
volume = {15},
number = {14},
pages = {},
doi = {10.3390/cells15141284},
pmid = {42505394},
issn = {2073-4409},
support = {S202610043026//National College Students Innovation and Entrepreneurship Training Program/ ; Beijing Sport University 2025KYPT05//China Fundamental Research Funds for the Central Universities/ ; },
mesh = {Humans ; *Alzheimer Disease/blood/epidemiology/therapy ; *Biomarkers/blood ; *Cardiovascular Diseases/blood/epidemiology ; *Exercise/physiology ; Comorbidity ; Animals ; },
abstract = {With the growing of the global population aging, the comorbidity of cardiovascular disease (CVD) and Alzheimer's disease (AD) has gradually become a major contributor to global disease burden, with the two diseases exhibiting interacting pathological characteristics. This review summarizes the mechanisms underlying CVD-AD comorbidity, including cerebral hypoperfusion and protein aggregation, oxidative stress and inflammation, as well as metabolic disorders and genetic factors. We also assess the value of blood biomarkers in this comorbidity, such as p-tau217, NT-proBNP, NfL, GFAP, and miRNAs. We then review the role of exercise in ameliorating this comorbidity, integrating its potential mechanisms into five aspects: repairing cerebral hypoperfusion and endothelial injury, accelerating Aβ clearance and inhibiting Tau protein hyperphosphorylation, reducing inflammation, protecting neuronal structure and the blood-brain barrier, and improving metabolic disorder. We also analyze in detail the relationship between exercise targets and blood biomarkers. Finally, we discussed the impact and application of different exercise modalities in this comorbidity, concluding with suitable exercise prescriptions and relevant safety considerations for each modality, further organized the mainstream pharmacological and nutritional intervention strategies for CVD-AD comorbidity, and objectively explored their potential interactions when combined with exercise interventions. Future research should integrate multi-omics technologies and gradually refine clinical data on comorbidity, with the aim of developing more targeted, personalized exercise prescriptions for patients with comorbidities, thereby providing scientific theoretical guidance for early risk prevention and disease management in patients with co-occurring CVD and AD.},
}
@article {pmid42505396,
year = {2026},
author = {Dou, J and Wang, J and Chen, S and Hsueh, EB and Scott, IL and Xue, F},
title = {Mediterranean Diet and Neurodegenerative Diseases: Recent Advances from the Gut-Immune-Brain Axis to Multi-Omics-Guided Precision Nutrition.},
journal = {Cells},
volume = {15},
number = {14},
pages = {},
doi = {10.3390/cells15141287},
pmid = {42505396},
issn = {2073-4409},
support = {20231023//Ministry of Industry and Information Technology/ ; SC1032511980070//Zhejiang Wanli University/ ; DZS2026009//Zhejiang Wanli University/ ; 1119540506//Zhejiang Wanli University/ ; JT2680100001//Zhejiang Wanli University/ ; },
mesh = {Humans ; *Diet, Mediterranean ; *Neurodegenerative Diseases/diet therapy/immunology ; Multiomics ; *Brain/metabolism ; Animals ; Gastrointestinal Microbiome ; *Precision Medicine ; },
abstract = {Neurodegenerative diseases like Alzheimer's disease (AD) and Parkinson's disease (PD) are regarded as systemic illnesses, mainly characterized by long-term neuroinflammation, metabolic dysregulation and barrier dysfunction. All these factors interact through the gut-immune-brain axis. The Mediterranean diet, rich in plant-based foods, olive oil, and fish, has been consistently associated with slower cognitive decline and reduced risk of neurodegeneration in observational studies and some clinical trials. This review provides a systems-level synthesis that distinguishes itself from previous narratives by integrating disease-specific mechanistic frameworks with multi-omics-guided precision nutrition strategies. We summarize recent evidence showing that this dietary pattern can remodel gut microbiota composition and enhance the production of bioactive metabolites such as short-chain fatty acids (SCFAs). These metabolites are associated with improved intestinal barrier integrity, reduced systemic inflammation, and potential modulation of brain functions. Within the central nervous system, diet-related metabolites have been linked to reduced neuroinflammation via modulation of microglial and astrocytic states. They have been linked to protection of mitochondrial function, maintenance of proteostasis, and preservation of blood-brain barrier (BBB) integrity. In AD and PD patients, adherence to this diet is associated with favorable changes in pathological hallmarks, including amyloid-beta (Aβ), tau, and α-synuclein accumulation. Nowadays, multi-omics tools, including single-cell transcriptomics, spatial transcriptomics and microbiome analysis, are widely used in this field, which helps researchers explore these complicated effects more deeply. Importantly, individual responses to the diet vary considerably due to differences in genetic background, gut microbial composition, and metabolic phenotypes, which underscore the need to move from generalized dietary guidelines toward personalized precision nutrition. The Mediterranean diet is not only a dietary pattern but also an effective way to modulate neuro-immune and metabolic networks. However, current evidence remains largely observational, and we critically discuss the need for more randomized controlled trials (RCTs) and standardized multi-omics data analysis frameworks. To sum up, the Mediterranean diet plays a neuroprotective role via the gut-immune-brain axis, and multi-omics techniques promote the development of precision nutrition. More trials and improved multi-omics systems are required to apply these research results in clinical practice.},
}
@article {pmid42505400,
year = {2026},
author = {Ma, L and Zhao, Y and Cai, C and Liu, Q and Hu, X and Wang, L},
title = {Microglia in Alzheimer's Disease: From Homeostatic Guardians to Multifaceted Drivers of Neuropathology.},
journal = {Cells},
volume = {15},
number = {14},
pages = {},
doi = {10.3390/cells15141291},
pmid = {42505400},
issn = {2073-4409},
mesh = {Humans ; *Alzheimer Disease/pathology/metabolism/immunology ; *Microglia/metabolism/pathology ; Animals ; *Homeostasis ; },
abstract = {Background: Alzheimer's disease (AD) affects >55 million people worldwide and lacks disease-modifying therapies. Microglia, the CNS resident immune cells, dynamically transition between protective and pathological states during AD progression. Recent advances in single-cell sequencing and metabolomics reveal that microglial roles extend beyond simple M1/M2 polarization. This review synthesizes these advances into a framework integrating microglial plasticity, metabolic reprogramming, and intercellular communication in AD. Methods: We reviewed recent (2020-2026) studies on microglial biology in AD, focusing on DAM (disease-associated microglia) ontogeny, metabolic reprogramming, immune checkpoints, and glial crosstalk. Results: Microglia exhibit spatiotemporal heterogeneity, shifting from protective phagocytic phenotypes (M2, DAM1/2) in early AD to pro-inflammatory and exhausted states (M1, terminal inflammatory microglia [TIM], lipid droplet-accumulating microglia [LDAM]) as pathology advances. Key pathways-TREM2/SYK phagocytosis, Piezo1 mechanotransduction, TAM (Tyro3, Axl, Mer) receptor signaling, and metabolic regulators (HK2, iron, APOE4-driven lipid metabolism)-orchestrate these transitions. Microglia also interact with astrocytes, T cells, and peripheral immune cells via IL-3, complement C3, MHC-I and MHC-II, forming glial-immune networks that modulate Aβ clearance, tau propagation, and synaptic integrity. Conclusions: Precisely targeting microglial functional states, rather than broad immunosuppression, is a promising disease-modifying strategy for AD. Future therapies should integrate metabolic reprogramming, glial network regulation, and immune checkpoint modulation to preserve protective microglial phenotypes in early AD while suppressing pathological activation and exhaustion in advanced disease.},
}
@article {pmid42505424,
year = {2026},
author = {Kshirsagar, S and Alvir, RV and Pradeepkiran, JA and Hindle, A and Vijayan, M and Ramasubramaniam, B and Kumar, S and Reddy, AP and Reddy, PH},
title = {RETRACTED: Kshirsagar et al. A Combination Therapy of Urolithin A+EGCG Has Stronger Protective Effects than Single Drug Urolithin A in a Humanized Amyloid Beta Knockin Mice for Late-Onset Alzheimer's Disease. Cells 2022, 11, 2660.},
journal = {Cells},
volume = {15},
number = {14},
pages = {},
doi = {10.3390/cells15141307},
pmid = {42505424},
issn = {2073-4409},
abstract = {The journal retracts the article titled "A Combination Therapy of Urolithin A+EGCG Has Stronger Protective Effects than Single Drug Urolithin A in a Humanized Amyloid Beta Knockin Mice for Late-Onset Alzheimer's Disease" [...].},
}
@article {pmid42505964,
year = {2026},
author = {Galizzi, G},
title = {Omega-3 Fatty Acids and Alzheimer's Disease: Toward a New Understanding of Neuroprotective Mechanisms and Intervention Strategies.},
journal = {Marine drugs},
volume = {24},
number = {7},
pages = {},
doi = {10.3390/md24070224},
pmid = {42505964},
issn = {1660-3397},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; Animals ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Fatty Acids, Omega-3/pharmacology/therapeutic use ; Docosahexaenoic Acids/pharmacology ; Dietary Supplements ; Brain/drug effects/metabolism ; Eicosapentaenoic Acid/pharmacology ; },
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by amyloid-β (Aβ) deposition, tau hyperphosphorylation, neuroinflammation, mitochondrial dysfunction, and oxidative stress. Despite recent advances, current therapies offer little benefit, and AD remains a significant challenge. Polyunsaturated fatty acids (PUFAs), particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have attracted attention for their neuroprotective effects primarily through anti-inflammatory and antioxidant properties, but also for their ability to influence membrane fluidity and neuronal function. DHA is the predominant omega-3 PUFA in nerve cell membranes and is critical for synaptic plasticity and cognitive function. Some evidence has demonstrated that marine omega-3 supplementation reduces Aβ deposition, modulates microglial activation, and prevents cognitive decline in animal models. Even with heterogeneous results, preclinical and clinical studies suggest that long-term DHA/EPA supplementation can improve cognitive function in subjects with mild cognitive impairment (MCI) and reduce neuroinflammation markers. However, individual variability and brain bioavailability pose significant challenges. This review summarizes and discusses the current knowledge on the importance of PUFAs for human health, exploring novel mechanistic hypotheses, such as the effect of omega-3 fatty acids on brain iron homeostasis, the microbiota-gut-brain axis, the glymphatic system, and miRNAs. Furthermore, it focuses on the therapeutic potential of PUFAs in the treatment of AD and proposes future directions for translational research.},
}
@article {pmid42506046,
year = {2026},
author = {Plantone, D and Manco, C and Righi, D and Lago, S and Sangiorgio, AR and Schino, V and Pardini, M and Stufano, A and Lucchese, G},
title = {Recent Insights into the Role of Herpesviridae in Alzheimer's Disease: A Structured Narrative Review Based on a Systematic Literature Search.},
journal = {Neurology international},
volume = {18},
number = {7},
pages = {},
doi = {10.3390/neurolint18070125},
pmid = {42506046},
issn = {2035-8385},
abstract = {Background/Objectives: Herpesviridae have been increasingly investigated as possible contributors to Alzheimer's disease (AD) because of their neurotropism, lifelong latency, and capacity to modulate inflammatory and amyloid-related pathways Methods: This structured narrative review, based on a systematic literature search, examined original studies published between December 2020 and December 2025 on the association between human herpesviridae and AD. Searches were conducted in PubMed, Web of Science, and Scopus using a PRISMA-informed screening framework. Results: The available evidence was heterogeneous across viruses and study designs. HSV-1 emerged as the most consistently implicated virus, supported by epidemiological, biomarker, neuroimaging, and experimental studies, although contradictory findings were also reported. VZV was mainly associated with AD through vascular, inflammatory, and vaccination-related evidence, with several studies suggesting lower dementia risk after zoster vaccination. CMV, EBV, and HHV-6 showed biologically plausible but less consistent associations, whereas HHV-7 and HHV-8 were supported only by limited or indirect evidence. Across studies, the proposed mechanisms included chronic neuroinflammation, vascular injury, amyloid and tau dysregulation, host immune responses, and cumulative infectious burden. Conclusions: Overall, the literature suggests that the relationship between herpesviridae and AD is not uniform and that HSV-1 appears to be the most relevant candidate. However, methodological heterogeneity, possible reverse causation, and unequal study intensity across viruses limit firm conclusions. More robust longitudinal and subtype-specific studies are needed to clarify causal relevance.},
}
@article {pmid42506060,
year = {2026},
author = {Aljuhani, M and Ashraf, A and Alqarni, A and Alshuhri, MS and Alkhybari, EM and Alharbi, A and Almudayni, A and Alablani, FJ and Akhmimi, A and Alhulail, AA},
title = {Cerebrospinal Fluid Transforming Growth Factor β Isoforms and Disease Progression in Alzheimer's Disease: Longitudinal Evidence from the ADNI Cohort.},
journal = {Neurology international},
volume = {18},
number = {7},
pages = {},
doi = {10.3390/neurolint18070138},
pmid = {42506060},
issn = {2035-8385},
support = {PSAU/2025/3/37092//Prince Sattam Bin Abdulaziz University/ ; },
abstract = {Background: The role of cerebrospinal fluid (CSF) transforming growth factor β (TGF-β) isoforms in Alzheimer's disease (AD) remains unclear. We examined associations of CSF TGF-β1, TGF-β2, and TGF-β3 with AD biomarkers, neurodegeneration, cognition, and clinical progression. Methods: In 294 ADNI participants with baseline CSF TGF-β measurements, adjusted regression, and mixed-effect models were used to evaluate associations with CSF biomarkers, neuroimaging, cognitive outcomes, and conversion. False-discovery-rate correction was applied. Results: Higher baseline TGF-β1 was associated with higher CSF total tau (β = 52.68 pg/mL per 1 SD increase; q < 0.001) and p-tau (β = 5.68 pg/mL; q < 0.001). Higher TGF-β2 was associated with faster hippocampal volume loss (β = -45.42 mm[3]/year; q < 0.001). No isoform was robustly associated with FDG-PET decline, cognitive decline, clinical conversion, or time to conversion. Conclusions: CSF TGF-β1 and TGF-β2 show distinct associations with tau-related pathology and hippocampal neurodegeneration, respectively, but do not appear to be prognostic biomarkers of clinical progression in AD.},
}
@article {pmid42506061,
year = {2026},
author = {Zeng, CW},
title = {Protein-First, but Not Protein-Only: Rethinking Neurodegenerative Diseases Through Transgenic Mouse Models.},
journal = {Neurology international},
volume = {18},
number = {7},
pages = {},
doi = {10.3390/neurolint18070139},
pmid = {42506061},
issn = {2035-8385},
abstract = {Neurodegenerative diseases represent a major and growing global health burden. Although these disorders are often clinically defined by symptoms and affected brain regions, many are mechanistically linked to abnormal protein accumulation, misfolding, impaired proteostasis, RNA dysregulation, mitochondrial dysfunction, and neuroinflammation. In this Perspective article, I discuss major neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, amyotrophic lateral sclerosis, frontotemporal dementia, Huntington's disease, prion diseases, spinocerebellar ataxias, and spinal muscular atrophy, through the lens of disease-associated proteins and experimental modeling. I argue that a protein-centered framework provides a useful approach for understanding disease mechanisms and selecting transgenic mouse models, while recognizing that aging, cellular context, neuroinflammation, mitochondrial dysfunction, vascular dysfunction, and other disease modifiers also shape neurodegeneration. Transgenic and genetically engineered mouse models have been essential for dissecting the pathogenic roles of amyloid-β, tau, α-synuclein, TDP-43, SOD1, FUS, C9ORF72-associated dipeptide repeat proteins, mutant huntingtin, prion protein, ataxins, and SMN deficiency. However, these models have important limitations, including artificial overexpression, familial mutation bias, species differences, and incomplete representation of aging-related sporadic diseases. Rather than seeking a single "best" model, a more productive strategy is to adopt model portfolios tailored to specific biological questions and to integrate mouse studies with human cellular models, postmortem tissue, omics approaches, and biomarker-based validation. Such an approach may improve mechanistic insight, strengthen translational relevance, and enhance the predictive value of preclinical neurodegenerative disease research.},
}
@article {pmid42506089,
year = {2026},
author = {Pinto, JO and Peixoto, B and Dores, AR and Barbosa, F},
title = {Towards a Multidimensional Model of Neurocognitive Disorders (MOND Model): Integrating Evidence from a Critical Review into a Model for Future Research.},
journal = {Journal of personalized medicine},
volume = {16},
number = {7},
pages = {},
doi = {10.3390/jpm16070363},
pmid = {42506089},
issn = {2075-4426},
support = {Artemisa Dores is a researcher of School of Health, Polytechnic Institute of Porto, Porto, Portugal, supported by FCT - Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e Tecnologia [Portuguese Foundation for Science and Technology] through R&amp;D Units funding (UIDB/05210/2020).//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e Tecnologia/ ; },
abstract = {The main purpose of this work is to critically review the literature on neurocognitive disorders (ND) diagnosis. A critical review was conducted in PubMed, Scopus, and EBSCO. Systematic reviews and meta-analyses focusing on ND diagnosis were included. The selected studies were critically analyzed and conceptually integrated to identify relevant dimensions for the diagnosis of ND. The review included 88 studies. Most studies focused on Alzheimer's disease and mild cognitive impairment. The literature remained predominantly centred on isolated diagnostic domains, and important limitations were consistently identified, including methodological heterogeneity, lack of standardized thresholds, and reduced clinical applicability. Based on the identified conceptual and methodological limitations, a Multidimensional Model of Neurocognitive Disorders (MOND model) for ND diagnosis was proposed. The MOND model was developed as a multidimensional, multilevel, transdiagnostic model integrating biological, neurocognitive, neuropsychiatric, motor, functional, frailty, reserve-related, and socio-environmental dimensions. The model may contribute to research, symptom classification, severity characterization, prognosis, and personalized intervention planning across different ND trajectories. Future studies using the MOND model should focus on refining algorithms to estimate the risk of ND.},
}
@article {pmid42506306,
year = {2026},
author = {Vamanu, A and Mastaleru, A and Schreiner, TG and Popescu, G and Roceanu, AM and Cucu, AI and Patrascu, A and Vulpoi, GA and Bilcu, RV and Cozma, RS and Olariu, R and Bistriceanu, CE and Covali, R and Cuciureanu, DI and Ciubotaru, A},
title = {Pharmacological and Clinical Heterogeneity of Anti-Amyloid Monoclonal Antibodies in Early Alzheimer's Disease: A Systematic Review and Meta-Analysis of Randomized Trials.},
journal = {Medical sciences (Basel, Switzerland)},
volume = {14},
number = {3},
pages = {},
doi = {10.3390/medsci14030337},
pmid = {42506306},
issn = {2076-3271},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; Randomized Controlled Trials as Topic ; *Antibodies, Monoclonal/therapeutic use/pharmacology ; *Amyloid beta-Peptides/antagonists &amp; inhibitors/immunology ; Antibodies, Monoclonal, Humanized/therapeutic use ; Biomarkers ; },
abstract = {Background: Anti-amyloid monoclonal antibodies represent the first disease-modifying therapeutic strategy targeting amyloid-β pathology in early Alzheimer's disease (AD). Although several agents have demonstrated the ability to reduce cerebral amyloid burden, their clinical efficacy and safety remain subjects of substantial scientific and regulatory debate. This study aimed to synthesize randomized evidence evaluating the benefit-risk profile of anti-amyloid monoclonal antibodies in biomarker-confirmed early AD. Methods: A systematic review and classical pairwise meta-analysis of randomized controlled trials (RCTs) was conducted following the PRISMA 2020 guidelines. PubMed/MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched for phase III placebo-controlled trials evaluating lecanemab, donanemab, aducanumab, and gantenerumab in patients with mild cognitive impairment due to AD or mild AD dementia with biomarker confirmation of amyloid pathology. The primary outcome was change from baseline in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) at the longest available follow-up. Safety outcomes included amyloid-related imaging abnormalities with edema or effusion (ARIA-E), amyloid-related imaging abnormalities with hemorrhage (ARIA-H), serious adverse events, and treatment discontinuation. Random-effects meta-analyses were performed. Results: Six randomized comparisons derived from four phase III trials involving 7695 participants met the eligibility criteria. Anti-amyloid monoclonal antibodies were associated with a statistically significant slowing of clinical progression compared with placebo (pooled mean difference in CDR-SB: -0.42 points; 95% CI -0.59 to -0.25; I[2] = 78%). The observed effect was primarily driven by trials of lecanemab and donanemab, whereas aducanumab demonstrated discordant results across trials and gantenerumab showed no clinically meaningful benefit. Despite statistical significance, the magnitude of the pooled effect approached the lower boundary of the minimal clinically important difference reported for CDR-SB in early AD. Treatment was associated with a markedly increased risk of ARIA-E (pooled risk ratio 10.1; 95% CI 7.8-13.0), with moderate heterogeneity across studies. Most ARIA-E events were asymptomatic and detected through protocol-mandated MRI monitoring. Conclusions: In biomarker-confirmed early Alzheimer's disease, anti-amyloid monoclonal antibodies produce a statistically significant but modest slowing of clinical decline accompanied by a substantially increased risk of ARIA. The benefit-risk profile appears heterogeneous across individual antibodies and may reflect pharmacological differences in amyloid targeting and clearance mechanisms. These findings support cautious, individualized use of anti-amyloid therapies and highlight the need for longer-term studies to determine whether short-term slowing of decline translates into clinically meaningful disease modification.},
}
@article {pmid42506310,
year = {2026},
author = {Filippi, L and Danieli, R},
title = {Muscarinic Receptor PET in Neurodegeneration: Promise, Pitfalls, and Translational Priorities.},
journal = {Medical sciences (Basel, Switzerland)},
volume = {14},
number = {3},
pages = {},
doi = {10.3390/medsci14030341},
pmid = {42506310},
issn = {2076-3271},
support = {(Ricerca Corrente) - no specific number//Ministero della Salute/ ; },
mesh = {*Positron-Emission Tomography/methods ; Humans ; *Receptors, Muscarinic/metabolism ; *Neurodegenerative Diseases/diagnostic imaging/metabolism ; Alzheimer Disease/diagnostic imaging/metabolism ; Animals ; Translational Research, Biomedical ; },
abstract = {Positron emission tomography (PET) of muscarinic acetylcholine receptors has evolved from a receptor-mapping exercise into a potential translational tool for probing cholinergic dysfunction in neurodegenerative disease. However, the field still lacks a clear hierarchy of clinical value across receptor subtypes, tracers, and quantitative analysis strategies, including acquisition protocols and kinetic modeling approaches. In the M2 arena, [[18]F]FP-TZTP has been associated with higher distribution volumes in older APOE-ε4 carriers, but the biological meaning of this signal remains uncertain in the absence of longitudinal conversion data and with quantification approaches that are difficult to implement routinely. Among M4 ligands, [[11]C]MK-6884 is the most advanced and reproducible tracer to date, yet its clinical evidence still rests on proof-of-concept studies, mainly in moderate-to-severe Alzheimer's disease, with important methodological limitations. In our view, muscarinic PET should now be reframed less as a stand-alone diagnostic biomarker and more as a platform for mechanistic and pharmacodynamic studies, especially for the development and monitoring of muscarinic-positive allosteric modulators. Future progress will depend on longitudinal multicenter validation, simplified quantification pipelines, and next-generation PET systems capable of capturing tracer kinetics more efficiently.},
}
@article {pmid42506367,
year = {2026},
author = {Wostyn, P and Goddaer, P},
title = {Gamma Oscillations, Sensory Stimulation, and Glymphatic Function: Toward User-Friendly Auditory Interventions for Brain Health in Aging and Neurodegeneration.},
journal = {Medical sciences (Basel, Switzerland)},
volume = {14},
number = {3},
pages = {},
doi = {10.3390/medsci14030398},
pmid = {42506367},
issn = {2076-3271},
mesh = {Humans ; *Aging/physiology ; Animals ; *Glymphatic System/physiology/physiopathology ; *Brain/physiopathology/physiology ; *Neurodegenerative Diseases/physiopathology/therapy ; *Gamma Rhythm/physiology ; Alzheimer Disease/physiopathology/therapy ; *Acoustic Stimulation/methods ; },
abstract = {The glymphatic system is a brain-wide clearance pathway that facilitates the removal of interstitial solutes, including amyloid-β, and plays a critical role in maintaining brain homeostasis. Impairments in glymphatic transport have been implicated in aging and neurodegenerative diseases, including Alzheimer's disease. While glymphatic activity is most pronounced during sleep, emerging evidence suggests that specific patterns of neural activity, including gamma-frequency oscillations entrained by sensory stimulation, can modulate glymphatic transport even during wakefulness. Preclinical studies further indicate that 40 Hz sensory stimulation, delivered via light, sound, or multisensory paradigms, can induce gamma oscillations, reduce pathological protein accumulation, and enhance cognitive performance in animal models of Alzheimer's disease. Early clinical investigations similarly suggest that gamma-frequency sensory stimulation may improve blood-based biomarkers, neuroimaging measures, and cognitive outcomes in patients with Alzheimer's disease. To translate gamma-frequency stimulation into broadly applicable preventive or therapeutic strategies, approaches must be both effective and tolerable for long-term use. Conventional auditory gamma stimulation can be perceived as acoustically rough or monotonous, reducing listener comfort and limiting acceptability for prolonged use in broader populations. User-friendly auditory formats, such as "gamma music" and the more recently introduced "immersive gamma music", have been proposed as potentially useful approaches for delivering gamma-frequency stimulation while improving listening comfort and facilitating sustained use. Collectively, gamma-frequency sensory stimulation represents a promising approach to support healthy brain aging and mitigate neurodegenerative processes, particularly when implemented via user-friendly auditory formats that facilitate repeated and long-term use. While these findings are encouraging, further research is needed to validate these approaches and determine their clinical relevance.},
}
@article {pmid42506779,
year = {2026},
author = {Talwar, A and Sherer, J and Abughosh, S and Chatterjee, S and Aparasu, RR},
title = {Cumulative Anticholinergic Burden and Risk of Delirium Among Older Adults with Alzheimer's Disease.},
journal = {Pharmacy (Basel, Switzerland)},
volume = {14},
number = {4},
pages = {},
doi = {10.3390/pharmacy14040089},
pmid = {42506779},
issn = {2226-4787},
abstract = {Delirium is a transient neuropsychiatric condition that is a severe and prevalent condition affecting 2.6 million older adults each year. Alzheimer's disease (AD) and anticholinergic medication use are risk factors for delirium. This study evaluated the association between cumulative anticholinergic burden (CAB) and risk of delirium among older adults with AD initiating cholinesterase inhibitors (ChEIs). This retrospective cohort study used 2013-2017 Medicare claims data, and included adults 65 years and older with AD who initiated any of the ChEIs (donepezil, rivastigmine, and galantamine) after a 12-month washout period. CAB, as the primary exposure, was measured on the index date and calculated as the monthly total standardized daily dose of anticholinergic medications. A multivariable Cox proportional hazards regression model with inverse probability of treatment weighting (IPTW) generated using generalized boosted models was used to evaluate the risk of delirium associated with the CAB. This study identified 143,320 older adults with AD who initiated ChEIs. Most patients were in the low/no burden (62.73%) group, followed by high burden (21.12%) and moderate burden (16.14%). Overall, delirium diagnosis was observed in 19.11% of the cohort. The Cox regression model with IPTW found that moderate (aHR, 1.56; 95% CI, 1.52-1.61; p < 0.0001) and high CAB (aHR, 1.45; 95% CI, 1.42-1.49; p < 0.0001) were associated with an increased risk of delirium compared to low/no burden. Among older adults with AD initiating ChEIs, moderate and high CAB were associated with an increased risk of delirium compared with low/no CAB. These findings highlight the need to carefully reduce the CAB, especially dose and duration, along with utilizing anticholinergic alternatives in older adults with AD.},
}
@article {pmid42506875,
year = {2026},
author = {Zhang, C and Zhang, Y and Wu, Z and Zhang, Y and Xue, F and Tan, Q and Zhong, X and Zhang, Y and Zhao, Z and Peng, Y and Chen, H and Li, F and Zhang, Y},
title = {Screening of cell-type-specific meta-programs for drug repurposing in Alzheimer's disease.},
journal = {Briefings in bioinformatics},
volume = {27},
number = {4},
pages = {},
doi = {10.1093/bib/bbag411},
pmid = {42506875},
issn = {1477-4054},
support = {LH2023C062//Natural Science Foundation of Heilongjiang Province/ ; 2024ZD0530500//National Science and Technology Major Program/ ; 62472131//National Natural Science Foundation of China/ ; },
mesh = {*Alzheimer Disease/drug therapy/genetics/pathology/metabolism ; *Drug Repositioning/methods ; Humans ; Transcriptome ; Gene Expression Profiling ; Multiomics ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder driven by complex cellular changes. To identify transcriptional signatures involved in AD pathology, we first analyzed nine single-cell/nucleus RNA-seq datasets from 67 high-pathology cases (Braak stages V/VI), generating an atlas of 363 243 cells. Using a multi-sample integration strategy, we identified 51 cross-sample meta-programs (MPs) across seven cell types that collectively capture key AD-related processes, including synaptic dysfunction and neuroinflammation. By screening bulk transcriptomes from 1208 ad and 725 normal samples, we found that 26 MPs (13 pathogenic and 13 protective) displayed differential activity in AD, characterized by up-regulation of microglia MPs and down-regulated of neuron MPs. Furthermore, spatial transcriptomics revealed that these MPs form spatially coherent communities associated with distinct cellular neighborhoods. Finally, we performed an integrative drug repurposing screen to identify candidate drugs predicted to regulate pathogenic MPs. In conclusion, we conducted an integrated multi-omics study to identify AD cell-type-specific MPs, and this framework can be applied to deconvolve cellular heterogeneity and screen candidate drugs for AD.},
}
@article {pmid42506897,
year = {2026},
author = {Zhao, Y and Jacques, PF and Lajous, M and Sebastiani, P and Ordovás, JM},
title = {Sustained fish intake and 21-year Alzheimer's disease risk: a target trial emulation.},
journal = {American journal of epidemiology},
volume = {},
number = {},
pages = {},
doi = {10.1093/aje/kwag140},
pmid = {42506897},
issn = {1476-6256},
abstract = {Increasing oily fish intake has been proposed as a strategy for Alzheimer's disease (AD) prevention, but evidence for long-term benefit remains limited. Using observational data from 2012 cognitively healthy adults in the Framingham Heart Study Offspring cohort, we emulated a target trial of seven isocaloric fish intake strategies to estimate 21-year AD risk. We modeled repeated measures of diet and adjusted for pre-baseline diet, baseline covariates, and time-varying confounding using the parametric g-formula. The estimated 21-year AD risk ranged from 10.33% (95% confidence interval [CI]: 8.41%, 12.92%) under no fish intake to 9.98% (95% CI, 6.64%, 13.31%) under ≥ 3 servings/week. Risk ratios relative to no intervention were close to one and risk differences were close to zero across all strategies. Substituting fish for meat yielded similar results. We observed no clear long-term protective effect of sustained fish intake on AD risk, though exploratory analyses suggested a possible protective effect among older participants during earlier follow-up, warranting further investigation. This study illustrates the use of target trial emulation to estimate long-term dietary effects while accounting for time-varying confounding and competing risks in nutritional epidemiology.},
}
@article {pmid42506911,
year = {2026},
author = {Chen, Y and Feng, Y},
title = {Social bonds to synaptic function: why relationship quality matters for memory decline in Alzheimer's disease.},
journal = {Aging &amp; mental health},
volume = {},
number = {},
pages = {1-6},
doi = {10.1080/13607863.2026.2709500},
pmid = {42506911},
issn = {1364-6915},
abstract = {ObjectivesAlzheimer's disease (AD) is a progressive neurodegenerative condition marked by deterioration in memory, cognition, and daily functioning. Research has traditionally focused on amyloid-β accumulation, tau pathology, and hippocampal degeneration, yet these mechanisms do not fully explain the psychosocial contexts in which memory decline occurs. Relationship quality may be an important but underexamined factor, as supportive, strained, or ambivalent relationships may shape stress, emotional regulation, and social engagement in ways relevant to brain health. This editorial develops a conceptual argument that relationship quality should be considered a context-dependent factor in AD research.MethodThe article focuses on three plausible social-neural pathways: BDNF-related neuroplasticity, inflammatory regulation, and HPA-axis/cortisol functioning. It also highlights the need to distinguish relationship quality from related constructs such as loneliness, social participation, social isolation, and social capital.ResultsRather than treating social relationships as universally protective, this editorial argues that they are better understood as context-dependent modulators whose relevance may vary by disease stage, individual vulnerability, cultural context, and the emotional quality of relationships.ConclusionRelationship quality acts as a context-dependent influencing factor and deserves more attention in future Alzheimer's disease research.},
}
@article {pmid42506941,
year = {2026},
author = {de Levante Raphael, D},
title = {Neuropsychiatric symptoms as early clinical indicators and functional biomarkers of cognitive decline in mild cognitive impairment and early Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261469114},
doi = {10.1177/13872877261469114},
pmid = {42506941},
issn = {1875-8908},
abstract = {Neuropsychiatric symptoms (NPS) have historically been considered secondary or late-stage features of Alzheimer's disease (AD), yet emerging evidence indicates that apathy, depression, anxiety, irritability, agitation, sleep disturbance, and psychosis frequently arise during prodromal phases, including mild cognitive impairment (MCI), and may precede measurable cognitive decline. This narrative review evaluates NPS as early clinical indicators and potential functional biomarkers of cognitive decline in MCI and early AD, emphasizing neurobiological mechanisms, prognostic significance, and translational relevance. A synthesis of epidemiological, longitudinal, neuroimaging, and biomarker studies published between 2012 and 2025 was conducted across major databases, integrating findings within the mild behavioral impairment (MBI) construct and the AT(N) biomarker framework. Across studies, NPS were found to affect approximately 43-80% of individuals with MCI and 75-90% with early AD, with lifetime prevalence approaching 97% across the disease course. Apathy, depression, anxiety, and irritability are particularly common in early stages and independently predict accelerated cognitive and functional decline, increased caregiver burden, and earlier institutionalization. NPS are associated with early tau pathology, neurotransmitter system dysfunction, and fronto-limbic network degeneration. Disparities in symptom burden, diagnostic access, and clinical outcomes are evident across racial, ethnic, sex-related, and cultural groups. Recognizing NPS as core features of early AD supports their integration into MBI- and AT(N)-informed diagnostic and intervention models to enhance early detection, personalize care, and reduce health inequities.},
}
@article {pmid42506942,
year = {2026},
author = {Xie, Z and Locke, D and Shandera-Ochsner, A and Hamadi, H and De Wit, L and Santos, O and Boots, EA and Aghamoosa, S and Grant, J and Smith, G and Chandler, M},
title = {Does concurrent pharmacotherapy enhance behavioral interventions for mild cognitive impairment? Evidence from the HABIT program.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261471921},
doi = {10.1177/13872877261471921},
pmid = {42506942},
issn = {1875-8908},
abstract = {BackgroundMild cognitive impairment (MCI) represents a critical window for both pharmacological therapies and non-pharmacological interventions to delay cognitive decline.ObjectiveTo evaluate whether combining pharmacotherapy with multicomponent behavioral interventions enhances outcomes relative to behavioral interventions alone.MethodsThe sample included people with MCI (pwMCI) of any etiology who completed the HABIT Healthy Action to Benefit Independence &amp; Thinking[®] program. Baseline pharmacotherapy (acetylcholinesterase inhibitor and/or glutamate regulators) use was dichotomized (yes/no). Multivariate linear mixed-effects models examined changes from baseline in care partner-reported everyday functional skills, quality of life, self-efficacy, anxiety, depression, and HABIT compliance at post-intervention, 6 months, and 12 months, adjusting for baseline cognitive impairment severity and relevant demographic covariates.ResultsAmong 1074 pwMCI, 413 (38.5%) were receiving pharmacotherapy at baseline. Pharmacotherapy use was more prevalent among White than non-White participants (39.4% versus 23.3%, p = 0.01). At baseline, pharmacotherapy users had more severe cognitive impairment and lower utilization of rehabilitation strategies (all p < 0.05). Both groups demonstrated significant improvements across all outcomes at post-intervention. During follow-up (mean score change compared to baseline), pharmacotherapy users showed greater increases in HABIT compliance at 6 months (3.2 versus 2.0) and 12 months (2.1 versus 1.4). In contrast, by 12 months, pharmacotherapy users experienced greater worsening of everyday functional skills related to memory (-2.1 versus -1.3) and executive function (-5.8 versus-3.7).ConclusionspwMCI undergoing pharmacotherapy entered the HABIT program with more advanced cognitive impairment. The pharmacotherapy was not associated with greater intervention-related benefit or attenuation of long-term cognitive decline.},
}
@article {pmid42506943,
year = {2026},
author = {Periyasamy, TS and Sekar, N and Lakshmanan, H},
title = {Integration of multi-omics and artificial intelligence for therapeutic insights in Alzheimer's disease: A comprehensive review.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261471812},
doi = {10.1177/13872877261471812},
pmid = {42506943},
issn = {1875-8908},
abstract = {Alzheimer's disease (AD) is a progressively worsening type of brain disorder that damages the nerve cells. It is marked by the buildup of amyloid-β plaques outside the cells, tau neurofibrillary tangles inside the cells, and overall molecular-level dysfunction. The therapies currently available mainly cater to alleviating the symptoms, whereas the newly approved disease-modifying antibodies, such as lecanemab and donanemab, bring out only limited clinical improvements. Being complicated and involving many factors, AD requires sophisticated computer-based methods to combine different biological data and find suitable therapy targets. In this review, we discuss how artificial intelligence (AI)-powered multi-omics data integration can be a catalyst in discovering drug targets, identifying biomarkers, and stratifying patients for AD. By utilizing machine learning techniques like random forests, graph neural networks, and deep learning, AI-led multi-omics methods have helped uncover new therapeutic targets. Models that were built using federated learning across various institutions outperformed single-center models with a higher area under the curve score (0.84, 0.94 versus 0.76, 0.85). AI-guided patient stratification lessened the clinical trial's sample size needs by 40, 55% while still retaining 80, 90% statistical power. Multi-omics analyses further pointed out that it is the downstream molecular pathways, and not amyloid pathology alone, that are significantly involved in disease progression, thereby questioning the effectiveness of single-target anti-amyloid therapies and endorsing combination treatment strategies. AI and multi-omics data combination can be a game-changer in facilitating new target discovery, making clinical trial design more efficient, and ushering in precision medicine in AD.},
}
@article {pmid42507054,
year = {2026},
author = {Otomi, Y and Shinya, T and Otsuka, H and Kasai, H and Matsushita, T and Takaoka, Y and Hiroshima, Y and Matsubara, T and Fujita, K and Tomioka, Y and Nakataki, M and Numata, S and Izumi, Y and Harada, M},
title = {Serial amyloid PET demonstrates marked reduction in amyloid burden following donanemab treatment: a real-world cohort study.},
journal = {Japanese journal of radiology},
volume = {},
number = {},
pages = {},
pmid = {42507054},
issn = {1867-108X},
support = {JP24K15767//Japan Society for the Promotion of Science/ ; },
abstract = {PURPOSE: To evaluate changes in amyloid burden on serial amyloid PET before and after donanemab treatment in a real-world clinical cohort.<br><br>METHODS: This retrospective study included 20 consecutive patients who underwent serial amyloid PET before and after donanemab treatment. Quantitative analysis was performed using Centiloid values and tracer-specific standardized uptake value ratios (SUVr). Visual assessment was also performed to determine amyloid-positive or amyloid-negative status before and after treatment.<br><br>RESULTS: Centiloid values significantly decreased from 52.3&#x2009;&#xb1;&#x2009;23.4 at baseline to&#x2009;-&#x2009;5.6&#x2009;&#xb1;&#x2009;16.5 at follow-up, with a mean change of&#x2009;-&#x2009;58.0 (p&#x2009;<&#x2009;0.001). All patients showed a reduction in Centiloid values. In the flutemetamol group (n&#x2009;=&#x2009;12), pons-referenced SUVr significantly decreased, while in the florbetapir group (n&#x2009;=&#x2009;8), cerebellar-referenced SUVr also showed significant reductions (both p&#x2009;<&#x2009;0.001). On visual assessment, 17 of 20 patients (85%) converted from amyloid-positive to amyloid-negative status after treatment.<br><br>CONCLUSION: Serial amyloid PET demonstrated a substantial reduction in amyloid burden following donanemab treatment in this real-world cohort. Quantitative amyloid PET, particularly using Centiloid scaling, may be a useful tool for monitoring treatment response in clinical practice.},
}
@article {pmid42507062,
year = {2026},
author = {Baccaro, VK and Hvid, LG and Jungersen, RC and Langeskov-Christensen, M},
title = {Exercise and Pain in Multiple Sclerosis, Parkinson's Disease, Alzheimer's Disease, and Stroke: A Systematic Review and Meta-analysis.},
journal = {Sports medicine (Auckland, N.Z.)},
volume = {},
number = {},
pages = {},
pmid = {42507062},
issn = {1179-2035},
abstract = {BACKGROUND: Pain affects up to 85% of people living with common neurodegenerative diseases, yet evidence on the analgesic effects of exercise remains limited. This systematic review and meta-analysis examined whether exercise reduces pain in people with multiple sclerosis (MS), stroke, Parkinson's disease (PD), and Alzheimer's disease (AD).<br><br>METHODS: A systematic search was conducted across six databases (PubMed, Embase, Cochrane Library, PEDro, CINAHL, and SPORTDiscus) from November 2024 up to November 2025 to identify randomized controlled trials examining the effects of exercise (across different modalities) on pain (across different outcomes) in MS, stroke, PD, or AD. Qualitative and quantitative analyses were performed. Quality was assessed using TESTEX.<br><br>RESULTS: A total of 39 studies were identified, of which 36 were included in the meta-analyses. The overall meta-analysis showed that exercise substantially reduced pain in people with neurodegenerative diseases compared with control conditions (-&#x2009;0.83 [-&#x2009;1.10;&#x2009;-&#x2009;0.57], standardized mean difference [95% CI]). Large comparable effects were observed in MS (22 studies;&#x2009;-&#x2009;0.63 [-&#x2009;0.89;&#x2009;-&#x2009;0.38]) and stroke (12 studies;&#x2009;-&#x2009;1.07 [-&#x2009;1.63;&#x2009;-&#x2009;0.52]). Only one eligible study was found for PD and AD, respectively, highlighting a critical gap in the literature.<br><br>CONCLUSIONS: This review provides strong evidence that exercise alleviates pain in people with MS and stroke and emphasizes its potential as a non-pharmacological analgesic strategy for managing pain in neurodegenerative diseases. More high-quality studies are needed, particularly in PD and AD.<br><br>TRIAL REGISTRY: PROSPERO (CRD42024583498).},
}
@article {pmid42507136,
year = {2026},
author = {Detter-Biesl, D and Rosendahl Huber, S and Er, S and Karrer, M},
title = {Assessing communication in people with dementia : A scoping review of existing tools.},
journal = {Zeitschrift fur Gerontologie und Geriatrie},
volume = {},
number = {},
pages = {},
pmid = {42507136},
issn = {1435-1269},
abstract = {BACKGROUND: Dementia is associated with progressive cognitive decline. Accompanying communication difficulties can negatively influence well-being and participation; however, individuals can retain meaningful communicative resources when adequately supported. Little is known about communication assessments that are usable across different healthcare professions and that address the full spectrum of communication behavior. This scoping review therefore maps available communication assessment instruments for people with dementia.<br><br>METHODS: We searched Web of Science, MEDLINE, CINAHL, and SpeechBITE for articles published between 2014 and 2024. Data on study characteristics and features of communication assessment tools (CATs) were extracted and synthesized narratively.<br><br>RESULTS: A&#xa0;total of 33&#xa0;articles met the inclusion criteria. They were published in various languages and conducted in diverse settings (e.g., long-term care, outpatient services, acute hospitals). Within these studies, 14&#xa0;CATs for use with people with dementia were identified. Most tools are applicable across dementia types, whereas some require minimal verbal abilities or are restricted to specific subgroups.<br><br>CONCLUSION: The instruments differ in how they conceptualize and assess communication, ranging from communication skills to lived communication experiences. Careful tool selection is required based on assessment goals, target groups and available language versions. Limited language accessibility and insufficient evidence on feasibility across different healthcare professions highlight key gaps for future research.},
}
@article {pmid42507235,
year = {2026},
author = {Stites, SD and Lee, K and Kuz, C and Mandell, D and Bogner, HR and Brown, R},
title = {Worry and Anxiety in the Era of Early Diagnosis and Disease Modifying Treatment for Alzheimer's Disease.},
journal = {Current psychiatry reports},
volume = {28},
number = {1},
pages = {},
pmid = {42507235},
issn = {1535-1645},
mesh = {Humans ; *Alzheimer Disease/diagnosis/psychology/therapy ; Early Diagnosis ; *Anxiety/psychology/diagnosis ; },
abstract = {PURPOSE OF REVIEW: Psychologists and psychiatrists are well-positioned to be at the forefront of addressing the challenges posed by anxiety in early diagnosis and treatment of Alzheimer's disease (AD) dementia that are unfolding in primary care settings. The present article provides a summary of emerging areas in Alzheimer's disease testing and research to guide clinical decisions and research pursuits.<br><br>RECENT FINDINGS: The present article provides an overview of how anxiety is understood in early diagnosis of dementia due to AD, its influence in AD-related mechanisms, and the implications of these findings on current research practices. We conducted focused literature reviews between January and June 2026 and synthesized the information to provide a narrative review. Overall, the clinical roles of anxiety in AD dementia are expanding- from being viewed primarily as reactions to cognitive decline to serving as informative features of the diagnostic process and clinical course of the disease.},
}
@article {pmid42507247,
year = {2026},
author = {Rožmarić, G and Hero, M and Papić, E and Grozdanić, N and Vuletić, V},
title = {Late-onset PSP/FTD-like atypical parkinsonism as a novel phenotype of POLG-related disease: a case report.},
journal = {Acta neurologica Belgica},
volume = {},
number = {},
pages = {},
pmid = {42507247},
issn = {2240-2993},
abstract = {POLG-related disease is a multisystem mitochondrial disorder that may mimic primary neurodegenerative syndromes. We report a 70-year-old man with progressive cognitive decline, rigid-akinetic parkinsonism, postural instability, vertical supranuclear gaze palsy, and prominent executive and semantic fluency deficits, forming a PSP/FTD-like phenotype. Brain MRI showed frontotemporal-predominant cortical atrophy and a hummingbird sign, while FDG-PET demonstrated frontal and bilateral parietotemporal hypometabolism with preserved occipital metabolism. Alzheimer disease CSF biomarkers were normal and RT-QuIC was negative. Pancytopenia with macrocytosis, liver cirrhosis, and myelodysplastic syndrome indicated multisystem involvement. Genetic testing identified biallelic POLG variants, one pathogenic and one likely pathogenic, confirming POLG-related disease. Levodopa produced partial improvement. This case expands the recognised late-onset POLG spectrum and supports POLG testing in atypical parkinsonism accompanied by cognitive, hepatic, or haematological abnormalities. Early diagnosis may prevent valproate-associated severe hepatotoxicity.},
}
@article {pmid42507320,
year = {2026},
author = {Wang, C and Han, X and Lin, Y and Pan, Y and Miao, Q and Wang, Y and Wang, SQ and Zhang, Z and Wang, L and Tang, ZR and Peng, Y and Yung, KK and Ma, N and Lu, D and Zhang, S and Shi, L},
title = {Betulinaldehyde Ameliorates Aβ-Induced Neurotoxicity and Cognitive Deficits by Modulating the eEF2K/eEF2 Pathway.},
journal = {CNS neuroscience &amp; therapeutics},
volume = {32},
number = {7},
pages = {e71050},
doi = {10.1002/cns.71050},
pmid = {42507320},
issn = {1755-5949},
support = {2022YFA1104900//National Key Research and Development Program of China/ ; 2022ZD0214400//The Brain Science and Brain-like Intelligence Technology-National Science and Technology Major Project/ ; 82371175//National Natural Science Foundation of China/ ; U24A20804//National Natural Science Foundation of China/ ; 2023A1515030012//Guangdong Basic and Applied Basic Research Foundation/ ; 2022B1515130007//Guangdong Basic and Applied Basic Research Foundation/ ; 2023B1515040015//Guangdong Basic and Applied Basic Research Foundation/ ; 202102070001//The Science and Technology Projects in Guangzhou/ ; 2023A0505050121//International Science and Technology Projects of Guangdong Province/ ; 20261073//The Research Project of Guangdong Provincial Bureau of Traditional Chinese Medicine/ ; },
mesh = {Animals ; *Amyloid beta-Peptides/toxicity ; *Elongation Factor 2 Kinase/metabolism ; Mice ; *Peptide Fragments/toxicity ; *Triterpenes/pharmacology/therapeutic use ; Signal Transduction/drug effects ; Humans ; *Neuroprotective Agents/pharmacology/therapeutic use ; Neurons/drug effects ; *Cognition Disorders/drug therapy/chemically induced ; Mice, Inbred C57BL ; },
abstract = {BACKGROUND: Alzheimer's disease (AD), the most common form of dementia, remains without effective therapies. Dysregulated eukaryotic elongation factor 2 kinase/eukaryotic elongation factor 2 (eEF2K/eEF2) pathway leads to aberrant protein synthesis and impaired neuronal function in AD, positioning this axis as a promising therapeutic target. However, effective pharmacological modulators of eEF2K/eEF2 remain limited. Betulinaldehyde (Betu), an active ingredient derived from traditional Chinese medicine, remains to be thoroughly evaluated as a potential neuroprotective agent.<br><br>PURPOSE: This study aims to investigate the therapeutic effects of Betu on AD and determine whether its activities are mediated through the eEF2K/eEF2 pathway.<br><br>METHODS: Neuronal cell models were used to assess the effects of Betu on &#x3b2;-amyloid 42 (A&#x3b2;42)-induced neuronal death, dendritic spine damage, protein synthesis inhibition, and eEF2 hyperphosphorylation. The eEF2K agonist nelfinavir (NFV) and the protein synthesis inhibitors cycloheximide (CHX) and anisomycin (AS) were used to investigate the involvement of the eEF2K/eEF2 pathway and its regulated protein synthesis in the action of Betu. The cellular thermal shift assay (CETSA) was used to detect potential interactions between Betu and eEF2K. Additionally, the effects of Betu on reactive oxygen species (ROS) levels and the associated pathways were evaluated. An A&#x3b2;42-induced mouse model of AD was used to evaluate the in&#xa0;vivo effects of Betu on cognitive decline, hippocampal neuropathological damage, and eEF2 hyperphosphorylation.<br><br>RESULTS: Betu significantly ameliorated the A&#x3b2;42-induced neuronal death and dendritic spine damage, restored protein synthesis, and reversed eEF2 hyperphosphorylation. The neuroprotective effects of Betu were effectively inhibited by the CHX, AS, or NFV treatment, and CETSA supported a potential interaction between Betu and eEF2K. Furthermore, Betu reversed A&#x3b2;42-induced ROS accumulation and upregulated nuclear factor-like 2 and heme oxygenase-1, potential downstream effectors of the eEF2K pathway. In an A&#x3b2;42-induced AD mouse model, Betu treatment markedly ameliorated cognitive decline, concomitant with attenuated neuropathological damage and restored eEF2 phosphorylation in the hippocampus.<br><br>CONCLUSION: These findings demonstrate that Betu protects against A&#x3b2;42-induced neurotoxicity by modulating the eEF2K/eEF2 pathway, highlighting its potential as a lead compound for AD.},
}
@article {pmid42507332,
year = {2026},
author = {Liao, C and Sun, D and Wang, X},
title = {Disease mechanisms and translational barriers guide nanocarrier design for nose to brain delivery in Alzheimer's disease.},
journal = {Discover nano},
volume = {21},
number = {1},
pages = {},
pmid = {42507332},
issn = {2731-9229},
support = {82572661//National Natural Science Foundation of China/ ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited disease-modifying treatment options, partly because many therapeutic agents show insufficient brain exposure and dose-limiting systemic adverse effects after conventional administration. Nose-to-brain (N2B) delivery has emerged as a non-invasive strategy to transport therapeutics to the central nervous system through the olfactory and trigeminal pathways, thereby partially bypassing the blood-brain barrier. Recent advances in nanomedicine and biomaterial engineering have further improved this approach by enhancing drug stability, nasal residence, mucosal transport, and brain-targeting efficiency. This review examines nanocarrier-enabled N2B delivery strategies for AD from a mechanism-guided perspective, highlighting how AD-related pathological processes shape the selection of therapeutic cargos and formulation designs. We discuss recent progress in the intranasal delivery of repurposed small molecules, natural products, insulin-related agents, peptides and proteins, extracellular vesicles, antibodies, and nucleic acid-based therapeutics. We further summarize major nanocarrier and formulation platforms, including lipid-based systems, polymeric nanoparticles, micelles, extracellular vesicles, in situ gels, and device-assisted delivery technologies. Particular attention is given to the design parameters that influence N2B performance, including particle size distribution/PDI, surface charge, mucus interaction, cargo protection, targeting modification, biodistribution, and deposition reproducibility. Finally, we critically evaluate the translational challenges that continue to limit clinical application, including species differences in nasal anatomy, dose-volume restrictions, device-dependent variability, limited human pharmacokinetic evidence, manufacturing complexity, long-term safety, and regulatory requirements. By integrating disease mechanisms, nanocarrier design, and translational considerations, this review provides a structured perspective for developing more rational and clinically feasible N2B nanodelivery systems for AD.},
}
@article {pmid42507559,
year = {2026},
author = {Xin, J and Tao, J and Chen, Q and Li, J and Wang, M and Wang, Z},
title = {CSD-GCN: Cross-Modal Self-Distillation Graph Convolutional Network for Alzheimer's Disease Diagnosis.},
journal = {IEEE transactions on computational biology and bioinformatics},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/TCBBIO.2026.3716969},
pmid = {42507559},
issn = {2998-4165},
abstract = {Alzheimer's disease (AD) is a prevalent neurode generative disorder that demands more comprehensive and precise modeling to unravel its complex pathological mechanisms and multidimensional brain network abnormalities. However, current brain network analysis approaches often suffer from limitations such as single-modal data processing and shallow fusion strategies, which hinder their ability to capture the multi scale connectivity patterns associated with AD effectively. To alleviate these limitations, a novel multi-modal fusion framework is proposed in this paper, namely a cross-modal self-distillation graph convolutional network (CSD-GCN). The framework can deeply integrate fMRI and DTI data to facilitate the systematic extraction of hierarchical features from multimodal brain net works. The architecture of CSD-GCN comprises three progressive layers: edge-to-edge (E2E), edge-to-node (E2N), and node-to graph (N2G). These layers are designed to perform multi-scale feature extraction, capturing neurodegenerative patterns ranging from local connection strengths to global topological structures. Moreover, the model incorporates a cross-modal self-knowledge distillation strategy and a cross-attention mechanism to enhance inter-modal feature alignment and fusion. These components collectively improve the generalization ability and discriminative capability of the learned representations. Experimental evaluations show that CSD-GCN outperforms existing methods in binary and ternary classification tasks for AD, with ablation studies confirming the individual effect of each component within the proposed framework.},
}
@article {pmid42507917,
year = {2026},
author = {Ruffini, G and Lopez-Sola, E and Palma, R and Sanchez-Todo, R and Vohryzek, J and Castaldo, F and Friston, K},
title = {Cross-Frequency Coupling as a Neural Substrate for Prediction Error Evaluation: A Laminar Neural Mass Modeling Approach.},
journal = {Neural computation},
volume = {38},
number = {8},
pages = {1299-1343},
doi = {10.1162/NECO.a.1537},
pmid = {42507917},
issn = {1530-888X},
abstract = {Predictive coding frameworks suggest neural computations rely on hierarchical error minimization, yet the neural implementation of this inference remains unclear. We propose that cross-frequency coupling (CFC) furnishes fundamental mechanism for this process. Using our laminar neural mass model (LaNMM), we demonstrate that signal-envelope coupling (SEC) an envelope-envelope coupling (EEC) instantiate a hierarchical comparator mechanism. Specifically, SEC generates prediction-error signals by subtracting top-down predictions from bottom-up oscillatory envelopes, while EEC operates at slower timescales to implement gating-a critical mechanism for precision weighting. To establish the face validity and clinical implications of this proposal, we model perturbations of these CFC mechanisms to investigate their roles in pathophysiological and altered neuronal function. In Alzheimer's disease, interneuron dysfunction disrupts the comparator, causing aberrant prediction error amplification in early stages and drastic attenuation in late phases. Conversely, serotonergic psychedelics increase excitatory gain, diminishing the modulatory effect of predictions and causing a failure of sensory attenuation. Collectively, these findings implicate multiscale cross-frequency coupling as a key computational mechanism supporting predictive coding and its disruption in disease.},
}
@article {pmid42508146,
year = {2026},
author = {Dzianok, P and Wojciechowski, J and Wolak, T and Kublik, E},
title = {Subtle cortical thinning in the temporal pole in middle-aged APOE-ε4 and PICALM (rs3851179) AA/AG carriers without dementia.},
journal = {Neurobiology of aging},
volume = {168},
number = {},
pages = {63-72},
doi = {10.1016/j.neurobiolaging.2026.07.004},
pmid = {42508146},
issn = {1558-1497},
abstract = {The symptoms of Alzheimer's disease (AD) are caused by neurodegeneration and atrophy in particular brain regions, especially in the temporal lobe. However, the influence of genetic risk on cortical thickness prior to dementia onset, remains unclear. This study aimed to explore the relationship between AD genetic risk (related to APOE and PICALM genes) and cortical thickness in selected regions of interest (ROIs) in middle-aged individuals without dementia. Sixty-nine (N = 69) participants (34 females, 35 males; age: 55.45 ± 3.19) underwent magnetic resonance imaging (MRI). They were divided into three groups based on their genetic AD risk: A+ P+ (APOE/PICALM risk variants), A+P- (APOE risk variant, PICALM neutral variants), and the N group (APOE/PICALM neutral alleles). Cortical thickness was analyzed using CAT12 software (surface-based morphometry with the Destrieux atlas) based on T1-weighted MR images in five ROIs referred to as "the cortical signature of AD" in previous studies. The A+P- group had a thinner right temporal pole cortex than non-carriers after controlling for sex, age, and Raven's Progressive Matrices scores. Although this finding did not survive FDR correction across the 10 tested regions, it is consistent with our hypotheses and prior literature. No other differences in cortical thickness were found in the analyzed regions of AD "signature". The observed effect was restricted to single-risk APOE carriers without PICALM risk alleles. Therefore, further research is needed to understand the genetic interplay between these two genes in conferring AD risk.},
}
@article {pmid42508236,
year = {2026},
author = {Kavitha, R and Premalatha, K},
title = {NeuroOmics-Net: An interpretable multimodal deep learning framework for Alzheimer's disease diagnosis and progression prediction using neuroimaging, EEG, and genomic data.},
journal = {Computers in biology and medicine},
volume = {214},
number = {},
pages = {111879},
doi = {10.1016/j.compbiomed.2026.111879},
pmid = {42508236},
issn = {1879-0534},
abstract = {Accurate diagnosis and progression prediction of Alzheimer's disease (AD) remain challenging due to the heterogeneous nature of the disease, which involves structural brain degeneration, electrophysiological dysfunction, and molecular dysregulation. Most existing deep learning approaches rely on a single modality or limited multimodal combinations, thereby failing to capture the complex cross-domain interactions underlying AD progression. Furthermore, the scarcity of large-scale datasets containing synchronized neuroimaging, electrophysiological, and genomic measurements restricts the development of comprehensive multimodal diagnostic systems. To address these challenges, this study proposes NeuroOmics-Net, a multimodal deep learning framework for Alzheimer's disease analysis that integrates structural magnetic resonance imaging (sMRI), electroencephalography (EEG), and gene expression data. The proposed framework combines a Hierarchical Multi-View Encoder (HME) for modality-specific feature extraction, a Cross-Omics Attention Fusion (CAF) module for adaptive integration of complementary biomarkers, and a Disease Progression Graph Learning (DPGL) module for modeling progression-related relationships across biological domains. To facilitate cross-modal integration from independent cohorts, Regularized Canonical Correlation Analysis (RCCA) is employed to align heterogeneous feature representations within a shared latent space. Experiments were conducted using publicly available datasets from ADNI, PhysioNet, and GEO repositories comprising 1120 diagnosis-aligned samples. The proposed framework achieved 94.3% classification accuracy and an AUC of 0.975 for distinguishing normal controls (NC), mild cognitive impairment (MCI), and Alzheimer's disease subjects, while attaining 93.7% accuracy for predicting conversion from stable mild cognitive impairment (sMCI) to progressive mild cognitive impairment (pMCI). However, a fairness sensitivity analysis using stratified demographic reweighting revealed accuracy ranging from 90.8% (low-education, high-comorbidity proxy subgroup) to 96.1% (low-risk, high-reserve proxy subgroup), a demographic parity gap of 5.3 percentage points, indicating that overall accuracy reflects a performance ceiling in a relatively homogeneous research cohort rather than a realistic estimate for demographically diverse clinical populations. Comparative evaluations demonstrated consistent improvements over state-of-the-art unimodal and multimodal deep learning models. Interpretability analysis further identified clinically relevant biomarkers, including hippocampal and entorhinal atrophy, theta-alpha EEG alterations, and APOE-associated molecular pathways. Because sMRI, EEG, and gene expression data were sourced from separate, unpaired cohorts with no subjects possessing all three synchronized measurements, all reported cross-modal associations reflect population-level statistical correspondence across diagnosis-matched groups rather than within-subject physiological coupling; no claim of intra-individual causal cross-modal interaction is made. These findings demonstrate that NeuroOmics-Net provides an effective computer-aided framework for multimodal biomedical data processing and Alzheimer's disease analysis. By integrating neuroimaging, electrophysiological, and genomic information, the proposed approach enables accurate diagnosis, progression prediction, and biologically interpretable decision support for clinical and translational applications.},
}
@article {pmid42499555,
year = {2026},
author = {Gao, M and Yan, Y and Wu, Y and Geng, Z and Wang, L and Zhou, S and Hu, P and Wu, X and Wang, K},
title = {Relationship between executive function and activities of daily living in Alzheimer's disease: a study based on the stop-signal task.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1837948},
pmid = {42499555},
issn = {1663-4365},
abstract = {BACKGROUND: Early clinical manifestations of Alzheimer's disease (AD) include an apparent decline in memory and executive function. Executive function is closely related to activities of daily living (ADL) and is important for maintaining an independent, high-quality lifestyle.<br><br>OBJECTIVE: This study aimed to explore the executive control ability and neuromechanisms of AD patients through stop-signal task (SST) elicited event-related potentials (ERPs) and their relationship with ADL.<br><br>METHODS: Thirty-six patients with AD and 36 sex and age matched healthy controls (HCs) were recruited. Electroencephalography (EEG) data recorded during the SST was compared between groups, and SST-related indicators were determined to assess executive control ability in AD patients. The relationship between ADL and SST-related indicators was explored. We performed Receiver Operating Characteristic (ROC) analysis on SST- and EEG-related indices.<br><br>RESULTS: Differences in the following indices were found between the two groups: Go accuracy (P< 0.001), Go omissions (P< 0.001), Go errors (P< 0.001), Go error reaction time (RT) (P< 0.001), failed stop RT (P = 0.021), all accuracies (P = 0.005), mean amplitude of N300 (P = 0.043), peak amplitude of N300 (P = 0.043), and peak latency of N300 (P< 0.001). And Go accuracy (r = -0.603, P = 0.005) and all accuracy (r = -0.624, P = 0.003) in the AD group were negatively partially correlated with ADL. These SST- and EEG-related indicators had an Area Under the Curve of 0.771 and 0.831, both of which could be used to jointly diagnose AD (both P< 0.001).<br><br>CONCLUSION: This study suggests that the worse the executive function of AD patients, the more serious the ADL impairment. AD patients have electrical abnormalities associated with executive control. Different SST- and EEG-related indicators can be used to diagnose AD. This provides a new avenue for further elucidation of the pathological mechanisms of AD.},
}
@article {pmid42499556,
year = {2026},
author = {Yang, HX and Su, BW and Bao, YN and Wang, WH and Lao, JY and Ji, HY and Han, S and Cui, XH and Ren, HW and Luan, ZL},
title = {JAK/STAT signaling pathway inhibitors in neurodegenerative diseases: current status and future perspectives.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1880374},
pmid = {42499556},
issn = {1663-4365},
abstract = {Neurodegenerative diseases (NDDs) are a major public health concern characterized by the progressive loss of neurons, ultimately leading to neuronal death and causing a sustained decline in brain function or physical motor abilities. Major examples include Alzheimer's disease (AD) and Parkinson's disease (PD). Currently, NDDs lack effective curative methods, and their pathological process primarily involves misfolded protein aggregation, oxidative stress, and neuroinflammation. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway, as a central hub for cytokine signaling, has recently been found to play a key role in neuroinflammation and immune regulation in NDDs. This review systematically elucidates the core mechanisms of the JAK/STAT pathway in NDDs, including the regulation of microglial and astrocytic reactivity, the impact on blood-brain barrier integrity, and involvement in energy metabolism abnormalities. On this basis, we have reviewed and evaluated various therapeutic strategies targeting this pathway, focusing on small-molecule JAK inhibitors such as baricitinib and tofacitinib, and have analyzed their mechanisms of action, preclinical efficacy, and potential side effects. In addition, this article provides a forward-looking perspective on the future research directions of the JAK/STAT pathway from the perspective of anti-neuroinflammation to promote neuroregeneration therapy, aiming to offer theoretical references and new ideas for the clinical translational research of this pathway.},
}
@article {pmid42499619,
year = {2026},
author = {Li, PS and Liu, Y and Zhao, MR and Zhu, YQ and Shi, YX and Jing, MD and Hu, XW and Jiang, CH and Liu, XD and You, YL and Wu, CJ and Bie, NN and Liu, XM},
title = {Zizybeoside II From Jujube Fructus Prolongs Lifespan and Mitigates Alzheimer's Disease Progression in Caenorhabditis elegans Through HSF-1/HSP-16.2 Pathway.},
journal = {Food science &amp; nutrition},
volume = {14},
number = {7},
pages = {e72151},
pmid = {42499619},
issn = {2048-7177},
abstract = {Jujube (Ziziphus jujuba Mill.) has been consumed as a nutraceutical and medicinal food in China for millennia. Recent studies have highlighted the nutritional and bioactive properties of jujube fruit extracts, with potential to mitigate Alzheimer's disease (AD) progression through longevity-enhancing effects. Our previous study explored the lifespan-extending mechanisms of Jujube Fructus extract (JE) in Caenorhabditis elegans (C. elegans). Here, we evaluated the efficacy of zizybeoside II (ZB), separated from JE through HPLC, in extending lifespan and ameliorating AD pathology in C. elegans. The results showed that ZB treatment significantly prolonged C. elegans lifespan while maintaining reproductive capacity, with concurrent enhancements in normal activity and stress resistance during aging. Additionally, we found that ZB effectively alleviated various β-Amyloid (Aβ)-induced neurotoxic phenotypes in AD worms, including paralysis and behavioral deficits. Mechanistic investigations in N2a/APP695 cells demonstrated that ZB reduced the accumulation of Aβ and phosphorylated tau (p-Tau) proteins, diminished oxidative stress levels through the HSF-1/HSP16.2 pathway, and thereby slowed the progression of AD. This study provides a theoretical basis for the subsequent clinical trials of ZB in delaying AD.},
}
@article {pmid42499998,
year = {2026},
author = {Ruesga Mundo, S},
title = {Neuroinflammation as a failure of allostatic integrity: a hierarchical-circular model of biological memory for pathogenesis in neurodegenerative and neuropsychiatric diseases.},
journal = {Frontiers in systems neuroscience},
volume = {20},
number = {},
pages = {1888548},
pmid = {42499998},
issn = {1662-5137},
abstract = {INTRODUCTION: Chronic neuroinflammation is a hallmark of neurodegenerative diseases (Alzheimer's disease, Parkinson's disease) and neuropsychiatric disorders (major depression, schizophrenia). However, current models fail to explain why some individuals develop persistent neuroinflammation while others maintain homeostasis, nor why similar inflammatory pathology produces such diverse clinical phenotypes.<br><br>HYPOTHESIS: We propose that pathological neuroinflammation emerges from a failure of allostatic integrity-the capacity of the organism to maintain adaptive circular information flow across five interconnected levels: (1) genetic architecture and morphogenetic programming, (2) epigenetic molecular memory, (3) allostatic load and systemic physiological adaptation, (4) the psychoneuroimmuneendocrine (PINE) network, and (5) interoceptive-neuronal integration. When this circular flow is disrupted, maladaptive stable states become entrenched, perpetuating chronic inflammation.<br><br>DEVELOPMENT OF THE HYPOTHESIS: Synthesizing evidence from longitudinal and mechanistic studies (with foundational older works cited where necessary), we discuss how: (a) early-life stress epigenetically programs inflammatory reactivity; (b) elevated allostatic load predicts chronic neuroinflammation; (c) PINE network dysregulation perpetuates pro-inflammatory signaling; and (d) interoceptive dysfunction may prevent the downregulation of inflammation. Allostatic integrity is introduced as a dynamic systems-level property hypothesized to moderate the relationship between inflammatory pathology and clinical expression.<br><br>TESTABLE PREDICTIONS: The framework generates falsifiable predictions: (1) composite indices of allostatic integrity will outperform single biomarkers in predicting transition to chronic neuroinflammation; (2) multidomain interventions targeting multiple levels will produce multiplicative (synergistic) effects; (3) patients with similar inflammatory profiles but contrasting allostatic integrity will show markedly different clinical trajectories; and (4) improvements in allostatic integrity will correlate with reduced neuroinflammation independent of direct anti-inflammatory therapies.<br><br>CONCLUSION: The Hierarchical-Circular Model reframes chronic neuroinflammation not as a linear cascade but as a potential systemic failure of biological memory and allostatic integrity. Pending empirical validation, this framework may offer a conceptual basis for biomarker development, multidomain prevention, and personalized treatment strategies.},
}
@article {pmid42500022,
year = {2026},
author = {Bhaskar, U and Carless, MA},
title = {Astrocyte epigenetics in development, aging, and neurodegeneration: a DNA methylation perspective.},
journal = {Frontiers in molecular neuroscience},
volume = {19},
number = {},
pages = {1876219},
pmid = {42500022},
issn = {1662-5099},
abstract = {Epigenetic modifications, including DNA methylation, have long been associated with developmental programming, as well as aging and disease states. However, our understanding of cell-specific epigenomic landscapes remains limited, especially in the context of brain aging and neurodegeneration. In cases of late-onset brain disorders, such as Alzheimer's disease, progressive supranuclear palsy, Parkinson's disease, and frontotemporal dementia, unraveling cell-specific epigenomic contributions is particularly necessary to better understand the molecular contributors to early disease states, which may help enhance diagnostic and therapeutic measures. While whole brain tissue and neuronal cell-type-specific methylomic contributions have been extensively studied, those of glia, including astrocytes, remain poorly elucidated. Given the key role of DNA methylation in guiding neurodevelopmental timing and gliogenic onset, it is likely that these modifications alter astrocyte functionality with age and disease. Here, we briefly review astrocyte development in the context of DNA methylation and highlight key instances where methylomic changes contribute to astrocyte maturation and functionality. We also point to evidence showing extensive transcriptomic and functional changes associated with aged and diseased astrocytes and explore the relevance of DNA methylation in these conditions. Ultimately, elucidating molecular drivers of disease states in astrocytes will allow for a better understanding of cell-specific contributions and pave the way for future research directed at cell-specific therapeutics.},
}
@article {pmid42500227,
year = {2026},
author = {Lee, S and Jang, T and Im, J and Pang, Y},
title = {Ultrafast Charge Transfer Dynamics of Thioflavin T Probed by Time-Resolved Raman Spectroscopy.},
journal = {ACS physical chemistry Au},
volume = {6},
number = {4},
pages = {678-686},
pmid = {42500227},
issn = {2694-2445},
abstract = {Thioflavin T (ThT) is a commonly used dye that probes amyloid fibrils associated with Alzheimer's and Parkinson's diseases. Binding to amyloid fibrils significantly enhances ThT fluorescence, while hindering the formation of the twisted intramolecular charge transfer (ICT) state in the dimethylaniline group. On the other hand, ThT fluorescence is strongly quenched in aqueous and aliphatic alcohol solutions with efficient ICT in the excited states. No direct experimental evidence for the structural changes of ThT with ICT has been reported yet. In this work, we report the structural changes of ThT during ICT by time-resolved Raman spectroscopic methods, which include the bend of the benzothiazole and the twist of the dimethylaniline group. Both femtosecond stimulated Raman spectroscopy and impulsive stimulated Raman spectroscopy suggest that the ICT coordinate of ThT can be strongly coupled with the low-frequency deformation modes. Time-dependent density functional theory calculations and the evaluated vibrational reorganization energies between the ground and excited states strongly support our experimental results based on time-resolved vibrational spectroscopy.},
}
@article {pmid42500646,
year = {2026},
author = {Wang, C and Yun, Q and Zhang, Z and Zhao, H and Lin, F and Cao, H},
title = {Association between Alzheimer's disease and MHC-I antigen processing and presentation pathway: a narrative review.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1877167},
pmid = {42500646},
issn = {1664-3224},
mesh = {Humans ; *Alzheimer Disease/immunology/metabolism ; *Antigen Presentation/immunology ; *Histocompatibility Antigens Class I/immunology/genetics/metabolism ; Animals ; Signal Transduction ; Microglia/immunology ; },
abstract = {Alzheimer's disease (AD) is the most common cause of dementia worldwide and remains a major public health burden. Although amyloid-beta deposition and tau pathology are the defining pathological features of AD, increasing evidence indicates that immune dysregulation and chronic neuroinflammation also contribute to disease onset and progression. However, the specific immune pathways involved in AD and their mechanistic relevance remain incompletely understood. The major histocompatibility complex class I (MHC-I) antigen processing and presentation pathway has attracted growing attention because of its classical role in adaptive immunity and its potential functions within the central nervous system. In this narrative review, we summarize current evidence linking AD to the MHC-I, or human leukocyte antigen class I (HLA-I), pathway from genetic, molecular, cellular, and immunological perspectives. Available studies implicate the broader HLA region in AD susceptibility and suggest that alterations in HLA-I-related loci, antigen-processing machinery, MHC-I-associated molecules, and downstream immune responses may contribute to disease heterogeneity. At the molecular and cellular levels, changes in MHC-I molecules, antigen-processing machinery, and associated signaling pathways have been reported in microglia, neurons, astrocytes, and oligodendroglial lineage cells. In parallel, changes involving β2-microglobulin and the presence of expanded or cytotoxic like CD8[+] T cells suggest that adaptive immune mechanisms may participate in AD pathology. Nevertheless, direct evidence demonstrating immune responses specific to particular antigens and restricted by HLA-I in human AD remains limited. Overall, current findings indicate that the MHC-I/HLA-I pathway may represent an important component of AD pathophysiology and contribute to disease progression by influencing immune homeostasis and cellular interactions within the central nervous system. Further studies integrating human tissue analysis, immunopeptidomics, spatial profiling, and paired T cell receptor approaches are needed to clarify its mechanistic, biomarker, and therapeutic significance.},
}
@article {pmid42500791,
year = {2026},
author = {Babiker Mohamed, RO and Elamin, AM and Ali Ahmed, SS and Mahmuod, SB and Mohamed Hamid, HA and Ahmed, RAA and Aboaly, MM},
title = {Association of sTREM2 and YKL-40 With Alzheimer's Disease Progression: A Systematic Review.},
journal = {Cureus},
volume = {18},
number = {6},
pages = {e111423},
pmid = {42500791},
issn = {2168-8184},
abstract = {Neuroinflammation is recognized as a core feature of Alzheimer's disease (AD). Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) and chitinase-3-like protein 1 (YKL-40) are fluid biomarkers of microglial and astrocytic reactivity associated with AD progression. However, their coupling to amyloid and tau pathology, stage-specific roles, and prognostic utility remain unclear. This systematic review synthesized evidence from 2021 to 2025 on associations of sTREM2 and YKL-40 with AD progression. This review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. PubMed/Medical Literature Analysis and Retrieval System Online (MEDLINE), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Institute of Electrical and Electronics Engineers (IEEE) Xplore, and Web of Science were searched (Jan 2021-Dec 2025), with citation searching. Duplicates were removed using EndNote X21 (Clarivate, London, UK). Two independent reviewers screened records using the Population, Intervention, Comparison, Outcomes, and Study Design (PICOS) criteria, with disagreements resolved by a third reviewer. Original human studies measuring sTREM2 and/or YKL-40 across the AD spectrum were included. Methodological quality was assessed using the Newcastle-Ottawa Scale (NOS). Due to heterogeneity in study design and outcomes, a narrative synthesis was performed. Thirteen studies were included: seven on sTREM2, five on YKL-40, and one on both. Six were low risk of bias, and seven were moderate. Cerebrospinal fluid (CSF) sTREM2 showed a biphasic pattern across disease stages, with early potential neuroprotective associations and later correlation with cortical atrophy and cognitive decline. A sex-APOE ε4 interaction was observed, with higher levels in female carriers. YKL-40 showed weak amyloid associations but strong coupling with tau pathology and neurodegeneration, influenced by vascular risk factors. Plasma YKL-40 predicted incident dementia and cognitive decline, and serum YKL-40 differentiated early dementia from controls with good diagnostic performance. sTREM2 and YKL-40 represent biologically distinct but complementary neuroinflammatory pathways in AD. sTREM2 reflects a stage-dependent microglial response, while YKL-40 reflects tau-associated astrocytic activation modulated by vascular factors. Longitudinal studies with concurrent biomarker assessment are needed to clarify their combined prognostic value.},
}
@article {pmid42500864,
year = {2026},
author = {Gold, ME and Chandrasekhar, S and Kulshreshtha, A and Britt, M and Guynn, N and Gold, DA and Jain, V and Razavi, AC and Vatsa, N and Yadalam, AK and Bennett, J and McLean, P and Dodson, S and Vaccarino, V and Quyyumi, AA and Lah, J and Levey, A and Benson, R and Lloyd-Jones, DM and Sperling, LS},
title = {Life's Essential 8: Essential for Brain and Cognitive Health.},
journal = {Journal of the American Heart Association},
volume = {},
number = {},
pages = {e039048},
doi = {10.1161/JAHA.124.039048},
pmid = {42500864},
issn = {2047-9980},
abstract = {Cognitive impairment and Alzheimer disease and related dementias are increasingly prevalent and carry significant morbidity. Growing evidence has highlighted the complex interactions between cardiovascular and brain health, implicating vascular dysfunction in the pathogenesis of many forms of cognitive impairment. The American Heart Association (AHA) and the American Stroke Association have outlined a comprehensive framework, known as Life's Essential 8, that includes 4 behavioral health factors (healthy dietary pattern, physical activity, avoidance of nicotine, and healthy sleep) and 4 health factors (cholesterol, blood glucose, blood pressure, body mass index) that collectively define optimum cardiovascular health. Modifiable risk factors account for an estimated 40% of worldwide dementia. Adherence to Life's Essential 8 principles may also help individuals mitigate the risk of cognitive impairment via improved cardiovascular health. However, a comprehensive understanding of the causal relationships between vascular and behavioral risk factors and Alzheimer disease and related dementias remains unclear and requires further study. This narrative review summarizes well-established data and highlights new data for how health and behavioral factors included in Life's Essential 8 also promote optimal brain and cognitive health.},
}
@article {pmid42500977,
year = {2026},
author = {Sodaei, F and Vind Knudsen, L},
title = {Interpreting early default mode network dysfunction across the Alzheimer's disease spectrum.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag253},
pmid = {42500977},
issn = {1460-2156},
}
@article {pmid42497446,
year = {2026},
author = {Kuo, YF and Tzeng, HM and Shan, Y and Jang, JH and Cram, P and Raji, MA},
title = {Association Between Annual Wellness Visits and Early Dementia Diagnoses: Roles of Post-Visit Healthcare Decisions.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70599},
pmid = {42497446},
issn = {1532-5415},
support = {5R01AG083102-03//National Institute on Aging of the National Institutes of Health/ ; P30-AG024832//National Institute on Aging of the National Institutes of Health/ ; },
abstract = {BACKGROUND AND OBJECTIVES: Early recognition of cognitive impairment (CI) and timely diagnoses of mild CI (MCI) and Alzheimer's Disease and Related Dementias (ADRD) are key to optimal dementia care. No previous research has examined the extent to which healthcare interventions/services (specific blood tests, specialist referrals, and brain imaging) conducted after annual wellness visits (AWVs) contribute to subsequent MCI/ADRD diagnosis. We assessed the role of post-AWV healthcare services on the association of incident AWVs with the first ADRD or MCI diagnosis in Medicare enrollees.<br><br>METHODS: Propensity score matching of AWVs generated an active comparator cohort of Texas fee-for-service Medicare enrollees who received a Primary Care Provider visit, but without AWVs in 2018 (n&#x2009;=&#x2009;66,443 in each group). Healthcare services (laboratory testing for CI: vitamin B12, thyroid stimulating hormone; specialist referrals: neurology, psychiatry; and brain images: CT, MRI) occurring after AWV and before the first MCI/ADRD diagnosis were examined.<br><br>RESULTS: Both groups had similar proportions of patients receiving specific blood tests, specialist referrals, and brain images in the 12&#x2009;months before AWV/index date. Among those with no previous specialist visits, 39.2% in the AWV group and 31.1% in the non-AWV group received laboratory testing in the follow-up period. Similarly, among those with no previous brain images, 12.4% in the AWV group and 13.1% in the non-AWV group received brain images in the follow-up period. AWV receipt was associated with a 28% increase in MCI diagnosis; mediation analyses indicated that 14% of this increase was explained through post-AWV laboratory testing. AWV receipt was not associated with an increase in ADRD diagnosis.<br><br>DISCUSSION: Medicare AWV had a large direct effect on MCI diagnosis, but not on dementia diagnosis, suggesting that cognitive assessment and clinical evaluations during AWV directly contributed to the early recognition of MCI.},
}
@article {pmid42497465,
year = {2026},
author = {Seijo, MA and Yohannes, PA and Rogers, AL and Gonzalez, JC and Banerjee, A and Kelley, H and Pierce, M and McQuail, JA and Hernandez, CM},
title = {Posttraumatic stress disorder is associated with Alzheimer's disease-relevant molecular alterations in the basolateral amygdala of older Veterans.},
journal = {Neurobiology of aging},
volume = {168},
number = {},
pages = {44-62},
doi = {10.1016/j.neurobiolaging.2026.07.006},
pmid = {42497465},
issn = {1558-1497},
abstract = {Posttraumatic stress disorder (PTSD) is associated with accelerated cognitive aging and increased risk for Alzheimer's disease (AD) and related dementias (ADRD), yet the biological substrates linking trauma-related psychiatric illness to altered brain aging trajectories remain poorly defined. The basolateral amygdala plays a central role in threat processing and emotional memory and exhibits persistent hyperactivity in PTSD, but its molecular and pathological state in aging individuals with PTSD has not been examined. Postmortem basolateral amygdala tissue from older adult donors (≥70 years) with lifetime PTSD (n = 5) and age-matched controls (n = 5) was obtained from the National PTSD Brain Bank. A multimodal analysis integrated immunohistochemical quantification of β-amyloid and phosphorylated tau pathology, targeted transcriptional profiling of AD-related genes, gene network analysis, and protein quantification of pathological, inflammatory, and synaptic markers. PTSD cases showed enrichment of combined tau-amyloid pathology within the basolateral amygdala and greater β-amyloid burden. Targeted transcriptomic profiling identified coordinated upregulation of genes involved in amyloid processing, lipid metabolism, proteostasis, and inflammatory signaling. Network analysis revealed an APP-centered molecular architecture with APOE, and MAPT as hubs. Protein analyses demonstrated increased amyloid-β and pTau231 abundance, markers of gliosis, and synaptic alterations characterized by elevated excitatory receptor expression and reduced inhibitory signaling. Collectively, these findings provide convergent human evidence that PTSD is associated with region-specific molecular alterations engaging pathways implicated in brain aging and neurodegenerative vulnerability. These data suggest that chronic trauma-related circuit dysregulation may intersect with aging-associated inflammatory and synaptic processes, promoting vulnerability to neurodegenerative change within emotionally salient brain circuits.},
}
@article {pmid42497520,
year = {2026},
author = {Qin, Y and Dong, X and Zhang, C and Nao, J},
title = {Magnolol as a promising multitarget agent for Alzheimer's disease: Evidence from a systematic evidence synthesis, network pharmacology, and molecular dynamics simulations.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {159},
number = {},
pages = {158586},
doi = {10.1016/j.phymed.2026.158586},
pmid = {42497520},
issn = {1618-095X},
abstract = {OBJECTIVE: This study provides systematic synthesis of therapeutic effects of magnolol (MN) in preclinical Alzheimer's disease (AD) models and integrates network pharmacology with molecular dynamics (MD) simulations to predict its core targets and binding stability.<br><br>METHODS: Systematic literature search was conducted in PubMed, CNKI, Wanfang, and Google Scholar up to January 1, 2026 following PRISMA guidelines. Network pharmacology, molecular docking, and 100 ns MD simulations were used to identify common targets, evaluate binding affinities, and assess complex stability.<br><br>RESULTS: Fourteen studies (seven in vivo, five in vitro, two combined) were included. MN consistently ameliorated cognitive deficits and neuropathology through antioxidant, anti-inflammatory, anti-apoptotic, and anti-acetylcholinesterase activities, while preserving mitochondrial and synaptic function. Network pharmacology identified 60 common targets; Protein-Protein Interaction (PPI) analysis revealed five hub genes: AKT1, MMP9, MMP2, ERBB2, and EGFR. Molecular docking showed binding energies below -4.0 kcal/mol for all five targets, and MD simulations confirmed stable binding, with the ERBB2-MN complex exhibiting the lowest root mean square deviation (RMSD) (1.2 &#xc5;) and favorable free energy landscape. Molecular Mechanics/Poisson-Boltzmann Surface Area (MM-PBSA) calculations further confirmed that magnolol exhibited binding affinities comparable to the reference co&#x2011;crystal ligands. Unlike prior reviews, this study uniquely combines systematic evidence synthesis with computational predictions, identifying ERBB2 as a novel stable target of MN.<br><br>CONCLUSION: MN exerts anti-AD effects via multi-pathway and multi-target regulation, with computational predictions aligning with experimental evidence, supporting MN as promising lead compound for AD drug development.},
}
@article {pmid42497576,
year = {2026},
author = {Zafari, R and Kamroo, A and Taherkhani, T and Nabizadeh, F and Aarabi, MH and , },
title = {Corrigendum to "DTI-ALPS index and its association with neuroinflammatory and neurodegenerative biomarkers and tau-PET in Alzheimer's continuum" [NSC 609C (2026) 101-115].},
journal = {Neuroscience},
volume = {612},
number = {},
pages = {90},
doi = {10.1016/j.neuroscience.2026.07.030},
pmid = {42497576},
issn = {1873-7544},
}
@article {pmid42497640,
year = {2026},
author = {Malcangio, M and Sideris-Lampretsas, G},
title = {Chronic pain in Alzheimer disease and the role of neuroimmune interactions.},
journal = {Pharmacological reviews},
volume = {78},
number = {5},
pages = {100149},
doi = {10.1016/j.pharmr.2026.100149},
pmid = {42497640},
issn = {1521-0081},
abstract = {Chronic pain conditions affect a large proportion of the global population and pain has tremendous personal and economic impact, affecting quality of life and ability to work while imposing a significant burden on families and health care systems. Neurological disorders and painful conditions are frequently accompanied by chronic pain, which is often jointly diagnosed with age-related neurodegenerative diseases, however, many patients do not receive adequate treatment. This review aims to create a working framework around the issue of under-recognized/undertreated chronic pain in Alzheimer disease by offering an in-depth overview of the mechanisms driving chronic pain and how we can leverage this knowledge to advance therapeutics approaches for these patients with an emphasis on the immune system. SIGNIFICANCE STATEMENT: Chronic pain conditions are prevalent among the aging population, and they positively associate with dementia. The incidence of chronic pain is associated with neuropsychiatric symptoms of dementia and pain management should aim for effective treatments regardless of cognitive status.},
}
@article {pmid42497677,
year = {2026},
author = {Domingo, JL and Colomina, MT},
title = {Aluminum and Alzheimer's disease in the 21st century: An umbrella review of evidence and controversies.},
journal = {Neurotoxicology},
volume = {116},
number = {},
pages = {103531},
doi = {10.1016/j.neuro.2026.103531},
pmid = {42497677},
issn = {1872-9711},
abstract = {The potential role of aluminum (Al) in the onset and progression of Alzheimer disease (AD) remains among the most enduring and divisive controversies in environmental neurotoxicology. Although numerous narrative reviews, systematic reviews, meta-analyses, mechanistic appraisals, and toxicological assessments have been published, their conclusions remain heterogeneous and at times contradictory. The present review of reviews critically integrates the PubMed-indexed review literature published in this century (January 1, 2000, and May 2, 2026), focusing on epidemiology, exposure sources, toxicokinetics, biological plausibility, experimental models, biomarkers, preventive measures, and unresolved methodological challenges. A predefined selection strategy was applied, prioritizing reviews that directly addressed Al and AD, employed systematic or meta-analytic approaches, examined epidemiological or mechanistic evidence, evaluated exposure assessment, or offered influential conceptual frameworks. Peripheral reviews were considered only when they provided essential context. The methodological quality of the included reviews was appraised qualitatively, considering transparency of the search strategy, reproducibility of methods, consideration of bias, and relevance to the review objectives. The strength of the evidence supporting each main conclusion was graded as strong, moderate, or limited. The evidence reviewed indicates that Al can promote several AD-related biological processes in experimental settings, including oxidative stress, mitochondrial dysfunction, neuroinflammation, glial activation, disrupted calcium signaling, amyloid beta aggregation, impaired amyloid clearance, tau phosphorylation, autophagy impairment, and epigenetic alterations. Epidemiological findings are less consistent, although several meta-analyses link chronic, occupational, or drinking-water Al exposure with cognitive decline and AD risk, despite limitations from exposure misclassification, confounding, and methodological heterogeneity. Overall, the evidence neither identifies Al as the principal cause of AD nor dismisses its relevance, supporting instead a contributory role within a multifactorial disease model, especially in susceptible individuals.},
}
@article {pmid42497727,
year = {2026},
author = {Xia, Y and Tsim, KWK and Wang, WX},
title = {Nanoplastics forming micro-sized agglomerates and exacerbating neurotoxicity in Alzheimer's disease.},
journal = {Journal of hazardous materials},
volume = {515},
number = {},
pages = {143074},
doi = {10.1016/j.jhazmat.2026.143074},
pmid = {42497727},
issn = {1873-3336},
abstract = {Micro/nanoplastics are quietly infiltrating human bodies through dietary intake, water consumption, and dermal exposure. Here, we assessed the interaction of nanoplastics (NPs) with β-amyloid (Aβ), helping to understand the likely mechanisms of NPs accumulation in brain and potential impacts on Alzheimer's disease (AD). SH-SY5Y cells served as an in vitro model of AD and were treated with fluorescently labeled NPs (NPf). In in vivo study, 5XFAD mice were fed with environmentally relevant doses of NPf for two weeks, and mouse behavior was analyzed by open field test. Brain tissue sections combined with confocal microscopy enabled the quantification and spatial localization of NPf in the brain. NPs aggregated with Aβ fibers and formed micrometer-sized agglomerates. In AD cell models, these agglomerates increased the intracellular NPs accumulation, reactive oxygen species formation and ethoxyresorufin-O-deethylase activity, ultimately inhibiting neurite outgrowth and causing cell death. In the AD mice, NPs exposure worsened the mice disease-related behaviors (e.g., reduced movement distance and speed) and resulted in larger NPs agglomerates and highly co-localization with Aβ in brain, consistent with the in vitro results. This study provided important data on NPs interaction with Aβ fiber from ex vivo to in vivo models, helping to understand the mechanisms of NPs accumulation in the brain.},
}
@article {pmid42497792,
year = {2026},
author = {Chowdhury, TD and Shafoyat, MU and Hemel, NH and Nizam, D and Sajib, JH and Islam, MT and Nyeem, TA and Farzana, M and Haque, SR and Hasan, M and Siddiquee, KNEA and Mannoor, K},
title = {Robust multi-parameter classification-QSAR-based prioritization: Evaluating ranking stability under weight uncertainty for BACE1 inhibitor discovery.},
journal = {Computational biology and chemistry},
volume = {125},
number = {},
pages = {109242},
doi = {10.1016/j.compbiolchem.2026.109242},
pmid = {42497792},
issn = {1476-928X},
abstract = {Alzheimer's disease remains a major therapeutic challenge, with β-secretase (BACE1) representing a key target for reducing amyloid-β production. Computational drug discovery workflows increasingly rely on multi-parameter prioritization integrating predictive modeling, structural analysis, and pharmacokinetic profiling. However, such approaches commonly depend on heuristic weighting schemes, and the robustness of resulting rankings under weight uncertainty remains poorly characterized. In this study, we developed a biology-informed multi-parameter prioritization framework integrating meta-ensemble classification-QSAR modeling, molecular docking, residue-level interaction analysis, ADMET profiling, and molecular dynamics simulations for BACE1 inhibitor discovery. Beyond compound ranking, the framework was designed to systematically evaluate the stability and reliability of prioritization outcomes. A curated dataset of 16,196 compounds was screened, yielding 153 predicted actives and 111 drug-like candidates. The meta-ensemble classification-QSAR model demonstrated strong predictive performance (accuracy = 0.852; ROC-AUC = 0.920), supported by cross-validation, external validation, and Y-randomization (p = 0.009). To address uncertainty in weight assignment, ranking robustness was quantitatively assessed using global sensitivity analysis under controlled perturbations and randomized weighting schemes. Results showed that rankings remained highly stable under moderate weight perturbations (Spearman ρ ≈ 0.998 for ±10% and 0.963 for ±25%), with partial degradation under randomized weights (ρ ≈ 0.821), indicating that prioritization is primarily driven by integrated multi-parameter signals rather than specific weight configurations. Post hoc optimization further confirmed the consistency of prioritized compounds. While Mol-3 exhibited the most favorable predicted binding free energy, Mol-2 demonstrated the most balanced overall computational profile when binding stability, catalytic interaction persistence, ADMET characteristics, and multi-parameter ranking criteria were considered collectively. Unlike conventional multi-parameter QSAR and scoring approaches that rely on fixed weighting schemes, the framework explicitly quantifies ranking robustness through perturbation, ablation, and optimization analyses. The proposed framework offers a structured and interpretable strategy for robust computational compound prioritization and highlights the importance of robustness analysis in computational drug discovery workflows.},
}
@article {pmid42497811,
year = {2026},
author = {Tağraf, B and Kaygusuz, D and Yerlikaya, D and Oğul, &#xd6;E and Hanoğlu, L},
title = {The effect of simultaneous application of plant-rich ketogenic diet and intermittent fasting on early-to-mid-stage Alzheimer's disease: a randomised controlled trial.},
journal = {The journal of nutrition, health &amp; aging},
volume = {30},
number = {9},
pages = {100930},
doi = {10.1016/j.jnha.2026.100930},
pmid = {42497811},
issn = {1760-4788},
abstract = {INTRODUCTION: This study evaluates the effect of simultaneous application of plant-rich ketogenic diet and intermittent fasting as an individualized adjunct to standard treatment on cognitive function in early/mid-stage Alzheimer's patients.<br><br>METHODS: This assessor-blinded, randomized controlled trial enrolled 60 Alzheimer's disease (AD) patients (CDR 1-2; aged 55-85), randomized to intervention (n = 30; intervention + standard care) or control (n = 30; standard care). Cognition and brain structure were assessed at baseline and 6 months. Individual cognitive changes were analyzed using Reliable Change Index (RCI).<br><br>RESULTS: Cognitive change scores differed significantly between groups (p < 0.001). The mean Mini Mental State Examination (MMSE) score increased by +0.9 in the intervention group, while a decrease of -1.5 points was observed in the control group. RCI analysis indicated stability in 93% of intervention and 70% of control participants, with cognitive improvement in 7% and 3.3%, respectively.<br><br>DISCUSSION: The intervention method has the potential to stabilize cognitive decline in AD and promote improvement at the individual level. The response to the intervention is closely related to the individual's metabolic phenotype and structural brain integrity.<br><br>ETHICAL APPROVAL: Istanbul Medipol University Non-Interventional Clinical Research Ethics Committee on March 6, 2025, under number 242 and the study was carried out in accordance with the Declaration of Helsinki and its later amendments.<br><br>CLINICALTRIALS: gov ID: NCT06898424.},
}
@article {pmid42497989,
year = {2026},
author = {Lin, MC and Chen, HY and Lin, TS and Lin, SJ and Lin, PJ and Liao, CY and Chan, NL and Lin, CH and Teng, SC},
title = {The Src family kinase YES regulates DNAJB6b chaperone activity to modulate tau aggregation in Alzheimer's disease.},
journal = {The Journal of biological chemistry},
volume = {},
number = {},
pages = {113363},
doi = {10.1016/j.jbc.2026.113363},
pmid = {42497989},
issn = {1083-351X},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a gradual deterioration of memory. While its prevalence increases with age, the underlying mechanisms remain incompletely understood. Here, we examine the biological consequences of phosphorylation-mediated chaperone activity in AD-associated tau aggregates. Increased phosphorylation of DNAJB6b at Y53 is observed in the brain lysates of AD patients. Our research found that an activated Src family kinase, YES, phosphorylates Y53 in the J-domain of DNAJB6b and enhances the binding between DNAJB6b and Hsp70. The strengthened association between DNAJB6b and Hsp70 may lead to the accumulation of tau aggregates. These findings suggest that up-regulation of YES kinase modifies DNAJB6b and that the resulting alteration in DNAJB6b-dependent tau disaggregation may contribute to an increased risk of AD.},
}
@article {pmid42498307,
year = {2026},
author = {Nelson, F},
title = {China has banned an unproven Alzheimer's operation and detained its inventor, but international clinical trials of dcLVA are still going ahead-why?.},
journal = {BMJ (Clinical research ed.)},
volume = {394},
number = {},
pages = {e100302},
doi = {10.1136/bmj-2026-100302},
pmid = {42498307},
issn = {1756-1833},
}
@article {pmid42498430,
year = {2026},
author = {Desai, KM and Thakkar, MD and Somaiya, TS and Thomas, DC},
title = {Neurodegenerative Diseases and Sleep Disorders: The Bidirectional Relationship.},
journal = {The Medical clinics of North America},
volume = {110},
number = {5},
pages = {889-905},
doi = {10.1016/j.mcna.2025.12.001},
pmid = {42498430},
issn = {1557-9859},
mesh = {Humans ; *Sleep Wake Disorders/diagnosis/complications/etiology/therapy/physiopathology ; *Neurodegenerative Diseases/complications/diagnosis/physiopathology ; Parkinson Disease/complications ; },
abstract = {Neurodegeneration is mostly irreversible and progressive. Neurodegenerative diseases (NDDs) represent a large group of disorders that have varied clinical and pathologic representations. These include Alzheimer's disease, Parkinson's disease, vascular dementia, and amyotrophic lateral sclerosis, among others. A common factor in all these NDDs is sleep disorders (SDs). NDDs and SDs are bidirectional. Screening for SDs should be an integral part of a workup of NDDs. Management of one can improve the prognosis of the other.},
}
@article {pmid42498651,
year = {2026},
author = {Lee, SH and Jung, W and Park, M and Cho, H and Cho, H and Oh, HS and Joo, B and Ahn, SJ and Lyoo, CH and Suh, SH},
title = {Development and Validation of a Machine Learning Classification Algorithm for Differentiating Frontotemporal Dementia from Alzheimer's Disease Using Automated Brain MRI Volumetry.},
journal = {AJNR. American journal of neuroradiology},
volume = {},
number = {},
pages = {},
doi = {10.3174/ajnr.A9546},
pmid = {42498651},
issn = {1936-959X},
abstract = {BACKGROUND AND PURPOSE: Frontotemporal dementia (FTD) is characterized by frontal and anterior temporal lobe atrophy and progressive changes in behavior, executive function, or language, and its clinical and imaging presentations may overlap with Alzheimer's disease (AD), complicating differential diagnosis. This study aimed to develop and validate a classification algorithm using automated brain volumetry to differentiate FTD from AD and cognitively normal (CN) individuals, incorporating asymmetry indices, external validation in a real-world clinical setting, and a radiologist reader study to assess clinical utility.<br><br>MATERIALS AND METHODS: This study included 758 subjects (FTD = 142, AD = 216, CN = 400) from the NIFD and ADNI databases for training and internal validation, and 89 subjects (FTD = 18, AD = 24, CN = 47) from a tertiary hospital for external validation. Automated brain volumetry was obtained from 3D T1-weighted MRI using deep learning, and regional volumes were normalized to intracranial volume with age- and sex-adjusted z-scores. Volumetric features were grouped into frontal, medial, and lateral regions, with left-right and anteroposterior asymmetry indices. An XGBoost classifier was trained using these features and MMSE scores to distinguish FTD, AD, and CN. A reader study assessed diagnostic performance and interpretation time with and without algorithm assistance.<br><br>RESULTS: The classifier achieved 91.40% accuracy, 87.02% sensitivity, 95.09% specificity, and an AUC of 95.41% in the internal validation cohort, using a feature set that included frontal, medial, and lateral regional volumes, asymmetry metrics, and residual-based ICV normalization. External validation yielded 88.80% accuracy, 82.87% sensitivity, 94.41% specificity, and an AUC of 92.94%. FTD-specific sensitivity and specificity in the external validation cohort were 61.07% (95% CI, 38.45-84.01) and 97.13% (95% CI, 92.86-100.00), respectively. Among experienced readers, accuracy was maintained, with a significant reduction in reading time (p < 0.001) when assisted by the algorithm. For the underexperienced reader, accuracy improved without a significant change in interpre tation time (p = 0.786).<br><br>CONCLUSIONS: The automated brain volumetry model demonstrated promising diagnostic accuracy for FTD and supported by asymmetry-based feature engineering, real-world external validation, and a radiologist reader study, may serve as a useful adjunct for differentiating FTD from AD and normal aging.},
}
@article {pmid42498669,
year = {2026},
author = {McDiarmid, A},
title = {Sustaining Drug Discovery Amid the Limits of Alzheimer's Disease Immunotherapies.},
journal = {eNeuro},
volume = {13},
number = {7},
pages = {},
doi = {10.1523/ENEURO.0112-26.2026},
pmid = {42498669},
issn = {2373-2822},
mesh = {Humans ; *Alzheimer Disease/therapy/immunology/drug therapy ; *Immunotherapy/methods ; *Drug Discovery ; Animals ; Amyloid beta-Peptides/metabolism ; },
abstract = {Accumulation of insoluble extracellular amyloid-β (Aβ) plaques and intraneuronal fibrillary hyperphosphorylated tau fibrils in the brain are widely believed to contribute to the progressive neurodegeneration and neuronal loss characteristic of the Alzheimer's disease and the associated dementia. Anti-amyloid immunotherapies that reduce cerebral Aβ burden in affected individuals have been approved based on biological outcomes from clinical trials. However, the extent to which Aβ clearance translates into improved meaningful clinical, cognitive, and functional benefit versus risk and cost is unclear based on available data. Here, the critical barriers that limit the impact of anti-amyloid immunotherapies, including aducanumab, lecanemab, and donanemab, are discussed. Treatment slows cognitive decline by ∼20-30% in certain patient subsets, but absolute improvements in cognitive and functional outcomes remain modest. Independent analyses of how treatment impacts health span suggests statistically significant trial results may not translate into significant real-world benefit. Response is most significant in cases of early-stage disease where levels of copathology tau are low. Edema and brain hemorrhage occur frequently, particularly in carriers of APOE-e4 alleles, an established genetic risk factor for Alzheimer's disease, raising safety concerns which led to some regulators banning treatment in this patient group. Strict clinical trial eligibility criteria, high treatment costs relative to patient benefit, intensive during-treatment monitoring, and the absence of population-level screening programs further limit treatment accessibility and generalizability. Emerging evidence of accelerated brain atrophy and immunotherapy tolerance further complicates benefit-risk consultation. Sustaining drug- discovery pipelines by exploring combination therapies, tau-targeted approaches, drug repositioning, and novel small molecules through will be essential to provide comprehensive treatment options and personalized treatment plans for affected patients.},
}
@article {pmid42498696,
year = {2026},
author = {Freije García, F and Martínez-Fernandez, C and Griñán Ferré, C and García Liñares, G},
title = {Sustainable Synthesis of 3-(1H-Indol-3-yl)propionic Acid Derivatives with Anti-Alzheimer Activity.},
journal = {ChemMedChem},
volume = {21},
number = {14},
pages = {e70395},
doi = {10.1002/cmdc.70395},
pmid = {42498696},
issn = {1860-7187},
support = {//Secretar&#xed;a de Ciencia y T&#xe9;cnica, Universidad de Buenos Aires/ ; PIP11220210100072//Consejo Nacional de Investigaciones Cient&#xed;ficas y T&#xe9;cnicas/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Indoles/chemistry/pharmacology/chemical synthesis/metabolism ; *Propionates/chemistry/chemical synthesis/pharmacology/therapeutic use ; Caenorhabditis elegans/drug effects ; Structure-Activity Relationship ; Lipase/metabolism ; Molecular Structure ; Dose-Response Relationship, Drug ; *Neuroprotective Agents/chemical synthesis/pharmacology/chemistry ; },
abstract = {A biocatalytic approach was applied to synthesizing esters and amides derived from 2-(1H-indol-3-yl)acetic (IAA), 3-(1H-indol-3-yl)propionic (IPA), and 4-(1H-indol-3-yl)butanoic (IBA) acids. Thirty-seven derivatives were obtained through lipase catalysis in mild reaction conditions with good to excellent yields and a reduced environmental impact. The scope of the reaction was explored in terms of enzyme source, solvent, temperature, substrate-to-nucleophile and enzyme-to-substrate ratios, and substrate versatility. Ten representative derivatives were evaluated as potential anti-Alzheimer's disease (AD) agents using Caenorhabditis elegans models. Among them, octyl 3-(1H-indol-3-yl)propanoate (6e), N-butyl-3-(1H-indol-3-yl)propanamide (10a), and (S)-N-(2-hydroxypropyl)-3-(1H-indol-3-yl)propanamide (13c) emerged as the most promising candidates, demonstrating significant improvements in AD pathology, including enhanced locomotion and mitochondrial function. In addition, the obtained compounds showed no toxicity in Vero cells, making them potential lead drug candidates.},
}
@article {pmid42498697,
year = {2026},
author = {Makhaeva, GF and Astakhova, TY and Grishchenko, MV and Shteinberg, TS and Kovaleva, NV and Boltneva, NP and Rudakova, EV and Pronkin, PG and Timokhina, EN and Radchenko, EV and Shchegolkov, EV and Burgart, YV and Saloutin, VI and Charushin, VN and Richardson, RJ},
title = {Influence of N-Functionalization of Amiridine on the Biological Activity of Its Conjugates as Multitarget Agents for Potential Treatment of Alzheimer's Disease.},
journal = {ChemMedChem},
volume = {21},
number = {14},
pages = {e70392},
doi = {10.1002/cmdc.70392},
pmid = {42498697},
issn = {1860-7187},
support = {24-63-00016//Russian Science Foundations/ ; },
mesh = {*Alzheimer Disease/drug therapy/metabolism ; Amyloid beta-Peptides/metabolism/antagonists &amp; inhibitors ; *Cholinesterase Inhibitors/chemistry/pharmacology/chemical synthesis ; Acetylcholinesterase/metabolism ; Butyrylcholinesterase/metabolism ; Humans ; Peptide Fragments/metabolism/antagonists &amp; inhibitors ; Structure-Activity Relationship ; Molecular Structure ; Molecular Docking Simulation ; Imines/chemistry ; },
abstract = {The goal of this mechanistic study was to elucidate the influence of N-functionalization of amiridine on the biological properties of its conjugates. We synthesized conjugates of amiridine and salicylimine/amine 9, 10 with linkers containing an N-acyl group at the amiridine fragment as analogs of our previously obtained hybrids 1, 2 containing an N-aminohexamethylene spacer. A comparative study of selected biological activities of N-acylalkylene conjugates 9, 10 with conjugates 1, 2 showed substantial decreases in anti-butyrylcholinesterase (BChE) activity (35-fold for the imine and 8-fold for the amine), loss of anti-acetylcholinesterase (AChE) activity, and disappearance of the ability to block amyloid beta (1-42) (Aβ42) self-aggregation. Similar effects were observed for the model compound N-hexylamiridine 3 and its N-acyl derivative 11. However, N-acyl functionalization at the amiridine pharmacophore did not reduce the ability of the conjugates to block AChE-induced β-amyloid aggregation and only slightly decreased their antiradical activity, maintaining the higher activity of amines compared to imines. These effects were consistent with results from quantum mechanical calculations and molecular docking, showing that N-acylation of amiridine decreased the proton affinity of its endocyclic N-atom. Consequently, the amiridine pharmacophore was essentially unprotonated, thereby diminishing the anticholinesterase activity of conjugates 9 and 10 and their ability to block Aβ42 self-aggregation.},
}
@article {pmid42498782,
year = {2026},
author = {Liu, Y and Hägg, S and Brikell, I and Chang, Z and Kuja-Halkola, R and D'Onofrio, BM and Larsson, H and Lichtenstein, P and Pettersson, E},
title = {Associations of general and specific psychopathology factors by age 35 with dementia after age 50: a Swedish population-based sibling comparison study.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42498782},
issn = {1476-5578},
support = {2023-01999//Vetenskapsr&#xe5;det (Swedish Research Council)/ ; STY-2023/0008//Forskningsr&#xe5;det om H&#xe4;lsa, Arbetsliv och V&#xe4;lf&#xe4;rd (Swedish Research Council for Health, Working Life and Welfare)/ ; FO2024-0067//Hj&#xe4;rnfonden (Swedish Brain Foundation)/ ; },
abstract = {Multiple psychiatric disorders are associated with later dementia, but it remains unclear whether these associations reflect a shared liability toward all psychiatric conditions (general psychopathology factor) or diagnosis-specific effects (specific psychopathology factors). In this Swedish register-based cohort study, we investigated these questions while adjusting for familial confounding shared by siblings (N = 2 543 621 individuals, 1 485 880 full-sibling pairs). Exposures were (i) six psychiatric diagnoses recorded by age 35 and (ii) a latent bifactor model fit to these diagnoses that identified one general and three specific (internalizing, externalizing, and psychotic) psychopathology factors. Outcomes were all-cause dementia and Alzheimer's disease recorded after age 50. For observed psychiatric diagnoses, we estimated between-individual (HR) and within-sibling hazard ratios (HRwn) using Cox regression; for latent factors, we estimated between-individual (OR) and within-sibling odds ratios (ORwn) using exploratory structural equation modelling. All psychiatric diagnoses were significantly associated with increased risk of all-cause dementia (HR range 2.03-3.59; HRwn range 1.72-2.94) and Alzheimer's disease (HR range 1.89-3.47; HRwn range 1.77-3.22). These associations were largely attributable to the general psychopathology factor, even after adjusting for familial confounding (ORwn with 95% CI: 1.25 [1.17-1.32] for dementia; 1.24 [1.16-1.32] for Alzheimer's disease). After accounting for the general factor, only the psychotic-specific factor remained associated (ORwn with 95% CI: 1.20 [1.07-1.36] for dementia; 1.20 [1.06-1.37] for Alzheimer's disease). These results suggest that liability toward general psychopathology and, independently, psychotic conditions, by early adulthood might be early markers of increased dementia risk and targets for timely identification and prevention.},
}
@article {pmid42498931,
year = {2026},
author = {Stackhouse, TL and Marxmiller, BD and Sullivan, SJ and McConnell, HL and Knittel, LM and De La Torre, R and Houser, A and Ismail, O and Zhang, W and Woltjer, RL and Mishra, A},
title = {Mild Subcortical Stroke Induces Widespread Chronic Reactive Astrogliosis That Is Largely Unaffected by Microglia and Age.},
journal = {ASN neuro},
volume = {18},
number = {1},
pages = {2702948},
doi = {10.1080/17590914.2026.2702948},
pmid = {42498931},
issn = {1759-0914},
mesh = {Animals ; *Microglia/pathology/physiology ; *Gliosis/pathology/etiology ; *Astrocytes/pathology ; *Aging/pathology ; Disease Models, Animal ; Male ; *Stroke/pathology/complications ; Mice, Inbred C57BL ; Mice ; Infarction, Middle Cerebral Artery/pathology/complications ; *Brain/pathology ; Glial Fibrillary Acidic Protein/metabolism ; },
abstract = {Ischemic stroke induces a plethora of pathophysiological changes, including neuroinflammation and chronic cerebrovascular dysfunction. In humans, even small, silent strokes can trigger these pathologies, which can spread to brain regions far beyond the infarct and persist chronically, ultimately worsening prognosis and increasing the risk for vascular dementia and Alzheimer's disease. The cause of this pathology is unknown, but reactive astrocytes and microglia are likely contributors. Here, we describe an optimized short-duration middle cerebral artery occlusion model that produces a clinically relevant small stroke mostly confined to subcortical regions, similar to many silent strokes in humans. We termed this model the mild subcortical infarct (MSCI). We then mapped the spatiotemporal extent of reactive astrocytes and microglia during the sub-acute period (1, 3, and 7 days) following MSCI. We observed that reactive astrogliosis develops more rapidly and spreads more extensively, compared to the reactive microglia response following this small infarct. Microglial depletion resulted in larger infarct sizes but did not prevent reactive astrocytes. Aging mice exposed to MSCI exhibited a comparably strong response of reactive astrocytes and microglia as young mice. Lastly, reactive astrocytes persisted for at least nine months after MSCI. We propose that this mild ischemia model is valuable for examining the chronic effects of subcortical stroke. It may be especially useful for investigating the functional impact of reactive astrogliosis in regions distal from the primary injury site.},
}
@article {pmid42498936,
year = {2026},
author = {Poffenberger, CN and Taylor, MM and Larson, K and Mufson, EJ and Dixon, KJ},
title = {Inhibition of Soluble TNF Mitigates Traumatic Brain Injury as a Risk Factor for the Development of Amyloidogenic Proteins and Functional Deficits in 3xTg-AD Mice.},
journal = {Journal of neurotrauma},
volume = {},
number = {},
pages = {8977151261469044},
doi = {10.1177/08977151261469044},
pmid = {42498936},
issn = {1557-9042},
abstract = {Traumatic brain injury (TBI) is a well-known risk factor for dementia with Alzheimer's disease (AD), and there are no known therapies that can mitigate this risk. Pre-clinical studies demonstrate a temporary upregulation of amyloid beta (Aβ) and corresponding neurological dysfunction following TBI with little-to-no studies developing interventions to prevent this pathophysiology. The pro-inflammatory cytokine tumor necrosis factor (TNF) has been shown to promote the development of AD, and here we investigate whether a clinically relevant biologic known as XPro1595 that neutralizes soluble TNF (solTNF) can mitigate TBI as a risk factor for the development of amyloidogenic proteins and corresponding neurological dysfunction. Following a single controlled cortical impact model of TBI or sham-injury, adult male 3xTg-AD mice were treated acutely with either XPro1595, a dominant-negative protein that neutralizes soluble TNF (10 mg/kg, S.C.), or vehicle solution. Between 6 h and 1 month post-injury (MPI), levels of cytokines, inflammatory markers, and AD-related proteins were evaluated in the ipsilateral hippocampus. Additionally, animals were behaviorally tested for deficits in cognition (learning and memory), as well as hindpaw mechanical hypersensitivity. TBI induced a significant increase in TNF (ELISA, 6 h) and TNFR1 (Western blot, 3 days post-injury [DPI]) expression, which correlated with an increase in BACE1, Aβ42, and caspase-3 at 3 and 7 DPI. Significant deficits in cognition and mechanical hypersensitivity were found at 7 DPI with similar trends at 1 MPI. In comparison, injured mice treated with XPro1595 had improvements in cognition and mechanical hypersensitivity (cf. vehicle-treated injured mice) and did not have these same increases in BACE1, Aβ42, and caspase-3 (levels were similar to sham-injured mice), likely by increasing NF-κB deactivation (pNF-κB [p65; Ser468]), indicative of a reduced inflammatory response. Overall, treatment with XPro1595 following TBI prevented the development of amyloidogenic proteins and corresponding neurological dysfunction. Clinically, these data support the use of XPro1595 as a clinically relevant therapeutic for patients with TBI to mitigate the risk of increased Aβ levels and neurological decline subacutely post-injury.},
}
@article {pmid42499147,
year = {2026},
author = {Ourry, V and Wagner, M and Groot, C and Boyle, R and Vogel, JW and Bartrés-Faz, D and Villeneuve, S},
title = {Theoretical and practical challenges for capturing reserve and resilience in aging and Alzheimer's disease: A narrative review.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71664},
doi = {10.1002/alz.71664},
pmid = {42499147},
issn = {1552-5279},
support = {//Canadian Institutes of Health Research (CIHR)/ ; //the J.-Louis L&#xe9;vesque Foundation/ ; //Brain Canada Foundation and a joint Alzheimer's Society Canada and Brain Canada Research/ ; 325497//the Fonds de Recherche du Qu&#xe9;bec-Sant&#xe9;/ ; KAW2020-0239//SciLifeLab &amp; Wallenberg Data Driven Life Science Program/ ; 2024-03642//Swedish Research Council/ ; StG-101221737/ERC_/European Research Council/International ; 2024//ICREA Academia Grant/ ; PID2022-137234OB-100//ICREA Academia Grant/ ; 10.13039/501100011033//MICIU/AEI/ ; /AG/NIA NIH HHS/United States ; /NH/NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/psychology/physiopathology ; *Aging/psychology/physiology ; *Cognitive Reserve/physiology ; *Resilience, Psychological ; Brain/physiopathology ; },
abstract = {The concepts of reserve and resilience in aging and Alzheimer's disease (AD) are widely used but their operationalization remains challenging and often lacks conceptual and methodological consistency. In this narrative review, we describe the chronological history of these concepts and then summarize and discuss key theoretical and practical issues, along with proposed solutions and different perspectives, in the context of aging and AD. Theoretical challenges include risk versus protective factors, dynamic brain and cognitive trajectories, overestimation of resilience and inflection points. Practical challenges include proxy measures, study designs, residual approaches, and influential cases. We highlight the need for greater methodological harmonization, improved validation of proxy, and lifespan longitudinal approaches. Addressing these challenges will strengthen interpretability, reproducibility, and causal inference, ultimately facilitating the translation of reserve and resilience research into preventive and therapeutic strategies.},
}
@article {pmid42499341,
year = {2026},
author = {Singh, B and Pigazzani, F and Manfredini, R},
title = {Circadian rhythms and chronotherapy in Alzheimer's disease: Mechanisms and therapeutic implications.},
journal = {Neuroprotection (Chichester, England)},
volume = {},
number = {},
pages = {},
pmid = {42499341},
issn = {2770-730X},
abstract = {Alzheimer's disease (AD), the most prevalent form of dementia, has been increasingly associated with disruptions in circadian rhythms and sleep-wake regulation. This narrative review synthesizes recent literature on how circadian dysfunction may contribute to AD pathogenesis, biomarker profiles, and treatment response. Mechanistic studies suggest important interactions between core clock genes and neurodegenerative cascades involving oxidative stress, neuroinflammation, glial reactivity, and proteostasis. Disruptions in circadian-regulated molecular pathways, including brain and muscle ARNT-like 1 (BMAL1)-sirtuin 1 (SIRT1), nuclear factor kappa B (NF-κB)-NOD-like receptor family pyrin domain containing 3 (NLRP3), and period circadian regulator 2 (PER2)-antioxidant signaling pathways, may compromise neuronal resilience and worsen AD-related pathology. Emerging evidence also suggests distinct circadian patterns in AD-relevant biomarkers, including melatonin, cortisol, orexin, core body temperature, blood-brain barrier permeability, and glial marker oscillations. These rhythmic patterns may have diagnostic and prognostic relevance and support the need for time-aware biomarker interpretation. Chronotherapeutic strategies targeting circadian biology, including melatonin receptor agonists, light therapy, time-restricted feeding, and circadian-aligned drug delivery systems, may help improve targeted clinical endpoints in AD. This review also discusses chronoepigenetics as an emerging area in which clock-regulated epigenetic modifications may influence neurodegenerative trajectories. Future directions include next-generation chronotherapeutic targets, such as glial clocks, clock-gated inflammatory mechanisms, and systemic comorbidities with circadian modulation, including diabetes and hypertension. Overall, the available evidence supports a close association between circadian disruption and both AD pathology and therapeutic response, while also highlighting important gaps in large-scale clinical trials. This time-oriented perspective may support the development of personalized, biomarker-guided, and rhythm-informed approaches to AD care. By bridging chronobiology and neurodegeneration, this review highlights how circadian precision medicine may refine future approaches to understanding and managing AD.},
}
@article {pmid42499412,
year = {2026},
author = {Kemp, AM},
title = {A community-based model for multimodal brain-health screening and Alzheimer's disease and related dementia risk prediction in mid-sized cities and surrounding rural communities: a mixed-methods evaluation.},
journal = {Innovation in aging},
volume = {10},
number = {8},
pages = {igag060},
pmid = {42499412},
issn = {2399-5300},
abstract = {BACKGROUND AND OBJECTIVES: Rural adults (those residing in nonmetropolitan counties) face persistent barriers to brain-health assessment that may help prevent or delay cognitive decline. This study reports protocol and pilot feasibility findings from year 1 of a 3-year longitudinal project evaluating Building a Rural Aging and Intervention Network: Factors that Impact Trajectories (BRAIN-FIT), a community-embedded program to improve access to multidomain screening and awareness of modifiable dementia risk factors.<br><br>RESEARCH DESIGN AND METHODS: Using a mixed-methods design, 119 adults aged 45 or older completed a single-day interdisciplinary screening incorporating clinical-standard measures (cardiovascular, physical, lifestyle, social-emotional, sensory, cognitive, and speech-language health), followed by individualized-results review. 63 participants completed a 4-week post-event behavior change evaluation.<br><br>RESULTS: BRAIN-FIT, delivered across 7 community sites in 3 cities through 18 events, enrolled 163 adults (aged 46-95; M&#x2009;=&#x2009;67.5) with socioeconomic and clinical heterogeneity. Engagement was strong: 119 consented to longitudinal participation, 95% completed all stations and rated the program highly feasible (3.7-4.4 out of 5). Screening identified prevalent modifiable risk factors: elevated cardiometabolic indicators, reduced physical endurance, sleep disturbance, and sensory impairment. Cognitive and language performance remained largely within functional limits, suggesting engagement during a preventive window.<br><br>DISCUSSION AND IMPLICATIONS: Community-embedded multimodal screening appears to be a viable program for identifying actionable brain-health risk prior to substantial decline. By reaching diverse adults outside traditional care pathways, BRAIN-FIT advances a pragmatic population-health approach to dementia prevention. Longitudinal follow-up will evaluate sustained behavior change, strengthen referral integration, and inform hybrid effectiveness-implementation trials to promote healthier aging trajectories.},
}
@article {pmid42499414,
year = {2026},
author = {Mohammed, W and Al Ameri, M and Al Marzooqi, S and Alsafar, H and Olbrich, R and Mousa, M and Barayan, D and Magalhaes, T and Quilez, J and Reche, J and Alkaf, B and Shatila, A and Marzouka, NAD and Iqbal, I and Yousif, A and Rahma, A and Al Mannaie, A},
title = {Landscape of Apolipoprotein (APOE) in the Emirati Population and Recommendations for a Genotyping Approach for Amyloid-Beta Monoclonal Antibodies (Aβ-mAbs) in Alzheimer's Disease Patients.},
journal = {Cureus},
volume = {18},
number = {7},
pages = {e113196},
pmid = {42499414},
issn = {2168-8184},
abstract = {BACKGROUND: Apolipoprotein E (APOE) genotyping is increasingly recognized as a biomarker to support treatment decisions for Alzheimer's disease (AD) with the introduction of anti-amyloid monoclonal antibodies as promising therapeutic options. Although not yet incorporated into formal pharmacogenomic guidelines, regulatory authorities acknowledge its potential role in advancing precision medicine approaches.<br><br>METHODS: We reviewed AD cases diagnosed in 2024 from the Department of Health - Abu Dhabi records and assessed monoclonal antibody prescribing patterns. APOE genotypes were determined using the two defining variants, APOE rs429358 and rs7412, using whole-genome sequencing data from 506,734 participants enrolled in the Emirati Genome Program.<br><br>RESULTS: In 2024, 1,285 individuals were diagnosed with AD. Aducanumab was prescribed to eight patients between 2022 and 2024. In the Emirati Genome Program cohort, the allele frequencies of rs429358 and rs7412 were 8.3% and 4.2%, respectively. The most prevalent APOE genotype was &#x3b5;3/&#x3b5;3 (77.9%). The APOE &#x3b5;4 risk allele was observed in 14.7% of participants, including 0.9% who were homozygous for &#x3b5;4, while the protective APOE &#x3b5;2 allele was present in 7.5%.<br><br>CONCLUSION: APOE profiling supports genotype-informed treatment strategies for anti-amyloid therapies. These findings establish a population-specific framework for integrating genetic information into the Emirati Genome Program pharmacogenomic report, enhancing precision medicine approaches for AD management in the UAE.},
}
@article {pmid42499533,
year = {2026},
author = {Shaer, NA and Al-Abbas, NS},
title = {In silico dysbiosis-associated neuroprotective metabolite insufficiency in Alzheimer's disease.},
journal = {Open medicine (Warsaw, Poland)},
volume = {21},
number = {1},
pages = {20261484},
pmid = {42499533},
issn = {2391-5463},
abstract = {Perturbation of oral and gut microbiomes has been implicated in alzheimer's disease (AD) along the oral-gut-brain axis; however, the extent of global community restructuring may differ between niches. The present work constitutes a computational interrogation of 16S rRNA profiles from eight-month-old APP/PS1 and wild-type mice, characterizing oral and gut community structure and predicted functional capacity through PICRUSt-driven, KEGG-anchored pathway inference. Comparative taxonomic interrogation disclosed patterns consistent with ectopic occurrence, whereby classically oral genera (Fusobacterium, Streptococcus) were preferentially enriched within intestinal assemblages and gut-typical genera (Muribaculum, Paramuribaculum) emerged as prominent constituents of the oral microbiota in APP/PS1 mice. These cross-niche enrichment patterns, together with significant oral community separation but non-significant gut beta-diversity separation by ANOSIM, were accompanied by predicted decrements in 85 orally enriched enzymes distributed across 25 KEGG pathways, approximately 40 % of which were associated with the biosynthesis of metabolites with reported neuroprotective properties, including glutathione, acetyl-CoA, succinate, malate, formate, lactate, acetate, and monoterpenoids. Systems-level synthesis of these predictions indicated convergent perturbation of antioxidant defenses, bioenergetic circuitry, and one-carbon metabolism, plausibly reflecting metabolic choke points that may favor cognitive deterioration. Although the oral microbiome showed significant inter-cohort separation, the gut microbiome did not, indicating that gut changes are best viewed as taxon-specific shifts within an otherwise stable community. These observations support a hypothesis-generating framework in which oral dysbiosis, selective gut alterations, and cross-niche enrichment patterns are linked to computationally inferred neuroprotective metabolite insufficiency, highlighting specific taxa, enzymes, and pathways as candidates for biomarker and microbiome-targeted therapeutic development in AD.},
}
@article {pmid42491893,
year = {2026},
author = {Munipalli, UMR and Annepu, V},
title = {A deep residual attention-Recurrent model for early and multi-stage Alzheimer's disease detection.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1798861},
pmid = {42491893},
issn = {1663-4365},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder that requires accurate and early diagnosis. Deep learning methods have shown significant potential for automated MRI-based AD classification.<br><br>METHODS: A hybrid deep learning framework integrating ResNet152V2, Convolutional Block Attention Module (CBAM), and Bidirectional Gated Recurrent Unit (Bi-GRU) was developed for three-class classification of Normal Cognition (NC), Mild Cognitive Impairment (MCI), and Alzheimer's Disease (AD). The model was trained using 2,100 ADNI subjects and externally validated using 900 OASIS subjects.<br><br>RESULTS: The proposed framework achieved 94.5% classification accuracy with an AUC of 95.0% on the ADNI dataset and 92.8% accuracy on the OASIS dataset. Comparative analyses demonstrated improvements of 5.2-7.0% over baseline models. Ablation studies confirmed the contribution of CBAM and Bi-GRU to overall performance.<br><br>DISCUSSION: The integration of deep residual feature extraction, attention-based refinement, and sequential modeling effectively captures disease-related anatomical patterns. The results suggest that the proposed framework may support automated multi-stage Alzheimer's disease classification and provide a foundation for future computer-aided diagnostic systems.},
}
@article {pmid42492000,
year = {2026},
author = {de Oliveira, AM and Vanetti, CLR and Alencar, F and da Conceição, ASGG and Martinez, LD and Sant Ana, LCFG and Carvalho, CL and Mattar, GP and Leduc, V and Cecilio, APA and de Almeida, VN and da Silva, MFR and Gonçalves, OR and Varotto, BLR and Serelli, LDS and Teixeira, EPPB and Forlenza, OV},
title = {Adaptation of the Direct Assessment of Functional Status (DAFS):a new tool to assess functional changes in people with Down syndrome.},
journal = {Dementia &amp; neuropsychologia},
volume = {20},
number = {},
pages = {e20250415},
pmid = {42492000},
issn = {1980-5764},
abstract = {UNLABELLED: Functional decline in activities of daily living (ADL) is considered a marker of ageing and Alzheimer's disease. However, there is a lack of performance-based instruments specifically designed to assess ADL in adults and older adults with Down syndrome.<br><br>OBJECTIVE: To describe the adaptation process of the Direct Assessment of Functional Status (DAFS) to assess the functional capacity of adults with Down syndrome.<br><br>METHODS: The Direct Assessment of Functional Status-Brazilian Version (DAFS-BR) was administered to 15 adults with Down syndrome (nine men and six women) who were divided into two diagnostic groups: stable cognition and suspected dementia or cognitive impairment. The process was conducted in two phases: phase one was characterized by an adaptation in the tasks. In phase two, (cultural and semantic) equivalences were verified, as well as structural aspects, including layout and instructions. This phase was essential for verifying the applicability and comprehensibility of newly adapted tasks.<br><br>RESULTS: The DAFS-BR was adapted for the time orientation, communication (telephone use), moneyhandling skills, and shopping skills domains, considering the target population.<br><br>CONCLUSION: The adaptation process of the DAFS-BR for people with Down syndrome was made considering linguistic, psychological, and cultural idiosyncrasies in the target population, with the input of experts with relevant experience in each domain. After psychometric studies, the Direct Assessment of Functional Status-Down Syndrome (DAFS-DS) could be considered the first ecological instrument for evaluating functional status in adults with Down syndrome in Brazil to enhance both clinical practice and research.},
}
@article {pmid42492030,
year = {2026},
author = {Turner, RS},
title = {Clinical Trial Outcomes in the Alzheimer's Disease Spectrum: What Should We Measure?.},
journal = {Neurology},
volume = {107},
number = {4},
pages = {e218468},
doi = {10.1212/WNL.0000000000218468},
pmid = {42492030},
issn = {1526-632X},
}
@article {pmid42492033,
year = {2026},
author = {Li, C and Fu, M and Berg, K and Wallach, J and Ling, K and Wei, R and Shi, L and Ross, J and Guan, X},
title = {Efficacy Measures Used in Alzheimer Disease Clinical Trials Between 2015 and 2025: A Systematic Review.},
journal = {Neurology},
volume = {107},
number = {4},
pages = {e218373},
doi = {10.1212/WNL.0000000000218373},
pmid = {42492033},
issn = {1526-632X},
mesh = {*Alzheimer Disease/drug therapy ; Humans ; *Clinical Trials as Topic ; *Outcome Assessment, Health Care ; Cognitive Dysfunction/drug therapy ; Treatment Outcome ; Biomarkers ; },
abstract = {BACKGROUND AND OBJECTIVES: Regulatory guidance has long emphasized clinically meaningful outcomes in Alzheimer disease (AD) drug trials. No contemporary review has examined the efficacy measures used for clinical trials of AD therapies. The objective of this study was to evaluate the clinical relevance and heterogeneity of efficacy measures used in phase II-IV AD drug trials over the past decade.<br><br>METHODS: We systematically searched PubMed, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov. All phase II-IV clinical trials of pharmacologic therapies in individuals with mild cognitive impairment due to AD or mild-to-moderate AD that were published, completed, or terminated between January 1, 2015, and November 15, 2025, or still ongoing as of November 15, 2025, were eligible for inclusion. We summarized the proportion of trials using clinical outcomes or biomarkers as primary or secondary efficacy measures, key clinical domains addressed, and the number of distinct measures using descriptive statistics. This study is registered with PROSPERO (CRD420251032087).<br><br>RESULTS: Among 238 included trials, 95.4% (227/238) used at least one clinical outcome and 73.5% (175/238) used at least one biomarker as efficacy measures. Cognitive abilities (87.0%, 207/238), global status (76.9%, 183/238), and functional ability (71.4%, 170/238) were the most frequently measured clinical domains, whereas patient (16.0%, 38/238) and caregiver (8.8%, 21/238) quality of life and significant disease-related life events (2.5%, 6/238) were less frequent. Only 21.8% (52/238) of trials adopted regulatory-recommended co-primary measures of cognition with either function or global status, whereas 8.4% (20/238) used biomarkers as the sole primary efficacy measure. We identified 318 distinct clinical outcome measures and 219 distinct biomarkers used across all trials, 6.9% (22/318) and 6.8% (15/219) of which were used in more than 5% of trials.<br><br>DISCUSSION: Efficacy measures in AD drug trials primarily focused on cognition, global status, and functional outcomes, which are important indicators of AD progression. However, other clinical domains that may also be meaningful to patients and caregivers were far less frequently assessed, while biomarker use is widespread. Substantial heterogeneity in efficacy measure use limits comparability across trials and highlights the need for standardized, consensus-based, clinically meaningful core measure sets for AD drug trials.},
}
@article {pmid42492268,
year = {2026},
author = {Luo, S and Guo, J and Xu, J and Song, J and Dai, Y and Xu, S},
title = {Natural polysaccharides as multi-target therapeutic candidates for Alzheimer's disease: Mechanisms, structure-activity relationships, and translational perspectives.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {159},
number = {},
pages = {158585},
doi = {10.1016/j.phymed.2026.158585},
pmid = {42492268},
issn = {1618-095X},
abstract = {BACKGROUND: Alzheimer's disease (AD) is increasingly recognized as a systems-level disorder involving amyloid-β (Aβ) deposition, tau pathology, oxidative stress, mitochondrial dysfunction, neuroinflammation, synaptic impairment, and microbiota-gut-brain axis dysregulation. Although previous reviews have summarized the anti-AD effects of natural polysaccharides according to individual pathological pathways, an integrated framework linking polysaccharide structure, gut microbial metabolism, peripheral immune regulation, and central AD pathology remains insufficiently developed.<br><br>PURPOSE: This review aims to provide an updated and integrative synthesis of natural polysaccharides as multi-target therapeutic candidates for AD, with particular emphasis on their mechanistic networks, structure-activity relationships, and translational potential.<br><br>METHODS: A systematic PubMed search was performed for studies published from January 1, 2016, to June 7, 2026. Eligible studies investigated natural polysaccharides as primary therapeutic interventions in in vivo AD models. Reviews, editorials, purely in vitro studies, studies using polysaccharides solely as drug-delivery carriers, synthetic derivatives, and inseparable compound formulations were excluded. Seventy-four original studies were included for mechanistic and structure-activity analyses.<br><br>RESULTS: Natural polysaccharides were found to regulate multiple interconnected AD-related processes, including A&#x3b2; production, aggregation, and clearance, tau phosphorylation, redox homeostasis, glial activation, inflammasome signaling, synaptic plasticity, cholinergic function, intestinal barrier integrity, gut microbiota composition, and short-chain fatty acid production. Unlike earlier pathway-based summaries, this review proposes a structure-microbiota-metabolite-barrier-inflammation-redox-brain pathology framework to explain how polysaccharide structural features may determine microbial utilization, metabolite generation, immune modulation, and downstream neuroprotective effects.<br><br>CONCLUSION: Natural polysaccharides represent promising multi-target candidates for AD prevention and treatment. Future studies should prioritize structurally defined polysaccharide fractions, causal microbiota validation, pharmacokinetic/pharmacodynamic profiling, biomarker-guided assessment, and rigorously designed clinical trials.},
}
@article {pmid42492404,
year = {2026},
author = {Yang, G and Du, Y and Hu, X and Shi, W and Yang, M and Wang, S and , },
title = {Taming arbitrary modality missingness and imbalance: A unified graph-MoE framework for Alzheimer's disease diagnosis.},
journal = {Medical image analysis},
volume = {113},
number = {},
pages = {104222},
doi = {10.1016/j.media.2026.104222},
pmid = {42492404},
issn = {1361-8423},
abstract = {Multimodal biomarkers hold significant potential for improving Alzheimer's disease (AD) diagnosis. However, existing multimodal learning methods typically rely on idealized assumptions of complete and balanced modality availability, which rarely hold in clinical practice. Real-world datasets are plagued by arbitrary modality missingness and, more critically, a long-tailed modality-combination imbalance stemming from hierarchical clinical protocols. These issues cause conventional models to be biased toward frequent combinations while failing on rare but diagnostically critical ones for early AD diagnosis. To address these challenges, we propose UniMIX-AD, a unified framework tailored for robust AD diagnosis under realistic, imperfect multimodal settings. UniMIX-AD integrates two core innovations: (i) a Unified Missing-modality Imputation (UMI) module that dynamically reconstructs representations of missing modalities by capturing cross-modal dependencies from any observed modality combination, ensuring comprehensive patient representations; and (ii) a Graph-coordinated Sparse Mixture-of-Experts (G-Sparse-MoE) that adaptively routes patients to specialized experts and facilitates structured knowledge transfer from frequent (head) to rare (tail) combinations, effectively alleviating the long-tailed modality-combination imbalance. Extensive experiments on the ADNI and OASIS-3 datasets demonstrate that UniMIX-AD consistently outperforms state-of-the-art methods, achieving a relative average accuracy improvement of 7.1% and a significant boost of up to 14.3% on tail modality combinations in ADNI.},
}
@article {pmid42492417,
year = {2026},
author = {Pilat, D and Baranger, K and Rivera, S},
title = {The multifaceted roles of IL-1β in Alzheimer's disease: From pathogenic amplifier to neuroimmune modulator.},
journal = {Cytokine &amp; growth factor reviews},
volume = {91},
number = {},
pages = {82-98},
doi = {10.1016/j.cytogfr.2026.07.004},
pmid = {42492417},
issn = {1879-0305},
abstract = {Alzheimer's disease (AD) is a progressive age-related neurodegenerative disorder and the most common form of dementia worldwide. Traditionally, its pathology has been defined by the presence of extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs), primarily composed of hyperphosphorylated tau (pTau), alongside widespread synaptic and neuronal loss. Despite decades of research, AD etiology remains only partially understood. While recent advances in amyloid-targeted therapies mark significant progress, most current approaches have fallen short of expectations. This gap has spurred the re-evaluation of the central mechanisms driving AD, with neuroinflammation emerging as a critical contributor rather than a mere bystander. Among the numerous inflammatory mediators implicated in AD, interleukin-1β (IL-1β) stands out for its dual role, associated with the exacerbation of pathological features but also with neuroprotective effects, including Aβ clearance and neuronal support. This apparent duality highlights the complexity of neuroinflammation in AD, suggesting that IL-1β can act as a context-dependent modulator, its effects shaped by factors such as timing, cellular origin, and disease stage. The purpose of this review is to summarize the evidence on IL-1β's role in AD pathophysiology and clarify its contribution to disease mechanisms and progression.},
}
@article {pmid42492469,
year = {2026},
author = {Hu, J and Wang, WX},
title = {Chronic lead exposure disrupts copper redox homeostasis and aggravates neurodegeneration.},
journal = {Environmental pollution (Barking, Essex : 1987)},
volume = {407},
number = {},
pages = {128818},
doi = {10.1016/j.envpol.2026.128818},
pmid = {42492469},
issn = {1873-6424},
abstract = {Lead (Pb) represents a critical environmental health concern due to its profound impact on neurodegenerative processes. However, its specific influence on copper (Cu) redox states and the associated neurotoxic mechanisms remain inadequately understood. In this study, male wild-type C57BL/6 and 5xFAD Alzheimer's disease (AD) model mice were used to investigate how chronic low-dose Pb exposure (200 μg/L via drinking water) exacerbated AD-related pathology through perturbation of Cu homeostasis. Elemental analysis revealed that Pb exposure depleted essential cerebral metals, including Ca, Mg, Fe, and Zn. In contrast to these metals, Cu showed concurrent accumulation in both the brain and bloodstream, particularly in the ADPb group, consistent with disturbed Cu homeostasis in the AD background. In situ fluorescent imaging demonstrated that Pb exposure significantly disrupted the Cu(I)/Cu(II) valence balance within the hippocampus. While the unexposed AD brain showed relatively higher Cu(I) signals, Pb exposure shifted the fluorescence pattern toward Cu(II). Behavioral assessments further indicated that Pb exposure was associated with reduced locomotor activity, anxiety-like responses, and accelerated spatial memory decay in AD mice. Histopathological and immunofluorescence evaluations structurally confirmed these functional deficits, revealing disorganized hippocampal cytoarchitecture, myelin loss, and accelerated Aβ plaque deposition in the ADPb group. Ultimately, these findings demonstrated that environmental Pb exacerbated AD progression not solely through direct physical toxicity, but fundamentally by disrupting the in situ Cu(II)/Cu(I) redox equilibrium. This study highlights Cu redox imbalance as a potential mediator linking Pb exposure with AD progression and warrants further biochemical validation.},
}
@article {pmid42492536,
year = {2026},
author = {Weber, MC and Goedecke, J and Fink, GR and Onur, OA},
title = {[Predicting and Preventing Alzheimer's Disease].},
journal = {Fortschritte der Neurologie-Psychiatrie},
volume = {},
number = {},
pages = {},
doi = {10.1055/a-2906-0084},
pmid = {42492536},
issn = {1439-3522},
abstract = {Alzheimer's disease is a long-term biological process whose neuropathological changes begin decades before clinical symptoms appear. Advances in biomarker diagnostics enable the early identification of pathological changes and a more precise classification of different disease stages. Since therapeutic options have shown only limited effects so far, modifiable risk factors and preventive lifestyle interventions are increasingly coming into focus.},
}
@article {pmid42492708,
year = {2026},
author = {Luo, C and Wu, G and Xiao, Z and Hu, R and Qiao, M and Li, W and Liu, C and Li, Z and Lan, C and Huang, Z},
title = {Retraction notice to "Role of miRNA regulation in IGFBP-2 overexpression and neuronal ferroptosis: Insights into the Nrf2/SLC7A11/GPX4 pathway in Alzheimer's disease" [International Journal of Biological Macromolecules 287 (2025) 138537].},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {153649},
doi = {10.1016/j.ijbiomac.2026.153649},
pmid = {42492708},
issn = {1879-0003},
}
@article {pmid42492887,
year = {2026},
author = {Xie, M and Niu, X and Shi, L},
title = {Integrated identification and validation of HSP90AA1 as a therapeutic target of Astragalus membranaceus in Alzheimer's disease.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.07.044},
pmid = {42492887},
issn = {1873-7544},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder lacking effective disease-modifying therapies. Astragalus membranaceus (AM) has shown potential neuroprotective effects, but its underlying mechanisms remain incompletely understood. In this study, a meta-analysis, network pharmacology, molecular simulation, and experimental validation were integrated to investigate the therapeutic potential of AM in AD. Meta-analysis of three randomized controlled trials showed that AM significantly improved Clinical Dementia Rating-Sum of Boxes scores, whereas no significant differences were observed for MMSE, memory-related outcomes, or SNSB-D. Network pharmacology identified 350 overlapping targets between AM and AD, with enrichment in pathways related to PI3K-Akt signaling and neural ligand-receptor interactions. HSP90AA1, PIK3CA, and ESR1 were identified as hub targets. Molecular docking predicted stable binding of astragaloside VII to the ATP-binding pocket of HSP90AA1 (-8.9 kcal/mol), which was further supported by molecular dynamics simulation and MM/PBSA analysis (-63.13 ± 4.82 kcal/mol). In Aβ-induced SH-SY5Y cells, astragaloside VII improved cell viability, reduced inflammatory cytokine production and the Aβ42/Aβ40 ratio, restored mitochondrial membrane potential, decreased reactive oxygen species accumulation, alleviated Tau hyperphosphorylation, and increased PSD95 expression. These effects were markedly attenuated following HSP90AA1 knockdown. Collectively, these findings suggest that AM may exert neuroprotective effects through HSP90AA1-associated regulation of multiple AD-related pathological processes and provide preliminary evidence supporting further mechanistic and translational studies.},
}
@article {pmid42493106,
year = {2026},
author = {Wu, L and Jiang, W and Zhao, N and Wang, F},
title = {Corrigendum to "Heparan sulfate from porcine mucosa promotes amyloid-beta clearance in APP/PS1 mice and alleviates Alzheimer's pathology" [Carbohydrate Polymers 285 (2022) 119205].},
journal = {Carbohydrate polymers},
volume = {388},
number = {},
pages = {125541},
doi = {10.1016/j.carbpol.2026.125541},
pmid = {42493106},
issn = {1879-1344},
}
@article {pmid42493137,
year = {2026},
author = {Cardoso, E and Serra, AC and Coelho, JFJ and Pereira, P},
title = {Glycopolymers as emerging modulators of Amyloid-β aggregation: structure-activity relationships and therapeutic potential.},
journal = {Carbohydrate polymers},
volume = {388},
number = {},
pages = {125572},
doi = {10.1016/j.carbpol.2026.125572},
pmid = {42493137},
issn = {1879-1344},
mesh = {Humans ; *Amyloid beta-Peptides/metabolism/chemistry/antagonists &amp; inhibitors ; *Alzheimer Disease/drug therapy/metabolism/pathology ; Structure-Activity Relationship ; Animals ; Protein Aggregates/drug effects ; *Protein Aggregation, Pathological/drug therapy/metabolism ; },
abstract = {Despite ongoing debate about the "amyloid hypothesis", the imbalance between the production and clearance of β-amyloid (Aβ) peptides in the brain remains one of the most compelling explanations for the progression of Alzheimer's disease. Current strategies therefore focus on discovering clinically relevant therapeutic agents that target Aβ peptides and amyloid structures. Because of their unique and attractive properties - biocompatibility, non-immunogenicity, non-toxicity, and ease of functionalization and production - the use of glycopolymers as amyloid inhibitors has generated interest in therapeutic research for Alzheimer's disease. This review provides a comprehensive and critical overview of the literature on glycopolymers in the treatment of Alzheimer's disease. It begins with a description of the disease's neuropathological mechanisms and the formulations approved by the FDA or currently in clinical trials. The second part discusses the use of glycopolymers as amyloid inhibitors, which prevent the formation of neurotoxic soluble oligomers and subsequent plaques observed in Alzheimer's disease. This is achieved by binding to monomers, blocking self-aggregation, and interrupting toxic interactions, offering a therapeutic strategy to halt disease progression. Finally, the main conclusions and perspectives on the use of glycopolymers as amyloid inhibitors are presented.},
}
@article {pmid42493280,
year = {2026},
author = {Faheem, MSB and Hassan, ST and Najmi, OEM and Waheed, A and Ullah, ZB and Sattar, Y and Alraies, MC},
title = {Rising burden of Alzheimer's mortality linked to hypertension: A U.S. population-based study, 1999-2023.},
journal = {Journal of the National Medical Association},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jnma.2026.06.020},
pmid = {42493280},
issn = {1943-4693},
abstract = {BACKGROUND: Hypertension (HTN) remains a key contributor to adverse outcomes in older adults with Alzheimer's disease (AD), which itself is the seventh leading cause of death in the U.S., affecting over 120,000 Americans annually. The co-existence of these conditions significantly increases the risk of morbidity and mortality, and despite their strong relationship, long-term mortality trends accounting for both conditions have not been assessed. This study examines trends and disparities in AD mortality among older patients (aged ≥ 65 years) with HTN in the U.S. from 1999 to 2023.<br><br>METHODS: Mortality records of older patients listing AD as the primary cause of death and HTN as a contributing cause were evaluated from 1999 to 2023 using the CDC WONDER database. Age-adjusted mortality rates (AAMRs) were computed per 100,000 population, and annual percent changes (APCs) were derived to assess temporal trends across different demographics and geographies.<br><br>RESULTS: Overall, 314,914 mortalities were attributed to AD in patients with HTN, with overall AAMRs increasing from 1999 (7.1) to 2023 (41.1). Females (AAMR: 31.6) experienced higher rates than males (AAMR: 20.7). Rates peaked among NH African Americans (AAMR: 31.8), followed by NH Whites (AAMR: 28.3) and Hispanics (AAMR: 22.3). Adults aged 85+ years (AAMR: 142.3) had higher rates compared with those aged 75-84 (AAMR: 25.1) and 65-74 years (AAMR: 2.5). Geographically, AAMRs were highest in the West region (AAMR: 31.5) and among non-metropolitan residents (AAMR: 27.9) compared to metropolitan residents (AAMR: 25.03). Trend analysis revealed statistically significant APCs (p&#x202f;<&#x202f;0.05) across all evaluated demographic and geographic subgroups.<br><br>CONCLUSION: This sharp, six-fold rise in AD and HTN-related mortality highlights a compounding public health challenge. The significant disparities observed in the disproportionate burden on females, NH African Americans, and non-metropolitan residents likely reflect intersecting biological vulnerabilities and structural inequities in healthcare access. These findings stress the urgent need for targeted health policy strategies and the proactive clinical management of comorbid conditions to protect these high-risk populations.},
}
@article {pmid42493523,
year = {2026},
author = {Elkotamy, MS and Elgohary, MK and Alkotami, AS and Eldesouki, MM and Elsayed, ZM and Mattar, AA and Abo-Ashour, MF and Tawfik, HO and Eldehna, WM and Abdel-Aziz, HA},
title = {In silico pipeline for GSK 3β inhibitor discovery in Alzheimer's disease using pharmacophore screening, docking, ADME filtering, and MD validation.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {42493523},
issn = {2045-2322},
mesh = {*Glycogen Synthase Kinase 3 beta/antagonists &amp; inhibitors/chemistry/metabolism ; *Alzheimer Disease/drug therapy ; Pharmacophore ; Molecular Dynamics Simulation ; Molecular Docking Simulation ; Humans ; *Drug Discovery/methods ; Ligands ; Blood-Brain Barrier/metabolism ; Drug Evaluation, Preclinical ; *Protein Kinase Inhibitors/chemistry/pharmacology ; },
abstract = {Glycogen synthase kinase-3β (GSK-3β) is a key therapeutic target for Alzheimer's disease, but identifying safe, brain-penetrant inhibitors remains difficult. This study aimed to discover novel CNS-active GSK-3β inhibitors using a rigorous multi-tier computational pipeline. The workflow combined ligand-based and structure-based pharmacophore modeling, virtual screening of the ZINCPharmer database, AutoDock Vina docking, ADME and blood-brain barrier (BBB) filtering with SwissADME, toxicity prediction using ProTox-3.0, and validation by 100-ns molecular dynamics simulations with MM/GBSA and MM/PBSA free energy calculations. Pharmacophore screening with a ≤ 1.0 Å RMSD cutoff identified 1,085 ligand-based and 36 structure-based hits. After docking and developability filtering, two BBB-permeant candidates were prioritized: SB1, a structure-based hit (predicted LD50 = 2500 mg/kg, toxicity class 5), and LB1, a ligand-based hit (predicted LD50 = 521 mg/kg, toxicity class 4). Molecular dynamics confirmed stable binding for both compounds. MM/GBSA analysis showed favorable binding free energies for SB1 (-27.68 kcal/mol) and LB1 (-25.74 kcal/mol), both surpassing the co-crystallized reference (-8.75 kcal/mol). These findings identify SB1 and LB1 as promising, safe, and brain-penetrant GSK-3β lead compounds for experimental validation in Alzheimer's disease.},
}
@article {pmid42493572,
year = {2026},
author = {},
title = {Early detection of Alzheimer's disease with circular RNA from blood.},
journal = {Nature medicine},
volume = {},
number = {},
pages = {},
pmid = {42493572},
issn = {1546-170X},
}
@article {pmid42493706,
year = {2026},
author = {Hoffman, I and Ross, JA and Tumasz, M and Thomas, SA and Van Bockstaele, EJ},
title = {Norepinephrine-mediated regulation of endogenous Aβ42 peptide levels: effects of noradrenergic depletion and restoration.},
journal = {MedScience},
volume = {},
number = {},
pages = {},
pmid = {42493706},
issn = {3091-4981},
abstract = {The locus coeruleus (LC), a cluster of noradrenergic neurons in the dorsal pons, is the brain's main source of norepinephrine (NE), crucial for memory, cognition, and stress response. NE dysregulation has been linked to mood disorders, chronic stress, and neurodegenerative diseases such as Alzheimer's disease (AD). Amyloid-β42 (Aβ42) is a key protein in AD pathology, and forms plaques that trigger neurodegeneration. Studies show elevated Aβ42 levels are associated with anxiety symptoms, even in cognitively normal individuals. Previous research suggests a positive correlation between NE and Aβ42, with Aβ42 present in NE-producing LC neurons. NE may affect Aβ42 levels through adrenergic receptors on neurons or microglia. However, the exact role of NE in modulating Aβ42 remains unclear. Using the NE depletion models, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4) lesions and dopamine β-hydroxylase (DBH) knockout (KO) mice, researchers found reduced Aβ42 levels without changes in amyloid precursor protein processing. A newer model, DBH internal ribosome entry site-Cre × floxed tyrosine hydroxylase (DBH-IRES-Cre × floxed-TH) preserved dopamine (DA) but eliminated NE in adrenergic neurons, further supporting the specific influence of NE on Aβ42. Findings indicate that decreased Aβ42 in NE-depleted mice stems not from altered DA but from NE loss. This highlights the NE-mediated regulation of endogenous Aβ42 and the role of NE in AD-related pathology.},
}
@article {pmid42493790,
year = {2026},
author = {Xiao, Y and Wang, S and Hou, Y and Shang, H},
title = {Application of the Allen Human Brain Atlas in Alzheimer's disease and Parkinson's disease.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {42493790},
issn = {2047-9158},
support = {2023NSFSC1576//National Science Fund of Sichuan Province/ ; 82301427//National Science Fund of China/ ; TJCZ202506//Rongcheng Talent Program/ ; 2021YFC2501200//National Key Research and Development Program of China/ ; 2022ZDZX0023//Sichuan Science and Technology Program/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/diagnostic imaging/pathology/metabolism ; *Parkinson Disease/genetics/diagnostic imaging/pathology ; *Brain/diagnostic imaging/metabolism/pathology ; *Atlases as Topic ; Transcriptome ; Gene Expression Profiling/methods ; },
abstract = {Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common age-related neurodegenerative disorders. Allen Human Brain Atlas (AHBA) provides high-resolution transcriptomic data across 102 brain regions with multi-site sampling from healthy controls, promoting the use of brain-wide transcriptomic data for imaging transcriptomics and cross-modal model construction. Increasingly, researchers are utilizing brain-wide transcriptomic datasets to investigate the transcriptome correlates of the neuroimage phenotypes in AD and PD. Leveraging the AHBA, researchers have analyzed the transcriptomic correlations of regional susceptibility to Aβ deposition, tau deposition, α-synuclein propagation, and disease-related multiple-dominal neuroimage phenotypes. These studies revealed that transcriptomic pathways related to metabolism, immunity, neurotransmission, and synaptic function play critical roles in the neuroimage phenotype of AD and PD. By incorporating transcriptomic data modeling, subsequent analyses further confirmed that transcriptomic differences provide the molecular basis for the varying susceptibility observed across brain regions. The analytical approaches of imaging transcriptomics, multimodal data integration strategies, and model construction methods used in AD and PD provide a novel perspective for exploration and can be extended to other neurodegenerative diseases. Future research is expected to utilize brain-wide transcriptomic data to uncover the gene expression mechanisms driving neurodegenerative disease phenotypes.},
}
@article {pmid42493810,
year = {2026},
author = {Piras, IS and Capuano, AW and Maher, AC and Schafer, R and Bonfitto, A and Song, S and Taguinod, F and Goldstein, F and Roberts, A and Okonkwo, O and Martersteck, A and , and Huentelman, MJ and Rogalski, E},
title = {SuperAging is not the inverse of common-variant Alzheimer's risk: evidence across genetic ancestries.},
journal = {Alzheimer's research &amp; therapy},
volume = {18},
number = {1},
pages = {},
pmid = {42493810},
issn = {1758-9193},
mesh = {Humans ; *Alzheimer Disease/genetics ; Female ; Genetic Risk Score ; Male ; Aged, 80 and over ; *Apolipoproteins E/genetics ; Genome-Wide Association Study ; *Genetic Predisposition to Disease/genetics ; *Aging/genetics ; Memory, Episodic ; *Longevity/genetics ; Aged ; Genotype ; },
abstract = {BACKGROUND: As longevity increases and the population over age 65 expands, advancing age remains the most reliable predictor of cognitive decline, highlighting the need to identify biological mechanisms that support exceptional cognitive aging. We tested whether lower inherited risk of Alzheimer's disease (AD) dementia predicts SuperAger status (adults ≥ 80 years with episodic memory at least as good as middle-age adults) using prospectively enrolled SuperAgers and Cognitively Average Controls (Controls) from the multisite SuperAging Research Initiative.<br><br>METHODS: We studied 231 participants (SuperAgers n&#x2009;=&#x2009;142; Controls n&#x2009;=&#x2009;89). We confirmed that the genetic ancestry structure across groups was comparable. We evaluated whether APOE status (&#x3b5;2, &#x3b5;3, &#x3b5;4) and three AD polygenic risk scores (PRS) derived from large contemporary Genome-Wide Association Studies (GWAS) (PRSLambert, PRSWightman, PRSBellenguez) predicted SuperAging status using logistic regression models adjusted for age, sex, and education, considering ancestry interactions.<br><br>RESULTS: APOE allele and genotype distributions did not differ between groups, and neither APOE nor any of the three PRS predicted SuperAger status. Results were unchanged when accounting for global non-European or African ancestry or principal components. In this well-characterized cohort, neither APOE nor contemporary PRS explained SuperAger status.<br><br>CONCLUSIONS: These findings suggest that the exceptional late-life memory phenotype that is characteristic of SuperAging is not explained by common-variant AD genetic risk captured by APOE or contemporary AD PRS, motivating a deeper investigation of potential rare genetic variations and experiential factors contributing to exceptional cognitive aging.},
}
@article {pmid42494057,
year = {2026},
author = {Li, Y and Leng, Q and Wang, Y},
title = {The impact of supplements on cognitive function for Alzheimer's disease or mild cognitive impairment: a systematic review and network meta-analysis.},
journal = {Nutritional neuroscience},
volume = {},
number = {},
pages = {1-19},
doi = {10.1080/1028415X.2026.2703619},
pmid = {42494057},
issn = {1476-8305},
abstract = {OBJECTIVE: Global aging is increasing the incidence of Alzheimer's disease (AD) and mild cognitive impairment (MCI). This network meta-analysis evaluates the effects of dietary supplements on cognitive function in AD/MCI patients.<br><br>METHODS: We systematically searched PubMed, Embase, Cochrane Library, and Web of Science for randomized controlled trials up to July 2024. Study quality was assessed using risk-of-bias tools, and a network meta-analysis was performed using R and STATA.<br><br>RESULTS: Analysis of 29 trials (n&#x2009;=&#x2009;2000) demonstrated that several supplements significantly improved Mini-Mental State Examination (MMSE) scores compared to placebo. Cosmos caudatus increased MMSE scores (MD&#x2009;=&#x2009;1.02, 95% CI 0.41-1.63, intervention vs placebo). In comparisons where placebo was the reference group, the following supplements were superior: plant extraction (MD&#x2009;=&#x2009;-1.54, 95% CI -1.88 to -1.19), probiotics with selenium (MD&#x2009;=&#x2009;-1.7, 95% CI -2.34 to -1.05), phosphatidylserine-100 mg (MD&#x2009;=&#x2009;-1.14, 95% CI -1.86 to -0.41), spirulina (MD&#x2009;=&#x2009;-0.68, 95% CI -1.23 to -0.13), and vitamin B (MD&#x2009;=&#x2009;-0.88, 95% CI -1.67 to -0.09). Probiotics with selenium showed the strongest effect. No supplement produced significant improvements on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog).<br><br>CONCLUSION: Specific supplements, including Cosmos caudatus, probiotic-selenium combinations, and plant extracts, are associated with improvements in MMSE scores among AD/MCI patients. The absence of effects on ADAS-Cog scores underscores the importance of assessment tool selection. This study provides evidence for considering nutritional interventions in cognitive support strategies.},
}
@article {pmid42494118,
year = {2026},
author = {Paul, S and Dubey, S and Tiwari, P},
title = {Integrative Insights Into DYRK1A From Molecular Function to Therapeutic Advancement.},
journal = {Chemical biology &amp; drug design},
volume = {108},
number = {1},
pages = {e70366},
doi = {10.1111/cbdd.70366},
pmid = {42494118},
issn = {1747-0285},
mesh = {Dyrk Kinases ; *Protein Serine-Threonine Kinases/metabolism/antagonists &amp; inhibitors/chemistry ; Protein-Tyrosine Kinases/metabolism/chemistry ; Humans ; *Protein Kinase Inhibitors/chemistry/pharmacology/metabolism/therapeutic use ; Structure-Activity Relationship ; Binding Sites ; Drug Design ; Adenosine Triphosphate/metabolism ; Proteolysis Targeting Chimera ; Tyrosine Kinase Inhibitors ; Animals ; },
abstract = {Dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A), located within the Down syndrome critical region and implicated in Alzheimer's disease (AD), Parkinson's disease (PD), and context-dependent cancer biology, represents a high-value yet challenging therapeutic target. This review compiles comprehensive structure-activity relationship (SAR) insights essential for medicinal chemists designing selective DYRK1A inhibitors. We detail the molecular architecture of the ATP-binding pocket of DYRK1A, key regulatory residues (Lys188, Phe238, Glu239, Leu241), and structure-function relationships governing inhibitor classes: ATP-competitive agents, ATP-non-competitive inhibitors, and Proteolysis-Targeting Chimeras (PROTAC) degraders with emphasis on functional group modifications and scaffold optimization strategies. Readers will gain actionable insights on binding mode predictions, potency-selectivity trade-offs, and prioritization of lead compounds for preclinical validation. The framework addresses pharmacokinetic property optimization and selectivity profiling across kinase families, enabling researchers to accelerate rational inhibitor design and facilitate translation of DYRK1A therapeutics into clinical trials for neurodegenerative and developmental disorders.},
}
@article {pmid42494202,
year = {2026},
author = {Ali, A and Maqsood, A and Mustafa, A and Hussain, Z and Ashraf, A and Sarfaraz, S and Butt, A and Shamoon, M and Ghafoor, LA and Azam, H and Abdullah, M and Pannun, AA and Shabbir, MA and Abdullah, A and Sharma, MK},
title = {Burden of Diabetes as a Contributing Cause in Dementia Mortality Among Older Adults in the United States, 1999-2020.},
journal = {Brain and behavior},
volume = {16},
number = {7},
pages = {e71616},
doi = {10.1002/brb3.71616},
pmid = {42494202},
issn = {2162-3279},
mesh = {Humans ; *Dementia/mortality/epidemiology ; United States/epidemiology ; Female ; Aged ; Cause of Death/trends ; *Diabetes Mellitus/epidemiology/mortality ; Male ; Aged, 80 and over ; Risk Factors ; },
abstract = {BACKGROUND: Diabetes is a well-established risk factor for cognitive decline and dementia; however, the extent to which diabetes is documented as a contributing cause on death certificates among decedents with dementia remains poorly characterized. This study aimed to evaluate temporal trends and demographic disparities in diabetes as a contributing condition among dementia-related deaths in older adults in the United States.<br><br>METHODS: We analyzed multiple-cause-of-death data from the CDC WONDER database for adults aged &#x2265;&#xa0;65 years with dementia listed as an underlying or contributing cause of death between 1999 and 2020. Diabetes was identified using ICD-10 codes E10-E14. We calculated age-adjusted mortality rates (AAMR), crude death rates (CDR), annual percentage changes (APC) using Joinpoint regression, and the proportion of dementia deaths with coexisting diabetes. Analyses were stratified by age, sex, race, and state.<br><br>RESULTS: Among 3,818,272 dementia-related deaths, 234,793 (6.2%) had diabetes documented as a contributing condition. The AAMR for dementia with diabetes increased from 8.7 per 100,000 in 1999 to 36.1 per 100,000 in 2020. Joinpoint regression identified a sharp increase from 1999 to 2009 (APC: +13.09%, 95% CI: 11.47-14.94, p&#xa0;<&#xa0;0.001), followed by a stable trend from 2009 to 2020 (APC: +0.84%, 95% CI: -0.55-2.11, p&#xa0;=&#xa0;0.187). Both dementia alone and dementia with diabetes demonstrated a sharp spike in 2020. The proportion of dementia deaths with coexisting diabetes was highest among decedents aged 65-74 years (8.5%) and decreased with age (85+ years: 5.3%). By race, American Indian/Alaska Native decedents had the highest proportion (10.4%), followed by Asian/Pacific Islander (9.2%), Black/African American (9.0%), and White (5.8%). Substantial state-level variation was observed across the United States.<br><br>CONCLUSIONS: The burden of diabetes, documented as a contributing condition among dementia-related deaths, increased substantially from 1999 to 2009 and remained relatively stable thereafter. Significant racial, age, and geographic disparities exist, with American Indian/Alaska Native decedents showing the highest proportion of coexisting diabetes. These findings highlight the burden of metabolic comorbidity among older adults with dementia and underscore the importance of continued surveillance and targeted public health strategies.},
}
@article {pmid42494763,
year = {2026},
author = {Zhou, M and Wang, X},
title = {Curcumin and piperine in neurodegenerative disorders: a systematic review of preclinical neuroprotective evidence.},
journal = {Frontiers in nutrition},
volume = {13},
number = {},
pages = {1855377},
pmid = {42494763},
issn = {2296-861X},
abstract = {BACKGROUND: Curcumin and piperine are phytochemicals with neuroprotective potential; however, curcumin's limited bioavailability restricts its therapeutic efficacy. Increasing evidence suggests that their co-administration may provide synergistic neuroprotective benefits. This systematic review evaluates the current preclinical evidence for curcumin-piperine (CUR-PP) combinations in neurodegenerative disorder models.<br><br>METHODS: We searched electronic databases for studies published between 2010 and 2026. Twenty unique preclinical studies, involving rodent models and neuronal cell cultures, met the eligibility criteria. Due to substantial methodological heterogeneity in study designs, dosing regimens, and outcome measures, a quantitative meta-analysis was not feasible. Findings were synthesized qualitatively, focusing on behavioral, biochemical, and molecular outcomes.<br><br>RESULTS: CUR-PP co-administration consistently demonstrated superior neuroprotective efficacy compared to monotherapy. The combination significantly improved cognitive and locomotor performance, mitigated oxidative stress, and modulated neuroinflammatory pathways. Nanoformulations, such as PLGA nanoparticles, further enhanced bioavailability and therapeutic impact across the included studies.<br><br>CONCLUSION: Preclinical data indicate that CUR-PP combinations exert synergistic neuroprotective effects, suggesting they are promising multi-target candidates for neurodegeneration. However, the therapeutic potential is currently limited by a reliance on preclinical models, substantial inter-study heterogeneity, and a total lack of clinical trial data, which prevents the establishment of validated human dosing protocols.},
}
@article {pmid42494770,
year = {2026},
author = {Woolsey, B and Sen, K},
title = {Dietary approaches to support cognition in older adults: a systematic review.},
journal = {Frontiers in nutrition},
volume = {13},
number = {},
pages = {1869091},
pmid = {42494770},
issn = {2296-861X},
abstract = {BACKGROUND: Older adults, particularly those residing in long-term care, experience disproportionate rates of cognitive decline and Alzheimer's disease (AD). While isolated nutrient supplementation has demonstrated limited clinical efficacy, comprehensive whole-food dietary patterns may offer significant neuroprotective benefits through complex nutrient synergy. This systematic review evaluates the efficacy of the Mediterranean, Nordic, Okinawan, and plant-based dietary approaches in mitigating cognitive decline and reducing dementia risk in older populations.<br><br>METHODS: The study protocol was prospectively registered with the International Prospective Register of Systematic Reviews (PROSPERO) under the registration ID CRD420261349593. Conducted in accordance with PRISMA 2020 guidelines, a systematic search of PubMed, Web of Science, CINAHL, and ScienceDirect was performed to identify peer-reviewed articles published between January 2021 and the present. Eligible studies included randomized controlled trials (RCT), prospective cohort studies, and longitudinal studies evaluating the impact of whole-food dietary patterns on cognitive outcomes in adults aged 60 and older.<br><br>RESULTS: Out of 622 initial records, 16 articles met all inclusion criteria. The synthesized evidence demonstrates that high adherence to these comprehensive dietary patterns is consistently associated with improved memory, enhanced executive function, and a reduced incidence of AD. These cognitive improvements are driven by interconnected physiological mechanisms, including reduced systemic inflammation, improved vascular integrity, favorable shifts in the gut microbiome, and optimized circulating endocannabinoid profiles. Additionally, the magnitude of these benefits is frequently modulated by individual biological factors, such as sex and APOE genotype.<br><br>CONCLUSION: Whole-food dietary patterns provide an effective, evidence-based framework for preserving cognitive resilience compared to single-nutrient interventions. Integrating these nutrient-dense diets into public health initiatives and long-term care settings offers a powerful strategy for neuroprotection, highlighting the need to advance personalized nutrition strategies in future clinical trials.},
}
@article {pmid42494775,
year = {2026},
author = {Lavigne, SB and Hromas, G and LaRoche, A and Parker, AS and Abdullah, MS and Fernandez, RA and Wang, CP and de Erausquin, G and Salardini, A and Tanner, J and Kautz, TF and Castro, J and Mendoza, C and Seshadri, S and Sullivan, AC},
title = {Frontotemporal dementia in Hispanic populations: Regional and national comparisons.},
journal = {Alzheimer's &amp; dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70396},
pmid = {42494775},
issn = {2352-8729},
abstract = {INTRODUCTION: Although Hispanic/Latine populations experience higher dementia rates, they remain underrepresented in frontotemporal dementia (FTD) research. This study examines clinical manifestations of FTD within a South Texas Hispanic/Latine cohort compared to national data.<br><br>METHODS: Participants diagnosed with FTD were included from (1) our FTD clinic, the South Texas Alzheimer's Disease Research Center, and local Advancing Research and Treatment in Frontotemporal Lobar Degeneration-Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects Longitudinal Frontotemporal Lobar Degeneration cohort (Hispanic: n&#xa0;=&#xa0;17; White non-Hispanic: n&#xa0;=&#xa0;22), and (2) the National Alzheimer's Coordinating Center dataset (Hispanic: n&#xa0;=&#xa0;24; White non-Hispanic: n&#xa0;=&#xa0;407; National Institute on Aging/National Institutes of Health Grant U24 AG072122). Clinical, neuroimaging, and neuropsychological data were harmonized for cross-cohort comparisons.<br><br>RESULTS: Hispanic participants presented with more movement-related symptoms and advanced cognitive impairment at diagnosis than non-Hispanic Whites. Diagnostic delays averaged 4 years from symptom onset. Educational disparities significantly contributed to health-care access differences.<br><br>DISCUSSION: Findings underscore diagnostic severity and systemic barriers faced by Hispanic populations with FTD, emphasizing the need for culturally sensitive diagnostic tools and interventions for equitable dementia care.},
}
@article {pmid42495050,
year = {2026},
author = {Jannati, A and Toro-Serey, C and Ciesla, M and Chen, E and Showalter, J and Bates, D and Pascual-Leone, A and Tobyne, S},
title = {Streamlining eligibility assessment for Alzheimer's disease-modifying therapies: Prediction of MMSE scores using the digital clock and recall.},
journal = {Frontiers in digital health},
volume = {8},
number = {},
pages = {1799372},
pmid = {42495050},
issn = {2673-253X},
abstract = {INTRODUCTION: The eligibility of anti-amyloid disease-modifying therapies (DMTs) and their integration into clinical practice in some institutions requires a specific range of Mini-Mental State Examination (MMSE) scores. Reliance on this pencil-and-paper psychometric instrument imposes operational burdens and risks of perpetuating health disparities, given the test's known educational and cultural biases. This study evaluates the efficacy of the Digital Clock and Recall (DCR™)-a rapid, FDA-listed digital cognitive assessment-to crosswalk to MMSE scores using machine learning, thereby offering a faster, scalable, and equitable mechanism for patient triage.<br><br>METHODS: We conducted a retrospective analysis using data from the multi-site Bio-Hermes-001 (BH) study (NCT04733989, N&#x2009;=&#x2009;945). Participants were clinically classified as cognitively unimpaired, mild cognitive impairment, or probable Alzheimer's dementia. We trained a Poisson elastic net regression model on 70% of the sample, using age and multimodal digital features derived from the DCR (including drawing kinematics and voice acoustics) to predict MMSE scores. The model was validated using the remaining 30% of Bio-Hermes-001 and an independent external validation cohort from the Apheleia study (NCT05364307, N&#x2009;=&#x2009;238).<br><br>RESULTS: The machine learning model predicted MMSE scores with a root-mean-squared error (RMSE) of 2.43 in the BH test set. This error margin falls within the established test-retest reliability range of the manual MMSE itself (&#x223c;4.0-4.2 points at short inter-test intervals), providing evidence that the predicted score is of comparable precision to a repeat human administration of the MMSE. External validation in the Apheleia cohort demonstrated robust generalizability (RMSE&#x2009;=&#x2009;2.62). In the BH held-out test set, the model showed comparable performance across Race (White RMSE&#x2009;=&#x2009;2.46; Non-White RMSE&#x2009;=&#x2009;2.25) and Ethnicity (Hispanic RMSE&#x2009;=&#x2009;2.19; Non-Hispanic RMSE&#x2009;=&#x2009;2.45), a balanced pattern also observed in the Apheleia-001 external cohort. Exploratory demographic analyses on prediction errors, including Age, Sex, Race, and Ethnicity, yielded significant differences only for Sex and Age in Apheleia, with signed errors becoming progressively more negative (i.e., increasing under-prediction) at older ages for the latter. This scarcity of statistical differences across cohorts suggested that our predictions were fair.<br><br>DISCUSSION: Machine learning can leverage multimodal features from the DCR to accurately and equitably crosswalk to MMSE scores in support of current guidelines, transforming a time-intensive manual test into a rapid, automated assessment. By deploying this "digital triage" engine, where traditional assessments are still used for DMT eligibility, healthcare systems can streamline the identification of DMT-eligible patients, reduce specialist referral bottlenecks, and ensure that access to life-altering therapies is determined by pathology rather than demography.},
}
@article {pmid42495266,
year = {2026},
author = {Martinez, R and Thakur, KT and Alviz, LF and Gardner, WM and Varela, FJ and Hennis, AJM and Oliveira E Souza, R},
title = {The burden of noncommunicable and injury-related nervous system disorders in the Americas, 1990-2023: an analysis of the Global Burden of Disease Study 2023.},
journal = {Lancet regional health. Americas},
volume = {62},
number = {},
pages = {101581},
pmid = {42495266},
issn = {2667-193X},
abstract = {BACKGROUND: Noncommunicable and injury-related nervous system disorders (NINSDs)-including cerebrovascular and neurodegenerative diseases, neurodevelopmental disorders, neuromuscular conditions, brain cancers, and traumatic brain injuries-are major contributors to morbidity, disability, and premature mortality in the Americas. However, comprehensive regional and national assessments remain limited. We assessed the burden of NINSDs and their attributable risk factors in the Americas from 1990 to 2023.<br><br>METHODS: We analysed prevalence, mortality, and disability-adjusted life years (DALYs), with 95% uncertainty intervals (UIs), for 19 NINSDs by age and sex across 38 countries and territories, using estimates from the Global Burden of Disease Study 2023. Temporal trends were assessed using annual percentage change (APC) estimated through log-linear regression. Burden attributable to modifiable risk factors was also examined.<br><br>FINDINGS: In 2023, an estimated 470 million (95% UI 418-523) people in the Americas were living with at least one NINSD. These conditions caused 1&#xb7;1 million (0&#xb7;8-1&#xb7;7) deaths and 37&#xb7;5 million (27&#xb7;9-51&#xb7;8) DALYs, representing 12% of the total burden from noncommunicable diseases in the region. Migraine, Alzheimer's disease and other dementias, ischaemic stroke, and intracerebral haemorrhage were the leading contributors to DALYs. From 1990 to 2023, age-standardised DALY rates declined for ischaemic stroke, haemorrhagic stroke, and neural tube defects, but increased for neurodegenerative disorders, including multiple sclerosis and motor neuron diseases. High systolic blood pressure was the leading risk factor for stroke subtypes, high fasting plasma glucose for dementias, and lead exposure accounted for nearly 60% of DALYs from idiopathic intellectual disability.<br><br>INTERPRETATION: NINSDs impose a substantial and persistent burden in the Americas, with disability increasingly outweighing premature mortality. Strengthening prevention of modifiable risk factors, integrating neurological health into noncommunicable disease strategies, and expanding long-term care, rehabilitation, and disability support are essential to address this growing challenge.<br><br>FUNDING: No funding to declare.},
}
@article {pmid42495541,
year = {2026},
author = {Li, Y and Xu, X and Meng, Z and Chen, L and Yu, Q and Wang, R and Ren, Y and Chen, F and Liang, G and Zhao, X and Yu, H and Wei, J},
title = {Tuberostemonine ameliorates Alzheimer's disease pathology by suppression of the p38 MAPK signaling pathway.},
journal = {iScience},
volume = {29},
number = {8},
pages = {116887},
pmid = {42495541},
issn = {2589-0042},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder with limited therapeutic options. Here, we report that tuberostemonine (Tub), an alkaloid from Stemona tuberosa, exerts neuroprotective effects in AD models. In Aβ1-42-treated PC12 cells, Tub reduced cytotoxicity, apoptosis, and oxidative stress while restoring mitochondrial function. In APP/PS1 transgenic mice, Tub administration improved cognitive performance, reduced amyloid-β plaque deposition, attenuated microglial activation, and attenuated neuronal loss, with efficacy superior to donepezil. Mechanistically, Tub selectively inhibited p38 MAPK phosphorylation without affecting ERK or JNK pathways, as confirmed by pharmacological inhibition and activation experiments. These findings identify Tub as a promising multi-target natural compound for AD intervention through p38 MAPK pathway modulation.},
}
@article {pmid42495562,
year = {2026},
author = {Pujar, KG and Purohit, D and Shetty, RP and S, P and Kolachi, KY and Bharathi H M, A and Achar, PG and P, P},
title = {Pharmacophore-driven design and biological evaluation of heterocyclic PDE4B inhibitors for Alzheimer's disease.},
journal = {RSC advances},
volume = {},
number = {},
pages = {},
pmid = {42495562},
issn = {2046-2069},
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative condition marked by a gradual loss of cognitive function, impaired synaptic signalling, and sustained neuroinflammatory responses. Among the molecular pathways associated with disease progression, cyclic adenosine monophosphate (cAMP) signalling, plays a crucial factor in disruption of cellular homeostasis. Phosphodiesterase-4 (PDE4), especially the PDE4B isoform, controls intracellular cAMP levels in neuronal and glial cells, which affects inflammatory signalling and synaptic plasticity in the brain. Therefore, selectively targeting PDE4B is a novel approach to identify the small molecule's therapeutic activity to restore the cAMP signalling, with parallel regulation of the dose-limiting side effects. GSK356278 and Rolipram are the known PDE4B modulators, which have been considered for the current study to generate significant pharmacophoric features and execute drug design as CNS-active PDE4B inhibitors. Six heterocyclic derivatives were designed and synthesised by altering the core scaffold in order to maximise hydrophobicity, CNS permeability, and Q-pocket engagement without depending on direct Zn[2+] or Mg[2+] coordination. Among these, molecule VCHH-19 and VCPH-19 demonstrated significant CNS compatibility and good binding stability. PC12 cell lines were chosen to verify the in vitro neuroprotective response, and the Drosophila model for in vivo for AD assessment. All of these results indicated the significance of pyridine-based heterocycles molecules as potential candidates for PDE4B-targeted AD treatment.},
}
@article {pmid42496006,
year = {2026},
author = {Jauregui, GV and Coomes, S and Emmett, E and Thatcher, A and Oyelakin, N and Čarna, M and Zelinkova, J and Novotny, JS and Polakova, N and Kuruvilla, T and Zorec, R and Verkhratsky, A and Parpura, V and Morgan, D and Moya, KL and Limback-Stokin, C and Stokin, GB},
title = {APP/Aβ Signaling Orchestrates Reactive Astrocyte Networks in Alzheimer's Disease.},
journal = {Journal of neurochemistry},
volume = {170},
number = {7},
pages = {e70526},
doi = {10.1111/jnc.70526},
pmid = {42496006},
issn = {1471-4159},
support = {LX22NPO5107//European Union Project Next Generation EU - Project National Institute for Neurological Research/ ; //National Natural Science Foundation of China/ ; //Zhejiang Province People's Government Awards/ ; P3-310//Slovenian Research and Innovation Agency grants/ ; J3-50104//Slovenian Research and Innovation Agency grants/ ; J7-3153//Slovenian Research and Innovation Agency grants/ ; J3-2523//Slovenian Research and Innovation Agency grants/ ; J4-60077//Slovenian Research and Innovation Agency grants/ ; I0-0034 Celica//Slovenian Research and Innovation Agency grants/ ; I0-0048 Cipkebip//Slovenian Research and Innovation Agency grants/ ; I0-0022 UL//Slovenian Research and Innovation Agency grants/ ; //EU Interreg Italia-Slovenia Immunocluster-2/ ; //Coherence/ ; },
mesh = {*Astrocytes/metabolism/pathology ; *Alzheimer Disease/metabolism/pathology ; Humans ; *Amyloid beta-Protein Precursor/metabolism ; Animals ; *Signal Transduction/physiology ; *Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) accumulation, neurofibrillary pathology, synaptic dysfunction, and chronic neuroinflammation, yet the mechanisms driving early, localized pathology remain elusive. While traditionally viewed through a neuron-centric lens, astrocytes express abundant amyloid precursor protein (APP)-predominantly Kunitz-type protease inhibitor (KPI)-containing isoforms-and possess the complete enzymatic machinery for APP processing and Aβ clearance. Astrocytic APP is a stress-responsive signaling molecule regulated by inflammatory, metabolic, excitotoxic, and mechanical insults. Under local tissue stress, reactive astrocytes upregulate APP and shift toward amyloidogenic processing. The resulting bioactive fragments, including Aβ, promote astrocyte activation, disrupt homeostatic functions, and trigger feed-forward upregulation of endogenous APP. We propose that this reciprocal coupling establishes a self-reinforcing network where APP integrates local stress and diffusible Aβ propagates reactive states across the astroglial syncytium. This framework positions astrocytic APP signaling as an upstream driver of localized amyloid accumulation, neuroinflammation, and sporadic AD progression.},
}
@article {pmid42496210,
year = {2026},
author = {Dunckley, N and Driver-Dunckley, ED and Zhang, N and Serrano, GE and Shill, HA and Mehta, SH and Belden, C and Tremblay, C and Atri, A and Adler, CH and Beach, TG},
title = {Greater burden of Alzheimer's Co-pathology in women with Parkinson's disease dementia.},
journal = {Journal of Parkinson's disease},
volume = {},
number = {},
pages = {1877718X261470295},
doi = {10.1177/1877718X261470295},
pmid = {42496210},
issn = {1877-718X},
abstract = {ObjectiveTo investigate sex differences in Alzheimer's disease (AD) related pathology among autopsy-confirmed Parkinson's disease (PD) cases.BackgroundAD and PD frequently co-occur in older adults, yet the influence of sex on AD pathology in the context of PD remains unexplored.MethodsAll subjects were enrolled in the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) and Brain and Body Donation Program (BBDP) and had annual standardized research clinical assessments by neuropsychologists, subspecialty behavioral and movement disorders neurologists, as well as comprehensive neuropathological examinations after death.ResultsAmong 230 autopsy-confirmed PD cases, females exhibited greater amyloid plaque pathology burden than males, regardless of a co-occurring AD diagnosis. Specifically, females with PD had significantly higher mean cortical total plaque scores (mean 6.5/15 vs. 4.9/15, p = 0.045) and greater CERAD neuritic plaque density (mean 1.7/3 vs. 1.3/3, p = 0.035). Females were also more likely to have a higher cortical plaque burden (plaque total ≥ 5: 56.8% vs. 39.7%, p = 0.015). In multivariable logistic regression models, female subjects showed greater than twice the odds of having an amyloid plaque burden ≥5 compared to males (OR = 2.18; 95% CI = 1.17-4.06; p = 0.014), when controlling for ApoE ε4 status, Lewy body density score, and age at death.ConclusionsFemale sex is associated with increased amyloid plaque pathology in PD, independent of ApoE ε4 status. These findings highlight a sex-specific vulnerability to AD pathology in PD patients and support the need for sex-informed approaches to reseach in mixed neurodegenerative disease.},
}
@article {pmid42496263,
year = {2026},
author = {Powell, DS and Nieman, CL and Thorsell, P and Phillips, NA and Ekström, I},
title = {Hearing Loss, Cognitive Decline, and Dementia: Clinical Intersections.},
journal = {Audiology research},
volume = {16},
number = {4},
pages = {},
doi = {10.3390/audiolres16040097},
pmid = {42496263},
issn = {2039-4330},
support = {P22-0785, 2023//Stiftelsen Riksbankens Jubileumsfond/ ; P30AG097158/AG/NIA NIH HHS/United States ; n/a//Swedish Dementia Foundation/ ; },
abstract = {Background/Objectives: Age-related hearing loss is one of the most prevalent chronic conditions in older adults and has emerged as a potentially modifiable risk factor for cognitive decline and dementia. Increasing evidence from epidemiological, neurobiological, and interventional studies has improved our understanding of the complex relationships between auditory dysfunction and cognitive aging. By highlighting findings in these areas, this review aims to aid clinicians and researchers gain a better understanding of the association between hearing loss, cognitive decline and dementia, and the importance of considering sensory decline during cognitive screening. Methods: This narrative review summarizes and integrates findings from epidemiological, neurobiological, and clinical studies examining relationships between hearing loss, cognitive decline, and dementia. Particular focus was placed on epidemiological associations, proposed mechanistic pathways, implications for screening and diagnostic assessment, and evidence regarding hearing rehabilitation interventions. Results: Accumulating evidence indicates that hearing loss is associated with accelerated cognitive decline and increased dementia risk. Proposed mechanisms include increased cognitive load, reduced sensory input, social isolation, depression, and shared neurodegenerative or vascular pathology, although causal pathways remain incompletely understood. Emerging evidence suggests that hearing rehabilitation may help preserve cognitive function in some groups, but findings remain heterogeneous. Clinical studies further support the importance of considering auditory function during cognitive assessment, as unrecognized hearing impairment may influence test performance, communication, and diagnostic accuracy. Conclusions: Current evidence supports hearing loss as an important factor in cognitive aging and dementia research and highlights the potential value of integrating hearing assessment and management into clinical and research settings.},
}
@article {pmid42496665,
year = {2026},
author = {Pinheiro, NR and Carneiro, CFD and Cancelliero, GS and Nogueira, GO and Almeida, GM and Fernandes, N and Wasilewska-Sampaio, AP and Martins, SM and Felix, A and Amaral, OB and Sebollela, A},
title = {Limitations and Strengths of the SH-SY5Y Neuroblastoma Cell Line as a Model of β-Amyloid Neurotoxicity: Lessons From a Systematic Review and Meta-Analysis.},
journal = {Journal of neurochemistry},
volume = {170},
number = {7},
pages = {e70523},
doi = {10.1111/jnc.70523},
pmid = {42496665},
issn = {1471-4159},
support = {18/10721-0//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de S&#xe3;o Paulo/ ; 22/12904-0//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de S&#xe3;o Paulo/ ; 21/12263-2//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de S&#xe3;o Paulo/ ; 21/10925-8//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de S&#xe3;o Paulo/ ; E-26/200.824/2021//Funda&#xe7;&#xe3;o Carlos Chagas Filho de Amparo &#xe0; Pesquisa do Estado do Rio de Janeiro/ ; E-26/204.061/2024//Funda&#xe7;&#xe3;o Carlos Chagas Filho de Amparo &#xe0; Pesquisa do Estado do Rio de Janeiro/ ; 310813/2021-2//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; //Instituto Serrapilheira/ ; //Coordena&#xe7;&#xe3;o de Aperfei&#xe7;oamento de Pessoal de N&#xed;vel Superior/ ; },
mesh = {Humans ; *Amyloid beta-Peptides/toxicity/metabolism ; *Neuroblastoma/pathology/metabolism ; Cell Line, Tumor ; Cell Survival/drug effects/physiology ; },
abstract = {The SH-SY5Y human neuroblastoma cell line is widely used as an in vitro model of β-amyloid (Aβ) neurotoxicity in Alzheimer's disease (AD). However, the lack of standardized protocols for assessing Aβ toxicity-including differentiation strategies for SH-SY5Y cells-limits the comparability of results across studies. To address these issues, we conducted a systematic review and meta-analysis to evaluate how methodological factors influence Aβ-induced toxicity in SH-SY5Y cells. We included 359 eligible studies encompassing 1192 MTT-based comparisons of cell viability between Aβ-treated and control SH-SY5Y cells. A three-level meta-analysis estimated mean cell viability after Aβ exposure at 63% of control levels (95% CI [61.6; 64.3]), with very high heterogeneity (I[2] = 99.6%). Meta-regression identified significant associations between increased toxicity and higher Aβ concentrations, longer exposure durations, and the use of peptide preparations described as fibrils. Conversely, differentiation protocols, duration, and cell density did not significantly influence toxicity outcomes. Reporting quality was often poor, with frequent omissions regarding cell line origin, authentication, contamination testing, Aβ preparation details, and nature of the experimental unit. Overall, our findings show robust Aβ toxicity in SH-SY5Y cells, primarily driven by dose, exposure time, and Aβ aggregation state, but not cell differentiation status. Our conclusions highlight the critical need for better reporting of Aβ exposure parameters to enhance reproducibility and translational potential in AD research.},
}
@article {pmid42496712,
year = {2026},
author = {Wittmann, FG and Zülke, AE and Vajnberger, M and Luppa, M and Riedel-Heller, SG},
title = {[Modifiable risk and protective factors for dementia: an overview of established and emerging evidence].},
journal = {Bundesgesundheitsblatt, Gesundheitsforschung, Gesundheitsschutz},
volume = {},
number = {},
pages = {},
doi = {10.1007/s00103-026-04279-7},
pmid = {42496712},
issn = {1437-1588},
abstract = {Alzheimer's disease and other dementias are among the most serious widespread diseases, with societal and healthcare-system relevance expected to increase further in the coming years. Projections of the future disease burden are correspondingly concerning. At the same time, considerable progress has been made in research, particularly in the field of risk reduction. A broad range of established protective and risk factors at the individual level has been identified, alongside a growing number of related intervention studies. Increasingly, however, attention is shifting toward population-based measures aimed at reducing dementia cases in the long term.This article provides an overview of the current state of research. First, drawing on recent data on disease burden, established risk factors are summarized. Building on this, more recent and previously less considered potential determinants are discussed. The review further outlines existing intervention approaches and examines the relevance of population-based prevention strategies for public health and health policy.},
}
@article {pmid42496756,
year = {2026},
author = {Sahu, SK and Nayak, M and Samal, A and Jena, S and Pradhan, J and Dandapat, J and Samanta, L and Jena, S},
title = {T3 and curcumin regulates collagen-IV and collagen-VI expression: role in suppression of amyloid-β via TGFβ1-Sp1 signaling in hypothyroid mice brain.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42496756},
issn = {1573-7365},
support = {26913/HED/HE-PTC-WB-02-17//OHEPEE and S&amp;T Department, Government of Odisha/ ; 584/83/OSHEC//OURIIP, OSHEC, Government of Odisha/ ; },
mesh = {Animals ; *Curcumin/pharmacology/therapeutic use ; *Hypothyroidism/metabolism/drug therapy ; *Amyloid beta-Peptides/metabolism/antagonists &amp; inhibitors ; *Triiodothyronine/pharmacology/therapeutic use ; Signal Transduction/drug effects ; Mice ; *Transforming Growth Factor beta1/metabolism ; *Collagen Type IV/metabolism/biosynthesis ; Male ; *Brain/metabolism/drug effects ; Mice, Inbred BALB C ; Sp1 Transcription Factor/metabolism ; },
abstract = {Hypothyroidism has been associated with cognitive disorders and high risk of neurodegenerative disorders like Alzheimer's disease (AD), which is caused by amyloid-β (Aβ) accumulation in brain. The aim of the study is to examine the therapeutic ability of triiodothyronine (T3) and curcumin in regulating two key extracellular matrix proteins (ECM), collagen IV and collagen VI in brain since both drugs have neuroprotective and anti-fibrotic effects. The study further explored the possible role of signaling molecules such as transforming growth factor β1 (TGFβ1) and specificity protein 1 (Sp1) in regulating the effects of T3 and curcumin on Aβ accumulation and ECM protein expression. Experiment was carried on Balb/c mouse model by inducing hypothyroidism with 0.05% PTU followed by treatment of T3, curcumin and a combination of both. The study revealed a significant increase in the expression of collagen IV and VI, along with elevated levels of TGFβ1 and Sp1 signalling proteins, in hypothyroid conditions in response to increased Aβ expression in both the cortex and hippocampus. Western blot and RT-PCR analysis showed that T3 and curcumin treatment downregulate the levels of ECM proteins, the APP gene, Aβ protein, and the signaling factors. The study found that T3 and curcumin treatment downregulates the collagen IV and VI expression by negatively regulating TGFβ1 and Sp1 when expression of APP and Aβ are low. T3 and coadministration of T3 with curcumin more effectively regulate thyroid function and ECM protein expression in both the cortex and hippocampus. Whereas curcumin alone exhibits limited impacts under the experimental conditions in our study, this may due to bioavailability, dosage or treatment duration which need to further investigation. Our results indicate a novel therapeutic approach for understanding Aβ pathology associated with hypothyroidism, emphasizing the potential association between thyroid hormone and nature-based compounds, such as curcumin, in modulating ECM dynamics and neuroprotection.},
}
@article {pmid42496783,
year = {2026},
author = {Roeder, HJ and Leira, EC},
title = {The Neurology of Menopause.},
journal = {Current neurology and neuroscience reports},
volume = {26},
number = {1},
pages = {},
pmid = {42496783},
issn = {1534-6293},
mesh = {Humans ; Female ; *Menopause/physiology ; *Nervous System Diseases/physiopathology ; },
abstract = {PURPOSE OF REVIEW: Menopause is a neuroendocrine process with important implications for neurological health. This review examines the complex, multidirectional relationships between menopause and major central nervous system conditions, including stroke, migraine, epilepsy, multiple sclerosis, Parkinson's disease, and Alzheimer's disease.<br><br>RECENT FINDINGS: Menopause may mark an inflection point for vascular injury, neurodegeneration, and disability accumulation in several neurological conditions. Perimenopausal hormonal fluctuations may exacerbate migraines and seizures in susceptible women. Research increasingly supports the critical window hypothesis for estrogen therapy and highlights the importance of distinguishing reproductive and chronological aging when interpreting neurologic trajectories. Menopause represents an important transition for many conditions. Hormone therapy has heterogenous effects with cognitive benefit in premature ovarian insufficiency, harm related to stroke risk in older women, and greater uncertainty in other conditions. Therefore, individualized risk-benefit assessment is essential. Research gaps remain significant, and menopause should be a priority area for neurologic research.},
}
@article {pmid42496794,
year = {2026},
author = {Chen, K and Zhang, X and Sun, H and Xu, Y and Yang, C},
title = {N[6]-Methyladenosine-Driven Nuclear Export of circKCNN2 Impairs GRP75 Function to Promote Neuronal Apoptosis.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42496794},
issn = {1559-1182},
mesh = {*Apoptosis/physiology/drug effects ; Humans ; *Adenosine/analogs &amp; derivatives/metabolism ; *Neurons/metabolism/pathology ; Active Transport, Cell Nucleus ; Cell Line, Tumor ; *Cell Nucleus/metabolism ; *Membrane Proteins/metabolism ; *HSP70 Heat-Shock Proteins/metabolism ; RNA Methylation ; Epitranscriptome ; },
abstract = {Emerging evidence implicates circular RNAs (circRNAs) in Alzheimer's disease (AD) pathogenesis. Notably, circKCNN2 correlates with clinical dementia severity in AD patients; however, its biological functions and regulatory mechanisms in neuronal systems remain poorly understood. Here, we elucidated the molecular mechanism by which circKCNN2 regulated neuronal apoptosis and delineated the underlying post-transcriptional regulatory axis. Using SH-SY5Y cells as an in vitro neuronal model, we manipulated circKCNN2 expression through overexpression and siRNA-mediated knockdown. Apoptosis was assessed by flow cytometry and TUNEL assays. Methylated RNA immunoprecipitation (MeRIP), RNA immunoprecipitation (RIP), MS2-based RNA pull-down coupled with mass spectrometry, fluorescence in situ hybridization, and nuclear/cytoplasmic fractionation were employed to characterize the underlying mechanism. circKCNN2 overexpression significantly induced apoptosis, whereas its knockdown attenuated apoptosis. circKCNN2 underwent N6-methyladenosine (m[6]A) modification. Mechanistically, METTL3-catalyzed m[6]A modification enabled YTHDC2 binding and facilitated the nuclear export of circKCNN2. Both METTL3 depletion and YTHDC2 overexpression caused nuclear retention and attenuated apoptosis. Furthermore, MS2-based RNA pull-down coupled with mass spectrometry identified GRP75 as a cytoplasmic interactor of circKCNN2. Functionally, GRP75 overexpression rescued circKCNN2-induced apoptosis. Our findings revealed a novel "modification-localization-function" cascade wherein the METTL3-YTHDC2-m[6]A axis dictates circKCNN2 nuclear-cytoplasmic trafficking and the subsequent inhibition of GRP75, thereby driving neuronal apoptosis. This mechanism established circKCNN2 as a pathogenic driver in AD and highlighted the m[6]A regulatory machinery as a potential target for further investigation.},
}
@article {pmid42496823,
year = {2026},
author = {Awwad, ZM},
title = {Dapagliflozin ameliorates Alzheimer's disease in rats via stimulating the protective arm of renin angiotensin system and suppressing neuroinflammation.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42496823},
issn = {1568-5608},
abstract = {Alzheimer's disease (AD) is associated with renin angiotensin system (RAS) overactivation that stimulates amyloid β-induced neurodegeneration. Activation of angiotensin II type 1 (AT1) receptor impairs the protective phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathway. The combination between angiotensin converting enzyme 2 (ACE2)/ angiotensin 1-7 (Ang 1-7) /Mas receptor (MAS1) axis activation and PI3K/Akt stimulation counteracts AT1-induced apoptosis. Dapagliflozin (DAPA) alters the imbalance between the two RAS arms favoring the protective arm. Accordingly, the aim of the current study was to evaluate the possible neuroprotective effects of DAPA in guarding against scopolamine (SCO)-induced AD in rats via inhibiting RAS classical arm, and activating RAS protective arm, as well as PI3K/Akt pathway. DAPA administration suppressed ACE expression and reduced the levels of Ang II and AT1 in the hippocampi, while elevated the hippocampal levels of ACE2 and Ang 1-7 in addition to boosting MAS1 hippocampal expression. Of note, DAPA prominently augmented the level of PI3K. Also it enhanced the activity of protein kinase A. Furthermore, the hippocampal levels of caspase-3, cytochrome-c, interleukin-6 and nuclear factor kappa B were suppressed, while guanine nucleotide-binding protein alpha-3 level was elevated by DAPA administration. DAPA also attenuated the histopathological SCO-induced damage in rats and enhanced their recognition memory and learning in novel object recognition test and Y-maze spontaneous alternation test. Hence, the current results represent the first evidence for proving that DAPA-induced activation of the protective RAS arm suppressed the cognitive deficits in SCO-induced AD in rats.},
}
@article {pmid42496889,
year = {2026},
author = {Altves, S and Guclu, E and Yetisgin, E and Bilecen, K and Vural, H},
title = {Systems pharmacology and targeted transcriptional profiling suggest the putative neuroprotective role of Leuconostoc mesenteroides in an in vitro Alzheimer's disease model.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42496889},
issn = {1573-4978},
mesh = {*Alzheimer Disease/metabolism/genetics/drug therapy ; Humans ; Amyloid beta-Peptides/metabolism ; *Neuroprotective Agents/pharmacology ; *Leuconostoc mesenteroides/metabolism ; Cell Line, Tumor ; Mitochondria/metabolism/drug effects ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Gene Expression Profiling/methods ; Mitochondrial Dynamics/drug effects ; Network Pharmacology/methods ; Molecular Docking Simulation ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder driven by amyloid-beta (Aβ) accumulation, mitochondrial failure, and neuroinflammation. While probiotics show therapeutic potential via the gut brain axis, the molecular mechanisms remain poorly understood. This study investigated the neuroprotective potential of Leuconostoc mesenteroides lysate and its bioactive metabolites in an Aβ-induced SH-SY5Y neuroblastoma model.<br><br>METHODS: SH-SY5Y cells were challenged with A&#x3b2; and treated with L. mesenteroides lysate. Neuroprotective effects were evaluated via ROS accumulation, SOD1, APOE, NOS2, and mitochondrial dynamics (MFF, OPA1) using qPCR and WB. Potential mechanisms of action were explored computationally through integrated genome mining (antiSMASH 7.0), molecular docking (CB-Dock2), and systems pharmacology analysis (STRING/KEGG/R-studio) to identify candidate metabolites and host targets.<br><br>RESULTS: L. mesenteroides lysate significantly attenuated A&#x3b2;-induced ROS levels and upregulated SOD1, enhancing antioxidant capacity. The lysate effectively downregulated APOE expression and restored mitochondrial homeostasis by reducing mitochondrial fission (MFF) and promoting fusion (OPA1). In silico analysis predected phytoene as a primary bioactive metabolite with significant theoretical binding affinity for APOE. Systems biology mapping revealed highly significant enrichment in PPAR signaling and cholesterol metabolism pathways (FDR&#x2009;<&#x2009;10&#x207b;&#x2075;). Specifically, Cellular Component analysis highlighted robust interactions within protein-lipid complexes (FDR&#x2009;=&#x2009;1.98e-16).<br><br>CONCLUSION: L. mesenteroides lysate counteracts A&#x3b2;-induced neurotoxicity by modulating oxidative stress and restoring mitochondrial bioenergetics. Collectively, our findings suggest a theoretical Phytoene-PPAR-APOE signaling axis as a predictive framework for the observed cellular effects. We emphasize that phytoene represents a predicted candidate metabolite requiring future chemical characterization and biological validation.},
}
@article {pmid42497020,
year = {2026},
author = {Li, C and Jiang, W and Lu, M},
title = {Metabolic endotoxemia in metabolic and neurodegenerative diseases.},
journal = {Acta biochimica et biophysica Sinica},
volume = {},
number = {},
pages = {},
doi = {10.3724/abbs.2026130},
pmid = {42497020},
issn = {1745-7270},
abstract = {Metabolic diseases, which include obesity, type 2 diabetes, atherosclerosis, and metabolic dysfunction-associated steatotic liver disease (MASLD), are significant global health challenges. Patients with these conditions frequently exhibit gut dysbiosis and compromised gut barrier integrity, which lead to excessive translocation of Gram-negative bacterial lipopolysaccharide (LPS or endotoxin) from the gut lumen into the systemic circulation. This results in chronically elevated systemic LPS levels, a condition termed "metabolic endotoxemia". Gut-derived LPS may stimulate inflammatory responses and oxidative stress when it translocates and is recognized by host Toll-like receptor 4 (TLR4) and caspase-4/-5/-11. Metabolic endotoxemia is a primary trigger for the low-grade inflammation that promotes the development of metabolic diseases. Emerging evidence also indicates that metabolic endotoxemia acts as a key driver in the pathogenesis of neurodegenerative disorders, such as Alzheimer's disease, by promoting chronic neuroinflammation. In this review, we discuss: (1) the molecular structure of LPS that determines its bioactivity and its recognition by host cells, (2) host regulation of its bioactivity, (3) its translocation from the gut lumen into the systemic circulation, and (4) how metabolic endotoxemia contributes to obesity, type 2 diabetes, atherosclerosis, MASLD, and Alzheimer's disease. We conclude by exploring potential interventions aimed at preventing or mitigating metabolic endotoxemia by promoting LPS degradation and inactivation.},
}
@article {pmid42497412,
year = {2026},
author = {Ghani, Z and Thant, PE and Saha, S and Anderberg, P and Aparicio, MQ and Barnestein-Fonseca, P and Cellek, S and Cleries, FM and Garolera, M and Guerrero-Pertiñez, G and Hayden, K and Moore, C and Zhang, J and Berglund, JS and Jarl, J},
title = {Effects of the Digital App "Support, Monitoring and Reminder Technology for Mild Dementia" (SMART4MD) on People With Mild Cognitive Impairment and Their Informal Caregivers: 18-Month Multicenter Pragmatic Randomized Controlled Trial.},
journal = {Journal of medical Internet research},
volume = {28},
number = {},
pages = {e83123},
doi = {10.2196/83123},
pmid = {42497412},
issn = {1438-8871},
mesh = {Humans ; *Caregivers/psychology ; *Cognitive Dysfunction/therapy ; *Mobile Applications ; *Reminder Systems ; Aged ; Quality of Life ; Male ; Female ; Telemedicine ; Aged, 80 and over ; *Dementia ; Digital Health ; Sweden ; Adherence Interventions ; Spain ; },
abstract = {BACKGROUND: Previous research has shown that mobile health (mHealth) interventions are effective in reminding older adults with chronic conditions about health care appointments and promoting adherence to medication schedules. However, the evidence is limited by the short duration and poor quality of the interventions.<br><br>OBJECTIVE: We evaluated the effectiveness of the Support, Monitoring and Reminder Technology for Mild Dementia (SMART4MD) tablet app in improving the quality of life (QoL) of people with mild cognitive impairment (PwMCI) and their caregivers through medication reminders and health care appointment alerts.<br><br>METHODS: An 18-month pragmatic randomized controlled trial was conducted in Spain and Sweden from December 2017 to September 2020 and included 1078 PwMCI and their informal caregivers.<br><br>RESULTS: For PwMCI, the intervention improved the primary outcome, composite Quality of Life in Alzheimer's Disease (QoL-AD) scale, at 18 months (mean difference 0.75, 95% CI 0.07-1.42; P=.03), and a similar effect was observed at 6 months (mean difference 0.73, 95% CI 0.09-1.36; P=.02). Confirmatory secondary outcomes for PwMCI, including medication adherence (P=.12) and Mini-Mental State Examination (MMSE) score (P=.45), did not differ significantly between groups at the 18-month follow-up. Exploratory analyses showed higher total accumulated quality-adjusted life years (QALYs) at 6 months for PwMCI (mean difference 0.035, 95% CI 0.02-0.05; nominal P<.001), informal caregivers (mean difference 0.050, 95% CI 0.04-0.07; nominal P<.001), and dyads (mean difference 0.085, 95% CI 0.06-0.11; nominal P<.001). A dropout rate of approximately 40% (429/1083, 39.61%) was observed in both the intervention and control groups.<br><br>CONCLUSIONS: The SMART4MD intervention was associated with a modest improvement in PwMCI's QoL as measured by the composite QoL-AD score. Evidence for benefits among informal caregivers and dyads was less consistent and should be interpreted as exploratory. Nominally significant findings for exploratory outcomes should be interpreted with caution, as they were not adjusted for multiplicity.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov NCT03325699; https://clinicaltrials.gov/ct2/show/NCT03325699.<br><br>RR2-10.2196/13711.},
}
@article {pmid42497445,
year = {2026},
author = {Tatekawa, H and Oura, T and Takeda, A and Omori, A and Atsukawa, N and Matsushita, S and Horiuchi, D and Takita, H and Mitsuyama, Y and Ban, Y and Shimono, T and Pfeuffer, J and Ueda, D and Itoh, Y and Miki, Y},
title = {Amyloid-β-Related Cortical Susceptibility Alterations in Individuals Under Assessment for Alzheimer's Disease: A χ-Separation Study.},
journal = {Journal of magnetic resonance imaging : JMRI},
volume = {},
number = {},
pages = {},
doi = {10.1002/jmri.70458},
pmid = {42497445},
issn = {1522-2586},
support = {25K19115//JSPS KAKENHI/ ; //Takeda Science Foundation/ ; },
abstract = {BACKGROUND: Assessment of amyloid-β (Aβ) burden and associated iron deposition and neurodegeneration is important for Alzheimer's disease (AD) management. Although quantitative susceptibility mapping (QSM) detects iron and myelin changes, conventional metrics suffer from signal cancelation between paramagnetic and diamagnetic components. Consequently, spatial interactions between these independent susceptibility sources and Aβ burden remain unestablished.<br><br>PURPOSE: To investigate spatial associations between regional A&#x3b2; burden and independent paramagnetic and diamagnetic susceptibility sources using &#x3c7;-separation.<br><br>STUDY TYPE: Prospective.<br><br>POPULATION: A total of 77 participants with mild cognitive impairment or dementia (mean age, 74&#x2009;years; women, 50) examined using QSM and amyloid positron emission tomography (PET) ([18]F-flutemetamol or [18]F-florbetapir).<br><br>FIELD STRENGTH/SEQUENCE: 3&#x2009;T/QSM (3-dimensional multi-echo gradient-echo sequence).<br><br>ASSESSMENT: &#x3c7;-separation decomposed QSM data into paramagnetic (&#x3c7;-para) and diamagnetic (&#x3c7;-dia) components. Centiloid-scale maps standardized PET quantification for voxel-wise analysis. The spatial relationship between A&#x3b2; load and susceptibility metrics was analyzed using voxel-wise correlations within AD-signature cortical regions.<br><br>STATISTICAL TESTS: Voxel-wise spatial associations between Centiloid values and QSM metrics were evaluated using Pearson's coefficients. Spatial association was considered statistically significant if the 99% confidence interval (CI) did not cross zero.<br><br>RESULTS: Conventional QSM showed near-zero cortical susceptibility and obscured pathological details owing to physiological cancelation. &#x3c7;-separation unmasked susceptibility sources. Local A&#x3b2; deposition was consistently associated with reduced absolute &#x3c7;-dia across cortical regions (mean r range: -0.267 to -0.098; all 99% CIs did not cross zero), consistent with alterations in net diamagnetic susceptibility sources, potentially involving myelin-related components. &#x3c7;-para showed weaker and regionally heterogeneous associations with A&#x3b2; burden, with a positive association most evident in the precuneus (mean r&#x2009;=&#x2009;0.072, 99% CI: 0.052-0.092).<br><br>DATA CONCLUSION: &#x3c7;-separation reveals region-specific cortical alteration associated with regional A&#x3b2; pathology. By separating these susceptibility sources, this method may provide complementary information to conventional QSM, offering a refined, noninvasive approach for characterizing amyloid-associated tissue changes in AD.<br><br>EVIDENCE LEVEL: 2.<br><br>TECHNICAL EFFICACY: Stage 2.},
}
@article {pmid42483783,
year = {2026},
author = {Wen, Y and Zhan, S and Duan, Y and Pang, M and Yan, J and Deng, M and Fan, H},
title = {Efficacy and Safety of Mesenchymal Stem Cell Therapy for Alzheimer's Disease: A Systematic Review and Meta-Analysis.},
journal = {Stem cells and development},
volume = {},
number = {},
pages = {15473287261468404},
doi = {10.1177/15473287261468404},
pmid = {42483783},
issn = {1557-8534},
abstract = {Alzheimer's disease (AD) is the leading cause of dementia, and effective disease-modifying therapies remain limited. Mesenchymal stem cells (MSCs) have shown therapeutic potential because of their neuroprotective and immunomodulatory properties, but clinical evidence remains inconclusive. We systematically evaluated the efficacy and safety of MSC therapy in AD. Following the PRISMA 2020 guidelines and a PROSPERO-registered protocol (CRD420261329891), we searched PubMed, the Cochrane Library, Embase, Web of Science, CNKI, and Wanfang from inception to March 1, 2026. Clinical studies of patients with primary AD treated with MSCs were included. Outcomes covered cognition, daily function, neuropsychiatric symptoms, biomarkers, imaging findings, and adverse events. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were pooled using R. Risk of bias was assessed with the RoB 2 tool, and evidence certainty was assessed with GRADE. Six studies involving 196 patients were included. Overall analyses showed no significant improvement in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) or Mini-Mental State Examination (MMSE) at 12-16 weeks or 24-26 weeks after MSC treatment versus placebo, with substantial heterogeneity. Dose-stratified analyses suggested significant benefits of low-dose MSCs on ADAS-Cog (SMD = -1.33, 95% CI: -2.35 to -0.31) and MMSE (SMD = 2.59, 95% CI: 0.52-4.66). MSC therapy significantly improved Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL; SMD = 3.27, 95% CI: 1.79-4.75), but not Neuropsychiatric Inventory (NPI) or Quality of Life in Alzheimer's Disease (QOL-AD) scale. Biomarker analyses showed no significant overall effects on Aβ42 or total tau, although subgroup analyses suggested possible increases in Aβ42 and reductions in total tau at certain doses. Imaging data from two studies indicated potential protective effects on hippocampal atrophy. MSC therapy was generally well-tolerated, although intracerebroventricular administration was associated with more transient adverse events. Evidence certainty was low to very low for most outcomes. MSC therapy for AD appears feasible and relatively safe, with potential cognitive and disease-modifying effects. However, current clinical evidence remains insufficient to confirm its efficacy.},
}
@article {pmid42483877,
year = {2026},
author = {S, V and K, V and Raja, R and A, R},
title = {Mathematical mapping of circadian genes in Alzheimer's disease.},
journal = {Chronobiology international},
volume = {},
number = {},
pages = {1-15},
doi = {10.1080/07420528.2026.2705386},
pmid = {42483877},
issn = {1525-6073},
abstract = {Sleep-wake disturbances commonly occur in Alzheimer's disease (AD). However, the precise mechanisms underlying the breakdown of the circadian gene network remain elusive. This study examined 23 circadian genes in 253 post-mortem samples (80 AD, 173 controls) from the hippocampus, entorhinal cortex, and superior frontal cortex, using three metrics: a Circadian Disruption Index (CDI), a Network Coherence Score (NCS), and a Circadian Entropy Index (CEI). AD brains showed a modest overall shift in circadian gene expression (CDI = 0.101), concentrated mainly in CRY2, PER3, and PER2. The PER3-CRY2 gene pair showed the most significant co-expression alteration of any gene pair examined, a 60.4% reduction in coherence (∆ρ 0.604). Network-wide coherence (NCS) and CEI, averaged across all 23 genes, did not differ significantly between the AD and control groups (NCS: 6.7% reduction, p = 0.356; CEI: -0.4% change, p = 0.923), suggesting the alteration is concentrated in specific gene relationships rather than global network collapse. Regional CDI did not differ significantly across brain areas (p = 0.724). A 10-gene panel classified AD versus control with cross‑validated area under the curve (AUC) = 0.759 ± 0.069 (nested cross-validation AUC = 0.759 ± 0.069, zero optimism bias), though external validation in an independent cohort (GSE5281) did not exceed chance level (AUC = 0.500). These results identify the PER3-CRY2 co-expression change as a specific, reproducible molecular signature of AD and support a validated circadian gene-based classifier, while showing that global circadian network disruption is not a consistent feature of this cohort. The findings identify a localized alteration in circadian gene co-expression in AD brain tissue, with potential implications for future therapeutic targeting of the PER3-CRY2 interaction.},
}
@article {pmid42483925,
year = {2026},
author = {Li, W and Guo, C and Jin, Y and Ji, H and Zhang, L and Li, W and Zhang, W and Fu, L},
title = {Ganoderma sinense Polysaccharides Improve Cognition in a Mouse Model of Alzheimer's Disease by Modulating Gut Microbiota and Short-Chain Fatty Acid Metabolism.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050473800260622054102},
pmid = {42483925},
issn = {1875-5828},
abstract = {INTRODUCTION: The number of patients with Alzheimer's Disease (AD) worldwide is expected to reach 152 million by 2050, but developing an effective AD treatment remains challenging. This study purified two polysaccharides (GSP1 and GSP2) from Ganoderma sinense, a traditional Chinese medicine, and investigated their potential therapeutic effects against AD.<br><br>MATERIALS AND METHODS: GSP1 and GSP2 were purified and characterized for key physicochemical properties, including monosaccharide composition and molecular weight. In vitro neuroprotective efficacy was evaluated using glutamate-challenged SH-SY5Y cells. For in vivo assessment, an AlCl&#x2083;/D-galactose induced AD mouse model was established to quantify cognitive/memory enhancement. Multiomic analysis of the gut microbiota, Short-Chain Fatty Acid (SCFAs) metabolomics, and behavioural tests were conducted to elucidate the therapeutic mechanisms of GSP1.<br><br>RESULTS: Both GSP1 and GSP2 conferred neuroprotection against toxin-induced damage. Notably, GSP1 demonstrated superior efficacy compared with GSP2, significantly enhancing cognitive/ memory performance and reducing amyloid-&#x3b2; plaque deposition. Furthermore, GSP1 changed gut microbial diversity and SCFA metabolic profiles. Critical genus-level correlations emerged: Turicibacter, Jeotgalicoccus, and Staphylococcus were positively associated with therapeutic outcomes, whereas Odoribacter was negatively associated.<br><br>DISCUSSION: Natural polysaccharides, particularly GSP1, demonstrate therapeutic potential against AD by modulating gut microbiota. Mechanistically, this effect is linked to reshaping microbial communities and affecting the production of neuroprotective SCFAs. Although these findings position GSP1 as a promising AD therapeutic candidate, deeper exploration of gut-brain axis mechanisms remains essential for clinical translation.<br><br>CONCLUSION: GSP1 emerges as a promising therapeutic candidate for AD, offering a new approach to developing AD-targeted pharmaceuticals and nutraceuticals.},
}
@article {pmid42483984,
year = {2026},
author = {Silva-Rodríguez, J and Zhang, L and Kleineidam, L and López-González, FJ and Wagner-Reguero, S and Martínez-Castillo, M and Sogorb-Esteve, A and Guamán-Chulunchana, ME and Pastor, AB and Moreno, N and Ruiz-Calvo, A and Sánchez-Martín, C and Alfayate, E and Molero-Cartón, M and Valeriano-Lorenzo, EL and Frades-Payo, B and Valentí, M and Zea-Sevilla, MA and Moscoso, A and Ramírez, A and Martino-Adami, P and Riedel-Heller, SG and Scherer, M and Jeromin, A and Calero, M and Del Ser, T and Schneider, A and Grothe, MJ and Sánchez-Juan, P},
title = {Prognostic value of plasma %p-tau217 in cognitively unimpaired older adults.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71599},
pmid = {42483984},
issn = {1552-5279},
support = {//CIEN&#xa0;Foundation/ ; //Reina Sof&#xed;a&#xa0;Foundation/ ; PI24/00089//Instituto de Salud Carlos III/ ; PI23/01314//Instituto de Salud Carlos III/ ; PMP22/00022//Instituto de Salud Carlos III/ ; RYC2023-043746-Y//Ministerio de Ciencia e Innovaci&#xf3;n/ ; CNS2024-154295//Ministerio de Ciencia e Innovaci&#xf3;n/ ; //Hertie Network of Excellence in Clinical Neuroscience/ ; 101155955//European Union's Horizon Europe research and innovation programme/ ; //Cure Alzheimer&#xa0;Foundation/ ; //the Alzheimer Forschung&#xa0;Initiative/ ; NW21-049A-F//Ministry of Culture and Science of the State of North Rhine-Westphalia/ ; //German Ministry of Education and Research/ ; //Verum Foundation/ ; //the Network of University Medicine/ ; //Target ALS/ ; FZK01EK2102A//German Federal Ministry of Education and Research/ ; FZK01GP2213A//German Federal Ministry of Education and Research/ ; FZK 01GP2213A//Bundesministerium f&#xfc;r Forschung und Technologie/ ; NW21-049 A-F//Ministerium f&#xfc;r Kultur und Wissenschaft des Landes Nordrhein-Westfalen/ ; N/A//Cure Alzheimer's Fund/ ; EXC2151-39087304//Deutsche Forschungsgemeinschaft/ ; },
mesh = {Humans ; *tau Proteins/blood ; Prognosis ; Female ; Disease Progression ; Aged ; Male ; Biomarkers/blood ; *Cognitive Dysfunction/blood/diagnosis ; Dementia/blood/diagnosis ; Phosphorylation ; Longitudinal Studies ; Aged, 80 and over ; },
abstract = {INTRODUCTION: We evaluated the prognostic value of baseline plasma phosphorylated tau 217 ratio (%p-tau217) for predicting long-term progression in cognitively unimpaired (CU) older adults.<br><br>METHODS: We analyzed 982 community-dwelling individuals followed annually for up to 12 years. Baseline %p-tau217 levels were quantified by mass spectrometry and stratified into four strata using previously defined cut-offs. Outcomes included longitudinal changes in cognition, neurodegeneration, and progression to mild cognitive impairment (MCI)/dementia. Results were replicated with immunoassays in the same and an independent primary care cohort (n&#xa0;=&#xa0;1204).<br><br>RESULTS: Participants with Elevated/High %p-tau217 exhibited accelerated cognitive decline, hippocampal atrophy, and significantly higher risks of progression to MCI (hazard ratio [HR]&#xa0;>&#xa0;6.0) and dementia (HR&#xa0;>&#xa0;9.9). The Low group demonstrated a 92.2% 10-year negative predictive value for any progression.<br><br>DISCUSSION: Our results suggest that %p-tau217 is a robust prognostic biomarker, accurately distinguishing CU individuals at minimal risk from those at high risk of future AD-related clinical and neurodegenerative decline. Similar performance was achieved by immunoassays.},
}
@article {pmid42484400,
year = {2026},
author = {Zawadzki, S and Okła, E and Ortega López, P and de la Mata, FJ and Ionov, M and Kreišmane, M and Skrastiņa, D and Jansons, J and Bryszewska, M and Miłowska, K},
title = {Multilevel Assessment of a Carbosilane Dendrimer-siRNA Nanoplatform: Cellular Compatibility, Blood-Brain Barrier Model Integrity, and Murine Model Biodistribution.},
journal = {ACS applied materials &amp; interfaces},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsami.6c06027},
pmid = {42484400},
issn = {1944-8252},
abstract = {The tight regulation of bidirectional solute flux between the systemic circulation and neural tissue by the blood-brain barrier (BBB) remains a principal obstacle to effective pharmacotherapy of the central nervous system. In this study, we evaluate the biocompatibility and biodistribution of a novel third-generation PEGylated carbosilane dendrimer (G3Si PEG6000) and its siRNA dendriplex with an APOE4-directed siRNA relevant to late-onset Alzheimer's disease using a tiered, upstream strategy that progresses from BBB-relevant monocultures to a capillary-weighted BBB model and in vivo/ex vivo biodistribution in mice, in accordance with current recommendations for nanomaterial testing. In endothelial cells, pericytes, and astrocytes, mitochondrial/redox profiling (MTT, DCF-ROS, and JC-1 ΔΨm) defined tolerated exposure ranges. Complexation with siRNA consistently attenuated apparent cytotoxicity across cell types, yet both free and complexed formulations elicited modest ROS and dose-dependent ΔΨm depolarization, indicating persistent mitochondrial stress. In the BBB model, responses were concentration- and formulation-dependent: 10 µM free dendrimers produced sustained impedance and nuclear confluence loss with sheet-like detachment, whereas the 0.1-2.5 µM free dendrimer and the dendriplex induced transient, recoverable perturbations or increases in impedance and proliferation. In vivo, whole-body IVIS imaging demonstrated prolonged systemic exposure for the dendriplex and an ex vivo kidney-dominant, liver-secondary distribution; no robust dendriplex signal was detected in brain fluorescence by planar NIR-I IVIS under the applied acquisition conditions. Collectively, these data indicate that siRNA complexation broadens the functional window at the BBB model with partially recoverable barrier effects and improved systemic exposure, while not substantially reducing mitochondrial or oxidative stress responses. The results provide a mechanistically informed basis for dose optimization and efficacy testing of this dendrimer-siRNA platform in CNS indications and for advancing this platform in further investigations targeting Alzheimer's disease.},
}
@article {pmid42484409,
year = {2026},
author = {Tulloch, R and Gaffiero, D},
title = {Menopause, brain health and hormone replacement therapy: gaps in knowledge and policy solutions from a Scottish perspective.},
journal = {Post reproductive health},
volume = {32},
number = {1},
pages = {77-81},
doi = {10.1080/20533691.2026.2631221},
pmid = {42484409},
issn = {2053-3705},
mesh = {Humans ; Female ; Scotland ; *Menopause/physiology/psychology ; Women's Health ; *Health Policy ; *Brain/physiology ; *Hormone Replacement Therapy ; Health Knowledge, Attitudes, Practice ; Alzheimer Disease/prevention &amp; control ; Primary Health Care ; Quality of Life ; },
abstract = {PURPOSE: This commentary argues for the systematic integration of brain health into menopause care and policy in the United Kingdom (UK). Using Scotland as a strategically bounded case study, it examines persistent knowledge gaps among women and primary care professionals and their implications for equitable menopause care.<br><br>KEY ISSUES: Menopause involves significant neuroendocrine changes that affect brain metabolism, structure, and cognition, contributing to women's disproportionate Alzheimer's disease risk. Although hormone replacement therapy may alleviate neurological and cognitive symptoms - and may offer neuroprotective benefits when initiated early - clinical uncertainty, stigma, and inconsistent guidance continue to delay recognition, support, and treatment. These gaps translate into avoidable cognitive decline, reduced quality of life, and marked inequities in access to menopause care.<br><br>IMPLICATIONS: Targeted primary care training, coherent public communication, and UK-specific investment in evidence-based menopause services are urgently required. This programme of research is situated within Scotland as a strategically bounded, devolved health system, allowing for a focused examination of how brain health is addressed within menopause policy and practice. By embedding brain health within Scotland's Women's Health Plan, the findings will inform future comparative and UK-wide research and contribute to the development of equitable, person-centred, and brain-health informed menopause care across the lifespan.},
}
@article {pmid42484463,
year = {2026},
author = {Chen, Y and Kwapong, WR and Chen, X and Gao, Y and Chu, M and Zhang, X and Wu, L},
title = {Retinal structural and microvascular alterations as biomarkers of cerebral pathology and cognitive decline in Alzheimer's disease: An OCT/OCTA study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261470439},
doi = {10.1177/13872877261470439},
pmid = {42484463},
issn = {1875-8908},
abstract = {BackgroundRetinal structural and microvascular alterations detected by optical coherence tomography (OCT) and OCT angiography (OCTA) have emerged as promising biomarkers of Alzheimer's disease (AD). However, the extent to which retinal changes reflect cerebral neurodegenerative and vascular pathology and contribute to cognitive impairment remains incompletely characterized.ObjectiveTo investigate the relationships among retinal OCT/OCTA metrics, cerebral neuroimaging markers, and global cognitive performance in patients with AD.Methods115 AD and 101 cognitively unimpaired controls underwent OCT/OCTA imaging, 3.0T brain magnetic resonance imaging, and neuropsychological assessment. Retinal structural measures, including peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell-inner plexiform layer (GCIPL) thicknesses, and retinal microvascular densities of the superficial vascular complex (SVC) and deep vascular complex were analyzed alongside white matter hyperintensity (WMH) volume, hippocampal volume, and cerebral small vessel disease (SVD) burden.ResultsCompared with controls, patients with AD exhibited significantly thinner pRNFL and GCIPL and lower SVC density (all p < 0.01). Retinal structural and microvascular alterations were associated with greater WMH burden, hippocampal atrophy, increased SVD burden, and lower Mini-Mental State Examination and Montreal Cognitive Assessment scores (all p < 0.05). Significant interactions were observed between GCIPL thickness and periventricular WMH volume in relation to cognitive performance. Mediation analyses demonstrated that WMH volume and SVD burden partially mediated the association between reduced SVC density and cognitive impairment.ConclusionsRetinal OCT/OCTA metrics are associated with cerebral neurodegenerative and vascular abnormalities and reflect cognitive dysfunction in AD, supporting their potential utility as accessible, noninvasive biomarkers for disease assessment and monitoring.},
}
@article {pmid42484467,
year = {2026},
author = {Ramos-Henderson, M and Aliaga-Gallardo, P and Aguilar-Riveros, C and Fuentes, L and Calderón, C and Domic-Siede, M},
title = {Associations between higher-order executive planning and subjective cognitive decline in middle-aged individuals.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261470712},
doi = {10.1177/13872877261470712},
pmid = {42484467},
issn = {1875-8908},
abstract = {BackgroundSubjective cognitive decline (SCD) is a recognized risk factor for future objective cognitive impairment and dementia. Although widely studied in older adults, SCD during midlife remains underexplored, despite this period representing a critical window for early detection. Higher-order executive functions, particularly cognitive planning, may be especially sensitive to subtle cognitive changes at this stage.ObjectiveTo examine the association between higher-order executive function performance and subjective cognitive decline in middle-aged individuals.MethodsThis cross-sectional study included 167 community-dwelling middle-aged adults (45-60 years) with SCD and normal global cognition. Participants completed the Subjective Cognitive Decline Questionnaire (SCDq), mood and sleepiness measures, structured executive function tests, and the Zoo Map Test (ZMT) to assess higher-order executive planning. Group comparisons, correlation analyses, and hierarchical linear regressions were performed.ResultsHigher SCD levels were associated with longer planning times and more planning errors on the ZMT. No associations were observed between SCD and global cognitive performance or structured executive function measures. In the hierarchical regression model, mood symptoms and daytime sleepiness explained 23% of SCD variance, while higher-order executive planning measures accounted for an additional 8.4%, yielding a final hierarchical model explaining 33.6% of the variance. Fully adjusted simultaneous model showed the same pattern.ConclusionsSCD in midlife is associated with subtle differences in higher-order executive functioning that emerge under high cognitive demand. Ecologically valid executive tasks may improve early detection of individuals at risk for future objective cognitive decline beyond traditional neuropsychological measures.},
}
@article {pmid42484558,
year = {2026},
author = {Arnold, MR and Westaway, SK and Woltjer, RL and Gray, NE and Quinn, JF},
title = {E326K GBA polymorphism is associated with clinical and pathological features of synucleinopathy in the absence of overt Parkinson's disease or Lewy body dementia.},
journal = {Journal of Parkinson's disease},
volume = {},
number = {},
pages = {1877718X261468542},
doi = {10.1177/1877718X261468542},
pmid = {42484558},
issn = {1877-718X},
abstract = {Heterozygote carriers of Gaucher's disease mutations and other polymorphisms in the glucocerebrosidase (GBA) gene show an increased incidence of Parkinson's disease. We hypothesized that common GBA polymorphisms would be associated with subtle parkinsonian features, mild cognitive impairment, and "silent" Lewy body (LB) pathology in aging individuals without a clinical diagnosis of parkinsonism. The most prevalent GBA variants, T369M and E326K, appear in the general population at rates of approximately 0.6% and 1%, respectively. We evaluated 845 participants from the Oregon Alzheimer's Disease Research Center (OADRC) with SNP data generated by the National Centralized Repository of Alzheimer's Disease (NCRAD). Twenty-one subjects were E326K carriers and eighteen were T369M carriers. Clinical measures and postmortem neuropathology were compared between each SNP group and non-carriers. Although there were no statistically significant clinical differences related to synucleinopathy across groups, neuropathological analyses revealed a significantly higher prevalence of LB pathology in E326K carriers compared to T369M carriers. When stratifying each genetic group by LB status (LB+ or LB-), LB+ E326K carriers demonstrated a significant reduction in Mini-Mental State Examination (MMSE) scores compared with LB- non-carriers and a modest decrease compared with T369M carriers. These preliminary findings from a small, uni-center cohort suggest that the E326K GBA polymorphism may predict LB pathology and subtle cognitive decline in aging individuals who lack overt parkinsonian symptoms. Further validation in a larger cohort is warranted. Identifying at-risk individuals through targeted genetic screening may ultimately support earlier intervention and preventative care strategies.},
}
@article {pmid42484559,
year = {2026},
author = {Ashar, MS and Anwar, M and Singh, AK and Pradhan, R and Gupta, A and Chakrawarty, A and Haldar, P and Tripathi, M and Dey, S},
title = {Quantitative correlation between extracellular matrix protein degradation and the progression of neurodegeneration in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261470815},
doi = {10.1177/13872877261470815},
pmid = {42484559},
issn = {1875-8908},
abstract = {BackgroundThe extracellular matrix (ECM) supports synaptic connections. Breakdown of ECM net component perineuronal nets (PNN) loses synaptic plasticity and causes the symptoms of neurological disorder like Alzheimer's diseases (AD).ObjectiveThis study analyzed PNN proteins and Tenascin-C (TNC), in the blood of AD, mild cognitive impairment (MCI) patients, and geriatric controls (GC), with correlation with tau and p-tau levels.MethodsThis case control study included 77 AD, 53 MCI patients, and 51 GC. Serum PNN and TNC levels were measured by surface plasmon resonance (SPR) method and validated by western blot. Statistical analyses included Kruskal-Wallis, logistic regression, Spearman correlation and receiver operating curve.ResultsPNN proteins and TNC were significantly elevated in AD compared to MCI and GC. Aggrecan and versican showed strong discriminatory power for AD from MCI, while TNC distinguished MCI from GC, indicating its potential for early detection of cognitive decline. Higher protein levels correlated with lower cognitive scores. Western blot result was consistent with SPR findings.ConclusionsThese results emphasize the significance of ECM proteins as biomarkers for cognitive impairments, showcasing their diverse diagnostic capabilities for AD. These findings provide further support for the involvement of PNN proteins in the pathophysiology of AD during early stage.},
}
@article {pmid42484690,
year = {2026},
author = {Yao, Q and Han, X and Cui, T and Li, D and Shan, A and Wang, X and Li, S and Luan, H and Zhu, Y and Wen, B and Sun, Y and Li, C and Sun, Q and Wei, C},
title = {Serial failure of the brain clearance continuum in Alzheimer's disease: mechanisms and therapeutic perspectives.},
journal = {Journal of neurology},
volume = {273},
number = {8},
pages = {},
pmid = {42484690},
issn = {1432-1459},
support = {2021ZD0201802//Innovation of Science and Technology 2030 - Major Project on Brain Science and Brain-Inspired Intelligence Research/ ; 82471450//National Nature Science Foundation of China/ ; XCSTS-SD2024-02//Xicheng District Science and Technology Special Project/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/physiopathology/therapy ; Animals ; *Brain/metabolism/physiopathology ; *Glymphatic System/metabolism/physiopathology ; *Choroid Plexus/metabolism/physiopathology ; Amyloid beta-Peptides/metabolism ; Meninges/metabolism ; *Cerebrospinal Fluid/metabolism ; },
abstract = {Alzheimer's disease (AD) is usually regarded as a neurodegenerative disorder defined by amyloid-β (Aβ) deposition and abnormal tau accumulation. Increasing evidence suggests that reduced clearance of metabolic waste and pathological proteins from the brain also contributes to disease onset and progression. Previous studies have often considered choroid plexus (CP) function, glymphatic exchange, and meningeal lymphatic drainage as separate clearance processes. A continuous framework linking these structures and functions is still lacking. This review integrates recent clinical and experimental evidence and proposes the brain clearance continuum as an interpretative framework. It describes three interlinked functional interfaces: the upstream choroid plexus-cerebrospinal fluid (CP-CSF) inflow interface, the midstream parenchymal perivascular exchange interface, and the downstream meningeal lymphatic outflow interface. Under physiological conditions, these interfaces support CSF movement, parenchymal solute exchange, and the outward removal of metabolic waste. In AD, disrupted CSF homeostasis, impaired perivascular exchange, and obstructed meningeal lymphatic outflow may interact, leading to serial failure of the brain clearance continuum. This process is closely associated with Aβ/tau accumulation, vascular dysfunction, neuroinflammation, and cognitive decline. We also summarise potential therapeutic strategies directed at different clearance interfaces, whilst emphasising that most evidence remains preclinical or exploratory. The brain clearance continuum provides a systematic framework for understanding clearance failure in AD. It may also offer a theoretical basis for future mechanistic studies and therapeutic development that are stratified by clearance interface and disease stage.},
}
@article {pmid42484748,
year = {2026},
author = {Abroumand Gholami, A and Ghadiminia, N and Akhrorova, S and Kubaev, A and Agamurodov, S and Salomova, F},
title = {Correspondence: Erythrina caffra in cadmium-induced Alzheimer's-like pathology: A new candidate or a familiar pattern?.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42484748},
issn = {1573-4978},
mesh = {*Alzheimer Disease/drug therapy/chemically induced/pathology/metabolism ; Animals ; *Cadmium/toxicity ; *Plant Extracts/pharmacology/therapeutic use ; *Erythrina/chemistry/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; Humans ; Rats ; Oxidative Stress/drug effects ; Disease Models, Animal ; },
abstract = {Cadmium neurotoxicity has been increasingly linked to neurodegenerative processes, and plant-derived compounds are being explored for their protective potential. The recent study by Ed-Day and colleagues investigated the neuroprotective effects of Erythrina caffra seed extract in a cadmium-induced Alzheimer's-like model in rats, reporting improvements in memory, cholinergic function, oxidative stress, and neuroinflammation. Four principal concerns are identified: (1) treatment protocol ambiguity, use of young rats to model an age-related disease, and unclear prevention-versus-therapy distinction; (2) memantine as positive control, mechanistically mismatched with cadmium toxicity pathways; (3) claim of Alzheimer's-like pathology without measuring Aβ plaques and tau tangles; and (4) no cadmium quantification in tissues or biofluids, leaving the mechanism, direct neuroprotection versus reduced bioavailability, unresolved. While the study offers promising preliminary evidence for the neuroprotective potential of E. caffra, its translational significance is constrained by these methodological and interpretative limitations. Addressing these concerns in future investigations would strengthen the evidence base for this medicinal plant's therapeutic potential.},
}
@article {pmid42484778,
year = {2026},
author = {Lill, CM and Homann, J and Ohlei, O and Smith-Byrne, K and Viallon, V and Huerta, JM and Artaud, F and Zhao, Y and Britten, A and Deecke, L and Dobricic, V and Mokoroa, O and Guevara, M and Petrova, D and Trupp, M and Sabin, J and Gröninger, M and Colorado-Yohar, SM and Alonso-Martin, S and Cabrera-Castro, N and Groppa, S and Robinson, O and Hansen, J and Eriksson, S and Sieri, S and Jimenez, A and Tong, TYN and Kaaks, R and Severi, G and Travis, R and Wareham, N and Benedet, AL and Zetterberg, H and Franke, A and Elbaz, A and Bertram, L and Vermeulen, R and Middleton, L and Masala, G and Sacerdote, C and Peters, S and Katzke, V and Ferrari, P and Gunter, MJ and Riboli, E},
title = {EPIC4ND-European Prospective Investigation into Cancer and Nutrition follow-up for neurodegenerative diseases.},
journal = {European journal of epidemiology},
volume = {},
number = {},
pages = {},
pmid = {42484778},
issn = {1573-7284},
support = {#008994//Michael J Fox Foundation/ ; JPND2021-650-289//EU Joint Programme - Neurodegenerative Disease Research/ ; LI 2654/3-1//Deutsche Forschungsgemeinschaft/ ; LI 2654/4-1 (Heisenberg)//Deutsche Forschungsgemeinschaft/ ; INTRAIBS-2020-06//Instituto de Investigaci&#xf3;n Biosanitaria ibs.GRANADA/ ; },
abstract = {The 'European Prospective Investigation into Cancer and Nutrition' cohort (EPIC) is a prospective study including ~ 520,000 participants recruited across Europe (1991-2000) with in-depth baseline data on nutritional, lifestyle, medical, and anthropometric variables, and baseline blood samples. Here we introduce EPIC4ND, a case-cohort study within EPIC designed to identify biomarkers predicting a future onset of dementia, Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). EPIC4ND comprises 6415 initially non-diseased participants (aged 35-80 years, mean age at baseline: 54 ± 9, 64% women) including 1899 incident cases with up to 30 years of follow-up and data on at least one omics domain available from pre-disease blood samples. EPIC4ND includes 4604 subcohort members (4441 non-cases and 163 incident cases) and 1811 additional incident cases ascertained from the broader EPIC cohort. Among the incident cases, there are 1190 dementia cases (818 AD), 610 PD cases, and 199 ALS cases. Additionally, 72 prevalent PD cases and 118 incident Parkinsonism cases are available for comparison. Molecular data generated encompass proteomics, genome-wide DNA methylation, and SNP genotyping with 4127 EPIC4ND participants (including 1635 incident cases) having data on all three domains. Smaller studies include data on metals, metabolites, and environmental chemicals, while ongoing efforts focus on ultrasensitive targeted biomarker measurements and small RNA sequencing. Genome-wide association studies and analyses of epidemiological risk factors validate the dataset by confirming many known risk factors. Leveraging these extensive pre-disease multi-layered omics data offers a unique opportunity to identify biomarker signatures predicting neurodegenerative diseases and to explore their interplay with epidemiological risk factors.},
}
@article {pmid42484938,
year = {2026},
author = {Wu, P and Liao, Y and Liu, C and Liu, X and Feng, Q and Cheng, X},
title = {The Clearance-Centered Bottleneck in Alzheimer's Disease: From Coupled Glymphatic-Lymphatic Circuits to Therapeutic Opportunities.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42484938},
issn = {1559-1182},
mesh = {Humans ; *Alzheimer Disease/therapy/pathology/metabolism/physiopathology/immunology ; *Glymphatic System/pathology/metabolism ; Animals ; Amyloid beta-Peptides/metabolism ; *Lymphatic System ; },
abstract = {While anti-amyloid-beta (Aβ) monoclonal antibodies have achieved substantial success in reducing plaque burden, their modest clinical impact highlights an "efficacy ceiling" that necessitates a re-evaluation of Alzheimer's disease (AD) pathogenesis. This review proposes a shift from an amyloid-centered paradigm to a "clearance-centered bottleneck" framework, conceptualizing brain homeostasis as a coupled glymphatic-lymphatic circuit. We identify three critical rate-limiting nodes-entry, transit, and exit-that govern this circuit. These nodes fail through distinct mechanisms: arterial stiffening (entry), aquaporin-4 (AQP4) depolarization (transit), and cerebral amyloid angiopathy with impaired meningeal lymphatic drainage (exit). This multilevel failure creates a self-sustaining "neuroimmune stalemate"-a state in which trapped antigens and inflammatory mediators perpetuate glial reactivity that further degrades the very clearance infrastructure needed to resolve it. Distinct from prior reviews of glymphatic dysfunction in isolation, this review contributes four interlinked advances: an integrated glymphatic-lymphatic coupled-circuit framework; a bidirectional immune-clearance crosstalk model; a critical appraisal of imaging endpoints graded by trial-readiness; and a combination therapy roadmap. To overcome the current therapeutic plateau, we advocate for multinode interventions that combine amyloid-targeting therapies with clearance-enhancing agents, supported by a readiness-tiered imaging strategy-standardized proxies such as DTI-ALPS and PVS burden as enrichment/secondary endpoints and dynamic contrast-enhanced MRI for mechanistic proof-of-concept.},
}
@article {pmid42484959,
year = {2026},
author = {Lin, Q and Qiu, N and Wang, X and Wei, YB and Liu, JJ},
title = {Chronic Pain and the Risk of Dementia: A Systematic Review and Meta-Analysis.},
journal = {Current pain and headache reports},
volume = {30},
number = {1},
pages = {},
pmid = {42484959},
issn = {1534-3081},
mesh = {Humans ; *Dementia/epidemiology/etiology ; *Chronic Pain/epidemiology/complications ; Risk Factors ; },
abstract = {BACKGROUND: The relationship between chronic pain and dementia risk has been extensively studied, but findings remain inconclusive. We conducted an updated meta-analysis to synthesize evidence from recent large-scale cohort studies.<br><br>METHODS: Two authors independently and systematically searched PubMed, Web of Science, Embase, Cochrane Library, and Chinese National Knowledge Infrastructure for cohort studies published through April 2025, with a minimum follow-up of one year. Hazard ratios (HRs) were considered equivalent to risk ratios (RRs) assuming low event rates. Random-effect models pooled risk ratios (RR) with 95% confidence intervals (CI). Subgroup analyses and meta-regression explored heterogeneity.<br><br>RESULTS: Of 3,823 publications, 30 studies met the inclusion criteria. After excluding five studies with overlapping populations, 25 studies involving 2,091,835 participants were pooled in the primary analysis. Individuals with chronic pain had a 28% higher dementia risk (RR&#x2009;=&#x2009;1.28, 95% CI&#x2009;=&#x2009;1.18-1.38). Heterogeneity was high (I&#xb2;=91%). Subgroup analyses showed migraine, headaches, arthritis-related pain, and widespread pain were associated with increased risk. The association was significant in Asia but not in America or Europe, and when using ICD (but not DSM) criteria. Chronic pain increased the risk of Alzheimer's disease and non-vascular dementia, but not vascular dementia. Study quality, region, measurement methods, and pain types influenced the relationship. Pain type was a source of heterogeneity.<br><br>CONCLUSIONS: In this meta-analysis of cohort studies, chronic pain was associated with an increased risk of dementia. Due to the observational nature of the included studies and high heterogeneity, this association should not be interpreted as causal. Further research is needed to determine whether pain management can mitigate dementia risk.},
}
@article {pmid42485421,
year = {2026},
author = {Yang, S and Cui, L and Zhang, J and Yang, Y and Huo, J and Ding, Y and Zhang, J and He, S and Li, J},
title = {Association of triglyceride-glucose index (TyG) and a body shape index (ABSI) with cognitive decline and dementia risk.},
journal = {PloS one},
volume = {21},
number = {7},
pages = {e0354418},
doi = {10.1371/journal.pone.0354418},
pmid = {42485421},
issn = {1932-6203},
mesh = {Humans ; *Triglycerides/blood ; *Dementia/blood/epidemiology ; *Cognitive Dysfunction/blood/epidemiology ; Female ; Male ; *Blood Glucose/analysis/metabolism ; Aged ; Risk Factors ; },
abstract = {BACKGROUND: Longitudinal evidence linking the body shape index (ABSI) to dementia and its subtypes remains scarce. Furthermore, the use of ABSI and TyG-ABSI as predictors of cognitive decline and dementia is infrequent. Therefore, this study aimed to examine the relationships between the triglyceride-glucose (TyG) index, ABSI, and TyG-ABSI indices and their predictive value for cognitive decline and dementia risk.<br><br>METHODS: This study included 370,744 participants from the UK Biobank. The TyG and ABSI indices were calculated using their respective formulas, while the TyG-ABSI index was derived by multiplying TyG and ABSI. Cognitive decline was defined as scoring in the bottom 25% on cognitive tests, while dementia was diagnosed from first-recorded incidents and algorithmically-defined outcomes. Logistic regressions were employed to assess the associations of TyG, ABSI and TyG-ABSI indices with cognitive decline; Cox regressions were used to analyze the associations of these indices with the risk of all-cause dementia (ACD) and its subtypes.<br><br>RESULT: The TyG, ABSI, and TyG-ABSI indices were all significantly associated with cognitive decline. Additionally, compared with the lowest quartiles, the highest quartiles of TyG, ABSI and TyG-ABSI indices were associated with a significantly increased risk of ACD by 33% (HR&#x2009;=&#x2009;1.33, 95% CI: 1.13-1.57), 79% (HR&#x2009;=&#x2009;1.79, 95% CI: 1.65-1.94) and 67% (HR&#x2009;=&#x2009;1.67, 95% CI: 1.54-1.82), respectively. These indices were also significantly associated with the risk of Alzheimer's disease (AD) and vascular dementia (VD) (all P&#x2009;<&#x2009;0.05).<br><br>CONCLUSION: The TyG, ABSI, and TyG-ABSI indices are significantly and positively linked to the risk of cognitive decline and dementia.},
}
@article {pmid42485548,
year = {2026},
author = {Moradi Sarcheshmeh, MS and Shahedi, A and Zabihirad, J and Taghipour, M and Kargar Jahromi, H and Delam, H},
title = {Global Prevalence of Urinary Incontinence in Individuals With Dementia: A Systematic Review and Meta-Analysis.},
journal = {Neurourology and urodynamics},
volume = {},
number = {},
pages = {},
doi = {10.1002/nau.70390},
pmid = {42485548},
issn = {1520-6777},
abstract = {BACKGROUND: Urinary incontinence (UI) is a common and debilitating complication in patients with dementia, significantly impacting quality of life, increasing caregiver burden, and accelerating institutionalization.<br><br>OBJECTIVE: Despite numerous studies, reported prevalence estimates vary widely, and a precise global pooled prevalence has not been established.<br><br>METHODS: This systematic review and meta-analysis followed PRISMA guidelines. A comprehensive search of PubMed/MEDLINE, Scopus, and Web of Science was conducted from November to December 2025, without publication year restrictions. Observational studies reporting the point prevalence of UI in dementia patients were included. Two independent reviewers screened studies, extracted data, and assessed methodological quality using the Newcastle-Ottawa Scale. A random-effects meta-analysis (restricted maximum likelihood method) was used to pool prevalence estimates. Heterogeneity was assessed using the I[2] statistic. Subgroup analyses were performed by setting and UI assessment method, and meta-regression examined associations with Human Development Index (HDI) and temporal trends.<br><br>RESULTS: Ten studies comprising 286,544 participants were included. The pooled global prevalence of UI in dementia patients was 39.7% (95% CI: 23.9%-58.1%), with substantial heterogeneity (I[2]&#x2009;>&#x2009;95%). Prevalence ranged from 4% in Taiwan to 88% in Japan. Subgroup analyses revealed significantly higher prevalence in clinic/hospital settings compared to community settings (47.5% vs. 28.7%, p&#x2009;=&#x2009;0.023), and in studies using single-question interviews versus medical record extraction (59.2% vs. 23.2%, p&#x2009;=&#x2009;0.016). Meta-regression showed a significant positive association with HDI (coefficient: 5.69, p&#x2009;<&#x2009;0.001). Sensitivity analysis confirmed the robustness of the pooled estimate.<br><br>CONCLUSION: Approximately 40% of dementia patients experience UI, with substantial variation by setting and assessment method. Standardized assessment protocols are needed to inform targeted interventions and reduce disease burden.},
}
@article {pmid42485607,
year = {2026},
author = {Chen, Y and Chen, A and Power, MC and Grodstein, F and Kapasi, A and Capuano, AW and Lange-Maia, BS and Moghtaderi, A and Stapp, EK and Bhattacharyya, J and Shah, RC and Barnes, LL and Bennett, DA and James, BD},
title = {Associations of Alzheimer Disease and Related Dementia Neuropathologies With Timely Diagnosis of Dementia in Healthcare Settings.},
journal = {Neurology},
volume = {107},
number = {3},
pages = {e218352},
doi = {10.1212/WNL.0000000000218352},
pmid = {42485607},
issn = {1526-632X},
mesh = {Humans ; Female ; Male ; *Alzheimer Disease/pathology/diagnosis ; Aged, 80 and over ; Retrospective Studies ; *Dementia/diagnosis/pathology ; Aged ; *Brain/pathology ; United States ; Cohort Studies ; Medicare ; },
abstract = {BACKGROUND AND OBJECTIVES: A timely diagnosis of dementia may provide valuable time for treatment and planning, yet underdiagnosis is common. This study investigated the relationship between presence of dementia pathologies and timeliness of dementia diagnosis by healthcare providers.<br><br>METHODS: This was a retrospective study using 5 cohorts at Rush Alzheimer's Disease Center. We included participants who met all of the following criteria: (1) incident dementia based on annual cohort assessments, (2) linkage to Medicare records, and (3) a completed postmortem brain autopsy. Postmortem neuropathologic examinations identified the presence of AD, limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), vascular pathologies, and neocortical Lewy bodies (LBs). In linked Medicare data, we defined timely diagnosis as the presence of claims with dementia diagnoses within 3 years before or 1 year after the cohort-based dementia onset. We used logistic regressions to quantify associations of neuropathology markers with timely diagnosis vs underdiagnosis.<br><br>RESULTS: Of the 500 eligible participants (71% female, 95% non-Latino White, mean [SD] age at cohort dementia onset = 88 [7] years, mean [SD] years from onset to death = 4 [3]), only 54% received a timely diagnosis. After controlling for demographics, time to death, and other neuropathologies, a pathologic diagnosis of AD (OR = 1.91, 95% CI 1.21-3.00) and moderate/severe LATE-NC pathologies (OR = 1.83, 95% CI 1.25-2.68) were independently associated with higher odds of timely diagnosis. Moderate/severe vascular pathologies (OR = 0.94, 95% CI 0.55-1.59) and neocortical LB pathologies (OR = 1.00, 95% CI 0.64-1.55) were not significantly associated with receipt of a timely diagnosis. In a separate multivariable logistic regression, we found that participants with 3 or 4 neuropathologies present had an over 2-fold increase in odds of timely diagnosis (OR = 2.24, 95% CI 1.32-3.82), compared with those with 1 or no neuropathology.<br><br>DISCUSSION: In deceased older adults with cohort-determined incident dementia, the healthcare system was twice as likely to capture those with pathologic diagnosis of AD, moderate/severe LATE-NC, and more than 3 copathologies in a timely manner. While findings from this predominantly White and highly educated sample warrant replication in broader population, this study is an important initial step toward understanding biological correlates of timely diagnosis of dementia.},
}
@article {pmid42485616,
year = {2026},
author = {Silva, JAFD and Nagra, A and Wadhwa, A and Mar, S and Tjoa, A and Flibotte, S and Barvalia, M and Matos, I and Priatel, J and Krebs, D and Harder, KW},
title = {A DLL1-culture system to propagate murine patrolling monocytes from bone marrow progenitors.},
journal = {Journal of leukocyte biology},
volume = {},
number = {},
pages = {},
doi = {10.1093/jleuko/qiag103},
pmid = {42485616},
issn = {1938-3673},
abstract = {Patrolling monocytes (pMos) scavenge debris from vessel walls and mediate antibody-dependent cellular phagocytosis, making them attractive cell therapy candidates for cancer, atherosclerosis, and Alzheimer's disease. However, methods to generate enhanced numbers of pMos are not available. To address this, we developed a two-step procedure to produce pMos in vitro from murine bone-marrow (BM). First, myeloid progenitors were expanded and enriched from BM using cytokines for four days. Second, expanded progenitors were differentiated into pMos on DLL1-expressing monolayers for eight days. We confirmed that in vitro grown pMos expressed the transcription factor Nr4a1 (Nur77) and other canonical pMos surface proteins, and depended on Notch signalling for their development. RNA sequencing revealed that in vitro pMos expressed hallmark pMos genes, including Cx3cr1, Itgax (CD11c), CD43, Fcγr4, and Cd274 (PD-L1), and their gene signatures clustered closely with in vivo blood and BM pMos. Transcriptomic and phenotypic analyses further demonstrated that in vitro pMos were distinct from classical BM macrophages. Phagocytosis assays demonstrated the function of in vitro pMos in cancer cell uptake. Adoptive transfer studies demonstrated that in vitro pMos persisted within the circulation and lung vasculature during the early post-transfer period compared with BM-derived macrophages, consistent with the vascular-patrolling properties of pMos. Adoptive transfer of pMos reduced lung tumour burden in a metastatic model, supporting an anti-tumoural role for pMos and their ability to mediate immune surveillance in vivo. These findings demonstrate that the DLL1 culture system allows for propagation of functional pMos, enabling studies of pMos biology and their therapeutic potential.},
}
@article {pmid42485924,
year = {2026},
author = {Xing, Z and Liu, Z and Zhang, DF and Xie, K and Fang, J and Bi, XA and Liu, T},
title = {Alzheimer's disease risk prediction via perceptual deformable attention generative adversarial network with large foundation models.},
journal = {Medical image analysis},
volume = {113},
number = {},
pages = {104225},
doi = {10.1016/j.media.2026.104225},
pmid = {42485924},
issn = {1361-8423},
abstract = {Predicting the risk of Alzheimer's disease (AD) is fundamental for early-stage intervention. Nevertheless, most methods struggle to extract multi-omics associative patterns due to the limited feature perception and inflexible disease modeling. This paper proposes a novel evolutionary pattern mining framework for precise disease risk prediction. Firstly, large foundational models are employed to automatically construct high-quality features. Second, a perceptual deformable attention mathematical model is proposed, which combines multi-scale sparse attention and deformable attention mechanisms to capture evolutionary patterns of fused multi-omics features. Finally, a Perceptual Deformable Attention Generative Adversarial Network (PDAT-GAN) is developed. PDAT-GAN can precisely simulate the evolutionary procedure of AD using multi-omics data, thereby achieving robust risk prediction and pathogeny extraction for AD. We validate the advanced performance and interpretability of PDAT-GAN on public datasets, underscoring significance of PDAT-GAN in supporting clinical intervention and pathogenetic research. The code of PDAT-GAN can be accessed at: .},
}
@article {pmid42486010,
year = {2026},
author = {Li, X and Li, S and Su, J and Zheng, F and Li, S and Zhao, X and Chen, D and Yan, J and Xia, C},
title = {Merocyanine derivatives as theranostic agents for cognitive improvement and real-time imaging of amyloid-β in APP/PS1 transgenic mice.},
journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy},
volume = {363},
number = {Pt 1},
pages = {128458},
doi = {10.1016/j.saa.2026.128458},
pmid = {42486010},
issn = {1873-3557},
abstract = {Amyloid-β (Aβ) is widely recognized as a biomarker for the diagnosis and treatment of Alzheimer's Disease (AD). In our previous work, a series of merocyanine fluorescent probes were designed, synthesized and evaluated for the imaging of Aβ plaques. Here, we further identified the representative probe D4, which not only demonstrates the characteristics of a highly sensitive fluorescent probe for real-time imaging of Aβ content in the brain of APP/PS1 mice, but also exhibited the ability to treat AD, including inhibition of Aβ aggregation (inhibition rate: 89.5%), antioxidant activity (3.4 times that of Trolox); AChE inhibitory activity (IC50 = 0.5 ± 0.0 μM) and the capacity to cross the BBB (Pe = 8.6 ± 0.7). Additionally, D4 dramatically attenuates Aβ-induced SH-SY5Y cell death by preventing the generation of ROS, and intravenous administration of 0.5 mg/kg D4 for 15 days significantly improved the cognitive ability of 7-month-old APP/PS1 mice by protecting hippocampal and cortex neurons from necrosis, attenuating oxidative stress in the hippocampus and cortex, and reducing Aβ burden deposition. These findings strongly suggest that D4 owns a high theranostic potential for treating AD.},
}
@article {pmid42486312,
year = {2026},
author = {Jafar, T and Chowdhury, NF and Irimia, A},
title = {Spatial Transcriptomic Decoupling and Magnetic Resonance Imaging Identify the Genetic and Cytoarchitectonic Correlates of Regional Vulnerability in Alzheimer's Disease.},
journal = {NeuroImage},
volume = {},
number = {},
pages = {122144},
doi = {10.1016/j.neuroimage.2026.122144},
pmid = {42486312},
issn = {1095-9572},
abstract = {The genetic and cytoarchitectonic factors associated with neurodegeneration in Alzheimer's disease (AD) remain poorly understood due to challenges linking gene expression to macroscale neuroanatomic features. Gray-white matter contrast C, an MRI-derived measure sensitive to relative cortical tissue contrast and myelin-related lipid content, declines with aging and AD. By relating C to spatial transcriptomics, we identify AD-related alterations in gene-C coupling. Spatial gene expressions facilitate comparing C between cognitively normal adults (CN, N = 1,447) and adults with AD (N = 1,447) from the National Alzheimer's Coordinating Center (NACC, N = 2,286) and the Alzheimer's Disease Neuroimaging Initiative (ADNI, N = 608). For 25 genes, expression significantly correlates with mean C in AD, but not CN, participants. Cell-type enrichment links AD-correlated genes to astrocytic, endothelial, neuronal markers, in cortical regions with age-related C decline. NACC findings are reproduced in ADNI. Amyloid and tau PET corroborate that regions with AD-related alterations in gene-C coupling also exhibit molecular AD signatures. This multimodal convergence supports spatial transcriptomic associations with cytoarchitectonic changes and AD pathology. We integrate transcriptomics with neuroimaging to identify how genes involved in AD are associated with cortical lipid content, providing novel insights into the genetics of neurodegeneration.},
}
@article {pmid42486320,
year = {2026},
author = {Dilip, PI and Daksh, R and Sharma, P and Khanna, S and Bojja, SL and Singh, AK and Nampoothiri, M},
title = {Repressor Element 1 Silencing Transcription Factor as a central regulator of autophagy and neuroinflammation in Alzheimer's disease.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {179168},
doi = {10.1016/j.ejphar.2026.179168},
pmid = {42486320},
issn = {1879-0712},
abstract = {Repressor element-1 silencing transcription factor (REST) is a critical epigenetic regulator involved in multiple cellular processes, including apoptosis, autophagy, and neuronal survival. By modulating the expression of neuronal and stress-response genes, REST contributes significantly to neuroprotection. REST is predominantly localised in the nucleus; however, in Alzheimer's Disease (AD), nuclear REST is reduced, leading to transcriptional dysregulation and contributing to AD pathology. The low levels of REST are associated with defective autophagy flux, including mitochondrial dysfunction and enhanced vulnerability to toxic protein aggregates, causing AD and other neurodegenerative disorders. Recent research shows that REST suppresses several apoptotic genes, modulating neuroinflammatory signalling and regulates autophagy. The specific regulatory mechanism of REST suggests new strategies for the prevention and treatment of AD and ageing. Despite REST's unique functions and importance in AD, its precise role and the molecular mechanisms underlying REST-mediated signalling pathways have not been comprehensively reviewed. The purpose of this review is to provide an overview of the structural and functional characteristics of REST, explore the mechanisms underlying REST-mediated autophagy, neuroinflammation and apoptosis in AD and discuss the emerging therapeutic implications of targeting REST.},
}
@article {pmid42486330,
year = {2026},
author = {Arriagada, J and Ardiles, &#xc1; and Mery, E and Garay, C and Conejera, F and Herrera, EA and Paula-Lima, A and Muñoz, P},
title = {Metformin enhances hippocampal excitatory synaptic transmission and preserves synaptic plasticity under amyloid-β oligomer-induced dysfunction.},
journal = {Neuropharmacology},
volume = {299},
number = {},
pages = {111116},
doi = {10.1016/j.neuropharm.2026.111116},
pmid = {42486330},
issn = {1873-7064},
abstract = {Early stages of Alzheimer's disease (AD) are characterized by synaptic dysfunction and alterations in synaptic plasticity that precede neuronal loss. Soluble amyloid-β oligomers (AβOs) are important contributors to these early synaptic alterations by disrupting excitatory neurotransmission and impairing hippocampal function. Metformin (Met), a widely used antidiabetic drug, has recently gained attention for its potential neuroprotective properties; however, its effects on hippocampal synaptic transmission and plasticity under amyloid-induced stress remain incompletely understood. In the present study, we investigated the effects of orally administered Met (200 mg/kg/day) on basal excitatory synaptic transmission, presynaptic release probability, and long-term synaptic plasticity in hippocampal slices from rats subjected to stereotaxic injection of AβOs into the CA1 region. Using field electrophysiological recordings, we show that Met significantly enhances basal excitatory synaptic transmission, increases presynaptic release probability, potentiates long-term potentiation (LTP), and attenuates long-term depression (LTD). Notably, Met prevented the impairments in synaptic transmission and plasticity induced by AβOs, maintaining synaptic responses at levels comparable to those observed in control animals. Together, these findings indicate that Met modulates hippocampal synaptic function and preserves physiological forms of synaptic plasticity under amyloid-induced stress conditions. Our results identify synaptic transmission and plasticity as functionally relevant targets of Met action and support further investigation of Met as a potential strategy for preserving synaptic function during the early stages of AD.},
}
@article {pmid42486339,
year = {2026},
author = {Yin, N and Ding, H and Su, R and Chen, Y and Zhou, L and Tao, Y and Chen, H and Sun, Z and Li, J},
title = {Multimodal Characterization of Age-Dependent Susceptibility to High-Cholesterol-Diet-Induced AD-like Alterations in WHBE Rabbits.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106229},
doi = {10.1016/j.neuint.2026.106229},
pmid = {42486339},
issn = {1872-9754},
abstract = {Rabbit models induced by a high-cholesterol diet can exhibit Alzheimer's disease (AD)-like neuropathological features, but susceptibility to diet-induced pathological alterations may vary with age and strain. This study aimed to investigate age-dependent susceptibility to high-cholesterol-diet-induced AD-like alterations in white-haired and black-eyed (WHBE) rabbits using a multimodal approach. Compared with the normal control group (NC), juvenile rabbits (2 months old) in the 2% high-cholesterol diet (CD) group showed disturbed plasma lipid and glucose metabolism, increased body weight, and reduced encephalization quotient (EQ). Neuropathologically, juvenile CD rabbits exhibited enhanced hippocampal Tau hyperphosphorylation and Aβ deposition. MRI demonstrated significant hippocampal atrophy and lateral ventricular enlargement, while [1]H-MRS revealed significant reductions in hippocampal N-acetylaspartate/Cr, glutamate (Glu)/Cr, and glycerophosphocholine (GPC)+phosphocholine (PCH)/Cr ratios. In the overall cohort, Tau protein expression was negatively correlated with (Glu+Gln)/Cr (rho = -0.50, P = 0.0096) and positively correlated with (GPC+PCH)/Cr (rho = 0.42, P = 0.0167), although these correlations lost significance after FDR correction in subgroup analyses. Additionally, Aβ expression was negatively correlated with age in pooled WHBE rabbits (rho = -0.35, P = 0.0437), with no significant metabolite correlations observed after multiple testing correction. Multiple linear regression further confirmed a significant 'Diet×Age' interaction for both Tau and Aβ, indicating the pathological effect of high-cholesterol diet was most prominent in juvenile animals. These findings suggest that juvenile WHBE rabbits are more vulnerable to high-cholesterol-diet-induced AD-like changes. This study provides a multimodal reference for optimizing rabbit AD models and exploring age-related neurodegenerative vulnerability.},
}
@article {pmid42486379,
year = {2026},
author = {LeFevre, JD and Robb, WH and Liu, D and Jackson, TB and Pechman, KR and Shashikumar, N and Vyas, Y and Landman, BA and Davis, LT and Hohman, TJ and Jefferson, AL},
title = {A comparative evaluation of multiple enlarged perivascular space segmentation tools.},
journal = {Magnetic resonance imaging},
volume = {},
number = {},
pages = {110749},
doi = {10.1016/j.mri.2026.110749},
pmid = {42486379},
issn = {1873-5894},
abstract = {BACKGROUND: Enlarged perivascular spaces (ePVS) are a marker of cerebral small vessel disease, potentially reflecting reduced waste clearance. Because manual quantification is unfeasible in large datasets, we developed and evaluated an automated tool.<br><br>METHODS: Detection Of Regions of Enlarged perivascular Spaces (DORES), a 3D nnU-Net-based deep learning algorithm was developed for ePVS segmentation using T1-weighted and fluid-attenuated inversion recovery magnetic resonance imaging (MRI). DORES was developed in two stages: an initial model trained on 35 manually segmented scans and a final model on 1460 pseudo-labeled sessions from the Vanderbilt Memory and Aging Project (VMAP). A subset of VMAP participants with 3&#x202f;T brain MRI underwent whole-brain manual ePVS tracing (n&#x202f;=&#x202f;35, 73&#x202f;&#xb1;&#x202f;9&#x202f;years, 51% male) and visual rating (n&#x202f;=&#x202f;388, 71&#x202f;&#xb1;&#x202f;8&#x202f;years, 54% male) by a neuroradiologist. DORES was evaluated and compared against three other segmentation tools using Dice and F1 scores, absolute volume and element differences, correlation, and agreement. External validation used an Alzheimer's Disease Neuroimaging Initiative 3 subset with manual tracings (ADNI3, n&#x202f;=&#x202f;18, 73&#x202f;&#xb1;&#x202f;9&#x202f;years, 67% female).<br><br>RESULTS: DORES achieved Dice scores of 0.61&#x202f;&#xb1;&#x202f;0.16 (white matter) and 0.72&#x202f;&#xb1;&#x202f;0.08 (basal ganglia) in VMAP, with strong correlations and agreement for ePVS count and volume. Performances modestly declined in ADNI3 across algorithms. Scanner-stratified analyses showed stronger correlations for Philips versus Siemens images in the basal ganglia, indicating scanner-dependent differences in measurement consistency.<br><br>CONCLUSIONS: DORES provides a multimodal nnU-Net-based pipeline for ePVS segmentation in older adults. The model demonstrates robust within-cohort performance and reasonable external validity, though scanner-related effects limit application across sites.},
}
@article {pmid42486551,
year = {2026},
author = {Supuran, CT and Capasso, C},
title = {Carbonic anhydrases I and II.},
journal = {The Enzymes},
volume = {59},
number = {},
pages = {29-67},
doi = {10.1016/bs.enz.2026.06.005},
pmid = {42486551},
issn = {0423-2607},
mesh = {Humans ; *Carbonic Anhydrase Inhibitors/pharmacology/therapeutic use/chemistry ; Animals ; *Carbonic Anhydrase II/metabolism/antagonists &amp; inhibitors/chemistry/genetics ; *Carbonic Anhydrase I/metabolism/antagonists &amp; inhibitors/chemistry/genetics ; },
abstract = {Carbonic anhydrase (CA, EC 4.2.1.1) isoforms I (CA I) and II (CA II) are widespread cytosolic proteins in most vertebrates. They are abundant in the red blood cells and many other tissues, being involved in physiological processes such as pH regulation, CO2/bicarbonate homeostasis, respiration, and secretion of electrolytes rich in acid or bicarbonate in the stomach, kidneys, cerebrospinal fluid, eyes, and bones. The genetics, biochemistry, expression, localization in tissues and organs, kinetic properties, and catalytic mechanisms of these enzymes are well understood at the molecular level. At least five different inhibition mechanisms were described with more than 50 chemotypes acting as inhibitors. The activation with amine/amino acid activators was also well studied. The physiological role of CA I is poorly understood, whereas CA II is a physiologically dominant isoform, playing crucial functions in a host of tissues/organs. Interfering with its activity by means of inhibitors has been and is currently exploited in therapy for the management of edema, glaucoma, epilepsy, obesity, acute mountain sickness, and idiopathic intracranial hypertension. Promising preclinical data pointed to the potential use of CA II inhibitors for the management of other conditions, such as neuropathic pain, cerebral ischemia, rheumatoid arthritis, Alzheimer's disease, osteoporosis, and obstructive sleep apnea. Many CA inhibitors are in clinical use for the management of such conditions, among which are acetazolamide, thiazides and high-ceiling diuretics, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide, brinzolamide, and antiepileptics such as sulthiame, topiramate and zonisamide, whereas SLC-0111 is in clinical development as an antitumor agent. CA activators are not yet used clinically, but they might have pharmacological applications in the management of neurodegeneration, emotional memory disorders, obsessive-compulsive disorders, phobias, generalized anxiety, and post-traumatic stress. Finding novel modulators of activity for these enzymes may lead to innovative therapeutic applications and deepen our understanding of enzymes, their inhibitors, and their activators.},
}
@article {pmid42486687,
year = {2026},
author = {Fang, Q and Guo, Y and Chen, L and Li, Y and Cai, Q and Zhang, J and Ma, X and Zeng, Y and Bai, G},
title = {A multimodal machine learning model integrating plasma biomarkers and MRI metrics for non-invasive prediction of amyloid-β pathology in mild cognitive impairment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261465672},
doi = {10.1177/13872877261465672},
pmid = {42486687},
issn = {1875-8908},
abstract = {BackgroundAccurate, non-invasive prediction of cerebral amyloid-β (Aβ) pathology in mild cognitive impairment (MCI) remains challenging yet critical for early intervention.ObjectiveTo develop a multimodal machine learning model integrating clinical features, plasma biomarkers, and structural MRI metrics for non-invasive Aβ prediction.MethodsData were obtained from the Alzheimer's Disease Neuroimaging Initiative. Participants with concurrent plasma biomarkers, 3D T1-weighted MRI, and amyloid assessments were included. Logistic Regression, Decision Tree, and Support Vector Machine models were constructed using clinical, plasma, MRI, and combined features. Performance was evaluated via internal validation and external testing in a cognitively unimpaired cohort using AUC, calibration curves, and decision curve analysis. The prognostic value of the model-derived Aβ risk probability was assessed using Cox regression in an independent longitudinal MCI cohort.ResultsThe optimal Logistic Regression model incorporated APOE ε4 status, Mini-Mental State Examination score, plasma p-Tau217, Aβ42/Aβ40 ratio, and bilateral hippocampal and left amygdalar volumes. The combined model achieved an AUC of 0.875 in internal validation and maintained robust performance in the external unimpaired cohort (AUC = 0.883), outperforming single-modality models. The predicted Aβ-positive risk probability effectively stratified disease progression risk in MCI patients (C-index = 0.771).ConclusionsA multimodal model integrating plasma and MRI features accurately predicts Aβ pathology and progression risk, offering a practical non-invasive tool for early Alzheimer's disease screening and risk stratification.},
}
@article {pmid42486877,
year = {2026},
author = {Kurz, C and Wüsten, NC and Tegethoff, P and Taute, M and Kehrls, M and Hufnagel, A and de Jonge, S and Deckert, A and Suchsland, MZ and König, A and Feustel, E and Heindl, P and Mattke, S and Perneczky, R},
title = {Adaptive pathways for multimodal community-based detection of cognitive impairment: the CogScreen I study.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {42486877},
issn = {2045-2322},
mesh = {Humans ; *Cognitive Dysfunction/diagnosis/blood ; Biomarkers/blood ; Female ; Aged ; Male ; Surveys and Questionnaires ; Dementia/diagnosis ; Aged, 80 and over ; Early Diagnosis ; Independent Living ; Amyloid beta-Peptides/blood ; },
abstract = {Early detection of cognitive impairment is essential for dementia prevention and timely care. However, implementation in primary care and community settings remains limited. Building dementia-prepared health systems requires scalable and adaptive pathways that integrate subjective, digital and biological indicators, while accounting for heterogeneity in risk, education and age. CogScreen I was a cluster-randomized trial conducted in Munich senior centers from March 2023 to March 2024. Recruitment focused on community-dwelling adults aged ≥ 60 years reporting subjective cognitive concerns. Centers were randomized to: (A) the Subjective Cognitive Decline Questionnaire (SCD-Q) only, (B) SCD-Q plus digital cognitive testing, or (C) SCD-Q plus digital testing plus blood biomarkers (Aβ1-42/1-40, pTau181, GFAP, NfL). The primary endpoints were feasibility and acceptability, assessed through structured questionnaires and follow-up interviews with participants and general practitioners. Secondary endpoints examined latent cognitive structures and biomarker associations. Exploratory factor and clustering analyses revealed multimodal subgroups across subjective, digital, and biological measures, which informed a hypothesis-generating three-tier adaptive detection framework (low, medium, high intensity). Among the 473 participants (mean age 74.1 ± 7.6 years; 66% female; 63% with tertiary education), both feasibility and acceptability were high: Participants described the assessments as personally relevant, clearly communicated, and medically meaningful, and appreciated the added value of digital testing and biomarkers. Digital cognitive testing and biomarkers captured distinct latent dimensions of learning/working memory, psychomotor attention, and glial and amyloid pathology. Exploratory multimodal clustering identified three dementia risk profiles-low concern, intermediate, and at risk-which informed an adaptive, tiered detection model. Notably, subjective cognitive concerns assessed by the SCD-Q were strongly associated with overall subjective symptom burden, supporting the use of brief self-report questionnaires as a pragmatic and scalable first-step stratification approach in community-based dementia detection. Community-based, tiered detection pathways for cognitive decline are feasible, acceptable, and meaningful to older adults. Exploratory multimodal profiling suggests that combining subjective, digital, and biological measures may support individualized assessment strategies. However, limited GP engagement highlights the need for stronger integration with primary care to ensure downstream diagnostics and prevention pathways. The proposed framework remains hypothesis-generating and requires prospective validation.Clinical trials registeredCogScreen has been registered at clinical trials (NCT06191952, 2023-12-20).},
}
@article {pmid42487022,
year = {2026},
author = {Xu, W and Chen, J and Zhou, Y and Liu, C and Han, Y and Zheng, K},
title = {Comparative efficacy and safety of photobiomodulation, transcranial direct current stimulation, and repetitive transcranial magnetic stimulation in Alzheimer's disease: a network meta-analysis of randomized controlled trials.},
journal = {Lasers in medical science},
volume = {41},
number = {1},
pages = {},
pmid = {42487022},
issn = {1435-604X},
support = {82371442//National Natural Science Foundation of China/ ; 2020YFC2004803//National Key Research and Development Program of China/ ; },
mesh = {Humans ; *Alzheimer Disease/therapy ; *Transcranial Direct Current Stimulation/adverse effects/methods ; *Transcranial Magnetic Stimulation/adverse effects/methods ; Randomized Controlled Trials as Topic ; *Low-Level Light Therapy/adverse effects/methods ; Treatment Outcome ; Cognition ; Cognitive Enhancement ; Bayes Theorem ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which current pharmacological therapies provide only modest and transient benefits, underscoring the need for effective non-pharmacological interventions. Non-invasive brain stimulation (NIBS), including photobiomodulation (PBM), transcranial direct current stimulation (tDCS), and repetitive transcranial magnetic stimulation (rTMS), is a promising approach. This study compared the efficacy, feasibility, and safety of PBM, tDCS, and rTMS in AD. We conducted a Bayesian network meta-analysis (NMA) of randomized controlled trials (RCTs), prospectively registered in PROSPERO (CRD420251006868) and reported according to PRISMA-NMA. The primary outcome was global cognitive performance, assessed by the Mini-Mental State Examination (MMSE) and the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog). Secondary outcomes were feasibility and safety, evaluated by dropout rates and adverse events, respectively. A total of 34 studies, comprising 35 RCTs (n = 1,559), were included, with one study contributing two independent randomized controlled trials. All three interventions improved global cognitive performance compared with control. PBM showed the highest estimated effects on both MMSE (MD = 3.14, 95% CrI: 1.71 to 4.60) and ADAS-Cog (MD = - 8.01, 95% CrI: -12.82 to - 3.13). In indirect comparisons, PBM was superior to rTMS for ADAS-Cog (MD = - 5.24, 95% CrI: -10.23 to - 0.12), while the MMSE comparison narrowly missed statistical significance (MD = 1.57, 95% CrI: -0.02 to 3.18). These findings were generally consistent across subgroups stratified by baseline cognition and intervention duration. PBM tended to rank highest for cognitive improvement with feasibility and safety comparable to tDCS and rTMS in AD. These findings support the therapeutic potential of PBM, and large-scale RCTs are needed to guide individualized treatment strategies, with implications for clinical decision-making in geriatric care.},
}
@article {pmid42487135,
year = {2026},
author = {Waghmare, SG and Krishna, MM and Maccoux, EC and Franitza, AL and Link, BA and E, L},
title = {Functional analysis of late-onset Alzheimer's disease risk genes in Caenorhabditis elegans identifies regulators of neuronal aging.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {42487135},
issn = {2047-9158},
support = {5520760//Advancing a Healthier Wisconsin Endowment/ ; 5520482//Advancing a Healthier Wisconsin Endowment/ ; AG087390/NH/NIH HHS/United States ; },
}
@article {pmid42487153,
year = {2026},
author = {Magalhães, TNC and Casseb, RF and Moraes, AS and Teixeira, CVL and Carletti, AM and De Rezende, TJR and Joaquim, HPG and Talib, LL and Forlenza, O and Cendes, F and Balthazar, MLF and Teunissen, CE},
title = {Relation of fluid neurodegeneration biomarkers with white matter integrity in Alzheimer's disease patients in Latin America.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261467065},
doi = {10.1177/13872877261467065},
pmid = {42487153},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is increasingly prevalent in Latin America. Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are promising biomarkers of neurodegeneration, but their relationship with white matter (WM) integrity remains unclear.ObjectiveTo investigate associations between fluid neurodegeneration biomarkers and WM microstructure in a Brazilian cohort of individuals across the AD continuum and cognitively healthy controls.MethodsNinety-one participants were included: 27 cognitively healthy controls (mean age = 68.3 ± 5.2 years) and 64 amyloid-positive individuals with mild cognitive impairment or AD dementia (mean age = 70.6 ± 6.9 years). AD participants were characterized by low cerebrospinal fluid (CSF) Aβ42 concentrations (<540 pg/mL) and altered Aβ42/p-Tau and Aβ42/t-Tau ratios. Serum and CSF concentrations of NfL and GFAP were measured using single-molecule array technology and examined in relation to diffusion tensor imaging metrics, including fractional anisotropy, mean diffusivity, radial diffusivity, and axial diffusivity (AxD).ResultsWithin the clinical AD group, higher serum NfL levels were associated with lower AxD in the left cingulum tract (r = -0.372, p = 0.007). In cognitively healthy controls, serum NfL showed positive correlations with AxD and mean diffusivity in the right cingulum (r = 0.650, p = 0.001 and r = 0.607, p = 0.003, respectively). No significant associations were observed between serum or CSF GFAP concentrations and diffusion tensor imaging metrics.ConclusionsSerum NfL was associated with anatomically specific WM microstructural changes, with differing patterns across clinical groups.},
}
@article {pmid42487190,
year = {2026},
author = {Aschenbrenner, DS},
title = {Antidepressant is approved to treat agitation in Alzheimer disease.},
journal = {The American journal of nursing},
volume = {126},
number = {8},
pages = {18-19},
doi = {10.1097/AJN.0000000000000354a},
pmid = {42487190},
issn = {1538-7488},
}
@article {pmid42487544,
year = {2026},
author = {Zhou, J and Li, S and Liu, H and Sun, Y and Wang, Z},
title = {The Effectiveness of Animal-Assisted Interventions for People Living With Dementia: An Overview of Systematic Reviews and Meta-Analysis.},
journal = {International journal of nursing practice},
volume = {32},
number = {4},
pages = {e70172},
doi = {10.1111/ijn.70172},
pmid = {42487544},
issn = {1440-172X},
support = {72274007//National Natural Science Foundation of China/ ; LJRC22YB03//Incubation Fund for Scientific Research and Innovation of Leading Talents of Unnamed Nursing of Peking University/ ; XJRC-2025-JY-YJ-GX-QNQZ-068//Xinjiang Talent Development Fund/ ; },
mesh = {*Dementia/therapy/psychology ; Humans ; *Animal Assisted Therapy ; Animals ; Quality of Life ; Systematic Reviews as Topic ; Activities of Daily Living ; },
abstract = {AIMS: This overview aims to provide high-quality evidence synthesis of animal-assisted interventions (AAIs) among people living with dementia.<br><br>BACKGROUND: Dementia has become the seventh leading cause of death in the world. Unfortunately, currently effective pharmacological interventions remain elusive. As a non-pharmacological treatment, AAI is gaining more attention while the effectiveness of AAI for people living with dementia remains unclear.<br><br>METHODS: EMBASE, PubMed, Cochrane Library, CINAHL, CNKI, VIP, CBM and Wanfang databases were searched from inception to March 2026. The AMSTAR2 was used to assess the methodological quality of the included reviews. Meta-analysis was conducted using STATA 16 for the original studies identified from the included reviews. Evidence quality of main outcomes was assessed according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) guidelines.<br><br>RESULTS: Sixteen systematic reviews were included in the overview. A significant improvement was found in depression among dementia patients, but not in agitation, quality of life (QOL), cognition and activities of daily living (ADL).<br><br>CONCLUSIONS: There is moderate evidence that AAI has positive effects on depression for people living with dementia. Despite searches, no sufficient evidence has been found to substantiate the positive effects of AAI on other outcomes in people living with dementia. Due to the small number of studies, small sample sizes and significant heterogeneity, more randomised controlled trials with large samples are needed.},
}
@article {pmid42487594,
year = {2026},
author = {Lonlab, K and Nitjapol, A and Thummayot, S and Tiyaboonchai, W and Jumnongprakhon, P},
title = {Targeting Aβ25-35-Induced Neuronal Senescence-Like Features Using Curcumin-Loaded Solid Self-Emulsifying Drug Delivery Systems.},
journal = {Current aging science},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118746098440081260430205824},
pmid = {42487594},
issn = {1874-6128},
abstract = {INTRODUCTION: Curcumin is widely recognized for its anti-neurodegenerative properties. However, its clinical utility is hindered by poor aqueous solubility and low bioavailability. To address these limitations, Curcumin-loaded Solid Self-Emulsifying Drug Delivery Systems (C-SSEDDS) have been formulated to improve pharmacokinetics and neuronal targeting. Despite these advancements, the molecular mechanisms underlying curcumin in Alzheimer's Disease (AD)-related neuronal senescence remain poorly understood. Therefore, this study provides novel molecular insights into the therapeutic potential of C-SSEDDS for targeting neuronal senescence- like features in the AD context.<br><br>METHODS: An in vitro model of neuronal senescence-like features was established by exposing SK-N-SH cells to 0.075 &#x3bc;M A&#x3b2;25-35 for 24 hours, resulting in a 20-30% decline in cell viability. Subsequently, cells were post-treated with C-SSEDDS at optimized non-toxic concentrations (0.1, 1, and 10 &#x3bc;g/mL curcumin equivalent) and 10 &#x3bc;g/mL commercial curcumin for 24, 48, and 72 hours in A&#x3b2;25-35-free media. The study comprehensively assessed cell viability, morphological alterations, and key biomarkers associated with neuronal senescence-like features, including senescence- associated beta-galactosidase (SA-&#x3b2;-gal) positive cells, Reactive Oxygen Species (ROS) levels, NLRP3, Sirt-1, and synaptophysin expression.<br><br>RESULTS: C-SSEDDS post-treatment significantly improved cell viability, reduced apoptotic cells, and decreased SA-&#x3b2;-gal positive cells in A&#x3b2;25-35-induced senescence-like SK-N-SH cells compared to the untreated A&#x3b2;25-35 group. It also effectively decreased intracellular ROS level and NLRP3 expression, and markedly upregulated Sirt-1 and synaptophysin expression. Notably, CSSEDDS demonstrated therapeutic efficacy superior to commercial curcumin and comparable to N-acetylcysteine (NAC).<br><br>DISCUSSION: In SK-N-SH cells exhibiting senescence-like features, the C-SSEDDS formulation effectively counteracts A&#x3b2;25-35-induced damage. It mitigates key drivers of cellular stress, including oxidative stress, inflammation-related markers, and apoptosis, while also enhancing Sirt-1 activity and promoting synaptic plasticity.<br><br>CONCLUSION: C-SSEDDS demonstrates significant potential as a promising therapeutic strategy against A&#x3b2;25-35 -induced neuronal stress and senescence-like changes in AD.},
}
@article {pmid42488138,
year = {2026},
author = {Magee, RG and Li, Y and Rovine, MJ and Pelak, VS and Hamedani, AG},
title = {Epidemiology of visuospatial impairment in older adults: the Harmonized Cognitive Assessment Protocol.},
journal = {Innovation in aging},
volume = {10},
number = {8},
pages = {igag059},
pmid = {42488138},
issn = {2399-5300},
abstract = {BACKGROUND AND OBJECTIVES: This study aimed to determine the prevalence of visuospatial impairment in a nationally representative sample of older adults and identify self- and informant-reported functional measures associated with visuospatial dysfunction.<br><br>METHODS: We analyzed data from 3496 participants aged &#x2265;65 years in the 2016 Harmonized Cognitive Assessment Protocol (HCAP), a sub-study of the Health and Retirement Study. Visuospatial function was assessed using the Consortium to Establish a Registry for Alzheimer's Disease constructional praxis and Mini Mental State Examination pentagon copy tasks. Impairment was defined as a factor score >1.5 SDs below expected relative to a robust normative sample. Cognitive status was classified by HCAP as normal, mild cognitive impairment (MCI), or dementia. Logistic regression models examined associations between visuospatial impairment and functional outcomes, adjusting for demographic, health, and general cognitive factors.<br><br>RESULTS: Visuospatial impairment was present in 435 participants (11.33%). Among these, 49.85% had MCI, and 39.97% had dementia. Over half of those with MCI and visuospatial impairment had no other cognitive domain affected. Visuospatial impairment was associated with increased odds of self-reported visual difficulty (OR 1.60, 95% CI: 1.20-2.15), difficulty using a map (OR 3.35, 95% CI: 2.35-4.80), and informant-reported navigation difficulties, including getting lost at home (OR 17.30, 95% CI: 8.02-37.31). Associations with driving, map use, and getting lost at home remained significant after adjusting for general cognition.<br><br>DISCUSSION AND IMPLICATIONS: Visuospatial impairment is common among older adults, frequently occurs in isolation in MCI, and is strongly associated with functional limitations, particularly in navigation and driving.},
}
@article {pmid42488179,
year = {2026},
author = {Taheri, H and Musaie, F and Mohammadzadeh, N and Tavassoli Naini, P and Novin, N and Salimi, O and Amini, A and Malekpour, H and Panahiyan, P and Malek, M and Fathiazar, A and Namadkolahi, R},
title = {Optimizing Alzheimer's prediction with dental care: comparing robust deep learning models in health and retirement study of America.},
journal = {American journal of neurodegenerative disease},
volume = {15},
number = {2},
pages = {16-24},
pmid = {42488179},
issn = {2165-591X},
abstract = {BACKGROUND: Previous research has illustrated links between dental care and Alzheimer's disease, the aim of this study was to examine whether dental care variables can enhance Alzheimer's risk prediction using two models including Long Short-Term Memory (LSTM) and Temporal Convolutional Network (TCN) models with health and retirement study data.<br><br>METHODS: 9,979 HRS participants without cognitive impairment were analysed in this study (mean age 67 years; and 59.8% female, waves 11-15: 2006/2008-2016). Analysis included 52 predictors including demographic, genetic (APOE &#x3b5;4), health (including dental visit frequency), and psychosocial domains. The outcomes as cognitive impairment and dementia were defined by Langa-Kabeto-Weir criteria. Class imbalance was addressed by SMOTE and missing data were mean imputed. We standardized and reshaped features into five-wave temporal sequences. Data were split into 3 sets: 70% training, 10% validation, and 20% test. LSTM (single layer, 64 units) and TCN (two dilated convolutional layers, 32 channels) models were trained for up to 50 epochs using binary cross-entropy loss with Adam optimizer, learning-rate reduction on plateau, and early stopping based on validation F1. The accuracy, precision, recall, F1, and AUC-ROC were evaluated via Five-fold stratified cross-validation; the optimization of classification thresholds was done by maximizing F1. McNemar's test compared final predictions.<br><br>RESULTS: It was evident that LSTM consistently outperformed TCN as demonstrated by the following results: test accuracy 99.78% vs 79.01%; AUC-ROC 99.95% vs 92.74%; F1-score 99.67% vs 75.27%. Cross-validation consistency (LSTM F1 ~99.6%&#xb1;0.1% vs TCN ~76.6%&#xb1;1.5%) and stable validation-test metrics (final validation loss 0.0136 vs 0.3312) showed robust LSTM performance without overfitting. moreover, McNemar's test showed a significant difference (statistic = 2605.36; P<0.001). models with dental care variables showed high sensitivity (~99.8%).<br><br>CONCLUSIONS: Enhancement in Alzheimer's disease risk prediction in older adults was evident when incorporating dental care variables in LSTM-based sequential modeling which suggest potential for early detection. However, further studies in diverse populations and assessment of feature importance is necessary because of reliance on self-reported dental care data and the study's HRS-specific sample.},
}
@article {pmid42488183,
year = {2026},
author = {Singhal, M and Lin, J and Delehanty, M and Karimi, A and Rittner, L and Bento, M},
title = {Geographic and demographic gaps in publicly available Alzheimer's disease datasets: A large language model-based discovery and analysis.},
journal = {Digital health},
volume = {12},
number = {},
pages = {20552076261470698},
pmid = {42488183},
issn = {2055-2076},
abstract = {INTRODUCTION: Alzheimer's disease (AD) affects millions worldwide, and researchers heavily rely on datasets for diagnosis and treatment. Identifying relevant datasets is challenging due to data gaps and bias related to the demographics and geographic origin.<br><br>METHOD: We investigated AD data gaps by identifying and manually curating publicly accessible AD datasets containing imaging and/or tabular data. We also extracted key information such as data availability, geographic location, and participant demographics. We used five Large Language Models (LLMs) to identify AD datasets, allowing us to explore potential datasets while also evaluating retrieval consistency across models.<br><br>RESULT: We identified 24 publicly accessible AD datasets (open access or controlled access via registration). These datasets enabled us to emphasize three critical gaps: (1) variability in AD dataset retrieval, as observed through differences in LLM outputs, related to dataset visibility and accessibility; (2) geographical imbalance, with North America contributing 55.6% of datasets, US alone 66.7%, followed by Europe at 36.1%, and smaller shares from South America 11.1%, Asia 8.3%, and Africa 2.8%; and (3) demographic deficits, with the majority of datasets predominantly White, as 9 of 24 had over 80% White participants. Among the seven datasets that reported any Black participant representation, the proportion of Black participants ranged from 15.3% to 18.8%.<br><br>CONCLUSION: These findings reveal significant disparities in the availability and retrieval of AD datasets, with most data concentrated in Western countries and critical gaps in demographic representation. LLMs show inconsistent retrieval, particularly for newer, smaller, or region-specific datasets, which may perpetuate existing biases.},
}
@article {pmid42488212,
year = {2026},
author = {Li, Z and Ming, Q and Fu, L and Yang, J and Lv, Y and Chen, B and Lu, Z},
title = {Nutritional substrates and microglial metabolic fitness in brain aging and Alzheimer's disease: from lipid handling to TREM2-linked translation.},
journal = {Frontiers in nutrition},
volume = {13},
number = {},
pages = {1886340},
pmid = {42488212},
issn = {2296-861X},
abstract = {Alzheimer's disease is increasingly viewed as a disorder in which age-related disturbances in microglial metabolism and the handling of nutritional substrates contribute to progressive loss of protective function. This review examines how lipids and ketone bodies shape microglial metabolic fitness in the aging brain and in Alzheimer's disease, and how these effects intersect with triggering receptor expressed on myeloid cells 2 (TREM2) signaling and translational biomarkers. Available evidence indicates that early compensatory glycolysis may give way to chronic bioenergetic failure, while cholesterol and lipoprotein trafficking, lipid droplet accumulation, ketone-body signaling, and TREM2-associated lysosomal pathways influence plaque engagement, phagocytosis, and inflammatory responses. The review also considers how apolipoprotein E genotype, brain region, sex, disease stage, and model system condition translation from experimental models to human disease. Fluid, imaging, and tissue readouts are therefore discussed as stage- and context-dependent proxies rather than fixed signatures. Overall, nutritional strategies and microglia-targeted interventions are most likely to be informative when aligned with disease stage and biological context.},
}
@article {pmid42488516,
year = {2026},
author = {Hajihosseini, S and Panahandeh, E and Rashidi, A and Soleimani, K and Parvandi, F and Rostami, N and Mottaghi, H and Rahmani, S and Belbasi, M and Bideshki, F and Faramin Lashkarian, M and Ebrahimi, MA and Alizadeh, H},
title = {Difficulty with taking medications and the future risk of Alzheimer's disease and related dementias: Health and Retirement Study of Americans.},
journal = {American journal of neurodegenerative disease},
volume = {15},
number = {1},
pages = {1-15},
pmid = {42488516},
issn = {2165-591X},
abstract = {BACKGROUND: This study aims to determine if self-reported issues with managing medication could be an early sign of cognitive decline, possibly pointing to a future diagnosis of Alzheimer's Disease and Related Dementias (ADRD). There is currently very little information available about the link between issues with medication management and the later diagnosis of an ADRD, despite the potential clinical importance of such a link.<br><br>METHODS: We analyzed Health and Retirement Study participants present and interviewed at Wave 11 (2012) and followed them through Wave 16 (2020). Medication-taking difficulty (R11MEDS) was classified as no difficulty/don't do vs. difficulty/can't do. Separate cohorts excluded prevalent dementia (R11DEMENE) or AD (R11ALZHEE). Incident outcomes were first respondent-reported physician diagnoses (RwDEMENE, RwALZHEE). Kaplan-Meier curves and multivariable Cox models estimated associations.<br><br>RESULTS: Of 18,878 dementia-free and 19,348 AD-free HRS respondents at Wave 11, 3.0-3.9% reported difficulty/could not take medications. Kaplan-Meier curves diverged early between exposure groups. In fully adjusted Cox models, medication-taking difficulty predicted higher hazards of incident all-cause dementia (HR 1.59, 95% CI 1.23-2.06) and AD (HR 1.57, 95% CI 1.09-2.27), with corroborating pooled logistic estimates.<br><br>CONCLUSION: Difficulty in Managing Medications is considered to be a robust prodromal indicator of ADRD, regardless of demographic influences. Therefore, the evaluation of an individual's ability to manage medications within routine assessment may represent a practical, costeffective means to identify cognitive decline and develop appropriate management strategies.},
}
@article {pmid42488555,
year = {2026},
author = {Zhao, Q and Li, S and Ju, Y and Kong, X and Liu, X},
title = {Modeling Alzheimer's disease with brain organoids: mechanisms, applications, and future directions.},
journal = {Frontiers in cell and developmental biology},
volume = {14},
number = {},
pages = {1791272},
pmid = {42488555},
issn = {2296-634X},
abstract = {Human pluripotent stem cell-derived brain organoids have emerged as a transformative platform for modeling Alzheimer's disease (AD), thus addressing long-standing translational obstacles posed by the disease's complex etiology and interspecies differences. This review systematically examines methodological advances in brain organoid technology, from basic fabrication and brain-region-specific organoids to multicellular assembloids that incorporate microglia and vascular components, with an emphasis on strategies for overcoming fetal-like phenotypes. We surveyed literature published between 2018 and April 2026 that focused on human iPSC-derived organoid models that recapitulate core AD pathologies, including Aβ plaques, tau tangles, neuroinflammation, and blood-brain barrier dysfunction. Key findings demonstrate that organoids effectively capture genotype-phenotype relationships for major AD genes (APP, PSEN1, PSEN2, and APOEε4), enable the dissection of signaling pathway dysregulation (Wnt/β-catenin), and when combined with CRISPR editing and single-cell multi-omics, reveal cell-type-specific disease mechanisms. Organoids have also been successfully applied to patient-specific "avatar" models and high-throughput drug screening, thus advancing precision medicine approaches. However, current technological bottlenecks-including a lack of functional vascularization, batch-to-batch variability, and insufficient standardization-limit the full recapitulation of chronic, age-dependent AD pathology. This review critically evaluates these limitations, addresses ethical considerations surrounding neural organoids, and looks forward to future integration with artificial intelligence, spatial omics, and multi-organ systems to accelerate the translation of organoid-based discoveries into clinical applications.},
}
@article {pmid42488639,
year = {2026},
author = {Zhao, X and Zhang, G and Wang, Z and Zhang, D and Xia, Z and Huo, C},
title = {Autoimmune signatures in neurodegenerative dementias: from peripheral immune activation to CNS pathology.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1893167},
pmid = {42488639},
issn = {1664-3224},
mesh = {Humans ; Animals ; *Dementia/immunology/pathology ; *Autoimmunity ; *Neurodegenerative Diseases/immunology/pathology ; Adaptive Immunity ; Autoantibodies/immunology ; *Central Nervous System/immunology/pathology ; T-Lymphocytes/immunology ; },
abstract = {Neurodegenerative dementias, including Alzheimer's disease, Parkinson's disease dementia, dementia with Lewy bodies, and related tauopathies, are traditionally defined by protein aggregation, neuronal dysfunction, synaptic loss, and glial-mediated neuroinflammation. However, emerging evidence indicates that adaptive immunity may also contribute to disease heterogeneity and progression. These disorders should not be considered classical autoimmune diseases, but they may display autoimmune-like signatures, including neural antigen-specific T cell responses, clonal expansion of T cells in blood or cerebrospinal fluid, CNS infiltration of adaptive immune cells, and brain-targeting autoantibodies. Recent studies have linked α-synuclein-specific T cell reactivity to early Parkinson's disease, identified clonally expanded CD8[+] T cells in Alzheimer's disease cerebrospinal fluid, and provided direct evidence of adaptive immune involvement in Lewy body dementia, including altered peripheral immunophenotypes and CD4[+] T cell-associated neurodegenerative mechanisms. Experimental tauopathy models further show that microglia-mediated T cell infiltration can drive neurodegeneration. Humoral autoreactivity and progression-associated immune changes further suggest that adaptive immune profiles may help define biologically distinct dementia subgroups. In this mini review, we summarize evidence connecting peripheral immune activation, intrathecal adaptive immune remodeling, and CNS pathology in neurodegenerative dementias. We also discuss how longitudinal blood-CSF profiling, single-cell/TCR/BCR sequencing, autoantibody profiling, and mechanistic validation may clarify whether these immune signatures are pathogenic, compensatory, or bystander responses.},
}
@article {pmid42488724,
year = {2026},
author = {Liu, F and Huang, Y and Wang, A and Liu, P and Wu, H and Fan, H},
title = {BDNF-amyloid-β Axis in Alzheimer's disease: molecular mechanisms and therapeutic perspectives.},
journal = {Frontiers in molecular neuroscience},
volume = {19},
number = {},
pages = {1884003},
pmid = {42488724},
issn = {1662-5099},
abstract = {Alzheimer's disease (AD), the most common cause of dementia in older adults, is characterized by progressive cognitive decline, synaptic dysfunction, and neuronal loss. Among the multifactorial mechanisms implicated in AD, reciprocal interactions between brain-derived neurotrophic factor (BDNF) and amyloid-β (Aβ) have attracted increasing attention as a convergent axis linking amyloid pathology to impaired neurotrophic support. BDNF promotes neuronal resilience, synaptic plasticity, and cognitive function primarily through the activation of its high-affinity receptor, tropomyosin receptor kinase B (TrkB), and downstream signaling pathways, including PI3K-Akt and MAPK/ERK. Human postmortem and biomarker studies mainly support associations between reduced BDNF signaling, synaptic dysfunction, and AD-related pathology. In contrast, cell-based and animal studies provide mechanistic evidence that BDNF/TrkB signaling may influence amyloid precursor protein (APP) processing and neuronal resistance to Aβ-induced stress. Conversely, mechanistic studies indicate that Aβ accumulation can suppress CREB-dependent BDNF expression, disturb BDNF transport, and impair TrkB receptor function. Thus, the BDNF-Aβ relationship is better interpreted as a stage- and context-dependent pathogenic coupling rather than a simple causal loop. This review synthesizes evidence from human studies, animal models, and cellular systems to clarify how BDNF-Aβ dysregulation contributes to AD progression and to discuss the translational potential of BDNF-oriented interventions.},
}
@article {pmid42488747,
year = {2026},
author = {Jiang, W},
title = {Pharmacological advances of honokiol: Mechanisms, targets and therapeutic potential (Review).},
journal = {Biomedical reports},
volume = {25},
number = {3},
pages = {103},
pmid = {42488747},
issn = {2049-9442},
abstract = {Honokiol (HKL), a bioactive biphenolic lignan isolated from the bark of Magnolia officinalis, possesses diverse pharmacological properties, including neuroprotective, antitumor, anti-inflammatory and metabolic regulatory effects. Despite its therapeutic promise, the clinical application of HKL is severely restricted by its hydrophobicity and low oral bioavailability. The present review systematically summarized 99 studies (90 original articles and nine reviews) on the pharmacological profile of HKL. It detailed HKL's molecular interactions with key signaling targets, such as sirtuin 3, NOD-like receptor family pyrin domain containing 3-cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes, Yes-associated protein/transcriptional coactivator with PDZ-binding motif, adenosine monophosphate-activated protein kinase and signal transducer and activator of transcription 3, which underly its efficacy against cancer (ovarian, liver, breast, colorectal, and lung), neurodegeneration (Alzheimer's and Parkinson's disease), metabolic disorders (diabetes, nonalcoholic fatty liver disease and obesity) and inflammatory and infectious diseases. Furthermore, the present review critically evaluated recently developed strategies to overcome its pharmacokinetic limitations. The present review offered an updated theoretical basis for understanding the structure-activity relationship of HKL and provided insights into its translation from bench to bedside.},
}
@article {pmid42488757,
year = {2026},
author = {Jorge, L and Oliveira, J and Martins, R and Lopes, T and Quental, H and Castelo-Branco, M},
title = {Distinct brain regions are affected by neurodevelopmental or pre-dementia changes in Down syndrome.},
journal = {Brain communications},
volume = {8},
number = {4},
pages = {fcag269},
pmid = {42488757},
issn = {2632-1297},
abstract = {Down syndrome, a condition characterized by triplication of chromosome 21, leads to a complex interplay between neurodevelopmental and dementia-related changes similar to the ones observed in Alzheimer's disease. Here we aimed to understand this interplay by using imaging biomarkers for different cognitive profiles in Down syndrome, and by analysing early developmental differences versus age-related changes. We analysed voxel-based morphometric measures of grey matter volume from high-resolution T1-weighted MRI in 23 adults with Down syndrome (18-59 years, five female) in preclinical/prodromal stages of Alzheimer's disease and 24 age- and sex-matched controls, along with cognitive assessments. Neuroanatomical group differences were assessed using two-sample t-tests. Age-related effects on brain integrity, and cognitive function were examined through voxel-wise regression analyses and correlation tests, respectively. Finally, structural correlates of episodic memory were explored across the whole brain at the voxel level within the Down syndrome group. Results revealed a neuroanatomic phenotype with both regional increases and decreases in grey matter volume compared to controls (false discovery rate, q ≤ 0.05). Based on regression analysis, we found the following patterns in regions that were differentially reduced in Down syndrome: same intercept and different age-related slope (defining specific age-related differences), different intercept (implying initial neurodevelopmental differences) and same slope (signalling no age-related differences). A notable example of the first was the left hippocampus and its subfields, and of the second was the orbitofrontal cortex. Follow-up whole brain analyses confirmed age-related changes in Down syndrome (false discovery rate, q ≤ 0.05) in the parietal and temporal cortices, extending into hippocampus, as compared to controls, independent of neurodevelopmental (non-age related) features, and most pronounced in the right hemisphere. Episodic and associative memory declined significantly with age (P = 0.016) in Down syndrome and correlated with shrinkage in regions vulnerable to Alzheimer's disease (P < 0.01), including the precuneus and posterior cingulate cortex. Our findings suggest that individuals with Down syndrome undergo early brain atrophy that occurs independently of baseline neurodevelopmental changes, particularly in the hippocampus and temporoparietal regions. Notably the posterior cingulate cortex and precuneus showed an association with episodic memory loss, a pattern that is consistent with Alzheimer's Disease. In sum we found a dichotomic distinction between brain regions affected by developmental or ageing changes in Down syndrome.},
}
@article {pmid42488758,
year = {2026},
author = {Krohn, F and Sarkar, M and Schütze, H and Iliopoulos, P and Penalba-Sánchez, L and Hämmerer, D and Yakupov, R and Lüsebrink, F and Spottke, A and Schneider, A and Roy, N and Incesoy, E and Heneka, M and Kilimann, I and Kleineidam, L and Teipel, SJ and Brosseron, F and Goerss, D and Glanz, W and Schmid, M and Rostamzadeh, A and Wagner, M and Fliessbach, K and Jessen, FO and Düzel, E and Betts, MJ},
title = {Substantia Nigra MRI markers are lower in Alzheimer's disease and are linked to general cognitive function.},
journal = {Brain communications},
volume = {8},
number = {4},
pages = {fcag238},
pmid = {42488758},
issn = {2632-1297},
abstract = {Individuals with Alzheimer's disease dementia show Alzheimer's disease pathology and a heterogeneous degeneration of the Substantia Nigra (SN) post-mortem. However, it is unclear how SN degeneration is related to cognitive dysfunction across the Alzheimer's disease dementia continuum. In this study, using data from the prospective DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE), we investigated whether in vivo SN MRI measures are lower in individuals with clinically defined Alzheimer's disease dementia than in healthy control subjects (HC) and if they are associated with hippocampal functional activity during the processing of novel visual stimuli and subsequent recognition memory. One hundred and sixty DELCODE participants (69 years ± 6 years, 88 men), including 79 HC, 70 individuals with subjective cognitive decline (SCD), 17 individuals with mild cognitive impairment (MCI) and 10 individuals with Alzheimer's disease dementia, completed a scene novelty and encoding task and a 3T SN-sensitive MRI scan, from which the two in vivo SN measures MRI contrast and volume were calculated and harmonized between scanner sites while preserving diagnostic group differences. For 71 individuals, CSF levels of phosphoTau, total tau and amyloid-beta 42/40 ratio (Aß42/40) were available. All individuals completed a neuropsychological task battery from which a global cognitive score was calculated. In separate models, we assessed the relationship between SN MRI markers and CSF levels of Alzheimer's disease, the global cognitive score, hippocampal novelty activation and recognition memory while accounting for age, sex, years of education and total intracranial volume (TIV). SN volume but not SN MRI contrast was lower in individuals with clinical Alzheimer's disease dementia [one-way analyses of covariance (ANCOVA); F(156,4) = 5.6665, P = 0.0010, n = 160]. SN MRI contrast and volume were not associated with Aß42/40, ptau and total tau CSF levels (all P > 0.1) or hippocampal novelty activation (all P > 0.1). Moreover, SN volume was positively associated with recognition memory (R [2] = 0.07, P < 0.001, n = 159), global cognition (R [2]= 0.38, P < 0.0001, n = 160) and years of education (R [2] = 0.03, P = 0.036, n = 160). Our study emphasizes the potential of using in vivo SN MRI markers to study the impact of SN degeneration on general cognitive impairment and recognition memory in an Alzheimer's disease dementia cohort. Our results motivate future longitudinal studies to explore how SN volume and SN contrast change with disease progression, how these are differentially associated with cognitive decline, and how SN volume and SN contrast might be related to other dopamine-dependent cognitive functions and dysfunctions.},
}
@article {pmid42489128,
year = {2026},
author = {Shen, Q and Chang, H and Li, J and Guo, H and Shi, W and Yan, Y and Ouyang, W and Zhang, Z and Wu, X and Xing, D and Yang, S},
title = {Photobiomodulation of immune crosstalk rescues neuroinflammation in Alzheimer's disease models.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag247},
pmid = {42489128},
issn = {1460-2156},
abstract = {Peripheral immune cell infiltration and crosstalk with brain-resident cells critically drive Alzheimer's disease (AD)-associated neuroinflammation, highlighting its therapeutic potential. Here, we found that photobiomodulation (PBM) markedly reduced cerebral CD8+ T cells infiltration in the cortex of AD (APP/PS1 and 3×Tg) mice, thereby improving cognition, and alleviating AD-related pathology by mitigating neuronal damage and gliosis. Immunofluorescence and transcriptomic analyses revealed that PBM inhibited the release of chemokines and pro-inflammatory cytokines from microglia, reducing endothelial adhesion molecules-mediated T cell migration. Concurrently, reduced secretion of tumor necrosis factor-α, interleukin-1α, and complement component 1q by pro-inflammatory microglia further diminished neurotoxic A1 astrocyte induction. Genetic overexpression or pharmacological inhibition further validated that PBM disrupted microglia NOD-like receptor protein 3 inflammasomes activation, attenuating astrocyte reactivity and T cells recruitment. These findings collectively suggest that the PBM-induced modulation of crosstalk between microglia, astrocytes, and CD8+ T cells is closely related to cognitive improvement. Reprogramming central-peripheral immune crosstalk with PBM resolves neuroinflammation and restores cognition in AD models-a translatable strategy for combating neurodegeneration.},
}
@article {pmid42489215,
year = {2026},
author = {Liu, C and Sakha, K and Anton, J and Cardenas-Rivera, A and Yaseen, MA},
title = {Prolonged systemic inflammation worsens impairments to astrocyte Ca[2+] and functional hyperemia in Alzheimer's disease.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71607},
doi = {10.1002/alz.71607},
pmid = {42489215},
issn = {1552-5279},
support = {//National Cancer Institute Cancer Center/ ; R01AA27097//Northeastern College of Engineering and the National Institutes of Health/ ; R56AG058849//Northeastern College of Engineering and the National Institutes of Health/ ; R21AG085655//Northeastern College of Engineering and the National Institutes of Health/ ; R01AA27097/AA/NIAAA NIH HHS/United States ; R56AG058849/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; *Astrocytes/metabolism ; *Alzheimer Disease/metabolism/pathology/physiopathology ; Mice ; *Inflammation/metabolism ; Mice, Transgenic ; *Hyperemia/metabolism/physiopathology ; *Calcium/metabolism ; Disease Models, Animal ; Lipopolysaccharides ; Male ; Calcium Signaling ; *Neuroinflammatory Diseases ; },
abstract = {INTRODUCTION: Chronic neuroinflammation in Alzheimer's disease (AD) alters astrocyte physiology and neurovascular unit function. AD patients frequently experience recurrent systemic inflammatory insults from comorbid conditions, which act as "secondary-hits" believed to worsen cognitive decline. The impact of these secondary insults on astrocyte-mediated neurovascular regulation remains unknown.<br><br>METHODS: We applied intravital two-photon microscopy to longitudinally investigate astrocytic Ca[2] [+] dynamics and functional hyperemia during sensory stimulation in APP/PS1dE9 mice before and during secondary lipopolysaccharide (LPS)-induced systemic inflammation.<br><br>RESULTS: AD mice exhibited diminished stimulation-evoked astrocytic Ca[2] [+] activity, while functional hyperemia remained largely preserved. LPS further suppressed astrocytic Ca[2] [+] responses and produced temporally specific vascular alterations, with AD and wild-type mice following divergent inflammatory trajectories.<br><br>DISCUSSION: Our findings provide the first in vivo longitudinal characterization of how secondary systemic inflammation disrupts astrocyte-mediated neurovascular regulation. The selective vulnerability of astrocytic Ca[2] [+] signaling relative to vascular output implicates recurrent inflammatory insults as a clinically relevant contributor to neurovascular dysfunction in preclinical AD.},
}
@article {pmid42489430,
year = {2026},
author = {Ishihara, K and Yasui, H and Harada, K and Amano, K and Saito, M and Kaneda, K and Katsuda, M and Kawashita, E and Hata, T and Annoura, R and Nishimura, K and Terasaki, R and Sago, H and Shimohama, S and Akiba, S and Yamakawa, K and Takata, K},
title = {Down syndrome-associated trisomic chromosomal regions modify amyloid-β accumulation and cause early death in a mouse model of aspects of Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261469121},
doi = {10.1177/13872877261469121},
pmid = {42489430},
issn = {1875-8908},
abstract = {BackgroundIndividuals with Down syndrome (DS), caused by triplication of chromosome 21 (Hsa21), face a significantly increased risk of early-onset Alzheimer's disease (AD) and epilepsy. However, the specific impact of Hsa21 genes on these risks is not yet fully understood.ObjectiveTo investigate how triplication of mouse chromosome 16 (Mmu16), homologous to Hsa21, affects amyloid-β (Aβ) accumulation in the brain and epileptic seizures in AD-DS model mice.MethodsTo generate AD-DS model mice, we crossed a mouse model of aspects of AD-an APPswe/PS1[dE9] mouse exhibiting brain Aβ accumulation and sudden death associated with epileptic seizures with DS mouse models carrying an extra copy of partial segments of mouse chromosome 16. We used three DS model lines: Ts1Cje, harboring a triplicated region encoding ∼70 Hsa21-homologous genes (Scaf4-Zbtb21); Ts1Rhr with triplication of the Cbr3-Fam3b region; and a newly developed Ts1Kei mouse carrying an extra copy of the Scaf4-Cbr1 region. Aβ accumulation was assessed by immunohistochemistry and enzyme-linked immunosorbent assay.ResultsCompared with APPswe/PS1[dE9] mice, Aβ deposition and insoluble Aβ levels in the brain decreased in APPswe/PS1[dE9]-Ts1Cje mice but not in APPswe/PS1[dE9]-Ts1Rhr mice. The high mortality in APPswe/PS1[dE9] mice was suppressed by either Ts1Cje- or Ts1Rhr-triplicated region. Despite a tendency for decreased Aβ accumulation in APPswe/PS1[dE9]-Ts1Kei mice, the study could not be finished due to the extremely high mortality.ConclusionsThe trisomic region in Ts1Kei mice is suggested to harbor genes associated with decreased Aβ accumulation. Alternatively, the trisomic region in Ts1Rhr mice contains genes suppressing sudden death in APPswe/PS1[dE9] mice.},
}
@article {pmid42489432,
year = {2026},
author = {Custodio, B and Montesinos, R and Agüero, K and Huilca, JC and Verastegui, G and Bartolo, P and Nuñez-Huanca, M and Albujar Pereira, MF and Godoy, ME and Ibáñez, A and Custodio, N},
title = {Recruitment challenges and strategies for engaging the Peruvian population in the ReDLat Study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261467782},
doi = {10.1177/13872877261467782},
pmid = {42489432},
issn = {1875-8908},
abstract = {BackgroundRecruitment for Alzheimer's disease and related dementias research remains challenging, particularly when reaching underrepresented groups such as Latin Americans.ObjectiveThis study aimed to (1) assess recruitment rates across strategies in the ReDLat study and (2) discuss lessons learned to inform future recruitment practices.MethodsThis retrospective study outlines the recruitment for ReDLat, a multi-partner consortium expanding dementia research in Latin America. Participants were recruited using: printed flyers, social media, word-of-mouth, and professional referrals. At initial contact, participants were asked how they learned about the study. Enrollment rates were calculated for each source, and differences across sources were examined using a Pearson chi-square test.ResultsBetween January 2023 and March 2025, 577 individuals expressed interest, of whom 69% (n = 397) were enrolled. Enrollment rates differed significantly across sources (χ[2] (3) = 41.66, p < 0.001); professional referrals achieved a substantially higher rate (81%) than printed flyers (51%), social media (55%), and word-of-mouth (60%), which showed broadly comparable rates. Printed flyers and social media generated broad interest but lower enrollment conversion. Among the 180 individuals not enrolled, the most frequent reason for non-participation was failure to meet inclusion criteria (54%), particularly among those reached via social media and word-of-mouth. Loss of contact accounted for 36% of non-participation.ConclusionsProfessional referrals were associated with the highest enrollment rate for the ReDLat study. These findings highlight the importance of leveraging community trust and professional networks to improve recruitment outcomes for dementia research in underrepresented populations.},
}
@article {pmid42489435,
year = {2026},
author = {El Jaouhari, S and Geetan, C and Farousi, B and Pilli, LI and Neal, D and Engelsma, T and Vullings, I and Uysal-Bozkir, &#xd6; and Van Deudekom, F and Muller, M and Vroomen, JM},
title = {Aging in place preferences of older adults with cognitive impairment and informal caregivers: A qualitative analysis of a discrete choice experiment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261469138},
doi = {10.1177/13872877261469138},
pmid = {42489435},
issn = {1875-8908},
abstract = {BackgroundThe Netherlands spends more on long-term care than any other country. In 2015, reforms aimed to promote aging in place (AIP) but have been associated with increased crisis-related hospitalizations, rising caregiver burden, and a need for safer AIP strategies. Little is known about how people with dementia and informal caregivers prioritize AIP care and how their preferences differ.ObjectiveTo identify and compare AIP care preferences of people with dementia and informal caregivers, highlighting shared and individual priorities.MethodsWe used a think-aloud protocol within a discrete choice experiment (DCE). Participants were recruited from outpatient clinics, daycare centers, and cultural organizations. To ensure inclusivity, a formal dementia diagnosis was not required given documented diagnostic delays, particularly in migrant communities. Forty participants (20 care recipients, 20 informal caregivers) completed choice tasks comparing care packages. The DCE comprised three rounds: an online survey for informal caregivers, interviews with the person with dementia, and a dyadic round. Think-aloud responses illuminated decision-making; audio was transcribed verbatim and thematically analyzed.ResultsFive themes shaped preferences: (1) burden of in-home care and care planning, (2) role of case managers, (3) accessibility and inclusivity of social activities, (4) trust in healthcare providers, and (5) reimbursements for home adaptations. Care recipients prioritized in-home care and social activities; caregivers emphasized case management. Both valued emotional support and full reimbursements for home adaptations.ConclusionsTailoring AIP strategies to the distinct needs of both groups is essential and can support more equitable, effective AIP models.},
}
@article {pmid42489438,
year = {2026},
author = {Saadawy, M and Majeed, M and Saadawy, E and , },
title = {APOE4-specific glymphatic effects on clinical progression in the Alzheimer's Disease Neuroimaging Initiative with pathological correlates in the A4 study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261469565},
doi = {10.1177/13872877261469565},
pmid = {42489438},
issn = {1875-8908},
abstract = {BackgroundThe APOE ε4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). However, some carriers show "clinical resilience", maintaining their cognition despite high risk.ObjectiveWe hypothesized that the glymphatic system, the brain's waste clearance pathway, may attenuate APOE ε4-mediated neurodegeneration, and tested this in two independent cohorts.MethodsWe analyzed 625 cognitively normal older adults from the Alzheimer's Disease Neuroimaging Initiative (ADNI) discovery cohort and 447 amyloid-positive participants from the preclinical Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) validation cohort. Glymphatic function was estimated using the analysis of diffusional kurtosis imaging along the perivascular space (DTI-ALPS) index in ADNI and choroid plexus (CP) [18]F-Flortaucipir PET uptake in the A4 study. Primary outcomes were clinical conversion to dementia (ADNI) and hippocampal tau pathology (A4).ResultsIn the discovery cohort, we observed a trend toward ALPS × APOE4 interaction (p = 0.057, not reaching conventional statistical significance). Carriers with preserved function (high ALPS) showed a reduced conversion risk (hazard ratio = 0.52, 95% CI: 0.27-0.99) compared to those with low function. In the validation cohort, glymphatic interface dysfunction (higher CP tau) strongly predicted hippocampal tau burden (p < 0.0001). However, the gene-specific interaction was not replicated (p = 0.928); clearance failure predicted pathology regardless of genotype. Exploratory fluid biomarker analyses in ADNI did not reveal significant interactions.ConclusionsThese findings suggest that preserved glymphatic function is associated with clinical resilience in APOE ε4 carriers, though the interaction was borderline (p = 0.057) and should be considered hypothesis-generating. The strong pathological associations with clearance integrity highlight a biologically plausible mechanism in AD pathogenesis that warrants further investigation.},
}
@article {pmid42489439,
year = {2026},
author = {Szapary, CL and Syme, M and Lyons, KS and Monin, JK and Cornelius, T and Heffner, KL and Vranceanu, AM},
title = {"From theory to methodology": Evaluating a workshop for designing mechanistic interventions for dementia dyads.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261467779},
doi = {10.1177/13872877261467779},
pmid = {42489439},
issn = {1875-8908},
abstract = {Background: Coping with the challenges of Alzheimer's disease and related dementias is a shared experience, impacting individuals living with the disease, their care partners, and their relationship. As the number of people affected by dementia continues to rise, so does the demand for evidence-based psychosocial interventions that support the well-being of both members of the dyad. However, the current dyadic dementia intervention (DDI) landscape remains limited in scope and rigor, often lacking strong relational theoretical underpinnings and clear mechanisms of action. Objective: To address this gap, a four-hour workshop was offered at the 2024 Gerontological Society of America Annual Scientific Meeting to equip researchers with the knowledge, confidence, and skills necessary to conduct methodologically rigorous DDI studies. Methods: The first hour of the workshop included didactic presentations on dyadic theory, intervention design, statistics, and dementia-specific considerations. Attendees then participated in small-group, problem-based experiential activities, applying the learned content to their own research projects with individualized feedback from workshop leaders. Results: Participants, primarily from the disciplines of nursing, psychology, and the social sciences, reported significant improvements in perceived knowledge and confidence from pre- to post-workshop and rated the experience as highly satisfactory. Conclusions: These findings suggest that a workshop combining didactic instruction with experiential, problem-based learning is both feasible and effective in strengthening researchers' self-efficacy and skills to advance DDI research.},
}
@article {pmid42489441,
year = {2026},
author = {Drenth, N and van Dijk, SE and Hafkemeijer, A and Rombouts, SARB and van der Grond, J and van Rooden, S},
title = {Early cerebral amyloid angiopathy-related pathology is associated with localized functional brain connectivity.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261469189},
doi = {10.1177/13872877261469189},
pmid = {42489441},
issn = {1875-8908},
abstract = {BackgroundThe mechanisms of early brain damage in cerebral amyloid angiopathy (CAA), a highly prevalent comorbid condition in Alzheimer's disease, are not completely understood. While current CAA diagnosis relies on late-stage MRI markers, impaired neurovascular coupling (NVC) has emerged as a promising early marker.ObjectiveTo investigate whether early vascular changes in CAA are associated with functional brain consequences, we examined the association between NVC and various functional connectivity metrics.MethodsWe analyzed MRI data from 93 older adults (71 ± 9 years old). A subgroup meeting Boston criteria v2.0 for possible or probable CAA (n = 46) was analyzed separately to investigate associations in confirmed CAA-related pathology. NVC (time to peak, time to baseline, and BOLD amplitude) was assessed in the occipital cortex using a visual stimulation task. Functional connectivity was assessed at multiple scales using resting-state fMRI, including within ten standard networks, between individual brain regions (edgewise analysis), and across the whole brain (graph theory).ResultsGeneral linear models, adjusted for age, sex, and clinical diagnosis, showed no significant associations between NVC and global connectivity metrics (networks and graph theory). Edgewise analyses revealed limited significant localized functional connections for each NVC measure. Findings were consistent across the total sample and the CAA subgroup.ConclusionsEarly CAA-related pathology is associated with localized rather than global functional connectivity. While large-scale connectivity remains preserved, edgewise analyses indicate subtle localized functional alterations. This suggests that functional connectivity disruption may originate as small-scale deficits that only progress into widespread, global impairment in advanced disease stages.},
}
@article {pmid42489442,
year = {2026},
author = {Keith, CM and Haut, MW and Worhunsky, P and Vieira Ligo Teixeira, C and Mehta, RI and Malone, J and Phelps, H and Ward, M and Miller, M and Pockl, S and Rajabalee, N and Marano, G and McCuddy, WT and D'Haese, PF and Rezai, A},
title = {Episodic memory and associated cortical atrophy in amnestic early-onset and late-onset Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261469183},
doi = {10.1177/13872877261469183},
pmid = {42489442},
issn = {1875-8908},
abstract = {BackgroundMemory consolidation problems are often prototypical in Alzheimer's disease (AD). However, it remains undetermined whether episodic memory presents similarly in early-onset Alzheimer's disease (EOAD) relative to the more commonly occurring late-onset Alzheimer's disease (LOAD).ObjectiveThis study examined episodic memory and its neuroanatomical correlates in amnestic early-onset (aEOAD) relative to amnestic late-onset AD (aLOAD).MethodsUsing our single center data set obtained from a memory clinic setting (N = 180), we examined group differences in multiple markers of episodic memory along with associations with volume and thickness of underlying signature brain regions.ResultsWe did not observe any difference for examined measures of memory performance between aEOAD and aLOAD. Associations between episodic memory processes and volume and thickness of the brain regions examined were also largely similar, except for a stronger relationship between memory consolidation and thinner left supramarginal gyrus observed in the aEOAD group.ConclusionsOverall, the current results support similar memory consolidation processes in early- and late-onset amnestic Alzheimer's disease, though the parietal cortex may play a larger role in memory consolidation in aEOAD.},
}
@article {pmid42489457,
year = {2026},
author = {Liu, Y and Qiu, Q and Yue, L and Hong, B and Su, N and Li, W and Xiao, S and Sun, L and Chen, J and , },
title = {Precuneus amyloid-β deposition involving the association of irritability and cognitive decline: A multi-cohort longitudinal study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261467432},
doi = {10.1177/13872877261467432},
pmid = {42489457},
issn = {1875-8908},
abstract = {BackgroundIrritability is increasingly recognized for its association with cognitive function, though its impact on cognitive decline and underlying mechanisms remain unclear.ObjectiveTo investigate the associations between irritability and cognition, identify potential neurobiological mechanisms.MethodsThis study included three cohorts: the Alzheimer's Disease Neuroimaging Initiative (ADNI, N = 722), the UK Biobank (UKB, N = 405,112), and the China Longitudinal Aging Study (CLAS, N = 240). Participants were classified into irritability-positive (+) and irritability-negative (-) groups based on assessment of irritability.We used Linear mixed-effects models to assess irritability-related cognitive trajectory, Cox regression to estimate cognitive decline, mediation analysis to test the effect of amyloid-β (Aβ) on the relationship between irritability and cognitive decline, and enrichment analysis to identify the underlying pathological mechanisms of irritability.ResultsIrritability was associated with increased cognitive decline in both ADNI (HR = 1.49, 95% CI: 1.12-1.98) and UKB (HR = 1.09, 95% CI: 1.04-1.15) cohorts, with baseline irritability linked to faster Mini-Mental State Examination decline (2.76 versus 1.88). Mediation analysis showed that cerebrospinal fluid (CSF) Aβ mediated 19-24% of irritability's effect on cognitive decline, while precuneus Aβ pathology mediated 30-41%. Imaging analysis revealed significant thinning of the left precuneus cortex in individuals with irritability. Proteomic analysis indicated underlying pathways involving enhanced energy metabolism and suppressed signal transduction, with modifiable factors (air pollution and physical inactivity) associated with irritability-related pathological proteins.ConclusionsOur findings indicate that irritability is significantly associated with cognitive decline. This association may be driven by mechanisms involving precuneus pathology, increased energy metabolism, and suppressed signal transduction, though these results warrant confirmation in future studies.},
}
@article {pmid42489522,
year = {2026},
author = {Denier-Fields, DN and Gangnon, RE and Rivera-Rivera, LA and Betthauser, TJ and Bendlin, BB and Johnson, SC and Engelman, CD},
title = {Better cardiovascular health, measured by Life's Simple 7, is associated with lower white matter hyperintensity burden and greater cerebral blood flow over time.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261467045},
doi = {10.1177/13872877261467045},
pmid = {42489522},
issn = {1875-8908},
abstract = {BackgroundLifestyle factors have been studied for dementia risk, but few studies have comprehensively assessed both Alzheimer's disease (AD) and cerebrovascular disease (CBVD) pathologies.ObjectiveOur research aims to determine the relationships between lifestyle and dementia pathologies.MethodsWe analyzed data from 1208 Wisconsin Registry for Alzheimer's Prevention (WRAP) participants. The cohort is enriched for participants with a family history of AD and a higher proportion of APOE ε4 carriers (n = 478); participants are primarily female (n = 827), non-Hispanic white (n = 1088), and highly educated (≥3 years professional or college education; n = 803), with an average baseline age of 64. Life's Simple Seven (LS7) scores were calculated from questionnaire data and clinical vitals. Brain health outcomes included CBVD biomarkers (white matter hyperintensities and arterial spin labeling [ASL] cerebral perfusion), AD biomarkers (amyloid Pittsburgh compound B index and tau standardized uptake value ratio Mayo meta-temporal composite), and cognitive outcomes (Preclinical Alzheimer Cognitive Composite Score 3 [PACC3], Delayed Recall, Immediate Learning, and Executive Function).ResultsHigher LS7 scores were significantly associated with lower white matter hyperintensity burden and higher ASL perfusion at the 6-8 year interval, with nominal associations observed at earlier time points and for global cognition (PACC3). No consistent associations were observed with amyloid or tau PET measures.ConclusionsThis study provides evidence that the beneficial effects of LS7 on cognition are primarily through cerebrovascular pathways rather than through AD pathology.},
}
@article {pmid42489523,
year = {2026},
author = {Gobbo, S and Romano, D},
title = {Reduced differentiation of personality in Alzheimer's disease-like dementia and associations between informant report of personality change and cognitive decline.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261469839},
doi = {10.1177/13872877261469839},
pmid = {42489523},
issn = {1875-8908},
abstract = {BackgroundPersonality changes are documented in Alzheimer's disease (AD), but research has focused almost exclusively on how much traits change rather than how the underlying personality structure reorganizes. Recent evidence from healthy aging shows that personality traits can de-differentiate over time, suggesting a decline of coherence of traits with age. Whether such personality de-differentiation also occurs in neurodegeneration and how personality and cognitive changes relate remains unknown.ObjectiveThis study aimed to examine structural changes in personality traits in individuals with AD-like dementias, using the HEXACO personality model administered cross-sectionally to informants and to a control group of informants of healthy older adults, and explore dimensional changes in the relationship between reported changes in personality and cognition.Methods207 informants of persons with AD-like dementia and 201 informants of healthy older adults completed the Hexaco Adjective Scales, referring both to the present time and to perceived changes in personality, and a questionnaire (e-Cog) to assess cognitive changes.ResultsPrincipal component analysis revealed a simplified personality structure in persons with AD but not in healthy older adults, with Emotionality not emerging as an independent factor in persons with AD. Network analyses indicated significant links between personality trait changes and declines across cognitive domains that differed between the two groups.ConclusionsAD-like dementias are characterized by a reduced differentiation of personality structure paralleling the simplification of cognitive organization, with the strongest impact observed in the Emotionality domain. Personality changes also co-occur with perceived cognitive decline, underscoring the need to integrate personality assessment in evaluating dementia.},
}
@article {pmid42489525,
year = {2026},
author = {Hewan, P and Wearn, A and Hogeveen, J and Williams, K and Spreng, RN and Turner, GR and , },
title = {Cortical microstructural integrity predicts an exploitation bias in older adulthood.},
journal = {The journals of gerontology. Series B, Psychological sciences and social sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/geronb/gbag132},
pmid = {42489525},
issn = {1758-5368},
abstract = {OBJECTIVES: Prefrontal regions are implicated in explore-exploit decision-making during foraging. Older adults often show an exploitation bias, and this age period is also marked by deteriorating prefrontal myelination. To investigate whether these phenomena are linked, we examined whether lower magnetization transfer saturation (MTsat), a myelin-sensitive quantitative MRI (qMRI) measure, in these regions predicts greater exploitation bias during foraging, and whether cortical microstructure is a better predictor of bias than macrostructure (i.e., cortical thickness).<br><br>METHODS: Cognitively healthy older adults with familial risk of Alzheimer's disease (AD) (N=118, 60-88 years) completed a foraging task indexing explore-exploit decision-making. qMRI was used to derive MTsat values for the frontopolar cortex (FPC), medial orbitofrontal cortex (OFC), rostral middle frontal gyrus (rMFG), dorsal anterior cingulate cortex (dACC), as well as the locus coeruleus (LC), a core subcortical region strongly implicated in explore-exploit decision-making. Secondary analyses examined associations between available AD risk markers and foraging.<br><br>RESULTS: Lower MTsat in the FPC, OFC, rMFG, and LC was associated with an exploitation bias, with LC and FPC emerging as the strongest predictors. No relationship was observed for the dACC. MTsat remained a significant predictor of foraging after controlling for cortical thickness. Observed associations were largely unrelated to AD risk markers.<br><br>DISCUSSION: Individual differences in cortical microstructural integrity within a well-defined explore-exploit circuit are associated with an exploitative decision-making bias in older adults. These findings highlight the value of qMRI microstructural integrity markers, beyond standard macrostructural assays, in characterizing the neural correlates of exploitation biases in later life.},
}
@article {pmid42489527,
year = {2026},
author = {Streit, WJ and Kuhrt, H and Bechmann, I},
title = {Elevated ferritin expression in microglia and extracellular amyloid-β deposition are associated with reduced neurofibrillary degeneration in human isocortex, but not allocortex.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261470454},
doi = {10.1177/13872877261470454},
pmid = {42489527},
issn = {1875-8908},
abstract = {BackgroundPrior work in preclinical late-onset Alzheimer's disease (LOAD) focused on neuritic plaque development suggested that intracellular ferritin expression in microglia and extracellular deposition of amyloid-β (Aβ) are innate neuroprotective mechanisms geared specifically towards limiting aging-dependent increases in intracerebral free iron which likely contribute to development of neurofibrillary degeneration (NFD).ObjectiveImprove understanding of LOAD pathogenesis.MethodsImmunohistochemical comparison of the extent of NFD with the intensity of ferritin expression and Aβ deposition in three brain regions, including temporal lobe (entorhinal cortex, hippocampus), frontal, and occipital cortex in 34 non-demented human subjects at Braak stages II-III.ResultsFerritin-positive microglia are present with similar quantity and intensity in the allo- and isocortices of every individual in the cohort. Extracellular Aβ deposition in the isocortex is observed before substantial NFD develops, but in the allocortex (temporal lobe) there are no Aβ deposits in 50% of subjects despite extensive NFD. Cytoskeletal lesions in the allocortex consist of atrophic grid cells, abundant pretangles, neuropil threads, neurofibrillary tangles, and neuritic plaques; isocortical sites show either no NFD at all or only minimal NFD presenting as solitary pretangles or tangles, neuropil threads, or droplet degeneration spheres from ferroptotic neurons. Presence of degenerating grid neurons in entorhinal cortex coincides with microglial apoptosis.ConclusionsNeuroprotection via ferritin expression and Aβ deposition is more effective in the isocortex than in allocortex. Findings support the hypothesis that degeneration or death of neuroprotective microglia promotes neuronal degeneration.},
}
@article {pmid42489531,
year = {2026},
author = {Farzeen, I and Nazir, MM and Jaan, Z and Ghaffar, W and Masood, A and Yasmeen, M and Ashraf, A and Różański, H},
title = {Biochemical modulators of synaptic plasticity: New horizons in Alzheimer's disease treatment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261469864},
doi = {10.1177/13872877261469864},
pmid = {42489531},
issn = {1875-8908},
abstract = {Synaptic dysfunction is the earliest and most critical pathological feature of Alzheimer's disease (AD), directly contributing to cognitive decline. This review provides an integrative overview of the molecular and biochemical modulators governing synaptic plasticity and their disruption in AD. We discuss how the collective impairment of Aβ aggregation, tau pathology, calcium imbalance, oxidative stress, and neuroinflammation affects dendritic spine morphology and synaptic connectivity. Particular attention is given to neurotrophins such as brain-derived neurotrophic factor and TrkB signaling, hormonal influences, likewise glucocorticoids, estrogens, testosterone, endocannabinoid pathways, lipid and cholesterol regulators like ApoE and lipid rafts, and epigenetic mechanisms that modulate synaptic resilience. We further evaluate the therapeutic potential of pharmacological agents, including cholinesterase inhibitors, NMDA receptor modulators, and multi-target directed ligands alongside nutraceuticals such as resveratrol, curcumin, omega-3 fatty acids, Withania somnifera, and Bacopa monnieri. Emerging technologies, including iPSC-derived neuronal models, optogenetics, and advanced neuroimaging biomarkers like SV2A PET, cerebrospinal fluid/plasma neurogranin, are also highlighted for their role in elucidating and monitoring synaptic integrity. Ultimately, targeting the biochemical modulators of synaptic plasticity offers a promising avenue for AD therapy, especially through combinatorial and precision-medicine strategies aimed at restoring synaptic function and cognitive performance.},
}
@article {pmid42489532,
year = {2026},
author = {Shin, SH and Mo, Y and Hwang, HS and Lee, M and Lee, JJ and Kim, C and Choi, HJ},
title = {MRI-free amyloid PET quantification using a deep learning model and white matter reference.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261470021},
doi = {10.1177/13872877261470021},
pmid = {42489532},
issn = {1875-8908},
abstract = {BackgroundAccurate quantification of standardized uptake value ratio (SUVR) in amyloid PET is essential for Alzheimer's disease (AD) diagnosis but typically requires MRI-based segmentation due to subtle uptake differences between gray and white matter.ObjectiveThis study aimed to develop and validate a 3-dimensional deep learning model capable of segmenting these tissues directly from PET images to enable MRI-free SUVR quantification for AD diagnosis.MethodsThis retrospective study included 385 participants who underwent brain amyloid PET and MRI. After excluding 12 data-corrupted cases, 373 subjects were divided into training (n = 318) and test (n = 55) sets. External validation used 625 PET/CT scans from the Alzheimer's Disease Neuroimaging Initiative. Model performance was assessed using Dice coefficients and intersection over union. PET-based SUVRs derived from model-generated masks were compared with MRI-based SUVRs using Spearman correlation, and their diagnostic utility was evaluated by group differences and receiver operating characteristic analysis.ResultsThe model achieved high Dice coefficients for grey matter (GM; 0.785 internal, 0.743 external) and white matter (WM; 0.838 internal, 0.803 external). PET/CT-based SUVR values strongly correlated with MRI references (Spearman's ρ ≥ 0.98, p < 0.001). PET/CT-derived SUVRGM and SUVRGM/WM predicted amyloid status (AUC 0.86 and 0.85, respectively) and cognitive impairment (AUC 0.78).ConclusionsDeep learning-based amyloid PET segmentation enables accurate MRI-free quantification of gray and white matter SUVRs. This approach simplifies clinical workflow while maintaining diagnostic performance comparable to MRI-based methods for AD diagnosis.},
}
@article {pmid42489536,
year = {2026},
author = {Costa, T and Sensi, SL and Høilund-Carlsen, PF and Robakis, NK and Vissel, B and Espay, AJ},
title = {Do anti-amyloid therapies demonstrate clinically meaningful benefit? A Bayesian reappraisal.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261469870},
doi = {10.1177/13872877261469870},
pmid = {42489536},
issn = {1875-8908},
abstract = {BackgroundRecent anti-amyloid trials have been interpreted as evidence of clinical benefit in Alzheimer's disease, although their relevance remains debated.ObjectiveTo reinterpret pooled randomized evidence on anti-amyloid therapies within a Bayesian framework focused on benefit and harm.MethodsPooled estimates from a recent Cochrane review were reanalyzed using posterior probability estimation with clinically relevant thresholds.ResultsThe probability that treatment effects reached clinically meaningful thresholds was generally low, whereas the probability of substantial harm, particularly amyloid-related imaging abnormalities, was high.ConclusionsCurrent randomized evidence suggests that statistically significant anti-amyloid effects may not translate into clinically meaningful benefit.},
}
@article {pmid42489538,
year = {2026},
author = {Wang, YC and Liu, TT and Huang, LY and Tan, CC and Tan, L and Xu, W},
title = {The interplay between impaired kidney function and hypertension in dementia: A 13-year longitudinal study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261470293},
doi = {10.1177/13872877261470293},
pmid = {42489538},
issn = {1875-8908},
abstract = {BackgroundHypertension and kidney function impairment (KFI) are established risk factors for dementia and may reinforce each other. However, whether their coexistence confers excess dementia risk remains unclear.ObjectiveTo examine the multiplicative and additive interactions between hypertension and KFI in relation to incident dementia and explore potential biological pathways.MethodsWe included 218,858 dementia-free adults followed for a mean of 13.2 years. KFI was defined as an estimated glomerular filtration rate <60 mL/min/1.73 m[2]. Cox proportional hazards models assessed independent associations and multiplicative interaction, while additive interaction was evaluated using the relative excess risk due to interaction (RERI), attributable proportion (AP), and synergy index (SI). Plasma proteomic data on 2911 proteins were available for 6127 participants.ResultsHypertension was associated with dementia risk (hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.17-1.31; p < 0.001), whereas KFI was not (HR, 1.02; 95% CI, 0.94-1.11; p = 0.571). A significant multiplicative interaction was observed (p = 0.018). KFI was associated with dementia only among participants with hypertension (HR, 1.15; 95% CI, 1.01-1.29; p = 0.023). A positive additive interaction was also observed (RERI, 0.27; 95% CI, 0.05-0.49; AP, 0.17; 95% CI, 0.05-0.29; SI, 1.84; 95% CI, 1.11-3.07), although it was attenuated after full adjustment. Proteomic analyses implicated immune and inflammatory pathways.ConclusionsHypertension may modify the association between impaired kidney function and dementia risk. Their coexistence may identify individuals at higher risk, but further studies are needed to confirm these findings and clarify the underlying mechanisms.},
}
@article {pmid42489907,
year = {2026},
author = {Noroozian, M and Givian, H and Vafaee, MS},
title = {Chronic schizophrenia versus Alzheimer's disease: neuroimaging perspectives on the late-life course of schizophrenia.},
journal = {Journal of neural transmission (Vienna, Austria : 1996)},
volume = {},
number = {},
pages = {},
pmid = {42489907},
issn = {1435-1463},
abstract = {Schizophrenia (SCZ) is a chronic mental disorder that typically starts in early adulthood. It is characterised by structural brain abnormalities that occur early in the course of the disease, such as changes in the synapses and alterations in the brain white matter, which consequently progress to brain atrophy in several regions of the brain, as well as white matter lesions. On the other hand, epidemiological evidence indicates improved survival and increased life expectancy among patients with SCZ, largely due to advances in diagnosis and medication management, resulting in a growing number of individuals reaching older age. In addition, several studies have shown accelerated aging and an increased risk of cognitive decline in these patients. Consequently, the healthcare system faces a growing challenge: older adults with chronic SCZ who are at increased risk of dementia (particularly Alzheimer-type dementia). Notably, many individuals with chronic SCZ have several modifiable risk factors for dementia, including obesity, diabetes, elevated low-density lipoprotein cholesterol (LDL), metabolic syndrome, physical inactivity, smoking, and social isolation which may result from a combination of long-term antipsychotic medication, lifestyle factors, and medical comorbidities. These factors overlap substantially with established risk factors for Alzheimer's disease (AD) and may contribute to increased vulnerability to cognitive decline and dementia in later life. The clinical presentation of older adults with chronic SCZ who develop progressive cognitive and functional decline may closely resemble AD, owing to overlapping features such as memory impairment, social withdrawal, psychomotor slowing, and gait disturbances associated with vascular and metabolic comorbidities. Distinguishing these conditions represents a major diagnostic challenge for cognitive neurologists and psychogeriatricians. Therefore, this narrative review critically examines the differential and overlapping neuroimaging features of chronic SCZ and AD to facilitate more accurate clinical assessment and diagnosis in late life.},
}
@article {pmid42489967,
year = {2026},
author = {Søraas, A and Engvig, A and Alnæs, D and Karim, LN and Danilova, E and Istre, MS and Nygaard, S and Utgård, TR and Ceprnjic, S and Reiakvam, O and Edvardsen, E and Westlye, LT and Nygaard, AB and Dahl, JA and Nissen-Meyer, LSH and Ihle-Hansen, H and Holland, P},
title = {Interstitial fluid rejuvenation through young-donor plasma exchange in cognitively impaired patients: a pilot safety and feasibility study.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42489967},
issn = {2509-2723},
abstract = {Heterochronic parabiosis improves physiological and cognitive function in aging rodents; these benefits appear to be derived from the removal of aged blood plasma components and the addition of younger ones. In humans, removing plasma from older individuals with Alzheimer's disease (AD) and replacing it with saline and albumin delayed cognitive deterioration in a large clinical trial. However, mimicking heterochronic parabiosis in humans by removing large volumes of a patient's blood plasma and replacing it with plasma from young and healthy donors has not been tested. Here, we have performed a pilot study to characterize the feasibility and safety of such a procedure, replacing between 16 and 26 L of patient blood plasma with young (ages 18-24) donor blood plasma for twelve patients who recently received a diagnosis of mild cognitive impairment with biomarker evidence of AD. The dose and time interval between plasma exchanges was tailored to maximize equilibration of donor plasma components into the interstitial fluid, with the aim of achieving what we term interstitial rejuvenation. We explored three permutations of a plasma exchange protocol with different treatment intensities and doses, each performed on three to five patients. We present data on safety, feasibility, patient burden, resource use of the treatments, preliminary measurements of clinical variables, and short-term cognitive trajectories in the patients. The procedures were feasible, and the adverse events observed were consistent with known risks of plasma exchange, supporting further investigation of treatment efficacy in a larger controlled trial. This safety and feasibility study was first registered 22 December 2023 at ClinicalTrials.gov and given the identifier NCT06234436.},
}
@article {pmid42489996,
year = {2026},
author = {Ahmed, HM and Al-Hussainy, AF and Arora, V and Rekha, MM and Kundlas, M and Chennakesavulu, K and Manu, M and Rizaev, J and Taher, SG and Alwan, M and Jawad, M and Mushtaq, H},
title = {Elevated CSF GAP-43 is associated with reduced cerebral glucose metabolism and cognitive impairment in individuals with mild cognitive impairment.},
journal = {Brain imaging and behavior},
volume = {20},
number = {4},
pages = {},
pmid = {42489996},
issn = {1931-7565},
mesh = {Humans ; *GAP-43 Protein/cerebrospinal fluid ; *Cognitive Dysfunction/cerebrospinal fluid/metabolism/diagnostic imaging ; *Glucose/metabolism ; Male ; Female ; Positron-Emission Tomography ; Alzheimer Disease/metabolism/cerebrospinal fluid/diagnostic imaging ; Aged ; Fluorodeoxyglucose F18 ; Biomarkers/cerebrospinal fluid ; *Brain/metabolism/diagnostic imaging ; Aged, 80 and over ; Neuropsychological Tests ; },
abstract = {Growth-associated protein 43 (GAP-43), a synaptic protein involved in neuronal plasticity, has emerged as a potential biomarker for Alzheimer's disease (AD) and mild cognitive impairment (MCI), with elevated levels linked to synaptic dysfunction. This dysfunction, in turn, has been associated with reduced cerebral glucose metabolism, which further exacerbates cognitive decline and accelerates disease progression. However, the link between CSF GAP-43 and cerebral glucose metabolism, measured by FDG-PET, remains less understood. This study aimed to investigate the relationship between CSF GAP-43 levels, cerebral glucose metabolism, and cognitive performance across different stages of cognitive impairment, specifically in individuals with AD (n = 83), MCI (n = 370), and cognitively normal (CN; n = 215). Cognitive function was assessed using the ADAS-Cog 13 scale, CSF GAP-43 levels were measured via ELISA, and cerebral glucose metabolism was analyzed with FDG-PET. The results showed that CSF GAP-43 levels were significantly elevated in the AD group compared to the CN and MCI groups (p < 0.001). In the MCI group, there was a modest but statistically significant negative association between CSF GAP-43 levels and cerebral glucose metabolism (β = -0.126, FDR p = 0.003), whereas this association was not significant in the CN (β = -0.031, FDR p = 0.612) or AD groups (β = 0.157, FDR p = 0.584). Mediation analysis, adjusted for age, sex, education, and APOE ε4 carrier status, showed that FDG-PET cerebral glucose metabolism partly and statistically mediated the association between CSF GAP-43 and cognitive performance only in the MCI group (β = 0.047, FDR-adjusted p = 0.009). These findings indicate that higher CSF GAP-43 was associated with lower cerebral glucose metabolism, which in turn was associated with worse cognitive performance in MCI. However, because of limitations, cross-sectional design, and modest magnitude of the effects, these results should be interpreted as statistical associations rather than evidence that CSF GAP-43 impairs glucose metabolism or cognition.},
}
@article {pmid42490036,
year = {2026},
author = {Just, C and Seibert, K and Chan, C and Maldonado-Correa, C and Jones, D},
title = {Considerations in Alzheimer's Disease in Women.},
journal = {Current neurology and neuroscience reports},
volume = {26},
number = {1},
pages = {},
pmid = {42490036},
issn = {1534-6293},
mesh = {Humans ; *Alzheimer Disease/diagnosis/metabolism ; Female ; *Sex Characteristics ; Biomarkers ; tau Proteins/metabolism ; },
abstract = {PURPOSE OF REVIEW: To examine sex differences in Alzheimer's disease and cognition with a focus on hormonal transitions, biomarker trajectory, and implications for diagnosis and treatment.<br><br>RECENT FINDINGS: Women account for nearly two-thirds of individuals with Alzheimer's disease and demonstrate important biological and clinical differences compared with men. APOE &#x3b5;4 confers greater risk in women, while menopause, depression, chronic stress, adverse pregnancy outcomes, and metabolic dysfunction may further increase vulnerability. Biomarker studies suggest that amyloid trajectories are broadly similar between sexes, but women exhibit earlier or greater tau accumulation once amyloid pathology is present. Women may maintain verbal memory performance longer than men despite underlying pathology, potentially delaying diagnosis. Emerging plasma biomarkers, particularly p-tau217, may improve early detection, monitoring, and treatment. Alzheimer's disease in women reflects a complex interaction between sex-specific biology, hormonal transitions, psychosocial factors, and neurodegenerative processes. Recognizing these differences has important implications for cognitive assessment, biomarker interpretation, diagnosis, and application of disease-modifying therapies.},
}
@article {pmid42490197,
year = {2026},
author = {Ko, E and Cho, H},
title = {Ethical Considerations of Artificial Intelligence in Dementia Research: A Review of Reviews.},
journal = {The Gerontologist},
volume = {},
number = {},
pages = {},
doi = {10.1093/geront/gnag158},
pmid = {42490197},
issn = {1758-5341},
abstract = {BACKGROUND AND OBJECTIVES: To examine the ethical considerations related to artificial intelligence technologies in dementia across diagnostic, management, and to synthesize these considerations using existing artificial intelligence and bioethical ethics principles.<br><br>RESEARCH DESIGN AND METHODS: The review of reviews synthesized evidence from published reviews addressing ethical considerations in published review-level evidence on ethical issues related to artificial intelligence for dementia and Alzheimer's disease. Findings were extracted and narratively synthesized. Ethical issues were mapped to the four UNESCO value domains and four traditional bioethical principles to provide an interpretive framework.<br><br>RESULTS: Eighteen reviews were included. Ethical concerns were related to algorithmic bias, limited diverse data, privacy, data security, data governance, fairness, and psychosocioeconomic and environmental well-being, and caregiving contexts. Based on UNESCO's four domains, six themes were identified: protection of human rights, technical trustworthiness, respect for human dignity, equity and access, governance, and environmental well-being. Ethical concerns prioritized the respect and protection of human rights and dignity, whereas environmental and ecosystem considerations were under focused. While many categories aligned with the traditional bioethical principles of autonomy, beneficence, non-maleficence, and justice, some concerns related to environmental well-being and data governance were difficult to classify within this framework.<br><br>DISCUSSION AND IMPLICATIONS: Our findings highlight the importance of embedding ethical principles in individual-level and system-level design implications to support the ethical and sustainable use of artificial intelligence in dementia care. This review will help healthcare professionals understand and address the ethical considerations in various dementia care settings where artificial intelligence is introduced or evaluated.},
}
@article {pmid42490359,
year = {2026},
author = {Lotfalinezhad, E and Freeman, S and Kearns, W and Chehrehgosha, M and Nadrian, H and Stokes, JE and Barati, F and Amirkhani-Ardeh, S and Mancheri, H and Jouybari, L and Genge, C},
title = {Navigating the Continuum: System-Level Requirements for High-Quality Dementia Care Transitions.},
journal = {American journal of Alzheimer's disease and other dementias},
volume = {41},
number = {},
pages = {15333175261471717},
doi = {10.1177/15333175261471717},
pmid = {42490359},
issn = {1938-2731},
mesh = {Humans ; *Dementia/therapy ; *Patient-Centered Care/standards ; *Quality of Health Care/standards ; *Continuity of Patient Care/standards ; },
abstract = {The worldwide rise in dementia cases is creating significant pressures on healthcare systems, clinicians, and decision-makers. As dementia does not follow a single predictable pathway, individuals commonly move across different care settings as their needs evolve, requiring coordinated and integrated responses across the healthcare system rather than isolated efforts within single services. This perspective study explores service quality and underlying structural challenges throughout the dementia care pathway with a particular concentration on transitions between various stages. Key barriers to successful implementation include fragmented service delivery, short-term funding structures, weak coordination across care settings, staffing constraints, and challenges in staff retention. These challenges undermine care standards and result in avoidable emergency department and acute care utilization that contribute to increasing health systems expenditures. Strengthening integrated, person-centered, and transition-oriented care frameworks is critical to enhance outcomes and support sustainable health system responses to an increasing global impact of dementia.},
}
@article {pmid42490402,
year = {2026},
author = {Lu, X and Shen, X},
title = {On the Directionality of Predictor-Outcome Assignment When Modeling Polygenic Risk for Alzheimer's Disease Alongside Sleep Arousal Phenotypes.},
journal = {Sleep},
volume = {},
number = {},
pages = {},
doi = {10.1093/sleep/zsag198},
pmid = {42490402},
issn = {1550-9109},
}
@article {pmid42490471,
year = {2026},
author = {Smith, JE},
title = {Alzheimer's trial results lend momentum to drugs targeting tau.},
journal = {Science (New York, N.Y.)},
volume = {393},
number = {6809},
pages = {343-344},
doi = {10.1126/science.aek8032},
pmid = {42490471},
issn = {1095-9203},
mesh = {*tau Proteins/metabolism/antagonists &amp; inhibitors ; *Alzheimer Disease/drug therapy/metabolism ; Humans ; Indoles ; },
abstract = {First drug to lower the protein and slow cognitive decline created buzz despite puzzling data.},
}
@article {pmid42490473,
year = {2026},
author = {Zhang, Y and Lu, X and Kunisky, AK and Alam, S and Tang, J and Zhang, R and Wang, S and Zhang, H and Baroudi, J and Ichcho, W and Jia, D and Ghorbanikalateh, S and Ghorbanikalateh, S and Wang, S and Bennett, DA and Mathys, H and Duan, Z and Ma, J},
title = {Single-cell multiomics connects 3D genome and transcriptome alterations in Alzheimer's disease.},
journal = {Science (New York, N.Y.)},
volume = {393},
number = {6809},
pages = {eadz1652},
doi = {10.1126/science.adz1652},
pmid = {42490473},
issn = {1095-9203},
mesh = {Humans ; *Alzheimer Disease/genetics/pathology ; *Chromatin/chemistry/metabolism/genetics/ultrastructure ; *Single-Cell Analysis ; *Transcriptome ; Multiomics ; Spatial Transcriptomics ; Brain/metabolism/pathology ; *Chromatin Assembly and Disassembly ; Gene Expression Regulation ; *Genome, Human ; Single-Cell Gene Expression Analysis ; },
abstract = {Alzheimer's disease (AD) disrupts brain function through cell type-specific transcriptomic and epigenomic alterations, yet the contribution of three-dimensional (3D) genome organization to AD remains poorly understood. We applied GAGE-seq (genome architecture and gene expression by sequencing) to jointly profile gene expression and 3D chromatin structure in single cells from postmortem brain tissue from AD patients and age-matched individuals without AD, revealing chromatin reorganization linked to cell type-specific dysregulation. Integrations with spatial transcriptomics and chromatin accessibility data uncovered altered niches reflecting genome compartment remodeling and regulatory element reorganization. Hicformer, a deep learning framework, showed that 3D genome features are essential for predicting disease-relevant, cell type-specific gene expression changes. Our results establish higher-order chromatin alterations as a component of AD-associated molecular pathology, providing a multiscale view of transcriptional regulation and 3D genome organization in neurodegeneration.},
}
@article {pmid42490707,
year = {2026},
author = {Cossette-Lefebvre, M and Bergeron, N},
title = {[Cooccurrence of catatonia, delirium and dementia in an elderly woman: A case report].},
journal = {Sante mentale au Quebec},
volume = {51},
number = {1},
pages = {95-104},
pmid = {42490707},
issn = {1708-3923},
mesh = {Humans ; Female ; *Catatonia/complications/diagnosis ; *Dementia/complications/diagnosis ; *Delirium/complications/diagnosis ; Aged ; },
abstract = {Catatonia is a severe but underrecognized neuropsychiatric syndrome that is frequently misdiagnosed as delirium or dementia in older adults, resulting in delayed and potentially inappropriate treatment. A 79-year-old woman was admitted for rapid cognitive decline, significant weight loss, and social withdrawal. Initial evaluations suggested major depressive disorder or dementia. Neurological investigations were inconclusive. Following the initiation of psychotropic medication, psychiatric assessment revealed mutism, posturing, and marked psychomotor retardation, fulfilling DSM-5 criteria for catatonia. A lorazepam challenge test confirmed the diagnosis. Psychotropic medications were discontinued, and lorazepam was titrated to 2 mg 4 times daily, resulting in significant clinical improvement. Subsequent brain positron emission tomography (PET) imaging along with clinical evidence supported the presence of an underlying Alzheimer's disease. However, the emergence of superimposed delirium required gradual benzodiazepine tapering. Memantine was subsequently introduced, allowing lorazepam withdrawal and full symptomatic remission. The patient was discharged home. During outpatient follow-up, recurrence of partial symptoms prompted consideration of alternative therapeutic strategies. This case underscores the importance of recognizing catatonia in older adults presenting with cognitive impairment. It highlights the diagnostic and therapeutic challenges posed by the coexistence of catatonia, delirium, and neurodegenerative disease, and emphasizes the need for early identification and a multidisciplinary approach to optimize outcomes.},
}
@article {pmid42490982,
year = {2026},
author = {Ramamurthy, B and Cho, A and Abdolmaleki, M and Fayez, N and Roby, D and Maynard, KB and Jefferson, AL and Bolton, C},
title = {Short-term psychological impacts of Alzheimer's disease risk disclosure based on blood-biomarker results.},
journal = {Alzheimer's &amp; dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70295},
doi = {10.1002/trc2.70295},
pmid = {42490982},
issn = {2352-8737},
abstract = {INTRODUCTION: Blood-based biomarkers (BBMs) of Alzheimer's disease (AD) provide important information about risk for dementia, but little is known about the psychological impact of sharing BBM results to participants with mild cognitive impairment (MCI). Most AD risk disclosure studies have been conducted in cognitively unimpaired individuals and have not used BBMs. This pilot randomized trial tests the hypothesis that disclosing AD risk based on BBMs is not associated with increased psychological harm compared to standard disclosure methods.<br><br>METHODS: Participants (n&#xa0;=&#xa0;27, 73 &#xb1; 11 years) with MCI were enrolled and randomized to the intervention (n&#xa0;=&#xa0;16) or control (n&#xa0;=&#xa0;11) arm. Participants received a risk estimate based on their age, sex, and equivalent Mini-Mental State Examination score for both groups, with plasma phosphorylated tau 181 results included for the intervention group. Participants completed questionnaires assessing depression, anxiety, and hopelessness prior to disclosure and 2 weeks later. A repeated measures multivariate analysis of variance (MANOVA) was used to determine changes in psychological responses over the follow-up period with a time x group interaction term assessing group differences.<br><br>RESULTS: Participants in the intervention and control group were similar across baseline demographic and clinical factors (P values &#x2265; 0.23). Repeated measures MANOVA showed a significant reduction in psychological symptoms from baseline to 2-week follow-up (P&#xa0;=&#xa0;0.006) in the combined sample. Follow-up univariate models showed the reduction was driven by a significant reduction in anxiety (mean &#xb1; standard deviation; baseline = 13.3 &#xb1; 7.7; follow-up = 9.8 &#xb1; 9.9; P&#xa0;=&#xa0;0.02). Time x group interaction was non-significant (P&#xa0;=&#xa0;0.31) indicating similar psychological responses across groups.<br><br>DISCUSSION: In this pilot study of participants with MCI, psychological response to learning risk of progression to dementia did not differ between those who received a risk estimate based on a BBM versus standard clinical information. Two weeks after disclosure, there was an overall decline in anxiety. These preliminary findings suggest that AD risk disclosure using BBMs is not associated with psychological distress.},
}
@article {pmid42490986,
year = {2026},
author = {Kim, GH and Yoon, HJ and Kim, EH and Kim, JY and Yeom, J and Kang, SY and Lee, B and Jeong, JH},
title = {Six-month real-world amyloid PET outcomes after lecanemab: Greater amyloid reduction at the MCI stage than in dementia.},
journal = {Alzheimer's &amp; dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70300},
doi = {10.1002/trc2.70300},
pmid = {42490986},
issn = {2352-8737},
abstract = {INTRODUCTION: Evidence from routine clinical practice regarding stage-dependent responses to lecanemab remains limited. We examined early amyloid positron emission tomography (PET) and clinical trajectories according to disease stage in a real-world cohort.<br><br>METHODS: Among 89 patients who received lecanemab, 50 individuals with baseline amyloid positivity and follow-up amyloid PET were included in the primary amyloid PET efficacy analysis. Amyloid burden was quantified using the Centiloid scale. Longitudinal Centiloid trajectories were analyzed using linear mixed-effects models including disease stage, time from baseline amyloid PET, and the disease stage &#xd7; time interaction, with adjustment for cumulative dose exposure, age, sex, and apolipoprotein E (APOE) &#x3b5;4 carrier status. Cognitive and functional outcomes were assessed using mixed-effects models.<br><br>RESULTS: Amyloid burden decreased substantially during follow-up. After adjustment for cumulative dose exposure, age, sex, and APOE &#x3b5;4 carrier status, the disease stage &#xd7; time interaction was significant (&#x3b2;&#xa0;=&#xa0;+1.62 Centiloid/month; 95% confidence interval, 0.80 to 2.43; p&#xa0;<&#xa0;0.001), indicating a faster rate of Centiloid reduction in patients with mild cognitive impairment (MCI) than in those with dementia (estimated -2.34&#xa0;vs. -0.72 Centiloid/month). Conversion to amyloid-negative status (full treatment-related amyloid clearance) occurred in 9 of 50 patients (18.0%) and was more frequent at the MCI stage (p&#xa0;=&#xa0;0.022). Patients treated at the MCI stage also showed more favorable short-term cognitive and functional trajectories than those treated at the dementia stage.<br><br>DISCUSSION: In real-world clinical practice, lecanemab treatment was associated with substantial amyloid reduction, with faster amyloid clearance observed at the MCI stage. These findings support the potential value of earlier intervention with anti-amyloid therapy, although longer follow-up and controlled comparisons are needed to determine whether early biomarker changes translate into sustained clinical benefit.},
}
@article {pmid42490993,
year = {2026},
author = {Fong, A and Tabaie, A and Paylor, S and Tran, T and Iqbal, R and Ratwani, RM and Zafari, Z and Bangerter, LR and Brandt, NJ},
title = {Real-world pharmacovigilance for anti-Aβ therapies using a large language model.},
journal = {Alzheimer's &amp; dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70412},
doi = {10.1002/dad2.70412},
pmid = {42490993},
issn = {2352-8729},
abstract = {INTRODUCTION: Anti-amyloid beta (Aβ) therapies for early Alzheimer's disease require enhanced safety monitoring, yet adverse event (AE) documentation is diffuse across heterogeneous electronic health record documents. Large language models (LLMs) may improve scalable pharmacovigilance.<br><br>METHODS: We analyzed 20,123 clinical documents from 46 patients who received at least one dose of anti-A&#x3b2; therapy (June 24, 2024-July 30, 2025) at a large mid-Atlantic health-care system. We compared standard expert review versus an LLM-augmented workflow applied to the same documents. Expert reviewers annotated therapy-related AEs (e.g., amyloid-related imaging abnormalities with edema or hemorrhage, headache, syncope, hypersensitivity, gastrointestinal symptoms, infusion reactions). Discordant cases were adjudicated to establish a reference label.<br><br>RESULTS: After adjudication, 76% (35/46) patients had an AE. The LLM-augmented workflow achieved 100% sensitivity (positive predictive value [PPV] 89.7%) versus expert review 88.6% sensitivity (PPV 100%).<br><br>DISCUSSION: Findings provide preliminary indications that LLMs may serve as a pharmacovigilance signal detection tool, with a need for further validation and evaluation of clinical integration.},
}
@article {pmid42491022,
year = {2026},
author = {Yao, W and Lv, T and Zheng, W and Liu, Y and Shi, X and Zhang, Y and Song, Y and Bai, Y and Bai, F},
title = {Associations between neuronavigated rTMS-mediated functional connectome plasticity and neurotransmitter receptors in Alzheimer's disease.},
journal = {Alzheimer's &amp; dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70294},
doi = {10.1002/trc2.70294},
pmid = {42491022},
issn = {2352-8737},
abstract = {INTRODUCTION: Cognitive improvement is mediated by repetitive transcranial magnetic stimulation (rTMS) in Alzheimer's disease (AD), and connectome gradient analysis has important potential to explore more comprehensive information for treatment efficacy. However, it remains unclear whether and how rTMS mediates connectome gradient reconstruction and its spatial neurotransmitter associations in subjects on the AD spectrum.<br><br>METHODS: A total of 84 subjects on the AD spectrum underwent 4 weeks of conventional neuronavigated rTMS targeting the left angular gyrus (20&#xa0;Hz, 20 sessions over 4 weeks, 20&#xa0;minutes per session), including 60 subjects with true stimulation and 24 with sham stimulation. This study identified functional connectome gradients and investigated their neuroplasticity between pre- and post-rTMS intervention. A support vector regression model was subsequently used to explore the cognitive prediction value of baseline measures. Finally, connectome&#x2012;neurotransmitter association analysis was used to investigate neurotransmitter profiles related to rTMS therapeutic efficacy.<br><br>RESULTS: These findings showed that rTMS treatment mainly mediated the decreased gradient values in the somatomotor regions and such baseline values of these regions showed preliminary predictive value for memory improvement after treatment (R [2]: 0.40-0.63, mean absolute error: 1.54-3.19, root mean square error: 1.98-3.94, p&#xa0;=&#xa0;0.0002). Moreover, connectome-neurotransmitter association analysis suggested spatial associations between these gradient changes and normative metabotropic glutamate receptor 5 (mGluR5) and 5-hydroxytryptamine receptor 2A (5HT2a) receptor distributions.<br><br>DISCUSSION: rTMS mediates plasticity in high-order metric levels in the brain and is linked to the spatial distributions of specific neurotransmitter receptors in subjects on the AD spectrum.},
}
@article {pmid42491041,
year = {2026},
author = {Wei, Z and Bai, L and Liu, X and Zhou, Y and Zheng, L and Zhang, B and Wang, L and Zou, W},
title = {Histone lactylation-mediated glycolysis-ferroptosis axis in neurological diseases.},
journal = {Frontiers in molecular neuroscience},
volume = {19},
number = {},
pages = {1820758},
doi = {10.3389/fnmol.2026.1820758},
pmid = {42491041},
issn = {1662-5099},
abstract = {Histone lactylation is an emerging epigenetic modification that covalently links the glycolytic metabolite lactate to histones, thereby establishing a direct link between cellular metabolic status and gene transcription programs. Recent studies have shown that this modification plays a key role in regulating cellular sensitivity to ferroptosis, forming a novel regulatory axis of "glycolysis-lactylation-ferroptosis." This article systematically reviews the biological functions of histone lactylation in the nervous system, with a focus on elucidating how it participates in the pathological processes of various neurological diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), cerebral stroke, and amyotrophic lateral sclerosis (ALS), by regulating the expression of ferroptosis-related genes. The article integrates the latest research on molecular mechanisms, explores the value of this regulatory axis as a potential biomarker for disease diagnosis and a therapeutic target, and provides an outlook on future research directions in this field.},
}
@article {pmid42491066,
year = {2026},
author = {Sah, RP and Cs, V and Jayaram, S and Yadav, AK and Pereira, P and Damodaran, J},
title = {Impact of Vitamin B12, Folate and Homocysteine in Modulating Cognitive Functions and the Brain's White Matter Hyperintensity in Alzheimer's Disease.},
journal = {Annals of neurosciences},
volume = {},
number = {},
pages = {09727531261457693},
doi = {10.1177/09727531261457693},
pmid = {42491066},
issn = {0972-7531},
abstract = {BACKGROUND: Deficiency of vitamin B12 and folate as surrogate factors attributed to cognitive deterioration among older adults with Alzheimer's disease (AD). Increased homocysteine levels >15 µmol/L (hyperhomocysteinaemia) due to insufficiency of vitamin B12 contribute to damage to the small blood vessels in the brain and aggravate the white matter lesion.<br><br>PURPOSE: The study aimed to determine the impact of B12, folic acid and homocysteine in modulating cognitive functions and white matter hyperintensity in AD.<br><br>METHODS: A case-control study of a total number of 82 patients (41 AD patients and 41 controls) was recruited. The cognitive functions were assessed by the Montreal Cognitive Assessment (MoCA), and white matter hyperintensity was marked by magnetic resonance imaging studies. The levels of vitamin B12, folic acid and homocysteine in serum were also assessed.<br><br>RESULTS: The noticeable changes were observed in the cognitive scores and levels of B12, folic acid and homocysteine in AD and controls and found statistically significant (p < .001). Spearman's rank correlations revealed that cognitive functions (MoCA score) showed a direct correlation with B12 (&#x3c1; = 0.513, p < .001). Conversely, MoCA was moderately negatively correlated with homocysteine (&#x3c1; = -0.422, p < .001). Participants with B12 deficiency showed a significantly higher frequency of white-matter hyperintensities (WMH) (&#x3c7;&#xb2; = 4.654, p = .031; Fisher's exact p = .048).<br><br>CONCLUSION: Nutrient deficiencies, especially B12, have a disruptive impact on cognitive domains and WMH in AD, which could be considered as key indicators to identify the disease severity among older adults. Recommendations of vitamin B12 plus supplements might be connected to clinical and public health initiatives to halt the rate of progression of cognitive decline in AD.},
}
@article {pmid42491111,
year = {2026},
author = {Paranawithana, I and Doré, V and Bourgeat, P and Poon, A and Toh, HB and Thientunyakit, T and Kaewchur, T and Sutherland, A and Gillman, AG and Huang, K and Feizpour, A and Fripp, J and Villemagne, VL and Rowe, CC},
title = {Visual read performance of [18]F-Florbetapir and [18]F-NAV4694 Aβ PET compared against Centiloid reference standard in a paired cohort.},
journal = {Alzheimer's &amp; dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70426},
doi = {10.1002/dad2.70426},
pmid = {42491111},
issn = {2352-8729},
abstract = {INTRODUCTION: Visual assessment remains standard practice to rule out amyloid-β (Aβ) pathology. [18]F-NAV4694 (NAV) has high affinity for Aβ potentially detecting lower levels than other F-18 Aβ tracers.<br><br>METHODS: One hundred fifty participants in the AIBL study underwent both [18]F-Florbetapir (FBP) and NAV A&#x3b2; PET scans. PET scans were assessed by six nuclear medicine physicians against Centiloid (CL) quantification. An optimized reference region was utilized for FBP as it improved CL-visual read correlations. Inter-reader agreement of visual assessment was measured using Fleiss' Kappa.<br><br>RESULTS: Mean peak accuracy for visual read exceeded 95% for both NAV and FBP. However, peak accuracy for NAV visual reads was achieved at 14-15CL compared to 38-46CL for FBP. Higher inter-reader agreement was observed for NAV compared to FBP.<br><br>DISCUSSION: For mild to moderate elevation in A&#x3b2;, visual read of NAV is more sensitive and consistent than visual read of FBP by both experienced and novice readers.},
}
@article {pmid42491145,
year = {2026},
author = {Daniel, TD},
title = {Oscillatory dynamics as the coordination layer of the organism: waves, Markov blankets, and the virtual space of cognition.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1836602},
doi = {10.3389/fnins.2026.1836602},
pmid = {42491145},
issn = {1662-4548},
abstract = {Neural oscillations are not a mechanism that implements cognition. We present a new theoretical framework through a synthesis of relevant literature that has emerged in recent years: metabolic activity in the body, including but not limited to neural tissue, gives rise to an oscillatory pattern that contains information accessible to individual cells. The resulting dynamical structure allows cognitive activity to map the body in fine detail, to perceive its surroundings, or to extend into representations of objects and possibilities never encountered in the world. This array of possibilities is enabled by the coordination of the body's components, which imposes invariant structural regularities among them, in turn creating a moment-to-moment series of states shared across a distributed network of cells. Metabolic success involves ensuring adequate access to nutrition and waste removal for every cell and, when achieved, can give rise to a series of leaps manifested as increased access to complex higher-order affordances. The body's metabolic activity yields observable coordination; however, the mental actions themselves are inscrutable, existing only within a virtual space that unfolds in the interplay of the constituents of a particular body. Access to advanced functions is categorical; this virtual space expands during development and contracts in response to reduced metabolic sufficiency. Markov blankets formalize this asymmetry: brain-scanning technology clarifies the substrate, but no amount of information about the substrate provides direct access to cognitive activity. Frequency bands of oscillation correspond to spatial scales of inter-blanket communication, with cross-frequency coupling carrying information up and down the nested hierarchy. Several clinical conditions-ME/CFS, Long Coronavirus Disease (COVID), cancer-related cognitive impairment, Alzheimer's disease, and age-related decline-share a common upstream mechanism within this framework: cellular damage degrades the substrate, which contracts the space of accessible cognitive operations and produces the categorical incapacity patients report. The framework generates a testable prediction: aperiodic spectral flattening should temporally precede the loss of specific oscillatory peaks as the substrate degrades.},
}
@article {pmid42491578,
year = {2026},
author = {Xie, B and Liu, J and Hao, Y and Fu, X and Yang, S and Guo, C and Yang, Y},
title = {Peripheral inflammation impairs glymphatic function, contributing to neurodegeneration in Alzheimer's disease.},
journal = {iScience},
volume = {29},
number = {7},
pages = {116581},
doi = {10.1016/j.isci.2026.116581},
pmid = {42491578},
issn = {2589-0042},
abstract = {Alzheimer's disease (AD) is associated with systemic immune alterations and glymphatic dysfunction, both of which are linked to brain structural and network changes that contribute to cognitive decline. In 570 participants with AD, mild cognitive impairment, or normal cognition, we combined peripheral immune profiling with multimodal magnetic resonance imaging (MRI) to evaluate glymphatic function, brain structure, and network organization. AD was characterized by reduced analysis along the perivascular space index, enlarged choroid plexus (CP) volume, increased white matter free water, reduced lymphocyte count, and elevated neutrophil-to-lymphocyte ratio (NLR). Immune indices, including NLR, platelet-to-lymphocyte ratio, systemic immune-inflammation index, and lymphocyte count, were associated with cognition and glymphatic-related MRI measures. Mediation analyses indicated that NLR influenced cognition indirectly through CP volume and downstream brain structural and network features. These findings link peripheral immune imbalance to cognitive decline through glymphatic and brain network alterations, supporting biomarker development and mechanism-guided therapeutic strategies.},
}
@article {pmid42491583,
year = {2026},
author = {Luo, C and Wang, R and Yang, F and Qin, L and Ren, Y and Guo, M and Cai, H and Feng, S and Li, N and Gao, H and Tang, Y and Chen, Q},
title = {Nonlinear L-shaped association between composite dietary antioxidant index and risk of dementia: a prospective cohort study.},
journal = {Frontiers in public health},
volume = {14},
number = {},
pages = {1839421},
doi = {10.3389/fpubh.2026.1839421},
pmid = {42491583},
issn = {2296-2565},
mesh = {Humans ; Male ; Prospective Studies ; *Antioxidants/administration &amp; dosage ; Female ; *Diet/statistics &amp; numerical data ; *Dementia/epidemiology ; United Kingdom/epidemiology ; Risk Factors ; Aged ; Proportional Hazards Models ; },
abstract = {OBJECTIVE: Dietary intake of antioxidants may decrease risk of dementia. However, the relationship between the composite dietary antioxidant index (CDAI) and dementia, has not yet been explored. This study investigated the relationship between CDAI and risk of dementia and to explore potential mediators of the relationship.<br><br>METHODS: Data were extracted from the prospective UK Biobank on 157,742 dementia-free participants, who were followed up for a median of 13.39 yr. Potential associations between CDAI at enrollment and subsequent development of all-cause dementia, Alzheimer's dementia or vascular dementia were assessed using Cox proportional hazards regression. Potential non-linear associations were explored using restricted cubic spline analysis. Exploratory analyses were performed to assess whether blood inflammatory markers and cortical/subcortical gray matter volumes accounted for part of the associations, using multivariable linear regression and mediation analyses.<br><br>RESULTS: During follow-up, 791 people developed Alzheimer's dementia, 322 developed vascular dementia, and 709 developed other types of dementia. Higher CDAI was significantly associated with lower risk of all-cause dementia and Alzheimer's dementia, and the association was stronger in women than in men (p for interaction < 0.05). The association was nonlinear and L-shaped (nonlinear p &#x2264; 0.001), with inflection points at 1.579 for all-cause dementia and 0.848 for Alzheimer's dementia. At CDAIs below these inflection points, each unit increase in CDAI was associated with 6.3% lower risk of all-cause dementia (HR 0.937, 95% CI 0.907-0.968, P < 0.001) and 6.5% lower risk of Alzheimer's dementia (HR 0.935, 95% CI 0.897-0.974, P = 0.001). Exploratory pathway analyses suggested that neutrophil and lymphocyte percentages modestly accounted for the association between CDAI and risk of all-cause dementia and Alzheimer's dementia.<br><br>CONCLUSIONS: CDAI may relate to risk of dementia in an L-shaped manner. Exploratory analyses suggested a possible role of systemic inflammation in this association.},
}
@article {pmid42491623,
year = {2026},
author = {Baker, S},
title = {Dr. David Perlmutter: New Steps to Targeting Brain Health and Alzheimer's Disease.},
journal = {Integrative medicine (Encinitas, Calif.)},
volume = {25},
number = {3},
pages = {38-43},
pmid = {42491623},
issn = {1546-993X},
}
@article {pmid42478074,
year = {2026},
author = {Kumar, N and Yarlagadda, V},
title = {Microbes and Microbial Chemical Matter in the Seeding of Alzheimer's Disease: Prospects for Orthogonal Therapies.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00255},
pmid = {42478074},
issn = {1948-7193},
abstract = {Alzheimer's disease (AD) remains the leading cause of dementia, with mortality rates having doubled over the past two to three decades and projected to rise with continued population aging. Despite its profound health and economic impact, effective therapeutic and preventive interventions remain limited, largely owing to an incomplete understanding of its etiopathogenesis. Emerging evidence indicates that microbes, including viruses, bacteria, and fungi, as well as their associated metabolites, toxins, and structural components, are involved in the development of AD. Microbial invasion, through dysbiosis or infection, can trigger neuroinflammation that drives overproduction of amyloid β peptide (AβP). AβP functions as a broad-spectrum antimicrobial agent, and its accumulation, a key pathological hallmark of AD, is promoted by microbial presence as part of the immune response. Maintaining microbial eubiosis, preventing infections that impact the nervous system (e.g., herpes zoster), supporting gut microbiome homeostasis through prebiotics, and the judicious use of antimicrobial interventions may mitigate AD onset and progression. This Review delineates the involvement of microbes and their components in the initiation of AD and presents the prospects of orthogonal therapies to control AD.},
}
@article {pmid42478598,
year = {2026},
author = {Martens, CR and Decker, KP and DeConne, TM and Sanjana, F and Horvat, F and Rizzi, NA and Awad, C and Habash, E and Hobson, JC and Kramer, MK and Armstrong, ML and Reisdorph, N and Pohlig, RT and Lanzi, AM and Johnson, CL and Cohen, ML and Ellison, JM},
title = {A phase-II randomized controlled pilot study of nicotinamide riboside supplementation in older adults with amnestic mild cognitive impairment.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71605},
pmid = {42478598},
issn = {1552-5279},
support = {K01AG054731/AG/NIA NIH HHS/United States ; P20GM113125/GM/NIGMS NIH HHS/United States ; },
mesh = {Humans ; Pilot Projects ; *Cognitive Dysfunction/drug therapy/diagnostic imaging ; Aged ; Double-Blind Method ; Female ; *Niacinamide/analogs &amp; derivatives/therapeutic use/administration &amp; dosage ; Male ; *Dietary Supplements ; Cerebrovascular Circulation/drug effects ; Pyridinium Compounds ; Neuropsychological Tests ; Cognitive Enhancement ; NAD/blood ; *Amnesia/drug therapy ; Blood Pressure/drug effects ; Treatment Outcome ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Declining nicotinamide adenine dinucleotide (NAD[+]) may elevate risk of Alzheimer's disease.<br><br>METHODS: We conducted a 12-week double-blind, randomized, placebo-controlled pilot study to evaluate the safety, tolerability, and preliminary efficacy of the NAD[+] precursor, nicotinamide riboside (NR), for enhancing cognitive function and cerebral blood flow (CBF) in adults with amnestic mild cognitive impairment (aMCI).<br><br>RESULTS: 42 participants completed the study (NR&#xa0;=&#xa0;22, placebo&#xa0;=&#xa0;20). Adherence was similar between groups with no serious adverse effects. Blood NAD[+] increased twofold in the NR group. There were no improvements in cognitive function (primary outcome), total CBF, or blood pressure (secondary outcomes). Exploratory analyses revealed potential increases in regional CBF, particularly in the hippocampus.<br><br>DISCUSSION: NR effectively raises NAD[+] in people with MCI but does not improve cognitive function, total CBF, or blood pressure over 12&#xa0;weeks. Future studies should investigate regional effects on CBF over longer treatment durations.},
}
@article {pmid42478649,
year = {2026},
author = {Sarkar, R and Banerjee, K and Das, S and Sadhukahn, I and Bose, B and Biswas, R and Pan, S and Adhikary, K and Maiti, R},
title = {Micronutrient-Assisted Biomaterial Strategies as Neuropharmacological Modulators of Neuroinflammation and Oxidative Stress in Neurodegenerative Diseases.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X485083260630050618},
pmid = {42478649},
issn = {1875-6190},
abstract = {Neurodegeneration results from the convergence of several molecular processes, including inflammation in the brain (i.e., neuroinflammation), elevated levels of free radicals that damage cells, mitochondrial dysfunction, and the inability to remove damaged proteins from the brain. Even though many agents provide neuroprotection in research models, their clinical use is limited because they cannot effectively cross the blood-brain barrier to reach the areas of the brain where they are needed. Limitations include the inability to cross the blood-brain barrier, poor bioavailability, rapid metabolism and clearance, non-specific targeting, efflux by transport proteins, toxicity, and low solubility and stability. The classification of micronutrients (e.g., vitamins, polyphenols, minerals), which are naturally present antioxidants and anti-inflammatory substances, plays a role in modulating the most important signaling pathways in the body, including those mediating the inflammatory response (i.e., NF-κB and NLRP3) and the process that causes glial cell death (i.e., JAK/STAT). Micronutrients have a significant drawback for therapeutic use because they are rapidly metabolized and cannot cross the blood-brain barrier. Developments in synthetic biomaterials and nanotechnology offer a potential avenue for addressing the challenges of delivering micronutrients to the brain by targeting them to specific areas and releasing them over a sustained period. This study presents current information on the mechanisms by which micronutrients modulate molecular pathways and their potential application in emerging biomaterials to develop a new class of neuroprotective therapeutic agents that may ultimately be used to treat patients with degenerative diseases (e.g., Alzheimer's, Parkinson's, and Huntington's). Additionally, clinical challenges are addressed to translate these products from the laboratory to the clinic. The idea presented in this review connects molecular neuromodulation via micronutrients and bioactive nutraceuticals with a new strategy for pharmacological delivery using biomaterials. Instead of considering nutrition and those biomaterials as separate therapeutic areas, an integrated mechanistic model is presented that shows how micronutrients can act as endogenous pathway regulators and how biomaterials can enhance pharmacokinetics and targeting.},
}
@article {pmid42478671,
year = {2026},
author = {Sato, K and Niimi, Y and Ihara, R and Iwata, A and Iwatsubo, T},
title = {Projected lecanemab wastage from vial discard: Simulation based on Japanese interim post-marketing surveillance summary statistics.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261469872},
doi = {10.1177/13872877261469872},
pmid = {42478671},
issn = {1875-8908},
abstract = {Lecanemab is dosed by body weight but supplied as fixed-size single-dose vials, which can leave unavoidable leftover drug after preparation. Using published summary statistics from the Japanese lecanemab post-marketing surveillance on body weight, we fitted a body-weight distribution and ran Monte Carlo simulations. Uncertainty was quantified by a parametric bootstrap. With current 200/500-mg vials, mean waste rate was 8.60%. A strategy with 200/250-mg vials reduced waste to 6.30%, and adding a 75-mg vial (≤4 vials/infusion) to 3.67%. At 10,000 person-years, annual waste cost was ∼¥2.36 billion under assumed pricing. Vial-size and dispensing optimization may help reduce avoidable waste.},
}
@article {pmid42478899,
year = {2026},
author = {Zhang, N and Chen, W and Wang, M},
title = {The liver-brain axis: A multidimensional regulatory network implicated in Alzheimer's disease pathogenesis and clinical implications.},
journal = {Animal models and experimental medicine},
volume = {},
number = {},
pages = {},
doi = {10.1002/ame2.70262},
pmid = {42478899},
issn = {2576-2095},
support = {Seed Program (YYZZ202409)//Capital Medical University Affiliated Beijing Friendship Hospital/ ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) deposition. The liver-brain axis underscores the central role of the liver in modulating cognitive function through multidimensional regulatory mechanisms. As a core metabolic and detoxification organ, the liver also helps maintain cerebral homeostasis via pathways including the urea cycle, antioxidant systems, ketone body metabolism, and bile acid regulation. Dysfunction of these processes may lead to ammonia accumulation, exacerbated oxidative stress, and Aβ clearance, thereby accelerating the pathological progression of AD. Liver-derived factors such as apolipoprotein E (APOE), C-reactive protein (CRP), fibroblast growth factor 21 (FGF21), and insulin-like growth factor 1 (IGF-1) significantly increase the risk of AD through dual mechanisms-inhibiting Aβ clearance and activating neuroinflammation, thereby directly affecting cognitive function via modulation of inflammation, metabolism, and blood-brain barrier (BBB) integrity. Neural interfaces formed by the hypothalamic-pituitary-target gland axis and the vagus nerve enable communication from the liver to the brain, with emerging evidence also supporting a reverse influence from the brain to the liver. Emerging technologies such as molecular tracing and nanocarriers provide new tools for deciphering dynamic interactions within the liver-brain axis. Liver-targeted metabolic interventions show potential for reversing cognitive impairment. Unlike previous reviews that mainly focused on single pathways, this review conceptualizes the liver-brain axis as a multidimensional regulatory network in AD. By clearly linking network nodes to potential therapeutic interventions, it provides us with a novel framework that not only describes the various mechanisms but also focuses on identifying actionable targets for disease prevention and treatment.},
}
@article {pmid42479092,
year = {2026},
author = {Goswami, A and Lagad, RR and Rafi, S},
title = {Decoding neuronal gene expression: integrative insights from omics and AI.},
journal = {Brain informatics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40708-026-00323-z},
pmid = {42479092},
issn = {2198-4018},
abstract = {Neuronal functional diversity and pathological vulnerability are governed by multi-layered regulatory programs. While high-throughput omics and neuroimaging provide high-resolution snapshots of these programs, bridging the gap between molecular dynamics and macro-scale brain architecture remains a significant informatics challenge. This review synthesizes the evolution of computational frameworks in neuro-omics-transitioning from descriptive co-expression modules to causal graph neural networks and cross-scale foundation models. We evaluate these methodologies within the context of Alzheimer's disease, schizophrenia, and epilepsy, identifying critical bottlenecks in data harmonization, spatial alignment, and causal interpretability.},
}
@article {pmid42479178,
year = {2026},
author = {Agrawal, S and Wagner, M and Leurgans, SE and Agarwal, P and van der Weerd, L and Bennett, DA and Bush, AI and Ayton, S and Schneider, JA},
title = {Cerebral amyloid angiopathy, brain iron concentrations, and cognitive decline in older people.},
journal = {Acta neuropathologica},
volume = {152},
number = {1},
pages = {},
pmid = {42479178},
issn = {1432-0533},
mesh = {Humans ; *Cerebral Amyloid Angiopathy/pathology/metabolism/complications/psychology ; Female ; *Iron/metabolism ; Aged, 80 and over ; *Brain/pathology/metabolism ; *Cognitive Dysfunction/pathology/metabolism ; Male ; Aged ; Aging/pathology ; Longitudinal Studies ; },
abstract = {Cerebral amyloid angiopathy (CAA) is a common brain pathology in older people and has been recently recognized as a major risk factor for amyloid-related imaging abnormalities during anti-amyloid antibody therapy. CAA pathophysiology may involve iron released from ruptured vessels, but the association between postmortem CAA and brain iron is unclear. This study investigates the association between CAA and brain iron and whether elevated iron modifies the association between CAA and cognitive decline. We studied 626 Rush Memory and Aging Project decedents (mean age at death = 90 [SD = 6.1] years, 70% women) who completed baseline and longitudinal cognitive assessments and underwent detailed neuropathologic evaluation for CAA, Alzheimer's disease neuropathologic changes (ADNC), and other brain pathologies. Brain iron content was assessed from the inferior temporal cortex using Inductively Coupled Plasma Mass Spectrometry (ICP-MS). Linear regression and mixed-effects models were used for analysis. CAA was common: 266 (42%) had mild, 153 (24%) had moderate, and 75 (12%) had severe CAA. In analyses adjusted for demographics, intermediate/high ADNC, and other pathologies, the presence and severity of CAA were associated with elevated cortical brain iron (Est = 0.033, SE = 0.011, p = 0.002; Est = 0.017, SE = 0.004, p < 0.001, respectively). When examining associations with nonlinear cognitive change before death (mean follow-up = 7.7 [SD = 3.9] years), both CAA and elevated iron were independently associated with faster annual rates of decline in global cognition and semantic memory (all p < 0.04). Elevated iron was also associated with faster declines in episodic and working memory and perceptual speed (all p < 0.02). When exploring whether brain iron modulates the association of CAA with cognitive decline, we found that CAA had steeper decline in perceptual speed when elevated iron was present compared to when low iron was present (p = 0.03). Together, these findings suggest that brain iron may contribute to the clinical impact of CAA in older age.},
}
@article {pmid42479245,
year = {2026},
author = {An, X and Wu, D and Wang, Y and Ren, Z and Yu, W},
title = {Seipin modulates Alzheimer's disease pathogenesis by regulating ferroptosis through a glycine-mediated metabolic pathway.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42479245},
issn = {1573-7365},
support = {82160225//the National Natural Science Foundation of China/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/genetics/pathology ; *Ferroptosis/physiology ; *GTP-Binding Protein gamma Subunits/metabolism/genetics ; *Glycine/metabolism ; Mice ; Mice, Transgenic ; Microglia/metabolism ; *Metabolic Networks and Pathways/physiology ; *Heterotrimeric GTP-Binding Proteins/metabolism/genetics ; Humans ; Hippocampus/metabolism ; },
abstract = {Alzheimer's disease (AD) remains an incurable neurodegenerative disorder with an elusive pathogenesis, where emerging evidence implicates metabolic dysregulation and ferroptosis in neuronal loss. Although the BSCL2 gene, which encodes Seipin, is crucial for lipid metabolism, its specific role in the progression of AD remains undefined. This study employed Mendelian randomization (MR) analysis, in vivo APP/PS1 mouse models, and in vitro BV2 microglial assays to elucidate the mechanistic axis linking BSCL2, metabolites, and ferroptosis in AD. MR analysis demonstrated a causal relationship between genetically predicted elevated BSCL2 expression and an increased risk of AD, partially mediated by glycine. Supporting these genetic findings, stereotactic knockdown of Seipin in the hippocampus of APP/PS1 mice significantly ameliorated cognitive deficits without inducing systemic metabolic toxicity. Mechanistically, Seipin deficiency reduced ferroptosis in both AD mouse brains and Aβ-stimulated microglia, as evidenced by the upregulation of anti-ferroptotic markers (GPX4, Nrf2, HO-1) and the suppression of pro-ferroptotic effectors (ACSL4, NCOA4). Moreover, glycine supplementation partially ameliorated the aggravated ferroptotic phenotype caused by Seipin overexpression, indicating a functional feedback mechanism in which glycine facilitates glutathione synthesis to mitigate Seipin-induced lipid peroxidation. These findings collectively identify Seipin as a novel regulator of ferroptosis in the pathogenesis of AD and underscore the potential of the BSCL2-glycine-ferroptosis axis as a therapeutic target. Future research should aim to elucidate the specific molecular interactions between Seipin and the iron-handling machinery and to validate glycine-based interventions in clinical settings as a means to prevent neurodegeneration.},
}
@article {pmid42479414,
year = {2026},
author = {Cai, Y and Chen, Y and Huang, G and Ren, M and Chai, Y and Gai, C and Huang, X and Yan, T},
title = {Integrated bioinformatics and experimental analysis identify apoptosis- and pyroptosis-related hub genes as candidate diagnostic biomarkers in Alzheimer's disease.},
journal = {Journal of applied genetics},
volume = {},
number = {},
pages = {},
pmid = {42479414},
issn = {2190-3883},
support = {KYCX24_2248//Postgraduate Research &amp; Practice Innovation Program of Jiangsu Province/ ; },
abstract = {Apoptosis and pyroptosis-mediated neuronal death represent major pathogenic mechanisms underlying Alzheimer's disease (AD). Given the potential crosstalk between these two forms of cell death, investigation of a single death pathway may be insufficient to identify robust diagnostic biomarkers for AD. Therefore, this study aimed to explore hub genes involved in both apoptosis and pyroptosis as potential diagnostic biomarkers for AD. First, 23 common cell death-related genes (CDRGs) were identified through bioinformatic analysis. Functional enrichment analyses using GO, KEGG, and GeneMANIA revealed significant associations between AD and biological processes including apoptosis, pyroptosis, and neuronal death. Subsequently, machine learning algorithms combined with ROC curve analysis identified CASP3, IL1B, NLRP3, and PYCARD as candidate biomarkers with potential diagnostic and therapeutic implications for AD. These findings were further validated by the in vitro experiments, which confirmed that the expression levels of these four biomarkers were consistent with the predicted results. Additionally, in patients with AD, CASP3, IL1B, NLRP3, and PYCARD were negatively correlated with macrophages. Collectively, these results suggest that the identified biomarkers may co-regulate apoptosis and pyroptosis through macrophages, thereby contributing to the pathogenesis of AD.},
}
@article {pmid42479540,
year = {2026},
author = {Zhang, J and Yu, P and Xu, M and Liang, F and Chen, Y and Dong, Y and Zhang, Y and Yu, S and Hua, F and Otu, HH and Libermann, TA and Inouye, SK and Marcantonio, ER and Yang, G and Xie, Z},
title = {Anesthesia and surgery induce sex-dependent Tau phosphorylation and behavior changes in aged mice.},
journal = {Anesthesiology},
volume = {},
number = {},
pages = {},
doi = {10.1097/ALN.0000000000006261},
pmid = {42479540},
issn = {1528-1175},
abstract = {BACKGROUND: Preoperative blood Tau phosphorylated at threonine 217 (Tau-PT217), a newly identified blood biomarker of Alzheimer's disease, is associated with postoperative delirium in patients. Anesthesia/surgery is also associated with postoperative increased blood Tau-PT217 amounts in patients. Moreover, in female aged mice, anesthesia/surgery increases Tau-PT217 in lungs, blood and brain tissues, leading to behavioral changes. However, whether these effects are sex-dependent remain largely undetermined.<br><br>METHODS: Eighteen-month-old female and male mice (C57BL/6J) underwent abdominal surgery under general anesthesia (1.4% isoflurane and 40% oxygen). Levels of Tau-PT217, inflammatory markers, and GSK3&#x3b2; activity were measured in lungs, blood, and brain tissues of aged mice using nanoneedle technology, Western blot, immunohistochemistry, RT-PCR and others. Postoperative delirium-like behavior was assessed using a battery of behavioral tests (buried food, open filed and Y maze). To explore causality, we performed orchiectomy and administered androgen receptor antagonist enzalutamide in aged male mice. Finally, testosterone was delivered via inhalation to aged female mice.<br><br>RESULTS: Anesthesia/surgery increased the amounts of Tau-PT217 in lungs (2.29&#xb1;0.16 fold versus 1.15&#xb1;0.71 fold, P<0.01), blood, and brain tissues of aged female, but not male, mice compared to control condition, leading to postoperative delirium-like behavior, as evidenced by increases in the composite Z score (3.74&#xb1;1.46 versus 0.60&#xb1;1.17, P<0.01), in the aged female, but not male, mice. Anesthesia/surgery elevated inflammatory markers and GSK3&#x3b2; activity in aged female mice, which exhibited lower baseline testosterone levels and androgen receptor expression in lungs compared to males. Both orchiectomy and enzalutamide treatment in male mice reduced testosterone levels and androgen receptor expression, leading to elevation of Tau-PT217 amounts and behavior changes following anesthesia/surgery. Conversely, testosterone inhalation in aged female mice mitigated the anesthesia/surgery-induced elevation of Tau-PT217 amounts and behavior changes.<br><br>CONCLUSIONS: Testosterone and androgen receptor signaling may contribute to the sex-dependent differences in Tau phosphorylation and postoperative behavior changes in aged mice.},
}
@article {pmid42479638,
year = {2026},
author = {Qin, R and Caiqi, L and Qingchun, Q and Xu, W and Lai, X and Chen, L},
title = {The burden of neurological diseases in East Asia: an analysis for the Global Burden of Disease Study 2023.},
journal = {Neuroepidemiology},
volume = {},
number = {},
pages = {1-25},
doi = {10.1159/000553093},
pmid = {42479638},
issn = {1423-0208},
abstract = {Background and Objectives Neurologic disorders represent a growing global health burden. According to the Global Burden of Disease Study 2023, they remain a major cause of morbidity and mortality worldwide. However, a comprehensive assessment specifically focused on East Asia has been lacking. This study investigates data from the GBD 1990-2023 study to provide detailed and updated insights into the burden of neurologic disorders in East Asia. Methods We analyzed the 1990-2023 burden of thirteen neurologic disorders in East Asia (e.g., stroke, dementia, epilepsy, migraine) using incidence, prevalence, deaths, and DALYs, stratified by sex, age, year, and location. Joinpoint regression assessed temporal trends and annual changes in age-standardized rates. Results In 2023, the neurologic disorders with the highest absolute DALYs in East Asia were stroke (44.42 million, 95% UI 39.17-49.56), Alzheimer's disease and other dementias (12.02 million, 95% UI 5.87-23.28), and migraine (6.80 million, 95% UI 4.56-9.33). Stroke was the leading cause of neurologic deaths (2.13 million, 95% UI 1.81-2.42), followed by Alzheimer's disease and other dementias (0.61 million, 95% UI 0.15-1.44) and Parkinson's disease (0.03 million, 95% UI 0.03-0.04 million). From 1990 to 2023, the overall Age-standardized DALY rates (ASDR) for neurologic disorders showed a slight decline (EAPC = -0.05; 95% CI: -0.1 to -0.01). However, both the absolute number of DALYs and the prevalence of neurological disorders demonstrated a steady increase, driven primarily by population growth and aging. This divergence between declining age-specific risk and rising absolute burden poses a mounting challenge for healthcare systems in the region. Substantial regional variation was observed in age-standardized rates across East Asia. Joinpoint regression analysis further revealed declining trends in the ASDR, ASIR, and ASPR for stroke, whereas Alzheimer's disease and other dementias showed significant increases across all three metrics. Migraine exhibited increases in ASDR, ASIR, and ASPR. Discussion This study provides the first comprehensive analysis of the burden of neurological disorders in East Asia from 1990 to 2023, revealing an urgent need for targeted public health strategies to address the growing challenge of neurological disorders.},
}
@article {pmid42479667,
year = {2026},
author = {Liang, C and Pearlson, G and Bustillo, J and Kochunov, P and Chen, J and Zhang, X and Jiang, R and Hutchison, KE and Sui, J and Fu, Z and Yang, X and Du, Y and Zhang, D and Qi, S and Calhoun, VD},
title = {Brain aging patterns among nine neurological disorders: A case-control study.},
journal = {PLoS medicine},
volume = {23},
number = {7},
pages = {e1004860},
pmid = {42479667},
issn = {1549-1676},
mesh = {Humans ; *Brain/diagnostic imaging/pathology ; Female ; *Aging/pathology ; Case-Control Studies ; Magnetic Resonance Imaging ; Male ; *Nervous System Diseases/diagnostic imaging/pathology/genetics ; Adult ; Middle Aged ; Neuroimaging ; Young Adult ; },
abstract = {BACKGROUND: The difference between neuroimaging-predicted brain age and chronological age, the predicted age difference (PAD), has been studied as a potential biomarker reflecting individual brain health. Although previous large-scale studies have shown that brain age deviations occur across multiple disorders, cross-disorder comparisons of PAD within a unified framework, together with identification of the neuroimaging features associated with these differences and their related gene expression profiles, remain limited. Our aims are to systematically compare brain aging across multiple common brain disorders and explore the brain patterns and biological processes underlying these differences.<br><br>METHODS AND FINDINGS: In this study, structural MRI data from 45,900 healthy controls (HCs) and 2,698 patients with developmental disorders (attention-deficit/hyperactivity disorder [ADHD] and autism spectrum disorder [ASD]), addiction (alcohol use disorder [AUD], tobacco use disorder [TUD], and AUD&amp;TUD-A&amp;TUD), dementia (Alzheimer's disease [AD], and mild cognitive impairment [MCI]) or other psychiatric disorders (schizophrenia [SZ], bipolar disorder [BP], and major depressive disorder [MDD]), were collected to generate PAD, along with transcriptome data. Then, we calculated the PAD difference between patient and HC as Cohen's d effect sizes, derived from a linear model that accounted for age, age2, sex, and site, and further identified the interpretable brain patterns associated with the PAD difference for each diagnostic group. Finally, enrichment analyses was conducted to identify the biological function of genes relatively over- or underexpressed in association with these patterns. Results showed that while PAD was consistently greater across disorders, different brain disorders showed different degrees of abnormality, the highest effects in dementia (AD: d&#x2009;=&#x2009;0.97, 95% confidence interval (CI) [0.82,1.13]; p&#x2009;<&#x2009;0.001 and MCI: d&#x2009;=&#x2009;0.45, 95% CI [0.34,0.56]; p&#x2009;<&#x2009;0.001), followed by addiction (A&amp;TUD: d&#x2009;=&#x2009;0.84, 95% CI [0.44,1.23]; p&#x2009;<&#x2009;0.001, TUD: d&#x2009;=&#x2009;0.72, 95% CI [0.49,0.96]; p&#x2009;<&#x2009;0.001, and AUD d&#x2009;=&#x2009;0.62, 95% CI [0.39,0.84]; p&#x2009;<&#x2009;0.001) and psychiatric disorders (SZ: d&#x2009;=&#x2009;0.53, 95% CI [0.30,0.76]; p&#x2009;<&#x2009;0.001, BP: d&#x2009;=&#x2009;0.46, 95% CI [0.22,0.69]; p&#x2009;<&#x2009;0.001 and MDD: d&#x2009;=&#x2009;0.28, 95% CI [0.11,0.46]; p&#x2009;<&#x2009;0.001), but not different from expected in developmental disorders (ASD: d&#x2009;=&#x2009;0.06, 95% CI [-0.04,0.16]; p&#x2009;=&#x2009;0.36) and ADHD: d&#x2009;=&#x2009;0.01, 95% CI [-0.14,0.15]; p&#x2009;=&#x2009;0.98). Furthermore, higher PAD values in patient groups were linked to specific spatial brain patterns, including the frontotemporal network in psychiatric disorders, default mode network-salience network-putamen-thalamus in addiction and fronto-occipital network in dementia. Prefrontal cortex involvement was common across disorders, and disorder-specific brain patterns associated genes were enriched in different biological processes. A limitation of our study is that psychiatric disorders and addiction have high comorbidity, and these potential confounders were not considered.<br><br>CONCLUSIONS: In summary, the different brain aging patterns, each based around specific underlying circuits, may serve as neuroimaging biomarkers for understanding the neural aging mechanisms in commonly occurring brain disorders. Future studies should test whether these disorder-specific brain aging patterns can serve as useful biomarkers to guide critical clinical decision-making.},
}
@article {pmid42479708,
year = {2026},
author = {Lee, Y and Kim, S and Kim, S and Kang, Y and , },
title = {Feature integration of [18F]FDG PET brain imaging using deep learning for sensitive cognitive decline detection.},
journal = {PloS one},
volume = {21},
number = {7},
pages = {e0341995},
pmid = {42479708},
issn = {1932-6203},
mesh = {Humans ; *Positron-Emission Tomography/methods ; *Fluorodeoxyglucose F18 ; *Deep Learning ; *Brain/diagnostic imaging ; Convolutional Neural Networks ; *Cognitive Dysfunction/diagnostic imaging ; Female ; Male ; Aged ; Alzheimer Disease/diagnostic imaging ; },
abstract = {BACKGROUND: Distinguishing individuals with cognitive decline (CD), including early Alzheimer's disease, from cognitively normal (CN) individuals is essential for improving diagnostic accuracy and enabling timely intervention. Positron emission tomography (PET) captures metabolic brain alterations associated with CD, but its broader application is often limited by cost and radiation exposure. To enhance the clinical utility of PET while addressing data limitations, we propose a data-efficient framework that integrates complementary multi-scale PET representations at voxel-level and region-level.<br><br>METHODS: Voxel-level features were extracted using convolutional neural networks (CNN) or principal component analysis networks (PCANet) from [&#xb9;&#x2078;F]FDG PET imaging. Region-level features were derived from standardized uptake value ratio measurements across predefined brain regions and processed using a deep neural network (DNN). These voxel- and region-level information are integrated through direct concatenation. For the final prediction, different machine learning models and ensemble technique were applied. The models were trained and validated using 5-fold cross-validation on PET scans from 252 participants in the Alzheimer's Disease Neuroimaging Initiative, comprising 118 CN and 134 CD subjects. Additional correlation analysis and disease classification comparison with the Mini-Mental State Examination (MMSE) were also performed.<br><br>RESULTS: In 5-fold cross-validation, CNN, PCANet, and DNN models achieved classification accuracies of 0.69&#x2009;&#xb1;&#x2009;0.04, 0.69&#x2009;&#xb1;&#x2009;0.06, and 0.82&#x2009;&#xb1;&#x2009;0.06, respectively. The integrated DNN-CNN model using direct concatenation yielded the highest accuracy (0.87&#x2009;&#xb1;&#x2009;0.05), with a 6.33% improvement in accuracy and reduced standard deviation relative to the DNN-only model. Overall, there were an increase of 14.22% in Recall (0.77 to 0.88) and an increase of 7.92% in F1-Score (0.82 to 0.88). Moreover, the predicted probability of CD showed a significant correlation with MMSE scores, and the model achieved higher accuracy, recall, and F1-score than MMSE-based classification.<br><br>CONCLUSION: Combining complementary voxel-level and region-level PET representations with deep learning improved classification performance over single-representation models, particularly by enhancing sensitivity to cognitive decline. These findings support the potential utility of multi-scale FDG-PET representations for machine learning-based cognitive decline detection.},
}
@article {pmid42479714,
year = {2026},
author = {Buard, G and Verny, M},
title = {[Focus on limbic-predominant age-related TDP-43 encephalopathy (LATE)].},
journal = {Geriatrie et psychologie neuropsychiatrie du vieillissement},
volume = {24},
number = {3},
pages = {0},
doi = {10.1684/pnv.2026.1294},
pmid = {42479714},
issn = {2115-7863},
abstract = {In 2019, an international working group described a new clinicopathological entity: limbic-predominant age-related TDP-43 encephalopathy (LATE). Neuropathologically, LATE is characterized by the abnormal accumulation of TDP-43 protein in limbic structures, particularly the hippocampus and parahippocampal regions. Clinically, LATE presents as a slowly progressive, isolated mesiotemporal amnestic syndrome, typically affecting individuals aged over 75 years. Brain MRI usually reveals marked hippocampal atrophy, while FDG-PET may demonstrate medial temporal hypometabolism. A diagnosis of probable LATE requires the exclusion of underlying amyloid pathology, although concomitant Alzheimer's disease pathology is common in older adults. To date, no symptomatic or disease-modifying pharmacological treatment has demonstrated efficacy in LATE. However, its clinical course appears to differ from that of typical Alzheimer's disease, with potentially slower progression and longer preservation of functional independence. LATE therefore represents a common and likely underrecognized cause of memory impairment in older adults, and its identification has important implications for diagnosis, prognosis, and therapeutic decision-making.},
}
@article {pmid42479744,
year = {2026},
author = {Bonarota, S and Caruso, G and Di Domenico, C and Di Lorenzo, F and Koch, G and Caltagirone, C and Bozzali, M and Serra, L},
title = {Are MMSE and ACE-R useful for detecting the earliest stages of Alzheimer's disease? A comparative study.},
journal = {Journal of neuropsychology},
volume = {},
number = {},
pages = {},
doi = {10.1111/jnp.70064},
pmid = {42479744},
issn = {1748-6653},
support = {//Ricerca Corrente 2026/ ; //Ministero della Salute-Ministry of Health/ ; },
abstract = {Subjective cognitive decline (SCD) is an at-risk condition for future cognitive decline, making its early identification crucial. We examined whether two widely used screening tools, the Addenbrooke's Cognitive Examination-Revised (ACE-R) and the Mini Mental State Examination (MMSE), can distinguish SCD individuals from healthy elderly (HS) and from individuals with objective cognitive impairment. 110 participants were recruited: 22 HS, 25 SCD, 31 amnestic mild cognitive impairment (aMCI), and 32 Alzheimer's disease (AD) patients. All participants underwent an extensive neuropsychological battery and the ACE-R, which incorporates the MMSE. Partial ACE-R (ACER_P) scores were derived. Between-group comparisons were performed and discriminant analyses were run to evaluate sensitivity, specificity, and accuracy of total ACE-R (ACER_TOT), ACER_P, and MMSE. Despite no screening test significantly distinguishing SCD from HS, a progressive downward trend emerged across groups, with AD performing worst, followed by aMCI, then SCD and HS. Discriminant analyses indicated ACER_TOT had the highest sensitivity for AD (84.4%), with overall accuracy of 59.1%. Sensitivity for HS (68.2%) and aMCI (51.6%) was good but weaker. ACER_P and MMSE yielded similar or lower accuracy. Importantly, all measures poorly detected SCD, with sensitivity below 30%, leading to frequent misclassification as HS or aMCI. Although ACE-R and MMSE are moderately effective for identifying AD, HS and aMCI, they fail to distinguish SCD from other groups. Given the higher risk of SCD of being in AD continuum, such misclassification may prevent appropriate clinical follow-up. More sensitive screening instruments are needed to capture subtle cognitive changes and support early intervention strategies.},
}
@article {pmid42479987,
year = {2026},
author = {Ghorbani, E and Hajihashemi, S and Fahanik-Babaei, J and Nazari, M},
title = {Chronic 40-Hz Light-Emitting Diode (LED) Therapy Attenuates Cognitive and Behavioral Deficits and Modulates BDNF and Caspase-3 Expression in a D-galactose/Aluminum Chloride-Induced Sporadic Alzheimer's-Like Rat Model.},
journal = {The International journal of neuroscience},
volume = {},
number = {},
pages = {1-17},
doi = {10.1080/00207454.2026.2706611},
pmid = {42479987},
issn = {1563-5279},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative condition marked by gradual deterioration of cognition, synaptic integrity, and neuronal viability. Experimental exposure to D-galactose (D-gal) combined with aluminum chloride (AlCl3) produces oxidative and inflammatory damage within the brain, closely resembling AD-related neuropathology. Photobiomodulation therapy (PBMT) has recently gained attention as a safe, non-pharmacological approach with neuroprotective potential; however, the impact of sustained 40-Hz light-emitting diode (LED) stimulation in this context remains insufficiently explored.<br><br>METHODS: In the present study, rats received D-gal (60&#x2009;mg/kg, i.p.) and AlCl3 (200&#x2009;mg/kg, oral) for six weeks to induce AD-like changes. The treatment group was exposed to 40-Hz pulsed LED light (425-550&#x2009;nm, 15&#x2009;min/session, three times weekly). Behavioral analyses were performed using the elevated plus maze (EPM), novel object recognition (NOR), and passive avoidance (PA) paradigms. Western blotting quantified brain-derived neurotrophic factor (BDNF) and cleaved-caspase-3 expression in whole brain tissue.<br><br>RESULTS: D-gal/AlCl3 administration produced anxiety-like behavior, recognition deficits, and impaired memory retention, accompanied by decreased BDNF and elevated caspase-3. Remarkably, 40-Hz LED exposure reversed these alterations, up-regulating BDNF and suppressing caspase-3, in parallel with improvements in cognitive and emotional outcomes.<br><br>CONCLUSION: These data suggest that 40-Hz LED stimulation confers neuroprotection in the D-gal/AlCl3-induced AD model, potentially through enhancement of neurotropic signaling and inhibition of apoptosis, supporting its promise as a non-invasive strategy against neurodegenerative decline.},
}
@article {pmid42479989,
year = {2026},
author = {Magee, RG and Xie, SX and Ohm, DT and Rhodes, E and Massimo, L and Van Deerlin, VM and Wolk, DA and Lee, EB and Mcmillan, CT and Irwin, DJ},
title = {Association Between Postmortem Pathologic Burden and the Rate of Clinical Progression in Patients With Frontotemporal Lobar Degeneration.},
journal = {Neurology},
volume = {107},
number = {3},
pages = {e218278},
doi = {10.1212/WNL.0000000000218278},
pmid = {42479989},
issn = {1526-632X},
mesh = {Humans ; Female ; *Frontotemporal Lobar Degeneration/pathology ; *Disease Progression ; Male ; Middle Aged ; Retrospective Studies ; Aged ; tau Proteins/metabolism ; *Brain/pathology ; DNA-Binding Proteins/metabolism ; Longitudinal Studies ; Autopsy ; },
abstract = {BACKGROUND AND OBJECTIVES: Histopathologic staging of Alzheimer disease has led to validation of imaging techniques that guide diagnosis and treatment. We previously constructed preliminary phases of the sequential progression of TDP-43 and tau to guide similar efforts in behavioral-variant frontotemporal dementia (bvFTD). In this article, we expand this work using digital pathology and longitudinal clinical data to more comprehensively model the relationship between clinical progression and the distribution and severity of postmortem frontotemporal lobar degeneration (FTLD) pathology.<br><br>METHODS: In this retrospective cohort study, 101 patients (42% female, median age at symptom onset = 63 years) were selected from the Penn Integrated Neurodegenerative Disease Database and had both longitudinal assessments and primary neuropathologic diagnosis of FTLD-Tau or FTLD-TDP. We used validated methods to quantify the burden of primary pathology from up to 6 cortical regions across hemispheres. FTLD-TDP pathologic phase was constructed from diagnostic pathology data based on published criteria. We tested the association between pathologic metrics and (1) disease duration or (2) the rate of clinic progression measured by 2 independent global measures (Clinical Dementia Rating Scale-Sum of Boxes [CDR-SB] and Mini-Mental State Examination [MMSE]). Linear regression and linear mixed-effects models were adjusted for hemisphere sampled, sex, age at onset, pathogenic variant status, and pathologic subtype.<br><br>RESULTS: Disease duration did not associate with pathologic burden in multiple regression (FTLD-TDP &#x3b2; = 0.01 [-0.06, 0.09]; p = 0.7; FTLD-Tau &#x3b2; = 0.1 [-0.4, 0.7]; p = 0.7). By contrast, mean TDP-43 burden, but not FTLD-Tau burden, was associated with both worse relative CDR-SB (&#x3b2; = 0.1 [0.06, 0.2]; p = 0.0001) and MMSE (&#x3b2; = -0.1 [-0.2, -0.03]; p = 0.009) among all FTLD-TDP patients. TDP-43 phase also associated with worse CDR-SB (&#x3b2; = 0.07 [0.02, 0.1]; p = 0.005) and MMSE (&#x3b2; = -0.2 [-0.3, -0.1]; p = 0.000005). TDP-43 burden (CDR-SB (&#x3b2; = 0.1 [0.03, 0.2]; p = 0.005 and MMSE (&#x3b2; = -0.2 [-0.4, -0.05]; p = 0.009)), but not phase (CDR-SB (&#x3b2; = 0.02 [-0.03, 0.08]; p = 0.4 and MMSE (&#x3b2; = -0.04 [-1, 0.07]; p = 0.5)), associated with relative decline in sensitivity analyses limited to bvFTD.<br><br>DISCUSSION: Greater TDP-43 burden was most closely associated with antemortem clinical decline rather than cumulative aggregation through the disease course. These human data suggest that the temporal dynamics of protein aggregation may differ among FTLD proteinopathies, with implications for the interpretation of FTLD-Tau and FTLD-TDP&#x2011;specific biomarkers as these are developed.},
}
@article {pmid42479994,
year = {2026},
author = {Oliveira-Junior, MS and Rodrigues, MS and Amaral, L and Povala, G and Rocha, A and Scop Medeiros, M and Abbas, S and Ferrari-Souza, JP and Saha, P and Lussier, FZ and Ferreira, PCL and Bauer-Negrini, G and Soares, C and Roh, HW and Zimmer, ER and Karikari, T and Karim, H and Rosa-Neto, P and Hong, CH and Tudorascu, D and Son, SJ and Bellaver, B and Pascoal, T},
title = {Association Between Plasma GFAP and Medial Temporal Atrophy and Cognition in Amyloid-Negative Cerebrovascular Disease.},
journal = {Neurology},
volume = {107},
number = {3},
pages = {e218336},
doi = {10.1212/WNL.0000000000218336},
pmid = {42479994},
issn = {1526-632X},
mesh = {Humans ; Male ; Female ; *Glial Fibrillary Acidic Protein/blood ; Atrophy/pathology ; Cross-Sectional Studies ; Aged ; *Temporal Lobe/pathology/diagnostic imaging ; *Cognitive Dysfunction/blood/pathology/diagnostic imaging ; *Cerebrovascular Disorders/blood/pathology/diagnostic imaging/complications ; Biomarkers/blood ; Magnetic Resonance Imaging ; Amyloid beta-Peptides/metabolism ; Gray Matter/pathology/diagnostic imaging ; Middle Aged ; *Cognition/physiology ; },
abstract = {BACKGROUND AND OBJECTIVES: Plasma glial fibrillary acidic protein (GFAP), a marker of astrocyte reactivity, is elevated across multiple neurodegenerative conditions, including Alzheimer disease. However, its role in neurodegeneration and cognitive decline driven by cerebrovascular pathology, independent of β-amyloid (Aβ) copathology, remains poorly characterized. We investigated whether plasma GFAP is associated with medial temporal atrophy and cognition across a spectrum of cerebrovascular burden in Aβ-negative cognitively impaired individuals.<br><br>METHODS: In this cross-sectional multicenter study, A&#x3b2; PET-negative cognitively impaired participants were recruited from South Korean memory clinics. Plasma GFAP was measured using ultrasensitive Simoa assays. White matter hyperintensity burden was graded using the Fazekas scale and stratified into low (LVP: Fazekas 1) and high (HVP: Fazekas 2-3) cerebrovascular burden groups. Medial temporal gray matter density was assessed using voxel-based morphometry, and hippocampal and amygdalar volumes were derived from T1-weighted MRI adjusted for intracranial volume. Linear regression, interaction, and bootstrap mediation models were used to assess associations among GFAP, brain structure, and cognition.<br><br>RESULTS: A total of 324 participants were included (LVP n = 203; HVP n = 121; median age 73 years [interquartile range 66-78]; 67.9% female). Compared with LVP, HVP participants were older (75 vs 71 years; p < 0.0001), had lower Mini-Mental State Examination (MMSE) scores (22.7 vs 24.5; p = 0.005), and higher plasma GFAP (136.7 vs 112.1 pg/mL; p = 0.001). Higher GFAP was associated with lower medial temporal gray matter density in HVP (&#x3b2; = -0.311; p = 0.001) but not LVP (&#x3b2; = -0.012; p = 0.858), with a significant GFAP-vascular burden interaction (&#x3b2; = -0.309; p = 0.008). In HVP, higher GFAP was associated with smaller hippocampal (&#x3b2; = -0.179; p = 0.044) and amygdalar volumes (&#x3b2; = -0.169; p = 0.049) and lower MMSE (&#x3b2; = -0.194; p = 0.039). Medial temporal atrophy statistically explained the GFAP-MMSE association (indirect &#x3b2; = -0.071, 95% CI -0.140 to -0.010; p = 0.016). Vascular comorbidities (diabetes, dyslipidemia, hypertension) did not modify the GFAP-cognition association.<br><br>DISCUSSION: In A&#x3b2;-negative cognitively impaired individuals with high cerebrovascular burden, elevated plasma GFAP is associated with medial temporal atrophy and cognitive decline, suggesting GFAP may capture astrocyte-reactivity relevant to vascular cognitive impairment beyond amyloid pathology. These cross-sectional findings require confirmation in longitudinal and ethnically diverse cohorts.},
}
@article {pmid42480159,
year = {2026},
author = {Zhou, M and Tong, X and Zhao, J and Cheng, M and Yang, L and Tian, L and Wan, N},
title = {DCL-SE: Dynamic curriculum learning for spatiotemporal encoding of brain imaging.},
journal = {Neural networks : the official journal of the International Neural Network Society},
volume = {205},
number = {Pt A},
pages = {109409},
doi = {10.1016/j.neunet.2026.109409},
pmid = {42480159},
issn = {1879-2782},
abstract = {High-dimensional neuroimaging analyses for clinical diagnosis are often constrained by compromises in spatiotemporal fidelity and the limited adaptability of large-scale, general-purpose models. To address these challenges, we introduce Dynamic Curriculum Learning for Spatiotemporal Encoding (DCL-SE), an end-to-end framework centered on data-driven spatiotemporal encoding (DaSE). We leverage Approximate Rank Pooling (ARP) to efficiently encode three-dimensional volumetric brain data into information-rich, two-dimensional dynamic representations, and then decode this representation through a DGM-implemented architectural curriculum, where the fixed hierarchical decoder progressively refines features from global anatomical structures to fine pathological details without introducing a threshold-controlled stage-switch scheduler. Evaluated across six publicly available datasets, including Alzheimer's disease and brain tumor classification, cerebral artery segmentation, and brain age prediction, DCL-SE consistently outperforms existing methods in accuracy, robustness, and interpretability. These findings underscore the critical importance of compact, task-specific architectures in the era of large-scale pretrained networks.},
}
@article {pmid42480386,
year = {2026},
author = {Koek, L and Jo, HN and Kennedy, MJ and Dell'Acqua, ML},
title = {Anchored kinase and phosphatase signaling networks in amyloid β-induced synaptic dysfunction.},
journal = {Molecular pharmacology},
volume = {108},
number = {8},
pages = {100141},
doi = {10.1016/j.molpha.2026.100141},
pmid = {42480386},
issn = {1521-0111},
abstract = {Impaired excitatory synaptic function and synapse loss are early hallmarks of Alzheimer's disease (AD). There is strong biochemical, genetic, physiological, and anatomical evidence that the accumulation of soluble amyloid beta (Aβ) oligomers in the brain leads to AD-related synapse dysfunction and cognitive impairment. Long-term potentiation (LTP), a key form of synaptic plasticity for learning and memory, is disrupted in several mouse models harboring familial early-onset AD-linked mutations that lead to Aβ accumulation, and even acute applications of Aβ oligomers block LTP within minutes and promote synapse loss within days. How does Aβ cause such profound synaptic dysfunction? It is increasingly appreciated that Aβ hijacks normal synaptic signaling pathways involved in plasticity, biasing them toward long-term depression (LTD) and eventual synapse elimination. LTP and LTD in the hippocampus are ultimately driven by insertion and removal of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptors (AMPARs) from synapses, respectively, in response to Ca[2+] signals generated by N-methyl-d-aspartate-type glutamate receptors or L-type voltage-gated Ca[2+] channels. Central to the signaling pathways regulating AMPAR trafficking during LTP and LTD is a postsynaptic Ser/Thr kinase/phosphatase signaling network that is coordinated by the scaffold protein A-kinase anchoring protein (AKAP) 79/150 (human79/rodent150; AKAP5/Akap5 gene). This AKAP-organized signalosome includes N-methyl-d-aspartate-type glutamate receptors, AMPARs, L-type voltage-gated Ca[2+] channels, G-protein-coupled receptors, adenylyl cyclase, the cyclic adenosine mono-phosphate (cAMP)-dependent protein kinase, and the Ca[2+]-calmodulin-dependent protein phosphatase 2B/calcineurin. This minireview will highlight recent findings that Gαs-coupled β2-adrenergic and Gαq-coupled group 1 metabotropic glutamate (mGlu1/5) receptors signal through AKAP79/150-anchored cAMP-dependent protein kinase and protein phosphatase 2B/calcineurin to mediate multiple aspects of Aβ synaptotoxicity. SIGNIFICANCE STATEMENT: Recent studies reveal that amyloid beta engages A-kinase anchoring protein-scaffolded G-protein-coupled receptor signaling pathways to disrupt synaptic plasticity and promote synapse loss. These pathways contain several potential therapeutic targets involved in both local cAMP-dependent protein kinase and calcineurin/protein phosphatase 2B (CaN) signaling that regulates L-type voltage-gated calcium channels, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, and N-methyl-d-aspartate receptors to impair synaptic plasticity as well as distal CaN signaling to the nucleus that regulates gene expression to drive synapse loss.},
}
@article {pmid42480581,
year = {2026},
author = {Cornish, B and Van Ooteghem, K and Pieruccini-Faria, F and Montero-Odasso, M and McIlroy, W},
title = {Ankle-worn Accelerometers for Gait Analysis in Individuals with Alzheimer's disease and Mild Cognitive Impairment: Reliability of a Finite State Machine Approach.},
journal = {Medical engineering &amp; physics},
volume = {},
number = {},
pages = {},
doi = {10.1088/1873-4030/ae8dd0},
pmid = {42480581},
issn = {1873-4030},
abstract = {Clinical gait analysis is essential for understanding motor and cognitive contributions to mobility impairment. Continued methodological advancement in gait analysis is needed to detect important and subtle changes in walking behaviour that will inform this understanding. This study evaluated the reliability of a Finite State Machine (FSM) algorithm for stride segmentation during preferred walking and dual task walking (DTW) and examined changes to temporal and accelerometry kinematic outcomes between tasks. Participants diagnosed with Alzheimer's disease or mild cognitive impairment completed a gait assessment as part of the Ontario Neurodegenerative Disease Research Initiative foundational study. Ankle worn accelerometers and a GAITRite walkway captured data during preferred walking and three DTW conditions (counting backwards by ones, animal naming, counting backwards by sevens). Acceleration data were processed using the FSM algorithm to extract temporal and accelerometry kinematic outcomes defined by the FSM intra stride segments. Stride time demonstrated excellent reliability (ICC≥0.97). Gait speed was significantly associated with gait variability during animal naming and counting backwards by sevens (p<0.05), but not during counting backwards by ones. The FSM approach showed changes to stride phases and accelerometry derived kinematics not seen with conventional stride-based approaches. There was a reduction in flat-foot phase and an increase in push-off phase across all dual-task conditions compared with PREF (p<0.05), where conventional stance-phase segmentation did not show consistent differences. Kinematic outcomes were also significantly lower during DTW conditions when compared to preferred walking trials (p<0.05) for the mid-swing peak amplitude and the slope of the accelerometer push-off. Findings demonstrate differences in performance between preferred and DTW conditions, the influence of gait speed on gait variability, and unique accelerometry derived kinematics. The FSM segmentation method advances gait assessment by providing precise stride characteristics using low cost, clinically accessible tools.},
}
@article {pmid42480738,
year = {2026},
author = {Yuan, X and McElroy, C and Kengwerere, MK and Zhu, CF and Qiang, W},
title = {Effects of broadband mid-infrared radiation and 1,8-cineole on β-amyloid aggregation: a biophysical characterization of moxibustion-based Alzheimer's therapeutic factors.},
journal = {International journal of biological macromolecules},
volume = {376},
number = {},
pages = {153610},
doi = {10.1016/j.ijbiomac.2026.153610},
pmid = {42480738},
issn = {1879-0003},
abstract = {Moxibustion is a traditional Chinese medicine (TCM) external therapy that shows notable preventive effects on Alzheimer's disease (AD). It has been postulated that the therapeutic effect of moxibustion may be mediated through the combined action of multiple factors, including heat, infrared radiation, and volatile combustion products of Artemisia argyi. However, direct evidence supporting the influence of moxibustion-related factors on AD-related pathological processes is limited, creating a knowledge gap between the clinical outcomes of moxibustion-based AD therapy and the modern biomedical understanding of its underlying mechanisms. We use biophysical approaches to investigate influences of two moxibustion-related factors, namely the broadband mid-infrared (mid-IR) radiation and 1,8-cineole (CIN), on the aggregation kinetics of β-amyloid (Aβ) peptides and the molecular structures of the resulting Aβ aggregates. Our results showed that Aβ fibrillation was decelerated with these influential factors. The macroscopic morphologies and packing, as well as the molecular-level structures of resultant Aβ aggregates are also significantly modulated. Overall, our results provide molecular-level insights into how these therapeutic factors may act on Aβ amyloidosis.},
}
@article {pmid42480871,
year = {2026},
author = {Zhang, X and Yang, X and Zhuang, D and Mu, Z and Ju, C},
title = {Retigabine alleviates cognitive deficits, decreases neuropathology and activates the AKT/GSK-3β pathway in APP/PS1 transgenic mice.},
journal = {Behavioural brain research},
volume = {},
number = {},
pages = {116391},
doi = {10.1016/j.bbr.2026.116391},
pmid = {42480871},
issn = {1872-7549},
abstract = {Neuronal hyperexcitability is crucial to the pathogenesis of Alzheimer's disease (AD). Activating the Kv7 channel is an effective way to reduce neuronal excitability. The Kv7 channel opener retigabine (RTG) has been demonstrated to alleviate spatial memory deficits in APP/PS1 transgenic mice. However, the mechanism by which RTG reduces cognitive deficits in APP/PS1 mice remains unclear. In this study, we revealed that RTG could ameliorate learning and spatial memory deficits in APP/PS1 mice during novel object recognition and Morris water maze tests. Meanwhile, RTG increased NeuN neuronal fluorescence intensity, increased the expression of the synaptic proteins postsynaptic density protein 95 (PSD95) and synaptophysin (SYN), improved synaptic plasticity, increased insulin-degrading enzyme (IDE) expression, decreased beta-secretase 1 (BACE1) expression, reduced Aβ1-40 and Aβ1-42 levels, and increased pAKT (ser473) and pGSK-3β (ser9) expression. These results indicated that RTG alleviates learning and spatial memory deficits in APP/PS1 mice, with potential mechanisms involving a reduction in neuronal loss, attenuation of synaptic damage, a decrease in β-amyloid (Aβ) deposition, and activation of the AKT/GSK-3β pathway.},
}
@article {pmid42481033,
year = {2026},
author = {Traub, J and Frey, A and Homola, G and Morbach, C and Frantz, S and Pham, M and Störk, S and Stoll, G and Otto, M and Oeckl, P},
title = {Longitudinal trajectories of neurodegenerative biomarkers in the blood of patients with chronic heart failure.},
journal = {ESC heart failure},
volume = {},
number = {},
pages = {},
doi = {10.1093/eschf/xvag202},
pmid = {42481033},
issn = {2055-5822},
abstract = {BACKGROUND AND AIMS: Chronic heart failure is associated with mild cognitive impairment, vascular dementia, and Alzheimer's disease, but the underlying mechanisms remain poorly defined. Blood-based neurodegenerative biomarkers may support early risk stratification and outcome prediction in heart failure.<br><br>METHODS: In the prospective Cognition.Matters-HF cohort study, serum neurofilament light chain, glial fibrillary acidic protein, and phosphorylated tau protein-181, as well as plasma amyloid-&#x3b2; peptides (A&#x3b2;38, A&#x3b2;40, A&#x3b2;42) and &#x3b2;-synuclein, were quantified longitudinally over 36 months using ultrasensitive immunoassays and immunoprecipitation mass spectrometry. Cerebral magnetic resonance imaging and standardized domain-specific cognitive testing were performed. Multivariable logistic regression was used to assess associations with future mild cognitive impairment, brain structural changes, and 5-year all-cause mortality.<br><br>RESULTS: Among 104 patients with chronic heart failure (10% female, age 64 &#xb1; 10 years), all biomarkers except neurofilament light chain increased significantly over 3 years (p < 0.05). Median annual percentage changes were 36.6% for phosphorylated tau protein-181, 4.6% for glial fibrillary acidic protein, 2.6% for &#x3b2;-synuclein, 0.6% for A&#x3b2;38, 0.5% for A&#x3b2;40, and 0.3% for A&#x3b2;42. In multivariable models adjusted for clinical confounders, increases in A&#x3b2;38 and A&#x3b2;42 independently associated with future mild cognitive impairment, pathological white matter hyperintensity progression (>5% per year), and 5-year mortality (all p < 0.05). Glial fibrillary acidic protein levels and phosphorylated tau protein-181 trajectories independently associated with pathological brain atrophy (>0.3% per year).<br><br>CONCLUSIONS: In clinically stable patients with chronic heart failure, longitudinal increases in circulating amyloid-&#x3b2; peptides associated with cognitive decline, structural brain changes, and mortality. Serial biomarker assessment provided stronger prognostic information than baseline measurements alone. Replication in larger cohorts is required.},
}
@article {pmid42481072,
year = {2026},
author = {Strating, TR and Haapanen, MJ and Ma, D and Gordon, EH and Rockwood, K and Hubbard, RE and Ward, DD},
title = {Frailty and accelerated dementia onset in genetic, sociodemographic and neuropathologic subgroups.},
journal = {Journal of neurology, neurosurgery, and psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1136/jnnp-2026-338460},
pmid = {42481072},
issn = {1468-330X},
abstract = {BACKGROUND: Quantifying how risk factors shape the timing of dementia onset can inform care and prevention strategies. We aimed to establish the degree to which and in whom frailty accelerates time to a diagnosis of dementia.<br><br>METHODS: Longitudinal data came from community-dwelling participants of the Rush Memory and Aging Project in Northeastern Illinois. At baseline, participants had data on age, education, sex, APOE &#x3b5;4 status and sufficient health/functional variables to calculate a frailty index score. In a subset of participants who underwent autopsy, neuropathologic burden was quantified using a 10-item index of markers of Alzheimer's disease and mixed brain pathology. Accelerated failure time models estimated associations of frailty and age at dementia diagnosis.<br><br>RESULTS: In 1614 participants (mean age 79.6 years, 75% female) over 23.9 years of follow-up, frailty (frailty index scores &#x2265;0.25) was associated with 3.6% younger age at dementia diagnosis (time ratio, TR 0.96 (95% CI 0.95, 0.98)), equating to 2-3 years earlier. That association was stronger in males than females, but present across each sex, education and APOE &#x3b5;4 subgroup. In the autopsy subset (n=906), frailty was associated with 9.8% younger dementia diagnosis among those who died with low neuropathologic burden (TR 0.90 (95% CI 0.85, 0.96)) but had no association in those with intermediate or high burden.<br><br>CONCLUSIONS: Frailty appears to independently accelerate dementia onset, particularly for individuals whose neurodegenerative lesions might be insufficient to explain their dementia diagnosis. Its routine measurement in clinical practice could hold benefit for risk stratification and care.},
}
@article {pmid42481198,
year = {2026},
author = {Ihalainen, L and Barbera, M and Törmäkangas, T and Hyvärinen, P and Willberg, T and Linder, P and Solomon, A and Dietz, A},
title = {Proof-of-concept randomised controlled trial of data-driven hearing rehabilitation versus standard care in older adults with hearing loss: the healthy hearing for healthy ageing protocol.},
journal = {BMJ open},
volume = {16},
number = {7},
pages = {e122681},
doi = {10.1136/bmjopen-2026-122681},
pmid = {42481198},
issn = {2044-6055},
mesh = {Humans ; *Hearing Aids ; Aged ; *Hearing Loss/rehabilitation/psychology ; Quality of Life ; Male ; Proof of Concept Study ; Female ; Speech Perception ; *Healthy Aging ; *Correction of Hearing Impairment/methods ; },
abstract = {INTRODUCTION: Hearing aids (HAs) can alleviate hearing loss; however, HA rehabilitation is frequently hampered by delayed diagnosis, suboptimal fitting and lack of systematic follow-up. Although the association between hearing loss and cognitive decline has been identified, evidence from randomised controlled trials remains limited. Addressing these gaps is essential for reducing hearing loss-related experiences and evaluating whether effective HA use could reduce the risk of cognitive decline.<br><br>METHODS AND ANALYSIS: The healthy hearing for healthy ageing study is a proof-of-concept, single-site, two-arm parallel-group 12-month randomised controlled trial with a 12-month extended follow-up. Up to two hundred participants with hearing loss and without cognitive decline referred for an initial HA rehabilitation are recruited and randomised 1:1 to either data-driven hearing rehabilitation or standard care. The primary outcome is the change in two speech perception in noise tests validated for the Finnish language: the Finnish matrix sentence test and the digits-in-noise test. The secondary outcomes are patient-reported outcomes (eg, Hearing in Real-Life Environment and Speech, Spatial and Quality questionnaires), quality of life (eg, 15D-questionnaire), cognitive (eg, Consortium to Establish a Registry for Alzheimer's Disease test) and psychosocial measures. Exploratory outcomes include event-related responses, cortical auditory evoked potentials, structural brain imaging and vision-related measures.<br><br>ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Regional Medical Research Ethics Committee of the well-being Services County of North Savo (approval no. 697/2023). Findings from this study will be disseminated through peer-reviewed publications, conference presentations and relevant clinical and patient communities.<br><br>TRIAL REGISTRATION NUMBER: NCT06495268.},
}
@article {pmid42481306,
year = {2026},
author = {Li, H},
title = {Retraction notice to "Molecular structure and protein function of mitochondrial fusion protein Mfn2 alleviate Alzheimer's disease: exercise assisted regulation" [Int. J. Biol. Macromol. 311 (2025) 143696].},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {153569},
doi = {10.1016/j.ijbiomac.2026.153569},
pmid = {42481306},
issn = {1879-0003},
}
@article {pmid42481337,
year = {2026},
author = {Huang, X and Wang, J and Zhao, X and Sooranna, SR and Liao, B and Jian, C and Shang, J and Li, X},
title = {Retraction notice to "Molecular mechanisms of MAPK9, BAX, and TFEB proteins: Genetic correlations between oxidative stress and autophagy pathways in Alzheimer's disease" [Int. J. Biol. Macromol. 309 (2025) 143196].},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {153568},
doi = {10.1016/j.ijbiomac.2026.153568},
pmid = {42481337},
issn = {1879-0003},
}
@article {pmid42481384,
year = {2026},
author = {Puljak, L and Kurtz, A and Koporc, Z},
title = {Evaluation of data from the hPSCreg®, a global registry for human pluripotent stem cell lines (hPSC-lines).},
journal = {Vox sanguinis},
volume = {},
number = {},
pages = {},
doi = {10.1111/vox.70332},
pmid = {42481384},
issn = {1423-0410},
abstract = {BACKGROUND AND OBJECTIVES: This descriptive retrospective study evaluated the content, completeness and usability of information available in the Human Pluripotent Stem Cell Registry (hPSCreg®), including registered cell lines, research projects, clinical studies, donor characteristics and regulatory information.<br><br>MATERIALS AND METHODS: We analysed data registered in hPSCreg&#xae; from January 2008 to December 2021. We analysed the data regarding cell lines, research projects, clinical studies, diseases, countries and legal issues.<br><br>RESULTS: There were 7538 total cell lines registered in the hPSCreg&#xae;. The most common derivation and generation countries were the United Kingdom, the United States, Germany and China. There were 3139 (46.5%) cell lines labelled as readily obtainable for a third party; few (7.2%) were labelled as available for commercial use. The most common diseases of the donor were Parkinson's disease, Alzheimer's disease and diabetes mellitus. Complete characterization data were available for the minority of the cell lines. The most common sponsor of research projects registered in the hPSCreg&#xae; was the European Union's Seventh Framework Programme (FP7). There were 97 registered clinical trials in the hPSCreg&#xae;. Challenges identified were incomplete user-entered information, entry of non-standardized information about diseases and continuing verification of the evolving legal status of embryonic stem cell (ESC) research per country.<br><br>CONCLUSION: The hPSCreg&#xae; represents an important international resource for stem cell research; however, this evaluation identified substantial variation in data completeness and standardization across registry fields. Future development should focus on improving the completeness of key metadata, standardization of terminology and systematic monitoring of registry data quality.},
}
@article {pmid42481480,
year = {2026},
author = {Rumpf, SL and Strübing, FL and Nalbach, K and Vargiu, CM and Berg, G and Lichtenthaler, SF and Parchi, P and Gao, P and Chen, W and Brendel, M and Gnörich, JS and Bernhardt, A and Dias Rodrigues, L and Höglinger, GU and Herms, J and Koeglsperger, T},
title = {Spatial multi-omics identifies early synaptic pruning and context-specific dopaminergic vulnerability in synucleinopathies.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {42481480},
issn = {2041-1723},
mesh = {Humans ; alpha-Synuclein/metabolism/genetics ; *Dopaminergic Neurons/metabolism/pathology ; *Parkinson Disease/pathology/metabolism/genetics ; Proteomics/methods ; Synapses/metabolism/pathology ; Alzheimer Disease/pathology/metabolism/genetics ; *Synucleinopathies/metabolism/pathology/genetics ; Male ; Spatial Transcriptomics ; Lewy Body Disease/pathology/metabolism/genetics ; Female ; Aged ; Multiomics ; *Neuronal Plasticity ; Complement C1q/metabolism ; Substantia Nigra/pathology/metabolism ; Aged, 80 and over ; Mesencephalon/metabolism/pathology ; },
abstract = {Parkinson's disease (PD) is characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta, but the molecular events preceding neuronal loss remain unclear. Here, we combine spatial transcriptomics, spatial proteomics, and α-synuclein (αSyn) seed amplification assays to profile post-mortem midbrain tissue from controls, incidental Lewy body disease (iLBD), PD, Alzheimer's disease (AD), and AD with Lewy body pathology (AD + LBP). We find that αSyn seeding activity correlates with dopaminergic neuron loss in PD-spectrum cases but not in AD-associated LBP, indicating disease-context dependent relationships between αSyn pathology and neurodegeneration. In iLBD, before overt substantia nigra Lewy pathology or detectable αSyn aggregation, we detect increased expression of the complement component C1QC together with loss of inhibitory synaptic markers. These findings support early complement-associated remodeling of inhibitory synapses as a potential pathogenic event preceding overt αSyn aggregation and neuronal degeneration in PD.},
}
@article {pmid42481525,
year = {2026},
author = {Lian, X and Chen, A and Zhu, X and Huang, Y and Yang, C and Huang, Y and Ran, M and Yin, L and Zhang, B},
title = {Early-life sugar rationing, brain aging, and long-term neurodegenerative and psychiatric health outcomes: a population-based natural experiment study.},
journal = {npj aging},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41514-026-00452-z},
pmid = {42481525},
issn = {2731-6068},
support = {2024A04J3999 and 2024A03J1178//Guangzhou Planned Project of Science and Technology/ ; K-20240111//KRT Plan of Guangdong Medical Development Foundation/ ; 82170234//National Natural Science Foundation of China/ ; 20241A011019//Health Science and Technology General Guidance Program of Guangzhou/ ; },
abstract = {Early-life nutrition is linked to adult brain health, yet evidence from quasi-experimental studies remains scarce. Leveraging the UK's historical sugar rationing as a natural experiment, we examined whether early-life sugar restriction reduces the risk of neurodegenerative and psychiatric disorders in later life. Among 60,394 UK Biobank participants (born 1951-1956), three groups were defined: in-utero-only, in utero plus 2 years, and non-rationed controls. Compared with non-rationed individuals, those exposed to sugar restriction during the first 1000 days after conception, showed significantly lower risks of all-cause dementia (by 27%), Alzheimer's disease (46%), depression (11%), and anxiety (20%). Dose-response analyses revealed stronger protective associations against depression and anxiety when postnatal sugar restriction extended beyond 6 months of age. Sex-stratified analyses showed consistent protective effects in women for Alzheimer's disease, depression, and anxiety. Neuroimaging revealed decelerated brain aging, reflected by a 0.39-year reduction in the brain age gap, alongside structural changes in reduced gray-white matter contrast and larger subcortical volumes, including the hippocampus and thalamus. Minimal associations were observed for in‑utero‑only exposure. These quasi-experimental findings suggest that early-life sugar restriction is associated with attenuated neurobiological aging and lower risks of dementia and psychiatric disorders, highlighting sugar intake as a potential modifiable factor of lifelong brain health.},
}
@article {pmid42481587,
year = {2026},
author = {Vogrinc, D and Holcar, M and Lenassi, M and Gregorič Kramberger, M and Emeršič, A and Čučnik, S and Dolžan, V and Goričar, K},
title = {Association of target miRNAs expression in blood plasma and cerebrospinal fluid with Alzheimer's disease biomarkers level and cognitive decline.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-63369-3},
pmid = {42481587},
issn = {2045-2322},
abstract = {Epigenetic changes can affect Alzheimer's disease (AD) susceptibility. miRNAs are novel potential circulating biomarkers of AD and mild cognitive impairment (MCI) that could support cerebrospinal fluid (CSF) biomarkers in earlier diagnosis of the disease or determination of disease stage. Our aim was to assess differences in expression of target miRNAs in patients with different stages of cognitive impairment and to evaluate the association with CSF biomarkers or cognitive test score (MMSE). We included 117 patients with cognitive impairment, among them 62 AD patients, 24 MCI patients with pathological CSF biomarker levels, and 31 MCI patients with normal CSF biomarker levels. Expression of seven target miRNAs was measured in patients' blood plasma, CSF and extracellular vesicles (EVs) enriched from plasma and CSF. None of the investigated miRNAs were differentially expressed between AD and MCI groups. Four miRNAs were associated with CSF biomarker levels, both in plasma (hsa-miR-375-3p) and CSF (hsa-miR-146a-5p, hsa-miR-29c, hsa-miR-107). The observed findings suggest that investigated miRNAs are not suitable for differentiation between different stages of cognitive impairment. However, miRNAs were associated with typical hallmarks of AD, which supports their important role in neurodegeneration. Therefore, miRNA regulatory networks could contribute to better understanding of the biological processes involved in cognitive impairment.},
}
@article {pmid42481708,
year = {2026},
author = {Qi, T and Fu, J and Wang, Y and Zhao, M and Zhang, Z and Peng, W and Liu, Q and Liu, M and Li, S and Duan, Q and Wang, C and Zhuang, J and Yan, X and Liu, Y and Wang, H and Huang, X},
title = {Computationally guided design of bioactive nanostructures for targeted clearance of amyloid-β aggregates in Alzheimer's disease.},
journal = {Nature nanotechnology},
volume = {},
number = {},
pages = {},
pmid = {42481708},
issn = {1748-3395},
support = {32425032//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32271448//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82472134//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82471465//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Targeted clearance of pre-existing amyloid-β (Aβ) aggregation remains a central challenge in Alzheimer's disease (AD) therapy. Here we report a computationally guided protein-gold hybrid nanostructure, Aβ3FTn[Au], that integrates Aβ-recognition motifs into self-assembled human ferritin nanocages containing structurally defined gold nanoclusters composed of 12 gold atoms with Au-Au distances of 2.4-4.5 Å, enabling the selective recognition and disassembly of aggregated human Aβ. Structural analysis, mutagenesis and molecular simulations identify key interactions between gold-coordinating residues within Aβ3FTn[Au] (H118, T122, C130) and the Met35 residue of Aβ, revealing a mechanism in which multivalent engagement destabilizes fibrillar interfaces and promotes progressive plaque disassembly. In 5 × familial AD transgenic mice, systemic administration of Aβ3FTn[Au] reduced cerebral amyloid burden, preserved synaptic integrity and improved cognitive performance. This work establishes a rationally designed bioactive nanomaterial for targeted remodelling of pathological protein aggregates.},
}
@article {pmid42481784,
year = {2026},
author = {Aghaei, M and Gheisavandi, O and Carpenter, BD and Vahabi, Z and Sharifi, F and Etesam, F},
title = {Validity and reliability of the Persian version of the Alzheimer's Disease Knowledge Scale among Iranian healthcare professionals and students.},
journal = {Discover mental health},
volume = {},
number = {},
pages = {},
doi = {10.1007/s44192-026-00546-w},
pmid = {42481784},
issn = {2731-4383},
abstract = {Alzheimer's disease (AD) is the leading cause of dementia worldwide. With rising prevalence in countries such as Iran, assessing healthcare professionals' knowledge of AD is essential. This study translated and adapted the Alzheimer's Disease Knowledge Scale (ADKS) into Persian and provided preliminary evidence of validity and reliability. A cross-sectional study was conducted with 304 healthcare professionals and students. The mean Persian version of the Alzheimer's Disease Knowledge Scale (ADKS-P) score was 20.27 (standard deviation (SD) = 3.62; possible range 0-30). The ADKS-P was developed using forward-backward translation, expert review, and pilot testing. Content validity, item-level performance, internal consistency estimated with Kuder-Richardson Formula 20 (KR-20), and two-week test-retest reliability were assessed. Known-groups validity was examined through education, occupation, and familiarity with dementia. All items met the critical Content Validity Ratio (CVR) threshold. Internal consistency was modest (KR-20 = 0.64), test-retest reliability was moderate (r = 0.53, p = 0.016), and several items showed weak discrimination (item-total r < 0.20 for 15 items; item 24 r = - 0.05). Higher ADKS-P scores were associated with greater education, professional role, and dementia familiarity. The ADKS-P offers a preliminary, culturally adapted tool for group-level baseline knowledge assessment in Persian-speaking contexts. Further refinement and validation are recommended before broader application.The study was approved by the ethics committee of the Tehran University of Medical Sciences (IR.TUMS.MEDICINE.REC.1401.202).},
}
@article {pmid42481826,
year = {2026},
author = {Wong, HY and Jin, C and Yuen, SL and Yang, X and Gill, SS and Xu, J and Lai, KPE and Fu, WY and Gao, W and Wang, X and Wang, J and Cao, H and Lv, G and Mok, KY and Tian, R and Fu, AKY and Chen, H and Ip, NY},
title = {DeepPlaque: a scalable multimodal platform for Aβ pathology and cell analysis in Alzheimer's disease.},
journal = {EMBO molecular medicine},
volume = {},
number = {},
pages = {},
pmid = {42481826},
issn = {1757-4684},
support = {T13-605/18W//Research Grants Council of Hong Kong (the Theme-Based Research Scheme)/ ; HKUST16104624 and HKUST16102824//Research Grants Council of Hong Kong (the General Research Fund)/ ; AoE/M-604/16//Areas of Excellence Scheme of the University Grants Committee/ ; ITCPD/17-9//the Innovation and Technology Fund for State Key Laboratory/ ; JLFS/M-604/24//SIAT-HKUST Joint Laboratory for Brain Science (Joint laboratory Scheme)/ ; 2023B1212120004//the Guangdong-Hong Kong Joint Laboratory for Psychiatric Disorders/ ; No. 62202403//the National Natural Science Foundation of China/ ; },
abstract = {Histological analysis is essential for understanding disease pathology and the microenvironment, particularly in Alzheimer's disease (AD), characterized by beta-amyloid (Aβ) plaques that exist as diffuse, fibrillar, and core species, with distinct toxicity levels. However, accurate classification of Aβ plaque types in postmortem brain tissues and profiling of surrounding cells present significant challenges. To address these challenges, we developed "DeepPlaque", an integrated system featuring "PlaqueNet", a deep learning model for automated classification of Aβ plaque species from diverse imaging platforms. DeepPlaque includes automated workflows for cellular phenotyping and proteomic profiling through targeted laser microdissection. PlaqueNet achieves expert-level accuracy (AUC > 90%) in classifying the 3 major Aβ plaque species, supporting consistent and large-scale annotation. By integrating spatial cellular phenotyping with laser microdissection, DeepPlaque enables high-throughput proteomic analysis of Aβ plaque niches, revealing that microglia are more abundant around core and fibrillar Aβ plaques, with increased expression of apolipoprotein E and amyloid precursor protein in core Aβ plaques. This customizable platform enhances the molecular and cellular characterization of Aβ plaque-associated environments, providing critical insights into AD pathology.},
}
@article {pmid42481875,
year = {2026},
author = {Sahin, U and Firat-Karalar, EN},
title = {The centrosome-cilium-centriolar satellite axis in neurodegenerative diseases.},
journal = {EMBO reports},
volume = {},
number = {},
pages = {},
pmid = {42481875},
issn = {1469-3178},
support = {101078097//EC | H2020 | PRIORITY 'Excellent science' | H2020 European Research Council (ERC)/ ; 3336//European Molecular Biology Organization (EMBO)/ ; 3622//European Molecular Biology Organization (EMBO)/ ; YIP//European Molecular Biology Organization (EMBO)/ ; (SU PREG)//Sabanci University President's Research/ ; },
abstract = {Neurodegenerative diseases (NDDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and hereditary ataxias, remain major global health challenges with limited therapeutic options. Although clinically and genetically diverse, these diseases share extensively studied cellular and molecular hallmarks, including protein aggregation, impaired proteostasis, cytoskeletal abnormalities, altered energy metabolism, nucleic acid damage, and chronic inflammation. Emerging evidence indicates that dysfunction of the centrosome-cilium-satellite axis intersects with these established pathways in disease- and cell type-specific contexts. This axis, composed of centrosomes, primary cilia, and centriolar satellites, coordinates cytoskeletal organization, ciliary signaling, trafficking, proteostasis, and stress responses and acquires specialized functions in neurons that support polarity, connectivity, and long-term maintenance. In this review, we outline the structure, function, and neuronal specializations of the centrosome-cilium-satellite axis, then examine how its dysfunction has been reported in neurodegenerative disease models. We also discuss centriolar satellites as regulators of centrosome and cilium biology whose disease-specific roles in classical NDDs remain comparatively underexplored, with insights from Huntington's disease and schizophrenia. Finally, we discuss therapeutic strategies aimed at restoring axis structure and dynamics, modulating ciliary signaling, and correcting disease-linked genetic or transcript-level defects, emphasizing mechanism-based approaches that require validation in disease-relevant models. Together, the centrosome-cilium-satellite axis provides an emerging framework for understanding context-dependent organelle dysfunction in neuronal vulnerability and neurodegeneration.},
}
@article {pmid42482153,
year = {2026},
author = {Li, X and Zhao, D and Jia, X and Du, G and Xu, J and Qi, Y and Chen, Y and Wu, Y and Gu, J and Zhu, J and Shang, X},
title = {Deciphering spatial heterogeneity by multimodal spatial transcriptomics modelling with SpatialModal.},
journal = {Bioinformatics (Oxford, England)},
volume = {},
number = {},
pages = {},
doi = {10.1093/bioinformatics/btag540},
pmid = {42482153},
issn = {1367-4811},
abstract = {MOTIVATION: Advances in spatial transcriptomics (ST) technologies have made it possible to jointly acquire gene expression and histological image information while preserving spatial coordinates. This breakthrough presents unprecedented opportunities for the precise dissection of spatial heterogeneity in complex tissues. However, existing computational methods remain limited in their capacity for effective integration and synergistic modelling of multimodal ST data.<br><br>RESULTS: We propose SpatialModal, a multimodal graph learning framework that learns robust joint representations by combining a hierarchical representation strategy with a dual-level contrastive learning mechanism. We perform extensive validation of SpatialModal across diverse ST datasets spanning human and mouse tissues. The results demonstrate that SpatialModal effectively reveals intricate brain architectures in humans and mice, dissects tumour microenvironment heterogeneity in breast cancer, delineates Alzheimer's disease patterns, and characterizes spatiotemporal developmental trajectories within the embryonic heart, underscoring its capability to decipher the spatial heterogeneity of biological tissues. Furthermore, SpatialModal exhibits remarkable versatility and robustness, maintaining superior efficacy even on unimodal datasets devoid of histological images, thereby ensuring its broad applicability across diverse ST platforms.<br><br>SpatialModal is implemented in Python and is freely available at https://github.com/xingyili/SpatialModal. The source code used in this study has been archived on Zenodo at DOI: https://doi.org/10.5281/zenodo.21264356. All datasets used in this study are publicly available at https://doi.org/10.5281/zenodo.18220735.},
}
@article {pmid42482244,
year = {2026},
author = {Bonnì, S and Esposito, R and Mencarelli, L and Di Lorenzo, F and Ricci, F and Di Iulio, F and Savastano, E and Candeo, F and De Masi, F and Coletta, A and Vinci, AC and Ferraresi, M and Mancini, M and Casula, EP and Borghi, I and Spampinato, DA and Maiella, M and Cinnera, AM and Assogna, M and Bruno, M and Nocilli, M and Ferrara, M and Russo, M and Tagliamonte, NL and Ferrari, C and Bertino, S and Calabrò, RS and Maggio, MG and De Luca, R and Burrascano, R and Gjonaj, E and Mirabile, A and De Pasquale, P and d'Avella, A and Quartarone, A and Koch, G},
title = {Personalized non-invasive combined magnetic and electrical stimulation of the default mode network in mild AD patients (CMES-AD): a multicentric randomized sham-controlled trial protocol.},
journal = {Alzheimer's research &amp; therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02145-x},
pmid = {42482244},
issn = {1758-9193},
support = {PNRR- MCNT2-2023-12377518//Ministero della Salute/ ; },
abstract = {BACKGROUND: Patients with Alzheimer's disease (AD) exhibit early alterations in the Default Mode Network (DMN), a key brain network involved in episodic memory where the precuneus plays a central role. Precision-targeted, non-invasive brain stimulation represents a promising strategy to improve cognitive function in individuals with dementia. The DMN can be modulated through personalized non-invasive electromagnetic stimulation, a therapeutic approach that enhances neural plasticity and stabilizes network connectivity. This trial implements an innovative therapeutic protocol based on precision delivery of personalized electromagnetic stimulation targeting the precuneus, the main hub of the DMN.<br><br>METHODS: This phase 2 multicenter, randomized, double-blind, sham-controlled, three-arm trial evaluates the safety and efficacy of combined repetitive transcranial magnetic stimulation (rTMS) and transcranial alternating current stimulation (tACS) targeting the precuneus in AD patients. rTMS will be applied using the intermittent theta burst stimulation (iTBS) protocol, while tACS will be delivered at gamma frequency (70&#xa0;Hz). Personalization of iTBS-tACS treatment is established using neuronavigated TMS with electroencephalography (TMS-EEG). The 24-week intervention starts with a 2-week intensive course of daily combined treatment over the precuneus (5 sessions per week), followed by a 22-week maintenance phase with weekly stimulation. The primary outcome measure is the change in the integrated Alzheimer Disease Rating Scale (iADRS) between baseline and week 24. Secondary outcomes include score changes in the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) scale, Clinical Dementia Rating Scale-Sum of Boxes (CDR-SoB), the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13), the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), the Frontal Assessment Battery (FAB), the Face-Name Association Task (FNAT), the Neuropsychiatric Inventory (NPI), and the Apathy Motivation Index (AMI). Exploratory outcomes will include changes in cortical activity and connectivity (assessed through TMS-EEG, MRI), in blood based biomarkers of neurodegeneration, synaptic activity and neural inflammation, and sensorimotor functions in virtual environments. Evaluation at week 12 and a follow-up assessment at week 32 will be conducted to assess short-term and follow-up treatment effects, respectively.<br><br>SIGNIFICANCE: This trial aims to provide evidence that personalized combined electrical and magnetic stimulation of the DMN may slow functional and cognitive decline in AD patients, contributing to the development of personalized interventions for AD treatment.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov, NCT07075770, registered 10 July 2025.},
}
@article {pmid42482583,
year = {2026},
author = {Yang, SM and Guo, WQ and Dong, WG and Huang, JY and Huang, ST and Huang, Y and Zhan, SJ and Lin, L and Wang, F and Liu, LL},
title = {[Effects of electroacupuncture on motor function and PGC-1α/FNDC5/BDNF pathway in muscle and brain of SAMP8 mice].},
journal = {Zhen ci yan jiu = Acupuncture research},
volume = {51},
number = {7},
pages = {887-895},
doi = {10.13702/j.1000-0607.20250437},
pmid = {42482583},
issn = {1000-0607},
mesh = {Animals ; *Electroacupuncture ; *Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism/genetics ; *Brain-Derived Neurotrophic Factor/metabolism/genetics ; Mice ; *Muscle, Skeletal/metabolism ; Male ; *Fibronectins/metabolism/genetics ; Humans ; *Brain/metabolism ; *Alzheimer Disease/genetics/metabolism/therapy/physiopathology ; Signal Transduction ; Motor Activity ; Acupuncture Points ; },
abstract = {OBJECTIVES: To observe the effect of electroacupuncture (EA) on motor function and skeletal muscle morphology in SAMP8 mice, and to explore the mechanisms of EA improving motor dysfunction in Alzheimer's disease from the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α)/fibronectin type Ⅲ domain-containing protein 5 (FNDC5)/brain-derived neurotrophic factor (BDNF) pathway.<br><br>METHODS: SAMP8 mice were randomly divided into model and EA groups, with 9 mice in each group. Nine anti-aging SAMR1 mice were used as control group. In the EA group, "Baihui"(GV20), "Dazhui"(GV14) and "Shenshu"(BL23) were needled with EA for 20 min every day, 8 d as a course of treatment, with an interval of 2 d between courses. A total of 3 courses was proceeded. The motor function of mice was detected by grasping test, swimming test, suspension test and hind limb clamping test. The morphological structure of gastrocnemius muscle was observed by HE staining. The positive expressions of PGC-1&#x3b1;, FNDC5 and BDNF in gastrocnemius muscle were observed by immunohistochemical staining. The expression levels of PGC-1&#x3b1;, FNDC5 and BDNF mRNAs in gastrocnemius muscle and cerebral motor cortex were detected by real-time fluorescence quantitative PCR. The expression levels of PGC-1&#x3b1;, FNDC5 and BDNF proteins in gastrocnemius muscle and cerebral motor cortex were detected by Western blot.<br><br>RESULTS: Compared with the control group, the peak grip strength, average and maximum swimming speed, and suspension test score of the model group were significantly decreased (P<0.01), and the hind limb clamping test score was significantly increased (P<0.01). The gastrocnemius muscle fibers were loose and irregularly arranged, the spacing was widened and the cytoplasmic staining was uneven. The positive expression area ratios of PGC-1&#x3b1;, FNDC5 and BDNF in gastrocnemius muscle were significantly decreased (P<0.01), and the relative expression levels of PGC-1&#x3b1;, FNDC5 and BDNF mRNAs and proteins in gastrocnemius muscle and cerebral motor cortex were significantly decreased (P<0.01). Compared with the model group, the peak grip strength, average and maximum swimming speed, and suspension test score of the EA group were significantly increased (P<0.01), and the hind limb clamping test score was significantly decreased (P<0.01). The muscle fibers were intact and arranged regularly, the spacing was narrowed, and the cytoplasmic staining was uniform.The positive expression area ratios of PGC-1&#x3b1;, FNDC5 and BDNF were significantly increased (P<0.01), and the relative expression levels of PGC-1&#x3b1;, FNDC5 and BDNF mRNAs and proteins in gastrocnemius muscle and cerebral motor cortex were significantly increased (P<0.01, P<0.05). The correlation analysis results of PGC-1&#x3b1;, FNDC5 and BDNF mRNA expression in gastrocnemius and cerebral motor cortex showed a highly positive correlation (r>0.70, P<0.01).<br><br>CONCLUSIONS: EA can improve motor dysfunction and skeletal muscle morphology in SAMP8 mice, and its mechanism may be related to up-regulation of PGC-1&#x3b1;, FNDC5 and BDNF expressions in gastrocnemius and cerebral motor cortex.},
}
@article {pmid42482587,
year = {2026},
author = {Li, L and Hong, C and Xie, WT and Zhang, RZ and Wei, YT and Ma, C and Yan, XK},
title = {[Research progress on acupuncture-moxibustion regulating brain energy metabolism to intervene in Alzheimer's disease].},
journal = {Zhen ci yan jiu = Acupuncture research},
volume = {51},
number = {7},
pages = {923-932},
doi = {10.13702/j.1000-0607.20250813},
pmid = {42482587},
issn = {1000-0607},
mesh = {Humans ; *Alzheimer Disease/therapy/metabolism/genetics ; *Energy Metabolism ; *Acupuncture Therapy ; *Brain/metabolism ; *Moxibustion ; Animals ; Mitochondria/metabolism ; },
abstract = {Alzheimer's disease (AD) is a common neurodegenerative disorder, and brain energy metabolism disorders are closely related to the onset of AD. Acupuncture-moxibustion is one of the effective treatments for AD, which can significantly improve AD symptoms and slow down the progression of the disease. The mechanism of its action has also been continuously studied. This article summarizes the relevant research on acupuncture-moxibustion regulating brain energy metabolism to improve AD. The results show that acupuncture-moxibustion mainly improves AD brain energy metabolism disorders from the following aspects: 1) regulating glucose metabolism disorders (promoting glucose transport, increasing glucose uptake and utilization, and regulating glycolytic activity in the brain), 2) regulating mitochondrial structure and dysfunction (improving mitochondrial structure and dynamics, enhancing electron transfer chain activity and ATP production, inhibiting abnormal opening of mitochondrial permeability transition pores), 3) improving insulin resistance and damage to the insulin signaling pathway, and 4) restoring amino acid and lipid metabolic imbalance. It plays a role in neuroprotection and delaying the progression of the disease.},
}
@article {pmid42482646,
year = {2026},
author = {Ren, C and Li, Z and Cai, J and Li, J and Hong, X},
title = {The Relationship between Biological Aging and Cognitive Function: A Machine Learning Model.},
journal = {Yonsei medical journal},
volume = {67},
number = {7},
pages = {563-575},
doi = {10.3349/ymj.2025.0195},
pmid = {42482646},
issn = {1976-2437},
support = {JLSWSRCZX2023-24//Jilin Provincial Medical and Health Talent Project/China ; },
mesh = {Humans ; *Machine Learning ; *Aging/physiology ; Female ; *Cognition/physiology ; Male ; Aged ; ROC Curve ; Middle Aged ; *Cognitive Dysfunction/physiopathology ; Nutrition Surveys ; Predictive Learning Models ; },
abstract = {PURPOSE: The relationship between cognitive impairment and biological age (BA) is unclear. This study aimed to investigate the association between BA and cognitive impairment.<br><br>MATERIALS AND METHODS: A total of 2202 participants from the 2011-2012 and 2013-2014 National Health and Nutrition Examination Survey were included. Klemera-Doubal method age (KDM-Age), phenotypic age (PhenoAge), and their acceleration values were calculated based on laboratory parameters. Six machine learning models were constructed to compare performance metrics such as area under the receiver operating characteristic curve (AUC-ROC) and accuracy, and Shapley additive explanations (SHAP) was used to interpret feature contributions.<br><br>RESULTS: After fully adjusting for confounders, each 1-year increase in PhenoAge was associated with a 6%, 8%, and 5% higher risk of cognitive impairment on the Consortium to Establish a Registry for Alzheimer's Disease (CERAD), Digit Symbol Substitution Test (DSST), and Animal Fluency Test (AFT) tests, respectively (all p<0.001); the highest quartile group exhibited a 5.98-17.48-fold increase in risk compared to the lowest. KDM-Age showed only a marginal association with DSST [odds ratio (OR)=1.02, p=0.049]. Among all models, the random forest (RF) performed best for CERAD prediction (AUC-ROC=0.997, sensitivity=99.5%), significantly outperforming the other algorithms (p<0.001). SHAP results demonstrated that sociodemographic factors had mean contribution values (0.014-0.135) significantly higher than those of BA indicators (<0.011), underscoring the dominant role of social determinants.<br><br>CONCLUSION: PhenoAge is a biological aging indicator with suggestive value for identifying the risk of cognitive impairment in older adults. Combining the RF model with key sociodemographic information may help facilitate early risk screening.},
}
@article {pmid42482698,
year = {2026},
author = {Almostafa, M and Ali, I and Yahya, G and Siddiqi, AR},
title = {Unveiling the structural insights and inhibitory potential of coumarin-1,2,3-triazole hybrids against BACE1: a promising approach for Alzheimer's disease therapy.},
journal = {Frontiers in chemistry},
volume = {14},
number = {},
pages = {1824875},
pmid = {42482698},
issn = {2296-2646},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid beta (Aβ) plaque accumulation, in which β-secretase (BACE1) plays a central role in the amyloidogenic pathway. Inhibition of BACE1 represents a promising therapeutic strategy; however, effective and safe inhibitors remain limited. This study aimed to identify novel coumarin-1,2,3-triazole hybrids as potential BACE1 inhibitors using comprehensive in silico approaches. Molecular shape and distance-based features derived from co-crystal ligands were used to generate and validate a pharmacophore model through ROC-based area under the curve analysis. A designed library of hybrids underwent pharmacophore-based virtual screening, yielding 92 hits with ≤0.6 RMSD. These compounds were further evaluated via structure-based molecular docking, from which six top candidates were selected, demonstrating superior docking scores relative to reported inhibitors. ADMET and density functional theory analyses indicated favorable pharmacokinetic profiles and electronic properties, highlighting potential reactive sites. The selected compound, CUM-0199, was subsequently validated through a 200 ns molecular dynamics simulation and MMGBSA binding free energy analysis, confirming structural stability and favourable binding affinity toward BACE1. Overall, the findings suggest CUM-0199 as a potential lead candidate for AD therapy, warranting further experimental validation and clinical investigation.},
}
@article {pmid42483155,
year = {2026},
author = {Na, C and Gupta, G and Kim, M and Choe, Y and Lee, J and Lee, CY and Lim, MH},
title = {Metal-organic macrocycles as molecular modulators of amyloid-β aggregation and cytotoxicity.},
journal = {Chemical science},
volume = {},
number = {},
pages = {},
pmid = {42483155},
issn = {2041-6520},
abstract = {Metal-organic macrocycles provide a versatile platform for integrating multiple chemical functions within a single, well-defined architecture, yet their potential for regulating pathological protein aggregation remains largely unexplored. Here we report rationally designed metal-organic macrocycles that combine piano-stool ruthenium or iridium complexes with a photoactivatable bis(difluoroboron)-1,2-bis((1H-pyrrol-2-yl)methylene)hydrazine (BOPHY)-based ligand to enable dual-mode modulation of amyloid-β (Aβ) aggregation associated with Alzheimer's disease. These macrocycles directly engage Aβ species through surface interactions and, upon light activation, induce oxidative modifications via singlet oxygen, collectively altering aggregation behavior and aggregate morphologies. As a result, they suppress the formation of toxic Aβ assemblies and attenuate Aβ-induced cytotoxicity. Overall, this work establishes metal-organic macrocycles as effective modulators of amyloidogenesis and provides a potential strategy for controlling complex protein aggregation processes in neurodegenerative diseases.},
}
@article {pmid42483205,
year = {2026},
author = {Beydoun, MA and Song, M and Yun, C and Noren Hooten, N and Weiss, J and Beydoun, HA and Duggan, MR and Walker, KA and Launer, LJ and Evans, MK and Zonderman, AB},
title = {The proteomic and metabolomic signature of inherited chromosomally integrated HHV-6 and its role in all-cause dementia and mortality risk: The UK Biobank study.},
journal = {Alzheimer's &amp; dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70286},
pmid = {42483205},
issn = {2352-8737},
abstract = {OBJECTIVE: To examine associations of inherited chromosomally integrated human herpesvirus 6 (iciHHV-6) with incident dementia and mortality, characterize proteomic and metabolomic correlates of carrier status, and evaluate whether these biomarkers relate to dementia and mortality risk.<br><br>METHODS: We analyzed UK Biobank participants &#x2265;50 years of age with plasma metabolomics (N&#xa0;=&#xa0;138,676) and proteomics (N &#x2264; 15,416) data and &#x2248;15 years of follow-up. Cox proportional hazards models adjusted for key confounding factors evaluated associations of iciHHV-6 with dementia and mortality. Multivariable linear models assessed iciHHV-6 associations with metabolomic and proteomic profiles. Mediation and interaction were evaluated using structural equation models and Cox models with biomarker interactions. Least absolute shrinkage and selection operator regression identified independent proteomic and metabolomic predictors using imputed biomarker data.<br><br>RESULTS: iciHHV-6 was associated with higher dementia risk (hazard ratio [HR]&#xa0;=&#xa0;1.32), particularly among women (HR&#xa0;=&#xa0;1.66) and individuals with elevated Alzheimer's disease polygenic risk (HR&#xa0;=&#xa0;1.49). Branched-chain amino acids (leucine and isoleucine) were elevated among carriers without mediating dementia risk. Proteomic analyses identified 126 nominally associated iciHHV-6-related proteins, many of which (Neurofilament Light Chain (NEFL), Glial Fibrillary Acidic Protein&#xa0;(GFAP), Yes-Associated Protein 1 (YAP1), Sialic Acid-binding Immunoglobulin-like Lectin 5 (SIGLEC5), Interleukin 19 (IL19), A Disintegrin And Metalloproteinase with Thrombospondin Motifs 16 (ADAMTS16), Sphingomyelin Phosphodiesterase 1 (SMPD1)) were also associated with dementia and/or mortality. Exploratory pathway analyses suggested enrichment of proteins related to immune regulation and post-translational modification. Predictive models identified NEFL, GFAP, Vascular Endothelial Growth Factor A (VEGF), Brevican (BCAN), remnant cholesterol, and polyunsaturated fatty acids as dementia predictors (area under the curve [AUC]&#xa0;=&#xa0;0.83), whereas NEFL, Growth Differentiation Factor 15 (GDF15) Latent Transforming Growth Factor Beta Binding Protein 2 (LTBP2), Ectodysplasin A2 Receptor (EDA2R) and Advanced Glycosylation End-product Specific Receptor (AGER) predicted mortality (AUC&#xa0;=&#xa0;0.70).<br><br>DISCUSSION: iciHHV-6 was associated with increased dementia risk, particularly among women and genetically susceptible individuals, with neuroimmune and metabolic biomarker profiles potentially relevant to brain aging and mortality risk.},
}
@article {pmid42483224,
year = {2026},
author = {Angom, RS and Li, Z and Rachamala, HK and Castanedes-Casey, M and Kulkarni, T and Chakravarty, T and Dutta, S and Wang, E and Dickson, D and Mukhopadhyay, D and Das, P},
title = {Correction: Vascular endothelial growth factor receptor-1 (VEGFR-1) knock-down is protective against hypoxia, Aβ1-42 oligomer and Aβ1-42 fibril-induced neuronal cell death: implications in AD pathogenesis.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1901421},
doi = {10.3389/fnins.2026.1901421},
pmid = {42483224},
issn = {1662-4548},
abstract = {[This corrects the article DOI: 10.3389/fnins.2026.1799391.].},
}
@article {pmid42483443,
year = {2026},
author = {Altuna, M},
title = {From cognitive screening to digital phenotyping: rethinking early detection of cognitive impairment in primary care.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1870463},
pmid = {42483443},
issn = {1664-2295},
abstract = {Early detection of cognitive impairment has become a clinical and public-health priority in the therapeutic era of Alzheimer's disease (AD). Brief instruments such as the Mini-Mental State Examination, Montreal Cognitive Assessment, Mini-Cog, Clock Drawing Test, Fototest, Memory Alteration Test, Eurotest, and AD8 remain widely used because they are inexpensive, clinically interpretable, and feasible in routine care. However, most were developed to identify established cognitive impairment rather than subtle mild cognitive impairment or biologically defined early AD. Ceiling effects, educational and cultural bias, examiner variability, and limited integration with functional, neuropsychiatric, subjective, and biomarker data restrict their value as stand-alone tools in contemporary diagnostic pathways. Digital cognitive assessment may address selected limitations of conventional screening by standardizing administration, reducing scoring variability, enabling repeated measurement, and capturing process-level features such as response latency, intra-individual variability, learning effects, speech and language markers, graphomotor dynamics, gaze, and ecologically sampled behavior. These signals may support earlier risk stratification and longitudinal monitoring, but they do not resolve diagnostic uncertainty or establish AD etiology on their own. This narrative review examines the transition from traditional cognitive screening to digital cognitive phenotyping. It considers established brief and contextual instruments, digitized conventional tests, remote repeated assessments, speech and language-derived digital cognitive biomarkers, digital clock drawing, prospective-memory tools, virtual reality and serious games, oculomotor and graphomotor metrics, passive sensing, multimodal platforms, and their integration with structural MRI, blood-based biomarkers, cerebrospinal fluid markers, and amyloid/tau PET. In the context of evolving AD criteria and disease-modifying therapies, digital screening should be understood as a governed triage and phenotyping layer rather than a stand-alone diagnostic label. A staged pathway is proposed that combines analog cognitive instruments, informant and functional measures, neuropsychiatric assessment, digital signals, and biological markers to support earlier, more equitable, and clinically actionable detection of cognitive impairment.},
}
@article {pmid42483593,
year = {2026},
author = {Zeng, HX and Li, G and Zeng, QG and Zhang, Q and Liu, L and Zeng, XW},
title = {Circular RNA circDNAJC5 Regulates Ultrafine Particle-Disrupted Microglial Lipid Metabolism via the Sphingolipid Signaling Pathway.},
journal = {Environment &amp; health (Washington, D.C.)},
volume = {4},
number = {7},
pages = {1454-1468},
pmid = {42483593},
issn = {2833-8278},
abstract = {Ultrafine particles (PM0.1) can penetrate the brain and disrupt microglial function. Dysregulated lipid metabolism in activated microglia contributes to the development of Alzheimer's disease (AD), yet the epigenetic mechanisms underlying PM0.1-induced lipid metabolic disruption remain poorly understood. Circular RNAs (circRNAs) are emerging regulators of lipid metabolism, prompting us to investigate their role in PM0.1-exposed microglia. In vitro models of PM0.1-treated microglia (HMC3 and BV2) were established. We identified circDNAJC5, a lipid metabolism-associated circRNA, as significantly downregulated during PM0.1-induced lipid metabolic disruption. circDNAJC5 silencing aggravated lipid dysregulation, whereas its overexpression mitigated PM0.1-induced metabolic alterations. circDNAJC5 functioned as a molecular sponge for miR-98-5p, thereby regulating sphingomyelin synthase 1 (SMS1), a key enzyme in the sphingolipid signaling pathway. circDNAJC5 downregulation and lipid metabolic abnormalities were further validated in the brains of PM-exposed mice and AD mouse models, as well as in the blood of elderly individuals with cognitive impairment and hyperlipidemia. These findings highlight an epigenetic mechanism linking environmental exposure to microglial lipid metabolism and suggest circDNAJC5 as a potential biomarker for neurodegenerative and metabolic disorders.},
}
@article {pmid42483652,
year = {2026},
author = {Chen, IW and Chang, LC and Lai, YC and Hung, KC},
title = {Association of low vitamin B12 status with incident dementia and stroke: an EHR database study.},
journal = {Frontiers in nutrition},
volume = {13},
number = {},
pages = {1877529},
pmid = {42483652},
issn = {2296-861X},
abstract = {BACKGROUND: Epidemiological evidence linking low vitamin B12 status to dementia risk remains inconsistent, partly reflecting differences in exposure definitions, study designs, and analytical approaches. This study evaluated the association between low vitamin B12 status and long-term risks of incident dementia, related neurocognitive, and cerebrovascular outcomes.<br><br>METHODS: This propensity score-matched retrospective cohort study used de-identified electronic health record data from the TriNetX Global Collaborative Network. Adults aged &#x2265;50&#x202f;years with two vitamin B12 measurements <300&#x202f;pg./mL within a 2-year window were matched 1:1 with patients who had two vitamin B12 measurements of 300-900&#x202f;pg./mL using the same framework. A 1-year landmark period was applied, with outcome follow-up beginning on day 366 after the index date. The primary outcome was incident all-cause dementia over 10&#x202f;years. Secondary outcomes included Alzheimer's disease, vascular dementia, other dementia subtypes, mild cognitive impairment, stroke, and all-cause mortality. An exposure-gradient analysis was performed among patients with vitamin B12 deficiency, defined as two measurements <200&#x202f;pg./mL.<br><br>RESULTS: After matching, 129,159 patients remained in each group. Low vitamin B12 status was associated with a higher risk of all-cause dementia (Hazard ratio [HR] 1.33, 95% confidence interval [CI] 1.27-1.39, p&#x202f;<&#x202f;0.001). Associations were also observed for Alzheimer's disease, vascular dementia, and other dementia subtypes (HRs 1.31-1.34), mild cognitive impairment (HR 1.33), stroke (HR 1.31), and all-cause mortality (HR 1.23; all p&#x202f;<&#x202f;0.001). Among patients with vitamin B12 deficiency, the association with all-cause dementia was stronger (HR 1.64, p&#x202f;<&#x202f;0.001). Results were consistent across six prespecified sensitivity analyses and sex-stratified subgroup analyses.<br><br>CONCLUSION: Low vitamin B12 status was associated with an increased long-term risk of incident all-cause dementia, with a numerically stronger association among patients with vitamin B12 deficiency. Given the observational design and potential residual bias, these findings should be interpreted as hypothesis-generating rather than causal. Further prospective studies with serial biomarker monitoring and interventional studies of vitamin B12 correction are needed to clarify this association.},
}
@article {pmid42483706,
year = {2026},
author = {Clavel-Pérez, PI and Phillips-Farfán, BV and Camacho-Castillo, L and Calderón-Garcidueñas, AL and Carvajal, K},
title = {Up regulated hippocampal insulin pathway and oxidative stress are related to opposite changes in olfaction and episodic memory in a compensatory metabolic syndrome model in rats.},
journal = {Frontiers in cellular neuroscience},
volume = {20},
number = {},
pages = {1845387},
pmid = {42483706},
issn = {1662-5102},
abstract = {Insulin resistance, a major component of metabolic syndrome (MetS), is involved in phosphorylated tau and beta amyloid buildup, linking MetS to neurodegenerative processes, e.g., Alzheimer's disease. One of the initial signs of neurodegeneration, in diseases such as Parkinson's and Alzheimer's, is olfactory dysfunction. Accordingly, in previous reports we found that high carbohydrate diet based on 30% sucrose in drinking water, increased visceral fat and insulin resistance, leading to an augment of oxidative stress and reduced brain energy metabolism, upregulating amyloidogenic genes (APP and BACE1) in hypothalamus and hippocampus. Thus, herein we comparatively evaluated the effect of sucrose induced MetS on episodic memory, olfaction, protein expression in amyloidogenic and insulin pathways, lipoperoxidation, antioxidant and BACE1 enzymatic activity between the hippocampus and olfactory bulb in male Wistar rats. Also, cellular structure of the olfactory bulb was analyzed. After 24 weeks of 30% sucrose consumption, we found preserved performance in a memory test; decreased hippocampal expression of APP and hyperactivation of the insulin pathway, low levels of lipoperoxidation, and high activity of antioxidant and BACE1 enzymes. Olfactory dysfunction was present in MetS rats, accompanied by morphological alterations in the olfactory bulb along with BACE1 increased activity. Thus, chronic high-sucrose consumption may prime the brain for neurodegenerative processes by modulating insulin signaling, oxidative stress homeostasis and amyloidogenic pathways in a region-dependent manner, with the olfactory system emerging as an early and sensitive target of metabolic dysfunction.},
}
@article {pmid42476266,
year = {2026},
author = {Zaman, W and Ayaz, A and Ullah, A},
title = {Decoding lactate signals in Alzheimer's disease: redox control, receptor pharmacology, lactylation chemistry, and neuroglial vulnerability.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {118275},
doi = {10.1016/j.bcp.2026.118275},
pmid = {42476266},
issn = {1873-2968},
abstract = {Alzheimer's disease (AD) develops within a metabolically heterogeneous brain in which lactate functions as an oxidative substrate, a redox-coupled metabolite, a proton-linked transport signal, a receptor ligand, and a precursor of lysine lactylation. These roles are often considered independently, obscuring why lactate supports neuronal function in some settings yet accompanies persistent inflammation and neurodegeneration in others. This review introduces a lactate signal-decoding framework that emphasizes cellular interpretation rather than concentration alone. The framework integrates the lactate/pyruvate ratio, the cytosolic reduced-to-oxidized nicotinamide adenine dinucleotide (NADH/NAD +) state, lactate dehydrogenase (LDH) isoenzyme context, proton-coupled monocarboxylate transport, extracellular pH, hydroxycarboxylic acid receptor 1 (HCAR1) signaling, and enzymatic or non-enzymatic lactylation. We compare neuronal, astrocytic, microglial, and neurovascular responses and examine how aging, apolipoprotein E ε4 (APOE4), amyloid pathology, hypoperfusion, sleep disruption, and systemic metabolic disease reshape them. Particular attention is given to the chemistry and analytical validation of histone and non-histone lactylation; the proposed interaction of tau lactylation with other post-translational modifications; and links to proteostasis, iron homeostasis, and mitochondrial quality control. As a hypothesis-generating model, AD progression may involve loss of coordination among lactate transport, oxidation, receptor signaling, pH control, and covalent modification. This framework prioritizes restoration of metabolic coordination over indiscriminate lactate suppression and identifies biomarker and experimental requirements for clinical translation.},
}
@article {pmid42476282,
year = {2026},
author = {Abbaszadeh, F and Amini, NB and Davoody, S and Rezaei, M and Ghasemi, R and Javadpour, P},
title = {Unlocking new uses: The promise of antidepressants in treating Alzheimer's and Parkinson's through Neuroinflammation modulation.},
journal = {Progress in neuro-psychopharmacology &amp; biological psychiatry},
volume = {},
number = {},
pages = {111848},
doi = {10.1016/j.pnpbp.2026.111848},
pmid = {42476282},
issn = {1878-4216},
abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), are characterized by progressive cognitive and motor decline, largely driven by chronic neuroinflammation and oxidative stress. Conventional therapies primarily provide symptomatic relief without targeting underlying disease mechanisms. Emerging evidence suggests that antidepressants, beyond their canonical role in mood regulation, exhibit anti-inflammatory, antioxidant, and neurotrophic effects that may modulate disease progression. Preclinical studies demonstrate that selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors (MAOIs) can reduce pro-inflammatory cytokines, attenuate glial activation, enhance neurotrophic signaling, and improve cognitive and motor function in experimental models of AD and PD. Clinical findings are mixed, with some antidepressants showing modest cognitive or symptomatic benefits, particularly in patients with comorbid depression, while others may pose risks due to anticholinergic effects or interference with neuronal autophagy. This narrative review synthesizes mechanistic and translational evidence on the off-label use of antidepressants for neurodegenerative diseases, highlighting the potential of drug repurposing to target neuroinflammation and support neuroprotection, while emphasizing the need for careful patient-specific therapy selection.},
}
@article {pmid42476327,
year = {2026},
author = {Pattnaik, PP and Prusty, SK and Pati, S and Jew, KA and Bora, AK and Sahoo, J and Sahu, PK},
title = {Exploring shared genetic pathways and gene interplay in major neurodegenerative diseases: a comprehensive review.},
journal = {Gene},
volume = {},
number = {},
pages = {150318},
doi = {10.1016/j.gene.2026.150318},
pmid = {42476327},
issn = {1879-0038},
abstract = {Neurodegenerative diseases are progressive disorders that involve the loss and dysfunction of neurons. Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Huntington's disease, Frontotemporal dementia are examples of diseases. While different clinically, these disorders have a common genetic, molecular and cellular basis. This review examines the common genetic pathways, along with the interactions between genes of major neurodegenerative diseases, with a focus on the key genes, such as APOE, SNCA, MAPT, TARDBP, LRRK2 and HTT. The common pathogenic mechanisms considered to play a major role in disease progression include protein misfolding and aggregation, mitochondrial dysfunction, oxidative stress, neuroinflammation, diminished autophagy, and impaired lysosomal function, as well as synaptic degeneration. The review also emphasizes the role of systems biology strategies, such as genome-wide association studies, transcriptomics, proteomics, metabolomics, interactome analysis, and multi-omics integration, to unveiling complex molecular networks in neurodegeneration. Furthermore, the emerging biomarker strategies and therapeutic strategies targeting convergence signaling pathways including NF-κB, PI3K-Akt-mTOR, MAPK and Wnt/β-catenin are summarized. The common genetic basis and the cross-connecting molecular mechanisms of the various neurodegenerative diseases could help in the discovery of new biomarkers and pan-therapeutic targets. Further advances in molecular genetics, computational biology and precision medicine are needed to enhance early detection and the creation of effective disease-modifying treatments.},
}
@article {pmid42476460,
year = {2026},
author = {Fowler, CF and Osipyan, E and Devenyi, GA and Madularu, D and Breitner, J and Near, J},
title = {Early treatment with naproxen alters hippocampal metabolites in the TgF344-AD rat model of Alzheimer's disease.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106226},
doi = {10.1016/j.neuint.2026.106226},
pmid = {42476460},
issn = {1872-9754},
abstract = {Alzheimer's disease (AD) is characterized by the appearance of brain pathology decades prior to clinical symptoms. The pre-symptomatic phase of AD provides opportunity for early detection and intervention. One early intervention that has been proposed is the use of non-steroidal anti-inflammatory drugs (NSAIDs), such as naproxen. However, evidence suggests that effects of naproxen intervention differ with stage of the disease, and the optimal intervention time is not clear. Accordingly, in this study, we investigated the impact of the timing of naproxen treatment in a rat model of AD. We used the TgF344-AD rat model of AD which develops characteristic pathological features of human AD, including abundant amyloid plaque pathology, astrogliosis, and microgliosis by 6 months of age, and neurofibrillary tangles and neuronal loss by 16 months of age. We examined the effects of naproxen treatment beginning at 1, 4, and 10 months of age in transgenic (Tg) animals and their wild-type (WT) littermates. We used longitudinal in vivo magnetic resonance spectroscopy (MRS) to study the impact of naproxen treatment on hippocampus neurochemistry. Previous studies have used MRS to non-invasively characterize the trajectory of altered hippocampal neurochemistry across the lifespan in the TgF344-AD rat model. In the current study, we employed MRS at 4, 10, and 16 months, i.e. prior to or after the appearance of amyloidosis and gliosis (6 months) and tau pathology (16 months), respectively, in Tg animals. Naproxen treatment altered neurochemistry in Tg animals only if administered beginning at 1 or 4 months of age, mitigating an otherwise observed increase in total choline and decrease in taurine. A more subtle effect was observed on the otherwise-expected increase in myo-inositol. These results highlight the possibility that earlier naproxen intervention could have distinct neurochemical effects compared to delayed treatment, though mechanistic implications remain to be clarified. Moreover, these findings support the use of MRS as a useful non-invasive method of monitoring treatment-related changes in neurochemistry in transgenic animal models.},
}
@article {pmid42476554,
year = {2026},
author = {Dyer, AH and Dolphin, H and Roitto, HM and O'Connor, A and Welsh, TJ and Kennelly, SP},
title = {Recent breakthroughs in blood-based biomarkers of Alzheimer disease: opportunities and challenges in older adults.},
journal = {Age and ageing},
volume = {55},
number = {7},
pages = {},
doi = {10.1093/ageing/afag213},
pmid = {42476554},
issn = {1468-2834},
mesh = {Humans ; Biomarkers/blood ; *Alzheimer Disease/blood/diagnosis ; Aged ; *tau Proteins/blood ; Predictive Value of Tests ; Age Factors ; *Aging/blood ; },
abstract = {Recent advances in Blood-Based Biomarkers (BBMs) are transforming the diagnostic landscape of Alzheimer Disease (AD), with plasma p-tau217 emerging as a highly accurate and scalable diagnostic marker of AD pathology. Across multiple analytical platforms, plasma p-tau217 has demonstrated consistently strong diagnostic performance for the detection of amyloid pathology. The interpretation of BBMs in older adults presents unique challenges due to the high prevalence of multimorbidity, chronic kidney disease, polypharmacy and frailty. Although these factors may influence absolute biomarker concentrations, current evidence suggests the diagnostic performance of p-tau217 remains largely preserved across diverse older populations when interpreted appropriately. Frailty may modify the relationship between AD pathology and clinical expression of mild cognitive impairment/dementia and may influence the absolute concentration of BBMs underscoring the importance of contextualising test results within a comprehensive assessment. Importantly, these factors should not preclude a clinical-biological diagnosis of AD. The clinical value of BBMs such as p-tau217 in older adults lies not in their use in isolation, but in their integration with a gerontologically attuned diagnostic pathway. Current evidence and international guidelines support the use of BBMs only in symptomatic older adults presenting to specialist services and not in asymptomatic individuals. This commentary reviews recent advances in BBM performance, emerging clinical guidelines, real-world evidence and potential diagnostic pitfalls relevant to older adults. We propose that incorporating BBMs within a Comprehensive Geriatric Assessment framework offers a pragmatic approach to achieving timely, accurate and equitable clinical-biological diagnosis whilst preserving the holistic, person centred principles of geriatric medicine.},
}
@article {pmid42476630,
year = {2026},
author = {Hanyu, H and Sano, M and Koyama, Y and Momose, T and Watanabe, S},
title = {Variations in Amyloid PET Positivity Among Patients With Different Alzheimer's Disease Subtypes.},
journal = {Geriatrics &amp; gerontology international},
volume = {26},
number = {7},
pages = {e70646},
doi = {10.1111/ggi.70646},
pmid = {42476630},
issn = {1447-0594},
}
@article {pmid42476773,
year = {2026},
author = {Fujii, S and Takahashi-Iwata, I and Matsushima, M and Yaguchi, H and Takatsuka, A and Hara, N and Ikeuchi, T and Yabe, I},
title = {A Novel p. (Leu173del) Mutation in the Presenilin 1 (PSEN1) Gene in Two Sisters with Dominantly Inherited Alzheimer's Disease.},
journal = {Internal medicine (Tokyo, Japan)},
volume = {},
number = {},
pages = {},
doi = {10.2169/internalmedicine.7327-26},
pmid = {42476773},
issn = {1349-7235},
abstract = {We report two sisters with dominantly inherited Alzheimer's disease carrying a novel presenilin 1 (PSEN1) mutation. Case 1 presented with depression at 39 years of age, gradually developed dementia and involuntary movements, and died at 51 years of age. Case 2 presented with dementia at 46 years of age, which progressed gradually, with no other neurological symptoms. The mother also had early onset dementia. A novel c.517_519del, p. (Leu173del) mutation in exon 6 of PSEN1 (NM_000021.3), confirmed by Sanger sequencing, was identified in both cases. Patients with PSEN1 mutations present with diverse neurological symptoms. Therefore, a careful follow-up is recommended.},
}
@article {pmid42476833,
year = {2026},
author = {Piao, S and Wang, J and He, K and Wang, N and Liu, X and Yang, L and Xie, F and Li, Y and Bao, Y},
title = {Multimodal Imaging of Tau Pathology and Network Connectivity Dynamics Across the Alzheimer's Continuum: A Pilot Study Using Second-Generation Tracer [[18]F]MK6240.},
journal = {Academic radiology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.acra.2026.06.040},
pmid = {42476833},
issn = {1878-4046},
abstract = {RATIONALE AND OBJECTIVES: Alzheimer's disease (AD) progression involves distinct spatiotemporal changes in functional connectivity (FC) within anterior-temporal (AT) and posterior-medial (PM) networks. This study characterizes FC alterations between medial temporal lobe (MTL) subregions and AT/PM networks across the AD continuum and examines their associations with tau/Aβ pathology and atrophy using second-generation tau-PET.<br><br>MATERIALS AND METHODS: Eighty-four participants, including 26 cognitively unimpaired A&#x3b2; negative(CU A&#x3b2;-), 19 cognitively unimpaired A&#x3b2; positive (CU A&#x3b2;+), 19 mild cognitive impairment A&#x3b2; positive(MCI A&#x3b2;+), 20 AD A&#x3b2; positive(AD A&#x3b2;+) underwent 3&#xa0;T MRI, resting-state fMRI, [&#xb9;&#x2078;F]florbetapir (A&#x3b2;), and [&#xb9;&#x2078;F]MK6240 (tau) PET. MTL subregions were segmented via ASHS-T1, while AT/PM networks were defined using Harvard-Oxford Atlas. Group differences in FC, A&#x3b2;/tau standard uptake value ratio(SUVR), and gray matter volume (GMV) were assessed. Network SUVR values, GMV and intra-FC correlation analyses and correlation coefficient matrix plots were calculated.<br><br>RESULTS: Compared to CU A&#x3b2;-, CU A&#x3b2;+ exhibited increased intra-/inter-network FC (peak in anterior MTL: p < 0.001), while MCI/AD groups showed progressive FC declines. Posterior network FC reduction was pronounced in AD (p < 0.01). Left BA35 connectivity increased in CU A&#x3b2;+, whereas AD demonstrated FC reductions in bilateral posterior cingulate/hippocampus. Network-level A/T/N-FC correlations were integrated in CU A&#x3b2;+ but modular in AD, with strong tau-GMV anticorrelation.<br><br>CONCLUSION: Early AD stages feature compensatory AT/anterior MTL hyperconnectivity, transitioning to PM/posterior MTL disintegration as pathology advances. Multimodal biomarker-FC coupling reflects dynamic network reorganization, highlighting MTL-AT/PM connectivity as a biomarker of disease progression.},
}
@article {pmid42476847,
year = {2026},
author = {Li, Z and Bai, X and Li, J and Geng, W and Xing, X and Liang, J and Li, J and Li, J},
title = {Corrigendum to "Network meta-analysis of different traditional Chinese medicine therapies as adjuvant treatments for Alzheimer's disease" [Compl. Ther. Clin. Pract. 64 (2026) 102075].},
journal = {Complementary therapies in clinical practice},
volume = {},
number = {},
pages = {102078},
doi = {10.1016/j.ctcp.2026.102078},
pmid = {42476847},
issn = {1873-6947},
}
@article {pmid42476928,
year = {2026},
author = {Jia, M and Mei, J and Guan, Y and Wang, Z and Ai, H},
title = {Alzheimer's Disease: A Review of Molecular Mechanisms and Interventions Targeting Aβ-Binding Receptors.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00207},
pmid = {42476928},
issn = {1948-7193},
abstract = {In the pathogenesis of Alzheimer's disease (AD), the aggregation of Aβ peptides into Aβ oligomers (AβOs) plays a critical neurotoxic role. By binding to various cell membrane receptors, AβOs can trigger abnormal intracellular signaling transduction, leading to neuronal damage. This article systematically summarizes the interaction mechanisms of nearly ten AβO-binding receptors and focuses on reviewing recent therapeutic strategies aimed at neuroprotection through interventions in AβO-receptor interactions or by blocking/modulating relevant receptor signaling pathways. The discussed content provides a molecular theoretical foundation and research perspectives for the rational design of anti-AD drugs targeting AβO receptors.},
}
@article {pmid42476932,
year = {2026},
author = {Yu, M and Tang, S and Huang, L and Wang, Y and Xu, J and Zhu, H and Yao, H},
title = {From Structure to Selectivity: Integrating CADD and AIDD in Rational Medicinal Chemistry Strategies for DYRK1A Inhibitor Discovery.},
journal = {Journal of medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jmedchem.6c00774},
pmid = {42476932},
issn = {1520-4804},
abstract = {Dual specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), a member of the CMGC kinase family, regulates diverse cellular processes and is implicated in Alzheimer's disease, Down syndrome, cancer, and diabetes. However, the clinical translation of DYRK1A inhibitors remains challenging due to limited selectivity arising from the high structural conservation of the ATP-binding pocket within the DYRK and CMGC kinase families, which represents the primary binding region for most DYRK1A inhibitors. Recent advances in computer-aided drug design (CADD), artificial intelligence-driven drug design (AIDD), and rational design strategies have enabled the discovery of small-molecule DYRK1A inhibitors with improved potency, selectivity, and drug-like properties. These approaches have expanded the structural diversity of DYRK1A inhibitors and provided new strategies to address selectivity and pharmacokinetic limitations. Particular emphasis is placed on how CADD and AIDD have expanded the accessible chemical space, informed structure-guided optimization, and enabled new paradigms for DYRK1A-focused drug discovery.},
}
@article {pmid42477094,
year = {2026},
author = {Bellomo, G and Vermunt, L and In 't Veld, S and Doecke, JD and Hok-A-Hin, YS and Veverová, K and Houtkamp, IM and Alcolea, D and Halbgebauer, S and Quesada, C and Mattsson, N and Martinez-Castillo, M and López-Martínez, MJ and Rábano, A and Boonkamp, L and Fowler, C and Fortea, J and Gaetani, L and Toja, A and Pijnenburg, Y and Lemstra, A and van der Flier, WM and Sánchez-Juan, P and Hort, J and Otto, M and Anderl-Staub, S and Sieben, A and de Viel, B and Engelborghs, S and Hansson, O and Masters, C and Lleó, A and Parnetti, L and Teunissen, CE and Del Campo, M},
title = {Plasma proteome profiling identified biomarkers for the differential diagnosis and molecular staging of neurodegenerative dementias.},
journal = {Nature aging},
volume = {},
number = {},
pages = {},
pmid = {42477094},
issn = {2662-8465},
support = {J99C18000210005//EU Joint Programme - Neurodegenerative Disease Research (Programi i P&#xeb;rbashk&#xeb;t i BE-s&#xeb; p&#xeb;r K&#xeb;rkimet mbi S&#xeb;mundjet Neuro-degjeneruese)/ ; 99C18000210005//EU Joint Programme - Neurodegenerative Disease Research (Programi i P&#xeb;rbashk&#xeb;t i BE-s&#xeb; p&#xeb;r K&#xeb;rkimet mbi S&#xeb;mundjet Neuro-degjeneruese)/ ; J99C18000210005//EU Joint Programme - Neurodegenerative Disease Research (Programi i P&#xeb;rbashk&#xeb;t i BE-s&#xeb; p&#xeb;r K&#xeb;rkimet mbi S&#xeb;mundjet Neuro-degjeneruese)/ ; J99C18000210005//EU Joint Programme - Neurodegenerative Disease Research (Programi i P&#xeb;rbashk&#xeb;t i BE-s&#xeb; p&#xeb;r K&#xeb;rkimet mbi S&#xeb;mundjet Neuro-degjeneruese)/ ; J99C18000210005//EU Joint Programme - Neurodegenerative Disease Research (Programi i P&#xeb;rbashk&#xeb;t i BE-s&#xeb; p&#xeb;r K&#xeb;rkimet mbi S&#xeb;mundjet Neuro-degjeneruese)/ ; J99C18000210005//EU Joint Programme - Neurodegenerative Disease Research (Programi i P&#xeb;rbashk&#xeb;t i BE-s&#xeb; p&#xeb;r K&#xeb;rkimet mbi S&#xeb;mundjet Neuro-degjeneruese)/ ; J99C18000210005//EU Joint Programme - Neurodegenerative Disease Research (Programi i P&#xeb;rbashk&#xeb;t i BE-s&#xeb; p&#xeb;r K&#xeb;rkimet mbi S&#xeb;mundjet Neuro-degjeneruese)/ ; J99C18000210005//EU Joint Programme - Neurodegenerative Disease Research (Programi i P&#xeb;rbashk&#xeb;t i BE-s&#xeb; p&#xeb;r K&#xeb;rkimet mbi S&#xeb;mundjet Neuro-degjeneruese)/ ; PF-PRF-934916//Parkinson's Foundation (Parkinson's Foundation, Inc.)/ ; ZEN24-1069572/ALZ/Alzheimer's Association/United States ; SG-23-1061717/ALZ/Alzheimer's Association/United States ; 2022-0231//Knut och Alice Wallenbergs Stiftelse (Knut and Alice Wallenberg Foundation)/ ; },
abstract = {Blood-based biomarkers are emerging as scalable tools for the diagnosis and monitoring of neurodegenerative diseases, but markers enabling differential diagnosis across major dementias remain limited. Here we show that large-scale plasma proteomics identifies disease-associated signatures across Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia. We analyzed 1,318 plasma samples from well-characterized international cohorts and identified more than 200 dysregulated proteins across disease groups. Glial fibrillary acidic protein showed the strongest increase along the Alzheimer's disease continuum, whereas integrin alpha-V and integrin alpha-M were consistently reduced in Lewy body disorders, including autopsy-confirmed cases. Elevated neurofilament light chain and lower glial fibrillary acidic protein were associated with frontotemporal dementia. We translated these findings into a 21-protein quantitative multiplex panel and validated it in an independent multicenter cohort (n = 805). These findings support plasma proteomics as an approach for biomarker-based differential diagnosis and disease staging across major neurodegenerative dementias.},
}
@article {pmid42477212,
year = {2026},
author = {Angelovski, A and Hribkova, H and Sedmik, J and Liscakova, B and Svecova, O and Cesnarikova, S and Amruz Cerna, K and Pospisilova, V and Kral, M and Kolajova, M and Klimes, P and Bohaciakova, D and Bebarova, M},
title = {Patient-Derived PSEN1 Cerebral Organoids Revealed Parallel Development of Amyloid-β Accumulation and Network Dysfunction.},
journal = {Cellular and molecular neurobiology},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10571-026-01779-7},
pmid = {42477212},
issn = {1573-6830},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterised by progressive dementia, brain atrophy, and ultimately death. Using cerebral organoids derived from human-induced pluripotent stem cells (hiPSCs) carrying the familial PSEN1 A246E variant, we investigated the temporal relationship between amyloid-β (Aβ) dysregulation and spontaneous neuronal activity. Multielectrode array recordings from the differentiation day 60 (DD60) to at least DD130 revealed that AD organoids exhibited transient hyperexcitability and hypersynchrony compared with wild-type (WT) controls, followed by a gradual decline in activity. During the enhanced excitability stage, both elevated Aβ42/40 and Aβ aggregate size showed positive correlations with the percentage of active electrodes and the global synchrony index (GSI) in AD organoids. These findings indicate that Aβ dysregulation might contribute to transient network hyperexcitability in early AD. The results also suggest that patient-derived cerebral organoids may serve as a translational model to examine early network dysfunction and inform future investigations of potential Aβ-induced changes in excitability during the preclinical stages of AD.},
}
@article {pmid42477313,
year = {2026},
author = {Pini, L and Imbimbo, BP and Pomara, N},
title = {Revisiting the cognitive potential of lithium in alzheimer's disease: the role of cholinergic system and brain connectivity.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-04307-9},
pmid = {42477313},
issn = {2158-3188},
abstract = {Recent evidence demonstrating a marked reduction in endogenous brain lithium levels in mild cognitive impairment and Alzheimer's disease (AD) has renewed interest in lithium as a physiological modulator of brain aging and neurodegeneration. Experimental data indicate that lithium deficiency accelerates amyloid-β deposition, tau pathology, synaptic and myelin loss, whereas physiological lithium replacement mitigates neuropathology and cognitive decline. Here, we argue that lithium's cognitive potential in AD has been underestimated due to the historical neglect of two interrelated mechanisms: modulation of the cholinergic system and preservation of brain connectivity. Lithium has long been shown to inhibit cholinesterase activity and to increase choline and glycine availability, suggesting a capacity to enhance central cholinergic tone. Given the established role of cholinergic dysfunction in AD, this mechanism may represent an unrecognized contributor to lithium's neurocognitive effects. In parallel, converging human neuroimaging evidence indicates that lithium modulates functional brain networks and is associated with improved white matter integrity, supporting a role in maintaining structural and functional connectivity. We propose brain connectivity as a systems-level integrator of lithium's effects on synaptic plasticity, neuroinflammation, myelination, and cholinergic signaling. Future trials in early AD should incorporate physiological-dose lithium, candidate cholinergic biomarkers, and multimodal connectivity imaging to clarify lithium's translational potential as a network-stabilizing intervention. To bridge prior clinical disappointments and the renewed lithium hypothesis, we further propose a de-risked trial strategy centered on biomarker-confirmed early disease, physiological-dose exposure, structured safety surveillance, and imaging-based target engagement.},
}
@article {pmid42477315,
year = {2026},
author = {Zhang, N and Ye, X and Wang, K and Hu, Y and Wang, Z and Huang, L and Chen, X and Yan, D and Fu, W and Xue, Q and Sun, S and Xu, Y and Tang, D and Chen, X and Zhou, L and Liu, J},
title = {GV-971 remodels the gut microbiota-bile acid-FXR axis to ameliorate obesity and metabolic dysfunction.},
journal = {Cell discovery},
volume = {12},
number = {1},
pages = {},
pmid = {42477315},
issn = {2056-5968},
abstract = {Obesity and its associated metabolic complications represent a global health crisis, yet effective microbiota-targeted pharmacotherapies remain limited. Here, we report that GV-971 (sodium oligomannate), a marine-derived oligosaccharide originally developed for Alzheimer's disease, exerts potent anti-obesity and metabolic benefits by reprogramming gut microbial and host signaling networks. In high-fat diet-induced obese mice, GV-971 reduced adiposity, improved glucose homeostasis, and alleviated hepatic steatosis without affecting food intake. Multi-omics and causal intervention experiments revealed that GV-971 selectively decreased the abundance of Clostridium scindens, a keystone bacterium responsible for secondary bile acid synthesis. This decrease downregulated the expression of the baiF gene encoding 7α-hydroxysteroid dehydrogenase, leading to reduced intestinal deoxycholic acid (DCA) levels and inhibition of intestinal farnesoid X receptor (FXR) signaling. Restoration of C. scindens abundance, baiF expression, or DCA supplementation abrogated the metabolic benefits of GV-971, confirming the causal role of the C. scindens-DCA-FXR axis. Mechanistically, inhibition of intestinal FXR promoted thermogenic gene expression and white adipose tissue browning, thus enhancing systemic energy expenditure. These findings uncover a bacterium-metabolite-host signaling pathway underlying the effects of GV-971 and establish microbiota-directed FXR modulation as a promising therapeutic approach for obesity and metabolic disease.},
}
@article {pmid42477465,
year = {2026},
author = {Wang, Y and Liu, L and Zhang, Y and Luo, P and Xiang, Q and Tang, L},
title = {Integrating transcriptome, metabolome and 16S rRNA sequencing to reveal the effect of celastrol on Alzheimer's disease in rats.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-61602-7},
pmid = {42477465},
issn = {2045-2322},
support = {2026JJ81247//The Natural Science Foundation of Hunan province/ ; LSKJ202465//Project of Regional Collaborative Innovation Special Program of Lhasa/ ; },
abstract = {Celastrol is a promising therapeutic candidate for neurodegenerative diseases. However, the underlying mechanism of celastrol on Alzheimer's disease (AD) remains poorly understood. This study aims to investigate the potential effect of celastrol on treating AD using multi-omics. The AD rat model was established using D-galactose combined with Aβ25-35 and subsequently treated with celastrol at doses of 0.7 mg/kg and 2.8 mg/kg respectively. Cognitive and memory impairments were assessed using the Morris water maze test. Neuronal damage in the hippocampal region was evaluated through Nissl staining. The expression levels of Iba1, Aβ1-42, and p-tau were determined using immunohistochemical staining, ELISA, and western-blotting. Transcriptomic and metabolomic analyses were performed to profile RNA and metabolite expression. The composition and diversity of gut microbiota were analyzed via 16S rRNA gene sequencing. Spearman correlation analysis was employed to integrate transcriptomic-metabolomic and 16S rRNA-metabolomic data. Compared with the AD group, a intervention of 2.8 mg/kg celastrol could significantly reduce the escape latency (p < 0.05), increase the frequency of crossing the target platform and duration in the target quadrant (p < 0.05). In addition, celastrol could significantly inhibited the expression levels of Iba1, TNF-α, and IL-1β (p < 0.05), reduce the number of damaged neurons (p < 0.05), and decrease the expression levels of p-tau and Aβ1-42 (p < 0.05). Furthermore, a total of 309 differentially expressed genes (DEGs) and 96 differentially expressed metabolites (DEMs) were detected between the celastrol and AD groups. Among the DEMs, phospholipids including 16:0-22:6 PE and 18:0-22:6 PC were significantly regulated by celastrol. 16S rRNA analysis indicated that celastrol could increase the Firmicutes/Bacteroidota ratio, as well as enhance the abundances of g_Romboutsia and g_Clostridium_sensu_stricto_1. Combined transcriptomic-metabolomic analysis indicated that the expressions of 16:0-22:6 PE and 18:0-22:6 PC might be regulated by multiple genes including LOC103689940, Impad1, and Sult1c2a. And combined 16S rRNA-metabolomic analysis indicated that 16:0-22:6 PE and 18:0-22:6 PC metabolism might be significantly correlated with g_Romboutsia, g_Clostridium_sensu_stricto_1, and g_Turicibacter. In conclusion, celastrol could improve cognitive and memory dysfunction in AD rats. The regulation of phospholipids or sphingolipid metabolism and gene expression in metabolic pathway might be linked with alteration in intestinal microbiota.},
}
@article {pmid42477561,
year = {2026},
author = {Farrokhi, MR and Askari, A and SoukhakLari, R and Moosavi, M},
title = {Cholinergic inhibition disrupts retrieval-specific phosphorylation of CaMKII-α and CaMKII-β alongside ERK hyperactivation in the hippocampus during novel object recognition memory.},
journal = {BMC neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12868-026-01027-0},
pmid = {42477561},
issn = {1471-2202},
support = {26573//Shiraz University of Medical Sciences/ ; 24393//Vice-Chancellor for Research, Shiraz University of Medical Sciences/ ; },
abstract = {BACKGROUND: Alzheimer's disease (AD), the most common form of dementia, is characterized by cholinergic dysfunction and early impairments in episodic and recognition memory. Although retrieval failure represents a hallmark of cognitive decline in AD, the task- and phase-specific molecular mechanisms underlying cholinergic-dependent memory retrieval remain poorly defined.<br><br>OBJECTIVE: This study investigated whether acute muscarinic cholinergic blockade disrupts the retrieval phase of recognition memory. We also examined the associated regulation of hippocampal calcium/calmodulin-dependent protein kinase II (CaMKII) isoforms &#x3b1; and &#x3b2;, together with extracellular signal-regulated kinase (ERK) signaling.<br><br>METHODS: Adult male SWR/J mice were trained in the NOR paradigm and administered scopolamine (1&#xa0;mg/kg, i.p.) or saline 30&#xa0;min prior to the retrieval phase. Recognition memory performance was assessed using the discrimination index and exploratory preference. Immediately following behavioral testing, hippocampal tissue was collected for Western blot analysis of phosphorylated and total CaMKII-&#x3b1;, CaMKII-&#x3b2;, and ERK.<br><br>RESULTS: Scopolamine significantly impaired recognition memory retrieval, as evidenced by a reduced discrimination index and decreased preference for the novel object, without diminishing overall exploratory activity. At the molecular level, scopolamine-induced cholinergic inhibition selectively decreased hippocampal phosphorylation of both CaMKII-&#x3b1; and CaMKII-&#x3b2; while increasing ERK phosphorylation, with no significant changes in total protein expression of any kinase.<br><br>CONCLUSIONS: These findings identify a retrieval-specific, scopolamine-induced molecular signature of cholinergic inhibition in the hippocampus, characterized by concurrent suppression of both CaMKII isoform activities (&#x3b1; and &#x3b2;) alongside dissociable ERK hyperactivation. By extending prior molecular observations from aversively motivated paradigms to an ethologically relevant model of recognition memory, this study provides mechanistic insight into how cholinergic dysfunction contributes to memory retrieval deficits and suggests that cholinergic signaling maintains the functional (CaMKII-&#x3b1;) and structural (CaMKII-&#x3b2;) dimensions of hippocampal memory retrieval machinery through coordinated kinase activation.},
}
@article {pmid42477703,
year = {2026},
author = {Yang, Y and Kwak, YT},
title = {Associations of Ginkgo biloba extract exposure with 12-month cognitive trajectories in amyloid PET-positive mild cognitive impairment and Alzheimer's disease: a pooled retrospective cohort study.},
journal = {BMC complementary medicine and therapies},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12906-026-05469-1},
pmid = {42477703},
issn = {2662-7671},
support = {HI22C0667//Korea Health Industry Development Institute/Republic of Korea ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) and mild cognitive impairment (MCI) show considerable heterogeneity in treatment response, underscoring the need for individualized therapeutic approaches. Ginkgo biloba extract is commonly used in cognitive disorders, but its efficacy in amyloid biomarker-confirmed populations remains unclear. To evaluate the association between Ginkgo biloba extract exposure and 12-month cognitive and functional change patterns in amyloid PET-positive MCI/AD, and to assess whether baseline plasma MDS-OAβ (amyloid oligomerization tendency) is associated with cognitive trajectory subgroup membership.<br><br>METHODS: In this 12-month retrospective study, 165 drug-na&#xef;ve amyloid PET-positive patients (83 with documented Ginkgo biloba extract use in routine care and 82 without documented Ginkgo use) were assessed for changes in Korean Mini-Mental State Examination (K-MMSE-2), Clinical Dementia Rating-Sum of Boxes (CDR-SB), Korean Instrumental Activities of Daily Living (K-IADL), and plasma MDS-OA&#x3b2; levels. K-means clustering was used to define three cognitive trajectory subgroups, and exploratory one-vs-rest adjusted logistic regression analyses were performed to examine baseline variables associated with trajectory group membership.<br><br>RESULTS: Three cognitive trajectories were identified: Improver (n&#x2009;=&#x2009;36), Stabler (n&#x2009;=&#x2009;113), and Decliner (n&#x2009;=&#x2009;16). Compared with patients without documented Ginkgo use, patients with documented Ginkgo exposure showed significantly greater cognitive gains (&#x394;K-MMSE-2&#x2009;+&#x2009;1.42 vs. -&#x2009;0.30, p&#x2009;=&#x2009;0.012), less IADL decline (p&#x2009;<&#x2009;0.001), and greater reductions in MDS-OA&#x3b2; levels (p&#x2009;<&#x2009;0.001). Baseline plasma MDS-OA&#x3b2; did not significantly differ among the trajectory groups and was not interpreted as a robust independent predictor of trajectory membership. Ginkgo use differed significantly across trajectory groups and was least frequent in the Decliner group.<br><br>CONCLUSIONS: In this amyloid PET-positive MCI/AD cohort, Ginkgo biloba extract exposure was associated with more favorable 12-month cognitive, functional, and plasma MDS-OA&#x3b2; changes. However, baseline MDS-OA&#x3b2; should be regarded as an exploratory biomarker rather than a validated predictor of improvement or Ginkgo-related benefit.},
}
@article {pmid42477717,
year = {2026},
author = {Deshayes, NAC and van Wetering, J and Wesseling, A and Vos, F and Ingrassia, A and Galis, Y and Jonkman, LE and Rozemuller, AJM and van de Berg, WDJ},
title = {Amygdalar nuclei vulnerability to protein aggregates in Lewy body diseases.},
journal = {Acta neuropathologica communications},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40478-026-02381-0},
pmid = {42477717},
issn = {2051-5960},
abstract = {The amygdala is highly vulnerable to protein aggregation and heavily affected in Lewy body diseases (LBDs). However, vulnerability might vary per amygdalar nucleus and it is unclear if the pattern of vulnerability across the nuclei differs between types of protein aggregation and between LBDs. In this study, we aimed to assess the vulnerability of amygdalar nuclei to multiple types of protein aggregation across LBDs. Post-mortem amygdala tissue of donors with incidental LBD (iLBD, n = 6), Parkinson's disease (PD; n = 18), dementia with Lewy bodies (DLB; n = 9) and Alzheimer's disease with Lewy bodies (AD + LB; n = 15) was immunostained with antibodies against alpha-synuclein (aSyn; EP1536Y and 5G4), amyloid beta (Aβ; 4G8), phosphorylated tau (p-tau; AT8) and phosphorylated TDP-43 (p-TDP-43; 11-9), and quantitatively analyzed using QuPath. Neuronal and astrocytic aSyn pathology were most pronounced in the parahippocampal-amygdaloid transition area (PHA) and the basal nucleus, a pattern shared by all disease groups. Vulnerability to Aβ pathology varied per group but was highest in the PHA in AD + LB, whereas diffuse plaques were most common in the accessory basal nucleus. The PHA of DLB and both the basal and accessory basal nucleus of AD + LB cases were most susceptible to p-tau pathology, with fine granular cytoplasmic neuronal tau inclusions being mostly observed in the basal nucleus and neurofibrillary tangles in the accessory basal nucleus. The nuclei in the ventromedial part of the amygdala (PHA, ventral part of the basal nucleus, and cortical nucleus) were found to be hotspots for protein aggregation across LBDs. aSyn pathology in these nuclei predominantly correlated with dementia, hallucinations and anxiety. Our results show that amygdalar nuclei vulnerability differs per protein aggregate and disease entity, although the PHA, basal nucleus and cortical nucleus are generally more vulnerable. Together, our study provides a deeper insight into the selective vulnerability of amygdalar nuclei to protein aggregates and their relation to clinical characteristics in LBDs.},
}
@article {pmid42477755,
year = {2026},
author = {Bayly, H and Tripodis, Y and Lenio, S and Patil, P and , },
title = {Reducing overconfident errors in clinical prediction models.},
journal = {BMC medical informatics and decision making},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12911-026-03681-0},
pmid = {42477755},
issn = {1472-6947},
abstract = {Machine Learning (ML) models are increasingly being used in clinical workflows. Evaluation of these models tends to focus on global performance metrics, which can obscure error patterns and lead to bias in clinical decision making. Here, we propose Proximal Error-Based Confidence Adjustment (PECA), a framework designed explicitly to improve the safety of ML predictions by reducing a model's confidence in regions of the feature space associated with historical prediction errors. Rather than optimizing global metrics alone, PECA targets confident misclassifications by attenuating prediction confidence proportional to similarity with previously observed errors. Across extensive simulations, PECA reduced the rate at which a model made confident misclassifications while preserving the overall predictive ability of the model. We applied this framework to a clinical trial enrollment workflow for Alzheimer's disease and demonstrated consistent results with the simulations while also demonstrating superior statistical power compared to baseline models. The results of this paper suggest that taming a model's tendency to predict overconfidently using historical error patterns may be a critical step towards safer and more reliable ML systems for digital public health.},
}
@article {pmid42477860,
year = {2026},
author = {Touroutoglou, A and Katsumi, Y and Hensel, J and Schindler, SE and Ibanez, L and Brickhouse, M and Eloyan, A and Eckbo, R and Zaitsev, A and La Joie, R and Thangarajah, M and Taurone, A and Vemuri, P and Jack, CR and Hammers, DB and Foroud, T and Aisen, P and Beckett, L and Koeppe, R and Kukull, WA and Toga, A and Atri, A and Clark, D and Day, GS and Duara, R and Graff-Radford, NR and Grant, IM and Honig, LS and Johnson, ECB and Jones, DT and Masdeu, JC and Mendez, MF and Musiek, E and Onyike, CU and Riddle, M and Rogalski, E and Salloway, S and Sha, S and Turner, RS and Wingo, TS and Wolk, DA and Womack, K and Carrillo, MC and Rabinovici, GD and Apostolova, LG and Dage, JL and Dickerson, BC and Eldaief, MC and , },
title = {Relationships of CSF biomarkers to cortical atrophy in early-onset Alzheimer's disease.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71479},
doi = {10.1002/alz.71479},
pmid = {42477860},
issn = {1552-5279},
support = {U24 AG072122/NH/NIH HHS/United States ; P30 AG010133/NH/NIH HHS/United States ; P30 AG062422/NH/NIH HHS/United States ; P30 AG066462/NH/NIH HHS/United States ; P30 AG066507/NH/NIH HHS/United States ; P30 AG062421/NH/NIH HHS/United States ; P30 AG066506/NH/NIH HHS/United States ; P30 AG072977/NH/NIH HHS/United States ; P30 AG066444/NH/NIH HHS/United States ; P30 AG066515/NH/NIH HHS/United States ; P30 AG062677/NH/NIH HHS/United States ; P30 AG072980/NH/NIH HHS/United States ; P30 AG072979/NH/NIH HHS/United States ; P30 AG066511/NH/NIH HHS/United States ; R01 DC014296/NH/NIH HHS/United States ; R21 DC019567/NH/NIH HHS/United States ; R21 AG073744/NH/NIH HHS/United States ; K01 AG084820/NH/NIH HHS/United States ; K23 DC016912/NH/NIH HHS/United States ; R01 AG085377/NH/NIH HHS/United States ; P50 AG005134/NH/NIH HHS/United States ; P30 AG062421/NH/NIH HHS/United States ; P41EB015896/NH/NIH HHS/United States ; S10RR021110/NH/NIH HHS/United States ; S10RR023043/NH/NIH HHS/United States ; S10RR023401/NH/NIH HHS/United States ; LEADS GENETICS-19-639372/ALZ/Alzheimer's Association/United States ; LDRFP-21-824473/ALZ/Alzheimer's Association/United States ; LDRFP-21-828356/ALZ/Alzheimer's Association/United States ; },
mesh = {Humans ; *Alzheimer Disease/cerebrospinal fluid/pathology ; Atrophy/pathology ; Biomarkers/cerebrospinal fluid ; Female ; Male ; Neurofilament Proteins/cerebrospinal fluid ; *Cerebral Cortex/pathology ; tau Proteins/cerebrospinal fluid ; Amyloid beta-Peptides/cerebrospinal fluid ; Middle Aged ; Peptide Fragments/cerebrospinal fluid ; Magnetic Resonance Imaging ; Aged ; },
abstract = {INTRODUCTION: Although cerebrospinal fluid (CSF) biomarkers reflect neurodegeneration in Alzheimer's disease (AD), it remains unclear whether these biomarkers track neurodegeneration in early-onset Alzheimer's disease (EOAD).<br><br>METHODS: In 80 EOAD patients, we examined correlations between eight CSF biomarker levels and cortical thickness decreases within the EOAD cortical atrophy signature. Significant correlations were then entered into a multiple regression analysis. We also examined contributions of EOAD atrophy and CSF biomarkers to cognitive impairment.<br><br>RESULTS: The levels of four CSF biomarkers correlated to EOAD signature atrophy. Stepwise regression analyses revealed that CSF neurofilament light chain (NfL) levels best predicted EOAD signature atrophy. Multiple regression showed EOAD signature atrophy combined with CSF NfL levels explained more variance in cognitive impairment than either factor alone.<br><br>DISCUSSION: Within EOAD patients, CSF NfL levels relate to the magnitude of cortical atrophy, and a combination of EOAD signature atrophy and CSF NfL levels most robustly predict cognitive impairment.},
}
@article {pmid42471087,
year = {2026},
author = {Yao, M and Liu, A and Xing, L and Song, J and Yang, Y and Yue, X and Li, H},
title = {Neurovascular unit senescence as a driver of blood-brain barrier dysfunction in Alzheimer's disease：Mechanisms, consequences, and therapeutic implications.},
journal = {Ageing research reviews},
volume = {121},
number = {},
pages = {103260},
doi = {10.1016/j.arr.2026.103260},
pmid = {42471087},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD) is a common age-related neurodegenerative disorder (NDD), with ageing as its primary risk factor. Cellular senescence, characterized by permanent cell-cycle arrest, apoptosis resistance and acquisition of the senescence-associated secretory phenotype (SASP), is the cellular hallmark of ageing. Recent evidence indicates that blood-brain barrier (BBB) dysfunction precedes cognitive decline and pathological protein deposition, representing an early event in AD, with the neurovascular unit (NVU) providing the structural and functional basis of the BBB. Mounting evidence shows that the core NVU cells-brain microvascular endothelial cells (BMECs), pericytes and astrocytes-enter senescence under AD-related conditions. SASP factors released by these cells disrupt BBB junction proteins and trans-BBB transport systems, and propagate senescence within the NVU via paracrine signaling. Peripheral inflammatory mediators and immune cells then traverse the compromised BBB, aggravating AD pathology, while accumulating Aβ, tau and reactive oxygen species (ROS) reciprocally accelerate NVU senescence, constituting a proposed vicious cycle. At the molecular level, the cGAS-STING pathway concurrently drives senescence maintenance, SASP induction and type I interferon (IFN-I)-mediated downregulation of BBB junction proteins, serving as a key convergence point linking NVU senescence to BBB injury. From the NVU perspective, this review systematically examines how cellular senescence drives BBB dysfunction and AD progression, clarifies the role of cGAS-STING as a molecular node, and discusses therapeutic strategies targeting NVU senescence to preserve BBB integrity, aiming to offer new insights into AD mechanisms and treatment.},
}
@article {pmid42471130,
year = {2026},
author = {Manouvriez, D and Kuchcinski, G and Lecerf, S and Lahousse, H and Rogeau, A and Villain, N and Kas, A and Pyatigorskaya, N and Nguyen, M and Petrovic, S and Cole, JH and Zabihi, M and Hache, B and Bertoux, M and Lebouvier, T and Roca, V and Lopes, R and , and , and , and , },
title = {PatientSpace: A multimodal graph-based latent representation framework for modeling neurodegenerative disease heterogeneity.},
journal = {NeuroImage},
volume = {},
number = {},
pages = {122136},
doi = {10.1016/j.neuroimage.2026.122136},
pmid = {42471130},
issn = {1095-9572},
abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal dementia (FTD) exhibit substantial biological and clinical heterogeneity, complicating diagnosis, subtype characterization, and prediction of disease progression. We introduce PatientSpace, a multimodal graph-based latent representation framework designed to model neurodegenerative disease heterogeneity using T1-weighted MRI and FDG-PET. PatientSpace is built upon a structured variational autoencoder that integrates multimodal neuroimaging features while organizing patients within a latent space constrained by age, diagnosis, and a consistency regularization term encouraging similarity between neuroimaging phenotypes. This design enables the construction of an interpretable patient graph in which neighborhood relationships reflect biological similarity. Applied to cohorts of cognitively normal individuals, AD, and FTD patients, PatientSpace revealed multiple disease clusters associated with distinct neuroimaging patterns and clinical severity. Diagnostic classification achieved performance comparable to state-of-the-art deep learning models, while graph-based neighborhood inference enabled prediction of structural volumes, metabolic activity, and cognitive severity. Projection of mild cognitive impairment (MCI) subjects from an independent cohort further showed that cluster membership was associated with differential risks of dementia conversion and distinct longitudinal trajectories. Together, these results demonstrate that PatientSpace provides an interpretable framework linking multimodal neuroimaging representations to disease subtypes, patient-level characterization, and progression modeling in neurodegenerative disorders.},
}
@article {pmid42471199,
year = {2026},
author = {Yang, S and Astill-Vaccaro, J},
title = {Transdermal Methylphenidate for Apathy in Alzheimer's Dementia.},
journal = {Journal of the Academy of Consultation-Liaison Psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jaclp.2026.07.005},
pmid = {42471199},
issn = {2667-2960},
}
@article {pmid42471426,
year = {2026},
author = {Ahmad, A and Khan, MM},
title = {DNA Sensing and Neuroinflammation: Mechanistic Insights into cGAS-STING Biology and Therapeutic Translation in Age-Related Neurodegenerative Diseases.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42471426},
issn = {1559-1182},
mesh = {Humans ; Animals ; *Neurodegenerative Diseases/metabolism/therapy/genetics/pathology ; cGAS-STING Signaling Pathway ; *Nucleotidyltransferases/metabolism ; STING Protein ; *Membrane Proteins/metabolism ; *Aging/pathology/metabolism/genetics ; Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase ; *Neuroinflammatory Diseases/metabolism/genetics/therapy ; *DNA/metabolism ; Inflammation ; },
abstract = {Emerging evidence suggests that some of the earliest events contributing to neurodegeneration may occur upstream of classical proteinopathies, underscoring the urgency of identifying molecular pathways that link age-associated genomic instability to chronic neuroinflammation. Among these, DNA sensing through the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) axis has emerged as an important mechanism by which nuclear and mitochondrial stress may promote innate immune activation. In aging and Alzheimer's disease (AD), oxidative stress, impaired DNA repair, and mitochondrial dysfunction can lead to the accumulation of cytosolic DNA and activation of cGAS-STING, contributing to sustained inflammatory signaling, cellular senescence, and synaptic dysfunction. In this review, we synthesize emerging mechanistic and translational insights linking cGAS-STING to genomic instability and neuroinflammation. We highlight the expanding roles of this pathway beyond classical immunity, including its influence on autophagy, cellular senescence, microglial activation, and neurovascular integrity as well as its interactions with key pathological features of age-related neurodegenerative disorders, particularly AD. Finally, we highlight recent advances in pharmacological and genetic modulation of cGAS-STING that support its potential as a therapeutic target for age-related neurodegenerative diseases. By reframing neurodegeneration through the lens of DNA sensing, this review provides an updated perspective on the potential role of cGAS-STING in age-related neurodegenerative diseases.},
}
@article {pmid42471447,
year = {2026},
author = {Zhu, Y and Brown, DC and Chen, C and Singh, RK and Bekena, S and Ances, BM and Lenze, EJ and Carr, DB and Trani, JF and Babulal, GM},
title = {Tau pathology and depression interact to accelerate driving decline in cognitively normal older adults.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42471447},
issn = {1476-5578},
support = {R01AG056466//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG067428//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
abstract = {Driving is a complex task that can be compromised by mood disorders and neurodegenerative conditions. Major depressive disorder (MDD) and Alzheimer's disease (AD) increase in prevalence with older age. Preclinical AD, identified through protein biomarkers, is strongly associated with an increased risk of developing AD. This study tracked the daily driving behaviors of older adults over an average period of 54 months and found participants with MDD and Positron Emission Tomography (PET) biomarker tau had a faster increase in risky driving behaviors, such as hard braking, and a slower decline in randomness of driving patterns, compared to healthy controls. Notably, participants with MDD were more likely to exhibit PET tau positivity than PET amyloid positivity, suggesting a potential interaction between MDD and tau pathology. These findings highlight the importance of monitoring older drivers for emerging functional vulnerability associated with mood disorders and neurodegeneration at an early stage.},
}
@article {pmid42471578,
year = {2026},
author = {Li, Z and Zeng, C and Ge, S},
title = {Bayesian brain edge-based connectivity (BBeC): a Bayesian model for brain edge-based connectivity inference.},
journal = {BMC bioinformatics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12859-026-06549-2},
pmid = {42471578},
issn = {1471-2105},
abstract = {BACKGROUND: Brain connectivity analysis based on magnetic resonance imaging is crucial for understanding neurological mechanisms. However, edge-based connectivity inference faces significant challenges, particularly the curse of dimensionality when estimating high-dimensional covariance matrices. Existing methods often struggle to account for the unknown latent topological structure among brain edges, leading to inaccurate parameter estimation and unstable inference.<br><br>METHODS: To address these issues, this study proposes a Bayesian hierarchical model based on a finite-dimensional Dirichlet distribution. Unlike non-parametric approaches, our method utilizes a finite-dimensional Dirichlet distribution to model the latent topological structure of brain networks, ensuring constant parameter dimensionality and improving algorithmic stability. We reformulate the covariance matrix structure to guarantee positive definiteness and employ a Metropolis-Hastings algorithm to simultaneously infer network topology and correlation parameters. Furthermore, to alleviate the computational burden of parameter inference in large-scale networks, we optimized the calculation process of the likelihood function to reduce the algorithm's time complexity. Our implementation is available at https://github.com/mimi6501/BBeC.<br><br>RESULTS: Simulations validated the recovery of both network topology and correlation parameters across various settings. Furthermore, we quantitatively compared the proposed framework with the Graphical Lasso and a Dirichlet process-based non-parametric Bayesian model. Experimental results show our model offers flexible parameter tuning while outperforming baselines in estimation accuracy and convergence stability. Sensitivity analysis reveals the diagonal adjustment parameter &#x3bb; has minimal impact on model accuracy, and parameter sampling order has negligible impact on final inference. When applied to the Alzheimer's Disease Neuroimaging Initiative dataset, the model successfully identified structural subnetworks. The identified clusters were not only validated by composite anatomical metrics but also consistent with established findings in the literature, collectively demonstrating the model's reliability. The estimated covariance matrix also revealed that intragroup connection strength is stronger than intergroup connection strength.<br><br>CONCLUSIONS: This study introduces a Bayesian framework for inferring brain network topology and high-dimensional covariance structures. The model configuration effectively reduces parameter dimensionality while ensuring the positive definiteness of covariance matrices. As a result, it offers an efficient and reliable tool for investigating intrinsic brain connectivity in large-scale neuroimaging studies.},
}
@article {pmid42471701,
year = {2026},
author = {Marshall, CR and Moser, FA and Scott, CF and Ventura-Antunes, L and Romero-Fernandez, W and Migas, &#x141;G and Tideman, LEM and Colley, ME and Dufresne, M and Schrag, MS and Van de Plas, R and Spraggins, JM},
title = {Multimodal molecular mapping of the vasculature in human cortex reveals lipid markers of cerebral amyloid angiopathy.},
journal = {Acta neuropathologica communications},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40478-026-02361-4},
pmid = {42471701},
issn = {2051-5960},
abstract = {Cerebral amyloid angiopathy (CAA) commonly co-occurs with Alzheimer's disease (AD), yet the molecular changes that accompany vascular [Formula: see text]-amyloid deposition in human tissue remain incompletely defined. Herein, we use a novel imaging approach that combines matrix-assisted laser desorption/ionization imaging mass spectrometry (IMS) with immunofluorescence microscopy on the same sections of postmortem human frontal cortex to map the lipid microenvironment of leptomeningeal vasculature in cases with and without CAA. Autofluorescence-guided regions-of-interest were imaged by IMS in both negative and positive ion modes and registered to post-IMS-acquired microscopy images. Immunofluorescence microscopy using markers for collagen IV, [Formula: see text]-smooth muscle actin ([Formula: see text]SMA), and thiazine red enabled automated segmentation of total, amyloid-positive, and amyloid-negative vasculature regions. A CAA index, the ratio of amyloid-positive area to total vasculature area in a region imaged by IMS, was used to define vasculature and classify each case into having CAA, or CAA-present, and not having CAA, or CAA-absent. An interpretable machine learning approach (XGBoost models with Shapley additive explanations for interpretation) was trained on pixel-level spectra and identified lipid signatures of vascular identity shared across groups as well as class-specific marker candidates that distinguished CAA-present from CAA-absent vasculature. CAA-absent vessels were characterized by higher contributions from phosphatidylserines (e.g., long-chain polyunsaturated PS species). Univariate differences were inconsistent between the two groups, but multivariate models in negative mode yielded stable discriminatory features. These results define spatial lipid correlates of vascular amyloid pathology in the human brain and establish a multimodal framework for mechanistically linking lipid metabolism, vascular integrity, and CAA in AD.},
}
@article {pmid42471719,
year = {2026},
author = {Yamada, K and Ishida, K and Sakamoto, A and Shimada, H and Watanabe, M and Shimojo, M and Igarashi, H and Iwatsubo, T},
title = {AQP4-dependent enhancement of glymphatic function attenuates tau pathology and neurodegeneration in PS19 mice.},
journal = {Molecular neurodegeneration},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13024-026-00977-7},
pmid = {42471719},
issn = {1750-1326},
support = {JP23wm0625001//AMED/ ; 23H0279//Japan Society for the Promotion of Science/ ; 25K10766, 20K21568, 18H02762//Japan Society for the Promotion of Science/ ; 2023-23012//Niigata University/ ; },
abstract = {BACKGROUND: The glymphatic system facilitates cerebrospinal fluid-interstitial fluid exchange and contributes to the clearance of pathogenic proteins from the brain. Glymphatic dysfunction has been associated with Alzheimer's disease and related tauopathies; however, whether impaired glymphatic transport causally drives tau accumulation and neurodegeneration, and whether its enhancement confers therapeutic benefit, remains unclear.<br><br>METHODS: Glymphatic water dynamics in PS19 tau transgenic mice were assessed using JJVCPE, a novel MRI-based approach for evaluating brain water exchange. The effect of pharmacological activation of aquaporin-4 (AQP4) with TGN-073 on glymphatic cerebrospinal fluid influx was examined in wild-type mice using dynamic contrast-enhanced MRI. Tau pathology, neurodegeneration, and cerebrospinal fluid tau levels were analyzed in PS19 mice following chronic TGN-073 treatment. AQP4-deficient PS19 mice were examined to determine target specificity.<br><br>RESULTS: PS19 mice exhibited significant impairment of glymphatic water exchange at early disease stages, which progressively worsened with ageing. Pharmacological activation of AQP4 with TGN-073 robustly enhanced glymphatic-related tracer influx, reduced tau accumulation, neuronal loss, and gliosis, and was accompanied by increased cerebrospinal fluid tau levels. TGN-073 also restored perivascular AQP4 enrichment without significantly altering overall AQP4 abundance. Importantly, these beneficial effects were abolished in AQP4-deficient PS19 mice, demonstrating that both glymphatic enhancement and suppression of tau pathology and neurodegeneration are AQP4-dependent.<br><br>CONCLUSIONS: Our findings support a mechanistic contribution of impaired glymphatic function to tau accumulation and neuronal vulnerability in tauopathy. Pharmacological activation of AQP4 enhances glymphatic function, restores perivascular AQP4 organization, and ameliorates tau pathology, neurodegeneration, and gliosis. These findings identify AQP4-mediated glymphatic modulation as a disease-relevant and therapeutically tractable pathway for tau-related neurodegenerative disorders.},
}
@article {pmid42471753,
year = {2026},
author = {Travison, TG and Davis-Plourde, K and Goldfeld, KS and Li, F and Lou, Y and Monin, JK and Taljaard, M and Turner, J and Vranceanu, AM and Allore, HG},
title = {The design of embedded pragmatic clinical trials: methodological developments and statistical lessons learned from the first cycle of the NIA IMPACT collaboratory.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71660},
pmid = {42471753},
issn = {1552-5279},
support = {U54AG063546/NH/NIH HHS/United States ; },
mesh = {Humans ; *Pragmatic Clinical Trials as Topic/methods ; *Research Design ; United States ; National Institute on Aging (U.S.) ; *Alzheimer Disease/therapy ; },
abstract = {INTRODUCTION: The National Institute on Aging-funded IMbedded Pragmatic Alzheimer's disease and AD-Related Dementias Clinical Trials (IMPACT) Collaboratory was established to build capacity for conducting embedded pragmatic clinical trials (ePCTs) within healthcare systems for people living with dementia and their care partners. Here we present methodology and describe lessons learned from the first five years of IMPACT's Design and Statistics Core (DSC).<br><br>METHODS: The DSC assembled a multidisciplinary team focused on advancing the design, analysis, and implementation of ePCTs.<br><br>RESULTS: The DSC developed and disseminated methods for design and sample size of cluster randomized designs with complex correlation structures; guidance for pilot ePCTs; approaches to patient-care partner ePCTs; approaches to testing health-equity-relevant hypotheses; and guidance for training quantitative and clinical scientists developing ePCTs.<br><br>DISCUSSION: Key gaps remain in applying dyadic designs and when studying heterogeneity of treatment effects, which will be major priorities for the next funding cycle.},
}
@article {pmid42471754,
year = {2026},
author = {Xia, CA and Salarian, M and Gartshore, CJ and Scaglione, A and Hayes, T and Liu, S and Tsai, HM and Echavarren, J and Cid, JM and Matzeu, A and Szardenings, AK},
title = {Development and characterization of a novel TDP-43 positron emission tomography tracer: [[18]F]JNJ-TDP43-1.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71675},
pmid = {42471754},
issn = {1552-5279},
support = {//Johnson &amp; Johnson/ ; },
mesh = {Animals ; *Positron-Emission Tomography/methods ; *DNA-Binding Proteins/metabolism ; *Brain/diagnostic imaging/metabolism ; Rats ; Mice ; Humans ; Male ; Disease Models, Animal ; TDP-43 Proteinopathies/diagnostic imaging ; *Radiopharmaceuticals/pharmacokinetics ; Fluorine Radioisotopes ; },
abstract = {INTRODUCTION: Neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), limbic-predominant age-related TDP-43 encephalopathy (LATE), and Alzheimer's disease (AD) are associated with TAR DNA-binding protein 43 (TDP-43) pathology. A positron emission tomography (PET) tracer targeting TDP-43 aggregates could improve early diagnosis and guide treatment development for TDP-43-related conditions.<br><br>METHODS: Specific binding was evaluated using fluorescent labeling of compound, surface plasmon resonance (SPR), and autoradiography (ARG). Brain PET imaging in rats, nonhuman primate (NHP), and a disease mouse model was performed to characterize tracer pharmacokinetics and in vivo target binding.<br><br>RESULTS: JNJ-TDP43-1 exhibited high binding affinity for pathological TDP-43 (Kd&#xa0;=&#xa0;7.1&#xa0;nM) and remarkable selectivity over other proteinopathies. PET imaging demonstrated robust brain uptake and rapid washout in rodents and NHP. In vivo target engagement was confirmed in an AAV-hTDP43 disease model.<br><br>DISCUSSION: [[18]F]JNJ-TDP43-1 is a promising PET ligand for early diagnosis and evaluating therapies in TDP-43-related diseases.},
}
@article {pmid42472451,
year = {2026},
author = {Docteur, NG and Huston, HGP and Krupa, AA and Callahan, BL},
title = {A systematic review of neuroimaging studies of adults aged 35 and older with clinical, symptomatic and genetic risk for attention-deficit/hyperactivity disorder.},
journal = {Dialogues in clinical neuroscience},
volume = {28},
number = {1},
pages = {259-276},
doi = {10.1080/19585969.2026.2700984},
pmid = {42472451},
issn = {1958-5969},
mesh = {Humans ; *Attention Deficit Disorder with Hyperactivity/genetics/diagnostic imaging ; *Neuroimaging/methods ; Adult ; *Brain/diagnostic imaging/pathology ; Middle Aged ; Aged ; *Genetic Predisposition to Disease ; Aging ; },
abstract = {Attention-deficit/hyperactivity disorder (ADHD) affects 2.5% of adults and is associated with cognitive decline and dementia. The neurobiological mechanisms contributing to adverse outcomes in ADHD are poorly understood. ADHD-related brain alterations may persist into later life and interact with ageing-related processes, potentially increasing susceptibility to neuropathology. This preregistered systematic review synthesised neuroimaging findings in adults aged 35 years and older with clinical, symptomatic, or genetic risk for ADHD, and summarised cognitive and clinical correlates. A search of five databases produced 13 included studies. Risk of bias was assessed using the Newcastle-Ottawa Scale. Most studies (11/13) had low risk of bias. Compared to controls, ADHD groups exhibited alterations in fronto-striatal, fronto-parietal, and limbic systems implicated in executive control and attention. Middle-aged adults with clinical ADHD showed more widespread cortical structural differences, whereas older adults demonstrated abnormalities primarily in frontal regions, possibly reflecting attenuation of differences through ageing. Two functional studies in those with clinical ADHD reported frontal hypoactivation alongside parietal hyperactivation, consistent with compensatory recruitment. Among undiagnosed samples, there were interactions between genetic risk for ADHD and Alzheimer's disease-related pathology affecting brain and cognitive outcomes. Overall, ADHD-associated neurobiological alterations appear to persist into older age. Longitudinal investigations are needed to clarify these relationships.},
}
@article {pmid42472492,
year = {2026},
author = {Damirchi, EK and Barani, A and Hamidi, SM and Ebrahimzadeh, MA},
title = {Melatonin hybrids as multifunctional therapeutic agents: A comprehensive review.},
journal = {European journal of medicinal chemistry},
volume = {318},
number = {},
pages = {119156},
doi = {10.1016/j.ejmech.2026.119156},
pmid = {42472492},
issn = {1768-3254},
abstract = {Compound hybridization has received attention due to its potential to address several diseases, including neurological disorders, cancer, infectious diseases, and others. Melatonin is a hormone with antioxidant, anti-inflammatory, and neuroprotective effects. Some drug design research has focused on synthesizing hybrid molecules in which melatonin is hybridized with other pharmacologically active compounds to increase therapeutic efficacy and reduce toxicity. These hybrids demonstrate improved binding affinity, selectivity, and pharmacokinetic characteristics compared to their separate components. This review shows the pharmacological assessment and therapeutic potential of diverse melatonin-based hybrids. These hybrids have exhibited significant efficacy in the treatment of complex diseases such as Alzheimer's disease, cancer, and inflammatory disorders. Hybridization leads to the synthesis of a new generation of structures that represent a promising therapeutic approach for disease treatment.},
}
@article {pmid42472573,
year = {2026},
author = {Yanagisawa, D and Ohgita, T and Kawashima, H and Yoshikawa, H and Saito, H and Tooyama, I and Takata, K},
title = {Neurotheranostics in Alzheimer's Disease: Current concepts and experimental strategies.},
journal = {Pharmacology &amp; therapeutics},
volume = {},
number = {},
pages = {109084},
doi = {10.1016/j.pharmthera.2026.109084},
pmid = {42472573},
issn = {1879-016X},
abstract = {In Alzheimer's disease (AD), pathological changes start decades before symptoms appear; by the time cognitive issues are noticeable, widespread neuronal and glial dysfunction and significant neuronal loss have already occurred. Recent regulatory approvals of monoclonal antibodies targeting aggregated amyloid-β (Aβ) species, including oligomers and fibrils, represent a major advance in disease-modifying therapy. However, therapeutic efficacy is strongly dependent on intervention at the earliest pathological stages, underscoring the importance of early diagnosis and treatment. Early diagnosis requires biomarkers that accurately reflect the initiation and progression of AD pathology as well as the development of methodologies capable of capturing these pathological states in vivo. Effective early treatment necessitates strategies that suppress the formation, activation, or toxicity of molecules that trigger downstream neurodegenerative cascades, thereby interrupting disease progression at its source. In parallel, advances in targeted brain delivery technologies are essential to enable sensitive detection and effective therapeutic modulation of central nervous system targets. Neurotheranostics is an integrated conceptual framework that aims to achieve early diagnosis and targeted therapy either simultaneously or in a coordinated manner using shared molecular targets and biological readouts. By unifying molecular imaging, biomarker analysis, and disease-modifying intervention, neurotheranostics aims to overcome the limitations of conventional diagnostic and therapeutic paradigms in neurodegenerative disorders, including AD. In this review, we summarize recent advances in neurotheranostic approaches for AD and highlight emerging molecular probes, low-molecular-weight compounds, and delivery technologies, including contributions from our studies.},
}
@article {pmid42472607,
year = {2026},
author = {Ren, K and Lu, D and Wang, L and Yang, J and Zhang, H},
title = {Phytochemicals modulating HSF-1-associated pathways: A systematic review of longevity-extending mechanisms in Caenorhabditis elegans.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103265},
doi = {10.1016/j.arr.2026.103265},
pmid = {42472607},
issn = {1872-9649},
abstract = {Aging is characterized by progressive loss of proteostasis, and heat shock transcription factor 1 (HSF1) is the master regulator of the cellular stress response, making it an attractive pharmacological target for interventions aimed at extending lifespan. However, a systematic synthesis of phytochemicals that modulate HSF1 has been lacking. Following PRISMA 2020 guidelines, we systematically searched PubMed, Web of Science, Scopus, Embase, and the Cochrane Library from March 2016 to March 2026, identifying 42 original studies that provided clear evidence of HSF-1 activation (nuclear translocation, phosphorylation, or transcriptional activity), together with downstream stress-response markers such as upregulation of heat shock protein genes by phytochemicals with lifespan-extending or health span-improving outcomes. All 42 studies exclusively used Caenorhabditis elegans as the model organism, and the phytochemicals were classified into six categories: plant extracts/mixtures (11 studies), flavonoids (9 studies), carbohydrates/sugars (8 studies), terpenoids (7 studies), phenolic compounds (4 studies), and alkaloids (3 studies). Across all studies, these phytochemicals extended lifespan, enhanced resistance to thermal and oxidative stress, and delayed neurodegenerative pathology (Alzheimer's, Parkinson's, and Huntington's disease models) through activation of HSF-1 and its cooperating transcription factors DAF-16/FOXO and SKN-1/Nrf2. While sharing a common dependency on HSF-1, different classes engaged additional signaling pathways including autophagy, mitochondrial unfolded protein response, insulin/IGF-1 signaling, and lipid metabolism, reflecting class-specific mechanistic signatures. This systematic review provides the first comprehensive evidence base for developing HSF-1-associated longevity strategies using phytochemicals; however, all available evidence is limited to C. elegans models, and urgent validation in mammals and clinical translation are needed before these findings can be applied to human aging.},
}
@article {pmid42472674,
year = {2026},
author = {Jancev, M and Eliasson, B and Biessels, GJ and DeVries, JH and Serné, EH and Visseren, FLJ and Rawshani, A and Rawshani, A and Cukierman-Yaffe, T and Sattar, N and Gerstein, HC and van Sloten, TT},
title = {Age of Type 1 Diabetes Onset and Dementia Risk: A Swedish Nationwide, Register-Based Cohort Study.},
journal = {Diabetes, obesity &amp; metabolism},
volume = {},
number = {},
pages = {},
doi = {10.1111/dom.71123},
pmid = {42472674},
issn = {1463-1326},
support = {2021.81.004//Diabetes Fonds/ ; 2024.35.001//Diabetes Fonds/ ; //European Foundation for the Study of Diabetes/ ; },
abstract = {AIMS: Individuals with Type 1 diabetes are at a higher risk of dementia compared to individuals without diabetes. Younger age at Type 1 diabetes onset has been linked to an increased risk of cardiovascular disease and higher mortality. This study aimed to determine whether younger age at Type 1 diabetes onset was also associated with all-cause dementia.<br><br>MATERIALS AND METHODS: This nationwide prospective cohort study used data from individuals with Type 1 diabetes from the Swedish National Diabetes Register. All-cause dementia, including Alzheimer's disease, vascular dementia and non-Alzheimer's-non-vascular dementia, was prospectively ascertained as ICD-10 codes. Age at onset was stratified into <&#x2009;10&#x2009;years, 10-17&#x2009;years and 18-30&#x2009;years. The 18-30&#x2009;years group was used as the reference group for all analyses. Cox regression modelling with age as the time-axis, from age at diabetes onset, was deployed to investigate dementia risk.<br><br>RESULTS: Of 43&#x2009;440 included individuals (mean age 33.0 (SD 14.0) years; 44% female), Type 1 diabetes developed before age 10 in 11&#x2009;776 individuals (27%), between age 10 and 17 in 15&#x2009;846 (36%) and between 18 and 30 (reference group) in 15&#x2009;818 (36%). During a median 29.3 [17.6-43.7] years follow-up, 530 (1.2%) developed all-cause dementia. Compared to the reference group, all-cause dementia risk was increased in individuals aged <&#x2009;10&#x2009;years at onset (HR 1.37 [95% CI 1.08-1.73]), but not in individuals aged 10-17&#x2009;years at onset (HR 1.04 [95% CI 0.85-1.26]) (fully adjusted model).<br><br>CONCLUSIONS: Type 1 diabetes onset before age 10 is associated with an increased risk of all-cause dementia compared to onset between ages 18 and 30.},
}
@article {pmid42472714,
year = {2026},
author = {Khan, M and Khan, T and Tariq, A},
title = {From biomarker expansion to equitable implementation in mild cognitive impairment.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {8},
pages = {},
pmid = {42472714},
issn = {1590-3478},
mesh = {Humans ; *Cognitive Dysfunction/diagnosis/cerebrospinal fluid ; *Biomarkers/cerebrospinal fluid ; *Alzheimer Disease/diagnosis/cerebrospinal fluid ; },
abstract = {The expanding role of cerebrospinal fluid (CSF) biomarkers in Alzheimer's disease diagnosis represents a major shift toward biologically driven dementia care. In response to the article by Poli et al., we discuss important considerations regarding the broader implementation of CSF biomarker testing in patients with mild cognitive impairment (MCI), particularly in the era of emerging anti-amyloid therapies. While biomarker-guided approaches may improve identification of atypical or non-amnestic Alzheimer's disease presentations, widespread adoption remains limited by disparities in diagnostic infrastructure, standardized testing availability, expertise in lumbar puncture procedures, and longitudinal monitoring capacity across healthcare systems. In addition, expanded eligibility for anti-amyloid therapies introduces challenges related to patient selection, treatment accessibility, and equitable allocation of healthcare resources. Ethical considerations surrounding biomarker disclosure and prognostic uncertainty also warrant continued discussion. We emphasize the need for future studies evaluating accessibility, cost-effectiveness, and standardized patient selection frameworks to support equitable integration of biomarker-guided dementia care into routine neurological practice.},
}
@article {pmid42472726,
year = {2026},
author = {Chen, Y and Li, Z and Luo, S and Li, Z and Jiang, Y and Chen, K and Wang, J and Zhang, Z and , },
title = {Apolipoprotein E ε4 and type 2 diabetes cooperatively accelerate amyloid beta and tau neurodegeneration.},
journal = {European journal of nuclear medicine and molecular imaging},
volume = {},
number = {},
pages = {},
pmid = {42472726},
issn = {1619-7089},
support = {2023YFC3605400//National Key Research and Development Program of China/ ; 2022ZD0211600//Science and Technology Innovation 2030 Major Projects/ ; Beijing Nova Program//Beijing Nova Program/ ; },
abstract = {PURPOSE: Both type 2 diabetes mellitus (T2DM) and Apolipoprotein E (APOE) ɛ4 allele are recognized risk factors for Alzheimer's disease (AD). However, the impact of the APOE ɛ4 allele on the accumulation of AD-related neuropathology in patients with T2DM remains unclear.<br><br>METHODS: We analyzed amyloid beta (A&#x3b2;) and tau deposition patterns via positron emission tomography (PET) imaging in 163 T2DM patients (64 &#x25b;4 carriers) and 1654 normal glucose metabolism subjects (687 &#x25b;4 carriers).<br><br>RESULTS: Findings reveal that A&#x3b2; deposition has a broader range of influence in diabetics carrying the &#x25b;4 allele, especially in the deep cortical areas. In terms of tau accumulation, diabetic carriers exhibit progression to the posterior and frontal cortices. Specifically, a greater A&#x3b2; PET burden is associated with higher levels of plasma A&#x3b2;42 and lower levels of cerebrospinal fluid (CSF) A&#x3b2;42, A&#x3b2;42/40, and A&#x3b2;42/38. A significant positive correlation was observed between tau PET burden and CSF tau and phosphorylated tau (pTau), and plasma pTau181. Importantly, higher A&#x3b2; and tau standardized uptake value ratio were associated with poorer memory performance and lower scores on the Montreal Cognitive Assessment.<br><br>CONCLUSIONS: These findings highlight the allele's region-specific synergism with T2DM in driving AD-related pathology, potentially informing the development of a neuroimaging-based grading system to evaluate diabetic neuropathology severity and progression dynamics.},
}
@article {pmid42472733,
year = {2026},
author = {Kwon, HS and Moon, SY and Hwang, M and Kim, HJ and Lee, SM and Jung, NY and Jang, H and Baek, JM and Kim, MJ and Han, MH and Zetterberg, H and Blennow, K and Apostolova, LG and Koh, SH and Kim, EJ and , },
title = {Blood-based multimodal biomarker models for differentiating early-onset Alzheimer's disease from frontotemporal dementia: a longitudinal study of early-onset dementia and family members (LEAF) study.},
journal = {Journal of neurology},
volume = {273},
number = {8},
pages = {},
pmid = {42472733},
issn = {1432-1459},
support = {2021-ER1004-01//Korea National Institute of Health research project/ ; 2024-ER1001-00//Korea National Institute of Health research project/ ; },
mesh = {Humans ; *Alzheimer Disease/blood/diagnosis ; Female ; *tau Proteins/blood ; Male ; *Frontotemporal Dementia/blood/diagnosis ; Biomarkers/blood ; *Glial Fibrillary Acidic Protein/blood ; Longitudinal Studies ; Middle Aged ; Diagnosis, Differential ; *Neurofilament Proteins/blood ; Age of Onset ; Aged ; Adult ; },
abstract = {BACKGROUND: Plasma phosphorylated tau (p-tau) biomarkers have improved the diagnosis of Alzheimer's disease (AD), but evidence in early-onset populations remains limited. We evaluated the diagnostic performance of plasma p-tau217 and p-tau181 levels in patients with early-onset AD (EOAD) and early-onset frontotemporal dementia (EOFTD).<br><br>METHODS: We analyzed 185 patients (EOAD&#x2009;=&#x2009;150, EOFTD&#x2009;=&#x2009;35) aged&#x2009;&#x2264;&#x2009;65&#xa0;years from the LEAF study (2021-2023). Plasma p-tau217, p-tau181, neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) levels were measured by immunoassays.<br><br>RESULTS: Both plasma p-tau217 (AUC&#x2009;=&#x2009;0.831) and p-tau181 (AUC&#x2009;=&#x2009;0.862) levels demonstrated high discriminative performance, with no significant difference between the two p-tau isoforms. P-tau levels were higher in patients with EOAD, whereas NfL levels were higher in EOFTD and were elevated in those with EOAD participants with severe hippocampal atrophy. Adding NfL, GFAP, and APOE &#x3b5;4 status further improved the discriminative accuracy for differentiating EOAD from EOFTD.<br><br>CONCLUSIONS: Plasma p-tau217 and p-tau181 are effective biomarkers for distinguishing biologically defined EOAD from EOFTD. Incorporating NfL, GFAP, and APOE &#x3b5;4 status further enhances diagnostic accuracy.},
}
@article {pmid42473039,
year = {2026},
author = {Koppisetti, RK and Barthélemy, NR and Horie, K and Ly, CV and Roberts, KF and Koutarapu, S and Perrin, RJ and Franklin, EE and Pedicone, C and Orrick, J and Melendez, J and Miller, TM and Sato, C and Ghoshal, N and Goate, AM and Karch, CM and Bateman, RJ and Mukherjee, S},
title = {Distribution of Big Tau Isoforms in the Human Central and Peripheral Nervous System.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78300},
pmid = {42473039},
issn = {1531-8249},
support = {UL1TR004419/TR/NCATS NIH HHS/United States ; 1U54NS123746-01/NS/NINDS NIH HHS/United States ; R01NS095773/NS/NINDS NIH HHS/United States ; R01NS110890/NS/NINDS NIH HHS/United States ; U54NS123985/NS/NINDS NIH HHS/United States ; P41GM103422/GM/NIGMS NIH HHS/United States ; P01AG026276/AG/NIA NIH HHS/United States ; P01AG03991/AG/NIA NIH HHS/United States ; P30AG066444/AG/NIA NIH HHS/United States ; },
abstract = {OBJECTIVE: Tau is widely studied in neurodegeneration, yet most work has focused on canonical brain tau isoforms. A longer isoform, "big tau," produced by inclusion of exon 4a, is expressed in the peripheral nervous system (PNS) and central nervous system (CNS) regions. We sought to characterize big tau composition, anatomic distribution, and disease relevance.<br><br>METHODS: Mass spectrometry (MS) was used to sequence big tau and map its distribution across the human nervous system. Postmortem samples included brain tissue from Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and controls; spinal cord and peripheral nerves. Big and canonical ("small") tau isoforms were also quantified in cerebrospinal fluid (CSF) from controls and participants stratified by amyloid status and cognitive impairment.<br><br>RESULTS: Human big tau results from insertion of either 355 or 251 amino acids encoded by exon 4a-long and exon 4a-short, respectively. Alternative splicing of exons 2, 3, and 10 generates multiple big tau isoforms. Total tau levels were approximately 1,000-fold higher in the brain than in the PNS; however, the relative abundance of big tau increased from the CNS to the PNS, comprising 50% of the total tau in the periphery and approximately 1% in the brain, primarily localized to the cerebellum. In CSF, big tau levels were unchanged by amyloid abnormalities or cognitive impairment, whereas canonical tau increased with AD pathology.<br><br>INTERPRETATION: Big tau represents a distinct tau population enriched in the PNS and uncoupled from disease-associated changes in brain-derived tau, suggesting that distinguishing big tau from canonical tau may improve interpretation of tau biomarkers and help differentiate CNS neurodegeneration from peripheral nerve pathology. ANN NEUROL 2026.},
}
@article {pmid42473091,
year = {2026},
author = {Jessup, RE and Ehrlich, RS and Teppang, KL and Dasgupta, S and Sigurdson, CJ and Yang, J},
title = {Development of Aryl Cyano Amides for Fluorescence Discrimination of Tau and Amyloid Beta Deposits in Tissue.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00316},
pmid = {42473091},
issn = {1948-7193},
abstract = {The accumulation of amyloid aggregates such as amyloid beta (Aβ) and tau deposits in the brain is a hallmark of many neurodegenerative diseases including Alzheimer's disease. Recent advances in optical imaging have shown that fluorescent probes can detect amyloids in living patients, potentially aiding in diagnosis. Here, we investigate structural modifications of amyloid-targeting Aryl Cyano Amide-based fluorophores aimed at enhancing their ability to discriminate between different amyloid aggregates, such as Aβ and tau. We identify two structural parameters that synergistically enable increased sensitivity to environmental polarity, which makes it possible to discriminate these amyloids through inspection of the color of fluorescence emission. This colorimetric discrimination can provide detailed information on amyloid composition and could expand the use of fluorescence imaging for diagnosis and monitoring of neurodegenerative diseases.},
}
@article {pmid42473207,
year = {2026},
author = {Dutta, S and Singh, MK and Dehury, B},
title = {Unlocking the Dynamics of Human SPPL2a: First Atomistic Characterization of an Alzheimer's-Linked Intramembrane Protease.},
journal = {Journal of chemical information and modeling},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jcim.6c01556},
pmid = {42473207},
issn = {1549-960X},
abstract = {The failure of γ-secretase inhibitors in clinical trials of Alzheimer's disease (AD) has shifted the focus toward more selective targets, specifically SPPL2a (signal peptide-peptidase-like 2a), which is emerging as a critical therapeutic target in AD because of its role in processing TMEM106B. While recent cryo-EM structures have provided essential static snapshots, the dynamic mechanisms governing substrate entry and inhibitor recognition remain unresolved. Here, we present the first microsecond-time scale, all-atom molecular dynamics characterization of human SPPL2a in its apo and inhibitor-bound states, alongside a comparative analysis of the γ-secretase catalytic subunit, PS1. Our simulations reveal that SPPL2a is highly dynamic and undergoes an inhibitor-induced disorder-to-order transition in the TM6a region, where the helicity increases from 10% to 77%. We characterized the lateral gate dynamics of TM2, revealing that inhibitor binding fundamentally remodels the interhelical contact network and quenches conformational sampling. Moreover, we identified a unique inhibitor-stabilized lipid hotspot at Trp189 and demonstrated that SPPL2a utilizes a distributed polar network for binding energy, in contrast to the concentrated aspartate-driven affinity of PS1. These findings provide a quantitative atomistic blueprint of SPPL2a dynamics, offering a structural basis that can be exploited for the design of selectivity-guided therapeutics to bypass the clinical failures associated with nonspecific intramembrane protease inhibition.},
}
@article {pmid42473218,
year = {2026},
author = {Keskin, A and Mogulkoc, R and Baltaci, AK},
title = {Relationship Between miRNA and Neurodegenerative Diseases Such as Alzheimer's disease, Parkinson's, Huntington's disease, Amyotrophic Lateral Sclerosis.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575484348260702044851},
pmid = {42473218},
issn = {1875-5607},
abstract = {The regulatory roles of miRNAs on CNS homeostasis, neuronal differentiation, and synaptic plasticity make these molecules indispensable for healthy brain functions. miRNA dysregulation, by triggering abnormal neurodevelopment, has a critical impact on the etiology and progression of neurodegenerative diseases. MicroRNAs (miRNAs) are short, single-stranded, non-coding ribonucleic acid (RNA) molecules, 18 to 24 nucleotides long. They play a role in posttranscriptional gene regulation by binding to complementary sequences on messenger RNA (mRNA), thereby promoting mRNA degradation or preventing translation into protein. MiRNAs are essential regulators of the genome because they bind targets and alter gene expression. MiRNA biogenesis and functions are tightly regulated, and their dysregulation is associated with various diseases, including cancer, cardiovascular diseases, and neurodegenerative disorders. In particular, disruption of the Blood-Brain Barrier in neurodegenerative diseases allows molecules to leak into the bloodstream, enabling the detection of miRNAs in other body fluids and making these fluids potential biomarker sources. In this context, miRNAs can be measured in blood, cerebrospinal fluid, and other biological samples. It has significant potential for early diagnosis, disease progression monitoring, and evaluation of treatment efficacy. In this review, the relationship between MiRNAs and neuronal degeneration diseases was evaluated. In this review, prepared in light of the current literature scanned through the PubMed database, we examined data from the last 5 years (2021-2026) on neurodegenerative diseases associated with miRNA dysregulation, including Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Huntington's Disease (HD).},
}
@article {pmid42473227,
year = {2026},
author = {Rodrigues, JFR and Rodrigues, LP and Rodrigues, FCP and Cavalcante, LL and Payão, SLM and Tavares, AR and Forlenza, OV and de Godoy, MF and Filho, GMA},
title = {Cardiovascular Comorbidities with Alzheimer's Disease: A Systematic Review and Meta-analysis.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050468989260629094050},
pmid = {42473227},
issn = {1875-5828},
abstract = {INTRODUCTION: Alzheimer's disease stands as the most prevalent form of dementia, characterized by a progressive decline in cognitive function and memory. Numerous risk factors have been linked to its development, creating a complex interplay of influences. In this study, we aim to delve into the relationship between cardiovascular disease and Alzheimer's disease, exploring how conditions affecting heart health may impact the onset and progression of this debilitating neurological disorder. Through this research, we could find potential connections that inform prevention strategies and therapeutic approaches.<br><br>MATERIALS AND METHODS: We adopted the PRISMA guidelines and defined the PECOS framework as follows: Population (P) = individuals; exposure (E) = cardiovascular disease; comparison (C) = without cardiovascular disease; outcome (O) = Alzheimer's disease; and study design(S) = all kinds of studies with an association between cardiovascular disease and Alzheimer's disease without time limits. A meta-analysis was conducted using case-control, cohort, and genetic studies to estimate Odds Ratios (ORs) or Hazard Ratios (HRs).<br><br>RESULTS: The pooling of data in meta-analysis demonstrated that a person with any Cardiovascular Disease (CVD), Heart Failure (HF), Coronary Artery Disease (CAD), Atrial Fibrillation (AF), Hypertension (HTN), and Myocardial Infarction (MI) had more risk of developing Alzheimer's disease [CVD: HR = 1.30 (CI: 1.27-1.33) / HF: HR = 1.63 (CI: 1.37-1.94) / CAD: HR = 1.43 (CI: 1.40-1.46) / AF: HR = 1.38 (CI: 1.34-1.42) / HTN: HR = 1.22 (CI: 1,10-1.35) / MI: HR = 1.07 (CI: 1,01-1.13)]. Cross-sectional studies demonstrated an association between cardiovascular diseases and Alzheimer's disease [OR = 1.29 (CI: 1.23-1.35)]. Mendelian randomization meta-analysis did not demonstrate a causal relation between cardiovascular disease and Alzheimer's disease [AF: OR = 1.03 (CI: 1.00-1.01) / HF: OR = 1.00 (CI: 0,79-1.36)]. A Mendelian randomization meta-analysis demonstrated that a person with AD had a higher risk of developing myocardial infarction [OR = 1.07 (CI: 1.03-1.10)].<br><br>DISCUSSION: This review examines the connection between AD and CVD, noting that HF increases the risk of developing AD with a hazard ratio of 1.63. It suggests that altered brain perfusion and hypoxia appear to be one important neurodegenerative factor. Some genetic changes in individuals with CVD made them more vulnerable to AD. Effective prevention and treatment of CVD can help reduce the risk of AD.<br><br>CONCLUSION: HF, AF, and CAD were the CVDs with the highest risk of developing AD. The results suggest that changes in cerebral blood perfusion are a principal neuropathological event that leads to genetic alterations that end in AD.},
}
@article {pmid42473272,
year = {2026},
author = {Kouchache, T and Chan, T and Sun, S and Liu, L and Delva, A and Gan-Or, Z and Rosa-Neto, P and Gagnon, JF and Dagher, A and Postuma, RB and Sharp, M},
title = {Association Between Plasma Phosphorylated Tau-217 and Cognition in Parkinson's Disease.},
journal = {Movement disorders : official journal of the Movement Disorder Society},
volume = {},
number = {},
pages = {},
doi = {10.1002/mds.70400},
pmid = {42473272},
issn = {1531-8257},
support = {N/A//Fonds de Recherche du Qu&#xe9;bec - Sant&#xe9;/ ; N/A//Healthy Brains for Healthy Lives/ Canada First Research Excellence Fund/ ; N/A//Parkinson Canada/ ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) co-pathology contributes to dementia in PD, but its role in earlier cognitive impairment remains uncertain.<br><br>OBJECTIVE: To determine if p-tau217, a biomarker of early AD, is associated with cognitive impairment in PD.<br><br>METHODS: Plasma p-tau217 levels in 167 PD patients without dementia and 63 controls were related to performance on standard neuropsychological testing, and to cognitive impairment as defined by a MoCA score <26 and by self-report. Plasma GFAP, NfL and APOE &#x3b5;4 carrier status were also examined.<br><br>RESULTS: No significant differences in p-tau217, GFAP and NfL level were observed between groups (pFDR&#x2009;>&#x2009;0.08). Higher p-tau217 was associated with worse visuospatial function and greater self-reported cognitive impairment, but these associations did not survive correction (pFDR&#x2009;>&#x2009;0.08). There was no association with cognitive impairment (pFDR&#x2009;>&#x2009;0.08).<br><br>CONCLUSION: These results suggest that co-morbid AD pathology is not a major contributor to early cognitive changes in this sample of PD patients without dementia. &#xa9; 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.},
}
@article {pmid42473545,
year = {2026},
author = {Gabriel, V and Chabran, E and Sourty, M and Cretin, B and Philippi, N and Muller, C and Anthony, P and Demuynck, C and de Sousa, PL and Botzung, A and Sanna, L and Bousiges, O and Blanc, F},
title = {Cerebrospinal fluid α-synuclein and Aβ42 link with default mode and salience networks connectivity in dementia with Lewy bodies.},
journal = {Alzheimer's &amp; dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70266},
pmid = {42473545},
issn = {2352-8737},
abstract = {INTRODUCTION: Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) are neurocognitive disorders characterized by distinct but often overlapping pathological processes. These include α-synuclein, amyloid-beta 42 (Aβ42), and tau protein aggregation. While cerebrospinal fluid (CSF) biomarkers provide in vivo insight into these pathologies, their relationship with large-scale brain network dysfunction remains poorly understood. This study aimed to investigate the associations between CSF biomarker concentrations and resting-state functional connectivity in patients with DLB, AD, and mixed AD/DLB.<br><br>METHODS: Sixty-nine DLB patients, 17 AD patients, and 24 patients with mixed AD/DLB underwent clinical and neuropsychological evaluations, lumbar puncture for CSF biomarker analysis (total &#x3b1;-synuclein, A&#x3b2;42, pTau181, and tTau), and resting-state functional MRI. Patients were stratified by disease stage for subgroup analyses. Besides CSF total &#x3b1;-synuclein levels,&#xa0;&#x3b1;-synuclein seeding activity was assessed using real-time quaking-induced conversion (RT-QuIC) assays. ROI-to-ROI analyses were conducted using the CONN toolbox to explore associations between CSF biomarker levels and functional connectivity within and between major brain networks.<br><br>RESULTS: In DLB patients, lower CSF &#x3b1;-synuclein levels correlated with increased connectivity within the default mode network (DMN) (p FDR < 0.05). In dementia-stage DLB (d-DLB), lower A&#x3b2;42 levels correlated with reduced connectivity within the salience network (SN) (p FDR < 0.05). In AD, higher tTau levels correlated with decreased connectivity between the DMN and the SN (p FDR < 0.05). No significant associations were observed for CSF pTau181 or any RT-QuIC metric in any group, and the mixed AD/DLB group showed no biomarker-connectivity correlations at all.<br><br>DISCUSSION: We identified distinct patterns of DMN and SN connectivity changes associated with CSF &#x3b1;-synuclein and A&#x3b2;42 levels, respectively. These findings reflect key functional disruptions that may contribute to core clinical symptoms. They underscore the value of combining CSF biomarkers with functional MRI to elucidate DLB pathophysiology.},
}
@article {pmid42473637,
year = {2026},
author = {Kashiwagi-Hakozaki, M and Uchigami, H and Naka, Y and Kokawa, A and Mano, T and Cho, J and Yamada, K and Miyashita, A and Hara, N and Ikeuchi, T and Serrano-Pozo, A and Frosch, MP and Hyman, BT and Toda, T and Fukayama, M and Ushiku, T and Wakabayashi, T and Iwatsubo, T and Hashimoto, T},
title = {Soluble high-molecular-weight amyloid-β species derived from amyloid-β-laden brains induce cerebral β-amyloidosis.},
journal = {Brain communications},
volume = {8},
number = {4},
pages = {fcag188},
pmid = {42473637},
issn = {2632-1297},
abstract = {Spatiotemporal spreading of amyloid-β peptide deposition as senile plaques is a key pathogenic process in the brains of patients with Alzheimer's disease; however, the molecular properties of amyloid-β strains that initiate the spreading of amyloid-β peptide as aggregation seeds in vivo remain poorly understood. In this study, we discovered that the intrahippocampal injection of soluble amyloid-β species with a molecular weight of >150 kDa isolated from the brains of plaque-laden amyloid-β precursor protein transgenic mice or patients with Alzheimer's disease using size-exclusion chromatography, dramatically accelerated β-amyloidosis in the transgenic mice brains. In contrast, intrahippocampal injection of soluble amyloid-β species with 50-70 kDa or 10-20 kDa never induced β-amyloidosis. Moreover, injection of the soluble amyloid-β species with >150 kDa into cerebrospinal fluid of young transgenic mice via the cisterna magna predominantly induced amyloid-β deposition within the wall of leptomeningeal arteries surrounding the brain, reminiscent of cerebral amyloid angiopathy. The seeding activity of the soluble high-molecular-weight amyloid-β was prevented by the immunodepletion of amyloid-β and abolished by formic acid denaturation, suggesting that these amyloid-β oligomers are crucial in inducing β-amyloidosis. Furthermore, we have shown that the soluble high-molecular-weight amyloid-β is present in the brains of patients with Alzheimer's disease and induced β-amyloidosis. These results indicate that the soluble high-molecular-weight amyloid-β oligomers may play an important role in the spatiotemporal spreading of amyloid-β deposition in Alzheimer's disease brains.},
}
@article {pmid42473871,
year = {2026},
author = {Guarnieri, B and Hoxhaj, D and Buracchi Torresi, F and Arnaldi, D and Bonanni, E and Carpi, M and Cremascoli, R and Liguori, C and Lombardi, G and Mainieri, G and Provini, F and Silvestri, R and Puligheddu, M and Tassoni, MM},
title = {A gradual and sustainable approach to diagnosing sleep and circadian disturbances in dementia.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71654},
doi = {10.1002/alz.71654},
pmid = {42473871},
issn = {1552-5279},
mesh = {Humans ; *Sleep Wake Disorders/diagnosis/etiology ; *Dementia/complications ; *Chronobiology Disorders/diagnosis/etiology ; Circadian Rhythm/physiology ; Polysomnography ; Surveys and Questionnaires ; },
abstract = {Evidence linking sleep and circadian disruptions to the course of dementias, particularly Alzheimer's disease, has expanded. Such alterations are detectable from preclinical stages and parallel the disease progression. Assessing and managing sleep and circadian disturbances in patients with dementia remains challenging. New technologies are emerging, but their validation is still pending. We prepared a clinical review outlining a stepped-care, gradual, and sustainable approach aimed at achieving the most accurate possible diagnosis of different sleep disturbances. This review encompasses diagnostic methods ranging from questionnaires to instrumental assessments, progressing from simpler to more complex techniques including biological evaluations of circadian rhythm alterations. This work reflects a scientific consensus within the "Sleep" study group of the Italian Association for Dementia (SINdem), supported by certified sleep specialists. The document aims to support clinicians in adopting a tailored approach to the evaluation of sleep disturbances in dementia offering a dynamic framework balancing complexity and feasibility.},
}
@article {pmid42473913,
year = {2026},
author = {Ay, U and Alaylioglu, M and Sahin, E and Oner, SSY and Iskan, G and Cakan, GCY and Kizilates-Evin, G and Hari, E and Kurt, E and Dursun, E and Bilgic, B and Hanagasi, H and Gurvit, H and Demiralp, T and Gezen-Ak, D and Samanci, B},
title = {Stage-Dependent β-Synuclein Links MRI and Cognitive Decline in Alzheimer's Disease.},
journal = {Annals of clinical and translational neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/acn3.70494},
pmid = {42473913},
issn = {2328-9503},
abstract = {OBJECTIVE: Synaptic degeneration drives cognitive decline in Alzheimer's disease (AD), but synaptic biomarkers are scarce. Brain-enriched β-synuclein emerged as a synaptic damage marker. We investigated its diagnostic, prognostic, and structural correlates across the AD continuum.<br><br>METHODS: In a tertiary-center cohort (n&#x2009;=&#x2009;306), CSF &#x3b2;-synuclein was measured. Cognitively unimpaired (CU), AD-MCI, AD dementia (ADD), and non-AD (FTD, PD, DLB, others) groups were included. ANCOVA compared groups (age/sex adjusted); ROC assessed diagnostic performance. Multivariable regression examined 2-year MMSE decline associations. Voxel-wise interaction models evaluated &#x3b2;-synuclein-gray matter volume (GMV) relationships.<br><br>RESULTS: CSF &#x3b2;-synuclein differed across groups (p&#x2009;<&#x2009;0.001), with highest levels observed in AD-MCI and lower levels in ADD. AD-MCI levels exceeded CU/ADD. AD-MCI versus CU AUC was 0.874. Baseline &#x3b2;-synuclein predicted greater MMSE decline in AD-MCI (&#x3b2;&#x2009;=&#x2009;0.72, p&#x2009;<&#x2009;0.001) and ADD (&#x3b2;&#x2009;=&#x2009;0.47, p&#x2009;=&#x2009;0.017). Voxel-wise analyses revealed stage-dependent &#x3b2;-synuclein-GMV reversals in precentral and temporoparietal regions.<br><br>CONCLUSION: CSF &#x3b2;-synuclein shows a stage-dependent pattern across the AD continuum, predicts cognitive decline, and dynamic structural coupling. It supports &#x3b2;-synuclein as a relevant synaptic biomarker in AD.},
}
@article {pmid42474014,
year = {2026},
author = {Yu, Y and Zhao, H and He, Y and Zhao, J and Yang, X and Liu, X and Cheng, X},
title = {Therapeutic Effects of the Traditional Chinese Formula Qifuyin on Cognition, Lipid Metabolism, and Gut Microbiota in ApoE4 Mice.},
journal = {Combinatorial chemistry &amp; high throughput screening},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113862073453341260621182306},
pmid = {42474014},
issn = {1875-5402},
abstract = {INTRODUCTION: Apolipoprotein E4 (ApoE4) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD). Qifuyin is a promising herbal formula used clinically for cognitive decline, but its effects on ApoE4-associated cognitive and systemic phenotypes remain unclear. This study aimed to evaluate the effects of Qifuyin on cognitive performance in ApoE4 transgenic mice and to preliminarily explore its associations with lipid metabolism and gut microbiota alterations.<br><br>METHODS: Ten-month-old ApoE4 transgenic mice were treated with Qifuyin by gavage for 321 days, once daily for the first 123 days and once every two days thereafter. Cognitive function was assessed using the step-down test, novel object recognition test (NORT), and Morris water maze test (MWM). Aging- and frailty-related phenotypes were evaluated using senescence grading scores. Serum triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and apolipoprotein B (ApoB) levels were measured to assess lipid metabolism. Gut microbiota composition and functional profiles were analyzed by 16S rRNA and metagenomic sequencing.<br><br>RESULTS: Qifuyin treatment significantly reduced error counts and prolonged latency in the stepdown test, increased the 24h preference index in the NORT, shortened escape latency, and increased platform crossings in the MWM in ApoE4 transgenic mice. High-dose Qifuyin reduced aging scores in males and in all doses in females and in the pooled dataset. Qifuyin decreased serum TG and ApoB levels, and increased serum HDL-C levels. 16S rRNA sequencing indicated that Qifuyin increased alpha diversity and shifted beta diversity toward the control profile. At the phylum level, Qifuyin altered the relative abundances of Firmicutes, Bacteroidota, Cyanobacteria, and Synergistota. At the family and genus levels, Qifuyin treatment was associated with increased abundances of Helicobacteraceae, Bacteroidaceae, Helicobacter, and Bacteroides, and a reduced abundance of Ruminococcaceae. Metagenomic annotation analysis showed altered abundances of K02003, K06147, COG1961, CBM37, and GH35-related features.<br><br>DISCUSSION: These findings suggest that Qifuyin may benefit ApoE4-associated cognitive and systemic dysfunction through its integrated effects on lipid metabolism and gut microbiota alterations. The microbiota-related changes observed in this study may provide a potential link between peripheral metabolic regulation and cognitive improvement, although their mechanistic significance requires further validation.<br><br>CONCLUSIONS: Qifuyin improved cognitive performance and lipid metabolism, and was associated with alterations in gut microbiota composition in ApoE4 transgenic mice. These findings suggest that Qifuyin may exert beneficial effects on cognitive and systemic phenotypes in this model, while the biological significance of specific microbial changes warrants further investigation.},
}
@article {pmid42474022,
year = {2026},
author = {Li, OY and Herrera Guerra, D and Anthony, M and Oh, K and Vankee-Lin, F and Turnbull, A},
title = {Combining MRI-Derived Imaging Measures and Peripheral Proteomics to Improve the Mechanistic Understanding of Alzheimer's Disease Beyond Core Pathology: A Scoping Review.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050472412260629113636},
pmid = {42474022},
issn = {1875-5828},
abstract = {INTRODUCTION/BACKGROUND: Alzheimer's Disease (AD) core pathology involves amyloidβ and ptau, leading to neurodegeneration (ATN model), yet individuals with comparable core pathology show considerable biological and clinical heterogeneity, motivating new models that consider non-specific processes and co-pathology. MRI and peripheral proteomics offer complementary, non-invasive approaches for capturing biological variation beyond core pathology, and many researchers have begun integrating them. However, no systematic overview of this literature exists. This scoping review evaluated studies combining MRI and peripheral plasma proteomics in AD within revised diagnostic frameworks, summarizing strengths and gaps.<br><br>MATERIALS AND METHODS: Following PRISMA 2020 guidelines, PubMed, Embase, and Scopus were searched through June 14, 2023, yielding 3,185 records; 63 studies met the inclusion criteria. For each study, study design, participant characteristics, proteomic platforms, imaging modalities, statistical approaches, and significant associations between non-core-pathological proteins and MRIderived measures were extracted.<br><br>RESULTS: Across studies, methodological variability was high. Grey matter volume was the most commonly examined imaging metric, followed by cerebrovascular dysfunction, cortical thickness, white-matter and whole-brain volume, and connectivity measures. Overall, 127 non-core-pathology proteins, mostly related to inflammation/immune function, were associated with MRI metrics, though only three appeared in five or more studies. Roughly half of the studies incorporated core AD biomarkers.<br><br>DISCUSSION: This scoping review of 63 studies demonstrates that integrating peripheral proteomics with MRI is an increasingly common approach in AD research, with GFAP, CRP, and IL-6 as the most frequently reported proteins, and grey matter volume and vascular dysfunction as the most commonly examined imaging phenotypes. However, effect sizes are generally modest, findings are heterogeneous, and many studies lack core AD biomarkers, highlighting the need for greater methodological consensus and more mechanistic, multimodal, and longitudinal research.<br><br>CONCLUSION: Integrating MRI and peripheral proteomics is increasingly common in AD research, but consensus on analytic and imaging approaches is limited. Heterogeneity in proteomic platforms and statistical methods constrains comparability; most associations are modest, and observational designs limit causal inference. Future work should emphasize methodological harmonization, reproducibility, multivariate and machine-learning approaches, and randomized trials to test mechanistic pathways.},
}
@article {pmid42474120,
year = {2026},
author = {Zhang, J and Wang, Y and Huang, X and Wu, H and Lin, Q and Gu, H and Jiang, L and Zhu, L and Xu, H},
title = {Radical-Mediated In Situ Fluorescence Dye Deposition: A Simple Interfacial Signal Amplification Reaction for Ultrasensitive Immunoassay on Barcode Beads.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e76670},
doi = {10.1002/advs.76670},
pmid = {42474120},
issn = {2198-3844},
support = {2023YFB3210301//National Key Research and Development Program of China/ ; 2024YFA0917700//National Key Research and Development Program of China/ ; 2024YFA1803501//National Key Research and Development Program of China/ ; 2023YFA1802000//National Key Research and Development Program of China/ ; 82272122//National Natural Science Foundation of China/ ; 82172062//National Natural Science Foundation of China/ ; 22507071//National Natural Science Foundation of China/ ; 20250202//SJTU Trans-Med Awards Research/ ; YG2024ZD12//Fundamental Research Funds for the Central Universities/ ; YG2024QNA09//Fundamental Research Funds for the Central Universities/ ; 24ZR1432500//Natural Science Foundation of Shanghai/ ; },
abstract = {Ultrasensitive detection of low-abundance protein biomarkers is crucial for early disease diagnosis but remains challenging for the conventional barcode beads-based suspension chip platform due to the limited detection sensitivity. Here, we report a conceptually novel reaction termed "radical-mediated in situ fluorescence dye deposition" (RIFD) as a simple interfacial signal amplification strategy to overcome the limitation. This first discovered RIFD follows a universal "three-element principle", where the coexistence of beads, free radicals, and dyes suffices for fluorescence labeling, eliminating the pre-conjugation of dyes to detection probes required in traditional methods. Mechanistic studies reveal that this radical-triggered RIFD possibly follows three distinct pathways, including amide condensation on lysine residues, covalent biphenyl formation on tyrosine residues, or radical-dye co-deposition. It facilitates local and ultrafast (within 5 min) dye-trapping specifically on target-positive barcode beads. Consequently, the established RIFD-based immunoassay achieves a limit of detection of 12 fg/mL for IL-10, a 100-fold improvement over the conventional suspension chip method, and also successfully differentiates Alzheimer's disease patients from healthy controls by quantifying low-abundance plasma p-Tau217. Multiplexed detection is further validated with a three-plex cytokines panel. Our reported RIFD represents a powerful in situ fluorescence labeling tool, advancing protein biomarker detection toward the sub-pg/mL level with broad implications for clinical diagnostics.},
}
@article {pmid42474289,
year = {2026},
author = {Fang, S and Sha, Y and Zhou, Y and Sun, G and Li, E and Yao, M and Zhou, L and Zhu, Y and Peng, B and Ni, J},
title = {Brain iron, cortical atrophy and cognition impairment in cerebral amyloid angiopathy: A quantitative susceptibility mapping study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261469524},
doi = {10.1177/13872877261469524},
pmid = {42474289},
issn = {1875-8908},
abstract = {BackgroundBrain iron deposition is associated with cognitive impairment in cerebral amyloid angiopathy (CAA) and Alzheimer's disease, but the exact mechanisms remain unclear.ObjectiveTo investigate whether cortical atrophy mediates iron-related cognitive impairment in CAA.MethodsWe prospectively enrolled CAA patients to collect clinical characteristics, conduct global cognitive assessment and magnetic resonance imaging. Iron levels of each brain region were quantified by susceptibility values from quantitative susceptibility mapping. Three-dimensional T1-weighted imaging was collected to calculate cortex volume. For statistical analyses, first, we conducted univariable linear regressions to identify regions with potential associations to cognitive impairment, with p < 0.1 as threshold. Second, we used elastic net analysis to identify regions where iron depositions strongly correlated with cognitive deficits. Finally, we conducted mediation analysis, using these selected regions to test whether iron-related cognitive dysfunction occurs through cortical atrophy.ResultsForty-four patients were included. The median age was 71.5 years old (IQR 62.3, 75.0), and twenty-two were male. Two-thirds of patients presented with mild cognitive impairment or dementia. Elastic net analysis revealed that iron accumulations in the right Rolandic area, left inferior occipital gyrus, left posterior cingulate gyrus and cerebellum were associated with worse cognitive performance. Mediation analysis showed significant total effect of iron in left posterior cingulate gyrus on Mini-Mental State Examination (β = -0.156, p = 0.002), but the average causal mediation effect was insignificant (p = 0.77).ConclusionsWhile regional iron deposition was associated with cognitive impairment in CAA, cortical atrophy did not significantly mediate this relationship in this exploratory study.},
}
@article {pmid42474291,
year = {2026},
author = {Nong, Y and Wellman, S and Zhang, H and Liu, YA and Argyrousi, EK and Arancio, O and Wang, Q},
title = {Long-term locus coeruleus stimulation exacerbates tau pathology in PS19 mice.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261468577},
doi = {10.1177/13872877261468577},
pmid = {42474291},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is the most common form of dementia, characterized by the accumulation of amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles. The locus coeruleus (LC) is among the first brain regions to show degeneration and tau pathology during the early stages of AD. Previous studies have demonstrated that short-term chemogenetic LC stimulation can improve memory performance in the TgF344-AD rat model, while long-term norepinephrine reuptake inhibition can worsen memory deficits in the ADLP[Tau] mouse model. However, the effects of long-term LC stimulation in tau mouse models on memory, synaptic plasticity, and tauopathy remain unclear.ObjectiveTo evaluate the impact of long-term LC stimulation on memory, synaptic plasticity, and tauopathy in PS19 mice using behavioral paradigms, electrophysiological recordings, and immunofluorescence analysis.MethodsThe radial arm water maze and fear conditioning test were conducted to assess memory performance in PS19 mice with and without long-term LC stimulation. Hippocampal long-term potentiation (LTP) was recorded to evaluate the effect of long-term LC stimulation on synaptic plasticity. Immunofluorescence was employed to examine tau phosphorylation, neurodegeneration, and neuroinflammation.ResultsLong-term LC stimulation in PS19 mice exacerbated spatial memory deficits in the water maze, impaired contextual fear memory, reduced hippocampal LTP, and increased asparagine endopeptidase (AEP) expression, tau hyperphosphorylation, and neuroinflammation.ConclusionsLong-term LC stimulation may exacerbate memory deficits in PS19 mice by impairing synaptic plasticity and increasing neural degeneration in the hippocampus. Increased AEP expression and tau hyperphosphorylation in the LC further suggest a possible association between LC overactivation and AEP-associated tau pathology.},
}
@article {pmid42474295,
year = {2026},
author = {Pereira De Souza, NA and Belfort Almeida Dos Santos, TT and Lima Nogueira, MM and Nascimento Dourado, MC},
title = {From mild cognitive impairment to moderate Alzheimer's disease: Associations between decision-making capacity and awareness.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261468737},
doi = {10.1177/13872877261468737},
pmid = {42474295},
issn = {1875-8908},
abstract = {BackgroundEvidence on how distinct stages of mild cognitive impairment (MCI) and Alzheimer's disease (AD) affect decisional capacity and disease awareness remains limited.ObjectiveWe aim to examine the impairment of decision-making capacity, hypothesizing that people with MCI would demonstrate greater capacity and awareness than those with AD. We also aim to explore associations with cognitive and clinical variables.MethodsWe conducted a cross-sectional study including 137 participants: MCI (n = 37), mild AD (n = 50), and moderate AD (n = 50). Standardized assessments were used to evaluate domains of decision-making capacity and awareness of the illness.ResultsPeople with MCI performed significantly better in understanding, appreciation, and reasoning domains, while expression of choice was preserved across all groups. Disease awareness was higher in MCI, whereas AD participants showed marked deficits, particularly in cognitive and functional domains. Differences in socioemotional awareness were less consistent.ConclusionsOur findings indicate a decline, from MCI to moderate AD, in decisional capacity and awareness, with expression of choice remaining relatively intact. These results have important ethical and clinical implications for shared decision-making and dementia care.},
}
@article {pmid42474304,
year = {2026},
author = {Tong, Y and Lv, X and Liu, J and Cheng, Z and Wang, J and Hua, W and Li, R and Zheng, J and Guo, G and Tang, S},
title = {Disease burden of Alzheimer's disease and other dementias in older adults.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261469808},
doi = {10.1177/13872877261469808},
pmid = {42474304},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease and other dementias are major contributors to mortality and disability in older adults worldwide, posing an escalating threat to individuals, families, and communities.ObjectiveThis study analyzed the global burden, sex disparities, and socioeconomic inequalities of Alzheimer's disease and other dementias among adults aged 65 and older from 1990 to 2021.MethodsData from the Global Burden of Disease Study 2021 were used to calculate age-standardized rates for prevalence, mortality, disability-adjusted life-years (DALYs). Joinpoint regression analyzed temporal trends. Sex differences were quantified and correlated with the Socio-demographic Index (SDI), while cross-country inequality was assessed using the slope index of inequality (SII) and concentration index.ResultsIn 2021, an estimated 49.1 million older adults lived with Alzheimer's disease and other dementias. Although age-standardized incidence rates were generally stable, a small increase occurred during the 2019-2021 COVID-19 pandemic. However, these observations cannot be inferred causality from the present data. Females bore a consistently higher burden than males, with disparities widening with age and lower SDI. Although sex differences in DALYs showed a slight global decline, the most significant disparities were found in Africa, Asia, and Australasia. Cross-country inequality (SII) decreased between 1990 and 2021.ConclusionsThe absolute burden of Alzheimer's disease and other dementias has grown substantially and disproportionately affects females. Persistent disparities necessitate targeted policies and investments to ensure equitable access to prevention, diagnosis, and care, particularly for women and populations in lower-SDI regions.},
}
@article {pmid42474305,
year = {2026},
author = {Han, X and Li, Y and Wang, J and Liu, X and Cao, E and Song, Y and Song, L and Cong, L and Zhang, Q and Tang, S and Wang, Y and Du, Y and Qiu, C},
title = {Early- and late-life brain reserve proxies and their interactions with education on cognitive outcomes in older adults: A population-based MRI study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261469556},
doi = {10.1177/13872877261469556},
pmid = {42474305},
issn = {1875-8908},
abstract = {BackgroundThe interplay between early- and late-life brain reserve (BR) and early-life education in shaping late-life cognitive function requires further elucidation.ObjectiveWe sought to examine the associations of early- and late-life BR and cognitive function among rural older adults in China, and to assess whether education influenced their relationships.MethodsIn this cross-sectional study (n = 1304), early-life and late-life BR were proxied by total intracranial volume (TIV) and the ratio of total normal brain tissue volume-to-TIV, respectively. Both measures were dichotomized into high and low BR according to their median. Education was classified as high (any formal schooling) and low (no formal schooling). We administered a neuropsychological test battery to assess memory, verbal fluency, executive function, and attention. Mild cognitive impairment (MCI) was diagnosed following Petersen's criteria. Regression analyses were performed.ResultsHigher late-life BR was associated with better performance across all cognitive domains (p < 0.01) and reduced likelihoods of MCI and amnestic MCI (p < 0.001). Joint-exposure analyses suggested that compared to participants with low BR and low education, individuals with both high late-life BR and high education showed best cognitive performance and lowest likelihoods of MCI, followed by those with low BR and high education. Moreover, higher late-life BR was linked to better executive function, attention, and global cognition only in participants with high education (p for interaction<0.05).ConclusionsLate-life BR has a stronger association with cognitive health than early-life BR, even among older adults without formal schooling. Furthermore, formal education may enhance the association between late-life BR and cognitive function.},
}
@article {pmid42474486,
year = {2026},
author = {Santos de Carvalho, RL and Dos Santos, LAP and Ferrison, J and Bomilcar, I and Bertrand, E and Dourado, MCN and Morris, RG and Mograbi, DC},
title = {"Has your Memory Been Letting you Down?" Use of Figurative Language Modulates Expression of Awareness of Impairments in Alzheimer's Disease.},
journal = {Journal of geriatric psychiatry and neurology},
volume = {},
number = {},
pages = {8919887261469563},
doi = {10.1177/08919887261469563},
pmid = {42474486},
issn = {1552-5708},
abstract = {IntroductionWe compared responses of people with Alzheimer's disease (PwAD) on the Assessment Scale of Psychosocial Impact of the Diagnosis of Dementia and an adapted figurative language version. We hypothesize that figurative language improves acknowledgment of difficulties, varying by awareness object.Methods27 mild to moderate PwAD completed measures of cognition, depression and self-reported impairments. Caregivers informed about functionality, apathy and neuropsychiatric symptoms.ResultsAcknowledgment of difficulties in activities of daily living was higher in the figurative version, while acknowledgment in the emotional domain was higher in the regular version, in both cases with medium effect sizes. No significant differences emerged for total scores, acknowledgement of cognitive deficits, or changes in social relationships, all with small effect sizes.DiscussionLanguage modulation altered acknowledgment by awareness object. Findings support clear, not complex language in assessments. Future studies should define strategies to improve awareness and its predictors across clinical groups.},
}
@article {pmid42474503,
year = {2026},
author = {Vourkas, O and Zhang, L and Jimenez-Pérez, A and Sánchez-Martín, C and Fernández-Álvarez, M and Rabano, A and Sánchez-Juan, P and Silva-Rodríguez, J and Grothe, MJ and , },
title = {[[18]F]FDG PET outperforms MRI for detecting early tau-related neurodegeneration.},
journal = {European journal of nuclear medicine and molecular imaging},
volume = {},
number = {},
pages = {},
pmid = {42474503},
issn = {1619-7089},
support = {RYC2023-043746-I//Ministerio de Ciencia e Innovaci&#xf3;n/ ; CNS2024-154295//Ministerio de Ciencia e Innovaci&#xf3;n/ ; PMP22/00022, PI20/01011, PI24/00089, TED2021-131676B-100//Instituto de Salud Carlos III/ ; E.6.4 FRS-CUERPOS DE LEWY//Reina Sofia Foundation/ ; },
abstract = {PURPOSE: Neurodegeneration is a hallmark of Alzheimer's disease (AD), measurable in-vivo with [[18]F]FDG PET or MRI. However, the relative sensitivities of these modalities at different stages of AD remain poorly understood. Here, we directly compared associations of hypometabolism and gray matter (GM) atrophy with tau pathology staging at autopsy.<br><br>METHODS: Eighty-eight individuals from the ADNI autopsy cohort with Braak tau staging and ante-mortem [[18]F]FDG PET and T1-weighted MRI scans were analyzed. Spearman correlations assessed associations between Braak stage and hypometabolism or GM atrophy across 52 regions of interest. Regions showing significant correlations were further assessed for differences between early/intermediate (II-IV; n=24) and advanced (V/VI, n=56) Braak stages compared to controls (0/I, n=8). To address the limited size of the pathological control group, analyses were replicated using a larger sample of age-matched cognitively unimpaired individuals with no evidence of amyloid or tau pathology on PET imaging (n=45).<br><br>RESULTS: Higher Braak stages were associated with [[18]F]FDG PET hypometabolism in temporo-parietal regions, with large effects detectable even at early/intermediate stages and further reductions in advanced stages. Concomitant MRI-derived GM atrophy showed similar but smaller effects, significant only for advanced stages. Direct cross-modality comparisons confirmed more pronounced hypometabolism than GM atrophy across most affected regions. Replication analyses using the larger cognitively unimpaired control sample yielded highly similar findings.<br><br>CONCLUSION: [[18]F]FDG PET hypometabolism is a sensitive and early marker of AD-related neurodegeneration, preceding MRI-detectable GM atrophy and more closely reflecting underlying tau pathology across disease stages.},
}
@article {pmid42474555,
year = {2026},
author = {Singh, P and Rath, SL},
title = {Neural network-enhanced investigation of ferroptosis and druggability in early-onset alzheimer's disease.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42474555},
issn = {1573-7365},
mesh = {*Ferroptosis/physiology/genetics/drug effects ; *Alzheimer Disease/metabolism/drug therapy/genetics ; Humans ; Biomarkers/metabolism ; MicroRNAs/genetics/metabolism ; Oxidative Stress/physiology ; *Neural Networks, Computer ; Machine Learning ; },
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder which is multifactorial in nature. Some of its characteristics are slow cognitive decline, memory problems and behavioral changes. AD patient brains show a progressive synaptic toxicity, autophagy, neuroinflammation, excess generation of reactive oxygen species (ROS), neuronal death and oxidative stress, which occurs due to disrupted metal homeostasis along with tau and amyloid-β protein deposition. Notably, lipid peroxidation, iron buildup and elevated oxidative stress in AD brains suggest a possible molecular connection between ferroptosis and AD neurodegeneration. This study explores the genetic and bioinformatics perspective on the relationship between ferroptosis and AD aiming to identify potential therapeutic potential biomarkers using Neural network (NN) and Machine learning models. Six ferroptosis related genes were found to be differentially expressed in AD. Further machine learning analysis shortlisted four key biomarker genes. An NN-based diagnostic prediction model was developed and validated using AUC-ROC anaysis, which gave high diagnostic values (AUC- 0.92) in the analysis. The findings highlight a strong correlation between ferroptosis and altered metabolic functions in AD. miRNA-gene interaction analysis revealed that two biomarker genes, CYBB and ACSL4 can be regulated by several regulatory miRNAs i.e., hsa-miR-146-5p, hsa-miR-106b-5p, hsa-miR-223-3p, hsa-miR-155-5p, hsa-miR-34a-5p, hsa-miR-125b-5p and hsa-miR-27a-3p suggesting their potential as early diagnostic potential biomarkers. Immune microenvironment analysis revealed strong neuroinflammatory responses in AD with increased infiltration of macrophages (M0, M1 and M2), monocytes and multiple T cell subsets. This heightened immune activity may be driven by ferroptosis-induced oxidative stress contributing to neuronal death. Furthermore, druggability of these targets was evaluated and several drugs were identified that may be potentially repurposed for therapeutic intervention in AD pathogenesis. This study presents a diagnostic predictive model integrating gene expression, miRNA regulation and immune infiltration analysis, offering a novel perspective on early AD detection. The identified ferroptosis-related potential biomarkers and regulatory miRNAs could serve as valuable tools for clinical diagnosis and targeted therapeutic intervention, advancing personalized treatment strategies for Alzheimer's disease.},
}
@article {pmid42474734,
year = {2026},
author = {Zheng, Y and Bhalala, OG and Chin, KS and Watson, R and Yassi, N},
title = {Use of blood-based neurofilament light chain as an endpoint in clinical trials of neurodegenerative conditions: a scoping review.},
journal = {Journal of neurology},
volume = {273},
number = {8},
pages = {},
pmid = {42474734},
issn = {1432-1459},
mesh = {Humans ; *Neurofilament Proteins/blood ; *Neurodegenerative Diseases/blood/diagnosis ; Biomarkers/blood ; *Clinical Trials as Topic ; },
abstract = {INTRODUCTION: Neurofilament light chain (NfL) is a structural axonal protein measurable in CSF and blood, increasingly investigated as a biomarker of neuroaxonal injury in clinical and research contexts. This review aims to explore the use of blood-based NfL as an endpoint in clinical trials of neurodegenerative conditions.<br><br>METHOD: A database search of MEDLINE and EMBASE was conducted to identify interventional clinical trials and/or related post hoc analyses for neurodegenerative diseases, published between 2013 and 2024 that reported the use of serum or plasma NfL as an endpoint. Additional studies from reference lists of included trials were manually considered for inclusion where relevant. Data were charted descriptively by disease type and summarised.<br><br>RESULTS: 49 studies were included, 29 in multiple sclerosis (MS), eight in amyotrophic lateral sclerosis (ALS), six in Alzheimer's disease (AD), and six in other diseases. Across studies, reductions in NfL often paralleled improvements in primary efficacy outcomes, supporting its use as a biomarker of disease activity and treatment response. However, several studies demonstrated a lack of concordance between change in NfL and in clinical outcomes, some of which may be related to the non-disease-modifying mechanisms of the interventions studied. This necessitates careful consideration when applying blood-based NfL as a biomarker endpoint for studies involving such interventions.<br><br>CONCLUSION: Blood NfL is a promising biomarker with potential utility as a surrogate endpoint in neurological clinical trials, particularly for diseases with active axonal injury. Further validation, particularly around disease- and intervention-specific interpretation, is needed before blood NfL can be incorporated more routinely as a clinical endpoint.},
}
@article {pmid42474786,
year = {2026},
author = {Kale, D and Dcunha, BV and Lakshmi, S and Raghu, SV and Elumalai, P},
title = {Neuroprotective potential of marine-derived polysaccharide against Aβ42-induced toxicity in a Drosophila Alzheimer's disease model.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42474786},
issn = {1573-4978},
support = {ICMR (2021 - 11092 No. 52/08/2022 BIO/BMS//ICMR/ ; },
mesh = {Animals ; *Polysaccharides/pharmacology/metabolism ; *Alzheimer Disease/metabolism/drug therapy ; *Amyloid beta-Peptides/metabolism/genetics/toxicity ; Oxidative Stress/drug effects ; *Neuroprotective Agents/pharmacology ; Drosophila melanogaster/metabolism ; Disease Models, Animal ; Humans ; Reactive Oxygen Species/metabolism ; Animals, Genetically Modified ; *Peptide Fragments/metabolism ; Antioxidants/pharmacology ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative condition caused by amyloid β (Aβ42) accumulation, neuroinflammation, oxidative stress and cholinergic dysfunction, resulting in neuronal death and cognitive decline. Excessive Aβ42 accumulation disrupts redox equilibrium, increases reactive oxygen species (ROS), and activates inflammatory and apoptotic pathways. Natural bioactive compounds with immunomodulatory and antioxidant properties are increasingly being explored as possible multi-target therapies. Alkylglycerol (AKG), a lipid-derived immunomodulator, and fucoidan, a sulfated polysaccharide found in brown algae, have both shown neuroprotective properties. This study examines the effectiveness of Fucoidan and AKG in preventing Aβ42-induced diseases in a Drosophila melanogaster model, both individually and in combination.<br><br>METHODOLOGY: Transgenic Drosophila expressing human A&#x3b2;42 in the brain were divided into control, A&#x3b2;42, Fucoidan-treated, AKG-treated, and combination-treated groups. Oxidative stress indicators such as nitric oxide (NO), hydrogen peroxide (H2O&#x2082;), malondialdehyde (MDA), and total ROS were measured using biochemical tests. To evaluate redox reactions, the activity of the antioxidant enzymes glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD) were evaluated. Cholinergic function was assessed by measuring acetylcholinesterase (AChE) activity. The analysis of gene expression focused on genes linked with oxidative stress (SOD, CAT, PHPGx, TRx1), inflammatory markers (TNF&#x3b1;, TNF&#x3b1;R), apoptotic regulator p53, and neurogenesis-related genes (Wnt pathway, SOX2, Nanog).<br><br>RESULTS AND DISCUSSION: A&#x3b2;42 expression disrupted neurogenic signaling and cholinergic balance while markedly increasing oxidative markers and inflammatory mediators. Although AKG and fucoidan separately decreased inflammation and oxidative stress, the combination treatment yielded the biggest results. Dual therapy increased the activity of antioxidant enzymes, decreased the activity of AChE, downregulated TNF&#x3b1; and p53, and restored the expression of Wnt, SOX2, and Nanog. These results demonstrate the translational potential of Fucoidan and AKG act for AD care by showing that their combined treatment helps to restore redox stability, suppress inflammation, boost neurogenesis, and mitigate A&#x3b2;42-induced neurotoxicity.},
}
@article {pmid42475091,
year = {2026},
author = {Wang, SH and Lin, MC and Fan, CC and Huang, WL and Hsu, CC and Wu, CS},
title = {Spousal Dementia Exposure and Risk of Dementia.},
journal = {JAMA network open},
volume = {9},
number = {7},
pages = {e2624175},
doi = {10.1001/jamanetworkopen.2026.24175},
pmid = {42475091},
issn = {2574-3805},
mesh = {Humans ; Female ; Male ; Taiwan/epidemiology ; Aged ; *Dementia/epidemiology ; *Spouses/statistics &amp; numerical data/psychology ; Risk Factors ; Cohort Studies ; Middle Aged ; Socioeconomic Factors ; Aged, 80 and over ; Incidence ; },
abstract = {IMPORTANCE: Previous studies suggest that spouses of individuals with dementia may be at increased risk of developing dementia, but evidence regarding subgroup variation and absolute risk remains limited.<br><br>OBJECTIVE: To examine whether spouses of individuals with dementia have an increased risk of developing dementia and to assess whether this association is modified by demographic, socioeconomic, and family context factors.<br><br>This nationwide population-based cohort study used Taiwan's National Health Insurance Research Database from 1998 to 2022, with follow-up through 2022. To address prior limitations of small sample size and limited subgroup evaluation, spouses of individuals with incident dementia were identified and matched 1 to 4 to unexposed controls by birth year, sex, income, and urbanicity. The analysis was conducted between July 15, 2025, and May 15, 2026.<br><br>EXPOSURE: Spousal exposure to incident dementia.<br><br>MAIN OUTCOMES AND MEASURES: Incident all-cause dementia, Alzheimer disease, and vascular dementia. Hazard ratios (HRs) and 5-year absolute risk differences were estimated using Cox regression and g-computation.<br><br>RESULTS: The matched cohort included 955&#x202f;105 individuals, with 118&#x202f;904 exposed women and 72&#x202f;117 exposed men as well as 475&#x202f;616 unexposed women and 288&#x202f;468 unexposed men. The largest proportion were aged 65 to 74 years at cohort entry, for women (47&#x202f;084 [39.6%]) and men (28&#x202f;477 [39.5%]). Spouses of individuals with dementia had a higher risk of all-cause dementia than unexposed spouses. For women, the HR was 1.74 (95% CI, 1.70-1.78), with a 5-year adjusted risk difference of 2.75 percentage points (pp) (95% CI, 2.63-2.87 pp). For men, the HR was 1.69 (95% CI, 1.64-1.73), with a 5-year adjusted risk difference of 3.49 pp (95% CI, 3.30-3.69 pp). Similar patterns were observed in analyses of Alzheimer disease and vascular dementia. Relative risks were more prevalent at younger ages, whereas absolute risk differences increased with age. For all-cause dementia, the association was attenuated among individuals with higher income or more children. Associations were otherwise broadly similar across sex and urbanicity.<br><br>CONCLUSIONS AND RELEVANCE: In this cohort study of married individuals in Taiwan, spouses of individuals with dementia had a higher risk of dementia than unexposed spouses. The association varied across family and socioeconomic contexts, highlighting the relevance of household context in dementia risk assessment.},
}
@article {pmid42475211,
year = {2026},
author = {Dong, Z and Liu, H and Ge, X and Zhang, H and Li, Z and Chen, Y and Li, W},
title = {Brain Region-Centered MultiModal Hypergraph Fusion for MCI Conversion Prediction.},
journal = {IEEE journal of biomedical and health informatics},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/JBHI.2026.3715131},
pmid = {42475211},
issn = {2168-2208},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder, with mild cognitive impairment (MCI) as its prodromal stage. Accurate MCI conversion prediction is critical for early intervention and resource allocation. Recently, deep learning-based multimodal neuroimaging fusion has become a hot research topic in AI-assisted AD diagnosis. Existing multimodal fusion approaches are limited by modality heterogeneity, insufficient ability to model inter-regional interactions, and insufficient interpretability. To address these challenges, BRC-MMHF, a Brain Region-Centered MultiModal Hypergraph Fusion framework, is proposed. In this framework, parameter-free channel exchange and ROI-level feature extraction mechanisms are employed to reduce modality heterogeneity and extract structurally consistent features from MRI and PET. A multimodal hypergraph models high-order inter regional cross-modal relationships, while a lesion-aware module highlights disease-relevant regions to enhance interpretability. Structured clinical data are incorporated through a lightweight tabular encoder to improve adaptability and diagnostic robustness. Experiments on the ADNI dataset show that BRC-MMHF achieves 80.79% accuracy and 89.78% AUC in MCI conversion prediction, outperforming a range of state-of-the-art methods based on MRI and PET imaging, while providing auxiliary interpretability.},
}
@article {pmid42475384,
year = {2026},
author = {Ma, L and Wang, D and Li, Z and Ye, G and Chen, M},
title = {Exosomal gene-based predictive model and therapeutic target identification for Alzheimer's disease: A bioinformatics analysis.},
journal = {PloS one},
volume = {21},
number = {7},
pages = {e0354014},
doi = {10.1371/journal.pone.0354014},
pmid = {42475384},
issn = {1932-6203},
mesh = {*Alzheimer Disease/genetics/drug therapy/metabolism ; Humans ; *Computational Biology/methods ; Molecular Docking Simulation ; *Exosomes/genetics/metabolism ; Gene Regulatory Networks ; Gene Expression Profiling ; Databases, Genetic ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a degenerative central nervous system disorder characterized by progressive cognitive and behavioral impairment. As nanoscale intercellular communication vesicles that carry AD-related pathological molecules, exosomes are promising biomarkers and therapeutic carriers for AD. In this study, we downloaded AD-related gene expression profiles and clinical data from the Gene Expression Omnibus (GEO) database (datasets GSE138260, GSE29378, GSE36980, and GSE5281). Through a series of bioinformatics analyses, clinical predictive model construction, pharmacological network analysis, and molecular docking simulations, we developed an exosomal gene-based predictive model for AD pathogenesis and identified potential pharmacological networks and molecular docking targets for AD treatment.<br><br>MATERIALS AND METHODS: AD-related gene expression and clinical data were retrieved from the GEO database. Bioinformatics analyses, clinical model construction, drug-gene network analysis, and molecular docking were subsequently performed to explore exosomal gene models for predicting AD pathogenesis, as well as potential pharmacological networks and molecular docking targets for AD therapy.<br><br>RESULTS: A five-exosomal-gene predictive model was established, comprising CD44, CXCR4, TUBB, PSMA5, and PSMB3. Pharmacological network analysis of these five genes revealed their significant associations with chelidonine, 2-chloro-1,4-dinitrobenzene, oxazolone, phencyclidine, thioridazine, and etodolac. Further molecular docking simulations identified key binding targets, including R41, Y42, R78, Y79, C77, I88, C97, A98, I96, I72, L70, E67, G103, I91, and T102.<br><br>CONCLUSIONS: Our comprehensive analyses successfully established a reliable exosomal gene-based model for predicting AD pathogenesis, and identified relevant pharmacological networks and core molecular docking targets, providing novel insights for AD diagnosis and targeted therapy.},
}
@article {pmid42475397,
year = {2026},
author = {Aponte, EA and Perumal, TM and Cormack, F and Chatham, CH},
title = {Beyond memory capacity: A probabilistic, dual store model of visuospatial working memory.},
journal = {PLoS computational biology},
volume = {22},
number = {7},
pages = {e1014535},
doi = {10.1371/journal.pcbi.1014535},
pmid = {42475397},
issn = {1553-7358},
abstract = {The last decades have seen a great improvement in our understanding of visuospatial working memory (VSWM). Despite this progress, less is known about how information is stored, retained, and removed from VSWM when novel information is presented sequentially. Here, we present a novel computational model of the dynamics of VSWM that extends and improves classical ideas. Our analysis relies on data from three clinical trials involving neurotypicals and people with autism performing a smartphone based sequential VSWM task. In addition, we applied the model to data from a large clinical trial in prodromal Alzheimer's disease. We demonstrate that visual information in our sequential task is stored in independent pools of contrasting resources, with perfect and imperfect retrieval rates. Our findings illustrate how computational models combined with remote cognitive testing are mature enough for applications in large-scale clinical research.},
}
@article {pmid42475419,
year = {2026},
author = {Elshekh, A and Abdelmaguid, AM and Eltanany, RMA and El-Kordy, YH and Khedr, AA and Mekkawy, SA and El-Khadragy, MF and Albrakati, A and Abdelfattah, MS and Abdel Moneim, AE},
title = {Computational Evaluation of Oleuropein Interactions with Alzheimer's Disease-Related Proteins Using Molecular Docking and Molecular Dynamics.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {232},
pages = {},
doi = {10.3791/71430},
pmid = {42475419},
issn = {1940-087X},
mesh = {*Molecular Dynamics Simulation ; Iridoid Glucosides ; *Alzheimer Disease/metabolism/drug therapy ; *Molecular Docking Simulation/methods ; *Iridoids/chemistry/metabolism ; Humans ; tau Proteins/metabolism/chemistry ; Amyloid beta-Peptides/metabolism/chemistry ; },
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder associated with amyloid aggregation, tau pathology, and neuroinflammation. In this study, an integrated computational workflow combining ADMET prediction, PASS-based activity screening, molecular docking, and molecular dynamics (MD) simulations was employed to evaluate the interactions of oleuropein with five AD-related protein targets, including β-amyloid, tau, apolipoprotein E4 (ApoE4), triggering receptor expressed on myeloid cells 2 (TREM2), and complement protein C1q. ADMET and PASS analyses predicted pharmacokinetic properties and potential biological activities associated with neurodegenerative disease-related pathways. Docking analysis predicted favorable binding affinities across the investigated targets, with the strongest predicted interaction observed for the C1q protein (-7.5 kcal/mol). Molecular dynamics (MD) trajectory analyses, including root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), radius of gyration (Rg), dynamic cross-correlation matrix (DCCM), principal component analysis (PCA), and distance-based metrics, were used to evaluate the dynamic behavior of the protein-ligand complexes during the simulations. The computational analyses suggested relatively stable interactions for tau, C1q, and TREM2 complexes, whereas β-amyloid and ApoE4 exhibited comparatively higher conformational variability during portions of the simulations. These findings provide a preliminary computational assessment of oleuropein interactions with AD-related proteins and may support future experimental studies investigating its potential biological relevance in neurodegenerative disease models.},
}
@article {pmid42475614,
year = {2026},
author = {Jarrell, L and Vanhoy, S},
title = {Doll therapy: Innovative treatment for patients with Alzheimer disease to improve patient and staff safety in a hospital setting.},
journal = {Nursing},
volume = {56},
number = {8},
pages = {56-61},
doi = {10.1097/NSG.0000000000000419},
pmid = {42475614},
issn = {1538-8689},
mesh = {Humans ; *Alzheimer Disease/therapy/psychology ; Female ; Male ; *Patient Safety/standards ; Aged ; *Play Therapy/methods ; Accidental Falls/prevention &amp; control ; Aged, 80 and over ; },
abstract = {BACKGROUND: Patients with Alzheimer disease may display negative neuropsychiatric symptoms that can pose patient safety risks.. Doll therapy is described in the literature as a successful diversional activity for these patients.<br><br>PURPOSE: This project aimed to provide doll therapy to patients with Alzheimer disease at their facility to reduce neuropsychiatric symptoms, improve patient safety, patient outcomes, and the patient and family experience, and to positively impact the health care team's experience when caring for this patient population.<br><br>METHODS: A total of 55 patients with a diagnosis of Alzheimer disease participated in the doll therapy program. Quantitative and qualitative data were collected and analyzed. These included patient's behavior prior to doll therapy and the patient's response to doll therapy.<br><br>RESULTS: Patients experienced a sense of purpose and comfort, as well as decreased risk for falls, physical workplace violence events, and being placed in restraints as a result of doll therapy.},
}
@article {pmid42475650,
year = {2026},
author = {Tang, C and Yang, J and Luo, W and Lei, X and Peng, X and Chen, Y and Guan, S and He, D},
title = {Rapidly Progressive Alzheimer Disease and Related Dementias as a Phase Transition: Symptom Cascades and Survival Inflection.},
journal = {Neurology},
volume = {107},
number = {3},
pages = {e218350},
doi = {10.1212/WNL.0000000000218350},
pmid = {42475650},
issn = {1526-632X},
mesh = {Humans ; Disease Progression ; Female ; *Alzheimer Disease/mortality/physiopathology/diagnosis ; Male ; Aged ; Retrospective Studies ; Longitudinal Studies ; Aged, 80 and over ; *Dementia/mortality ; },
abstract = {BACKGROUND AND OBJECTIVES: Rapidly progressive Alzheimer disease and related dementias (rpADRD) is a clinically urgent syndrome characterized by accelerated deterioration. Because it is often confounded by acute etiologies, its definition remains poorly characterized. We aimed to evaluate rpADRD as a distinct clinical state, testing the hypothesis that it represents a clinical "phase transition" rather than a simple linear acceleration of typical neurodegenerative decline. Our objective was to define this transition threshold and quantify its impact on survival and disease trajectory.<br><br>METHODS: We conducted a retrospective cohort study using longitudinal data from participants recruited across US Alzheimer's Disease Research Centers. We defined incident rpADRD as dementia development (global Clinical Dementia Rating [CDR] &#x2265;1) within 1 year of symptom onset, or progression to moderate-to-severe impairment (global CDR &#x2265;2) within 2 years. To isolate primary neurodegeneration, we excluded prion, infectious, metabolic, toxic, and autoimmune etiologies. We used time-dependent Cox regression, multistate modeling, and restricted cubic spline analyses to model nonlinear survival dynamics.<br><br>RESULTS: The final analysis cohort included 2,307 participants (mean baseline age 78.9 years; 57.1% female). Over a mean follow-up of 7.3 years, 270 patients (11.7%) developed incident rpADRD. Patients transitioning to rpADRD were older than non-rpADRD patients (mean 80.0 vs 78.8 years). Crucially, the transition to rpADRD was strongly associated with increased subsequent mortality (hazard ratio = 4.03; 95% CI 3.53-4.61, p < 0.001). Multistate and spline modeling confirmed that this shift represents a distinct, nonlinear clinical phase transition rather than a linear exacerbation of functional decline. Furthermore, this critical tipping point was reliably preceded by an early cascade of neuropsychiatric symptoms.<br><br>DISCUSSION: These findings validate a clinical "phase transition" model for rpADRD, demonstrating that survival decline is not merely a linear function of disease severity. Rather, rpADRD constitutes a distinct state of clinical homeostatic failure fundamentally shifting subsequent mortality risk, often predicted by early neuropsychiatric symptoms. Recognizing this nonlinear shift is vital for accurate prognostication and segregation of rapidly progressing phenotypes in trials. Major limitations include reliance on observational data, potential recall bias regarding symptom onset, and the exclusion of neuroimaging and fluid biomarkers because of high missingness.},
}
@article {pmid42475746,
year = {2026},
author = {Yang, A and Manaswi, A and Fischer, MW and Fischer, IC and Na, PJ and Pietrzak, RH},
title = {Comorbid Cardiovascular Disease and Posttraumatic Stress Disorder in Older US Veterans: Prevalence, Health Burden, and Functional Impairment.},
journal = {The primary care companion for CNS disorders},
volume = {28},
number = {4},
pages = {},
doi = {10.4088/PCC.26m04187},
pmid = {42475746},
issn = {2155-7780},
mesh = {Humans ; *Veterans/statistics &amp; numerical data ; *Stress Disorders, Post-Traumatic/epidemiology ; Male ; United States/epidemiology ; *Cardiovascular Diseases/epidemiology ; Prevalence ; Aged ; Comorbidity ; Female ; Middle Aged ; Aged, 80 and over ; },
abstract = {Objective: Cardiovascular disease (CVD) and posttraumatic stress disorder (PTSD) are prevalent and disabling conditions among older US veterans. Both are independently associated with poor physical, mental, and functional outcomes, but little is known about the combined burden. This study aims to examine the prevalence, risk correlates, health comorbidities, and functional outcomes of comorbid CVD+PTSD in older US veterans. Methods: Data were analyzed from 3,001 US veterans aged 60 years and older who participated in the 2019-2020 National Health and Resilience in Veterans Study. Self-reported CVD, PTSD, health comorbidities, and functional outcomes were examined using weighted bivariate and multivariable analyses. Results: A total of 23.1% of veterans had CVD only, 5.5% PTSD only, and 2.2% comorbid CVD+PTSD. Veterans with CVD+PTSD were more likely to report combat exposure, childhood adversity, and greater lifetime trauma compared to other groups. Relative to controls, they had particularly elevated odds of major depressive disorder (MDD), generalized anxiety disorder (GAD), cognitive disorder (ie, mild cognitive impairment, dementia, or Alzheimer disease), sleep disorder, and concussion/traumatic brain injury (TBI; odds ratios [ORs] = 4.78-13.27). Compared to CVD-only veterans, those with CVD+PTSD had higher odds of GAD, MDD, cognitive disorder, sleep disorder, suicidal ideation, and chronic pain (ORs = 1.89-9.64). Relative to PTSD-only veterans, they had greater odds of kidney disease, concussion/TBI, MDD, and sleep disorder (ORs = 2.67-4.85). Veterans with CVD+PTSD also showed moderately greater impairments in psychosocial and cognitive functioning compared to single-diagnosis groups (d's = 0.50-0.66). Conclusions: Older veterans with comorbid CVD+PTSD have a markedly elevated burden of health and functional difficulties, underscoring the importance of integrated, trauma-informed care to improve outcomes in this high-risk population. Prim Care Companion CNS Disord 2026;28(4):26m04187. Author affiliations are listed at the end of this article.},
}
@article {pmid42475908,
year = {2026},
author = {Shin, H and Lim, S and Yeom, J and Jeong, HC and Yoon, T},
title = {Irreversible mechanical weakening of amyloid-β K16 mutants via electrostatic torque.},
journal = {Bioelectrochemistry (Amsterdam, Netherlands)},
volume = {173},
number = {},
pages = {109394},
doi = {10.1016/j.bioelechem.2026.109394},
pmid = {42475908},
issn = {1878-562X},
abstract = {BACKGROUND: Amyloid-beta (Aβ) fibrils act as the structural core of Alzheimer's disease pathology and maintain exceptional mechanical stability through dense β-sheet networks. However, the molecular mechanisms through which external physical stimuli disrupt these robust scaffolds remain poorly understood, particularly the residue-specific responses.<br><br>METHODS: Here, we systematically evaluated the structural collapse and mechanical attenuation of A&#x3b2; fibrils and their K16 mutants, including the charge-reversal K16D and bulky K16W, under a 1.0&#xa0;V/nm electric field (EF) using molecular dynamics (MD) simulations.<br><br>RESULTS: We demonstrated that this external stimulus persistently disrupts the &#x3b2;-sheet hydrogen-bond network within the simulated recovery window and leads to a drastic reduction in Young's modulus driven by dipole-field misalignment. Notably, this response was highly mutation dependent since the K16D mutant exhibited severe orientation-dependent collapse due to an amplified electrostatic torque, whereas K16W maintained its structural resistance via enhanced steric packing. Furthermore, EF induced a sustained increase in the solvent-accessible surface area (SASA).<br><br>CONCLUSION: These findings suggest that external EF can serve as a potent physical modulator to destabilize pathogenic amyloid aggregates, potentially overcoming the physical barrier of dense plaques, enhancing the penetration and efficacy of therapeutic agents.},
}
@article {pmid42476126,
year = {2026},
author = {Lee, J and Gilligan, M and Skoblow, HF and Huo, M and Ogle, DM and Killoren, SE},
title = {Hair Cortisol Concentration among Siblings Caring for a Parent with Dementia: A Dyadic Approach to Sibling Relationship Quality and Perceived Caregiving Stress.},
journal = {Biopsychosocial science and medicine},
volume = {},
number = {},
pages = {},
doi = {10.1097/PSY.0000000000001511},
pmid = {42476126},
issn = {2998-8756},
abstract = {OBJECTIVE: Sibling relationship quality and perceived caregiving stress contribute to dementia caregivers' well-being. However, few studies have examined the biopsychosocial mechanisms underlying sibling interdependence in the caregiving context, particularly using cortisol. The aim of this study was to examine the dyadic associations between sibling relationship quality (i.e., closeness, tension, ambivalence: simultaneous positive and negative feelings), perceived caregiving stress (i.e., emotional and physical stress experienced by caregivers) and hair cortisol concentration (HCC) among siblings caring for a parent with Alzheimer's disease and related dementias (ADRD).<br><br>METHODS: Data came from 66 sibling dyads (M age=56.5; 91% women) caring for a parent with ADRD. Participants reported their sibling relationship quality and perceived caregiving stress through a self-report survey. Cortisol was extracted from hair samples using optimized liquid chromatography-tandem mass spectrometry.<br><br>RESULTS: The actor-partner interdependence model revealed that individuals exhibited higher HCC when they felt emotionally closer to their sibling (i.e., actor effect), as well as when their sibling reported greater ambivalence toward them and more severe emotional caregiving stress (i.e., partner effects). Neither the actor nor partner effects of sibling tension or physical caregiving stress on HCC were significant.<br><br>CONCLUSIONS: This study contributes to the understanding of the biopsychosocial processes shaping siblings' experiences in parental dementia caregiving by highlighting the dyadic associations between sibling relationship quality, perceived caregiving stress, and HCC.},
}
@article {pmid42469972,
year = {2026},
author = {Li, X and Li, L and Ren, Y and Shi, L and Sun, M and Liu, Z},
title = {A bibliometric analysis of research trends and mechanisms of olfactory dysfunction in Alzheimer's diseases from 2008 to 2024.},
journal = {Medicine},
volume = {105},
number = {29},
pages = {e49799},
pmid = {42469972},
issn = {1536-5964},
support = {2025JC-YBQN-1144//Project of Shaanxi Provincial Department of Science and Technology/ ; },
mesh = {*Alzheimer Disease/complications/physiopathology ; *Bibliometrics ; Humans ; *Olfaction Disorders/physiopathology/etiology ; *Biomedical Research/trends ; },
abstract = {BACKGROUND: Olfactory dysfunction (OD) and Alzheimer disease (AD) represent significant global public health challenges. Growing evidence underscores the need to clarify the neuropathological mechanisms underlying their association. Our study intends to analyze global research trends and overlapping molecular mechanisms underlying OD and AD.<br><br>METHODS: Reviews and articles on OD and AD published between 2008 and 2024 were extracted from the Web of Science Core Collection. CiteSpace and VOSviewer were applied to for the analysis and visualization of the publication outputs, as well as the distribution of countries/regions, institutions and authors, the journals output, keywords co-occurrence, and reference citations. Molecular targets and associated pathways were investigated by GeneCards, STRING, and Metascape databases.<br><br>RESULTS: One thousand nine hundred sixteen publications were identified, demonstrating steady growth in research output across 7006 institutions from 398 countries. The USA emerged as the top contributor, excelling in both publication output and citation impact. The University of Pennsylvania, University of California San Francisco, and Chinese Academy of Sciences stood out as the top influential institutions. Among 10,476 authors, Thomas Hummel from Technische Universit&#xe4;t Dresden, Germany, emerged as the most prominent scholar. In terms of journals, Journal of Alzheimer's Disease leaded in publications in this field. Keywords including "Alzheimer's disease," "olfactory bulb," and "cognitive impairment" represent the current research focuses. A total of 1779 overlapping genes were identified between OD and AD. ACTB, AKT1, TP53, CTNNB1, and INS were identified as the most central regulatory genes. Enrichment analyses revealed involvement in PI3K-Akt, mitogen-activated protein kinases, and cyclic adenosine monophosphate signaling pathways, as well as biological functions related to signaling receptor activator activity, growth factor activity, and cytokine activity.<br><br>CONCLUSION: Our study uncovers the dynamic research trends on OD and AD, while we further identified shared molecular mechanisms underlying these 2 disorders. Early olfactory risk assessment, diagnosis, and intervention may serve as critical components in the prevention and management in AD.},
}
@article {pmid42469999,
year = {2026},
author = {Xu, D and Zhou, W and Qiu, H},
title = {Association between dietary antioxidant quality score and cognitive function in older adults: A cross-sectional study based on NHANES 2011-2014.},
journal = {Medicine},
volume = {105},
number = {29},
pages = {e49758},
doi = {10.1097/MD.0000000000049758},
pmid = {42469999},
issn = {1536-5964},
mesh = {Humans ; *Antioxidants/administration &amp; dosage ; Cross-Sectional Studies ; Female ; Aged ; *Cognition/physiology/drug effects ; Nutrition Surveys ; Male ; *Diet ; Middle Aged ; *Cognitive Dysfunction/epidemiology ; Aged, 80 and over ; },
abstract = {The aim of this study was to examine the connection between the dietary antioxidant quality score (DAQS) and cognitive impairment in older adults. This cross-sectional study of 2713 older adults aged ≥ 60 years from the 2011 to 2014 National Health and Nutrition Examination Survey cohort evaluated cognitive performance at quartile thresholds using the digit symbol substitution test, the animal fluency test, and the consortium to establish a registry for Alzheimer disease word learning test. Vitamins A, C, E, zinc, selenium, and magnesium consumption were used to calculate the DAQS score. Multiple linear regression and logistic regression analyses were used to evaluate the association between DAQS and the cognitive capacities of senior citizens. In the fully adjusted model, higher DAQS was linked to less cognitive impairment (odds ratio = 0.34, 95% confidence interval: 0.22-0.53). According to our research, older adults' cognitive decline is adversely correlated with higher DAQS, and improving their antioxidant intake may help them improve cognitive function.},
}
@article {pmid42470017,
year = {2026},
author = {Wang, X and Deng, L and Wang, T and Luo, S},
title = {Exploring the cognitive effects of arthritis: A Mendelian randomization study and cross-sectional analysis of NHANES data.},
journal = {Medicine},
volume = {105},
number = {29},
pages = {e49805},
doi = {10.1097/MD.0000000000049805},
pmid = {42470017},
issn = {1536-5964},
mesh = {Humans ; Mendelian Randomization Analysis ; *Arthritis, Rheumatoid/genetics/psychology/blood ; Female ; *Osteoarthritis/genetics/psychology/blood ; Cross-Sectional Studies ; Polymorphism, Single Nucleotide ; Male ; Nutrition Surveys ; Aged ; Middle Aged ; *Cognition/physiology ; Growth Differentiation Factor 5/genetics ; Linkage Disequilibrium ; },
abstract = {This study aimed to investigate the relationship between cognitive performance and the pathogenesis of osteoarthritis (OA) and rheumatoid arthritis (RA), emphasizing the role of plasma metabolites and proteins. Using National Health and Nutrition Examination Survey 2011 to 2014 data, cognitive functions of participants aged >60 years were evaluated, examining their correlation with OA and RA. Covariates, including demographics and health-related factors, were included. Genetic causality was determined using Mendelian randomization with single-nucleotide polymorphisms from the UK Biobank and other datasets. Linkage disequilibrium score regression and colocalization analyses were performed to validate genetic correlations and identify shared genetic variants. Cognitive performance was assessed in 387 and 237 OA and RA patients, respectively, compared with 1569 controls. OA patients had significantly lower Consortium to Establish a Registry for Alzheimer's Disease-4 cognitive scores (odds ratio [OR]: 0.962, P = .001), while RA patients had lower digit symbol substitution test scores (OR: 0.980, P = .001). Mendelian randomization revealed a negative causal association between cognitive performance and OA (OR: 0.767, P = .001) and RA (OR: 0.712, P = .006). Plasma components, including bone sialoprotein 2, NKP44, and the metabolite X-11478, were causally linked to cognitive performance. Mediation analysis identified mediators, including FGR and 6CKine. Linkage disequilibrium score regression revealed a genetic correlation between cognitive performance and OA and RA, with colocalization analysis identifying shared genetic factors. GDF5 and TRAIP were associated with OA, and EHMT2 with RA. Cognitive factors, influenced by plasma components, may influence OA and RA onset. This relationship highlights the need for integrated interventions targeting cognitive function and joint health.},
}
@article {pmid42470073,
year = {2026},
author = {Chen, K and Deng, Y and Yan, D and Wang, J and Ding, Y},
title = {Clinical characteristics of patients with Alzheimer's disease and caregiver burden, mental health, and sleep quality: A cross-sectional comparative study in psychiatric hospitals and nursing homes.},
journal = {Medicine},
volume = {105},
number = {29},
pages = {e49761},
doi = {10.1097/MD.0000000000049761},
pmid = {42470073},
issn = {1536-5964},
mesh = {Humans ; *Alzheimer Disease/psychology ; Cross-Sectional Studies ; Female ; *Hospitals, Psychiatric/statistics &amp; numerical data ; *Nursing Homes ; Male ; *Caregivers/psychology ; Aged ; *Sleep Quality ; *Mental Health ; Aged, 80 and over ; Cost of Illness ; China ; Middle Aged ; Depression/epidemiology ; Anxiety/epidemiology ; Sleep Wake Disorders ; },
abstract = {As Alzheimer's disease (AD) care shifts to institutions, differences between psychiatric hospitals and nursing homes remain unclear. We compared AD patients and professional caregivers across these settings and explored institution-specific links between caregiver burden, mental health, and sleep quality. A cross-sectional study (January to November 2024) enrolled 121 AD patients and 123 caregivers from 2 psychiatric hospitals and 2 nursing homes in Shanghai. Assessments used standardized scales. Analyses included nonparametric tests, χ2 tests, Spearman correlations, and stepwise regression. Post hoc power was adequate for moderate-to-large effects. AD patients in psychiatric hospitals are more severe, and caregivers face greater burden and psychological risk. Tailored, institution-specific mental health interventions are needed. Psychiatric hospital patients had poorer cognition and greater functional dependence (P < .001). Hospital caregivers reported higher burden, depression, anxiety, and worse sleep in specific domains (P < .05; effect sizes r = 0.18-0.47). Burden correlated positively with depression, anxiety, and poor sleep (r = 0.397-0.458). In the total sample, anxiety and poor sleep predicted burden (adjusted R2 = 0.285). In psychiatric hospitals, sleep quality was the dominant predictor (β = 0.483). In nursing homes, anxiety and workload predicted burden (adjusted R2 = 0.418); sleep quality was a negative predictor (β = -0.222), likely from floor effects and adaptive coping.},
}
@article {pmid42470526,
year = {2026},
author = {Fu, Y and Gao, PY and Xu, W and Tan, L},
title = {Associations of Insulin Sensitivity with Risk of All-Cause and Cause-Specific Dementia: A Prospective Cohort Study.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42470526},
issn = {1559-1182},
support = {2022ZD0211600//Brain Science and Brain-like Intelligence Technology - National Science and Technology Major Project/ ; 82271475//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Insulin Resistance/physiology ; *Dementia/epidemiology/metabolism ; Female ; Male ; Prospective Studies ; Risk Factors ; Aged ; Genetic Predisposition to Disease ; },
abstract = {Impaired insulin sensitivity has been implicated in neurodegeneration, but whether clinically accessible indices of insulin sensitivity predict dementia risk in the general population remains unclear. We examined associations of the estimated glucose disposal rate (eGDR), a validated marker of insulin sensitivity, with incident all-cause dementia (ACD), Alzheimer's disease (AD), and vascular dementia (VaD), and assessed whether eGDR modifies genetic susceptibility to AD. We included 290,898 dementia-free participants from the UK Biobank. eGDR was calculated using waist circumference, hypertension, and glycated hemoglobin. AD polygenic risk score (AD-PRS) was categorized into tertiles. Longitudinal associations were assessed using Kaplan-Meier (KM) survival analysis and Cox proportional hazards models, with restricted cubic splines employed to examine potential non-linear relationships. Joint effects and interactions between eGDR and AD-PRS were evaluated. The robustness of findings was tested through extensive subgroup and sensitivity analyses. Over a mean follow-up of 13.23 years, 4794 participants developed ACD, 2138 developed AD, and 1070 developed VaD. KM curve revealed that dementia incidence differed significantly across eGDR quartiles (all log-rank P < 0.001). RCS showed significant non-linear inverse associations between eGDR and dementia risk (all P for non-linearity < 0.001). In fully adjusted Cox models, each 1-unit higher eGDR was associated with lower risk of ACD (HR 0.92, 95% CI 0.90-0.94), AD (0.94, 0.92-0.97), and VaD (0.82, 0.78-0.85). Compared with eGDR-Q1, Q4 had lower risks of ACD (HR 0.67), AD (HR 0.70), and VaD (HR 0.42) (all P < 0.001). eGDR modified AD genetic risk (P for interaction < 0.001); participants with low AD-PRS and high eGDR had the lowest AD risk (HR 0.17, 95% CI 0.12-0.23 vs. high AD-PRS and low eGDR group). Findings were consistent across subgroup and sensitivity analyses. Higher eGDR, indicative of greater insulin sensitivity, was associated with reduced risk of incident all-cause and cause-specific dementia, with a significant non-linear inverse dose-response relationship observed. Individuals with both high eGDR low high AD-PRS exhibited the lowest risk of developing AD. These findings suggest that insulin sensitivity may represent a modifiable target for dementia prevention, particularly among individuals with elevated genetic susceptibility.},
}
@article {pmid42470846,
year = {2026},
author = {Rollo, E and Tafuri, B and Tamburrino, L and Urso, D and Giugno, A and Vilella, D and Zecca, C and De Blasi, R and Gnoni, V and Logroscino, G},
title = {Association of hypoxic burden with brain atrophy in Alzheimer's disease.},
journal = {Journal of the neurological sciences},
volume = {489},
number = {},
pages = {126088},
doi = {10.1016/j.jns.2026.126088},
pmid = {42470846},
issn = {1878-5883},
abstract = {BACKGROUND: Obstructive Sleep Apnea (OSA) is a common comorbidity in Alzheimer's Disease (AD) and may exacerbate neurodegeneration. This study investigates the association between a novel metric of OSA severity-hypoxic burden (HB)-and measures of AD-related neurodegeneration.<br><br>METHODS: In this retrospective exploratory study, patients with AD at stage 3 and stage 4 (NIA-AA 2018 criteria), enrolled at a Center for Neurodegenerative Diseases, underwent a complete sleep assessment including polysomnography and 3&#xa0;T brain Magnetic Resonance Imaging. Correlation analyses were conducted between HB and brain volumes.<br><br>RESULTS: Twenty-two patients (36.4% males, mean age 69.8&#xa0;&#xb1;&#xa0;7.5) were enrolled. OSA was diagnosed in 40.9% of patients. HB inversely correlated with left hippocampus (&#x3c1;&#xa0;=&#xa0;-0.553, p&#xa0;=&#xa0;0.02) and left amygdala (&#x3c1;&#xa0;=&#xa0;-0.496, p&#xa0;=&#xa0;0.04) volumes. AD patients with OSA showed significantly reduced left hippocampal volume than those without OSA (p&#xa0;=&#xa0;0.038).<br><br>CONCLUSIONS: This study highlights that greater OSA severity, measured by HB, correlates with left hippocampus and amygdala atrophy, suggesting a possible association between chronic hypoxia and neurodegeneration in AD.},
}
@article {pmid42470860,
year = {2026},
author = {Fornaro, M and Di Lorenzo, C and Esposito, A and Perona, D},
title = {Cardiovascular risks in psychiatric disorders and psychiatric risks in cardiovascular disorders: implications for prevention and clinical management - a large-scale umbrella review encompassing 76 meta-analyses.},
journal = {Journal of psychosomatic research},
volume = {210},
number = {},
pages = {112930},
doi = {10.1016/j.jpsychores.2026.112930},
pmid = {42470860},
issn = {1879-1360},
abstract = {OBJECTIVE: Psychiatric and cardiovascular disorders often co-occur, complicating their assessment and management. No umbrella review(UR) has summarized the meta-analytic evidence on the co-occurrence of psychiatric and cardiovascular disorders and assessed its credibility.<br><br>METHODS: Meta-analytic systematic reviews of observational studies documenting the prevalence, risk factors, and outcomes associated with the co-occurrence of cardiovascular and psychiatric disorders, indexed from inception through March.16.2026, and meeting established diagnostic criteria, were included. Meta-analytic association and prevalence estimates were recalculated and graded based on established or adapted criteria. The AMSTAR-2 assessed the quality of the meta-analyses, while several subgroup analyses and meta-regressions aimed to explain the heterogeneity.<br><br>RESULTS: We included 76 meta-analyses yielding 131 meta-analytic estimates. Based on pre-existing meta-analytic evidence, 22/24 prevalence estimates (91.7%) met moderate/strong credibility criteria. Strong credibility emerged for: orthostatic hypotension in Lewy body(58%;95%C.I.&#xa0;=&#xa0;50-66%) and Alzheimer's dementias(28.0%&#xa0;=&#xa0;95%C.I.&#xa0;=&#xa0;17.0-40.0%); pericardial effusion in anorexia nervosa(25.0%;95%C.I.&#xa0;=&#xa0;17.0-34.0%); in heart failure(HF): major depressive disorder(MDD)(41.9%;95%C.I.&#xa0;=&#xa0;36.7-47.1%), mild cognitive impairment(MCI)(41.4%;95%C.I.&#xa0;=&#xa0;38.3-45.6%), anxiety(32.0%;95%C.I.&#xa0;=&#xa0;26.5-37.6%), MDD&#xa0;+&#xa0;anxiety(24.7%;95%C.I.&#xa0;=&#xa0;17.9-34.3%), and dementia(19.8%;95%C.I.&#xa0;=&#xa0;12.9-27.8%); in atrial fibrillation(AF): MCI(26.0%;95%C.I.&#xa0;=&#xa0;21.0-30.0%), anxiety in patients undergoing pulmonary vein isolation(PVI)(25.0%;95%C.I.&#xa0;=&#xa0;12.0-46.0%), MDD in PVI patients (20.0%;95%C.I.&#xa0;=&#xa0;13.0-29.0%); in coronary artery disease: MDD&#xa0;+&#xa0;anxiety(19.8%;95%C.I.&#xa0;=&#xa0;16.0-24.6%): in schizophrenia spectrum disorders: clozapine-associated-cardiomyopathy(0.6%;95%C.I.&#xa0;=&#xa0;0.2-2.3%); clozapine-associated-cardiomyopathy absolute death rates (0.0003;95%C.I.&#xa0;=&#xa0;0.0001-0.0012); clozapine-associated-cardiomyopathy case fatality rate (0.078;95%C.I.&#xa0;=&#xa0;0.018-0.285). Several additional disorders were multimorbid in>5% of people, yet with a lower credibility rating. No re-pooled risk factors/outcomes reached strong credibility criteria.<br><br>CONCLUSIONS: The present study provides an atlas of cardiovascular and psychiatric multimorbidity across varying levels of credibility, reinforcing the need for an integrated, multidisciplinary approach to patient care and for more research on actionable risk/protective factors and outcomes.},
}
@article {pmid42470923,
year = {2026},
author = {Aydoğdu, GS and Ağagündüz, D and Roviezzo, F and Romano, B and Capasso, R},
title = {Therapeutic potential of curcumin in Alzheimer's disease: Multi-target mechanisms of action, experimental and clinical evidence, safety aspects.},
journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie},
volume = {202},
number = {},
pages = {119776},
doi = {10.1016/j.biopha.2026.119776},
pmid = {42470923},
issn = {1950-6007},
abstract = {Alzheimer's disease is a neurodegenerative disorder characterized by memory loss and impaired cognitive functions; its prevalence is increasing with the growth of the global elderly population. Unfortunately, early diagnostic and treatment methods developed by modern medicine have limited effectiveness for this disease. This situation has increased interest in natural ingredients, such as curcumin, which have beneficial effects on health. Some preclinical studies evaluating the efficacy of curcumin in Alzheimer's disease suggest that it may have preventive, protective, and therapeutic effects through various mechanisms, including anti-amyloidogenic effects, improvement of tau pathology, cholinesterase inhibition, anti-inflammatory and antioxidant effects, metal chelation, microbiota modulation, and epigenetic regulation. Similarly, some preclinical studies indicate that curcumin-based probes may offer a promising approach to the diagnosis of Alzheimer's disease. However, inconsistencies exist between preclinical and clinical studies. Curcumin's low bioavailability and high systemic elimination may be among the most significant causes of these inconsistencies. It is also thought that this situation may be related to differences and limitations in preclinical and clinical study designs. There is a need for preclinical studies that follow comprehensive, standardized protocols and for larger-scale, long-term, well-designed clinical trials to evaluate the effectiveness of curcumin in the early diagnosis, prevention, and treatment of Alzheimer's disease. In addition, potential risks, such as the toxicological effects of curcumin with increased bioavailability and curcumin-drug interactions in Alzheimer's patients, should be evaluated.},
}
@article {pmid42471032,
year = {2026},
author = {Barrera-Chamorro, L and Gonzalez-de la Rosa, T and Arzalluz-Luque, J and Torrecillas-Lopez, M and Marquez-Paradas, E and Claro-Cala, CM and Navarro-Hortal, MD and Eichau, S and Garcia-Sanchez, MI and Montserrat-de la Paz, S},
title = {Sustainable next-generation prebiotics for brain health: microbiota-gut-brain axis in neurodegenerative and demyelinating diseases.},
journal = {Critical reviews in food science and nutrition},
volume = {},
number = {},
pages = {1-22},
doi = {10.1080/10408398.2026.2703335},
pmid = {42471032},
issn = {1549-7852},
abstract = {Neurodegenerative and neuroinflammatory diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis, are increasingly associated with disruption of the microbiota-gut-brain axis. Common alterations include reduced beneficial microbial taxa, impaired short-chain fatty acid production, intestinal and blood-brain barrier dysfunction, and sustained inflammatory responses. These findings support the development of microbiota-targeted dietary interventions. This review summarizes current evidence on polyphenols, bioactive peptides, and pectin-derived oligosaccharides (POS) as prebiotic or prebiotic-like compounds with potential activity through the microbiota-gut-brain axis. Particular attention is given to structure-function relationships, host-microbe interactions, and the sustainable recovery of these compounds from food by-products. Preclinical studies suggest that these bioactives may reduce microglial activation, improve mitochondrial function, strengthen intestinal and blood-brain barrier integrity, and enhance cognitive or motor performance. Early clinical studies also indicate possible benefits on mood, selected cognitive outcomes, metabolic regulation, and inflammatory biomarkers, although evidence remains limited. Microbiota-derived metabolites from polyphenols, such as urolithins, together with glycomacropeptide and POS, appear to be key mediators. However, clinical validation in major neurodegenerative diseases remains fragmented. Standardized formulations, mechanistic trials, harmonized endpoints, and precision-nutrition strategies are required to confirm their therapeutic potential.},
}
@article {pmid42471071,
year = {2026},
author = {Hu, K and Gao, W and Pan, J and Xu, X and You, P and Li, K and Yang, G and Wang, D and Jiang, M and Wang, X and Zhao, Y and Xu, Y},
title = {Ginkgo biloba Extract 50 alleviates memory and synaptic plasticity deficits by inhibiting neuroinflammation via the blockage of ATP-P2X7R axis in presenilin 1/2 conditional double knockout mice.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {122199},
doi = {10.1016/j.jep.2026.122199},
pmid = {42471071},
issn = {1872-7573},
abstract = {Ginkgo biloba L. has been widely utilized in traditional Chinese medicine for its potential to enhance memory-related functions. In traditional medical practices, it is also commonly prescribed for conditions associated with cognitive decline and age-related disorders. These ethnopharmacological uses are closely linked to neurodegenerative disorders, in which neuroinflammation plays a central role. Ginkgo biloba has shown anti-inflammatory and neuroprotective properties, yet its underlying mechanisms in modulating neuroinflammation are still not fully understood.<br><br>AIM OF THE STUDY: Neuroinflammation is critically involved in cognitive impairment and neurodegenerative diseases, while therapeutic options remain limited. Ginkgo biloba extract 50 (GBE50) is a standardized formulation with potential neuroprotective properties. This study aimed to assess its effects on neuroinflammation-associated cognitive dysfunction and to clarify the mechanisms involved.<br><br>METHODS: Presenilin 1/2 conditional double knockout mice served as a cognitive impairment model, with behavioral tests used to evaluate cognitive function. The constituents of GBE50 were identified by UPLC-Q-TOF-MS, and ATP content was quantified using biochemical assays. The expression of P2X7 receptor, NLRP3 inflammasome-related proteins, inflammatory cytokines, and synaptic markers was determined at both mRNA and protein levels using qRT-PCR and Western blotting. Microglial activation and P2X7R distribution were assessed via immunofluorescence, and hippocampal synaptic plasticity was examined using LTP recordings.<br><br>RESULTS: Using UPLC-Q-TOF-MS, 51 compounds were characterized in GBE50, mainly flavonoids and terpene lactones, which are likely responsible for its biological activities. Treatment with GBE50 markedly alleviated cognitive impairment in PS cDKO mice. It downregulated P2X7R and key components of the NLRP3 inflammasome (NLRP3, NEK7, Caspase-1, and ASC), while also reducing the transcription of pro-inflammatory cytokines including Il-1&#x3b2;, Il-18, and Tnf-&#x3b1;. In parallel, GBE50 restored synaptic protein levels and improved long-term potentiation deficits.<br><br>CONCLUSION: Collectively, our findings suggest that modulation of the ATP-P2X7R-NLRP3 axis contributes to the neuroprotective effects of GBE50 in AD, highlighting this pathway as a promising therapeutic target for preventing AD-related neurodegeneration.},
}
@article {pmid42471077,
year = {2026},
author = {Liu, Y and Li, Y and Zhou, Y and Hei, Y and Wang, S and Bajpai, AK and Chang, X and Wang, X and Xu, F and Yao, C},
title = {STAT3 mediated the isoleucine-induced Alzheimer's disease progression.},
journal = {Brain research},
volume = {},
number = {},
pages = {150472},
doi = {10.1016/j.brainres.2026.150472},
pmid = {42471077},
issn = {1872-6240},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder that significantly impacts millions globally, with rising prevalence among the aging population, emphasizing the need for effective interventions. Isoleucine, a branched-chain amino acid, crosses the blood-brain barrier and plays a role in various neurological disorders. In this study, we investigated the association of isoleucine with AD traits using the BXD mouse reference population, revealing significant correlations with Y-maze performance, anxiety assays, contextual fear conditioning, and the age of onset for working memory deficits. In vitro, exogenous isoleucine supplementation in HT22 and PC12 cells increased amyloid precursor protein (APP) and phosphorylated tau (p-tau) levels. Subsequent analysis identified 2,000 probes correlated with isoleucine and revealed STAT3 as a candidate downstream regulator. Overexpression of STAT3 increased APP and p-tau levels, and STAT3 inhibition abolished this effect, suggesting that isoleucine modulates AD progression via STAT3 activation. Mendelian randomization analysis further supported a causal relationship between elevated isoleucine levels and AD risk. This work provides insights into isoleucine as a potential risk factor for AD and identifies STAT3 as a mediator of isoleucine-related AD susceptibility.},
}
@article {pmid42468111,
year = {2026},
author = {Bittner, T and Lopera, F and Rios-Romenets, S and Schiffman, C and Clayton, D and Hibar, D and Kollmorgen, G and Dolton, M and Poon, V and Nguyen, J and Giraldo-Chica, M and Acosta-Baena, N and Espinosa, A and Villegas, G and Muñoz, C and Serna, L and Alvarez, S and Protas, H and Luo, J and Sohankar, J and Chen, Y and Ghisays, V and Malek-Ahmadi, M and Ashton, NJ and Denkinger, MN and Cai, Y and Xu, YR and Ostaszewski, B and Selkoe, DJ and Alexander, RC and Quiroz, YT and Su, Y and Chen, K and Doody, RS and Langbaum, JB and Tariot, PN and Sink, KM and Reiman, EM},
title = {Baseline and placebo-related imaging, cerebrospinal fluid, plasma biomarker, and cognitive findings in unimpaired PSEN1 E280A mutation carriers and non-carriers in the Alzheimer's Prevention Initiative Autosomal Dominant Alzheimer's Disease Colombia Trial.},
journal = {EBioMedicine},
volume = {130},
number = {},
pages = {106390},
doi = {10.1016/j.ebiom.2026.106390},
pmid = {42468111},
issn = {2352-3964},
abstract = {BACKGROUND: The Alzheimer's Prevention Initiative Autosomal Dominant Alzheimer's Disease (ADAD) Colombia Trial evaluated the biological, cognitive, and clinical effects of crenezumab, an anti-oligomeric and monomeric amyloid-beta (Aβ) monoclonal antibody, in 30-60-year-old PSEN1 E280A mutation carriers without cognitive impairment from the world's largest ADAD kindred, finding no significant treatment effects on Alzheimer's disease progression. This article describes baseline biomarker, cognitive, and clinical measurements and placebo-related longitudinal changes in the randomised prevention trial's mutation carrier and non-carrier groups.<br><br>METHODS: Crenezumab and placebo-treated mutation carriers and placebo-treated non-carriers were assessed using amyloid and fluorodeoxyglucose positron emission tomography (PET), magnetic resonance imaging, plasma, and optional tau PET and cerebrospinal fluid (CSF) biomarker, cognitive, and clinical measurements over 5-8 years.<br><br>FINDINGS: 94% of the 252 kindred members (85 crenezumab-treated mutation carriers, 84 placebo-treated carriers, and 83 placebo-treated non-carriers) completed the trial. 55% of the carriers had baseline PET evidence of substantial A&#x3b2; plaques. 32.9% and 6.8% of amyloid PET-positive and PET-negative carriers, respectively, 36.5%, 13.2%, and 0% of pTau217-positive, pTau217-intermediate, and pTau217-negative carriers, respectively, and no non-carriers became cognitively impaired over the next 5 years. Carriers were distinguished from non-carriers by several baseline and longitudinal A&#x3b2;, tau, neurodegenerative, and inflammatory biomarker measures, but not by CSF oligomeric A&#x3b2; measurements.<br><br>INTERPRETATION: Despite the absence of significant treatment effects, these findings and the trial itself continue to inform the course of preclinical ADAD, advance Alzheimer's disease prevention research, and provide a shared resource of data and samples for the field (ClinicalTrials.gov ID: NCT01998841; trial completed).<br><br>FUNDING: National Institute on Aging, Banner Alzheimer's Institute, Genentech, Inc., and F. Hoffmann-La Roche Ltd.},
}
@article {pmid42468194,
year = {2026},
author = {Castro, MM and Pavón, RA and Moroni, AD and Melcon, M and Menite, NE and Villafañe, G and Genaro, AM and Palumbo, ML},
title = {Reduced serum IL-6 as a potential peripheral marker of amnestic mild cognitive impairment: A pilot study.},
journal = {Medicina clinica},
volume = {166},
number = {9},
pages = {107540},
doi = {10.1016/j.medcli.2026.107540},
pmid = {42468194},
issn = {1578-8989},
abstract = {INTRODUCTION AND OBJECTIVE: Mild cognitive impairment (MCI) represents an intermediate state between age-related cognitive changes and early stages of dementia. People with amnestic subtype (aMCI) show higher risks of progression to dementia due to Alzheimer's disease. In this pilot study, the aim was to investigate whether cytokines could be potential peripheral markers associated with MCI.<br><br>METHODS: Women were recruited in Jun&#xed;n city, Buenos Aires, Argentina. Their cognitive performance was evaluated using a neuropsychological battery. Serum levels of IFN-&#x3b3;, IL-1&#x3b2;, IL-2, IL-4 and IL-6 were analyzed by ELISA, and the type 2/type 1 balance was determined. Correlations between both parameters, as well as within-group analysis cytokines levels were evaluated.<br><br>RESULTS: After cognitive evaluation, participants were classified as healthy controls (HC: n=14) or as aMCI (n=7). IL-6 levels were significantly decreased in the aMCI group compared with HC (p=0.047). IFN-&#x3b3; showed no robust correlations within the HC group but presented a strong negative correlation with IL-2 (p=0.005) and IL-4 (p=0.052) in aMCI. Several correlations were found between cytokine levels, the type 2/type 1 balance and neurocognitive tests.<br><br>CONCLUSIONS: We concluded that IL-6 decreased levels, altered correlation in cytokine profiles, together with performance on the neuropsychological battery, may serve as potential blood-markers of amnestic mild cognitive impairment.},
}
@article {pmid42468248,
year = {2026},
author = {Zhao, B and Shang, S and Zhang, M and Guo, X and Zhou, R and Qu, Q and Cao, H},
title = {Comparison of sleep characteristics between Alzheimer's disease dementia and Parkinson's disease dementia.},
journal = {Sleep medicine},
volume = {147},
number = {},
pages = {109140},
doi = {10.1016/j.sleep.2026.109140},
pmid = {42468248},
issn = {1878-5506},
abstract = {BACKGROUND: Alzheimer's disease (AD) dementia and Parkinson's disease dementia (PDD) both frequently involve sleep disturbances, but the characteristics of sleep disruption differ between the two patient groups, and the extent of these differences remains unclear.<br><br>METHODS: We consecutively enrolled 105 patients with AD and 104 with PDD from a memory clinic. All participants underwent assessments of global cognition (MMSE, MoCA), daily living (ADL), anxiety and depression (HAMA, HAMD), and sleep characteristics (PSQI, RBD, daytime nap questionnaire, Epworth Sleepiness Scale). Multivariable regression analyses were conducted to examine whether sleep characteristics differed independently between the two groups. ROC curves evaluated discriminative performance.<br><br>RESULTS: Global PSQI scores did not differ between the two groups. In univariate analyses, PDD patients reported worse subjective sleep quality (the first PSQI component), more sleep disturbances, greater use of hypnotics, higher daytime nap frequency and duration, and a much higher prevalence of RBD. After full adjustment, PDD remained independently associated with poorer sleep quality (B&#x202f;=&#x202f;0.355, 95% CI: 0.092-0.619, p&#x202f;=&#x202f;0.008), higher daytime nap frequency (B&#x202f;=&#x202f;2.124, 95% CI: 1.327-2.920, p&#x202f;<&#x202f;0.001), and RBD (OR&#x202f;=&#x202f;18.482, 95% CI: 3.297-103.603, p&#x202f;=&#x202f;0.001). A combination of sleep items (sleep quality, nap frequency, RBD) distinguished PDD from AD with an AUC of 0.763.<br><br>CONCLUSIONS: Despite a comparable total PSQI score, PDD patients showed significantly poorer sleep quality (the first PSQI component), more frequent daytime napping, and a much higher prevalence of RBD compared with AD patients. Subjective sleep profiling may help to understand the differential sleep burden in these common dementias.},
}
@article {pmid42468306,
year = {2026},
author = {Khalafi, M and Hojjati, SH and Wang, XH and Tanzi, EB and Liao, V and Kumar, S and Parikh, NS and Chiang, GC},
title = {Liver steatosis and cognitive performance in aging: A pilot cross-sectional study.},
journal = {Clinical imaging},
volume = {138},
number = {},
pages = {110903},
doi = {10.1016/j.clinimag.2026.110903},
pmid = {42468306},
issn = {1873-4499},
abstract = {PURPOSE: Metabolic dysfunction-associated steatotic liver disease (MASLD) has been linked to dementia. We investigated whether liver steatosis or fibrosis is associated with early cognitive changes, while exploring related mechanisms like body mass index (BMI) and cerebral β-amyloid deposition.<br><br>METHODS: In this cross-sectional study, we enrolled 26 cognitively unimpaired individuals, who underwent amyloid PET and comprehensive clinical, neurological, and neuropsychological evaluations, including the Telephone Interview for Cognitive Status (TICS). Liver steatosis and fibrosis were quantified noninvasively using vibration-controlled transient elastography (FibroScan&#xae;; Echosens, Paris, France) with an M-probe, with the controlled attenuation parameter (CAP) used to quantify liver steatosis. Multivariate regression models were used to assess relationships between liver and cognitive measures, adjusting for age.<br><br>RESULTS: In our cohort (mean age 72.2&#xa0;&#xb1;&#xa0;8.4&#xa0;years), greater liver steatosis was associated with lower TICS scores, using both the CAP score (&#x3b2;&#xa0;=&#xa0;-0.03, p&#xa0;=&#xa0;0.021) and steatosis grade (&#x3b2;&#xa0;=&#xa0;-1.39, p&#xa0;=&#xa0;0.023). Higher liver stiffness was also negatively associated with TICS scores (&#x3b2;&#xa0;=&#xa0;-1.39, p&#xa0;=&#xa0;0.042). BMI was significantly associated with greater cerebral amyloid burden (&#x3b2;&#xa0;=&#xa0;9.03, p&#xa0;=&#xa0;0.01), higher steatosis grade (&#x3b2;&#xa0;=&#xa0;0.30, p&#xa0;=&#xa0;0.03), and higher CAP scores (&#x3b2;&#xa0;=&#xa0;9.47, p&#xa0;=&#xa0;0.003).<br><br>CONCLUSION: Liver steatosis associates with lower cognitive scores in older adults. BMI associates with both steatosis and amyloid burden, which may reflect co-occurring metabolic pathways. These findings provide evidence for targeting metabolic health to preserve cognition and mitigate Alzheimer's pathology.},
}
@article {pmid42468396,
year = {2026},
author = {Du, H and Zhao, P and Yang, Z and Li, B and Bao, Y and Shi, X},
title = {Development and validation of a parsimonious and noninvasive clinical decision machine learning model for predicting the risk of long-term mild cognitive impairment in older adults: A multinational cohort study.},
journal = {International journal of medical informatics},
volume = {220},
number = {},
pages = {106612},
doi = {10.1016/j.ijmedinf.2026.106612},
pmid = {42468396},
issn = {1872-8243},
abstract = {BACKGROUND: Early identification of mild cognitive impairment (MCI) is crucial for delaying the progression of dementia. However, existing prediction models often require expensive testing or invasive biomarkers, limiting their scalability in primary care settings.<br><br>METHODS: Data were drawn from three prospective cohorts: the Chinese Longitudinal Healthy Longevity Survey (CLHLS), the English Longitudinal Study of Ageing (ELSA), and the Health and Retirement Study (HRS). We included 11,069 participants aged &#x2265;60&#xa0;years who were free of cognitive impairment at baseline. Incident MCI was defined via cohort-specific assessments. The CLHLS was used for internal training and testing, and the ELSA and HRS were used for independent external validation. After feature selection via Shapley additive explanations (SHAP) and recursive feature elimination, 9 machine learning models were developed. Model performance was evaluated on the basis of discrimination, calibration, and clinical utility. SHAP was used for model interpretation.<br><br>RESULTS: Over the 6-year follow-up period, 2486 participants developed MCI (CLHLS: n&#xa0;=&#xa0;1008; ELSA: n&#xa0;=&#xa0;488; HRS: n&#xa0;=&#xa0;990). Five easily accessible baseline predictors were selected: age, sex, education, instrumental activities of daily living, and baseline cognitive score. The gradient boosting classifier demonstrated favorable overall performance, achieving an internal area under the curve (AUC) of 0.869 (95% CI 0.84-0.90). It maintained robust generalizability during external validation in the ELSA (AUC 0.786, 95% CI 0.76-0.81) and HRS (AUC 0.745, 95% CI 0.73-0.76) cohorts. Furthermore, an interactive web tool incorporating Shapley additive explanations was deployed to conduct a transparent risk assessment.<br><br>CONCLUSIONS: This study developed and externally validated a parsimonious, cross-national machine learning model utilizing five noninvasive features to predict long-term MCI risk. Integrated with a transparent SHAP framework and deployed as an interactive web application, it provides a cost-effective clinical decision support tool for early MCI screening in primary care (https://mcipredictor.streamlit.app/).},
}
@article {pmid42468562,
year = {2026},
author = {Lim, L and Little, D and Redman, S and Cookson, AN},
title = {Machine learning for predicting full-count FDG PET brain images from low-count acquisitions in suspected dementia: a clinical and quantitative evaluation.},
journal = {Physics in medicine and biology},
volume = {},
number = {},
pages = {},
doi = {10.1088/1361-6560/ae8c9f},
pmid = {42468562},
issn = {1361-6560},
abstract = {Objective.Artificial intelligence methods for denoising low-count FDG PET brain images are usually evaluated using image quality metrics alone, with limited direct clinical assessment, particularly in suspected dementia. This study evaluated a machine-learning image quality transfer (IQT) method for predicting full-count FDG PET brain images from low-count acquisitions using both quantitative metrics and blinded clinical assessment. Approach.Forty-one FDG PET/CT patients with suspected dementia were retrospectively included, with low-count images simulated using 5% of list-mode data. An IQT random forest model employing patch-wise regression was evaluated using image quality metrics, regional Z-scores, and blinded radiologist assessment against standard-count references. Main results.AI-predicted images showed an average peak signal to noise ratio (PSNR) improvement of approximately 4 dB and reduced root mean square error (RMSE) compared with low-count images. Clinically, uninterpretable scans were reduced to 0% for each reader, down from 20% and 50% respectively, with a shift from tentative to confident agreement with the reference standard reports. By contrast, the structural similarity index measure (SSIM) and regional Z-score agreement showed no improvement. Significance.In patients with suspected dementia, where motion and limited tolerance of long acquisitions are common, this study demonstrates for the first time the potential of an image quality transfer (IQT) method to improve the clinical usability of low-count FDG PET scans. The findings also indicate the importance of task-based clinical evaluation, since quantitative metrics alone were insufficient to capture the clinically relevant improvements observed in image interpretability and reader confidence.},
}
@article {pmid42468638,
year = {2026},
author = {Fu, T and Wei, C and Shen, D and Zhong, J and Liu, B and Xu, F},
title = {Ceanothane-type triterpenoids: Phytochemistry, biosynthesis, pharmacological activities, and therapeutic potential.},
journal = {Fitoterapia},
volume = {},
number = {},
pages = {107390},
doi = {10.1016/j.fitote.2026.107390},
pmid = {42468638},
issn = {1873-6971},
abstract = {Ceanothane-type triterpenoids (CTTs) are a class of natural triterpenoids characterized by a distinctive 5/6/6/6/5 pentacyclic skeleton featuring a five-membered A-ring. They are mainly distributed in plants of the Rhamnaceae family, such as Ziziphus, Hovenia, Paliurus. To date, 64 natural CTTs and 28 synthetic derivatives have been reported. This review systematically summarizes their structural classification, pharmacological activities, putative biosynthetic pathways, and pharmacokinetic profiles. CTTs exhibit a broad spectrum of bioactivities, including antitumor, antimicrobial, antiinflammatory, hepatoprotective, anti-Alzheimer's disease (AD), antimalarial, and immunomodulatory effects, with mechanisms involving multi-target regulation. Furthermore, we discuss current challenges and future perspectives in structural modification, structure-activity relationship (SAR) studies, and mechanistic exploration, aiming to provide a comprehensive reference for the further development of CTTs as therapeutic agents.},
}
@article {pmid42468644,
year = {2026},
author = {Li, M and Zhao, Y and Xu, B and Wang, L and Luo, W and Tan, R and Zhang, X and Jiang, H},
title = {Polygonatum sibiricum polysaccharides and Alzheimer's disease: A review of preparation, structure, mechanisms, and application.},
journal = {Fitoterapia},
volume = {},
number = {},
pages = {107393},
doi = {10.1016/j.fitote.2026.107393},
pmid = {42468644},
issn = {1873-6971},
abstract = {Polygonatum sibiricum is a well-established botanical resource with dual medicinal and edible applications. Polygonatum sibiricum polysaccharides (PSP), the principal bioactive constituent of P. sibiricum, have long attracted research interest due to their structural diversity and broad spectrum of biological activities. Beyond its well-documented antioxidant, antibacterial, anti-inflammatory, antitumor, and anti-aging properties, PSP has recently demonstrated promising therapeutic potential in alleviating Alzheimer's disease (AD). However, current research findings on PSP remain fragmented, and a comprehensive framework elucidating the specific mechanisms by which it ameliorates AD is lacking. Based on this, this review begins with the extraction, isolation, purification, and structural characterization of PSP, systematically summarizes the multiple mechanisms by which PSP ameliorates AD, and provides an overview of its structural modification, toxicological studies, and multi-domain applications, aiming to offer theoretical support for the further development and translational application of PSP in the prevention and treatment of AD.},
}
@article {pmid42468665,
year = {2026},
author = {Girish Oswal, D and Rane, M},
title = {Is Urolithin A(UA) a Pharmacologically Credible Neuro-Nutraceutical? A Critical Review of Mechanisms, Brain Exposure, and Evidence Gaps in Alzheimer's and Parkinson's Disease.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106224},
doi = {10.1016/j.neuint.2026.106224},
pmid = {42468665},
issn = {1872-9754},
abstract = {Urolithin A(UA) is a gut microbiota-derived metabolite of dietary ellagitannins and ellagic acid, generated by specific gut bacterial species and absent from food in free form. Preclinical evidence indicates that UA restores PINK1/Parkin-mediated mitophagy, attenuates NF-κB, NLRP3 inflammasome and cGAS-STING-driven neuroinflammation, and preserves synaptic and cognitive function across rodent and cell-culture models of Alzheimer's disease, Parkinson's disease, and age-related cognitive decline. However, circulating UA in humans exists predominantly as phase II glucuronide and sulfate conjugates rather than free aglycone, and human clinical evidence to date establishes UA's safety, favorable pharmacokinetics, mitochondrial target engagement, and benefits to muscle strength and physical function in middle-aged and older adults, with no completed trial yet evaluating cognitive or neurodegenerative disease-modifying outcomes. This review critically examines whether UA's neuroprotective mechanisms are pathway-specific and supported by convergent preclinical and human data, while explicitly separating mechanistic plausibility from demonstrated clinical efficacy.UA therefore represents a promising but still investigational neuro-nutraceutical candidate, with a mechanistic foundation strong enough to justify dedicated, CNS-endpoint-focused clinical trials as the next logical step toward establishing its neuroprotective potential in humans.},
}
@article {pmid42468794,
year = {2026},
author = {Li, J and Wang, Y and Ma, X and Bi, X and Wu, T and Zhang, N and Wang, F and Liu, T and Geng, F},
title = {Microneedle-mediated drug delivery systems for brain diseases.},
journal = {Nanomedicine : nanotechnology, biology, and medicine},
volume = {},
number = {},
pages = {102996},
doi = {10.1016/j.nano.2026.102996},
pmid = {42468794},
issn = {1549-9642},
abstract = {Brain diseases pose a major global health challenge, with the blood-brain barrier (BBB) as the core obstacle for intracranial drug delivery. Microneedles, a minimally invasive technology, can bypass the BBB via intracranial implantation, nose-to-brain, trigeminal nerve, and transdermal systemic routes. This review covers the structural classification, biomaterials, and bypass BBB delivery mechanisms of brain-targeted microneedles. Using glioblastoma, Alzheimer's disease, and Parkinson's disease as models, we overview preclinical microneedle formulations and key signaling pathways, and establish a matching framework linking therapeutic targets, drugs, and microneedle types. We further analyze clinical translation bottlenecks including limited drug loading, unclear long-term biosafety, manufacturing challenges, and regulatory gaps, and propose future directions in technical innovation, standardized evaluation, and regulatory improvement. This work may guide the rational design and clinical translation of microneedle-mediated brain-targeted drug delivery systems.},
}
@article {pmid42468803,
year = {2026},
author = {Zhang, X and Huang, Q and Huang, J and Zhang, P and Feng, X and Li, Z and Raper, DMS and Mao, C},
title = {Frailty-related plasma proteomic signatures and key biomarkers for new-onset dementia and its subtypes: A prospective cohort study.},
journal = {Journal of advanced research},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jare.2026.07.040},
pmid = {42468803},
issn = {2090-1224},
abstract = {BACKGROUND: Frailty is a well-established clinical risk factor for dementia, but its underlying mechanisms remain poorly defined. We aimed to investigate whether proteomic signatures and individual proteins linked to frailty could predict and characterize the association between frailty and dementia.<br><br>METHODS: We analyzed over 52,000 UK Biobank participants free of dementia at baseline, with plasma profiles of 2,915 proteins. Physical frailty (PF) and a 49-item frailty index (FI) were assessed. Proteomic signatures were derived using multivariable linear regression and 100 repeated LASSO selections. Incident dementia was ascertained via linkage to hospital and mortality records. Associations with incident dementia were assessed using multivariable Cox proportional hazards models, dose-response, and mediation analyses.<br><br>RESULTS: During 13.6&#x202f;years of follow-up, 1,437 participants developed dementia. Proteomic signatures for PF and FI were independently associated with dementia risk (hazard ratios [HRs] up to 2.80). Stratification by signature quintiles showed clear gradients in both absolute and relative dementia risk. For all-cause dementia, cumulative incidence ranged from 1.19% to 5.27% (HR up to 3.29), and for vascular dementia, from 0.16% to 1.19% (HR up to 4.53). Similar trends were observed for Alzheimer's dementia. Mediation analysis indicated that proteomic signatures statistically accounted for 46%-53% of the association between frailty and dementia risk. Key proteins, including GDF15, HPGDS, ITGAV, SPP1, CHGA, and LGALS4, were identified as top contributors and mapped to immune-inflammatory, neuroimmune, and extracellular matrix pathways.<br><br>CONCLUSION: Frailty-related proteomic signatures and key proteins predict dementia risk and capture biological features beyond clinical frailty. These molecular markers may facilitate early risk stratification and support future research into prevention strategies.},
}
@article {pmid42468901,
year = {2026},
author = {Halabian, N and Park, C and Omoto, L and Bocca, LF and Palacios, G and Wu, K and Hamani, C and Rabin, J and Abrahao, A and Davidson, B and Lipsman, N and Meng, Y},
title = {Focused ultrasound blood brain barrier opening for targeted therapeutics in neurodegenerative diseases.},
journal = {Biological psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.biopsych.2026.07.008},
pmid = {42468901},
issn = {1873-2402},
abstract = {Therapeutic focused ultrasound (FUS) leverages the non-invasive ultrasonic waves to modify the biological tissue. When administered alongside intravenous microbubbles, low-intensity FUS enables transient, targeted disruption of the blood-brain barrier (BBB), permitting passage of systemically administered therapeutics into the central nervous system (CNS) with high spatial precision. The ability to selectively modulate BBB permeability at the disease site has the potential to substantially expand the number of therapeutics that can be utilized in treating illnesses afflicting the CNS. Herein, we review the current applications of FUS for treating neurodegenerative disorders and diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic lateral sclerosis (ALS). We discuss the research developments to date and future directions.},
}
@article {pmid42468989,
year = {2026},
author = {Baraniuk, C},
title = {Alzheimer's drug lecanemab: FDA approves easier initial use, with "huge implications" for UK.},
journal = {BMJ (Clinical research ed.)},
volume = {394},
number = {},
pages = {e100318},
doi = {10.1136/bmj-2026-100318},
pmid = {42468989},
issn = {1756-1833},
}
@article {pmid42469165,
year = {2026},
author = {Ichimata, S and Hata, Y and Yoshida, K and Tanaka, R and Murayama, S},
title = {Clinicopathological and molecular heterogeneity of amyloid-β in unnatural deaths under 70 years: A forensic autopsy-based study.},
journal = {Brain pathology (Zurich, Switzerland)},
volume = {},
number = {},
pages = {e70124},
doi = {10.1111/bpa.70124},
pmid = {42469165},
issn = {1750-3639},
support = {//Uehara Memorial Foundation/ ; },
abstract = {This study investigated the clinicopathological characteristics and molecular spectrum of amyloid-beta (Aβ) in unnatural deaths among relatively young individuals with moderate-to-severe Aβ deposition, including cases of early-onset Alzheimer's disease. A total of 856 forensic autopsy cases aged 40-69 years were analyzed. Detailed semiquantitative and quantitative immunohistochemical analyses were performed in the neocortex, striatum (caudate nucleus, putamen, and nucleus accumbens [NAc]), and amygdala using antibodies targeting multiple Aβ species (Aβ38, Aβ39, Aβ40, Aβ42, Aβ43, pyroglutamate-modified Aβ at the third glutamate residue [AβNp3E], and serine 8-phosphorylated Aβ), as well as phosphorylated tau. Ward's hierarchical cluster analysis was also performed. Thirty-three cases (eight females; 3.9%), including six early-onset Alzheimer's disease cases, were identified. Three cases exhibited genetic abnormalities (one with Down syndrome and two with presenilin 1 [PSEN1] mutations). Marked regional heterogeneity in Aβ molecular profiles was observed, particularly within the striatum. Notably, the NAc displayed a distinct pattern of Aβ deposition and occasional NAc-predominant cerebral amyloid angiopathy. Cases with cognitive impairment (CI) demonstrated more advanced Aβ and tau pathology than CI-negative cases; notably, interstitial Aβ42 and Aβ43 burdens were significantly elevated across all regions. Strikingly, siblings carrying the same PSEN1 mutation-one with CI and the other without-exhibited divergent pathological patterns. Although suicide accounted for approximately one-third of cases, a higher neocortical Aβ burden was associated with a lower frequency of suicide, and no significant difference in suicide rates was observed compared with cases lacking substantial Aβ deposition. Cluster analysis identified a subgroup characterized by relatively elevated striatal Aβ deposition, particularly AβNp3E. Collectively, these findings indicate that the severity of Aβ deposition is not directly associated with suicide. However, early involvement of the NAc may contribute to depressive states, and region-specific Aβ species-particularly Aβ42, Aβ43, and AβNp3E-may be associated with increased cognitive vulnerability in this age group.},
}
@article {pmid42469217,
year = {2026},
author = {Dodd, RB and Enomoto, M and Zhou, Y and Satoh, K and Zhang, Y and Chen, F and Acheson, B and Ghaffari, D and Sayn-Wittgenstein, E and Manning, JJ and Dukas, GV and Patel, R and Burguete, AS and Kralovec, MJ and Rashid, M and Hall, JL and Tamucci, KA and Chatila, Z and Liu, M and Lee, AJ and Vardarajan, BN and Taga, MF and Pollari, S and Rabinovitch, A and Rillahan, CD and Bobkov, AA and Sergienko, E and Meadows, W and Qamar, S and Randle, SJ and Johnson, CM and Sevalle, J and Griffin, J and Bohm, C and Ikura, M and Xian, X and Herz, J and Kelly, MA and West, J and Satapathy, S and Wilson, MR and Javitch, JA and Fraser, PE and Bennett, DA and De Jager, PL and Fishelson, Z and Frenkel, D and Asher, WB and Bradshaw, EM and George-Hyslop, PS},
title = {CD33 and clusterin interact biophysically and genetically to modulate Alzheimer risk.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-026-75140-3},
pmid = {42469217},
issn = {2041-1723},
support = {203249/Z/16/Z//Wellcome Trust (Wellcome)/ ; 406915//Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Sant&#xe9; du Canada)/ ; },
abstract = {Mechanisms linking CD33 variants to Alzheimer Disease (AD) are poorly defined. Here, we combine structural, cellular, and genetic analyses to delineate how the CD33[M] splice isoform, upregulated in carriers of CD33 risk alleles, modulates microglial function. We show that CD33[M] ectodomain dimerizes, enabling binding of large multi-sialylated molecules. We demonstrate that another AD risk protein - clusterin (CLU) ± Aβ oligomers (but not ApoE) binds with nanomolar avidity to CD33[M], but not CD33[m]. We show that in human monocytes CD33[M]:CLU binding induces CD33[M] ITIM phosphorylation, recruits SHP-1, suppresses Aβ phagocytosis, and impairs clearance of amyloid plaques. We identify a soluble CD33[M] ectodomain fragment (sCD33[M]) - absent from CD33[m]-expressing cells - which could contribute to the role of CD33[M] in AD. Genetic analyses confirm that CD33:CLU interaction modulates amyloid burden, cognition, and disease risk. These findings define a mechanistic CLU:Aβ:CD33[M] axis, highlighting CD33[M] dimerization and ligand-binding sites as potential therapeutic targets.},
}
@article {pmid42469559,
year = {2026},
author = {Walker, L and Attems, J and Donaghy, P},
title = {Neuropathological correlates of imaging in dementia with Lewy bodies.},
journal = {Journal of neural transmission (Vienna, Austria : 1996)},
volume = {},
number = {},
pages = {},
pmid = {42469559},
issn = {1435-1463},
abstract = {Dementia with Lewy bodies (DLB) is a common yet underdiagnosed neurodegenerative dementia, characterised neuropathologically by nigrostriatal dopaminergic degeneration and widespread α-synuclein aggregation. Clinical diagnosis remains challenging due to marked heterogeneity in presentation and substantial overlap with Alzheimer's disease (AD), resulting in diagnostic delays and frequent misdiagnosis. The ability to identify underlying pathological processes ante-mortem is essential to improve diagnostic accuracy, refine prognosis, stratify patients for clinical trials, and ultimately enable personalised therapeutic approaches. Over recent decades, major advances have been made in the development of neuroimaging biomarkers that reflect key features in Lewy body disease pathology, many of which have informed diagnostic criteria. In addition to dopaminergic dysfunction and α-synuclein pathology, co-existing neuropathologies including amyloid-β, tau, neuroinflammation, and vascular changes are increasingly recognised as important modifiers of clinical phenotype and disease trajectory in DLB. This review summarises the current landscape of neuroimaging modalities in DLB and critically examines their relationships with confirmed neuropathological correlates. We discuss indicative biomarkers such as striatal dopamine imaging and [123]I-metaiodobenzylguanidine myocardial scintigraphy, alongside supportive imaging markers derived from structural magnetic resonance imaging and Fluorodeoxyglucose Positron Emission Tomography (FDG-PET). Emerging PET approaches targeting α-synuclein, as well as established amyloid and tau-PET techniques for assessing co-pathologies, are reviewed in the context of post-mortem validation studies. Finally, we consider Translocator protein PET imaging as a marker of neuroinflammation and highlight key methodological limitations and knowledge gaps. Together, these neuroimaging-pathological correlations provide critical insights into disease mechanisms and outline future directions toward earlier, biologically informed diagnosis and precision medicine in DLB.},
}
@article {pmid42469568,
year = {2026},
author = {Kaushik, S and Fatima, JE and Raheem, A and Barbhuiya, MA and Thirupathi, AT and Singh, LP and Khan, PA and Aparna, TN and Pramanik, S and Shahid, MAA},
title = {Nanomedicine targeting neuroinflammatory pathways in Alzheimer's disease: a new frontier in inflammopharmacology.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42469568},
issn = {1568-5608},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative illness characterized by progressive cognitive impairment, synaptic compromise, and relentless neuroinflammation. Increasing evidence suggests that neuroinflammatory cascades orchestrated by microglial activation, astrocytic malfunction, cytokine hyperproduction, and inflammasome signalling are at the core of AD pathogenesis. Conventional anti-amyloid and cholinergic treatments are only symptomatic and neglect the inherent neuroimmune dysregulation. Nanomedicine is a revolutionary frontier in inflammopharmacology, which enables the accurate modulation of neuroinflammatory circuits and enhanced brain delivery of medicines. Nanocarriers designed by engineering, including liposomes, polymeric nanoparticles, dendrimers, and exosomes, allow for targeted delivery across the BBB, increase drug bioavailability, and provide controlled release. The nano-systems are capable of inhibiting pro-inflammatory signalling, such as NF-κB and MAPK pathways, reducing oxidative stress, and enhancing microglial M2 polarization and thus restoring neuronal homeostasis. Recent developments in surface-functionalized and stimuli-responsive nanoplatforms further enable active targeting through receptor-mediated pathways and theranostic imaging in real-time. Comparative studies show that interventions based on nanocarrier-based therapies enhance therapeutic efficacy and safety profiles in preclinical AD models. Future directions include integrating AI-driven nano-design, gene and siRNA delivery, and precision neuropharmacology to enable personalized anti-inflammatory therapies. Substantial progress, translational challenges remain regarding long-term biocompatibility, large-scale production, and clinical validation. Nanomedicine against neuroinflammatory pathways represents a new paradigm for Alzheimer's treatment, linking molecular pharmacology and sophisticated nanotechnology to next-generation neuroinflammatory medicine.},
}
@article {pmid42469606,
year = {2026},
author = {Low, A and Gunter, JL and Hu, M and Raghavan, S and Przybelski, SA and Schwarz, CG and Kantarci, K and Lowe, VJ and Petersen, RC and Graff-Radford, J and Jack, CR and Vemuri, P},
title = {Perivascular Spaces as Determinants of Amyloid, Tau, and Vascular Biomarker Progression.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78299},
pmid = {42469606},
issn = {1531-8249},
support = {R01 AG056366/NH/NIH HHS/United States ; R37 AG011378/NH/NIH HHS/United States ; U01 AG006786/NH/NIH HHS/United States ; R01 AG034676/NH/NIH HHS/United States ; U01 NS100620/NH/NIH HHS/United States ; P30 AG062677/NH/NIH HHS/United States ; },
abstract = {OBJECTIVE: Magnetic resonance imaging (MRI)-visible enlarged perivascular spaces (PVS) are markers of cerebral small vessel disease (SVD) and aging, processes implicated in both neurodegenerative and cerebrovascular pathologies. However, longitudinal positron emission tomography (PET) studies examining PVS as a mechanism underlying Alzheimer's disease (AD) pathophysiological progression are lacking. Our overall objective was to investigate the associations of baseline PVS burden with white matter hyperintensity (WMH) volume, amyloid-PET, and tau-PET, both cross-sectionally and longitudinally.<br><br>METHODS: We examined 2,229 participants across the aging-AD spectrum from the Mayo Clinic Study of Aging (MCSA) and the Mayo Alzheimer's Disease Research Center (ADRC) (mean age&#x2009;=&#x2009;68.59&#x2009;&#xb1;&#x2009;12.70 and 48.94% women). PVS and WMH were quantified using a novel in-house algorithm. Amyloid on [[11]C]Pittsburgh Compound B (PiB)-PET and tau on AV1451-PET were measured. Cross-sectional regional and global associations were examined using canonical correlation analysis (CCA). Longitudinal associations were examined using age- and sex-adjusted linear mixed effect (LME) models with natural splines and subject-wise 10-fold cross-validation.<br><br>RESULT: Three distinct associations were observed: (1) PVS in the basal ganglia (PVS-BG) was associated with greater WMH volume both cross-sectionally and longitudinally; (2) PVS-BG covaried with higher PiB standardized uptake value ratio (SUVR) cross-sectionally, with longitudinal trajectory associations limited to amyloid-negative individuals; (3) PVS in the centrum semiovale (PVS-CSO) was not associated with amyloid or tau, but was associated with occipital WMH, a pattern characteristic of CAA.<br><br>INTERPRETATION: Findings lend support for PVS-BG as an early indicator of small vessel dysfunction and WMH pathogenesis. Individuals with higher PVS-BG burden exhibited higher WMH burden and faster WMH progression, suggesting that PVS-BG may identify individuals at increased risk of progressive SVD. Evidence linking PVS to downstream AD biomarker progression was weaker. Findings support the relevance of PVS-CSO to CAA, suggesting that they may reflect changes occurring early in the disease process. ANN NEUROL 2026.},
}
@article {pmid42469846,
year = {2026},
author = {Tang, X and Chen, R and Xing, J and Huang, Q and Luo, L and Ouyang, C and Ma, F and Wen, J and Zhang, J and Kong, L and Cai, Y and Wang, Y and Cui, L},
title = {Metabolic reprogramming via SIRT2-deficient microglial large extracellular vesicles ameliorates alzheimer's pathology.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-026-03956-3},
pmid = {42469846},
issn = {1742-2094},
support = {20252BAC200485//Natural Science Foundation of Jiangxi Province/ ; 2025R201//Zhanjiang Science and Technology Plan Talent Enclave Special Project/ ; 82101269//National Natural Science Foundation of China/ ; 82071190//National Natural Science Foundation of China/ ; 2024A1515011464//Natural Science Foundation of Guangdong Province, China/ ; 2024B1515230001//Natural Science Foundation of Guangdong Province, China/ ; GCC2021010//high-level talents scientific research start-up funds of the Affiliated Hospital of Guangdong Medical University/ ; GCC2022001//the high-level talents scientific research start-up funds of the Affiliated Hospital of Guangdong Medical University/ ; GJPY004//National-Level Talent Cultivation Funding Program of The Affiliated Hospital of Guangdong Medical University/ ; },
abstract = {BACKGROUND: Current therapies for Alzheimer's disease (AD) offer only symptomatic relief, highlighting the urgent need for disease-modifying approaches capable of halting or reversing neurodegeneration. Extracellular vesicles (EVs) have attracted growing interest as therapeutic vehicles owing to their inherent capacity to bypass the blood-brain barrier and deliver complex biological cargo to the central nervous system.<br><br>METHODS: Here, we examined whether large EVs (LEVs) derived from microglia with stable Sirtuin-2 knockdown (SIRT2-KD) confer the neuroprotective effects associated with SIRT2 inhibition. LEVs harvested from SIRT2-KD microglia were administered intranasally to APP/PS1 mice. We assessed microglial uptake of LEVs, along with subsequent changes in cellular metabolism, migration toward amyloid-beta (A&#x3b2;) plaques, phagocytic activity, and downstream pathological and behavioral outcomes. Proteomic and acetylomic profiling were employed to characterize the molecular cargo of LEVs-SIRT2-KD.<br><br>RESULTS: LEVs-SIRT2-KD were readily internalized by microglia in vivo following intranasal delivery. Uptake of these vesicles markedly enhanced microglial bioenergetics, driving coordinated upregulation of both oxidative phosphorylation and glycolysis. This metabolic shift was accompanied by improved microglial recruitment to A&#x3b2; plaques and increased phagocytic clearance. Consequently, treated mice showed reduced A&#x3b2; plaque deposition, restored synaptic integrity, and reversal of cognitive deficits. Proteomic and acetylomic analyses revealed that LEVs-SIRT2-KD are selectively enriched in proteins and acetylation modifications linked to energy metabolism and phagocytic function, offering a mechanistic basis for the observed metabolic reprogramming.<br><br>CONCLUSION: Together, these results identify LEVs as a critical vesicle subtype mediating the effects of SIRT2 knockdown and support a cell-free therapeutic strategy for AD centered on EVs-driven metabolic reprogramming of microglia.},
}
@article {pmid42469894,
year = {2026},
author = {Jiang, Z and Ding, Y},
title = {Coffee as a polypharmacological modulator of mitochondrial health: from molecular mechanisms to translational implications.},
journal = {Journal of translational medicine},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12967-026-08662-5},
pmid = {42469894},
issn = {1479-5876},
support = {LQ24H160009//Zhejiang Provincial National Natural Science Foundation of China/ ; LHZY24H020002//Hangzhou Joint Fund of the Zhejiang Provincial Natural Science Foundation of China/ ; },
abstract = {BACKGROUND: Coffee is one of the most widely consumed beverages worldwide, yet its biological effects have often been attributed primarily to caffeine. Emerging evidence suggests that coffee contains a complex array of bioactive compounds, including chlorogenic acids, trigonelline, diterpenes, and melanoidins that collectively exert pleiotropic effects on cellular metabolism. However, a comprehensive framework linking the full spectrum of coffee-derived bioactives to mitochondrial health and chronic disease prevention is still lacking.<br><br>MAIN BODY: This review proposes an integrated perspective on coffee as a systemic "mitochondrial network optimizer." We present this model as an integrative framework and hypothesis rather than an established causal model. We synthesize molecular, pre-clinical, and clinical evidence suggesting that coffee bioactives converge on key regulatory nodes, namely the AMPK/SIRT1/PGC-1&#x3b1; axis, Nrf2/ARE antioxidant pathway, PINK1/Parkin-mediated mitophagy, and mitochondrial calcium signaling to coordinately enhance mitochondrial biogenesis, quality control, redox defense, and metabolic efficiency. These multi-targeted mechanisms provide a plausible biological basis for the consistent epidemiological associations between moderate coffee consumption and reduced risk of metabolic diseases (type 2 diabetes, non-alcoholic fatty liver disease), neurodegenerative disorders (Parkinson's, Alzheimer's), and cardiovascular conditions. Furthermore, we critically examine key determinants of response heterogeneity, including non-linear hormetic dose-response relationships, inter-individual variability (CYP1A2 genotype, gut microbiota, sex), and the impact of coffee processing and brewing methods on bioactive composition.<br><br>CONCLUSIONS: Collectively, these findings support the hypothesis that coffee may serve as a paradigm of polypharmacological dietary intervention that targets fundamental pathways of mitochondrial resilience. Moving beyond reductionist views centered on single compounds, we propose that the holistic effects of coffee are best understood through systems-level modulation of mitochondrial homeostasis. Future research should prioritize precision nutrition approaches stratified by genotype, microbiome, and metabolic phenotype, to translate these mechanistic insights into personalized dietary recommendations and the development of mitochondria-targeted nutraceuticals. We caution that this integrative framework requires direct validation in human causal studies.},
}
@article {pmid42469913,
year = {2026},
author = {Janahi, M and Lorenzini, L and Oxtoby, NP and Barkhof, F and Mokrab, Y and Schott, JM and Altmann, A and Initiative, FTADN},
title = {Multi-threshold polygenic risk improves hippocampal-based cognitive decline prediction.},
journal = {Genome medicine},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13073-026-01722-x},
pmid = {42469913},
issn = {1756-994X},
support = {MR/T046422/1/MRC_/Medical Research Council/United Kingdom ; 733051106/ZONMW_/ZonMw/Netherlands ; ANR-19-JPW2-000//Agence Nationale de la Recherche/ ; 1191535//National Health &amp; Medical Research Council, Australia/ ; 2019-2.1.7-ERA-NET-2020-00008//National Research, Development and Innovation Office, Hungary/ ; },
abstract = {BACKGROUND: Predicting cognitive decline from brain MRI is a central question in neuroscience. Hippocampal volume (HV) is a key cognitive biomarker, and normative models can be augmented with multimodal information. Here we augment normative models with genetic information and show improvements in cognitive decline prediction across multiple experimental setups.<br><br>METHODS: We improve normative models for HV by integrating multi-threshold polygenic scores (PGS) with demographic and imaging data using Gaussian Process Regression (GPR). Models were trained on 23,997 participants from UK Biobank (UKBB) and validated on 3,000 out-of-sample participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the European Prevention of Alzheimer's Disease (EPAD) cohorts.<br><br>RESULTS: Our genetically-informed models significantly strengthened associations across six experimental designs and 13 key neurocognitive measures, including Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR), and Alzheimer's Disease Assessment Scale (ADAS), while enhancing prediction of future cognitive decline.<br><br>CONCLUSIONS: Together, these findings underscore the promise of integrating multi-threshold PGS with neuroimaging-based predictive models to improve prognostication and early intervention strategies for neurodegenerative diseases.},
}
@article {pmid42461334,
year = {2026},
author = {Alavi, SE and Ebrahimi Shahmabadi, H and Love, RM and Kurumathur, AV and Sharma, LA and Sharma, A},
title = {Oral Microbial Extracellular Vesicles as Novel Mediators of Alzheimer's Pathogenesis: A Critical Review of the Periodontal-Brain Axis.},
journal = {Neurotoxicity research},
volume = {44},
number = {4},
pages = {},
pmid = {42461334},
issn = {1476-3524},
mesh = {Humans ; *Extracellular Vesicles/metabolism ; *Alzheimer Disease/metabolism/pathology/microbiology ; Animals ; *Porphyromonas gingivalis/metabolism ; *Brain/metabolism/pathology ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder whose origins extend beyond the brain. Chronic periodontitis has emerged as a modifiable risk factor, and extracellular vesicles (EVs) have recently been proposed as important mediators of the periodontal-brain axis. Periodontal pathogens such as Porphyromonas gingivalis (P. gingivalis) release bacterial EVs enriched with virulence factors including gingipains, lipopolysaccharide, and regulatory RNAs. These vesicles can enter systemic circulation, interact with the blood-brain barrier, activate microglia, and trigger inflammatory signaling pathways such as NF-κB and NLRP3. These processes contribute to neuroinflammation, amyloid-β accumulation, and tau hyperphosphorylation, hallmarks of AD pathology. Host-derived EVs further contribute to this complex signaling network by facilitating intercellular communication and potentially propagating pathogenic proteins while also carrying protective molecules. Preclinical studies suggest that periodontal-derived vesicles can reach the hippocampus and impair cognition, while clinical studies have detected P. gingivalis DNA and gingipains in AD brain tissues. EV-associated biomarkers in blood or cerebrospinal fluid and engineered therapeutic vesicles represent promising tools for early diagnosis and intervention. Targeting oral microbial EVs may therefore offer novel avenues for AD prevention and therapy.},
}
@article {pmid42461590,
year = {2026},
author = {Servais, A and Frick, A and Meyer, F and Bastin, C and Delhaye, E},
title = {Lifetime familiarity and episodic familiarity: The role of the transentorhinal cortex in aging.},
journal = {Neuropsychology},
volume = {},
number = {},
pages = {},
doi = {10.1037/neu0001102},
pmid = {42461590},
issn = {1931-1559},
support = {//SAO/Fondation Recherche Alzheimer/ ; //Fonds De La Recherche Scientifique/ ; //Uli&#xe8;ge; Faculty of Medicine/ ; //Fonds Sp&#xe9;ciaux de la Recherche/ ; //ULi&#xe8;ge/ ; //Fonds L&#xe9;on Fredericq/ ; //Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e Tecnologia/ ; },
abstract = {OBJECTIVE: The transentorhinal cortex (tErC), which includes the medial portion of the perirhinal (PrC) and the anterolateral portion of the entorhinal cortices (alErC), is among the first brain regions affected by Alzheimer's disease (AD). Yet, its precise cognitive role remains controversial. Recent models propose that this region supports episodic familiarity and lifetime familiarity, and that it is particularly involved in tasks requiring fine conceptual discrimination between similar objects. The present study examined episodic and lifetime familiarity across three tasks to understand how the tErC supports familiarity, using materials with varying conceptual overlap and lifetime familiarity levels in both normal and pathological aging, encompassing different levels of tErC integrity.<br><br>METHOD: Fifty-eight older adults (aged 55+), including healthy individuals and patients with mild cognitive impairment or subjective cognitive decline, completed familiarity tasks. tErC volume was measured via high-resolution magnetic resonance imaging and was associated with tasks performance using repeated-measures Analyses of covariance or stepwise linear regressions.<br><br>RESULTS: The tErC volume was associated with familiarity performance selectively in task conditions involving high conceptual overlap between targets and lures.<br><br>CONCLUSIONS: Results indicate that tErC integrity is selectively related to familiarity-based performance when recognition requires resolving interference between conceptually similar items. We discuss how combining tasks assessing different aspects of familiarity could help identify early cognitive decline. We suggest this approach should be tested in patients with AD biomarkers. (PsycInfo Database Record (c) 2026 APA, all rights reserved).},
}
@article {pmid42461890,
year = {2026},
author = {Calandri, IL and Bocancea, DI and Allegri, RF and Suemoto, CK},
title = {Registry-Based Dementia Incidence in Argentina: A Nationwide, Decade-Long Analysis by Age, Sex, and Etiology.},
journal = {Neuroepidemiology},
volume = {},
number = {},
pages = {1-24},
doi = {10.1159/000553538},
pmid = {42461890},
issn = {1423-0208},
abstract = {BACKGROUND: National data on dementia incidence is scarce in low- and middle-income countries, limiting public health surveillance and planning. In Argentina, no nationwide estimates of dementia incidence exist despite rapid population aging. Administrative disability registries do not capture clinical disease onset; rather, they record certification events and therefore provide a registry-based proxy for population-level dementia surveillance in settings without prospective incidence cohorts.<br><br>METHODS: We conducted a population-based registry study using data from Argentina's National Registry of Persons with Disabilities between 2016 and 2022, excluding pandemic-disrupted years (2020-2021). Incident registry entries with dementia recorded as the primary cause of disability were identified using ICD-10 codes for Alzheimer's disease and related disorders (ADRD), vascular dementia, and other etiologies. Crude and age-standardized incidence (ASI) of dementia certification per 100,000 inhabitants were estimated by sex, age group, dementia subtype, and early- (<65 years) versus late-onset (&#x2265;65 years) dementia. Pre-specified sensitivity analyses quantified capture fraction against regional cohorts and adjusted temporal trends for an exogenous proxy of registry maturation.<br><br>RESULTS: In 2022, the registry-based crude dementia incidence was 47.7 per 100,000 inhabitants (95% CI: 46.6-48.7). Crude incidence was higher in women than men, whereas age-standardized incidence was comparable between sexes (48.1 vs. 45.5 per 100,000). Incidence increased steeply with age, from 0.9 per 100,000 at ages 40-45 to nearly 480 per 100,000 among individuals aged &#x2265;95 years. ADRD predominated from approximately 55-60 years onward, while other etiologies were relatively more frequent at younger ages. Late-onset dementia incidence (&#x2265;65 years) was substantially higher than early-onset dementia (<65 years) (130.9 vs. 6.3 per 100,000). Provincial age-standardized rates varied from 4.7 to 137.7 per 100,000, and were strongly associated with care access metrics. Between 2016 and 2022, age-standardized incidence increased significantly (p<0.001); however, capture fractions of 6 to 12% relative to regional cohorts and a 45% attenuation of the temporal coefficient after adjustment for registry maturation.<br><br>CONCLUSIONS: This study provides the first nationwide characterization of registry-based dementia certification incidence in Argentina. Distinct age-, sex-, and etiology-specific patterns highlight different epidemiological scenarios for early- and late-onset dementia. Because these estimates reflect administrative certification rather than clinical disease onset and are subject to differential ascertainment, they should be interpreted as a lower bound of true incidence; nonetheless, they constitute a feasible and informative surveillance approach for countries lacking national clinical registries and can support health system planning and prevention strategies.},
}
@article {pmid42461977,
year = {2026},
author = {Zhu, C and Song, L and Mao, S and Li, K and Lin, X},
title = {Receptor-Ligand-Mediated Anchoring of Polyphenol Quantum Dots to Membrane Fragments for Precision Delivery in Alzheimer's Disease Therapy.},
journal = {ACS applied materials &amp; interfaces},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsami.6c10322},
pmid = {42461977},
issn = {1944-8252},
abstract = {Polyphenol-based carbon dots (PCDs) hold great promise for Alzheimer's disease (AD) treatment owing to their inherent antioxidant activity, ultrasmall size, and favorable blood-brain barrier (BBB) permeability. Nevertheless, rapid immune clearance and poor lesion targeting severely hinder their clinical translation. Conventional cell membrane coating is poorly compatible with ultrasmall PCDs, causing incomplete encapsulation, active site masking, and membrane protein inactivation. Herein, we fabricated a novel biomimetic nanostructure (MQCM) by anchoring mannose-modified quercetin nanodots (MQNDs) onto BV2 cell membrane fragments (CMFs) via specific mannose-CD206 receptor-ligand interactions. This unique binding strategy endowed MQCM with a high anchoring efficiency (84.3%) and improved structural stability. Distinct from conventional nonspecific membrane coating that shields active sites and impairs nanoparticle functionality, this design avoids such drawbacks and completely preserves the intrinsic bioactivity of MQNDs and membrane proteins. The optimized MQCM displays high BBB permeability (42.35%), precise BV2 targeting, and lesion-responsive drug release. BV2-derived CMFs prolong blood circulation and lesion retention of MQNDs, while the released MQNDs exert multiple anti-AD effects by regulating ROS homeostasis, inhibiting Aβ fibrillation, and promoting Aβ autophagy. Collectively, this integrated biomimetic system offers a precise AD therapeutic strategy and advances the clinical translation of PCD-based nanomedicines.},
}
@article {pmid42462262,
year = {2026},
author = {Liang, S and Lapane, KL and Ott, BR and Tjia, J and Baek, J and Yuan, Y and Alcusky, M},
title = {Comparing Effectiveness of Antidepressants for Nursing Home Residents With Dementias and Depressive Symptoms.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70582},
pmid = {42462262},
issn = {1532-5415},
support = {5R01AG068450/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: Alzheimer's disease and related dementias (ADRD) are frequently accompanied by depressive symptoms, which may accelerate cognitive decline and increase mortality. Antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), are commonly prescribed, yet comparative effectiveness evidence in nursing home residents with ADRD is scarce.<br><br>METHODS: We conducted a retrospective cohort study using linked CMS data (2011-2018) of long-stay nursing home residents aged &#x2265;&#x2009;65&#x2009;years with ADRD and baseline depressive symptoms who newly initiated an SSRI or SNRI. Depressive symptoms were measured with the Patient Health Questionnaire-9 (PHQ-9; self-report or observed) at baseline and 60-120&#x2009;days after initiation. Outcomes were the change in PHQ-9 scores (continuous) and clinically meaningful improvement. Analyses used overlap propensity score and inverse probability of censoring weighted linear and log-binomial models with generalized estimating equations to account for clustering of nursing home residents. Intention-to-treat (ITT) analyses, as-treated, and subgroup analyses were conducted.<br><br>RESULTS: Among 19,397 SSRI initiators and 2581 SNRI initiators, 66.9% had mild depressive symptoms at baseline. Median time from initiation to follow-up assessment was 85&#x2009;days. In ITT analyses, mean PHQ-9 change was -2.38 for SSRIs and -2.24 for SNRIs (adjusted difference: -0.15; 95% CI, -0.42 to 0.11); clinically meaningful improvement occurred in 55.2% versus 56.9% (risk difference: -1.57; 95% CI, -3.66 to 0.52). As-treated analyses yielded similar results, and findings were consistent across subgroups defined by baseline depression severity, cognitive function, dementia type, and sensitivity analyses.<br><br>CONCLUSIONS: SSRIs and SNRIs were similarly effective for depressive symptoms in nursing home residents with ADRD. Given this and modest improvement rates, antidepressant selection should be individualized, emphasizing safety and resident characteristics. Additional research is needed to inform the decision to treat or not to treat, specific medication selection, and when to stop treatment in this population.},
}
@article {pmid42462283,
year = {2026},
author = {Meng, W and Yang, Q and Xu, J and Huang, Y and Wang, C and Song, Q and Song, L and Bian, J and Ma, Q and Ma, A and Yin, R},
title = {Identifying sex-specific sub-phenotypes of Alzheimer's disease progression using longitudinal electronic health records.},
journal = {EBioMedicine},
volume = {130},
number = {},
pages = {106391},
doi = {10.1016/j.ebiom.2026.106391},
pmid = {42462283},
issn = {2352-3964},
abstract = {BACKGROUND: Alzheimer's Disease (AD) is a complex neurodegenerative disorder, with women comprising nearly two-thirds of individuals with AD. However, sex-specific heterogeneity in AD progression remains insufficiently understood. A data-driven approach is needed to characterise such heterogeneity from longitudinal electronic health records (EHRs).<br><br>METHODS: We developed a deep learning-based framework to uncover sex-specific AD sub-phenotypes using longitudinal EHRs from OneFlorida+ Clinical Research Consortium. We constructed temporal representations of these EHRs and employed an autoencoder architecture to generate latent embeddings, followed by clustering to derive sex-specific sub-phenotypes with associated progression patterns. We also performed statistical and survival analyses to unravel the characteristics of our identified sub-phenotypes.<br><br>FINDINGS: From 1665 individuals with AD (961 females, 704 males), we identified five major sex-specific sub-phenotypes of AD with distinct progression pathways and comorbidity patterns. Female-dominant sub-phenotypes presented later AD onset, longer disease duration, and enrichment of respiratory and neurological disorders. Male-dominant sub-phenotypes exhibited earlier onset, shorter duration, and higher prevalence of endocrine and metabolic conditions. Survival analysis showed significant differences in time to AD onset across sub-phenotypes.<br><br>INTERPRETATION: Our findings revealed distinct disease trajectories and comorbidity patterns between male- and female-dominant subgroups with AD. This study provides insight into sex-specific AD progression and demonstrates a data-driven framework for characterising disease heterogeneity using longitudinal EHRs.<br><br>FUNDING: This study was supported by grants from the Florida Department of Health, the Centers for Disease Control and Prevention, the National Institute of Environmental Health Sciences, and the NIHNational Center for Advancing Translational Sciences.},
}
@article {pmid42462317,
year = {2026},
author = {Ban, Y and Miao, W and Jin, X and Chen, S and Lou, X and Wu, JL and Li, N},
title = {The underappreciated diversity of functional pigments in red yeast rice revealed by an integrated multi-engine mining strategy (IMMS).},
journal = {Food chemistry},
volume = {525},
number = {Pt 1},
pages = {150424},
doi = {10.1016/j.foodchem.2026.150424},
pmid = {42462317},
issn = {1873-7072},
abstract = {Red yeast rice (RYR) is a popular functional food, while its functional components remain severely understudied. This study developed an integrated multi-engine mining strategy (IMMS) ingeniously combining feature-based molecular networking, building blocks-based molecular networking, SIRIUS, PEAKS, and BUDDY to comprehensively analyze RYR components. Employing IMMS, 219 pigments (208 red, 6 orange, 5 yellow) and 104 peptides were first identified, including 185 potential new pigments, with red and yellow pigments showing higher contents. Notably, red pigments demonstrated optimal plasma exposure and brain distribution in rats after oral RYR. Bioactivity analysis first revealed that six typical pigments, especially red, suppressed oxidative stress and neuroinflammation related to Alzheimer's disease in L-Glu-induced HT-22 cells and LPS-induced BV-2 cells, potentially via the Keap1-Nrf2 and IDO1 pathways, respectively. These findings significantly expanded the pigment diversity and RYR components, facilitating the discovery of functional components and providing a foundation for RYR's development as an anti-Alzheimer's functional food.},
}
@article {pmid42462433,
year = {2026},
author = {Bernardes, LMM and Marquez, AS and do Prado Mascarenhas, FNA and de Freitas, LF and Ferreira, DC and Malta, SM and Moreira, AS and Mendonça, TP and Bernardo de Sousa, JN and Silva, &#xcd;F and Correia, LIV and Martins, MM and Ferreira, RB and Zhu, A and Zhang, H and Adebiyi, O and Leung, AK and Espindola, FS and Leite, ML and Ueira-Vieira, C and Mendes-Silva, AP},
title = {Acetonic extract of Saskatoon berry attenuates amyloid-associated neurotoxicity in cellular and Drosophila melanogaster Alzheimer's disease models.},
journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie},
volume = {202},
number = {},
pages = {119774},
doi = {10.1016/j.biopha.2026.119774},
pmid = {42462433},
issn = {1950-6007},
abstract = {Saskatoon berry (Amelanchier alnifolia) is rich in polyphenols known to modulate oxidative stress and neuroinflammation, key mechanisms involved in Alzheimer's disease (AD), yet its neuroprotective potential in this context remains unexplored. Here, we investigated two Saskatoon berry extracts, acetonic and ethanolic, using integrated chemical, computational, cellular and in vivo approaches. Antioxidant activity was confirmed in multiple assays, with stronger radical scavenging and moderate reducing capacity. Chemical profiling revealed solvent-dependent differences in phenolic and flavonoid content. In neuroglial models, the ethanolic extract showed mild-cytotoxicity, whereas the acetonic extract exhibited a favorable safety profile. In an amyloid-beta-induced cellular model, the acetonic extract produced only modest effects on viability. Furthermore, fibroblasts assays showed increased total ATP under non-inflammatory conditions, whereas in the LPS-stimulated inflammatory model the extract increased mitochondrial membrane potential. In contrast, in vivo studies using Drosophila melanogaster AD models showed protective effects of the acetonic extract, including reduced ThT-reactive fluorescence and increased retinal thickness, while improved survival was observed in w[1118] flies. Gene expression analysis of flies' brain tissue showed altered expression of selected mitochondrial- and immune-related genes. The AD-like model showed increased expression of co1, nd1, tfam and dipt, which were significantly reduced following treatment. Overall, these findings identify Saskatoon berry as a novel natural source of bioactive compounds with anti-Alzheimer's potential and suggest that the in vivo protective effects may involve mitochondrial homeostasis and immune-related processes, warranting future mechanistic studies and neuronal-specific validation in more complex organisms.},
}
@article {pmid42462519,
year = {2026},
author = {Morsy, NA and El-Shiekh, RA and Ebrahium, MM and Srour, AM},
title = {Rational design and synthesis of dispiroindene-pyrrolidinedione scaffolds as multi-target directed ligands: potent AChE inhibitors with antioxidant activity and favorable biocompatibility in SH-SY5Y cells.},
journal = {Bioorganic chemistry},
volume = {180},
number = {},
pages = {110245},
doi = {10.1016/j.bioorg.2026.110245},
pmid = {42462519},
issn = {1090-2120},
abstract = {Addressing the urgent need for multi-target therapies in Alzheimer's disease, we report the rational design and one-pot, multi-component synthesis of novel substituted dispiroindene-pyrrolidinedione scaffolds (4a-r). Systematic biological evaluation identified five lead compounds (4g, 4j, 4k, 4m, and 4p) with potent inhibitory activity. Derivative 4k emerged as the primary lead, exhibiting an IC50 for Acetylcholinesterase (AChE) of 2.58 ± 0.11 μM and a remarkable selectivity index of 15.71, significantly exceeding that of donepezil (4.37), the reference drug. Concurrently, the series demonstrated notable affinity for Butyrylcholinesterase (BChE), with several derivatives exhibiting submicromolar to low micromolar inhibition. Furthermore, these scaffolds demonstrated superior antioxidant potential; notably, compound 4p achieved an IC50 value of 25.23 ± 1.25 μM, demonstrating an approximate 5-fold increase in radical scavenging potency relative to ascorbic acid (128.20 μM). In vitro safety assays on SH-SY5Y human neuroblastoma cells confirmed excellent biocompatibility, with compound 4m displaying an IC50 of 125.00 ± 6.91 μM, nearly four times less toxic than donepezil (32.84 μM). Molecular docking validated these results, showing robust π-π stacking and halogen-based stabilization within the catalytic anionic site. These findings, supported by ADME profiles predicting high blood-brain barrier permeability, position the dispiroindene-pyrrolidinedione framework as a highly effective, low-toxicity, multi-functional candidate for the development of Alzheimer's disease therapeutics.},
}
@article {pmid42462634,
year = {2026},
author = {Wang, X and Tong, J and Wang, M and Du, B and Wang, H and Liu, H and Yang, X and Mu, R and Wang, K and Liu, X and Wang, Q},
title = {Amyloid-like nanofilm-decorated antifouling field effect transistor biosensor array for enhancing Alzheimer's disease diagnosis.},
journal = {Biosensors &amp; bioelectronics},
volume = {312},
number = {},
pages = {119030},
doi = {10.1016/j.bios.2026.119030},
pmid = {42462634},
issn = {1873-4235},
abstract = {Alzheimer's disease (AD) is a common neurodegenerative disorder. Compared to the limited specificity of single-biomarker detection, the combined detection of multiple biomarkers can significantly improve the accuracy of AD diagnosis. In this study, a field-effect transistor (FET) biosensor array integrating four independently functionalized regions was fabricated by modifying carbon nanotube (CNT) surfaces with amyloid bovine serum albumin (AL-BSA) nanofilm as an antifouling layer, enabling the simultaneous detection of multiple tau proteins. The proposed FET biosensor exhibited excellent anti-fouling performance while maintaining high sensitivity, with detection limits as low as 3.3 fg/mL, 0.17 fg/mL, 0.02 fg/mL, and 2.5 fg/mL for p-tau181, p-tau217, p-tau231, and t-tau, respectively. Evaluation of 35 clinical serum samples indicated that p-tau181 outperformed the other three tau proteins as an AD diagnostic biomarker. By further incorporating a support vector machine (SVM)-based machine learning algorithm and employing multi-biomarker co-detection, the accuracy of AD diagnosis can be improved to nearly 100%. This study provides a novel strategy for array FET biosensors with high clinical application potential for the precise detection of AD.},
}
@article {pmid42462667,
year = {2026},
author = {Yang, F and Chen, Y and Yan, Y and Zhao, R and Deng, L and Tian, D and Wang, Q and Xie, M},
title = {RVG-functionalized microglial membrane-coated cerium-gallic acid metal-organic frameworks for multi-target Alzheimer's therapy.},
journal = {Journal of colloid and interface science},
volume = {724},
number = {Pt 2},
pages = {141133},
doi = {10.1016/j.jcis.2026.141133},
pmid = {42462667},
issn = {1095-7103},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by aberrant β-amyloid (Aβ) aggregation, oxidative stress, neuroinflammation, and disrupted metal ion homeostasis, which limit the efficacy of conventional single-target therapies. To address these intertwined pathological processes, we developed a multifunctional nanotherapeutic platform based on a cerium-gallic acid bio-metal-organic framework (CeGA-MOF). Reversible Ce[3+]/Ce[4+] redox cycling enables efficient reactive oxygen species (ROS) scavenging, while gallic acid serves as both an organic ligand and metal chelator, inhibiting metal ion-mediated Aβ aggregation and alleviating oxidative stress-associated neurotoxicity, along with its intrinsic anti-inflammatory activity. To enhance in vivo stability and brain delivery, CeGA-MOF was coated with microglial membranes and functionalized with rabies virus glycoprotein (RVG) peptide, yielding a biomimetic nanosystem, CeGA-MOF/B/R. The microglial membrane provides immune evasion and inflammation-guided targeting, while RVG facilitates blood-brain barrier penetration. In vitro, CeGA-MOF/B/R effectively chelates Cu[2+], Zn[2+], and Fe[3+], suppresses metal ion-induced Aβ aggregation, and protects neurons. In APP/PS1 transgenic mice, it reduced cerebral Aβ, promoted anti-inflammatory microglial polarization, and improved learning and memory, highlighting its potential as a biomimetic nanoplatform for synergistic AD therapy.},
}
@article {pmid42463036,
year = {2026},
author = {Cheng, M and Zheng, X and Wei, YD and Ge, JF},
title = {Role of Abca7-related microglial responses in linking type 2 diabetes mellitus to Alzheimer's Disease progression: Evidence from single-cell transcriptomic analysis and experimental validation in animal and cell models.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {179152},
doi = {10.1016/j.ejphar.2026.179152},
pmid = {42463036},
issn = {1879-0712},
abstract = {Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) share overlapping pathological mechanisms characterized by neuroinflammation and metabolic dysfunction, yet the underlying mechanisms remain elusive. In this study, we aimed to investigate the potential involvement of Abca7 in the microglial responses linking AD and T2DM. Single-cell RNA sequencing (scRNA-seq) data from the hippocampi of db/db and db/m mice were analyzed to characterize cellular heterogeneity. To validate the bioinformatic findings, an AD mouse model was established by a single intracerebroventricular injection of Aβ1-42. Behavioral performances were observed, and the protein expression of Abca7 and typical neuropathological features of AD were detected. In parallel, in vitro studies were conducted using BV2 microglial cells exposed to Aβ1-42 following Abca7 knockdown. The scRNA-seq analysis revealed significant alterations in endothelial cells, microglia, and oligodendrocytes in db/db mice. Microglia emerged as central regulators of neuroinflammatory responses, with Abca7 identified as a hub gene linked to both T2DM and AD pathology. Consistently, the expression of Abca7 in the hippocampus of AD mice was markedly elevated and positively correlated with the cognitive impairments and Aβ/Tau pathology. Moreover, the knockdown of Abca7 could protect BV2 cells against Aβ-induced injuries and hyperactivation which could be partly ascribed to the suppression of NF-κB signaling and oxidative stress. Overall, these results suggest Abca7 may play a linking role in the microglial response between T2DM and AD, which is partly supported by in vivo and in vitro results of its effect on the hyperactivation of microglia in AD-like pathologies.},
}
@article {pmid42463181,
year = {2026},
author = {Kuznetsov, AV},
title = {Predicting biological age using an accumulated neurotoxicity biomarker for amyloid Beta oligomers.},
journal = {Mathematical medicine and biology : a journal of the IMA},
volume = {},
number = {},
pages = {},
doi = {10.1093/imammb/dqag005},
pmid = {42463181},
issn = {1477-8602},
abstract = {This study proposes using accumulated neurotoxicity, defined as the time integral of Aβ oligomer concentration, as a biomarker for neuronal aging. A relationship between biological age and accumulated neurotoxicity is proposed. Numerical analysis guided the development of a new analytical solution linking the biological and calendar ages of neurons. The effects of Aβ monomer and oligomer half-lives-key indicators of proteolytic efficiency-on biological age are examined. Both constant and age-dependent (exponentially increasing) half-life scenarios are considered. The findings indicate that increasing the half-life of Aβ monomers and oligomers with age accelerates biological aging. Reducing Aβ monomer production is shown to slow biological aging, with a linear relationship established between these two quantities. Additionally, biological age is found to depend linearly on the half-deposition time of Aβ oligomers into senile plaques. The model demonstrates that biological age is irreversible, providing a theoretical explanation for why plaque-clearing therapies cannot reverse established cognitive impairment. The model also demonstrates that biological age is path-dependent rather than state-dependent.},
}
@article {pmid42463287,
year = {2026},
author = {Maass, A and Garcia-Garcia, B and Behrenbruch, N and Schumann-Werner, B and Molloy, EN and Schwarck, S and Rullmann, M and Hochkeppler, A and Fischer, L and Büchel, AT and Bernal, J and Vockert, N and Incesoy, EI and Glanz, W and Butryn, M and Schulze, P and Baldauf, K and Stephens, AW and Schildan, A and Patt, M and Behnisch, G and Morgado, B and Esselmann, H and Seidenbecher, CI and Schott, BH and Wiltfang, J and Barthel, H and Sabri, O and Kreissl, MC and Düzel, E},
title = {Associations of [[18]F]PI-2620 Binding with Memory and Phosphorylated Tau 217 in Cognitively Unimpaired Older Adults.},
journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine},
volume = {},
number = {},
pages = {},
doi = {10.2967/jnumed.125.271927},
pmid = {42463287},
issn = {1535-5667},
abstract = {[[18]F]PI-2620 is a second-generation tau PET tracer that may detect early tau accumulation in aging. We investigated whether temporal lobe [[18]F]PI-2620 binding is associated with age, sex, genetic Alzheimer disease (AD) risk, plasma biomarkers of AD (plasma phosphorylated tau 217 [p-tau217], Aβ1-42/Aβ1-40), astrogliosis (glial fibrillary acidic protein), and domain-specific cognition in cognitively unimpaired (CU) older adults. Methods: In this study, 166 CU older adults (mean age, 72 ± 7 y; females, 46%; apolipoprotein ϵ4 [APOE4] carriers, 23%) and 13 young adults underwent extensive cognitive testing, blood sampling, MRI, and dynamic [[18]F]PI-2620 PET (0-60 min postinjection). Associations of regional [[18]F]PI-2620 distribution volume ratio (DVR) with age, sex, APOE4 genotype, and plasma biomarkers were examined using region-of-interest and voxelwise analyses. Additional imaging markers of age-related pathology included hippocampal volume, medial temporal lobe thickness, white matter (WM) hyperintensities, perivascular spaces, and hippocampal perfusion (R1-derived maps). Associations among temporal lobe DVR, other imaging markers, and domain-specific cognitive performance (from factor analysis) were tested. Results: In older adults, temporal [[18]F]PI-2620 binding was higher in women (β = 0.543, P < 0.001) and APOE4 carriers (β = 0.395, P = 0.030) and was positively associated with plasma p-tau217 (β = 0.22, P = 0.008). Voxelwise analyses showed age-related increases in basal ganglia signal, whereas WM signal was higher in younger adults. In a multiple regression model, higher temporal DVR (β = -0.36, P = 0.003) and lower hippocampal volume (β = 0.22, P = 0.007) predicted worse episodic memory and, together with demographic factors, explained approximately 30% of the variance. Conclusion: Temporal [[18]F]PI-2620 binding is associated with genetic AD risk, plasma p-tau217, female sex, and episodic memory deficits in CU older adults, supporting its sensitivity to early tau pathology, while highlighting the need to consider potential WM binding.},
}
@article {pmid42463411,
year = {2026},
author = {Shi, Y and Liao, X and Yu, G},
title = {Advances in Tricyclic Compounds for the Treatment of Alzheimer's Disease.},
journal = {ChemMedChem},
volume = {21},
number = {14},
pages = {e70384},
doi = {10.1002/cmdc.70384},
pmid = {42463411},
issn = {1860-7187},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Neuroprotective Agents/chemistry/pharmacology/therapeutic use ; Structure-Activity Relationship ; Animals ; *Cholinesterase Inhibitors/chemistry/pharmacology ; Molecular Structure ; Oxidative Stress/drug effects ; },
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder involving interconnected pathological pathways, including cholinergic dysfunction, Aβ deposition, tau hyperphosphorylation, neuroinflammation, oxidative stress, and dysregulation of metal ion homeostasis. Recently, the "one drug, one target" paradigm has faced certain clinical limitations, driving a paradigm shift toward multi-target therapeutic strategies. In this context, tricyclic scaffolds, characterized by rigid fused-ring skeletons, excellent structural tunability, and favorable neuropharmacological properties, have emerged as promising scaffolds for developing multi-target AD therapeutics. These molecules can interact with multiple AD-related targets through stable π-π stacking and hydrophobic interactions. Some tricyclic scaffolds, such as tetrahydrocarbolines, share structural similarity with endogenous neurotransmitters, suggesting potential involvement in modulating cognitive and mood-related pathways, along with favorable BBB permeability and neuro-compatibility. Accordingly, this review begins by outlining the distinct pathological mechanisms underlying AD, followed by a summary of recent progress on tricyclic compounds, encompassing both single-target and multi-target-directed molecules, with an emphasis on structure-activity relationships and mechanisms of action, aiming to offer new insights and strategies for combating this devastating disease.},
}
@article {pmid42463545,
year = {2026},
author = {Trares, K and Duman, D and Beyer, L and Michaelian, JC and Stocker, H and Holleczek, B and Beyreuther, K and Schöttker, B and Gerwert, K and Brenner, H},
title = {Predictive value of plasma p-tau217 for Alzheimer's dementia compared to other blood-based biomarkers.},
journal = {EMBO molecular medicine},
volume = {},
number = {},
pages = {},
pmid = {42463545},
issn = {1757-4684},
abstract = {Phosphorylated-tau (p-tau217) is a promising blood-based biomarker for Alzheimer's dementia (AD) in clinical settings. However, research from prospective cohort studies is sparse. We measured plasma p-tau217 levels in baseline blood samples of 779 participants in a population-based cohort of older adults followed over 17 years. Associations with AD were assessed and compared to those with previous measurements of p-tau181, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP). Comparisons to the amyloid beta (Aβ) misfolding biomarker were performed in a subgroup analysis. P-tau217, NfL and GFAP showed strong associations with AD risk, especially within the first 9 years of follow-up, outperforming p-tau181. Over the later years of follow-up, the predictive accuracy of p-tau217 was significantly reduced. In contrast, the Aβ misfolding biomarker demonstrated superior performance especially as a preclinical indicator of the risk of AD many years before diagnosis. The combination of p-tau217 with NfL, GFAP, basic demographic and genetic information, as well as the misfolding biomarker yielded an AUC 0.86 for AD diagnoses over the entire 17-year follow-up period.},
}
@article {pmid42463666,
year = {2026},
author = {Bjørnholm, KD and Li, H and Del Gaudio, F and Mocci, G and Shao, W and Baldisseri, E and Rao, SB and Lindblad, C and Fletcher-Sandersjöö, A and Vázquez-Liébanas, E and Pietilä, R and Muhl, L and Jiang, R and Kalantzi, C and Cheung, J and Jin, S and Svensson, M and Lesnik Oberstein, SAJ and Syvänen, S and Mäe, MA and Torp, R and Lendahl, U and Karlström, H and Thelin, EP and Nilsson, P and Vanlandewijck, M},
title = {Heterogenous microglial reactivity contrasts with stable vascular transcriptional programs in mouse models of Alzheimer's, CADASIL, and Traumatic Brain Injury.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {42463666},
issn = {2041-1723},
mesh = {Animals ; *Microglia/metabolism/pathology ; *Alzheimer Disease/genetics/pathology/metabolism ; Disease Models, Animal ; Mice ; Humans ; *Brain Injuries, Traumatic/genetics/pathology/metabolism ; *CADASIL/genetics/pathology/metabolism ; Transcriptome ; Mice, Transgenic ; Male ; Brain/blood supply/pathology/metabolism ; Single-Cell Analysis ; },
abstract = {The extent to which the cerebrovasculature is affected in various brain disorders is still not well understood. To address this, we established a transcriptomic repository of major vascular cell types and microglia to compare the global transcriptomic response in mouse models of three human brain disorders linked to neuroinflammation and associated vascular reactivity: Alzheimer's disease (AD), traumatic brain injury (TBI), and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Single-cell analysis of >250,000 cells at different disease stages led to identification of two previously unknown vascular cell subtypes, expanded the endothelial zonation spectrum and allowed for a detailed analysis of the cellular and molecular responses. Surprisingly, most vascular cell types lacked major transcriptomic changes across the three conditions, while microglia exhibited significant, disease-specific transcriptional changes. Notably, microglial responses converged between late-stage TBI and AD, offering insights into the predisposition for neurodegeneration following TBI.},
}
@article {pmid42463670,
year = {2026},
author = {Anwer, D and A, A and Marchi, A and Kerkhoven, E and Polster, A},
title = {Network-based discovery of regulatory drivers of cognitive decline in alzheimer's disease.},
journal = {npj aging},
volume = {12},
number = {1},
pages = {},
pmid = {42463670},
issn = {2731-6068},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder marked by progressive cognitive decline, yet its transcriptional regulatory architecture remains poorly understood. Here, we model sample-specific gene regulatory networks (GRNs) from dorsolateral prefrontal cortex transcriptomes of 87 individuals with AD and 67 non-cognitively impaired (NCI) controls and use a machine learning classifier to detect consistent disease-specific network features. This sample-specific network approach captures inter-individual variation in transcriptional regulation and revealed 22 key transcription factor-gene regulations that distinguish AD from NCI with 96% weighted accuracy. The key transcription factor-gene interactions were enriched in pathways central to AD pathology, including synaptic signalling, mitochondrial function, proteostasis, and neuroinflammation. Network analysis uncovered significant differences in regulatory connectivity between AD and controls, with ZNF225, ZNF849, and ZNF548 emerging as AD-specific regulatory hubs. Moreover, several key regulatory edges showed significant correlations with longitudinal cognitive decline, supporting their clinical relevance. Our findings highlight pervasive transcriptional dysregulation in AD, emphasizing sample-specific GRN modelling's value in uncovering regulatory mechanisms.},
}
@article {pmid42463907,
year = {2026},
author = {Yang, D and Guo, W and Wang, B},
title = {The Exercise-CTSS-AD Axis: a novel framework for understanding exercise-induced neuroprotection in Alzheimer's disease.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42463907},
issn = {1573-7365},
mesh = {*Alzheimer Disease/metabolism/therapy ; Humans ; Animals ; *Cathepsins/metabolism ; *Neuroprotection/physiology ; *Exercise/physiology ; Blood-Brain Barrier/metabolism ; Amyloid beta-Peptides/metabolism ; },
abstract = {Disease-modifying therapies for Alzheimer's disease (AD) targeting amyloid-β and tau have consistently failed, highlighting the urgent need for innovative therapeutic strategies. Cathepsin S (CTSS), a lysosomal cysteine protease upregulated in AD, functions as a "multifaceted disruptor" that interconnects neuroinflammation, blood-brain barrier (BBB) dysfunction, and Aβ metabolic dysregulation. Although exercise is a validated non-pharmacological intervention that mitigates AD pathology, its multi-target molecular mechanisms remain elusive. Here, we propose and substantiate the "Exercise-CTSS-AD Axis" hypothesis, positing that exercise confers neuroprotection by suppressing CTSS through synergistic anti-inflammatory, anti-aging, and metabolic regulatory pathways. Exercise-induced myokines and clearance of senescent cells inhibit CTSS transcription, while AMPK-TFEB axis activation enhances lysosomal function to repress CTSS enzymatic activity. This systemic CTSS suppression preserves BBB integrity, ameliorates microglia-driven neuroinflammation, and restores Aβ homeostasis by reducing production and enhancing clearance. Our framework provides a unifying molecular explanation for the pleiotropic benefits of exercise, positions CTSS as a quantifiable biomarker for personalized exercise regimens, and supports an innovative combinatorial strategy: "Exercise + low-dose CTSS inhibitors" as a disease-modifying therapy for AD.},
}
@article {pmid42463911,
year = {2026},
author = {Wang, Y and Xiong, X and Zhang, R and Xiao, L and Ruan, X and Ni, T and Liu, Z and Chen, J and Qin, S and Du, Z and Zhang, Y and Wu, L},
title = {Developmental priming of adult proteostasis and longevity by NuA4 complex activity in early life.},
journal = {The EMBO journal},
volume = {},
number = {},
pages = {},
pmid = {42463911},
issn = {1460-2075},
support = {32271357//MOST | National Natural Science Foundation of China (NSFC)/ ; 32071151//MOST | National Natural Science Foundation of China (NSFC)/ ; 2022XHSJJ005//MOST | NSFC | NSFC-Zhejiang Joint Fund | | Zhejiang Provincial Program for the Cultivation of High-Level Innovative Health Talents/ ; },
abstract = {Proteostasis collapse, a hallmark of aging and neurodegeneration like Alzheimer's disease (AD), causes irreversible damage in late life. Whether late-life proteostasis capacity is developmentally programmed remains unclear, as mechanistic studies requiring lifelong tracking and molecular manipulation are challenging or impossible in long-lived species. Using C. elegans as a lifelong, genetically tractable AD model, we uncover a critical early-life window during which reducing TIP60/NuA4 acetyltransferase complex activity enduringly enhances proteostasis and extends lifespan. Mechanistically, NuA4 reduction depletes H4K16ac, triggering a compensatory, early-life-biased, XBP-1-mediated unfolded protein response (UPR[ER]). This UPR[ER] activation remodels endoplasmic reticulum (ER) morphology and reprograms lipid metabolism, driving selective oleic acid (OA) accumulation. Crucially, this developmentally-installed OA reservoir confers lasting resilience against proteotoxic stress, an effect mimicked by OA supplementation. Together, these findings establish a chromatin-ER-lipid axis that developmentally primes adult proteostasis and suggest early-life interventions as a strategy to promote healthy aging and resilience to proteotoxic stress.},
}
@article {pmid42463967,
year = {2026},
author = {Xu, X and Liu, D and Sun, X and Yang, K and Lv, P and Lu, J and Ruan, W and Xia, X and Chen, J and Chen, Y and Wang, H and Wu, X and Ge, D and Yang, B and Wan, M and Liang, H and Lan, X and Gai, Y and Zhang, B},
title = {In vivo multimodal PET/MRI imaging and plasma biomarkers implicate glymphatic dysfunction linking neuroinflammation to tau pathology in the early Alzheimer's disease continuum.},
journal = {European journal of nuclear medicine and molecular imaging},
volume = {},
number = {},
pages = {},
pmid = {42463967},
issn = {1619-7089},
support = {2022ZD0211800//Instituto Nacional de Ci&#xea;ncia e Tecnologia Centro de Estudos das Adapta&#xe7;&#xf5;es da Biota Aqu&#xe1;tica da Amaz&#xf4;nia/ ; },
abstract = {PURPOSE: Neuroinflammation is a key factor contributing to cognitive decline in Alzheimer's disease (AD). This study aims to investigate the mechanistic associations among neuroinflammation, glymphatic dysfunction, tau pathology, and cognitive decline in AD spectrum.<br><br>METHODS: The study included 355 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and a supportive cohort of 59 individuals from Wuhan Union Hospital (WHUH). Tau pathology was quantified using [18]F-AV1451 positron emission tomography (PET). Glymphatic function was estimated through diffusion tensor image analysis along the perivascular space (DTI-ALPS). Neuroinflammation was assessed via plasma glial fibrillary acidic protein (GFAP) in two cohorts and translocator protein (TSPO) PET imaging with [18]F-DPA-714 in supportive cohort. Correlation analyses and mediation models were employed to evaluate the directional relationships among tau deposition, inflammation, glymphatic function, and cognition.<br><br>RESULTS: Higher levels of inflammation were significantly associated with lower DTI-ALPS index (&#x3b2; = -0.171, P&#x2009;=&#x2009;0.046), which in turn was associated with higher tau burden (&#x3b2;&#x2009;=&#x2009;0.162, P&#x2009;=&#x2009;0.010). Path analysis revealed significant indirect associations linking neuroinflammation to cognitive performance through glymphatic dysfunction and tau pathology, with total indirect effects of -&#x2009;0.165 (95% CI, -&#x2009;0.266 to -&#x2009;0.105) in ADNI and -&#x2009;0.143 (95% CI, -&#x2009;0.386 to -&#x2009;0.013) in WHUH. These findings support a hypothesized inflammation-glymphatic-tau pathway rather than a definitive causal cascade.<br><br>CONCLUSION: Our findings are consistent with a hypothesized inflammation-glymphatic-tau association in which greater neuroinflammation is linked to reduced glymphatic function and higher regional tau burden, particularly in preclinical and prodromal stages.<br><br>This study obtained ethical approval from the Institutional Review Committee of Nanjing Drum Tower Hospital (ChiCTR-BRC-17011316, date:20170506; ChiCTR1900022526, date:20190415).},
}
@article {pmid42464002,
year = {2026},
author = {Delaporte, M},
title = {Associations Between Occupational Trajectories at Ages 35-55 and Later-Life Cognition in Older Adults in Chile.},
journal = {The journals of gerontology. Series B, Psychological sciences and social sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/geronb/gbag142},
pmid = {42464002},
issn = {1758-5368},
abstract = {OBJECTIVES: As global rates of Alzheimer's Disease and Related Dementias (AD/ADRD) increase, understanding the factors that contribute to cognitive aging is crucial. This study examined the association between occupational skill trajectories between ages 35 and 55 and cognitive function among older Chilean adults aged 60 and above. It explored how different patterns of occupational trajectories relate to cognitive performance.<br><br>METHODS: The analysis used data from the Chile-Cog study, which applied the Harmonized Cognitive Assessment Protocol (HCAP) to a nationally representative sample of Chilean adults in 2019. These cognitive assessments were linked to detailed occupational histories from the Chilean Social Protection Survey (SPS). Using Sequence Analysis, occupational trajectories between ages 35 and 55 were classified into nine groups for women and six groups for men. Cognitive function was measured using a composite cognitive score based on the HCAP items. Linear regression models estimated the associations between occupational trajectory groups and cognitive outcomes, separately for women (n=1,009) and men (n=769).<br><br>RESULTS: Individuals with longer participation in middle- and high-skill occupations showed better cognitive performance at older ages, whereas prolonged periods in low-skill jobs or not employed were associated with lower scores. However, no strong evidence emerged on associations between specific trajectories of occupational mobility and cognitive outcomes.<br><br>DISCUSSION: The findings suggest that cumulative time in higher-skill occupations may be more important for cognitive aging than occupational mobility itself. This study contributes to understanding how occupational trajectories shape cognition in later life and offers insights for countries undergoing economic and demographic transitions.},
}
@article {pmid42464008,
year = {2026},
author = {Lim, S and Lee, Y and Yun, CS and Kim, K and Yun, CH and , },
title = {Change in Amyloid-β Deposition and Diffusion Tensor Image Analysis along the Perivascular Space Index in Incident Neurodegenerative Disease.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78301},
pmid = {42464008},
issn = {1531-8249},
support = {//National Research Foundation of Korea (NRF)/ ; },
abstract = {OBJECTIVE: We investigated the longitudinal association between cognitive decline, amyloid-β deposition, and perivascular diffusivity using diffusion tensor image analysis along the perivascular space (DTI-ALPS) index.<br><br>METHODS: This 2-year longitudinal study included 211 participants from the Alzheimer's Disease Neuroimaging Initiative, categorized into sustained cognitively normal, incident mild cognitive impairment, persistent mild cognitive impairment, and incident Alzheimer's disease (AD). The DTI-ALPS index and amyloid-&#x3b2; standardized uptake value ratio (SUVR) from amyloid positron emission tomography were obtained at baseline and follow-up. Linear mixed-effects models were used to examine longitudinal changes in the DTI-ALPS index and their associations with cognitive decline and amyloid-&#x3b2; accumulation. Multiple mediation analyses were performed to evaluate whether amyloid burden and gray matter atrophy mediated the relationship between changes in the DTI-ALPS index and cognitive performance. Additional analyses assessed the effect of baseline amyloid-&#x3b2; positivity.<br><br>RESULTS: The incident mild cognitive impairment and incident AD groups showed greater longitudinal declines in the DTI-ALPS index than the sustained cognitively normal group. Longitudinal reductions in the DTI-ALPS index were associated with greater cognitive decline and increased amyloid-&#x3b2; accumulation. Mediation analyses showed no significant indirect effects through SUVR or gray matter volume. Although baseline amyloid-&#x3b2; positivity alone was not associated with longitudinal DTI-ALPS changes, significant interactions with clinical progression were observed.<br><br>INTERPRETATION: Longitudinal alterations in the DTI-ALPS index are associated with cognitive decline and amyloid-&#x3b2; accumulation. These findings support the DTI-ALPS index as a non-invasive imaging marker reflecting disease progression in AD. ANN NEUROL 2026.},
}
@article {pmid42464060,
year = {2026},
author = {Tekin, BN and Kaya, S and Erkoç Ataoğlu, NE and Teleş, M},
title = {The Effect of Caregiver Burden on Healthy Lifestyle Behaviours of People Caring for Patients With Alzheimer's Disease: A Cross-Sectional Study.},
journal = {Scandinavian journal of caring sciences},
volume = {40},
number = {3},
pages = {e70295},
doi = {10.1111/scs.70295},
pmid = {42464060},
issn = {1471-6712},
mesh = {Humans ; *Alzheimer Disease/nursing ; Cross-Sectional Studies ; Male ; Female ; *Caregivers/psychology ; Aged ; *Healthy Lifestyle ; Middle Aged ; Aged, 80 and over ; Turkey ; },
abstract = {OBJECTIVES: This study aimed to determine the effects of caregiver burden on the healthy lifestyle behaviours of people caring for patients with Alzheimer's disease.<br><br>METHODS: The Caregiver Burden Inventory (CBI) and the Healthy Lifestyle Behaviour Scale-II (HLBS-II) were administered to caregivers of Alzheimer's disease patients who were admitted to the Neurology Department Dementia Outpatient Clinic of a university hospital in Ankara (n&#x2009;=&#x2009;84). Independent sample t-test, one-way ANOVA, Pearson correlation and linear regression analysis were used in the study.<br><br>RESULTS: A moderate, negative and statistically significant correlation was found between CBI and HLBS-II (r&#x2009;=&#x2009;-0.40; p&#x2009;<&#x2009;0.001). The effect of CBI on HLBS-II was significant even in the presence of control variables (b&#x2009;=&#x2009;-0.29; p&#x2009;<&#x2009;0.05). The increase in social burden (b&#x2009;=&#x2009;-0.92; p&#x2009;<&#x2009;0.05) and developmental burden (b&#x2009;=&#x2009;-0.65; p&#x2009;=&#x2009;0.053) of the CBI dimensions caused a decrease in healthy lifestyle behaviours.<br><br>CONCLUSIONS: Effective home care for Alzheimer's patients requires caregivers to maintain their own good health. This study demonstrates that increased caregiver burden, particularly in social and developmental domains, negatively impacts their healthy lifestyle behaviours. Policies should focus on reducing this burden to enhance caregiver well-being and ensure sustainable home care.},
}
@article {pmid42464289,
year = {2026},
author = {Zhan, X and Liu, C and Yu, C and Lindblom, N and Deierborg, T and Kobro-Flatmoen, A and Gouras, GK and Wen, G},
title = {Passive amyloid-β immunotherapy in Alzheimer's disease: a multicellular clearance system beyond plaque removal.},
journal = {Molecular neurodegeneration},
volume = {21},
number = {1},
pages = {},
pmid = {42464289},
issn = {1750-1326},
mesh = {*Alzheimer Disease/therapy/immunology ; Humans ; *Amyloid beta-Peptides/immunology/metabolism ; Animals ; *Plaque, Amyloid/immunology/therapy ; *Immunotherapy/methods ; *Immunization, Passive/methods ; Brain/metabolism ; },
abstract = {Passive immunotherapy targeting amyloid-β (Aβ) has emerged as a major therapeutic strategy for Alzheimer's disease (AD), yet its clinical benefits remain modest and are frequently accompanied by vascular adverse events such as amyloid-related imaging abnormalities (ARIA). While the removal of extracellular Aβ plaques is associated with therapeutic efficacy, accumulating evidence suggests that additional cellular and vascular mechanisms may also contribute to complementary therapeutic outcomes alongside plaque removal. Recent studies show that Aβ antibodies are broadly distributed within the brain and interact with multiple neural and immune cell populations, rather than being limited to Aβ plaques. These observations support an expanded view of passive Aβ immunotherapy as a multicellular coordinated clearance process. Aβ antibodies engage diverse cellular and anatomical compartments, including neurons, glial cells, perivascular macrophages, peripheral immune cells, and meningeal lymphatic pathways, thereby influencing Aβ dynamics across intracellular and extracellular pools. Within this framework, therapeutic outcomes are influenced not only by plaque clearance but also by interactions between Aβ antibodies and cellular and anatomical compartments that regulate Aβ clearance and treatment-associated vascular response. This perspective may help explain variability in clinical efficacy and the emergence of vascular side effects, while also providing additional considerations for optimizing Aβ antibody design and therapeutic strategies.},
}
@article {pmid42464353,
year = {2026},
author = {Al-Awlaqi, A and Berckmans, L and De Waegenaere, S and Vanherle, S and Griffis, J and Dewachter, I and Verhoye, M and Adhikari, MH},
title = {Resting-state functional dynamics alterations relate to plasma amyloid markers and statistically explain memory impairments in the TgF344-AD model of Alzheimer's disease.},
journal = {Alzheimer's research &amp; therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02146-w},
pmid = {42464353},
issn = {1758-9193},
support = {G045420N//Fonds Wetenschappelijk Onderzoek/ ; SAO-FRA 2020/027//Internationale Stichting Alzheimer Onderzoek/ ; 50751//Bijzonder Onderzoeksfonds UAntwerp/ ; },
abstract = {BACKGROUND: Resting-state functional MRI studies of Alzheimer's disease (AD) show lower functional connectivity (FC) of AD-relevant regions and resting-state networks in patients and transgenic rodent models at symptomatic stages. However, at early stages of the disease, both hyper and hypo connectivity has been reported. Traditional FC overlooks temporal fluctuations in connectivity and network dynamics at a short timescale captured by transient brain states such as co-activation patterns (CAPs). CAPs have been shown to be more sensitive than FC to detect early alterations in neurodegenerative diseases and therefore can shed light on hyper versus hypo connectivity observed at early stages. Moreover, how brain functional signatures of Alzheimer's disease are related to its behavioral and pathological markers and whether they have prognostic relevance remain scarcely investigated.<br><br>METHODS: We acquired high temporal resolution resting-state functional MRI data in the TgF344-AD model rats and age-matched wild-type animals at 4 and 10 months of age corresponding to the pre-plaque and plaque stages, respectively and delineated brain functional alterations using FC and CAPs in the model animals. We also assessed the levels of amyloid beta (A&#x3b2;) in blood and working and reference memory performance in the same animals at the plaque stage and investigated their statistical relationship with pre-plaque and plaque-stage changes in FC and CAPs.<br><br>RESULTS: TgF344-AD rats had significantly elevated blood A&#x3b2; levels, committed more working and reference memory errors and showed reduced hippocampal FC with the lateral cortical and default-mode-like network compared to wild-type animals at the plaque stage. FC at the pre-plaque stage did not differ between TgF344-AD and wild-type rats. TgF344-AD rats showed hyper- and hypo-activation in the default-mode-like-network and hippocampal regions at pre-plaque and plaque stages, respectively, in multiple CAPs. Blood A&#x3b2; levels were statistically explained more accurately by plaque-stage, than pre-plaque stage, FC values and CAP activations. CAP activations, especially at the pre-plaque stage, outperformed FC in accurate statistical explanation of memory impairments.<br><br>CONCLUSION: Our findings demonstrate pre-plaque stage hyperconnectivity not in the traditional, static measure of functional connectivity but in transient, dynamic brain states and that these early brain functional signatures have prognostic relevance for memory deficits in a translational rat model of Alzheimer's disease.},
}
@article {pmid42464410,
year = {2026},
author = {Malichova, F and Swann, P and Kigar, SL and Savinykh Yarkoni, N and Goddard, J and Lai, KO and Chouliaras, L and Surendranathan, A and Turner, L and Savulich, G and Bevan-Jones, R and Ashton, NJ and Blennow, K and Zetterberg, H and Needham, E and Jones, J and McEwan, WA and Rowe, JB and O'Brien, JT and Malpetti, M},
title = {Blood-based immunophenotyping of T cell profiles in patients with neurodegenerative disorders.},
journal = {Alzheimer's research &amp; therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02144-y},
pmid = {42464410},
issn = {1758-9193},
abstract = {BACKGROUND: There is increasing evidence for the role of central and peripheral inflammation across neurodegenerative disorders, with animal models and post-mortem studies identifying T-cell infiltration in the brain associated with pathology and neurodegeneration. Peripheral T-cell changes have been measured in Alzheimer's disease (AD), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP). This study examines a unique cohort of blood-based T-cell profiles across a range of neurodegenerative dementias including AD, DLB, FTD, corticobasal syndrome (CBS), PSP, and aged-matched healthy controls. Then it also explores their associations with dementia-relevant plasma biomarkers and clinical outcomes.<br><br>METHODS: Freshly prepared peripheral blood mononuclear cells (PBMCs) from 174 participants (AD&#x2009;=&#x2009;20, DLB&#x2009;=&#x2009;24, FTD&#x2009;=&#x2009;19, CBS&#x2009;=&#x2009;18, PSP&#x2009;=&#x2009;58, controls&#x2009;=&#x2009;35) were studied using a flow-cytometry panel designed to analyse major T-cell subpopulations, including memory and T-helper subtypes. Neurodegeneration-relevant biomarkers (p-tau217, p-tau231, GFAP, NfL, and A-beta42/40) were measured in plasma samples. T-cell populations were compared between groups and in association with biomarkers, and principal components analysis (PCA) was used to identify T-cell profiles and their association with dementia-relevant biomarkers in diagnostic classification and survival prediction.<br><br>RESULTS: There was a significant reduction in the fraction of CD3+&#x2009;cells in patients with DLB compared to other diagnostic groups, and an increase in relative Th1/17-like cell levels in patients with FTD compared to controls. This increase in Th1/17-like cells correlated with NfL and GFAP plasma levels in patients with FTD. PCA identified five components primarily representing CD4+&#x2009;memory cell population subsets. After sex and age adjustments, component 4 marked by effector memory types including Th2-like, Th-like1 and Th1/17-like cells was a significant predictor of FTD, however was not as accurate as plasma NfL. Higher scores in specific T-cell components (1 and 3) were associated with reduced mortality across all diseases, with component 3 remaining a significant predictor even when controlling for traditional neurodegenerative biomarkers like NfL and p-tau217.<br><br>CONCLUSIONS: This study provides evidence that T-cell dysregulation is not unified in patients with neurodegenerative diseases. We observe different involvement across different dementia types establishing adaptive immunity as a key contributor to disease heterogeneity. However, although plasma biomarkers such as NfL and p-tau217 exhibit superior diagnostic accuracy for clinical classification, peripheral T-cell signature were associated with survival outcomes across diagnostic groups, highlighting their promise for prognostic applications and disease monitoring. The characterisation of T-cell populations across neurodegenerative conditions may inform target development and patient stratification for new interventional trials.},
}
@article {pmid42464798,
year = {2026},
author = {Alluri, R and Kilari, EK and Pasala, PK and Kopalli, SR and Koppula, S},
title = {RETRACTED: Alluri et al. Repurposing Diltiazem for Its Neuroprotective Anti-Dementia Role Against Intra-Cerebroventricular Streptozotocin-Induced Sporadic Alzheimer's Disease-Type Rat Model. Life 2023, 13, 1688.},
journal = {Life (Basel, Switzerland)},
volume = {16},
number = {7},
pages = {},
doi = {10.3390/life16071175},
pmid = {42464798},
issn = {2075-1729},
abstract = {The journal retracts the article titled "Repurposing Diltiazem for Its Neuroprotective Anti-Dementia Role against Intra-Cerebroventricular Streptozotocin-Induced Sporadic Alzheimer's Disease-Type Rat Model" [...].},
}
@article {pmid42464964,
year = {2026},
author = {Dajani, I and Mahboob, A and Ibrahim, SS and Ibrahim, RS and Sedighi, M and Shirzadi, Z and Mahinrad, S and Sabatini, S and Khatoonabadi, AR and Prina, M and Castro, CB and Mantegna, JL and Akkari, PA and Hosseini, AA and Martins, RN and Burley, CV and Dunne, J and Stephan, BC and Sohrab, HR and Chaari, A},
title = {Dementia in the Middle East and North Africa: an integrative narrative review of epidemiology, risk structure, and health system implications.},
journal = {Journal of global health},
volume = {16},
number = {},
pages = {04181},
doi = {10.7189/jogh.16.04181},
pmid = {42464964},
issn = {2047-2986},
mesh = {Humans ; Africa, Northern/epidemiology ; Middle East/epidemiology ; *Dementia/epidemiology ; Risk Factors ; Prevalence ; },
abstract = {BACKGROUND: Dementia prevalence in the Middle East and North Africa (MENA) is projected to rise exponentially, with estimates suggesting increases of 367% by 2050. This region faces distinctive challenges, including rapid demographic transition, high rates of modifiable risk factors, and fragmented health systems. This paper examines region-specific risk factors and pooled prevalence rates of dementia across the MENA region.<br><br>METHODS: We conducted a narrative review of dementia risk factors in the MENA region, including analysis of population-attributable risk (PAR) estimates and pooled estimates of dementia prevalence among adults aged 50 years and older.<br><br>RESULTS: Dementia prevalence was estimated at 1.84% among individuals aged 50 years and older, increasing to 3.81% among those aged 60 years and older, with substantial variability across countries. Smoking (>30%), physical inactivity (&#x2009;~&#x2009;50%), and high burdens of diabetes, hypertension, and obesity were consistently associated with increased dementia risk. Additional region-specific drivers include nutritional transitions, gut dysbiosis, consanguinity, and environmental risk factors such as air pollution and climate-related heat stress. Critical barriers to prevention and care include limited research infrastructure, low health literacy, stigma, and inequitable health care access.<br><br>CONCLUSIONS: Dementia prevalence in MENA is rising rapidly, driven by demographic change and high exposure to modifiable risk factors that are relatively region-specific in terms of their contribution. Strengthening prevention, early detection, and equitable access to care should be regional health priorities.},
}
@article {pmid42465239,
year = {2026},
author = {Dong, R and Wang, M and Wang, GT and DeWan, AT and Leal, SM},
title = {LDSC regression-based heritability estimates can be biased when summary statistics are obtained from meta-analysis or imputed variants.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.05.736573},
pmid = {42465239},
issn = {2692-8205},
abstract = {MOTIVATION: Linkage disequilibrium score (LDSC) regression is a popular method to estimate heritability for complex traits using summary statistics and linkage disequilibrium (LD) reference panels, offering a practical alternative to methods requiring individual-level data. Despite its widespread use, LDSC regression can produce biased heritability estimates. The properties of LDSC regression were investigated using summary statistics from several large-scale Alzheimer's disease (AD) studies and a variety of LD reference panels. These heritability estimates were compared with those obtained from individual-level data.<br><br>RESULTS: When LDSC regression was applied to summary statistics obtained from meta-analysis, it led to an underestimation of heritability. This can occur if meta-analysis is used to combine studies of different ancestries leading to the caveat of the lack of an appropriate LD reference panel. Additionally meta-analyses often include studies with different phenotype definitions, that not only impacts heritability estimates but also makes them uninterpretable. Summary statistics generated from imputed variants, even those with high imputation accuracy, can lead to underestimation of heritability. For example, the heritability estimates for AD were reduced from 0.265 (se 0.148) to 0.160 (se 0.041) when imputed variants (INFO>0.9) were included compared to analyzing only genotype array variants. A decrease in heritability estimates was also observed when individual-level imputed variant data were analyzed using GCTA-GREML. Our findings highlight the caveats of estimating heritability using meta-analysis summary statistics or imputed data instead of genotyped or sequence data.},
}
@article {pmid42465252,
year = {2026},
author = {Balistreri, A and Gomulinski, M and Chapman, MR and Kelly, JW},
title = {The Microglial Protein sTREM2 Inhibits the Bacterial Functional Amyloid CsgA and Suppresses Amyloid-Dependent Biofilm Formation.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.03.736422},
pmid = {42465252},
issn = {2692-8205},
abstract = {Protein misfolding and aggregation, including amyloid fibril formation, underlie a large class of human diseases including prominent neurological disorders such as Alzheimer's and Parkinson's disease. A small number of human proteins have been identified that inhibit amyloidogenesis. One such protein is sTREM2, a soluble receptor liberated from microglia, the resident macrophages of the central nervous system. The extracellular domain of TREM2 is shed upon proteolytic cleavage to create sTREM2, which has previously been shown to inhibit amyloid-β aggregation in vitro . TREM2 is also expressed by intestinal macrophages, which are known to directly bind the bacterial amyloid curli and mount cytokine responses upon exposure. Here we show that sTREM2 is a sub-stoichiometric inhibitor of CsgA amyloidogenesis, CsgA being the major protein component of curli that drives biofilm formation in uropathogenic Escherichia coli and many other proteobacteria. In vitro , sTREM2 potently and sub-stoichiometrically inhibited CsgA amyloidogenesis in a dose-dependent manner. Kinetic modeling indicated that sTREM2 slowed primary and secondary nucleation, rather than altering fiber elongation. When added exogenously to bacterial growth medium, sTREM2 significantly suppressed curli-dependent pellicle biofilm formation without affecting bacterial growth. These findings establish sTREM2 as a member of the small group of human proteins capable of inhibiting bacterial functional amyloidogenesis, suggesting that gut-resident TREM2-expressing macrophages, which are already known to interact with curli, may employ sTREM2 as a physiologically relevant defense against bacterial amyloid formation.},
}
@article {pmid42465255,
year = {2026},
author = {Giorgio, J and Morin, TM and Chen, HY and Berry, AS and Breakspear, M and Jagust, WJ},
title = {Dopamine Compensates for Amyloid-Induced Default Mode Network Dysfunction to Support Learning.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.07.736872},
pmid = {42465255},
issn = {2692-8205},
abstract = {Throughout the preclinical phase of Alzheimer's disease (AD) β-amyloid (Aβ) accumulates preferentially within the default mode network (DMN), yet the functional and behavioural consequences of this pathological burden remain poorly understood. Using task-based fMRI combined with Aβ, tau, and dopamine PET in cognitively normal older adults, we show that Aβ burden impairs learning independent of tau, but this learning performance is recovered with higher dorsolateral striatal dopamine synthesis capacity. Investigating the neural mechanisms that support this learning, we observe that Aβ positive individuals show attenuated DMN activity to error related feedback, a metric that relates to poorer learning. When estimating the effective connectivity during feedback, computational modelling reveals that Aβ induces dis-inhibition of the DMN during error processing. Critically, dopamine synthesis capacity in the dorsolateral striatum rebalances effective connectivity between the DMN and frontostriatal network, thereby opposing Aβ related disruption. These findings establish a systems-level framework in which Aβ impairs learning by disrupting dynamic DMN modulation during feedback, a disruption for which dopaminergic function can partially compensate. This suggests that learning in the presence of Aβ may be subserved by dopamine-dependent network rebalancing, a candidate mechanism of cognitive resilience to support learning in preclinical AD.},
}
@article {pmid42465266,
year = {2026},
author = {Tsantilas, KA and Riffle, M and Merrihew, GE and Wu, CC and Keele, GR and Maurais, A and Johnson, RS and Luciano, A and Robinson, L and Churchill, GA and MacCoss, MJ},
title = {Circulating extracellular vesicles in plasma carry accessible molecular signatures of aging in mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.10.737625},
pmid = {42465266},
issn = {2692-8205},
abstract = {Cells release membrane-bound extracellular vesicles into the bloodstream laden with proteins that may reflect their physiological state. How this circulating EV proteome changes across life remains poorly understood. Identifying molecular signatures of aging in accessible biofluids could facilitate earlier intervention and monitoring of age-related disease. Many circulating aging proteome studies rely on affinity-based platforms which suffer from poor cross-species translation, ambiguous signal attribution, and inconsistent agreement between platforms. Here, we present a characterization of the aging plasma EV proteome from a cross-sectional cohort of 86 male and female C57BL/6J mice (5-31 months). We leveraged a species-agnostic EV enrichment (Mag-Net) and mass spectrometry to detect 2,575 protein groups from 15,969 peptides. Protein abundance heterogeneity increased with age and the abundance of 272 proteins were significantly correlated with chronological age including established senescence and frailty markers. Proteins increasing with age were enriched in genome maintenance pathways, while those decreasing were associated with the extracellular matrix organization and lipid metabolism. Notably, several of the strongest age-increased proteins converged on Alzheimer's and Parkinson's disease pathology. We observed sexual divergence in the aging EV proteome not previously characterized at this resolution. A proteomic clock built from this data accurately predicts chronological age, and peptide-level analysis reveals aging signals invisible at protein-level. These findings demonstrate that EV-enriched plasma proteomics can identify known aging markers, reveal novel sex-specific age-related changes, and generate predictive models of chronological age. This study provides a species-agnostic foundation for proteomic clocks that complement epigenetic approaches to monitor aging and evaluate healthspan.},
}
@article {pmid42465286,
year = {2026},
author = {Lai, HY and Kalavros, N and Chung, V and Kaplan, ES and Anastassiou, D and Cai, L and Chen, E and Vélez, IG and Gürsoy, G and Herrera, LJ and Li, X and Londin, E and Loher, P and Nazeraj, I and Ortuño, F and Yang, TO and Rigoutsos, I and Rojas, I and , and Andreoletti, G and Foschini, L and Heath, L and Oskotsky, T and Sirota, M and Stolovitzky, G and Travaglini, KJ and Zou, J and Gabitto, MI},
title = {The SEA-AD DREAM Challenge: Community benchmarking human and AI agent solutions for Alzheimer's disease neuropathology prediction from single-nucleus transcriptomics.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.02.736180},
pmid = {42465286},
issn = {2692-8205},
abstract = {Single-nucleus transcriptomic atlases offer an unprecedented opportunity to connect cellular molecular states with Alzheimer's disease (AD) neuropathology, but whether these profiles encode reproducible, predictive information about pathological burden remains unclear. We present the SEA-AD DREAM Challenge, an open, international, model-to-data competition built on the Seattle Alzheimer's Disease Brain Cell Atlas to predict Alzheimer's disease neuropathological severity from single-nucleus RNA-sequencing data. Participants developed containerized models to predict categorical neuropathological staging, including overall Alzheimer's disease neuropathologic change, Braak stage, Thal phase, and CERAD score, as well as quantitative amyloid-β and phospho-tau burden measured by 6E10 and AT8 immunohistochemistry. Across 17 eligible teams from 15 countries, the crowdsourcing framework enabled systematic comparison of diverse computational approaches and surfaced a broad landscape of modeling strategies and candidate predictive features. Top-performing methods achieved near-perfect prediction of categorical staging, with the best submission reaching a quadratic weighted kappa of 1.0 for the Overall AD Neuropathological Change score (ADNC), and competitive prediction of quantitative pathological burden in held-out data, with a best concordance correlation coefficient of 0.48. Post hoc perturbation analyses revealed that top categorical-stage predictions relied heavily on donor-level metadata-driven signals rather than transcriptomic features, whereas quantitative pathology prediction was more robust and supported by transcriptomic and cell-type-associated features with potential biological relevance to AD progression. The challenge also introduced the first AI Agent Track in a DREAM Challenge, providing an early benchmark for autonomous and human-guided agentic model development in single-cell neuroscience. This work demonstrates that single-nucleus transcriptomes encode substantial information about Alzheimer's disease pathology, establishes a reproducible benchmark for molecular neuropathology prediction, and highlights critical principles for designing privacy-preserving, leakage-aware community challenges using deeply phenotyped human brain data.},
}
@article {pmid42465304,
year = {2026},
author = {Bai, H and Liu, Y and Seluanov, A and Gorbunova, V},
title = {Age-Associated Behavioral Alterations in Laboratory-Housed Octodon degus.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.07.737045},
pmid = {42465304},
issn = {2692-8205},
abstract = {UNLABELLED: Octodon degus are long-lived, diurnal, and highly social rodents increasingly used in studies of aging and neurodegeneration. However, behavioral profiles of aged laboratory-housed degus remain incompletely characterized, limiting the interpretation of aging-associated functional and molecular phenotypes in this species. Here, we evaluated age-associated changes in locomotor activity, open-field exploration, social novelty behavior, and manually scored ethological responses in young and old degus maintained under long-term laboratory housing conditions. Automated behavioral tracking was performed during open-field testing and three-chamber social behavior testing. During open-field testing, old degus showed increased locomotor activity compared with young animals, including greater total distance moved, higher mean velocity, increased moving frequency, and longer cumulative movement duration. Old degus also showed increased center-zone duration and reduced thigmotaxis score. Manual ethological scoring revealed increased rearing and fecal boli in old animals during open-field exposure. In the three-chamber social behavior assay, young degus showed higher investigation frequency toward the novel intruder than toward the familiar cagemate, whereas old degus showed a lower social novelty discrimination index compared with young animals. Sex-stratified analyses did not identify significant male-female differences within young or old groups for the major open-field or social novelty metrics examined. Together, these findings indicate that aging in laboratory-housed degus is associated with a mixed behavioral profile involving increased stress-related ethological responses and reduced social novelty preference reminiscent of dementia-like behavioral changes observed in Alzheimer's disease. This behavioral framework provides a practical reference for future studies examining behavioral heterogeneity and molecular correlates of brain aging in degus.<br><br>LAY SUMMARY: Octodon degus are long-lived, highly social rodents that are increasingly used to study aging and age-related neurodegenerative disorders. However, interpreting behavioral changes in aged degus requires a clear understanding of how aging affects activity, exploration, social behavior, and stress-related responses under laboratory housing conditions. In this study, we compared young and old degus using open-field testing, three-chamber social behavior testing, automated video tracking, and manual scoring of selected behaviors. Aged degus did not show a simple reduction in behavioral activity. Instead, they showed increased movement during behavioral testing, increased rearing behavior, greater exploration of the center of the open-field arena, and increased fecal output during open-field exposure. These findings suggest that aged degus show increased exploratory activity together with altered stress-related responses in a novel environment. Aged degus also showed reduced preference for investigating a novel social partner, consistent with a dementia-like cognitive impairment. Together, these results define a behavioral profile of aged laboratory-housed degus and provide a practical reference for future studies using this species to investigate aging, social behavior, and neurodegeneration-related phenotypes.},
}
@article {pmid42465306,
year = {2026},
author = {Mulholland, MM and Magden, ER and Scholtzova, H and Hopkins, WD},
title = {A Comparative Study of Plasma Biomarkers of Neurodegeneration in Rhesus Monkeys (Macaca mulatta) and Baboons (Papio anubis).},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.02.735676},
pmid = {42465306},
issn = {2692-8205},
abstract = {Many nonhuman primate species recapitulate the neuropathological features of sporadic Alzheimer's disease (AD) to varying degrees. As with humans, the assessment of AD-related pathology in nonhuman primates has historically relied on the use of postmortem brain tissues. In vivo alternatives, such as PET imaging tracers and fluid biomarkers, have been developed for use in humans but require further validation in nonhuman primates before replacing postmortem analyses. Here we employed the Nucleic Acid-Linked Immuno-Sandwich Assay (NULISA [TM]) CNS Disease panel to compare age-related changes in plasma biomarkers in two nonhuman primate species (rhesus monkeys and baboons). In addition, we examined whether amyloid and tau biomarkers were associated with brain atrophy, as measured by gray matter volume. We found significant associations between age and multiple biomarkers of neurodegeneration for both species, as well as significant differences in the patterns of these associations between the two species. For the phosphorylated tau measures, though rhesus monkeys had higher values, baboons showed significant and stronger associations with age. By contrast, rhesus monkeys exhibited an earlier age-related decline in Aβ42/Aβ40 ratio than baboons. Finally, in both species, lower Aβ42/Aβ40 ratios were associated with lower gray matter volumes. This is the first systematic comparative study of age-related changes in neurodegeneration biomarkers in two closely related nonhuman primates using comparable age ranges and sample sizes, and the same multiplex assay. Future studies should examine longitudinal changes in these biomarkers as well as validate the plasma findings using cerebral spinal fluid.},
}
@article {pmid42465338,
year = {2026},
author = {Dooling, BR and Vielle, A and Lucero, EM and Rydland, C and Quang, D and Summers, R and Esquer, H and Coughlan, C and Galbraith, MD and Espinosa, JM and LaBarbera, DV and Chial, HJ and Potter, H and Ledreux, A and Johnson, NR},
title = {Trisomy 21 cerebral organoids exhibit Alzheimer's disease amyloid and apolipoprotein E co-pathologies.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.01.735908},
pmid = {42465338},
issn = {2692-8205},
abstract = {Adults with Down syndrome (DS) develop Alzheimer's disease (AD) brain pathology by age 40 due to triplication of the Amyloid Precursor Protein (APP) gene on chromosome 21. Inheritance of the apolipoprotein E-e4 (APOE4) allele of the APOE gene on chromosome 19 remains the greatest genetic risk factor for AD in the typical population, yet its role in DS-associated AD (DS-AD) neuropathogenesis in people with DS is unclear. We generated human induced pluripotent stem cell (hiPSC)-derived neurons, astrocytes, and cerebral organoids (COs) using cells from people with DS and from euploid individuals. Aged DS COs were smaller than aged euploid COs and showed robust amyloid-β neuropathology that was positively correlated with the levels of apoE expression. We then captured extracellular vesicles (EVs) from the conditioned media of COs and observed a decrease in the levels of secreted AD-related proteins, including amyloid, contained within the EVs and in the media from which the EVs were isolated. We also identified distinct neuronal and astrocytic gene expression signatures in DS COs relative to euploid COs, including a set of genes known to interact with both APOE and APP at the gene and/or protein levels. Lastly, we determined that, despite differences in the expression levels of the specific genes involved, several common pathways were upregulated in T21 hiPSC-derived neurons, astrocytes, and COs, including apoptosis, the endolysosome, and structural stabilization pathways. Taken together, our findings provide novel insights into molecular mechanisms that may contribute to DS-AD and indicate that apoE plays an important role in the disease process.},
}
@article {pmid42465384,
year = {2026},
author = {Fuchs, U and Schröder, S and Pena, T and Krüger, DM and Burkhardt, S and Schütz, AL and Sananbenesi, F and Fischer, A},
title = {The lncRNA Gm16685 / MITA1 modulates inflammatory astrocyte reactivity through PCBP2 associated regulation of IKKβ signaling.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.03.736437},
pmid = {42465384},
issn = {2692-8205},
abstract = {Long non-coding RNAs (lncRNAs) are increasingly recognized as regulators of cellular identity and disease associated gene expression programs, yet their role in astrocyte reactivity remains poorly understood. Here, we profiled lncRNA expression in primary mouse astrocytes exposed to inflammatory activation paradigms that model microglia driven signaling. This identified a conserved set of activation responsive lncRNAs, among which Gm16685 emerged as one of the most strongly induced candidates. Gm16685 and its human homolog MITA1 were enriched in the nucleus, and MITA1 expression was increased in selected human datasets from Alzheimer's disease, Parkinson's disease and frontotemporal dementia patients. Functional depletion of Gm16685 attenuated inflammatory gene expression and several activation associated astrocyte phenotypes, including reactive oxygen species production, glutamate handling, phagocytic activity and proliferation. Time-resolved transcriptomic analysis indicated that Gm16685 is required for the timely induction of inflammatory response genes. Mechanistically, Gm16685 / MITA1 interacted with the RNA binding protein PCBP2, and Gm16685 depletion was associated with reduced PCBP2 protein abundance, altered splicing of Inhibitor of NF-κB Kinase Subunit Beta (IKKβ) and a shift in downstream inflammatory signaling. Together, our findings identify Gm16685 / MITA1 as a conserved lncRNA regulator of astrocyte reactivity and suggest that non-coding RNA dependent control of RNA binding proteins contributes to inflammatory signaling in neurodegenerative disease relevant contexts.},
}
@article {pmid42465390,
year = {2026},
author = {Zhan, J and Yang, CA and Nellis, M and Tan, Y and Smith, MR and Alvarez, J and Liang, D and Dunlop, A and Martin, G and Go, YM and Jones, DP},
title = {Development of a metabolomics-based index to monitor dietary effects on chronic inflammation: The Dietary Metabolomics Inflammation Index.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.06.736618},
pmid = {42465390},
issn = {2692-8205},
abstract = {BACKGROUND: The Dietary Inflammatory Index (DII) is widely used to assess the inflammatory potential of diet, but it relies on self-reported dietary assessment and does not directly capture individual differences in metabolism as an intermediate connection to inflammation. High-resolution metabolomics provides objective measurements that complement dietary assessment to support precision nutrition to control inflammation.<br><br>OBJECTIVE: We developed, tested, and applied a Dietary Metabolite Inflammatory Index (DMII) to assess diet-related chronic inflammation using metabolites measured by liquid chromatography-high-resolution mass spectrometry.<br><br>METHODS: DII was calculated using dietaryindex R package with Block Food Frequency Questionnaire (FFQ) data. To develop the DMII, chronic inflammation-related dietary metabolites corresponding to the DII food parameters were found through a literature review. Dietary metabolites were identified and quantified by authentic standards by our established laboratory procedures. DMII uses the same inflammatory effect scores as the DII. Three DMII versions were developed: concentration-based, median-based, and quintile-based DMII. Mean and standard deviation of 29 dietary metabolites were calculated by using 3025 human plasma samples from 3 studies. DMII was tested in the Center for Health Discovery and Well-Being cohort (CHDWB) and the Atlanta African American Maternal and Child cohort (ATLAA) using chronic inflammation biomarkers, including high-sensitivity C-reactive protein (hs-CRP), CRP, and IL-6. The median-based DMII was further applied to four Alzheimer's disease metabolomics datasets as a proof-of-concept application.<br><br>RESULTS: In the CHDWB study, concentration-based DMII had a weak positive correlation with Block FFQ-derived DII and strongly correlated with median-based and quintile-based DMII. In the same study, all three DMII versions had significant positive correlations with hs-CRP and IL-6. In the ATLAA study, only concentration-based DMII was positively associated with CRP and IL-6. Higher median-based DMII was associated with higher odds of Alzheimer's disease.<br><br>CONCLUSIONS: DMII provides a metabolomics-based framework for assessing diet-related chronic inflammation using metabolomics data. This metabolomics approach may complement self-reported dietary assessment to use diet and nutrition to help protect against chronic disease linked to inflammation.},
}
@article {pmid42465421,
year = {2026},
author = {Ambaw, Y and Nana, A and Zhuoning, L and Singh, S and Monetti, M and Miller, BL and Spina, S and Grinberg, LT and Seeley, WW and Walther, TC and Farese, R},
title = {Shared lipidome and proteome signatures of frontotemporal lobar degeneration and Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.11.737778},
pmid = {42465421},
issn = {2692-8205},
abstract = {Frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD) differ in their clinical features and genetic etiologies but share progressive cognitive decline. Emerging evidence implicates lipid dysregulation in neurodegeneration, but its extent across FTLD subtypes and how it compares to AD are unclear. Here, we performed integrated lipidomic and proteomic analyses of matched frontal (disease-vulnerable) and occipital (relatively spared) post-mortem cortices from individuals with genetic and sporadic FTLD-TDP, FTLD-tau (Pick disease's, PiD), AD, and controls. FTLD and AD exhibited convergent lipid alterations, including reduced levels of cardiolipins and phosphatidylethanolamines, alongside increased gangliosides, diacylglycerols, cholesterol esters, acylcarnitines, and coenzyme Q, with generally greater changes in FTLD frontal cortex. FTLD displayed additional alterations, including reductions in bis(monoacylglycerol)phosphate, ceramides, phosphatidylserines, phosphatidylinositols, and sulfatides. These lipid changes were accompanied by proteomic alterations involving lysosomal proteins, phospholipases, phospholipid remodeling enzymes, and fatty acid oxidation pathways. Although lipidomic and proteomic signatures were broadly shared across FTLD subtypes, GRN associated FTLD-TDP and PiD showed the most extensive alterations. Triglycerides were selectively reduced in PiD in association with decreased DGAT1 expression, whereas cholesterol esters were elevated across all subtypes except C9orf72 associated FTLD-TDP. These findings identify shared disruptions in lipid homeostasis and lysosomal lipid metabolism across FTLD and AD, highlighting convergent metabolic pathways underlying neurodegeneration.},
}
@article {pmid42465448,
year = {2026},
author = {Dunlop, SR and Lincoln, SJ and Peng, Z and Graff-Radford, NR and Lachner, C and Day, GS and Tranovich, JF and Reichard, RR and Dickson, DW and Petersen, RC and Boeve, BF and Nguyen, A and Grinberg, LT and Graff-Radford, J and Algeciras-Schimnich, A and Murray, ME},
title = {Targeted proteomics of postmortem human brain reveals neurobiologic heterogeneity in Alzheimer's disease using NULISA technology.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.01.735558},
pmid = {42465448},
issn = {2692-8205},
abstract = {BACKGROUND: Alzheimer's disease (AD) is clinicopathologically heterogeneous. A proportion of patients living with AD present clinically at a younger onset of cognitive symptoms before 65 years old and/or non-amnestic clinical syndromes. Neuropathologically, corticolimbic distribution of neurofibrillary tangle pathology occurs on a continuum with some cases having greater cortical tau pathology relative to limbic regions and others with relatively restricted accumulation in limbic structures. These patterns of corticolimbic tangle distribution are associated with clinical presentation and age at onset. This study sought to examine protein expression differences across the spectrum of clinicopathologic heterogeneity using the NULISA targeted proteomics platform.<br><br>METHODS: A series of thirteen neuropathologically diagnosed AD cases from Mayo Clinic prospectively followed research studies were selected to reflect heterogeneity of clinical syndromes and corticolimbic distribution of tangle pathology. Frozen postmortem brain tissue samples were isolated from inferior parietal cortex and homogenized in RIPA buffer for analysis using Alamar Biosciences' NULISA CNS disease 120 panel. Applying a conservative detection threshold of 75% level of detection for the novel application of NULISA in human brain, we evaluated levels of 69 of 129 protein targets across samples. We examined associations between age at onset cognitive symptoms and corticolimbic distribution of tangles (CLix) separately with individual protein targets using linear regression analysis.<br><br>RESULTS: AD cases with a younger age at onset had higher measured levels of ubiquitin, while older age was associated with higher levels of total tau, CRH, and NPTX2. Investigations of corticolimbic heterogeneity revealed AD cases with lower CLix score (i.e., cortical predominant distribution of tau) had higher measured p-tau181, p-tau231, ubiquitin, and p62. AD cases with higher CLix (i.e., relative cortical sparing) had higher levels of total tau, CRH, NPTX2, MDH1, and HBA1. Brain-derived total tau consistently showed a stronger association in both models.<br><br>CONCLUSION: This work demonstrates the utility of postmortem proteomics for investigating biomarkers associated with AD clinicopathologic heterogeneity. We observed proteomic differences in synapse integrity, tau post-translational modification, and ubiquitination associated with age at symptomatic onset and corticolimbic distribution of tangle pathology.},
}
@article {pmid42465460,
year = {2026},
author = {Kehmeier, MN and Choi, YD and Cullen, AE and Zimmerman, B and Leonhardt, T and Snyder, M and Cleveland, T and Setthavongsack, N and Woltjer, RL and Pike, MM and Alkayed, NJ and Walker, AE},
title = {APOE4 genotype and old age interact to impact cerebrovascular function, brain volume, and neuroinflammation in mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.07.736860},
pmid = {42465460},
issn = {2692-8205},
abstract = {Old age and the apolipoprotein E ε4 (APOE4) genotype are two of the greatest risk factors for late-onset Alzheimer's disease (LOAD). However, the interaction between these is poorly understood, as most preclinical studies use young mice. Therefore, we assessed the interaction between APOE genotype and age across a comprehensive set of cerebrovascular and related outcomes. We performed in vivo imaging, ex vivo cerebral artery studies, behavioral tests, and molecular analyses in male and female homozygous APOE3 and APOE4 mice at ∼6 months (young) and ∼24 months (old). APOE4 interacted with old age to lead to deficits in brain volume and greater microglia content. Old APOE4 mice also exhibited greater cerebral artery vasoconstriction to endothelin-1 (ET-1) than old APOE3 mice, a response concomitant with age-and genotype-related differences in the expression of ET-1 receptors and endothelin-converting enzyme. While we found several interactions between age and APOE genotype, only age impacted cognitive function, cerebral artery endothelial function, and arterial stiffness. In summary, we found that brain volume, neuroinflammation, and ET-1-related outcomes were influenced by the interaction of APOE genotype and age, while other outcomes were affected only by age. As such, an altered ET-1 response and greater neuroinflammation may contribute to the increased risk for LOAD in APOE4 carriers.},
}
@article {pmid42465478,
year = {2026},
author = {Surabhi, S and Jenny, A},
title = {Actin nucleation promoting factors drive Arp2/3 dependent endosomal microautophagy.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.09.737473},
pmid = {42465478},
issn = {2692-8205},
abstract = {Autophagy is a catabolic process that degrades damaged organelles and aggregation-prone proteins and plays key roles during development and in maintaining cellular homeostasis. It can be induced by stress including starvation, oxidative stress, or accumulation of misfolded proteins. Autophagy declines with age and there is great interest in manipulating autophagy to improve neurodegenerative diseases, as its stimulation shows promise to improve diseases including Huntington, Alzheimer, and Parkinson. Endosomal microautophagy (e-MI) is a type of autophagy in which cytosolic proteins are delivered to late endosomes and degraded upon incorporation into intraluminal vesicles of multivesicular bodies. Here, we report that the actin nucleation-promoting factors (NPFs) known to activate the Arp2/3 complex to promote branched actin assembly can alter the dynamics of e-MI. We found that upon stress exposure, overexpression of the NPFs WASp, Wash, or SCAR results in an expedited induction of e-MI. Strikingly, Wash is uniquely required for physiological e-MI induction implying that NPFs are not functionally redundant for e-MI. We show that the WASH complex regulates e-MI on late endosomes acting via Arp2/3 and thus likely branched actin. Surprisingly, the regulation of e-MI by Wash is independent of retromer that is known to recruit Wash to early endosomes for its role in recycling of membrane proteins and rather reflects a novel degradative aspect of Wash function. Taken together, we identified a novel function of NPFs as upstream regulators of e-MI that could be used to activate e-MI ectopically to improve aggregate clearance during neurodegeneration.},
}
@article {pmid42465485,
year = {2026},
author = {Ji, Y and Mandal, P and Liu, J and Hu, W and Colón, BD and Wan, C and Pan, RW and Guo, D and Zhang, L and Gu, X and Yang, Y and Huang, K and Shi, R and Qi, C and Yuan, C and Rochet, JC and Baloni, P and Liu, F and Xu, R},
title = {Patient-derived tau-seeded human neuronal chimeras recapitulate mature Alzheimer's tau pathology and uncover human-specific neuronal vulnerability.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.06.736894},
pmid = {42465485},
issn = {2692-8205},
abstract = {Tau pathology is a central hallmark of Alzheimer's disease (AD) and strongly correlates with cognitive decline, yet the development of tau-targeted therapies has been hindered by the inability of existing models to capture human-specific disease features, particularly the mature forms of AD tau pathology. Moreover, species-specific mechanisms underlying tau pathology remain poorly understood. Here, we establish a patient-derived tau-seeded human neuronal chimera model by transplanting human pluripotent stem cell (hPSC)-derived neural progenitor cells into neonatal mouse brains, followed by intracerebral injection of pathological tau seeds from postmortem AD brains. Human neurons matured in vivo and recapitulated adult human tau features, including all six isoforms with an approximately 1:1 3R:4R ratio. Upon seeding, aged human neurons without FTD mutations faithfully developed robust, mature AD tau pathology, including neurofibrillary tangles (NFTs) and neuropil threads composed of paired helical filaments (PHFs) and straight filaments (SFs) containing 3R and 4R tau, closely mirroring advanced-stage AD. This pathology accumulated and spread across anatomically connected regions, accompanied by neurodegeneration, elevated plasma pTau-217, and memory deficits. Strikingly, tau pathology was largely restricted to human neurons, revealing a pronounced human-specific vulnerability. Mechanistically, snRNA-seq showed that human neurons exhibited higher basal expression of tau-uptake genes and widespread synaptic suppression following tau exposure, whereas mouse neurons remained transcriptomically resilient. Finally, the familial AD mutation PSEN2 N141I exacerbated tau pathology and synaptic loss in human neurons. Together, this model recapitulates the molecular, structural, and functional hallmarks of mature AD tau pathology in human neurons in vivo and reveals intrinsic, species-specific vulnerability, providing a human-relevant in vivo platform for mechanistic studies and therapeutic development.},
}
@article {pmid42465495,
year = {2026},
author = {Liou, K and Thomopoulos, SI and Villalon Reina, JE and Yoo, H and Shuai, Y and Chehrzadeh, S and Arani, A and Borowski, B and Reid, RI and Vemuri, P and Jack, CR and Weiner, M and Jahanshad, N and Thompson, PM and Nir, TM},
title = {Comparing Harmonization Approaches for Protocol-Related Variability in Multisite Diffusion MRI Data.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.07.737018},
pmid = {42465495},
issn = {2692-8205},
abstract = {Diffusion MRI (dMRI) enables assessment of white matter microstructural abnormalities in Alzheimer's disease (AD), and multisite datasets enable more robust modeling of non-biological variation that can confound analyses. The Alzheimer's Disease Neuroimaging Initiative (ADNI) includes over 10 dMRI protocols, necessitating robust methods to model protocol-related variability when pooling data. Here, we compared three harmonization approaches: (1) mixed-effects models, (2) ComBat-GAM, and (3) eHarmonize, a reference-based lifespan method. We assessed their ability to reduce protocol-related variability in diffusion tensor imaging fractional anisotropy (FA) and mean diffusivity (MD) while preserving associations with cognitive impairment (CI), and amyloid-beta (Aβ) and tau PET burden in 1,086 ADNI3/4 participants. All approaches yielded more closely aligned FA/MD distributions across protocols. Associations with clinical indicators of CI were highly consistent across approaches, whereas PET associations were less widespread and more variable. Overall, multiple strategies effectively modeled protocol-related variability while preserving AD-related associations.},
}
@article {pmid42465681,
year = {2026},
author = {Gorbunova, G and Yashkin, AP and Kravchenko, J and Ukraintseva, S and Stallard, E and Yashin, A and Akushevich, I},
title = {Disease-specific drivers of sex- and locality-related disparities in life expectancy at age 65: two decades of progress before COVID-19.},
journal = {Innovation in aging},
volume = {10},
number = {8},
pages = {igag065},
pmid = {42465681},
issn = {2399-5300},
abstract = {BACKGROUND AND OBJECTIVES: The distribution of life expectancy at age 65 (LE65) in the United States is characterized by profound sex- and locality-related disparities. Quantifying the disease-specific drivers of these disparities prior to the coronavirus disease 2019 (COVID-19) pandemic provides a critical baseline for understanding subsequent health shocks.<br><br>METHODS: Using CDC WONDER data (1999-2018) and Pollard's decomposition method, we analyzed cause-specific contributions to disparities in LE65, establishing a pre-pandemic baseline for trends in years of life lost (YLL) at age 65.<br><br>RESULTS: Sex-related disparities (YLLsex) narrowed, particularly in disadvantaged localities, driven by reductions in YLL from macrovascular diseases and lung cancer. Conversely, locality-related disparities (YLLloc) widened, especially for females, due to increasing YLL from Alzheimer's disease and the persistent impacts of diabetes, chronic lower respiratory diseases, and heart failure. This created a pre-existing landscape of vulnerability concentrated in low-LE states.<br><br>DISCUSSION AND IMPLICATIONS: The 2 decades before COVID-19 saw a critical divergence: progress in reducing sex-based gaps was offset by rapidly widening geographic disparities. The systemic failures that drove the increasing burden of chronic conditions in disadvantaged regions likely predetermined the populations most vulnerable to the pandemic's shock. Our findings highlight that building future resilience requires targeted investments to address these specific, pre-existing health challenges.},
}
@article {pmid42465697,
year = {2026},
author = {Wu, Y and Zhang, C and Yan, J and Lin, L and Tian, Y and Fu, Z and Sun, X},
title = {Glymphatic dysfunction in Alzheimer's disease: a systematic review and meta-analysis of the DTI-ALPS index as an imaging biomarker.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1832525},
pmid = {42465697},
issn = {1663-4365},
abstract = {INTRODUCTION: Although the diffusion tensor image analysis along the perivascular space (DTI-ALPS) index is widely utilized as a proxy for glymphatic function in Alzheimer's Disease (AD) research, its association with core AD pathological biomarkers remains inconclusive due to inter-study heterogeneity. This systematic review aimed to investigate associations between the DTI-ALPS index and AD biomarkers and to elucidate potential sources of heterogeneity.<br><br>METHODS: The study protocol adhered to PRISMA guidelines and was registered with PROSPERO (CRD420251266067). We systematically searched Web of Science, PubMed, and ScienceDirect from January 1, 2017 to September 18, 2025 for studies examining the relationship between the DTI-ALPS index and core AD biomarkers. Random-effects meta-analyses were conducted when studies employed comparable methodologies and reported effect sizes while narrative synthesis was performed otherwise. Methodological quality was assessed using the Newcastle-Ottawa Scale (NOS) and the risk of bias was evaluated using the Risk of Bias in Systematic reviews (ROBIS) tool.<br><br>RESULTS: Thirty-six studies were included. Meta-analyses revealed significant correlations between the DTI-ALPS index (N = 22) and A&#x3b2; PET deposition (N = 9), MMSE (N = 15), and MoCA (N = 10) scores. Conversely, the association with tau PET deposition (N = 3) was not significant after adjusting for publication bias. Regarding clinical staging, indices were significantly lower in AD and mild cognitive impairment groups compared to controls but no difference was found between the two patient groups. Based on meta-regression and narrative synthesis results, we identified methodological variability and AD pathological complexity as primary sources of heterogeneity.<br><br>DISCUSSION: Consequently, we proposed the "GS Hub Integrative Framework." This framework posits that vascular, genetic, lifestyle, and environmental risk factors converge on glymphatic dysfunction (DTI-ALPS index) as a central hub, accelerating A&#x3b2;/tau accumulation, neurodegeneration, and cognitive decline. Future methodological standardization and refined patient stratification are essential for clinical translation.<br><br>https://www.crd.york.ac.uk/PROSPERO/view/CRD420251266067, identifier: CRD420251266067.},
}
@article {pmid42465698,
year = {2026},
author = {Almalki, DF and Alkabkabi, RA and Wayyani, RA and Alharthi, AS and Aljuhani, HA and Mahyub, RM and Bakhsh, HS and Alomani, AM and Almhmadi, NN and Aljohani, AA and Tawakul, AA},
title = {Chronic stress, cortisol dysregulation, and neurodegenerative vulnerability: mechanistic pathways linking HPA-axis dysfunction to Alzheimer's disease risk.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1883880},
pmid = {42465698},
issn = {1663-4365},
abstract = {Chronic psychological stress is increasingly recognized as a silent risk factor of long-term brain vulnerability and a potential modifier of neurodegenerative disease trajectories. The persistent activation of the hypothalamic-pituitary-adrenal (HPA) axis and the consequent dysregulation of cortisol exert extensive influences on neural, immune, and metabolic pathways linked to cognitive decline and dementia. This review synthesizes current mechanistic and clinical evidence concerning the effects of chronic stress-induced HPA-axis dysfunction on neurodegenerative susceptibility and Alzheimer's disease risk. A structured narrative synthesis was conducted using literature from PubMed/MEDLINE, Scopus, and Web of Science, integrating multidisciplinary evidence from established biological and mechanistic domains. Present evidence suggests that prolonged exposure to glucocorticoids is associated with structural and functional alterations in the brain, including hippocampal atrophy, prefrontal cortical dysfunction, reduced synaptic plasticity, and increased amygdala activity. Chronic dysregulation of cortisol may result in neuroinflammation, disruption of the blood-brain barrier, induce mitochondrial dysfunction, and impair neuronal integrity. These interconnected mechanisms contribute to amyloid accumulation, tau pathology, and the progressive decline of neural resilience. Rather than serving as the root cause, chronic psychological stress can increase the likelihood of neurodegeneration by triggering complex interactions between the neuroendocrine and neuroimmune systems that accelerate the already existing pathological pathways toward neurodegeneration. Recognizing chronic stress as a potentially modifiable biological risk factor may improve early risk stratification and identification of HPA-axis dysregulation, ultimately driving preventive strategies targeting stress-related neurobiological pathways.},
}
@article {pmid42465724,
year = {2026},
author = {Zhang, C and Song, D},
title = {Implications of autolysosome- astrocyte-associated signature in the pathogenesis of Alzheimer's disease: evidence from artificial intelligence and multi-omics and clinical validation.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1867831},
pmid = {42465724},
issn = {1662-4548},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta plaques and neurofibrillary tangles. Dysfunctional cellular clearance mechanisms, particularly autophagy-lysosomal pathways, and reactive astrocytosis are prominent pathological features, yet their interrelationship remains poorly defined.<br><br>OBJECTIVE: This study aimed to decipher a novel co-expression molecular signature linking autolysosomal dysfunction and astrocyte reactivity in AD pathogenesis.<br><br>METHODS: We performed Limma, WGCNA and Xcell algorithms in AD patient hippocampus bulk profiles for enrichment of astrocyte and autolysosome (AA)-associated DEGs. Next, explainable machine learning and consensus clustering enables the identification of AA-associated diagnostic model and molecular subgroups for AD patients at bulk level. Besides, AA-associated central pathogenic factor was identified, and its corresponding biological implications for AD were assessed at AD patient hippocampus single-cell level in temporal and spatial manners. Next deep learning algorithm (Drugreflector) and molecular docking enriched natural compounds for the treatment of AD by targeting AA-associated hub gene. Finally, AD clinical peripheral blood samples were collected for estimation of hub gene expression patterns.<br><br>RESULTS: 5 AA-associated shared DEGs can elaborate diagnostic and patient stratification capacity for AD patients. HMGCR can be considered as astrocyte-distributed central pathogenic and Berberine-oriented therapeutic target for AD patients.<br><br>CONCLUSION: Our findings unveil AA-associated diagnostic model and molecular subgroups coupled with HMGCR center pathogenic and druggable role in AD, which represents an actionable clinical target for AD patients.},
}
@article {pmid42465730,
year = {2026},
author = {de Leeuw, DM and Duits, FH and Dicks, E and Vromen, EM and Teunissen, CE and Barkhof, F and van der Flier, WM and Visser, PJ and Tijms, BM},
title = {Neuroplasticity and immune system are related to altered grey matter networks: a cohort study in sporadic Alzheimer's disease.},
journal = {Brain communications},
volume = {8},
number = {4},
pages = {fcag257},
pmid = {42465730},
issn = {2632-1297},
abstract = {Grey matter network topology is altered in Alzheimer's disease and these alterations are related to cognitive decline. Understanding the biological underpinnings of loss of brain connectivity may provide insights into mechanisms related to developing Alzheimer's dementia (i.e. dementia A+). We investigated which biological processes as measured in CSF proteomics were associated with loss of brain connections across the Alzheimer's disease continuum. We included 347 individuals with abnormal CSF amyloid [mean age ± standard deviation (SD) 66 ± 8; 98 cognitively unimpaired-A+, 88 mild cognitive impairment-A+, 161 dementia A+] and 146 cognitively unimpaired individuals with normal CSF amyloid (mean age ± SD 62 ± 8) and available T1w MRI-scans and CSF proteomic data (3097 proteins using tandem mass tag spectrometry) from the Amsterdam Dementia Cohort. We used an automated pipeline to construct grey matter networks from 3D-T1 sequences and for each network, calculated the small-worldness coefficient, which we previously found to be robustly related to cognitive decline. Linear models were applied to test associations between CSF protein levels and connectivity measures using an interaction term for clinical stage while controlling for connectivity density, age and sex. We validated our results in data from the Alzheimer's disease Neuroimaging Initiative (ADNI). Pathway enrichment analysis was performed for proteins associated with loss of brain connectivity (P < 0.05) using the Gene Ontology database. Individuals across the Alzheimer's disease continuum had lower small-worldness coefficients compared with controls (ANOVA P < 0.001). In amyloid positive individuals, higher levels of 222 proteins and lower levels of 482 proteins were associated with lower small-worldness coefficients and were enriched for innate immune system and neuroplasticity pathways, respectively. Stratified for disease stage, most protein associations with lower small-worldness coefficients were found in mild cognitive impairment A+ (n = 527 proteins) and dementia A+ (n = 799 proteins) with considerable overlap (n = 239 proteins). Proteins in these stages were enriched for complement activation and synaptic integrity. In cognitive unimpairment A+, we found proteins enriched for processes involved in apoptosis. We did not find any enriched biological processes in controls. Repeating analyses in ADNI indicated that similar biological processes were associated with altered grey matter network connectivity. Higher CSF levels of proteins involved in immune responses and lower levels of proteins related to neuroplasticity were associated with lower small-worldness coefficients across the Alzheimer's disease continuum. This suggests that preserving cognitive function in the presence of amyloid and prevention of dementia A+ may require therapies that strengthen synapses and targets the innate immune system in addition to amyloid and tau.},
}
@article {pmid42465741,
year = {2026},
author = {Zhang, R and Chen, K},
title = {Exercise-conditioned extracellular vesicles in Alzheimer's disease: a multi-organ signaling network linking peripheral adaptation to brain pathology.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1856546},
pmid = {42465741},
issn = {1664-3224},
mesh = {*Alzheimer Disease/metabolism/pathology/physiopathology ; Humans ; *Extracellular Vesicles/metabolism ; Animals ; *Exercise/physiology ; *Brain/pathology/metabolism ; Signal Transduction ; Blood-Brain Barrier/metabolism ; Adaptation, Physiological ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder in which amyloid-β accumulation, tau pathology, chronic neuroinflammation, cerebrovascular impairment, and synaptic dysfunction act as interconnected rather than independent processes. Physical exercise is protective against several of these features, but how its peripheral effects produce coordinated changes in the brain remains only partly defined. Soluble exerkines explain part of this benefit, but they act individually, do not protect labile cargo such as RNA, and carry little information about their cell of origin. Extracellular vesicles (EVs) offer a complementary mechanism. By packaging diverse cargo within a membrane, they co-deliver several signals at once, protect labile cargo in transit, and carry a profile that partly reflects the state and origin of the releasing cell. In this review, we develop a multi-organ signaling framework in which exercise-conditioned EVs link peripheral exercise adaptation to AD-related brain pathology. We examine how exercise reshapes EV biogenesis, the circulating EV pool, and EV engagement with the neurovascular interface. We then map how exercise-conditioned EVs intersect with amyloid aggregation and clearance, tau propagation, neuroinflammation, blood-brain barrier integrity, and synaptic and neurogenic resilience, and which tissues contribute to the exercise-responsive EV pool. Several bottlenecks keep the field at the level of association rather than causation, including cargo heterogeneity, uncertain tissue-of-origin attribution, and the gap between describing cargo and demonstrating its function. This framework outlines a realistic, staged route from current associative evidence toward clinical application, in which exercise-conditioned EVs serve first as biomarkers of exercise responsiveness and later as engineered therapeutic platforms for AD.},
}
@article {pmid42465883,
year = {2026},
author = {Park, J and Le Guen, Y and Peña-Tauber, A and Greicius, MD},
title = {Longitudinal plasma proteomics separates diagnostic differences from progression-linked changes in Alzheimer's disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.01.26356385},
pmid = {42465883},
abstract = {Most plasma proteomic studies in Alzheimer's disease (AD) compare cases and controls cross-sectionally, leaving unresolved which AD-associated proteins mark diagnostic states and which are linked to disease progression. Using longitudinal SomaScan profiling from the Global Neurodegeneration Proteomics Consortium (13,449 participants, 17,269 samples, 7,362 aptamers), we separated baseline AD differences from AD-specific change over time. Linear mixed-effects models requiring concordant baseline and AD-by-time effects defined a 30-protein signature. We prioritized proteins across five evidence domains: clinical progression, AD biomarker alignment, cerebrospinal fluid concordance, independent prospective replication in UK Biobank and genetic support from Mendelian randomization and rare-variant burden. Thirteen proteins were supported in two or more domains and six in three. EDA2R, HPGDS, ITGAV and CLEC3B converged across clinical, biomarker and prospective evidence. Signature proteins aligned more strongly with tau and neuronal-injury markers than with A β 42/40. ANTXR1 showed direction-concordant plasma pQTL Mendelian randomization and nominal rare-variant burden signals, supporting its prioritization within the longitudinal AD signature. By distinguishing diagnostic-state markers from progression-linked changes, this longitudinal, multi-domain approach prioritizes proteins for validation as markers of AD progression and for mechanistic and therapeutic follow-up.},
}
@article {pmid42465907,
year = {2026},
author = {Jordan, DM and Kritzer, E and Thompson, RC and Lund, AN and Patel, T and Buxbaum Grice, A and John, DA and , and , and , and Goate, AM and Glicksberg, BS and Golestani, N and Koromina, M and Renton, AE and Beckmann, ND},
title = {Genetic Associations with Temporal Modeling of Alzheimer's Disease Progression Supports a Novel Paradigm for Disease Risk.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.07.26356710},
pmid = {42465907},
abstract = {A major challenge in Alzheimer's disease (AD) research is predicting who will develop AD, how it progresses, and how to slow, prevent, or reverse progression. Here, we apply a data-driven timeline inference framework to sparse longitudinal blood metabolomics data to reconstruct AD timelines and derive individual-specific timeline progression rates. Inferred temporal locations for each metabolomics sample along the AD timeline closely track clinical severity, while timeline progression rates capture inter-individual differences in the speed of pathophysiological progression. Genome-wide association studies of timeline progression rate identify novel loci distinct from those in AD case-control studies, notably showing no effect of the major risk locus APOE . These findings support a multidimensional paradigm of AD risk in which disease potential and progression act as partially independent factors. By explicitly modeling disease dynamics, this work reveals genetic contributions not captured by traditional approaches and provides a framework for studying AD and other progressive disorders.},
}
@article {pmid42465939,
year = {2026},
author = {Reinhardt, A and Jiang, Z and Li, T and Tang, B and Qian, X and Huang, S and Ibrahim, JG and Li, Y and Zhao, B and Sullivan, P and Stein, J and Zhu, H},
title = {A spatially resolved genomic-molecular atlas of human white‑matter microstructure.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.06.26357381},
pmid = {42465939},
abstract = {Human white matter has been linked to inherited variation, circulating molecular state and brain disease, but these layers have rarely been mapped onto the same tract anatomy. Here we measured genetic effects along 6,090 atlas-aligned fiber pathways sampled at 609,000 locations in 72,185 UK Biobank participants, and integrated proteomic and metabolomic profiles within the same anatomical frame. Genetic effects were not whole-tract properties: each locus formed a spatial footprint along fiber trajectories, ranging from single locations to broad multi-tract patterns and reflecting regional polygenicity rather than tract heritability. This map identified 258, 186 and 298 previously unreported loci for fractional anisotropy, mean diffusivity and axial diffusivity; spatial patterns replicated in adults and 157 of 315 FA loci replicated in adolescence in ABCD. Mendelian randomization linked localized genetic effects to neurodegenerative and psychiatric traits, with Alzheimer's disease showing directional effects across 12 of 17 tracts. Multi-omic analyses identified 97 proteomic and 161 metabolomic associations, with the broadest signals from lipid metabolites including linoleic acid and phosphatidylcholines. The strongest lipid-metabolite and genetic signals converged in the corpus callosum, placing inherited variation, disease risk and systemic lipid metabolism on the same localized tract segments.},
}
@article {pmid42466090,
year = {2026},
author = {Medicine, CRIN},
title = {RETRACTION: A Severe Alzheimer's Disease Patient Improved by Intravenous Mesenchymal Stem Cell Transplant.},
journal = {Case reports in neurological medicine},
volume = {2026},
number = {},
pages = {9873498},
doi = {10.1155/crnm/9873498},
pmid = {42466090},
issn = {2090-6668},
abstract = {[This retracts the article DOI: 10.1155/2024/8353492.].},
}
@article {pmid42466122,
year = {2026},
author = {Liang, X and Ning, T and Wang, Y and Zhan, L},
title = {Integrating serum pharmacology, network pharmacology, and molecular biology analysis to reveal the mechanisms of Baihe Dihuang decoction in treating Alzheimer's disease.},
journal = {Frontiers in microbiology},
volume = {17},
number = {},
pages = {1765044},
pmid = {42466122},
issn = {1664-302X},
abstract = {AIM: This study aimed to evaluate the potential neuroprotecive effects of Baihe Dihuang Decoction (BDD) in APP/PS1 double-transgenic (TG) mice and to investigate the role of the gut-brain axis (GBA) using an integrated approach combining serum pharmacology, network pharmacology, and molecular biology.<br><br>MATERIALS AND METHODS: The blood-borne bioactive components of BDD were initially identified using UPLC-Q-Orbitrap HRMS. Subsequently, network pharmacology was employed to prioritize key therapeutic targets and elucidate the primary pathways underlying the anti-Alzheimer's disease (AD) effects of BDD. The neuroprotective efficacy of BDD in TG mice was systematically evaluated using the morris water maze (MWM) test, histopathological observation (HE staining), transmission electron microscope (TEM) test, and ELISA-based inflammatory cytokine assays. The potential mechanisms were further elucidated by integrating network pharmacology with 16S ribosomal RNA (16S rRNA) sequencing. Finally, molecular docking and Western blotting (WB) were performed to validate the interactions within the identified pathways.<br><br>RESULTS: A total of 49 BDD-derived compounds were identified in serum samples. Network pharmacology revealed 116 common targets of BDD against AD. Remarkably, KEGG analysis highlighted 57 signaling pathways potentially involved in the anti-AD effects of BDD. Pharmacodynamic analysis showed that BDD ameliorated cognitive impairment in TG mice, mitigated pathological damage, and suppressed the release of IL-6, IL-1&#x3b2;, and TNF-&#x3b1; in the colon, brain, and serum. Moreover, 16S rRNA sequencing indicated that BDD modulated gut microbiota (GM) structure and restored intestinal flora imbalance in TG mice. Integrative analysis of network pharmacology and GM analysis identified several Key pathways (FoxO, MAPK, PI3K-Akt, HIF-1, Th17, IL-17, and Toll/Imd) and core anti-AD targets (TLR4, PTGS2, SIRT1, BDNF, NF-&#x3ba;B, STAT3, JAK2, EGFR, GSK3&#x3b2;, and CD86). Molecular docking results showed that the five complexes with the lowest docking scores (TLR4-salidroside, NF-&#x3ba;B-glabranin, TRKB-alantolactone, PTGS2-3'_4'_dihydroxyflavone, and SIRTI-abietic acid) exhibited strong binding affinity. QSAR and WB analyses further demonstrated the modulatory effects of BDD on these five core targets.<br><br>CONCLUSION: This study demonstrated that BDD effectively restored GM structure and ameliorated cognitive impairment in TG mice, thereby exerting therapeutic effects against AD. These findings support BDD as a potential traditional Chinese medicine (TCM) strategy for AD treatment.},
}
@article {pmid42466407,
year = {2026},
author = {Hammad, G and Seret, E and Schmidt, C and Vandewalle, G},
title = {Determinants of fractal motor activity regulation: insights from a large community-dwelling multi-ethnic population.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10237495/v1},
pmid = {42466407},
issn = {2693-5015},
abstract = {Background: Quantification of alterations in fractal motor activity regulation (FMAR) has the potential to improve early detection of Alzheimer's disease. To improve the clinical relevance of such marker, our analysis aims to investigate potential determinants such as age, sex, physical activity and race and ethnicity in a large community-dwelling multi-ethnic cohort of older Asian, Black, Hispanic and White individuals. Methods: We analysed week-long actigraphy recordings from 1508 older adults (55 to 90 years) of the MESA Sleep dataset. Long-range correlations in activity levels, a marker of fractal regulation, were assessed via a scaling exponent extracted with a Detrended Fluctuation Analysis over two different time ranges. Bayesian linear models were used to compare scaling exponent values between ethnic groups and test their associations with various determinants, such as age, sex and physical activity levels. Results: We found opposite effects of age on FMAR at both short and long time scales, respectively (ßAge=0.014, 95% C.I. [0.009,0.019] and ßAge=-0.015, 95% C.I. [-0.026,-0.005]), as well as differences between women and men at long time scales (ßSexMen=+0.028, 95% C.I. [0.012,0.044]). We also confirmed that higher activity levels were linked to less degraded FMAR (ßMDA=0.007, 95% C.I. [0.003,0.011] at short time scales and ßMDA=0.032, 95% C.I. [0.024,0.041] at long time scales). Finally, we observed that Black and Hispanic participants, as well as Asian participants, exhibiting lower values in scaling exponents at short and long time scales, respectively (ßBlack=-0.026, 95% C.I. [-0.035,-0.017], ßHispanic=-0.018, 95% C.I. [-0.027,-0.009] and ßAsian=-0.065, 95% C.I. [-0.091,-0.039]), compared to White participants. Conclusion: Using a large multi-ethnic cross-sectional dataset, our analysis provided support and clarified the interaction effect of age and sex on FMAR. It also confirmed, in humans, the influence of activity levels on FMAR observed in rodents and demonstrated for the first time that FMAR alterations are modulated by race and ethnicity.},
}
@article {pmid42466408,
year = {2026},
author = {Zhao, F and Puerta, R and Wang, Y and Beckett, E and García-González, P and Valero, S and Sanz, P and Kautz, T and Cavazos, JE and Fernandez, MV and Cano, A and Seshadri, S and Boada, M and Garbarino, VR and Ruiz-Laza, A and Gnpc, TGNPC},
title = {Lactoferrin Levels in Cerebrospinal Fluid Exhibit Differential Associations with Alzheimer's Disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-9678397/v1},
pmid = {42466408},
issn = {2693-5015},
abstract = {Lactoferrin has been proposed as a minimally invasive biomarker for Alzheimer's disease (AD), but its relationship with established AD pathology remains uncertain. We analyzed paired cerebrospinal fluid (CSF) and plasma SOMAscan proteomic profiles from 1,367 participants in the ACE Alzheimer Center Barcelona cohort, focusing on two lactoferrin-targeting SOMAmers, Seq.14755.4 (LTF1) and Seq.2780.35 (LTF2). LTF1 and LTF2 showed distinct distributions and weak concordance across fluids, indicating that they should not be treated as interchangeable lactoferrin measures. In CSF, LTF2 was associated with lower Aβ42 and AD biomarker-defined status, whereas LTF1 showed subgroup-dependent associations with tau markers that were partly influenced by major CSF proteomic axes and reference-gene adjustment. Neither CSF nor plasma LTF signals predicted conversion from mild cognitive impairment to dementia. GNPC analyses supported the non-interchangeability and compartment specificity of LTF signals and identified a reproducible plasma LTF2-centered network enriched for innate immune and granule biology. These findings suggest that lactoferrin-related signals are assay-, compartment-, and network-context dependent rather than standalone AD biomarkers.},
}
@article {pmid42466706,
year = {2026},
author = {Zheng, C and Li, F and Wang, R and Li, B and Jiao, J and Yuan, K and Wang, Z and Li, T and Deng, Y and Wang, Z and Peng, J and Gao, C and Rong, S},
title = {The relationship between low-sodium salt substitutes and cognitive function among middle-aged and older adults: The Chinese Square Dance Cohort.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261468778},
doi = {10.1177/13872877261468778},
pmid = {42466706},
issn = {1875-8908},
abstract = {BackgroundPrevious studies have indicated that high sodium intake is associated with poorer cognitive function, and low-sodium salt substitutes (LSSS) can reduce sodium intake.ObjectiveWe hypothesized that the use of LSSS is linked to better cognitive performance.MethodsIn this cross-sectional study, participants reported using LSSS or regular salt via questionnaire. Cognitive function was evaluated using Auditory Verbal Learning Test (AVLT), Verbal Fluency Test (VFT), Digit Symbol Substitution Test (DSST), and Trail Making Test-B (TMT-B). Z-scores were utilized to standardize the results, with composite z-score reflecting global cognitive function. Mild cognitive impairment (MCI) was determined by Petersen's criteria, and subclassified into amnestic MCI (aMCI) and non-amnestic MCI (naMCI). Multiple linear regression and logistic regression analyses were performed to assess the associations of the use of LSSS with cognitive function and MCI.ResultsAmong 4201 participants (median age 64 years, 85.91% female), 639 (15.21%) self-reported using LSSS. Compared to those who used regular salt, the use of LSSS was associated with higher composite z-score, VFT, and DSST, with β values (95%CIs) of 0.10 (0.05, 0.15), 0.16 (0.08, 0.24), and 0.17 (0.10, 0.23), respectively. The prevalence of MCI was 8.29% in the LSSS group and 12.80% in the regular salt group, the use of LSSS was related to lower odds of naMCI (OR = 0.63, 95%CI: 0.41, 0.96).ConclusionsOur findings indicate that the use of LSSS was related to better cognitive performance and lower odds of naMCI, suggesting that replacing regular salt with LSSS may be a promising dietary strategy for cognitive aging worthy of further investigation.},
}
@article {pmid42466721,
year = {2026},
author = {Marinelli, L and Puce, L and Diotti, D and Currà, A and Vestito, L and Mori, L and Ponzano, M and Cervia, A and Cotellessa, F and Schenone, C and Monacelli, F and Trompetto, C},
title = {Clinical dissociation and electromyographic convergence of paratonia in cognitive impairment including Alzheimer's disease: Evidence for a shared central inhibitory mechanism.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261468799},
doi = {10.1177/13872877261468799},
pmid = {42466721},
issn = {1875-8908},
abstract = {BackgroundDespite a shared conceptual framework linking both components to impaired inhibitory control, clinical evidence suggests that facilitatory and oppositional paratonia are not equally related to cognitive deterioration, with facilitatory paratonia showing a stronger association with cognitive impairment. Whether this apparent divergence reflects true neurophysiological differences or arises from limitations intrinsic to clinical assessment remains unclear. Electromyography (EMG)-based assessment offers a direct approach to quantify involuntary muscle activation and reduce measurement-related confounding factors.ObjectiveTo determine whether the reported clinical divergence between facilitatory and oppositional paratonia reflects distinct neurophysiological mechanisms or is primarily driven by measurement-related factors.MethodsEighty-six participants (46 cognitively impaired and 40 cognitively healthy) underwent clinical and EMG-based assessment of paratonia during passive elbow movements. Associations with global cognitive status (Mini-Mental State Examination) and discriminative performance between cognitively impaired and healthy subjects were evaluated.ResultsClinically assessed facilitatory paratonia showed stronger associations with cognitive status and better discriminative performance than oppositional paratonia. In contrast, EMG-based assessment revealed comparable associations with cognitive status and similar discriminative performance for both paratonia components.ConclusionsEMG assessment reveals a neurophysiological convergence between facilitatory and oppositional paratonia, supporting a shared central inhibitory mechanism. Our findings indicate that the apparent clinical distinction between facilitatory and oppositional paratonia does not reflect a true pathophysiological separation, but is largely driven by limitations inherent to clinical assessment. In this context, facilitatory paratonia emerges as the most informative bedside marker of cognitive impairment.},
}
@article {pmid42466724,
year = {2026},
author = {Grueso, S and Sánchez-Benavides, G and Santos-Santos, M and Subirats, L and Prados, F and Grau-Rivera, O and Calabria, M},
title = {Bilingualism and cognition: The impact of age of acquisition, language use, and proficiency in cognitively unimpaired older adults.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261469525},
doi = {10.1177/13872877261469525},
pmid = {42466724},
issn = {1875-8908},
abstract = {BackgroundThe positive effect of bilingualism as a cognitive reserve factor in aging remains inconclusive, with inconsistencies often stemming from treating bilingualism as a dichotomous variable rather than a dynamic, multidimensional experience.ObjectiveTo investigate the impact of bilingualism on cognition in cognitively unimpaired older adults, focusing on age of language acquisition (AoA), proficiency, and usage throughout life.MethodsData from 2415 participants (aged 45-74) from the Alzheimer's and Families (ALFA) study were analyzed. Cognitive assessments included the Mini-Mental State Examination to assess global cognition, semantic verbal fluency for semantic lexical retrieval, Memory Binding Test for verbal episodic memory, and WAIS-IV subtests for processing speed (Coding), visual-spatial reasoning (Visual Puzzles), non-verbal abstract reasoning (Matrix Reasoning), verbal short-term memory and attention (Digit Span Forward) and working memory (Digit Span Backward and Sequencing). We defined three groups based on AoA (Early/Late) and proficiency (High/Low) of Catalan: 1) Early High-Proficiency bilinguals (n = 1559); 2) Late High-Proficiency bilinguals (n = 537) and 3) Late Low-Proficiency bilinguals, primarily Spanish-dominant (n = 319).ResultsEarly and Late High-Proficiency bilingual groups outperformed Late Low-Proficiency bilinguals in verbal semantic fluency and processing speed. Additionally, Early High-Proficiency bilinguals scored significantly higher in verbal short-term memory than both Late AoA groups.ConclusionsThe effects of bilingualism are domain-specific and primarily driven by high proficiency and active language use rather than AoA alone. These findings suggest that maintaining high L2 proficiency throughout the lifespan contributes to cognitive reserve, enhancing attentional control and processing speed in healthy aging.},
}
@article {pmid42466729,
year = {2026},
author = {Huoponen, S and Kettunen, J and Mežinska, S and Haaranen, A and Malm, T and Jolkkonen, J},
title = {Nurses' Attitudes Toward Innovative Neurotherapies in Memory Disorders: A Pilot Study.},
journal = {CNS neuroscience &amp; therapeutics},
volume = {32},
number = {7},
pages = {e71015},
doi = {10.1002/cns.71015},
pmid = {42466729},
issn = {1755-5949},
support = {357769//Research Council of Finland/ ; },
mesh = {Humans ; *Memory Disorders/therapy/drug therapy ; Female ; *Attitude of Health Personnel ; Pilot Projects ; Male ; *Nurses/psychology ; Finland ; Surveys and Questionnaires ; Adult ; Middle Aged ; *Health Knowledge, Attitudes, Practice ; },
abstract = {BACKGROUND: As the aging population increases, the prevalence of Alzheimer's disease and other memory disorders increases, and emerging neurotherapies offer new hope, yet little is known about nurses' knowledge and perspectives on these innovations, despite their critical role in patient care. This study aimed to investigate nurses' attitudes, expectations, concerns, and perspectives toward innovative therapies for memory disorders.<br><br>METHODS: A multiple-choice questionnaire (24 items) in Finnish was developed to explore nurses' views. The questionnaire was distributed via email to nursing homes in the Wellbeing Services County of North Savo, Finland, in autumn 2024. Composite scores for perceived benefits, perceived barriers, enabling factors, professional role-related responsibilities, and worries were generated for statistical analyses.<br><br>RESULTS: A total of 132 nurses responded to the survey, most of whom were practical nurses working in nursing homes. Overall familiarity with innovative neurotherapies was low, and many participants indicated that they were not at all familiar with these treatments. Opinions on the future role of such therapies in managing memory disorders varied, with some considering them significant or moderately important. Several respondents also expressed serious concerns regarding the efficacy and potential side effects of these therapies. Regression analyses showed that lower composite outcome scores were consistently associated with being a social and healthcare student, being somewhat familiar with innovative neurotherapies, and, in some models, with shorter work experience or specific workplace settings. However, adjusted R[2] values ranged from 0.09 to 0.18, indicating that demographic and professional background factors explained only a modest proportion of variance in the composite outcomes.<br><br>CONCLUSION: Nurses currently have limited familiarity with innovative neurotherapies, but there is cautious optimism about their future role in treating memory disorders, including Alzheimer's disease.},
}
@article {pmid42467046,
year = {2026},
author = {Makita, K and Nishihara, T and Arakaki, Y and Ohida, T and Goto, K and Kutsuna, N},
title = {Hospital Budget Impact and Provider-Side Economic Evaluation of Lecanemab and Donanemab Under Japan's National Fee Schedule: A Head-to-Head Linear Model.},
journal = {Value in health regional issues},
volume = {},
number = {},
pages = {101675},
doi = {10.1016/j.vhri.2026.101675},
pmid = {42467046},
issn = {2212-1102},
abstract = {OBJECTIVES: The study aimed to assess the provider-side financial viability of antiamyloid disease-modifying therapies for early Alzheimer's disease in Japan, we developed a linear hospital-provider model that separates a short inpatient diagnostic phase from an outpatient infusion phase.<br><br>METHODS: Using public National Health Insurance tariffs, official 2025 drug prices, and workflow-based labor costing with time-driven activity-based costing, we estimated per-case outpatient margins and program-level break-even case volumes. Scenarios examined fee-for-service versus diagnosis procedure combination/per-diem payment system hospitals, magnetic resonance imaging surveillance intensity, purchase discounts, wage growth, routine-workflow staff time, and the scheduled 15% lecanemab price reduction effective November 1, 2025.<br><br>RESULTS: At 1.5 T with no assumed wage growth, donanemab yielded positive outpatient margins from + 37,670JPY at no purchase discount to + &#xa5;110 777 at a 2.6% discount. Lecanemab at 50 kg yielded -&#xa5;9048 at no discount and broke even at a discount of 0.304% before the scheduled price reduction and 0.358% after it. At 55 to 60 kg, the equal-discount threshold at which lecanemab overtook donanemab shifted from about 6.2% before the price reduction to 20.9% after it. Sensitivity analyses showed purchase discounts were the dominant driver, whereas labor and workflow inputs affected lecanemab more because it requires more infusions per year.<br><br>CONCLUSIONS: Under Japan's fee schedule, both therapies were financially viable across typical purchase-discount ranges in scenario analyses, but findings should be interpreted as provider-margin estimates rather than comparative clinical judgments.},
}
@article {pmid42467182,
year = {2026},
author = {Imabayashi, E and Morris, A and Iaccarino, L and Arora, AK and Kamiki, E and Lu, M},
title = {[18]F-flortaucipir PET imaging: Biodistribution in the Japanese population and diagnostic accuracy by Japanese readers.},
journal = {Annals of nuclear medicine},
volume = {},
number = {},
pages = {},
pmid = {42467182},
issn = {1864-6433},
support = {Eli Lilly and Company//Eli Lilly and Company/ ; Avid Radiopharmaceuticals//Avid Radiopharmaceuticals/ ; },
abstract = {OBJECTIVE: [18]F-flortaucipir (Tauvid™) is an [18]F-labeled diagnostic positron emission tomography (PET) radiopharmaceutical, which was developed to detect tau pathology in the brain and to estimate the density and/or distribution of aggregated tau neurofibrillary tangles for patients being evaluated for Alzheimer's disease (AD). The objective of this article is to report findings from two studies. The primary objective of the first (dose and biodistribution) study was to investigate the consistency of [18]F-flortaucipir PET biodistribution between Japanese and non-Japanese individuals. In the second (reader) study, the comparability of visual reads performed by Japanese and US expert readers who followed the same training program was evaluated.<br><br>METHODS: This article reports findings from two separate studies and datasets. In the dose and biodistribution study, whole-body distribution of [18]F-flortaucipir was assessed (N&#x2009;=&#x2009;9). Standardized uptake value ratios, normalized to the entire cerebellum, were calculated, and whole-body effective dose was calculated using a 73.7&#xa0;kg bodyweight model. In the reader study (Study A27; I7E-AV-A27), five Japanese physicians visually interpreted 60 PET scans randomly selected from a previous US reader study (Study FR01; NCT03901092). Scan positivity was determined based on increased activity of [18]F-flortaucipir in posterolateral temporal, occipital, or parietal/precuneus regions with or without frontal activity. Each scan was visually interpreted by all Japanese readers, who determined whether scans were consistent with an AD or non-AD pattern. Concordance between Japanese and US readers who underwent the same training on the interpretation of [18]F-flortaucipir PET images was then evaluated (reader study primary endpoint).<br><br>RESULTS: The biodistribution of [18]F-flortaucipir was consistent between Japanese and non-Japanese individuals. When interpreting [18]F-flortaucipir PET images to distinguish between AD versus non-AD patterns, Japanese and US readers who underwent the same training showed 100% agreement on the majority reads, with a Cohen's Kappa value of 1.<br><br>CONCLUSIONS: [18]F-flortaucipir whole-body biodistribution for Japanese individuals was consistent with that of non-Japanese individuals. After completing the same training, Japanese readers showed high concordance with US readers on the interpretation of [18]F-flortaucipir PET images to distinguish between AD and non-AD patterns. Data and scans were from previous studies registered with ClinicalTrials.gov (registration numbers: NCT04474405; NCT03901092).},
}
@article {pmid42467190,
year = {2026},
author = {Siriwattanasathien, Y and Yotmanee, P and Lehboon, K and Chokchaisiri, R and Nunparn, K and Chunglok, W and Suksamrarn, A},
title = {Isolation, modification, structure-activity relationship (SAR) and molecular docking studies of isoflavones from Derris scandens as potent dual AChE/BuChE inhibitors.},
journal = {Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents},
volume = {},
number = {},
pages = {},
pmid = {42467190},
issn = {1554-8120},
support = {Contract No. 10/2025//Walailak University Graduate Scholarship/ ; DBG6180030//The Thailand Research Fund/ ; },
abstract = {The stems of Derris scandens are rich sources of isoflavonoids including a new isoflavone and nine known isoflavones. Some isolated isoflavones exhibited considerable acetyl cholinesterase (AChE) and butyryl cholinesterase (BuChE) inhibitory activities. Preliminary SAR studies have indicated that one of the essential structural requirements for a 5,7,4'-trioxygenated isoflavone to exhibit high ChE inhibitory activities is the presence of prenyl group(s). Structural modifications of the isoflavone 5 to ester and ether derivatives did not enhance the ChE inhibitory potential. Molecular docking studies have indicated that, if the isoflavone structure is more flexible, the better binding of isoflavone molecule to the receptor should be achieved. The more flexible dihydro analog of the prenyl moiety was therefore prepared from the isoflavone 5 to give corresponding dihydro analog 19 and the tetrahydro analog 20. It was found that the dihydro analog 19 was the most active analog for AChE and BuChE inhibitions, with the IC50 values of 0.41 ± 0.07 µM and 0.64 ± 0.01µM, respectively. It was 3.3- and 4.8-fold, respectively, more active than galanthamine. In addition, the dihydro analog 19 exhibited lower cytotoxicity toward Vero and RAW 264.7 cells than the isoflavone 5. Molecular docking studies indicated that 19 could simultaneously interact with the PAS, AS and CT of AChE and BuChE. The presence of an isopentyl group on isoflavone ring B is necessary for the dihydro analog to exhibit anti-ChE activity. Hence, an isoflavone with an isopentyl group on ring B, a prenyl group on ring A and suitable hydroxy groups on the aromatic ring could be a possible lead candidate for a dual-target-directed ligand for the treatment of Alzheimer's disease.},
}
@article {pmid42467268,
year = {2026},
author = {Feder, B and Polli, G and Laurenzi, S and Righetti, S and Tessari, B and Terruzzi, S and Papagno, C},
title = {A novel writing to dictation test to investigate lexical and sublexical processes: Italian normative data and preliminary clinical feasibility in Mild Cognitive Impairment and Alzheimer's disease.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {8},
pages = {},
pmid = {42467268},
issn = {1590-3478},
mesh = {Humans ; Male ; *Cognitive Dysfunction/diagnosis/psychology/physiopathology ; Female ; *Alzheimer Disease/diagnosis/psychology ; Aged ; *Neuropsychological Tests ; Italy ; Aged, 80 and over ; Feasibility Studies ; Reproducibility of Results ; Middle Aged ; *Writing ; },
abstract = {Writing abilities can be interpreted within dual-route models, which distinguish lexical and sublexical processes. The present study aimed to validate a novel writing to dictation test to assess both lexical and sub-lexical spelling abilities in an Italian population. A sample of 392 healthy participants provided robust normative data, revealing significant effects of age, education, and sex on spelling performance. Test-retest analyses indicated satisfactory reliability and minimal learning effects. The clinical feasibility of the test was explored in patients with amnestic Mild Cognitive Impairment (MCI) and Alzheimer's disease (AD). MCI patients mainly showed selective difficulties in spelling words with unpredictable orthography, suggesting early lexical impairment, whereas AD patients exhibited more severe and heterogeneous deficits involving both lexical and sublexical processes. Qualitative error analysis revealed multiple dysgraphic patterns, particularly in the AD group. Spelling performance did not significantly correlate with other cognitive domains, which may suggest a relative specificity of writing impairment. While the test provides a useful tool for assessing spelling abilities and characterizing writing to dictation disorders in neurodegenerative conditions, limitations related to sample stratification and socio-demographic representation were noted. The study underscores the importance of including standardized writing to dictation assessments in neuropsychological evaluations.},
}
@article {pmid42467293,
year = {2026},
author = {Hassan, MA and Al Amin, M and Sweilam, SH and Abohassan, M and Krishnan, K and Gupta, JK and Jahnavi, P and Vodeti, R and Radha, R and Gupta, PS and Reddy, KTK},
title = {Resveratrol and neuroprotection: modulation of cellular dynamics and signaling networks in neurodegenerative diseases.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42467293},
issn = {1568-5608},
abstract = {Progressive loss of neurons, oxidative stress, neuroinflammation, and mitochondrial dysfunction are hallmarks of neurodegenerative diseases (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Resveratrol, a polyphenolic phytoalexin mainly found in grapes and red wine, is a promising treatment candidate due to its diverse biological effects and neuroprotective properties. This review demonstrates the regulatory effects of resveratrol on cellular signaling pathways linked to NDs and its neuroprotective mechanisms. Resveratrol enhances neuronal survival, boosts mitochondrial biogenesis, and mitigates oxidative stress by affecting key molecular pathways, including SIRT1/AMPK, PI3K/Akt, MAPK, and Nrf2/ARE. The PI3K/Akt and ERK1/2 pathways promote neuronal regeneration by modulating pro-apoptotic and anti-apoptotic factors. Resveratrol inhibits NF-κB, reducing cytokine release and microglial activation, thereby exhibiting anti-inflammatory properties. It improves cognitive function, synaptic plasticity, and neuronal survival. Despite an increasing pharmacological profile, its practical applicability is limited by inadequate bioavailability, rapid metabolism, and restricted brain penetration. This review demonstrates resveratrol's effect on interconnected signaling networks related to neurodegeneration. We critically compare evidence from preclinical and clinical studies, demonstrating both therapeutic potential and translational limitations. Emerging nanotechnology-based delivery strategies are demonstrated to overcome bioavailability and blood-brain barrier penetration challenges. These insights provide a translational perspective for the future development of resveratrol-based interventions in NDs.},
}
@article {pmid42467720,
year = {2026},
author = {Piotrowski, SL and Li, X and Fitzpatrick, CE and Tucker, A and Lee, A and Leibovitch, E and Monaco, MCG and Grosskopf, AK and Peterson, R and Dwyer, JE and Warner, A and Starost, MF and Simpson, RM and Sukoff Rizzo, SJ and Silva, AC and Allen-Worthington, K and Narver, H and Krug, LT and Jacobson, S},
title = {Callitrichine herpesvirus 3 in the common marmoset is a model of Epstein-Barr virus infection and associated lymphoma.},
journal = {PLoS pathogens},
volume = {22},
number = {7},
pages = {e1014450},
doi = {10.1371/journal.ppat.1014450},
pmid = {42467720},
issn = {1553-7374},
abstract = {Herpesviruses, such as Epstein-Barr virus (EBV), are thought to potentially play a significant role in multiple disease processes, including neoplasia, multiple sclerosis (MS), and more recently, Alzheimer's disease (AD). Animal models remain vital tools for understanding these diseases and developing therapeutics. Callitrichine herpesvirus 3 (CalHV-3) was identified in the early 2000s in the common marmoset (Callithrix jacchus). Although phylogenetically related to human EBV, the biological similarities between CalHV-3 and EBV have not been thoroughly characterized. Over 450 marmosets from five biomedical research colonies in the United States were screened for CalHV-3 using droplet digital PCR (ddPCR). Peripheral blood mononuclear cells (PBMCs) were magnetically separated to determine viral loads in B-cell selected and B-cell depleted populations. A CalHV-3 infected cell line was reactivated to determine gene expression profiles using quantitative-Reverse Transcription PCR (q-RT-PCR). Archived cases of lymphoma in the marmoset were immunophenotyped by immunohistochemistry (IHC). In the neoplastic tissue, CalHV-3 viral loads were measured by ddPCR, and viral transcripts were visualized using RNAscope. The prevalence of CalHV-3 in these research colonies ranged from 19-63%. The virus was detected longitudinally in PBMCs and saliva. Infected marmosets had CalHV-3 viral loads enriched in B-cells. All cases of B-cell lymphoma in the marmoset were positive for CalHV-3 DNA, with transcripts of EBV latent and lytic gene homologs detected in neoplastic tissue. Like EBV, CalHV-3 is characterized by persistent infection, shedding in saliva, B-cell tropism, latent and lytic gene expression profiles, and lymphomagenesis in a subset of infected animals. These results further suggest that CalHV-3 in the common marmoset may serve as a translational model of EBV infection and associated diseases.},
}
@article {pmid42467872,
year = {2026},
author = {Grill, JD and Graff-Radford, J},
title = {The Promise and Peril of Alzheimer Disease Prevention.},
journal = {Neurology},
volume = {107},
number = {3},
pages = {e218348},
doi = {10.1212/WNL.0000000000218348},
pmid = {42467872},
issn = {1526-632X},
mesh = {Humans ; *Alzheimer Disease/prevention &amp; control/diagnosis ; },
abstract = {Interventions to delay or prevent Alzheimer disease dementia hold the promise of sizable personal and public benefit. The nomenclature, research designs, and interpretation of results for studies assessing prevention outcomes, however, are inconsistent and would benefit from greater consensus about the necessary requirements for specific intervention claims. Moreover, the public space includes substantial media attention, direct-to-consumer diagnostics, and marketing of unproven interventions for brain health and dementia prevention. This article outlines these issues in hopes of catalyzing further consensus building and alerting professional and regulatory agencies to these topics.},
}
@article {pmid42467931,
year = {2026},
author = {Kim, Y and Lee, G and An, S and Park, H and Kim, H and Kim, J and Kang, S and Kim, S and Kwon, D and Park, J and Hwang, Y and Kim, S and Yuan, X and Jeong, J and Lee, H and Kim, HK and Kim, J},
title = {Therapeutic Gene Editing of APOE4 in Sporadic Alzheimer's Disease via Prime Editor 7.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e76658},
doi = {10.1002/advs.76658},
pmid = {42467931},
issn = {2198-3844},
support = {NRF-2022R1A6A1A03053343//Ministry of Education, Republic of Korea/ ; RS-2025-02223734//Korea Health Industry Development Institute (KHIDI)/ ; RS-2024-00433755//Ministry of Science and ICT and Ministry of Health and Welfare, Republic of Korea/ ; },
abstract = {The apolipoprotein E4 (APOE4) allele is the strongest genetic risk factor for sporadic Alzheimer's disease (AD), driving Aβ accumulation, tau pathology, and synaptic dysfunction. Allele-specific correction of APOE4 represents a promising therapeutic strategy to mitigate disease progression. In this study, we developed an APOE4-specific prime editing strategy based on an optimized APOE4-targeting pegRNA, enabling precise and efficient conversion of the APOE4 allele to the lower-risk APOE3 variant. We found that PE7 targeting the APOE4 allele achieved robust and specific editing without detectable off-target effects. This correction reduced ApoE4 protein levels and attenuated key AD-related pathologies, including Aβ42 accumulation, tau phosphorylation, and activation of the ERK1/2 pathway in APP/APOE4 knock-in (KI) mice. Notably, PE7 treatment enhanced neuronal survival and improved cognitive performance in these mice. Furthermore, in human induced neurons derived from APOE3/4 heterozygous AD patient fibroblasts, PE7 consistently corrected the APOE4 allele and suppressed both amyloid- and tau-associated pathologies. These findings establish PE7-mediated APOE4 correction as a precise and efficient therapeutic genome-editing strategy with translational potential for sporadic AD.},
}
@article {pmid42468094,
year = {2026},
author = {Feng, Q and Song, Y and Pan, Z and Liu, W and Xu, H and Wang, L and Cheng, H and Wang, P and Chen, G},
title = {Heterostructure nanozyme-synergistically modulated electrochemiluminescence/photoelectrochemical sensing platform for detection of Alzheimer's disease biomarkers in plasma samples.},
journal = {Biosensors &amp; bioelectronics},
volume = {312},
number = {},
pages = {119004},
doi = {10.1016/j.bios.2026.119004},
pmid = {42468094},
issn = {1873-4235},
abstract = {In this work, a PtPd/CeO2 heterostructure nanozyme-synergistically modulated ternary ZnS/CdS/Bi2Se3 electrochemiluminescence/photoelectrochemical (ECL/PEC) aptasensor was designed for simultaneous detection of amyloid-β peptides (Aβ1-40 and Aβ1-42), as the key plasma biomarkers of Alzheimer's disease (AD). Benefiting from the bimetallic alloy effect and the support-active component synergy, PtPd/CeO2 heterostructure efficiently accelerated interfacial electron transfer, leading to both an improved catalytic reaction kinetic rate and enhanced adsorption and activation of reactants. Ternary ZnS/CdS/Bi2Se3 achieved photocurrent self-enhancement via synergistic bandgap excitation and multi-interface charge transfer effects among its components, thereby significantly boosting the response signals of both ECL and PEC. Through the integration of aptamer-mediated specific target recognition and toehold-triggered strand displacement reaction (TSDR)-based signal amplification, this aptasensor realized the simultaneous detection of Aβ1-42 and Aβ1-40. Notably, practical validation of the aptasensor for Aβ1-42/Aβ1-40 ratio detection in actual plasma specimens demonstrated the feasibility of minimally invasive liquid biopsy with high patient compliance and great potential for large-scale screening and early diagnosis of AD.},
}
@article {pmid42456344,
year = {2026},
author = {An, P and Li, M and Zhang, S and Lian, D and Li, C and Wang, C and Yu, M and Wang, D and Kong, L and Ren, J and Li, Y and Wang, H and Yang, X and Wu, Z},
title = {Liquid crystal biosensing platform based on whispering gallery mode laser for Aβ42 detection.},
journal = {Colloids and surfaces. B, Biointerfaces},
volume = {268},
number = {Pt 1},
pages = {115985},
doi = {10.1016/j.colsurfb.2026.115985},
pmid = {42456344},
issn = {1873-4367},
abstract = {Alzheimer's disease (AD) is an irreversible and progressively worsening neurodegenerative disorder. Amyloid beta (Aβ42) plays a crucial role in the early diagnosis of this disease. However, the concentration of Aβ42 in the blood is extremely low, which poses a challenge for Aβ42 detection. Herein, a liquid crystal (LC) biosensing platform based on whispering gallery mode (WGM) laser was developed for rapid and real-time monitoring of the AD-related biomarker Aβ42. The LC microcavities were functionally modified using cetyltrimethyl ammonium bromide (CTAB) and RNA aptamers. Based on this, the quantitative monitoring mechanism of Aβ42 was analyzed, stemming from the interaction between the negatively charged RNA aptamer and CTAB, leading to the reorientation of LC molecules. This alters the refractive index distribution within the microcavity, thereby enabling the shift of the WGM spectrum. The dynamic changes of molecular orientation in the LC microcavity were monitored by polarization optical microscopy and spectral analysis. The experimental results showed that the total shifts in the resonance spectrum were directly proportional to the concentration of Aβ42 within the range of 0-1000 pg/mL. The sensitivity of the sensor is 0.003 nm/pg/mL. The experiment further confirmed the practicability of this sensor in the mouse serum. The sensor is inexpensive, easy to manufacture and fast and it is potentially useful for AD-related biomarker screening after further validation.},
}
@article {pmid42456348,
year = {2026},
author = {Hashim, KN and Matsuba, Y and Hashimoto, S},
title = {Thioredoxin-dependent redox homeostasis modulates tau-seeded aggregation in HEK293 TauRD biosensor cells.},
journal = {Biochemical and biophysical research communications},
volume = {830},
number = {},
pages = {154297},
doi = {10.1016/j.bbrc.2026.154297},
pmid = {42456348},
issn = {1090-2104},
abstract = {Tau aggregation is a central pathological feature of Alzheimer's disease (AD) and other tauopathies. Although oxidative stress has been implicated in AD pathogenesis, the effects of intracellular redox perturbation on tau-seeded aggregation remain incompletely understood. In this study, we investigated the role of thiol redox homeostasis in tau-seeded aggregation using HEK293 TauRD fluorescence resonance energy transfer biosensor cells. Intracellular redox conditions were manipulated using the glutathione synthesis inhibitor l-buthionine-(S,R)-sulfoximine (BSO) and through overexpression or knockdown of thioredoxin (TXN), a key regulator of cellular thiol redox balance. BSO treatment significantly reduced intracellular glutathione levels without causing overt cytotoxicity, confirming successful redox alteration. However, BSO treatment failed to significantly alter tau-seeded aggregation. By contrast, TXN knockdown resulted in a modest but reproducible reduction in seeded aggregation efficiency without affecting total tau reporter expression. These findings indicate that acute glutathione depletion alone is insufficient to modulate tau-seeded aggregation in this cellular model. Furthermore, disruption of the TXN system inluences tau seeding in a manner that cannot be explained simply by increased oxidative stress. Together, our results suggest that thiol redox homeostasis contributes to the regulation of tau-seeded aggregation through mechanisms beyond a simple shift toward an oxidizing intracellular environment.},
}
@article {pmid42456517,
year = {2026},
author = {Liao, R and Jin, H and Guo, Y and Jiang, X and Liu, Y and Yu, T and Li, H and Yin, P},
title = {A dual-recognition ratiometric fluorescent probe for selective imaging of cysteine in Alzheimer's disease models.},
journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy},
volume = {363},
number = {Pt 2},
pages = {128448},
doi = {10.1016/j.saa.2026.128448},
pmid = {42456517},
issn = {1873-3557},
abstract = {Alzheimer's disease (AD) is strongly associated with redox imbalance and metabolic dysregulation, in which cysteine (Cys), an essential biothiol and endogenous antioxidant, plays a key role in neuronal redox homeostasis. However, selective and ratiometric imaging of Cys in AD-related biological systems remains challenging because of interference from structurally similar biothiols and complex pathological microenvironments. Herein, we developed probe 1, a coumarin-based dual-recognition ratiometric fluorescent probe for selective Cys imaging. Probe 1 displayed a rapid, sensitive, and distinct ratiometric fluorescence response toward Cys with a pronounced emission blue-shift. Owing to its dual-recognition design, probe 1 exhibited excellent selectivity for Cys over homocysteine, glutathione, and other biologically relevant species, as well as good photostability, low cytotoxicity, and favorable biocompatibility. Probe 1 enabled reliable visualization of endogenous and exogenous Cys in living cells and was further applied to monitor Cys fluctuations in zebrafish and AD mouse models. These results demonstrate that probe 1 provides an effective ratiometric imaging tool for tracking Cys-related redox alterations in AD-associated biological systems and offers a useful platform for exploring the role of Cys metabolism in AD progression.},
}
@article {pmid42456683,
year = {2026},
author = {Bouzigues, A and Grassi, M and Cantoni, V and Premi, E and Bellini, S and Binetti, G and Logroscino, G and Russell, LL and Ferry-Bolder, E and Foster, PH and van Swieten, JC and Jiskoot, LC and Seelaar, H and Sanchez-Valle, R and Laforce, R and Graff, C and Galimberti, D and Vandenberghe, R and de Mendonça, A and Di Fede, G and Santana, I and Gerhard, A and Langheinrich, T and Levin, J and Nacmias, B and Otto, M and Bertoux, M and Lebouvier, T and Ducharme, S and Butler, C and le Ber, I and Bruffaerts, R and Solje, E and Kinnunen, M and Krüger, J and Finger, E and Tartaglia, MC and Masellis, M and Rowe, JB and Synofzik, M and Moreno, F and Ghidoni, R and Migliaccio, R and Rohrer, JD and Borroni, B and , },
title = {Survival estimates and their predictors in genetic frontotemporal dementia: an international, retrospective, cohort study.},
journal = {The Lancet. Neurology},
volume = {25},
number = {8},
pages = {731-740},
doi = {10.1016/S1474-4422(26)00197-3},
pmid = {42456683},
issn = {1474-4465},
mesh = {Humans ; *Frontotemporal Dementia/genetics/mortality/diagnosis ; Retrospective Studies ; C9orf72 Protein/genetics ; tau Proteins/genetics ; Female ; Male ; Middle Aged ; Aged ; Cohort Studies ; Progranulins/genetics ; Mutation ; Kaplan-Meier Estimate ; },
abstract = {BACKGROUND: What drives the heterogeneity of survival estimates in genetic frontotemporal dementia is unknown. We sought to understand the natural history and predictors of disease trajectory, which are crucial not only for effective care but also for the design of therapeutic clinical trials and efficacy evaluation.<br><br>METHODS: In this international, cohort study, we used the Kaplan-Meier method to retrospectively assess survival estimates in patients enrolled in the GENFI cohort, which included 32 research sites located in Belgium, Canada, Finland, France, Germany, Italy, the Netherlands, Portugal, Spain, Sweden, and the UK, and comprised participants carrying a causal C9orf72 expansion or a causal mutation in GRN or MAPT genes. Survival was calculated as the time from symptom onset to time of death or censoring date; median survival estimate for all patients was the primary endpoint. Cox proportional hazards models were used to identify predictors of survival, which were subsequently externally validated in an independent cohort. We further designed a structural equation model to assess the relationships between predictors, applying a least absolute shrinkage and selection operator method.<br><br>FINDINGS: Of 278 participants of the GENFI cohort included in this study, 160 (58%) were men and 118 (42%) were women. 162 died during follow-up (58%) and 116 were still alive (42%) on June 1, 2024, the chosen censoring date. 138 participants carried a C9orf72 expansion, 94 carried a GRN mutation, and 46 a MAPT mutation. 179 participants were diagnosed with behavioural variant frontotemporal dementia, 46 with primary progressive aphasia, and 31 with frontotemporal dementia-amyotrophic lateral sclerosis. 22 participants had other diagnoses. The median survival estimate for all patients with genetic frontotemporal dementia was 6&#xb7;94 years (95% CI 6&#xb7;59-7&#xb7;80) from symptom onset. The median survival estimate for patients with GRN mutations was 6&#xb7;63 years (6&#xb7;08-7&#xb7;98), for patients with a C9orf72 expansion was 7&#xb7;04 years (6&#xb7;45-8&#xb7;77), and for patients with MAPT mutations was 8&#xb7;56 years (7&#xb7;06-13&#xb7;50). Older age at onset, shorter disease duration from onset to enrolment in the GENFI study, clinical presentation (ie, frontotemporal dementia-amyotrophic lateral sclerosis), domain of first symptom (ie, motor or language onset), and geographical area of residency (ie, central and southern Europe) were associated with poorer prognosis. Genetic group did not directly affect survival estimates; rather its effect was mediated by age at onset and clinical phenotype. We computed a genetic frontotemporal dementia survival risk index, which can be used at an individual patient level.<br><br>INTERPRETATION: Our results highlight that motor impairment in addition to cognitive and behavioural symptoms should be considered when estimating prognosis in genetic frontotemporal dementia. Individual risk scores might be of help for patient stratification in future therapeutic trials, although refinement and prospective validation are now needed.<br><br>FUNDING: Italian Ministry of Health (Ricerca Corrente), Fondation Philippe Chatrier, and Fondation Vaincre Alzheimer.},
}
@article {pmid42456853,
year = {2026},
author = {Chang, J and Gao, PY and Gao, Y and Wu, ZY and Wang, ZB and Chen, O and Kulick, ER and Zhao, G and Tang, Y},
title = {Mental health, biological aging, and lifestyle mediate the associations between social determinants of health and dementia.},
journal = {Journal of advanced research},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jare.2026.07.036},
pmid = {42456853},
issn = {2090-1224},
abstract = {INTRODUCTION: Social determinants of health (SDoH) encompass non-medical factors including economic stability, education, social engagement, and environmental conditions that significantly influence health outcomes. Comprehensive evaluation of weighted SDoH scores and their underlying mechanisms in dementia risk remains limited.<br><br>OBJECTIVES: To investigate longitudinal associations between SDoH and dementia risk, and explore mediating pathways through mental health, biological aging, lifestyle, and inflammation using directed acyclic graph theory.<br><br>METHODS: We constructed a weighted SDoH score encompassing seven components across four domains: economic stability, education, social contact, and environmental factors. Cox models assessed dementia risk across SDoH tertiles. Mediation analyses examined pathways through mental health, biological aging, lifestyle, and inflammatory markers. Life expectancy differences were calculated using flexible parametric survival models.<br><br>RESULTS: A total of 359,419 UK Biobank participants (mean age: 56.26&#x202f;years; 52.53% female) with a median follow-up of 13.46&#x202f;years were included. We found that participants with favorable SDoH levels had a lower risk of developing all-cause dementia (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.53-0.60), Alzheimer's disease (HR, 0.62; 95% CI, 0.56-0.68), and vascular dementia (HR, 0.48; 95% CI, 0.41-0.55) compared to those with unfavorable SDoH levels. SDoH emerged as the 2nd most important factor affecting dementia risk after age. The associations between SDoH and incident dementia were mediated by mental health, biological aging, and lifestyle factors. Specifically, depression, frailty, PhenoAge, and smoking mediated 24.00%, 13.60%, 6.33%, and 2.82% of the association, respectively. At age 65, participants with dementia who had favorable SDoH levels had an average life expectancy of 0.909 (95% CI 0.002-1.816) years longer than those with unfavorable SDoH levels.<br><br>CONCLUSION: Favorable SDoH levels significantly reduce dementia risk, with mental health, biological aging, and lifestyle serving as key mediating pathways, emphasizing the importance of comprehensive social interventions for dementia prevention.},
}
@article {pmid42456864,
year = {2026},
author = {Séguy, L and Guyon, L and Corvaisier, S and Maurel, M and Verdié, P and Herbinet, R and Pluart, LL and Dehouck, L and Sevin, E and Fenart, L and Gosselet, F and Lagadu, S and Née, G and Fréret, T and Since, M and Delépée, R and Dallemagne, P and Lisowski, V and Groo, AC and Malzert-Fréon, A},
title = {Enhancing brain delivery of tegaserod for Alzheimer's disease: a pharmaceutical comparison of two nanocarrier-based strategies.},
journal = {International journal of pharmaceutics},
volume = {},
number = {},
pages = {127181},
doi = {10.1016/j.ijpharm.2026.127181},
pmid = {42456864},
issn = {1873-3476},
abstract = {Tegaserod is a serotonin receptor agonist with potential neuroprotective properties for Alzheimer's disease. Due to its low druggability profile and to avoid detrimental side effects, a brain-targeted formulation is required. Nanocarriers targeting the blood-brain barrier (BBB) with a shuttle peptide, such as peptide-22, or enabling direct nose-to-brain delivery were considered as valuable approaches. This study aimed to compare two types of lipid-based nanocarriers and determine the best formulation for intravenous (IV) or intranasal (IN) administration. Tegaserod-loaded nanoemulsions and liposomes were successfully developed, improving the solubilization of tegaserod in injectable formulations. Their properties were optimized for the IV route, and the two formulations were compared in terms of granulometric properties, stability, stealth properties, and transport across a human model of the human BBB. Based on these evaluations, peptide-22-decorated tegaserod-loaded nanoemulsions were the most promising for IV administration. In addition, tegaserod-loaded nanoemulsions or liposomes were incorporated in a gelling formulation with properties optimized for the IN route, focusing on gelation temperature, osmolarity, and pH. Due to its rheological profile and behavior at room temperature, gel-embedded liposomes emerged as the most suitable formulation for the IN route. The successful development of these nanocarriers will facilitate further preclinical evaluation of tegaserod in Alzheimer's disease.},
}
@article {pmid42456879,
year = {2026},
author = {Taei, AA and Karimani, F and Kaveh, N and Khodabakhsh, P and Dehaqani, MA and Dargahi, L},
title = {Forty-hertz auditory stimulation restored hippocampal-prefrontal synchrony and attenuated hippocampal hyperexcitability in an STZ-induced Alzheimer's model.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115931},
doi = {10.1016/j.expneurol.2026.115931},
pmid = {42456879},
issn = {1090-2430},
abstract = {Dysfunction of neuronal networks such as aberrant excitability and disrupted oscillatory activity, especially within theta and gamma bands, in memory-related areas including the hippocampus and prefrontal cortex, is increasingly recognized as an important contributor to cognitive impairment in Alzheimer's disease (AD). In this context, targeting network dysfunction via gamma sensory entrainment, such as 40 Hz auditory stimulation, has emerged as a promising non-invasive therapeutic approach; however, the therapeutic mechanisms by which 40 Hz auditory stimulation ameliorates network-level deficits remain poorly understood. We studied the effects of long-term 40 Hz auditory stimulation in STZ-induced AD rats on the hippocampal-prefrontal network activity. Daily auditory stimulation was applied for 21 days, and its impact was assessed using electrophysiological recordings, behavioral testing, histological staining, and molecular analyses. STZ-treated rats exhibited impaired theta-gamma coupling, reduced hippocampal-prefrontal theta coherence, increased interictal epileptiform discharges, and significant deficits in spatial memory. These network abnormalities were associated with Aβ accumulation, tau hyperphosphorylation, altered expression of insulin/PI3K/Akt pathway-associated genes, and reduced expression of neurogenesis-related markers. Remarkably, 40 Hz auditory stimulation reversed many of these impairments: it restored functional connectivity and cross-frequency coupling, reduced epileptiform activity, improved memory performance, attenuated Aβ and tau pathology, partially normalized insulin/PI3K/Akt pathway-associated gene expression, and upregulated genes related to adult neurogenesis. Our findings indicated that 40 Hz auditory stimulation can effectively target both neural circuit dysfunction and molecular markers of AD, highlighting its potential as a simple, accessible, and multifaceted therapeutic strategy.},
}
@article {pmid42456960,
year = {2026},
author = {Yang, F and Zhao, Y},
title = {Di(2-ethylhexyl) phthalate exposure aggravates amyloid-beta-induced toxicity in transgenic AD Caenorhabditis elegans via lysosomal dysfunction and oxidative stress.},
journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association},
volume = {},
number = {},
pages = {116276},
doi = {10.1016/j.fct.2026.116276},
pmid = {42456960},
issn = {1873-6351},
abstract = {Di(2-ethylhexyl) phthalate (DEHP) is a widely used plasticizer and environmental contaminant. DEHP exposure has been linked to neurotoxicity in Alzheimer's disease (AD), yet the underlying mechanisms remain unclear. Here we found that DEHP exacerbated amyloid-beta (Aβ)-induced toxicity in transgenic AD Caenorhabditis elegans (C. elegans) models. Meanwhile the accumulation of SQST-1 was increased, indicating that the autophagic flux was impaired. Consistently, Aβ deposition was elevated in DEHP-treated AD C. elegans. Further investigation revealed that DEHP treatment resulted in lysosomal dysfunction accompanied by a significant decrease in lysosome number. The expression of hlh-30, a key transcription factor involved in lysosomal biogenesis, as well as its downstream lysosome-related genes, including cup-5, vha-17, and lmp-1, was reduced by DEHP. Moreover, hlh-30 RNAi abolished the exacerbation of Aβ toxicity by DEHP, indicating that the modulation of hlh-30 was a critical mechanism underlying the effects of DEHP. Additionally, DEHP aggravated oxidative stress in AD C. elegans, while the antioxidant N-acetylcysteine alleviated lysosomal impairment and reduced Aβ deposition, suggesting that the elevated oxidative stress was a key contributor to DEHP-induced lysosomal dysfunction and autophagy impairment. These findings highlight lysosomal impairment as a key mechanism contributing to DEHP-exacerbated toxicity in AD models, and suggest the possibility of using antioxidants to prevent DEHP-induced toxicity.},
}
@article {pmid42457037,
year = {2026},
author = {Fernando, MG and Sullivan, K and Simons, M and Squillace, A and Kiat, H and Martins, RN},
title = {Nutritional Strategies Targeting Glucose Metabolism to Slow Cognitive Ageing: A Scoping Review of Human Trials.},
journal = {The American journal of clinical nutrition},
volume = {},
number = {},
pages = {101434},
doi = {10.1016/j.ajcnut.2026.101434},
pmid = {42457037},
issn = {1938-3207},
abstract = {Cerebral glucose hypometabolism is a hallmark of cognitive aging and Alzheimer's Disease (AD), underscoring the need for nutritional strategies that support brain energy metabolism. This scoping review synthesized evidence from human interventions evaluating alternative energy substrates and nutrients that support cerebral energy metabolism and their effects on cognition in older-adults. The review followed PRISMA-ScR guidelines. MEDLINE, EMBASE, and Scopus were searched for studies published during 2014-2024, involving adults aged ≥60 years, with Mild Cognitive Impairment (MCI), AD, subjective cognitive decline, or normal cognition. Thirty-two studies were included, investigating Medium Chain Triglycerides (MCTs), ketogenic diets, omega-3 fatty acids, amino acids, histidine-containing dipeptides, serotonin precursors, and dietary fat modification. Cognitive outcomes were global and domain-specific measures including memory, executive function, and attention, while other outcomes included functional capacity, neuroimaging markers, inflammation, mood, and quality-of-life. Omega-3 supplementation showed mixed evidence with cognitive benefits reported particularly in MCI populations receiving higher DHA doses and longer intervention durations (≥1 g/day, ≥6 months). Ketogenic/MCT-based strategies improved cognitive function in MCI and early-AD, with effects tied to plasma ketone levels; however, benefits were not consistently observed. Limited evidence suggested that anserine/carnosine supplementation may improve verbal memory and executive function, particularly in adults aged ≥70 years and APOE4 carriers. L-arginine improved global cognition in frail hypertensive older-adults, while tryptophan and amino acid interventions demonstrated domain-specific or age-dependent effects, rather than consistent improvements. Findings were heterogeneous across interventions and populations. Cognitive benefits were most evident in early disease-stages, with sufficient dosing and adherence. Several studies reported favourable biomarker, inflammatory, metabolic, or quality-of-life outcomes despite limited cognitive effects. Overall, nutritional strategies targeting brain energy metabolism show promise for supporting cognitive health. However, substantial heterogeneity, small sample sizes, short intervention durations, and inconsistent cognitive outcomes limit the strength of the evidence. Future research should prioritise biomarker-based, longer-term, and multimodal approaches to clarify efficacy and clinical applicability.},
}
@article {pmid42457038,
year = {2026},
author = {Dhana, K and Aggarwal, NT and Ventrelle, J and Voigt, RM and Liu, X and Agarwal, P and Tangney, C and Arfanakis, K and Sacks, FM and Barnes, LL},
title = {Adherence to the MIND Diet and Longitudinal Changes in Global Cognition: A Post-Hoc Analysis of the MIND Trial.},
journal = {The American journal of clinical nutrition},
volume = {},
number = {},
pages = {101433},
doi = {10.1016/j.ajcnut.2026.101433},
pmid = {42457038},
issn = {1938-3207},
abstract = {BACKGROUND: A three-year randomized trial comparing the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet with a control diet found no significant differences in cognitive outcomes by intervention assignment, potentially due to variability in dietary adherence.<br><br>OBJECTIVE: We examined whether adherence to the MIND diet, validated using plasma nutrient biomarkers, was associated with longitudinal changes in global cognition.<br><br>METHODS: The MIND trial enrolled 604 community-dwelling adults aged 65-84 years without cognitive impairment at baseline. MIND diet adherence was quantified as the change in MIND scores from baseline, with higher values indicating greater adherence, and validated using blood levels of antioxidant nutrients, including lutein-zeaxanthin and &#x3b2;-carotene. Participants were classified into categories of no, moderate, or substantial improvement in MIND diet score. Linear mixed-effects models with random intercepts and slopes were used to estimate annual changes in global cognition.<br><br>RESULTS: Of 590 participants (mean age 70.3 years and 65% females) included in the analysis, 116 (19.7%) showed no improvement, 224 (38.0%) modest improvement, and 250 (42.3%) substantial improvement in their MIND diet score. Compared with participants with no change in MIND score, those with greater improvement (mean absolute increase of 4 points on the 0-14 scale) demonstrated a significant annual increase in global cognitive composite scores (&#x3b2; = 0.035; 95% CI: 0.006, 0.064), along with higher plasma lutein-zeaxanthin (&#x3b2; = 0.088; 95% CI: 0.038, 0.137) and &#x3b2;-carotene (&#x3b2; = 0.075; 95% CI: 0.001, 0.150). Modest improvement was not associated with significant changes in cognitive function. The associations between changes in MIND score and cognition were not modified by dietary intervention arm (p-for-interactions > 0.167).<br><br>CONCLUSIONS: Participants with greater increases in MIND diet scores from baseline, indicating higher adherence, showed significant improvements in global cognitive function compared with those whose scores did not increase during the trial. Clinical Trial Registry (clinicaltrials.gov) number: NCT02817074.},
}
@article {pmid42457366,
year = {2026},
author = {Herring, C and Cimiotti, JP and Hepburn, K and Dunbar, S and Higgins, MK and Butts, B},
title = {Psychometric Evaluation of the Pittsburgh Sleep Quality Index in Family Caregivers.},
journal = {Journal of nursing measurement},
volume = {},
number = {},
pages = {},
doi = {10.1891/JNM-2025-0121},
pmid = {42457366},
issn = {1945-7049},
abstract = {Background and Purpose: Poor sleep quality is common among family caregivers and contributes to negative physical and mental health outcomes. This study examined the psychometric properties of the Pittsburgh Sleep Quality Index (PSQI) in caregivers of individuals with heart failure (HF) and Alzheimer's disease (AD). Methods: Baseline data from 269 family caregivers were used to assess the psychometric properties of the PSQI. Results: The PSQI showed acceptable reliability (Cronbach's α: HF = .76; AD = .74). Exploratory factor analysis supported a two-factor model in both groups, revealing both shared and condition-specific subscale loadings. Conclusion: Findings support the PSQI's reliability and construct validity in family caregivers, indicating its utility in identifying sleep disturbances in these high-risk populations.},
}
@article {pmid42457594,
year = {2026},
author = {Acosta-Guzmán, P and Bedoya-Malagón, D and Mercado-Coy, L and Morantes, SJ and Guevara-Pulido, J},
title = {Computer-Aided Drug Design, Synthesis, and In Vitro Safety Evaluation of Carprofen Analogs for Novel Alzheimer's Disease Therapeutics.},
journal = {ChemMedChem},
volume = {21},
number = {14},
pages = {e70393},
pmid = {42457594},
issn = {1860-7187},
support = {PCI 2024-0004//Universidad El Bosque/ ; },
mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Drug Design ; *Carbazoles/chemistry/chemical synthesis/pharmacology ; Amyloid beta-Peptides/metabolism/antagonists &amp; inhibitors ; *Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis/chemistry/pharmacology ; Peptide Fragments/metabolism/antagonists &amp; inhibitors ; *Computer-Aided Design ; Structure-Activity Relationship ; Humans ; Molecular Structure ; Animals ; Mice ; Dose-Response Relationship, Drug ; },
abstract = {Nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, naproxen, and indomethacin, have reduced amyloid beta (Aβ) levels and improved cognitive function in mouse models of Alzheimer's disease (AD). The objective of the current research is to evaluate different NSAIDs using computer-aided drug design (CADD) to explore their potential as new treatments for AD. CADD is an advanced technique for designing biologically active molecules and involves two primary approaches: structure-based virtual screening and ligand-based virtual screening. After identifying the NSAID with the highest affinity for amyloid Aβ1-42 fibrils (PDB 2BEG), we designed analogs through bioisosteric modifications. Twenty derivatives were created, and two carprofen analogs with the most promising properties were synthesized, yielding 75% success with compound A-1 and 70% with compound A-2. These analogs exhibited lower predicted IC50 values (1.57 μM) and more negative interaction energies (-6.43 and -6.67 kcal/mol for A-1 and A-2, respectively) compared to carprofen. Safety evaluations in L929 cells indicated that these compounds were safe at concentrations of 40 µM. In conclusion, two carprofen analogs were successfully designed and synthesized, demonstrating higher affinity for the amyloid Aβ1-42 fibrils, better-predicted IC50 values than carprofen, and safety in the L929 in vitro assay.},
}
@article {pmid42457676,
year = {2026},
author = {Hyeon, SJ and Kim, SC and Chu, J and Kim, Y and Kim, C and Park, U and Tufail, Z and Thi Thanh Nguyen, P and Eom, A and Kim, S and Kim, Y and Lee, E and Kim, S and Lee, SE and Woo, J and Lee, JA and Lee, KE and Stein, TD and Lee, H and Lee, J and Ryu, H},
title = {Targeting the microglial phosphatidylethanolamine synthesis pathway promotes GABARAP-associated phagocytosis and Aβ clearance in Alzheimer's disease.},
journal = {Signal transduction and targeted therapy},
volume = {11},
number = {1},
pages = {},
pmid = {42457676},
issn = {2059-3635},
support = {NRF-2020M3E5D9079742//National Research Foundation of Korea (NRF)/ ; NRF-2022R1A2C3013138//National Research Foundation of Korea (NRF)/ ; NRF-2021R1C1C2095827//National Research Foundation of Korea (NRF)/ ; NRF-2022R1A6A3A01086375//National Research Foundation of Korea (NRF)/ ; 2E32901//Korea Institute of Science and Technology (KIST)/ ; 2E32922//Korea Institute of Science and Technology (KIST)/ ; R01NS109537//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; },
mesh = {*Alzheimer Disease/genetics/pathology/metabolism/drug therapy ; Animals ; *Microglia/metabolism/pathology ; *Phagocytosis/genetics/drug effects ; Mice ; *Phosphatidylethanolamines/genetics/biosynthesis ; *Amyloid beta-Peptides/genetics/metabolism ; *Adaptor Proteins, Signal Transducing/genetics ; *Microtubule-Associated Proteins/genetics ; Humans ; *Apoptosis Regulatory Proteins/genetics ; Signal Transduction ; },
abstract = {Alzheimer's disease (AD) is a major cause of dementia and a prevalent age-related neurodegenerative disorder characterized by progressive cognitive impairment and memory loss. Although metabolic activation or dysfunction of microglia is implicated in AD pathogenesis, the phospholipid metabolism-associated signaling mechanisms within microglia remain poorly defined. In this study, we demonstrate that quinolinic acid (QA), a byproduct of tryptophan catabolism via the kynurenine pathway, activates the microglial Kennedy pathway-responsible for de novo phosphatidylethanolamine (PE) biosynthesis-by upregulating the enzymes EPT1 and ETNK1. This activation markedly enhances the synthesis of PE species enriched in polyunsaturated fatty acids. Concurrently, QA significantly increases the expression of gamma-aminobutyric acid receptor-associated protein (GABARAP), promotes its lipidation, and facilitates the GABARAP-associated phagocytosis (GAP) of Aβ oligomers by microglia. Knockdown of EPT1 and ETNK1 attenuated QA-induced PE synthesis and impaired the GAP of Aβ oligomers, whereas inhibition of GABARAP lipidation via STBD1 deconjugase substantially reduced QA-mediated GAP. QA administration upregulated microglial Gabarap expression and decreased the Aβ plaque burden in the hippocampus of AD (5xFAD) mice, whereas Gabarap knockdown abrogated QA-induced microglial clearance of Aβ. Collectively, these findings reveal a paradoxically beneficial role of QA in activating a microglia-specific signaling cascade that promotes PE biosynthesis and GAP, thereby enhancing Aβ clearance and mitigating AD pathology. Targeting the microglial PE synthesis pathway and GAP may represent a promising therapeutic strategy to ameliorate Aβ accumulation and slow AD progression.},
}
@article {pmid42457956,
year = {2026},
author = {Luquez, T and Algoo, J and Chiu, R and Mares, JA and Yadav, A and Lam, M and Gaur, P and Lai, X and Lee, DI and Paryani, F and Batchelor, R and Belli, I and Henry, J and Hoter-Ishay, B and Mattison, C and Starr, L and Lama, T and Karaahmet, B and Cao, W and De Jager, PL and Taga, M and Barnes, LL and Marquez, DX and Bennett, DA and Zhang, Y and Menon, V},
title = {Cell-type signatures of Alzheimer's disease shared across population groups.},
journal = {Nature},
volume = {},
number = {},
pages = {},
pmid = {42457956},
issn = {1476-4687},
abstract = {Genomic studies at single-cell resolution have identified several cell types associated with clinical and pathological traits in Alzheimer's disease[1-9], but have not examined associations that are shared across populations. To bridge this gap, here we use single-nucleus RNA sequencing and assay for transposase-accessible chromatin with sequencing to profile cortical and subcortical regions in post-mortem brain-tissue samples from Latin, white (excluding Latin) and African American (excluding Latin) individuals. Using discrete and continuous dissections of molecular programs, we identify cell-type-specific clusters associated with Alzheimer's disease in a region-specific manner across all three population groups, including microglial (GPNMB[+] and CD74[+] subgroups), astrocytic (SERPINH1[+], CD44[+] and WIF1[+] subgroups) and neuronal (SST[+] GABAergic and superficial-layer glutamatergic) signatures. We also report continuous gene-expression factors in astrocytes and oligodendrocytes that are not captured by discrete cluster assignments, but which show strong associations with disease phenotypes; these factors are enriched for genes associated with annotated functions such as lipid processing and neurotransmitter reuptake. Finally, we find that molecular programs reveal six distinct subgroups of individuals with cognitive impairment that span all three populations, are not captured by neuropathology, and are instead distinguished by molecular signatures that are not universally present but are nonetheless associated with ante-mortem impairment. Overall, our study identifies key cell types and gene programs implicated in Alzheimer's disease that are shared across population groups, and underscores how representative sampling can capture both shared signatures and disease heterogeneity, thereby enabling better prioritization of key cell types for further investigation.},
}
@article {pmid42458012,
year = {2026},
author = {Croese, T and Mummery, CJ and Bregman, N and Bracha, D and Baruch, K and Kertser, A and Raveh, S and Shochat, E and Schwartz, M},
title = {Immunotherapy with a short-lived anti-PD-L1 antibody in Alzheimer's disease: a phase 1b, randomized, double-blind trial.},
journal = {Nature medicine},
volume = {},
number = {},
pages = {},
pmid = {42458012},
issn = {1546-170X},
support = {5R01AG071810-02//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; PTCG-20-701033/ALZ/Alzheimer's Association/United States ; },
abstract = {While Alzheimer's disease (AD) is initiated by amyloid plaque accumulation, its progression involves local neuroinflammation that the brain cannot resolve when age-related dysfunction of the systemic immune system limits peripheral immune support. Preclinical studies using rodent models showed that transient systemic blockade of programmed death-ligand 1 is associated with reduced neuroinflammation, neuroprotection and attenuation of disease progression. Based on the underlying mechanism, a new short-lived anti-programmed death-ligand 1 antibody with Fc-effector silencing and reduced FcRn binding (IBC-Ab002) was engineered. Here, we report a randomized, double-blind, phase 1b first-in-human trial in early AD, with safety and tolerability as the primary endpoint. Forty participants were enrolled across five ascending dose cohorts (1-30 mg kg[-1]), with dosing administered four times at 3-month intervals. Treatment was well tolerated, with no treatment-related serious adverse events or evidence of amyloid-related imaging abnormalities. Exploratory analyses at week 48 showed directional changes in cerebrospinal fluid biomarkers of neuronal and synaptic damage favoring the 30 mg kg[-1] dose, although no doses reached statistical significance given the limited sample size. The safety and tolerability profile supports further clinical development of systemic, intermittently administered IBC-Ab002 in early AD. ClinicalTrials.gov registration: NCT05551741 .},
}
@article {pmid42458104,
year = {2026},
author = {Suma Narayanappa, T and Ananthanarayana, V and Chinnathambi, S},
title = {Tau-mediated Mechanisms in Alzheimer's Disease Pathogenesis.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42458104},
issn = {1559-1182},
mesh = {Humans ; *tau Proteins/metabolism ; *Alzheimer Disease/metabolism/pathology ; Animals ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of extracellular amyloid-β plaques and intracellular neurofibrillary tangles of Tau. It is clinically accompanied by progressive cognitive impairment and behavioral deficits. Despite extensive AD research involving amyloid-β, pharmacological strategies targeting Aβ have shown limited clinical efficacy or adverse effects in clinical trials, while lecanemab and donanemab have shown to modestly but significantly slow cognitive decline in phase III clinical trials. However, the overall limited success of Aβ-directed therapies has shifted the attention to Tau protein. Therefore, understanding the pathology and pathogenesis of Tau in the contribution to AD is important for early diagnosis and effective treatment. Under physiological conditions, Tau stabilizes microtubules, axonal transport, and synaptic integrity. However, pathological post-translational modifications have been shown to disrupt Tau-microtubule interactions, promoting its aggregation and release into the extracellular region. Increasing evidence suggests the prion-like propagation of extracellular Tau drives the disease progression across the neuronal and glial cells leading to synaptic dysfunctions. The recent diagnostic approaches involving Tau-PET and Tau-based biofluid biomarkers have improved the detection of AD pathology. Therefore, effective clearance of Tau in AD requires understanding the molecular and cellular mechanisms regulating the pathological Tau degradation. This review explains the mechanistic contribution of extracellular Tau in AD pathogenesis and the cellular consequences. This will provide a foundation for understanding the influence of Tau on AD, the discovery of potential therapeutic strategies and new treatment methods for AD.},
}
@article {pmid42458109,
year = {2026},
author = {Buonocore, J and Fortunato, F and Fratto, E and Sammarra, I and Gambardella, A and Quattrone, A and Quattrone, A},
title = {Risk of epilepsy in people with adult-onset hydrocephalus: insights from the UK Biobank.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {8},
pages = {},
pmid = {42458109},
issn = {1590-3478},
mesh = {Humans ; Female ; *Hydrocephalus/epidemiology/complications ; *Epilepsy/epidemiology ; Male ; United Kingdom/epidemiology ; Aged ; Middle Aged ; Cohort Studies ; UK Biobank ; Age of Onset ; Risk Factors ; Biological Specimen Banks ; Incidence ; Adult ; Aged, 80 and over ; },
abstract = {AIM: We aim to determine whether individuals with adult-onset hydrocephalus have an increased risk of incident epilepsy over time.<br><br>METHODS: We analysed data from the UK Biobank cohort. Diagnoses of "hydrocephalus" and "epilepsy" were identified through ICD-10-coded health records, excluding congenital and secondary cases. The association between these two diseases was investigated using logistic regression (adjusted for age and sex); subsequently, we performed a sampled cohort study to evaluate the hazard ratio (HR) for incident epilepsy in people with adult-onset hydrocephalus using Cox proportional hazards models with a dedicated sensitivity analysis including different sets of covariates such as demographic, lifestyle, vascular, and genetic factors.<br><br>RESULTS: Our cohort included 483,790 controls, 5,028 individuals with epilepsy, and 320 with adult-onset hydrocephalus. Hydrocephalus and epilepsy were strongly associated (OR: 9.6, 95% CI: 6.4-13.8, p&#x2009;<&#x2009;0.001). Adjusted Cox models demonstrated a markedly increased risk of incident epilepsy in people with adult-onset hydrocephalus, with HR values ranging from 14.62 (95% CI: 7.91-27.00, p&#x2009;<&#x2009;0.001) to 23.80 (95% CI: 12.87-44.03, p&#x2009;<&#x2009;0.001) across models, after adjusting for multiple covariates. Results were also consistent after excluding people with comorbid neurodegenerative dementias such as Alzheimer's disease.<br><br>CONCLUSIONS: We demonstrated a markedly increased risk of epilepsy in adult-onset hydrocephalus, independent of vascular and neurodegenerative comorbidities and not attributable to shunt-related complications. These findings underscore the importance of increased diagnostic vigilance, as seizures may be under-recognized in this population, and support further research to clarify mechanisms and optimize management strategies.},
}
@article {pmid42458137,
year = {2026},
author = {Lopes, LG and Oliveira, AS and Fingergut, CC and Brito, GNE and Gonzalez, JVP and Donato, KO and Cruz, MME and Salles, C},
title = {Association between circadian rhythm disturbances and cognitive decline in the elderly: a systematic review.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {8},
pages = {},
pmid = {42458137},
issn = {1590-3478},
mesh = {Humans ; *Cognitive Dysfunction/physiopathology/complications/epidemiology ; *Chronobiology Disorders/complications/epidemiology/physiopathology ; Aged ; Circadian Rhythm/physiology ; },
abstract = {BACKGROUND: Circadian rhythm dysregulation may contribute to sleep-wake disorders and cognitive impairment. In the elderly, circadian abnormalities have been observed in Mild Cognitive Impairment (MCI), suggesting a possible association between neurocognitive deficits and circadian dysfunctions.<br><br>OBJECTIVE: To analyze the association between circadian rhythm disturbances and cognitive decline in the population aged&#x2009;&#x2265;&#x2009;60 years.<br><br>METHODS: This systematic review included studies evaluating the association between circadian rhythm disturbances and cognitive decline in elderly individuals aged 60 years or older, with self-reported or objectively measured sleep data and cognitive assessment via questionnaires. Studies tracking progression from MCI to Alzheimer's disease (AD) were retained, as they capture circadian changes across the MCI-to-dementia continuum. Studies that evaluated other sleep disorders and/or other conditions of cognitive impairment exclusively or that did not specify the mean age of the participants were excluded.<br><br>RESULTS: Ten studies were included, totaling 5,731 participants (5,707 eligible for analysis). Circadian exposures were organized into three domains: (1) actigraphic rest-activity rhythm metrics (amplitude, robustness, interdaily stability, intradaily variability, and acrophase); (2) sleep quality and architecture parameters (efficiency, fragmentation, latency, WASO, and melatonin timing); and (3) circadian-disrupting lifestyle exposures (rotating night shift work). Across these domains, circadian dysregulation was consistently associated with a higher risk of development or progression of MCI and dementia.<br><br>CONCLUSION: Circadian and sleep disturbances negatively impact cognitive health in the elderly, reinforcing the need for further research on this association and its public health implications.},
}
@article {pmid42458155,
year = {2026},
author = {Gupta, A and Vasundhara, M},
title = {Acetylcholinesterase inhibiting withanolides from Curvularia pseudobrachyspora, an endophytic fungus of Withania somnifera (L.) Dunal.},
journal = {Brazilian journal of microbiology : [publication of the Brazilian Society for Microbiology]},
volume = {57},
number = {1},
pages = {},
pmid = {42458155},
issn = {1678-4405},
mesh = {*Cholinesterase Inhibitors/chemistry/pharmacology/isolation &amp; purification/metabolism ; *Withania/microbiology ; *Acetylcholinesterase/metabolism/chemistry ; *Withanolides/chemistry/pharmacology/isolation &amp; purification/metabolism ; Antioxidants/chemistry/pharmacology ; *Endophytes/isolation &amp; purification/chemistry/metabolism/genetics/classification ; *Ascomycota/chemistry/isolation &amp; purification/metabolism/genetics/classification ; Inhibitory Concentration 50 ; Molecular Structure ; },
abstract = {Alzheimer's disease is the most prominent neurological illness, and the present investigation sets out to determine the impact of bioactive substances from endophytic fungi on acetylcholinesterase (AChE) inhibition. Medicinal plant Withania somnifera (L.) Dunal was used to isolate endophytic fungi, and WSE42 (out of 49 isolates) exhibited higher AChE inhibition (78.57%) and free radical scavenging activity (82.47%) in its methanolic crude extract. WSE42 was identified as Curvularia pseudobrachyspora (accession number-PP837926), and among all the fractions collected by column chromatography, two fractions (F3 and F4) exhibited potential for AChE inhibition with IC50 of 17.99 µg/ml and 19.91 µg/ml, respectively. These two fractions were found to show IC50 values in the range of 36-44 µg/ml for antioxidant potential. Structural elucidation studies revealed the compound to be 2,3-dihydrowithaferin A (F3) and withanolide Z (F4). Thus, this study ascertained the potential of withanolides as AChE inhibitors and antioxidant molecules that can play a key role in the management of Alzheimer's disease.},
}
@article {pmid42458180,
year = {2026},
author = {Bleher, D and Poxleitner, M and Grotegerd, AK and Hihn, O and Kuebler, L and Bowden, G and Schaller, M and Maier, FC and Weigelin, B and Pichler, BJ and Maurer, A and Herfert, K},
title = {Preclinical evaluation of [[18]F]fluoroethylresorufin as PET tracer for cerebral amyloid angiopathy.},
journal = {EJNMMI research},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13550-026-01470-4},
pmid = {42458180},
issn = {2191-219X},
abstract = {BACKGROUND: Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of β-amyloid (Aβ) in cerebral vessel walls, predominantly Aβ1-40, and frequently co-occurs with Alzheimer's disease (AD). Reliable in vivo discrimination between vascular and parenchymal Aβ deposits (PEA) in AD is crucial for the assessment of CAA-related risks in anti-Aβ immunotherapies. Current Aβ PET tracers lack the ability to distinguish between vascular and parenchymal Aβ. The phenoxazine derivatives resorufin and ethyl-resorufin were previously shown to bind preferably to CAA over PEA. We therefore evaluated the fluorine-18-labeled resorufin derivative, [[18]F]fluoroethylresorufin ([[18]F]FER) as a potential PET tracer for selective in vivo detection of vascular Aβ.<br><br>RESULTS: The binding specificity of [[3]H]FER was assessed using recombinant A&#x3b2;1-40 and A&#x3b2;1-42 fibrils as well as in vitro autoradiography on mouse brain tissue of APP23 (CAA+/PEA+) and APPPS1 (CAA-/PEA+) models, and compared to those of [[3]H]PIB. [[18]F]FER and its deuterated analog were synthesized for evaluation of brain pharmacokinetics, metabolism, and in vivo binding using PET imaging in wild-type, APPPS1, and APP23 mice. [[3]H]FER bound with higher affinity to A&#x3b2;1-40 (Kd = 9.4 nM) than to A&#x3b2;1-42 (Kd = 89.1 nM), consistent with its intended CAA selectivity. Autoradiography revealed preferential labeling of vascular amyloid in APP23 mice, with minimal binding in APPPS1 and wild-type tissue. In vivo, [[18]F]FER exhibited high brain uptake (peak SUV&#x2009;=&#x2009;1.5) and rapid clearance, but metabolic degradation was fast, with ~&#x2009;45% parent fraction remaining in the brain at 15&#xa0;min. Deuteration did not improve stability but did improve washout kinetics. PET imaging with (d4)-[[18]F]FER demonstrated a cortical uptake pattern similar to [[11]C]PIB, indicating non-selective binding in vivo.<br><br>CONCLUSIONS: [[18]F]FER showed promising in vitro affinity for vascular amyloid but lacked in vivo selectivity, likely due to rapid metabolism and high lipophilicity. These findings highlight the challenges of achieving in vivo CAA specificity and provide guidance for the optimization of future tracers targeting vascular A&#x3b2; pathology.},
}
@article {pmid42458498,
year = {2026},
author = {Wang, H and Wen, R and Parker, E and Yang, L},
title = {TREM2 in neurodegenerative diseases and acute neurological injuries: mechanisms to targeted therapies.},
journal = {Cell communication and signaling : CCS},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12964-026-03083-9},
pmid = {42458498},
issn = {1478-811X},
support = {32300959//National Natural Science Foundation of China/ ; SL2024A04J00578//Guangzhou Scientific Research Grant/ ; 22KJ04//SCNU Young Faculty Development Program/ ; },
abstract = {Triggering receptor expressed on myeloid cells 2 (TREM2) is a critical myeloid receptor expressed on the surface of central nervous system microglia, capable of integrating signals from lipids, damage-associated molecular patterns, and abnormal protein aggregates to regulate phagocytosis, metabolic adaptation, inflammatory remodeling, and pathology-associated responses. Accumulating evidence indicates that TREM2 is neither uniformly protective nor uniformly pathogenic; rather, its biological effects are highly context-dependent, governed collectively by disease stage, pathological substrates, cellular compartments, and the local microenvironment. By coupling with TYROBP/DAP12 or DAP10, TREM2 actively drives the state remodeling of pathology-associated microglia. It profoundly influences the onset and progression of neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS), as well as acute central nervous system injuries, including ischemic stroke, spinal cord injury (SCI), and traumatic brain injury (TBI). Concurrently, soluble TREM2 (sTREM2) holds significant potential not only as a biomarker but also as a context-dependent effector molecule actively participating in pathological regulation. This review synthesizes current advancements by focusing on four core themes: the structural and signaling logic of the TREM2 axis; its regulation of disease-associated microglia (DAM) remodeling; the cross-disease significance of sTREM2; and the mechanistic basis for the divergent outcomes observed with TREM2-targeted therapies across different experimental models and disease stages. The objective is to elucidate the context-dependent roles of TREM2 by analyzing consensus mechanisms, sources of discrepancy, and translational implications, thereby providing a theoretical framework and strategic direction for more precise TREM2-targeted interventions.},
}
@article {pmid42458598,
year = {2026},
author = {Giusti, V and Park, J and Giusto, E and Masatti, L and Ramos-Gonzalez, P and Iovino, L and Sandre, M and Emmi, A and Kaur, G and Coletto, E and Van Acker, ZP and Annaert, W and Calura, E and Petrelli, F and Porzionato, A and De Caro, R and Cavaliere, F and Chung, WS and Civiero, L},
title = {Atypical chemokine receptor 3 regulates synaptic removal in disease astrocytes.},
journal = {Molecular neurodegeneration},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13024-026-00976-8},
pmid = {42458598},
issn = {1750-1326},
support = {IBS-R025-A1//Ministry of Science and ICT, Republic of Korea/ ; GR-2016-02363461//Ministero della Salute/ ; },
abstract = {Astrocytes participate in the clearance of obsolete or unwanted neuronal synapses. However, the molecular machinery involved in synapse recognition remains unclear, particularly in pathological conditions. Here, we investigated the phagocytic process of astrocytes through individual gene silencing using a druggable gene library. Our study demonstrates that the Atypical chemokine receptor 3 (Ackr3) is a major player of astrocyte-mediated synapse engulfment. Mechanistically, we showed that Ackr3 recognizes phosphatidylethanolamine (PE)-bound C-X-C motif chemokine 12 (CXCL12) at synaptic terminals, thus serving as a novel marker of synaptic dysfunction. Notably, both ACKR3 and CXCL12 are upregulated in post-mortem brains of Alzheimer's disease (AD) patients, and AD mouse models. Genetic downregulation of Ackr3 in AD mice significantly reduces astrocyte-mediated synaptic elimination and rescues pathological phenotypes, including synapse loss and cognitive impairment. Overall, this work unveils a novel, possibly targetable mechanism of astrocyte-mediated synaptic engulfment implicated in neurodegenerative disease.},
}
@article {pmid42458615,
year = {2026},
author = {Wen, J and Lan, G and Fu, Y and Jiang, W and Xu, B and Zhang, J and , },
title = {Sequential associations of myelin dysfunction with Aβ and Tau pathology in Alzheimer's disease: a dynamic myelin perturbation.},
journal = {Alzheimer's research &amp; therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02139-9},
pmid = {42458615},
issn = {1758-9193},
abstract = {BACKGROUND: Myelin dysfunction has emerged as a potentially pivotal factor in Alzheimer's disease (AD); however, its temporal dynamics and relationship with hallmark pathological processes remain incompletely understood. This study aimed to investigate dynamic demyelination and its association with the progression of Aβ and Tau pathology in AD.<br><br>METHODS: A total of 1,237 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with 18F-florbetapir (FBP) PET imaging were included. White matter SUVR (WM SUVR), defined as the adjusted FBP signal in white matter, was used as a proxy measure of myelin integrity. Cross-sectional and longitudinal analyses were conducted to examine associations between WM SUVR and AD progression, as well as AD-related biomarkers. Using cortical A&#x3b2; accumulation as a temporal reference, we further evaluated two-year changes in cortical A&#x3b2; and cumulative Tau PET signals in individuals with and without reduced myelin integrity (WM&#x2009;-&#x2009;vs. WM&#x2009;+&#x2009;uptake).<br><br>RESULTS: WM SUVR demonstrated a gradual decline with advancing AD severity. Lower WM SUVR was associated with changes in A&#x3b2;42/40 and pTau181 levels in both cerebrospinal fluid (CSF) and plasma. In early-stage AD, the WM&#x2009;-&#x2009;group exhibited a higher two-year rate of cortical A&#x3b2; accumulation compared with the WM&#x2009;+&#x2009;uptake group. At comparable levels of cortical amyloid, the WM&#x2009;-&#x2009;group showed significantly higher Tau PET signals in temporal meta-regions of interest and more extensive cortical spread in later stages.<br><br>CONCLUSIONS: Progressive myelin dysfunction is observed across the course of AD as a notable perturbation within neurodegenerative processes. Early alterations in myelin integrity are associated with subsequent A&#x3b2; accumulation, whereas later changes coincide with increased Tau aggregation. These findings support a conceptual framework in which myelin degeneration shows temporally structured associations with AD pathology and may serve as a sensitive marker of vulnerability, particularly in early disease stages.},
}
@article {pmid42458616,
year = {2026},
author = {Muk, T and Wretlind, A and Hooshmand, K and Clos-Garcia, M and Liu, Y and Simonsen, AH and Winchester, LM and Ahluwalia, TS and Proitsi, P and Marioni, RE and Kümler, T and Hasselbalch, SG and Legido-Quigley, C and , },
title = {Steroid hormones in Alzheimer's disease: a molecular analysis of blood and cerebrospinal fluid.},
journal = {Alzheimer's research &amp; therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02117-1},
pmid = {42458616},
issn = {1758-9193},
support = {R344-2020-989//Lundbeck Fonden/ ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) disproportionately affects women, yet existing studies have been limited to single biofluids, individual hormones, or single dementia subtypes, leaving sex-stratified profiles across the cognitive impairment spectrum poorly defined. Here we address this gap by simultaneously quantifying nine steroid hormones spanning glucocorticoid (cortisol, 11-deoxycortisol), mineralocorticoid (aldosterone), progestogen (progesterone, 17-hydroxyprogesterone), androgen (testosterone, dihydrotestosterone), and estrogen (estradiol, estrone) pathways in paired CSF and plasma across five cognitive categories: no cognitive impairment, mild cognitive impairment (MCI) with AD pathology, MCI without AD pathology, AD dementia, and vascular dementia.<br><br>METHODS: Steroid hormones were quantified by liquid chromatography-tandem mass spectrometry in paired cerebrospinal fluid (CSF) and plasma samples drawn from the same individuals from a cross-sectional study including 204 participants across five cognitive categories at the Danish Dementia Research Centre. Gender-stratified generalized linear models adjusted for age were applied. Cortisol findings were validated externally using the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort (n&#x2009;=&#x2009;426).<br><br>RESULTS: Female participants with AD exhibited elevated CSF cortisol (fold change [FC]&#x2009;=&#x2009;1.13; P&#x2009;=&#x2009;.04) and CSF 11-deoxycortisol (FC&#x2009;=&#x2009;1.01; P&#x2009;=&#x2009;.03), alongside reduced plasma progesterone (FC&#x2009;=&#x2009;0.90; P&#x2009;=&#x2009;.04). Male participants with AD showed elevated plasma aldosterone (FC&#x2009;=&#x2009;1.19; P&#x2009;=&#x2009;2.81e-03; q&#x2009;=&#x2009;0.02). CSF cortisol correlated with amyloid-&#x3b2;42 and phosphorylated tau in female participants. ADNI validation confirmed elevated plasma cortisol in AD, with a larger effect in female participants.<br><br>CONCLUSIONS: Gender-dependent steroid hormone dysregulation in dementia highlights cortisol and aldosterone as potentially modifiable targets warranting further investigation.},
}
@article {pmid42458698,
year = {2026},
author = {Kim, JY and Park, HC and Park, SW and Rhee, CS},
title = {Sensory Impairment and Risk of Neurodegenerative Diseases: A Nationwide Cohort Study in Korea.},
journal = {Clinical and experimental otorhinolaryngology},
volume = {},
number = {},
pages = {},
doi = {10.21053/ceo.2026-00075},
pmid = {42458698},
issn = {1976-8710},
abstract = {OBJECTIVES.: Sensory impairments are common in older adults. However, their association with neurodegenerative diseases across multiple sensory domains remains unclear. This study aimed to investigate the associations between visual, hearing, and olfactory impairments and incident neurodegenerative diseases.<br><br>METHODS.: We analyzed data from the Korean National Health Insurance Service-Health Screening Cohort (2002-2015), excluding participants with pre-existing sensory impairment or neurodegenerative disease during a washout period (2002-2004). Sensory impairment was classified as visual, hearing, olfactory, or multisensory between 2005 and 2015. The outcomes were overall neurodegenerative diseases and their subtypes (Alzheimer's disease and related dementias, Parkinson's disease, and Huntington's and other neurodegenerative disorders). Kaplan-Meier curves and adjusted Cox models were used.<br><br>RESULTS.: Among the 410,749 participants, 389,659 were controls and 21,007 had sensory impairment (hearing, 16,651; olfactory, 642; visual, 3,426; multisensory, 288). The incidence differed by sensory status (log-rank p < 0.001) and was highest in multisensory impairment. Versus controls, multisensory impairment had the largest adjusted risk for overall neurodegenerative disease (Hazard ratio [HR] 5.23, 95% confidence interval [CI] 4.20-6.52) and across major disease subtypes (Alzheimer's disease, HR 4.43; Parkinson's disease, HR 5.07; and Huntington's and other neurodegenerative disorders, HR 9.90). In post hoc analyses using multisensory impairment as a reference, all single-sensory impairment groups showed significantly lower hazards.<br><br>CONCLUSION.: : Sensory impairment across the visual, hearing, and olfactory domains was associated with an increased risk of neurodegenerative 73 diseases, showing a graded pattern with a greater sensory burden. The sensory status may serve as an accessible early risk marker for neurodegenerative diseases in older adults.},
}
@article {pmid42458746,
year = {2026},
author = {Rankin, KP and Ulugut, H and Radke, A and Grossman, S and Poorzand, P and Shany-Ur, T and Kramer, JH and Rabinovici, GD and Seeley, WW and Rosen, HJ and Gorno-Tempini, ML and Possin, KL and Sturm, VE and Miller, BL},
title = {The Dynamic Affect Recognition Test: Construction and Validation in Neurodegenerative Syndromes.},
journal = {Assessment},
volume = {},
number = {},
pages = {10731911261457141},
doi = {10.1177/10731911261457141},
pmid = {42458746},
issn = {1552-3489},
abstract = {Practical, neurologically validated measures of emotion identification are still needed in the dementia field. The Dynamic Affect Recognition Test (DART) was designed to identify emotion reading deficits in persons with dementia (PWD). Participants included 257 early-stage PWD and 115 healthy controls (HC) who underwent DART and magnetic resonance imaging (MRI). DART performance was worse in PWD than in HC, with the lowest scores observed in the semantic behavioral variant of frontotemporal dementia (sbvFTD). DART showed strong diagnostic specificity (areas under the curve (AUCs) ≥82% comparing syndromes), with the highest performance distinguishing syndromes with prominent socioemotional impairment, particularly sbvFTD. DART performance was associated with other emotion identification measures and predicted real-world socioemotional sensitivity. Poorer DART performance predominantly correlated with focal atrophy in right-sided emotion processing areas, including the insula, temporal pole, and caudate head. The DART is a brief, clinically practical, video-based test of emotion identification designed for PWD that accurately reflects the neuroanatomy involved in emotion.},
}
@article {pmid42458794,
year = {2026},
author = {Chaturvedi, N and Mishra, V and Haque, S and Khatoon, S and Rawal, K and Kumar, V},
title = {Leveraging Advanced AI Frameworks for Dual PPAR α/γ Agonist Discovery in Alzheimer's Disease.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00148},
pmid = {42458794},
issn = {1948-7193},
abstract = {The dual activating potential of peroxisome proliferator-activated receptors (PPAR) α and γ offers a promising way to address metabolic issues, neuroinflammation, and protein balance in the development of Alzheimer's disease (AD). The current study intends to underscore the emerging importance of artificial intelligence (AI) in the accelerated discovery and optimization of dual PPAR α/γ modulators based on machine learning (ML), deep learning (DL), and generative modeling. The role of autonomous and agentic-AI systems in hypothesis generation, lead optimization, and closed-loop screening processes is highlighted. In addition, AI-enabled digital twin frameworks are emerging as powerful tools to integrate multiomics, neuroimaging, and clinical data for virtual modeling of disease progression and therapeutic response. Furthermore, the importance of explainable AI (XAI) in improving the interpretability and mechanistic insights of drug-receptor interaction models is underscored. Taken together, this review integrates recent studies illustrating the utility of AI-optimized dual PPAR α/γ agonists in enhancing lead selection, dose-response prediction, and therapeutic outcome prediction, thus bridging pharmacological computation and neuroimmune targeting for next-generation precision medicine approaches in AD therapy.},
}
@article {pmid42458948,
year = {2026},
author = {Huang, CX and Pan, Y and Xiao, H and Wang, JH and Liu, J},
title = {Cerebral Glucose Hypometabolism in Alzheimer's Disease: A Meta-Analysis and Transcriptomic-Neuroimaging Study.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050470646260624045159},
pmid = {42458948},
issn = {1875-5828},
abstract = {INTRODUCTION: Cerebral glucose hypometabolism is known to occur in Alzheimer's Disease (AD). However, the spatial pattern of these metabolic alterations remains inconsistent across studies, and the molecular mechanisms linking regional metabolic vulnerability to gene expression profiles are poorly understood, thus highlighting the neuroimaging-transcriptomics gap.<br><br>METHODS: We performed a coordinate-based meta-analysis of 18F-fluorodeoxyglucose positron emission tomography data from 17 studies. This involved 888 AD individuals and 529 healthy controls. Spatial correlation analysis of metabolic alterations and transcriptomic gene data from the Allen Human Brain Atlas was performed. Enrichment analysis was conducted to explore biological processes associated with the identified genes.<br><br>RESULTS: Compared with healthy controls, AD patients showed significant glucose hypometabolism in regions including the bilateral precuneus, median cingulate/paracingulate gyri, posterior cingulate gyri, angular gyri, inferior parietal gyri, supramarginal gyri, middle occipital gyri, middle temporal gyri, inferior temporal gyri, the left inferior frontal gyrus (triangular part), and anterior cingulate/ paracingulate gyrus. Spatial correlation analysis revealed that these changes were correlated with 2,701 genes. The identified genes were mainly involved in biological processes such as the DNA metabolic process, chromatin remodeling, chromatin/kinase binding, and mitochondrion organization.<br><br>DISCUSSION: The meta-analysis and transcriptomic-neuroimaging study revealed consistent patterns of brain metabolism and AD-associated gene sets. We also identified related biological processes. These results link microscale gene expression to macroscale glucose hypometabolism and offer new mechanism perspectives.<br><br>CONCLUSION: This study maps AD-related glucose hypometabolism to specific transcriptional profiles, providing novel insights into the molecular basis of metabolic alterations in AD.},
}
@article {pmid42458952,
year = {2026},
author = {Li, Y and Wei, Y and Zhao, J and Quan, P and Wang, C and Jiang, M},
title = {Syntaxin-4 at the Crossroads of Synaptic Plasticity and Neurodegeneration: From Molecular Mechanisms to Biomarker and Therapeutic Potential.},
journal = {CNS &amp; neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273465885260623094946},
pmid = {42458952},
issn = {1996-3181},
abstract = {Syntaxin-4 (Stx4), a member of the Qa-SNARE protein family, is a pivotal regulator of membrane trafficking. Stx4 is predominantly localized at the postsynaptic membrane of neurons and in glial cells, where it is essential for synaptic plasticity and the maintenance of neuronal homeostasis. Stx4 facilitates the activity-dependent exocytosis of glutamatergic receptors, thereby governing the balance between Long-Term Potentiation (LTP) and Long-Term Depression (LTD). Emerging evidence suggests that dysregulation of Stx4 is intricately linked to the pathogenesis of neurodegenerative diseases. In Alzheimer's disease, Stx4 is involved in synaptic dysfunction and cognitive impairment through its interactions with amyloid-β (Aβ) and tau pathologies, affecting receptor recruitment at dendritic spines. In Parkinson's Disease (PD), Stx4 contributes to α-synuclein proteostasis, dopaminergic signaling, neuroinflammation, and the maintenance of blood-brain barrier integrity. While its presence in cerebrospinal fluid highlights its potential as a candidate biomarker for these diseases, further validation is required to establish clinical utility. This review summarizes current mechanistic insights into Stx4's multifaceted roles in the neurodegenerative disorders and explores the therapeutic prospects of targeting Stx4-mediated pathways due to its translational potential.},
}
@article {pmid42458986,
year = {2026},
author = {Armenteros-Martínez, E and Chacón-Gordillo, P and Ortiz-Godoy, B and Morales-Caruncho, X},
title = {Photography as a medium for reflecting on Alzheimer's disease in vocational training in nursing care assistance.},
journal = {Arts &amp; health},
volume = {},
number = {},
pages = {1-17},
doi = {10.1080/17533015.2026.2702898},
pmid = {42458986},
issn = {1753-3023},
abstract = {BACKGROUND: Alzheimer's disease poses not only clinical but also profound emotional and relational challenges, requiring healthcare professionals to develop empathetic and communicative competences alongside technical skills. In vocational healthcare education, arts-based approaches may contribute to a more humanised understanding of the disease. This study explores the potential of photographic artistic creation as a tool for raising awareness and fostering reflective learning about Alzheimer's disease during the initial training of auxiliary nursing care professionals.<br><br>METHODS: A qualitative collective case study was conducted using an arts-informed research approach. Participants were 30 students enrolled in an Intermediate Vocational Training Programme in Auxiliary Nursing Care in southern Spain. Students engaged in a guided creative process involving photographic artworks reflecting different aspects of Alzheimer's disease. Data sources included the photographs, written reflective reports, participant observation, and an open-ended questionnaire. Visual and thematic analyses were undertaken.<br><br>RESULTS: The photographic artworks revealed that students were able to visually represent key cognitive, emotional, and social dimensions of Alzheimer's disease, including memory loss, disorientation, dependence, and affective suffering. The images also demonstrated sensitivity towards the lived experience of people with the disease. Most participants reported a positive perception of photography and art as resources for enhancing communication and empathy with patients.<br><br>CONCLUSIONS: The findings highlight the pedagogical and humanising value of photography within vocational healthcare education. Photographic artistic creation emerges as an effective reflective tool for developing professional competences related to empathy, communication, and holistic care in future auxiliary nursing care professionals working with people with Alzheimer's disease.},
}
@article {pmid42459054,
year = {2026},
author = {Kotan, S and Akan, A},
title = {Deep Model Families for EEG-Based Multi-Class Dementia Classification.},
journal = {International journal of neural systems},
volume = {},
number = {},
pages = {2750005},
doi = {10.1142/S0129065727500055},
pmid = {42459054},
issn = {1793-6462},
abstract = {Deep learning (DL) has shown considerable promise for EEG-based dementia assessment; however, rigorous cross-family comparisons under leakage-free and clinically meaningful evaluation protocols remain limited. To address this gap, we benchmarked twelve DL architectures from four major families - recurrent neural networks (RNNs), temporal convolutional networks (TCNs), Transformers, and self-supervised learning (SSL) - for the multi-class differentiation of Alzheimer's disease (AD), frontotemporal dementia (FTD), and healthy controls (HC). The analysis was conducted on a clinically acquired EEG dataset comprising 36 AD patients, 23 FTD patients, and 29[Formula: see text]HC participants. To prevent subject-level data leakage, we employed strict subject-independent five-fold cross-validation, and to improve clinical relevance, final predictions were aggregated at the subject level using majority voting across EEG segments. Model performance was evaluated using classification metrics, learning stability, statistical ranking, computational efficiency, and interpretability analysis. Among all benchmarked architectures, the self-supervised SimCLR-Time framework achieved the strongest subject-level performance, reaching a mean accuracy of [Formula: see text] and a weighted F1-score of [Formula: see text]. The time-series transformer (TST) was the best-performing fully supervised model, with an accuracy of [Formula: see text], followed closely by the hybrid LSTM-FCN model at [Formula: see text]. In contrast, the EEG-Seq2Seq model showed the weakest performance ([Formula: see text]). Computational profiling further showed that TCN-Attention offered a favorable trade-off between accuracy and edge-oriented efficiency, while SimCLR-Time combined strong diagnostic performance with the fastest inference latency. In addition, Integrated Gradients-based saliency analysis suggested that the top-performing model relied on structured spatiotemporal EEG patterns rather than arbitrary temporal artifacts. Overall, these findings provide a controlled within-dataset benchmark for multi-class dementia classification from raw EEG and suggest that self-supervised and attention-based architectures are promising directions for clinically oriented EEG decision-support systems. However, external validation on larger and more heterogeneous cohorts remains necessary before broader generalization can be claimed.},
}
@article {pmid42459068,
year = {2026},
author = {Nooreen, Z},
title = {A Comprehensive Review on Compounds and Herbal Approaches against Amyloid Beta Aggregation in Alzheimer's Disease.},
journal = {Central nervous system agents in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715249416202251209125536},
pmid = {42459068},
issn = {1875-6166},
abstract = {Alzheimer's disease is a neurodegenerative disorder that affects brain cells over time, progressively reducing cognitive function, interfering with memory retention, and making daily tasks more difficult. The development of amyloid-beta (Aβ) plaques plays an important role in the progression of the disease, contributing to neurological swelling and cognitive impairment. Aβ induces oxidative damage and produces anti-inflammatory cytokines while reducing the association with vascular RAGE and acetylcholine. This article aims to present the latest and relevant research on treatment approaches targeting amyloid beta, including synthetic compounds, phytomolecules, and plant extracts. Novel delivery approaches are also covered. Memantine, latrepirdine, somatostatin, diosgenin, cirsiliol, amentoflavone, luteoloside, and many other synthetic compounds have been reported to generally inhibit Aβ aggregation, thereby reducing plaque development. Phytomolecules such as brazilin, (+)-catechin, ginnalin A, bacoside-A, bakuchiol, curcumin, homotaurine, icariin, genistein, fucosterol, and quercitrin also alleviate symptoms via various mechanisms. Additionally, plant extracts from Annona atemoya, Lycium barbarum, Humulus lupulus, Oroxylum indicum, Salvia macilenta, Trichosanthis Semen, Camellia sinensis, Betula utilis, Cirsium japonicum, Elaeagnus glabra, Orthosiphon aristatus, Metasequoia glyptostroboides, Zizania latifolia, and Benincasa hispida are discussed briefly with their mechanisms of action. The present review also addresses the pathogenesis, risk factors, symptoms, and diagnosis of amyloid beta aggregation. Data were collected from PubMed, ScienceDirect, SciFinder, Scopus, and Google Scholar.},
}
@article {pmid42459087,
year = {2026},
author = {Zhao, D and Kong, W and Narengaowa, and Yu, H and Zhao, X and Hu, J and Zhao, J},
title = {Cathepsin B Deficiency Attenuates Tau Spreading via Modulation of Proteasome Activity in Neurons.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X469170260620084429},
pmid = {42459087},
issn = {1875-6190},
abstract = {INTRODUCTION: The stereotypical propagation of pathological tau aggregates is a defining feature of Alzheimer's disease (AD) and related tauopathies. While interneuronal tau spreading drives clinical progression, the specific molecular pathways governing tau secretion and its subsequent proteostasis remain elusive.<br><br>METHODS: We investigated the role of the cysteine protease Cathepsin B (CatB) using an adenoassociated virus (AAV)-mediated tau spreading mouse model. In parallel, an in vitro neuronal coculture system was employed to dissect the impact of CatB deficiency or pharmacological inhibition on tau secretion, uptake, lysosomal integrity, and proteasomal degradation.<br><br>RESULTS: CatB was significantly upregulated specifically in donor and recipient neurons during tau spreading, whereas it remained unchanged in microglia and astrocytes. Genetic deletion of CatB significantly reduced tau release from donor neurons without altering endocytic uptake in recipient neurons. Although CatB inhibition impaired lysosomal acidification, it paradoxically decreased tau propagation, potentially through a compensatory shift toward ubiquitin-proteasome systemmediated degradation, as observed in our in vitro models. This shift in the degradative axis effectively depleted the intracellular pool of tau available for secretion.<br><br>DISCUSSION: Our findings identify CatB as a critical neuronal regulator of the degradative balance governing tau spreading. We demonstrate that CatB deficiency limits tau propagation by shifting tau clearance toward the proteasome.<br><br>CONCLUSION: CatB is a strategic therapeutic target for mitigating tau-mediated neurotoxicity.},
}
@article {pmid42459149,
year = {2026},
author = {Panza, F and Dibello, V and Daniele, A and Lozupone, M},
title = {Do sigma-1 receptor agonists offer therapeutic promise for Alzheimer's disease?.},
journal = {Expert opinion on pharmacotherapy},
volume = {},
number = {},
pages = {},
doi = {10.1080/14656566.2026.2706070},
pmid = {42459149},
issn = {1744-7666},
abstract = {INTRODUCTION: Alzheimer's disease (AD) remains a major unmet medical need despite recent advances in amyloid-targeting therapies. The modest efficacy, safety concerns, and limited accessibility of monoclonal antibodies highlighted the need for alternative/complementary therapeutic strategies. The sigma-1 receptor (σ-1 R), a ligand-operated chaperone involved in cellular stress responses, has emerged as a promising target in neurodegeneration.<br><br>AREAS COVERED: The present Special Report provided a focused overview of &#x3c3;-1&#x2009;R agonists in AD, emphasizing their mechanistic role in modulating calcium homeostasis, mitochondrial function, autophagy, and neuroinflammation. We discussed clinical-stage compounds, including blarcamesine, evaluating their potential effects on both cognitive decline and neuropsychiatric symptoms. In addition, we highlighted emerging precision medicine approaches, including biomarker development and patient stratification.<br><br>EXPERT OPINION: &#x3c3;-1&#x2009;R agonists represented a novel therapeutic class that may enhance neuronal resilience rather than directly targeting specific pathological aggregates. This mechanism positions them as attractive candidates for combination strategies and for broader patient populations, including those ineligibles for biologic therapies. However, challenges remained, including incomplete understanding of receptor biology in aging and disease, variability in clinical response, and the need for robust biomarkers of target engagement. Future research should prioritize well-designed clinical trials and integrative biomarker strategies to define their role in AD treatment paradigms.},
}
@article {pmid42459361,
year = {2026},
author = {Huang, X and Zhang, M and Chen, F},
title = {Integrating anatomical priors and clinical semantics for MRI-based diagnosis and care support in Alzheimer's disease.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1852056},
pmid = {42459361},
issn = {1662-4548},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder, and magnetic resonance imaging (MRI) has become an important tool for its auxiliary diagnosis because it can reveal key structural abnormalities, including hippocampal and parahippocampal atrophy, ventricular enlargement, temporal cortical degeneration, and gray matter loss. However, reliable stage-aware classification remains challenging because current methods are still limited in handling weak anatomical boundaries, low-contrast lesions, subtle inter-stage differences, and the semantic gap between neuroimaging features and clinical descriptions. To address these issues, we propose AFCG-Net, a diagnosis-guided and frequency-aware cross-modal network for joint MRI-text diagnosis. The framework consists of three stages: anatomy-guided visual encoding, cross-modal semantic alignment, and gated fusion with anatomical priors. Specifically, ASFG enhances visual representations through multi-scale modeling and low frequency-guided refinement, CASF strengthens the consistency between clinical semantics and imaging features, and AGDF performs anatomy-guided deep fusion to improve both discriminability and interpretability. Experiments on a combined cohort of 4,197 original MRI-text samples, including 2,106 self-collected samples and 2,091 ADNI samples, show that AFCG-Net achieves Precision, Recall, and F-score values of 96.3%, 96.5%, and 95.8%, respectively. The proposed method achieves the best results in the Mild dementia and Moderate dementia categories, while also showing stronger performance in the more challenging Non-dementia and Very Mild dementia categories. These results suggest that AFCG-Net provides an effective and interpretable multimodal solution for AD-assisted diagnosis.},
}
@article {pmid42459412,
year = {2026},
author = {Babu, D and Ramanathan, P and Patel, S},
title = {Biogenic selenium nanoparticles: a multifunctional tool for combating oxidative stress and chronic diseases.},
journal = {3 Biotech},
volume = {16},
number = {8},
pages = {327},
pmid = {42459412},
issn = {2190-572X},
abstract = {Selenium nanoparticles (SeNPs) have attracted considerable attention, as they demonstrate high biocompatibility, the potential to regulate the redox state, and a strong antioxidant effect. Compared to traditional selenium supplements, SeNPs have low toxicity levels but retain their therapeutic value in treating oxidative stress and related chronic diseases. This review contains detailed discussions of the methods of SeNP synthesis, including physical, chemical, and biological methods, especially toward the green approaches of SeNP synthesis using plants and microbes. Moreover, the article discusses the wide biomedical uses of SeNPs, such as their application in diabetes, Alzheimer's disease, cancer, and polycystic ovary syndrome (PCOS). Mechanistically, SeNPs reduce oxidative stress, alter apoptotic molecules, and improve the action of chemotherapeutic agents including doxorubicin, cisplatin, and paclitaxel, while also exhibiting activity against multidrug-resistant microorganisms including methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, and Klebsiella pneumoniae. They also have the potential to be used in nanomedicine because they can serve as specific drug carriers. Further studies are needed to establish uniform synthesis procedures and to assess long-term safety in preparation of clinical translation. Although there has been an increasing literature on the synthesis of biogenic SeNPs and their biomedical uses, there are still some areas of knowledge gaps. The comparative analysis of physicochemical characteristics of different synthesis methods (such as particle size, yield, stability, and repeatability) based on downstream therapeutics has never been conducted in the past literature. In addition, other key selenoproteins, i.e., thioredoxin reductase (TRxR) and glutathione peroxidase 4 (GPx4), as possible neuroprotectants of SeNPs have not been adequately examined in the literature. In order to address these gaps, this review provides a synthesis of the available information on biogenic SeNPs, especially how it works, critically evaluating its pharmacological efficacy and translational maturity in these unexplored fields.},
}
@article {pmid42459522,
year = {2024},
author = {Westfall, HA and Lee, MD},
title = {An Extension and Clinical Application of the SIMPLE Model to the Free Recall of Repeated and Semantically Related Items: Extending the SIMPLE Model of Memory.},
journal = {Computational brain &amp; behavior},
volume = {7},
number = {1},
pages = {65-79},
pmid = {42459522},
issn = {2522-087X},
abstract = {A task used in clinical settings to assess memory is a surprise free recall of animal names originally encountered as part of an earlier triadic comparison task. Modeling the free recall is challenging, because learning occurs incidentally, items are presented multiple times, and the items have semantic relationships to each other. To address this challenge, we extend the SIMPLE (Brown et al., 2007) model of memory, which assumes to-be-remembered items are stored as separate logarithmically-compressed temporal traces. The ability to retrieve these traces depends on the acuity of memory probes and the semantic similarity between the items represented by the traces. We apply this model to a real-world clinical data set including healthy controls, people with mild cognitive impairment, and people with Alzheimer's dementia. We find that the groups with memory impairment have worse temporal acuity and make less use of semantic information.},
}
@article {pmid42459525,
year = {2026},
author = {Majumdar, S and Samaiya, PK and Ahmed, S and Prajapati, SK},
title = {Imaging biomarkers in neurodegenerative diseases: advances and challenges.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1813588},
pmid = {42459525},
issn = {1663-4365},
abstract = {Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), represent a major global health burden. Imaging biomarkers have emerged as important tools for improving the diagnosis, monitoring, and biological characterization of neurodegenerative diseases. Structural MRI, diffusion tensor imaging (DTI), functional MRI (fMRI), positron emission tomography (PET), hybrid PET/MRI and molecular imaging have transformed our ability to investigate neurodegeneration in vivo non-invasively. This review highlights updated information on how each imaging modality offers a unique window into different disease pathophysiology including regional atrophy, amyloid-β, tau, dopaminergic terminal degeneration, synaptic density (SV2A), and neuroinflammation. We also focused on the translational and evidence supporting biomarkers, appropriate use criteria for amyloid and tau PET imaging, and standardized quantification methods such as the Centiloid scale. The growing role of multimodal fusion, where imaging is increasingly integrated with scalable fluid biomarkers to enable "blood-first" strategies where high-risk patients are selectively referred to advanced imaging, improving feasibility and equity. Despite tremendous progress, there are still issues with their standardization, sensitivity, specificity, and clinical translation. Moreover, the review emphasizes the frontiers of α-synuclein and glial state-specific PET ligands, advanced diffusion models, and dynamic connectivity analysis to support precision medicine and mechanism-based trial design for NDDs.},
}
@article {pmid42459526,
year = {2026},
author = {Cai, M and Lei, H and Zhang, Y and Zou, J and Cao, W and Wang, Y and Wei, K},
title = {APOE ε4-associated hippocampal atrophy trajectories across the Alzheimer's disease continuum: a systematic review, meta-analysis, and longitudinal validation.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1847611},
pmid = {42459526},
issn = {1663-4365},
abstract = {BACKGROUND: Predicting patient-specific neurodegenerative trajectories is essential for targeted interventions in Alzheimer's disease. Although the APOE-ε4 allele is the predominant genetic risk factor for hippocampal atrophy, whether its structural impact reflects a static developmental phenotype or an accelerated neurodegenerative process conditional on amyloid pathology remains unresolved.<br><br>OBJECTIVES: To quantify the effect of APOE-&#x3b5;4 on hippocampal volume via cross-sectional meta-analysis, and to validate the gene-dose effect through independent longitudinal modeling in two cohorts.<br><br>ELIGIBILITY CRITERIA: Original observational neuroimaging studies reporting hippocampal volume stratified by APOE genotype in human participants across the Alzheimer's disease continuum.<br><br>INFORMATION SOURCES: PubMed, Embase, Web of Science, and Cochrane Library were searched from inception to August 2025.<br><br>RISK OF BIAS: Methodological quality was assessed using the Newcastle-Ottawa Scale (NOS) adapted for cross-sectional studies.<br><br>The meta-analysis included 18 studies (N = 4, 311) and indicated reduced hippocampal volume in carriers (ICV-corrected stratum: SMD = -0.41, 95% CI [-0.67, -0.16], p = 0.004; I [2] = 74.0%), with the effect absent in uncorrected analyses. Longitudinal gene-dose models, run independently in the post-QC NACC LMM sample (N = 3, 239; imaging extraction N = 3, 248) and ADNI (N = 1, 150) cohorts and combined via fixed-effect meta-analysis, demonstrated a dose-dependent acceleration of hippocampal atrophy: homozygotes exhibited a pooled additional volume loss of -58.25 mm[3]/year (95% CI [-89.26, -27.23], p = 2.33 &#xd7; 10[-4]; I [2] = 0%) and heterozygotes -34.32 mm[3]/year (95% CI [-52.31, -16.32], p = 1.85 &#xd7; 10[-4]) relative to non-carriers.<br><br>LIMITATIONS: Biomarker-stratified analyses used baseline-only CSF measurements subject to time-varying confounding and should be interpreted as exploratory. Moderate between-cohort heterogeneity was observed for the heterozygote effect (I [2] = 63.0%).<br><br>CONCLUSIONS AND IMPLICATIONS: These findings provide two-cohort evidence for a dose-dependent APOE-&#x3b5;4 effect on hippocampal atrophy rates. Exploratory biomarker-stratified analyses in ADNI suggest this acceleration may be conditional on amyloid-&#x3b2; positivity, a hypothesis requiring validation with time-varying causal models.<br><br>https://www.crd.york.ac.uk/PROSPERO/view/CRD420251243460, PROSPERO: CRD420251243460.},
}
@article {pmid42459527,
year = {2026},
author = {Shi, J and Li, X and Guan, L and Sun, Y},
title = {Transcranial direct current stimulation to improve cognitive function in patients with vascular cognitive impairment: a literature review.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1829594},
pmid = {42459527},
issn = {1663-4365},
abstract = {Vascular pathology represents the second most common cause of cognitive impairment after Alzheimer's disease and contributes substantially to mixed dementia involving both vascular and neurodegenerative mechanisms. Vascular cognitive impairment (VCI) emerges as a term encompassing cognitive impairments resulting from stroke, cerebral small vessel disease (CSVD), or other forms of vascular pathology. While numerous studies have demonstrated the beneficial effects of transcranial direct current stimulation (tDCS) on mild cognitive impairment and dementia, evidence specifically addressing its efficacy in VCI remains limited. We conducted a structured narrative review to summarize the effects of tDCS on cognitive rehabilitation in individuals with VCI. Studies were included if participants had cognitive impairment related to vascular pathology and if cognitive severity ranged from mild cognitive impairment to dementia. Eighteen studies met the inclusion criteria. Among the included studies, 15 were conducted in post-stroke cognitive impairment (PSCI) populations, whereas only three studies focused on non-stroke VCI. Across the included studies, tDCS has demonstrated promising effects on global cognition and executive function in PSCI populations. Combining tDCS with cognitive or motor rehabilitation appeared to further facilitate cognitive recovery in PSCI populations. Neuroimaging and EEG findings suggest that tDCS may be associated with cognitive improvement through potential modulation of cortical excitability, neural oscillatory activity, and functional connectivity. In addition, preliminary evidence suggests tDCS may have the potential to modulate cerebral blood flow, indicating a potential modulatory effect on neurovascular coupling. However, most available studies were conducted in patients with PSCI, with insufficient evidence in non-stroke VCI populations related to CSVD. Furthermore, the neurophysiological mechanisms by which tDCS modulates vascular and cognitive function remain poorly understood, warranting further investigation in future studies.},
}
@article {pmid42459754,
year = {2026},
author = {Meyer-Tönnies, MJ and Schwarz, L and Wucherer, D and Hoffmann, W and Thyrian, JR and Tzvetkov, MV},
title = {Pharmacogenetic analyses in people with dementia in Northeast Germany.},
journal = {Alzheimer's &amp; dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70423},
pmid = {42459754},
issn = {2352-8729},
abstract = {INTRODUCTION: Pharmacogenetics-guided prescribing may reduce adverse drug reactions by 30%. European and American expert groups (Dutch Pharmacogenetics Working Group and Clinical Implementation Consortium) issue genotype-based dosage recommendations, but pharmacogenetic testing is still not routinely used. Here, we assess the potential of pharmacogenetic testing to optimize pharmacotherapy in people with dementia (PwD).<br><br>METHODS: We genotyped variants in CYP2D6 , CYP2C9, CYP2C19, CYP3A4, CYP3A5, and SLCO1B1 genes and related them to individual medication data in 115 PwD from an epidemiological cohort from Northeast Germany.<br><br>RESULTS: The vast majority of PwD (93%) carried at least one actionable variant. Fourteen (12%) had at least one strongly actionable variant. Four of them (4%) took the drug affected and carried the strongly actionable genetic variant.<br><br>DISCUSSION: Pharmacogenetic testing may contribute to improved pharmacotherapy in PwD. The potential improvements were mainly for medications commonly taken by elderly, but also for medications used to treat or associated with progression of dementia.},
}
@article {pmid42459766,
year = {2026},
author = {Karthik, V and Hosangadi, M and Kudale, S and Umakanthan, OC},
title = {AI-driven drug discovery using transformer-based molecular representation learning.},
journal = {Frontiers in artificial intelligence},
volume = {9},
number = {},
pages = {1807340},
pmid = {42459766},
issn = {2624-8212},
abstract = {The vast majority of chemically plausible, drug-like molecules remain unexplored due to the combinatorial scale of chemical space and the limited throughput of experimental screening. This is complicated by the lack of data and the inability to extrapolate predictive models to chemotypes that are not represented well. We introduce a transformer-based molecular modeling framework for target-specific potency prediction, trained on curated BindingDB bioactivity data across Alzheimer's, diabetes, and cancer targets to deliver accurate pIC50 regression and binary activity classification. It uses curated bioactivity data from BindingDB to build target-specific datasets and uses a Byte Latent Transformer (BLT) that is trained directly on SMILES strings to predict changes in compound activity and potency based on quantitative structure-activity relationships. The transformer captures both syntactic and higher-level chemical features of SMILES representations and performs byte-level predictions using a latent model trained on the same molecular information. Potency predictions are executed inside an engine of chemically described molecular search engine, which executes stochasticity, SMILES-based amount mutations benefit by the envisaged activity, drug-like rules, and adaptive seeking heuristics to prevent local minima. Optimized candidate molecules and local optima are generated through guided SMILES mutations, preserving structural diversity around high-potency leads. The framework delivers highly accurate pIC50 regression (R [2] 0.95-0.98) and binary activity classification across Alzheimer's, diabetes, and cancer targets, enabling robust virtual screening and lead prioritization for diverse biological targets.},
}
@article {pmid42459797,
year = {2026},
author = {Hung, IY and Wang, WT and Liu, PH and Cheng, WJ},
title = {Magnesium deficiency and long-term incident dementia among COVID-19 survivors: a propensity score-matched cohort study.},
journal = {Frontiers in nutrition},
volume = {13},
number = {},
pages = {1871623},
pmid = {42459797},
issn = {2296-861X},
abstract = {BACKGROUND: COVID-19 survivors face an elevated risk of long-term cognitive decline, yet potentially modifiable factors that shape post-COVID dementia trajectories remain insufficiently characterized. Low magnesium status has been linked to dementia risk in general populations, but whether low magnesium status is associated with long-term dementia risk among COVID-19 survivors remains unclear.<br><br>METHODS: This propensity score-matched retrospective cohort study used the TriNetX Global Collaborative Network to examine the association between low serum magnesium (< 1.7 mg/dL on two measurements) and incident dementia among hospitalized COVID-19 survivors aged &#x2265; 55 years (2020-2023). A 1-year landmark period was imposed to reinforce temporal separation between exposure and outcome. The primary outcome was overall incident dementia over 5 years. Secondary outcomes included Alzheimer's disease, vascular dementia, other dementia types, and mild cognitive impairment.<br><br>RESULTS: After matching, 58,991 patients with low magnesium and 58,991 controls were included. Magnesium deficiency was associated with a higher risk of overall dementia [2.12% vs. 1.77%; hazard ratio (HR) 1.39, 95% confidence interval (CI) 1.28-1.51; P < 0.001; E-value 2.13). Among secondary outcomes, low magnesium was associated with higher risks of Alzheimer's disease (HR 1.34; P = 0.005), vascular dementia (HR 1.50; P = 0.001), other dementia types (HR 1.38; P < 0.001), and mild cognitive impairment (HR 1.27; P < 0.001). The association between magnesium deficiency and overall incident dementia persisted across sensitivity analyses and sex-stratified subgroups.<br><br>CONCLUSION: In this observational study, low serum magnesium was associated with increased long-term dementia risk among COVID-19 survivors. Because eligibility required repeated magnesium testing and follow-up healthcare visits were marginally more frequent in the low-magnesium group, selection bias and differential dementia detection cannot be excluded. These hypothesis-generating findings warrant prospective validation.},
}
@article {pmid42459803,
year = {2026},
author = {Sandes, SHC and Amorim-Neto, DP},
title = {Editorial: Beyond the plate: the role of diet and the microbiota-gut-brain axis in neurodegenerative diseases.},
journal = {Frontiers in nutrition},
volume = {13},
number = {},
pages = {1894989},
doi = {10.3389/fnut.2026.1894989},
pmid = {42459803},
issn = {2296-861X},
}
@article {pmid42459821,
year = {2026},
author = {Campbell, LM and Aghamoosa, S and Horn, O and Fleischmann, HH and Lopez, J and Rbeiz, KS and Madden, K and Antonucci, M and Revuelta, G and McTeague, LM and Benitez, A},
title = {Feasibility of Interleaving Computerized Cognitive Training With Repetitive Transcranial Magnetic Stimulation: Pilot Studies in Mild Cognitive Impairment Due to Alzheimer's Disease and Stroke.},
journal = {JMIR neurotechnology},
volume = {5},
number = {},
pages = {e81437},
pmid = {42459821},
issn = {2817-092X},
abstract = {BACKGROUND: Repetitive transcranial magnetic stimulation induces neural plasticity, which may be maximized via adjunctive interventions.<br><br>OBJECTIVE: This study aimed to examine the feasibility and acceptability of interleaving computerized cognitive training (CCT) with accelerated intermittent theta burst (iTBS) repetitive transcranial magnetic stimulation in 2 open-label phase I trials of amnestic mild cognitive impairment (aMCI; NCT04503096) and poststroke mild cognitive impairment (psMCI; NCT04655963).<br><br>METHODS: Participants (aMCI: n=21; and psMCI: n=14) received 24 sessions of accelerated iTBS over 3 days (8 sessions per day). During the 10- to 15-minute intervals between iTBS sessions, participants engaged in CCT via the BrainHQ platform. During the 4-week follow-up period, participants were asked to complete 20 minutes daily of BrainHQ. Both studies offered identical compensation for daily practice, but the aMCI group received weekly reminders, whereas the psMCI group did not. Study-specific questionnaires assessed BrainHQ acceptability (administered post-treatment and at follow-up).<br><br>RESULTS: During in-laboratory treatment, the groups completed similar amounts of BrainHQ (aMCI: median 107, IQR 92-121 min; and psMCI: median 111, IQR 93-137 min; P=.51). However, engagement differed during the unmonitored follow-up (aMCI: median 450, IQR 167-581 min,; and psMCI: median 142, IQR 0-477 min); practice time increased in the aMCI group but decreased in the psMCI group over the 4 weeks (P=.001). Both groups generally rated BrainHQ positively at both time points in terms of their experience with the platform, exercises, and perceived benefit for their mood and functioning.<br><br>CONCLUSIONS: Combined treatment with CCT and accelerated iTBS is feasible and acceptable in people with mild cognitive impairment. Standardized dosing of CCT is feasibly achieved when interleaved with iTBS sessions and completed in-laboratory, but ecological adherence to CCT in an unmonitored, self-directed context likely requires additional supports and may be influenced by patient characteristics.},
}
@article {pmid42459872,
year = {2026},
author = {Munawwar, R and Sarfaraz, S and Ikram, R and Anser, H},
title = {The Therapeutic Potential of Phaseolus vulgaris in Alzheimer's Disease: Insights From Experimental Rodent Model.},
journal = {Scientifica},
volume = {2026},
number = {},
pages = {6739059},
pmid = {42459872},
issn = {2090-908X},
abstract = {Alzheimer's disease (AD) is a devastating neurological ailment affecting millions of people worldwide. For this neurological disease, there are numerous pharmacological and supportive treatments available. Several organic products are currently being investigated for AD. In a recent study, a variety of methods were used to conduct research and evaluate this advantageous effect, including passive avoidance tests, histopathology, biogenic amine assessment, and GC-MS analysis. For this study, three groups were made of albino rats of both genders. Group I was the negative control group (administered standard diet), Group II was treated with 500 mg/kg beans, and Group III was given 1000 mg/kg. All three groups were induced Alzheimer's by giving 2.5 mg/kg diazepam prior to the start of the treatment. The results showed that a significantly higher dosage level of 1000 mg/kg was most effective at preventing dementia in AD-induced rats as compared to the lower dose evaluated. Passive avoidance tests, GC-MS analysis, which revealed acetylcholine activity and other beneficial compounds like squalene, isoglutamine, and pyrrolizine, as well as histopathological analysis, all supported the effectiveness of this nutritional option. The findings unmistakably demonstrated that 1000 mg/kg red beans are very helpful in reducing dementia in AD-induced rats.},
}
@article {pmid42459904,
year = {2024},
author = {Bozyel, R and Barut, BO and Madenci, OC},
title = {The relationship between the diagnostic value of salivary cortisol levels and behavioral symptoms in patients with Alzheimer's disease.},
journal = {Dusunen adam : Bakirkoy Ruh ve Sinir Hastaliklari Hastanesi yayin organi},
volume = {37},
number = {1},
pages = {34-43},
pmid = {42459904},
issn = {1309-5749},
abstract = {OBJECTIVE: Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and elevated cortisol levels are frequently observed in Alzheimer's disease (AD) patients. This study aimed to explore the potential use of saliva cortisol levels as an early marker for the initial clinical stages of AD and to investigate the correlation between saliva cortisol levels and behavioral symptoms in AD patients.<br><br>METHOD: The sample included 81 participants of similar ages: AD patients (n=30), individuals with subjective memory loss (SML) (n=31), and a healthy control group (n=20). Saliva samples were collected at 08:00 and 16:00, and cortisol levels were compared across these groups. The Mini-Mental State Examination (MMSE), adjusted for educational level, was administered to all participants. The SML and healthy groups completed the Subjective Memory Complaints Questionnaire (SMCQ) and the Geriatric Depression Scale (GDS). Caregivers of AD patients were interviewed using the Neuropsychiatric Inventory (NPI) to assess the relationship between cortisol levels and behavioral symptoms in AD patients.<br><br>RESULTS: Evening cortisol levels in the AD group were significantly higher than those in the SML group (p<0.001). However, when examining salivary cortisol levels, no significant differences were detected between the SML group and the healthy controls. A negative correlation was found between salivary cortisol levels and MMSE scores in AD patients. Additionally, a positive correlation was observed between evening cortisol levels and several items in the NPI among AD patients.<br><br>CONCLUSION: Although no significant changes in salivary cortisol levels were found in the SML group, which does not support its use as an early indicator of AD, the results suggest that the HPA axis may be a cause of behavioral problems, particularly in patients with severe AD.},
}
@article {pmid42460153,
year = {2026},
author = {Zhang, Y and Zhang, Z and Qiu, S and Hu, Y},
title = {Disease-predominant loci across Alzheimer's disease, Parkinson's disease and Lewy body dementia: evidence from the UK Biobank prospective cohort, conditional GWAS and colocalization.},
journal = {Frontiers in genetics},
volume = {17},
number = {},
pages = {1865257},
pmid = {42460153},
issn = {1664-8021},
abstract = {BACKGROUND: Alzheimer's disease (AD), Parkinson's disease (PD) and Lewy body dementia (LBD) overlap clinically, pathologically and genetically, complicating interpretation of cross-disorder genome-wide association study (GWAS) signals.<br><br>METHODS: We analysed 322,963 UK Biobank participants with bidirectional time-varying Cox models, one-year and two-year lag analyses, and competing-risk sensitivity models to quantify AD-PD clinical co-occurrence. We then analysed European-ancestry AD, PD and LBD GWAS summary statistics using linkage disequilibrium score regression (LDSC), GCTA-mtCOJO/GSMR, MAGMA, stratified LDSC, brain eQTL/mQTL SMR with HEIDI filtering, and Bayesian colocalization for selected methylation probes. Conditional loci were compared with original GWAS loci to separate shared liability from retained disorder-predominant associations.<br><br>RESULTS: PD was associated with subsequent AD (fully adjusted HR 2.27, 95% CI 1.94-2.65; P = 6.40E-25), and AD was associated with subsequent PD (HR 3.14, 95% CI 2.56-3.85; P = 2.10E-28). Lag and competing-risk sensitivity analyses remained concordant. LDSC estimated positive genetic correlations for AD-PD (rg = 0.20; P = 0.0086) and PD-LBD (rg = 0.61; P = 0.0005). Conditioning reduced genome-wide significant loci from 14 to 9 for AD, from 24 to 21 for PD and from 5 to 2 for LBD. Retained loci included AD signals near CR1, BIN1, CLU, SPI1, MS4A, PICALM, ABCA7 and APOE; PD signals near GBA, NUCKS1, TMEM163, STK39, GAK/TMEM175, BST1, SNCA, LRRK2, MAPT and RIT2; and LBD signals near SNCA/MMRN1 and APOE. MAGMA and S-LDSC highlighted amyloid, lipid, immune, synaptic-vesicle and brain-tissue enrichment patterns. Brain QTL analyses prioritized retained eQTL and mQTL signals, and colocalization supported shared PD-GWAS/mQTL signals at HLA-DRB5, ARHGAP27, CRHR1, MAPT and KANSL1.<br><br>CONCLUSION: AD and PD show bidirectional clinical co-occurrence, whereas conditional genetic analyses retain a smaller set of disease-predominant loci and regulatory signals across AD, PD and LBD. These findings refine cross-disorder interpretation and nominate loci for independent genetic and functional validation.},
}
@article {pmid42460155,
year = {2026},
author = {Gharbi, A and Sghaier, I and El Habibi, M and Abida, Y and Souissi, A and Atrous, A and Zantour, M and Kacem, I and Gargouri Berrechid, A and Ben Djebara, M and Gouider, R},
title = {Clinical and neuropsychological profile of Alzheimer's disease in Tunisia and the impact of APOE gene.},
journal = {Frontiers in genetics},
volume = {17},
number = {},
pages = {1831886},
pmid = {42460155},
issn = {1664-8021},
abstract = {INTRODUCTION: Alzheimer's disease (AD), the leading cause of major neurocognitive disorder (MNCD) worldwide and in Tunisia, is strongly associated with Apolipoprotein E (APOE). In the present study our aims are to characterize the clinical profile of Tunisian patients, determine APOE allelic and genotypic frequencies, and asses their influence on disease phenotype.<br><br>METHODS: We included patients with a clinical diagnosis of probable or possible AD, who consulted in the Department of Neurology at Razi University Hospital over a span of 21&#xa0;years. Demographic, clinical, and neuropsychological data were assessed. APOE genotyping was performed and its correlation to AD clinical features was evaluated.<br><br>RESULTS: Among 1,010 AD patients, the sex ratio was 0.62, with a mean age at onset of 68.9 &#xb1; 9.8&#xa0;years. Consanguinity was reported in 30.2% of cases, and a family history of major neurocognitive disorder in 65.3%. The mean Mini-Mental State Examination (MMSE) and Frontal Assessment Battery (FAB) scores were 14.1 &#xb1; 7.7 and 6.5 &#xb1; 4.8, respectively. Overall, 47.0% of patients carried the APOE &#x3b5;4 allele. The APOE &#x3b5;3/&#x3b5;3 genotype was the most frequent (45.94%), followed by APOE &#x3b5;3/&#x3b5;4 (40.99%). Age at onset was significantly earlier in APOE &#x3b5;4 carriers compared to non-carriers (68.17 &#xb1; 10.05 vs. 69.53 &#xb1; 9.61&#xa0;years; p = 0.027). Baseline cognitive performance was also significantly lower in APOE &#x3b5;4 carriers, with reduced MMSE (11.65 &#xb1; 6.77 vs. 16.40 &#xb1; 7.85; p < 0.001) and FAB scores (5.46 &#xb1; 4.09 vs. 7.35 &#xb1; 5.11; p < 0.001). Neuropsychiatric assessment revealed significant associations between APOE &#x3b5;4 carriage and visual hallucinations (p = 0.0015), aggressivity (p = 0.0022), disinhibition (p = 0.0039), and aberrant motor behavior (p = 0.0054). Finally, stratified analysis of the AD cohort according to educational attainment and APOE risk allele status demonstrated distinct patterns of cognitive impairment across the different subgroups.<br><br>DISCUSSION: The APOE &#x3b5;4 allele, frequent in North African AD, appears to function not only as a genetic risk factor for AD, but also as a potential indicator, influencing disease onset and clinical severity.},
}
@article {pmid42460246,
year = {2026},
author = {Esmailzadeh, A and Norouzkhani, N and Sezavar Dokhtfaroughi, S and Rasoulian, A and Mazaheri Habibi, MR},
title = {Wearable Electronic Devices for Alzheimer's Disease Care: A Systematic Review of Applications, Benefits, and Challenges.},
journal = {Health science reports},
volume = {9},
number = {7},
pages = {e72806},
pmid = {42460246},
issn = {2398-8835},
abstract = {BACKGROUND AND AIMS: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, behavioral disturbances, and loss of functional independence. As the global prevalence of AD continues to rise, traditional episodic care models are increasingly inadequate for providing continuous and individualized support. Wearable electronic devices offer a potential alternative by enabling non-invasive, real-time monitoring in everyday settings. This systematic review synthesizes current evidence on the applications, reported outcomes, and implementation challenges of wearable and wearable-adjacent technologies in AD care.<br><br>METHODS: A systematic literature search was conducted in September 2025 across five databases: PubMed, Scopus, Web of Science, Cochrane Library, and Google Scholar, using keywords and MeSH terms related to wearable electronic devices, smart glasses, smartwatches, and Alzheimer's disease. The review protocol was prospectively registered in PROSPERO (CRD420251158703). Two independent reviewers screened records and extracted data in accordance with PRISMA 2020 guidelines. Methodological quality was assessed using a validated 10-item appraisal tool.<br><br>RESULTS: Of 1399 identified records, ten studies met the eligibility criteria. For structured synthesis, the included technologies were organized into four architectural categories: body area network-based sensor systems, augmented reality smart glasses, hybrid wearable-mobile platforms, and wearable-adjacent assistive technologies. Across studies, the included technologies were applied to physiological monitoring, mobility and gait assessment, cognitive and spatial support, and caregiver communication. Findings suggest preliminary feasibility across these domains; however, small sample sizes, heterogeneous outcome measures, and predominantly early-phase study designs limit the strength of available evidence.<br><br>CONCLUSION: Current evidence suggests that wearable and wearable-adjacent technologies may contribute to multiple aspects of AD care, particularly in home-based settings. Translation into routine practice requires prospective, adequately powered studies with standardized outcome frameworks, alongside regulatory alignment and patient-caregiver co-design to address persistent usability barriers.},
}
@article {pmid42460524,
year = {2026},
author = {Cai, X and Bai, Y and Ma, F and Xu, R and Xie, Y and Cao, X},
title = {Mechanisms and Therapeutic Targeting of the cGAS-STING Pathway in Central Nervous System Disorders.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X472988260627201746},
pmid = {42460524},
issn = {1875-6190},
abstract = {OBJECTIVE: The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway is a core DNA-sensing axis in innate immunity and has been increasingly implicated in the pathogenesis of multiple Central Nervous System (CNS) disorders. This review summarizes current knowledge of cGAS-STING signaling in CNS disorders and evaluates its therapeutic potential.<br><br>METHODS: Relevant studies on cGAS-STING signaling in CNS disorders were collected from PubMed and Web of Science, with emphasis on disease mechanisms, neuroinflammatory regulation, and pathway-targeted therapeutic strategies.<br><br>RESULTS: In the CNS, cGAS-STING signaling exhibits marked region-, cell-, and pathology-dependent heterogeneity. Aberrant DNA sensing activates this pathway and amplifies neuroinflammation, cellular stress, and tissue injury in Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosis (ALS), ataxia-telangiectasia (A-T), and ischemic and hemorrhagic stroke. Pharmacological inhibition of cGAS, cyclic GMP-AMP (cGAMP), or STING, together with emerging delivery strategies, has shown promise in preclinical models.<br><br>DISCUSSION: Clinical translation remains limited by incomplete validation of pathway specificity, limited human evidence, restricted brain delivery, and inconsistent efficacy assessment.<br><br>CONCLUSION: The cGAS-STING pathway links aberrant DNA sensing to innate immune activation and CNS pathology. Clarifying its disease-, cell-, and stage-specific roles may support future targeted therapeutic strategies for CNS disorders.},
}
@article {pmid42460525,
year = {2026},
author = {Liu, Y and Yang, J and Su, J and Hao, L},
title = {High Levels of Plasma Neurturin Partially Mediate the Protective Effect of Reduced Ruminococcus2 Abundance on Multiple Sclerosis: A Mendelian Randomization Study.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X468669260626223524},
pmid = {42460525},
issn = {1875-6190},
abstract = {BACKGROUND: Genetic evidence implicates the contribution of the gut-brain axis to neurodegenerative diseases (NDDs). Alterations in gut microbiota and inflammation are key pathophysiological contributors. Elucidating the genetic basis and the role of cytokines can provide insights into mechanisms linking gut microbial composition to neurodegeneration.<br><br>METHODS: Using aggregated statistics from five large-scale Genome-Wide Association Studies (GWAS) on Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, multiple sclerosis, and amyotrophic lateral sclerosis, bidirectional two-sample Mendelian Randomization (MR) was used to examine the associations. A two-step multivariable Mendelian randomization approach incorporates data from 91 cytokines to explore potential mediators.<br><br>RESULTS: The study reveals 18 positive and 17 negative effects between gut microbiota and NDDs, as well as 10 positive and 10 negative effects between cytokines and NDDs. Remarkably, mediation analysis identified a causal pathway, with evidence that plasma neurturin levels partially mediate the association from genus Ruminococcus2 to multiple sclerosis, with a mediation proportion of 19.19% (OR = 1.038, 95% CI = 1.001-1.086, P = 0.044). No pleiotropy or heterogeneity was detected.<br><br>DISCUSSION: These MR findings provide compelling evidence for a genetically anchored gutimmune-brain network in NDDs, with cytokines as intermediates. Bidirectional effects highlight disease-specific microbial signatures and inflammatory contexts. The Ruminococcus2-neurturin pathway in multiple sclerosis may offer mechanistic specificity, aligning with neurotrophic and anti-inflammatory signaling pathways.<br><br>CONCLUSION: This study emphasizes the importance of gut microbiota alterations in NDDs and explores inflammation's partial intermediary role. The findings suggest potential targets for personalized neurodegeneration prevention strategies.},
}
@article {pmid42460734,
year = {2026},
author = {Khan, SF and Shahid, M and Simjee, SU},
title = {Phytohemagglutinin: A Tool for Inducing Neuroinflammation Mediated In Vitro and In Vivo Modeling of Alzheimer's Disease Pathology.},
journal = {Cell biochemistry and function},
volume = {44},
number = {7},
pages = {e70269},
doi = {10.1002/cbf.70269},
pmid = {42460734},
issn = {1099-0844},
support = {//Institutional Faculty Research/ ; },
mesh = {*Alzheimer Disease/pathology/metabolism/chemically induced ; Animals ; Disease Models, Animal ; *Neuroinflammatory Diseases/pathology/chemically induced/metabolism ; *Phytohemagglutinins/pharmacology ; Humans ; Neurons/metabolism/drug effects/pathology ; Cells, Cultured ; Mice ; Male ; },
abstract = {Alzheimer's disease (AD) is an irreversible neurodegenerative disorder and the major cause of dementia globally. One of the major barriers to curing AD is the lack of experimental models that fully recapitulate the complexity of human AD pathology. Evidence supports the notion that neuroinflammation is a key pathological contributing factor of AD. Therefore, various external stimuli are used to recapitulate the AD-like pathology, i.e., LPS, scopolamine, and aluminum chloride. Although PHA is reported for its pro-inflammatory activity, using PHA to recapitulate the AD-like pathology is relatively new. The current study was designed to evaluate the PHA potential to recapitulate the AD-like pathology in primary neuronal culture as well as in vivo AD modeling. Since LPS is widely used, in the current study, it was used to compare it with the experimental findings using PHA. Confirmation of AD-like pathology was carried out through gene and protein expression in the in vitro study, while in vivo results were verified through behavioral and histopathological assays. It was observed that PHA mimics the AD-like pathology at the cellular level by aggregating, shrinking, and disrupting synaptic plasticity of primary neuronal cells. An elevated level of BACE1 and amyloid-β and hyperphosphorylated tau protein expression, along with reduced levels of the ADAM10 gene, evidently proves that PHA induces the AD-like pathology. Disrupted cognitive and memory patterns confirm the initiation of AD pathogenesis in the in vivo study, which is further confirmed by observing the amyloid plaques stained by Congo red (CR) dye. Based on these findings, it is concluded that PHA is a potent inducer to recapitulate neuroinflammatory-mediated AD-like pathology both in vitro and in vivo.},
}
@article {pmid42460792,
year = {2026},
author = {Shelby, G and Corbett, AH and Parker, RR},
title = {The role of ZC3H14 (MSUT2) in neurodevelopment and tauopathies.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag245},
pmid = {42460792},
issn = {1460-2156},
abstract = {The process of neurodevelopment and neuropathology can be influenced by RNA binding proteins. The RNA binding protein ZC3H14 (also referred to as MSUT2) is of particular interest for two reasons. First, homozygous loss-of function alleles in ZC3H14 are associated with an inherited form of intellectual disability. Second, in model systems, loss of ZC3H14 can suppress the toxicity of tau aggregates, which are hallmark diagnostic features of Alzheimer's disease and other neurodegenerative diseases referred to as "tauopathies". In this review, we discuss both the normal functions of ZC3H14 and how alterations in these functions may affect cognitive function or tau pathology. Although not fully understood, an emerging theme is that alterations in RNA regulation due to ZC3H14 loss can affect neuronal function.},
}
@article {pmid42460827,
year = {2026},
author = {},
title = {A Unique EEG-Hyfusion Fully Automated Stacked Model for Classification of Alzheimer's Disease and Fronto-Temporal Dementia.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {233},
pages = {},
doi = {10.3791/6684},
pmid = {42460827},
issn = {1940-087X},
mesh = {Humans ; *Alzheimer Disease/classification/diagnosis/physiopathology ; *Electroencephalography/methods ; *Dementia/classification/diagnosis ; },
abstract = {This corrects the article 10.3791/69762.},
}
@article {pmid42461071,
year = {2026},
author = {Mattke, S and Chen, J and Hanson, M and Johnson, KG and Leahy, C and Merrill, DA and Shada, V and Ruiz, JG},
title = {Projected effect of a high performing blood test on wait times for determination of Alzheimer's disease pathology in the United States.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261467345},
doi = {10.1177/13872877261467345},
pmid = {42461071},
issn = {1875-8908},
abstract = {BackgroundBlood tests for Alzheimer's disease (AD) are emerging as alternative to amyloid positron emission tomography (PET) scans and analysis of cerebrospinal fluid (CSF). However, their effect on clinical decision-making and subsequent wait times in the diagnostic process remain unclear.ObjectiveTo estimate wait times in the diagnostic process to determine potential eligibility for amyloid-targeting treatments.MethodsWe used a structured expert consultation process to elicit how a blood test to rule out or to confirm AD pathology would inform decisions in primary and secondary care and a Markov model to project how those decisions would affect wait times for specialist visits and amyloid PET scans.ResultsCompared with referral decisions based on the results of a brief cognitive assessment, the addition of an AD blood test is projected to reduce wait times for subsequent specialist appointments by 35%. A blood test for confirmation of AD pathology would also eliminate wait times for amyloid PET scans.ConclusionsHigh-performing AD blood tests have the potential to streamline the diagnostic journey and reduce wait times.},
}
@article {pmid42461168,
year = {2026},
author = {Davis, AH and Ramos, MD},
title = {Mapping Artificial Intelligence Applications in Dementia Caregiving: A Scoping Review of Technologies, Functions, and Evidence Gaps.},
journal = {Journal of gerontological nursing},
volume = {},
number = {},
pages = {1-9},
doi = {10.3928/00989134-20260709-02},
pmid = {42461168},
issn = {0098-9134},
abstract = {PURPOSE: As symptoms progress in people with Alzheimer's disease and related dementias (ADRD), caregivers assume increasing responsibility. The objective of the current study was to summarize evidence on artificial intelligence (AI) technologies designed to support caregivers of people with ADRD.<br><br>METHOD: A comprehensive literature search was conducted in CINAHL and PubMed. A scoping review methodology was used to synthesize study designs, AI modalities, caregiver populations, intervention settings, outcomes measured, and key findings.<br><br>RESULTS: Forty-three studies were included. Identified technologies included physical robots, conversational agents, and predictive algorithms. These AI interventions supported caregivers through education, task assistance, social support, and clinical management.<br><br>CONCLUSION: As the population of older adults with ADRD grows, so will demand for caregiver support. Current research demonstrates a wide range of AI applications. Future research should focus on rigorous, long-term empirical evaluation of these technologies.},
}
@article {pmid42448200,
year = {2026},
author = {Murugan, AK},
title = {Oral disease-associated proteins implicated in neuronal disorders: Emerging roles in diagnosis and treatment.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {153500},
doi = {10.1016/j.ijbiomac.2026.153500},
pmid = {42448200},
issn = {1879-0003},
abstract = {Oral health plays a crucial role in maintaining cognitive functions, reflecting a complex interplay between the oral cavity and brain health. Emerging evidence indicates that various oral disease-associated protein molecules are implicated in the pathogenesis of diverse neuronal disorders, including neurodegenerative diseases. This review comprehensively summarizes oral disease-related protein molecules implicated in several neuronal disorders, including Alzheimer's disease, Parkinson's disease, neurodegeneration, neuroinflammation, dementia, cognitive decline, and brain fog in two different contexts. Firstly, it describes protein molecules under the classical oral disease condition [Aβ42, total-Tau, phosphorylated-Tau, α-synuclein, DJ-1, lactoferrin, MMP-2/8/9, IL-6, IL-1β, TNF-α, CRP, S100A8, S100A9, S100B, RAGE, LCN2, cathepsin B/L, HSP70/90, NfL, CXCL2/8, C3/4, defensins (α and β), and lysozyme]. Secondly, in COVID-19 context [ACE2, TMPRSS2, furin-1, NRP1, spike, T1R, and T2R]. It explores oral proteins implicated in neuronal disorders, highlighting their roles in activating inflammatory pathways, contributing to memory impairment, and mediating taste dysfunction in the context of COVID-19. Furthermore, the review delineates the mechanisms underlying the oral-brain axis, highlighting the roles of systemic inflammation, microbial interactions, and blood-brain barrier dysfunction in mediating these effects. It also highlights the innovative diagnostic potential of oral disease-associated proteins as non-invasive biomarkers for early detection and monitoring of neuronal disorders in both classical and COVID-19 contexts. In addition, the emerging therapeutic significance of these proteins is discussed, emphasizing their potential as molecular targets for the prevention and treatment of neurological diseases. Understanding oral disease-associated protein molecules provides novel insights into early diagnosis and progression of neuronal disorders.},
}
@article {pmid42448252,
year = {2026},
author = {Ahn, HS and Gourrierec, TL and Jung, Y and Kim, S and Hwang, SH and Park, J and Lee, DY and Sohn, CH and Park, SH},
title = {Estimating blood-brain barrier exchange rate using diffusion-weighted arterial spin labeling and physics-guided neural networks.},
journal = {NeuroImage},
volume = {},
number = {},
pages = {122132},
doi = {10.1016/j.neuroimage.2026.122132},
pmid = {42448252},
issn = {1095-9572},
abstract = {This study proposes physics-guided neural network (PgNN) approaches for estimating perfusion and blood-brain barrier (BBB) water permeability parameters from multi-slice, multi-delay diffusion-weighted arterial spin labeling (DW-ASL) MRI. To enable simultaneous estimation of perfusion and permeability-related parameters, a water-impermeable arterial compartment was incorporated into a two-compartment perfusion kinetic model, allowing estimation of the water exchange rate (kw), cerebral blood flow (CBF), and arterial transit time (ATT). DW-ASL data were acquired using pseudo-continuous arterial spin labeling with 2D gradient-echo echo-planar imaging and bipolar diffusion gradients in sixteen subjects (nine young healthy adults, three elderly healthy adults, and four elderly patients with Alzheimer's disease). Multiple post-labeling delays were achieved by permuting the slice acquisition order. Two PgNN frameworks were developed. First, PgNN based on a multi-layer perceptron (MLP) was trained using synthetic DW-ASL signals generated from the physical model and adapted to each test dataset. Second, a 3D U-Net-based PgNN was devised to adapt to test data using the physical model without pretraining. Neither approach required training with real in vivo data. The proposed methods were compared with conventional alternating direction method of multipliers (ADMM) and nonlinear least squares (NLS). Both PgNN approaches demonstrated improved accuracy and noise robustness compared with ADMM and NLS. The estimated kw was lower and ATT higher in older than young subjects, with the kw reduction being more pronounced in the Alzheimer's disease subgroup. These results indicate that the proposed frameworks provide stable quantitative estimation of perfusion and BBB permeability parameters from multi-slice, multi-delay DW-ASL.},
}
@article {pmid42448384,
year = {2026},
author = {Mani, LY and Unwin, RJ},
title = {Relationship between cognitive impairment and chronic kidney disease.},
journal = {Practical neurology},
volume = {26},
number = {4},
pages = {313-318},
doi = {10.1136/pn-2025-004837},
pmid = {42448384},
issn = {1474-7766},
mesh = {Humans ; *Renal Insufficiency, Chronic/complications/epidemiology/psychology ; *Cognitive Dysfunction/epidemiology/etiology/diagnosis ; *Cognition Disorders ; },
abstract = {Cognitive impairment is an under-recognised but clinically significant complication of chronic kidney disease (CKD). The global prevalence of CKD is approximately 10%, and it frequently affects neurological function, and particularly executive and language domains. This article encourages neurologists and neuropsychiatrists to consider CKD as a potential contributor to cognitive decline. By recognising the characteristic cognitive profile associated with CKD, and distinguishing it from coexisting neurodegenerative pathology, clinicians can implement early interventions that improve outcomes. We outline mechanisms that link CKD to cognitive dysfunction, present diagnostic approaches and offer multidisciplinary strategies for assessment and management.},
}
@article {pmid42448407,
year = {2026},
author = {Rangappa, N and Upadhyay, R and Lakshman, N and Ramasamy, S and Sevanan, M and Justin, A and Chinnathambi, S},
title = {Small molecular therapeutic targets for neurodegenerative diseases.},
journal = {Advances in protein chemistry and structural biology},
volume = {153},
number = {},
pages = {135-167},
doi = {10.1016/bs.apcsb.2025.10.012},
pmid = {42448407},
issn = {1876-1631},
mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism/pathology/genetics ; Animals ; *Molecular Targeted Therapy ; },
abstract = {Neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis disease are characterized by progressive neuronal loss, protein aggregation, and synaptic dysfunction. These diseases share common pathological mechanisms including oxidative stress, mitochondrial impairment, chronic neuroinflammation, protein misfolding, and epigenetic dysregulation. Current therapies offer only symptomatic relief and fail to halt disease progression. Recent advances in transcriptomics and proteomics have enabled the identification of shared molecular pathways and druggable targets across multiple neurodegenerative diseases. The key targets, such as BDNF-TrkB, TREM2, SIRT1, PINK1-Parkin, GSK-3β, NLRP3, and mTOR have shown promise in preclinical models, offering opportunities for broad-spectrum therapeutic development. Importantly, blood-brain barrier disruption and neuroinflammatory crosstalk exacerbate disease pathology and hinder drug delivery. Innovative strategies involving nanocarriers, gene therapy, and epigenetic modulation are emerging to overcome these barriers. This review highlights the convergence of disease mechanisms, discusses common molecular signatures and therapeutic vulnerabilities, and explores novel small molecular interventions targeting shared pathways mainly in AD and PD. A deeper understanding of aging-associated molecular dysfunction is essential to design sustainable, disease-modifying therapeutics with cross-disease relevance.},
}
@article {pmid42448408,
year = {2026},
author = {Velmurugan, G and Krishnan, D and Upadhyay, R and Sivasamy, R and Sevanan, M and Chinnathambi, S},
title = {Signaling cascades of microtubule-associated protein Tau in Alzheimer's disease.},
journal = {Advances in protein chemistry and structural biology},
volume = {153},
number = {},
pages = {169-190},
doi = {10.1016/bs.apcsb.2025.10.013},
pmid = {42448408},
issn = {1876-1631},
mesh = {Humans ; *tau Proteins/metabolism ; *Alzheimer Disease/metabolism/pathology ; *Signal Transduction ; Mitochondria/metabolism/pathology ; Protein Processing, Post-Translational ; Animals ; Phosphorylation ; Neurons/metabolism/pathology ; },
abstract = {Accumulation of neurofibrillary tangles (NFTs) in the neuronal cells is the predominant features of Alzheimer's diseases (AD) and other Tauopathies. Studies on molecular mechanism of human neurodegenerative disease shows that the substantial posttranslational modifications (PTMs) of Tau is essential for the conversion of monomeric soluble form into the aberrant insoluble aggregates in pathological condition. During pathogenesis of AD, Tau phosphorylation state is altered by the activation of various kinases and phosphates and eventually Tau become hyperphosphorylated. Hyperphosphorylated Tau detach from microtubules and aggregate intracellularly in affected neurons. This pathological Tau invades the subcellular organelles including mitochondria and leads to degeneration and cell death. Ageing is the crucial factor causing alteration in brain including, structural and functional role of Tau. Pathological Tau disrupts signaling cascades of mitochondria, energy-associated mechanism and this causes the elevation of oxidative stress in the neurons. Furthermore, hyperphosphorylated Tau also inhibits the mitophagy and autophagy-lysosomal pathway, resulting in the buildup of dysfunctional mitochondria in the affected neurons. This review highlights the major signaling cascades involved in Tau PTMs and its interlinked role in mitochondrial damage in aging population in AD.},
}
@article {pmid42448409,
year = {2026},
author = {Upadhyay, R and Velmurugan, G and Krishnan, D and Sivasamy, R and Sevanan, M and Chinnathambi, S},
title = {Understanding molecular role of lipids for Alzheimer's disease.},
journal = {Advances in protein chemistry and structural biology},
volume = {153},
number = {},
pages = {191-210},
doi = {10.1016/bs.apcsb.2025.10.011},
pmid = {42448409},
issn = {1876-1631},
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; *Lipid Metabolism ; Animals ; Membrane Microdomains/metabolism/pathology ; Oxidative Stress ; *Lipids ; Neurons/metabolism/pathology ; },
abstract = {Human health and neurological functions are significantly impacted by lipids, the fundamental building block of cell membranes. The central nervous system is rich in lipids, and they are evidently disturbed in neurological conditions and neurodegenerative diseases like Alzheimer's disease (AD). Alteration in lipid profile is highly linked with aging. During early onset of AD, there is a noted lipid peroxidation and modifications of fatty acids at the level of lipid rafts in the neuronal cells. AD is an age-linked neurodegenerative condition with multifaceted etiology, with combining genetic and environmental risk factors, which lacks disease-modifying therapies. While the aberrant deposition of lipids was shown in the initial studies of AD neuropathology. Clinically, lipidomic and metabolomic research have constantly exposed the changes in the levels of various lipid classes emerging in early onset of AD individuals. Also, decades of investigations have discovered multifactorial link between lipid metabolism and key AD pathogenic pathway such as amyloidogenesis, bioenergetic deficit, oxidative stress, neuroinflammation, and myelin degeneration. Herewith, we highlighted the features that impact lipid composition in neuronal cells, and the association of different lipids with known aspects of AD pathogenesis, and potential therapeutics that aim lipid crossroads.},
}
@article {pmid42448482,
year = {2026},
author = {Wang, T and Lin, S and Xu, C and Chen, Y and Sui, Y and Sun, J and Wang, R and Chen, H and Lian, J and Wang, W},
title = {Multimodal MRI Reveals Stage-Specific Reorganization of Structure-Function Coupling from Compensatory to Decoupled States in Cerebral Small Vessel Disease.},
journal = {Academic radiology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.acra.2026.06.044},
pmid = {42448482},
issn = {1878-4046},
abstract = {RATIONALE AND OBJECTIVES: Cerebral small vessel disease (CSVD) affects white matter integrity and can alter the brain's network architecture. However, the relationship between structural and functional connectivity in CSVD remains underexplored. This study aims to investigate the differences in topological properties of structural and functional brain networks across CSVD burden groups.<br><br>MATERIALS AND METHODS: This cross-sectional study utilized data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu), concentrating on participants who had both DTI and resting-state fMRI data. Participants were classified into non-CSVD (CSVD-n), mild CSVD (CSVD-m), or severe CSVD (CSVD-s) groups based on a CSVD burden score ranging from zero&#xa0;to four. Structural networks were reconstructed from DTI data using deterministic tractography, while functional networks were derived from resting-state fMRI data through Pearson's correlation of regional time series. Graph theoretical analyses were conducted using GRETNA in MATLAB to calculate global and nodal metrics, as well as structure-function coupling indices. Group comparisons were performed using one-way ANOVA (one-way analysis of variance), with age, sex, and education as covariates. Statistical significance was assessed at a two-tailed p < 0.05, adjusted for multiple comparisons across nodes and networks using false discovery rate (FDR) correction.<br><br>RESULTS: The study included 280 participants (mean 75.0&#xb1;7.9y, median 76y; 49.6% female). The participants were divided into groups: CSVD&#x2011;n (118, 42.1%), CSVD&#x2011;m (80, 28.6%), and CSVD&#x2011;s (82, 29.3%). Analysis of structural networks revealed that CSVD&#x2011;s exhibited reduced global/local efficiency (7.42&#xb1;2.63 vs. 8.42&#xb1;2.75, p = 0.03; 16.00&#xb1;4.77 vs. 17.83&#xb1;5.16, p = 0.02) and increased path length (0.15&#xb1;0.04 vs. 0.13&#xb1;0.04, p = 0.003). Nodal damage was observed in the left hippocampus in CSVD&#x2011;m (p = 0.0008) and was widespread in CSVD&#x2011;s (all p&#xa0;<&#xa0;0.001). In terms of functional networks, no global differences were found (all p&#xa0;>&#xa0;0.05); however, CSVD&#x2011;s exhibited nodal changes in the cingulate/Heschl gyrus (p&#xa0;<&#xa0;0.001). Regarding coupling, CSVD&#x2011;m showed increased coupling in the insula/orbitofrontal regions (p = 0.002-0.041) and decreased coupling in the pallidum (p = 0.026). Conversely, CSVD&#x2011;s demonstrated increased coupling in the olfactory/occipital/temporal regions (p = 0.001-0.023) and decreased coupling in the rolandic operculum (p = 0.019) and hippocampus (compared to CSVD&#x2011;m, p = 0.009). Furthermore, left insular coupling was correlated with MoCA (r=-0.245, p = 0.015).<br><br>CONCLUSION: In the mild CSVD group, researchers observed increased coupling in regions such as the insula and orbitofrontal cortex. In contrast, the severe CSVD group exhibited widespread structural network differences, decreased coupling in the hippocampus and rolandic operculum, and functional nodal alterations. These cross-sectional comparisons among CSVD burden groups reveal a pattern of differences consistent with stage-like progression. However, causality cannot be inferred from this cross-sectional design.},
}
@article {pmid42448639,
year = {2026},
author = {Aktaş, E and Yurt, &#x130; and Cerlet, YN and Hanağası, HA},
title = {Rethinking Alzheimer's Disease Therapy: From Amyloid-Centric Approaches to Multi-Target Phytochemical Strategies.},
journal = {Journal of neurochemistry},
volume = {170},
number = {7},
pages = {e70506},
doi = {10.1111/jnc.70506},
pmid = {42448639},
issn = {1471-4159},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Phytochemicals/therapeutic use/administration &amp; dosage ; Animals ; *Amyloid beta-Peptides/metabolism/antagonists &amp; inhibitors ; Oxidative Stress/drug effects/physiology ; tau Proteins/metabolism ; },
abstract = {Alzheimer's disease (AD) is the leading cause of dementia, characterized by irreversible neuronal loss and progressive cognitive decline. The disease is driven by complex and interconnected pathological processes, including amyloid-β plaque deposition and tau neurofibrillary tangle formation, which converge on neuroinflammation, oxidative stress, synaptic dysfunction, and widespread neuronal network failure. Although recently approved antibody-based therapies such as lecanemab and donanemab effectively reduce cerebral amyloid burden, their clinical benefits remain modest and are accompanied by significant safety concerns, including amyloid-related imaging abnormalities (ARIA). Current pharmacological strategies predominantly rely on single-target mechanisms, an approach increasingly recognized as insufficient to address the multifactorial neurobiology of AD. This review critically evaluates the limitations of conventional amyloid-centric therapeutic strategies and contrasts them with emerging multi-target approaches based on phytochemicals. We synthesize current experimental and translational evidence to present a mechanistic framework illustrating how plant-derived bioactive compounds, including flavonoids and polyphenols, function as systems-level modulators of AD pathology rather than purely symptomatic agents. Particular emphasis is placed on their coordinated actions on amyloid processing via BACE1 inhibition, restoration of tau homeostasis through GSK-3β/PP2A regulation, attenuation of neuroinflammatory signaling, enhancement of endogenous antioxidant defenses through Nrf2 activation, and preservation of synaptic integrity. When considered collectively, the available evidence supports the concept that multi-target phytochemical strategies represent a biologically congruent and neurologically relevant paradigm for Alzheimer's disease therapy. Future progress will likely depend on integrating these compounds into broader polypharmacological and multidomain intervention frameworks, together with lifestyle-based strategies, repurposed drugs, anti-amyloid therapies, and rigorous translational validation.},
}
@article {pmid42448663,
year = {2026},
author = {Xu, X and Fan, SS and Wu, H and Du, Y and Bo, Y and He, J and He, Y and Cheng, N and Meng, XY},
title = {Integrative multi-omics reveals MHC class II-mediated neuroinflammation and systemic metabolic dysregulation as transdiagnostic drivers in major brain disorders.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-04280-3},
pmid = {42448663},
issn = {2158-3188},
support = {62402006//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82303057//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Psychiatric, neurodevelopmental, and neurodegenerative disorders, including Alzheimer's disease (AD), attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BIP), major depressive disorder (MDD), and schizophrenia (SCZ), exhibit complex etiologies driven by immune and metabolic dysregulation. While distinct in their clinical onset, these conditions share overlapping molecular vulnerabilities. This study pioneers an integrative multi-omics framework, combining multi-tissue TWAS, cross-disorder pleiotropy analyses, Mendelian Randomization (MR), predictive machine learning, and BV2 microglial profiling. Crucially, our analysis uncovered a robust "Dual-Axis" etiological architecture. First, a systemic metabolic axis emerged as a primary driver, particularly involving FADS2-mediated lipid dysregulation and gut-brain axis interactions. This axis shares mechanisms between bipolar disorder and schizophrenia, with Multi-tissue TWAS revealing peripheral contributions (e.g., liver, colon) to CNS pathology. Second, MHC Class II-mediated pathways, driven by HLA-DRA, HLA-DRB1, HLA-DQB1, and HLA-DQA1, emerged as a transdiagnostic neuroinflammatory nexus across AD, BIP, MDD, and SCZ, orchestrating antigen presentation to CD4[+] T-helper cells. To bridge these genomic findings with cellular function, BV2 microglial profiling was performed to provide a cellular-context reference specifically for the identified immune risk component. This cellular model confirmed that the immunogenetic risk burden maps to a specific proinflammatory activation state characterized by upregulated neurotoxins (Lcn2, Nos2, Ccl2) and suppressed lipid transport/phagocytosis (Apoe, Cd68). Machine learning models leveraging these signatures achieved robust predictive performance, particularly for BIP and MDD. MR analyses uncovered causal roles of immune, lipid, and microbial pathways, with shared metabolic signatures (e.g., N-acetylarginine) across disorders. Integration with traditional medicine databases linked lipid metabolism to Artemisia argyi, suggesting novel therapeutic avenues. This integrative approach redefines the molecular framework of these disorders by highlighting systemic metabolic dysregulation and strongly implicating MHC Class II-mediated neuroinflammation as two convergent drivers, advancing precision psychiatry through targeted immunotherapies and metabolic modulators.},
}
@article {pmid42448676,
year = {2026},
author = {Luu, D and Twisselmann, AM and Tennant, VR and Hall, BJ and Mahajan, A and Kim, A and Terner, J and Davison, ML and Wheeler, K and Ching, CRK and Hall, J and Borzage, MT and Johnson, L and Toga, AW and O'Bryant, SE and Yaffe, K and Braskie, MN and , },
title = {Depression and hippocampal subfield volume in older adults.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-04223-y},
pmid = {42448676},
issn = {2158-3188},
support = {U19AG078109//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U19AG078109//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U19AG078109//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U19AG078109//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U19AG078109//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U19AG078109//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U19AG078109//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U19AG078109//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U19AG078109//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U19AG078109//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U19AG078109//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U19AG078109//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U19AG078109//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG054073//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG058533//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG070862//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; P41EB015922//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U19AG078109//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U19AG078109//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; S10OD032285//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; },
abstract = {Depression is associated with a higher risk for developing Alzheimer's Disease (AD) [1], but the mechanisms that underlie the complex relationship between depression and AD remain largely elusive. The hippocampus is a region of the brain that is commonly affected by both AD and depression and serves as a focal point for our study. We aim to understand the relationship of 1) depression and antidepressant medications to hippocampal subfield volume during normal aging, and 2) whether AD risk, as measured by amyloid and tau pathology and APOE4 status, impacts these relationships. We studied 2009 ethno-racially diverse cognitively unimpaired older adults aged 50 to 90 years who either had depression (n = 630) or were not depressed (n = 1379). Participants with depression were further stratified by antidepressant medication usage. High-resolution MRI scans were used to calculate hippocampal subfield volumes that included the CA1, the subiculum, and a composite region that included the CA2, CA3, and the dentate gyrus (CA23DG). Having depression was associated with a smaller CA23DG, independent of amyloid and tau pathology in the brain. Within the subgroup of participants with depression, those who used antidepressant medications had smaller CA1 and CA23DG volumes than those who did not use these medications.},
}
@article {pmid42448798,
year = {2026},
author = {Radhakrishnan, K and Zhang, Y and Mustapha, O and Weigel, TK and Upchurch, CM and Tian, X and Herbert, F and Huang, W and Leitinger, N and Eyo, UB and Ai, H and Ferris, HA},
title = {7-ketocholesterol contributes to microglia-driven increases in astrocyte reactive oxygen species in a mouse model of Alzheimer's disease.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-61753-7},
pmid = {42448798},
issn = {2045-2322},
support = {T32GM139787/NH/NIH HHS/United States ; R01AL168194/NH/NIH HHS/United States ; RF1AG077773/NH/NIH HHS/United States ; RF1AG077773/NH/NIH HHS/United States ; },
abstract = {Oxidative stress is a prominent feature of Alzheimer's disease (AD). Within this context, cholesterol undergoes oxidation, producing the pro-inflammatory product 7-ketocholesterol (7-KC). In this study, we observe elevated levels of 7-KC in the brains of the 3xTg mouse model of AD. To further understand the contribution of 7-KC on the oxidative environment, we developed a method to express a genetically encoded fluorescent hydrogen peroxide (H2O2) sensor in astrocytes, the primary source of cholesterol in the brain. With this sensor, we showed that 7-KC increases H2O2 levels in astrocytes in vivo, but not when directly applied to astrocytes in vitro. When 7-KC was applied to a microglia cell line alone or mixed astrocyte and microglia cultures, it resulted in microglia activation and increased oxidative stress in astrocytes. Depletion of microglia from 3xTg mice resulted in reduced 7-KC and reduced reactive oxygen species in astrocytes. Taken together, these findings suggest that 7-KC, via microglia activation, contributes to increased astrocyte oxidative stress in the 3xTg mouse model of AD. This study contributes to understanding one of the drivers of the vicious cycle of oxidative stress seen in mouse models of AD whereby increased reactive oxygen species drive cholesterol oxidation, resulting in additional oxidative stress.},
}
@article {pmid42448890,
year = {2026},
author = {Aumont, E and Trudel, L and Hall, BJ and Chan, T and Hosseini, SA and Macedo, AC and Therriault, J and Arias, JF and Lebrun, A and Oliva-Lopez, D and Rahmouni, N and Bezgin, G and Stevenson, J and Servaes, S and Fonov, V and Hsiao, C and Hopewell, R and Vitali, P and Klostranec, J and Montembeault, M and Iturria-Medina, Y and Baker, SL and Gauthier, S and Rosa-Neto, P},
title = {Using CA1 rather than the whole hippocampus to capture tau-PET Braak stage II.},
journal = {European journal of nuclear medicine and molecular imaging},
volume = {},
number = {},
pages = {},
pmid = {42448890},
issn = {1619-7089},
support = {2020-VICO-279314//Fonds de Recherche du Qu&#xe9;bec - Sant&#xe9;/ ; 2024 VICO-356138//Fonds de Recherche du Qu&#xe9;bec - Sant&#xe9;/ ; CFI Project 34874//Fondation Brain Canada/ ; 33397//Fondation Brain Canada/ ; 152985//Institute of Aging/ ; 159815//Institute of Aging/ ; 162303//Institute of Aging/ ; Postdoctoral fellowship//Institute of Aging/ ; MOP-11-51-31//Consortium canadien en neurod&#xe9;g&#xe9;n&#xe9;rescence associ&#xe9;e au vieillissement/ ; NIRG-12-92090/ALZ/Alzheimer's Association/United States ; NIRP-12-259245/ALZ/Alzheimer's Association/United States ; },
abstract = {PURPOSE: Tau-PET enables in-vivo staging of Alzheimer disease (AD) pathology, including early Braak stage II involvement of the hippocampus. Conventional whole-hippocampus definitions combine heterogeneous subfields and are susceptible to off-target signal that varies across tracers, limiting sensitivity, specificity, and longitudinal interpretability of early tau accumulation.<br><br>METHODS: Cross-sectional and longitudinal analyses were conducted in the TRIAD (N&#x2009;=&#x2009;456) and the ADNI (N&#x2009;=&#x2009;497) observational cohorts with tau-PET with [[18]F]MK-6240 or [[18]F]flortaucipir and structural MRI. A CA1-specific Braak stage II region of interest was compared with a whole-hippocampus approach. Outcomes included Braak stage concordance, longitudinal stability, tau-PET progression, and biological plausibility assessed by amyloid-PET burden and extrahippocampal tau signal.<br><br>RESULTS: Spatial analyses localised early hippocampal tau-PET signal predominantly to the anterior CA1. Whole-hippocampus measures were more frequently influenced by off-target signal consistent with choroid plexus contamination. Participants classified as CA1-based Braak stage II showed higher amyloid-PET burden, more consistent tau accumulation in the Braak stage III region, and more stable longitudinal progression. CA1-based staging yielded fewer discordant classifications and fewer stage regressions at follow-up.<br><br>CONCLUSION: CA1-specific tau-PET quantification improves biological plausibility and longitudinal consistency of Braak stage II classification by targeting the hippocampal subfield most vulnerable to early tau pathology and mitigating off-target contamination. CA1-based Braak stage II participants showed greater coherence with the biological framework of AD than those staged using the whole hippocampus. Applicable to available PET resolution, this approach may enhance characterisation of early AD and support participant selection in trials targeting preclinical tau accumulation.},
}
@article {pmid42448968,
year = {2026},
author = {Costa, AP and Acquarone, E and Lazarian, A and Herman, M and Wartchow, KM and Bartelo, N and Dartora, WJ and Krumsiek, J and Li, XL and Baskin, JM and Arancio, O and Hussaini, SA and McIntire, LB},
title = {Temporal and spatial control of phosphatidylinositides using optogenetics ameliorates behavioral deficits in an Alzheimer's disease mouse model.},
journal = {Communications biology},
volume = {},
number = {},
pages = {},
doi = {10.1038/s42003-026-10517-0},
pmid = {42448968},
issn = {2399-3642},
support = {W81XWH-19-1-0817/GRANT12727289//U.S. Department of Defense (United States Department of Defense)/ ; GRANT13369767/GRANT13710486//U.S. Department of Defense (United States Department of Defense)/ ; 1R56AG072794/1R01AG072794//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; TL1TR001875/UL1TR001873//U.S. Department of Health &amp; Human Services | NIH | National Center for Advancing Translational Sciences (NCATS)/ ; R01GM151682//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; 1R01NS110024//U.S. Department of Health &amp; Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; },
abstract = {Deficits in levels of phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] mediate Alzheimer's disease (AD) pathogenesis and etiology. The depletion of PI(4,5)P2 has been reported in AD in both human brain and animal models. Repletion of the synaptic pool of PI(4,5)P2, through haploinsufficiency of the degrading enzyme, Synaptojanin 1, ameliorated behavioral deficits in a mouse model of AD, in spite of accumulating amyloid. In order to refine the contribution of PI(4,5)P2 to AD, we used optogenetic translocation of the PI(4,5)P2-synthesizing enzyme, phosphoinositide phosphate 4 kinase2A (PIP4K2A) to the plasma membrane using light inducible dimerizable cryptochrome 2 (CRY-2) and the transcription factor CRY2-binding domain (CIBN) fused to the plasma membrane-targeting motif (CAAX). Spatiotemporally controlled production of phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] at the plasma membrane induced amelioration of behavioral deficits in a mouse model of AD. Imaging mass spectrometry confirmed alteration of specific PI(4,5)P2 acyl species, di-oleate, indicating that precise PI(4,5)P2 species may ultimately be leveraged for therapeutic intervention.},
}
@article {pmid42449057,
year = {2026},
author = {Bukar, AM and Che Mohd Nassir, CMN and Ayuba, M and Manoharan, SD and Usman, AS and Umar, BI and Hein, ZM and Mohd Moklas, MA and Mehat, MZ and Abdul Hamid, H},
title = {Ficus deltoidea Preserves Hippocampal Neuronal Integrity and Redox Balance in Oxidative Stress-Driven Alzheimer's Disease-Like Rat Model.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42449057},
issn = {1559-1182},
mesh = {Animals ; *Oxidative Stress/drug effects ; *Alzheimer Disease/pathology/drug therapy/metabolism ; Male ; Rats, Wistar ; *Ficus/chemistry ; *Hippocampus/pathology/drug effects/metabolism ; Disease Models, Animal ; *Neurons/drug effects/metabolism/pathology/ultrastructure ; Oxidation-Reduction/drug effects ; Aluminum Chloride ; *Plant Extracts/pharmacology/therapeutic use ; Galactose ; Neuroprotective Agents/pharmacology/therapeutic use ; Antioxidants/pharmacology ; Rats ; Maze Learning/drug effects ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia worldwide, with oxidative stress playing a central role in its pathogenesis. Ficus deltoidea (FD), a medicinal plant rich in flavonoids vitexin and isovitexin, possesses potent antioxidant and anti-inflammatory properties, yet its neuroprotective efficacy in AD remains incompletely characterized. This study investigated the protective effects of FD in a D-galactose- and aluminum chloride (AlCl3)-induced oxidative stress-driven AD-like rat model using behavioral, histological, ultrastructural, and biochemical approaches. Fifty-four male Wistar rats were assigned to six groups: control, AD-like model, donepezil (1 mg/kg), and FD-treated groups (50, 100, and 200 mg/kg) for 10 weeks. Anxiety-like behavior and spatial working memory were assessed using the elevated plus maze (EPM) and T-maze tests, respectively. Hippocampal neuronal integrity was evaluated by hematoxylin and eosin (H&amp;E) staining and transmission electron microscopy (TEM), while oxidative stress biomarkers (MDA, CAT, T-SOD, CuZn-SOD, and HO-1) were quantified using ELISA. FD treatment, particularly at 200 mg/kg, significantly improved spatial working memory and normalized anxiety-related behavior, with treatment responses approaching those observed in the donepezil-treated group. Histological analyses revealed preservation of pyramidal neurons across CA1, CA2, CA3, and dentate gyrus subregions, while ultrastructural studies demonstrated marked protection of mitochondrial integrity, myelin sheath organization, and smooth endoplasmic reticulum morphology. Biochemically, FD significantly reduced lipid peroxidation and enhanced endogenous antioxidant defenses. In conclusion, FD exerted significant neuroprotective effects characterized by preservation of hippocampal structure, maintenance of neuronal ultrastructure, and restoration of redox homeostasis in an oxidative stress-driven AD-like model. These findings demonstrate that FD mitigates oxidative stress-associated neuronal injury and cognitive impairment in a D-galactose and AlCl3-induced AD-like rat model, supporting its potential as a phytotherapeutic candidate for oxidative stress-related neurodegeneration. However, further studies are required to determine its effects on canonical Alzheimer's disease pathologies, including amyloid and tau abnormalities.},
}
@article {pmid42449130,
year = {2026},
author = {Macedo, AC and Trudel, L and Therriault, J and Rahmouni, N and Aumont, &#xc9; and Bezgin, G and Hosseini, SA and Tissot, C and Chan, T and Servaes, S and Hall, B and Wang, YT and Quispialaya-Socualaya, K and Woo, MS and Fernandez-Arias, J and Stevenson, J and Zheng, Y and Gonçalves, MP and Lussier, FZ and Ferrari-Souza, JP and Ferreira, PCL and Bellaver, B and Povala, G and Amaral, LSD and Massarweh, G and Soucy, JP and Meeker, KL and Braskie, MN and Betthauser, TJ and Christian, BT and Rea Reyes, RE and Caldwell, JK and Ashton, NJ and Karikari, TK and Zetterberg, H and Blennow, K and Zimmer, ER and Benedet, AL and Johnson, SC and Pascoal, TA and Rosa-Neto, P and , },
title = {Spatiotemporal dynamics of tau extent and load increase in Alzheimer's disease across four longitudinal cohorts.},
journal = {Nature aging},
volume = {},
number = {},
pages = {},
pmid = {42449130},
issn = {2662-8465},
support = {F225864C02; M159875C51//McGill University (McGill)/ ; },
abstract = {This longitudinal study including four independent cohorts assessed the spatiotemporal dynamics of tau extent and load changes in Alzheimer's disease using tau positron emission tomography data from 2,459 participants, including 898 followed for up to 7 years. Regional standardized uptake value ratios indexed tau load, whereas the spatial extent of tauopathy (SEOT) (proportion of abnormal voxels) measured tau extent. We observed burden-dependent longitudinal dynamics of tau progression: SEOT showed greater sensitivity to increases over time in regions with low baseline tau burden, whereas the standardized uptake value ratio was more informative for tracking accumulation once regional burden was established. This pattern was consistent across Braak regions and cohorts and was reflected in differential associations with other Alzheimer's disease severity markers. These findings refine models of tau propagation by suggesting that tau positron emission tomography changes may be differentially captured by extent-based and load-based metrics at different stages of disease progression, highlighting SEOT as a promising surrogate outcome for trials.},
}
@article {pmid42449162,
year = {2026},
author = {Zhang, F and Petersen, M and Mapstone, M and Hall, J and Handen, B and Christian, B and Head, E and Rosas, HD and Lai, F and Lee, JH and Krinsky-McHale, SJ and Schmitt, FA and Harp, J and Hom, C and Lott, IT and Hartley, S and Zaman, S and Ances, BM and Ptomey, L and Burns, JM and Cohen, AD and Brickman, AM and Bryant, SEO and , },
title = {Blood biomarkers predict conversion from cognitively stable to mild cognitive impairment or Alzheimer's disease in Down syndrome at 16-month follow-up in ABC-DS.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71659},
doi = {10.1002/alz.71659},
pmid = {42449162},
issn = {1552-5279},
support = {/AG/NIA NIH HHS/United States ; //National Institute for Child Health/ ; U01 AG051406/AG/NIA NIH HHS/United States ; U01 AG051412/AG/NIA NIH HHS/United States ; U19 AG068054/AG/NIA NIH HHS/United States ; P50 AG008702/AG/NIA NIH HHS/United States ; P30 AG062421/AG/NIA NIH HHS/United States ; AG016573//NIH Programs/ ; P50 AG005133/AG/NIA NIH HHS/United States ; P50 AG005681/AG/NIA NIH HHS/United States ; P30 AG062715/AG/NIA NIH HHS/United States ; P30 AG066519/AG/NIA NIH HHS/United States ; P30 AG066468/AG/NIA NIH HHS/United States ; P30 AG072973/AG/NIA NIH HHS/United States ; //Eunice Kennedy Shriver Intellectual and Developmental&#xa0;Disabilities/ ; UL1 TR001873/TR/NCATS NIH HHS/United States ; UL1 TR002373/TR/NCATS NIH HHS/United States ; UL1 TR001414/TR/NCATS NIH HHS/United States ; UL1 TR001857/TR/NCATS NIH HHS/United States ; UL1 TR002345/TR/NCATS NIH HHS/United States ; UL1 TR002366/TR/NCATS NIH HHS/United States ; U24 AG21886/TR/NCATS NIH HHS/United States ; },
mesh = {Humans ; *Down Syndrome/blood/complications ; *Biomarkers/blood ; *Alzheimer Disease/blood/diagnosis ; Female ; Male ; *Cognitive Dysfunction/blood/diagnosis ; Disease Progression ; Longitudinal Studies ; Follow-Up Studies ; Middle Aged ; Support Vector Machine ; Sensitivity and Specificity ; },
abstract = {INTRODUCTION: Individuals with Down syndrome (DS) face high risk for Alzheimer's disease (AD), yet presymptomatic detection of cognitive decline is hindered by lifelong intellectual disability.<br><br>METHODS: Using data from the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS), blood samples from 246 participants were analyzed, yielding 404 longitudinal observations (45 Converters, 359 Stable) collected at 0, 16, and 32 months were analyzed. A Support Vector Machine was trained on 25 plasma biomarkers spanning neurodegeneration, inflammation, and vascular health, along with demographic factors (age, sex, ethnicity, karyotype, apolipoprotein E [APOE &#x3b5;4]). Batch-effect correction and feature selection were applied, resulting in 13 key markers.<br><br>RESULTS: The refined model achieved 92.4% sensitivity, 59.9% specificity, and an area under the curve (AUC) of 77.9%, accurately identifying individuals at risk of cognitive decline up to 16 months before clinical progression.<br><br>DISCUSSION: This multi-domain, blood-based machine learning approach demonstrates that plasma biomarkers are valuable non-invasive tools for early detection and risk stratification of cognitive decline in DS.},
}
@article {pmid42449163,
year = {2026},
author = {Adefisan-Adeoye, AO and Oluwadamilare, H and Aisedion, M and Shittu, TS and Amangele, T and Adeoye, TD and Unuofin, JO and Orimolade, BM and Lebelo, SL and Adaramoye, OA},
title = {Neuromodulatory effects of berberine chloride against aluminum chloride/D-Galactose induced Alzheimer-like neurodegeneration model in rats.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-61600-9},
pmid = {42449163},
issn = {2045-2322},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, oxidative stress, neuroinflammation, and neuronal loss. This study evaluated the neuroprotective potential of berberine chloride (BC) against D-Galactose (D-Gal) and aluminum chloride (AlCl3)-induced Alzheimer-like neurodegeneration models in rats using donepezil as a standard drug. Animals were randomly assigned into four groups: control, AD-model (D-Gal 60 mg/kg/day, i.p.+AlCl3 200 mg/kg/day, orally), BC-treated (100 mg/kg/day), and donepezil-treated (2 mg/kg/day). The AD model exhibited significant cognitive deficits, evidenced by reduced spontaneous alternation (39%↓), prolonged escape latency (38%↑), and diminished locomotor activity. BC markedly enhanced endogenous antioxidant defense, elevating superoxide dismutase and catalase activities by 165% and 145% (p < 0.05), while reducing lipid peroxidation and nitric oxide levels in brain tissue (67%↓). BC also markedly suppressed advanced glycation end (AGEs) products by 37% (p < 0.05). Furthermore, BC improved cholinergic function by significantly lowering serum acetylcholinesterase activity (30%↓) and ameilorated hepatic and renal biochemical indices-AST (42%↓), ALT (55%↓), and urea (55%↓). Histopathological examination revealed preservation of hippocampal and cortical neuronal architecture, with reduced neurodegeneration and gliosis in BC-treated animals. Collectively, these findings demonstrate that BC exerts potent neuroprotective, antioxidant, anti-glycation, and anti-inflammatory effects, highlighting its promise as a multi-target candidate for cognitive impairment.},
}
@article {pmid42449182,
year = {2026},
author = {},
title = {Correction to "Systemic piezo1 activation improves cerebrovascular function in Alzheimer's disease".},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71677},
doi = {10.1002/alz.71677},
pmid = {42449182},
issn = {1552-5279},
}
@article {pmid42449187,
year = {2026},
author = {Hansen, N and Sadlonova, M and Esselmann, H and Celano, CM and Derad, C and Asendorf, T and Hohberg, M and Chebbok, M and Heinemann, S and Morgado, B and Titsch, T and Packroß, K and Knopp, CM and Becker, MM and Günther, I and Krasiuk, I and Rediske, AI and Süttmann, NP and Itting, PT and Wirths, O and Kutschka, I and Baraki, H and von Arnim, CAF and Wiltfang, J and , },
title = {Early Alzheimer´s disease blood biomarkers are associated with a higher risk for postoperative long-term cognitive decline: Insights from the FINDERI study.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71631},
doi = {10.1002/alz.71631},
pmid = {42449187},
issn = {1552-5279},
support = {#F/65/21//German Heart Foundation/German Foundation/ ; UIDB/04501/2020//iBiMED/ ; },
mesh = {Humans ; *Biomarkers/blood ; Female ; *Alzheimer Disease/blood ; Male ; tau Proteins/blood ; Amyloid beta-Peptides/blood ; *Postoperative Cognitive Complications/blood ; Aged ; Risk Factors ; *Cardiac Surgical Procedures/adverse effects ; Peptide Fragments/blood ; *Cognitive Dysfunction/blood ; Apolipoprotein E4/blood ; Apolipoproteins E/blood ; *Postoperative Complications/blood ; Neuropsychological Tests ; },
abstract = {BACKGROUND: The study aim is to investigate whether blood biomarkers (BBMs) of Alzheimer's disease (AD) pathology are associated with postoperative cognitive dysfunction (POCD) after cardiac surgery.<br><br>METHODS: Cognitive performance was assessed before and 12 months postoperatively using the Montreal Cognitive Assessment (MoCA) and categorized into stages-minimal (1), notable (2), and substantial (3) decline-in the FIND DElirium RIsk factors (FINDERI) study of patients undergoing cardiac surgery. BBMs were measured preoperatively (amyloid beta [A&#x3b2;]1-42, A&#x3b2;1-40, phosphorylated tau 181 [p-tau181], p-tau217, apolipoprotein E &#x3b5;4 [apoE4] and apoE).<br><br>RESULTS: A total of 394 patients completed follow-up investigations. POCD Stage 1 was observed in 105 (26.6%), POCD Stage 2 in 52 patients (13.2%), and POCD Stage 3 in 30 patients (7.6%). The AT[217]term (ratio A&#x3b2;1-40/1-42 * p-tau217) was significantly associated with POCD stages in multiple logistic regression.<br><br>DISCUSSION: Early Alzheimer's BBMs are associated with POCD in patients, suggesting that our exploratory findings assessing BBMs may support risk stratification, inform decision-making, and contribute to strategies aimed at preventing POCD.},
}
@article {pmid42449193,
year = {2026},
author = {Shaikh, M and Fletcher, P and Zaman, S and , and Brown, S},
title = {Structural MRI across lifespan reveals differential thalamic trajectories in Down syndrome.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71671},
doi = {10.1002/alz.71671},
pmid = {42449193},
issn = {1552-5279},
support = {ARUK-RF2021B-001//Alzheimer's Research&#xa0;UK/ ; NIHR203312//NIHR Cambridge Biomedical Research Centre/ ; },
mesh = {Humans ; *Down Syndrome/pathology/diagnostic imaging/blood ; *Thalamus/pathology/diagnostic imaging ; Male ; Female ; *Magnetic Resonance Imaging ; Middle Aged ; Adult ; Biomarkers/blood ; tau Proteins/blood ; Amyloid beta-Peptides/blood ; Alzheimer Disease/pathology ; Neurofilament Proteins/blood ; },
abstract = {INTRODUCTION: Up to 90% of Down syndrome (DS) patients develop Alzheimer's disease (AD). Sleep disturbance, affecting over 75% of DS patients, is implicated in AD pathogenesis. The thalamus, central to sleep and arousal, shows early vulnerability in DS-related AD.<br><br>METHODS: Structural 3T MRI scans from 253 DS participants (119 males, mean age 43.0&#xa0;&#xb1;&#xa0;9.4 years) and 36 controls (30 males, mean age 43.1&#xa0;&#xb1;&#xa0;12.2 years) from the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) study were analyzed, alongside neurodegenerative plasma biomarker assays (phosphorylated tau [pTau]181, pTau217, neurofilament light chain [NfL], amyloid beta [A&#x3b2;]40, A&#x3b2;42).<br><br>RESULTS: In DS, intracranial volume-adjusted thalamic volume declined with age (t&#xa0;=&#xa0;-2.589, p&#xa0;=&#xa0;0.00987), approximating 2.5% loss per decade. This was linear, gray matter involution-independent, and heterogeneous across nuclei, correlating negatively with pTau and NfL. Controls exhibited no significant volumetric changes.<br><br>DISCUSSION: Anteromedial and posterior thalamic shrinkage in DS AD mirrors sporadic AD. Associations with neurodegenerative biomarkers support thalamic atrophy as a sensitive marker of DS-related AD progression.},
}
@article {pmid42449194,
year = {2026},
author = {Kennedy, JT and Wisch, JK and Handen, BL and Hartley, S and Brickman, AM and Lee, JH and Krinsky-McHale, S and Lai, F and Rosas, H and Head, E and Christian, B and Zaman, S and Lott, IT and Hom, C and Ptomey, LT and Burns, JM and Cohen, A and Tudorascu, D and Laymon, C and Lao, P and Petersen, M and Schmitt, F and Ances, BM},
title = {Age predicts Alzheimer's in Down syndrome better than MRI, plasma, or cognition.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71661},
doi = {10.1002/alz.71661},
pmid = {42449194},
issn = {1552-5279},
support = {/AG/NIA NIH HHS/United States ; U01 AG051406/AG/NIA NIH HHS/United States ; U01 AG051412/AG/NIA NIH HHS/United States ; U19 AG068054/AG/NIA NIH HHS/United States ; P50 AG008702/AG/NIA NIH HHS/United States ; P30 AG062421/AG/NIA NIH HHS/United States ; P50 AG16537//The Alzheimer's Disease Research Centers Program/ ; P50 AG005133/AG/NIA NIH HHS/United States ; P50 AG005681/AG/NIA NIH HHS/United States ; P30 AG062715/AG/NIA NIH HHS/United States ; P30 AG066519/AG/NIA NIH HHS/United States ; U54 HD090256/HD/NICHD NIH HHS/United States ; U54 HD087011/HD/NICHD NIH HHS/United States ; P50 HD105353/HD/NICHD NIH HHS/United States ; UL1 TR001873/TR/NCATS NIH HHS/United States ; UL1 TR002373/TR/NCATS NIH HHS/United States ; UL1 TR001414/TR/NCATS NIH HHS/United States ; UL1 TR001857/TR/NCATS NIH HHS/United States ; UL1 TR002345/TR/NCATS NIH HHS/United States ; U24 AG21886//National Centralized Repository for Alzheimer Disease and Related Dementias/ ; //Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; //NIHR Cambridge Biomedical Research Centre and the Windsor Research Unit, CPFT, Fulbourn Hospital Cambridge, UK/ ; },
mesh = {Humans ; *Down Syndrome/complications/blood/diagnostic imaging ; *Alzheimer Disease/diagnosis/blood/complications/diagnostic imaging ; Female ; Magnetic Resonance Imaging ; tau Proteins/blood ; Male ; Biomarkers/blood ; Middle Aged ; Cognitive Dysfunction/diagnosis ; Aged ; *Cognition/physiology ; *Aging ; Amyloid beta-Peptides/blood ; ROC Curve ; Neuropsychological Tests ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) dementia in Down syndrome (DS) occurs at predictable ages. It is unclear whether age can differentiate across AD stages (amyloid positivity, tau positivity, mild cognitive impairment [MCI], dementia).<br><br>METHODS: Using data from the Alzheimer's Biomarker Consortium-Down Syndrome, we analyzed how well age differentiated stage using receiver operating characteristic curves. We compared areas under the curve (AUC) for age to AUCs for imaging, biofluid, cognitive, motor, and behavioral variables.<br><br>RESULTS: Sample varied by stage and variable. Up to 148 variables and 461 participants were analyzed. Age effectively differentiated amyloid positivity, tau positivity, and MCI (AUCs&#xa0;>&#xa0;0.85) but poorly discriminated MCI from dementia (0.588). No variable was better than age in distinguishing stages, except for MCI/dementia.<br><br>DISCUSSION: Our results show that age alone is effective at staging DS AD. Age is the most reliable correlate of amyloid, tau status, and cognitive impairment in DS and could screen for future clinical trials.},
}
@article {pmid42449255,
year = {2026},
author = {Okutucu, M and Arpa, M},
title = {Evaluation of serum semaphorin-3A and interleukin 6 levels in patients with neovascular age-related macular degeneration.},
journal = {BMC ophthalmology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12886-026-05128-6},
pmid = {42449255},
issn = {1471-2415},
abstract = {PURPOSE: To determine whether serum semaphorin 3 A (Sema3A) and interleukin 6 (IL-6) play a role in the common etiopathogenesis of nAMD and nAMD-associated systemic diseases by evaluating these mediators levels.<br><br>METHODS: This prospective case-control study included 74 patients divided into nAMD (n&#x2009;=&#x2009;33) and a control group (n&#x2009;=&#x2009;41). Serum Sema3A and IL-6 levels were analyzed using the enzyme-linked immunosorbent assay.<br><br>RESULTS: The nAMD group had a statistically higher IL-6 level [5,9 (1-16,9) pg/mL], compared to the control group [1,5 (0,38&#x2009;-&#x2009;2,96) pg/mL] (p&#x2009;<&#x2009;0.001). On the other hand, the Sema3A level of the nAMD group was lower at [26,3 (11,5-100) ng/mL] compared to the control group at [44,7 (16,8-100) ng/mL] (p&#x2009;<&#x2009;0.001). The IL-6 level in the hypertension (+) group [2,5 (0,5-16,9) pg/ml] was significantly higher than that in the hypertension (-) group [1,7 (0,4-15,3) pg/ml] (p&#x2009;<&#x2009;0.001). No significant difference was found between the hypertension (+) and hypertension (-) groups in terms of SEMA3A level. There was a negative correlation between serum SEMA3A and serum IL-6 levels of the whole participants (p&#x2009;<&#x2009;0.001, r=-0.471).<br><br>CONCLUSIONS: Decreased levels of the anti-inflammatory and anti-angiogenic mediator Sema3A and increased levels of inflammatory mediator IL-6 detected in nAMD suggest that these molecules may play a role in systemic manifestations of this syndrome, such as inflammation, cardiovascular diseases, atrial fibrillation, and Alzheimer's disease.<br><br>CLINICAL TRIAL NUMBER: Not applicable.},
}
@article {pmid42449379,
year = {2026},
author = {Suksangkharn, Y and Schott, BH and Zeidman, P and Vockert, N and Lattmann, R and Schütze, H and Yakupov, R and Peters, O and Hellmann-Regen, J and Preis, L and Ersözlü, E and Priller, J and Spruth, EJ and Beckmann, J and Schneider, A and Fliessbach, K and Wiltfang, J and Bartels, C and Rostamzadeh, A and Glanz, W and Incesoy, EI and Teipel, S and Kilimann, I and Goerss, D and Laske, C and Spottke, A and Kronmüller, M and Brosseron, F and Lüsebrink, F and Schmid, M and Kleineidam, L and Stark, M and Hetzer, S and Dechent, P and Jessen, F and Maass, A and Düzel, E and Ziegler, G},
title = {Disruption of temporo-parietal network in Alzheimer's disease and its association with memory impairment.},
journal = {Alzheimer's research &amp; therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02138-w},
pmid = {42449379},
issn = {1758-9193},
abstract = {Alzheimer's disease (AD) is characterised by the accumulation of β-amyloid (Aβ) and tau proteins, resulting in neurodegeneration and cognitive decline. Although Aβ and tau disrupt synaptic function, the association linking these molecular pathologies to network-level dysfunction and memory impairment remains poorly understood. Here, we investigated the effects of Aβ and tau pathology (CSF Aβ42/40 ratio and tau phosphorylated at position 181, p-tau-181, respectively) on effective connectivity related to memory encoding, which may provide a link between synaptic pathology and cognitive outcomes. Functional magnetic resonance imaging (fMRI) during visual memory encoding was acquired from 205 participants in the multicentric DZNE Longitudinal Cognitive Impairment and Dementia Study (DELCODE) across the AD spectrum. Effective connectivity was assessed using Dynamic Causal Modelling (DCM) of task-fMRI data, focusing on the parahippocampal place area (PPA), hippocampus (HC), and precuneus (PCU)-regions central to memory encoding. Disruptions in connectivity between temporal and parietal lobes were associated with both memory impairment and indices of AD pathology. Specifically, reduced positive effective connectivity from the PCU to the PPA and from the HC to the PCU were linked to higher p-tau-181 levels, with an amplification effect observed in the presence of amyloid accumulation for the latter connectivity. The disruption from the PCU to the PPA was found to be associated with decreased memory performance. Together, these findings indicate that temporo-parietal connectivity is associated with both AD molecular pathology and, for a subset of connections, with memory performance.},
}
@article {pmid42449394,
year = {2026},
author = {Hu, W and Zou, Y and Yin, J and Liu, L and Ding, Y and Gao, X and Li, Y and Kong, X},
title = {Unknotting the nexus of asthma and neuroinflammation: from brain network alterations to therapeutic implications.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-026-03955-4},
pmid = {42449394},
issn = {1742-2094},
support = {2023059//Tianjin Municipal Health Commission Research Project/ ; 2024021//Tianjin Traditional Chinese Medicine Key Research Area Project/ ; 2023ZD036//Tianjin Municipal Education Commission Research Project/ ; ZR2024QH041//Natural Science Foundation of Shandong Province/ ; QDKY2023ZD02//Scientific Research Foundation of Qilu Hospital of Shandong University/ ; 2024-WJKY155//Medical and Health Scientific Research Project of Qingdao/ ; },
abstract = {Asthma is increasingly recognized as a systemic inflammatory syndrome that extends beyond the respiratory tract, with emerging evidence highlighting its relevance to neuroinflammation. The lung-brain axis-via interconnected inflammatory, vascular, metabolic, neural, and microbial pathways-provides a framework for understanding how chronic pulmonary disease may sustain or exacerbate neuroinflammatory processes. Mechanistically, asthma promotes blood-brain barrier disruption, systemic inflammation that seeds central neuroinflammation, oxidative stress, mitochondrial dysfunction, gut-lung-brain microbial crosstalk, and sleep fragmentation, all of which are biologically plausible drivers of sustained neuroinflammatory states and consequent neurodegenerative vulnerability. Epidemiological studies link asthma to increased risks of all-cause dementia and Alzheimer's disease, though cohort findings vary. Neuroimaging and biomarker evidence further support neuroinflammatory involvement, revealing altered hippocampal metabolism, white matter abnormalities, elevated plasma glial fibrillary acidic protein and neurofilament light chains, and cerebrospinal fluid markers of synaptic injury in severe or poorly controlled asthma-each reflecting neuroinflammatory or neurodegenerative sequelae. Links with Parkinson's disease and other neurodegenerative disorders remain more preliminary. Notably, asthma severity, phenotype, exacerbation frequency, and corticosteroid burden modulate neurological risk, suggesting that optimal disease control-potentially enhanced by biologic therapies-may confer neuroprotective benefits by dampening neuroinflammation. In conclusion, asthma should not be viewed solely as an airway disorder but as a potentially modifiable contributor to long-term brain vulnerability via neuroinflammatory pathways within the lung-brain axis. Future longitudinal studies integrating detailed phenotyping, biomarkers, and neuroimaging are needed to establish causality and guide anti-neuroinflammatory therapeutic strategies.},
}
@article {pmid42449395,
year = {2026},
author = {Jang, H and Kim, JW and Hwang, JW and Jeong, DW and Ka, J and Kang, DM and Suh, CH and Choi, Y and Oh, M and Kim, JS and Lim, JS and Lee, JH},
title = {Real-world safety and implementation challenges of lecanemab therapy for Alzheimer's disease in South Korea: a single-center experience.},
journal = {Alzheimer's research &amp; therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02141-1},
pmid = {42449395},
issn = {1758-9193},
support = {RS-2022-KH125667//Korea Health Technology R&amp;D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health &amp; Welfare and Ministry of science and ICT, Republic of Korea/ ; 2022-IF-0022//Asan Institute for Life Sciences/ ; },
abstract = {BACKGROUND: Lecanemab, an amyloid-targeting monoclonal antibody, was recently approved for early symptomatic Alzheimer's disease in South Korea. Asians were underrepresented in prior trials, and real-world data from Korea remain scarce, particularly regarding treatment settings, adverse events, and barriers to scalability. We assessed the feasibility and safety of lecanemab among Korean patients in a real-world tertiary hospital.<br><br>METHODS: A total of 112 patients initiated lecanemab treatment between December 2024 and October 2025 at Asan Medical Center. Prevalence of infusion-related reactions (IRRs), Amyloid-Related Imaging Abnormalities (ARIA), treatment discontinuation, and factors limiting implementation were evaluated.<br><br>RESULTS: Among 112 patients (mean age 71 years; 59% female), IRRs occurred in 41 (37%) and were generally mild or moderate under active surveillance. Among 105 at-risk patients who received at least four infusions and had at least one monitoring MRI, ARIA developed in 20 (19%): ARIA-E/H in 6 (5.7%) and isolated ARIA-H in 14 (13.3%). Only 1 patient with isolated ARIA-H presented with transient confusion. Patients with ARIA-E/H were younger, whereas those with ARIA-H were older and more likely to have baseline microhemorrhages. Eleven out of 105 were APOE &#x3b5;4/&#x3b5;4 homozygotes, of whom 5 developed ARIA. The rapid increase in treatment demand exceeded outpatient infusion capacity, resulting in progressively longer waiting times-up to 20 weeks 9 months after program initiation.<br><br>CONCLUSION: This single-center experience from a tertiary referral hospital in Korea demonstrates that lecanemab treatment was feasible and generally well-tolerated, with manageable adverse events including ARIA and IRRs; however, limited infusion capacity, lack of reimbursement, and patient concentration in tertiary centers highlight the need for referral networks and system-level strategies to improve nationwide accessibility.},
}
@article {pmid42449404,
year = {2026},
author = {Azami, H and Antonacci, Y and Blumberger, DM and Brooks, H and Faes, L and Fischer, CE and Flint, A and Herrmann, N and Kumar, S and Gallagher, D and Mah, L and Mulsant, BH and Schoer, N and Pollock, BG and Rajji, TK and , },
title = {Three-order interactions in the alpha band of default mode network EEGs based on O-information rate: insights from aging and Alzheimer's disease.},
journal = {Alzheimer's research &amp; therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02131-3},
pmid = {42449404},
issn = {1758-9193},
abstract = {BACKGROUND: Alpha-band default mode network (DMN) connectivity declines with aging and Alzheimer's disease (AD), yet most electroencephalography (EEG) connectivity studies used pairwise (two-order) measures, such as mutual information rate (MIR). We leveraged O-information rate (OIR) to quantify three-order interactions and to separate redundant from synergistic information processing across frontal, temporal, and parietal DMN regions. We hypothesized that, extending established findings of reduced pairwise connectivity, (i) OIR (and its components) would be reduced in older versus younger adults and in AD versus healthy controls (HC); (ii) combining MIR with OIR would improve classification compared with MIR alone; and (iii) OIR measures would correlate positively with global cognition (as assessed by the Montreal Cognitive Assessment (MoCA)).<br><br>METHODS: Resting-state EEG from two samples-healthy adult lifespan aging (95 younger; 93 older) and AD spectrum (44 HC; 84 amnestic mild cognitive impairment [aMCI]; 41 AD)-was source-localized using eLORETA to DMN regions. Alpha band (8-13&#xa0;Hz) MIR and OIR were computed through multivariate spectral analysis. Group differences were tested using t-tests or analysis of covariance (ANCOVA) with multiple comparison correction. Classification (OIR, MIR, demographic, and combined feature sets) used cross-validated logistic-regression, linear-SVM, and random-forest models, with bootstrap 95% confidence intervals and DeLong tests for AUC comparisons.<br><br>RESULTS: OIR and its redundancy component were significantly reduced in older versus younger adults and in AD versus HC/aMCI, with no HC-aMCI differences. The synergy component showed no group differences. MIR decreased broadly with aging and fronto-parietally in AD. Regarding classification (AD spectrum dataset, cross-validated AUC), OIR-based metrics outperformed MIR (AD vs. HC: 0.93 vs. 0.73; AD vs. aMCI: 0.93 vs. 0.71; aMCI vs. HC: 0.48 vs. 0.46). Combining demographics with all information-theoretic features improved AD vs. HC (0.98; DeLong p&#x2009;=&#x2009;0.023) but not AD vs. aMCI (0.93), where OIR alone was already at ceiling; no feature set exceeded chance for aMCI vs. HC. After correction, OIR and its redundancy component correlated positively with MoCA scores; MIR and the synergy component did not.<br><br>CONCLUSIONS: Alpha-band three-order DMN interactions-particularly redundant information processing-decline with aging and AD and provide additional information beyond two-order connectivity for diagnostic classification. OIR offers complementary measures to traditional metrics, and future studies should examine its value when combined with more established AD biomarkers.},
}
@article {pmid42449489,
year = {2026},
author = {Research International, B},
title = {RETRACTION: Effects of Phoenix dactylifera against Streptozotocin-Aluminium Chloride Induced Alzheimer's Rats and Their In Silico Study.},
journal = {BioMed research international},
volume = {2026},
number = {1},
pages = {e9797803},
doi = {10.1155/bmri/9797803},
pmid = {42449489},
issn = {2314-6141},
}
@article {pmid42449500,
year = {2026},
author = {Buckley, RF and Townsend, DL and Birkenbihl, CJ and Cuppels, M and Coughlan, GT and Seto, MT and Brown, JA and Properzi, MJ and Hönig, MC and Li, A and Schultz, AP and Chhatwal, J and Yang, HS and Arnold, S and Kivisäkk, P and James, BD and O'Bryant, S and Rissman, RA and Petersen, M and Caldwell, JZK and Betthauser, T and Oomens, JE and Carrigan, M and Healy, B and Condado, JG and Johnson, SC and Yau, WW and Langford, O and Farrell, M and Amariglio, RE and Rentz, DM and Papp, KV and Brookmeyer, R and Hohman, TJ and Donohue, M and Aisen, PS and Johnson, KA and Sperling, RA and , and , },
title = {Prognostic Value of Blood-Based P-Tau217 Levels for Progression to Cognitive Impairment.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2026.12556},
pmid = {42449500},
issn = {1538-3598},
abstract = {IMPORTANCE: Blood-based biomarkers for Alzheimer disease, particularly plasma phosphorylated tau 217 (p-tau217), accurately reflect early Alzheimer disease brain pathology in cognitively unimpaired individuals, but estimates of absolute risk of progression to cognitive impairment across multiple cohorts are needed.<br><br>OBJECTIVE: To estimate absolute risk of progression to cognitive impairment and rates of cognitive decline based on plasma p-tau217 across cognitively unimpaired older adults.<br><br>Longitudinal cohort study using harmonized data from 2684 cognitively unimpaired older adults (defined within cohort) across 6 observational and clinical trial cohorts based in North America, Japan, and Australia. The earliest enrollment was in 2004, with most recent follow-up in 2025.<br><br>EXPOSURE: Baseline plasma p-tau217.<br><br>MAIN OUTCOMES AND MEASURES: The primary outcome was time to progression to cognitive impairment (mild cognitive impairment, dementia, or 2 consecutive global Clinical Dementia Rating scores &#x2265;0.5). The secondary outcome was longitudinal change on the latent Preclinical Alzheimer Cognitive Composite (PACC; higher values indicate better performance).<br><br>RESULTS: Among the 2684 participants (median [IQR] age, 69.6 [66.2-74.2] years; 1697 [63%] female), there were 478 events of progression to cognitive impairment over a median follow-up of 5.4 years (maximum follow-up of 13.5 years). Each 1-SD increase in baseline p-tau217 level was associated with an increased risk of progression to cognitive impairment (hazard ratio, 1.38 [95% CI, 1.30-1.46]), and the association remained significant after adjustment, including &#x3b2;-amyloid positron emission tomography scan Centiloids (hazard ratio, 1.32 [95% CI, 1.24-1.41]). Participants with high (1.1-2.4 SD) and very high (>2.5 SD) baseline p-tau217 had 24% (95% CI, 20%-28%) and 38% (95% CI, 33%-43%) absolute risk of progression over 5 years, respectively, and risk was markedly higher over 10 years, although longer-term estimates were constrained by limited data. Elevated p-tau217 was also associated with faster cognitive decline based on change in latent PACC score. Among the overall sample, baseline latent PACC scores ranged from -0.8 to 2.7. The 5-year annualized decline for the very high p-tau217 group was -0.07 latent PACC units/y (95% CI, -0.10 to -0.05), relative to 0.03 units/y (95% CI, 0.02-0.04) in the low p-tau217 group.<br><br>CONCLUSIONS AND RELEVANCE: In a pooled sample of multiple selected cohorts of cognitively unimpaired older adults, higher plasma p-tau217 levels were consistently associated with increased risk of clinical progression and accelerated cognitive decline. By providing time-specific absolute risk estimates, these findings support the potential of p-tau217 for prognostic model development, with direct implications for future trial design. Further validation in unselected populations is needed to inform individual prognosis and clinical decision-making in cognitively unimpaired individuals.},
}
@article {pmid42449502,
year = {2026},
author = {Schindler, SE and Wolk, DA},
title = {Predicting Risk of Cognitive Impairment With Alzheimer Disease Blood Biomarkers.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2026.13322},
pmid = {42449502},
issn = {1538-3598},
}
@article {pmid42449559,
year = {2026},
author = {Tsai, HY and Chang, CI and Yeh, YT and Tsai, PL and Lin, YL and Ho, CT and Chen, YK},
title = {An acetylated nobiletin derivative alleviates methylglyoxal-induced cognitive impairment and modulates gut microbiota.},
journal = {Journal of the science of food and agriculture},
volume = {},
number = {},
pages = {},
doi = {10.1002/jsfa.70887},
pmid = {42449559},
issn = {1097-0010},
support = {//National Science and Technology Council/ ; },
abstract = {BACKGROUND: Nobiletin, a citrus polymethoxyflavone recognized as a functional food component with diverse health benefits, has been reported to exhibit antioxidant, anti-inflammatory and neuroprotective properties. Methylglyoxal (MG), a highly reactive dicarbonyl compound and precursor of advanced glycation end products, contributes to oxidative stress, tau hyperphosphorylation and amyloid-β (Aβ) accumulation, which are key events linking diabetes to Alzheimer's disease. In this study, an acetylated derivative of nobiletin, 5-acetoxy-6,7,8,3',4'-pentamethoxyflavone (5-AN), was evaluated for its neuroprotective and gut microbiota-modulating effects against MG-induced Alzheimer-like cognitive deficits in mice.<br><br>RESULTS: Oral administration of 5-AN (10 and 20&#x2009;mg&#x2009;kg[-1]&#x2009;day[-1] for 13&#x2009;weeks) improved behavioral performance in MG-treated mice, with the 20&#x2009;mg&#x2009;kg[-1] group showing significant improvement in spatial learning, recognition memory and anxiety-like behavior. Immunohistochemical and Western blot analyses showed that 5-AN reduced hippocampal tau phosphorylation and A&#x3b2; accumulation at the same time as restoring phosphoinositide 3-kinase (PI3K)/Akt/glycogen synthase kinase-3&#x3b2; signaling, enhancing brain-derived neurotrophic factor expression and reducing cleaved caspase-3 expression. Gut microbiota analysis showed that MG exposure induced dysbiosis, characterized by reduced Bacteroides_H acidifaciens and increased MG-associated taxa such as Alistipes and Dysosmobacter, whereas 5-AN supplementation significantly reversed these alterations. Functional prediction analysis further indicated that MG-induced dysbiosis was associated with disruptions in neuroimmune-related pathways, including circadian entrainment, Th17 cell differentiation, interleukin-17 signaling and PI3K/Akt signaling, whereas 5-AN supplementation significantly restored these pathways.<br><br>CONCLUSION: These findings indicate that acetylated nobiletin may serve as a promising food-derived bioactive compound for mitigating cognitive impairment through coordinated modulation of neuronal function and gut microbiota. &#xa9; 2026 Society of Chemical Industry.},
}
@article {pmid42449771,
year = {2026},
author = {Sotoudeh, H and Alizadeh, M},
title = {The Centiloid Scale in Amyloid PET Imaging: Current Role in Alzheimer's Disease Diagnosis, Treatment Planning, and Monitoring During Anti-Amyloid Therapy: A Clinical Perspective.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {16},
number = {13},
pages = {},
doi = {10.3390/diagnostics16131989},
pmid = {42449771},
issn = {2075-4418},
abstract = {Amyloid positron emission tomography (PET) has become a critical tool in the diagnosis and treatment of Alzheimer's disease (AD). The Centiloid (CL) scale, a tracer/scanner-independent, standardized quantification unit introduced in 2015, transforms tracer- and scanner-specific standardized uptake value ratios (SUVRs) into a common metric anchored at 0 CL in young cognitively unimpaired individuals and 100 CL in patients with mild-to-moderate AD. This review synthesizes current evidence on the clinical role of the CL scale across three domains: (1) diagnostic classification, with established thresholds of <10 CL for amyloid negativity and >30 CL for high-certainty amyloid positivity; (2) treatment eligibility, where a 2024 Alzheimer's Association Research Roundtable consensus of global experts recommended a 24-30 CL threshold for initiating lecanemab or donanemab therapy in patients with mild cognitive impairment (MCI) or mild AD dementia; and (3) longitudinal therapy monitoring, in which serial CL measurements provide objective evidence of amyloid clearance. We also review the emerging 'gray zone' (10-30 CL) as a distinct clinical entity with elevated progression risk, the critical role of CL quantification in complementing visual reads in borderline cases, technical limitations, and the future integration of CL in clinical practice. This review also critically addresses the ongoing debate on whether amyloid clearance represents a reliable surrogate for clinical benefit, strategies for managing discordant biomarker findings, and the practical feasibility of serial amyloid PET in routine care. With FDA approval of both lecanemab and donanemab, familiarity with the CL scale as a functional treatment biomarker is increasingly relevant for neuroradiologists and nuclear medicine physicians in the modern AD care pathway. As with all imaging modalities, the CL has physiologic and technical limitations. Although the CL scale was designed to reduce heterogeneity across tracers and scanner platforms, the impact of different commercial quantification software packages on CL output remains incompletely characterized. Consistent use of a single software platform for longitudinal monitoring in individual patients is therefore recommended.},
}
@article {pmid42449811,
year = {2026},
author = {Gasmi, K and Ammar, LB and Krichen, M and Alghuried, A},
title = {FLAME: Federated Learning and Aggregated Multi-Model Ensemble for Multi-Class Alzheimer's Disease Stage Classification from Structured Clinical Data.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {16},
number = {13},
pages = {},
doi = {10.3390/diagnostics16132029},
pmid = {42449811},
issn = {2075-4418},
support = {PSAU/2024/03/31787//Prince Sattam Bin Abdulaziz University/ ; },
abstract = {Background/Objectives: The precise identification of Alzheimer's disease (AD) stages through clinical data is crucial for early diagnosis and suitable therapy. This classification remains troublesome due to overlap in cognitive profiles across different phases of illness progression. This study presents a comprehensive and advanced diagnostic system, termed FLAME, featuring an enhanced federated learning architecture for privacy-preserving multi-institutional implementation. It provides a systematic review of machine learning (ML) and deep learning (DL) models for the classification of five stages of Alzheimer's disease (AD). The models include cognitively normal (CN), subjective memory complaints (SMC), early mild cognitive impairment (EMCI), late mild cognitive impairment (LMCI), and Alzheimer's disease (AD). Methods: Sixteen traditional machine learning models and eleven deep learning architectures-including FT-Transformer and NODE-were evaluated using a structured clinical dataset comprising 362 features. A hybrid ensemble was created at the probability level by combining the two top-performing models, LightGBM and a five-layer DNN. The weights of this ensemble were automatically optimised using a Genetic Algorithm (GA) with Macro-F1 as the fitness criterion, confirmed stable across 30 independent runs (w★=0.5024±0.0001). A federated learning architecture was then established, deploying the DNN across non-IID clients while keeping LightGBM centralised. We examine four distinct aggregation algorithms: FedAvg, FedProx, FedNova, and SCAFFOLD. Results: Among all deep learning architectures, FT-Transformer achieved the highest standalone performance (accuracy = 0.7810, κ = 0.7081). The five-layer deep neural network (DNN) was selected as the DL representative for the hybrid ensemble. LightGBM attained superior machine learning performance (accuracy = 0.8156, κ = 0.7537), confirmed deterministic across 10 seeds. The LightGBM vs. XGBoost difference is not statistically significant (McNemar p=0.4227). The GA-optimised hybrid ensemble (w = 0.685) surpassed both individual baselines across all evaluation metrics. The FedNova hybrid design achieved superior overall performance in federated configurations, surpassing all centralised arrangements in accuracy (accuracy = 0.8213, κ 0.7614). Conclusions: Evolutionary ensemble optimisation combined with federated learning provides a robust, scalable, and privacy-preserving solution for AD stage classification, offering a clinically viable framework for real-world multi-institutional decision-support systems. However, the AD class remains severely under-recalled across all configurations (F1 ≤ 0.21), identifying this as the primary open challenge for clinical translation.},
}
@article {pmid42449815,
year = {2026},
author = {Camoni, L and Dondi, F and Pietrzak, A and Rinaldi, R and Tomasoni, F and Cossandi, M and Lucchini, S and Viganò, GL and Spiazzi, L and Bertagna, F},
title = {Technical Optimization Strategies for Amyloid PET Under Challenging Acquisition Conditions: A Comprehensive Narrative Review.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {16},
number = {13},
pages = {},
doi = {10.3390/diagnostics16132033},
pmid = {42449815},
issn = {2075-4418},
abstract = {Amyloid PET is increasingly used to confirm cerebral amyloid burden, but standard acquisition may be compromised by head motion, limited patient cooperation, reduced effective counts, premature scan termination, or non-repeatable imaging conditions. This comprehensive narrative review used a structured evidence-mapping approach in accordance with SANRA quality criteria. A structured literature search was performed in PubMed/MEDLINE, Scopus, and Web of Science up to 15 March 2026. Eligible studies included clinical, phantom, or hybrid studies addressing acquisition-time reduction, injected-activity reduction or low-count imaging, motion correction, or artificial intelligence-based image enhancement. Findings were synthesized narratively because of substantial heterogeneity in tracers, scanners, protocols, reconstruction methods, populations, comparators, and endpoints. Sixteen studies were included. Moderate reductions in acquisition time or effective counts generally preserved semiquantitative performance, whereas visual interpretation became more vulnerable under more aggressive reductions, borderline amyloid status, or reduced image quality. Artificial intelligence-based restoration improved image-quality metrics and supported interpretation of short- or low-count acquisitions, but evidence remained model-specific. Motion correction was supported by one amyloid-specific [[18]F]flutemetamol PET/CT study and should be interpreted as a potentially useful but under-replicated strategy. Current evidence supports cautious, tracer-, scanner-, reconstruction-, and task-specific optimization under challenging acquisition conditions rather than universal protocol reduction or direct generalization to motion-prone, poorly cooperative, or non-repeatable acquisition scenario. Reduced protocols, artificial intelligence-based restoration, and motion correction should remain locally validated supportive strategies, not substitutes for standard acquisition.},
}
@article {pmid42449841,
year = {2026},
author = {Schlichtmann, B and Arslan, B and Johnson, K and Patzlaff, J and Unruh, D and Szabo, M and Holland, M and Todtleben, J and Salvati, M and Tan, K and Andreasson, U and Hinson, J and Levin, S and Zetterberg, H and Benedet, AL and Hill, HA},
title = {Analytical Performance and Evaluation in Clinical Cohorts of a Fully Automated Immunoassay for Plasma Glial Fibrillary Acidic Protein.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {16},
number = {13},
pages = {},
doi = {10.3390/diagnostics16132060},
pmid = {42449841},
issn = {2075-4418},
support = {2023-00356//Swedish Research Council/ ; },
abstract = {Background/Objectives: This study aimed to perform analytical validation and evaluation of the clinical performance of the Access Glial Fibrillary Acidic Protein (GFAP) research-use-only (RUO) immunoassay (Beckman Coulter) in plasma. Methods: A fully automated GFAP immunoassay was developed and evaluated for analytical validity and clinical performance. Analytical validation assessed precision, sensitivity, linearity, analytical specificity, and the stability of calibrators and samples. Evaluation of predefined clinical performance criteria included method comparison against the Quanterix Simoa GFAP Advantage Plus (RUO) assay and assessment of GFAP levels between participants with Alzheimer's disease (AD) and healthy controls. Results: The Access GFAP (RUO) immunoassay met all analytical criteria. Precision yielded coefficients of variation (CVs) < 10% across all concentration ranges. Sensitivity parameters included a lower limit of quantification (LLoQ) of 0.083 pg/mL and an analytical measurement range of 0.083-640 pg/mL. Linearity demonstrated <9% deviation across the measurement range. Interference testing showed <7% deviation for cross-reactants, common medications and AD-specific therapeutics. Plasma samples remained stable over 48 h at room temperature (<4% deviation) and five freeze-thaw cycles (<9% deviation). Method comparison demonstrated strong correlation with Simoa GFAP (R = 0.945) but systematic proportional bias, yielding 3% (slope = 0.030) of Simoa values. Samples from participants with AD exhibited significantly elevated GFAP levels (median 9.0 pg/mL, IQR: 5.3-19.1) versus controls (median 3.4 pg/mL, IQR: 1.5-6.5; p < 0.001). Conclusions: The high-throughput Access GFAP (RUO) immunoassay achieved all analytical performance criteria and demonstrated differences in GFAP levels between AD and healthy control sample cohorts. These findings support its use in research settings and as a foundation for future clinical implementation and may inform future studies evaluating cross-platform harmonization and potential clinical applications.},
}
@article {pmid42449859,
year = {2026},
author = {Syed, AH and Alhayyani, S},
title = {An Exploratory Six-Probe Blood RNA Signature for Predicting 12-Month Cognitive Decline Along the Alzheimer's Disease Continuum: An Interpretable Machine Learning Study.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {16},
number = {13},
pages = {},
doi = {10.3390/diagnostics16132078},
pmid = {42449859},
issn = {2075-4418},
support = {IPP: 569-830-2025//Deanship of Scientific Research (DSR) at King Abdulaziz University/ ; },
abstract = {Background/Objectives: Predicting how fast a patient with Alzheimer's disease will decline over the next year remains a challenge. Existing blood transcriptomic studies have not established whether probe selection is reproducible, whether the signal is transcriptional or reflects immune cell shifts, or whether they generalise across platforms. Methods: We applied five steps to 96 ADNI-GO whole-blood microarray samples (Affymetrix HG-U219; 12-month MMSE change): PyImpetus Markov Blanket selection, Elastic Net with leave-one-out cross-validation (LOOCV), SHAP attribution, MCP-counter cell-type deconvolution, and cross-platform mapping into AddNeuroMed (GSE63060, n = 329, Illumina). Feature selection preceded cross-validation without constituting data leakage. Results: The same six probes emerged across four independent runs (Jaccard J = 0.214, p = 0.03): AQP7, RPS5, CHD2, SNX5, ASS1, and an uncharacterised chr12q15 transcript. The panel achieved LOOCV MAE = 1.388 and R[2] = 0.247, outperforming the full-probe baseline by 14.9%. All probes survived immune cell correction with signs intact. SNX5 replicated in AddNeuroMed (r = -0.170, p = 0.002). Conclusions: The exploratory six-probe blood RNA panel predicts 12-month cognitive decline (LOOCV R[2] = 0.247) with transcriptional origin confirmed by cell-type deconvolution and cross-platform evidence for SNX5. External testing in ADNI-2 (n = 91, R[2] = -0.222) showed that generalisation depends on visit-timepoint matching, indicating clinical utility cannot yet be claimed and defining conditions for prospective validation. Code and a research prototype tool are publicly available.},
}
@article {pmid42449943,
year = {2026},
author = {Oloruntimehin, S and Malogolovkin, A},
title = {Trends in the Engineering of Adeno-Associated Virus (AAV) for Precision Gene Delivery to the Central Nervous System (CNS).},
journal = {International journal of molecular sciences},
volume = {27},
number = {13},
pages = {},
doi = {10.3390/ijms27135668},
pmid = {42449943},
issn = {1422-0067},
mesh = {Humans ; *Dependovirus/genetics ; *Genetic Therapy/methods ; Animals ; *Gene Transfer Techniques ; *Central Nervous System/metabolism ; *Genetic Vectors/genetics/administration &amp; dosage ; Gene Therapy Agents ; Muscular Atrophy, Spinal/therapy/genetics ; *Central Nervous System Diseases/therapy/genetics ; },
abstract = {Rare genetic disorders of the central nervous system (CNS) remain some of the most complex and challenging diseases to treat for several reasons. Targeting the CNS, especially the brain, presents one of the greatest obstacles in gene therapy using adeno-associated virus (AAV) vectors. Although various AAVs have been identified for their ability to transduce different cells in the CNS, their effectiveness and efficiency are significantly limited by the presence of neutralising antibodies (NAbs) and restricted cargo capacity. Despite these challenges, our understanding of AAV structure and technological advances continue to enable researchers to develop innovative strategies that have resulted in groundbreaking, FDA-approved therapeutic products now available for Leber congenital amaurosis (LCA) (Luxturna[®]), spinal muscular atrophy (SMA) (Zolgensma[®]), and the two recent gene therapy products for aromatic L-amino acid decarboxylase (AADC) deficiency, Kebilidi[®] and Upstaza[®], which currently hold FDA and EMA approval, respectively. This review aims to highlight recent advances in the field of AAV gene therapy for neurological disorders, identify research gaps, and suggest areas for future investigation to enable potential breakthroughs particularly in neurodegenerative, neurodevelopmental, and neuromuscular disorders. We foresee that more tissue- and cell-specific AAV vectors designed using AI-powered platforms will emerge to precisely and efficiently target specific brain regions, transforming how CNS disorders are treated.},
}
@article {pmid42449980,
year = {2026},
author = {Li, Y and Zhao, H and Wu, J and Hu, Y and Pan, J and Frimpong, AO and Xie, B and Yang, W and Sun, M and Chen, W and Wang, P and Shao, C},
title = {Vitamin K2 Promotes Mitochondrial Structural and Functional Homeostasis to Ameliorate Alzheimer Pathology by Targeting the EGFR-Ras-ERK Signaling Axis.},
journal = {International journal of molecular sciences},
volume = {27},
number = {13},
pages = {},
doi = {10.3390/ijms27135708},
pmid = {42449980},
issn = {1422-0067},
mesh = {Animals ; *Alzheimer Disease/metabolism/drug therapy/pathology ; *Mitochondria/drug effects/metabolism/ultrastructure ; ErbB Receptors/metabolism ; Homeostasis/drug effects ; *Vitamin K 2/pharmacology ; Humans ; *MAP Kinase Signaling System/drug effects ; Drosophila melanogaster ; *ras Proteins/metabolism ; Signal Transduction/drug effects ; Disease Models, Animal ; Reactive Oxygen Species/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by β-amyloid (Aβ) accumulation and a breakdown of mitochondrial homeostasis. Vitamin K2 (VK2) has emerged as a potential neuroprotective agent, yet the specific molecular cascades linking its intervention to the restoration of mitochondrial integrity remain poorly understood. This study utilizes an AD Drosophila model to investigate the efficacy of VK2 and elucidates its multidimensional regulatory mechanisms. Behavioral analysis showed that VK2 significantly rescued locomotor impairments, improving both vertical climbing and horizontal walking performance. Crucially, VK2 intervention achieved a systemic rescue of mitochondrial health: transmission electron microscopy (TEM) confirmed the preservation of mitochondrial ultrastructure and cristae density, while biochemical assays demonstrated a robust recovery of bioenergetic markers, including ATP levels and the NAD[+]/NADH ratio. Furthermore, VK2 treatment stabilized the mitochondrial membrane potential (MMP) and effectively attenuated the accumulation of reactive oxygen species (ROS). To identify the molecular drivers of this recovery, an unbiased integration of human clinical transcriptomic data and network pharmacology prioritized the EGFR-Ras-ERK signaling axis as a central hub. In vivo validation confirmed that VK2 suppresses the pathological overactivation of this cascade. VK2 reduced EGFR phosphorylation in parallel with the effects observed for the EGFR inhibitor Gefitinib. Collectively, our findings show that VK2 ameliorates locomotor deficits and mitochondrial dysfunction in Aβ42-expressing flies and that these effects are associated with suppression of the EGFR-Ras-ERK signaling axis. Further studies are required to establish direct target engagement and pathway causality.},
}
@article {pmid42450002,
year = {2026},
author = {Kim, Y and Jung, YK},
title = {Proteasome Dysfunction and Aggregation-Prone Proteins in Neurodegenerative Diseases: From Mechanisms to Therapeutic Opportunities.},
journal = {International journal of molecular sciences},
volume = {27},
number = {13},
pages = {},
doi = {10.3390/ijms27135730},
pmid = {42450002},
issn = {1422-0067},
support = {RS-2025-00519823//National Research Foundation of Korea/ ; RS-2024-00439842//National Research Foundation of Korea/ ; },
mesh = {Humans ; *Proteasome Endopeptidase Complex/metabolism ; *Neurodegenerative Diseases/metabolism/therapy/pathology/drug therapy ; Animals ; Proteostasis ; *Protein Aggregation, Pathological/metabolism ; *Protein Aggregates ; Proteotoxic Stress ; Ubiquitin/metabolism ; Proteolysis ; Oxidative Stress ; },
abstract = {Neurodegenerative diseases are characterized by the accumulation of misfolded and aggregation-prone proteins, reflecting a failure of proteostasis. The ubiquitin-proteasome system (UPS), a major pathway for selective intracellular protein degradation, is essential for maintaining neuronal protein homeostasis. Proteasome dysfunction has been implicated in several major neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), although its extent and mechanisms vary across disease contexts. In this review, we examine current evidence for proteasome dysfunction in neurodegeneration and discuss how disease-associated proteins impair proteasome function through direct inhibition, defective substrate processing, and sequestration into protein aggregates. We also address the contribution of oxidative stress, neuroinflammation, and aging to proteasome dysregulation. Finally, we highlight emerging therapeutic strategies aimed at restoring proteasome function, including pharmacological activation, modulation of proteasome assembly and stability, and targeted protein degradation approaches. Understanding the context-dependent nature of proteasome dysfunction will be important for developing effective proteostasis-based therapies.},
}
@article {pmid42450004,
year = {2026},
author = {Petrov, W and Ślebioda, D and Kozińska, R and Kukla, K and Petrov, P and Sroka, M and Tesyna, J and Puźniak, G and Kudliński, M and Rejda, T and Skowron, I and Chłopaś-Konowałek, A},
title = {Analysis of the Efficacy of Acetylcholinesterase Inhibitors in the Treatment of Alzheimer's Disease, Literature Review.},
journal = {International journal of molecular sciences},
volume = {27},
number = {13},
pages = {},
doi = {10.3390/ijms27135733},
pmid = {42450004},
issn = {1422-0067},
mesh = {Humans ; *Cholinesterase Inhibitors/therapeutic use/pharmacology ; *Alzheimer Disease/drug therapy/metabolism ; Animals ; Acetylcholinesterase/metabolism ; Rivastigmine/therapeutic use ; },
abstract = {The term 'dementia' encompasses a diverse group of progressive neurodegenerative disorders, the common feature of which is the deterioration of higher cortical functions. This process not only involves memory deficits and language communication disorders, but also executive dysfunction and loss of emotional control, which ultimately leads to a complete loss of the patient's independence. Within this group of disorders, Alzheimer's disease (AD) presents the most serious clinical challenge, characterized by a unique neuropathological triad: the presence of extracellular β-amyloid plaques, intracellular neurofibrillary tangles of tau protein, and widespread dysfunction of cholinergic transmission. The cholinergic hypothesis remains the cornerstone of the current understanding of cognitive impairment in AD. It posits that progressive dementia is caused by the selective degeneration of neurons in the anterior basal forebrain, resulting in a drastic reduction in acetylcholine (ACh) levels in the synaptic cleft. In the absence of a causal treatment, acetylcholinesterase inhibitors (AChEIs) remain the standard of care. Their pharmacological action is based on the inhibition of the AChE enzyme, which allows neurotransmission deficits to be compensated for by prolonging the half-life of acetylcholine at the synapse. This literature review presents a synthesis of the efficacy and safety of classic and novel AChEIs. A comprehensive search of the PubMed, Scopus, and Cochrane Library databases was conducted for clinical data published up to 2026. Evidence from key trials indicates that standard AChEIs induce significant cognitive stabilization compared to placebo, with rivastigmine maximizing daily living parameters via transdermal delivery. However, their therapeutic impact remains strictly symptomatic without arresting neurodegeneration. Conversely, emerging agents like huperzine A and the translation-blocker Posiphen demonstrate disease-modifying potential by modulating CSF biomarkers associated with amyloid and tau proteins. Clinically, while traditional regimens are limited by gastrointestinal toxicities, transitioning toward innovative multi-target structures represents a necessary shift to address both cognitive decline and neurodegeneration.},
}
@article {pmid42450018,
year = {2026},
author = {Kang, H and Kim, H and Kim, WJ and French, L and Oh, H and An, SSA},
title = {Vitronectin Modulates Plasma Aβ Oligomerization Propensity Within Altered Albumin Interactome Networks in Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {13},
pages = {},
doi = {10.3390/ijms27135744},
pmid = {42450018},
issn = {1422-0067},
support = {S3355514//Ministry of SMEs and Startups/ ; },
mesh = {*Vitronectin/metabolism/blood ; *Alzheimer Disease/metabolism/blood/pathology ; *Amyloid beta-Peptides/blood/metabolism/chemistry ; Humans ; Protein Binding ; Protein Multimerization ; Proteomics/methods ; Protein Interaction Maps ; *Albumins/metabolism ; Biomarkers/blood ; },
abstract = {Amyloid beta (Aβ) oligomers are key mediators of synaptic dysfunction and neural circuit impairment in Alzheimer's disease (AD). While plasma Aβ oligomerization propensity (OAβ) correlates with cerebral amyloid pathology and cognitive decline, the systemic modulators of OAβ remain poorly understood. In this study, we identified the albumin interactome (albumin and its associated proteins) as a critical regulator of OAβ. Selective depletion of the albumin interactome from plasma eliminated the OAβ difference between amyloid PET (A-PET)- and A-PET+ individuals. Proteomic analysis revealed widespread network alterations within the albumin interactome of A-PET+ individuals. Notably, vitronectin (VTN) was identified as a key hub protein that was significantly reduced in A-PET+ individuals. Functional assays and in silico modeling demonstrated that VTN directly bound to Aβ and inhibited its oligomerization. Additionally, plasma VTN levels distinguished A-PET status. These findings suggest that systemic changes in the albumin interactome, particularly the reduction in VTN, are associated with dysregulated Aβ dynamics in plasma. Our results provide novel insights into systemic mechanisms underlying AD pathology and identify VTN as a potential peripheral modulator and biomarker of cerebral amyloid pathology.},
}
@article {pmid42450021,
year = {2026},
author = {Kang, HY and Jang, BK and Yun, SH and Jeong, HY and Park, E and Oh, KI and Jeong, J and Jeong, SY},
title = {Aronia Bioactive Fraction-Alginic Acid Nanocomplex-Modulates Tau Phosphorylation and Aggregation in Cell Models of Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {13},
pages = {},
doi = {10.3390/ijms27135748},
pmid = {42450021},
issn = {1422-0067},
support = {RS-2022-KH130303//Ministry of Health and Welfare/ ; RS-2021-KH113820//Ministry of Health and Welfare/ ; RS-2025-25303051//Ministry of Health and Welfare/ ; },
mesh = {*tau Proteins/metabolism ; Humans ; *Alzheimer Disease/metabolism/drug therapy/pathology ; Phosphorylation/drug effects ; *Alginic Acid/pharmacology/chemistry ; HEK293 Cells ; Glycogen Synthase Kinase 3 beta/metabolism ; Protein Aggregates/drug effects ; Cell Line, Tumor ; *Plant Extracts/pharmacology/chemistry ; Proto-Oncogene Proteins c-akt/metabolism ; },
abstract = {Preventing or reversing Tau hyperphosphorylation and aggregation represent critical objectives in the development of effective therapies for Alzheimer's disease. The present study investigated the potential of a novel Aronia bioactive fraction-alginic acid nanocomplex (AANCP)-to simultaneously inhibit pathological features of Alzheimer's disease. Evaluations of Aronia bioactive fraction (ABF) and low-molecular-weight alginic acid (LAA), utilized both individually and as AANCP, were conducted in HEK293-TauP301L and SH-SY5Y-TauP301L cell models of Alzheimer's disease. Both ABF and LAA reduced the expression of total Tau and Tau phosphorylated at Ser396 in a concentration-dependent manner, with AANCP demonstrating significant synergistic activity of its components. Notably, the optimal AANCP ratio was 1:1 and 1:8 for inhibiting Tau phosphorylation and Tau aggregation, respectively. Mechanistically, AANCP inhibited Tau phosphorylation by upregulating p-Akt (phosphorylated protein kinase B) and p-GSK-3β (phosphorylated glycogen synthase kinase-3 beta), while also enhancing the activity of methylated PP2A, a key Tau phosphatase. Furthermore, AANCP exhibited superior efficacy in inhibiting heparin-induced Tau aggregation compared to the individual components. Analysis of autophagy markers indicated that the nanocomplex enhanced Tau clearance, as shown by increased LC3-II and Beclin-1 levels and reduced p62 levels. These results suggest AANCP as a promising therapeutic candidate that simultaneously reduces Tau phosphorylation and aggregation and facilitates autophagic Tau clearance, offering a potent, synergistic strategy for treating Alzheimer's disease.},
}
@article {pmid42450026,
year = {2026},
author = {Stępnik, K},
title = {Curcumin in Alzheimer's Disease: From Mechanistic Insights to Translational Challenges and Emerging Curcuminoid Strategies.},
journal = {International journal of molecular sciences},
volume = {27},
number = {13},
pages = {},
doi = {10.3390/ijms27135754},
pmid = {42450026},
issn = {1422-0067},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Curcumin/therapeutic use/pharmacology/analogs &amp; derivatives/chemistry ; Animals ; Oxidative Stress/drug effects ; Diarylheptanoids/therapeutic use/pharmacology ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder driven by complex interactions between protein aggregation, oxidative stress, neuroinflammation, and cellular dysfunction. Among plant-derived compounds, curcumin has emerged as one of the most extensively studied polyphenols due to its broad spectrum of biological activities. This review provides a critical synthesis of the mechanistic, preclinical, and clinical evidence on curcumin in AD. Experimental studies consistently demonstrate that curcumin modulates key pathogenic processes, including neuroinflammatory signaling, oxidative stress, and amyloid-β aggregation, with more limited evidence for effects on tau pathology. While in vitro studies offer detailed mechanistic insights, in vivo models provide more integrated evidence, including improvements in cognitive performance and reductions in pathological markers. Despite this strong preclinical foundation, the clinical evidence remains limited and inconsistent. Randomized controlled trials have not demonstrated clear therapeutic efficacy, with outcomes strongly influenced by formulation, bioavailability, and study design. Poor solubility, rapid metabolism, and limited brain exposure remain key translational barriers. In response, increasing attention has been directed toward formulation strategies and structurally related compounds. Emerging curcuminoids, such as bisdemethoxycurcumin (BDMC), are discussed as potential next-generation candidates. Preliminary evidence suggests that BDMC may modulate oxidative stress, autophagy, astrocyte senescence, and amyloid-related processes, although the data remain largely preclinical. Overall, curcumin represents a mechanistically rich and preclinically promising multi-target compound but with unresolved translational limitations. Future research should prioritize pharmacokinetic optimization, formulation-dependent validation, and exploration of novel curcuminoid strategies to bridge the gap between experimental findings and clinical application in AD.},
}
@article {pmid42450031,
year = {2026},
author = {Olegário, RL and Nóbrega, OT and Almeida, NR and Soto, DAS and Brito, CJ and Bispo, DDC and von Glehn, F and Páez, A and Dang-Vu, TT and Camargos, EF},
title = {Diffusion Tensor Imaging Along the Perivascular Space (DTI-ALPS) as a Neuroimaging Biomarker of Glymphatic Function in Neurodegenerative Diseases: A Systematic Review.},
journal = {International journal of molecular sciences},
volume = {27},
number = {13},
pages = {},
doi = {10.3390/ijms27135758},
pmid = {42450031},
issn = {1422-0067},
support = {88887.841787/2023-00//Coordena&#xe7;&#xe3;o de Aperfeicoamento de Pessoal de N&#xed;vel Superior/ ; 00193-00002602/2022-69//Foundation for Research Support of the Federal District/ ; 88881.218726/2025-01//Coordena&#xe7;&#xe3;o de Aperfeicoamento de Pessoal de N&#xed;vel Superior/ ; },
mesh = {Humans ; *Glymphatic System/diagnostic imaging/metabolism ; *Diffusion Tensor Imaging/methods ; *Neurodegenerative Diseases/diagnostic imaging/metabolism ; Biomarkers/metabolism ; *Neuroimaging/methods ; Alzheimer Disease/diagnostic imaging ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; },
abstract = {The glymphatic system has been proposed as a brain-wide pathway that promotes the exchange between cerebrospinal and interstitial fluids and facilitates the clearance of metabolic waste products, including amyloid-β and tau proteins. Diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) has emerged as a non-invasive magnetic resonance imaging technique proposed to indirectly assess glymphatic-related fluid dynamics. This systematic review evaluated the methodological consistency and clinical applicability of the ALPS index in neurodegenerative diseases. A structured search of PubMed (MEDLINE) and Web of Science identified human studies published up to January 2026 investigating DTI-ALPS in neurodegenerative conditions. Data regarding study populations, MRI acquisition parameters, image-processing methods, statistical approaches, and clinical associations were extracted and synthesized. Ten studies met the inclusion criteria. Across studies, lower ALPS index values were generally associated with cognitive impairment, amyloid burden, and disease severity, particularly in Alzheimer's disease. Several studies incorporated multimodal biomarkers, including amyloid positron emission tomography and cerebrospinal fluid markers, thereby improving the biological interpretation of DTI-ALPS findings. However, substantial methodological heterogeneity was identified across studies, including variability in region-of-interest placement, diffusion acquisition protocols, and image-processing pipelines. Furthermore, the interpretation of diffusivity metrics as direct measures of glymphatic flow remains controversial. Current evidence suggests that DTI-ALPS may represent a promising non-invasive imaging marker of glymphatic-related alterations; however, its biological specificity and clinical applicability remain insufficiently established. Standardized acquisition protocols, harmonized analytical pipelines, and longitudinal multicenter studies are required to clarify its role in neurodegenerative disease research.},
}
@article {pmid42450103,
year = {2026},
author = {Pluta, R and Ułamek-Kozioł, M and Kocki, J and Bogucka-Kocka, A and Czuczwar, SJ and Bogucki, J},
title = {LRP1 and RAGE Expression in the Frontal Cortex in the Alzheimer's Disease Ischemia Model During 2 Years of Follow-Up.},
journal = {International journal of molecular sciences},
volume = {27},
number = {13},
pages = {},
doi = {10.3390/ijms27135831},
pmid = {42450103},
issn = {1422-0067},
mesh = {*Alzheimer Disease/metabolism/genetics/pathology ; *Receptor for Advanced Glycation End Products/genetics/metabolism ; *Low Density Lipoprotein Receptor-Related Protein-1/genetics/metabolism ; Animals ; *Frontal Lobe/metabolism/pathology ; *Brain Ischemia/metabolism/genetics/pathology ; Disease Models, Animal ; Male ; Humans ; Rats ; },
abstract = {Exploration of the gene-level changes that occur during post-ischemic neurodegeneration in the frontal cortex is crucial for understanding the development of dementia. An ischemic model of Alzheimer's disease was used to evaluate changes in the expression of the receptor for advanced glycation end products (RAGE) and low-density lipoprotein receptor-related protein 1 (LRP1), which are associated with amyloid and tau protein, in the frontal cortex after 10 min of cerebral ischemia, with survival at 2, 7, and 30 days and 0.5, 1, 1.5, and 2 years. LRP1 and RAGE expression was assessed by reverse transcription-quantitative polymerase chain reaction. After two days and 1.5 and 2 years post-ischemia, LRP1 expression was increased, after 7 days and 0.5 years it was decreased, and after 30 days and 1 year it oscillated around control values. The decrease in RAGE expression was statistically significant compared to the control group after 2 and 7 days and after 0.5 years, and after 30 days it oscillated around the control value, while after 1-2 years it increased significantly. RAGE and LRP1 expression showed the same pattern of changes from day 7 to year 2, peaking at 1 and 1.5 years, respectively. Another peak of RAGE overexpression was noted 2 years after ischemia. After 1, 1.5 and 2 years, overexpression of RAGE and LRP1 was observed after ischemia, with the dynamics of LRP1 changes being lower. Overall, the data showed a predominance of RAGE expression over LRP1 expression at 1-, 1.5-, and 2-years post-ischemia. The modification of LRP1 and RAGE after ischemia is useful in studying the molecular ischemic pathways involved in the development of Alzheimer's disease.},
}
@article {pmid42450155,
year = {2026},
author = {Untiveros, G and St Germain, R and Barrington, B and Kujawa, SA and Prakapenka, AV and Strizzi, L},
title = {Presenilin-1 Affects Melanoma Cell Behavior in an Amyloid Precursor Protein-Rich, Alzheimer's Disease-like, Microenvironment.},
journal = {International journal of molecular sciences},
volume = {27},
number = {13},
pages = {},
doi = {10.3390/ijms27135885},
pmid = {42450155},
issn = {1422-0067},
mesh = {*Presenilin-1/metabolism/genetics ; Humans ; Animals ; *Amyloid beta-Protein Precursor/metabolism/genetics ; *Melanoma/metabolism/pathology ; *Tumor Microenvironment ; *Alzheimer Disease/metabolism/pathology ; Mice ; Cell Line, Tumor ; Amyloid beta-Peptides/metabolism ; Cell Movement ; },
abstract = {Recent studies report inverse relationships between the incidence of Alzheimer's Disease (AD) and certain malignancies, including melanoma. This has encouraged research into factor(s) in AD that can exert antitumor effects. Presenilin-1 (PS-1) is part of the enzymatic complex that cleaves amyloid precursor protein (APP) into amyloid-beta (Aβ) products that are linked to the neuronal damage seen in AD. PS-1 can also degrade β-catenin and reduce the effectiveness of the "wingless-related integration" (WNT) signaling pathway. Little is known about the relationship between the AD microenvironment, PS-1, and melanoma. We hypothesize that melanoma growth in AD depends on the degree of PS-1-dependent processing of APP into cytotoxic Aβ by melanoma cells. To determine how melanoma reacts to an APP-rich, AD-like microenvironment, PS-1-high (WM1552C) and PS-1-low (C8161) melanoma cells were treated with soluble recombinant human APP (rhAPP). We found that rhAPP treatment significantly reduced cellular activity in WM1552C but not in C8161 cells. Moreover, Aβ products were significantly higher in conditioned media from rhAPP-treated WM1552C compared to controls. Treatment with PS-1 inducing DAPT or PS-1 function inhibiting MRK-560 reversed the effects of rhAPP treatment, respectively in C8161 and WM1552C cells. Furthermore, we found that migration of WM1552C was significantly reduced in the presence of either soluble rhAPP or mouse AD brain tissue, compared to C8161, suggesting that in WM1552C the combination of PS-1 activity and the presence of APP/Aβ in the microenvironment interferes with cell migration. In summary, PS-1 function may predict how melanoma will grow in an APP/Aβ-rich microenvironment, such as AD.},
}
@article {pmid42450159,
year = {2026},
author = {Świątek, A and Kusiak, A and Maj, A},
title = {Salivary Biomarkers in Alzheimer's Disease: Emerging Diagnostic Tools and Their Association with Periodontal Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {13},
pages = {},
doi = {10.3390/ijms27135888},
pmid = {42450159},
issn = {1422-0067},
mesh = {Humans ; *Alzheimer Disease/diagnosis/metabolism ; *Biomarkers/metabolism/analysis ; *Saliva/metabolism/chemistry ; *Periodontal Diseases/metabolism/complications/diagnosis ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disorder and a leading cause of dementia worldwide. Current diagnostic methods, including cerebrospinal fluid analysis and neuroimaging, are often invasive, expensive, and not suitable for large-scale screening. Therefore, increasing attention has been directed toward the identification of non-invasive biomarkers. Saliva has emerged as a promising diagnostic biofluid containing proteins, metabolites, inflammatory mediators, exosomes, and nucleic acids potentially associated with neurodegenerative processes. This review aimed to summarize current evidence regarding salivary biomarkers in Alzheimer's disease and to discuss their diagnostic potential, limitations, and association with periodontal disease within the framework of the oral-brain axis. A literature search was conducted using PubMed, Scopus, and Google Scholar databases for studies published between 2018 and 2026. Relevant English-language articles focusing on salivary biomarkers, Alzheimer's disease, periodontitis, and oral-brain axis interactions were included. Current evidence suggests that salivary biomarkers such as amyloid-beta, tau protein, lactoferrin, exosomes, oxidative stress markers, metabolites, and nucleic acid-based biomarkers may reflect the pathological mechanisms associated with Alzheimer's disease. In addition, increasing evidence supports a relationship between chronic periodontal inflammation, oral pathogens, and neurodegenerative processes. However, substantial heterogeneity among studies, methodological variability, and a lack of standardized protocols currently limit the reproducibility and clinical applicability of saliva-based diagnostics. Salivary biomarkers represent a promising non-invasive approach for the early detection and monitoring of Alzheimer's disease. Nevertheless, further large-scale, longitudinal, and standardized studies are necessary to validate their diagnostic utility and support their implementation in routine clinical practice.},
}
@article {pmid42450256,
year = {2026},
author = {Shiyab, AS and Reed, EG},
title = {Peripheral and Central miRNA Signatures in Alzheimer's Disease: Tissue-Specific Variability, Sex-Associated Differences, and Implications for Blood-Based Biomarkers.},
journal = {International journal of molecular sciences},
volume = {27},
number = {13},
pages = {},
doi = {10.3390/ijms27135990},
pmid = {42450256},
issn = {1422-0067},
support = {1R01AG075897-05/NH/NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/genetics/blood/metabolism/diagnosis ; *MicroRNAs/genetics/blood/metabolism ; *Biomarkers/blood ; Brain/metabolism/pathology ; Animals ; Female ; Organ Specificity ; Male ; Gene Expression Profiling ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and significant neuropathological changes. Early and accurate diagnosis remains a major challenge, highlighting the need for reliable, minimally invasive biomarkers. MicroRNAs (miRNAs), small non-coding RNAs that regulate gene expression, have emerged as promising candidates. Their expression is altered in the brains of AD patients, reflecting disease-specific pathological processes, and they are detectable in peripheral biofluids. However, discrepancies in miRNA profiles between the brain and the circulation, and between patient populations remain a significant limitation, raising questions about their origin, transport across the blood-brain barrier, and their reliability in reflecting central nervous system pathology. This review provides a comprehensive overview of current research comparing miRNA expression profiles in brain tissue and blood in AD, with a focus on their biological relevance, mechanisms of release and transport, and diagnostic potential. We also discuss the challenges associated with cross-tissue variability, methodological inconsistencies, and the need for standardized approaches. Finally, we highlight future directions, including multi-tissue analyses and integration with other noninvasive modalities, to improve the clinical utility of miRNA-based biomarkers in AD.},
}
@article {pmid42450333,
year = {2026},
author = {Tao, H and Fujisawa, K},
title = {Energy Homeostasis Disruption in Neurological Disorders: Mitochondrial Dysfunction, High-Energy Phosphate Transfer, and Extracellular ATP-Dependent Purinergic Dysregulation.},
journal = {International journal of molecular sciences},
volume = {27},
number = {13},
pages = {},
doi = {10.3390/ijms27136066},
pmid = {42450333},
issn = {1422-0067},
mesh = {Humans ; *Energy Metabolism ; *Homeostasis ; *Adenosine Triphosphate/metabolism ; Animals ; *Mitochondria/metabolism/pathology ; *Nervous System Diseases/metabolism/pathology ; },
abstract = {Mitochondrial dysfunction and impairment of high-energy phosphate transfer are increasingly recognised as shared pathogenic features across neurological disorders. Because neurons require large amounts of ATP to sustain synaptic transmission, ion gradients, axonal transport, and intracellular signalling, they are especially vulnerable to disturbances in energy metabolism. Neurological dysfunction, therefore, cannot be explained solely by reduced mitochondrial ATP production. It also involves failure of the creatine kinase/phosphocreatine (CK/PCr) and adenylate kinase/AMP-activated protein kinase (AK-AMPK) systems, which normally support local ATP buffering, high-energy phosphate transfer, and intracellular energy homeostasis. In parallel, extracellular ATP-dependent purinergic dysregulation contributes to glia-mediated inflammation, synaptic dysfunction, and cell death, linking intracellular energy failure to abnormal intercellular signalling. In this review, we integrate these mechanisms into a shared pathological continuum of disrupted energy homeostasis. We then compare Alzheimer's disease, Parkinson's disease, and epilepsy as representative disorders with shared and disease-specific manifestations of this continuum, characterised respectively by chronic cerebral energy crisis, selective metabolic fragility, and acute energy overload with purinergic dysregulation. Finally, we discuss how this comparative perspective may help identify shared therapeutic opportunities while preserving disorder-specific interpretation.},
}
@article {pmid42450350,
year = {2026},
author = {Liu, X and Watanabe, S and Coleman, S and Shih, V and Telfer, WR and Kansagra, VD and Drak, L and Pesaladinne, LR and Kim, D and Sudan, S and Singhal, A and Toyo-Oka, K},
title = {ADNP Functions During Early Brain Development and Their Relevance to ASD and ADNP Syndrome.},
journal = {International journal of molecular sciences},
volume = {27},
number = {13},
pages = {},
doi = {10.3390/ijms27136085},
pmid = {42450350},
issn = {1422-0067},
support = {R21MH132839/MH/NIMH NIH HHS/United States ; AR220067//United States Department of Defense/ ; },
mesh = {Humans ; *Brain/metabolism/growth &amp; development/embryology ; *Autism Spectrum Disorder/metabolism/genetics ; Animals ; *Nerve Tissue Proteins/metabolism/genetics ; Neurogenesis ; Neurodevelopment ; Homeodomain Proteins ; },
abstract = {The Activity-Dependent Neuroprotective Protein (ADNP) is an important regulator of early brain development, especially during cortical neurogenesis and neurite formation. De novo point mutations or haploinsufficiency of the ADNP gene result in ADNP syndrome, which is also known as Helsmoortel-Van der Aa syndrome, a complex neurodevelopmental disorder recognized as a leading single-gene cause of syndromic autism spectrum disorder (ASD) and intellectual disability. ADNP works as both a transcription factor and a microtubule (MT) regulator. As a transcription factor, ADNP is a key component of chromatin remodeling complexes such as ChAHP (CHD4 (Chromodomain Helicase DNA-binding Protein 4)-ADNP-HP1 (Heterochromatin Protein 1)) and SWI/SNF (Switch/Sucrose Non-Fermentable), and it tightly regulates the expression of numerous essential developmental genes. ADNP also modulates the Wnt/β-catenin signaling pathway. During neural differentiation, ADNP is redistributed from the nucleus to the cytoplasm, and this redistribution is regulated by binding to 14-3-3 proteins, which are phosphorylated by protein Kinase C (PKC). After relocating to the cytoplasm, ADNP functions as an MT regulator by binding to microtubule end-binding proteins (EB1 and EB3) and Tau to control neurite formation. Previous studies have focused on NAP (also known as Davunetide, a peptide derived from ADNP) in MT regulation and its therapeutic potential for autism spectrum disorder (ASD) and neurodegenerative diseases, such as Alzheimer's disease. This review highlights the functions of full-length ADNP and NAP in early brain development, particularly in neurogenesis and neurite formation during cortical development. We will also discuss the potential of NAP as a therapeutic medication for neurodevelopmental disorders, especially ASD and ADNP syndrome.},
}
@article {pmid42450355,
year = {2026},
author = {Arendash, GW},
title = {Neuronal Microtubules and Radiofrequency Waves: The Quantum Core of Human Consciousness, Memory, and Pathway to Memory Enhancement/Recovery.},
journal = {International journal of molecular sciences},
volume = {27},
number = {13},
pages = {},
doi = {10.3390/ijms27136090},
pmid = {42450355},
issn = {1422-0067},
support = {AG025711, 1R43NS090653-01A, and 9R44AG073096-02A1//NIA-designated Florida Alzheimer's Disease Research Center/ ; },
mesh = {Humans ; *Microtubules/metabolism ; *Memory/physiology/radiation effects ; *Consciousness/physiology ; *Radio Waves ; Animals ; *Neurons/metabolism ; Quantum Theory ; },
abstract = {A unifying theory of both human consciousness and memory is presented that is based on neuronal microtubules (MTs) being central to both, and different populations of pyramidal cells in neocortex and hippocampus being responsible for consciousness or memory. First, two quantum theories of consciousness are presented-the Orchestrated Objective Reduction (Orch OR) theory of Penrose/Hameroff and the Environmental-Induced Decoherence Theory (EID) theory of Neven. A Hybrid (MT/EID) theory is proposed in the context of "consciousness"-dedicated pyramidal cells in Layer V of the cerebral cortex. This MT/EID theory involves the MT vibrations of the Orch OR Theory, along with the continual superposition qubit (SPQ) formation and SPQ entanglement of the EID Theory to collectively induce SPQ formation/entanglement in Layer V of the cerebral cortex. Orch OR's objective reduction (collapse of the waveform) is not included in this Hybrid theory because the system of SPQs themselves continuously collapses due to EID. For memory, it is proposed that Orch OR forms its basis with three specific modifications: (1) presenting "endogenous" radiofrequency (RF) vibrations generated by neuronal microtubules as forming a microtubule/RF wave "vibrational fabric" involving microtubular crystalline water cores, (2) refining Orch OR for memory by proposing SPQ formation for short-term memory and objective reduction of those qubits primarily in "memory-dedicated" pyramidal cells within cortical Layers II/III for long-term memory storage through "Quantum Darwinism" (SPQ/OR), and (3) integrating SPQ/OR with the ability of "externally" applied RF waves at 1 GHz to beneficially influence human memory through microtubule-enhancing mechanisms. It is proposed that a vibrational fabric consisting of MTs, RF waves, and generated photons provides the Photonic/RF-wave quantum coherence necessary for brain memory processing. Strong evidence for beneficial effects of exogenous RF wave treatment on memory is provided by a new bioengineered technology-Transcranial Radiofrequency Wave Treatment (TRFT; also known as TEMT). This evidence is presented in both pre-clinical and clinical studies involving normal and Alzheimer's Disease (AD) transgenic mice, and AD patients bearing memory loss. In support of MT involvement in memory, TRFT would appear to be an ideal non-pharmacologic technology to beneficially modulate the microtubule/RF wave vibrational fabric-an intraneuronal fabric that may be at the deep core of human memory, and thus the key to Alzheimer's Disease memory rescue.},
}
@article {pmid42450365,
year = {2026},
author = {Alkandari, AF and Madhyastha, S and Rao, MS},
title = {Correction: Alkandari et al. N-Acetylcysteine Amide Against Aβ-Induced Alzheimer's-like Pathology in Rats. Int. J. Mol. Sci. 2023, 24, 12733.},
journal = {International journal of molecular sciences},
volume = {27},
number = {13},
pages = {},
doi = {10.3390/ijms27135898},
pmid = {42450365},
issn = {1422-0067},
abstract = {In the original publication [...].},
}
@article {pmid42450578,
year = {2026},
author = {Li, J and Cheng, S and Zhang, W and Qiao, S and Zhang, L and Yao, M and Zhang, Y and Wang, B and Wu, C},
title = {Mulberroside A Alleviates Scopolamine-Induced Cognitive Deficits by Suppressing Neuroinflammation and Oxidative Stress via the Dubosiella-Associated Microbiota-Gut-Brain Axis.},
journal = {Biology},
volume = {15},
number = {13},
pages = {},
doi = {10.3390/biology15131030},
pmid = {42450578},
issn = {2079-7737},
support = {262102310255//Henan Provincial Science and Technology Key Project/ ; 26A180030//Key Scientific Research Foundation of Henan Colleges and Universities/ ; 252300423668//Natural Science Foundation of Henan/ ; ZKNUC2024030//Zhoukou Normal University High-level Talent Start-up Foundation/ ; },
abstract = {Mulberroside A (MsA) possesses neuroprotective effects, but whether it alleviates Alzheimer's disease (AD)-like cognitive impairment through the microbiota-gut-brain axis remains unclear. Using a scopolamine-induced mouse model of acute cognitive impairment (male ICR mice, n = 10/group), we demonstrated that daily administration of MsA (10, 20, and 30 mg/kg/day) for 5 weeks significantly ameliorated cognitive performance in novel object recognition and Morris water maze tests. At the optimal dose (30 mg/kg/day), MsA suppressed hippocampal microglial activation, reduced pro-inflammatory cytokines (IL-6, IL-1β, TNF-α), and attenuated oxidative stress by decreasing malondialdehyde (MDA) while restoring superoxide dismutase (SOD) and glutathione (GSH) levels. MsA also strengthened intestinal barrier integrity (ZO-1, occludin) and significantly altered the gut microbiota, notably increasing the beneficial genus Dubosiella. Brain metabolomics indicated that MsA reversed scopolamine-induced metabolic disturbances, mainly restoring phospholipid balance. Correlation analysis demonstrated a strong gut-brain connection, with Dubosiella abundance positively associated with neuroprotective phospholipids and negatively with stress markers. Furthermore, fecal microbiota transplantation from MsA-treated donors successfully replicated these behavioral improvements in recipient mice, underscoring the functional involvement of the reshaped microbiome rather than a simple autonomous recovery. These results suggest that MsA alleviates AD-like cognitive impairment by reducing neuroinflammation and oxidative stress through microbiota remodeling, enhancing the intestinal barrier, and modulating the Dubosiella-associated gut-metabolite-brain axis, making MsA a promising multi-target nutraceutical for ameliorating AD-like cognitive deficits.},
}
@article {pmid42450618,
year = {2026},
author = {Yang, Y and Li, Q and Luo, S and Sun, J and Ouyang, Y},
title = {Establishment and Characterization of an Aβ-Related Alzheimer's Disease-like Tree Shrew Model Following CA1-Coordinate-Directed Stereotaxic AAV Delivery of Human Triple-Mutant APP.},
journal = {Biology},
volume = {15},
number = {13},
pages = {},
doi = {10.3390/biology15131071},
pmid = {42450618},
issn = {2079-7737},
support = {2023GXNSFDA026069//Guangxi Natural Science Foundation, China/ ; 32260137//National Natural Science Foundation of China/ ; },
abstract = {Alzheimer's disease (AD) is characterized by cognitive decline and amyloid-β (Aβ)-related pathology. Non-rodent models that capture selected aspects of human AD remain limited. We established and characterized a human APP-driven, Aβ-related AD-like tree shrew model following AAV-mediated delivery of triple-mutant human amyloid precursor protein (hAPP-SLA) carrying the Swedish, Austrian, and London mutations by bilateral stereotaxic injection directed at CA1 coordinates. Adult tree shrews received bilateral AAV-hAPP-SLA injections directed at CA1 coordinates and were evaluated by bioluminescence imaging, behavioral testing, PCR, RT-qPCR, Western blotting, ELISA, and histopathology. Vector-associated reporter signals remained detectable for 6 months. The experimental group showed exogenous hAPP expression and reduced endogenous tsAPP expression, increased relative hippocampal Aβ42 protein level, enhanced 4G8-reactive APP/Aβ-related signals, elevated total Aβ immunoreactivity, increased serum Aβ42/Aβ40 ratio, cytoarchitectural alterations, reduced Nissl staining, and Thioflavin S-reactive aggregate-associated signals. AT8 (Ser202/Thr205), GFAP, and Iba-1 immunoreactivity increased, whereas Synaptophysin and PSD-95 immunoreactivity was reduced. These changes were accompanied by reduced short-delay recognition-related performance and reduced social approach and social novelty preference. Aged tree shrews showed partly overlapping alterations. This model provides a non-rodent platform for studying human APP-driven Aβ-related pathology.},
}
@article {pmid42450638,
year = {2026},
author = {Tang, C and Shi, L and Xu, S},
title = {Integrating Structural and Metabolic Neuroimaging Biomarkers for Alzheimer's Disease Diagnosis and Cognitive Score Estimation via Cross-Modal Gated Learning.},
journal = {Biology},
volume = {15},
number = {13},
pages = {},
doi = {10.3390/biology15131091},
pmid = {42450638},
issn = {2079-7737},
abstract = {Structural atrophy and metabolic dysfunction provide complementary biomarkers for Alzheimer's disease (AD), and their joint modeling may support diagnostic assessment and cognitive score estimation. However, many multimodal methods rely on global fusion and insufficiently enhance cross-modal consistency before interaction, limiting the discriminative quality and clinical relevance of learned representations. We propose CGMF-Net, a cross-modal gated learning framework for joint AD classification and clinical score estimation using paired structural MRI (sMRI) and fluorodeoxyglucose PET (FDG-PET) data. CGMF-Net extracts multi-scale representations from both modalities, introduces a Cross-Modal Similarity Gate to strengthen consistent structural-metabolic responses before fusion, and employs bi-directional cross-attention to capture complementary interactions. The shared representation is optimized with classification supervision, MMSE-based auxiliary regression, and HSIC regularization to improve discriminability and reduce redundant coupling between directional representations. Experiments on ADNI demonstrate that CGMF-Net achieves the best overall classification performance among the compared methods, with 94.22% ACC and 97.74% AUC for AD vs. CN, and 86.67% ACC and 94.84% AUC for AD vs. MCI, while also showing favorable ADNI-2 to ADNI-1 generalization and competitive estimation of ADAS13, CDRSB, and MMSE. These results suggest that cross-modal gated learning provides clinically relevant multimodal representations for AD diagnosis and cognitive score estimation.},
}
@article {pmid42451075,
year = {2026},
author = {Wang, JQ and Hu, BB and Wang, YY and Lu, YW and Gong, XJ and Tang, S and Song, LJ and Sun, YS and Zhang, JT and Wang, Z and Li, W},
title = {Maltol Protects Neuronal Cells by Alleviating Chronic Neuroinflammation, Pyroptosis, and Ferroptosis via HSP70 Upregulation in Microglia.},
journal = {Nutrients},
volume = {18},
number = {13},
pages = {},
doi = {10.3390/nu18132071},
pmid = {42451075},
issn = {2072-6643},
support = {No. 82104465//National Natural Science Foundation of China/ ; 2023YFD1601600//National Key Research and Development Program/ ; },
mesh = {*Microglia/drug effects/metabolism ; Animals ; *HSP70 Heat-Shock Proteins/metabolism/genetics ; *Pyroptosis/drug effects ; *Neurons/drug effects/metabolism ; Mice ; Up-Regulation/drug effects ; Humans ; Toll-Like Receptor 4/metabolism ; *Neuroinflammatory Diseases/drug therapy/metabolism ; Oxidative Stress/drug effects ; Signal Transduction/drug effects ; *Neuroprotective Agents/pharmacology ; Myeloid Differentiation Factor 88/metabolism ; Cell Line ; *Pyrones/pharmacology ; Male ; },
abstract = {Objectives: Neuroinflammation is recognized as a significant characteristic of Alzheimer's disease (AD). Currently, there is a notable absence of effective pharmacological agents to prevent or treat neuroinflammatory processes associated with AD. Heat shock protein 70 (HSP70) is pivotal in the progression of neuroinflammation. In this study, we explored the potential of maltol, a Maillard reaction product derived from red ginseng, as a therapeutic agent for neuroinflammation. Methods: In vitro, HMC3 microglial cell models were developed to examine the regulatory effects of gradient concentrations of maltol (12.5, 25, 50 μM) on the TLR4/MyD88/NF-κB p65 signaling pathway, neuroinflammation, and pyroptosis. Analyses of the GEO database and Gene Set Enrichment Analysis (GSEA) were performed to identify the core targets of maltol, followed by HSP70 gene silencing experiments to validate the targeted regulatory mechanism. Results: Maltol significantly mitigated LPS-induced neuronal damage and cognitive deficits in mice. It effectively suppressed microglia-mediated neuroinflammation and pyroptosis, reversed oxidative stress-induced neuronal ferroptosis, and inhibited neuronal apoptosis. In vitro experiments demonstrated that maltol obstructed TLR4/MyD88 binding, thereby inhibiting NF-κB p65-mediated neuroinflammation and pyroptosis, while also alleviating excessive ROS accumulation to enhance oxidative stress and ferroptosis. Bioinformatics analysis identified HSP70 as a crucial target for the anti-inflammatory and antioxidant effects of maltol. Subsequent gene silencing experiments confirmed that maltol exerted its inhibitory effects on LPS-induced neuroinflammation and pyroptosis in an HSP70-dependent manner. Conclusions: Maltol exhibits significant protective effects against Alzheimer's disease-related neuroinflammation, oxidative stress, pyroptosis, and ferroptosis through the targeting of HSP70. This study elucidates the molecular mechanisms by which maltol improves neuroinflammatory injury and provides a novel theoretical foundation and therapeutic strategy for the intervention of Alzheimer's disease neuroinflammation using traditional Chinese medicine.},
}
@article {pmid42451086,
year = {2026},
author = {Soni, N and Debnath, N and Rekapally, E and Jabbar, A and Tyagi, SC and Bissa, B and Tyagi, N},
title = {Vitamin D Signaling in Neurodegenerative Disorders: Mechanisms, Therapeutic Potential, and Clinical Implications.},
journal = {Nutrients},
volume = {18},
number = {13},
pages = {},
doi = {10.3390/nu18132082},
pmid = {42451086},
issn = {2072-6643},
support = {971566; 24 TPA1304527 and 25 TPA1481771 to Neetu Tyagi.//American Heart Association/ ; },
mesh = {Humans ; *Vitamin D/metabolism/therapeutic use ; *Neurodegenerative Diseases/metabolism/drug therapy/etiology ; *Signal Transduction ; Vitamin D Deficiency/complications ; Animals ; Oxidative Stress/drug effects ; Receptors, Calcitriol/metabolism ; Blood-Brain Barrier/metabolism ; Neuroprotective Agents ; },
abstract = {Vitamin D has long been recognized for its role in calcium homeostasis and bone metabolism; however, it is now emerging as an important regulator of central nervous system (CNS) function. Recent evidence suggests that vitamin D signaling contributes to the pathogenesis and progression of several neurodegenerative disorders. Vitamin D exerts neuroprotective effects through multiple mechanisms, including regulation of calcium homeostasis, modulation of immune responses, reduction in oxidative stress, stimulation of neurotrophic factors, and maintenance of blood-brain barrier (BBB) integrity. Vitamin D receptors and metabolizing enzymes are widely distributed across several brain regions, highlighting their direct involvement in neuronal function. This review summarizes the biosynthesis, metabolism, and signaling pathways of vitamin D. It explores its role in neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), stroke, and traumatic brain injury (TBI). Evidence from experimental and clinical studies indicates that vitamin D deficiency is associated with an increased risk and severity of these conditions, while supplementation may provide therapeutic benefits.},
}
@article {pmid42451124,
year = {2026},
author = {Abdulraheem, RA and Martins, RN and Krishnamoorthy, R and Alshuniaber, MA and Bharadwaj, P and Li, Z and Coorey, R and Jayasena, V and Johnson, SK and Fernando, WMADB},
title = {Neuroprotective Effects of Sorghum Polyphenol in Alzheimer's Disease: In Vitro and In Silico Analyses.},
journal = {Nutrients},
volume = {18},
number = {13},
pages = {},
doi = {10.3390/nu18132121},
pmid = {42451124},
issn = {2072-6643},
mesh = {*Polyphenols/pharmacology/isolation &amp; purification ; *Alzheimer Disease/drug therapy/metabolism ; *Sorghum/chemistry/genetics ; *Neuroprotective Agents/pharmacology ; Amyloid beta-Peptides/metabolism ; Oxidative Stress/drug effects ; Humans ; Cell Survival/drug effects ; *Plant Extracts/pharmacology ; Animals ; Computer Simulation ; Peptide Fragments/metabolism ; Mitochondria/drug effects/metabolism ; Mice ; Cell Line ; Signal Transduction/drug effects ; },
abstract = {BACKGROUND/OBJECTIVE: Accumulation of amyloid-beta (Aβ) senile plaques in the human brain is a major hallmark of Alzheimer's disease (AD), which manifests as progressive decline in memory and cognitive functions and currently lacks effective disease-modifying therapies. Emerging evidence demonstrates that polyphenol-rich plant foods are potential complementary therapies for AD.<br><br>METHODS: In this study, we investigated crude polyphenol extracts (CPEs) and purified polyphenol extracts (PPEs) from three sorghum genotypes for their ability to inhibit A&#x3b2;42-induced toxicity in MC-65 cells. Thioflavin T fluorescence, cell viability, mitochondrial function, oxidative stress assays, and Western blotting, along with RNA sequencing and computational analyses, were used to characterise both functional and transcriptomic responses of the cells to polyphenol treatments.<br><br>RESULTS: CPEs and PPEs inhibited A&#x3b2;42 aggregation by 67-76% and significantly reduced A&#x3b2; oligomer species. The extracts increased cell viability against A&#x3b2;-induced toxicity by more than 70%, decreased intracellular oxidative stress, and enhanced mitochondrial activity by over 80%. Transcriptomic profiling revealed differential modulation of genes associated with ferroptosis and MAPK/NF- &#x3ba;B signalling pathways, indicating regulation of inflammatory and oxidative-stress responses are mechanisms underlying the observed neuroprotection.<br><br>CONCLUSIONS: This study demonstrates that polyphenol extracts from black and red sorghum genotypes exert strong multitarget neuroprotection against A&#x3b2;42 toxicity in MC-65 cells. These findings support further evaluation of sorghum-derived polyphenols as complementary therapeutic candidates for AD, with in vivo studies required to establish efficacy and translational potential.},
}
@article {pmid42451136,
year = {2026},
author = {Yu, Y and Ya, W and Zhang, J and Wang, J and Sun, B},
title = {Recent Advances in Medium-Chain Triglycerides in Chronic Disease Prevention.},
journal = {Nutrients},
volume = {18},
number = {13},
pages = {},
doi = {10.3390/nu18132133},
pmid = {42451136},
issn = {2072-6643},
support = {20240484678//Beijing Nova Program/ ; 32401988//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Triglycerides/chemistry/metabolism/administration &amp; dosage/pharmacology ; Chronic Disease/prevention &amp; control ; Animals ; Energy Metabolism ; Lipid Metabolism ; Gastrointestinal Microbiome/drug effects ; },
abstract = {Medium-chain triglycerides (MCTs) are functional lipids with unique physicochemical properties and metabolic advantages. Recently, their regulatory roles in various chronic diseases have attracted considerable attention. This review systematically summarizes recent research progress and the proposed mechanisms of MCTs and their metabolites in metabolic diseases, neurological disorders, gut health, and muscle function. In the metabolic field, MCTs offer potential nutritional strategies for managing obesity, type 2 diabetes mellitus (T2DM), and various metabolic liver diseases. These effects are primarily mediated by improving insulin sensitivity, regulating lipid metabolism, and modulating energy expenditure. In neurological diseases, MCTs demonstrate potential for preventing and treating Alzheimer's disease (AD), Parkinson's disease (PD), and epilepsy through multiple pathways, including ketogenic energy supply, anti-inflammatory and antioxidant effects, and mitochondrial protection. Regarding gut health, MCTs and their derivatives may benefit digestive health by modulating gut microbiota and enhancing barrier function. For muscle health, MCTs help optimize energy metabolism and protein homeostasis, showing promise for countering sarcopenia and improving exercise performance. In conclusion, the prospects for MCTs are broad. Future research should focus on promoting their scientific application in precision nutrition and disease therapy, and more rigorous clinical trials are needed to confirm their efficacy and safety.},
}
@article {pmid42451200,
year = {2026},
author = {Mora-Ortiz, M and Cardelo, MP and Porras-Pérez, E and Serrán-Jiménez, A and Ledesma-Escobar, CA and Priego-Capote, F and Conde-Gavilán, C and Agüera-Morales, E and Pineda Reyes, R and Malagon, MM and Yubero-Serrano, EM and Camargo, A and Katsiki, N and López-Miranda, J and Perez-Martinez, P},
title = {Gut Microbiota Composition and Plasma Metabolomic Profile Are Associated with Amyloid Pathology and Cognitive Performance in Patients with Mild Cognitive Impairment.},
journal = {Nutrients},
volume = {18},
number = {13},
pages = {},
doi = {10.3390/nu18132200},
pmid = {42451200},
issn = {2072-6643},
support = {PI16/01777//Instituto de Salud Carlos III/ ; PI-0055-2021//Regional Government of Andalusia/ ; },
mesh = {Humans ; *Cognitive Dysfunction/blood/microbiology/metabolism/psychology ; Male ; *Gastrointestinal Microbiome/physiology ; Female ; Aged ; *Amyloid beta-Peptides/blood ; Metabolomics ; Biomarkers/blood ; Cross-Sectional Studies ; Double-Blind Method ; *Cognition ; Cross-Over Studies ; *Metabolome ; Peptide Fragments/blood ; RNA, Ribosomal, 16S ; },
abstract = {BACKGROUND/OBJECTIVES: The gut-brain axis and systemic metabolic dysregulation are increasingly implicated in Alzheimer's disease (AD) pathogenesis. This study aimed to characterize gut microbiota and plasma metabolomic profiles associated with amyloid pathology and cognitive impairment in patients with mild cognitive impairment (MCI).<br><br>METHODS: A cross-sectional multi-omics baseline analysis was performed in 47 MCI patients enrolled in a randomized, double-blind, crossover dietary intervention trial (NCT05029765). Gut microbiota composition was assessed by 16S rRNA sequencing (n = 47), and plasma metabolomics by untargeted LC-MS/MS (n = 45 after exclusion of two PCA-defined metabolomic outliers). Patients were stratified according to plasma amyloid-beta 42/40 ratio (BA42/40) and ADAScog11 score, representing complementary biomarkers of amyloid burden and cognitive impairment, respectively.<br><br>RESULTS: Higher amyloid burden and worse cognitive performance were associated with significant gut microbiota alterations, including increased alpha diversity and distinct beta diversity profiles. Differential abundance analyses consistently showed enrichment of Bacteroides-associated taxa and Akkermansia, alongside depletion of short-chain fatty acid-producing genera such as Faecalibacterium, Blautia, and Phascolarctobacterium. Plasma metabolomics identified a coherent signature associated with elevated BA42/40, characterized by accumulation of secondary bile acid sulfates and depletion of sphingolipids, neuroactive steroids, and anti-inflammatory lipid mediators, including pregnenolone sulfate, resolvin E1, and anandamide. A valid OPLS-DA discriminant model was obtained for BA42/40, whereas no predictive model was achieved for ADAScog11. Critically, this dissociation, characterized by significant microbiota differences but no metabolomic separation for ADAScog11, is itself an informative finding, suggesting that gut microbiota dysbiosis and plasma metabolomic alterations are not equally coupled to both dimensions of MCI pathophysiology.<br><br>CONCLUSIONS: MCI patients with greater amyloid pathology and cognitive impairment exhibited gut microbiota dysbiosis. However, metabolic associations were observed only for BA42/40, but not for ADAScog11. These findings provide a mechanistic framework for evaluating the impact of Mediterranean diet and probiotic interventions in the longitudinal phase of the trial.},
}
@article {pmid42451206,
year = {2026},
author = {Rao, RV and Subramaniam, KG and Gregory, J and Bredesen, AL and Coward, C and Okada, S and Kelly, L and Bredesen, DE},
title = {KetoFLEX 12/3 Diet and Cognitive Health: A Precision-Nutrition Perspective on Mechanisms, Emerging Evidence, and Future Directions.},
journal = {Nutrients},
volume = {18},
number = {13},
pages = {},
doi = {10.3390/nu18132206},
pmid = {42451206},
issn = {2072-6643},
mesh = {Humans ; *Alzheimer Disease/diet therapy ; *Precision Medicine/methods ; *Diet, Ketogenic/methods ; *Cognition ; Cognitive Enhancement ; *Cognitive Dysfunction/diet therapy ; Brain/metabolism ; },
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by impaired glucose metabolism, mitochondrial dysfunction, inflammation, oxidative stress, and progressive cognitive decline. Because currently available pharmacological therapies provide only modest symptomatic benefit, nutrition-based interventions are increasingly being explored as complementary strategies for supporting brain metabolism and cognitive resilience. The KetoFLEX 12/3 dietary pattern, developed within the ReCODE (Reversal of Cognitive Decline) program, is a plant-rich, mildly ketogenic nutrition and lifestyle framework that integrates low-glycemic nutrition, time-restricted eating, and personalized metabolic optimization. The diet emphasizes deeply pigmented non-starchy vegetables, extra-virgin olive oil, nuts and seeds, omega-3-rich seafood, and minimally processed foods while limiting refined carbohydrates, sugars, processed foods, and selected grains and dairy products. Emerging mechanistic and clinical evidence suggests that KetoFLEX 12/3 may influence several pathways relevant to AD pathophysiology, including insulin signaling, mitochondrial bioenergetics, neuroinflammation, oxidative stress, autophagy, detoxification pathways, and gut-brain axis function. Observational findings from ReCODE-related studies have reported improvements in metabolic parameters, mood-related outcomes, cognitive measures, and brain volumetrics in participants adhering to multimodal precision-medicine interventions incorporating the KetoFLEX principles. Compared with traditional dietary models such as the Mediterranean or MIND diets, KetoFLEX 12/3 places greater emphasis on mild nutritional ketosis, meal timing, and metabolic personalization based on factors such as ApoE genotype and insulin sensitivity. The objective of this Perspective is to examine the mechanistic rationale, emerging evidence, limitations, and future research priorities for KetoFLEX 12/3 as a precision-nutrition framework for cognitive health in AD. Although much of the current evidence remains mechanistic, observational, or derived from multimodal intervention studies, the framework offers a biologically plausible precision-nutrition model that may inform future research and clinical investigation in cognitive decline.},
}
@article {pmid42451343,
year = {2026},
author = {Ramineni, V and Kim, JH and Kwon, GR},
title = {Interpretable 2D Deep Learning for Alzheimer's Detection from sMRI: A Lightweight Residual CNN Approach with Comprehensive Preprocessing and Stratified Data Partitioning.},
journal = {Sensors (Basel, Switzerland)},
volume = {26},
number = {13},
pages = {},
doi = {10.3390/s26134100},
pmid = {42451343},
issn = {1424-8220},
mesh = {*Alzheimer Disease/diagnostic imaging/diagnosis ; *Deep Learning ; Convolutional Neural Networks ; *Magnetic Resonance Imaging/methods ; Humans ; Image Processing, Computer-Assisted/methods ; Neuroimaging/methods ; },
abstract = {Neuroimaging is a promising modality for early AD detection, facilitating timely clinical intervention. This study proposes an enhanced deep learning framework that extracts critical AD biomarkers from structural MRI (sMRI) data acquired from the ADNI. Our novel CNN architecture integrates conventional convolutional layers with residual and skip connections for efficient feature extraction, achieving substantially lower computational cost than standard deep architectures such as VGG-16 (138 M), while remaining more parameter-intensive than highly compact architectures such as MobileNet and EfficientNet, which are designed explicitly for resource-constrained deployment. A comprehensive preprocessing pipeline converts 3D MRI scans into 2D slices through quality control (discarding slices with mean intensity < 5% of the maximum), bilinear resizing to 96 × 96 pixels, normalization using training-set statistics, and data augmentation. Stratified, subject-level data partitioning combined with robust statistical validation via bootstrapping demonstrates superior multiclass classification performance across AD, early and late MCI, and cognitively normal groups compared to state-of-the-art methods. Additionally, Grad-CAM-based interpretability maps were generated to highlight disease-relevant brain regions, confirming consistent activation around the hippocampus and temporal lobe.},
}
@article {pmid42451432,
year = {2026},
author = {Bensefia, A and Al Hashlamoun, N},
title = {Handwriting as a Biomarker for Early Detection of Parkinson's and Alzheimer's Diseases: A Comprehensive Guide for Researchers.},
journal = {Sensors (Basel, Switzerland)},
volume = {26},
number = {13},
pages = {},
doi = {10.3390/s26134190},
pmid = {42451432},
issn = {1424-8220},
mesh = {*Handwriting ; *Alzheimer Disease/diagnosis ; Humans ; *Parkinson Disease/diagnosis ; *Biomarkers ; Early Diagnosis ; Deep Learning ; Convolutional Neural Networks ; },
abstract = {Neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease (AD) present a significant and growing challenge to the healthcare systems worldwide. Both conditions are progressive and often undetected early, making timely diagnosis crucial. Recently, breakthroughs in computer vision and artificial intelligence have enabled the development of non-invasive and cost-effective screening and decision-making tools, allowing for earlier detection of the disease. This review serves as a comprehensive guide, providing structured insights into computational research methods for automated detection of PD and AD, with focus on handwriting analysis as a subtle behavioral biomarker of neurological impairment. A range of methodologies is examined, including static and dynamic handwriting assessment, feature engineering procedures, deep learning and classical ML-based approaches. The analysis emphasizes the most effective methods, the handwriting features found to be most revealing, the datasets most used in the literature, and the performance levels reported for each disease. Several studies report that transfer learning based on convolutional neural networks and transformer-based architectures for Parkinson's disease diagnosis is regularly able to achieve high accuracy, frequently above 95% on benchmark datasets. In contrast, Alzheimer's disease research is progressively benefitting from multimodal approaches combining kinematic and spatial handwriting features to capture cognitive and motor changes. Structured summaries of publicly available handwriting datasets are provided, and critical advancements, ongoing challenges, and future research priorities are discussed. The integration of insights across the studies, through this work, aims to assist researchers and clinicians in the development and translation of handwriting-based, AI-guided diagnostic tools for neurodegenerative diseases.},
}
@article {pmid42451691,
year = {2026},
author = {Singh, AA and Arukha, AP and Song, M},
title = {Indole-Derived Compounds as Redox-Modulators: Antioxidant Mechanisms in Neuronal Protection.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {13},
pages = {},
doi = {10.3390/molecules31132323},
pmid = {42451691},
issn = {1420-3049},
mesh = {Humans ; *Antioxidants/pharmacology/chemistry ; *Indoles/chemistry/pharmacology ; Animals ; *Neuroprotective Agents/pharmacology/chemistry ; Oxidation-Reduction/drug effects ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Neurons/drug effects/metabolism ; Oxidative Stress/drug effects ; Signal Transduction/drug effects ; Reactive Oxygen Species/metabolism ; },
abstract = {Neurodegenerative diseases, such as Alzheimer's, Parkinson's, and Amyotrophic lateral sclerosis, are distinguished by progressive neuronal dysfunction caused primarily by oxidative stress, mitochondrial impairment, neuroinflammation, and redox imbalance. Growing evidence suggests that indole-derived compounds have significant neuroprotective potential due to their antioxidant, anti-inflammatory, and redox-modulating properties. This review summarizes the structural and biological significance of indole scaffolds, focusing on the mechanisms by which natural, endogenous, microbiota-derived, and synthetic indole compounds protect neuronal networks. Indole-3-carbinol, 3,3'-diindolylmethane, indole-3-propionic acid, and melatonin are major indole derivatives that control important neuroprotective pathways like Nrf2/ARE signaling, mitochondrial bioenergetics, neurotrophic factor expression, apoptotic regulation, and suppression of proinflammatory mediators. These compounds also maintain synaptic plasticity, reduce reactive oxygen species production, and improve neuronal survival in neurodegenerative disease models. Additionally, updated information from translational and clinical research indicates that indole-based compounds may have promising therapeutic applications; however, obstacles like low bioavailability, metabolic instability, and blood-brain barrier penetration continue to be major obstacles to clinical application. Development in nanoparticle delivery systems, microbiome-targeted interventions, and rational structural optimization may improve therapeutic efficacy and translational potential. Overall, indole-derived compounds are a versatile class of redox modulators with potential applications in the prevention and treatment of neurodegenerative diseases via integrated antioxidant and neuroprotective mechanisms.},
}
@article {pmid42452303,
year = {2026},
author = {Patil, N and Chandel, V and Rana, A and Jain, M and Kaushik, P},
title = {Correction: Patil et al. Investigation of Cannabis sativa Phytochemicals as Anti-Alzheimer's Agents: An In Silico Study. Plants 2023, 12, 510.},
journal = {Plants (Basel, Switzerland)},
volume = {15},
number = {13},
pages = {},
doi = {10.3390/plants15132041},
pmid = {42452303},
issn = {2223-7747},
abstract = {In this publication [...].},
}
@article {pmid42452600,
year = {2026},
author = {Latella, D and Scorza, C and Bonanno, M and Calderone, A and Quartarone, A and Quattrini, F and Calabrò, RS},
title = {Neurogenic Pelvic Floor Dysfunctions Across Neurological Disorders: Mechanisms, Phenotypes, and Precision Rehabilitation Pathways-A Narrative Review.},
journal = {Journal of clinical medicine},
volume = {15},
number = {13},
pages = {},
doi = {10.3390/jcm15135140},
pmid = {42452600},
issn = {2077-0383},
support = {RRC-2025-23686388//Ministry of Health/ ; },
abstract = {Background: Pelvic floor dysfunction (PFD) is frequent in neurological disorders, but it is often approached as a secondary urological or gynecological problem rather than a functional rehabilitation target. Neurological disease can disturb cortical, pontine, spinal, sacral, autonomic, somatic, and sensory pathways that regulate bladder storage, voiding, bowel evacuation, sexual function, and pelvic pain modulation. Methods: This narrative review synthesized biomedical evidence identified through PubMed searches from database inception to 2 May 2026. Search concepts included neurogenic lower urinary tract dysfunction, urinary and bowel dysfunction, sexual dysfunction, pelvic pain, pelvic floor rehabilitation, biofeedback, electrical stimulation, neuromodulation, telerehabilitation, robotics, and major neurological disorders. The review was oriented according to the Scale for the Assessment of Narrative Review Articles (SANRA) and was not designed as a systematic review or meta-analysis. Results: Evidence from multiple sclerosis, stroke, Parkinson's disease, Alzheimer's disease and related dementias, spinal cord injury, and fibromyalgia or nociplastic pain syndromes supports a phenotype-based framework in which pelvic floor muscle training, bladder and bowel training, biofeedback, neuromuscular electrical stimulation, posterior tibial nerve stimulation, sacral neuromodulation, telerehabilitation, robotics, and multidisciplinary care are considered complementary rather than interchangeable strategies. Conclusions: PFD in neurological disorders may be more appropriately conceptualized as a multidimensional neurorehabilitation target. Effective care depends on disease-informed phenotyping, individualized rehabilitation goals, attention to cognition and adherence, and standardized outcome measurement. Future studies should test phenotype-specific pathways that integrate bladder, bowel, sexual, pain, participation, safety, and caregiver outcomes.},
}
@article {pmid42452755,
year = {2026},
author = {Bijoch, J and Jędrasiak, K},
title = {Red Complex Pathogens, Periodontal Dysbiosis and Periodontal Therapy in Alzheimer's Disease and Dementia.},
journal = {Journal of clinical medicine},
volume = {15},
number = {13},
pages = {},
doi = {10.3390/jcm15135296},
pmid = {42452755},
issn = {2077-0383},
abstract = {This narrative review synthesizes evidence linking periodontal dysbiosis with Alzheimer's disease, all-cause dementia, and dementia-relevant mechanisms, focusing on the red complex pathogens P. gingivalis, T. denticola, and T. forsythia and on the translational meaning of periodontal therapy. A PubMed-centered literature search up to May 2026 informed this synthesis (a narrative review, not a registered systematic review or meta-analysis) of 46 periodontal-scope sources, supplemented by five contextual references identified outside the periodontal search (51 references in total). P. gingivalis shows the strongest mechanistic support, including gingipains, lipopolysaccharide, outer membrane vesicles, endothelial stress, and neuroinflammatory signaling; T. denticola shows moderate biological plausibility; and T. forsythia remains mainly hypothesis-generating. Human studies associate periodontitis, tooth loss, oral-hygiene indicators, and periodontal-care exposure with dementia-relevant outcomes, but residual confounding, reverse causation, dental-care access, and heterogeneous endpoints preclude causal inference. Notably, direct targeting of a single periodontal pathogen has not shown clinical benefit, as the gingipain inhibitor atuzaginstat failed in the GAIN trial, contrasting with the modest success of amyloid-targeting therapies. Current evidence supports graded plausibility rather than causal certainty, and a registered multi-database systematic review with neurological endpoints is needed before meta-analytic clinical claims can be made.},
}
@article {pmid42452962,
year = {2026},
author = {Al-Ghraiybah, NF and Alkhalifa, AE and Spivey, D and Averill, T and Engelkemier, B and Haro Lopez, P and Stuckey, MG and Jenkins, L and Kaddoumi, A},
title = {Serotonergic System Dysregulation in Alzheimer's Disease.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00236},
pmid = {42452962},
issn = {1948-7193},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by several key hallmarks, including the accumulation of amyloid-β (Aβ), neurofibrillary tangles (NFTs), neuroinflammation, and blood-brain barrier (BBB) dysfunction. Similar to other neurodegenerative diseases, AD involves disturbances in neurotransmitter homeostasis. However, the serotonergic system is complex, involving numerous mechanisms and pathways, which complicates the establishment of direct correlations with AD. This review examines the serotonergic system, focusing on alterations in serotonin (5-HT), its transporter, and its receptors in the context of AD, to identify current knowledge gaps and highlight ongoing research directions. It also emphasizes the role of 5-HT in vascular regulation and BBB integrity, and links the gut-brain axis to the serotonergic system.},
}
@article {pmid42453112,
year = {2026},
author = {Giorelli, M and Paola, CAD and Vallarelli, R and Negri, F and Morgese, R and Balzano, RF and Fazio, PD and Tatò, D and Procacci, C and Masi, G and Carpagnano, FL and Dimatteo, T},
title = {Preparedness and quality of dementia care in an Italian health authority when introducing anti-Aβ therapies.},
journal = {Alzheimer's &amp; dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70403},
pmid = {42453112},
issn = {2352-8729},
abstract = {INTRODUCTION: We aimed to assess dementia care organizations within a southern Italian local health authority (Azienda Sanitaria Locale di Barletta Andria Trani) and to propose an equitable implementation framework for anti-amyloid therapies.<br><br>METHODS: We performed a retrospective analysis of dementia-related outpatient activity in 2024 patients across 18 district clinics (primary care clinics) and three specialized centers for cognitive disorders and dementia (specialized memory centers), integrating booking, clinical, imaging, and prescribing data.<br><br>RESULTS: Among 1158 initial evaluations, specialized memory centers showed substantially higher quality indicators than district clinics: Mini-Mental State Examination documentation (80.0% vs. 6.6%, p < 0.001), full clinical documentation (95.5% vs. 10.0%), higher use of magnetic resonance imaging and amyloid positron emission tomography, and 5-fold higher rate of prescribing acetylcholinesterase inhibitors. Validated radiological scoring and biomarker facilities (cerebrospinal fluid, apolipoprotein E genotyping) were largely unavailable.<br><br>DISCUSSION: Major organizational gaps limit readiness for disease-modifying Alzheimer's disease therapies. A four-tier hub-and-spoke model may improve equity, efficiency, and safe implementation.},
}
@article {pmid42453113,
year = {2026},
author = {Jung, YH and Lee, ES and Park, YJ and Lee, S and Chung, SJ and Lim, JJ and Kim, SW and Kang, HJ and Eo, JS and Oh, K and Koh, SB and Kim, HS and Kang, SH},
title = {Association of plasma irisin levels with amyloid burden in the Alzheimer's disease spectrum.},
journal = {Alzheimer's &amp; dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70418},
pmid = {42453113},
issn = {2352-8729},
abstract = {INTRODUCTION: This study investigated the association between plasma myokines, including irisin, and cerebral amyloid burden across the Alzheimer's disease (AD) continuum.<br><br>METHODS: A total of 100 participants were classified into four groups: amyloid-negative cognitively unimpaired (A- CU), amyloid-positive CU (A+ CU), A+ mild cognitive impairment (MCI), and A+ dementia of the Alzheimer's disease type (DAT). All participants underwent neuropsychological testing, brain magnetic resonance imaging, amyloid positron emission tomography, and plasma myokine assessment. Multivariable linear regression and mediation analyses were performed adjusting for covariates.<br><br>RESULTS: Irisin levels were significantly lower in all AD continuum groups compared to A- CU participants (p&#xa0;<&#xa0;0.001), while brain-derived neurotrophic factor (BDNF) and fibroblast growth factor 21 (FGF21) showed no group differences. Higher irisin levels were associated with lower amyloid burden (r&#xa0;=&#xa0;-0.24, p&#xa0;=&#xa0;0.019). Mediation analysis demonstrated that amyloid burden mediated the relationship between irisin and cognitive outcomes, whereas no such effects were observed for BDNF or FGF21.<br><br>DISCUSSION: Irisin may play a key role in the muscle-brain axis by linking amyloid pathology to cognitive decline in AD.},
}
@article {pmid42453150,
year = {2026},
author = {Shim, Y and Lim, EY},
title = {Baseline facial emotion recognition is associated with clinical decline across the Alzheimer's disease spectrum: a multi-instrument longitudinal assessment study.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1863175},
pmid = {42453150},
issn = {1663-4365},
abstract = {BACKGROUND: Facial emotion recognition (FER) is increasingly recognized as a functionally relevant domain in the Alzheimer's disease (AD) spectrum, yet whether baseline FER is associated with subsequent clinical decline remains insufficiently established.<br><br>METHODS: We studied 328 participants [subjective cognitive decline (SCD) n&#x202f;=&#x202f;94, mild cognitive impairment (MCI) n&#x202f;=&#x202f;142, AD dementia n&#x202f;=&#x202f;92] from a longitudinal memory clinic cohort; 148 had follow-up assessments (mean 1.59&#x202f;&#xb1;&#x202f;0.67&#x202f;years). FER was assessed using the Korean version of the Florida Affect Battery (K-FAB; five subtests, FER_mean). Linear mixed-effects models examined group-differential trajectories of the Mini-Mental State Examination (MMSE), Clinical Dementia Rating-Sum of Boxes (CDR-SOB), and FER_mean, adjusted for age, sex, education, and baseline values.<br><br>RESULTS: FER_mean decreased stepwise across groups at baseline (SCD 17.3&#x202f;&#xb1;&#x202f;1.5, MCI 16.4&#x202f;&#xb1;&#x202f;2.1, AD 15.3&#x202f;&#xb1;&#x202f;2.0; p&#x202f;<&#x202f;0.001). CDR-SOB showed more consistent group-differential longitudinal trajectories: MCI increased at +0.550 points/year (p&#x202f;<&#x202f;0.001), with SCD significantly slower (&#x3b2;&#x202f;=&#x202f;-0.491, p&#x202f;=&#x202f;0.008) and AD faster (&#x3b2;&#x202f;=&#x202f;+0.371, p&#x202f;=&#x202f;0.038). FER_mean showed a modest decline in MCI (&#x3b2;&#x202f;=&#x202f;-0.169/yr., p&#x202f;=&#x202f;0.078) and SCD showed significantly attenuated decline relative to MCI (&#x3b2;&#x202f;=&#x202f;+0.376, p&#x202f;=&#x202f;0.035). Lower baseline FER was associated with faster CDR-SOB worsening (&#x3c1;&#x202f;=&#x202f;-0.221, p&#x202f;=&#x202f;0.006) but not MMSE decline (&#x3c1;&#x202f;=&#x202f;0.093, p&#x202f;=&#x202f;0.255). FER change rates showed a weak, non-significant correlation with MMSE change (&#x3c1;&#x202f;=&#x202f;0.004, p&#x202f;=&#x202f;0.960) but a modest significant correlation with CDR-SOB change (&#x3c1;&#x202f;=&#x202f;-0.195, p&#x202f;=&#x202f;0.018), suggesting partially distinct longitudinal patterns.<br><br>CONCLUSION: Baseline FER was modestly associated with longitudinal worsening in clinical severity (CDR-SOB), but not cognitive screening performance (MMSE) across the pre-dementia to dementia spectrum. FER trajectories showed limited correlation with traditional measures. These findings indicate that FER may have a potential complementary role of social cognitive assessment in the AD continuum, pending further validation.},
}
@article {pmid42453256,
year = {2026},
author = {Asyah, SKA and Saad Algethami, E and Alzaidi, BA and Althomali, RN and Alzahrani, NJ and Alhothaly, SK and Alsulaimani, WT and Almalki, AA and Ghazy, RM},
title = {Prevalence and risk factors of cognitive impairment among geriatric patients at Prince Sultan Military Hospital, Taif, Saudi Arabia.},
journal = {Journal of family medicine and primary care},
volume = {15},
number = {4},
pages = {1666-1673},
pmid = {42453256},
issn = {2249-4863},
abstract = {BACKGROUND: Cognitive impairment and dementia represent a growing public health challenge among the aging population in Kingdom of Saudi Arabia. This study aimed to determine the prevalence of cognitive impairment and identify associated risk factors.<br><br>METHODS: A cross-sectional study was conducted at the Prince Sultan Military Hospital Geriatric Clinic in Taif from November 2024 to May 2025. A sample of patients aged &#x2265;65 years were recruited via simple random sampling. Data on sociodemographics, clinical history, and lifestyle were collected. Cognitive function was screened using the Arabic version of the Eight-item Alzheimer's Dementia (AD8) questionnaire, administered to knowledgeable informants who had known the participant for at least 5 years with a score &#x2265; 2 indicating likely impairment.<br><br>RESULTS: The study sample consisted of 182 geriatric patients. Bivariate analysis revealed that cognitive impairment was significantly associated with below-average income (P = 0.01), requiring daily assistance (P = 0.001), depression (P = 0.034), hypothyroidism (P = 0.026), lack of regular exercise (P = 0.01), and subjective cognitive complaints (P < 0.001). After multivariable adjustment using stepwise logistic regression, independent predictors of cognitive impairment were: any cognitive complaint (aOR = 17.99, 95% CI: 7.8-46.3, P < 0.001), hypothyroidism (aOR = 4.27, 95% CI: 1.4-14.3, P = 0.014), below-average income (aOR = 3.40, 95% CI: 1.6-7.8, P = 0.003), and lack of regular exercise (aOR = 2.61, 95% CI: 1.1-6.2, P = 0.027).<br><br>CONCLUSION: This study found a high prevalence of cognitive impairment among geriatric clinic patients in Taif. Key predictors include modifiable risks like physical inactivity, treatable conditions such as hypothyroidism, and socioeconomic and personal factors. The findings support routine cognitive screening and highlight priority areas for multidisciplinary interventions to reduce cognitive decline.},
}
@article {pmid42453339,
year = {2026},
author = {Thapa Magar, TB and Kim, M and Kim, Y and Choi, EY and Choi, YK and Kim, DE and Kim, KB and Park, JE},
title = {Pharmacokinetics, Target Engagement of an Immunoproteasome Subunit Low-Molecular-Mass Polypeptide‑2 (LMP2) Inhibitor AR-01, and Its Anti-Alzheimer's Effects in Rodents.},
journal = {ACS pharmacology &amp; translational science},
volume = {9},
number = {7},
pages = {1869-1880},
pmid = {42453339},
issn = {2575-9108},
abstract = {Previously, we reported that AR-01, an irreversible macrocyclic peptide epoxyketone, selectively inhibits the immunoproteasome catalytic subunit LMP2 (low-molecular mass polypeptide-2). We also showed that LMP2 inhibition produces anti-Alzheimer's effects in animal models of Alzheimer's disease (AD) by suppressing microglia-mediated inflammation. As such, AR-01 is being developed as a potential treatment for AD. Typically, CNS drugs with peptide backbones face significant challenges due to unfavorable properties for crossing the blood-brain barrier. In this report, we evaluated the pharmacokinetic properties of AR-01, including brain permeability (i.e., brain-to-plasma partition coefficient), in healthy mice and rats as part of early stage drug development. We also verified AR-01 target engagement in the brain using two alternative approaches: (i) LMP2 activity assay and (ii) LMP2 band shift on Western blotting, which is caused by the formation of an irreversible LMP2:AR-01 adduct. The results confirmed that a single intravenous administration of AR-01 inactivates LMP2 in the mouse brain in a dose-dependent manner. Multiple doses of AR-01 led to cumulative LMP2 adduct formation in the mouse brain and improved cognitive function in 5xFAD mice, a widely used model of amyloidogenesis. Taken together, the results suggest that AR-01 has promising pharmaceutical properties as an AD therapeutic.},
}
@article {pmid42453345,
year = {2026},
author = {Anil, V and Sherin, DR},
title = {Recent Advances in Organofluoroprobes for Brain Imaging: Progress, Challenges, and Future Directions.},
journal = {ACS pharmacology &amp; translational science},
volume = {9},
number = {7},
pages = {1652-1703},
pmid = {42453345},
issn = {2575-9108},
abstract = {The precise and early diagnosis of neurodegenerative diseases remains a major challenge because of their highly complex and multifactorial pathophysiology. However, in recent years, the potential of organofluoroprobes(?)organic molecules designed to function as fluorescent probes in bioimaging(?)has become increasingly prominent. These probes enable visualization of essential biomarkers, including amyloid-beta (Aβ), tau, reactive oxygen and nitrogen species (ROS/RNS), neurotransmitters, and abnormal metal ions, facilitating early detection and monitoring of diseases such as Alzheimer's and Parkinson's. This review focuses on small-molecule organofluoroprobes, which consist of curcumin-, boron-dipyrromethane (BODIPY)-, cyanine-, coumarin-, benzothiazole-, thiophene-, naphthalene-, oxazine-, and organometallic-based systems. We also address biomarker-activated probes, nanoengineered aggregation-induced emission (AIE) luminogens, and photoacoustic probes that provide greater tissue penetration and multimodal imaging. Nevertheless, these imaging probes still have shortcomings, including poor specificity, limited penetration through the blood-brain barrier (BBB), and inefficient near-infrared II (NIR-II) emission. Notably, the design and optimization of fluoroprobes are being revolutionized by the integration of artificial intelligence (AI) and computational methods, such as deep learning, generative models, and virtual screening. These approaches provide new avenues for predictive modeling of physicochemical properties, target affinity and in vivo performance, thereby significantly reducing the time and cost of development. The review concludes by discussing current challenges and future perspectives, including the convergence of AI-assisted molecular design and synthetic chemistry in bioimaging, ultimately leading to the clinical translation of next-generation brain imaging probes.},
}
@article {pmid42453424,
year = {2026},
author = {Ding, Y and Li, SY and Zhang, WF and Chu, MM and Wang, XJ and Zhang, YG and Zhang, HW and Zhang, YT and Xu, L and Liu, X and Morita, T and Baba, O and Ren, ZJ and Zhang, YJ and Zhang, ZY and Li, L},
title = {PYGL-driven glycogenolysis impairs microglial autophagic flux via SNAP29 O-GlcNAcylation in Alzheimer's disease.},
journal = {Acta pharmaceutica Sinica. B},
volume = {16},
number = {7},
pages = {4367-4388},
pmid = {42453424},
issn = {2211-3835},
abstract = {Aberrant metabolic alterations underlie microglial dysfunction, which plays an important role during neurodegenerative progression. However, the role of aberrant glycogen metabolism remains elusive. Here, we identified glycogen accumulation and upregulated glycogenolytic enzymes in brain microglia from patients with Alzheimer's disease (AD) and transgenic animal models. Particularly, the principal microglial glycogenolytic enzyme PYGL exhibited the most notable spatiotemporal upregulation during disease progression. Specific knockdown of microglial PYGL ameliorated neuropathological changes and cognitive deficits in AD mice. Bioinformatics analysis and experimental validation confirmed that enhancing microglial autophagic flux-dependent Aβ clearance was the underlying mechanism. Furthermore, among all possible glycogenolytic pathways, PYGL downregulation primarily reduced hexosamine biosynthesis pathway activity, diminished UDP-GlcNAc and O-GlcNAcylation of the autophagy key protein SNAP29, and thereby facilitated formation of the SNARE complex, which is essential for autophagosome-lysosome fusion. These findings reveal a glycogenolysis-driven post-translational pathway regulating microglial autophagy, establishing PYGL as a therapeutic target for AD.},
}
@article {pmid42453520,
year = {2026},
author = {Tsai, ST and Liew, HK and Wang, MJ and Hung, WT and Huang, HY},
title = {Tracking pericyte dysfunction in Alzheimer's disease: The emerging role of cerebrospinal fluid platelet-derived growth factor receptor-β.},
journal = {Tzu chi medical journal},
volume = {38},
number = {3},
pages = {275-288},
pmid = {42453520},
issn = {2223-8956},
abstract = {Growing human and experimental evidence redefine Alzheimer's disease (AD) as a neurovascular disorder because the early neurovascular unit (NVU) injury triggers proteinopathy. Among NVU, pericytes are a pivotal regulator of capillary tone, blood-brain barrier (BBB) integrity, and amyloid-β (Aβ) clearance. Injured or lost pericytes promote non-selective transcytosis, induce endothelial de-zonation, weaken tight junctions, and drive heterogeneous capillary flow and rarefaction. Here, we collect data from clinical imaging, cerebrospinal fluid (CSF) biomarkers, and transgenic mice with platelet-derived growth factor receptor-β (PDGFRβ) signal defects to discuss the role of CSF soluble PDGFRβ (sPDGFRβ) as a marker of BBB damage across the AD continuum. During normal aging, sPDGFRβ rises slightly, consistent with low-grade pericyte stress. In mild cognitive impairment, sPDGFRβ is elevated and associates with BBB breakdown and accelerated cognitive decline, often independent of core AD biomarkers, suggesting early vascular changes before AD onset. In early AD, pericyte dysfunction (characterized by elevated sPDGFRβ) attenuates pericyte-dependent Aβ processing and endothelial lipoprotein receptor-related protein 1-mediated Aβ efflux, leading to impaired perivascular drainage and favoring Aβ40-rich vascular deposition and capillary cerebral amyloid angiopathy. During AD progression, despite persistent leakage, sPDGFRβ frequently plateaus, reflecting severe pericyte depletion and reduced discrimination of disease stage. We propose a practical approach that integrates sPDGFRβ with BBB imaging analysis and Aβ biomarkers to distinguish between parenchymal-dominant and vascular-dominant pathology in AD. These indicators can identify patients at high risk of developing amyloid-related imaging abnormalities during anti-amyloid therapy and can serve as pharmacodynamic endpoints for BBB-stabilizing or pericyte-targeted interventions to advance personalized dementia care.},
}
@article {pmid42453526,
year = {2026},
author = {Varinthra, P and Ibiayo, AG and Liu, CH and Pakaprot, N and Paromi, IN and Do, TT and Raza, M and Liu, IY},
title = {Therapeutic advances in Alzheimer's disease: Current strategies and future possibilities.},
journal = {Tzu chi medical journal},
volume = {38},
number = {3},
pages = {263-274},
pmid = {42453526},
issn = {2223-8956},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder causing memory, cognitive, and behavioral impairments in older adults and poses a major worldwide health challenge. The pathophysiology of AD is highly complex and multifactorial, arising from interrelated processes such as amyloid-β (Aβ) aggregation, tau hyperphosphorylation, synaptic dysfunction, neuroinflammation, mitochondrial impairment, and oxidative stress. In addition, both genetic predisposition and environmental or lifestyle factors play critical roles in disease susceptibility and progression. Despite decades of investigation, therapeutic options with robust disease-modifying potential remain limited. Based on published studies from 2021 to 2025, current treatments primarily focus on symptomatic management with cholinesterase inhibitors, N-methyl-D-aspartate receptor antagonists, and combined therapies, complemented by nonpharmacological interventions to support cognition and quality of life. Recently, advances in disease-modifying strategies, particularly monoclonal antibodies targeting Aβ, tau-directed therapies, and approaches modulating neuroinflammation, have generated cautious optimism for shifting the treatment paradigm. Importantly, emerging evidence suggests that specific herbal extracts with antioxidant, anti-inflammatory, and neuroprotective properties may serve as promising adjuncts to conventional therapy. Effective long-term management of AD may ultimately require multimodal strategies that integrate pharmacological, herbal, and lifestyle interventions with precision medicine approaches guided by biomarkers and neuroimaging. This minireview summarizes current therapeutic strategies, emerging advances, and persistent challenges, while highlighting future directions to enable earlier intervention and more effective modulation of disease progression.},
}
@article {pmid42453588,
year = {2026},
author = {Li, C and Lin, C and Li, Z and Lv, F and Yang, W and Ji, L and Cai, X},
title = {Anti-obesity medications and cognitive disorder risk: a discrepancy between RCTs and real-world evidence.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1859388},
pmid = {42453588},
issn = {1663-9812},
abstract = {OBJECTIVES: To investigate the association between anti-obesity medication (AOM) use and the risk of cognitive disorder in individuals with overweight and obesity.<br><br>METHODS: We systematically searched PubMed, Embase, the Cochrane Central Register of Controlled Trials, Web of Science and Clinicaltrials.gov from inception to August 2025 for randomized controlled trials (RCTs) and observational studies of AOMs. Relative risks were calculated using a random-effect model.<br><br>RESULTS: Our analysis included 4 RCTs (n = 35,924; 17,963 AOM users, 17,961 placebo recipients) and 2 retrospective cohort studies (n = 2,303,492; 1,151,746 GLP-1RA users, 1,151,746 non-users). In RCTs, the use of AOMs was not associated with a lower risk of cognitive disorder (RR = 0.94, 95% CI 0.39 to 2.25, P = 0.88) or dementia (RR = 1.02, 95% CI 0.41 to 2.54, P = 0.97) versus placebo. Every 5-kg weight reduction mediated by AOMs was not associated with a decreased risk of cognitive disorder (RR = 0.95, 95% CI 0.44 to 2.05, P = 0.82) compared with placebo. Meta-regression further confirmed that neither absolute weight loss nor weight reduction difference between AOM and placebo groups was associated with a reduced risk of cognitive disorder. However, retrospective cohort studies showed that GLP-1RA users had lower risks of cognitive disorder (OR = 0.44, 95% CI 0.21 to 0.91, P = 0.03) and Alzheimer's disease (OR = 0.43, 95% CI 0.19 to 0.97, P = 0.04) than non-users.<br><br>CONCLUSION: While short-term RCTs did not observe a substantial cognitive benefit of AOMs, real-world evidence indicated that GLP-1RAs may offer potential protection against cognitive disorders. These divergent findings highlight the need for long-term prospective trials with dedicated cognitive endpoints.},
}
@article {pmid42453713,
year = {2026},
author = {Arachchige, ASPM and Schmiliver, B and Alves, GAM},
title = {Alzheimer's disease: A comprehensive review of epidemiology, pathophysiology, diagnosis, and treatment.},
journal = {AIMS neuroscience},
volume = {13},
number = {2},
pages = {208-243},
pmid = {42453713},
issn = {2373-7972},
abstract = {Alzheimer's disease (AD) is the most common cause of dementia, representing a major global public health challenge as populations age. It accounts for roughly 60%-80% of all dementia and is characterized by progressive cognitive decline, memory impairment, and eventual loss of independence in daily functioning. The disease unfolds over decades, with neuropathological alterations preceding the onset of clinical symptoms by many years. Alzheimer's disease is closely linked to the accumulation and deposition of cerebral amyloid-β (Aβ) and represents the most common cerebral amyloid deposition disorder. Recent advances in molecular biology, neuroimaging, and biomarker science have revealed a complex, multifactorial pathogenesis involving protein misfolding, neuroinflammation, synaptic dysfunction, vascular factors, and network-level propagation of pathology. This review synthesizes current knowledge on AD terminology, epidemiology and risk factors, clinical phenotypes and natural history, pathophysiological mechanisms, diagnostic approaches (including imaging and fluid biomarkers), and established as well as emerging therapeutic strategies, while also outlining key challenges and future directions.},
}
@article {pmid42453899,
year = {2026},
author = {Smirnov, DS and Dickinson, SM and Estrella, MF and Goodwill, VS and Headley, AJ and Pizzo, DP and Galasko, D and Salmon, DP and Hiniker, A},
title = {Neurofibrillary tangle distribution in posterior cortical atrophy and typical early-onset Alzheimer's Disease.},
journal = {Free neuropathology},
volume = {7},
number = {},
pages = {18},
pmid = {42453899},
issn = {2699-4445},
abstract = {Background and objectives: Posterior Cortical Atrophy (PCA) is a focal variant of Alzheimer's Disease (AD) characterized by disproportionate and early visuospatial deficits with relative sparing of other cognitive abilities. PCA commonly arises before age 65, consistent with early onset AD (EOAD). Because studies of PCA pathology in patients with detailed cognitive assessment are rare, relationships between severity and distribution of neurofibrillary tangle (NFT) density and visuospatial deficits in PCA are not fully known. Our objectives were to: (1) determine if ratio of NFT density in occipital cortex (OC) versus hippocampus (HC) is higher in PCA than typical EOAD and (2) determine if this ratio correlates with severity of visuospatial deficits in EOAD generally. Methods: We determined density of tau NFT pathology in primary visual cortex (OC), midfrontal cortex (MF), and HC and calculated ratios of these densities for EOAD patients with PCA (n = 12) or non-PCA (n = 33) clinical phenotypes. Groups were compared using linear regression that adjusted for age at death and sex. Correlation between NFT density and visuospatial and other cognitive domain scores were examined using linear regression that adjusted for age at cognitive testing, education, sex and test-death interval. Analyses were repeated with the non-PCA EOAD patients grouped into those with mild (EOAD-Typical, n = 21) or severe (EOAD-Visual, n = 12) visuospatial impairment. Results: PCA patients had lower HC (β = -11.7 ± 5.7, p = 0.045) and a trend toward higher OC (β = 6.9 ± 3.7, p = 0.07) NFT density, and higher OC/HC (β = 0.30 ± 0.14, p = 0.04) and OC/MF (β = 0.56 ± 0.16, p = 0.001) ratios, than typical non-PCA EOAD patients. The EOAD-Visual had higher OC/HC NFT ratios (β = 0.38 ± 0.13, p = 0.008) than the EOAD-Typical non-PCA patients even though they did not meet clinical criteria for PCA. Correlations between OC/HC NFT ratios and visuospatial domain scores were strong (β = -1.29 ± 0.45, p = 0.008) and remained significant when limited to the non-PCA EOAD group (β = -1.22 ± 0.43, p = 0.008). Discussion: PCA is associated with a distribution of NFT pathology (i.e., high OC/HC NFT ratio) that coincides with early predominant visuospatial impairment. Non-PCA EOAD with a memory-predominant presentation and concomitant visuospatial impairment has an NFT distribution profile similar to PCA. NFT pathology in occipital cortex may moderate degree of visuospatial impairment in EOAD regardless of clinical syndrome.},
}
@article {pmid42453957,
year = {2026},
author = {Geraiely, B and Kianmehr, E and Iraji, A and Bukhari, SNA and Mohammadi, H and Mojtabavi, S and Mahdavi, M and Saeedi, M},
title = {Design and synthesis of new donepezil-based chalcones as multi-target-directed ligands against Alzheimer's disease: biological evaluation, molecular dynamics, and zebrafish model studies.},
journal = {RSC advances},
volume = {},
number = {},
pages = {},
pmid = {42453957},
issn = {2046-2069},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disease characterized by several hallmarks, including cholinergic dysfunction, aggregation of amyloid beta (Aβ), oxidative stress, and metal ion dyshomeostasis. A series of donepezil-derived chalcones 7a-q were synthesized and tested for their ability to inhibit cholinesterase (ChE) and amyloid beta (Aβ) aggregation, antioxidant properties, and metal chelation. Of these, compound 7j with a 2-chloroaryl moiety showed moderate anti-AChE activity (IC50 = 17.96 µM) and showed potent inhibition of Aβ aggregation, both in the presence of self-induced (72.5%) and AChE-induced (77.6%) conditions, and had good Cu[2+] chelation ability, which was confirmed by ultraviolet-visible (UV-vis) spectroscopy. Compound 7p, an analog containing furan, exhibited both anti-ChE activity (IC50 = 22.70 µM for AChE and 19.14 µM for BuChE, respectively) and moderate anti-Aβ aggregation activity, as well as moderate antioxidant activity. The two compounds were found to be safe, also in PC12 cells and SH-SY5Y cells. Their results are all encouraging for their use as multi-target directed ligands (MTDLs) against AD. Finally, the molecular dynamics simulations in the active site of AChE of compound 7j showed stable binding for 100 nanoseconds. In vivo experiments in zebrafish showed that compound 7p markedly enhanced locomotor and exploratory behavior, with a therapeutic profile compared to the standard drug donepezil, and compound 7j exhibited moderate therapeutic effects.},
}
@article {pmid42454127,
year = {2026},
author = {Hu, H and Wang, Y and Xu, Y and Chen, L},
title = {Diabetic retinopathy and the risk of all-cause dementia, Alzheimer's disease, and vascular dementia: a systematic review and meta-analysis.},
journal = {Frontiers in medicine},
volume = {13},
number = {},
pages = {1716648},
pmid = {42454127},
issn = {2296-858X},
abstract = {BACKGROUND: Existing evidence on the association between diabetic retinopathy (DR) and the risk of all-cause dementia (ACD), Alzheimer's disease (AD), and vascular dementia (VD) remains inconsistent. To address this gap, we performed a systematic review and meta-analysis to quantitatively assess the relationship between DR patients and subsequent dementia risk, aiming to inform evidence-based prevention strategies.<br><br>METHODS: We systematically searched PubMed, Embase, and Web of Science for cohort studies investigating the association between DR and the risk of ACD, AD, and VD. The searches covered all available literature from the inception of database to September 2025. After literature screening, data extraction, and risk-of-bias assessment, meta-analysis was conducted using Stata 14.0. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated.<br><br>RESULTS: A total of 10 studies involving 1,720,128 participants were included. The meta-analysis showed that DR was significantly associated with higher risks of ACD (HR&#x202f;=&#x202f;1.24, 95%CI [1.14, 1.36], p&#x202f;<&#x202f;0.00001), VD (HR&#x202f;=&#x202f;1.20, 95%CI [1.05, 1.37], p&#x202f;=&#x202f;0.009), and AD (HR&#x202f;=&#x202f;1.23, 95%CI [1.11, 1.37], p&#x202f;<&#x202f;0.00001).<br><br>CONCLUSION: Current evidence indicates that DR is associated with an elevated risk of ACD, AD, and VD. Clinically, early screening and regular monitoring of cognitive function should be strengthened in patients with DR, and these assessments should be integrated into comprehensive diabetes care. Given the inherent limitations of this study, further high-quality prospective cohort studies are needed to confirm these findings.},
}
@article {pmid42454188,
year = {2026},
author = {Du, X and Xu, S and Zhou, X and Zhou, H and Jin, B and Peng, Z and Nüssler, AK and Liu, L and Chen, J and Yang, W},
title = {Biological properties and potential pathogenic mechanisms of oral bacterial-derived extracellular vesicles in oral and systemic diseases.},
journal = {Extracellular vesicles and circulating nucleic acids},
volume = {7},
number = {2},
pages = {813-832},
pmid = {42454188},
issn = {2767-6641},
abstract = {This review summarizes the biological characteristics of oral bacterial extracellular vesicles (O-BEVs) and their proposed roles in disease pathogenesis. As nanosized lipid bilayer structures secreted by oral bacteria, O-BEVs encapsulate virulence factors, nucleic acids, and metabolites, enabling them to traverse biological barriers and modulate host cellular functions. Studies suggest that O-BEVs are involved in the progression of oral diseases, including periodontitis, dental caries, and oral cancer through mechanisms such as immune activation, tissue destruction, and cellular behavior modulation. Furthermore, O-BEVs can enter the systemic circulation. Through synergistic interactions among their protein, lipid, and nucleic acid components, O-BEVs activate inflammatory pathways and compromise barrier integrity, thereby contributing to the pathogenesis of systemic diseases, including Alzheimer's disease, atherosclerosis, diabetes mellitus, rheumatoid arthritis, adverse pregnancy outcomes, and osteoporosis. However, most current evidence derives from preclinical (in vitro and animal) studies, while direct clinical evidence linking O-BEVs to human diseases remains limited, and causal relationships have not been firmly established. Understanding the mechanisms of O-BEVs may enable targeted diagnostic approches, therapies, and prevention strategies along the "oral-systemic axis", with important clinical and public health implications.},
}
@article {pmid42454195,
year = {2026},
author = {Fan, H and Wang, S and Li, Z and Yu, T and Ma, C and Sun, C},
title = {Stem cell extracellular vesicles for neuropsychiatric disorders and translation.},
journal = {Extracellular vesicles and circulating nucleic acids},
volume = {7},
number = {2},
pages = {764-785},
pmid = {42454195},
issn = {2767-6641},
abstract = {Neuropsychiatric disorders represent a major global health challenge due to their high prevalence, chronic disability, and substantial socioeconomic burden. Although stem cell-based therapies offer regenerative potential, their clinical application is limited by poor post-transplantation survival, restricted targeted integration, and potential tumorigenicity. Stem cell-derived extracellular vesicles (SC-EVs), particularly exosomes, have emerged as a promising cell-free therapeutic approach. These vesicles can cross the blood-brain barrier (BBB) and exhibit high biocompatibility and low immunogenicity. This review summarizes the cellular origins and biogenesis of SC-EVs and evaluates current preclinical and clinical evidence supporting their therapeutic potential. Particular attention is given to acute ischemic stroke and progressive neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease. In addition, the molecular mechanisms underlying their neuroprotective and regenerative effects are discussed, with a focus on modulating neuroinflammation, promoting neurogenesis, and enhancing synaptic plasticity. Finally, key advances and major challenges in the clinical translation of SC-EVs are outlined. Integrating current evidence, this review provides a framework and practical perspective for the continued development of SC-EV-based therapies for complex neurological disorders.},
}
@article {pmid42454499,
year = {2026},
author = {Johnson, AL and Wyman, MF and Gjertsen, M and Shapiro, S and Bouges, S and Singer, J and Chin, N},
title = {A Model for Implementing Psychotherapy for Individuals With Cognitive Impairments.},
journal = {Clinical gerontologist},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/07317115.2026.2699243},
pmid = {42454499},
issn = {1545-2301},
abstract = {OBJECTIVES: Individuals with mild cognitive impairment (MCI) and Alzheimer's disease and Alzheimer's disease-related dementias (AD/ADRD) are at greater risk for mental health concerns than those without cognitive impairments. We report the implementation of psychological services for patients with MCI and mild AD/ADRD within a large public health-care system in the United States.<br><br>METHODS: Preimplementation process included identifying a clinic champion. Referrals were initially provided by the clinic champion and then opened to the entire Memory Assessment Clinic with predetermined eligibility guidelines. Patients were seen on a short-term basis, using CBT- or ACT-based therapy. Initial sessions were conducted in person; follow-up sessions were in person and via telehealth.<br><br>RESULTS: Patients saw an average of a 2.2-point reduction in depression symptoms and a 2-point reduction in anxiety symptoms. Implementation barriers and facilitators are listed in the full-text of the article.<br><br>CONCLUSIONS: This clinic implementation demonstrates the feasibility of evidence-based psychotherapy clinics within existing geriatric clinics. Future work should examine the impact of CBT and ACT to treat anxiety and depression in patients with these neurocognitive disorders. CLINICAL IMPLICATIONS: Patients with MCI and mild AD/ADRD show a clear interest in psychotherapy services, and initial efficacy data suggest there is a clinical benefit for mental health symptoms.},
}
@article {pmid42454584,
year = {2026},
author = {Ahmadi, B and Armstrong, M and Asken, BM and Reisi-Gahrooei, M and Babajani-Feremi, A and , and , },
title = {Deep learning-based MRI analysis reveals Lewy body co-pathology accelerates brain aging in Alzheimer's disease.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71593},
doi = {10.1002/alz.71593},
pmid = {42454584},
issn = {1552-5279},
support = {//Mangurian-Fixel-McKnight Collaboration/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/diagnostic imaging/cerebrospinal fluid ; *Magnetic Resonance Imaging/methods ; Female ; *Brain/pathology/diagnostic imaging ; *Aging/pathology ; *Deep Learning ; Aged ; Male ; Aged, 80 and over ; alpha-Synuclein/cerebrospinal fluid ; *Lewy Bodies/pathology ; Atrophy/pathology ; Amyloid beta-Peptides/cerebrospinal fluid ; *Lewy Body Disease/pathology ; Neuroimaging ; Cognitive Dysfunction/pathology ; },
abstract = {INTRODUCTION: Lewy body (LB) co-pathology is common in Alzheimer's disease (AD), yet its in vivo impact on neurodegeneration remains unclear.<br><br>METHODS: We trained a 3D-DenseNet on multi-cohort T1-weighted magnetic resonance imaging (MRI) from cognitively unimpaired individuals to estimate brain age (BA) and applied it to cognitively impaired Alzheimer's Disease Neuroimaging Initiative (ADNI) participants stratified by cerebrospinal fluid (CSF) p-tau181/A&#x3b2;42 (AD) and &#x3b1;-synuclein seed amplification assay (LB) status into: AD+LB+, AD+LB-, AD-LB+, and AD-LB-. We compared baseline and longitudinal brain-age gap (BAG), identified saliency-derived anatomical contributors, assessed regional atrophy and cognition, and evaluated whether BAG explains LB-related clinical decline within AD.<br><br>RESULTS: The model robustly captured normative aging. AD+LB+ exhibited the greatest and fastest-increasing BAG, with saliency maps emphasizing regions that also showed steeper longitudinal atrophy and concordant cognitive decline, and BAG mediated a substantial portion of LB-related cognitive impairment within AD+.<br><br>DISCUSSION: LB co-pathology confers an additional neurodegenerative burden in AD, underscoring the importance of combined biomarker assessment and targeted interventions.},
}
@article {pmid42454694,
year = {2026},
author = {Zakaria, FN and Baharuldin, MTH and Mat Taib, CN and Hamid, HA and Hamid, HA and Chiroma, SM and Moklas, MAM},
title = {Delta-9-tetrahydrocannabinol delineates D-galactose and aluminium chloride-induced cognitive dysfunction and neurodegeneration in the hippocampus of the Wistar rat model.},
journal = {Journal of biosciences},
volume = {51},
number = {},
pages = {},
pmid = {42454694},
issn = {0973-7138},
mesh = {Animals ; Aluminum Chloride/toxicity ; Galactose/toxicity ; Rats ; Male ; Rats, Wistar ; *Dronabinol/pharmacology ; Neurogenesis/drug effects ; Disease Models, Animal ; *Alzheimer Disease/drug therapy/chemically induced/pathology/genetics ; Doublecortin Protein ; Hippocampus/drug effects/pathology/metabolism ; *Cognitive Dysfunction/chemically induced/drug therapy/pathology/genetics/metabolism ; tau Proteins/genetics/metabolism ; Dentate Gyrus/drug effects/pathology/metabolism ; Calbindins/genetics/metabolism ; Chlorides/toxicity ; Aluminum Compounds/toxicity ; Glial Fibrillary Acidic Protein/genetics/metabolism ; Amyloid beta-Protein Precursor/genetics/metabolism ; Maze Learning/drug effects ; Cognition/drug effects ; Nerve Tissue Proteins ; Antigens, Nuclear ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterised by neurodegeneration and a decline in cognition and memory. D-galactose (D-gal) and aluminium chloride (AlCl3) have been used to induce cognitive deterioration in rat models that mimic the alterations observed in AD. This study assessed the neurotherapeutic effect of Δ9-tetrahydrocannabinol (Δ9THC) on cognitive abilities, brain morphology, neurogenesis activity and neuropathological markers in Wistar rats induced by D-gal plus AlCl3. Male albino Wistar rats received D-gal (60 mg/kg, intraperitoneally) and AlCl3 (200 mg/kg, orally) daily for 10 weeks. The rats were then treated with increasing concentrations of Δ9THC (0.75, 1.5 and 3.0 mg/kg) for 28 days. Cognitive performance was evaluated using the novel object recognition and modified elevated plus maze tests. Dentate gyrus viable granule cells, neurogenesis markers, amyloid precursor protein and phosphorylated tau (p‑tau Thr231) were assessed histologically and molecularly. Δ9THC treatment improved cognitive performance, prevented granule cell loss in the dentate gyrus, increased neurogenesis-related markers (GFAP+, DCX+, calbindin+ and NeuN immunoreactivity), and reduced amyloid precursor protein and p‑tau Thr231 expression. These findings suggest that Δ9THC possesses promising therapeutic potential against Alzheimer's disease.},
}
@article {pmid42454751,
year = {2026},
author = {Biessels, GJ and Debette, S and Elahi, FM and Geranmayeh, F and Hansra, G and Hughes, TM and Ihara, M and Isaacs, J and Jokinen, H and Nott, A and Pendlebury, S and Peters, R and Schneider, J and Smith, C and Smith, EE and Vemuri, P and Wardlaw, J and Webb, A and Wilcock, DM and Hainsworth, AH},
title = {The Vascular Contribution to Dementia. World Stroke Organisation Scientific Statement.},
journal = {International journal of stroke : official journal of the International Stroke Society},
volume = {},
number = {},
pages = {17474930261470506},
doi = {10.1177/17474930261470506},
pmid = {42454751},
issn = {1747-4949},
abstract = {Alzheimer's disease (AD) and cerebrovascular pathology are the two most common causes of dementia, frequently co-occurring in older people. Community-based neuropathology studies indicate that vascular disease accounts for approximately one third of the population attributable risk of dementia, controlling for other pathologies (including AD). The proportion with vascular disease as co-pathology is likely to be higher (50-70%).The most common vascular substrate is cerebral small vessel disease, which includes small artery fibrosis (arteriolosclerosis), vascular amyloid deposits (cerebral amyloid angiopathy) and monogenic forms of small vessel disease, the commonest being Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). Post-stroke cognitive impairment following both ischaemic stroke and intracerebral haemorrhage also contribute. In this World Stroke Organisation (WSO) scientific statement we assembled a multi-disciplinary international group of experts to review the vascular contribution to dementia, encompassing both vascular and neurodegenerative dementia. This statement has been reviewed and approved by the WSO executive.We summarize the epidemiology, neuropathology, cognitive profile, clinical impact and management of vascular disease in dementia, and discuss the recent VasCog-2-WSO diagnostic criteria. We consider the substantial overlap with clinical stroke and with AD dementia. We catalogue transcriptomic and proteomic studies that have revealed novel candidate molecules (COL4A1/4A2, HTRA1, TRIM47, FOXF2) as possible treatment targets. We appraise imaging-based biomarkers relevant to vascular disease, and potential biochemical markers (VEGF-A, PLGF, IL-6, MMP9, CTSB). We highlight the potential for vascular interventions to treat not only vascular dementia, but also the vascular component of neurodegenerative dementia. We review recent clinical trials targeting multiple pathways, including nitric oxide signalling, high blood pressure, the GABAergic system, angiogenic activity, microglial inhibition, PDE3 and PDE5 inhibition, as well as dietary supplementation with omega-3-fatty acid, s-equol and vitamin E. Finally, we consider upcoming opportunities and challenges relevant to vascular disease in dementia.},
}
@article {pmid42455059,
year = {2026},
author = {Ahmad, S and Jo, MH and Ikram, M and Khan, A and Kim, MO},
title = {RETRACTED: Ahmad et al. Deciphering the Potential Neuroprotective Effects of Luteolin Against Aβ1-42-Induced Alzheimer's Disease. Int. J. Mol. Sci. 2021, 22, 9583.},
journal = {International journal of molecular sciences},
volume = {27},
number = {14},
pages = {},
doi = {10.3390/ijms27146230},
pmid = {42455059},
issn = {1422-0067},
abstract = {The journal retracts the article titled "Deciphering the Potential Neuroprotective Effects of Luteolin against Aβ1-42-Induced Alzheimer's Disease" [...].},
}
@article {pmid42455424,
year = {2026},
author = {Quan, S and Fu, X and Cai, H and Zhang, W and Geng, Y and Tian, Q and Ren, Z and Xu, Y and An, C and Li, J and Wang, W and Jia, L},
title = {Higher physical activity levels mitigate synaptic protein loss and cognitive deterioration in aging and in Alzheimer's disease: a 10-year longitudinal study.},
journal = {Molecular biomedicine},
volume = {7},
number = {1},
pages = {},
pmid = {42455424},
issn = {2662-8651},
support = {82471210//National Natural Science Foundation of China/ ; U24A20681//National Natural Science Foundation of China/ ; Z201100005520016//Beijing Brain Initiative of the Beijing Municipal Science &amp; Technology Commission/ ; 7202061//Beijing Municipal Natural Science Foundation/ ; 2022-2-2017//Capital's Funds for Health Improvement and Research/ ; 2022ZD0211600//STI 2030-Major Projects/ ; 2022ZD0211605//STI 2030-Major Projects/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/physiopathology/blood ; *Aging/metabolism ; Longitudinal Studies ; Female ; Aged ; Male ; *Synapses/metabolism ; *Cognition ; Aged, 80 and over ; Disease Progression ; },
abstract = {Synaptic degeneration is a hallmark of Alzheimer's disease (AD) and is closely linked to cognitive decline. Although physical activity (PA) can preserve synaptic integrity and cognitive function, its long-term effects during aging and AD progression remain poorly characterized. Here, we conducted a 10-year longitudinal study to investigate the effects of different PA levels on synaptic proteins and cognitive function during aging and in AD progression. The study included 231 cognitively normal older adults (preclinical AD, 116; controls, 115), who were stratified based on their PA intensity. Plasma was collected every 2 years to quantify four synaptic proteins (GAP43, neurogranin, SNAP25, and synaptotagmin 1) in neuron-derived extracellular vesicles (EVs), with concurrent cognitive assessments. The results indicated that all synaptic proteins declined over time, with a greater reduction in AD than in normal aging (P < 0.05). Synaptic protein levels did not differ between PA groups at baseline (P > 0.05), but at the 10-year follow-up, participants with higher PA had significantly greater synaptic protein levels than those with lower PA in both AD and controls (P < 0.05). Consistently, higher PA alleviated synaptic protein loss during aging (P < 0.05). Furthermore, higher PA was associated with slower cognitive decline in patients with preclinical AD (P < 0.05). Our study suggests that higher levels of PA may mitigate age- and AD-related synaptic deterioration, thereby contributing to cognitive resilience in late life.},
}
@article {pmid42455433,
year = {2026},
author = {Shokr, MM and Abu-Elsaoud, AM and Al Raish, SM},
title = {Plant-derived Natural Products in Neurological and Psychiatric Disorders: Mechanisms of Action and Synergistic Roles with Probiotics.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42455433},
issn = {1559-1182},
mesh = {Humans ; *Biological Products/therapeutic use/pharmacology ; Animals ; *Mental Disorders/drug therapy ; *Probiotics/therapeutic use/pharmacology ; *Nervous System Diseases/drug therapy ; Neuroprotective Agents/therapeutic use/pharmacology ; Drug Synergism ; },
abstract = {Plant-derived natural products have emerged as promising therapeutic agents for neurological and psychiatric disorders due to their diverse bioactive compounds and multi-target mechanisms of action. This review provides a mechanistic overview of medicinal plants and probiotics in modulating key pathological processes underlying disorders such as Alzheimer's disease, epilepsy, autism spectrum disorder, and major depressive disorder. A systematic literature search was conducted across PubMed, Scopus, and Web of Science databases to identify relevant studies examining the neuroprotective, metabolic, and anti-inflammatory effects of plant-derived compounds, probiotics, and SGLT2 inhibitors. The findings highlight shared mechanisms, including attenuation of oxidative stress, suppression of neuroinflammation, modulation of mitochondrial function, and regulation of the gut-brain axis. Bioactive compounds such as polyphenols, flavonoids, alkaloids, and terpenoids demonstrate significant potential in improving neuronal survival and synaptic plasticity. Probiotics further contribute through microbiota-mediated regulation of neurotransmitters and immune responses. SGLT2 inhibitors are discussed as a comparative pharmacological model exhibiting overlapping mechanisms. Collectively, these integrative approaches provide a mechanistic framework for understanding how plant-derived compounds, probiotics, and metabolically active pharmacological models may influence shared pathways involved in neurological and psychiatric disorders. However, most proposed neuroprotective and synergistic effects require further validation through standardized formulations, well-designed clinical trials, and careful safety assessment before they can be translated into routine clinical practice.},
}
@article {pmid42455475,
year = {2026},
author = {Maity, D and Gowtham, A and Mishra, Y and Kaundal, RK},
title = {Exosome Biology at the Interface of Neurodegeneration and Therapeutic Innovation.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42455475},
issn = {1559-1182},
mesh = {Humans ; *Exosomes/metabolism ; Animals ; *Neurodegenerative Diseases/therapy/metabolism/pathology ; Biomarkers/metabolism ; },
abstract = {Neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, are defined by progressive neuronal loss, protein misfolding, and chronic neuroinflammation, yet effective disease-modifying therapies remain absent. Exosomes have emerged as key mediators of central nervous system communication and are increasingly central to the biology of neurodegeneration. These nanoscale vesicles transport proteins, lipids, and nucleic acids across cellular and anatomical barriers, influencing synaptic function, immune signaling, and metabolic homeostasis. Under pathological conditions, exosomes facilitate the spread of misfolded proteins such as amyloid-β, p-tau, α-synuclein, and TDP-43, thereby accelerating network-level degeneration. At the same time, their cargo exhibits disease-specific molecular signatures detectable in peripheral biofluids, supporting their development as minimally invasive biomarkers for early diagnosis and longitudinal monitoring. Advances in exosome engineering further underscore their potential as therapeutic delivery vehicles capable of crossing the blood-brain barrier and targeting pathogenic pathways with RNA-based therapeutics, proteins, or gene-editing systems. Together, these findings position exosomes as pivotal contributors to both the mechanistic progression and translational targeting of neurodegenerative diseases.},
}
@article {pmid42455572,
year = {2026},
author = {Ng, TKS and Beck, T and Sudhini, Y and Wilson, RS and Evans, DA and Rajan, KB},
title = {Salivary Cortisol and Cognitive Decline and Alzheimer Disease in Older Adults.},
journal = {JAMA network open},
volume = {9},
number = {7},
pages = {e2622955},
doi = {10.1001/jamanetworkopen.2026.22955},
pmid = {42455572},
issn = {2574-3805},
mesh = {Humans ; *Hydrocortisone/analysis/metabolism ; Female ; *Alzheimer Disease/epidemiology/metabolism ; Aged ; *Saliva/chemistry ; Male ; Chicago/epidemiology ; *Cognitive Dysfunction/metabolism/epidemiology ; Prospective Studies ; Aged, 80 and over ; Circadian Rhythm ; Hypothalamo-Hypophyseal System ; },
abstract = {IMPORTANCE: Alterations in hypothalamic-pituitary-adrenal axis activity have been implicated in cognitive aging, yet large, racially diverse studies using physiologically active salivary cortisol studies are limited.<br><br>OBJECTIVE: To determine whether diurnal salivary cortisol indices are associated with cognitive outcomes, including incident Alzheimer disease (AD), and whether distributions and associations differ by race.<br><br>This prospective cohort study was conducted from 2000 to 2011, with 11 years of follow-up, as part of the Chicago Health and Aging Project, a community-based study of older adults in urban Chicago. Participants provided salivary cortisol samples across a day (waking, afternoon, and bedtime) and completed cognitive assessments. Analyses were conducted from June to October 2025.<br><br>EXPOSURES: Five salivary cortisol indices capturing intraday variability (coefficient of variation [CV]), cumulative exposure (mean cortisol and area under the curve with respect to ground [AUCg]), and diurnal change (diurnal slope and AUC with respect to increase [AUCi]).<br><br>MAIN OUTCOMES AND MEASURES: Outcomes of interest were global cognition, cognitive decline, and incident AD, adjusted for demographic, health, and behavioral factors.<br><br>RESULTS: Among 3895 participants (mean [SD] age, 76.7 [6.8] years; 2509 [64.4%] women; 2503 Black participants [64.3%] and 1392 White participants [35.7%]), all cortisol indices were cross-sectionally associated with cognitive performance. Longitudinally, compared with the first quintile (Q1), medium to high cortisol intraday variability (CV) was associated with slower decline (Q3: &#x3b2;&#x2009;=&#x2009;0.02 [95% CI, 0.001 to 0.04]; P&#x2009;=&#x2009;.04; Q4: &#x3b2;&#x2009;=&#x2009;0.03 [95% CI, 0.01 to 0.04]; P&#x2009;=&#x2009;.003), whereas the highest cumulative exposure was associated with faster decline (mean cortisol Q5: &#x3b2;&#x2009;=&#x2009;-0.02 [95% CI, -0.04 to -0.004]; P&#x2009;=&#x2009;.02; AUCg Q5: &#x3b2;&#x2009;=&#x2009;-0.02 [95% CI, -0.03 to 0.00]; P&#x2009;=&#x2009;.046). Diurnal change indices (slope, AUCi) were not associated with decline or incident AD. Black participants exhibited lower cortisol exposure but flatter slopes and lower intraday variability, reflecting a blunted diurnal rhythm; associations with decline were similar across races.<br><br>CONCLUSIONS AND RELEVANCE: In this cohort study of Black and White older adults, altered diurnal cortisol patterning was associated with faster cognitive decline but not short-term AD risk. These findings support salivary cortisol as a potential early biomarker of neurocognitive aging. Racial differences in cortisol patterning suggest differential biological embedding of stress, consistent with structural inequities.},
}
@article {pmid42455771,
year = {2026},
author = {Alageel, NA and Hughes, CM and Alwhaibi, M and Barry, HE},
title = {Hospital pharmacists' knowledge about and attitudes towards dementia: a cross-sectional survey study.},
journal = {The International journal of pharmacy practice},
volume = {},
number = {},
pages = {},
doi = {10.1093/ijpp/riag092},
pmid = {42455771},
issn = {2042-7174},
support = {//PhD Scholarship from King Saud University/ ; },
abstract = {OBJECTIVES: This study explored hospital pharmacists' knowledge about and attitudes towards dementia, identified factors influencing these outcomes, and determined their educational experiences and future training needs.<br><br>METHODS: A cross-sectional survey study conducted among pharmacists in eight tertiary hospitals in Riyadh, Saudi Arabia, between December 2024 and March 2025. Eligible participants (n&#x2009;=&#x2009;372) were directly involved in dispensing medications for people with dementia (PwD). Data were collected using a self-administered questionnaire comprising the Alzheimer's Disease Knowledge Scale, Dementia Attitudes Scale, and questions on demographics, prior dementia education, and training needs. Descriptive statistics summarized responses, and regression analyses identified predictors of respondents' knowledge and attitudes using Statistical Package for the Social Sciences v30.<br><br>KEY FINDINGS: In total, 224 pharmacists responded (response rate: 60.2%). Most respondents were female (n&#x2009;=&#x2009;122, 54.5%), with a median age of 32&#xa0;years, and 37.1% (n&#x2009;=&#x2009;83) had graduated within the previous 5 years. The mean knowledge score was 18.90/30, with greatest gaps in the risk factors and caregiving domains. The mean attitude score was 93.50/140, indicating generally positive attitudes. Female gender (&#x3b2;&#x2009;=&#x2009;0.22, P&#x2009;<&#x2009;.001) and professional experience with PwD (&#x3b2;&#x2009;=&#x2009;0.14, P&#x2009;=&#x2009;.039) were linked to greater knowledge, while having a relative with dementia (&#x3b2;&#x2009;=&#x2009;0.20, P&#x2009;=&#x2009;.004) and higher knowledge scores (&#x3b2;&#x2009;=&#x2009;0.20, P&#x2009;=&#x2009;.003) were associated with more positive attitudes. Most respondents (n&#x2009;=&#x2009;208, 93.0%) had never undertaken dementia-related training but expressed interest in future education.<br><br>CONCLUSIONS: Hospital pharmacists in Saudi Arabia demonstrated moderate knowledge and generally positive attitudes towards dementia. However, notable knowledge gaps and limited prior training were identified, highlighting the need for targeted educational initiatives.},
}
@article {pmid42455814,
year = {2026},
author = {Browne, B and Rogers, I and Ali, K and Tabet, N and Ford, E},
title = {Identifying the determinants of hospital readmission in dementia patients - A retrospective cohort study using electronic healthcare records in England.},
journal = {PloS one},
volume = {21},
number = {7},
pages = {e0351331},
doi = {10.1371/journal.pone.0351331},
pmid = {42455814},
issn = {1932-6203},
mesh = {Humans ; *Patient Readmission/statistics &amp; numerical data ; *Dementia/mortality/epidemiology/therapy ; England/epidemiology ; Retrospective Studies ; Female ; *Electronic Health Records/statistics &amp; numerical data ; Male ; Aged, 80 and over ; Aged ; Risk Factors ; },
abstract = {BACKGROUND: People living with dementia are at an increased risk of multiple hospital admissions due to acute illness, underlying vulnerability, progression of behavioural symptoms of dementia, or breakdown of care provision. Reducing readmission rates is a key clinical priority. This study used linked electronic health records from general practice and hospitals in England, to investigate the determinants associated with hospital readmissions and estimate the mortality risk of older adults with dementia within one year of hospital readmission.<br><br>METHODS: A retrospective cohort study using Clinical Practice Research Datalink and linked data. Patients were included if they were&#x2009;>&#x2009;65y, diagnosed with dementia, and had a recorded acute general hospital admission. Outcome variables were readmission to hospital within 180 days of discharge, and in the readmitted group, mortality within one year of readmission. Demographics, long term conditions, polypharmacy, antipsychotic medication, medication review, post-discharge primary care appointments, and living in residential care were examined as determinants using stepwise logistic regression for readmission, and Cox regression for survival models.<br><br>RESULTS: 30,527 patients were included, median age 84y (62.7% female), with 12,351 (40.5%) readmitted within 180 days of discharge. Being male, having multiple long-term conditions, having a medication review or attending a primary care appointment post-discharge were positively associated with readmissions, while Alzheimer's type dementia, having 'Other' ethnicity, and living in residential care were negatively associated. We found a significant effect on mortality risk of age, sex, type of dementia, having two or more long-term conditions, body mass index, antipsychotic medication, polypharmacy, and living in residential care.<br><br>CONCLUSION: The findings of this cohort study suggest that biological, psychological, and social factors interact to influence hospital readmissions in older adults with dementia. Multiple long-term conditions emerged as the strongest determining factor for readmission, while age was important in survival. Future research should assess psychosocial factors such as social support, caregiver burden, and mental well-being. These findings have important implications for strengthening community-based healthcare for adults with dementia, to reduce hospital readmission.},
}
@article {pmid42455917,
year = {2026},
author = {Kirac-Aydin, A and Pandey, BP and Mohanty, S and Mondal, R and Biswas, A and Pattnaik, AK and Mondal, S and Basavanakatti, VN and Bayrak, N and Jayaprakash, V and Kim, H and TuYuN, AF},
title = {Discovery of a Potent and Selective MAO-B Inhibitor From a Donepezil-Linked Chalcone Library With Promising Antiparkinsonian Activity.},
journal = {Drug development research},
volume = {87},
number = {5},
pages = {e70349},
doi = {10.1002/ddr.70349},
pmid = {42455917},
issn = {1098-2299},
support = {FDK-2024-40841//The Scientific Research Projects Coordination Unit of Istanbul University/ ; RS-2024-00347522//The National Research Foundation of Korea (NRF) funded by the Korean Government/ ; },
mesh = {*Monoamine Oxidase Inhibitors/pharmacology/chemistry ; Animals ; Monoamine Oxidase/metabolism ; Humans ; *Donepezil/chemistry/pharmacology ; Cholinesterase Inhibitors/pharmacology/chemistry ; *Chalcones/chemistry/pharmacology ; Rats ; Structure-Activity Relationship ; Molecular Docking Simulation ; Drug Discovery ; },
abstract = {A focused library of 19 donepezil-linked chalcones (DLCs) was efficiently synthesised through microwave-assisted Claisen-Schmidt condensation and subsequently profiled for their inhibitory activities against cholinesterases (AChE and BuChE) as well as monoamine oxidases (MAO-A and MAO-B). The DLCs exhibited potent and selective inhibition of MAO-B, with IC50 values ranging from 0.019 to 18.98 μM, whereas activity toward MAO-A was moderate to low (IC50 = 0.81 to > 20 μM). Among the tested DLCs, DLC9 and DLC14 showed the highest MAO-B inhibitory potential with IC50 values of 0.054 ± 0.004 μM and 0.019 ± 0.0015 μM, respectively, and high selectivity indexes (> 370 and > 1052, respectively), whereas DLC12 displayed notable MAO-A inhibition (IC50 = 0.81 ± 0.035 μM). Kinetic and reversibility studies revealed that the selected two lead DLCs (DLC9 and DLC14) acted as mixed-type reversible MAO-B inhibitors, with Kᵢ values of 20.0 ± 2.83 nM and 10.0 ± 2.82 nM, respectively. Furthermore, IC50 values of AChE inhibitory activities ranged from 5.40 to > 40 µM, whereas those of BuChE inhibitory activity range from 4.30 to > 40 µM. DLC6 showed the best AChE inhibitory potential with IC50 values of 5.40 ± 0.29 µM, while DLC13 revealed effective BuChE inhibitory potential with an IC50 value of 4.30 ± 0.89 µM. Molecular docking studies performed on hMAO-A and hMAO-B revealed that DLC14 establishes favourable π-π stacking within the aromatic cage of hMAO-B and maintains complementary hydrophobic contacts along the substrate cavity, whereas DLC6 lacks this key interaction due to steric interference of the ethoxy substituent. Among the three most potent MAO-B inhibitors (DLC2, DLC9, and DLC14), DLC2 exhibited the most favourable microsomal stability with the longest half-life and lowest intrinsic clearance, whereas DLC14 showed comparable metabolic profiles in rat and human liver microsomes. Experimental BBB permeability assays were hindered by compound-membrane interactions; however, in silico predictions indicated satisfactory oral bioavailability and brain penetration for all three candidates. In the MPTP-induced rat model of parkinsonism, the selective MAO-B inhibitor DLC14 and the non-selective inhibitor DLC6 significantly improved motor deficits and behavioural impairments across open field, pole, bar, rotarod, and forced swim tests, with progressive improvements observed up to Day 28. Notably, DLC14 consistently outperformed DLC6 and demonstrated an efficacy profile comparable to that of Selegiline, highlighting its therapeutic potential as an antiparkinsonian agent. These results indicate that DLC14 is potent and selective MAO-B inhibitor and could serve as promising candidate for the treatment of neurodegenerative disorders, such as Parkinson's disease.},
}
@article {pmid42456192,
year = {2026},
author = {Soussi, C and Gonneaud, J and Cabé, N and Laniepce, A and Marchant, NL and Collette, F and de Flores, R and Foyard, E and Landeau, B and Mezenge, F and Chételat, G and Segobin, S and Pitel, AL and , },
title = {Higher amyloid deposition and lower white matter volume in cognitively healthy seniors exceeding French alcohol recommendations.},
journal = {EBioMedicine},
volume = {130},
number = {},
pages = {106376},
doi = {10.1016/j.ebiom.2026.106376},
pmid = {42456192},
issn = {2352-3964},
abstract = {BACKGROUND: Older adults are particularly vulnerable to alcohol's effects. Our aim was to establish whether differences in neurocognitive health exist between cognitively healthy seniors, depending on whether they follow recent French health recommendations for stricter drinking limits beyond age 65.<br><br>METHODS: We conducted a retrospective cross-sectional study including 133 community-dwelling cognitively healthy participants aged over 65 from the Age-Well Study. Based on their compliance with recommendations, participants were classified as lower-risk or higher-risk. Neurocognitive health was assessed comprehensively through standard cognitive testing, and voxel-wise analyses of structural integrity and cortical amyloid PET burden.<br><br>FINDINGS: Higher-risk participants displayed more neocortical amyloid deposition (F = 7.577; p = 0.007; d = 0.553) and lower cerebral volume, in the absence of a difference in cognition (p > 0.1).<br><br>INTERPRETATION: These results highlight that alcohol consumption exceeding age-specific recommendations is associated with lower brain integrity, notably including elevated amyloid burden, a biomarker strongly linked with higher risk of Alzheimer's disease-related cognitive decline and dementia. Our findings emphasise the importance of strict adherence to lower-risk thresholds in older populations.<br><br>FUNDING: European Union's Horizon 2020 Research and Innovation Programme (No 667696); Institut National de la Sant&#xe9; et de la Recherche M&#xe9;dicale (INSERM); Fondation Entrepreneurs MMA; FONDATION ALZHEIMER; R&#xe9;gion Normandie; Fondation Recherche Alzheimer; Association France Alzheimer; Fondation de France; Institut pour la Recherche en Sant&#xe9; Publique (IRESP).},
}
@article {pmid42456217,
year = {2026},
author = {Kim, E and Raji, MA and Polychronopoulou, E and Tzeng, HM and Milani, SA and Kuo, YF},
title = {Annual wellness visits, cognitive function, and early dementia diagnosis.},
journal = {Archives of gerontology and geriatrics},
volume = {150},
number = {},
pages = {106355},
doi = {10.1016/j.archger.2026.106355},
pmid = {42456217},
issn = {1872-6976},
abstract = {BACKGROUND: Diagnosing dementia early optimizes care and enables timely interventions for modifiable contributors. Impact of Medicare Annual Wellness Visits (AWVs) on rate of mild cognitive impairment (MCI) detection remains unclear.<br><br>OBJECTIVE: To assess association between AWVs and timeliness of diagnosis of MCI and Alzheimer's disease-related dementias (ADRD), adjusting for factors (not accounted for in prior studies) including education, poverty, residence, serial cognitive measures before and after AWV, instrumental activity of daily living, behavioral factors and non-clinical determinants of health-captured in Health and Retirement Study (HRS) survey database.<br><br>METHODS: Data from the Health and Retirement Study (HRS) linked to Medicare claims (2011-2019) were used. Propensity score-matched cohorts (AWV vs. non-AWV) were created for four calendar years. HRS survey-based scores before and after AWVs measured cognitive function. Kaplan-Meier and Cox models were used to estimate the risk of MCI/ADRD diagnoses within two years.<br><br>RESULTS: Demographic variables were well-matched (absolute standard difference < 10%). Both groups had similar cognitive decline, but the AWV group had higher cognitive scores before and after AWV than non-AWV group. MCI diagnoses were higher in the AWV group, while both groups had similar time to diagnosis for ADRD, independent of behavioral factors and non-clinical determinants of health.<br><br>CONCLUSION: AWVs are associated with earlier detection of MCI, which may guide patient-provider decisions on evaluations for modifiable factors (e.g. physical inactivity, smoking, hypothyroidism, sleep apnea) linked to cognitive decline and subsequent dementia.},
}
@article {pmid42442677,
year = {2026},
author = {Shu, XD and Liu, HF and Liao, YQ and Pu, WJ and Zhao, T and Pan, WD and Zhang, N and Li, JY},
title = {Saebias A-G, eudesmane sesquiterpenes from Salvia plebeia with potential for Alzheimer's disease prevention via anti-neuroinflammatory and neuroprotective effects.},
journal = {Phytochemistry},
volume = {},
number = {},
pages = {115024},
doi = {10.1016/j.phytochem.2026.115024},
pmid = {42442677},
issn = {1873-3700},
abstract = {Saebias A-G (1-7), seven previously undescribed eudesmane sesquiterpenoids compounds and seventeen known compounds were isolated from Salvia plebeia R.Br. Among them, compound 1 is a unique C16-type eudesmane sesquiterpenoid featuring a 6/6/5-membered scaffold, 2-3 are nor-eudesmane sesquiterpenoids and 5 contains a rare 6/6/3/5 tetracyclic skeleton. Their structures including absolute configurations were elucidated by extensive spectroscopic methods, single-crystal X-ray crystallographic and ECD calculation. All compounds were evaluated for their inhibitory effect on nitric oxide (NO) production induced by lipopolysaccharide (LPS) in BV-2 cells and neuroprotective effect induced by H2O2 in PC12 cells. The results showed that four compounds exhibited significant NO inhibitory effects, with IC50 values ranging from 0.76 to 3.72 μM. Among them, compound 2 showed significant inhibitory effect, which significantly suppressed the production of IL-6, IL-1β, and iNOS in a concentration-dependent manner. The PC12 cells damage induced by H2O2 was attenuated by compounds 2, 10, 11, 13, 15, and 23. Moreover, compounds 2 and 11 delayed H2O2 induced damage, stabilized reactive oxygen species (ROS), mitochondrial membrane potential (MMP) and apoptosis expression levels. Notably, compound 2 exerted dual anti-neuroinflammatory and neuroprotective activities, and its multi-target pharmacological profile makes it a promising candidate for the prevention and treatment of Alzheimer's disease. These studies provide new potential neuroprotective agents for the prevention and treatment of neurodegenerative diseases.},
}
@article {pmid42442754,
year = {2026},
author = {Sonnenberg, A and Bakis, LK and Kohen, R},
title = {Gastrointestinal Diagnoses and Symptoms in Medicare Patients With Neuropsychiatric Diseases.},
journal = {Journal of clinical gastroenterology},
volume = {},
number = {},
pages = {},
doi = {10.1097/MCG.0000000000002422},
pmid = {42442754},
issn = {1539-2031},
abstract = {BACKGROUND AND AIMS: Many patients with psychiatric and neurological diseases suffer from gastrointestinal symptoms. Our study aimed to analyze the frequency of gastrointestinal disease in patients with underlying neuropsychiatric diagnoses.<br><br>METHODS: The study utilized the 2018 Inpatient Standard Analytic File of the Centers for Medicare and Medicaid Services (CMS), which contains the electronic health records of 6,462,321 unique patients. The concurrence of 2 diagnoses was assessed by calculating odds ratios (OR) with their 95% CIs, adjusted for the confounding influences of demographic characteristics (age, sex, ethnicity).<br><br>RESULTS: Dementia was most strongly associated with dysphagia (2.85, 2.83 to 2.88). Schizophrenia was associated with functional GI disorders (1.62, 1.60 to 1.64), constipation (1.67, 1.65 to 1.69), and dyspepsia (2.02, 1.88 to 2.17). Bipolar disorder was most significantly associated with irritable bowel syndrome (1.83, 1.79 to 1.87) and dyspepsia (1.88, 1.77 to 2.01). Depression was significantly associated with all types of upper and lower GI symptoms with significant ORs ranging from 1.33 to 2.14. Amyotrophic lateral sclerosis was strongly associated with complaints of functional GI disorder (2.32, 2.18 to 2.46), constipation (2.37, 2.23 to 2.51), dysphagia (11.77, 11.19 to 12.39), flatulence and bloating (2.75, 2.14 to 3.54). Parkinson disease was mostly associated with constipation (1.79, 1.77 to 1.82) and dysphagia (2.96, 2.92 to 3.00). In Alzheimer disease, only symptoms of dysphagia (2.15, 2.12 to 2.17) stood out. Multiple sclerosis was associated with most GI diagnoses (OR ranging from 1.32 to 2.06), except for abdominal pain and reflux symptoms.<br><br>CONCLUSIONS: Concurrence of gastrointestinal and neuropsychiatric diagnoses is common. Caring for patients with neuropsychiatric diseases, physicians need to be aware of and proactively search for the presence of concurrent gastrointestinal disease.},
}
@article {pmid42442802,
year = {2026},
author = {Robles, CV and Robles, CV and Revilla, APA and de Jesús Valencia Suárez, V and Santander, MAS},
title = {The Role of Genetic Alterations in the Emergence of Alzheimer's Disease in Down Syndrome: A Review.},
journal = {The European journal of neuroscience},
volume = {64},
number = {1},
pages = {e70623},
doi = {10.1111/ejn.70623},
pmid = {42442802},
issn = {1460-9568},
mesh = {Humans ; *Down Syndrome/genetics/complications ; *Alzheimer Disease/genetics/epidemiology ; Amyloid beta-Protein Precursor/genetics ; Dyrk Kinases ; },
abstract = {Down syndrome (DS), the most common chromosomal disorder, is associated with an accelerated aging process, increasing the risk of early-onset Alzheimer's disease. This review examines genetic factors involved in the development of Alzheimer's disease (AD) in people with DS. A systematic search in major databases was conducted, and articles from 2020 to 2025 that met the predefined inclusion criteria were included. The results showed that the prevalence of AD was above 60% in people with DS older than 65 years, the mean age at diagnosis was 53 years, and the mortality occurred around 59 years. The main genetic factor identified was the overexpression of the APP gene, along with other genes such as DYRK1A, RCAN1, SOD1, APOEε4, and genes involved in the immune response, as well as posttranscriptional dysregulation. Diagnosis remains a challenge due to the pre-existent intellectual disability and the atypical clinical presentation of the disease; however, the development of adapted neuropsychological tests, biomarkers, and neuroimaging techniques is expected to facilitate early diagnosis. The connection between both diseases is the result of multiple genetic factors that lead to early onset and accelerated progression of AD. It is essential to achieve timely diagnosis and provide early treatment to improve quality of life of both patients and their caregivers.},
}
@article {pmid42442908,
year = {2026},
author = {Dongre, S and Soni, N and Bissa, B},
title = {Role of ESCRT pathway and autophagy in neurodegenerative diseases.},
journal = {International review of neurobiology},
volume = {187},
number = {},
pages = {1-16},
doi = {10.1016/bs.irn.2026.05.022},
pmid = {42442908},
issn = {2162-5514},
mesh = {Humans ; *Endosomal Sorting Complexes Required for Transport/metabolism ; *Autophagy/physiology ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; },
abstract = {Neurodegenerative diseases are characterized by progressive neuronal dysfunction and loss resulting from impaired proteostasis and vesicular trafficking. Neurons are particularly vulnerable to these processes due to their post-mitotic nature and complex architecture. Autophagy and the endolysosomal system constitute the primary degradative pathways responsible for maintaining neuronal homeostasis. However, increasing evidence indicates that their effective function critically depends on coordination with the endosomal sorting complexes required for transport (ESCRT). Beyond their canonical role in multivesicular body biogenesis and membrane scission, ESCRT components are now recognized as essential regulators of autophagosome closure, amphisome formation, autophagosome-lysosome fusion, and endolysosomal membrane repair. Disruption of this ESCRT-autophagy interface has emerged as a common pathological feature across major neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis/frontotemporal dementia. This review synthesizes evidence from genetic, biochemical, and neuropathological studies to highlight shared molecular nodes, such as ESCRT-III components, the VPS4 ATPase, the adaptor protein ALIX, and late endosomal regulators, including Rab7, that couple membrane remodeling to autophagic flux. Failure of these regulatory checkpoints destabilizes endolysosomal integrity, arrests autophagic maturation, and promotes the accumulation of toxic protein species, thereby driving progressive neuronal degeneration. By framing neurodegeneration through the lens of ESCRT-autophagy coupling failure, this review provides a unified mechanistic perspective that links diverse pathogenic proteins to shared cellular vulnerabilities and identifies ESCRT-mediated membrane dynamics as a critical determinant of neuronal survival.},
}
@article {pmid42442909,
year = {2026},
author = {Iqbal, S and Shen, B},
title = {Crosstalk in Alzheimer's-delirium nexus: Molecular mechanisms and therapeutic repurposing.},
journal = {International review of neurobiology},
volume = {187},
number = {},
pages = {133-157},
doi = {10.1016/bs.irn.2026.01.004},
pmid = {42442909},
issn = {2162-5514},
mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy ; Animals ; *Drug Repositioning ; *Blood-Brain Barrier/metabolism ; },
abstract = {Alzheimer's disease (AD) and delirium, though distinct in clinical tempo, converge mechanistically at the intersection of neurovascular dysfunction, glial activation, and metabolic collapse. This chapter explores the integrative framework of neurovascular-glia crosstalk, emphasizing how endothelial injury, astrocytic reactivity, and microglial hyperactivation collectively undermine brain energy metabolism. We highlight evidence that blood-brain barrier[c] (BBB) breakdown, mitochondrial insufficiency, and oxidative stress establish a "metabolic vulnerability state" predisposing the AD brain to delirium. Single-cell and transcriptomic analyses delineate shared molecular circuits involving MAPK, TP53, APOE, and δ-secretase (LGMN)-the latter regulated by disease-relevant miRNAs such as miR-124 and miR-146a. These networks couple neuroinflammation with impaired energy dynamics, bridging chronic neurodegeneration and acute encephalopathic stress. We further discuss how tyrosine-kinase signaling, serotonergic dysregulation, and glial-vascular miscommunication coalesce into a unified pathophysiological axis. Therapeutic repurposing strategies-ranging from tyrosine kinase inhibitors (nilotinib, imatinib) to metabolic modulators (metformin, pioglitazone)-offer promising cross-disease interventions. Finally, we underscore the transformative role of artificial intelligence (AI) and large language models (LLMs) in accelerating drug repurposing through integrative omics and pathway-based reasoning. Together, these advances redefine the AD-delirium nexus as a systems-level disorder of energy and communication, opening translational avenues for precision therapeutics that restore neurovascular balance and cognitive resilience.},
}
@article {pmid42442911,
year = {2026},
author = {K C, B and Priyadarshini, P},
title = {Bioenergetic impairment-induced Tau acetylation: Converging pathways in Alzheimer's disease.},
journal = {International review of neurobiology},
volume = {187},
number = {},
pages = {17-38},
doi = {10.1016/bs.irn.2026.05.020},
pmid = {42442911},
issn = {2162-5514},
mesh = {Humans ; *Alzheimer Disease/metabolism ; *tau Proteins/metabolism ; Acetylation ; *Energy Metabolism/physiology ; Animals ; },
abstract = {Alzheimer's disease (AD) is increasingly recognized as a metabolic disorder in which disruptions in cellular energy metabolism play a central role in its progression. The dysregulated metabolism of carbohydrates, proteins, fatty acids, and nucleic acids collectively impairs neuronal bioenergetics, leading to mitochondrial dysfunction and reduced ATP production. This impaired energy metabolism trigger a cascade of cellular stress responses, including endoplasmic reticulum (ER) stress, oxidative and inflammatory responses, and increased generation of amyloid-β (Aβ), thereby exacerbating neuronal vulnerability. A critical downstream consequence of bioenergetic failure is the altered epigenetic and post-translational regulatory enzymes, particularly the acetyltransferase EP300 and the NAD[+]-dependent deacetylases known as sirtuins. An imbalance in the activity of these enzymes promotes the abnormal tau acetylation, which disrupts tau-microtubule interactions and promotes tau aggregation, ultimately accelerating neurodegeneration. Emerging evidence suggests tau acetylation as a mechanistic link between metabolic dysfunction and hallmark pathological characteristics of AD, suggesting bioenergetic impairment directly regulate tau pathology. Thus, understanding the metabolic pathways that drive tau acetylation may offer new therapeutic targets aimed at restoring neuronal energy balance, re-establishing acetylation homeostasis, and potentially slowing the progression of AD.},
}
@article {pmid42442912,
year = {2026},
author = {Pereira, MVS and de Jesus, JR},
title = {Metallospecies and their biological functions in Alzheimer's disease.},
journal = {International review of neurobiology},
volume = {187},
number = {},
pages = {193-217},
doi = {10.1016/bs.irn.2026.02.005},
pmid = {42442912},
issn = {2162-5514},
mesh = {*Alzheimer Disease/metabolism ; Humans ; *Metals/metabolism ; Animals ; *Brain/metabolism ; },
abstract = {This chapter critically explores the role of metallospecies homeostasis in the pathophysiology of Alzheimer's disease (AD), going beyond the traditional amyloid protein-centered approach. The discussion integrates biochemical, molecular, and analytical perspectives to elucidate how metal-biomolecule interactions influence protein misfolding, protein aggregation, and neurotoxicity. Furthermore, the chapter reviews cutting-edge metallomic approaches, including advanced speciation analyses and metal bioimaging techniques, to demonstrate how these tools allow for the precise characterization of the chemical identity, coordination environment, and spatial distribution of metal species in brain tissue. By discussing mechanistic insights with analytical advances, this chapter provides a comprehensive framework for understanding the contribution of metal dysregulation to AD and identifies new directions for diagnosis and therapeutic intervention.},
}
@article {pmid42442913,
year = {2026},
author = {Rajkhowa, S and Tripathi, T},
title = {Liquid-liquid phase separation of tau in Alzheimer's disease.},
journal = {International review of neurobiology},
volume = {187},
number = {},
pages = {219-279},
doi = {10.1016/bs.irn.2026.01.009},
pmid = {42442913},
issn = {2162-5514},
mesh = {Humans ; *tau Proteins/metabolism ; *Alzheimer Disease/metabolism ; Phase Separation ; Animals ; *Neurofibrillary Tangles/metabolism ; *Protein Aggregation, Pathological/metabolism ; Protein Processing, Post-Translational ; },
abstract = {Tau is a microtubule-associated protein that plays a central role in neuronal stability and axonal transport. However, under pathological conditions, it undergoes structural and functional changes that lead to Alzheimer's disease (AD) and related tauopathies. Recent evidence highlights liquid-liquid phase separation (LLPS) as a critical mechanism underlying tau aggregation and the subsequent formation of neurofibrillary tangles (NFTs). This chapter explores the properties of tau, including its intrinsically disordered nature, isoforms, and post-translational modifications (PTMs), that predispose it to LLPS. We discuss the thermodynamic and molecular principles of LLPS, with emphasis on the interplay between multivalent interactions, crowding effects, RNA binding, and cofactors that modulate the formation of tau condensates. Special attention is given to the transition from dynamic, reversible tau droplets to irreversible fibrillar assemblies. The chapter further examines how truncation and PTM cross-talk alter the phase behavior and aggregation propensity of tau. Cellular implications of tau LLPS, including its role in stress granules, synaptic dysfunction, and seeding of NFTs, are also analyzed. Finally, we highlight the regulatory roles of chaperones, metal ions, and interacting proteins and underscore the therapeutic potential of targeting tau phase separation. Together, this synthesis positions the LLPS of tau as a pivotal event in AD pathogenesis and a promising target for therapeutic intervention.},
}
@article {pmid42442914,
year = {2026},
author = {Karmakar, A and Roycowdhury, P and Sengupta, P and Mukhopadhyay, D},
title = {Metabolic reprogramming in Alzheimer's disease: Interaction between receptor tyrosine kinase signaling, noncoding RNAs, and Neuron-Glia energy networks.},
journal = {International review of neurobiology},
volume = {187},
number = {},
pages = {281-330},
doi = {10.1016/bs.irn.2026.02.007},
pmid = {42442914},
issn = {2162-5514},
mesh = {Humans ; *Alzheimer Disease/metabolism ; Animals ; *Energy Metabolism/physiology ; Signal Transduction/physiology ; *Neurons/metabolism ; *RNA, Untranslated/metabolism ; Metabolic Reprogramming/physiology ; *Neuroglia/metabolism ; *Receptor Protein-Tyrosine Kinases/metabolism ; },
abstract = {Alzheimer's disease (AD) is increasingly understood as a disorder involving impaired brain energy metabolism rather than being solely caused by amyloid and tau pathology. This chapter offers a comprehensive overview of how glucose hypometabolism, mitochondrial dysfunction, and disrupted neuron-astrocyte metabolic coupling collectively creates an "energy crisis" in vulnerable neuronal circuits. Early issues with glucose transport (GLUT1/3/4), reduced glycolytic flux, TCA cycle problems, and excessive mitochondrial fission all contribute to decreased ATP production and increased oxidative stress. Along with these metabolic disturbances, receptor tyrosine kinase (RTK) pathways-including insulin/IGF-1, TrkB/BDNF, FGFRs, and EGFR-lose their regulatory control, leading to insulin resistance, synaptic failure, and increased vulnerability to Aβ and tau toxicity. The chapter also highlights noncoding RNAs (miRNAs and lncRNAs) as key post-transcriptional regulators of metabolic and RTK signaling networks. Harmful miRNAs (such as miR-34a, miR-210-3p) suppress glycolytic enzymes and mitochondrial genes, while protective miRNAs (miR-23a/b, miR-455-3p, miR-195) decrease in AD. Metabolic lncRNAs, like EPB41L4A-AS1, decline with age and contribute to NAD[+] depletion and bioenergetic imbalance. Recognizing the link between RTK dysregulation and ncRNA-driven metabolic control reveals new therapeutic possibilities to restore mitochondrial function, enhance neurotrophic support, and re-establish energy balance in the AD brain.},
}
@article {pmid42442916,
year = {2026},
author = {Chaudhary, S and Verma, S and Kumari, V and Tare, M},
title = {Metabolic drivers of Alzheimer's disease pathogenesis: Impairments in glucose utilization, lipid homeostasis, and alternative substrate metabolism.},
journal = {International review of neurobiology},
volume = {187},
number = {},
pages = {349-383},
doi = {10.1016/bs.irn.2026.05.019},
pmid = {42442916},
issn = {2162-5514},
mesh = {Humans ; *Alzheimer Disease/metabolism ; *Lipid Metabolism/physiology ; *Glucose/metabolism ; Animals ; *Homeostasis/physiology ; Mitochondria/metabolism ; Energy Metabolism/physiology ; },
abstract = {Alzheimer's disease (AD) is one of the widespread neurodegenerative disorders, marked by the accumulation of amyloid-β plaques, neurofibrillary tangles of hyperphosphorylated Tau protein, and the gradual loss of neurons. While genetic and environmental factors have been associated with its onset, metabolic dysfunction has also been identified as one of the initial and most significant contributors its pathogenesis. The mitochondria are at the centre of this problem; their compromised function affects some crucial aspects of the neuronal health. Neurons have high energy demands so they are quite sensitive to the changes in the supply of the fuel. During AD pathogenesis, the loss of glucose transporters and the downregulation of key glycolytic enzymes deprives neurons of essential energy reserve. This metabolic dysregulation is further exacerbated by dysregulated lipid metabolism, pathological lipid droplet accumulation and ApoE4-driven failures in lipid trafficking which collectively leads to the oxidative stress, neuroinflammation, and Aβ aggregation. This situation is further aggravated by amino acid imbalances specifically within the glutamate-glutamine cycle. To counter this, ketone bodies have emerged as an alternative fuel source, capable of partially bypassing the impaired glucose oxidation while also demonstrating neuroprotective properties. Moreover, systemic metabolic disorders including type 2 diabetes mellitus, insulin resistance, obesity, and metabolic syndrome significantly amplify these deficits, functioning as major risk factors for AD onset and progression. Even the gut-brain axis plays a role in adding to the complexity. Taken together, these metabolic health changes not only reshape our understanding of AD but also open potential prospects for early detection through metabolic biomarkers and for novel therapeutic strategies targeting mitochondrial bioenergetics, glucose restoration, and ketogenic interventions.},
}
@article {pmid42442917,
year = {2026},
author = {Yadav, K and Tiwari, SS},
title = {Glial molecular signatures as a liquid biopsy marker in Alzheimer's disease diagnosis.},
journal = {International review of neurobiology},
volume = {187},
number = {},
pages = {385-411},
doi = {10.1016/bs.irn.2026.02.001},
pmid = {42442917},
issn = {2162-5514},
mesh = {Humans ; *Alzheimer Disease/diagnosis/metabolism ; Biomarkers/metabolism ; *Neuroglia/metabolism ; Liquid Biopsy/methods ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; Animals ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative condition that is characterized by the misfolding of Amyloid Precursor Protein, hyperphosphorylation of tau protein, and neuroinflammation. This leads to the formation of extracellular senile amyloid beta plaque and neurofibrillary tangles in neurons, leading to neuronal degeneration. AD is the biggest cause of dementia globally. Currently, no therapies are available for AD and early diagnosis of the disease is a challenge. The most common fluid biomarkers for AD are: p-tau181, p-tau231, p-tau217, Aβ42/Aβ40 ratio, Neurogranin (Ng), Alzheimer's-associated neuronal thread protein (AD7c-NTP). All these biomarkers are detected in Blood, CSF, Saliva, and Urine with the help of different assays, PET scan, and MRI Imaging. These biomarkers are of neuronal origin and indicate neuronal stress. Brain also contains glial cells along with the neurons, which interact with the neurons in health and disease conditions. These glial cells also release molecules in disease induced stress. These markers can be used for early and differential diagnosis of AD and other dementia conditions. Studies also show that these glia biomarkers are released decades before the actual neuron degeneration begins. In this review, we will discuss these glial cells biomarkers identified in liquid biopsy for AD detection and progression.},
}
@article {pmid42442918,
year = {2026},
author = {Singh, P and Vaidya, B and Upadhayay, P and Sharma, SS and Datusalia, AK},
title = {Insulin resistance and obesity: Drivers of energy crisis for Alzheimer's disease.},
journal = {International review of neurobiology},
volume = {187},
number = {},
pages = {39-90},
doi = {10.1016/bs.irn.2026.05.018},
pmid = {42442918},
issn = {2162-5514},
mesh = {Humans ; *Alzheimer Disease/metabolism ; *Energy Metabolism/physiology ; *Obesity/metabolism/complications ; *Insulin Resistance/physiology ; Animals ; *Brain/metabolism ; Mitochondria/metabolism ; },
abstract = {Alzheimer's disease (AD) is increasingly recognized as a disorder driven not only by classical neuropathological hallmarks but also by profound disturbances in brain energy metabolism. Growing evidence points to insulin resistance and obesity as major contributors to this metabolic crisis, linking peripheral metabolic dysfunction to central neurodegenerative processes. This chapter explores AD in the light of bioenergetic failure, highlighting the epidemiological and mechanistic connections between impaired insulin signaling, excess adiposity, and cognitive decline. The chapter further highlights how obesity-related inflammation, adipokine imbalance, and gut-brain axis dysregulation accelerates central insulin resistance and neuronal vulnerability. Evidence for glucose hypometabolism, mitochondrial failure, and disrupted astrocyte-neuron metabolic coupling in AD is reviewed, positioning amyloid and tau pathology as downstream consequences of sustained energy insufficiency. Finally, emerging therapeutic strategies aimed at restoring metabolic balance ranging from insulin-based interventions to lifestyle and mitochondria-targeted approaches are discussed, underscoring the potential of metabolic restoration as a disease-modifying strategy in Alzheimer's disease.},
}
@article {pmid42442919,
year = {2026},
author = {Jangra, J and Mahindru, I and Kumar, R},
title = {Therapeutic targeting of brain bioenergetics in Alzheimer's disease addressing insulin resistance, glucose hypometabolism, and mitochondrial dysfunction.},
journal = {International review of neurobiology},
volume = {187},
number = {},
pages = {91-132},
doi = {10.1016/bs.irn.2026.05.005},
pmid = {42442919},
issn = {2162-5514},
mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy ; *Energy Metabolism/physiology/drug effects ; *Insulin Resistance/physiology ; *Glucose/metabolism ; Animals ; *Mitochondria/metabolism/drug effects ; *Brain/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive, age-associated multifactorial neurodegenerative disorder characterised by cognitive decline, synaptic dysfunction, and neuronal loss. Despite over a century of research, effective disease-modifying therapies remain elusive owing to its conundrum pathophysiology. In recent years, AD is increasingly recognised as a complex metabolic disorder characterised by impaired cerebral glucose metabolism, insulin resistance, and mitochondrial dysfunction. These interconnected metabolic disturbances emerge early in the disease state and collectively potentiate other pathologies such as accumulation of amyloid-β (Aβ) plaques, tau hyperphosphorylation, oxidative stress, neuroinflammation, and synaptic dysfunction, thereby establishing bioenergetic failure as a primary factor governing AD progression rather than a downstream phenomenon. While traditional drug development strategies targeting Aβ have failed in clinical trials (limited to monoclonal antibodies), emerging therapeutic models integrating energy failure, thiamine signalling, and insulin-like growth factor (IGF) signalling as upstream events show significant promise in countering downstream neurodegeneration. This chapter summarises the mechanistic framework linking bioenergetic breakdown to AD pathology, with potential therapeutic opportunities aimed at restoring mitochondrial function, enhancing glucose utilisation, and correcting insulin signalling, further opening new avenues for multimodal interventions and identification of progressive metabolic dysfunction biomarkers to aid diagnostic processes.},
}
@article {pmid42443051,
year = {2026},
author = {Huang, Y and Gamble, JM and Juurlink, DN and Alsabbagh, MW},
title = {Hospitalization for Malignant Arrhythmias Following Initiation of Donepezil: A Retrospective Cohort Study.},
journal = {Pharmacoepidemiology and drug safety},
volume = {35},
number = {7},
pages = {e70426},
doi = {10.1002/pds.70426},
pmid = {42443051},
issn = {1099-1557},
mesh = {Humans ; *Donepezil/adverse effects/administration &amp; dosage ; Female ; Retrospective Studies ; *Cholinesterase Inhibitors/adverse effects/administration &amp; dosage ; Male ; *Hospitalization/statistics &amp; numerical data ; *Arrhythmias, Cardiac/epidemiology/chemically induced ; Canada/epidemiology ; Aged, 80 and over ; Aged ; Galantamine/adverse effects/administration &amp; dosage ; Rivastigmine/adverse effects/administration &amp; dosage ; Cohort Studies ; Proportional Hazards Models ; },
abstract = {PURPOSE: Limited evidence suggests donepezil might pose an increased risk of malignant arrhythmias. We examined whether donepezil initiation was associated with a higher risk of hospitalization for malignant arrhythmia compared to other acetylcholinesterase inhibitors.<br><br>METHODS: Population-based cohort study using linked administrative databases from seven Canadian provinces (BC, AB, SK, MB, ON, PEI, NL). We included individuals aged &#x2265;&#x2009;66 who were new users of donepezil, galantamine, or rivastigmine from April 1st, 2011, to January 31st, 2019. We used multivariable Cox proportional hazards regression to estimate the risk of hospitalization for malignant arrhythmia among new donepezil users compared to new users of galantamine or rivastigmine.<br><br>RESULTS: We identified 162&#x2009;616 subjects (mean age 82, 40% male). Most (127&#x2009;103; 78%) were treated with donepezil, while 25&#x2009;597 (15.7%) received galantamine, (n&#x2009;=&#x2009;6541; 4.0%) received oral rivastigmine, and (n&#x2009;=&#x2009;3375; 2.1%) received transdermal rivastigmine. The median age was 82&#x2009;years, and 59.8% were women. Baseline characteristics were generally well balanced. During a median follow-up of 386&#x2009;days (maximum 2616&#x2009;days), we identified 90 hospitalizations for malignant arrhythmias, including 58 in the donepezil group (23 per 100&#x2009;000 person-years) and 32 for other AChEIs (44 per 100&#x2009;000 person-years). Cumulative incidence curves showed a lower risk among donepezil initiators (Log-Rank p&#x2009;=&#x2009;0.0026; Wilcoxon p&#x2009;=&#x2009;0.0008). Crude regression suggested a reduced hazard (HR 0.52; 95% CI 0.34-0.80), which persisted after adjustment (aHR 0.55; 95% CI 0.36-0.85). In drug-specific analyses, donepezil initiators had a lower hazard relative to galantamine (aHR 0.49; 95% CI 0.31-0.77) but not rivastigmine (aHR 0.90; 95% CI 0.36-2.27). Sensitivity analyses-including alternative diagnosis field definitions, restricted follow-up, modified exclusion criteria, and propensity score adjustment-yielded consistent findings. No clear dose-response pattern was observed for any AChEI.<br><br>CONCLUSION: In this population-based cohort study, initiation of donepezil was not associated with an increased risk of malignant arrhythmias compared to initiation of galantamine or rivastigmine.},
}
@article {pmid42443082,
year = {2026},
author = {Li, J and Zhou, B and Yang, Y and Wang, J and Cheng, L and Zhu, C and Zhou, T and Yang, Y and Yin, W and Zhang, Y and Liu, R and Wang, L and Pu, Y and Li, Z},
title = {[Effects of moxibustion at the acupoints of governor vessel on cognitive function and gut microbiota in Alzheimer's disease model mice based on brain-gut axis].},
journal = {Zhongguo zhen jiu = Chinese acupuncture &amp; moxibustion},
volume = {46},
number = {7},
pages = {1115-1124},
doi = {10.13703/j.0255-2930.20250414-k0003},
pmid = {42443082},
issn = {0255-2930},
mesh = {Animals ; *Moxibustion ; *Alzheimer Disease/therapy/microbiology/psychology/physiopathology/metabolism/genetics ; Mice ; Male ; *Cognition ; Humans ; Disease Models, Animal ; Mice, Inbred C57BL ; *Acupuncture Points ; *Gastrointestinal Microbiome ; Amyloid beta-Peptides/metabolism/genetics ; Tumor Necrosis Factor-alpha/metabolism/genetics ; Interleukin-6/metabolism/genetics ; *Brain/metabolism/physiopathology ; *Brain-Gut Axis ; Hippocampus/metabolism ; },
abstract = {OBJECTIVE: To observe the effects of moxibustion at the points of governor vessel on cognitive function and gut microbiota in Alzheimer's disease (AD) model mice, and explore the mechanism of moxibustion at governor vessel in treatment of AD.<br><br>METHODS: Eighteen APP/PS1 mice were randomly divided into a model group and a moxibustion group, with 9 mice in each group; and the other 9 C57BL/6J mice were collected as a blank group. In the moxibustion group, mild-warm moxibustion was operated at "Baihui" (GV20), suspended moxibustion was at "Fengfu" (GV16) and "Dazhui" (GV14), 20 min in each intervention. Moxibustion was delivered once daily for 2 weeks. The water maze test and the novel object recognition experiment were employed to evaluate the cognitive function of mice, and the contents of &#x3b2;-amyloid 40 (A&#x3b2;40), &#x3b2;-amyloid 42 (A&#x3b2;42), tumor necrosis factor-&#x3b1; (TNF-&#x3b1;) and interleukin-6 (IL-6) in the hippocampus of mice were detected by ELISA, the morphology of hippocampal tissues was observed by HE staining, and the structure of fecal gut microbiota in mice was analyzed by 16S rRNA gene sequencing. The correlation of gut microbiota with the hippocampal A&#x3b2;40, A&#x3b2;42, TNF-&#x3b1; and IL-6 contents was analyzed.<br><br>RESULTS: Compared with the blank group, in the model group, the escape latency was extended (P<0.01), the number of platform crossings decreased (P<0.01), the target quadrant residence time ratio was reduced (P<0.01); the preference index in the novel object experiment increased (P<0.001), and the discrimination coefficient decreased (P<0.001). The contents of A&#x3b2;40, A&#x3b2;42, TNF-&#x3b1; and IL-6 in the hippocampus rose (P<0.05), the hippocampal neuron structure was imcomplete, with irregular size and arrangement, the neurons were vacuolar and some showed pyknosis and were reduced in number. ACE, Chao1 and Shannon indexes decreased (P<0.001) and the Simpson index rose (P<0.001). The relative abundance of Proteobacteria and Deferribacteres was reduced (P<0.001), that of Lactobacillus and Pasteurella was elevated (P<0.01), while that of Alistipes decreased (P<0.01). Compared with the model group, in the moxibustion group, the escape latency was shortened (P<0.05), the number of crossing the platform increased (P<0.05), and the target quadrant residence time ratio was higher (P<0.05); the preference index decreased (P<0.001), and the discrimination coefficient increased (P<0.001). The contents of A&#x3b2;40, A&#x3b2;42, TNF-&#x3b1; and IL-6 in the hippocampus decreased (P<0.01). Hippocampal tissue injury was attenuated. ACE, Chao1 and Shannon indexes increased (P<0.05), and Simpson index decreased (P<0.05). The relative abundance of Proteobacteria and Deferribacteres increased (P<0.05), that of Lactobacillus decreased (P<0.001). The correlation was presented between gut microbiota and the contents of hippocampal A&#x3b2;40, A&#x3b2;42, TNF-&#x3b1; and IL-6 in the moxibustion group.<br><br>CONCLUSION: Moxibustion at governor vessel points can improve cognitive function in AD mice, reduce A&#x3b2; accumulation, inhibit neuroinflammation, which may be related to the recovery of gut microbiota homeostasis.},
}
@article {pmid42443333,
year = {2026},
author = {Russo, L and Chakrabarti, KS and Backer, R and Overkamp, K and Gambarelli, S and Willbold, D and Sicoli, G and Rezaei-Ghaleh, N},
title = {Soluble zinc-induced amyloid β oligomers probed through fluorine NMR spectroscopy.},
journal = {Communications chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s42004-026-02121-4},
pmid = {42443333},
issn = {2399-3669},
support = {RE 3655/2-3//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; },
abstract = {Divalent zinc ions (Zn) interact with amyloid β (Aβ) peptides and influence its Alzheimer disease (AD)-related aggregation. Little is known about the structural properties of Zn-induced Aβ oligomers. Here, we report recombinant production of fluorinated Aβ40 at Phe4, Tyr10, Phe19 and Phe20 residues and utilize these fluorinated residues as proxies to interrogate Zn-induced Aβ40 oligomers. Our NMR and CW EPR results confirm Zn binding to the N-terminal region of Aβ40 and demonstrate the reversible oligomerization and irreversible aggregation of Aβ40 upon Zn addition. The [19]F NMR relaxation and dark-state exchange saturation transfer (DEST) data provide dynamical information on free Aβ40 and demonstrate that monomeric Aβ40 is in exchange with small Zn-induced Aβ40 oligomers with less than about 60 kDa molecular weight on a millisecond timescale. The [19]F ENDOR data suggest that the distance between the N-terminally attached nitroxide spin and fluorinated residues within the Zn-Aβ40 aggregates is larger than about 1.5 nm. Our results shed light on the properties of soluble Zn-induced Aβ oligomers and pave the way for further structural characterization of these Aβ aggregates.},
}
@article {pmid42443387,
year = {2026},
author = {Kim, WS and Halliday, GM},
title = {Astrocytic lipid dysregulation as an early driver of neurodegeneration.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {42443387},
issn = {1759-4766},
abstract = {Astrocytes have traditionally been cast as supportive glia, but they are increasingly recognized as metabolic hubs that regulate cholesterol synthesis, fatty acid detoxification, lipid droplet dynamics and redox homeostasis in the CNS. Neurons have a limited intrinsic capacity for lipid storage and detoxification and rely heavily on astrocytes to maintain a safe lipid environment. Emerging evidence indicates that dysregulation of astrocytic lipid homeostasis precedes overt neuronal degeneration in a range of neurodegenerative diseases, including Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, frontotemporal dementia and Huntington disease. Perturbations in astrocytic lipid handling can drive maladaptive reactive states, promote oxidative stress, impair lysosomal and mitochondrial function and disrupt neuron-glia lipid exchange, collectively creating an environment that leads to neurodegeneration. Therefore, lipid dysregulation within astrocytes could trigger or amplify neuronal vulnerability. In this Review, we assess evidence that astrocytic lipid metabolism is not solely protective or pathological but has instructive physiological roles and that astrocytic lipid dysregulation is an early driver of neurodegeneration. We critically evaluate disease-specific evidence, distinguishing correlative observations from causal mechanisms. We propose that targeting of astrocytic lipid homeostasis represents a promising strategy for preventing or minimizing neurodegeneration and opens new avenues for early detection and biomarker development.},
}
@article {pmid42443390,
year = {2026},
author = {Qiu, Y and Wu, S and Zhong, Y and Fan, D and Tong, Q and Xiong, J and Xu, K and Liu, G and Liu, E and Li, X and Huang, K},
title = {PIAS1-mediated GSK3β SUMOylation exacerbates tauopathy and cognitive deficits in Alzheimer's disease models.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42443390},
issn = {1476-5578},
support = {82495174//National Natural Science Foundation of China (National Science Foundation of China)/ ; 91949201//National Natural Science Foundation of China (National Science Foundation of China)/ ; 81801062//National Natural Science Foundation of China (National Science Foundation of China)/ ; 242300421081//Natural Science Foundation of Henan Province (Henan Province Natural Science Foundation)/ ; },
abstract = {Age-related neurodegenerative disorders, such as Alzheimer's disease (AD), are characterized by the accumulation of pathological Tau protein (tauopathy), which drives neurotoxicity and cognitive decline. Although SUMOylation significantly influences tauopathy, the underlying mechanisms remain largely elusive. Here, utilizing a bimolecular fluorescence complementation (BiFC) assay to monitor Tau-Tau aggregation and screen for SUMO E3 ligases, we identified PIAS1 as a critical driver of Tau pathology. Genetic analysis of the UK Biobank cohort revealed that single nucleotide polymorphisms in the PIAS1 gene (rs8036154 and rs112677781) are significantly associated with a reduced risk of AD. Consistent with this clinical relevance, PIAS1 expression is upregulated in postmortem AD brains, aging PS19 tauopathy mice, aged wild-type mice, aged lemurs, and neurons stimulated with amyloid-beta or lipopolysaccharide. Viral-mediated modulation of PIAS1 in vivo demonstrated that PIAS1 promotes Tau hyperphosphorylation and aggregation, thereby exacerbating synaptic dysfunction and cognitive deficits. Mechanistically, we found that PIAS1 directly interacts with and mediates the SUMOylation of glycogen synthase kinase 3 beta (GSK3β) at lysine residues 183 and 271. This specific SUMOylation reduces inhibitory phosphorylation at Ser9, consequently enhancing GSK3β-mediated Tau kinase activity. Importantly, we engineered a cell-permeable blocking peptide designed to disrupt the PIAS1-GSK3β interaction. Administration of this peptide effectively suppressed GSK3β activation and mitigated tauopathy and neurodegeneration in both in vitro and in vivo models. Together, our findings uncover a novel PIAS1-GSK3β signaling axis in tauopathy and provide a promising targeted therapeutic strategy for Alzheimer's disease.},
}
@article {pmid42443567,
year = {2026},
author = {Muratori, BG and Caetano, CR and da Veiga, IET and Soliani, AG and E Silva, SMS and Gava, JP and Ceridório, LF and Caselli, L and Ureshino, RP and Prado, CM and Cerutti, SM},
title = {Standardized Extract of Ginkgo biloba L. Reverses Memory Impairment in Older Female Mice with Basal Forebrain Cholinergic Dysfunction.},
journal = {Neurochemical research},
volume = {51},
number = {4},
pages = {},
pmid = {42443567},
issn = {1573-6903},
mesh = {Animals ; Female ; Ginkgo biloba ; *Plant Extracts/therapeutic use/pharmacology ; *Memory Disorders/drug therapy/metabolism ; Ginkgo Extract ; Amyloid beta-Peptides/metabolism ; Mice ; Aging/drug effects ; tau Proteins/metabolism ; Vesicular Acetylcholine Transport Proteins/genetics/metabolism ; *Prosencephalon/drug effects/metabolism ; Mice, Inbred C57BL ; Peptide Fragments ; },
abstract = {Aging induces neurochemical changes, particularly in the dentate gyrus (DG), that impair memory. In late-onset Alzheimer's disease (LOAD), neuronal loss in regions like the entorhinal cortex (EC) and hippocampus proper (HP), along with amyloid-β (Aβ) plaques, tau tangles, and reduced cholinergic signaling, accelerates cognitive decline. Building on our group's previous findings of cognitive benefits and neuroprotection from Ginkgo biloba L. leaf extract (EGb), and considering the limited success of current therapies, EGb has emerged as a promising multi-target strategy for reversing memory impairments. This study evaluates the effects of chronic EGb treatment on memory, anxiety-like behaviors, and motor activity in older female wild-type and VAChT knockdown KD[HET] and KD[HOM] mice, which show 45% and 65% reductions in VAChT expression, respectively. We assessed the impact of EGb on Aβ1-42 peptide and phosphorylated tau (pTauT231) by quantifying Aβ IR[+] and pTau IR[+] cells in the dCA1, dCA3, and dDG, via immunohistochemistry. Results showed that aging led to short- and long-term memory deficits, which were exacerbated in the VAChT KD[HOM] mice. However, EGb treatment reversed these deficits in a dose-dependent manner by modulating Aβ and pTau-IR[+] cells in the dCA1, and dDG regions. In vitro, EGb significantly inhibited Aβ aggregation through interactions with Aβ and the POPC monolayer. These findings suggest that EGb may provide a promising therapeutic strategy for AD, improving cognition and offering neuroprotection by targeting key neuropathological features like Aβ plaques and phosphorylated tau.},
}
@article {pmid42443581,
year = {2026},
author = {Wu, Q and Jin, Y},
title = {Rethinking blood-brain barrier permeability in Alzheimer's disease: insights from APOE genotype-specific associations.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {8},
pages = {},
pmid = {42443581},
issn = {1590-3478},
}
@article {pmid42443606,
year = {2026},
author = {Akbari, V and Bahramikia, S},
title = {Tau physiology and pathology: impacts on cellular structures and neurodegenerative diseases.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42443606},
issn = {1568-5608},
abstract = {This review explores the crucial roles of the tau protein in neuronal integrity and its dysregulation in neurodegenerative diseases (NDs), particularly tauopathies. Key features include abnormal tau phosphorylation, leading to insoluble aggregates and neuronal dysfunction. Various therapeutic strategies, such as reducing tau phosphorylation, inhibiting aggregation, and enhancing clearance through autophagy and immunotherapies, are discussed. Promising candidates such as anle138b and methylene blue display efficacy in preclinical models. The interplay between tau and Aβ pathology is also highlighted, emphasizing the complexity of therapeutic approaches. A thorough understanding of tau functions is essential for developing targeted treatments to combat tau-related neurotoxicity and advance therapies for Alzheimer's disease (AD). This article examines the dual role of tau in physiology and pathology, highlighting its effects at both the cellular and subcellular levels. These findings underscore the critical importance of the tau protein in preventing NDs and suggest that a deeper understanding of its functions could improve treatment strategies for tau-related disorders.},
}
@article {pmid42443949,
year = {2026},
author = {He, Z and Chu, B and Yang, J and Gu, J and Chen, Z and Liu, L and Morrison, T and Belloy, ME and Qi, X and Hejazi, N and Mathur, M and Le Guen, Y and Tang, H and Hastie, T and Ionita-Laza, I and Candès, E and Sabatti, C},
title = {CIT-Lasso: a scalable approach beyond guilty by association for identifying causal variants from genome-wide summary statistics.},
journal = {Genome biology},
volume = {27},
number = {1},
pages = {},
pmid = {42443949},
issn = {1474-760X},
support = {AG066206//NIH/NIA/ ; AG066515/GF/NIH HHS/United States ; EB001988-21/GF/NIH HHS/United States ; AG075238/GF/NIH HHS/United States ; 814641//Simonsen Foundation/ ; },
mesh = {*Genome-Wide Association Study/methods ; Humans ; Alzheimer Disease/genetics ; *Genetic Variation ; Phenotype ; Polymorphism, Single Nucleotide ; },
abstract = {We present CIT-Lasso, a framework that uses only summary statistics to identify, genome-wide, sets of variants carrying non-redundant information on a phenotype, distinguishing likely causal variants from correlated variants that are merely associated. The open-source implementation completes genome-wide analysis in under 15 min on one CPU. In simulations, it outperforms existing methods in false discovery rate control, power, and fine-mapping resolution. Applied to an Alzheimer's disease meta-analysis, it identified 82 loci, 37 beyond conventional GWAS; prior MPRA and CRISPR-Cas9 studies corroborate prioritized variants. Results on other 67 large-scale GWAS reveal the method's generalizability to make discoveries beyond conventional GWAS pipeline.},
}
@article {pmid42443967,
year = {2026},
author = {Zou, M and Zhao, T and Wu, W and Zhang, J and Pan, P and Yan, J and Li, Q and Zhou, Y},
title = {Microglial mitophagy as an immunometabolic checkpoint in alzheimer's disease: linking mitochondrial quality control to neuroinflammation.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-026-03946-5},
pmid = {42443967},
issn = {1742-2094},
support = {LJGXCG2025-F13//Heilongjiang Province "Double First-Class" Discipline Collaborative Innovation Achievement Project/ ; 2024yjscx022//Heilongjiang University of Chinese Medicine Graduate Innovative Research Project/ ; },
abstract = {AD is a complex neurodegenerative disorder characterized by chronic neuroinflammation. Microglia, the brain's resident immune cells, centrally regulate AD pathophysiology. Recent studies have highlighted microglial mitophagy as an important interface linking mitochondrial quality control to innate immune responses.Intact mitophagy facilitates the timely clearance of damaged mitochondria, thereby limiting the release of mitochondrial DAMPs (e.g., mtDNA and mtROS) and helping restrain aberrant activation of the cGAS-STING pathway and the NLRP3 inflammasome.In the AD pathological milieu, however, factors including Aβ deposition, tau pathology, and genetic risk variants such as TREM2 and APOE4 disrupt mitophagy at multiple levels-from initiation and recognition to lysosomal degradation. This review systematically summarizes the molecular regulatory network of microglial mitophagy, with a particular focus on the mechanisms by which AD-associated pathological factors impair this process. We further discuss potential mechanisms through which mitophagic dysfunction may contribute to the amplification of neuroinflammation, including the release of mitochondrial DAMPs, the reprogramming of TBK1 signaling, and intercellular interactions. Finally, we outline current therapeutic strategies aimed at restoring mitophagy and discuss their potential to modulate neuroinflammatory responses and AD-related pathological processes, while highlighting the challenges and future directions in this emerging field.},
}
@article {pmid42443969,
year = {2026},
author = {Lam, JYL and Bu, G},
title = {Breaking the glial loop: astrocytic PAD2 and citrullinated vimentin drive microglial dysfunction in Alzheimer's disease.},
journal = {Molecular neurodegeneration},
volume = {21},
number = {1},
pages = {},
pmid = {42443969},
issn = {1750-1326},
support = {16100424, 16101825, T12-611/25-N, N_HKUST639/25//Hong Kong Research Grants Council/ ; ITCPD/17-9//Innovation and Technology Commission/ ; },
mesh = {*Alzheimer Disease/metabolism/pathology ; *Microglia/metabolism/pathology ; *Vimentin/metabolism ; *Astrocytes/metabolism ; Humans ; Animals ; *Protein-Arginine Deiminase Type 2/metabolism ; Citrullination/physiology ; },
abstract = {Zhang et al. reveal that astrocytic PAD2-mediated citrullination of vimentin drives a TLR4-dependent pro-inflammatory loop in microglia, linking glial crosstalk to impaired amyloid clearance and identifying a potential therapeutic and biomarker pathway in Alzheimer's disease.},
}
@article {pmid42444063,
year = {2026},
author = {Zhang, L and He, K and Zhang, H and Wu, L and Gao, C and Liu, A and Qiu, S and Sun, Q and Gao, Q},
title = {EXPRESS: Ultrasound Enhances Glymphatic-Associated Solute Transport via Piezo1-Related Mechanotransduction in 5xFAD Mice.},
journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism},
volume = {},
number = {},
pages = {271678X261470064},
doi = {10.1177/0271678X261470064},
pmid = {42444063},
issn = {1559-7016},
abstract = {BACKGROUND: Glymphatic dysfunction impairs Aβ clearance and contributes to Alzheimer's disease (AD) progression. Low-intensity transcranial focused ultrasound (LITFUS) can enhance glymphatic cerebrospinal fluid transport, but its therapeutic effects on Aβ clearance and cognitive decline remain unclear.<br><br>METHODS: 5xFAD mice received bilateral hippocampal LITFUS for 4 weeks. Glymphatic transport was assessed by fluorescent tracer injection and ex vivo imaging. A&#x3b2; deposition, Iba1 immunoreactivity, and cognitive function were evaluated by immunohistochemistry and behavioral tests. Piezo1 involvement was examined using GsMTx4, qPCR, and Western blotting of isolated brain vascular fractions. Safety was assessed by blood-brain barrier permeability and H&amp;E staining.<br><br>RESULTS: LITFUS increased brain-wide CSF tracer influx and hippocampal interstitial solute clearance in 5xFAD mice. It reduced A&#x3b2; deposition in the hippocampus and prefrontal cortex, decreased Iba1 immunoreactivity, and improved learning and memory. These effects were associated with increased Piezo1 expression and enhanced CaMKII/eNOS signaling in brain vascular fractions, and were attenuated by GsMTx4. No blood-brain barrier disruption or histological injury was detected.<br><br>CONCLUSION: LITFUS enhances glymphatic transport, reduces cerebral A&#x3b2; burden, and improves cognition in 5xFAD mice, possibly through Piezo1-related mechanotransduction, supporting its potential as a noninvasive AD therapy.},
}
@article {pmid42444286,
year = {2026},
author = {Carrese, C and Bonomi, CG and Bernocchi, F and Donna, MGD and Poli, M and Greco, G and Mercuri, NB and Martorana, A and Motta, C},
title = {Vascular-Apoptotic Crosstalk in Alzheimer's Disease: The Possible Role of Vascular Senescence in Blood-Brain Barrier Dysfunction.},
journal = {European journal of neurology},
volume = {33},
number = {7},
pages = {e70679},
doi = {10.1111/ene.70679},
pmid = {42444286},
issn = {1468-1331},
mesh = {Humans ; *Blood-Brain Barrier/physiopathology/metabolism/pathology ; Female ; *Apoptosis/physiology ; *Alzheimer Disease/cerebrospinal fluid/physiopathology/pathology ; Male ; *Tumor Suppressor Protein p53/cerebrospinal fluid ; Aged ; *Endothelin-1/cerebrospinal fluid ; bcl-X Protein/cerebrospinal fluid ; Amyloid beta-Peptides/cerebrospinal fluid ; Aged, 80 and over ; Biomarkers/cerebrospinal fluid ; Peptide Fragments/cerebrospinal fluid ; tau Proteins/cerebrospinal fluid ; },
abstract = {BACKGROUND: Blood-brain barrier (BBB) dysfunction is an early feature of Alzheimer's disease (AD), influenced by amyloid pathology, astrocyte activation, and vasoactive mediators such as endothelin-1 (ET-1). ET-1 has been implicated in apoptosis and vascular senescence through induction of p53, a pro-apoptotic factor, whereas BCL-X exerts antiapoptotic effects. We investigated the interplay between ET-1, p53, and BCL-X in AD and their contribution to BBB permeability.<br><br>METHODS: We studied 101 individuals (70 AD, 31 controls) who underwent cerebrospinal fluid (CSF) analysis for A&#x3b2;42, p-tau, ET-1, p53, BCL-X, and the CSF/serum albumin quotient (QAlb), an index of BBB permeability. Correlations between biomarkers were explored, followed by multiple regression and mediation analysis to assess whether p53 mediated the ET-1-BBB relationship.<br><br>RESULTS: No absolute differences in ET-1, p53, or BCL-X were found between AD and controls. However, in AD, ET-1 correlated positively with p53 and negatively with BCL-X, whereas no such associations were seen in controls. None of these biomarkers related to the p-tau/A&#x3b2;42 ratio. Regression analysis identified both ET-1 and p53 as independent predictors of BBB permeability. Mediation analysis further revealed that ET-1 influenced BBB permeability both directly and indirectly through p53.<br><br>CONCLUSION: Our findings suggest that AD is characterized less by absolute biomarker changes and more by altered interrelationships linking ET-1, apoptosis, and BBB integrity. ET-1 may promote BBB dysfunction partly via p53, which is consistent with the mechanisms of vascular senescence. These results highlight apoptosis-vascular interactions as potential drivers of BBB impairment in AD.},
}
@article {pmid42444329,
year = {2026},
author = {Petrisko, TJ and Chu, SH and Gomez-Arboledas, A and Zhang, B and Tenner, AJ},
title = {Young Adult Microglial Deletion of C1q Reduces Engulfment of Synapses and Partially Mitigates Cognitive Impairment in an Aggressive Alzheimer's Disease Mouse Model.},
journal = {Glia},
volume = {74},
number = {9},
pages = {e70189},
doi = {10.1002/glia.70189},
pmid = {42444329},
issn = {1098-1136},
support = {R01 AG060148/AG/NIA NIH HHS/United States ; T32 AG000096/NH/NIH HHS/United States ; 24AARF-1241864/ALZ/Alzheimer's Association/United States ; 2021-A-020-FEL//Larry L. Hillblom Foundation/ ; //Edythe M. Laudati Memorial Fund/ ; CA-62203/CA/NCI NIH HHS/United States ; GM-076516//Center for Complex Biological Systems Support at UC Irvine/ ; },
mesh = {Animals ; *Microglia/metabolism/pathology ; *Alzheimer Disease/pathology/metabolism/genetics ; *Complement C1q/genetics/deficiency/metabolism ; *Synapses/metabolism/pathology ; Disease Models, Animal ; Mice, Transgenic ; Mice ; *Cognitive Dysfunction/metabolism/pathology/genetics ; Male ; Mice, Inbred C57BL ; Hippocampus/metabolism/pathology ; Plaque, Amyloid/pathology/metabolism ; },
abstract = {C1q is a multifunctional protein, including its role as the initiating protein of the classical complement cascade. While classical pathway activation is involved in synaptic pruning during nervous system development, it also contributes to inflammation and cognitive decline in Alzheimer's disease (AD). Constitutive genetic C1q deficiency has been shown to reduce glial activation and attenuate neuronal loss in AD mouse models, but the specific contributions of microglial C1q to AD pathology while avoiding deficits during post-natal development remain unaddressed. To dissect specific role(s) of microglial C1q in AD progression, we crossed the Cx3cr1[CreERT2] mouse model that deletes C1q from microglia in young adulthood (8 weeks of age) to the aggressive Arctic48 (Arc) amyloidosis mouse model. At 10 months, young adult microglial C1q deletion (Arc C1q[ΔMG]) was associated with improved spatial memory performance, despite unchanged amyloid plaque burden. Furthermore, Arc C1q[ΔMG] mice exhibited reduced hippocampal C3 protein levels without altering C3 mRNA. No changes were observed in C5aR1, astrocyte GFAP, or microglial Iba1 protein expression. However, Arc C1q[ΔMG] mice demonstrated region specific reductions in microglial synaptic engulfment, alongside decreased phagolysosome-associated amyloid in both microglia and astrocytes, and reduced hippocampal amyloid compaction. These findings support a role for C1q in astrocytic C3 induction and the engulfment of both synapses and amyloid. Importantly, young adult microglial C1q inhibition confers cognitive benefits without exacerbating amyloid pathology, suggesting a therapeutic window in which targeting microglial C1q may help preserve synaptic integrity and modulate the neuroinflammatory processes during the later stages of AD.},
}
@article {pmid42444486,
year = {2026},
author = {Li, Q and Fan, B and Xiao, Y and Zhang, Z and Zhao, S and Liao, B and Zeng, J and Shan, X and Ye, H and Wen, Y and Zhang, L and Guo, H and Xiao, F and Zhu, H},
title = {Branched-chain amino acids and gut microbiota: coregulation and impact on neurological function via the gut-brain axis.},
journal = {Gut microbes},
volume = {18},
number = {1},
pages = {2698204},
doi = {10.1080/19490976.2026.2698204},
pmid = {42444486},
issn = {1949-0984},
mesh = {*Amino Acids, Branched-Chain/metabolism ; Humans ; *Gastrointestinal Microbiome/physiology ; Animals ; *Brain/metabolism/physiology ; *Nervous System Diseases/metabolism/microbiology ; *Gastrointestinal Tract/microbiology/metabolism ; },
abstract = {Diseases that cause neurological dysfunction, such as Parkinson's disease (PD), Alzheimer's disease (AD), and maple syrup urine disease (MSUD), among others, are characterized by complex and multifaceted etiologies. There is growing evidence that branched-chain amino acids (BCAAs), regulated by the gut microbiota, play a critical role in the development of the central nervous system (CNS) disorders. This review focuses on the potential role of branched-chain amino acid metabolism in regulating brain function and gut microbiota. First, we summarize the current understanding of BCAAs, encompassing their biochemical metabolism, function, and systemic metabolic mechanisms. Subsequently, we delve into the mechanisms through which the gut microbiota regulates branched-chain amino acid metabolism, along with its mechanistic insights and recent evidence of its impact on neurological disorders. Finally, we discuss future research directions and challenges regarding gut BCAAs metabolism as a potential treatment for brain and gastrointestinal dysfunction.},
}
@article {pmid42444499,
year = {2026},
author = {Sellitepe, HE and Aksel, AB and Zıvalı, H and Pehlivanlar Yavrucu, E and Sağlık Özkan, BN and Doğan, &#x130;S and Özcan Kosif, K},
title = {Structure-Guided Optimization of 1,2,4-Triazole-Thione-Based Mannich Derivatives as Dual-Target Modulators: AChE/MAO-B.},
journal = {Chemical biology &amp; drug design},
volume = {108},
number = {1},
pages = {e70347},
doi = {10.1111/cbdd.70347},
pmid = {42444499},
issn = {1747-0285},
mesh = {*Triazoles/chemistry/metabolism ; *Acetylcholinesterase/metabolism/chemistry ; *Cholinesterase Inhibitors/chemistry/metabolism/pharmacology/chemical synthesis ; *Monoamine Oxidase/metabolism/chemistry ; Humans ; Molecular Docking Simulation ; *Monoamine Oxidase Inhibitors/chemistry/metabolism/pharmacology ; Butyrylcholinesterase/metabolism/chemistry ; Structure-Activity Relationship ; Animals ; Alzheimer Disease/drug therapy ; Binding Sites ; },
abstract = {Diseases such as Alzheimer's, Parkinson's, and depression result from neurotransmitter imbalances. In particular, for AD, it is critical to inhibit AChE to preserve the decline in acetylcholine levels and to block excessive MAO-B activity, which leads to nerve damage and cognitive impairment. As current scientific research has moved away from the "one drug for one target" approach toward a "multi-target" strategy, dual-acting inhibitors that simultaneously inhibit both AChE and MAO-B enzymes are considered the most promising new drug candidates for the treatment of Alzheimer's disease. In this study, we investigated the inhibition of AChE, BChE, MAO-A, and MAO-B in the pathophysiology of AD as a working group. Within the scope, 10 new compounds (5a-j) were synthesized, consisting of a phenolic ring, a secondary or tertiary amine tail, and a 1,2,4-triazole core. The cholinesterase and MAO inhibitory profiles of the compounds were investigated using both in vitro and in silico methods. Compound 5b exhibited dual inhibitory activity against AChE and MAO-B enzymes, with IC50 values of 0.136 ± 0.006 μM and 0.108 ± 0.005 μM, respectively. In accordance with 5b, it interacted with crucial amino acids of the hAChE and hMAO-B enzymes in the docking studies. These results suggest that 5b is a dual-target inhibitor of AChE and MAO-B and represents a promising therapeutic option for the treatment of Alzheimer's disease.},
}
@article {pmid42444503,
year = {2026},
author = {Li, H and Li, Y and Liang, W and Wu, L and Han, C and Ren, Q and Liu, X and Cai, Y and Wang, Z},
title = {A First-In-Class Antibody Enabling Detection of Altered Peripheral Non-Phosphorylated Clusterin With Translational Potential in Dementia.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {40},
number = {14},
pages = {e72124},
doi = {10.1096/fj.202601699RR},
pmid = {42444503},
issn = {1530-6860},
support = {81870832//MOST | National Natural Science Foundation of China (NSFC)/ ; },
mesh = {*Clusterin/immunology/blood/metabolism ; Humans ; Animals ; Phosphorylation ; *Dementia/diagnosis/blood/metabolism ; Mice ; Biomarkers/blood/metabolism ; *Alzheimer Disease/diagnosis/blood/metabolism ; *Antibodies, Monoclonal/immunology ; Female ; Male ; Brain/metabolism ; },
abstract = {Clinical diagnosis of dementia, with Alzheimer's disease (AD) as the major form, relies heavily on memory tests and the caregiver descriptions, both of which are subjective. The discovery of reliable biomarkers may facilitate objective diagnosis. The protein clusterin (CLU), encoded by a well-established AD risk gene, is consistently elevated in AD patients, but its biomarker utility is limited by high interindividual variability. As CLU is produced in most organs and tissues, quantifying CLU secreted specifically from the brain into the bloodstream may help the development of new diagnostic methods. CLU in blood can be phosphorylated at T393-S394 and/or S396, but these phosphorylations are absent in brain parenchyma. Peripherally administered non-phosphorylated CLU has been shown to reduce neuroinflammation and AD pathology in mouse models. A monoclonal antibody, 3D3F10, targeting non-phosphorylated CLU at T393-S394 or S396 was generated. This antibody showed an ability to distinguish serum samples of dementia and non-dementia (p < 0.001, AUC = 0.897, sensitivity: 81.8%, specificity: 95.5%, Youden index: 0.77), but did not distinguish Parkinson's disease. The direction of the change contradicted our initial hypothesis, and further analyses suggested that phospho-CLU in dementia patients is unlikely to originate from the brain. These results established 3D3F10 as a novel tool for modification-specific CLU detection, indicated a potential of non-phospho-CLU as a biomarker for dementia, and peripheral phospho-CLU might play a role in pathogenesis.},
}
@article {pmid42444591,
year = {2026},
author = {Yang, X and Li, M and Yao, Z and Hu, Y and Wang, Z and Shi, W and Sun, B},
title = {Self-Assembly of Antigenic Peptide Nanofibrils Templates the Growth of Silica Nanoparticles for Nanovaccines.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e76636},
doi = {10.1002/advs.76636},
pmid = {42444591},
issn = {2198-3844},
support = {U22A20455//National Natural Science Foundation of China/ ; 2022YFC2304305//National Key Research and Development Program of China/ ; 2025YFC2311603//National Key Research and Development Program of China/ ; },
abstract = {The low immunogenicity of peptide vaccines remains a critical challenge in immunotherapy. While peptide nanofibrils can function as self-delivery systems to activate antigen-presenting cells (APCs), most existing designs rely on complex covalent conjugation to β-sheet-forming motifs. Moreover, the diverse surface properties of various antigenic peptides complicate the rational selection of appropriate adjuvants. Herein, we develop a nanovaccine platform in which antigenic peptides self-assemble into nanofibrils without the need for exogenous β-sheet-forming sequences. Silica nanoparticles (SiO2 NPs) are nucleated and grown directly along these fibrils, resulting in SiO2@fibril nanovaccines with a unique "beads-on-a-string" morphology. Using amyloid-β(1-42) (Aβ42) and human papillomavirus (HPV) type 16 E7 (E7) as model antigens, we demonstrate that these nanovaccines significantly enhance the maturation and activation of bone marrow-derived dendritic cells (BMDCs). In an Alzheimer's disease animal model using APP/PS1 mice, SiO2@Aβ42 nanovaccines improve motor and cognitive function. Additionally, in an HPV animal model using TC-1 tumor-bearing mice, SiO2@E7 nanovaccines suppress tumor growth and increase survival rate. This strategy provides a universal and modular adjuvant platform for peptide-based nanovaccines.},
}
@article {pmid42444711,
year = {2026},
author = {Chen, AA and Seidlitz, J and Gardner, M and Bethlehem, RAI and Dorfschmidt, L and Kafadar, E and Benitez, A and Jensen, JH and Vandekar, S and Satterthwaite, TD and Alexander-Bloch, AF},
title = {Calibration of MRI-based reference intervals to new samples.},
journal = {Imaging neuroscience (Cambridge, Mass.)},
volume = {4},
number = {},
pages = {},
pmid = {42444711},
issn = {2837-6056},
abstract = {Reference intervals, defined as intervals containing a new observation with a specified probability relative to reference data, would be clinically useful in assessing brain magnetic resonance imaging (MRI). Brain charts, which are estimates of MRI phenotypes across covariates such as age and sex, can be used to construct reference intervals. However, the reference data used to fit intervals often differ from a new sample in terms of study design, MRI acquisition, and image preprocessing. Application of MRI reference intervals to new samples remains a challenging problem. Here, we propose a new method called reference interval calibration via conFormal prediction (ReForm) that adjusts reference intervals for a new sample. Our method builds on recent work in conformal prediction, which yields intervals with guaranteed coverage for new observations. Through resampling experiments in Lifespan Brain Chart Consortium cortical thickness data, we compare ReFormed reference intervals with refitting intervals, statistical harmonization methods, and model-based adjustment of intervals. Notably for patient privacy concerns, ReForm does not require sharing of reference data. Yet, our empirical results demonstrate that ReForm controls FPR similarly or better than alternative methods that require sharing reference data. Finally, we provide recommendations for practical applications of ReForm and an R package (https://github.com/andy1764/ReForm) for calibrating reference intervals using ReForm.},
}
@article {pmid42444728,
year = {2026},
author = {Tristão-Pereira, C and Vasquez, D and Alcina, J and Baena, A and Aguillon, D and Ospina Lopera, P and Londono, N and Ramos, C and Martinez, L and Alvarez, S and Vidal, M and Gonzalez, I and Malotaux, V and He, B and Giudicessi, A and Ramirez-Gomez, L and Gatchel, J and Ismail, Z and Quiroz, YT},
title = {Associations among mild behavioral impairment, cognition, and brain pathology in preclinical autosomal dominant Alzheimer's disease.},
journal = {Alzheimer's &amp; dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70424},
pmid = {42444728},
issn = {2352-8729},
abstract = {INTRODUCTION: The Mild Behavioral Impairment Checklist (MBI-C) captures neuropsychiatric symptoms in individuals at risk of dementia. In this study, we examined MBI-C scores in autosomal dominant Alzheimer's disease (ADAD).<br><br>METHODS: We included 83 cognitively unimpaired presenilin-1 E280A mutation carriers and 114 non-carriers with MBI-C, obfjective cognition, and subjective cognitive decline (SCD) assessments. Study sub-samples underwent neuroimaging to assess Alzheimer's disease (AD) pathology and neurodegeneration.<br><br>RESULTS: MBI-C total scores were greater in carriers than non-carriers (r rb&#xa0;=&#xa0;0.19 [95% confidence interval (CI) 0.05, 0.31], P&#xa0;=&#xa0;0.009), driven by impulse dyscontrol symptoms. Elevated MBI-C scores were associated with higher study partner-reported SCD scores (&#x3b2; =&#xa0;0.28 [95% CI 0.07, 0.050], P&#xa0;=&#xa0;0.008) and with greater neocortical amyloid beta (&#x3b2; =&#xa0;0.46 [95% CI 0.17, 0.075], P&#xa0;=&#xa0;0.003) among carriers.<br><br>DISCUSSION: Our study reveals that mild behavioral impairment symptoms may emerge before cognitive decline in ADAD and supports the MBI-C as a tool for detecting early behavioral changes linked to AD pathology and identifying at-risk individuals for clinical trials and early intervention.},
}
@article {pmid42444729,
year = {2026},
author = {Matheson, MJ and Labounek, R and Block, AD and Strong, C and Robertson, AJ and Hansen, A and Kremer, M and Petersen, AJ and Hill, A and Asken, BM and Nestrasil, I and Lenglet, C and Li, D and Henderson, JN and Mantyh, WG and , },
title = {APOE ε4 and Alzheimer's disease biomarkers in an American Indian community.},
journal = {Alzheimer's &amp; dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70421},
pmid = {42444729},
issn = {2352-8729},
abstract = {INTRODUCTION: Apolipoprotein E (APOE) ε4's effect on Alzheimer's disease (AD) depends on ancestry and environmental risk factors. The APOE ε4-AD link in American Indian (AI) populations appears attenuated, with current understanding largely informed by a single research study. This study seeks to extend this evidence in an AI population in Minnesota.<br><br>METHODS: Cross-sectional analysis of APOE &#x3b5;4, medical comorbidities, and AD plasma biomarkers with 182 tribal elders.<br><br>RESULTS: Median age was 67; 70% were female; median Mini-Mental State Examination score was 29. Age-, sex-, and chronic kidney disease-adjusted log odds ratios with 95% confidence intervals for&#xa0;APOE &#x3b5;4&#xa0;carrier status on amyloid beta 42/40, tau phosphorylated at threonine 217 (p-tau217), and glial fibrillary acidic protein (GFAP) were 0.86 (0.80 to 0.94), 1.04 (0.87 to 1.25), and 1.00 (0.86 to 1.16).<br><br>CONCLUSION: Compared to non-Hispanic White populations, APOE &#x3b5;4&#xa0;has an attenuated effect on p-tau217 or GFAP in AI tribal elders. Limitations of this study include survival bias and race-associated differences in social determinants of health that can influence the observed results.},
}
@article {pmid42444751,
year = {2026},
author = {Zivko, C and Sagar, R and Ahmed, W and Xydia, A and Farinelli, F and Ostlund, I and Das, D and Maher, BJ and Lyketsos, CG and Mahairaki, V},
title = {Heterogeneous responses to memantine in Alzheimer's disease: A precision medicine approach using iPSC models.},
journal = {Alzheimer's &amp; dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70271},
pmid = {42444751},
issn = {2352-8737},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by progressive cognitive and functional decline. Memantine, a commonly prescribed N-methyl-D-aspartate receptor antagonist, appears to slightly delay symptom progression in moderate or advanced stages of AD. Clinical response is highly variable across patients with some benefiting but others not. Induced pluripotent stem cell (iPSC)-derived neurons can provide a donor-dependent model to predict the therapeutic efficacy of memantine.<br><br>METHODS: We generated iPSC-derived cortical neurons from 19 individuals (12 AD and 7 cognitively unimpaired [CU]). Assays for calcium influx and oxidative stress were developed and optimized for neurons. Memantine was tested under different treatment conditions. Neurons were exposed to glutamate/glycine to induce calcium influx and menadione to generate oxidative stress. Memantine treatment was applied either acutely (1&#xa0;hour) or as a 24-hour pre-treatment to evaluate its neuroprotective effects.<br><br>RESULTS: Peripheral blood mononuclear cell-derived iPSCs were successfully differentiated into functional neurons, exhibiting comparable electrophysiological properties between AD and CU lines. Calcium influx assays revealed a heterogeneous response among AD and CU neurons, with AD neurons generally displaying higher baseline fluorescence. Memantine treatment for 24 hours significantly reduced calcium influx, with a -9.85% average reduction and a range of -0.39% to -39%. Similarly, reactive oxygen species assays showed menadione-induced oxidative stress was attenuated by 24-hour memantine pre-treatment for a mean -26.05% reduction and a range of -4.23% to -72.21%. The observed variability indicates differential susceptibility to excitotoxicity reduction and or oxidative stress mitigation across lines.<br><br>DISCUSSION: This exploratory study establishes a robust in vitro platform to test memantine efficacy using iPSC-derived neurons to model calcium dysregulation and oxidative stress in AD. The observed variability in response highlights the importance of personalized approaches in AD treatment, emphasizing the potential for iPSC-based platforms in precision medicine.},
}
@article {pmid42444752,
year = {2026},
author = {Ding, Z and Gibson, KA and Nascari, DG and Tallant, LE and Bouchal, SM and Dickson, DW and Fryer, JD},
title = {Anti-amyloid nanobody-Fc fusion protein drives potent amyloid clearance through microglial recruitment.},
journal = {Alzheimer's &amp; dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70269},
pmid = {42444752},
issn = {2352-8737},
abstract = {INTRODUCTION: Anti-amyloid beta (Aβ) monoclonal antibodies are effective at lowering amyloid in Alzheimer's disease (AD). However, whether Fc-mediated effector function is absolutely required for efficacy is not completely understood. This is important for optimizing therapeutic efficacy and mitigating side effects such as amyloid-related imaging abnormalities (ARIA). Antibodies lacking Fc effector function, like single-domain antibodies (nanobodies), offer a unique tool to dissect these mechanisms, as their small size facilitates blood-brain barrier (BBB) penetration and allows Fc-mediated functions to be studied independently.<br><br>METHODS: We immunized a llama with A&#x3b2; aggregates and constructed a phage display library to screen for aggregate-specific nanobodies. Lead candidates were characterized by epitope mapping and binding affinity to amyloid plaques in both murine and human AD brain tissues. We further assessed their BBB permeability and evaluated their efficacy in clearing pre-existing plaques in amyloid precursor protein (APP)/presenilin 1 (PS1) mice.<br><br>RESULTS: We identified two lead nanobodies, 3A11 and 2D10, that bind distinct epitopes and specifically bind A&#x3b2; plaques in murine and human AD brain tissues. Following systemic administration, the monovalent, unmodified (Fc-less) 2D10 nanobody, but not 3A11, successfully crossed the BBB and engaged amyloid plaques in APP/PS1 mice. However, despite robust target engagement, the Fc-less 2D10 failed to recruit microglia or reduce plaque burden. In contrast, an engineered 2D10-Fc fusion antibody potently cleared amyloid plaques, achieving a reduction in pathology comparable to aducanumab treatment. This efficacy was directly correlated with Fc-mediated microglial recruitment and activation, demonstrating that the Fc domain is essential for phagocytic plaque removal.<br><br>DISCUSSION: Our findings demonstrate that Fc effector function is indispensable for microglial-mediated amyloid clearance in vivo. By clarifying this fundamental mechanism, this study provides a framework for the rational design of next-generation immunotherapies. Furthermore, 2D10-Fc represents a promising therapeutic candidate, combining the high-affinity targeting of nanobodies with the effector power necessary for robust plaque clearance.},
}
@article {pmid42444987,
year = {2026},
author = {Quijano-Guerrero, DP and Estrada-Rodríguez, AE and Caballero-Rodríguez, M and de León-Rivera, DL and Rodríguez-Padilla, C and Valdes, VJ and Caballero-Hernández, D and Vidaltamayo, R and Martínez-Torres, AC and Zomosa-Signoret, V},
title = {The amino acid substitutions A30W, K28A, and M35C alter amyloid-β peptide toxicity in cell culture and in an in vivo model of amyloidosis in Caenorhabditis elegans.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1843210},
pmid = {42444987},
issn = {1663-4365},
abstract = {The buildup of toxic aggregates formed by the amyloid-β peptide 1-42 (Aβ42) is a central process in Alzheimer's disease (AD) pathology. The peptide's self-assembly and toxicity are highly dependent on its primary amino acid sequence and can be altered by modifying key residues. Specifically, the single amino acid substitutions A30W, K28A, and M35C can reduce the aggregation and toxicity of the Aβ42 peptide. In this study, we further evaluated the effects of these mutations in a C6 rat glioma cell line and in the Caenorhabditis elegans strains CL2006 and CL4176, which express muscular Aβ42 as an in vivo model. Our results showed that the A30W, K28A, and M35C substitutions reduce apoptosis induction in cell culture, in contrast to the WT Aβ42 peptide. In C. elegans, the three variants extended the lifespan of CL2006 worms by reducing fibrillar aggregates or altering aging, whereas the M35C peptide delayed the paralysis of CL4176 worms. Additionally, the substitutions altered oxidative stress and autophagy in control worms. Taken together, these results suggest that the A30W, K28A, and M35C substitutions reduce Aβ42 toxicity in cell culture and in C. elegans and could protect the nematode against Aβ42 toxicity.},
}
@article {pmid42445022,
year = {2026},
author = {Abdel-Rahman, SA and Gabr, M},
title = {High-Throughput CETSA Identifies Small Molecule Modulators of ILT3 (LILRB4) with Functional Activity in Human iPSC-Derived Microglia for Alzheimer's Disease.},
journal = {ACS medicinal chemistry letters},
volume = {17},
number = {7},
pages = {1647-1654},
pmid = {42445022},
issn = {1948-5875},
abstract = {Immune inhibitory signaling in microglia contributes to impaired amyloid-β (Aβ) clearance and neuroinflammation in Alzheimer's disease (AD), yet small molecule modulators targeting these pathways remain largely unexplored. Here, we report the development of a high-throughput cellular thermal shift assay (HT-CETSA) platform for identification of small molecule binders targeting the inhibitory immune receptor ILT3 (LILRB4). Screening of ∼40 000 compounds yielded multiple validated hits, including IB15C, a submicromolar ILT3 binder identified through preliminary structure-activity relationship optimization. Orthogonal validation by microscale thermophoresis, surface plasmon resonance, docking, and site-directed mutagenesis confirmed direct and target-specific ILT3 engagement. Functionally, IB15C disrupted the ILT3-ApoE interaction and restored microglial activity in human iPSC-derived microglia, reducing SHP1/2 and NF-κB signaling, suppressing IL-1β secretion, and enhancing Aβ uptake. IB15C also demonstrated favorable in vitro pharmacokinetic and safety properties, supporting further development of ILT3-targeted neuroimmune therapeutics.},
}
@article {pmid42445281,
year = {2026},
author = {Li, X and Liu, X and Sheng, H and Guo, J and Zhang, L and Fei, T and Gao, Y},
title = {Advances in research on pharmacological mechanisms of anatabine: from nicotinic modulation to multitarget therapeutic potential.},
journal = {Experimental biology and medicine (Maywood, N.J.)},
volume = {251},
number = {},
pages = {11069},
pmid = {42445281},
issn = {1535-3699},
mesh = {Humans ; *Alkaloids/pharmacology/therapeutic use ; Animals ; *Pyridines/pharmacology/therapeutic use ; *Receptors, Nicotinic/metabolism/drug effects ; Neuroprotective Agents/pharmacology ; Antioxidants/pharmacology ; Anti-Inflammatory Agents/pharmacology ; },
abstract = {Anatabine, a characteristic minor alkaloid derived from tobacco byproducts, exhibits unique structural analogy to nicotine but possesses a superior safety profile and lower addictive liability, rendering it a promising natural multi-target therapeutic candidate. Accumulating preclinical evidence has demonstrated that anatabine exerts neuroprotective, anti-inflammatory, and antioxidant effects mainly through modulating α7/α4β2 nicotinic acetylcholine receptors, suppressing NF-κB/STAT3 inflammatory signaling, and activating the Nrf2-mediated antioxidant pathway. It effectively ameliorates typical pathological alterations, including β-amyloid deposition, tau hyperphosphorylation, and microglial overactivation, thereby improving cognitive and behavioral deficits in neurodegenerative disease models. Additionally, anatabine displays broad pharmacological potentials in chronic inflammation, autoimmune thyroiditis, asthma, and hypertension. Differing from previous reviews that merely focused on single receptor regulation, the present work systematically summarizes the multi-target pharmacological characteristics of anatabine, comprehensively collates its preclinical efficacy across multiple disease categories, and highlights its advantages over nicotine in safety and addiction risk. Furthermore, we analyze the current limitations, druggability optimization challenges, and clinical translation prospects, and propose sustainable strategies for high-value utilization of tobacco byproducts. This review provides an updated and systematic theoretical basis for further mechanism exploration and therapeutic development of anatabine.},
}
@article {pmid42445345,
year = {2026},
author = {Fu, X and Niu, X and Lin, X and He, W and Liao, C and Xin, T and Li, S and Wang, SX and Liu, JQJ and Li, B and Cheng, J},
title = {Changes in cortical plasticity induced by paired associative stimulation in people with mild cognitive impairment and Alzheimer's disease: a systematic review and meta-analysis.},
journal = {Frontiers in neural circuits},
volume = {20},
number = {},
pages = {1853684},
pmid = {42445345},
issn = {1662-5110},
mesh = {Humans ; *Alzheimer Disease/physiopathology/therapy ; *Cognitive Dysfunction/physiopathology/therapy ; *Neuronal Plasticity/physiology ; *Transcranial Magnetic Stimulation/methods ; Evoked Potentials, Motor/physiology ; Motor Cortex/physiopathology ; },
abstract = {BACKGROUND: Paired associative stimulation (PAS) is a non-invasive neuromodulation paradigm capable of inducing long-term potentiation (LTP)- or long-term depression (LTD)-like plasticity. It has been used to probe neuroplasticity and corticospinal excitability alterations in Alzheimer's disease (AD) and mild cognitive impairment (MCI). However, existing studies report inconsistent directions and magnitudes of PAS-induced plasticity changes across the AD continuum.<br><br>METHODS: We searched PubMed, Web of Science, Embase, and the Cochrane Library from database inception to December 2025. Eligible studies were case-control studies and randomized controlled trials (RCTs) that assessed PAS-induced cortical plasticity in individuals with AD or MCI, with healthy older adults as controls. Study quality was evaluated using the Newcastle-Ottawa Scale (NOS) for non-randomized studies and the Cochrane Risk of Bias tool (RoB 2) for RCTs. This review was registered in PROSPERO (CRD420251178441).<br><br>RESULTS: Five studies met the inclusion criteria. Four studies quantified motor cortical plasticity using changes in motor-evoked potential (MEP) amplitude (total N&#x202f;=&#x202f;135; 64 MCI/AD and 71 controls). The pooled analysis showed no significant difference in PAS-induced MEP changes between participants with MCI/AD and healthy controls [mean difference (MD)&#x202f;=&#x202f;0.06, 95% CI (-0.05, 0.17), p&#x202f;=&#x202f;0.32]. This pooled estimate was restricted to MEP-based outcomes and should be interpreted as an exploratory synthesis of motor-system readouts rather than definitive evidence of preserved cortical plasticity in MCI or AD. The remaining RCT, which assessed dorsolateral prefrontal cortex (DLPFC) plasticity using a repetitive PAS (rPAS) intervention without MEP outcomes, also found no significant improvement in prefrontal plasticity relative to control stimulation.<br><br>CONCLUSION: Based on the currently available MEP-based evidence, PAS-induced motor-system plasticity findings in individuals with MCI or AD remain inconclusive. Given the limited number of studies and heterogeneity in experimental designs, the pooled negative results should not be interpreted as evidence that cortical plasticity is preserved. Corticospinal hyperexcitability and network-level PAS findings should be regarded as preliminary, hypothesis-generating observations requiring validation in larger, longitudinal, and biomarker-characterized cohorts.},
}
@article {pmid42445350,
year = {2026},
author = {Kasai, T and Akazawa, K and Kitani-Morii, F and Naeshiro, Y and Suo, H and Fujino, Y and Yoshida, M and Shimizu, T and Sakai, K and Watanabe, K and Mizuta, I and Ohara, T},
title = {Enlarged Centrum Semiovale Perivascular Spaces as a Noninvasive Imaging Marker of Vascular Amyloid Deposition in Amyloid-Positive Individuals without Cerebral Amyloid Angiopathy-Related Hemorrhages.},
journal = {Dementia and geriatric cognitive disorders extra},
volume = {16},
number = {1},
pages = {85-94},
pmid = {42445350},
issn = {1664-5464},
abstract = {INTRODUCTION: Anti-amyloid therapy has increased the need for noninvasive methods to assess vascular amyloid. Reductions in cerebrospinal fluid (CSF) Aβ40 and Aβ42 are characteristic of cerebral amyloid angiopathy (CAA), but lumbar puncture limits their use in routine practice. Magnetic resonance imaging-visible perivascular spaces in the centrum semiovale (CSO-PVS) have emerged as a potential imaging marker, although their relevance in amyloid-positive individuals without CAA-related hemorrhages remains uncertain.<br><br>METHODS: We retrospectively analyzed 30 patients with mild cognitive impairment due to Alzheimer's disease (AD) or mild AD who exhibited reduced CSF A&#x3b2;42/40 ratio and no CAA-related hemorrhagic findings. CSO-PVS were visually quantified and dichotomized into high- and low-degree groups using the median raw count. CSF A&#x3b2;40, A&#x3b2;42, and p-tau181 levels were compared between groups.<br><br>RESULTS: Patients with high-degree CSO-PVS demonstrated significantly lower CSF A&#x3b2;40 levels than those with low-degree CSO-PVS (p = 0.0235), while CSF A&#x3b2;42 showed a borderline reduction (p = 0.0502). The composite index A&#x3b2;40 &#xd7; A&#x3b2;42 was also reduced in the high-degree group (p = 0.0264). CSF p-tau181 levels were significantly lower in the high-degree group than in the low-degree group (p = 0.0264).<br><br>CONCLUSION: A higher CSO-PVS burden was associated with lower CSF A&#x3b2;40 and A&#x3b2;42 levels, suggesting that CSO-PVS dilation may serve as a noninvasive surrogate marker of vascular amyloid deposition in amyloid-positive patients undergoing anti-amyloid therapy.},
}
@article {pmid42445718,
year = {2026},
author = {Kang, L and Salas-Hernandez, JL and Xu, R},
title = {Central neural circuits and their associated mechanisms of inter-organ crosstalk.},
journal = {Frontiers in cell and developmental biology},
volume = {14},
number = {},
pages = {1830768},
pmid = {42445718},
issn = {2296-634X},
abstract = {The central nervous system (CNS), which comprises the brain and spinal cord, serves as the core regulatory hub for maintaining homeostasis and coordinating diverse physiological functions. These functions include interoception, cognition, and social behavior. The intricate architecture and extensive connectivity of the CNS enable integration of multi-system responses, thereby ensuring bodily stability and adaptability. The CNS exerts profound regulatory influences on fundamental life-sustaining processes and higher-order cognitive and social functions. This is mediated by distinct neural circuits and molecular mechanisms. CNS dysfunction is strongly associated with the pathogenesis of neurological disorders (Alzheimer's disease, Parkinson's disease, stroke and epilepsy), metabolic diseases (obesity and diabetes), and cardiovascular conditions (hypertension and atherosclerosis). Given the pivotal role of the CNS in both physiological regulation and disease progression, a comprehensive understanding of CNS mechanisms is critical for identifying therapeutic targets. This review systematically examines the regulatory functions of the CNS in physiology and disease. Moreover, this review analyzes the underlying molecular and circuit-level mechanisms, and discusses potential therapeutic strategies. By elucidating the systemic interactions of the CNS, this study aims to highlight its potential as a target for innovative interventions in disease prevention, diagnosis, and treatment.},
}
@article {pmid42445988,
year = {2026},
author = {Delaney, HJ and Islam, S and Healy, D and Oglesby, R and Konda, M and Rietman, GM and Lynch, R and Nazmi, A and Murray, JT and Cunningham, MO and Cunningham, C},
title = {CSF1R inhibition exacerbates gamma oscillation disruption and induces network hyperexcitability in APP/PS1 mice.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag147},
pmid = {42445988},
issn = {1460-2156},
abstract = {Alzheimer's Disease is the most common neurodegenerative disease worldwide, but significant gaps in pathophysiological understanding have hampered development of disease-modifying therapies. In Alzheimer's disease, neurophysiological function is impaired, with gamma frequency oscillations - thought to be essential for higher-order cognitive processes - disrupted in both patients and animal models. However, the mechanisms driving these disruptions are unclear and, in particular, the role of neuroinflammation in these changes is poorly understood. In this study, we investigated neuronal network dynamics in acute brain slices from APP/PS1 transgenic mice. Gamma frequency oscillations had significantly reduced amplitude in APP/PS1 brain slices at 9-11 months, accompanied by an increase in beta frequency power and heightened epileptiform activity. This is suggestive of a slowing in neuronal oscillations, considered a neurophysiological hallmark of Alzheimer's disease. Immunohistochemical analysis revealed a reduction in parvalbumin- and somatostatin-positive inhibitory interneuron populations. Treatment with gabazine demonstrated increased network sensitivity to GABAA receptor antagonism, further indicating compromised inhibitory control in APP/PS1. As these altered oscillatory dynamics correlated with microglial reactivity, we hypothesised a causal role for microglia. Administration of the CSF1R inhibitor GW2580 reduced microglial proliferation, attenuated development of the disease-associated microglial phenotype and partially rescued synaptic loss; but, had no significant impact on amyloid plaque burden or cognitive deficits. Unexpectedly, GW2580 treatment exacerbated neuronal network hyperactivity and the incidence and complexity of epileptiform activity. Microglia in GW2580-treated mice showed reduced CD68 expression and decreased engulfment of synaptic elements, potentially facilitating the persistence of hyperexcitable synapses. These findings support a role of microglia in regulating neuronal network homeostasis and caution against indiscriminate suppression of microglial activity in Alzheimer's disease. Therapeutic strategies targeting microglia must account for their homeostatic functions to avoid adverse effects on neuronal network stability.},
}
@article {pmid42446082,
year = {2026},
author = {Montes-Martinez, M and Welter, LS and Boon, P and Bassetti, CLA and Berger, T and Deuschl, G and Moro, E and Kruse, C and Lolich, M and Konti, M and Arvandi, M and Mühlberger, N and Engelborghs, S and Jessen, F and Saleh, Y and Di Lorenzo, F and Filippi, M and Georges, J and Bougea, A and Siebert, U and Lindgren, P and Dodel, R},
title = {The economic burden of dementia in Europe: COIN-Eu dementia.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261465575},
doi = {10.1177/13872877261465575},
pmid = {42446082},
issn = {1875-8908},
abstract = {BackgroundDementia, with Alzheimer's disease as its most common underlying cause, is a major contributor to disability, dependency, and death, imposing significant societal and economic burdens across Europe. Despite its growing prevalence, cross-country cost estimates remain scarce and highly heterogeneous, limiting comparability.ObjectiveTo estimate country-level societal costs of dementia in Europe and to derive aggregate European cost estimates, including direct costs, indirect costs (productivity losses), and informal care costs.MethodsA standardized review of dementia cost assessments conducted in Europe was performed. Heterogeneous cost-estimation approaches were harmonized using pooling and health-economic imputation techniques to address data gaps and generate country-level estimates. All cost estimates were converted to 2019 euros using Consumer Price Indices and Purchasing Power Parities (PPP). Informal care costs were analyzed separately to reflect their complexity and substantial contribution to total costs.ResultsForty-five studies were identified. Annual societal costs of dementia in high-income European countries totaled €221.4 billion (€PPP, 2019; €25,218 per patient) for 8.8 million people with dementia. Informal care and direct costs accounted for 58% and 42% of total costs, respectively. Indirect costs contributed minimally to total costs. Substantial variation in per patient costs across countries was observed.ConclusionsDementia care imposes substantial societal burdens, largely driven by informal care. Owing to data availability, estimates were limited to high-income European countries. Future research should focus on standardizing cost assessment methods, improving informal care valuation, expanding evidence from low- and middle-income countries, and evaluating the financial impact of emerging treatments and prevention strategies.},
}
@article {pmid42446245,
year = {2026},
author = {Froud, SA and Levett, BA and Jiang, J and Core, LB and Koohi, N and Tutton, M and Green, T and Bamiou, DE and Marshall, CR and Hardy, CJD and Warren, JD},
title = {Speech-In-Noise Perception in Alzheimer's Disease and Primary Progressive Aphasia.},
journal = {European journal of neurology},
volume = {33},
number = {7},
pages = {e70701},
doi = {10.1111/ene.70701},
pmid = {42446245},
issn = {1468-1331},
support = {AS-PG-16-007/ALZS_/Alzheimer's Society/United Kingdom ; 627/ALZS_/Alzheimer's Society/United Kingdom ; G105//Royal National Institute for Deaf People/ ; PA23_Hardy//Royal National Institute for Deaf People/ ; NIHR204280//National Institute for Health and Care Research/ ; NIHR302201//National Institute for Health and Care Research/ ; //The National Brain Appeal (Frontotemporal Dementia Research Studentship in Memory of David Blechner)/ ; },
mesh = {Humans ; *Aphasia, Primary Progressive/physiopathology/pathology/complications/diagnostic imaging ; Female ; Male ; Aged ; *Alzheimer Disease/physiopathology/pathology/complications/diagnostic imaging ; *Speech Perception/physiology ; Magnetic Resonance Imaging ; *Noise ; Middle Aged ; Brain/pathology/diagnostic imaging ; Neuropsychological Tests ; },
abstract = {BACKGROUND: Understanding speech despite background noise is essential for everyday communication, but makes heavy neural processing demands. It is therefore potentially vulnerable to neurodegenerative diseases, particularly those led by communication deficits (primary progressive aphasia). However, how speech-in-noise perception is affected in these diseases is poorly understood.<br><br>METHODS: Here we addressed this in 59 patients representing typical Alzheimer's disease and canonical logopenic, nonfluent/agrammatic and semantic variant syndromes of primary progressive aphasia, compared with 24 cognitively-well, older controls. We administered a digit triplet test of speech-in-noise perception based on the task used in the UK Biobank study, alongside pure tone audiometry and a general neuropsychological assessment. Voxel-based morphometry of patients' brain MRI scans was used to identify structural neuroanatomical associations of speech-in-noise perception.<br><br>RESULTS: After adjusting for age, peripheral hearing and general cognitive function, the Alzheimer's, logopenic and nonfluent primary progressive aphasia groups performed significantly worse on speech-in-noise perception than controls. The nonfluent primary progressive aphasia and Alzheimer groups additionally had significantly worse peripheral hearing function than controls. Speech-in-noise perceptual performance correlated with grey matter atrophy in the right supramarginal gyrus.<br><br>CONCLUSION: Profiles of central (brain) and peripheral hearing impairment stratify major dementias, with implications for diagnosis and development of interventions to improve real-world communication in people living with dementia.},
}
@article {pmid42446257,
year = {2026},
author = {Buneeva, OA and Fedchenko, VI and Kaloshina, SA and Kaloshin, AA and Zgoda, VG and Medvedev, AE},
title = {Interaction of renalase and its peptides RP211-223 and RP224-232 with the mitochondrial fraction of rat brain: a link to neurodegeneration?.},
journal = {Biomeditsinskaia khimiia},
volume = {72},
number = {3},
pages = {220-229},
doi = {10.18097/PBMCR1704},
pmid = {42446257},
issn = {2310-6972},
mesh = {Animals ; *Mitochondria/metabolism ; Rats ; *Brain/metabolism ; *Peptide Fragments/metabolism/chemistry ; *Monoamine Oxidase/metabolism/chemistry ; *Peptides/metabolism/chemistry ; Male ; Protein Binding ; *Neurodegenerative Diseases/metabolism ; Proteomics ; },
abstract = {Renalase (RNLS) is a protein exhibiting various functions inside and outside cells. A series of synthetic peptides, corresponding to the fragments of the RNLS amino acid sequence, may reproduce the effects of the full-length RNLS. In this study we have investigated the interaction of proteins in the mitochondrial brain fraction of rats with the full-length RNLS and its peptides RP211-223 (peptide 1) and RP224-232 (peptide 2) immobilized on CNBr-activated Sepharose. Proteomic profiles of proteins bound to the full-length RNLS and its peptide RP211-223 were significantly different, whereas RP224-232 bound a small number of proteins (6), similar to those bound to the full-length RNLS. However, most proteins bound to RNLS and its peptides were multifunctional and associated with neurodegenerative pathology (Alzheimer's and Parkinson's diseases, etc.).},
}
@article {pmid42446473,
year = {2026},
author = {Tian, M and Ye, K and Chen, X and Liu, L and Han, X and Zheng, T and Gao, X and Xia, Q and Li, F and Wang, D},
title = {Multilayer Proteome and Metabolome-Based Validation Uncovers Combined Regulatory Roles and Predictive Values of 6 RNA Modifications and Cellular Senescence in Alzheimer's Disease.},
journal = {CNS neuroscience &amp; therapeutics},
volume = {32},
number = {7},
pages = {e71021},
doi = {10.1002/cns.71021},
pmid = {42446473},
issn = {1755-5949},
mesh = {Humans ; *Alzheimer Disease/metabolism/genetics/diagnosis ; *Cellular Senescence/physiology ; *Proteome/metabolism/genetics ; *Metabolome/physiology ; Machine Learning ; Brain/metabolism ; Proteomics/methods ; Male ; Female ; Predictive Value of Tests ; },
abstract = {AIMS: Existing studies have revealed that RNA modification regulators and cellular senescence can affect the Alzheimer's disease (AD) process. This study investigated the synergistic mechanism in the brains of AD.<br><br>METHODS: Based on brain tissue proteomics of patients with AD, we screened out the subtypes of patients that are coordinately regulated by cellular senescence-related proteins and RNA modification regulators. Transcriptome datasets were used to validate and evaluate 20 hub proteins identified using 100 integrated machine learning algorithms. Finally, protein and metabolic data were employed to explore the characteristics of metabolic subtypes and pathways in AD progression.<br><br>RESULTS: The diagnostic model had good diagnostic performance, as revealed by the average area under the receiver operating characteristic curve (AUC)&#x2009;=&#x2009;0.885 of the internal datasets and the average AUC&#x2009;=&#x2009;0.89 of transcriptome datasets. Risk score can be used to assess disease progression and the corresponding changes in metabolic characteristics. Finally, metabolic analysis indicates significant abnormalities in amino acid and lipid metabolism during the progression of AD.<br><br>CONCLUSION: We revealed the potential role of RNA modification regulators and cellular senescence-related proteins in AD pathogenesis and related diagnostic markers through proteomic analysis and machine learning-based methods.},
}
@article {pmid42446545,
year = {2026},
author = {Zhou, XW and Zhang, CY and Liu, Q and Wang, YX and Qin, SH and Ma, ZY},
title = {Design, synthesis, biological evaluation, and computational studies of N-benzoylethylenediamine derivatives as cholinesterase inhibitors.},
journal = {Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents},
volume = {},
number = {},
pages = {},
pmid = {42446545},
issn = {1554-8120},
support = {H2024201041//S&amp;T Program of Hebei/ ; },
abstract = {In this study, a series of N-benzoylethylenediamine derivatives (16a-16u) was rationally designed and successfully synthesized using a strategy that combines cholinesterase (ChE) inhibition with antioxidant activity. The inhibitory activities of all compounds against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), along with their antioxidant capacity, were systematically evaluated in vitro. Most compounds exhibited moderate to potent inhibition against both enzymes. Notably, compound 16 L showed the best dual inhibitory activity, with IC50 values of 1.71 µM for AChE and 2.38 µM for BuChE, both superior to those of the reference drug, galantamine. (AChE: IC50 = 5.17 µM, BuChE: IC50 = 11.06 µM). Furthermore, the DPPH radical scavenging assay indicated that compound 16a exhibited the strongest antioxidant activity (IC50 = 27.69 µM), which was slightly stronger than that of the positive control ascorbic acid (IC50 = 32.59 µM). Enzyme kinetic studies revealed that compound 16 L acts as a mixed-type inhibitor of AChE. Molecular docking results further demonstrated that 16 L interacts with both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE, consistent with the kinetic data; however, for BuChE, 16 L interacts only with the CAS. Molecular dynamics (MD) simulations confirmed the stability of the 16 L-AChE/BuChE complexes. Collectively, these findings validate compound 16 L's research value as a dual inhibitor of AChE and BuChE.},
}
@article {pmid42446550,
year = {2026},
author = {Zhou, XW and Wang, YX and Du, WR and Zhang, CY and Qin, SH and Ma, ZY},
title = {Design, synthesis, biological evaluation, and computational studies of chalcone scaffolds as cholinesterase inhibitors.},
journal = {Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents},
volume = {35},
number = {5},
pages = {903-918},
pmid = {42446550},
issn = {1554-8120},
support = {H2024201041//Hebei Natural Science Foundation/ ; },
mesh = {*Cholinesterase Inhibitors/chemical synthesis/chemistry/pharmacology ; Butyrylcholinesterase/metabolism/chemistry ; Acetylcholinesterase/metabolism/chemistry ; *Drug Design ; Molecular Docking Simulation ; Structure-Activity Relationship ; Antioxidants/chemistry/pharmacology/chemical synthesis ; Animals ; Biphenyl Compounds/antagonists &amp; inhibitors ; *Chalcone/chemistry/pharmacology/chemical synthesis ; Molecular Structure ; Kinetics ; Picrates/antagonists &amp; inhibitors ; },
abstract = {A series of chalcone derivatives (8a-8v) was designed and synthesized, and their inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were evaluated. The inhibitory activities of AChE and BuChE were measured using the Ellman method. The results showed that most compounds exhibited moderate to weak inhibitory activity against both AChE and BuChE. Among them, compound 8g displayed potent AChE inhibitory activity with an IC50 of 2.59 μM and moderate BuChE inhibitory activity with an IC50 of 8.89 μM. The inhibitory effects of compound 8g on both enzymes surpassed those of the positive control, galantamine. Next, the antioxidant activity of these compounds was assessed using the DPPH (2,2-diphenyl-1-picrylhydrazyl) radical scavenging assay, revealing that compound 8j had the strongest antioxidant activity, with an IC50 of 65.84 μM, while the others showed weak antioxidant activity. Enzyme kinetic studies confirmed that compound 8g acts as a mixed-type inhibitor. Molecular docking indicated that compound 8g interacts with both the catalytic active site (CAS) and peripheral anion site (PAS) of AChE. Molecular dynamics (MD) simulations verified the stability of the 8g-AChE/BuChE complex. Overall, these experimental results suggest that the designed and synthesized cholinesterase inhibitor (ChEI) 8g has potential for further development.},
}
@article {pmid42446696,
year = {2026},
author = {Kanwal, A and Rasool, N},
title = {4-methylbenzyl 5-arylthiophene-2-carboxylates as Multitarget Directed Ligands Scaffolds (MTDLs): Synthesis, in-silico docking studies, and evaluation of dual selective enzymatic inhibition (AChE &amp; MAO-B).},
journal = {Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents},
volume = {35},
number = {2},
pages = {425-436},
pmid = {42446696},
issn = {1554-8120},
mesh = {*Monoamine Oxidase/metabolism/chemistry ; *Monoamine Oxidase Inhibitors/chemical synthesis/chemistry/pharmacology ; *Cholinesterase Inhibitors/chemical synthesis/chemistry/pharmacology ; Ligands ; *Molecular Docking Simulation ; *Thiophenes/chemistry/pharmacology/chemical synthesis ; *Acetylcholinesterase/metabolism/chemistry ; *Carboxylic Acids/chemistry/pharmacology/chemical synthesis ; Structure-Activity Relationship ; Humans ; },
abstract = {Single-target ligands have insufficient effectiveness in treating Alzheimer's disease (AD), leading to the development of new pharmacological strategies, particularly multi-target-directed ligands (MTDLs) that tackle the multifactorial nature of the impairment. Among these, dual inhibition of acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B) represents a promising approach for enhancing therapeutic outcomes. Here, analogs of 4-methylbenzyl 5-arylthiophene-2-carboxylates (5a-5h) were identified as dual inhibitors of AChE and MAO-B. In vitro evaluations demonstrated that 5a-5d exhibited the most promising inhibition potential towards targeted enzymes (AChE and MAO-B), having IC50 values 0.72 ± 0.01 µM to 1.69 ± 0.04 µM for AChE and 0.19 ± 0.03 µM to 2.69 ± 0.10 µM for MAO-B. Docking analysis is consistent with the in vitro studies, critically unveiling bindings, commonly hydrogen interactions, π-Sulphur, π-π interaction, π-alkyl, and alkyl-alkyl ligand and enzyme binding interactions. These results underscore the promise of these dual inhibitors in tackling the complex pathology of AD.},
}
@article {pmid42446728,
year = {2026},
author = {Tak, C and Bhujbal, SP and Hah, JM},
title = {Protein kinases as therapeutic targets in Alzheimer's disease: challenges, insights, and new frontiers.},
journal = {Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents},
volume = {35},
number = {4},
pages = {726-756},
pmid = {42446728},
issn = {1554-8120},
support = {NRF-RS-2020-NR049583 (Center for Proteinopathy)//National Research Foundation of Korea grant/ ; NRF-RS-2024-00333784 (J.-M.H.)//National Research Foundation of Korea/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism/enzymology ; *Protein Kinases/metabolism ; *Protein Kinase Inhibitors/pharmacology/chemistry/therapeutic use ; Animals ; tau Proteins/metabolism ; Molecular Targeted Therapy ; },
abstract = {Alzheimer's disease (AD) remains the leading cause of dementia worldwide, imposing an enormous and growing societal burden with more than 55 million people affected globally. Despite decades of intensive investigation, existing therapeutic options provide only modest symptomatic relief and fail to prevent or slow disease progression, emphasizing the critical need for interventions that target the fundamental molecular mechanisms of neurodegeneration. Pathologically, Alzheimer's disease is characterized by extracellular accumulation of amyloid-β plaques, intracellular neurofibrillary tangles formed by hyperphosphorylated tau, profound synaptic loss, chronic neuroinflammation, and extensive neuronal degeneration. Although amyloid-focused strategies have long dominated drug development, their limited clinical benefit and safety liabilities highlight the multifactorial nature of AD and the need to move beyond amyloid-centric paradigms. Protein kinases have emerged as key integrators of multiple pathogenic processes in AD, governing tau phosphorylation, amyloid precursor protein processing, synaptic signaling, and neuroimmune responses. Aberrant kinase signaling drives tau pathology and propagation, promotes amyloidogenic pathways, disrupts synaptic function, and perpetuates inflammatory cascades. While extensive work on kinases such as GSK-3β, CDK5, JNKs, and CSF1R has firmly established the relevance of kinase dysregulation in AD, no kinase-directed therapy has yet translated into clinical success. This review highlights emerging kinase targets beyond these classical pathways, including Fyn, Casein Kinase 1 Delta (CK1δ), Tau-Tubulin Kinase 1 (TTBK1), and Dual Leucine Zipper Kinase (DLK), which are supported by mechanistic insights and compelling preclinical evidence. Continued advances in brain-penetrant, isoform-selective, and mechanism-driven kinase inhibitor design may enable the development of next-generation disease-modifying therapies for Alzheimer's disease.},
}
@article {pmid42446837,
year = {2026},
author = {Hsu, CY and Raval, AD and Bainsal, N and Kaur, I and Baig, MR and Turakulov, R and Sapaev, I and Hjazi, A and Alghazali, T and Smerat, A},
title = {Molecular Regulation of Pyroptosis in Alzheimer's Disease: Linking Neuroinflammation, Cell Death, and Therapeutic Targeting.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42446837},
issn = {1559-1182},
mesh = {Humans ; *Pyroptosis/physiology/drug effects ; *Alzheimer Disease/pathology/metabolism/therapy ; Animals ; *Neuroinflammatory Diseases/pathology/metabolism ; *Cell Death/physiology ; *Molecular Targeted Therapy ; Inflammasomes/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by profound cognitive decline, wherein chronic neuroinflammation plays a pivotal pathogenic role. Central to this inflammatory milieu is pyroptosis, a highly inflammatory form of programmed lytic cell death mediated by gasdermin proteins. This comprehensive review provides an in-depth synthesis of the cellular and molecular mechanisms underlying pyroptosis in AD. We detail the distinct roles of microglia as primary initiators responding to amyloid-beta (Aβ) and tau aggregates, alongside the specific vulnerabilities of neurons facing oxidative stress, astrocytes impacting metabolic support, and endothelial cells whose pyroptotic death contributes directly to blood-brain barrier disruption. At the molecular level, the priming and activation of the NLRP3 and NLRP1 inflammasomes by diverse triggers, including classical markers like Aβ, environmental neurotoxicants and metabolic stressors, converge on caspase-1 and caspase-8 activation. This cascade culminates in gasdermin D (GSDMD) and gasdermin E (GSDME) pore formation, leading to cellular lysis and the massive release of pro-inflammatory cytokines such as IL-1β and IL-18. Furthermore, this paper explores the emerging and critical concept of PANoptosis, highlighting the intricate crosstalk between pyroptosis, apoptosis, and necroptosis within PANoptosome complexes triggered by mitochondrial dysfunction. We evaluate current and prospective therapeutic strategies, ranging from multi-target natural and traditional herbal remedies to advanced nanomedicine, synthetic small molecules, and epigenetic gene therapies. By integrating insights from blood-based pyroptosis-associated molecular signatures and advanced targeted drug delivery systems, we emphasize the critical need for personalized, multi-targeted approaches to successfully harness pyroptosis modulation in the clinical management and treatment of AD.},
}
@article {pmid42446869,
year = {2026},
author = {de Souza, MRM and Lindner, MR and Mladinich-Valenti, M and Gorbunova, EE and Kirillov, V and Byrne, AG and Laird, AY and Finnerty, CE and Ikeda, P and Vorkas, CK and Kaur, R and Gomes, YCP and Chatel-Chaix, L and Kim, HK and Mackow, ER},
title = {Single-cell analysis of Powassan virus-infected brains reveals age-dependent neuroinflammatory crosstalk and progressive Alzheimer's-like APP/Aβ accumulation.},
journal = {mBio},
volume = {},
number = {},
pages = {e0129426},
doi = {10.1128/mbio.01294-26},
pmid = {42446869},
issn = {2150-7511},
abstract = {Powassan virus (POWV) causes lethal encephalitis in the elderly and long-term neurological sequelae in survivors. Mirroring human disease, POWV strain LI9 directs age-dependent lethality in C57BL/6 (B6) mice, resulting in spongiform encephalitis, gliosis, and inflammatory cytokine/chemokine responses in the CNS. However, the mechanisms underlying age-dependent lethality and persistent neurodegenerative disease in POWV survivors remain to be resolved. Here, we analyzed cellular CNS responses to POWV LI9 infection in young (10-week-old) and aged (50-week-old) mice using single-cell RNA sequencing. Infection of young mice resulted in inflammatory CNS infiltrates (NK, CD4/CD8 T cells, and monocytes) and interferon responses that coincide with peak viral burden. In contrast, the CNS of aged infected mice instead featured upregulated astrocyte and neuronal genes associated with neurodegenerative and Alzheimer's disease pathways and the transition of homeostatic microglia to a Trem2-ApoE-linked disease-associated microglial transcriptional state. Histological analysis revealed that amyloid precursor protein (APP)/amyloid-β (Aβ) accumulated in the CNS following POWV infection and that POWV envelope protein and APP/Aβ were selectively localized within layers L5/L6 of the cerebral cortex. POWV kinetically increased perinuclear APP/Aβ accumulation during acute infection and was highly expressed in the CNS of POWV survivors. Our findings reveal that POWV triggers glial cell responses and a neurodegenerative disease-associated microglia program of Alzheimer's-like APP/Aβ accumulation in mice, which is consistent with long-term neurological sequelae in human POWV survivors.IMPORTANCEPowassan virus (POWV) causes lethal encephalitis and long-term cognitive deficits in survivors. Using an age-dependent murine model, we reveal that POWV-infected young mice direct robust CNS inflammatory infiltrates associated with viral clearance, whereas aged mice exhibit impaired immune responses and a shift from homeostatic to neurodegenerative glial cell states. POWV prompted the induction of disease-associated microglia (DAM) and Trem2-ApoE axis transcriptional responses that are hallmarks of APP/amyloid-β (Aβ) accumulation in Alzheimer's disease (AD). Remarkably, POWV induced progressive APP/Aβ accumulation in young and aged mice that persisted in survivors after viral clearance. This suggests that POWV induces an APP/Aβ neurodegenerative process and provides a potential cause of long-term neurological sequelae observed in human POWV survivors. Our data suggest that POWV initiates or exacerbates AD-like neuropathology and further rationalizes investigating the role of APP/Aβ responses in other encephalitic viruses.},
}
@article {pmid42446988,
year = {2026},
author = {Khursheed, A and Shang, Q and Zhang, H and Tian, Y and Szwedziak, P and Volkov, VA and Viles, JH},
title = {3D nanoscale imaging of amyloid-β oligomer interactions with extracellular vesicles by cryo-ET.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {123},
number = {29},
pages = {e2610068123},
doi = {10.1073/pnas.2610068123},
pmid = {42446988},
issn = {1091-6490},
support = {BB/Y001931/1//UKRI | Biotechnology and Biological Sciences Research Council (AFRC)/ ; BB/Y001931/1//UKRI | Biotechnology and Biological Sciences Research Council (AFRC)/ ; BB/Y001931/1//UKRI | Biotechnology and Biological Sciences Research Council (AFRC)/ ; 32501123//MOST | National Natural Science Foundation of China (NSFC)/ ; },
mesh = {*Amyloid beta-Peptides/metabolism/chemistry ; Humans ; *Extracellular Vesicles/metabolism/ultrastructure ; Cryoelectron Microscopy/methods ; Alzheimer Disease/metabolism/pathology ; *Imaging, Three-Dimensional/methods ; Cell Membrane/metabolism ; Electron Microscope Tomography/methods ; Animals ; Lipid Bilayers/metabolism ; },
abstract = {Central to Alzheimer's disease pathology are prefibrillar oligomer assemblies of amyloid-β (Aβ) peptide. A widely discussed hypothesis proposes that amyloid-β oligomers insert into neuronal lipid membranes, disrupting their integrity and causing a loss of cellular homeostasis in Alzheimer's disease. This membrane disruption is believed to be a major source of Aβ-induced neurotoxicity. Cryo electron tomography (cryo-ET) has facilitated 3D nanoscale imaging of Aβ-membrane interactions under near-native conditions. Analyses of small extracellular vesicles (sEVs) reveals that Aβ oligomers including annular and curvilinear extended oligomers (CLEOs) exhibit extensive binding to cell-derived lipid membranes, including insertion into and carpeting of the lipid bilayer. Notably, these oligomeric assemblies were also internalized and concentrated within the cell-derived exosomes and other small sEVs. Enrichment of Aβ oligomers within the vesicles typically ranged between 5 to 20 times the external Aβ levels depending on the vesicle size and curvature. In contrast, monomeric and fibrillar forms of Aβ displayed minimal membrane interaction. Once internalized CLEOs appear to be trapped in an oligomeric form and do not readily go on to form fibrils. Studies with vesicles of brain lipid extract indicate the Aβ internalization does not require the presence of a membrane protein. Our in vitro studies underscore the membrane-disruptive capacity of oligomeric Aβ species and suggest a role of sEVs in concentrating toxic Aβ oligomers and transporting oligomers across the brain interstitium.},
}
@article {pmid42446992,
year = {2026},
author = {Wong, DYK and Fu, WY and Uhm, H and Jiang, Y and Yip, YCC and Mok, VCT and Kwok, TCY and Ouyang, L and Fu, AKY and Ip, NY},
title = {Repurposing trazodone for Alzheimer's disease to modulate soluble ST2 levels and alleviate Alzheimer's pathology.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {123},
number = {29},
pages = {e2536489123},
doi = {10.1073/pnas.2536489123},
pmid = {42446992},
issn = {1091-6490},
support = {the Theme-Based Research Scheme [T13-605/18 W] the General Research Fund HKUST16104624 HKUST16102824//the Research Grants Council of Hong Kong/ ; AoE/M-604/16//the Areas of Excellence Scheme of the University Grants Committee/ ; NA//the InnoHK initiative of the Innovation and Technology Commission of the Hong Kong Special Administrative Region Government/ ; Joint Laboratory Funding Scheme [JLFS/M-604/24]//the SIAT-HKUST Joint Laboratory for Brain Science/ ; 2023B1212120004//the Guangdong-Hong Kong Joint Laboratory for Psychiatric Disorders/ ; ITCPD/17-9//the Innovation and Technology Fund for State Key Laboratory/ ; },
mesh = {*Alzheimer Disease/drug therapy/pathology/metabolism ; Animals ; *Drug Repositioning ; Humans ; Mice ; *Trazodone/pharmacology/therapeutic use ; Microglia/metabolism/drug effects/pathology ; *Interleukin-1 Receptor-Like 1 Protein/metabolism/genetics ; Amyloid beta-Peptides/metabolism ; Mice, Transgenic ; Amyloid beta-Protein Precursor/genetics ; Male ; Female ; Disease Models, Animal ; },
abstract = {Alzheimer's disease (AD) is a multifactorial disorder involving various pathological mechanisms, such as amyloidosis, immune dysfunctions, and synaptic impairments, which are important therapeutic targets. Repurposing drugs to target these mechanisms offers a promising approach to reduce the costs and duration of drug development. Genetic studies underscore the critical role of microglial clearance of amyloid-beta (Aβ) in AD pathogenesis. Specifically, soluble ST2 (sST2)-one of the two major isoforms of the ST2 protein encoded by the IL1RL1 (interleukin-1 receptor-like 1) gene-acts as a decoy receptor isoform that interferes with IL-33/ST2 signaling and has been identified as a disease-modifying factor that impairs microglial Aβ clearance functions. In this study, we investigated drug repurposing opportunities to modulate sST2 levels and alleviate AD pathologies. Unbiased screening of commonly used medications in AD patients, followed by validation in model systems, identified trazodone-an antidepressant used to treat major depressive disorder-as a leading negative regulator of sST2. Trazodone primarily suppresses sST2 expression through its antagonistic effects on adrenergic signaling. In the APP/PS1 transgenic mouse model of AD, trazodone treatment enhanced microglial interaction with Aβ and alleviated Aβ pathology. Furthermore, trazodone reduced neurodegeneration and rescued synaptic deficits in APP/PS1 mice. Comprehensive molecular profiling of APP/PS1 mouse brains showed that trazodone restored the expression of synaptic proteins critical for synaptic integrity and plasticity. Overall, these findings demonstrate that trazodone is a promising repurposing candidate for AD that targets underlying immune dysfunctions and synaptic impairment.},
}
@article {pmid42447006,
year = {2026},
author = {Calis, M and Altuntas, V and Kahveci, T},
title = {MOSAIC: MOtif Set with mAximal InfluenCe on network.},
journal = {IEEE transactions on computational biology and bioinformatics},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/TCBBIO.2026.3713273},
pmid = {42447006},
issn = {2998-4165},
abstract = {Biological networks, characterized by complex interactions among genes, proteins, and metabolites, are often modeled as graphs to study their organizational principles and dynamics. Network motifs-recurring, statistically significant subgraphs provide critical insights into the functional properties and structural organization of these networks. Existing research has explored various facets of motif detection, including enumeration, edge and node independence, dynamic updates, multi-layered networks, and stochastic settings. Although there have been studies in exploring the functionality of individual motif instances, a significant gap remains in understanding how collections of motif instances act as a group to influence the overall functionality of the network. In this paper, we aim to fill this gap. We model the influence of collections of motifs as a novel problem, which we call the Closest $k$-Motif Set Selection problem. We prove that this problem is NP-hard and develop MOSAIC (MOtif Set with mAximal InfluenCe), a novel greedy algorithm to address this problem. MOSAIC operates in two phases: an initialization phase for computing distances between motifs and nodes, and an update phase that incrementally selects motif instances to optimize their collective impact on the network. We prove that MOSAIC is efficient with a low degree polynomial time complexity. Our experimental results demonstrate that MOSAIC achieves optimal or near-optimal results, and scales to the entire human network efficiently. Our experiments on the human transcriptional regulatory network demonstrate that MOSAIC can identify Alzheimer's genes effectively, and select Alzheimer's genes that are missed by state-of-the-art node-based selection methods. This work advances our understanding of motif-based network analysis and opens new avenues for exploring the functional implications of network motifs.},
}
@article {pmid42447315,
year = {2026},
author = {Villain, M and Beauchêne, D and Mével-Becker, M and Tarabon-Prévost, C and Ferrieux, S and Hauw, F and Hahn, V and Epelbaum, S and Pradat-Diehl, P},
title = {Lost in Scheduling? A Reliable Tool for Detecting Subtle Cognitive Decline in Mild Cognitive Impairment and Mild Alzheimer's Disease.},
journal = {American journal of speech-language pathology},
volume = {},
number = {},
pages = {1-10},
doi = {10.1044/2026_AJSLP-24-00133},
pmid = {42447315},
issn = {1558-9110},
abstract = {PURPOSE: Neurodegenerative diseases, notably Alzheimer's disease (AD), present a significant public health challenge. This study aims to evaluate the effectiveness of the Ecological Assessment Battery for Numbers (EABN) in detecting subtle cognitive decline in mild cognitive impairment (MCI) and mild AD, focusing on everyday life mathematical situations.<br><br>METHOD: This cross-sectional study involved 66 participants (21 mild AD, 23 MCI, and 22 controls). Clinical assessments included the Mini-Mental State Examination (MMSE), the EABN, and the Numerical Activities of Daily Living questionnaire. Statistical analyses utilized nonparametric tests, Spearman rank correlation, and receiver operating characteristic curve analyses.<br><br>RESULTS: The EABN demonstrated an area under the curve (AUC) of 0.83 (95% confidence interval [0.73, 0.92]) in distinguishing patients and controls. Patients with pathologically high EABN scores were significantly older, and a positive correlation was observed between EABN and MMSE scores (r = .30; p = .04). The Appointment subtest within EABN emerged as the most discriminative (AUC = 0.86). Among MCI patients with pathological EABN scores, 70% progressed to AD or amyloid angiopathy.<br><br>CONCLUSIONS: This study reveals early manifestation of mathematical cognition impairments in cognitive decline, even before patient-reported complaints. The EABN, a practical tool for ecological assessment, could aid in early diagnosis and guide interventions. Integrating mathematical cognition assessment into routine care aligns with recommendations for cognitive rehabilitation in MCI patients, potentially preventing autonomy loss. These findings underscore the significance of a comprehensive approach to patient management, incorporating ecological assessments for nuanced diagnostics and early intervention in neurodegenerative diseases.},
}
@article {pmid42447420,
year = {2026},
author = {Paez, A and Piñol-Ripoll, G and Carnes-Vendrell, A and Dakterzada, F and Barbé, F and Zetterberg, H and Dang-Vu, TT},
title = {Orexin, Sleep, and Cognition in Alzheimer Disease: Non-REM Oscillatory Activity and Neural Resilience.},
journal = {Neurology},
volume = {107},
number = {3},
pages = {e218307},
doi = {10.1212/WNL.0000000000218307},
pmid = {42447420},
issn = {1526-632X},
abstract = {BACKGROUND AND OBJECTIVES: Sleep-wake dysregulation and elevated CSF orexin have been implicated in Alzheimer disease (AD). Sleep spindles (SPs) and slow oscillations (SOs) are linked to cognition and neurodegeneration; however, their relationship with CSF orexin concentrations in symptomatic AD has not been characterized. We investigated whether nonrapid eye movement (NREM) SP-SO activity is associated with CSF orexin and whether these oscillatory features moderate associations between orexin, cognition, neuropsychiatric symptom severity, and AD biomarkers.<br><br>METHODS: This prospective observational cohort study was conducted at a tertiary memory clinic in Lleida, Spain. Individuals aged &#x2265;60 years with biomarker-confirmed mild-to-moderate AD (National Institute on Aging-Alzheimer's Association criteria) underwent overnight polysomnography and morning CSF sampling. SP and SO were detected using validated automated algorithms with independent verification and visual quality control. CSF was assayed for orexin-A, amyloid-&#x3b2;42 (A&#x3b2;42), phosphorylated tau181 (pTau181), total tau, and YKL-40. Cognitive performance Alzheimer's Disease Assessment Scale-Cognitive Subscale ([ADAS-Cog], Mini-Mental State Examination (MMSE), California verbal learning test, ROCF) and neuropsychiatric symptoms (NPI) were assessed longitudinally over 36 months. Associations were examined using generalized linear models with robust estimators adjusted for age, sex, A&#x3b2;42, and apnea-hypopnea index. Multiple comparisons were controlled using false discovery rate correction. Interaction terms assessed moderation effects.<br><br>RESULTS: Sixty participants (30 women; mean age 74.7 years) were included. Longer SO duration and higher SP density and power were associated with lower CSF orexin concentrations (SP density: &#x3b2; = -187.37 pg/mL, 95% CI -344.93 to -29.80). Orexin was not associated with global sleep continuity metrics. Higher CSF orexin concentrations were associated with worse global cognition (ADAS-Cog: &#x3b2; = 0.014, 95% CI 0.003-0.024; MMSE: &#x3b2; = -0.01, 95% CI -0.011 to -0.004) and greater neuropsychiatric symptom severity (NPI at: &#x3b2; = 0.03, 95% CI 0.011-0.041). Higher orexin was also associated with higher pTau181 (&#x3b2; = 0.11, 95% CI 0.04-0.19), total tau, and YKL-40 (&#x3b2; = 0.37, 95% CI 0.17-0.57). Significant orexin &#xd7; SP-SO interactions were observed, such that greater oscillatory activity attenuated the adverse associations between orexin and cognitive outcomes, independent of A&#x3b2;42 and tau.<br><br>DISCUSSION: In biomarker-confirmed AD, NREM SP and SO activity are associated with CSF orexin concentrations and moderate associations between orexin and longitudinal cognitive and neuropsychiatric outcomes. Limitations include the observational design and absence of a comparator group, precluding causal inference and limiting contextualization relative to normal aging. NREM oscillatory metrics and orexin concentrations may represent complementary physiologic markers for disease monitoring and therapeutic targeting.<br><br>Role of Hypoxia and Sleep Fragmentation in AD; ClinicalTrials.gov Identifier: NCT02814045.},
}
@article {pmid42447555,
year = {2026},
author = {Wei, F and Song, H and Zhou, X and Hu, Z and Gao, N and Chen, Y and Li, Z and Feng, L},
title = {Ultrasensitive electrochemiluminescence aptasensor for Tau protein based on gold nanoparticle-modified perovskite nanocrystals.},
journal = {Biosensors &amp; bioelectronics},
volume = {312},
number = {},
pages = {119018},
doi = {10.1016/j.bios.2026.119018},
pmid = {42447555},
issn = {1873-4235},
abstract = {Early diagnosis for Alzheimer's disease (AD) is vital for effective therapeutic intervention and improved patient prognosis. In this work, we developed a highly sensitive electrochemiluminescence (ECL) aptasensor for detecting a key AD biomarker, Tau protein. An all-inorganic perovskite CsPbBr3 nanocrystals (NCs) were used as ECL emitters and were encapsulated with polyvinylpyrrolidone (PVP) to improve the stability of CsPbBr3 NCs in aqueous solution. Moreover, -PVP encapsulation significantly enhanced the ECL response via coordination between the lone-pair electrons of oxygen atoms and Pb[2+]. The obtained CsPbBr3@PVP composite was further functionalized with gold nanoparticles, which served as anchoring sites for the immobilization of a Tau-specific aptamer. The sensing mechanism relies on the specific recognition between the surface-bound aptamer and the Tau protein. The formation of the aptamer-target complex impeded the ECL reaction efficiency of the system, resulting in an "off" ECL sensing response. This strategy enables ultrasensitive detection of Tau protein with a wide linear range from 10 fg/mL to 10[8] fg/mL and a detection limit as low as 0.80 fg/mL. The aptasensor also demonstrated satisfactory recoveries of 97.2% to 108.6% in mouse cerebrospinal fluid with relative standard deviations below 6.5%, indicating its promising potential for early diagnosis of AD.},
}
@article {pmid42447729,
year = {2026},
author = {C, S and Munirathinam, R},
title = {Dynamic Bayesian spectrum optimization and LSTM integration for accurate EEG-based dementia detection.},
journal = {Psychiatry research. Neuroimaging},
volume = {362},
number = {},
pages = {112280},
doi = {10.1016/j.pscychresns.2026.112280},
pmid = {42447729},
issn = {1872-7506},
abstract = {Dementia is a neurodegenerative disorder marked by cognitive decline affecting daily activities, including various conditions, however, early detection and classification of dementia using EEG signals is crucial. Hence, a novel "Dynamic Bayesian Morlet-Hilbert Consensus Spectrum Optimization" is proposed to enhance the accuracy of dementia diagnosis, specifically for Alzheimer's Disease and Mild Cognitive Impairment. Additionally, Cholinergic System Dysfunction, characterized by non-uniform brain degeneration, complicates EEG feature extraction due to heterogeneous neural activity patterns, and existing models struggle to accurately interpret these patterns. Thus, a novel Adaptive Morlet Consensus Beamforming Transform is introduced to capture heterogeneous neural activity patterns and adapt to complex brain regions, thereby improving the identification of biomarkers associated with cholinergic system dysfunction. Furthermore, existing models often overlook the striatum due to its intricate structure and the cholinergic system's impact on cognitive functions, making it challenging to accurately assess cholinergic dysfunction. So, a novel Multilayer Adaptive Dynamic Causal Frequency Decomposition is introduced to detect subtle variations in brain function, improving the identification of early-stage dementia-related changes linked to cholinergic system dysfunction. Moreover, the striatum, a complex structure with subregions, exhibits varying impacts of cholinergic dysfunction, causing significant variability in cognitive and motor functions. Therefore, a novel Bayesian Hilbert-ElasticNet Spectrum Optimization is introduced to effectively capture the spectral and temporal dynamics of EEG signals to classify subtle variations in dementia. The results demonstrate that the methodology significantly improves classification performance, achieving an accuracy of 98.23%, along with precision and F1-Score rates of 98.84% and 97.52%, respectively, while minimizing RMSE and enhancing processing efficiency.},
}
@article {pmid42447755,
year = {2026},
author = {Parnetti, L and Gaetani, L},
title = {Beyond diagnosis: can fluid tau biomarkers stage Alzheimer's disease? Lessons from down syndrome.},
journal = {EBioMedicine},
volume = {130},
number = {},
pages = {106393},
doi = {10.1016/j.ebiom.2026.106393},
pmid = {42447755},
issn = {2352-3964},
}
@article {pmid42447765,
year = {2026},
author = {Schunack, J and Riepe, G and Textoris-Taube, K and Wallach, I and Mülleder, M and Liotta, A and Jendrach, M and Berndt, N},
title = {Activity-dependent metabolic vulnerability in the APPPS1 Alzheimer's disease mouse model during isoflurane anesthesia.},
journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie},
volume = {201},
number = {},
pages = {119608},
doi = {10.1016/j.biopha.2026.119608},
pmid = {42447765},
issn = {1950-6007},
abstract = {General anesthesia is an essential component of modern surgical and diagnostic care. Although it is overall safe in younger and healthy individuals, the situation is markedly different in patients with underlying neurological conditions like Alzheimer´s disease (AD), where perioperative neurological complications are common. However, the underlying mechanisms and tissue-level interaction between AD-related pathology, cerebral energy metabolism, and anesthetic exposure remain incompletely understood. We investigated acute entorhinal cortex slices from wild-type (WT) and AD-like APPPS1 transgenic mice under control conditions and sequentially exposed them to 1% and 3% isoflurane. Depth-resolved oxygen measurements were used to calculate the cerebral metabolic rate of oxygen (CMRO2), while extracellular potassium dynamics were recorded using ion-sensitive microelectrodes. Glial markers were assessed by immunohistochemistry, and proteomic profiling was integrated with kinetic metabolic modeling. APPPS1 brain slices showed reduced stimulation-induced increases in CMRO2 compared with WT tissue, indicating diminished metabolic reserve, whereas unstimulated oxygen consumption differed modestly between genotypes. Isoflurane suppressed CMRO2 in a concentration-dependent manner in both genotypes. Extracellular potassium levels increased with isoflurane, whereas stimulation-induced potassium transients were reduced, with largely preserved clearance dynamics across genotypes. Immunohistochemistry confirmed microglial activation in APPPS1 tissue but revealed no acute isoflurane-induced glial response. Proteomics consequently indicated immune and inflammatory remodeling, whereas metabolic modeling suggested reduced glycolytic capacity under high energetic demand. Thus, APPPS1 entorhinal cortex tissue retains unstimulated metabolic function but exhibits impaired metabolic reserve during neuronal activation.},
}
@article {pmid42447924,
year = {2026},
author = {Nitrini, R and Takada, LT and Brucki, SMD},
title = {The past, present, and future of Alzheimer's disease-part 3: the future.},
journal = {Arquivos de neuro-psiquiatria},
volume = {84},
number = {6},
pages = {1-10},
doi = {10.1055/s-0046-1824435},
pmid = {42447924},
issn = {1678-4227},
abstract = {Predicting future advances in science is practically impossible because unexpected discoveries can radically change the march of ongoing processes. Predicting the nearest future may have a slightly greater chance of success. First, the diagnosis of risk factors for Alzheimer's disease (AD), based on the preponderant role of genetics, will be made very early. Diagnosis will be made with biomarkers prior to clinical manifestations. Furthermore, the prevention of AD and of dementia due to AD will be possible with better control of the many risk factors for dementia, healthier lifestyles, multi-target drugs, and genetic therapy. The relationship between AD and aging will be better understood, opening possibilities for intervention in aging itself. As the pathophysiology of AD is not unique, treatment will be individualized, according to the stage and characteristics of the disease. Most clinical trials will have surrogate markers as primary outcomes. Treatments to decrease the velocity or arrest the evolution of mild cognitive impairment (MCI) and mild dementia caused by AD will be available. Additionally, artificial intelligence (AI) will aid in the diagnosis and selection of the best treatments. Access to the new methods for diagnosing and treating AD is currently limited to a small parcel of the population, especially in low- and middle-income countries, because of their high costs. Due to the high prevalence of AD, it is possible these will become less expensive in the future. The possibility of reversing dementia once it has set in will probably have to wait for longer.},
}
@article {pmid42448048,
year = {2026},
author = {Waseem, A and Ghosh, S and Kumari, M and Raza, SS and Verma, S},
title = {Modulation of Inflammasome Biology in Age-Associated Neurodegenerative Diseases: Therapeutic Potential of Endogenous Gasotransmitters and Synthetic Molecules.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103257},
doi = {10.1016/j.arr.2026.103257},
pmid = {42448048},
issn = {1872-9649},
abstract = {Inflammasomes, particularly the NLRP3 complex, play a central role in coordinating innate immune activation and neuroinflammatory responses within the cytosol. Persistent or dysregulated nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) activation promotes caspase-1-dependent maturation of interleukin (IL)-1β and IL-18 and triggers gasdermin D (GSDMD)-mediated pyroptosis, thereby contributing to the pathogenic cascades underlying Alzheimer's disease (AD) and Parkinson's disease (PD). Endogenous gasotransmitters, including hydrogen sulfide (H2S) and nitric oxide (NO), have emerged as critical modulators of redox homeostasis, mitochondrial function, and inflammatory signaling pathways that directly or indirectly regulate NLRP3 inflammasome activity. Accumulating evidence suggests that these gaseous mediators exert potent neuroprotective effects by attenuating inflammasome activation, limiting oxidative and nitrosative stress, and preserving neuronal integrity. Despite their therapeutic potential, the pleiotropic and concentration-dependent actions of gasotransmitters pose substantial challenges for precise delivery and controlled bioavailability. However, donors or hybrid molecules, such as peptide conjugates, provide a suitable platform for sustained, controlled release of these gaseous molecules, overcoming their dose-dependent toxicity and facilitating protective biological effects. To date, the most advanced therapeutic strategies have focused on pharmacological inhibition of the NLRP3 inflammasome using synthetic compounds. Preclinical and emerging clinical studies demonstrate that such agents significantly modulate inflammasome-associated downstream signaling events through diverse molecular mechanisms. This review integrates current insights into NLRP3 inflammasome-driven pathology in age-associated neurodegenerative disorders, highlights the regulatory roles of endogenous gasotransmitters, and evaluates the therapeutic prospects of synthetic inflammasome-targeting agents for the treatment of neurodegenerative diseases in the aging population.},
}
@article {pmid42435702,
year = {2026},
author = {González-Rodríguez, VM and Martín-López, E},
title = {[In response to 'Advances and controversies in the treatments of Alzheimer's disease'].},
journal = {Atencion primaria},
volume = {58},
number = {8},
pages = {103570},
doi = {10.1016/j.aprim.2026.103570},
pmid = {42435702},
issn = {1578-1275},
}
@article {pmid42435703,
year = {2026},
author = {Ghose, A and Paidesetty, SK and Prusty, SK and Satapathy, BS and Panda, PK and Pakeeraiah, K and Mishra, A and Dandela, R},
title = {Rationally designed phytochemical-derived carbamate hybrids unveiling potent inhibition of cholinesterase and amyloid-β peptides.},
journal = {Bioorganic chemistry},
volume = {180},
number = {},
pages = {110242},
doi = {10.1016/j.bioorg.2026.110242},
pmid = {42435703},
issn = {1090-2120},
abstract = {Alzheimer's disease (AD) is most likely to be caused by the accumulation of Aβ and dysfunction of the cholinergic pathology. Oxidative damage, alterations of brain glucose metabolism, and cognitive impairment are all demonstrated in the STZ models. In order to overcome such effects, a new set of phenolic-carbamate conjugates (5a-5h) was synthesized, and their structures were elucidated using FTIR, UV, and NMR spectroscopy. The in silico studies confirmed excellent binding capabilities against AChE and Aβ targets. In vitro antioxidant assays depicted a significant free radical scavenging ability, with compound 5c exhibiting the enhanced effect. Cell line study with SH-SY5Y and PC12 cells showed greater % cell viability. AChE activity demonstrated compound 5c has significant effectiveness (IC50 = 1.98 uM). Neurobehavioral activity showed an improvement in learning and memory during behavioural assessments. In vivo antioxidant study showed greater scavenging activity (SOD, CAT, GSH), reduced of oxidative stress (MDA, NO), and the improvement in total antioxidant activity. Overall, the compound 5c has demonstrated significant results comprising decreased cholinesterase and Aβ inhibition deciphering enhanced cholinergic restoration. Hippocampal integrity was preserved, as it was confirmed by histopathological examination. It concludes that bromo-vanillyl carbamate derivative 5c (30 mg/kg) has potent antioxidant, anti-amyloid, and neuroprotective characteristics, rendering it a promising multitarget lead that warrants further investigation for the treatment of AD.},
}
@article {pmid42435764,
year = {2026},
author = {Zhang, C and Zhang, J and Wang, Y and Wang, Y and Lin, P and Wang, Y and Tang, Z and Yu, J and Zhou, Q and Cui, F},
title = {Neuron-Targeted Exosomal Delivery of siRNA Against RIPK3 Slows Neurodegenerative Progression in Alzheimer's Disease.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e76558},
pmid = {42435764},
issn = {2198-3844},
support = {2023YFA1801900//National Key R&amp;D Program of China/ ; 82572678//National Natural Science Foundation of China/ ; JJ2024YX0560//Natural Science Foundation of Heilongjiang Province/ ; 2022CY CX0202//"Spring Goose" Talent Team Support Program of Heilongjiang Province/ ; 21032240006//Funding Program for Preferential Returned Scholars of Heilongjiang Province/ ; 20240NTJ 018//Young Elite Scientist Sponsorship Program of Heilongjiang Province/ ; },
abstract = {A major challenge in RNA therapeutics for central nervous system disorders is the lack of delivery systems capable of crossing the blood-brain barrier (BBB) while achieving cell-type-specific targeting. Herein, we develop an engineered exosomal siRNA delivery platform for systemic, neuron-targeted RNA transport to the brain. The platform leverages exosomes derived from an immortalized mouse hippocampal neuronal cell line as a biomimetic and functionally privileged material source, enhancing neuronal uptake and intracellular delivery efficiency. Through surface functionalization with a rabies virus glycoprotein-derived peptide, the system enables receptor-mediated BBB transcytosis and programmable siRNA loading. In human cortical organoids, the platform achieves efficient cytosolic delivery and robust gene silencing in neurons, demonstrating high delivery precision and bioavailability. As a proof of concept, targeting receptor-interacting protein kinase 3 (RIPK3) modulates necroptosis, a key pathway in inflammatory neurodegeneration. In transgenic mouse models, systemic administration suppresses RIPK3/MLKL signaling, reduces neuronal loss, and alleviates neuroinflammation and tau-associated pathology. Transcriptomic analyses further indicate stabilization of neuronal homeostasis across vulnerable brain regions. Collectively, the study establishes a modular and programmable exosomal RNA delivery platform and highlights age-defined, cell-derived biomaterials as a generalizable strategy for overcoming delivery barriers in neurological diseases.},
}
@article {pmid42435857,
year = {2026},
author = {Yagi, Y and Oda, S and Tatsumi, H},
title = {Cellular Basis of Medium Flow-Mediated Reduction of Aβ Neurotoxicity in Cultured Neurons.},
journal = {Neuroscience research},
volume = {},
number = {},
pages = {105090},
doi = {10.1016/j.neures.2026.105090},
pmid = {42435857},
issn = {1872-8111},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by elevated concentrations of amyloid β1-42 (Aβ1-42) in the brain, where it exerts neurotoxic effects. A recent study demonstrated that medium flow at approximately 10 μm/s reduces Aβ1-42 neurotoxicity in explant brain cultures containing neurons and beating ependymal cilia; however, the underlying mechanisms remain unclear. Neurons migrating from the explant and located within 300 μm of the beating cilia were exposed to cilia-generated medium flow, allowing analysis of Aβ1-42 toxicity under fluid flow conditions. Aβ1-42-containing putative EV-related extracellular particles (putative EV-related Eps), with diameters of 100-400nm were detected in the culture medium and exhibited neurotoxic effects. Pharmacological inhibition of EV release and endocytosis reduced intracellular accumulation of Aβ1-42 and attenuated neuronal toxicity. Under medium flow, fewer putative EV-related EPs bound to neurons, and their binding duration was significantly shortened. Rhodamine-conjugated concanavalin A staining revealed enhanced cell-surface glycan labeling in damaged neurons on the non-ciliated side compared with neurons on the ciliated side. These results suggest that shear stress reduces neuronal accumulation of Aβ1-42-containing putative EV-related EPs, likely through modulation of cell-surface glycosylation composition.},
}
@article {pmid42435996,
year = {2026},
author = {Shang, Y and Zhai, Z and Cong, L and Dong, X},
title = {Targeting the APOE4-driven peripheral-central immune axis: A new frontier for Alzheimer's disease therapy.},
journal = {Pharmacological research},
volume = {231},
number = {},
pages = {108339},
doi = {10.1016/j.phrs.2026.108339},
pmid = {42435996},
issn = {1096-1186},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder and a growing global health challenge. Despite decades of research dominated by the amyloid cascade hypothesis, single-target therapies aimed at Aβ or tau have largely failed, underscoring the need for a broader framework. Emerging evidence implicates neuroimmune dysfunction as a central driver of AD pathology, with the "peripheral-central immune axis" emerging as a critical node. The APOE4 allele, the strongest genetic risk factor for sporadic AD, plays a pivotal role in both central nervous system (CNS) lipid metabolism and peripheral immune homeostasis. This review synthesizes the association between APOE4 and peripheral immune dysregulation and its impact on neurodegeneration. We discuss APOE expression in CNS and peripheral immune cells, highlighting APOE4-associated alterations in monocyte/macrophage polarization, T cell subsets via IL-7/IL-7R downregulation, and gut microbiota composition. We delineate mechanisms by which APOE4 is associated with blood-brain barrier compromise, may promote conditions for immune cell trafficking, and contributes to neuroinflammation. Integrating preclinical and clinical evidence, we propose an "APOE4-associated peripheral-central immune infiltration cascade" as a unifying framework for understanding systemic AD pathogenesis. Finally, we review emerging therapeutic strategies targeting peripheral immunity and APOE, discussing multi-target approaches guided by APOE genotype and immune biomarkers, shifting from a CNS-centric toward a systemic immunomodulatory paradigm for precision medicine.},
}
@article {pmid42436002,
year = {2026},
author = {Han, J and Wu, S and Cui, X and Zhou, X and Yu, Q and Cheng, Q and Lu, Z and Zong, S},
title = {CAPNS1 restoration partially alleviates mitochondrial dysfunction and synaptic deficits in Alzheimer's disease through the Ca2[+]-CaMKIIβ-MAPK-PGC-1α axis.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.07.021},
pmid = {42436002},
issn = {1873-7544},
abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by brain atrophy and cognitive decline. While the amyloid cascade hypothesis remains the dominant framework, accumulating evidence indicates that mitochondrial dysfunction critically contributes to AD progression. Although improving mitochondrial function has been shown to rescue cognitive deficits in AD models, the underlying molecular mechanisms remain elusive. In this study, we identified a significant reduction in calpain small subunit 1 (CAPNS1) expression in both AD patient samples and male transgenic mouse models. Decreased CAPNS1 levels were strongly correlated with mitochondrial ultrastructural damage, reduced mitochondrial DNA (mtDNA) copy number, and progressive synaptic loss. Mechanistically, we found that CAPNS1 positively regulated mtDNA transcription and mitochondrial gene expression, and pharmacological data suggested the involvement of the Ca[2][+]-CaMKIIβ-MAPK-PGC-1α signaling axis, a master pathway governing mitochondrial biogenesis and respiratory capacity. This activation subsequently restored cellular ATP production and reduced mitochondrial reactive oxygen species accumulation. Importantly, neuronal-specific CAPNS1 upregulation in APP/PS1 transgenic mice markedly improved mitochondrial cristae integrity, reversed hippocampal long-term potentiation deficits, increased dendritic spine density, and partially alleviated spatial memory deficits in behavioral tests. We noted that loss-of-function experiments (e.g., CAPNS1 knockdown or knockout) were not performed in this study, and the proposed Ca[2][+]-CaMKIIβ-MAPK-PGC-1α axis should therefore be interpreted as a suggestive working model requiring further validation. Collectively, our findings indicate that CAPNS1 serves as a key regulator of mitochondrial function. By linking Ca[2][+] signaling to mitochondrial gene expression and synaptic integrity, CAPNS1 represents a promising therapeutic target for ameliorating synaptic loss and cognitive decline in AD.},
}
@article {pmid42436132,
year = {2026},
author = {Da Silva Oliveira, B and Innocenti, M and Granucci, F},
title = {Calcineurin/NFAT signaling in the temporal integration of Ca[2+] stress in neurodegeneration.},
journal = {Cell death discovery},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41420-026-03251-3},
pmid = {42436132},
issn = {2058-7716},
abstract = {The calcineurin (CaN)/nuclear factor of activated T cells (NFAT) signalling axis is a Ca[2+]-responsive pathway that translates intracellular Ca[2+] signals into long-term transcriptional programmes. Chronic disruption of intracellular Ca[2+] homoeostasis is a convergent feature of neurodegenerative disorders, particularly Alzheimer's disease (AD) and Parkinson's disease (PD). In these conditions, sustained or repetitive Ca[2+] elevations promote prolonged activation of the CaN/NFAT pathway, thereby linking Ca[2+] dysregulation to persistent cellular responses. In this review, we summarise the molecular organisation and regulation of the Ca[2+]/CaN/NFAT pathway and discuss its physiological roles in neurons and glial cells, including synaptic plasticity, neurodevelopment, neurogenesis, and neuroinflammatory responses. We critically examine experimental evidence linking CaN/NFAT signalling to AD and PD, distinguishing direct mechanistic roles from associative and model-dependent findings. Across disease contexts, the CaN/NFAT axis appears to function as a molecular node at which diverse insults, including amyloid-β and tau aggregates, α-synuclein toxicity, mitochondrial dysfunction, and chronic inflammatory cues, converge under conditions of sustained Ca[2+] dysregulation. We propose that the pathological relevance of CaN/NFAT lies less in pathway activation per se than in its capacity to convert chronic Ca[2+]-dependent stress signals into persistent transcriptional states affecting synaptic integrity, inflammatory tone, and cellular resilience. We conclude by discussing current therapeutic strategies targeting this pathway, their limitations, and the need for temporally and cell-type-specific modulation.},
}
@article {pmid42436138,
year = {2026},
author = {Li, CH and Cheng, TW and Lin, CH},
title = {Plasma pTau217 and pTau231 predict progression to dementia in Parkinson's disease: a prospective longitudinal study.},
journal = {NPJ Parkinson's disease},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41531-026-01469-7},
pmid = {42436138},
issn = {2373-8057},
support = {114-BIH019//National Taiwan University Hospital Hsinchu Branch/ ; 114-2314-B-002 -119 -MY3//National Science and Technology Council/ ; },
abstract = {This prospective study evaluated the prognostic utility of Alzheimer's disease-related plasma biomarkers (phosphorylated tau [pTau217 and pTau231], the amyloid-β [Aβ] 42/40 ratio) and neurofilament light chain (NfL) in 123 Parkinson's disease (PD) patients and 40 controls. Over a mean 5.1-year follow-up, 35 of 109 initially non-demented PD patients (32.1%) progressed to dementia. Plasma pTau217 and NfL levels were elevated, whereas the Aβ42/40 ratio was reduced, in cognitively impaired PD groups versus controls. Baseline pTau217 accurately differentiated dementia converters from non-converters (AUC = 0.877; 95% CI: 0.798-0.956). Patients with pTau217 ≥ 0.268 pg/mL had a higher risk of dementia progression (HR: 5.49; 95% CI: 2.37-12.74). This risk was further elevated in patients in the highest quartile (≥ 0.36 pg/mL; HR: 11.35; 95% CI: 2.60-49.59) versus the lowest quartile (< 0.20 pg/mL). Similarly, the pTau231 cut-off (≥ 2.575 pg/mL) predicted an increased risk of dementia (HR: 3.89; 95% CI: 1.67-9.03). Both pTau217 and pTau231 demonstrated high predictive performance in Cox models (C-index: 0.806 and 0.796, respectively). Plasma NfL exhibited longitudinal increases during follow-up. Baseline plasma pTau217 and pTau231 serve as surrogate markers for predicting dementia progression in PD. Further validation of these biomarker cut-off values is warranted.},
}
@article {pmid42436226,
year = {2026},
author = {Onishchenko, D and Mastrianni, JA and Chattopadhyay, I},
title = {Passive early screening for Alzheimer's disease and related dementias using EHR comorbidity patterns.},
journal = {NPJ digital medicine},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41746-026-02954-2},
pmid = {42436226},
issn = {2398-6352},
support = {852418/ALZ/Alzheimer's Association/United States ; P30 AG066619/AG/NIA NIH HHS/United States ; },
abstract = {Early identification of Alzheimer's disease and related dementias (ADRD) remains limited by specialized tests and late-stage diagnosis. The Zero-burden Risk Assessment (ZeBRA) is an AI-driven score that predicts incident ADRD up to a decade before diagnosis using only routine electronic health record (EHR) data, without laboratory tests, imaging, or questionnaires. Trained on 487,989 cases and 12,483,718 controls from nationwide U.S. insurance claims and validated on held-out National samples and two independent cohorts, ZeBRA achieved AUC = 0.93 and 0.83 in the 50+ cohort for 1-year and 10-year horizons, respectively, with positive likelihood ratios exceeding 10 in the National 50+ held-out cohort at 95% specificity and stable discrimination over time. Performance was consistent across age, sex, race, and ethnicity subgroups. In a prospective feasibility pilot, higher ZeBRA scores showed concordance with lower Montreal Cognitive Assessment (MoCA) scores, indicating greater cognitive impairment (R = -0.78, 95% CI: -0.94 to -0.37). Compared with prior EHR-based models, ZeBRA provides superior accuracy, cross-site generalizability, and noise-corrected interpretability via our novel Λ-OR attribution metric. Scalability and low burden suggest application in population-level early detection and presymptomatic trial enrichment.},
}
@article {pmid42436274,
year = {2026},
author = {Maserati, MS and Zama, F},
title = {Quantifying golden-ratio deviations in the tree drawing test to identify patients with Alzheimer's disease.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-61257-4},
pmid = {42436274},
issn = {2045-2322},
abstract = {The golden ratio ([Formula: see text]) exhibits unique autosimilarity properties that appear throughout biological systems, including human physiology and neural organization. The Tree Drawing Test (TDT), a simple cognitive assessment tool that mainly implies visuospatial, praxic and executive functions, may capture φ-based organizational principles that become disrupted in neurodegenerative conditions. This study examined the relationship between golden ratio proportions and cognitive impairment in tree drawings through quantitative analysis of a large cohort of cognitively impaired patients. We evaluated 613 Alzheimer's disease (AD) patients, 328 mild cognitive impairment (MCI) patients, and 438 healthy controls who completed the TDT. Five novel golden ratio-based deviation indices were developed to quantify proportional relationships between trunk and crown dimensions; among these, the trunk-based index [Formula: see text]showed the most consistent group separation (Distance-to-Diameter Ratio [Formula: see text]; Fisher Ratio [Formula: see text]), with all three pairwise diagnostic comparisons reaching [Formula: see text] (Mann-Whitney U, Bonferroni-corrected) in the full sample and across sex and education strata. Within a multinomial logistic regression framework with stratified 5-fold cross-validation, [Formula: see text]retained independent discriminative value after adjustment for age, education, and the established Space Occupation (SO) index, reaching a macro-averaged AUC of 0.834 (AD vs. rest: 0.855, 95% CI [Formula: see text]; CNTRL vs. rest: 0.911, 95% CI [Formula: see text]; MCI vs. rest: 0.736); the Likelihood Ratio Test confirmed that [Formula: see text]contributes information not captured by SO, age, and education combined ([Formula: see text], [Formula: see text]), and convergent results under two independent matched-subgroup strategies indicated that age and education differences do not explain this signal. Pre-specified operational cut-offs derived from the cohort yielded clinically interpretable sensitivity/specificity trade-offs, with AUC [Formula: see text] [0.894, 0.927] for healthy-control identification using the full multivariate model. As a secondary descriptive observation, group means of [Formula: see text]approximated the Fibonacci values F(5), F(7), F(9); a permutation-based null model (B [Formula: see text], [Formula: see text]) and a Fibonacci-vs-Lucas specificity comparison (100% vs. 0% confidence-interval containment) indicated that this alignment is unlikely to arise by chance and is specific to φ-convergent sequences, although the algebraic link between [Formula: see text]and φ implies that this finding should be regarded as a starting point for future studies rather than as proof of a biological mechanism. Within these limitations, golden-ratio-based TDT measures provide a quantitative complement, not a replacement, to traditional TDT indices for cognitive impairment assessment and require confirmation in independent multi-centre samples before clinical adoption.},
}
@article {pmid42436416,
year = {2026},
author = {Tang, L and Wu, N and Zhu, Y and Xu, H and Mo, Y},
title = {Bioinformatic analysis of differentially expressed mitochondrion-related genes, immune cell infiltration, and diagnostic value in Alzheimer's disease.},
journal = {BMC neurology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12883-026-05144-5},
pmid = {42436416},
issn = {1471-2377},
support = {2024Y12//2024 Ningbo Municipal Health Science and Technology Plan Project/ ; },
abstract = {BACKGROUND: Mitochondrial dysfunction and neuroinflammation are critically implicated in the pathogenesis of Alzheimer's disease (AD). However, a systematic exploration of key mitochondrion-related genes (MRGs) in AD, and their specific roles in reshaping the immune microenvironment and serving as diagnostic biomarkers, remains insufficient.<br><br>METHODS: To address this, we conducted an integrative bioinformatics analysis. Differentially expressed MRGs were identified from public AD transcriptomic datasets. Their biological functions were elucidated through enrichment analyses. The correlations between core MRGs and ssGSEA-derived immune-cell signature enrichment scores were quantified using transcriptome-based computational analysis. Finally, machine learning models were constructed and validated to assess the diagnostic potential of identified MRG signatures.<br><br>RESULTS: A robust set of dysregulated MRGs was identified in AD brains, showing predominant enrichment in pathways of oxidative phosphorylation and energy metabolism. Notably, the expression of key MRGs correlated significantly with altered infiltration abundances of specific immune cell types, including neutrophil-, eosinophil-, NK CD56bright cell-, and T follicular helper cell-related signatures. A diagnostic model constructed from a refined MRG signature exhibited promising predictive accuracy, with area under the curve (AUC) values reaching approximately 0.82 in the training cohort and around 0.74 in independent validation cohorts.<br><br>CONCLUSION: Our study defines a novel landscape of MRGs in AD, deciphers their tight crosstalk with the immune microenvironment, and establishes a promising MRG-based signature for AD diagnosis. These findings provide fresh insights into the potential molecular interplay between mitochondrial dysfunction and neuroinflammation in AD and nominate candidate mitochondrion-related biomarkers and regulatory mechanisms that warrant further experimental and clinical validation.},
}
@article {pmid42436528,
year = {2026},
author = {Abzhandadze, T and Hoang, MT and Bao, X and Åkerman, M and Norgren, J and García Pascual, B and Mo, M and Eriksdotter, M and Xu, H and Garcia-Ptacek, S},
title = {Thresholds for meaningful change in Mini-Mental State Examination scores in rare dementias.},
journal = {Alzheimer's research &amp; therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02136-y},
pmid = {42436528},
issn = {1758-9193},
abstract = {BACKGROUND: We conceptualize the Real-World Reassessment Threshold (RWRT) as representing the smallest change that exceeds expected measurement variability while accounting for clinically expected cognitive decline over the assessment interval, whereas the minimum clinically important difference (MCID) indicates the smallest change likely to be clinically meaningful. To date, no study has empirically defined the RWRT or MCID for Mini-Mental State Examination (MMSE) scores in Lewy body dementia (LBD) or frontotemporal dementia (FTD), limiting the interpretation of longitudinal changes and clinical trial designs. We therefore aimed to estimate 12-month, diagnosis-specific MMSE thresholds for RWRT and MCID among individuals with LBD and FTD, and to evaluate the generalizability of these thresholds in an independent validation cohort.<br><br>METHODS: This registry-based cohort study included individuals diagnosed with LBD or FTD from the Swedish Registry for Cognitive/Dementia Disorders (SveDem, 2007-2022) with a 91-400-day MMSE follow-up, and an independent validation cohort from the U.S. National Alzheimer's Coordinating Center (NACC). The RWRT was estimated using distribution-based methods based on intraclass correlation coefficients (ICCs). MCID was estimated using both anchor-based and distribution-based (0.5 standard deviation) approaches.<br><br>RESULTS: We included 1,158 individuals from SveDem (873 LBD, 285 FTD) and 1,060 individuals from NACC (469 LBD, 591 FTD). Over the 91-400-day follow-up interval, MMSE scores demonstrated moderate to high reliability (ICC 0.70-0.90), corresponding to RWRT estimates ranged from 5 to 7 MMSE points. Anchor-based MCIDs differed by diagnosis, with a mean threshold of 0.7 points in LBD and 3.8 points in FTD in SveDem; similar diagnosis- and baseline severity-dependent patterns were observed in NACC. In contrast, distribution-based MCIDs were consistent across diagnoses, clustering around 2-3 MMSE points.<br><br>CONCLUSIONS: MMSE changes of less than five points over one year may reflect expected test variability combined with expected individual decline. However, average changes of 2-3 points may still be meaningful when combined with a clinical anchor of change, depending on diagnosis and disease stage. These results emphasize the importance of using both RWRT and MCID when evaluating MMSE change and selecting clinical trial endpoints.},
}
@article {pmid42436533,
year = {2026},
author = {Bentivenga, GM and Mammana, A and Baiardi, S and Vittoriosi, E and Mastrangelo, A and Ruggeri, E and Vargiu, CM and Polischi, B and Stanzani-Maserati, M and Rizzo, G and Pantieri, R and Raggi, A and Capellari, S and Parchi, P},
title = {Analytical and clinical validation of a novel proximity extension assay-based plasma biomarker panel in a cohort of prevalent neurodegenerative dementias.},
journal = {Alzheimer's research &amp; therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02142-0},
pmid = {42436533},
issn = {1758-9193},
support = {Ricerca Corrente//Ministero della Salute/ ; },
abstract = {BACKGROUND: Blood-based biomarkers are increasingly recognized as promising tools for the diagnosis and monitoring of neurodegenerative diseases, offering a minimally invasive alternative to cerebrospinal fluid (CSF) testing. We evaluated the analytical performance and clinical utility of the Olink Target 48 Neurodegeneration panel, a novel multiplex proteomic platform based on the proximity extension assay (PEA) technology, in a large, clinically diverse dementia cohort.<br><br>METHODS: We retrospectively analyzed plasma samples from 238 patients with Alzheimer's disease (AD), dementia with Lewy bodies, frontotemporal dementia, progressive supranuclear palsy, and corticobasal degeneration, along with 65 healthy controls, quantifying 41 proteins in each sample. We assessed analytical performance using intra- and inter-assay coefficients of variation, evaluated diagnostic accuracy through receiver operating characteristic curve analysis, and investigated associations between biomarker levels, clinical severity measures, and pathology-specific CSF biomarkers for AD and Lewy body pathology (LBP) using general linear models.<br><br>RESULTS: The platform quantified 32 proteins with variable analytical performance; nine were excluded due to poor detectability. Strong correlations were observed between PEA-based measurements and established immunoassays for plasma pTau217, NEFL, and GFAP (all p&#x2009;<&#x2009;0.001). Plasma pTau217 demonstrated superior diagnostic accuracy for AD, achieving an area under the curve (AUC) exceeding 0.91 against all comparison groups. Novel ratios combining NEFL with markers of immune function or synaptic integrity (NEFL/ITGB2, NEFL/ITGAM, NEFL/SCG2) achieved AUCs exceeding 0.93 for discriminating patients from controls, significantly outperforming NEFL alone (all p&#x2009;<&#x2009;0.001). Thirteen proteins, spanning markers of neuroaxonal damage, myelin-associated processes, and immune function (i.e., Abeta40, Abeta42, BMP7, CLSTN3, ENO2, KLK8, MMP10, NEFL, NPTXR, OMG, RTN4R, SCG2, SDC4, all p&#x2009;<&#x2009;0.01) showed significant independent associations with disease stage as measured by the Clinical Dementia Rating scale. Four proteins (i.e., pTau217, GFAP, SYT1, and SDC4) were significantly associated with AD pathology, while three (ENO2, ITGAM, and ITGB2) showed significant associations with LBP (all p&#x2009;<&#x2009;0.05).<br><br>CONCLUSIONS: This multiplex platform provides multiplex biomarker measurements with potential utility for AD diagnosis and disease staging across neurodegenerative disorders. These findings support further validation studies for its implementation in clinical and research settings.},
}
@article {pmid42436578,
year = {2026},
author = {van Tol, BGJ and Groot, C and Vermeiren, MR and van de Giessen, E and Pijnenburg, YAL and Coomans, EM and Ossenkoppele, R},
title = {A probabilistic framework for clinicopathological Alzheimer's disease using tau-PET.},
journal = {Alzheimer's research &amp; therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02133-1},
pmid = {42436578},
issn = {1758-9193},
abstract = {BACKGROUND: [[18]F]flortaucipir tau-PET detects neurofibrillary tangle (NFT) pathology in Alzheimer's disease (AD), one of the core pathological hallmarks of the disease. In clinical settings, tau-PET is usually interpreted qualitatively, and therefore quantitative estimates of how scan results alter the probability that AD explains a patient's symptoms are lacking. Here, we evaluate the probability of clinicopathological AD given a positive or negative tau-PET scan and examine how patient age and amyloid-PET status modulate this probability.<br><br>METHODS: We computed positive and negative predictive values (PPV/NPV) of tau-PET for clinicopathological AD, defined as mild cognitive impairment or dementia with AD as the primary etiology. To account for potential pathological and clinicopathological mismatches, PPV and NPV were modeled using literature-derived sensitivity and specificity estimates of [[18]F]flortaucipir PET for postmortem Braak V/VI NFT pathology, together with literature-derived age-dependent tau-PET positivity rates in cognitively unimpaired individuals. We also considered hypothetical clinician-estimated pre-PET AD probabilities. PPV and NPV were calculated for tau-PET and for sequential amyloid- and tau-PET scenarios.<br><br>RESULTS: Tau-PET PPV for clinicopathological AD was generally high, particularly in individuals with higher clinician-estimated pre-PET AD probabilities, and showed minor age-related declines (e.g., 84% at ages 50-55 vs. 75% at ages 85-90, at 50% pre-PET probability). Tau-PET NPV was consistently higher than PPV and showed negligible age-related decline (e.g., 92% at ages 50-55 vs. 90% at ages 85-90, at 50% pre-PET probability). A positive tau-PET following positive amyloid-PET substantially increased PPV, particularly in older individuals (e.g., PPV increased from 56% to 83% at ages 75-80 and 30% pre-PET probability), whereas the corresponding gain in NPV after tau-PET following amyloid-PET was smaller.<br><br>CONCLUSIONS: Tau-PET demonstrates high PPV and NPV for clinicopathological AD. A positive tau-PET following positive amyloid-PET further increases the probability of clinicopathological AD, particularly in older adults. This underscores tau-PET's clinical utility and highlights the effect of age and pre-PET certainty on post-PET AD probabilities.},
}
@article {pmid42436821,
year = {2026},
author = {Shan, G and Zhang, Y and Ding, AA},
title = {Statistical inference for saved time based on disease progression curves in Alzheimer's disease research.},
journal = {Contemporary clinical trials communications},
volume = {52},
number = {},
pages = {101664},
pmid = {42436821},
issn = {2451-8654},
abstract = {Saved time is an easy interpretation metric that provides information to patients on how long a new treatment can delay the disease progression in time as compared to the placebo. The frequently used projection approach for saved time estimation utilizes limited information from the available data. To address that limitation, the area above the disease progression curve was proposed to estimate saved time by using more information from data. However, it is a challenge to derive the closed-form statistical inference (e.g., confidence interval of saved time) as area above the curve is quadratic relative to visit time and saved time based on the curves is nonlinearly related to the area above the curve. In this article, we derived the closed-form variance of saved time based on the area above curve approach by using Taylor expansion. We then compared the performance of the closed-form method and the existing simulation-based method to construct the confidence interval for saved time based on the area above curve approach with regard to coverage probability and interval width under various scenarios. The simulation results indicate that the proposed closed-form method has similar performance as compared to the existing method, while the closed-form method can be computationally easy in practice without additional simulations in the existing method. Data from the completed phase 2 donanemab trial were used to illustrate the application of the proposed method.},
}
@article {pmid42436978,
year = {2026},
author = {Ishida-Takaku, T and Sohrabi, M and Pecoraro, HL and Combs, CK},
title = {Alzheimer's disease-related mutations in APP influence colorectal tumor formation in a sex-dependent manner.},
journal = {iScience},
volume = {29},
number = {7},
pages = {116645},
pmid = {42436978},
issn = {2589-0042},
abstract = {Cancer and Alzheimer's disease (AD) are age-associated diseases. Studies have indicated common mechanisms and interactions between these conditions. Epidemiological data demonstrate negative correlations between several cancers and AD. Despite this, few studies have explored their mutual influence on pathological outcomes. We utilized a human amyloid precursor protein (APP) mutant knock-in AD mouse model to investigate how familial mutations influence colorectal cancer development. Using a colitis-associated colorectal cancer (CAC) model, APP mutations promoted colon tumor formation in male mice but inhibited it in female mice. Correspondingly, inflammatory changes were reduced in the colons of female mice. Transcriptome analysis revealed differential expression, particularly in the enrichment of neuronal marker, steroid hormone, and immune cell signaling pathways. Additionally, distinct macrophage subtypes and neuronal profiles were observed in the colons of male and female APP mutant mice. These findings provide the first elucidation of the sex-dependent effects of APP mutations on colon cancer formation.},
}
@article {pmid42437010,
year = {2026},
author = {Igase, K and Igase, M and Matsuda, H and Hara, J and Bock, JR and Sadamoto, K and Shankle, WR},
title = {Relation between voxel-based specific regional analysis system for Alzheimer's disease (VSRAD) on 3-tesla MRI and cognitive performances: Practical application in clinical settings.},
journal = {IBRO neuroscience reports},
volume = {21},
number = {},
pages = {275-278},
pmid = {42437010},
issn = {2667-2421},
abstract = {BACKGROUND: Voxel-based specific regional analysis system for Alzheimer's disease (VSRAD) software using MRI scanner allows quantification of hippocampal and parahippocampal atrophy in the medial temporal structures by Z-score, and this score is widely used in clinical Alzheimer's disease (AD) diagnosis. However, it is unclear whether the Z-score is useful to discriminate normal aging from cognitive impairment (CI) or mild cognitive impairment (MCI). The present study examined the associations between VSRAD Z-score and cognitive performance quantified by Memory Performance Index (MPI) and determined a Z-score cut-off value.<br><br>METHOD: Three-tesla brain MRI was conducted in 100 outpatients without dementia, and all MRI data were analyzed using VSRAD. The target region of interest (ROI) mainly consisted of the para hippocampal gyrus. The degree of atrophy in the ROI was obtained from the averaged positive Z-score of the ROI. Cognitive performance was evaluated with the Japanese version of the MCI screen (MCIS). Patients were classified into normal (NL) and below normal (BNL) cognitive groups by MPI. The relation between MPI and VSRAD Z-score were assessed with logistic regression analysis, and the cut-off value for Z-score was determined by receiver operating characteristic curve analysis.<br><br>RESULTS: Sixty-two percent (62%) were identified as the BNL group by MPI. Univariate analyses found that the BNL group had a significantly higher age, shorter years of education, and higher Z-score in VSRAD compared to the NL group, but no statistically significant difference was observed between genders. Bivariate correlation found that MPI, which is adjusted for age, gender, and years of education, was significantly correlated with Z-score assessed by VSRAD (Pearson's r&#x202f;=&#x202f;-0.52, p&#x202f;<&#x202f;.001). A subsequent logistic regression of VSRAD Z-score on BNL classification was used to generate a receiver operating characteristic curve (AUC = 0.75). The Youden index was applied to identify a cut-off value of VSRAD Z-score of 1.14 (sensitivity = 62.9%; specificity = 84.2%) to classify MPI <&#x202f;50.2 (BNL) with overall accuracy of 73.5%.<br><br>CONCLUSIONS: VSRAD Z-score using VSRAD software was one independent factor significantly associated with cognitive performance measured by MPI. The determination of a cut-off value for Z-score (1.14) that can help discriminate normal patients from those with MCI.},
}
@article {pmid42437499,
year = {2026},
author = {Brown, CA and Robinson, JL and Das, SR and McGrew, E and Suh, E and Van Deerlin, VM and Irwin, DJ and Nasrallah, IM and Mechanic-Hamilton, D and Yushkevich, PA and Wolk, DA and Lee, EB},
title = {Clinicopathologic Evaluation of Amyloid Clearance in Alzheimer Disease.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2026.13058},
pmid = {42437499},
issn = {1538-3598},
abstract = {IMPORTANCE: The long-term efficacy of amyloid-targeting therapies hinges on their ability to slow downstream neuropathologic change, but little is known about the influence of amyloid clearance on tau pathology and neurodegeneration.<br><br>OBJECTIVE: To determine the postmortem and in vivo association between amyloid levels and downstream neuropathology after treatment with aducanumab in a patient with patchy areas showing minimal residual amyloid levels.<br><br>This clinicopathologic case report from a single academic memory center includes a male carrier of the p.R47H TREM2 variant, which is associated with a higher risk of Alzheimer disease, who was in his 50s, had mild cognitive impairment, and received aducanumab while participating in a randomized clinical trial. Fourteen untreated controls, who were matched by age or presence of the TREM2 variant, also are included.<br><br>EXPOSURES: The male carrier of the p.R47H TREM2 variant had received 30 doses of aducanumab (cumulative dose of 280 mg/kg) over 4.5 years.<br><br>MAIN OUTCOMES AND MEASURES: Neuropathologic evaluation at autopsy, positron emission tomography to measure standardized uptake value ratio as a measure of amyloid and tau levels, and magnetic resonance imaging to determine longitudinal change in cortical thickness.<br><br>RESULTS: Four years after receiving the final dose of aducanumab, the patient died. An autopsy showed variable levels of amyloid pathology, including brain regions with very low levels of amyloid juxtaposed with brain regions that had typically high levels of amyloid in the deep cortical layers and only low levels of amyloid in the superficial cortical layers. Compared with the brain regions of the untreated controls, the brain regions of the patient after treatment with aducanumab showed low levels of amyloid that were preferentially found in the gyral crests, were associated with less tau pathology at autopsy, and were associated with slower longitudinal atrophy on in vivo magnetic resonance imaging (&#x3b2;&#x2009;=&#x2009;-0.50 [95% CI, -0.62 to -0.37]; t&#x2009;=&#x2009;-7.96 and P&#x2009;<&#x2009;.001). In contrast, the patient's brain regions with high amyloid burden were preferentially found in the sulcal depths and had similar levels of tau pathology as seen at autopsy in the untreated controls.<br><br>CONCLUSIONS AND RELEVANCE: In this case report, areas of extensive amyloid clearance after amyloid-targeting therapy were associated with less downstream neuropathologic change. In addition, amyloid clearance appears to preferentially occur in the gyral crests. Future studies should evaluate the differential mechanisms involved in amyloid clearance from superficial and deep cortical layers and in gyri and sulci because extensive amyloid clearance may be necessary to achieve downstream neuropathologic benefit after removal of amyloid.},
}
@article {pmid42437964,
year = {2026},
author = {Couch, E and Gantenberg, JR and Belanger, E},
title = {Adoption of Alzheimer's disease biomarkers by primary care clinicians: findings from the National Dementia Workforce Study.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71665},
doi = {10.1002/alz.71665},
pmid = {42437964},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/diagnosis/diagnostic imaging ; *Biomarkers ; United States ; Cross-Sectional Studies ; *Primary Health Care/statistics &amp; numerical data ; Female ; Male ; *Physicians, Primary Care/statistics &amp; numerical data ; Magnetic Resonance Imaging ; Neuropsychological Tests/statistics &amp; numerical data ; Medicare ; Positron-Emission Tomography ; },
abstract = {INTRODUCTION: Biomarkers for Alzheimer's disease (AD) are now available for clinical use; however, little is known about their use in primary care.<br><br>METHODS: Cross-sectional analysis of 2024 data from the National Dementia Workforce Study, a nationally representative survey of primary care providers (PCPs) who treat Medicare beneficiaries with dementia. We used survey weights to generate nationally representative estimates of self-reported biomarker use.<br><br>RESULTS: Among 2574 PCPs, computed tomography/magnetic resonance imaging (CT/MRI) (79%) and neuropsychological testing (71%) were most commonly used, followed by positron emission tomography (PET) (18%), plasma (16%), genetic (14%), and CSF testing (9%). PCPs confident in diagnosing dementia and from specialist settings were more likely to report ordering PET, plasma, genetic, and CSF testing.<br><br>DISCUSSION: This study describes patterns in the adoption of AD biomarkers in the year after Medicare expanded coverage for some biomarkers, providing a baseline for measuring changes in biomarker use. Guidelines are needed to inform PCP decision-making for biomarkers.},
}
@article {pmid42437974,
year = {2026},
author = {Rutter, LA and Hamilton, LJ},
title = {Depressive symptom instability predicts incident mild cognitive impairment and dementia in older adults.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71672},
doi = {10.1002/alz.71672},
pmid = {42437974},
issn = {1552-5279},
support = {//NIH/ ; K01 AG086598/AG/NIA NIH HHS/United States ; R37AG057739-07/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Cognitive Dysfunction/epidemiology/diagnosis ; *Dementia/epidemiology/diagnosis ; *Depression/epidemiology ; Female ; Male ; Aged ; Longitudinal Studies ; Aged, 80 and over ; Incidence ; Risk Factors ; United States/epidemiology ; },
abstract = {INTRODUCTION: Neuropsychiatric symptoms frequently precede Alzheimer's disease and related dementias, yet risk prediction models typically rely on baseline depression severity or diagnostic status. We examined whether instability in depressive symptoms predicted incident mild cognitive impairment (MCI) or dementia.<br><br>METHODS: Data were drawn from 11,951 older adults enrolled across 42 US Alzheimer's Disease Research Centers and followed for up to 19 years. Depressive symptoms were assessed using the Geriatric Depression Scale and characterized using rule-based groupings and latent class trajectories. The Structured Life-Course Modeling Approach (SLCMA) was used to compare four competing temporal hypotheses of risk. Cox models adjusted for demographic factors and apolipoprotein E (APOE) &#x3b5;4 status.<br><br>RESULTS: Fluctuating depressive symptom trajectories were associated with increased risk of incident cognitive impairment. Symptom instability showed the lowest prediction error in exploratory SLCMA analyses.<br><br>DISCUSSION: Instability in depressive symptoms may represent an early and clinically accessible risk marker for MCI and dementia.},
}
@article {pmid42437975,
year = {2026},
author = {Thanou, E and Ganz, A and Pita-Illobre, D and Koopmans, F and Hoozemans, JJM and Rozemuller, A and Holstege, H and Smit, AB and Li, KW},
title = {Proteomics of post mortem brains in early- and late-onset Alzheimer's disease: Unraveling differential Aβ effects and potential AD biomarkers.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71662},
doi = {10.1002/alz.71662},
pmid = {42437975},
issn = {1552-5279},
support = {765704//EU Marie Curie ITN EuroNeurotrophin/ ; OCENW.KLEIN.558//Dutch Research Council (NWO)/ ; //OPD-ZonMW via the MODEM consortium/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/metabolism ; Biomarkers/metabolism ; *Proteomics ; *Amyloid beta-Peptides/metabolism ; Female ; tau Proteins/metabolism ; Male ; Aged ; *Brain/metabolism/pathology ; Aged, 80 and over ; Age of Onset ; Proteome ; Autopsy ; Phosphorylation ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) occurs primarily as late‑onset (LOAD) and less frequently as early‑onset (EOAD). Its defining pathologies are hyperphosphorylated tau tangles and amyloid beta (Aβ) plaques.<br><br>METHODS: We analyzed the proteomes of 115 post mortem temporal lobe samples by mass spectrometry and searched with a dedicated AD spectral library including tau post&#x2011;translational modifications and A&#x3b2; isoforms to examine global protein changes in LOAD and EOAD.<br><br>RESULTS: AD tissues showed mitochondrial and synaptic pathway downregulation and immune and small&#x2011;molecule metabolic process upregulation, with EOAD exhibiting larger fold changes. AD biomarkers were elevated, and two multi&#x2011;phosphorylated tau peptides (p&#x2011;tau231/p-tau235 and p-tau231/p-tau235/p-tau237) were detected predominantly in AD. A&#x3b2; was present in 45% of cognitively unimpaired elderly controls, with subtle proteome changes resembling an early stage of neurodegeneration.<br><br>DISCUSSION: EOAD appears more aggressive. Tau p-tau231/p-tau235 and p-tau231/p-tau235/p-tau237 hold promise as novel AD biomarkers. A&#x3b2;'s detection in cognitively unimpaired elderly controls precedes clinical AD symptoms.},
}
@article {pmid42438039,
year = {2026},
author = {Batool, M and Iqbal, J and Saif, H},
title = {Loneliness as an Interface Between Alzheimer's Disease and Suicidal Behaviour: A Methodological Concern.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {26},
number = {4},
pages = {e70194},
doi = {10.1111/psyg.70194},
pmid = {42438039},
issn = {1479-8301},
}
@article {pmid42438228,
year = {2026},
author = {Oh, JM and Jeong, WK and Son, HJ and Kim, SY and Oh, TW and Ji, M and Nam, JW and Baek, M and Park, JH and Shin, WH and Kim, HJ and Choi, B and Paik, MJ and Kim, H},
title = {Ameliorative Effects of a Naphthoquinone Derivative With β-Amyloid Aggregation Inhibitory Activity on Cognitive Impairment and Metabolite Analysis of the Blood and Brains of Mice.},
journal = {Drug development research},
volume = {87},
number = {5},
pages = {e70345},
doi = {10.1002/ddr.70345},
pmid = {42438228},
issn = {1098-2299},
support = {RS-2024-00347522//National Research Foundation of Korea (NRF)/ ; },
mesh = {Animals ; *Amyloid beta-Peptides/metabolism/antagonists &amp; inhibitors ; Mice ; Brain/metabolism/drug effects ; Male ; *Naphthoquinones/pharmacology/chemistry/therapeutic use ; Humans ; *Cognitive Dysfunction/drug therapy/metabolism ; Peptide Fragments/metabolism ; Alzheimer Disease/drug therapy/metabolism ; Scopolamine ; Madin Darby Canine Kidney Cells ; *Neuroprotective Agents/pharmacology ; Cognitive Enhancement ; },
abstract = {Accumulation of amyloid-β (Aβ) plaques is an important cause of Alzheimer's disease (AD) pathogenesis. In this study, we evaluated Aβ aggregation inhibitory activity of synthesized naphthoquinone derivatives as well as improvement in cognitive functions and metabolite profiling of brain tissues using scopolamine (SCO)-induced mice. Compound 888 (2-(4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)naphthalene-1,4-dione, [TPN]) showed the highest Aβ aggregation inhibitory activity (IC50 = 0.14 μM), and was more potent than the reference compound curcumin (IC50 = 1.63 μM). Compound TPN showed effective monoamine oxidase (MAO)-A, MAO-B, acetylcholinesterase, and butyrylcholinesterase inhibitions at 10 μM, likely as candidates for multitarget-directed ligands. TPN was permeable through the blood-brain barrier, and non-toxic to MDCK and SH-SY5Y cells. TPN displayed prolonged and stable interactions with Aβ42 during molecular dynamics simulations, in contrast to the short-lived contacts observed for curcumin. Cognitive impairment was significantly improved by TPN-treatment in behavioral tests. TPN treatment attenuated Aβ-related protein expression, inflammatory responses, oxidative stress-related changes, and apoptosis-related alterations, while preserving hippocampal pyramidal neurons and their typical morphology. In metabolite profiling, TPN modulated a narrower set of pathways mainly related to amino acid and kynurenine metabolism, whereas donepezil induced broader adjustments involving amino acid, mitochondrial/energy, and lipid-related pathways compared to those in the serum and cortex of the SCO group, in contrast to those in the hippocampus. Collectively, a potent Aβ aggregation inhibitor TPN showed significant cognitive improvement, accompanying by neuroprotective effects, decreasing inflammation, and retaining neuron structures, exhibiting changed metabolic profiles compared to the control treatments. These findings suggest that TPN has cognitive-protective and neuroprotective potential under scopolamine-induced impairment conditions and warrants further validation in AD-relevant models.},
}
@article {pmid42438357,
year = {2026},
author = {Simrén, J and Benedet, AL and Di Molfetta, G and Pola, I and Tan, K and Cantoni, V and Libri, I and Rivolta, J and Ghidoni, R and Zetterberg, H and Borroni, B and Ashton, NJ},
title = {Plasma Proteomic Changes in GRN and C9orf72 Frontotemporal Dementia.},
journal = {European journal of neurology},
volume = {33},
number = {7},
pages = {e70704},
doi = {10.1111/ene.70704},
pmid = {42438357},
issn = {1468-1331},
support = {//Bluefield Project/ ; //Beiglers stiftelse/ ; //Stiftelsen f&#xf6;r Gamla Tj&#xe4;narinnor/ ; },
mesh = {Humans ; *C9orf72 Protein/genetics ; *Progranulins/genetics ; *Frontotemporal Dementia/blood/genetics ; Female ; Biomarkers/blood ; Male ; Proteomics ; Middle Aged ; Cross-Sectional Studies ; Aged ; Neurofilament Proteins/blood ; },
abstract = {BACKGROUND: Biomarkers reflecting the complex pathophysiology of genetic frontotemporal dementia (FTD) will be increasingly important with the advent of therapeutic trials aiming to slow or prevent the disease. In this study, we aimed to identify blood biomarker candidates using a multiplex panel of CNS-related proteins.<br><br>METHODS: We cross-sectionally evaluated 67 carriers (21 presymptomatic and 46 symptomatic) of pathogenic FTD-causing mutations in the GRN (n&#x2009;=&#x2009;30 symptomatic) and C9orf72 (n&#x2009;=&#x2009;16 symptomatic) genes and 42 matched non-carriers. Clinical severity was estimated using the CDR Dementia Staging Instrument with National Alzheimer Coordinating Centre Frontotemporal Lobar Degeneration component (CDR plus NACC FTLD). A total of 124 CNS-related proteins were measured in plasma using the NUcleic acid Linked Immuno-Sandwich Assay (NULISA) CNS panel. Group-level changes were then investigated using linear and non-linear regression models.<br><br>RESULTS: In GRN- and C9orf72-FTD, neurofilament light (NfL) was the most clearly altered protein compared with non-carriers (GRN: &#x3b2; [95% CI]&#x2009;=&#x2009;4.0 standard deviations [3.6-4.4], C9orf72: &#x3b2;&#x2009;=&#x2009;2.8 [2.2-3.4]), followed by neurofilament heavy (NfH; GRN: &#x3b2;&#x2009;=&#x2009;0.83 [0.39-1.3], C9orf72: &#x3b2;&#x2009;=&#x2009;1.4 [0.8-2.0]). Proteins exclusively altered in GRN-FTD included glial fibrillary acidic protein (GFAp; &#x3b2;&#x2009;=&#x2009;0.50 [0.20-0.81]) and vascular cell adhesion protein 1 (VCAM1; Standardized &#x3b2;&#x2009;=&#x2009;-0.90 [-1.4 to -0.38]), changing with increasing disease severity. Neuronal pentraxin receptor (NPTXR; &#x3b2;&#x2009;=&#x2009;-0.94 [-1.5 to -0.4]) was selectively reduced in C9orf72-FTD. Nominally changed proteins in C9orf72-FTD included several inflammatory mediators.<br><br>CONCLUSIONS: Using this multiplex panel, established markers recapitulated&#xa0;previously established trends, while less-studied biomarker candidates were also identified. If validated in independent cohorts, these candidates could broaden the repertoire of blood biomarkers reflecting genetic FTD pathophysiology.},
}
@article {pmid42438681,
year = {2026},
author = {Zuo, M and Zhu, H and Liu, Z and Zhang, Q and Song, S},
title = {TF-JointMAE: a self-supervised multi-representation EEG learning framework for Alzheimer's disease spectrum classification.},
journal = {Cognitive neurodynamics},
volume = {20},
number = {1},
pages = {133},
pmid = {42438681},
issn = {1871-4080},
abstract = {UNLABELLED: Accurate identification of Alzheimer's disease (AD) and its early stages, namely subjective cognitive decline (SCD) and mild cognitive impairment (MCI), is crucial for timely intervention. Electroencephalography (EEG) is widely used for AD assessment due to its non-invasiveness and high temporal resolution; however, its non-stationarity, noise interference, and individual variability make classification more difficult. To address this, this paper proposes a self-supervised learning framework, TF-JointMAE (Temporal-Frequency Joint Masked Autoencoder), that jointly models temporal and time-frequency representations of EEG and incorporates age information as a conditional physiological prior within a unified embedding space. By performing self-supervised masked autoencoder pre-training on multiple public EEG datasets, the model learns consistent and robust EEG representations, thereby improving AD-spectrum classification under limited-label conditions. On the publicly available CAUEEG dataset (Normal, SCD, MCI, Dementia) and the olfactory EEG dataset (Normal, MCI, Dementia), TF-JointMAE achieved test accuracies of 77.97% and 96.43%, respectively, and demonstrated higher discriminative stability in the MCI category. Further occlusion-sensitivity analysis revealed that the model showed varying sensitivity to EEG channels and time-frequency regions across cognitive states. These results demonstrate that TF-JointMAE effectively improves the robustness of EEG representations, providing potential auxiliary support for AD-spectrum classification and clinical decision-making. All source code is publicly available to support reproducibility (https://github.com/redpig-zhu/TF-JointMAE).<br><br>SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11571-026-10501-8.},
}
@article {pmid42438728,
year = {2025},
author = {Moon, H and Du, JH and Lei, J and Roeder, K},
title = {AUGMENTED DOUBLY ROBUST POST-IMPUTATION INFERENCE FOR PROTEOMIC DATA.},
journal = {The annals of applied statistics},
volume = {19},
number = {2},
pages = {1006-1027},
pmid = {42438728},
issn = {1932-6157},
abstract = {Quantitative measurements produced by mass spectrometry proteomics experiments offer a direct way to explore the role of proteins in molecular mechanisms. However, analysis of such data is challenging due to the large proportion of missing values. A common strategy to address this issue is to utilize an imputed dataset, which often introduces systematic bias into downstream analyses if the imputation errors are ignored. In this paper we propose a statistical framework, inspired by doubly robust estimators, that offers valid and efficient inference for proteomic data. Our framework combines powerful machine learning tools, such as variational autoencoders, to augment the imputation quality with high-dimensional peptide data, and a parametric model to estimate the propensity score for debiasing imputed outcomes. Our estimator is compatible with the double machine learning framework and has provable properties. Simulation studies verify its empirical superiority over other existing procedures. In application to both single-cell proteomic data and bulk-cell Alzheimer's disease data our method utilizes the imputed data to gain additional, meaningful discoveries and yet maintains good control of false positives.},
}
@article {pmid42438861,
year = {2026},
author = {Liu, X and Lin, T and Jiang, Y and Luo, S and Chen, S and Chai, Y and Yang, Z and Wei, Y and Wang, H and Li, X and Xiang, YT and Sha, F and Tang, J},
title = {Antidepressant use and dementia, cognitive measures, and neuroimaging outcomes: A population-based cohort study.},
journal = {Psychological medicine},
volume = {56},
number = {},
pages = {e225},
doi = {10.1017/S0033291726104942},
pmid = {42438861},
issn = {1469-8978},
support = {82404371//National Natural Science Foundation of China/ ; 72304267//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Antidepressive Agents/therapeutic use/adverse effects ; Female ; Male ; *Dementia/epidemiology/diagnostic imaging ; Aged ; Neuroimaging ; Prospective Studies ; *Cognition/drug effects ; United Kingdom/epidemiology ; Middle Aged ; Magnetic Resonance Imaging ; Brain/diagnostic imaging ; Cohort Studies ; UK Biobank ; },
abstract = {BACKGROUND: Prior observational studies have reported conflicting results regarding whether antidepressant treatment reduces long-term dementia risk, likely due to confounding by indication and reverse causation. We aimed to investigate the association between baseline antidepressant use and incident dementia, incorporating cognitive and neuroimaging outcomes.<br><br>METHODS: We conducted a prospective cohort study using UK Biobank participants free of dementia at baseline. Antidepressant use was self-reported at baseline (2006-2010). Incident dementia was identified through linked electronic health records until December 19, 2022. Cox proportional hazards models estimated hazard ratios (HRs) for all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VD), adjusting for sociodemographic, lifestyle, health-related, antidepressant indication factors, and co-medication of other anticholinergics. In subsamples, cognitive performance (n&#xa0;=&#xa0;57,330) and structural brain imaging (n&#xa0;=&#xa0;42,276) were examined as intermediate outcomes.<br><br>RESULTS: Among 461,464 participants, 33,721 (7.3%) reported baseline antidepressant use. Over a mean follow-up of 13.4&#xa0;years, 7,922 (1.7%) developed incident dementia. Baseline antidepressant use was associated with higher risks of all-cause dementia (adjusted HR: 1.47, 95% CI 1.36-1.60), AD (1.53, 1.36-1.73), and VD (1.44, 1.23-1.70). Users performed worse on fluid intelligence and prospective memory tasks and showed lower total and gray matter volume, regional reductions in the hippocampal gray matter and basal nucleus, and greater white matter hyperintensity volume.<br><br>CONCLUSIONS: Baseline antidepressant use was linked to a higher risk of dementia, poorer cognitive performance, and adverse brain structural changes. These findings underscore the importance of judicious prescribing, regular cognitive monitoring, and consideration of non-pharmacological approaches in clinical care.},
}
@article {pmid42438933,
year = {2026},
author = {Ke, Q and Xiong, Y and Cai, Z and Chen, F and Zhou, Z and Chen, Z and Huang, Y and Fang, S and Wu, P and Wang, S and Wang, HX},
title = {Peptide-Functionalized Hydroxypropyl Cellulose Mitigates Amyloid-β Protein Induced Endothelial Leakiness and Enhances Cognitive Function in Alzheimer's Disease.},
journal = {Angewandte Chemie (International ed. in English)},
volume = {},
number = {},
pages = {e1351374},
doi = {10.1002/anie.1351374},
pmid = {42438933},
issn = {1521-3773},
support = {21875060//National Natural Science Foundation of China/ ; 51402095//National Natural Science Foundation of China/ ; 51903076//National Natural Science Foundation of China/ ; 23JRRA0925//Natural Science Foundation of Gansu Province/ ; HKLB2410//Hubei Key Laboratory for Precision Synthesis of Small Molecule Pharmaceuticals/ ; HKLA2503//Hubei Key Laboratory for Precision Synthesis of Small Molecule Pharmaceuticals/ ; 2024DJC023//Department of Science and Technology of Hubei Province/ ; 2025CDB034//Department of Science and Technology of Hubei Province/ ; 2026AFB734//Department of Science and Technology of Hubei Province/ ; 2026AFB408//Department of Science and Technology of Hubei Province/ ; },
abstract = {Amyloid-β (Aβ) plays a central role in Alzheimer's disease (AD) pathogenesis by inducing endothelial leakiness and disrupting blood-brain barrier (BBB) integrity via direct binding to endothelial tight junction proteins. In this work, a peptide-functionalized cellulose derivative (HPC-pet) was synthesized by conjugating hydroxypropyl cellulose (HPC) with the Aβ-targeting KLVFFAED peptide (pet). Integrative experimental and theoretical investigations were performed to characterize the efficacy and underlying mechanism of HPC-pet in mitigating amyloid - β protein-induced endothelial leakage (APEL), as well as to profile its pharmacokinetic behavior. Benefiting from the synergistic effects between HPC matrix and pet moieties, HPC-pet is capable of suppressing Aβ aggregation progression and encapsulating formed Aβ oligomers. In vitro cellular assays suggested that HPC-pet interferes with the binding of Aβ to endothelial junction proteins and mitigates APEL. Computational modeling further analyzed the intermolecular binding patterns among Aβ, HPC, and VE-cadherin to elucidate the molecular interaction mechanism. Consistent with in vitro and computational results, HPC-pet can efficiently traverse the BBB and mitigate APEL. Following sustained in vivo delivery of HPC-pet to AD mice, reduced cerebral Aβ plaque burden and improved cognitive function were detected. This strategy safeguards endothelial function from Aβ oligomer-mediated damage, offering a promising candidate for intervening Aβ-driven AD progression.},
}
@article {pmid42439012,
year = {2026},
author = {Sachdeva, G and Kumar, G and Kumar, B},
title = {Systematic review- hormone replacement therapy in postmenopausal women with medical co-morbidities.},
journal = {Post reproductive health},
volume = {},
number = {},
pages = {1-12},
doi = {10.1080/20533691.2026.2690376},
pmid = {42439012},
issn = {2053-3705},
abstract = {BACKGROUND: Safety and efficacy of HRT in women with chronic medical conditions remain incompletely understood. As life expectancy rises and the use of HRT becomes more common, condition-specific recommendations are crucial to support clinical decisions.<br><br>OBJECTIVES: Systematic review on disease-specific effects of HRT in peri- and postmenopausal women with chronic medical disorders.<br><br>DATA SOURCES: Comprehensive search of PubMed, Embase, Cochrane Central Register of Controlled Trials, and Web of Science was conducted from inception to 31 August 2025. Cross reference was undertaken.<br><br>ELIGIBILITY CRITERIA: Systematic reviews, meta-analysis, Randomised controlled trials, cohort, and case-control studies examining oral, transdermal, or other HRT formulations in peri- or postmenopausal women with chronic diseases were included. Case reports, editorials, conference abstracts, and non-English publications were excluded.<br><br>METHODOLOGY: Titles, abstracts, and full-text articles were independently evaluated by three reviewers. Data extraction included study design, participant characteristics, HRT regimen, and outcomes.<br><br>RESULTS: Fifty-four studies met inclusion criteria, covering neurological (epilepsy, migraine, Alzheimer's, Parkinson's, multiple sclerosis, meningioma), metabolic, cardiovascular, autoimmune, renal, hepatic, and endocrine conditions. Oral estrogen formulations may increase risk whereas transdermal preparations may confer lower thrombotic and hepatic risk (limited evidence). Neurological benefits were observed in Parkinson's disease and multiple sclerosis, but evidence was limited for Alzheimer's disease and migraine. HRT was generally safe in stable autoimmune conditions. Cardiovascular safety is supported in women without pre-existing disease.<br><br>CONCLUSIONS: HRT should be individualised according to comorbidities, formulation, and route, with preference for transdermal or low-dose regimens in high-risk populations.<br><br>UNLABELLED: Registration: PROSPERO ID CRD420251233527.},
}
@article {pmid42439047,
year = {2026},
author = {Hicken, MT and DeAngelis, R and Rigby, D and Burnside, L and Adar, S and Burgard, S and Davis, BA and Donnelly, R and Finlay, JM and Hajat, A and Lee, J and Perry, BL and Thorpe, LE and Umberson, D},
title = {The social environment and cognitive aging over the life course: laying out critical concepts and research gaps.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71648},
doi = {10.1002/alz.71648},
pmid = {42439047},
issn = {1552-5279},
support = {R01AG060011/AG/NIA NIH HHS/United States ; R01AG065319/AG/NIA NIH HHS/United States ; R01AG076032/AG/NIA NIH HHS/United States ; R37AG57739/AG/NIA NIH HHS/United States ; P30AG066614/AG/NIA NIH HHS/United States ; U25AG088894/AG/NIA NIH HHS/United States ; R01MD013299/MD/NIMHD NIH HHS/United States ; },
mesh = {Humans ; *Social Environment ; *Cognitive Aging/psychology ; *Aging/psychology ; Residence Characteristics ; Alzheimer Disease ; },
abstract = {The social environment refers to our interpersonal relations, workplaces, and neighborhoods, towns, or cities in which we live. A growing literature indicates that social environments are related to cognitive aging and risk of Alzheimer's disease and related dementias (AD/ADRD). Still, relatively little is known about how social-environmental exposures affect cognitive function over the life course and into older ages. Addressing this limitation, our paper outlines key features of the social environment and recommends priority areas of research on the social environment and cognitive aging. We divide our discussion into three subdomains: social connections, residential context, and work context. We then identify important gaps in the conceptual and empirical literature before outlining avenues for future research to strengthen our understanding of how social-environmental exposures over the life course link with cognitive function and AD/ADRD risk in late life.},
}
@article {pmid42439335,
year = {2026},
author = {Singh, S and Singh, S and Khandelwal, V and Bharti, U and Singh, PK},
title = {Gut Microbiota in Neuroinflammation, Neurodegenerative Disorders, and Neuropsychiatric Disorders: A Comprehensive Narrative Review.},
journal = {CNS &amp; neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273455874260702045636},
pmid = {42439335},
issn = {1996-3181},
abstract = {Neurodegenerative and neuropsychiatric illnesses are characterized by neuroinflammation, which is driven by microglial activation, cytokine production, and breakdown of the blood-brain barrier (BBB). It is currently known that the gut microbiota plays an important role in modulating neuroimmune signaling, which in turn may trigger anxiety-like behaviors and depressive phenotypes through the microbiota-gut-brain axis. This review aims to integrate the most recent mechanistic knowledge on treatment strategies targeting the gut microbiota to modulate neuroinflammation. This review article discusses preclinical and clinical studies that investigated microbial composition, metabolite profiles, and host-microbe interactions involved in neuroinflammatory processes. However, special attention was given to signaling via the vagus nerves and bile acids, as well as to tryptophankynurenine metabolism and short-chain fatty acids (SCFAs). To examine the potential connection between the two, researchers used animal models such as germ-free animals and antibiotic-injected mice for fecal microbiota transplantation (FMT). This article defines dysbiosis as amplifying neuroinflammatory responses by altering microglial phenotypes, disrupting the blood-brain barrier, and triggering the production of pro-inflammatory cytokines. In contrast, microbiome diversity rehabilitation through the use of probiotics, prebiotics, synbiotics, and dietary modifications reduces neuroinflammatory markers and enhances cognitive and behavioral status. Clinical trials have shown considerable promise in diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), autism spectrum disorder (ASD), and depression. However, variability in treatment protocols, treatment resistance, and host-specific factors continue to pose significant challenges. This narrative review integrates mechanistic insights into microglial activation, cytokine signaling, blood-brain barrier regulation, vagal pathways, tryptophan metabolism, and short-chain fatty acids with emerging clinical evidence and therapeutic strategies, including probiotics, prebiotics, dietary modulation, and personalized microbiome-based interventions. Despite promising therapeutic potential, microbiome engineering faces important challenges, including safety concerns, lack of standardized intervention protocols, and substantial inter-individual variability in host-microbiome responses, which currently limit clinical translation. This review focuses on both neurodegenerative and neuropsychiatric disorders, examining shared neuroinflammatory mechanisms mediated by the gut-brain axis and evaluating microbiotatargeted therapeutic strategies across these disease categories. The review discusses both preventive strategies, including dietary modulation, prebiotics, and lifestyle-based microbiome interventions, as well as therapeutic approaches such as microbiota-targeted treatments aimed at mitigating neuroinflammation and disease progression.},
}
@article {pmid42439337,
year = {2026},
author = {Chavan, V and Jadhav, S and Jatrate, F and Jondhalkar, G and Jangme, C and Mhettar, P},
title = {Stimuli-responsive Lipid-based Nanoplatforms for Targeted Therapy of Brain Diseases: Current Challenges and Future Directions.},
journal = {Central nervous system agents in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715249462564260518110221},
pmid = {42439337},
issn = {1875-6166},
abstract = {The reported research revealed the peculiarity of stimuli-responsive lipidic nanocarriers for localised therapy in distinct brain diseases, as it is supremely challenging due to the complexity of the brain. The pitfalls of conventional carriers could be carefully addressed utilising these smart lipidic nanoparticles due to their versatile features. The meticulous depiction of cardinal strategies for boosting barrier penetration with a mechanism paves the roadmap for lipidic nanoparticles in targeting. The present review article offers viewpoints on the application of distinct endogenous stimuli, like pH, hypoxia, and enzymes, along with exogenous stimuli, such as temperature, magnetism, and light. Each stimulus elaborated their exploitation of pathophysiological changes during diseased conditions, and its mechanism of utilisation in treating the diseases protects healthy cells from damage. Importantly, the detailed emphasis on the role of lipidic nanocarriers and their key advantages, including biosafety, biocompatibility, and high payload, offers a new avenue for targeted therapies. The stimuli-responsive lipid-nanoparticle-mediated targeted therapy in conditions like neurodegenerative diseases (Alzheimer's and Parkinson's), tumours like glioblastoma multiforme (GBM), infectious conditions like meningitis, and traumatic conditions like intracerebral haemorrhage are discussed in this work. Despite advancements, fewer issues like nanotoxicity, controlled size, scalability, and distribution within the brain appear to have more solutions. In future multi-stimuli applications, biomolecule integration and clinical translation could resolve many of the drawbacks of the present situation. Concisely, in the future, stimuli-responsive lipid nanoparticles will serve as an intriguing approach for targeted therapy in brain diseases.},
}
@article {pmid42439488,
year = {2026},
author = {Kittle, K and Perales-Puchalt, J and Flatt, JD and VanKim, N and Anderson, JG},
title = {Exploring Psychosocial Factors and Health Measures Among Hispanic/Latino/a/e/x (H/L) and Non-H/L White LGBTQ+ Unpaid Caregivers of People Living With Dementia.},
journal = {Research on aging},
volume = {},
number = {},
pages = {1640275261469198},
doi = {10.1177/01640275261469198},
pmid = {42439488},
issn = {1552-7573},
abstract = {PurposeExamine differences in socioenvironmental factors, risk and protective factors, and health between Hispanic/Latino/a/e/x (H/L) and non-H/L White LGBTQ+ caregivers of individuals with Alzheimer's disease and related dementias (ADRD).MethodsUtilizing secondary survey data, we used unadjusted logistic regression and examined distributions of risk and protective factors and health between H/L and non-H/L White LGBTQ+ ADRD caregivers.ResultsH/L caregivers reported lower levels of perceived stress (15.1 vs. 19.3) and caregiver stigma (47.2 vs. 53.8). H/L caregivers reported fewer months of caregiving (22.8 vs. 28.7) and fewer used respite services (37.9% vs. 53.7%). Fewer H/L caregivers reported one or more chronic conditions (21.4% vs. 37.3%), but their self-rated global health was significantly lower (26.8 vs. 32.5). Transgender H/L caregivers reported the lowest use of respite services and lowest rates of chronic conditions.ConclusionDespite less risk, H/L caregivers reported poorer self-reported health, highlighting disparities possibly shaped by intersecting identities.},
}
@article {pmid42439628,
year = {2026},
author = {Chmiel, J and Gawełczyk, W and Soczyńska, J and Leszek, J},
title = {Lymphoid-like Suppressive Microglia in Alzheimer's Disease: A New Neuroimmune Regulatory Axis?.},
journal = {Cells},
volume = {15},
number = {13},
pages = {},
doi = {10.3390/cells15131151},
pmid = {42439628},
issn = {2073-4409},
mesh = {*Alzheimer Disease/immunology/pathology ; Humans ; *Microglia/immunology/pathology/metabolism ; Animals ; Proto-Oncogene Protein Spi-1 ; *Neuroimmunomodulation ; *Lymphocytes/immunology/pathology ; Trans-Activators/metabolism ; },
abstract = {Microglia are central regulators of Alzheimer's disease pathogenesis, but their roles cannot be reduced to a simple protective-versus-harmful dichotomy. Genetic, single-cell, and spatial studies have shown that Alzheimer 's-associated microglia occupy diverse disease-linked states shaped by amyloid plaques, tau pathology, lipid stress, complement activation, astrocyte signaling, aging, and immune genetic risk. Among the regulatory nodes controlling these states, SPI1, which encodes the myeloid transcription factor PU.1, has emerged as a key determinant of microglial identity and disease responsiveness. Human genetic studies suggest that reduced SPI1 expression may be protective, whereas experimental data indicate that excessive PU.1 suppression can impair essential microglial functions. This review examines the emerging concept that partial, plaque-associated reduction in PU.1 may enable a distinct lymphoid-like immunoregulatory microglial program marked by CD28 expression. Recent evidence suggests that PU.1-low CD28-positive microglia may restrain neuroinflammation and amyloid pathology, raising the possibility that Alzheimer's plaques induce not only inflammatory and phagocytic microglial responses, but also endogenous suppressive programs that limit tissue damage. We discuss this proposed PU.1/CD28 regulatory axis in relation to disease-associated microglia, TREM2-APOE signaling, complement-mediated synapse loss, antigen-presentation pathways, plaque-niche biology, and therapeutic microglial reprogramming. We also highlight major unresolved questions, including whether PU.1-low CD28-positive microglia are present and functional in human Alzheimer's disease, whether they are specific to amyloid-rich niches or extend to tau and mixed pathologies, and how such states could be safely manipulated without disrupting essential immune surveillance. We propose that lymphoid-like suppressive microglia represent a promising but still unproven framework for understanding protective neuroimmune regulation in Alzheimer's disease and for developing state-specific microglial therapies.},
}
@article {pmid42439636,
year = {2026},
author = {Baldo, KAT and Gozlan, E and Chidebe, EO and Awogbindin, I and Ocaña Prieto, M and Dalmacio, LM and Ben-Azu, B and Frenkel, D and Tremblay, M&#xc8;},
title = {Human Microglial Molecular Alterations in Aging and Alzheimer's Disease.},
journal = {Cells},
volume = {15},
number = {13},
pages = {},
doi = {10.3390/cells15131159},
pmid = {42439636},
issn = {2073-4409},
support = {52867-59420//Joint Canada-Israel Research Program, Canadian Institutes of Health Research (CIHR), the International Development Research Center (IDRC), the Israel Science Foundation (ISF), and the Azrieli Foundation/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/metabolism/genetics ; *Microglia/metabolism/pathology ; *Aging/pathology/metabolism/genetics ; Oxidative Stress ; Cellular Senescence ; Animals ; Brain/pathology ; },
abstract = {Microglia, the resident innate immune cells of the central nervous system, are central players in brain development, healthy aging, and degenerative pathology, including Alzheimer's disease (AD). Aging is a major risk factor for AD, and various studies have identified alterations in microglial molecular signatures and morphological patterns that overlap with microglial states during aging. However, the mechanisms underlying the divergence of aging trajectories toward disease remain unclear. Thus, understanding the molecular changes in microglia during aging and AD pathology is crucial to elucidating the mechanisms that drive disease progression. In this review, we examine current advances in understanding the phenotypic alterations in human microglia, highlighting gene signatures and morphological changes that may aid in defining microglia's molecular and functional programs in healthy aging and over the course of AD. We further explore the roles of oxidative stress and cellular senescence in driving the development of a chronic reactive state in microglia during aging, which may also contribute to the complex process underlying the onset and progression of AD pathology. This review highlights the advancements in therapeutic strategies focused on targeting pertinent pathological microglial changes during aging and in disease to mitigate the AD neurodegenerative process.},
}
@article {pmid42439654,
year = {2026},
author = {Wrasidlo, W and Masliah, E},
title = {Emerging New Pathways in Malignant Neoplasms and Neurodegenerative Disorders: Perspectives for Therapeutics.},
journal = {Cells},
volume = {15},
number = {13},
pages = {},
doi = {10.3390/cells15131177},
pmid = {42439654},
issn = {2073-4409},
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/therapy/pathology ; *Neoplasms/metabolism/therapy/pathology ; Signal Transduction ; Animals ; Aging ; Proteotoxic Stress ; },
abstract = {Neurodegenerative disorders such as Alzheimer's disease (AD) and malignant neoplasms are among the most prevalent age-associated diseases worldwide. Although cancer is characterized by uncontrolled proliferation, resistance to apoptosis, and metabolic reprogramming, AD and other neurodegenerative disorders such as Lewy body disease (LBD) including Parkinson's Disease (PD) and fronto-temporal lobar degeneration (FTLD) are defined by synaptic dysfunction, neuronal loss, neuroinflammation, and impaired proteostasis with misfolded protein aggregates. Despite these contrasting phenotypes, converging epidemiological and molecular data support an inverse relationship between cancer and neurodegenerative disorders, whereby a history of cancer is associated with reduced AD risk, whereas AD is linked to a lower incidence of multiple malignancies. These observations suggest that oncogenesis and neurodegeneration may represent divergent outcomes of shared biological processes dysregulated during aging. This conundrum likely reflects differential regulation of core cellular pathways governing cell survival, stress responses, metabolism, and genomic integrity but could also reflect the differential influence of aging pathways and secreted growth factors. Pro-survival and proliferative signaling pathways commonly activated in cancer, including PI3K-AKT-mTOR signaling, altered p53 function, enhanced DNA damage tolerance, and anabolic metabolism, are often impaired in AD, LBD and FTLD, where neurons exhibit heightened vulnerability to stress, mitochondrial dysfunction, defective autophagy, and activation of pro-apoptotic cascades. Conversely, tumor-suppressive mechanisms that restrain proliferation may protect against malignancy but increase susceptibility to degeneration in post-mitotic neurons. Aging-related processes such as cellular senescence, immune dysregulation, and loss of proteostasis may further exert divergent effects in oncogenesis and neurodegeneration. This review aims to clarify associations between specific cancer types and neurodegenerative disorders, examine shared and opposing selected molecular mechanisms linking specific cancers and neurodegeneration, and contextualize these relationships within broader aging pathways (e.g., cell senescence, proteostasis). By integrating epidemiological, mechanistic, and therapeutic perspectives, we highlight unifying biological principles and translational opportunities at the intersection of cancer, neurodegeneration, and aging.},
}
@article {pmid42439669,
year = {2026},
author = {Robert, J},
title = {What Are the Potential Therapeutic Benefits of Targeting Blood-Borne Lipoproteins in the Treatment of Alzheimer's Disease?.},
journal = {Cells},
volume = {15},
number = {13},
pages = {},
doi = {10.3390/cells15131191},
pmid = {42439669},
issn = {2073-4409},
mesh = {Humans ; *Alzheimer Disease/drug therapy/blood/therapy ; *Lipoproteins/blood/metabolism ; Animals ; Amyloid beta-Peptides/metabolism ; Lipoproteins, HDL ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, the deposition of amyloid-β (Aβ) plaques, the formation of neurofibrillary tangles, and cerebrovascular dysfunction. Evidence suggests that blood-borne lipoproteins play a role in the disease's pathophysiology by influencing the cerebrovasculature and amyloid metabolism. Low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL) can contribute to oxidative stress, endothelial dysfunction, vascular dysfunction, and the accumulation of amyloidogenic peptides, thereby exacerbating neurodegeneration. The role of lipoprotein(a) (Lp(a)) remains unclear, whereas high-density lipoprotein (HDL) is recognized for its cerebroprotective properties, including anti-inflammatory and vasoreactive functions. These properties help to maintain neuronal homeostasis and facilitate the clearance of Aβ from the brain. This review summarizes the current evidence regarding the role of lipoproteins in AD and discusses how therapeutic strategies targeting lipoprotein pathways, such as lipid-lowering agents and HDL mimetics developed for cardiovascular diseases, may benefit patients with AD.},
}
@article {pmid42439681,
year = {2026},
author = {Li, X and Wang, X and Dou, J and Wang, J and Xue, F},
title = {Rethinking Anti-Inflammatory Therapy in Alzheimer's Disease: From Broad Suppression to Stage-State-Space Neuroimmune Reprogramming.},
journal = {Cells},
volume = {15},
number = {13},
pages = {},
doi = {10.3390/cells15131208},
pmid = {42439681},
issn = {2073-4409},
support = {20231023//Ministry of Industry and Information Technology/ ; DZS2026009//Zhejiang Wanli University/ ; SC1032511980070//Zhejiang Wanli University/ ; JT2680100001//Zhejiang Wanli University/ ; },
mesh = {*Alzheimer Disease/immunology/drug therapy/pathology/therapy ; Humans ; Animals ; *Anti-Inflammatory Agents/therapeutic use/pharmacology ; Microglia/metabolism ; Inflammation ; *Neuroimmunomodulation ; Astrocytes ; Neuroinflammatory Diseases ; },
abstract = {Alzheimer's Disease (AD) is now understood as a biologically diverse condition, with amyloid and tau pathology evolving within dynamic neuroimmune networks. This challenges the traditional view that AD-related inflammation can be broadly suppressed therapeutically. We review evidence showing that neuroinflammation in AD is stage-dependent, cell-state-specific, spatially organized, and functionally complex. Microglia and astrocytes can aid in plaque containment, debris clearance, synaptic balance, metabolic adaptation, and tissue repair, but may also exacerbate injury through type-I interferon, inflammasome, complement, tumor necrosis factor, and lipid pathways. Many failed anti-inflammatory trials likely stem from mismatches in targets, timing, spatial considerations, pathway redundancy, and biomarker selection, rather than invalidating neuroinflammation as a therapeutic target. Recent single-cell and spatial transcriptomic, proteomic, metabolomic, and network-medicine studies offer a framework for precision intervention by identifying inflammatory endotypes, anatomical niches, and pathway modules. We propose the Stage-State-Space Neuroimmune Reprogramming Model (S3-NRM), aligning AD immunotherapy with disease stage, glial/endotype state, and spatial inflammatory niche, guided by fluid, imaging, and omics biomarkers. Future therapies should selectively suppress harmful immune responses while preserving beneficial glial functions.},
}
@article {pmid42439701,
year = {2026},
author = {Delgado, AM and Greer, BD and Maul, RW and Gearhart, PJ},
title = {Hunting for an Antigen: Humoral Immunity in Alzheimer's Disease.},
journal = {Cells},
volume = {15},
number = {13},
pages = {},
doi = {10.3390/cells15131227},
pmid = {42439701},
issn = {2073-4409},
support = {AG000777//National Institute on Aging, NIH/ ; },
mesh = {Humans ; *Alzheimer Disease/immunology/pathology ; *Immunity, Humoral/immunology ; Animals ; Blood-Brain Barrier/immunology/pathology ; *Antigens/immunology ; B-Lymphocytes/immunology ; },
abstract = {Alzheimer's disease (AD) is the leading cause of dementia, affecting millions of individuals on a global scale. A fatal and incurable neurodegenerative disease, AD is defined by various molecular and cellular abnormalities, such as the formation of intracellular neurofibrillary tangles and extracellular amyloid plaque deposition, leading to increased neuroinflammation, parenchymal tissue breakdown, and cognitive deficiencies. These pathological conditions are associated with the disruption of the blood-brain barrier (BBB), which is the protective network of cells responsible for maintaining homeostasis at the borders of the central nervous system (CNS). The breakdown of the BBB results in a dysregulation of the neuroimmune axis. The induction of inflammatory and autoimmune responses has been a key topic of study in AD, particularly surrounding innate immune cell activation. Recent discoveries focusing on the adaptive immune branch in the diseased CNS show evidence of effector and memory T cell activation and expansion, highlighting the complex relationship of the neuroimmune axis. It is speculated that humoral immunity might play a significant role in pathology through the production of autoantibodies. However, the contribution of B cells and plasma cells is unclear. We aim to review the literature addressing the following questions: are B cells protective or pathogenic in the CNS during AD, and do their antibodies have specific antigenic targets within this niche? The characterization of humoral contributions to immune dysregulation in AD is critical to the development of novel therapeutic strategies to slow or prevent neurodegeneration and cognitive impairment.},
}
@article {pmid42439703,
year = {2026},
author = {Clemente, E and Sivasubramanian, R and Kordes, S and Bhatia, P and Hans, R and Vogel, S and Baumann, M and Klebl, B and Sterneckert, J},
title = {Reducing PI4KIIIα Levels or Activity Limits Tau Seed Internalization and Assembly in Human Cortical Neurons.},
journal = {Cells},
volume = {15},
number = {13},
pages = {},
doi = {10.3390/cells15131228},
pmid = {42439703},
issn = {2073-4409},
support = {01EK1606A//Federal Ministry of Research, Technology and Space/ ; core funding//TUD Dresden University of Technology/ ; },
mesh = {Humans ; *tau Proteins/metabolism/genetics ; *Neurons/metabolism/pathology ; *Cerebral Cortex/pathology/metabolism ; Induced Pluripotent Stem Cells/metabolism ; *Phosphotransferases (Alcohol Group Acceptor)/metabolism ; Minor Histocompatibility Antigens ; },
abstract = {Tau protein aggregation and spreading are central features of neurodegenerative diseases such as Alzheimer's disease and frontotemporal dementia. Here, we investigated the role of phosphatidylinositol 4-kinase type IIIα (PI4KIIIα) in regulating tau propagation. We first used tau biosensor cells to demonstrate that both pharmacological inhibition and genetic reduction in PI4KIIIα effectively reduce the seeding of tau aggregation by extracellular seeds. To extend these findings to a more physiologically relevant system, we generated induced pluripotent stem (iPS) cell-derived cortical neurons carrying pathogenic MAPT mutations. These neurons rapidly acquired tauopathy-associated features, including expression of disease-relevant isoforms such as 4R tau, thereby enabling in vitro modeling of tau pathology. Using this model, we established phenotypic assays to monitor tau propagation and aggregation and applied them to test candidate small molecules. Notably, inhibition of PI4KIIIα consistently reduced seeding of tau assemblies in human neurons, highlighting this kinase as an important player in the seeding of tau pathology. Collectively, our work identifies PI4KIIIα as a regulator of tau pathology and provides new experimental platforms to dissect the molecular mechanisms of tau propagation. These findings open potential avenues for the development of strategies to slow or prevent tau-mediated neurodegeneration in the central nervous system.},
}
@article {pmid42439783,
year = {2026},
author = {Ono, RMS and Lima, JEBF and Lira, JASP and Sanches, FCA and Piassi, LO and Coelho, LBV and Moreira, NCS and Sakamoto-Hojo, ET},
title = {Molecular and cellular processes connecting type 2 diabetes to Alzheimer's disease, focusing on oxidative stress, metabolic dysfunction, and neurodegeneration.},
journal = {Genetics and molecular biology},
volume = {49Suppl 1},
number = {Suppl 1},
pages = {e20250233},
doi = {10.1590/1678-4685-GMB-2025-0233},
pmid = {42439783},
issn = {1415-4757},
abstract = {Advancing age has been associated with an imbalance between a gradual increase in reactive oxygen species (ROS) production and a decline in the efficiency of antioxidant defense mechanisms. Due to the fact that organisms are constantly exposed to endogenous and exogenous ROS sources, this condition of oxidative stress promotes a systemic pro-oxidant state that, in conjunction with many other risk factors, progressively worsens throughout life, triggering the development of chronic diseases, such as type 2 diabetes (T2D) and Alzheimer's disease (AD). These diseases have emerged as closely interconnected conditions that share some common molecular and cellular mechanisms. In this review, on the light of literature data, we explore the interconnection between several pathological processes implicated in both diseases, focusing on a series of cellular and molecular alterations, from metabolic dysfunction to neurodegeneration (including insulin resistance, oxidative stress, mitochondrial and endoplasmic reticulum dysfunction, among others). We highlight how the connection between those processes may culminate in the development of neurodegeneration and disease progression. Furthermore, we discuss the challenges and limitations to model those diseases, emphasizing some aspects of the current knowledge in terms of providing new perspectives to the development of multi-target therapeutic approaches.},
}
@article {pmid42439854,
year = {2026},
author = {Assafa, TE and Dzikovski, B and Lai, AL and Freed, JH and Srivastava, M},
title = {Detergent-like Toxicity Mechanism of Amyloid Cylindrins Revealed by Cross-Link Spin Labeling Electron Spin Resonance.},
journal = {Journal of the American Chemical Society},
volume = {},
number = {},
pages = {},
doi = {10.1021/jacs.6c03827},
pmid = {42439854},
issn = {1520-5126},
abstract = {Amyloid oligomers are considered to be the most toxic species in neurodegenerative diseases, such as Alzheimer's, and Parkinson's, among others. A major challenge in studying amyloid oligomers has been their heterogeneous character, coupled with a lack of methods that can probe targeted, localized structural information. In this paper, we show that in detergent micelles, the oligomeric state of amyloid cylindrin peptide K11 V increases from a hexamer to an octamer. This reveals a detergent-like toxicity mechanism of the K11 V peptide, in which the octamer-form extracts lipids from biological membranes. The findings are confirmed by Alphafold simulations, showing that the octamer has a β-barrel structure, with a pore stabilized by using the unbranched hydrophobic tails of the detergent molecules. The experimental results are obtained by a unique electron spin resonance (ESR)-based methodology that can be applied to amyloidogenic proteins to uncover inaccessible amyloid oligomer structures. The process involves (1) stabilization of the minimal amyloid oligomer domain, using a cross-linking bifunctional nitroxide spin label, combined with (2) an oligomer stabilizing mutation, (3) DEER spectroscopy, which can be performed in a native environment, and (4) T1-edited DEER measurements, which can validate structure in samples with heterogeneous populations, combined with (5) a model-free distance reconstruction approach that can analyze distance distributions with inverted distance components, ideal for analysis of T1-edited DEER.},
}
@article {pmid42440180,
year = {2026},
author = {Mohamadpour, M and Amandadi, M and Javan, M and Hosseinkhani, S},
title = {A Combination of Artemisinin, N-acetylcysteine, Resveratrol, and Hesperidin Ameliorates Hippocampal Damage and Pathological Features in an Experimental Model of Alzheimer's Disease.},
journal = {Neurochemical research},
volume = {51},
number = {4},
pages = {},
pmid = {42440180},
issn = {1573-6903},
mesh = {Animals ; *Resveratrol/therapeutic use/administration &amp; dosage ; *Alzheimer Disease/drug therapy/pathology/chemically induced/metabolism ; *Hippocampus/drug effects/pathology/metabolism ; *Hesperidin/therapeutic use/administration &amp; dosage ; *Acetylcysteine/therapeutic use/administration &amp; dosage ; Male ; *Artemisinins/therapeutic use/administration &amp; dosage ; *Neuroprotective Agents/therapeutic use/administration &amp; dosage ; Rats ; Disease Models, Animal ; Drug Therapy, Combination ; Streptozocin ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; Maze Learning/drug effects ; Rats, Sprague-Dawley ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive impairment and pathological accumulation of amyloid-β and tau proteins. This study investigated the potential neuroprotective effects of a combined treatment consisting of artemisinin, N-acetylcysteine, resveratrol, and hesperidin in a streptozotocin (STZ)-induced intracerebroventricular (ICV) rat model of AD. Twenty 8-week-old rats were divided into four groups: control, SHAM, STZ-ICV, and STZ-ICV receiving oral administration of the compound combination for 30 days. Cognitive performance was evaluated using the Morris water maze and passive avoidance tests. Neurodegenerative and molecular changes were assessed through Western blot analysis of phosphorylated tau, amyloid-β-related markers, and apoptosis- and inflammation-associated proteins. Histological analyses included Nissl staining and immunofluorescence for amyloid deposition and caspase-3 expression. Results demonstrated that STZ-ICV administration induced significant cognitive impairment, neuronal loss, and increased amyloid-β and phosphorylated tau levels. Treatment with the combined compounds partially improved behavioral performance and was associated with reductions in amyloid-β deposition, tau phosphorylation, and caspase-3 expression, along with improved neuronal preservation in the hippocampus. These findings suggest that the combined administration of artemisinin, N-acetylcysteine, resveratrol, and hesperidin exerts multi-target neuroprotective effects in an experimental AD model, potentially through modulation of oxidative stress, neuroinflammation, and apoptotic pathways. However, further studies are required to evaluate pharmacokinetics, safety, and translational relevance before clinical application.},
}
@article {pmid42440182,
year = {2026},
author = {Chijioke, BS and Ben-Azu, B and Esuku, DT and Nekabari, MK and Usin, SG and Friday, FB and Iwhiwhu, P and Moses, AS and Chidebe, EO and Nwawuba, S},
title = {Silymarin attenuates senescence-exacerbated amyloidogenesis, neuroinflammation, and oxidative stress in lipopolysaccharide-induced memory impairment in aging mice.},
journal = {Biogerontology},
volume = {27},
number = {4},
pages = {},
pmid = {42440182},
issn = {1573-6768},
mesh = {Animals ; *Oxidative Stress/drug effects ; *Silymarin/pharmacology ; Lipopolysaccharides ; Female ; *Memory Disorders/chemically induced/drug therapy/metabolism ; *Aging/drug effects/metabolism ; Mice ; Antioxidants/pharmacology ; *Neuroinflammatory Diseases/metabolism/drug therapy ; Doxycycline ; },
abstract = {Accelerated cellular perturbations such as cellular senescence, neuroinflammation and oxidative stress are hallmarks of Alzheimer's disease, a neurodegenerative disease associated with memory decline. However, the senolytic effects of silymarin, a flavonolignan with known antioxidant and anti-inflammatory properties, on memory decline remain unknown. Hence, we investigated the effect of silymarin on doxycycline-mediated senescence and exacerbated neuroinflammation in lipopolysaccharide-induced memory-impaired mice. Five groups of adult Swiss female mice (n = 10) were exposed to doxycycline-induced accelerated senescence for 21 days, followed by lipopolysaccharide-induced neuroinflammation from days 15-21, and silymarin (50 and 100 mg/kg, p.o.) or donepezil (1 mg/kg, p.o.) treatments. Spatial and non-spatial memory, and social and motor function tests in mice were assessed. Biochemical assays were performed on the prefrontal cortex and hippocampus to assess senescence-associated secretory phenotypes (SASPs), including SA-β-galactosidase activity, cytokines (TNF-α, IL-6, IL-10), amyloid-beta levels, acetylcholinesterase activity, oxidative stress markers, and molybdoenzymes. Doxycycline-lipopolysaccharide-exacerbated memory impairments were reversed by silymarin, accompanied by reduced molybdoenzymes, malondialdehyde, nitrite, and elevated antioxidants (glutathione, superoxide-dismutase, catalase) in the prefrontal cortex and hippocampus. Additionally, silymarin reverses doxycycline-exacerbated lipopolysaccharide-induced increases in IL-6 and TNF-α release and myeloperoxidase activity while also reducing IL-10 levels. Similar to donepezil, silymarin reduced heightened acetylcholinesterase activity associated with doxycycline-enhanced lipopolysaccharide-induced accumulation of cortical SA-β-galactosidase and amyloid-β levels, relative to the doxycycline-lipopolysaccharide group. These findings suggest that silymarin ameliorates doxycycline-lipopolysaccharide-exacerbated memory impairment and modulates senescence and neuroinflammation by reducing oxidative stress, SASP marker levels, and amyloid-beta concentrations in the prefrontal cortex and hippocampus of mouse brains.},
}
@article {pmid42440193,
year = {2026},
author = {Adiniaev, Y and Omar, M and Daniel, O and Timor, TM and Barash, Y and Brook, OR and Klang, E and Gorenshtein, A},
title = {Generative large language models in the clinical management of Alzheimer's disease and mild cognitive impairment.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {8},
pages = {},
pmid = {42440193},
issn = {1590-3478},
mesh = {Humans ; *Alzheimer Disease/therapy/diagnosis ; *Cognitive Dysfunction/therapy/diagnosis ; *Large Language Models ; Generative Artificial Intelligence ; },
abstract = {BACKGROUND: Dementia affects over 55 million people worldwide. Mild cognitive impairment (MCI) often precedes Alzheimer's disease (AD). Clinical management requires integrating uncertain evidence from neuropsychological testing, neuroimaging, and biomarkers. Large language models (LLMs) also generate probabilistic outputs, but whether they can reliably support diagnostic, therapeutic, or educational tasks in AD and MCI has not been systematically examined.<br><br>METHODS: We searched PubMed, Scopus, and PubMed Central (January 2023 to April 2026) for studies evaluating generative LLMs on clinical tasks in Alzheimer's disease (AD) or mild cognitive impairment (MCI). Risk of bias was assessed using QUADAS-AI and AXIS. Narrative synthesis followed the SWiM guideline.<br><br>PROSPERO: CRD420261372436.<br><br>RESULTS: Eleven studies were included: diagnosis (n&#x2009;=&#x2009;3), treatment guidance (n&#x2009;=&#x2009;2), and patient/caregiver education (n&#x2009;=&#x2009;8); two studies contributed to multiple domains. Diagnostic models achieved high internal accuracy (0.94-0.97) but declined on external validation; three-way classification accuracy dropped approximately 7% points, and MMSE-prediction R&#xb2; collapsed from 0.90 to 0.25 on an external dataset. Treatment guidance approached but did not match structured clinical guidelines. Educational outputs were rated moderate to high quality but lacked source attribution and exceeded recommended reading levels; retrieval augmentation improved usability without improving accuracy. Hallucination was quantified in only 2 of 11 studies, and no study evaluated prospective clinical use.<br><br>CONCLUSIONS: Current evidence does not support the use of LLMs for diagnosis, treatment selection, or patient education in AD/MCI without clinician oversight. These findings reflect the specific model versions, prompting strategies, and evaluation conditions in place at the time of each study, and are further limited by small heterogeneous evaluations, sparse hallucination measurement, and absence of prospective clinical validation.},
}
@article {pmid42440235,
year = {2026},
author = {Arruda, JE and Dundon, NM and Jefferson, A and Jester, H and Ortega, A and Folk, E and Ibrahim, S and Mrahi, N and Wade, A},
title = {Improving the Reliability of the Flash Visual Evoked Potential P2 (FVEP-P2).},
journal = {Applied psychophysiology and biofeedback},
volume = {},
number = {},
pages = {},
pmid = {42440235},
issn = {1573-3270},
abstract = {Unlike the pattern-reversal visual evoked potential, the flash visual evoked potential (FVEP) has had limited clinical use because of lower reproducibility and higher inter- and intra-individual variability. One potential explanation involves the time-locked nature of FVEP recordings, where activity such as unintentional suppression of eyes-closed alpha can lead to overlapping potentials that might obscure the FVEP-P2. The present investigation evaluated the reliability of the FVEP-P2 in young healthy controls across five sessions after applying narrow-band filtering (1-7 Hz) and additional notch filtering to remove alpha and beta activity. It was hypothesized that spectral entrainment would occur within the alpha and that correction for this entrainment would significantly improve the reliability of FVEP-P2. 27 younger, healthy participants aged 18-39 years (M = 24.48, SD = 5.26; 17 females) took part in the study, all reporting no history of photosensitivity or seizures, neurological disorders, or color deficiency. Each participant experienced five sessions of 100 strobe flashes with their eyes closed. The FVEP-P2 associated with each trial was identified using an automated algorithm. Narrow-band filtering (1-7 Hz) significantly improved FVEP-P2 latency reliability compared to the uncorrected condition. Notch filters targeting alpha and beta separately did not produce significant improvements, suggesting additive or overlapping contributions. FVEP-P2 amplitude reliability also improved with filtering, primarily because of attenuating alpha-band interference. Narrow-band and notch filtering mitigated alpha- and beta-band interference, enhancing the test-retest reliability of the FVEP-P2. These findings establish a clearer physiological basis for FVEP unreliability and demonstrate that spectral correction can elevate the FVEP-P2 to clinically acceptable reliability levels, supporting the continued clinical utility of the FVEP, particularly in patients for whom pattern-reversal stimuli are unsuitable (e.g., infants, comatose, or uncooperative individuals) and as a candidate biomarker in mild cognitive impairment and Alzheimer's disease (Arruda et al., 2020; Fix et al., 2014).},
}
@article {pmid42440317,
year = {2026},
author = {Miner, AE and Zetterberg, H and Blennow, K and Groh, JR and Singh, A and Dieckhoff, K and Tripodis, Y and Adler, CH and Balcer, LJ and Bernick, C and Peskind, E and Asken, BM and Tanner, JA and Rabinovici, GD and Banks, SJ and Barr, WB and Wethe, JV and Cantu, RC and Dodick, DW and Mez, J and Palmisano, JN and Martin, B and Stein, TD and McKee, AC and Cummings, JL and Shenton, ME and Reiman, EM and Stern, RA and Ashton, NJ and Alosco, ML and , },
title = {Plasma Phosphorylated Tau 217 in Participants at Risk for Chronic Traumatic Encephalopathy.},
journal = {JAMA network open},
volume = {9},
number = {7},
pages = {e2622966},
doi = {10.1001/jamanetworkopen.2026.22966},
pmid = {42440317},
issn = {2574-3805},
mesh = {Humans ; Male ; *Chronic Traumatic Encephalopathy/blood/diagnosis ; *tau Proteins/blood ; Biomarkers/blood ; Case-Control Studies ; Middle Aged ; Longitudinal Studies ; Phosphorylation ; Amyloid beta-Peptides/blood ; Aged ; Adult ; },
abstract = {IMPORTANCE: In vivo biomarkers for detecting neuropathologies from repetitive head impacts (RHI), including chronic traumatic encephalopathy (CTE), are needed.<br><br>OBJECTIVE: To evaluate the utility of plasma phosphorylated tau 217 (p-tau217), assess its performance as a beta-amyloid (A&#x3b2;) biomarker in participants with RHI exposure at risk for CTE, and explore concordance with CTE neuropathology in a postmortem subsample.<br><br>This longitudinal, multicenter, case-control study used data from the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of CTE (DIAGNOSE CTE) Research Project, collected from September 2016 to October 2023. Participants were former American football players (case participants) and asymptomatic men unexposed to RHI (control participants). A subsample had available neuropathologic data.<br><br>EXPOSURES: RHI, traumatic encephalopathy syndrome (TES) diagnoses, and levels of CTE certainty.<br><br>MAIN OUTCOMES AND MEASURES: Plasma p-tau217 (classified as positive [&#x2265;0.63 pg/mL], intermediate [0.40-0.62 pg/mL], and negative [<0.40 pg/mL]), A&#x3b2;-positron emission tomography (PET; 18F-florbetapir; with A&#x3b2;-positive defined as a standardized uptake value ratio [SUVR] &#x2265;1.10), and tau-PET (18F-flortaucipir). TES diagnoses were assigned by multidisciplinary consensus conference. Analyses of postmortem brains controlled for age, race, and APOE &#x3b5;4 status.<br><br>RESULTS: Among 231 participants (mean [SD] age, 57.75 [8.25] years), 177 were former football players (117 professional and 60 college) and 54 were unexposed participants. Former football players had higher baseline mean (SD) p-tau217 concentrations than unexposed participants (0.35 [0.26] pg/mL vs 0.27 [0.14] pg/mL; P&#x2009;=&#x2009;.008), although this was driven by a higher proportion of A&#x3b2;-PET-positive participants among former players. Plasma p-tau217 increased over time across the sample (B&#x2009;=&#x2009;0.207 [95% CI, 0.117-0.298]; P&#x2009;<&#x2009;.001), with no significant time&#x2009;&#xd7;&#x2009;exposure group interactions. Among football players, p-tau217 showed no time&#x2009;&#xd7;&#x2009;group interactions with TES diagnosis, TES-CTE certainty, or RHI metrics. Higher p-tau217 concentration correlated with higher global A&#x3b2;-PET SUVR (B&#x2009;=&#x2009;0.058 [95% CI, 0.053-3.501; P&#x2009;=&#x2009;.01), with a few discordant cases (5 participants were p-tau217-negative and A&#x3b2;-PET-positive; 7 participants were p-tau217-positive and A&#x3b2;-PET-negative). P-tau217 had similar areas under the curve for projecting A&#x3b2;-PET positivity as cerebrospinal fluid (CSF) p-tau181/A&#x3b2;42 and CSF A&#x3b2;40/42 measures (p-tau217: AUC, 0.88 [95% CI, 0.80-0.96]; CSF p-tau181/A&#x3b2;42: AUC, 0.89 [95% CI, 0.79-1.00]; CSF A&#x3b2;40/42: AUC, 0.85 [95% CI, 0.72-0.98]). Among 9 brain donors, 6 had CTE (stages II-IV; none with Alzheimer disease). Seven had negative or intermediate p-tau217, concordant with A&#x3b2;-PET. Two p-tau217 outliers with stage III CTE had normal concentrations upon additional testing.<br><br>CONCLUSIONS AND RELEVANCE: The findings of this study suggest that plasma p-tau217 concentration is unlikely to be useful for the detection of CTE, but it does show utility for ruling out A&#x3b2; pathology in participants at risk for CTE.},
}
@article {pmid42440519,
year = {2026},
author = {Lee, CC and Calegari, F},
title = {Enhancing adult neurogenesis attenuates hippocampal-related behavioral deficits in an Alzheimer's mouse model.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1833016},
doi = {10.3389/fnins.2026.1833016},
pmid = {42440519},
issn = {1662-4548},
abstract = {Alzheimer's disease (AD) is the most prevalent form of dementia, characterized by progressive memory loss, cognitive decline, and emotional dysregulation. Adult hippocampal neurogenesis (AHN) critically contributes to cognition and mood but undergoes precipitous decline during AD progression. Here, we investigated whether enhancing AHN through genetic expansion of endogenous neural stem cells (NSC) ameliorates AD-related phenotypes. Using lentiviral overexpression of the cell cycle regulators Cdk4 and CyclinD1 in the dentate gyrus of 3xTg-AD mice, we show that enhancing AHN is accompanied by partial improvements in selected behavioral measures associated with hippocampal function, including in the open-field test and Morris water maze. These findings indicate that the AD-compromised neurogenic niche remains responsive to NSC-targeted stimulation and support the use of AHN as a potential additional avenue for multi-modal therapeutic strategies for AD.},
}
@article {pmid42440553,
year = {2026},
author = {Dhivyabharathi, VR and Suresh Kumar, S},
title = {Hybridization of fuzzy logic based relevance vector and multi kernel image enhancement for Alzheimer's disease diagnosis.},
journal = {Health information science and systems},
volume = {14},
number = {1},
pages = {72},
doi = {10.1007/s13755-026-00465-8},
pmid = {42440553},
issn = {2047-2501},
abstract = {Alzheimer's disease (AD) is a progressive neurological disorder impacting a significant segment of the global population. Magnetic resonance imaging (MRI) is used to visualize brain structures and detect changes associated with AD. Early detection remains a major challenge, particularly for multiclass classification of disease severity. This paper presents an integrated hybrid framework for AD diagnosis combining Variational Mode Decomposition, fuzzy clustering, and multi-kernel learning. The proposed method comprises: (i) Variational Mode and Non-convex Optimized pre-processing for noise removal, (ii) Fuzzy Relevance Vector Machine-based segmentation to identify regions of interest, and (iii) Multi-Kernel SVM based clustering for classifying mild, moderate, and non-demented cases. The framework is validated on the Alzheimer's Disease Multiclass Images Dataset. Performance is evaluated using peak signal-to-noise ratio (PSNR), segmentation accuracy, training time, and precision. The results demonstrate that systematic integration of these established techniques achieves competitive performance, with average PSNR of 28.45 dB, segmentation accuracy of 91%, and precision of 90.6%.},
}
@article {pmid42440589,
year = {2026},
author = {Huang, X and Xu, G and Zhou, Y and Wang, D and Ai, L and Liu, H and Fan, A and Wang, L and Zhang, P},
title = {P2-engineered exosomes encapsulating curcumin alleviate cognitive decline in AD-like mice by improving microglia-related neuropathology.},
journal = {Materials today. Bio},
volume = {39},
number = {},
pages = {103388},
doi = {10.1016/j.mtbio.2026.103388},
pmid = {42440589},
issn = {2590-0064},
abstract = {Natural exosomes, as drug carriers, can deliver anti-inflammatory agents across the blood-brain barrier (BBB) to lesion sites in the brain, thereby demonstrating immense potential in the treatment of brain inflammation-related diseases. However, the application of natural exosomes is constrained by their poor targeting ability. Herein, we report a novel drug delivery system (P2-Exo-Cur) constructed by engineering exosomes to display the P2 peptide on their surface, thereby enabling targeted delivery of curcumin to microglia. Our results revealed that P2-Exo-Cur possesses a nanoscale membrane structure and can efficiently deliver curcumin to microglia both in vitro and in vivo. This technology provides a microglia-targeted delivery approach for anti-inflammatory agents such as curcumin, while overcoming the undesirable off-target effects that limit their efficacy. Furthermore, treatment of lipopolysaccharide (LPS)-induced inflammatory BV2 cell models with P2-Exo-Cur significantly suppressed the polarization of BV2 cells toward the M1 phenotype, as well as the secretion of pro-inflammatory cytokines. Finally, we also validated the excellent therapeutic potential of this technology in the 5xFAD mouse model. In conclusion, in this study, we for the first time constructed engineered exosomes that can specifically bind to the NCAM protein on microglia to achieve precise delivery of curcumin by expressing the P2 peptide on their surface, exerting beneficial effects in AD treatment without causing significant adverse effects. This strategy may offer a non-invasive and innovative therapeutic method for the management of brain inflammation-related diseases.},
}
@article {pmid42440665,
year = {2026},
author = {Han, J and Sun, Y and Song, Y and Wu, Y and Wang, X},
title = {The latest research progress of ligustilide in the prevention and treatment of central nervous system disorders.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1843537},
doi = {10.3389/fphar.2026.1843537},
pmid = {42440665},
issn = {1663-9812},
abstract = {BACKGROUND: Ligustilide (LIG), a natural phthalide compound mainly isolated from Angelica sinensis and Ligusticum chuanxiong, has attracted increasing attention because of its diverse pharmacological activities, including anti-inflammatory, antioxidant, anti-apoptotic, and neuroprotective effects. Emerging studies suggest that LIG may have therapeutic relevance in central nervous system (CNS) disorders.<br><br>PURPOSE: This review systematically summarizes the pharmacological effects, molecular mechanisms, pharmacokinetic characteristics, metabolism, safety profile, and therapeutic potential of LIG in CNS disorders.<br><br>METHODS: Relevant studies published up to 26 October 2025 were retrieved from PubMed, Web of Science, and Scopus using keywords related to ligustilide, central nervous system disorders, pharmacokinetics, metabolism, and toxicity. After removing duplicate records and excluding reviews, editorials, and irrelevant articles, 55 eligible original studies were included in this review.<br><br>RESULTS: Current evidence indicates that LIG exerts neuroprotective effects in multiple CNS disorders, including ischemic stroke, cerebral ischemia-reperfusion injury, vascular dementia, Alzheimer's disease, Parkinson's disease, traumatic brain injury, and anxiety disorders. Its mechanisms mainly involve modulation of PI3K/Akt, MAPK, NF-&#x3ba;B, Nrf2/ARE, AMPK, and other signaling pathways, leading to reduced oxidative stress, inflammation, apoptosis, and mitochondrial dysfunction. In addition, available studies suggest that LIG can cross the blood-brain barrier and shows relatively favorable safety in preclinical models.<br><br>CONCLUSION: LIG demonstrates broad neuroprotective potential in preclinical studies and may represent a promising candidate for CNS disease intervention. However, its poor chemical stability, low oral bioavailability, limited toxicity evaluation, and lack of clinical evidence remain major challenges for translational application. Further studies are required to optimize delivery strategies and validate its efficacy and safety in clinical settings.},
}
@article {pmid42440686,
year = {2026},
author = {Feng, X and Bi, S and Shi, C and Chang, Q and Zhang, J and Zhuang, Y},
title = {Comparison of safety of lecanemab and donanemab: a real-world disproportionality analysis using the FDA adverse event reporting system.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1868789},
doi = {10.3389/fphar.2026.1868789},
pmid = {42440686},
issn = {1663-9812},
abstract = {BACKGROUND: Lecanemab and donanemab are anti-amyloid-β (Aβ) monoclonal antibodies recently approved for the treatment of Alzheimer's disease (AD). Although both agents have demonstrated therapeutic potential, their post-marketing adverse event reporting profiles remain insufficiently characterized and compared in spontaneous reporting systems. This study aimed to systematically compare adverse event signals associated with these two drugs using the FDA Adverse Event Reporting System database, with sex-stratified and sensitivity analyses performed to support the main findings.<br><br>METHODS: FAERS reports up to the fourth quarter of 2025 were retrospectively analyzed. Reports in which lecanemab or donanemab was recorded as the primary suspect drug were included. AEs were classified by system organ classes (SOCs) and preferred terms (PTs) according to the Medical Dictionary for Regulatory Activities (MedDRA). Signal detection was performed using four algorithms: reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS). Sex-stratified analysis, sensitivity analysis after excluding reports involving concomitant medications, and time-to-onset (TTO) analysis based on the Weibull shape parameter model were also conducted. False discovery rate (FDR) correction was applied to analyses involving multiple P values.<br><br>RESULTS: A total of 3,640 AE reports were identified, including 2,602 for lecanemab and 1,038 for donanemab. Nervous system disorders was the most frequently reported SOC and the only SOC meeting the positivity criteria across all four algorithms for both drugs. At the PT level, the frequently reported events for both drugs were mainly concentrated in amyloid-related imaging abnormality (ARIA)-related events, including ARIA with oedema/effusion (ARIA-E) and ARIA with microhaemorrhages/haemosiderin deposition (ARIA-H), headache, and infusion-related reactions. The strongest disproportionality reporting signals were mainly observed for ARIA-related preferred terms and cerebral microhaemorrhage. In separate FAERS-based disproportionality analyses, lecanemab showed stronger disproportionality reporting signals for ARIA-H, whereas donanemab showed stronger disproportionality reporting signals for ARIA-E. In addition, drug-specific PT signal distributions differed between the two agents. Several potential novel PT signals were also identified. Sex-stratified analysis suggested differences in the distribution of certain PT signals between female and male reports. Sensitivity analysis supported the stability of most core signals. The median TTO was 46 days for lecanemab and 31 days for donanemab, and Weibull analysis suggested different temporal patterns of AE occurrence.<br><br>CONCLUSION: Using four signal detection algorithms, this study compared real-world adverse event reporting profiles associated with lecanemab and donanemab. The two drugs showed both shared and distinct adverse event reporting profiles, particularly in ARIA subtype-related disproportionality signals, drug-specific PT signals, potential novel reporting signals, sex-stratified reporting patterns, and TTO characteristics. These findings provide pharmacovigilance evidence for targeted safety monitoring and hypothesis generation, but should not be interpreted as causal associations or true incidence estimates.},
}
@article {pmid42440728,
year = {2026},
author = {Badesso, S and Espelosín, M and Alonso, C and Montilla, A and Collantes, M and Cuadrado-Tejedor, M and García-Osta, A},
title = {Reprogramming lipid metabolism for cognitive restoration in Alzheimer's via PLA2G4E.},
journal = {Alzheimer's &amp; dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70285},
doi = {10.1002/trc2.70285},
pmid = {42440728},
issn = {2352-8737},
abstract = {INTRODUCTION: Growing evidence implicates dysregulated brain lipid metabolism in Alzheimer's disease (AD) pathogenesis, influencing membrane integrity, neuroinflammation, and amyloid beta and tau pathology, thereby representing a promising therapeutic target. However, therapeutic strategies targeting lipid pathways remain largely unexplored.<br><br>METHODS: The therapeutic potential of PLA2G4E, previously identified in our earlier work, was validated in the APP[NL-G-F] AD mouse model using a translational gene-delivery approach with a blood-brain barrier-penetrant adeno-associated vector (AAV) (AAVP31) to achieve widespread brain expression. Brain lipidomics was performed to investigate the molecular mechanisms underlying treatment effects.<br><br>RESULTS: PLA2G4E expression rescued memory deficits, reduced tau phosphorylation, and improved brain glucose metabolism and cognitive performance in AD models and aged wild-type mice. These effects were accompanied by partial normalization of disease-associated lipid metabolic alterations.<br><br>DISCUSSION: These findings support PLA2G4E as a promising therapeutic target in AD and provide mechanistic evidence linking modulation of lipid metabolic pathways to synaptic and cognitive rescue.},
}
@article {pmid42440762,
year = {2026},
author = {Xing, X and Wang, K and Feng, Y and Wu, C and Jia, L and Li, H and Wen, Z and Tang, Y and Wang, Z and Zhang, X and Li, X and Hua, Y and Zhang, L and Dong, X},
title = {Post-marketing safety of lecanemab: a real-world study based on FAERS database, multicenter cohort and network pharmacology.},
journal = {Frontiers in psychiatry},
volume = {17},
number = {},
pages = {1822543},
doi = {10.3389/fpsyt.2026.1822543},
pmid = {42440762},
issn = {1664-0640},
abstract = {INTRODUCTION: Lecanemab is a monoclonal antibody targeting amyloid-beta (Aβ) approved for treating Alzheimer's disease (AD) with mild cognitive impairment or mild dementia. Continuous monitoring of its real-world safety profile remains essential. This study aimed to analyze lecanemab-related adverse events (AEs) using the FDA Adverse Event Reporting System (FAERS) database and a multicenter cohort, and explored mechanisms via network pharmacology.<br><br>METHODS: We conducted an updated disproportionality analysis of FAERS data from 2023 to 2024 to identify disproportionate reporting signals (SDRs). A multicenter retrospective cohort study was performed, including lecanemab users from June 2024 to February 2025. Data were collected from electronic medical records of five tertiary hospitals. AEs were identified and influencing factors of AE occurrence were analyzed. Additionally, a drug-gene interaction network was constructed to explore potential mechanisms.<br><br>RESULTS: In the FAERS analysis of 2,764 AEs from 1,389 lecanemab users, 12 of 41 positive SDRs were prioritized, with 75% (9/12) being nervous system disorders, primarily amyloid-related imaging abnormalities (ARIA). In the cohort study, 29.05% (43/148) of patients experienced AEs, with infusion-related reactions being most common. Age was identified as a risk factor for AE occurrence [OR (95% CI): 1.109 (1.011-1.215), P&#xa0;=&#xa0;0.028], while pre-treatment significantly reduced AE incidence. Gene enrichment analysis suggested potential links between lecanemab-related genes and AEs.<br><br>DISCUSSION: This study provides real-world evidence on the risk profile of lecanemab, highlighting the importance of continued safety monitoring. These findings may inform discussions about the risks associated with anti-amyloid treatments and warrant further confirmation in large-scale prospective studies.},
}
@article {pmid42440891,
year = {2026},
author = {Lautenbacher, S and Schreiber, V and Grupp, C and Carbon, CC and Kellner, H and Kunz, M},
title = {Pain differences in cognitive impairment appear only during active motor tasks.},
journal = {Frontiers in pain research (Lausanne, Switzerland)},
volume = {7},
number = {},
pages = {1849507},
doi = {10.3389/fpain.2026.1849507},
pmid = {42440891},
issn = {2673-561X},
abstract = {Cognitive impairment in older adults has been associated with altered pain processing and potentially increased pain vulnerability, although findings are inconsistent. We hypothesized that cognitive impairment has a stronger impact on movement-related pain in everyday contexts than on pain sensitivity assessed in passive laboratory settings. Thirty-eight cognitively healthy and 38 cognitively impaired older adults (50% women; groups age- and sex-matched), classified using the CERAD scale (Consortium to Establish a Registry for Alzheimer's Disease), completed standardized motor tasks (walking, bed mobility, lifting tasks) and experimental pressure and heat pain assessments. Pain intensity (NRS) was recorded for all tasks. Perceived exertion was assessed during motor tasks, and clinical pain status was determined via a structured interview. Groups did not differ in baseline clinical pain or experimental pain sensitivity. However, cognitively impaired participants reported significantly higher movement-related pain during motor tasks. In a blockwise regression model, movement-related pain was significantly predicted by clinical pain and experimental pain sensitivity; however cognitive status (CERAD) explained additional variance to a similar amount. In conclusion, reduced cognitive functioning significantly predicted increased pain during active, everyday motor tasks. This may reflect diminished capacities for recall, planning, and execution of pain-minimizing movement strategies. These findings underscore the importance of assessing pain in behaviorally relevant contexts where movement provokes pain, to better understand pain mechanisms in cognitively impaired older adults.},
}
@article {pmid42440956,
year = {2025},
author = {Alcina, J and Munera, D and Martinez, L and Giudicessi, A and Bonillas Félix, NA and Medrano, R and Martinez, JE and Solis, I and Tristão-Pereira, C and Malotaux, V and He, B and Ribas, A and Ramirez, NJ and Ramirez-Gomez, LA and Vila-Castelar, C and Gonzalez Catalan, M and Saldana, DG and Gatchel, JR and Quiroz, YT},
title = {Mild behavioral impairment and its relationship to cognition in community-dwelling older adults from the Boston Latino Aging Study.},
journal = {Alzheimer's &amp; dementia (Amsterdam, Netherlands)},
volume = {17},
number = {2},
pages = {e70121},
doi = {10.1002/dad2.70121},
pmid = {42440956},
issn = {2352-8729},
abstract = {BACKGROUND: Mild behavioral impairment (MBI) is associated with cognitive decline and dementia risk. This study assessed the relationship between MBI severity and cognition in community-dwelling older Latino adults.<br><br>METHODS: The cognitive function index (CFI) assessed subjective cognition, and the MBI-Checklist (MBI-C; self-report) measured MBI symptoms in 168 older Latinos (134 cognitively unimpaired, 34 with mild cognitive impairment). The Mini-Mental State Examination (MMSE) and NEUROPSI Delayed Word List Recall measured cognitive function. Linear regressions examined the impact of MBI-C symptoms on cognition, controlling for age, sex, and education.<br><br>RESULTS: The MBI domain of decreased motivation predicted subjective cognition and delayed verbal recall performance. The mood dysregulation domain predicted only subjective cognition. Neither domain predicted total MMSE scores.<br><br>DISCUSSION: MBI symptoms of decreased motivation and mood dysregulation influenced poorer subjective and objective cognition in Latinos, potentially signaling prodromal Alzheimer's related changes. These findings highlight the need to assess neuropsychiatric symptoms in this population.<br><br>HIGHLIGHTS: Decreased motivation predicted worse subjective cognition and verbal memory.Mood dysregulation only predicted worse subjective cognition.These findings were adjusted for age, sex, and education in Latino older adults.},
}
@article {pmid42441284,
year = {2026},
author = {Schlein, ML and Stephen, CA and Caldwell, GA and Ciesla, L and Caldwell, KA},
title = {An Alzheimer's disease-associated mutant of C. elegans displays mechanosensory sensitivity following exposure to lavender extracts.},
journal = {microPublication biology},
volume = {2026},
number = {},
pages = {},
doi = {10.17912/micropub.biology.002220},
pmid = {42441284},
issn = {2578-9430},
abstract = {Lavandula angustifolia (lavender) extract displayed antioxidant properties in mammalian studies and has been promoted as a candidate neurotherapeutic for Alzheimer's disease (AD). To better inform its clinical utility, we exposed wildtype (N2) and spr-4 mutant strains of C. elegans to extracts from this lavender species and examined animals for neurobehavioral changes in a mechanosensory phenotype. Importantly, spr-4 encodes the worm ortholog of repressor element 1-silencing transcription factor (REST), an established genetic modifier of AD. While low concentrations of lavender did not alter behavioral responses, spr-4 mutants selectively displayed neuronal vulnerability at the highest concentration tested, thereby revealing dose-responsive, lavender-associated neurotoxicity.},
}
@article {pmid42441387,
year = {2026},
author = {},
title = {Ceperognastat in Early Symptomatic Alzheimer Disease: Research Summary.},
journal = {JAMA},
volume = {},
number = {},
pages = {e2612911},
doi = {10.1001/jama.2026.12911},
pmid = {42441387},
issn = {1538-3598},
}
@article {pmid42441390,
year = {2026},
author = {Blazhenets, G and Soleimani-Meigooni, DN and Chiotis, K and Allen, IE and Rabinovici, GD and La Joie, R and , and Apostolova, LG and Asken, BM and Bejanin, A and Benzinger, TLS and Betthauser, TJ and Bluma, M and Bombois, S and Bourgeat, P and Bouteloup, V and Braskie, MN and Brendel, M and Brickman, AM and Bryant, N and Bullich, S and Carrillo, MC and Casaletto, K and Cash, DM and Chang, CC and Chang, HI and Chao, Y and Chêne, G and Chételat, G and Coath, W and Collij, LE and Colmant, L and Corrada, MM and Craft, S and Dickerson, BC and Dubois, B and Dufouil, C and Fajardo, A and Farrar, G and Fortea, J and Frings, L and Frisoni, GB and Gardner, RC and Garibotto, V and Gnörich, JS and Gordon, BA and Gu, Y and Guan, Y and Guo, T and Hanseeuw, BJ and Hansson, O and Harrison, TM and Huang, Q and Huang, SH and Iaccarino, L and Ishii, K and Ishi, K and Jagust, WJ and Johnson, SC and Kato, T and Katsumi, Y and Kaye, J and Koeppe, RA and Kolinger, GD and Kramer, JH and Landau, SM and Landeau, B and Lao, PJ and Lee, S and Lleó, A and Lopresti, BJ and Lowe, VJ and Luchsinger, JA and Malpetti, M and Mao, X and March, A and Masters, CL and Meyer, PT and Mezenge, F and Mormino, EC and Franquesa-Mullerat, M and Nakamura, A and Nordberg, A and O'Brien, JT and O'Bryant, SE and Pappas, I and Peretti, DE and Quenon, L and Rowe, CC and Rowe, JB and Rudolph, MD and Salvadó, G and Schott, JM and Schwartz, DL and Schwarz, CG and Seo, SW and Shekari, M and Silbert, LC and Smith, R and Snyder, HM and Sokolowski, A and Sperling, RA and Sun, P and Taggett, JZ and Toga, AW and Touroutoglou, A and Vaillancourt, DE and van de Giessen, E and Vijverberg, J and Vemuri, P and Villain, N and Villemagne, VL and Villeneuve, S and Wang, WE and Weiner, M and Woodworth, D and Xiao, C and Xie, F and Yoon, Y and Young, CB and Yun, M and , },
title = {Amyloid PET Quantitation and Centiloid Thresholds in the Diagnosis of Alzheimer Disease: An Individual Participant Data Meta-Analysis.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2026.13116},
pmid = {42441390},
issn = {1538-3598},
abstract = {IMPORTANCE: Amyloid positron emission tomography (PET) is increasingly used in research and clinical settings to determine the etiology of cognitive decline and eligibility for amyloid-targeting therapies. To assist with amyloid PET evaluation and to guide clinical decision-making, images can be quantified in a standardized unit called Centiloid, the interpretation of which can vary according to the method and threshold used.<br><br>OBJECTIVE: To collect Centiloid values from available studies and determine robust positivity cutoffs using data-driven methods and correspondence with visual reads.<br><br>DATA SOURCES: PubMed search (October 2024) identified studies with Centiloid values. Corresponding authors were invited to share individual participant data. Additional data were obtained through access-controlled repositories and conference outreach (July 2024-July 2025).<br><br>STUDY SELECTION: Studies were included if they provided Centiloids, radiotracer, age, and sex.<br><br>DATA EXTRACTION AND SYNTHESIS: Each study was analyzed using a unified statistical pipeline; study estimates were pooled using random-effects meta-analysis.<br><br>MAIN OUTCOMES AND MEASURES: Gaussian mixture models (GMMs) were fitted to Centiloid values for each study. In studies with a bimodal distribution (per integrated completed likelihood), single cutoffs for positivity were set as mean plus 2 SDs of the lower gaussian component. Using GMMs, a double-cutoff approach defined a lower certainty range using a 90% posterior probability cutoff for assignment to the low (amyloid-negative) vs high (amyloid-positive) component. An alternative Centiloid cutoff was derived from maximizing the correspondence (Cohen &#x3ba;) with the binary visual reads when available.<br><br>RESULTS: This meta-analysis included cross-sectional amyloid PET scans acquired with 5 radiotracers from 49&#x202f;227 participants across 53 studies from 15 countries (mean age, 71 years; 54% female, 62% cognitively impaired). The data-driven GMM approach identified a bimodal distribution in 51 studies (n&#x2009;=&#x2009;48&#x202f;786), resulting in a single cutoff for positivity of 18 Centiloids (95% CI,16-19; I2&#x2009;=&#x2009;97%). The double-cutoff approach revealed high confidence for interpreting scans as negative when Centiloid values were lower than 11 (95% CI, 9-13; I2&#x2009;=&#x2009;95%) and interpreting scans as positive if Centiloid values were higher than 26 (95% CI, 24-28; I2&#x2009;=&#x2009;95%). In analyses of correspondence with binary (positive or negative) visual reads of amyloid PET scans (n&#x2009;=&#x2009;35&#x202f;045; 36 studies), Centiloids were highly predictive of visual positivity (Cohen &#x3ba;, 0.86; 95% CI, 0.83-0.89; I2&#x2009;=&#x2009;96%) with a cutoff of 27 Centiloids (95% CI, 24-30; I2&#x2009;=&#x2009;80%).<br><br>CONCLUSIONS AND RELEVANCE: In this individual participant data meta-analysis, positivity cutoffs converged around 18 Centiloids (data-driven) and 27 Centiloids (visual reads). Findings from a double-cutoff analysis suggest that scans in the 11 to 26 Centiloid range should be interpreted with caution depending on the context of use.},
}
@article {pmid42441396,
year = {2026},
author = {Fleisher, AS and Munsie, L and Mancini, M and Cheng, YJ and Guo, J and Nuthall, H and Otero, DS and Kotari, V and Kielbasa, W and Hutton, M and Brys, M and Mergott, DJ and Mintun, M and Hansson, O},
title = {Ceperognastat in Early Symptomatic Alzheimer Disease: A Randomized Clinical Trial.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2026.12768},
pmid = {42441396},
issn = {1538-3598},
abstract = {IMPORTANCE: Inhibiting O-linked N-acetylglucosaminidase (OGA) is hypothesized to slow accumulation of aggregated, hyperphosphorylated tau and neurofibrillary tangle formation.<br><br>OBJECTIVE: To evaluate the efficacy and safety of the potent oral OGA inhibitor ceperognastat in early symptomatic Alzheimer disease (AD).<br><br>This double-blind, randomized, placebo-controlled phase 2 study was conducted at 72 sites in 5 countries from September 2021 to August 2024, with a posttreatment observational extension period through May 2025. The primary outcome population comprised participants with early symptomatic AD and biomarker evidence of tau pathology, including low to medium baseline tau levels (excluding individuals with high levels), as measured by positron emission tomography (PET) with flortaucipir F18.<br><br>INTERVENTION: Participants were randomized 1:1:1 to receive once-daily, oral ceperognastat at doses of 0.75 mg (n&#x2009;=&#x2009;110) or 3 mg (n&#x2009;=&#x2009;108) or placebo (n&#x2009;=&#x2009;108).<br><br>MAIN OUTCOMES AND MEASURES: The primary outcome was change in Integrated AD Rating Scale (iADRS) score. The success criterion was a 60% or greater probability of achieving greater than or equal to 25% slower progression vs placebo using a bayesian probabilistic disease progression model. The 6 secondary outcomes were Alzheimer's Disease Assessment Scale-Cognitive Subscale, 13-item version; Alzheimer's Disease Cooperative Study-Activities of Daily Living scale; Clinical Dementia Rating-Sum of Boxes; Mini-Mental State Examination; tau PET; and volumetric magnetic resonance imaging.<br><br>RESULTS: Of the 327 randomized participants (mean age, 73.4 years; 201 [61.5%] females), 259 (87 receiving ceperognastat 0.75 mg, 86 receiving ceperognastat 3 mg, and 86 receiving placebo) with low to medium baseline tau levels were included in the primary outcome population (mean age, 74.3 years; 161 [62.2%] females). In this population, no clinically meaningful benefit vs placebo was observed for the primary end point (iADRS score) at 100 weeks: posterior mean change from baseline was -8.39 with ceperognastat 0.75 mg, -13.27 with ceperognastat 3 mg, and -10.07 with placebo. The disease progression ratio relative to placebo was 0.84 (95% credible interval [CrI], 0.66-1.04) for the ceperognastat 0.75 mg group and 1.32 (CrI, 1.10-1.58) for the ceperognastat 3 mg group, corresponding to 16% less and 32% greater progression, respectively. No benefits were demonstrated for secondary clinical end points. From baseline to 76 weeks, least-squares mean change in standardized uptake value ratio on PET showed a statistically significantly smaller increase (P&#x2009;=&#x2009;.04) vs placebo only for the ceperognastat 3 mg group in the lateral temporal lobe. Volumetric magnetic resonance imaging showed less whole brain volume loss in participants treated with ceperognastat vs placebo (43.2% [ceperognastat 0.75 mg] and 49.5% [ceperognastat 3 mg] less vs placebo; both P&#x2009;<&#x2009;.001). The ceperognastat 3 mg group had more serious (ceperognastat 0.75 mg: n&#x2009;=&#x2009;13 [12.0%]; ceperognastat 3 mg: n&#x2009;=&#x2009;29 [26.4%]; placebo: n&#x2009;=&#x2009;17 [15.7%]) and severe (ceperognastat 0.75 mg: n&#x2009;=&#x2009;7 [6.5%]; ceperognastat 3 mg: n&#x2009;=&#x2009;15 [13.6%]; placebo: n&#x2009;=&#x2009;7 [6.5%]) treatment-emergent adverse events.<br><br>CONCLUSIONS AND RELEVANCE: Ceperognastat did not slow disease progression of early symptomatic AD.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05063539.},
}
@article {pmid42441398,
year = {2026},
author = {Rabinovici, GD and Grill, JD},
title = {Ceperognastat in Alzheimer Disease: Lessons From a Negative Clinical Trial.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2026.12323},
pmid = {42441398},
issn = {1538-3598},
}
@article {pmid42441402,
year = {2026},
author = {Vetere, LM and Galas, AM and Vaughan, N and Kohler, C and Feng, Y and Christenson Wick, Z and Philipsberg, PA and Liobimova, O and Gordon, KE and Fernandez-Ruiz, A and Cai, DJ and Shuman, T},
title = {Medial entorhinal-hippocampal desynchronization parallels the emergence of memory impairment in a mouse model of Alzheimer's disease pathology.},
journal = {Cell reports},
volume = {45},
number = {7},
pages = {117646},
doi = {10.1016/j.celrep.2026.117646},
pmid = {42441402},
issn = {2211-1247},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive impairments in episodic and spatial memory, as well as circuit and network-level dysfunction. While functional impairments in medial entorhinal cortex (MEC) and hippocampus (HPC) have been observed in patients and rodent models of AD, it remains unclear how communication between these regions breaks down in disease, and what specific physiological changes are associated with the onset of memory impairment. Here, we use silicon probes to simultaneously record neural activity in MEC and HPC before or after the onset of spatial memory impairment in the 3xTg mouse model of AD pathology. We find that reduced hippocampal theta power, reduced MEC-CA1 theta coherence, and altered phase locking of MEC and hippocampal neurons all coincide with the emergence of spatial memory impairment in 3xTg mice. Together, these findings suggest that disrupted temporal coordination of neural activity in the MEC-hippocampal system parallels the emergence of memory impairment in a model of AD pathology.},
}
@article {pmid42441421,
year = {2026},
author = {Wang, L and Cai, Q and Yang, Y and Zhou, Y and Liu, Y and Wu, P and Liu, J and Liu, Y},
title = {A Multitarget Nanosystem Loaded with Donepezil for Alzheimer's Disease Treatment by Activating Mitophagy and Reshaping the Inflammatory Microenvironment.},
journal = {ACS applied materials &amp; interfaces},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsami.6c05393},
pmid = {42441421},
issn = {1944-8252},
abstract = {A paradigm shift from single-target interventions toward multitarget synergistic actions is increasingly recognized as a promising therapeutic approach for Alzheimer's disease (AD). Given this, an oxidative stress-responsive nanocomposite, RuO2-TPP/Don@BSA (RDB), was developed to enable effective AD therapy via a "cocktail strategy". Utilizing bovine serum albumin (BSA), the system crosses the blood-brain barrier (BBB) through gp60 receptor-mediated endocytosis. Within the AD brain microenvironment, RDB undergoes disulfide bond cleavage in response to elevated H2O2 levels, thereby releasing donepezil (Don) and RuO2-TPP in a stimuli-responsive manner. Meanwhile, RuO2-TPP escapes from lysosomes, targets mitochondria, and interrupts the oxidative stress cascade, further repairing mitochondrial dysfunction and activating mitophagy. Moreover, RDB promotes the polarization of microglia from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, thereby reshaping the inflammatory microenvironment of AD. Finally, RDB demonstrated significant efficacy in APP/PS1 transgenic AD mice, markedly reducing hippocampal expression of GFAP and Iba-1, concomitant with a notable improvement in cognitive dysfunction. In summary, these findings establish RDB as a multitarget synergistic therapeutic system that offers a promising strategy for the treatment of AD.},
}
@article {pmid42441515,
year = {2026},
author = {Xu, S and Zhang, J and Mao, R and Yang, S and Zhao, D and Yang, W},
title = {Evaluating Triptolide Effects on Hippocampal Gephyrin, Collybistin, and Autophagy in an Aβ1-42 Mouse Model.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {232},
pages = {},
doi = {10.3791/70397},
pmid = {42441515},
issn = {1940-087X},
mesh = {Animals ; *Amyloid beta-Peptides/administration &amp; dosage ; *Hippocampus/drug effects/metabolism/pathology ; Mice ; *Diterpenes/pharmacology ; *Phenanthrenes/pharmacology ; *Alzheimer Disease/metabolism/drug therapy ; Mice, Inbred C57BL ; Disease Models, Animal ; *Membrane Proteins/metabolism/biosynthesis ; *Peptide Fragments/administration &amp; dosage ; Epoxy Compounds/pharmacology ; *Carrier Proteins/metabolism/biosynthesis ; *Autophagy/drug effects ; Male ; },
abstract = {Alzheimer's disease is associated with synaptic dysfunction, but standardized procedures for evaluating how Aβ-induced pathology affects inhibitory synapse-associated proteins and autophagy-related signaling after candidate intervention remain limited. This protocol describes a workflow for establishing an Aβ1-42-induced Alzheimer's disease-like mouse model and assessing the effects of triptolide on hippocampal Gephyrin, Collybistin, PI3K/Akt/GSK-3β signaling, and autophagy-related markers. Adult C57BL/6J mice receive bilateral intracerebroventricular injection of Aβ1-42 prepared under aggregation-inducing conditions, followed by daily intraperitoneal administration of triptolide with or without the PI3K inhibitor LY294002. Spatial learning and memory are evaluated using Morris water maze testing. Hippocampal neuronal injury and Aβ deposition are assessed by hematoxylin and eosin staining and Aβ immunohistochemistry, and hippocampal lysates are analyzed by Western blotting to quantify Gephyrin, phosphorylated Gephyrin, Collybistin, PI3K/Akt/GSK-3β signaling proteins, LC3-II/I, and p62. Key procedural considerations include standardized Aβ1-42 preparation, accurate stereotaxic injection, consistent behavioral testing conditions, blinded region-of-interest selection, and standardized image and densitometry analysis. Using this workflow, Aβ1-42 administration produced spatial learning and memory deficits, hippocampal neuronal injury, Aβ deposition, reduced Gephyrin and Collybistin expression, altered PI3K/Akt/GSK-3β signaling, and increased LC3-II/I and p62 accumulation. Triptolide partially reversed these behavioral, histological, and molecular changes, whereas LY294002 attenuated its effects. This protocol can be used to evaluate Aβ-induced hippocampal molecular alterations and candidate interventions, while recognizing that this model does not reproduce the chronic, multifactorial progression of human Alzheimer's disease.},
}
@article {pmid42441681,
year = {2026},
author = {Carrasco-Vega, S and Millavil-Cofré, C and Soto-Labbé, M and Julio-Ramos, T and Godoy-Díaz, &#xc1; and Toloza-Ramirez, D},
title = {[Social Cognition and Theory of Mind as a Differential Marker Between Alzheimer's Disease and Behavioral Variant Frontotemporal Dementia].},
journal = {Revista medica de Chile},
volume = {154},
number = {4},
pages = {577-590},
doi = {10.4067/s0034-98872026000400577},
pmid = {42441681},
issn = {0717-6163},
mesh = {Humans ; *Theory of Mind/physiology ; *Alzheimer Disease/diagnosis/psychology/physiopathology ; *Frontotemporal Dementia/diagnosis/psychology/physiopathology ; *Social Cognition ; Diagnosis, Differential ; Neuropsychological Tests ; Biomarkers ; },
abstract = {UNLABELLED: While language, memory, and executive function have been proposed as differential markers between Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD), recent studies emphasize the role of Social Cognition (SC) and Theory of Mind (ToM) in distinguishing between these conditions.<br><br>AIM: To characterize SC and ToM performance in patients with AD and bvFTD.<br><br>METHODOLOGY: This review followed PRISMA guidelines and included studies published between January 2015 and March 2024 from PubMed, Scopus, and Web of Science.<br><br>RESULTS: Fourteen studies were critically analyzed. Findings suggest that SC and ToM are impaired in both disorders. In AD, the main deficits involve emotional recognition and perception, and social behavior. In bvFTD, common impairments include decision-making, emotion recognition, social behavior, and empathy loss.<br><br>CONCLUSIONS: SC and ToM may support the differential diagnosis between AD and bvFTD, particularly in early stages. Further research is needed to develop standardized assessments for clinical use to detect and classify the severity of SC and ToM decline.},
}
@article {pmid42441749,
year = {2026},
author = {Wolff, T and Joblin, C and Banner, K and Murawski, A and Janulis, P and Ramirez-Zohfeld, V and Olvera, C and Lindquist, L and Birkett, M},
title = {Caregiver Networks of Older Adults With Alzheimer Disease: Design and Protocol for a Multisite Study Using Network Canvas.},
journal = {JMIR research protocols},
volume = {15},
number = {},
pages = {e98270},
doi = {10.2196/98270},
pmid = {42441749},
issn = {1929-0748},
mesh = {Humans ; *Caregivers/psychology ; *Alzheimer Disease/psychology/complications ; Aged ; *Social Support ; Female ; Male ; Research Design ; Social Networking ; },
abstract = {BACKGROUND: Patients with Alzheimer disease commonly rely on family caregivers for daily functioning. Research shows that relationships between caregivers and persons with memory loss have important effects on the health and well-being of both caregivers and persons with memory loss. However, most studies rely on a single caregiver-person with memory loss dyad as the unit of analysis, thereby neglecting the broader network of caregivers who collectively shape care experiences and outcomes.<br><br>OBJECTIVE: This study develops a conceptual and methodological framework for studying caregiver networks and investigates how the properties of caregiver networks relate to health and well-being outcomes for both persons with memory loss and caregivers. It measures and maps the social networks of caregivers of persons with memory loss while examining population heterogeneity in caregiver relationships and identifying network-based predictors of well-being for both caregivers and persons with memory loss.<br><br>METHODS: Our team is conducting a large multilocation (Illinois, Indiana, and Hawaii) study comprising 200 caregiver networks of persons with memory loss, supported by data from persons with memory loss and their caregivers. Networks will be collected using cutting-edge Network Canvas software tools, developed by members of our team within the Complex Data Collective, and analyzed using both quantitative and mixed methods.<br><br>RESULTS: This study was funded in August 2023 by the National Institutes of Health (R01AG083034), with an expected end date of July 2028. This study protocol was approved by the institutional review board of Northwestern University (STU00219675) and was piloted internally before participant recruitment began in January 2025. As of March 2026, a total of 155 participants have been enrolled. Enrollment is planned to end by April 2027, with results expected between August 2027 and November 2027.<br><br>CONCLUSIONS: This study advances research on caregivers of persons with memory loss by operationalizing a scalable and replicable approach to measuring caregiver networks. The ability to easily measure and identify structural features of caregiver systems helps in identifying predictors of caregiver experiences and outcomes and provides large benefits for the caregiver-person with memory loss research community.},
}
@article {pmid42441927,
year = {2026},
author = {Coysh, T and Laban, R and Veleva, E and Heslegrave, AJ and Darwent, L and Holm-Mercer, L and Mok, TH and Hart, MS and Lunn, MP and Keshavan, A and Schott, JM and Jaunmuktane, Z and Brandner, S and Gonzalez-Ortiz, F and Blennow, K and Zetterberg, H and Collinge, J and Mead, S},
title = {Performance of Alzheimer Disease Plasma Biomarkers in Patients With Prion Diseases.},
journal = {Neurology},
volume = {107},
number = {3},
pages = {e214712},
doi = {10.1212/WNL.0000000000214712},
pmid = {42441927},
issn = {1526-632X},
abstract = {BACKGROUND AND OBJECTIVES: Prion diseases can mimic Alzheimer disease (AD) at presentation. Alzheimer's Association AD diagnostic criteria suggest that a single abnormal highly specific plasma biomarker (including p-tau217) is sufficient for a biological diagnosis. We investigated the performance of AD plasma biomarkers in distinguishing AD and prion diseases.<br><br>METHODS: We examined plasma biomarker data from patients with prion disease from a prospective cohort study recruited through the UK National Prion Clinic. Prion diseases were diagnosed clinically or with autopsy confirmation, and AD was diagnosed clinically with CSF biomarker confirmation. Plasma p-tau217, p-tau181, A&#x3b2;42/40 ratio, brain-derived tau (BD-tau), neurofilament light chain (NfL), and glial fibrillary acid protein (GFAP) were measured using Simoa. Median biomarker values in different groups were compared with Kruskal-Wallis test, and area under the receiver operating characteristic curve was used to compare accuracy in distinguishing prion diseases from sporadic AD (sAD). Lumipulse p-tau217 and NfL were measured in a validation study in a different laboratory.<br><br>RESULTS: In the main study, we analyzed 345 samples from 278 individuals (mean age 58 [SD 13.5], 48.2% female), including 204 with prion diseases (121 sporadic Creutzfeldt-Jakob disease [CJD], 11 iatrogenic CJD, 9 variant CJD, 47 slow-progressing inherited prion disease (IPD) and 16 fast-progressing IPD), 33 with AD, and 41 healthy controls. For discriminating prion disease without AD copathology from sAD, none of p-tau217 (area under the curve [AUC] [95% CI] 0.605 [0.486-0.724]), p-tau181 (AUC 0.554 [0.446-0.661]), or GFAP (AUC 0.514 [0.389-0.640]) performed well. A&#x3b2;42/40 discriminated moderately (AUC 0.770 [0.684-0.856]). NfL/p-tau217 ratio (AUC 0.996 [0.987-1.000]), NfL (AUC 0.988 [0.974-1.000]), BD-tau/p-tau217 ratio (AUC 0.963 [0.929-0.996]), and BD-tau (AUC 0.934 [0.890-0.978]) discriminated very well. In an independent validation study, consecutive samples were analyzed from 32 patients with sAD and 35 patients with sporadic Creutzfeldt-Jakob disease (mean age 65.0 [SD 6.4], 56.7% female). NfL/p-tau217 again discriminated almost perfectly (AUC 0.986 [95% CI 0.966-1.000]).<br><br>DISCUSSION: Plasma p-tau217 and p-tau181 are increased in both AD and prion diseases (regardless of burden of AD copathology). Diagnosing AD with a single abnormal p-tau plasma biomarker risks misdiagnosing prion diseases as AD. Plasma NfL/p-tau217 discriminates near-perfectly and could act as a flag to suspect prion diseases where this is a diagnostic possibility.<br><br>CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that plasma NfL/p-tau217 discriminates patients with CJD from those with AD.},
}
@article {pmid42441928,
year = {2026},
author = {Bellomo, G and Gaetani, L},
title = {Plasma P-Tau217: A Powerful Alzheimer Disease Biomarker in the Right Clinical Context.},
journal = {Neurology},
volume = {107},
number = {3},
pages = {e214821},
doi = {10.1212/WNL.0000000000214821},
pmid = {42441928},
issn = {1526-632X},
}
@article {pmid42442024,
year = {2026},
author = {Andreeva, T and Tuparev, N and Taneva, SG},
title = {Multimodal biophysical markers of neurodegeneration: Morphology, mechanics, and thermodynamics.},
journal = {Current opinion in structural biology},
volume = {100},
number = {},
pages = {103330},
doi = {10.1016/j.sbi.2026.103330},
pmid = {42442024},
issn = {1879-033X},
abstract = {The identification of novel noninvasive biomarkers remains a major challenge in the diagnosis of neurodegenerative diseases. Significant efforts focus on fluid biomarkers, including proteins, peptides, and miRNAs, detectable in blood plasma and peripheral blood cells. Here, we review recent findings on blood plasma and peripheral blood cells physical parameters in Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis emphasizing atomic force microscopy and calorimetry assay. Alterations in morphology, nanostructure, and stiffness of red blood cells and platelets, together with thermodynamic signatures of red blood cells and plasma, provide sensitive indicators of disease-related changes. These integrated biophysical parameters not only distinguish neurodegeneration from healthy states but also enable discrimination among different neurodegenerative disorders, highlighting their potential as minimally invasive diagnostic markers.},
}
@article {pmid42442298,
year = {2026},
author = {Akca, S and Ilkar Erdagi, S and Sari, S and Ozbagci, DI},
title = {Eugenol-derived carbamates as sub-nanomolar dual cholinesterase inhibitors with neuroprotective activity against Alzheimer's disease: Structure-activity relationships and molecular dynamics insights.},
journal = {Bioorganic chemistry},
volume = {180},
number = {},
pages = {110233},
doi = {10.1016/j.bioorg.2026.110233},
pmid = {42442298},
issn = {1090-2120},
abstract = {Carbamate-based cholinesterase inhibitors represent a clinically validated therapeutic strategy for Alzheimer's disease (AD); however, sub-nanomolar AChE inhibitory activity within natural phenol-derived scaffolds has not been previously reported. To address this gap, a series of eleven eugenol-based carbamate derivatives (E1-E11) was rationally designed, synthesized, and evaluated as multifunctional anti-AD agents. Systematic variation of the carbamate N-substituent enabled fine modulation of inhibitory potency and isoform selectivity, revealing well-defined structure-activity relationships. Among the synthesized compounds, E11 emerged as the most potent AChE inhibitor (IC50 = 0.62 nM), surpassing rivastigmine (0.80 nM), the only clinically approved carbamate-based inhibitor, while displaying a markedly AChE-selective profile (SI = 24.0). To our knowledge, this represents the most potent AChE inhibitory activity reported for a carbamate within a natural phenol-derived framework. E10 established a genuine dual inhibitory profile (AChE IC50 = 4.25 nM; BChE IC50 = 3.20 nM), relevant to multitarget therapy across AD disease stages. Enzyme kinetic studies confirmed mixed-type inhibition for both lead compounds, with nanomolar Ki values indicating simultaneous engagement of the catalytic and peripheral anionic sites. These findings were corroborated by 200 ns molecular dynamics simulations and MM-PBSA binding free energy analyses, which revealed stable dual-site binding modes consistent with the kinetic data. Although DPPH radical scavenging was attenuated by carbamate masking of the phenolic hydroxyl group, CUPRAC analysis revealed significant electron transfer-based antioxidant capacity for E10 and E11. Importantly, both lead compounds demonstrated significant neuroprotective effects in H2O2-challenged HT-22 mouse hippocampal neuronal cells, a well-established oxidative stress model relevant to AD neurodegeneration, with acceptable cytotoxicity profiles. In silico ADME profiling predicted favorable gastrointestinal absorption, blood-brain barrier permeability, and absence of P-glycoprotein efflux liability for all compounds. Collectively, these findings establish eugenol-based carbamates as a pharmacologically competitive and structurally accessible multifunctional scaffold for AD, with E10 and E11 identified as priority candidates for further preclinical investigation; however, the present study is limited to in vitro and in silico evaluation, and in vivo pharmacological assessment and detailed metabolic profiling, particularly regarding the predicted mild CYP450 liability of the aryl-substituted derivatives, are warranted in future studies.},
}
@article {pmid42442374,
year = {2026},
author = {Crivelli, L and Suemoto, CK and Sosa, AL and Lopera, F and Aguillón, D and Allegri, RF and Nitrini, R and Calandri, IL and Velilla-Jiménez, L and Yassuda, MS and Acosta-Baena, N and Salinas, RM and Charamelo, A and Derio, CD and Acosta, DM and León-Salas, JM and Duque-Peñailillo, L and Cusicanqui, MI and Custodio, N and Anchia-Alfaro, A and Núñez-Herrera, A and Rubens, A and Leites, A and Vigil-Martínez, A and Damian, A and Flores-Blanco, BM and Custodio, B and Laforcada, C and Márquez, C and Friedlaender, CV and Espinoza-Cruz, CG and Cañadas, C and Peixoto, C and Muñoz, DH and Slezak, DF and Felix, E and Aguirre-Salvador, E and Surace, EI and Mariani, F and De La Torre, GR and Verástegui, G and Keller, G and Peixoto, GH and Morilla, HA and Jiménez-Velázquez, IZ and More, JY and Rodríguez, JF and Tosatti, JAG and de Faria Rocha, JV and Saldarriaga-Hernández, J and Huilca, JC and García-Molina, JT and Martínez-Galindo, JG and Duran, JC and Rodriguez, JG and Gomes, KB and César-Freitas, KG and Agüero, K and Mora-Villalobos, L and Asprilla, LO and de Souza, LC and Soto, L and Cortabarría, L and Baldeón, L and Carreira, LL and Marin-Buitrago, L and Moreno, MC and Barbosa, MT and Torheim, M and Magalhães, MAZ and da Graça Morais Martin, M and Martin, ME and Torres, MF and Menéndez, M and Hernandez, MA and Granizo, MS and Gutiérrez, M and Corvalán, N and Mora, PJ and Peguero, P and Ramírez-Santos, R and Fernández, RS and Montesinos, R and Ospina-Henao, S and Montes, SY and Santero, S and Brucki, SMD and Josephy-Hernandez, S and Vazquez, TC and Bérgamo, Y and Bocanegra, Y and Muñoz, YA and Vicuña, Y and Lora, ZDC and Kivipelto, M and Raman, R and Espeland, MA and Baker, LD and Snyder, HM and Sevlever, GE and Carrillo, MC and Caramelli, P and , },
title = {Multidomain lifestyle intervention for the prevention of cognitive decline in at-risk older adults in Latin America (LatAm-FINGERS): a single-blind, multicentre, randomised controlled trial.},
journal = {Lancet (London, England)},
volume = {},
number = {},
pages = {},
doi = {10.1016/S0140-6736(26)01278-X},
pmid = {42442374},
issn = {1474-547X},
abstract = {BACKGROUND: Latin America faces a high dementia burden, with increased prevalence of factors associated with cognitive decline. Multidomain lifestyle interventions might delay cognitive decline, but populations from Latin America remain under-represented in dementia prevention trials. We aimed to investigate the feasibility of a culturally adapted, multidomain, systematic lifestyle intervention and investigate its effects on global cognitive function in at-risk older adults (aged 60-77 years).<br><br>METHODS: The LatAm-FINGERS Initiative for Cognitive Change (hereafter referred to as LatAm-FINGERS) was a single-blind, multicentre, randomised clinical trial conducted in 11 Latin American countries (Argentina, Bolivia, Brazil, Chile, Colombia, Costa Rica, Dominican Republic, Ecuador, Mexico, Peru, and Uruguay). Individuals aged 60-77 years with high risk of dementia (cardiovascular risk factors, ageing, and dementia risk score &#x2265;6), and suboptimal cognitive performance were randomly assigned (1:1) to receive either a 2-year systematic lifestyle intervention (SLI group) or a flexible lifestyle intervention (FLI group). Randomisation was stratified by the study centre to ensure balance and implemented using permuted blocks of eight. Participants and intervention staff were not masked to group assignment, but individuals who assessed outcomes were masked throughout the trial. The SLI provided structured multidomain lifestyle interventions with supervised support and monitoring; FLI offered health advice. Primary outcomes were trial feasibility (evaluated using selected RE-AIM measures: Reach, Implementation, and Maintenance) and the intervention's effects on global cognitive composite trajectories over 2 years (change in the global cognitive composite score over 2 years). This trial is registered at ClinicalTrials.gov (NCT06492967) and has been completed.<br><br>FINDINGS: Participants were enrolled between Oct 27, 2021, and July 7, 2023; the last participant completed follow-up on Nov 7, 2025. Among 1719 assessed, 1065 participants included in the analytic sample were randomly assigned to the SLI group (n=539) or the FLI group (n=526). Mean age was 67&#xb7;5 years (SD 4&#xb7;7), 795 (75%) of 1065 participants were women, and 270 (25%) were men. Self-reported race and ethnicity were: 624 (59%) Mestizo, 288 (27%) White, 72 (7%) Mulatto, 25 (2%) Mixed or other, 18 (2%) Black, 14 (1%) Indigenous, and 24 (2%) did not report race or ethnicity. 877 (82&#xb7;3%) of 1065 completed the 2-year follow-up. Recruitment effectiveness (Reach) was 62&#xb7;0%; mean adherence to the SLI group (Implementation) was 71&#xb7;6% over the entire trial; and frequencies of complete cognitive outcomes data (Maintenance) were 87&#xb7;9% at 6 months, 85&#xb7;3% at 12 months, 81&#xb7;4% at 18 months, and 84&#xb7;8% at 24 months in the SLI group compared with 86&#xb7;3% at 6 months, 78&#xb7;9% at 12 months, 73&#xb7;4% at 18 months, and 79&#xb7;8% at 24 months in the FLI group. Dropouts were higher in the FLI group than in the SLI group (20&#xb7;2% vs 15&#xb7;2%; p=0&#xb7;042). Global cognitive composite scores increased over time in both groups, with a mean annual change of 0&#xb7;31 SD (95% CI 0&#xb7;28-0&#xb7;34) per year in the SLI group and 0&#xb7;20 SD (0&#xb7;17-0&#xb7;23) per year in the FLI group (mean between-group difference of 0&#xb7;11 SD per year [0&#xb7;06-0&#xb7;15; p<0&#xb7;0001]). Overall, 478 adverse events were reported (412 in the SLI group and 66 in the FLI group). The most common adverse events were musculoskeletal symptoms (113 [21%] in the SLI group, 13 [2%] in the FLI group), upper respiratory infections (50 [9%] in the SLI group, one [<1%] in the FLI group), and COVID-19 infection (31 [6%] events in the SLI group). Serious adverse events occurred in 50 (9%) participants in the SLI group and 24 (5%) participants in the FLI group; none were related to the intervention. There were eight deaths (three in the SLI group and five in the FLI group), and none were related to the intervention.<br><br>INTERPRETATION: A culturally adapted multidomain lifestyle intervention was feasible across Latin America and resulted in greater cognitive improvements than a flexible health-advice intervention in older adults at risk of cognitive decline. These findings extend the evidence base for multidomain lifestyle interventions to populations historically under-represented in dementia research, supporting their feasibility and scalability as strategies to reduce cognitive decline risk amid the rapidly growing burden of dementia in low-income and middle-income countries.<br><br>FUNDING: Alzheimer's Association.<br><br>TRANSLATIONS: For the Spanish and Portuguese translations of the abstract see Supplementary Materials section.},
}
@article {pmid42442404,
year = {2026},
author = {Marsden, M and McLaren, JE and Bevan, RJ and Penn-Ripley, D and Somerville, M and Lauder, SN and Jones, MH and Maros, LB and McGurk, MR and Gallimore, A and Price, DA and Miners, KL and Ladell, K and Siebzehnrubl, FA and Hughes, TR and Humphreys, IR and Clement, M},
title = {Cytomegalovirus-induced T cell responses accelerate Alzheimer's disease progression in mice.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag043},
pmid = {42442404},
issn = {1460-2156},
support = {//Jane Hodge Foundation/ ; MR/X00922X/1/MRC_/Medical Research Council/United Kingdom ; 207503/Z/17/Z/WT_/Wellcome Trust/United Kingdom ; //Brain Tumour Charity/ ; MR/V000489/1//MRC/ ; MR/S07709/1//MRC/ ; MR/X018318/1//MRC/ ; },
abstract = {Infections have long been implicated as causative factors in Alzheimer's disease (AD). Multiple studies have further suggested a key role for herpesviruses, such as cytomegalovirus (CMV). Using transgenic 3xTg-AD mice, we demonstrate that systemic infection with the β-herpesvirus murine CMV (MCMV) accelerates the development of cognitive decline, tauopathy and synaptic loss in the hippocampus, all of which are key features of AD. Accelerated disease progression after infection was associated with substantial lymphocyte infiltration into the brain, dominated by MCMV-specific effector memory CD8+ T cells expressing CXCR3. T cell receptor analyses revealed that clonally diverse virus-specific CD8+ T cells were selectively recruited into the brain during the development of AD. T cell depletion or treatment with the antiviral drug valganciclovir during chronic infection reduced lymphocytic infiltrates in the brain and reversed cognitive decline. These data provide a mechanistic link between chronic viral infections and the development of AD.},
}
@article {pmid42442566,
year = {2026},
author = {Coccurello, R},
title = {Sleep-Related Alzheimer's Disease Vulnerability in Aging: A Muscle-Metabolic Perspective.},
journal = {Neuroscience and biobehavioral reviews},
volume = {},
number = {},
pages = {106869},
doi = {10.1016/j.neubiorev.2026.106869},
pmid = {42442566},
issn = {1873-7528},
abstract = {Sleep disruption is a hallmark of aging and a plausible driver of Alzheimer's disease vulnerability. Reduced slow-wave sleep, increased fragmentation, and circadian instability may facilitate amyloid-β accumulation, tau propagation, neuroinflammation, oxidative stress, and impaired glymphatic clearance. Yet the physiological factors that predispose older adults to unstable sleep remain insufficiently integrated into models of brain aging. This Review advances a sleep-muscle-brain framework in which sarcopenia, sarcopenic obesity, and insulin resistance are conceptualized as modifiable muscle-metabolic conditions that may bias sleep continuity and shape the biological impact of sleep disruption. We examine irisin/FNDC5-BDNF signaling as a hypothesis-generating candidate modifier of metabolic regulation, neurotrophic support, and brain resilience, while emphasizing that direct evidence for a causal role in human sleep regulation remains insufficient. Irisin-related pathways intersect with insulin sensitivity, inflammatory control, and BDNF-dependent synaptic plasticity, all of which are relevant to the physiological context in which sleep disruption may influence Alzheimer's disease pathophysiology. We propose that age-related attenuation of muscle endocrine signaling, together with insulin resistance and low-grade inflammation, may lower the threshold at which sleep fragmentation translates into amyloid/tau dyshomeostasis, glial activation, and network dysfunction. Rather than treating sleep disturbance as an isolated brain-centered risk factor, this framework positions sleep as a biobehavioral hub through which peripheral aging processes can modulate neurodegenerative resilience. The Review integrates evidence from sleep neuroscience, geroscience, metabolism, and neurodegeneration, and identifies experimentally testable predictions. A sleep-muscle-brain perspective may help refine risk stratification and guide multimodal interventions combining sleep optimization, resistance exercise, metabolic targeting, and Alzheimer's disease biomarker monitoring.},
}
@article {pmid42428106,
year = {2026},
author = {Kleiman, MJ and O'Shea, D and Rader, K and Baig, M and Camacho, S and Salcedo, A and Galvin, JE},
title = {The Puppy Escape Narrative: Validation of an Openly Available Recall Task for MCI Detection.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
pmid = {42428106},
abstract = {INTRODUCTION: Narrative recall is widely used to detect cognitive impairment, but dominant instruments carry proprietary restrictions. The Craft Story 21 (CS), the non-proprietary NACC UDS4 standard, is not available standalone. Here, we validate the freely available Puppy Escape (PE).<br><br>METHODS: 346 participants (153 cognitively normal, 106 subjective cognitive impairment, 87 mild cognitive impairment) completed PE and CS. Analyses evaluated convergent and criterion validity, MCI-vs-control discrimination, and incremental validity.<br><br>RESULTS: PE and CS converged (r=.43-.47) and were equivalent on 10/12 neuropsychological measures. PE Delayed discriminated MCI from controls (d=1.03; ROC-AUC equal to CS, DeLong p=.510) and added variance beyond CS (&#x394;R[2]=+.054, p<.001). Automated subscores revealed MCI deficits in location, action, and name content. PE-18 short form retained discrimination (d=1.02) with 18 items.<br><br>DISCUSSION: PE matched CS across all validation domains and captured complementary diagnostic information. PE and PE-18 are available via online registration explicitly permitting industry-sponsored research and fee-for-service clinical use.},
}
@article {pmid42435305,
year = {2026},
author = {Quintanar, L and Juárez-Romero, GU and López-Herrera, GR},
title = {Metal Binding to Tau Protein: Physiological and Pathological Relevance.},
journal = {Biochemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.biochem.6c00323},
pmid = {42435305},
issn = {1520-4995},
abstract = {The microtubule-associated protein tau is an intrinsically disordered protein that exhibits a remarkable diversity of functions, while its amyloid aggregation is the hallmark of tauopathies, including Alzheimer's disease. This perspective article discusses recent advances in understanding copper and zinc binding to tau, the nature of the metal binding sites, and its physiological and pathological relevance. First, an argument for a potential role of metal binding in the interactome and diverse functionality of tau is provided, since metal coordination occurs in regions of tau engaged in its interaction with key binding partners. Then, the role of metal binding to tau in modulating its structural dynamics and amyloid aggregation behavior is discussed, with an emphasis on a potential role of metal ions in the morphological diversity of tau fibrils. Finally, the interplay between metal binding and post-translational modifications (PTMs) of tau is examined in physiological and pathological contexts, discussing how PTMs may influence metal coordination and how metals may modulate PTM processing of tau. Overall, this perspective delineates the exciting future of bioinorganic research related to tau protein, underscoring the importance of investigating the role of metal ions in tau biology as functional modulators and/or drivers of pathological transitions, linking metal homeostasis to tau physiology and disease.},
}
@article {pmid42435422,
year = {2026},
author = {Atefi, GL and Marshall, CR and Cooper, C and Banerjee, S and Mukadam, N and , },
title = {Attitudes Towards Brain Health and Dementia Risk Reduction Among Minoritised Ethnic Communities in the United Kingdom: A Cross-Sectional Survey Analysis.},
journal = {International journal of geriatric psychiatry},
volume = {41},
number = {7},
pages = {e70238},
doi = {10.1002/gps.70238},
pmid = {42435422},
issn = {1099-1166},
support = {NIHR206110//NIHR Policy Research Unit in Dementia and Neurodegeneration/ ; WE.15-2021-02//Alzheimer Nederland/ ; },
mesh = {Humans ; Female ; *Dementia/prevention &amp; control/ethnology/psychology ; Male ; Cross-Sectional Studies ; *Health Knowledge, Attitudes, Practice/ethnology ; United Kingdom ; Aged ; South Asian People ; Risk Factors ; Risk Reduction Behavior ; White People/psychology ; Social Stigma ; Aged, 80 and over ; Black People/psychology ; *Ethnicity/psychology ; African People ; Middle Aged ; Asia, Southern ; White ; },
abstract = {BACKGROUND: There is much excitement about the potential for dementia prevention by targeting modifiable risk factors, yet sociodemographic disparities in dementia-related knowledge, stigma, and risk factor awareness remain underexplored. This study examines these differences among minoritised ethnic communities in the UK.<br><br>METHODS: As part of a project by the NIHR Dementia and Neurodegeneration Policy Research Unit at Queen Mary (DeNPRU-QM), dementia knowledge, stigma, and risk factor awareness of 3500 participants were assessed in a secondary analysis of data from two national surveys conducted in 2023 by Alzheimer's Research UK. Linear regression models were used to examine associations between ethnicity and knowledge-related outcomes, while ordinal logistic regression was used for stigma, adjusting for age, sex, education, social grade, chronic conditions, and knowing someone with dementia.<br><br>RESULTS: Compared to White participants, South Asian (Coef.&#xa0;=&#xa0;-0.45, 95% CI [-0.55, -0.34], p&#xa0;<&#xa0;0.001) and Black participants (Coef.&#xa0;=&#xa0;-0.17, 95% CI [-0.27, -0.06], p&#xa0;<&#xa0;0.005) had lower knowledge about dementia. Compared to White participants, Black participants had higher odds of reporting greater stigma (OR&#xa0;=&#xa0;2.55, 95% CI [2.10, 3.09], p&#xa0;<&#xa0;0.001), as did South Asian participants (OR&#xa0;=&#xa0;1.62, 95% CI [1.34, 1.97], p&#xa0;<&#xa0;0.001) and participants from Other ethnic groups (OR&#xa0;=&#xa0;1.55, 95% CI [1.17, 2.07], p&#xa0;=&#xa0;0.003). Black individuals also had lower knowledge of dementia risk factors compared to White participants (Coef.&#xa0;=&#xa0;-0.655, 95% CI [-1.110, -0.200], p&#xa0;=&#xa0;0.005). Education level, chronic health conditions, gender, profession, and knowing someone with dementia were also associated with some outcomes, although associations varied by outcome.<br><br>CONCLUSION: Ethnic disparities exist in dementia knowledge, stigma, and dementia risk factor awareness. Any future public information campaign around dementia risk reduction and timely diagnosis should ensure cultural competency and include strategies to reach minoritised ethnic communities. Policymakers should consider how prevention might be promoted in all health and social care encounters, since people with chronic conditions who may not be eligible for primary health checks had lower levels of knowledge about dementia.},
}
@article {pmid42435542,
year = {2026},
author = {Zhou, S and Chen, H and Wang, F and Jiang, JH},
title = {Near-infrared phenothiazine-fused rhodol with large Stokes shift for fluorogenic imaging of butyrylcholinesterase in vivo.},
journal = {Talanta},
volume = {311},
number = {},
pages = {130248},
doi = {10.1016/j.talanta.2026.130248},
pmid = {42435542},
issn = {1873-3573},
abstract = {Butyrylcholinesterase (BChE) is a serine hydrolase that plays diverse roles in physiological and pathological processes, and imaging BChE activity is of great importance for disease diagnosis and drug development. Here we develop a new activatable near-infrared (NIR) fluorescent probe, DR760, for high contrast imaging of BChE activities in vivo. A new NIR fluorophore with a large Stokes shift is engineered by fusing phenothiazine with rhodol. We further develop a fluorogenic probe for BChE by caging the hydroxyl group with a cyclopropyl ester moiety. It is shown that BChE-mediated release of the caging group results in a fluorescence enhancement of 81-fold at 760 nm. The probe is further explored to image BChE activity and monitor changes in BChE activity in a drug-treated Alzheimer's disease (AD) cellular model. The capability of the probe for imaging BChE activity in vivo is demonstrated using a tumor-bearing mice model. Collectively, this study shows that DR760 affords a new molecular tool for detecting BChE activity in vitro and in vivo.},
}
@article {pmid42435584,
year = {2026},
author = {Arranz, J and Lantero-Rodríguez, J and Braun-Wohlfahrt, LS and Vaqué-Alcázar, L and Rodríguez-Baz, &#xcd; and Kac, PR and Arslan, B and Maure-Blesa, L and Pertierra, L and Videla, L and Carmona-Iragui, M and Benejam, B and Del Hoyo Soriano, L and Barroeta, I and Fernández, S and Bejanin, A and Lleó, A and Ashton, NJ and Zetterberg, H and Fortea, J and Alcolea, D and Montoliu-Gaya, L},
title = {CSF and plasma tau biomarkers in the Down syndrome-Alzheimer's disease continuum.},
journal = {EBioMedicine},
volume = {130},
number = {},
pages = {106370},
doi = {10.1016/j.ebiom.2026.106370},
pmid = {42435584},
issn = {2352-3964},
abstract = {BACKGROUND: Nearly all individuals with Down syndrome (DS) develop Alzheimer's disease (AD) dementia, primarily due to overexpression of the APP gene. Although specific cerebrospinal fluid (CSF) and plasma tau biomarkers have been investigated in DS-AD, how different tau species change in the DS-AD continuum in comparison to sporadic AD remains uncertain.<br><br>METHODS: In this cross-sectional study, we analysed CSF and plasma tau biomarkers in 461 samples from the DABNI and SPIN cohorts, including individuals with DS, cognitively normal euploid participants, and patients with sporadic AD. Biomarker differences were assessed using linear regression with Tukey post hoc comparisons. LOESS modelling was applied to estimate the age at which tau biomarkers became abnormal.<br><br>FINDINGS: We analysed 461 participants from the DABNI and SPIN cohorts. Both CSF and plasma tau biomarkers increased during the asymptomatic stages of DS and in euploid controls, coinciding with A&#x3b2; positivity; across the DS clinical spectrum the largest increases were observed for CSF NTA-tau (fold-change [fc] = 6.46-6.94), CSF p-tau217 (fc = 6.43-6.74) and plasma p-tau217 (fc = 4.63-6.54) (linear regression adjusted for age, sex and APOE-&#x3b5;4 with Tukey post-hoc tests; all p < 0.001). During the dementia stages, CSF tau biomarkers showed only modest further increases (no CSF biomarker differed between pDS and dDS; all p &#x2265; 0.268), whereas plasma tau biomarkers retained a broader dynamic range across symptomatic phases (pDS vs dDS: plasma p-tau217 p = 0.001, p-tau181 p = 0.002, p-tau231 p = 0.004). Plasma p-tau217 showed the highest diagnostic accuracy, with areas under the curve (AUC) of 0.91-0.97 for biological categorisations and numerically higher values than CSF in symptomatic stages (pDS vs dDS: plasma p-tau217 AUC = 0.69 [95% CI 0.58-0.80] vs CSF p-tau217 AUC = 0.53 [95% CI 0.41-0.65]; DeLong test p = 0.019). In LOESS analyses, tau biomarkers diverged from age-matched controls in the late 30s to early 40s (e.g., plasma p-tau217 &#x2248; 37.3 years, CSF p-tau181 &#x2248; 38.1 years) and reached abnormality (+2 SD) over an approximately 20-year span between the fourth and sixth decades, outlining differential but temporally compressed increases. Finally, during symptomatic stages, tau biomarker levels remained stable in DS-AD, in contrast to sporadic AD, where levels declined with advancing age.<br><br>INTERPRETATION: These findings highlight the complementary roles of CSF and plasma tau biomarkers in tracking disease progression: CSF biomarkers capture early pathological changes, whereas plasma biomarkers more effectively reflect disease progression within symptomatic stages. Furthermore, tau biomarkers might support disease staging and monitor clinical progression in DS-AD, but with the need to adapt biomarker frameworks to this specific population.<br><br>FUNDING: La Caixa Foundation, Instituto de Salud Carlos III, Generalitat de Catalunya, National Institute on Ageing, Wellcome Trust, J&#xe9;r&#xf4;me Lejeune Foundation, Medical Research Council, Alzheimer's Association, National Institute for Health Research, EU Joint Programme-Neurodegenerative Disease Research, Alzheimer's Society.},
}
@article {pmid42435587,
year = {2026},
author = {Domínguez-García, A and Delgado-Uriarte, JC and Cervantes-Arriaga, A},
title = {Precision therapeutics and innovative clinical trial design in neurodegenerative diseases.},
journal = {Revista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion},
volume = {78},
number = {4},
pages = {100050},
doi = {10.1016/j.ric.2026.100050},
pmid = {42435587},
issn = {2564-8896},
abstract = {Neurodegenerative diseases are biologically heterogeneous disorders characterized by progressive neuronal dysfunction, overlapping molecular pathologies, and limited disease-modifying therapies. Advances in biomarker development, molecular staging, and precision medicine are reshaping therapeutic strategies and clinical trial design across Parkinson's disease, Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, Huntington's disease, and related disorders. This review summarizes emerging therapeutic approaches, including monoclonal antibodies targeting protein aggregation, immune-modulating and metabolic interventions, antisense oligonucleotides, gene replacement and genome-editing strategies, stem cell-based therapies, and neurosurgical delivery platforms and neuromodulation technologies. It also examines evolving clinical trial methodologies such as biomarker-enriched recruitment, adaptive and delayed-start designs, platform trials, decentralized models, and master protocols. Additional emphasis is placed on diagnostic biomarkers, multimodal artificial-intelligence pipelines, systems-biology perspectives, network-based therapeutic strategies, and the reproducibility and interpretability requirements for computational tools. Despite recent progress, major challenges remain, including biological heterogeneity, limited translatability of preclinical models, delivery barriers, long-term safety concerns, and inequities in access to biomarker-based care and trial participation. Future directions will require combination therapies, integrated biomarker pipelines, preventive strategies, and pragmatic trial systems capable of translating biological advances into durable and equitable clinical benefit.},
}
@article {pmid42435662,
year = {2026},
author = {Kim, KY and Ham, H and Yoon, EJ and Kim, E and Kim, YK and Lee, JY and , },
title = {Relative importance of blood-based biomarkers for Alzheimer's disease-specific neurodegeneration and cognitive decline.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {9},
pages = {100644},
doi = {10.1016/j.tjpad.2026.100644},
pmid = {42435662},
issn = {2426-0266},
abstract = {BACKGROUND: Although blood-based biomarkers are now available for diagnosing Alzheimer's disease (AD), the best biomarker for AD-specific neurodegeneration and cognitive decline remains unclear. This study aimed to determine the relative importance of four plasma biomarkers-phosphorylated tau (p-tau) 217, p-tau181, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP)-in AD-specific neurodegeneration and cognition.<br><br>METHODS: We analyzed cross-sectional data from two independent, ethnically distinct cohorts spanning the clinical spectrum from cognitively unimpaired to dementia: 150 participants from the SAMD cohort (100% Asian) and 284 participants from the ADNI cohort (94.0% White). Plasma biomarker levels were quantified using Single-Molecule Array (Simoa) assays. We employed dominance analysis to determine the hierarchical contributions of these biomarkers to AD signature regions of interest (ROI) thickness (entorhinal, inferior temporal, middle temporal, and fusiform regions), total cognition, and memory, stratified by amyloid-PET status. Three sensitivity analyses were further conducted to validate the findings across these cohorts, mitigating potential biases arising from differences in demographic characteristics and clinical severity. All analyses were adjusted for age, sex, education, and APOE &#x3b5;4 status.<br><br>RESULTS: The dominance hierarchy differed markedly according to the amyloid status. Plasma GFAP and p-tau217 emerged as the dominant predictors for AD signature ROI thickness and cognitive impairment in amyloid-positive participants. Specifically, GFAP demonstrated superior dominance in explaining cortical atrophy within the SAMD cohort, whereas p-tau217 was the dominant predictor in the ADNI cohort. P-tau217 generally outperformed the others in explaining total cognition and memory in the amyloid (+) group. In contrast, among amyloid (-) participants, plasma NfL showed greater explanatory power than GFAP for both neurodegeneration and cognitive decline across both cohorts.<br><br>CONCLUSION: The efficacy of plasma biomarkers in reflecting AD-related neurodegeneration varies significantly depending on the presence of amyloid pathology. While GFAP and p-tau217 are robust indicators of AD-associated changes linked to plaque pathology, NfL better reflects non-specific neurodegeneration involving axonal damage. Consequently, a stratified approach based on amyloid status is essential for the optimal application of blood-based biomarkers in monitoring disease progression and evaluating therapeutic efficacy in future clinical trials and precision medicine.},
}
@article {pmid42428132,
year = {2026},
author = {Mei, Z and Howard, N and Harvey, DJ and , and Fox, E and Seyfried, NT and Wingo, TS and Wingo, AP},
title = {CSF proteome-wide study of neuropsychiatric symptoms of dementia.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
pmid = {42428132},
abstract = {INTRODUCTION: Neuropsychiatric symptoms in dementia (NPS) are common and among the most troubling aspects of living with dementia, yet their underlying mechanisms remain unclear. Here, we aimed to identify cerebrospinal fluid (CSF) proteins associated with NPS.<br><br>METHODS: Proteomes were profiled from CSF collected at baseline from participants of the Alzheimer's Disease Neuroimaging Initiative (ADNI) using mass spectrometry. Here, we included participants having positive AD CSF biomarkers (i.e., pTtau181 / A&#x3b2;42 ratio >0.025) and mild cognitive impairment or AD dementia (n=419). Eight NPS domains were assessed longitudinally with the Neuropsychiatric Symptom Inventory Questionnaire. Severity of cognitive impairment was evaluated using the CDR-SB. Proteome-wide differential expression analysis for each NPS domain at baseline was performed. Significant protein-NPS associations underwent mediation analysis to test whether they were mediated by cognitive impairment severity. Cox proportional hazard was modeled for baseline CSF proteins and incident NPS. Additionally, we tested whether candidate NPS causal proteins previously identified in brain are associated with NPS in CSF.<br><br>RESULTS: We identified 8 CSF proteins associated with apathy at baseline (FDR q<0.05) after adjusting for sex, age, and education - NTNG2, S100A1, FZD1, FSTL5, CDH7, CHODL, FBXO2, and CACNA2D2. Mediation analysis revealed these associations were independent of cognitive impairment severity in four proteins and only partially mediated by cognitive impairment severity in the remaining four proteins. Among the 10 NPS candidate causal proteins previously identified in brain and detected in CSF, the abundance of two proteins (CPD, GRN) in CSF was associated with baseline disinhibition and of two other proteins (PIK3IP1, PCMT1) with both baseline apathy and incident apathy after adjusting for sex, age, and education.<br><br>DISCUSSION: These findings suggest that proteomic alterations in apathy in MCI/AD encompass synaptic connectivity, calcium regulation, Wnt-signaling, and neuronal proteostasis, highlighting potential CSF biological processes and biomarker candidates for apathy.},
}
@article {pmid42428551,
year = {2026},
author = {Li, W and Yu, X and Guo, C and Huang, Y and Wei, Z and Liu, Y and Wang, JZ and Liu, R and Ji, W and Duan, Q and Wang, J and Wang, G and Wang, X},
title = {Acylglycerol Kinase Inhibition Restores Mitophagy and Alleviates Alzheimer's Disease Pathology.},
journal = {MedComm},
volume = {7},
number = {7},
pages = {e70863},
pmid = {42428551},
issn = {2688-2663},
abstract = {Mitophagy is a conserved cellular process that removes dysfunctional or excess mitochondria. Increasing evidence suggests that impaired mitophagy plays a crucial role in AD development. Promoting mitophagy has been shown to be protective in models of AD, representing an important target of Alzheimer's disease (AD). However, the molecular mechanisms underlying impaired mitophagy in AD are still elusive. Here, we provide evidence that highly expressed acylglycerol kinase (AGK), a mitochondrial lipid kinase associated with mitochondrial protein transport, glycolysis, and platelet formation, is a key mediator of mitophagy in AD. We found that AGK promoted the binding of ATPase family AAA domain containing 3A to translocase of the inner mitochondrial membrane 23 and sequentially increased mitochondrial import of PTEN-induced putative kinase 1, leading to the decrease of mitophagy. Further investigations revealed that the AGK downregulation in neuronal cells and APP/PS1 mice enhanced mitophagy, increased mitochondrial membrane potential, decreased pathological Tau/Aβ and neuroinflammation, and alleviated cognitive dysfunctions in the mice. Altogether our findings indicate that AGK plays a critical role in mediating mitophagy defects in AD; furthermore, downregulation of AGK promotes mitophagy and the decrease of Aβ and pathological Tau, providing an encouraging therapeutic treatment for AD.},
}
@article {pmid42428693,
year = {2026},
author = {Li, J and Zhu, Q and Qin, J and Xue, H},
title = {Oral Microbiota and Alzheimer's Disease: A Bidirectional Mendelian Randomization Study Based on East Asian Ethnicity.},
journal = {Health science reports},
volume = {9},
number = {7},
pages = {e72632},
pmid = {42428693},
issn = {2398-8835},
abstract = {BACKGROUND AND AIMS: The "oral-microbiota-brain axis" has been hypothesized to contribute to Alzheimer's disease (AD) pathogenesis, but causal evidence remains limited. We performed a bidirectional Mendelian randomization (MR) study to investigate potential genetic causality between oral microbiota and AD in East Asians.<br><br>METHODS: Two-sample MR integrated genome-wide data from 2984 Chinese participants (saliva/tongue dorsum microbiomes) and 7036 Japanese participants (3962 AD cases/4074 controls). Genetic instruments were selected using pragmatically moderated significance thresholds (forward: p&#x2009;<&#x2009;5&#x2009;&#xd7;&#x2009;10[-4]; reverse: p&#x2009;<&#x2009;5&#x2009;&#xd7;&#x2009;10[-5]), with causality assessed via inverse-variance weighted (IVW) regression and four Supporting methods. Sensitivity analyses validated robustness. We examined 3117 microbial taxa-AD pairs, followed by exploratory Gene Ontology (GO) enrichment analysis.<br><br>RESULTS: Forward MR identified 12 candidate causal taxa: five with risk-increasing associations (e.g., Prevotella sp. MGS2526, OR&#x2009;=&#x2009;1.32 [1.14-1.52], p&#x2009;=&#x2009;1.4&#x2009;&#xd7;&#x2009;10[-4]) and seven with protective associations (e.g., Streptococcus mitis MGS519, OR&#x2009;=&#x2009;0.81 [0.69-0.94], p&#x2009;=&#x2009;7.9&#x2009;&#xd7;&#x2009;10[-3]). Reverse MR suggested AD may influence the abundance of three microbial species (e.g., Streptococcus sanguinis MGS515, OR&#x2009;=&#x2009;1.04 [1.01-1.07], p&#x2009;=&#x2009;3.6&#x2009;&#xd7;&#x2009;10[-3]). Exploratory GO analysis highlighted enrichment in pathways related to synaptic transmission and nutrient metabolism.<br><br>CONCLUSION: This study provides genetic evidence consistent with a bidirectional relationship between oral microbiota and AD in East Asians, nominating 15 microbial taxa as candidates for further investigation. The implicated biological pathways offer hypotheses for mechanistic links via the oral-microbiota-brain axis. These findings advance the etiological understanding of AD and highlight priority targets for future experimental and clinical validation.},
}
@article {pmid42428696,
year = {2026},
author = {O'Kelly, M and Lanata, SC and Kleen, JK},
title = {Mapping the space of dementia with EEG in stained glass.},
journal = {Frontiers in dementia},
volume = {5},
number = {},
pages = {1820301},
pmid = {42428696},
issn = {2813-3919},
abstract = {Dementia conditions, including Alzheimer's disease, are progressive disorders for which effective treatments remain under development. Accordingly, interventions that improve quality of life are an important focus of patients, caregivers, and providers, including traditional art forms like painting and sculpture. In this Perspective article, we discuss the use light as a unique form of art to create transformative spaces that stimulate the senses and potentially support wellbeing. We outline an art-science collaborative initiative in which the patients themselves contribute, including through the recording and conversion their EEG brainwave activity to 2D time-frequency spectrogram representations. These representations are transferred to the ancient art of stained glass and installed into the patient's own home. This intervention creates a novel dynamic environment of illumination and colour saturation, derived from the patient and in sync with ever-changing solar and climate influences. Details of the approach and options for meaningful patient-centred customization are described, with illustrations of the procedures and resulting installations, along with thoughts for future improvements.},
}
@article {pmid42428835,
year = {2026},
author = {Hua, OH and Tran Thai, H and Hoang Son, NL and Le Ha, V and Huyen Tran, T and Phung Nguyen, V and Van Anh, TT and Le Thi, H and Duc Cuong, N and Van Tat, P},
title = {Development of Novel Inhibitors for Alzheimer's Disease from Erythrina variegata L. Extract-Derived Clusters Using Molecular Docking, QSAR Modeling, Quantum Chemical Calculations, and Molecular Dynamics Simulations.},
journal = {ACS omega},
volume = {11},
number = {26},
pages = {39390-39416},
pmid = {42428835},
issn = {2470-1343},
abstract = {The objective of this investigation is to identify and enhance compounds from the medicinal plant Erythrina variegata L. that possess potential inhibitory activity against acetylcholinesterase (AChE). Consequently, this investigation will contribute to the pursuit of supportive therapeutic agents for Alzheimer's disease. The initial research matrix was composed of nanocluster materials that were derived from the crude extract. The identification of 13 compounds was achieved by utilizing an ultraperformance liquid chromatography system in conjunction with quadrupole time-of-flight mass spectrometry for structural elucidation. Compound VN62 was chosen due to its favorable binding energy (ES = -8.038 kcal/mol) and RMSD = 1.388 Å, as evidenced by molecular docking simulations and analytical results with the AChE protein (PDB ID: 1EVE). The pIC50 values were predicted using reliable QSAR models, such as QSARGA‑MLR, QSARGA‑ANN, and QSARKPLS‑LF, which were constructed on this basis. Five novel derivatives (VN62N1-VN62N5) were designed from VN62, subsequently semisynthesized, and structurally confirmed using spectroscopic methods, guided by QSAR and docking results. The AChE inhibitory activity was assessed in vitro, and VN62 demonstrated an IC50 of 1.34 μg/mL (pIC50 = 5.498). Conversely, the newly designed derivatives demonstrated a trend toward enhanced activity. Furthermore, a multicriteria evaluation model integrating QSAR, docking, ADMET, and quantum descriptors identified VN62N4 as the top-ranked candidate overall. Molecular dynamics simulations over 400 ns confirmed the structural stability of the VN62N4-AChE complex, as evidenced by stable RMSD, low RMSF in active-site residues, and persistent hydrogen bonding and hydrophobic interactions. The findings verify the efficacy of a comprehensive, multimethod in silico screening strategy in directing the development of AChE inhibitors.},
}
@article {pmid42428879,
year = {2026},
author = {Hermosillo-Abundis, C and Arias-Carrion, O and Contreras-Ibáñez, C and Mendez-Rojas, MA},
title = {From Air to Brain: Environmental Nanoparticles as Modifiable Risk Factors for Neurodevelopmental, Neurodegenerative, and Mental Disorders.},
journal = {ACS omega},
volume = {11},
number = {26},
pages = {38267-38287},
pmid = {42428879},
issn = {2470-1343},
abstract = {Ultrafine particles (≤100 nm) and other environmental nanoparticles have emerged as biologically active pollutants that can cross biological barriers, including the blood-brain barrier and the placenta. Growing evidence implicates ultrafine particles in a wide range of neuropsychiatric conditions, yet their effects remain poorly integrated into clinical and public health frameworks. In this review, we distinguish between size-defined ultrafine particles (UFPs, ≤100 nm), composition-defined environmental nanoparticles originating from combustion and secondary formation processes, and engineered nanomaterials (ENPs), which differ in physicochemical properties, exposure scenarios, and regulatory status. This narrative systematic review synthesizes findings from human and experimental studies on the neuropsychiatric and neurodevelopmental effects of environmental nanopollutants. A structured search was conducted in PubMed, Web of Science, Scopus, and Google Scholar up to November 2025, following explicit inclusion and exclusion criteria. Eligible studies included peer-reviewed human and animal research assessing mental health or neurological outcomes of nanopollutant exposure. Epidemiological studies(?)primarily involving traffic-related air pollution and mixed combustion-derived ultrafine particle exposures(?)suggest associations with increased risk of cognitive impairment, autism spectrum disorder, depression, schizophrenia, and neurodegenerative diseases, including Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis. Prenatal and early life exposures were linked to cortical thinning, altered neurodevelopmental trajectories, and early proteinopathies. Underlying mechanisms include neuroinflammation, oxidative stress, and protein aggregation. Despite methodological heterogeneity, the evidence supports the urgent need for regulation and prevention. Environmental nanopollutants constitute an under-recognized, modifiable risk factor for neuropsychiatric and neurodegenerative conditions. A paradigm shift is needed to incorporate environmental exposure history into mental health research, risk assessment, and prevention strategies. Regulatory action targeting nanopollutant emission and exposure, particularly in vulnerable populations, is critical to mitigating long-term neurological consequences.},
}
@article {pmid42429089,
year = {2026},
author = {Zhang, Z and Li, D and Liu, J and Lu, L and Cai, W and Yu, G},
title = {[Mechanism of Bushen Yijing Formula in improving cognitive function in Alzheimer's disease model mice].},
journal = {Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences},
volume = {},
number = {},
pages = {1-12},
doi = {10.3724/zdxbyxb-2025-0747},
pmid = {42429089},
issn = {1008-9292},
abstract = {OBJECTIVES: To explore the mechanism of Bushen Yijing Formula (BSYJF) in the treatment of Alzheimer's disease (AD) through an integrated approach combining transcriptomics, network pharmacology, and molecular docking.<br><br>METHODS: Twelve amyloid precursor protein/presenilin-1 (APP/PS1) transgenic mice were randomly divided into normal control, model, and BSYJF groups. The treated group received daily intragastric administration of BSYJF for 12 consecutive weeks. Cognitive function and hippocampal amyloid &#x3b2;-protein (A&#x3b2;) deposition were assessed using behavioral tests and immunohisto-chemistry. Hippocampal tissues were subjected to transcriptomic sequencing to identify differentially expressed genes (DEGs). Functional enrichment analyses were performed using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA). In parallel, active compounds of BSYJF were screened via the TCMSP and PubChem databases, and AD-related targets were retrieved from GeneCards and other disease databases. Core targets were identified by intersecting these targets with transcriptomic DEGs. Molecular docking and molecular dynamics simulations were employed to evaluate binding affinity between active compounds and core targets, and qPCR was used to validate expression changes of core target genes.<br><br>RESULTS: BSYJF treatment improved cognitive function and reduced hippocampal A&#x3b2; deposition in APP/PS1 mice. Transcriptomic analysis revealed 73 DEGs between the model and BSYJF groups. GO analysis identified enrichment in 281 biological processes, 104 cellular components, and 120 molecular functions. KEGG analysis highlighted 110 pathways, and GSEA supplemented 322 enriched gene sets, many related to the immune system, neurodegenerative diseases, and signaling pathways such as Th17 cell differentiation and NF-&#x3ba;B. Integrated analysis with network pharmacology prioritized 10 core targets. Molecular docking and molecular dynamics simulations indicated strong structural stability and binding affinity of BSYJF bioactive constituents to these core targets. qPCR results confirmed that BSYJF downregulated the expression of Aurkb, Nr1i3, and Ttk, while upregulating Apob and Ces1d, consistent with the transcriptomic findings.<br><br>CONCLUSIONS: Transcriptomics, bioinformatics analysis, and animal experiments suggest that BSYJF may regulate immune-inflammatory responses and alleviate neuronal damage through a multi-component, multi-target, and multi-pathway approach, thereby improving cognitive function in AD model mice.},
}
@article {pmid42429097,
year = {2026},
author = {Lu, Y and Li, D and Hu, Y and Lu, L and Yu, G},
title = {[Bushen Yijing formula attenuates amyloid β-protein deposition and oxidative damage in Caenorhabditis elegans].},
journal = {Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences},
volume = {},
number = {},
pages = {1-13},
doi = {10.3724/zdxbyxb-2025-0419},
pmid = {42429097},
issn = {1008-9292},
abstract = {OBJECTIVES: To investigate the protective effects of Chinese medicine Bushen Yijing formula against amyloid β-protein (Aβ) deposition and oxidative damage using an in vitro culture model of Caenorhabditis elegans.<br><br>METHODS: An in vitro culture system of C. elegans (strains N2, CL4176, TJ356, and LG333) was employed. The herbal components of the formula were water&#x2011;extracted, freeze&#x2011;dried into lyophilized powder, and added to the culture medium at different concentrations. Oxidative stress was induced by paraquat exposure. Evaluated parameters included lifespan; time to paralysis and pharyngeal A&#x3b2; deposition in CL4176; levels of total antioxidant capacity, superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), malondialdehyde (MDA), and reactive oxygen species (ROS) measured by commercial kits; apoptosis detected by acridine orange staining; nuclear translocation of DAF&#x2011;16::GFP in TJ356 nematodes and SKN-1::GFP in LG333 nematodes observed under fluorescence microscopy. Molecular docking and dynamics simulations were further performed to assess the binding stability of the active components catalpol and tetrahydroalstonine (THA) with the core targets FOXO and Nrf2. All experiments were performed in triplicate and independently repeated three times.<br><br>RESULTS: Compared with the normal control group, Bushen Yijing formula significantly extended the lifespan of N2 nematodes under both oxidative stress and normal conditions (all P<0.01), compared with the control group of the AD model, prolonged the time to paralysis and reduced pharyngeal A&#x3b2; deposition in CL4176 (all P<0.01). Compared with the control group in the paraquat-induced oxidative stress model in N2, Bushen Yijing formula elevated total antioxidant capacity, SOD, CAT, and GSH levels (all P<0.01), decreased MDA and ROS levels (all P<0.05), and attenuated apoptosis. Moreover, the formula promoted nuclear translocation of DAF&#x2011;16 and SKN&#x2011;1 (all P<0.01). Molecular docking revealed that binding energies of catalpol and THA with FOXO and Nrf2 were all below &#xff0d;7.00 kcal/mol, and dynamics simulations confirmed high stability and favorable affinity for the FOXO-catalpol, Nrf2-catalpol, and Nrf2-THA complexes.<br><br>CONCLUSIONS: Bushen Yijing formula alleviates A&#x3b2; deposition and its neurotoxicity, enhances antioxidant capacity, and attenuates oxidative stress injury in model nematodes, likely through stable binding and regulation of the FOXO/Nrf2 signaling pathway.},
}
@article {pmid42429220,
year = {2026},
author = {Feter, N and Nanda, A and Hourihan, S and Aslan, D and Feter, J and Sayre, MK and Bharadwaj, PK and Ally, M and Song, H and Arora, A and Maltagliati, S and Lai, MHC and Wilcox, RR and Klimentidis, YC and Alexander, GE and Raichlen, DA},
title = {Associations of distinct sedentary behaviors with cortical, subcortical, and white matter hyperintensity volumes: Evidence from the ARIC study.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71582},
pmid = {42429220},
issn = {1552-5279},
support = {P30AG019610/NH/NIH HHS/United States ; R56AG067200/NH/NIH HHS/United States ; R01AG064587/NH/NIH HHS/United States ; R01AG072445/NH/NIH HHS/United States ; //Arizona Department of Health Services/ ; //McKnight Brain Research Foundation/ ; 75N92022D00001/HL/NHLBI NIH HHS/United States ; 75N92022D00002/HL/NHLBI NIH HHS/United States ; 75N92022D00003/HL/NHLBI NIH HHS/United States ; 75N92022D00004/HL/NHLBI NIH HHS/United States ; 75N92022D00005/HL/NHLBI NIH HHS/United States ; U01HL096812//ARIC Neurocognitive Study/ ; U01HL096814//ARIC Neurocognitive Study/ ; U01HL096814//ARIC Neurocognitive Study/ ; U01HL096899//ARIC Neurocognitive Study/ ; U01HL096902//ARIC Neurocognitive Study/ ; U01HL096917//ARIC Neurocognitive Study/ ; /NS/NINDS NIH HHS/United States ; /AG/NIA NIH HHS/United States ; /DC/NIDCD NIH HHS/United States ; //National Instituteon Aging's Intramural Research Program/ ; //National Institute of Neurological Disease and Stroke Intramural Research Program/ ; },
mesh = {Humans ; Female ; *Sedentary Behavior ; *White Matter/diagnostic imaging/pathology ; Magnetic Resonance Imaging ; Male ; Middle Aged ; *Brain/diagnostic imaging/pathology ; Longitudinal Studies ; Aged ; },
abstract = {INTRODUCTION: Longitudinal studies linking sedentary behavior (SB) in different contexts to brain structure and white matter hyperintensity (WMH) volume remain limited.<br><br>METHODS: We analyzed data from the Atherosclerosis Risk in Communities (ARIC) study (n&#xa0;=&#xa0;1,712). Self-reported SB was assessed at visit 1 (1987-1989), with neuroimaging (3T magnetic resonance imaging [MRI]) at visit 5 (2011-2013). Participants were non-demented adults (57% women; 53[5.2] years) who reported frequency of TV watching and occupational sitting. Outcomes included cortical, subcortical, and Alzheimer's disease-signature regions (ADSR), and total WMH brain volumes.<br><br>RESULTS: Frequent TV watching was associated with increased WMH volume and reduced frontal, occipital, and ADSR volumes. Sitting during work, which is more cognitively active, was linked to lower WMH and larger frontal (males only), occipital, and parietal volumes. Results remained consistent when adjusted for physical activity.<br><br>DISCUSSION: SB is associated with structural brain and WMH volumes. Cognitively active SB may preserve brain structure and cerebrovascular health.},
}
@article {pmid42429357,
year = {2026},
author = {Jin, Z and Peng, Y and Sheng, M and Zheng, Y and Wang, Q and Chen, Y and Zhang, T and Li, Z and Huang, Y and Huang, J and Yang, X},
title = {Interface Self-Assembly of Au10 Nanoclusters for Enhanced Electrochemiluminescence and Alzheimer's Disease Biomarker Detection.},
journal = {Small (Weinheim an der Bergstrasse, Germany)},
volume = {},
number = {},
pages = {e74501},
doi = {10.1002/smll.74501},
pmid = {42429357},
issn = {1613-6829},
support = {22393930//National Natural Science Foundation of China/ ; 22034006//National Natural Science Foundation of China/ ; SKL202302029//Science and Technology Development Plan Project of Jilin Province, China/ ; },
abstract = {Atomically precise metal nanoclusters (NCs), as ultrasmall materials with well-defined composition and structure, exceptional biocompatibility, and unique optical properties, position them as strong candidates in the field of electrochemiluminescence (ECL). However, the ECL efficiency of NCs is relatively low, which dramatically constrained their applications due to the demands of detection sensitivity and brightness. In this study, we report the interface self-assembly of Au10 nanoclusters for the first time, and ultimately formed a fibrous structure with a high aspect ratio, Au10-Fiber, which is an innovative approach that significantly enhances the ECL activity of Au10 NCs. By employing time-dependent and in situ spectroscopic techniques, we visually monitored the dynamic assembly process, and elucidated the interface self-assembly mechanism mediated by aurophilic interaction and π-π stacking. The increase in local electronic density, enhanced conductivity of the ordered structure, and accelerated electron transfer within the π-conjugated system collectively contributed to the significant enhancement of the ECL performance, thereby revealing the key structural factors responsible for ECL enhancement. As a proof of concept, we successfully constructed an ECL immunosensor based on Au10-Fiber for the detection of Alzheimer's disease biomarker Aβ1-42, achieving a detection limit below 3.33 fg/mL.},
}
@article {pmid42429480,
year = {2026},
author = {Ng, CA and Lim, MJH and Chong, EJY and Colombo, G and Schinazi, VR and Venketasubramanian, N and Chen, CL},
title = {A comparison of the Quick Dementia Rating System and Montreal Cognitive Assessment for detecting mild cognitive impairment and dementia assessed by the Clinical Dementia Rating Scale.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261467344},
doi = {10.1177/13872877261467344},
pmid = {42429480},
issn = {1875-8908},
abstract = {BackgroundThe Clinical Dementia Rating (CDR) scale is widely used for staging mild cognitive impairment (MCI) and dementia but suffers from lengthy administration time (45-60 min). The Montreal Cognitive Assessment (MoCA; 10-15 min) and Quick Dementia Rating System (QDRS; 3-5 min) are promising brief alternatives, although it remains unclear which tool performs better in discriminating between cognitive and functional impairment stages.ObjectiveTo compare the performance of the QDRS and MoCA in identifying MCI, dementia, and individuals eligible for disease modifying therapies and clinical trials (DMTT).Methods376 older adults (34.8% NCI, 33.0% MCI, 32.2% dementia) recruited from the memory clinic (n = 284, 75.5%) and community (n = 92, 24.5%) in Singapore completed the QDRS, MoCA, and CDR. No cognitive impairment (NCI), MCI, and dementia were staged as CDR-Global Scores (CDR-GS) of 0, 0.5, and ≥1, respectively. The DMTT subgroup was defined as CDR-GS of 0.5-1. Discriminative performance was determined by area under the curve (AUC) and compared using DeLong's test. Agreement with CDR classifications was determined on McNemar's test.ResultsBoth QDRS and MoCA demonstrated fair-to-excellent discrimination across CDR-staged groups (MCI: AUC 0.79-0.84; Dementia: AUC 0.92-0.97; DMTT: AUC 0.85-0.91), with no significant differences in discrimination observed. The QDRS correctly identified a greater proportion of MCI (55.6% versus 19.4%; p < 0.001) and DMTT (58.9% versus 41.7%; p < 0.001) versus the MoCA.ConclusionsThe QDRS and MoCA are practical brief alternatives to the CDR. The QDRS was advantageous for identifying MCI and DMTT, whereas both were effective screening tools for dementia.},
}
@article {pmid42429504,
year = {2026},
author = {Lu, K and Lu, Y and Tang, R and Dong, X and Zhuang, P and Gao, Y and Cheng, M and Wang, Y and Wang, Y},
title = {Mechanisms of autophagy-lysosome pathway impairment in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261460879},
doi = {10.1177/13872877261460879},
pmid = {42429504},
issn = {1875-8908},
abstract = {The autophagy-lysosomal pathway is key for the removal of harmful substances in cells. This article integrates evidence that highlights the role of lysosomal function and the autophagy-lysosomal pathway in maintaining intracellular homeostasis and the effects of their dysfunction on protein secretion and metabolic disorders, leading to the pathogenesis of Alzheimer's disease (AD) and other tau diseases. Dysfunction of the autophagy-lysosomal pathway is believed to be the main factor leading to the accumulation of amyloid-β and tau proteins, which are also pathological features of AD. This article also discusses why autophagy is indispensable in the early to mature stages of neuronal development and how damage to the function of autophagy can cause neurodevelopmental abnormalities and neurodegenerative diseases. We also summarized the potential role of oligodendrocytes. We believe that its relationship with lysosomes can provide a new perspective and research direction for future research on neurodegenerative diseases. Autophagy-lysosomal pathway damage is considered to be a key factor in the pathology and diagnosis of multiple sclerosis, but we believe that the challenge associated with its transformation into clinical treatment is enormous. These findings suggest that enhancing or improving autophagy function may be an effective treatment method to alleviate the condition of AD patients, which can provide new strategies for clinical treatment and intervention of AD in the future.},
}
@article {pmid42429744,
year = {2026},
author = {Wu, Y and Xiang, F and Li, M and Zhang, H and Wu, M and Zhang, Y and Pu, X and Guo, Y and Li, K},
title = {SMDNet: A Self-Training-Aware and Multi-Modal-Adaptive Deep Learning Network for Low-Data Aβ42 Probe Design and Optimization.},
journal = {Journal of medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jmedchem.6c01102},
pmid = {42429744},
issn = {1520-4804},
abstract = {Amyloid-β (Aβ) plaque accumulation is a crucial hallmark of Alzheimer's disease, and fluorescence imaging can support disease diagnosis and monitoring. However, Aβ42 probe development is often hindered by trial-and-error experiments due to subtle structure-property effects. Here, we developed SMDNet, a self-training-aware and multimodal-adaptive deep learning (DL) framework for low-data Aβ42 probe design and optimization. SMDNet combines iterative self-training with confidence-aware and distribution-aware sampling to improve data quality, while integrating molecular graphs, fingerprints and protein descriptors through cross-attention and protein-conditional adaptive layer normalization. Ablation studies, external validation and generalization analyses confirmed the strong predictive ability of SMDNet. Interpretability analyses further highlighted chemically meaningful substructures associated with model predictions. As a proof of concept, SMDNet guided the rational design of five ThT-derived probe candidates, with TA3 showing favorable binding affinity and high-contrast imaging performance. Additional validation on coumarin- and naphthalimide-based candidates further supported useful predictive discrimination across distinct fluorescent scaffold classes.},
}
@article {pmid42429753,
year = {2026},
author = {Banerjee, G and van Veluw, SJ},
title = {Untangling the web of APOE, cerebral amyloid angiopathy and Alzheimer's disease.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag243},
pmid = {42429753},
issn = {1460-2156},
}
@article {pmid42430015,
year = {2026},
author = {Khodaei, M and Bidabad, B and Shiri, ME and Sedaghat, MK},
title = {Ricci Flow-Based Approach for Early Diagnosis of Alzheimer's Disease.},
journal = {Neuroinformatics},
volume = {24},
number = {3},
pages = {},
pmid = {42430015},
issn = {1559-0089},
mesh = {*Alzheimer Disease/diagnostic imaging ; Humans ; *Magnetic Resonance Imaging/methods ; Early Diagnosis ; *Hippocampus/diagnostic imaging/pathology ; Female ; Aged ; Male ; Discriminant Analysis ; *Image Interpretation, Computer-Assisted/methods ; Aged, 80 and over ; Imaging, Three-Dimensional/methods ; },
abstract = {Early diagnosis of Alzheimer's disease (AD) is increasingly important due to its rising prevalence and significant impact on individuals, families, and healthcare systems. Hippocampal atrophy is a well-established and significant biomarker for AD. Advanced techniques like MRI imaging and surface parameterization have shown considerable promise in improving the accuracy and speed of AD diagnosis. This study aims to utilize the Ricci flow method to map the 3D hippocampal surface to a 2D sphere and extract relevant features for early AD detection. The process involves several key steps: inputting an MRI scan and preprocessing to isolate the hippocampal surface, applying the Ricci flow to map this surface to a sphere, constructing a feature vector using Linear Discriminant Analysis (LDA) and Kernel LDA, and employing various classifiers to diagnose AD, with model evaluation based on the ADNI dataset. Experimental results reveal that combining Ricci flow-based feature extraction with Kernel LDA significantly improves diagnostic accuracy. The model achieves classification accuracies of 97.28% (NC/AD), 96.14% (NC/EMCI), 96.45% (NC/MCI), 94.83% (EMCI/LMCI), 95.84% (MCI/AD), and 95.37% (LMCI/AD). Additionally, it attains 93.65% and 92.30% accuracy in three-way and four-way classification tasks, respectively. These results outperform most reviewed studies and are comparable to others. This research highlights the potential of merging advanced 3D imaging techniques with mathematical models to enhance diagnostic precision, emphasizing the critical role of early detection in the effective treatment and management of Alzheimer's disease.},
}
@article {pmid42430052,
year = {2026},
author = {Castagna, A and Cotroneo, AM and Mosele, M and Sapone, P and Martinelli, E and Rahmati, M and Smith, L and Veronese, N},
title = {Hyperhomocysteinemia, a risk factor for various health conditions: an umbrella review of systematic reviews with meta-analysis.},
journal = {Aging clinical and experimental research},
volume = {},
number = {},
pages = {},
doi = {10.1007/s40520-026-03433-0},
pmid = {42430052},
issn = {1720-8319},
abstract = {BACKGROUND: Hyperhomocysteinemia, an elevation of plasma homocysteine levels, has been implicated in multiple diseases, yet its causal role remains debated. This umbrella review systematically evaluated and graded the evidence from published systematic reviews and meta-analyses on associations between hyperhomocysteinemia and diverse health outcomes.<br><br>METHODS: We searched Medline, Embase, and Web of Science up to March 5, 2025. Eligible studies were systematic reviews and meta-analyses of observational studies reporting associations between hyperhomocysteinemia and any health outcome. Methodological quality was assessed using AMSTAR-2, and the certainty of evidence was graded using GRADE.<br><br>RESULTS: A total of 104 meta-analyses including 2,110 studies and 953,793 participants were analyzed, covering 126 outcomes. Eighty-three percent of outcomes showed significant associations with hyperhomocysteinemia. Nine outcomes were supported by high, 18 by moderate, 73 by low, and 26 by very low certainty of evidence. High-certainty evidence supported associations between hyperhomocysteinemia and increased risks of stroke, intracerebral haemorrhage, fracture (hip and total), and chronic kidney disease. Moderate-certainty evidence linked hyperhomocysteinemia to dementia, Alzheimer's disease, mortality, and selected cardiovascular and pregnancy outcomes. Most meta-analyses were of low or critically low methodological quality.<br><br>CONCLUSIONS: Across nearly one million participants, hyperhomocysteinemia was consistently associated with adverse health outcomes, particularly vascular, neurological, skeletal, and renal conditions. While causality cannot be inferred, the evidence supports hyperhomocysteinemia as a potentially modifiable risk factor meriting targeted preventive and interventional research.<br><br>PROTOCOL REGISTRATION: https://osf.io/dezms.},
}
@article {pmid42430077,
year = {2026},
author = {Li, L and Wang, S and Duan, L and Zhang, L and Yan, H and Zhu, Y and Tao, L and Gao, Y},
title = {Targeting IL-33 in Precision Neuroimmunology: Cellular Mechanisms and Therapeutic Strategies for CNS Disorders.},
journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology},
volume = {21},
number = {1},
pages = {},
pmid = {42430077},
issn = {1557-1904},
support = {SYS2019027//Suzhou Municipal Science and Technology Bureau/ ; 82471418, 82001382//National Natural Science Foundation of China/ ; SBK2020040785//Jiangsu Provincial Natural Science Foundation of China/ ; KJXW2019018//a project of invigorating healthcare through science, technology, and education/ ; },
mesh = {*Interleukin-33/immunology/antagonists &amp; inhibitors/metabolism ; Humans ; Animals ; *Central Nervous System Diseases/immunology/drug therapy/metabolism ; *Neuroimmunomodulation/drug effects/physiology/immunology ; *Precision Medicine/methods/trends ; },
abstract = {Interleukin-33 (IL-33), an alarmin cytokine of the IL-1 family, has emerged as a pivotal regulator of neuroimmune interactions in the central nervous system (CNS). Acting through its receptor ST2, IL-33 orchestrates diverse immune responses by modulating microglial polarization, shaping T cell differentiation, activating type 2 innate lymphoid cells (ILC2s), and engaging mast cell-macrophage regulatory circuits. Across distinct neurological disorders, including epilepsy, stroke, traumatic brain injury (TBI), Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), cerebral malaria, and glioma, IL-33 exerts both protective and pathogenic effects in a context-dependent manner. In epilepsy, IL-33 modulates neuroinflammation and neuronal excitability; in stroke, it attenuates acute neurovascular injury while influencing post-stroke remodeling; in AD, it enhances amyloid-β clearance and mitigates chronic neuroinflammation; in MS, it regulates autoimmune demyelination via T cell and innate immune pathways. These shared yet disease-specific mechanisms underscore IL-33's central role in neuroimmune homeostasis and its potential as a precision therapeutic target. Future research integrating multi-disease models, temporal disease staging, and single-cell multi-omics will be essential to define the conditions under which IL-33 modulation yields maximal therapeutic benefit.},
}
@article {pmid42430091,
year = {2026},
author = {You, Y and Duan, D and Xiang, Q},
title = {The Role of PGC-1α in Neurodegenerative Diseases: Molecular Mechanisms, Translational Challenges, and Therapeutic Potential.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42430091},
issn = {1559-1182},
mesh = {Humans ; *Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism ; *Neurodegenerative Diseases/metabolism/therapy ; Animals ; Mitochondria/metabolism ; *Translational Research, Biomedical ; *Translational Science, Biomedical ; },
abstract = {Neurodegenerative diseases (NDDs) are progressive disorders in which mitochondrial dysfunction, oxidative stress, proteostasis failure, neuroinflammation, and synaptic damage progressively interact to drive neuronal vulnerability. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) links metabolic adaptation to stress-response pathways that are repeatedly disrupted in Alzheimer's disease, Parkinson's disease, Huntington's disease, polyglutamine (PolyQ) disorders, and amyotrophic lateral sclerosis. Rather than providing only an updated catalogue of studies, this review organizes the evidence into a cross-disease rheostat framework that explains why PGC-1α modulation is protective in some settings but incomplete or maladaptive in others. Current findings indicate that PGC-1α supports mitochondrial biogenesis, oxidative phosphorylation, antioxidant defense, mitophagy, autophagy, protein quality control, and inflammatory balance. However, its effects are highly context dependent. In several models, restoration of PGC-1α-related signaling improves mitochondrial function and reduces neuronal injury, whereas broad, sustained, or cell-inappropriate activation may produce limited benefit or undesirable outcomes. These observations suggest that PGC-1α is not a simple neuroprotective switch, but a flexible regulatory hub whose therapeutic value depends on cell type, isoform profile, disease stage, and activation level. Emerging strategies, including small-molecule modulators, gene delivery, antisense-based approaches, nanoparticle systems, and exercise-related interventions, remain largely preclinical and face major barriers related to CNS delivery, pathway selectivity, dose and cell-type control, peripheral safety, and validated target-engagement biomarkers. Nevertheless, clinical translation requires stronger causal validation, reliable target-engagement biomarkers, selective delivery methods, and long-term safety assessment. Future research should focus on precision-based modulation of PGC-1α to determine when and how this pathway can be safely used for disease modification. Such a careful approach may help transform PGC-1α from a broad experimental target into a clinically relevant strategy for well-defined neurodegenerative phenotypes.},
}
@article {pmid42430332,
year = {2026},
author = {Sánchez-Escudero, JP and Díaz González, DC and Aguillón-Niño, DF and Garcia-Barrera, MA and Aguirre-Acevedo, DC and Trujillo-Orrego, N},
title = {NavegApp, a serious game for assessing spatial cognition: Diagnostic accuracy in preclinical and prodromal Alzheimer's disease.},
journal = {PLOS digital health},
volume = {5},
number = {7},
pages = {e0001521},
pmid = {42430332},
issn = {2767-3170},
abstract = {Alzheimer's Disease (AD) is the leading cause of dementia worldwide, yet early detection remains challenging due to limited access to biomarker-based diagnostic tools, especially in low- and middle-income countries. This study aims to evaluate the diagnostic accuracy of NavegApp, a serious game developed to assess Spatial Cognition (SC), in distinguishing individuals at various stages of AD, including asymptomatic and symptomatic PSEN1-E280A mutation carriers. A cross-sectional sample of 226 participants underwent neurological and neuropsychological evaluations alongside NavegApp targeting allocentric navigation, mental rotation, and visuospatial memory. Results showed excellent diagnostic accuracy for distinguishing symptomatic PSEN1-E280A carriers from asymptomatic carriers and healthy controls, particularly in allocentric navigation metrics (AUC-ROC = 0.94-0.97). However, in asymptomatic participants, diagnostic performance was modest (AUC ≈ 0.57-0.60), indicating limited discriminative capacity at the preclinical stage. Cross-sectional comparisons detected prodromal-stage deficits in visuospatial and mental rotation tasks, whereas diagnostic accuracy for distinguishing sporadic MCI from health controls was moderate to low. These findings demonstrate the feasibility of NavegApp as a digital tool for cognitive assessment, with potential applicability in cognitive screening for underserved communities. Further research must validate its use across diverse settings and establish its integration into clinical practice for early AD detection.},
}
@article {pmid42430835,
year = {2026},
author = {Kalra, P and Grewal, AK},
title = {Glymphatic dysfunction in neurodegeneration: From impaired clearance to mechanism-driven therapeutic innovation.},
journal = {Current opinion in pharmacology},
volume = {89},
number = {},
pages = {102647},
doi = {10.1016/j.coph.2026.102647},
pmid = {42430835},
issn = {1471-4973},
abstract = {Glymphatic system refers to a system that involves perivascular clearance mechanisms within the brain, which are crucial for the elimination of neurotoxic proteins such as amyloid-β (Aβ) and tau proteins in Alzheimer's disease (AD), α-synuclein in Parkinson's disease (PD), and mutant huntingtin (mHTT) in Huntington's disease (HD). There is mounting evidence suggesting that glymphatic dysfunction is an important cause of neurodegenerative diseases, characterized by failure of cerebrospinal fluid-interstitial fluid (CSF-ISF) exchange due to abnormal clearance. Mechanistically, this dysfunction is affected by aging, astroglial aquaporin-4 (AQP4) depolarization, vascular impairment, sleep abnormalities, oxidative damage, and neuroinflammation. Additionally, aberrant glymphatic flow acts as a crucial link between peripheral and central pathologies, amplifying neurodegeneration via altered solute transport and inflammation signaling. Glymphatic dysfunction has been found to be involved in diseases such as AD, PD and HD, thus indicating the widespread significance of glymphatic pathology. Therapeutically, targeting glymphatic function through modulation of AQP4 polarization, improving sleep-dependent clearance, and decreasing oxidative and inflammatory mechanisms may provide promising strategy for disease modification. This review provides a comparative and mechanistic overview of glymphatic dysfunction across AD, PD, and HD, highlighting peripheral-central interactions, biomarkers, imaging approaches, and therapeutic strategies, while addressing unresolved issues related to transport mechanisms, causality versus epiphenomenon, and translational limitations.},
}
@article {pmid42430935,
year = {2026},
author = {Esmaeeli, S},
title = {IL-10 and β-endorphin: A paradoxical loop of microglial clearance in Alzheimer's disease.},
journal = {Revista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion},
volume = {78},
number = {4},
pages = {100049},
doi = {10.1016/j.ric.2026.100049},
pmid = {42430935},
issn = {2564-8896},
}
@article {pmid42430964,
year = {2026},
author = {Daffner, KR and Riera, K and Ghorayeb, GR and McFeeley, BM and Weizenbaum, E and Willment, K and Gale, SA},
title = {Suboptimal adherence to brain health recommendations in patients pursuing anti-amyloid antibody therapy for Alzheimer's disease: Report from the Brain Health Vital Signs project.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {8},
pages = {100640},
doi = {10.1016/j.tjpad.2026.100640},
pmid = {42430964},
issn = {2426-0266},
abstract = {BACKGROUND: Consensus is consolidating around a set of lifestyle and medical factors that can promote brain health and reduce the risk of dementia for older adults and further decline for those with early Alzheimer's disease (AD) and related disorders. Little is known about the degree to which recommended brain-healthy behaviors have been adopted by patients with early AD pursuing anti-amyloid antibody therapy (AAT), a proactive group interested in doing what is under their control to help preserve cognitive and functional status. Here, initial results of a clinically relevant quality improvement study are reported.<br><br>OBJECTIVE: To determine the extent to which patients pursuing AAT for AD adhere to consensus-based brain health recommendations.<br><br>PARTICIPANTS: One hundred fifty patients with mild cognitive impairment (MCI) or mild dementia due to AD seeking AAT were studied and compared to a group of 117 patients with MCI or mild dementia who were not pursuing AAT.<br><br>MEASUREMENTS: Using a clinical survey tool developed for the project, patients were assessed on 15 modifiable risk factors for cognitive decline and dementia, including 11 via e-survey (diet, physical activity, cognitive activity, sleep, social engagement, smoking status, alcohol consumption, hearing, vision, mood/stress, and purpose in life) and 4 via electronic medical record (EMR) (blood pressure, BMI, LDL cholesterol level, and HbA1c). For each factor, the percentage of each of the two patient groups that was not optimally adhering to brain health-related guidelines was calculated. For each individual, the total number of factors not optimally being followed was determined.<br><br>RESULTS: Less than 3% of patients with early AD pursuing AAT were following or had anthropometric measures/lab values in line with all 15 brain health recommendations. The five factors with the lowest adherence rates involved physical activity, mood/stress, HbA1c, blood pressure, and BMI, with 44-63% of the AAT group suboptimally following consensus-based guidelines. For 11 of 15 factors, >25% of the group were not adhering to guidelines. No robust differences in degree or pattern of adherence to guidelines were observed between patients pursuing and not pursuing AAT. There were no data in the EMR for HbA1c in >42% of patients and for LDL in >23% of patients in either group.<br><br>CONCLUSIONS: Suboptimal adherence to brain health recommendations may be common among patients with early AD, whether they are pursuing AAT or not. These results suggest that healthcare systems may need to develop more effective strategies and individualized interventions for addressing modifiable risk factors for cognitive decline and dementia, and more efficacious procedures for ensuring that relevant, actionable data associated with brain health are updated in the EMR.},
}
@article {pmid42430965,
year = {2026},
author = {Kiser, H and Budu-Aggrey, A and Bailey, JNC and Villaplana-Velasco, A and Bernabeu, MO and Jiang, X and Owen, CG and Haines, JL and Pasquale, LR and MacGregor, S and Gao, XR and Wiggs, JL and Jiang, C and Choquet, H and , and Smith, GD and Kehoe, PG and Davies, NM and Hanson, AL and Anderson, EL and Atan, D},
title = {Can we identify people with Alzheimer's disease from examination of the eye? A bidirectional Mendelian randomization (MR) study.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {8},
pages = {100635},
doi = {10.1016/j.tjpad.2026.100635},
pmid = {42430965},
issn = {2426-0266},
abstract = {BACKGROUND: Neurodegeneration in Alzheimer's disease (AD) is thought to be driven by amyloid-beta and tau deposition in the cerebral vasculature and brain. As the eye is an extension of the central nervous system, this study aimed to determine which neurovascular and neuroretinal changes in the eye are caused by AD rather than associations of the disease.<br><br>METHODS: Bidirectional two-sample univariable and multivariable Mendelian randomization (MR) methods were applied. Instrumental variables were derived from genome-wide association studies (GWAS) of AD and the following ocular features: thickness measurements of central macula (MT), retinal nerve fibre layer (mRNFL), ganglion cell-inner plexiform layer (mGCIPL), outer nuclear layer (ONL), inner segment layer (IS), and outer segment (OS) from macular region OCT scans; arteriolar tortuosity (AT), venular tortuosity (VT), venular width (VW), fractal dimension (FD), vertical cup-to-disc ratio (VCDR), optic cup area (OCA), and optic disc area (ODA) derived from other imaging methods.<br><br>RESULTS: There was strong evidence that genetic liability to AD affected the retinal vasculature by specifically increasing AT (&#x3b2; = 0.007;95%CI=0.002,0.011;p-value=0.005) in UK Biobank participants (n=52,798). AD may influence the mRNFL (&#x3b2;=-0.047,95%CI=-0.119,0.023,p-value=0.18) and mGCIPL (&#x3b2;=-0.061;95%CI=-0.14,0.025,p-value=0.16) of the inner retina and OS layer (&#x3b2; = 0.044;95%CI=-0.0001,0.08;p-value=0.05) but the evidence was weak. Multivariable MR analysis showed that a causal relationship between optic disc area and AD (OR=0.76;95%CI=0.62,0.93,p-value=0.009) was probably mediated by refractive error.<br><br>CONCLUSION: Early cerebrovascular signs of AD may be detected by examination of the eye. Further investigation is required to determine the clinical utility of eye screening for dementia.},
}
@article {pmid42431159,
year = {2026},
author = {Singh, RK and Bekena, S and Walker, AIB and Zhu, Y and Trani, JF and Babulal, GM},
title = {Associations among cognitive performance, VCAM-1, and GFAP in black adults: The ARCHES study.},
journal = {Neurobiology of aging},
volume = {168},
number = {},
pages = {14-22},
doi = {10.1016/j.neurobiolaging.2026.07.003},
pmid = {42431159},
issn = {1558-1497},
abstract = {Astrocytic injury and endothelial activation are interconnected processes within the neurovascular system that may contribute to variability in cognitive performance among cognitively unimpaired adults. Glial fibrillary acidic protein (GFAP) reflects astrocytic injury, while vascular cell adhesion molecule-1 (VCAM-1) reflects systemic endothelial activation. We examined whether VCAM-1 modifies associations between GFAP and cognition in cognitively unimpaired Black adults. This cross-sectional analysis included 313 Black adults aged ≥ 45 years enrolled in the Aging Research Characterizing Health Exposome via Social Drivers (ARCHES) study. Cognitive performance was assessed using the Preclinical Alzheimer Cognitive Composite (PACC) as the primary outcome and the Montreal Cognitive Assessment (MoCA) as a secondary outcome. Plasma GFAP and VCAM-1 were quantified using ultrasensitive immunoassays (NULISA™; Alamar Biosciences). Gaussian generalized linear models tested main effects and a VCAM-1 × GFAP interaction, adjusting for age, sex, and years of education; sensitivity analyses additionally adjusted for the Area Deprivation Index (ADI), body mass index (BMI), and apolipoprotein E (APOE) ε4 genotype. VCAM-1 and GFAP did not show independent associations with PACC; however, the VCAM-1 × GFAP interaction was significant (β = -1.36 × 10[-6], 95% CI: -2.43 × 10[-6] to -2.94 × 10[-7], p = 0.013; FDR p = 0.030; standardized β = -0.118) and remained significant after additional adjustment for ADI, BMI, and APOE ε4 status. Associations were not significant for MoCA. These findings suggest that VCAM-1 may modify the relationship between GFAP and cognitive performance in cognitively unimpaired Black adults.},
}
@article {pmid42431348,
year = {2026},
author = {Ma, Q and Ding, Z and Wang, R and Jin, J and Wang, H and Li, Y and Liu, Z and Wang, X and Yin, T},
title = {40 Hz-rTMS modulates spike-LFP coupling and improves cognitive function in 5xFAD mice.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115909},
doi = {10.1016/j.expneurol.2026.115909},
pmid = {42431348},
issn = {1090-2430},
abstract = {OBJECTIVE: Spike-local field potential (LFP) coupling plays a pivotal role in mediating cross-scale neural communication. Although abnormal coupling has been reported in Alzheimer's disease (AD) models in vitro, in vivo evidence remains lacking. This study aimed to characterize in vivo spike-LFP coupling in 5XFAD mice and investigate whether 40 Hz repetitive transcranial magnetic stimulation (rTMS) can ameliorate related deficits.<br><br>METHODS: We performed chronic in vivo electrophysiological recordings of spikes and LFPs were performed in the hippocampal dentate gyrus (DG) via. Phase-locking and coherence analysis were employed to quantify spike-LFP coupling. Cognitive function was evaluated using the Y-maze, novel object recognition, and Morris water maze tasks. The correlation between spike-LFP coupling and cognitive performance was analyzed by the Spearman method.<br><br>RESULTS: In wild-type (WT) sham mice, DG spikes exhibited tightly confined phase preferences (&#x3b8; oscillation: 108&#xb0;-126&#xb0;; high &#x3b3; (H&#x3b3;) oscillation: 198&#xb0;-216&#xb0;). In contrast, 5XFAD mice displayed severely dispersed spike-phase distributions and reduced coupling intensity, with mean vector length decreasing by 19.90% (spike-&#x3b8;) and 23.8% (spike-H&#x3b3;) compared with that in WT-sham controls. Following 14 consecutive days of 40&#x202f;Hz rTMS intervention, 5XFAD mice exhibited significant increases in mean vector length (&#x3b8;: +39.44%; H&#x3b3;: +31.47%) and normalized spike-LFP phase distributions. Notably, rTMS treatment also markedly rescued learning, memory, and cognitive flexibility in 5XFAD mice. Spike-LFP coupling strength was significantly correlated with learning and memory performance.<br><br>CONCLUSION: These preliminary findings suggest that 40&#x202f;Hz rTMS modulates pathological spike-LFP coupling in 5XFAD mice, laying the groundwork for therapeutic exploration.},
}
@article {pmid42431350,
year = {2026},
author = {Gallardo, D and Steward, O},
title = {Development and characterization of a novel transgenic strain to selectively label neurons that degenerate in 5xFAD mice.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115914},
doi = {10.1016/j.expneurol.2026.115914},
pmid = {42431350},
issn = {1090-2430},
abstract = {This paper describes a novel double transgenic-based platform developed by crossing a murine model of Alzheimer's disease (AD), 5xFAD mice with Rosa[tdTomato (tdT)] reporter mice, to track degeneration of specific populations of neurons. 5xFAD[+/-]/Rosa[tdT] mice received intra-spinal cord injections of AAV-retrograde (rg)/Cre at 2-3 months of age to retrogradely transduce and induce tdT expression by corticospinal neurons (CSNs) in layer V of the sensorimotor cortex as well as neurons in the red nucleus and reticular formation that project to the spinal cord. Brains and spinal cords were collected 2-3 weeks post-injection or between 7 and 10 and 11-15 months of age. Immunohistochemical studies of transgene expression throughout the brain and spinal cord using an antibody selective for human APP (hAPP) revealed age-dependent accumulation of clusters of hAPP-positive granules in areas containing hAPP-labeled neuronal cell bodies. Surprisingly, there were also hAPP-positive granules in regions containing axons and synaptic terminals from hAPP expressing neurons. Moreover, tdT expressed by CSNs accumulated in the same granules as hAPP, and both tdT and hAPP were present in clusters of granules with other markers of AD pathology. Quantitative assessments confirmed age-related degeneration of layer V CSNs accompanied by progressive accumulation of clusters of tdT and hAPP-positive granules. Overall, our results indicate that accumulation of aggregated hAPP in areas containing axons and synaptic terminals from hAPP expressing neurons is a prominent feature of AD pathophysiology in 5xFAD mice and that accumulation of clusters of hAPP granules provides a secondary measure to track neurodegeneration of identified populations of genetically labeled neurons.},
}
@article {pmid42431381,
year = {2026},
author = {Farmani, HR and Xia, J and Olichney, J and Rasnani, MH and Khatoonabadi, AR},
title = {Semantic processing and ERP responses in mild cognitive impairment (MCI): A scoping review article.},
journal = {Behavioural brain research},
volume = {},
number = {},
pages = {116365},
doi = {10.1016/j.bbr.2026.116365},
pmid = {42431381},
issn = {1872-7549},
abstract = {INTRODUCTION: Mild Cognitive Impairment (MCI) is a transitional stage between normal aging and dementia and is associated with an increased risk of Alzheimer's disease. Event-related potentials (ERPs) provide sensitive measures of neural processing and may detect cognitive dysfunction before it is evident on behavioral assessment. This review examined ERP studies of language processing in individuals with MCI compared with healthy elderly (HE) participants.<br><br>METHODS: A scoping review was conducted according to the Arksey and O'Malley framework and reported following PRISMA-ScR guidelines. PsycINFO and PubMed were searched for peer-reviewed studies published between January 2000 and April 2025. Studies employing ERP measures during language-based tasks in MCI and HE groups were included.<br><br>RESULTS: Eleven studies met the inclusion criteria. Across a range of language paradigms, individuals with MCI showed alterations in ERP components associated with semantic and memory processing, particularly the N400, frontal N400 (FN400), Late Positive Component (LPC/P600), N200, and P300. Common findings included reduced amplitudes, prolonged latencies, and altered scalp distributions relative to HE participants. Several studies reported ERP abnormalities despite comparable behavioral performance, suggesting that electrophysiological measures may reveal subtle cognitive dysfunction not captured by conventional neuropsychological testing. Longitudinal evidence further indicated that abnormal N400 and LPC responses may predict progression to Alzheimer's disease.<br><br>CONCLUSION: ERP measures consistently differentiate MCI from healthy aging and represent promising non-invasive biomarkers for detecting early cognitive decline and monitoring disease progression.},
}
@article {pmid42431472,
year = {2026},
author = {Kurz, CI and Tegethoff, P and Gelz, J and Gkempelsi, I and Hufnagel, A and Neziraj, F and Schuhbauer, P and Rahn, H and Boeck, M and Keidel, LF and Perneczky, R},
title = {The DECISION Study: Protocol for the Development and Internal Validation of a Multimodal Decision-Making Capacity Framework.},
journal = {Journal of clinical epidemiology},
volume = {},
number = {},
pages = {112417},
doi = {10.1016/j.jclinepi.2026.112417},
pmid = {42431472},
issn = {1878-5921},
abstract = {BACKGROUND: Decision-making capacity (DMC) is a prerequisite for valid informed consent, as well as being a key methodological requirement in clinical and epidemiological research. For individuals with neurocognitive disorders, DMC assessment is frequently based on subjective clinical judgement, with limited standardization and significant variability across settings. Current instruments are resource-intensive and not sufficiently adapted for stage-specific or real-world applications.<br><br>OBJECTIVE: To develop and internally validate a structured multimodal framework for assessing decision-making capacity in individuals across the Alzheimer's disease continuum.<br><br>METHODS: We propose a modular assessment framework that operationalizes the core domains of decision-making capacity: understanding, appreciation, reasoning and expression of choice. This is complemented by neuropsychological profiling, informant-based measures and structured decision scenarios. Internal validation will be performed against established functional reference standards, including the MacArthur Competence Assessment Tool for Treatment (MacCAT-T), while the Clinical Dementia Rating (CDR) will be used for disease characterization only. Primary analyses focus on feasibility, reliability, and criterion validity. Biomarkers and neuroimaging measures are examined as exploratory contextual correlates of decisional vulnerability and are not used to define decision-making capacity. The co-design approach thus integrates both patient and caregiver perspectives as well as clinician and expert input, with focus group interviews providing a complementary, structured format to capture interdisciplinary professional perspectives.<br><br>RESULTS: The protocol is designed to generate evidence regarding feasibility, reliability, and criterion validity of a multimodal DMC assessment framework. It provides standardized scoring and quantifiable outputs, as well as a basis for stage-sensitive interpretation. Exploratory analyses will further evaluate associations between functional decision-making capacity and markers of neurodegenerative disease burden. This methodological framework provides a standardized, reproducible approach to assessing decision-making capacity in cognitively vulnerable populations.<br><br>CONCLUSIONS: Developed within the German legal framework, it integrates cognitive, functional and contextual dimensions to support more transparent and quantifiable capacity assessment. Following external validation, the framework may inform future clinical studies, observational research, and ethically robust consent procedures in cognitively impaired populations.},
}
@article {pmid42431913,
year = {2026},
author = {Roobini, S and Kavitha, MS and Karthik, S},
title = {Novel approach to early prediction of alzheimer's disease progression using integrated deep regulatory genetic neural network and optimized deep belief networks.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-55178-5},
pmid = {42431913},
issn = {2045-2322},
abstract = {UNLABELLED: To enhance the prediction progression of Alzheimer's Disease is very excavating process.<br><br>PROBLEM STATEMENT: It is often very difficult to implement in the chronic neurodegenerative disease-related preprocessed gene expression data. Especially, Alzheimer's Disease (AD) prediction is a very crucial process in AD metadata diagnosis. Novelty: To explore this challenging prediction process in brain disease prediction, this research presents a proposed deep learning model, namely the Integrated Deep Regulatory Genetic Neural Network and Optimised Deep Belief Networks (IDRODN). This integration increases the affluence of prediction progression from genomic data. These prediction systems help identify early AD.<br><br>METHOD: This research utilizes the IDRODN, which can predict and confine each network's neurons and hidden layers against the benchmark dataset of Alzheimer's gene expression and uncertainty to predict Alzheimer's Disease.<br><br>KEY RESULTS: The comparative analysis on data from the Alzheimer's disease gene expression data Initiative database has achieved an accuracy of 98.3%. In addition, it has achieved a high F1 score of 0.986 for predicting different stages from Gene expression data.<br><br>IMPLICATIONS: This shows the most accurate technique for predicting Alzheimer's Disease (AD) using the prognostic IDRODN model.},
}
@article {pmid42431966,
year = {2026},
author = {Tan, D and Song, L and Tang, Y and Han, A},
title = {An interpretable multimodal framework using compact biomarkers and Kolmogorov-Arnold networks improves the early diagnosis of Alzheimer's disease.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-59430-w},
pmid = {42431966},
issn = {2045-2322},
abstract = {Early diagnosis of Alzheimer's disease (AD), especially accurate identification at the mild cognitive impairment (MCI) stage, is crucial for slowing disease progression. Although deep learning has achieved promising performance in AD diagnosis, existing multimodal models often operate as "black boxes," lacking the transparency required for clinical practice and failing to explicitly model deep interactions between imaging and clinical features. To address these limitations, this study proposes an interpretable multimodal framework, namely the Compact Biomarker Kolmogorov-Arnold Network (CBKAN). Specifically, we introduce EHCTNet with disease-specific attention to extract features from 3D MRI data, and innovatively constrain the encoder to output a set of compact biomarkers instead of traditional high-dimensional abstract vectors, mimicking the diagnostic logic of clinicians (e.g., judging brain atrophy). In addition, a hybrid feature Transformer is used to fuse these imaging biomarkers with clinical and genetic data, explicitly capturing complementary relationships across modalities. Finally, the Kolmogorov-Arnold Network (KAN) is adopted as the classifier to effectively model the highly nonlinear characteristics of AD progression. Experiments on 800 subjects from the ADNI dataset show that CBKAN achieves 91.1% accuracy and an F1-score of 0.910 in the AD/MCI/CN classification task, significantly outperforming existing mainstream methods. Statistical analyses validate the effectiveness of each component of the model. The proposed model provides a potentially interpretable and high-performing decision-support framework for early Alzheimer's disease diagnosis, although its cross-cohort generalizability and real-world clinical utility require further validation in independent external datasets.},
}
@article {pmid42432263,
year = {2026},
author = {Choudhary, N and Rana, S and Vashisht, K and Sharma, V and Bhatia, V and Ashawat, MS and Kushawaha, SK},
title = {Repurposing apremilast for alzheimer's disease: multitarget modulation of cAMP‑PI3K/Akt-GSK‑3β and NF‑κB signaling.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42432263},
issn = {1573-7365},
mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Thalidomide/analogs &amp; derivatives/therapeutic use/pharmacology ; Animals ; *NF-kappa B/metabolism ; Signal Transduction/drug effects ; *Glycogen Synthase Kinase 3 beta/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; *Drug Repositioning/methods ; Cyclic AMP/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Neuroprotective Agents/therapeutic use/pharmacology ; Anti-Inflammatory Agents, Non-Steroidal/therapeutic use ; *Phosphodiesterase 4 Inhibitors/therapeutic use/pharmacology ; },
abstract = {Alzheimer's disease (AD), the leading cause of dementia worldwide, represents a growing global health challenge driven by population aging, the absence of effective disease-modifying therapies, and its inherently multifactorial pathogenesis. This pathogenesis is characterized by amyloid-β (Aβ) aggregation, tau hyperphosphorylation, persistent neuroinflammation, oxidative stress, and synaptic dysfunction. Conventional single-target interventions have consistently failed against this complex interplay of molecular events, thereby highlighting the need for multitarget, systems pharmacology approaches capable of simultaneously modulating convergent pathways. Apremilast (APR), an FDA-approved, orally bioavailable phosphodiesterase-4 (PDE4) inhibitor, has recently emerged as a favorable drug repurposing candidate capable of elevating intracellular cAMP and triggering a cascade of neuroprotective mechanisms. Preclinical investigations from Aβ-challenged neuronal cultures to high-fat diet/streptozotocin-induced rodent models of AD demonstrate that APR attenuates Aβ-induced cytotoxicity, improves cognitive performance, and preserves neuronal and synaptic integrity. Mechanistically, APR mitigates NF-κB-mediated neuroinflammation through IκBα stabilization, thereby reducing the release of proinflammatory cytokines such as TNF-α and IL-6; activates the Nrf2/HO-1 antioxidant defense pathway, and, via cAMP-dependent PI3K/Akt signaling, inhibits GSK-3β to prevent tau hyperphosphorylation, synaptic loss, and neuronal degeneration. This review synthesizes current mechanistic evidence supporting apremilast as a potential multitarget repurposing candidate in AD, thereby addressing key knowledge gaps in the current literature. All supporting evidence was compiled from peer-reviewed sources indexed in PubMed, Web of Science, and Scopus. Guided by network pharmacology and systems biology frameworks, APR's polypharmacological profile positions it as a compelling multitarget candidate for advanced in vivo validation, human iPSC-derived neuronal studies, and AI-driven therapeutic discovery pipelines.},
}
@article {pmid42432296,
year = {2026},
author = {Yang, S and Kim, SH and Choi, J and Lee, Y and Jung, J and Joo, JY},
title = {Integrative multi-omics analyses reveal nuclear noncoding RNA-mediated regulatory landscape in Alzheimer's disease.},
journal = {Archives of pharmacal research},
volume = {},
number = {},
pages = {},
pmid = {42432296},
issn = {1976-3786},
support = {RS-2023-00217123//National Research Foundation of Korea grant funded by the korea government/ ; },
abstract = {Alzheimer's disease (AD) progression involves complex molecular mechanisms underlying neuronal dysfunction. While emerging evidence on long noncoding RNAs (lncRNAs) is accumulating, the relevance of nuclear noncoding RNAs (ncRNAs) to neurodegenerative diseases remains poorly understood. Small Cajal body-specific RNA 13 (scaRNA13) is a nuclear ncRNA implicated in RNA species regulation, which remains insufficiently characterized in neuronal systems and AD pathogenesis. Here, we performed integrative analyses of human postmortem brain transcriptomes and AD mouse models to examine scaRNA13 expression across disease stages, sex, and brain regions. RNA-seq and proteomic analyses were used to assess scaRNA13-associated changes in gene expression, splicing, and RNA-protein interactions. Functional assays in neuronal cells were conducted to evaluate the effects of scaRNA13 perturbation on RNA processing, protein synthesis, and tau-related pathology. scaRNA13 was aberrantly upregulated in AD patient brains with a pronounced elevation observed in female patients at advanced stages. Perturbation of scaRNA13 altered splicing patterns and global translational capacity, accompanied by altered tau aggregation- and phosphorylation-related phenotypes in neuronal cell systems. These findings support scaRNA13 as an AD-associated nuclear ncRNA candidate and suggest that scaRNA13 perturbation is associated with changes in RNA processing, translational regulation, and tau-related cellular phenotypes in neuronal cell systems.},
}
@article {pmid42432341,
year = {2026},
author = {Kaushik, AS and Singh, N},
title = {Microglial synaptic pruning in early Alzheimer's disease: emerging roles of the IL-1β-NLRP3 axis.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42432341},
issn = {1568-5608},
abstract = {Alzheimer's disease is a progressive neurodegenerative disorder characterized by early synaptic dysfunction that precedes overt neuronal loss and cognitive decline. While amyloid-β and tau pathologies have long dominated disease models, growing evidence highlights neuroinflammation as a critical driver of early pathological changes. In particular, microglia-mediated inflammatory signaling has emerged as a key regulator of synaptic integrity. This review focuses on the interleukin-1β (IL-1β)-NLRP3 inflammasome axis as a central mechanism linking innate immune activation to aberrant synaptic pruning in early Alzheimer's disease. Activation of the NLRP3 inflammasome in microglia by amyloid-β and related danger signals leads to caspase-1-dependent maturation and release of IL-1β. Elevated IL-1β amplifies inflammatory signaling, alters microglial phenotype, and promotes complement-mediated tagging of synapses, resulting in excessive elimination of functional synaptic connections. Experimental evidence from in vitro systems, transgenic mouse models, and pharmacological inhibition studies supports a causal role for this axis in synapse loss, impaired synaptic plasticity, and cognitive deficits. Importantly, these inflammatory and synaptic alterations occur at early disease stages, underscoring their relevance to disease initiation rather than late-stage neurodegeneration. The review further discusses the impact of IL-1β-NLRP3 signaling on neuronal network function, hippocampal plasticity, and cognitive performance, as well as its translational implications. Therapeutic strategies targeting inflammasome activation or IL-1β signaling show promise in preserving synaptic function in preclinical models. Overall, the IL-1β-NLRP3-synapse axis represents a compelling framework for understanding early Alzheimer's disease pathology and offers a rational target for early intervention strategies to slow disease progression.},
}
@article {pmid42432671,
year = {2026},
author = {Chen, F and Wang, L and Liu, H and Khan, Q and Tang, B and Bao, N},
title = {The role of AI-assisted drug repurposing in neurological disorders: a systematic review of validation strategies, challenges and opportunities.},
journal = {Journal of nanobiotechnology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12951-026-04551-7},
pmid = {42432671},
issn = {1477-3155},
abstract = {Neurological disorders refer to a diverse group of conditions that affect the brain, peripheral nerves, and spinal cord and impair socioemotional, cognitive, motor, and sensory functions. Alzheimer's disease (AD), Multiple Sclerosis (MS), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS) are some of the well-known neurodegenerative diseases that affect millions of people worldwide. Despite the advanced technologies and nano-drug delivery systems, the success rate of developing drugs for neurological disorders is significantly low. Among several constraints, including gastrointestinal irritation, rapid metabolism, and low stability, the blood-brain barrier (BBB) emerges as one of the key challenges in the development and application of drugs against neurological disorders. These challenges necessitate innovative approaches to develop cost-effective therapeutic strategies. Drug repurposing, the discovery of new therapeutic benefits of existing drugs, is a promising drug discovery approach for discovering potential treatment options for complex neurological disorders. This review aims to explore the advanced and significant progress in drug repurposing for major neurological disorders, including MS, AD, PD, ALS, HD, stroke, and neuropsychiatric conditions. It places an explicit emphasis on discussing the potential role of artificial intelligence (AI)-assisted drug repurposing and understanding of the biological mechanisms in discovering new drugs for these neurological conditions. This also examines current challenges in drug repurposing and provides a critical review of the available opportunities and limitations in AI-assisted drug repurposing.},
}
@article {pmid42432701,
year = {2026},
author = {Zhang, Y and Han, P and Zhang, X},
title = {Tertiary lymphoid structures in neuroinflammation coordinate neuroimmune homeostasis and pathological progression.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-026-03961-6},
pmid = {42432701},
issn = {1742-2094},
support = {82573713//National Natural Science Foundation of China/ ; YDZJ202501ZYTS114//Natural Science Foundation of Jilin Province/ ; },
abstract = {The central nervous system (CNS) has long been considered immune privilege due to the blood-brain barrier, lack of traditional lymphatic drainage, and unique immune microenvironment. However, recent neuroimmunology research has demonstrated that the CNS maintains continuous communication with the peripheral immune system via meningeal lymphatic vessels, lymphoid systems, and border-associated macrophages. This paradigm shift has brought tertiary lymphoid structures (TLSs), ectopic lymphoid aggregates induced by chronic inflammation, infection, or tumors, into focus as key players in neuroimmune interactions. TLSs exert a dual effect in neuroinflammation. In infectious diseases like viral encephalitis, they promote local antibody production and T cell responses, aiding pathogen clearance. In contrast, in multiple sclerosis, autoimmune encephalitis, Alzheimer's disease, and Parkinson's disease, TLSs may sustain chronic inflammation, drive autoantibody production, and accelerate neurodegeneration. This review systematically summarizes the composition, induction mechanisms, and functional heterogeneity of TLSs across neurological diseases. We discuss their protective versus pathogenic roles in neuroinflammation and highlight their diagnostic value and therapeutic potential, aiming to provide new insights for precision intervention in neuroimmunological disorders.},
}
@article {pmid42432729,
year = {2026},
author = {Wu, J and Zhao, J and Chen, S and Xu, F},
title = {Reshaping the immune landscape: next-generation microglia-targeted therapies for Alzheimer's disease.},
journal = {Biological research},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40659-026-00716-8},
pmid = {42432729},
issn = {0717-6287},
support = {BK20251842//Natural Science Foundation of Jiangsu Province/ ; HAKY202400313//Northern Jiangsu Clinical Medicine Research Institute's 2024 Projects/ ; XYFC202302//The Development Fund of Affiliated Hospital of Xuzhou Medical University/ ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a significant global health challenge characterized as a multifactorial neurodegenerative disorder, involving amyloid-β (Aβ) and Tau aggregation, neuroinflammation and progressive neuronal injury. While Amyloid-targeted therapies have achieved a breakthrough in prevention of Aβ aggregation, the strategies face notable limitations in achieving curative outcomes and management of amyloid-independent central nervous system (CNS) dysfunction. Consequently, targeting microglia, the central immune cells of the brain, has emerged as a promising strategy to enhance the specificity and efficacy of AD interventions.<br><br>MAIN BODY: Accumulating evidence indicates microglial dysfunction is not a passive immune bystander of AD, but serves as a critical mechanistic nexus linking A&#x3b2; accumulation and AD symptomatic phenotype. This review critically examines the "next generation" of microglial therapeutics, moving beyond broad immunosuppression to precision phenotype modulation. We highlight breakthrough strategies in recent years including immune reconstitution, metabolic reprogramming, nanomaterial-mediated drug delivery, and the revolutionary potential of iPSC-derived microglia replacement. By elucidating the rationale underlying the specific strategies based on microglial biofunction and potential molecular mechanism in AD pathology, we provide an overview of current development of clinical trials and cutting-edge modalities aimed at restoring microglial homeostasis, affording an opportunity to alter the AD trajectory.<br><br>CONCLUSION: This review aims to delineate the path from bench to bedside and propose promising pathways to overcome current bottlenecks in AD drug development.},
}
@article {pmid42432740,
year = {2026},
author = {Dashora, C and Patel, AB},
title = {In vivo evidence for soluble Aβ oligomer-driven neuronal metabolic dysfunction in 5xFAD mice.},
journal = {Alzheimer's research &amp; therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02130-4},
pmid = {42432740},
issn = {1758-9193},
support = {NCP/MLP-0139, MLP002604//Council of Scientific and Industrial Research, India/ ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by the extracellular accumulation of amyloid-β (Aβ). Brain glucose hypometabolism, an early feature of AD, reflects neuronal metabolic dysfunction before the onset of clinical symptoms. While Aβ plaques are central to AD pathogenesis, the mechanisms by which different Aβ species, such as plaques and soluble oligomers, drive cell-type-specific neurometabolic dysfunction during disease progression remain poorly understood. This study evaluated the roles of different Aβ species in the neurometabolic trajectory across the presymptomatic, symptomatic, and advanced stages of AD.<br><br>METHODS: 5xFAD and wild-type (WT) mice were investigated for cognitive performance, quantitative A&#x3b2; levels, and glial activation markers at 3, 6, and 12 months of age. Neuronal and astroglial metabolic activities were evaluated ex vivo using state-of-the-art [1]H-[[13]C]-NMR spectroscopy in conjunction with administration of [1,6-[13]C2]glucose and [2-[13]C]acetate, respectively.<br><br>RESULTS: The 5xFAD mice exhibited cognitive decline from 6 months that further deteriorated by 12 months. There was a marked increase in A&#x3b2;-plaque burden and soluble oligomers from 3 to 12 months of age. These mice showed a significant reduction in hippocampal glutamatergic (0.145&#x2009;&#xb1;&#x2009;0.031 vs. 0.172&#x2009;&#xb1;&#x2009;0.016 &#xb5;mol/g/min, p&#x2009;=&#x2009;0.035) and GABAergic neuronal metabolic activity (0.027&#x2009;&#xb1;&#x2009;0.006 vs 0.033&#x2009;&#xb1;&#x2009;0.003 &#xb5;mol/g/min, p&#x2009;=&#x2009;0.028) as early as 3 months of age, with similar reductions observed in the cerebral cortex. The neurometabolic impairments further aggravated with age. Astrocytic metabolic activity was not significantly changed till 6 months but was increased at 12 months in 5xFAD mice in both the cerebral cortex (0.101&#x2009;&#xb1;&#x2009;0.014 vs. 0.084&#x2009;&#xb1;&#x2009;0.006 &#xb5;mol/g/min, p&#x2009;=&#x2009;0.011) and hippocampus (0.103&#x2009;&#xb1;&#x2009;0.006 vs. 0.089&#x2009;&#xb1;&#x2009;0.012 &#xb5;mol/g/min, p&#x2009;=&#x2009;0.011). The increase in astrocytic metabolic activity paralleled reactive gliosis, suggesting a shift from early neuronal metabolic impairment to heightened astroglial metabolic activity and inflammatory glial responses during the advanced AD stage. Notably, A&#x3b2;40 oligomers exhibited a greater sensitivity to impairment in neuronal glucose oxidation and cognitive function than A&#x3b2;42 oligomers or fibrillar plaques.<br><br>CONCLUSIONS: These findings delineate a sequential neurometabolic cascade during AD progression, characterized by early neuronal glucose hypometabolism, subsequent cognitive decline linked to soluble A&#x3b2;40 oligomers, and late-stage astroglial metabolic activation. Collectively, these results suggest that soluble A&#x3b2;40 oligomers exhibit the greatest sensitivity to neurometabolic and cognitive impairment during AD.},
}
@article {pmid42432783,
year = {2026},
author = {Choi, Y and Lee, S and Ashim, J and Yu, W and Cho, E and Lee, HW and Park, JS and Yoon, JH and Kim, HJ and Cheon, M},
title = {Cross-disease LC-MS/MS plasma proteomics identifies reproducible shared and disease-enriched biomarker signatures in neurodegenerative disorders.},
journal = {Acta neuropathologica communications},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40478-026-02377-w},
pmid = {42432783},
issn = {2051-5960},
support = {RS-2024-00454715//the National Research Foundation of Korea (NRF) grant funded by the Korean government/ ; RS-2024-00343239//the National Research Foundation of Korea (NRF) grant funded by the Korean government/ ; RS-2023-00230402//the Ministry of Environment of Korea/ ; 26-BR-04-01//the KBRI basic research program through the Korea Brain Research Institute funded by the Ministry of Science and ICT/ ; 26-BR-02-03, 26-BR-02-05, 26-BR-04-01//the KBRI basic research program through the Korea Brain Research Institute funded by the Ministry of Science and ICT/ ; 26-BR-02-03, 26-BR-02-05, 26-BR-04-01, 26-BR-06-02//the KBRI basic research program through the Korea Brain Research Institute funded by the Ministry of Science and ICT/ ; RS-2024-00512888//the Korea Technology and Information Promotion Agency for SMEs (TIPA) funded by the Ministry of SMEs and Startups/ ; },
abstract = {Neurodegenerative diseases (NDDs) exhibit considerable molecular heterogeneity, making it difficult to pinpoint robust, disease-specific biomarkers. Although proteomic studies have deepened our understanding of individual disorders, systematic cross-disease comparisons with cross-platform validation remain scarce, especially for rare conditions like spinal and bulbar muscular atrophy (SBMA). To address this gap, we conducted a comparative plasma proteomic analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in 264 participants across major neurodegenerative and related diagnostic groups, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), SBMA, and cognitively healthy controls. This unified framework allowed us to capture both disease-specific and shared protein signatures across neurodegenerative conditions. Candidate proteins were then validated in the UK Biobank (Olink Explore) and the Global Neurodegeneration Proteomics Consortium (SomaScan). Of 23 proteins assessed in the UK Biobank, four unique proteins (yielding six disease-protein associations) showed nominally significant and directionally concordant changes; of 20 proteins represented by 27 probes tested in the Global Neurodegeneration Proteomics Consortium, seven proteins reached nominal significance, all with full directional concordance across both cohorts. Notably, IGFBP2 was consistently elevated in AD and PD across independent datasets, pointing to shared metabolic dysregulation, while ADIPOQ showed parallel increases in the same conditions, reinforcing convergent shifts in energy metabolism. By contrast, CRTAC1 and COMP were selectively reduced in motor neuron diseases, suggesting disease-enriched alterations in extracellular matrix composition. Taken together, our findings provide a cross-disease, cross-platform framework for uncovering reproducible proteomic biomarkers and shed light on both overlapping and distinct molecular pathways in neurodegeneration.},
}
@article {pmid42432887,
year = {2026},
author = {Ye, H and Wang, JL and Xu, QH and Gao, YL},
title = {Refining the link between REM sleep behavior disorder and neurodegeneration: Genetic correlation, Mendelian randomization, and colocalization evidence.},
journal = {Medicine},
volume = {105},
number = {28},
pages = {e48922},
doi = {10.1097/MD.0000000000048922},
pmid = {42432887},
issn = {1536-5964},
mesh = {Humans ; *REM Sleep Behavior Disorder/genetics/complications ; Mendelian Randomization Analysis ; *Neurodegenerative Diseases/genetics ; Linkage Disequilibrium ; Genome-Wide Association Study ; Alzheimer Disease/genetics ; Parkinson Disease/genetics ; },
abstract = {Observational studies have proposed a link between isolated rapid eye movement sleep behavior disorder (iRBD) and several neurodegenerative diseases. We employed genome-wide linkage disequilibrium score regression (LDSC), standard two-sample Mendelian randomization (MR), and colocalization analysis to assess the causal links between iRBD and these neurodegenerative conditions. iRBD demonstrated a positive causal association with Alzheimer disease (odds ratio [OR] = 1.02, 95% confidence interval [CI]: 1.00-1.03, P = 1.10E-02), Parkinson disease (OR = 1.10, 95% CI: 1.03-1.16, P = 2.96E-03), and multiple sclerosis (OR = 1.09, 95% CI: 1.02-1.17, P = 1.61E-02). A strong positive genetic correlation with dementia with Lewy bodies was observed (rg = 1.6313, P = .0002), along with a causal association (OR = 1.45, 95% CI: 1.03-2.06, P = 3.53E-02), further supported by colocalization analysis. No significant causal relationship was identified between iRBD and amyotrophic lateral sclerosis (all P > .05). Additionally, reverse Mendelian randomization analyses did not reveal any causal relationships between the neurodegenerative diseases studied and iRBD. Our findings provide robust genetic evidence supporting a causal relationship between iRBD and the risk of multiple neurodegenerative diseases, highlighting the potential for shared pathophysiological mechanisms.},
}
@article {pmid42432965,
year = {2026},
author = {Wu, Z and Zhang, L and Feng, W and Huang, Y},
title = {Association between relative fat mass and cognitive impairment in older adults: A cross-sectional study using NHANES 2011-2014 data.},
journal = {Medicine},
volume = {105},
number = {28},
pages = {e49621},
doi = {10.1097/MD.0000000000049621},
pmid = {42432965},
issn = {1536-5964},
mesh = {Humans ; Cross-Sectional Studies ; Female ; Aged ; *Cognitive Dysfunction/epidemiology ; Nutrition Surveys ; Male ; United States/epidemiology ; Middle Aged ; Body Mass Index ; *Adiposity/physiology ; Waist Circumference ; Risk Factors ; Logistic Models ; },
abstract = {Relative fat mass (RFM), derived from height and waist circumference, may better reflect overall and central adiposity than body mass index. This study examined the association between RFM and cognitive impairment among older adults in the United States. We conducted a cross-sectional analysis using National Health and Nutrition Examination Survey 2011-2014 data, including 2730 participants aged ≥ 60 years with valid anthropometric data, cognitive assessment data, and covariate information required for the primary analysis. Cognitive function was evaluated using the Consortium to Establish a Registry for Alzheimer Disease (word learning &amp; delayed recall tests), animal fluency, and digit symbol substitution tests. Cognitive impairment was defined as performance below the education-specific 25th percentile of a standardized global cognition z-score. Weighted logistic regression models estimated associations between RFM and cognitive impairment, adjusting for demographic, socioeconomic, lifestyle, and clinical factors. Nonlinearity was tested using restricted cubic spline and two-piecewise regression analyses. In the base-adjusted model, RFM was not significantly associated with cognitive impairment. After full adjustment for demographic, socioeconomic, lifestyle, dietary, and clinical factors, higher RFM was associated with increased odds of cognitive impairment (odds ratio = 1.05; 95% confidence interval: 1.02-1.09). Sensitivity analyses excluding participants with very high body mass index, trimming RFM outliers, modeling log-transformed RFM, and using waist circumference as an alternative adiposity measure yielded directionally consistent results. The relationship was linear (P_overall = .042; P_nonlinear = .253), with stronger associations in participants aged < 70 years, and those with hypertension or prior stroke. Hypertension (10%) and physical inactivity (9.4%) partially mediated this relationship, whereas depression and diabetes showed minimal effects. Higher RFM was associated with greater odds of test-based cognitive impairment among United States older adults after multivariable adjustment. The observed associations involving hypertension and physical activity status were exploratory and should not be interpreted as causal. Future longitudinal studies are needed to clarify temporality and evaluate the potential clinical utility of RFM in cognitive risk assessment.},
}
@article {pmid42433162,
year = {2026},
author = {Greco, A and Baretta, R and Fonzo, AD and Armirotti, A and Cinti, S and Mirasoli, M and Frasconi, M and Corbo, C},
title = {Engineering Nanoplatforms for Alzheimer's Disease Detection via Biomolecular Corona Proteomic and Lipidomic Profiling.},
journal = {Advanced healthcare materials},
volume = {},
number = {},
pages = {e71441},
doi = {10.1002/adhm.71441},
pmid = {42433162},
issn = {2192-2659},
support = {M4.C2.1.1//Next Generation EU PRIN 2022/ ; 2022WN89PC//Next Generation EU PRIN 2022/ ; (FAQC 2022) to C.C.//University of Milan Bicocca/ ; },
abstract = {The escalating global prevalence of Alzheimer's disease (AD) requires the development of sensitive, non-invasive diagnostic strategies capable of detecting pathological changes previous the clinical onset. By exploiting the spontaneous formation of the biomolecular corona (BC) around nanoparticles (NPs), it's possible to capture a rich, disease-specific fingerprint from the plasma that reflects systemic alterations often invisible to traditional diagnostic assays. In the present study, we demonstrate the efficacy of an innovative nanotechnological platform utilizing a synergistic dual-silica NPs system (comprising amino- and sulfonate-functionalized surfaces) integrated with proteomic and lipidomic profiling of the NP-associated BC. Our results revealed a significant enrichment of ribosomal machinery in the BC of AD patients, contrasted by a simultaneous decrease of glycolytic enzymes and mitochondrial respiratory components. This metabolic impairment is further corroborated by the lipidomic profile, which shows a reduction in short-chain acyl-carnitines (C2, C3, C5) and essential membrane phospholipids. Additionally, the observed loss of structural proteins, such as Cofilin-1 and Vinculin, contributes to a comprehensive molecular fingerprint unique to the AD phenotype.},
}
@article {pmid42433176,
year = {2026},
author = {Del Giovane, M and Giunchiglia, V and David, MCB and Kolanko, MA and Trender, WR and Hellyer, PJ and Kaur, H and Sharp, DJ and Carswell, C and Malhotra, PA and Hampshire, A},
title = {Digital Cognitive Phenotyping for Differential Diagnosis and Monitoring in Neurological Conditions.},
journal = {Annals of clinical and translational neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/acn3.70451},
pmid = {42433176},
issn = {2328-9503},
support = {//Imperial College Biomedical Research Centre/ ; 608 AS-CTF-22-013/ALZS_/Alzheimer's Society/United Kingdom ; MR/W00710X/1/MRC_/Medical Research Council/United Kingdom ; MR/W016095/1/MRC_/Medical Research Council/United Kingdom ; MR/W030098/1/MRC_/Medical Research Council/United Kingdom ; UKDRI-7201//UK Dementia Research Institute/ ; },
abstract = {OBJECTIVE: To assess the utility, accessibility, and equivalence to supervised scales of online cognitive assessment in older individuals with cognitive impairment.<br><br>METHODS: Patients with Alzheimer's disease (AD, n&#x2009;=&#x2009;31), idiopathic normal pressure hydrocephalus (iNPH, n&#x2009;=&#x2009;26), and traumatic brain injury (TBI, n&#x2009;=&#x2009;23) completed online cognitive tasks (Cognitron). We evaluated cognition relative to a large normative dataset (N&#x2009;&#x2248;&#x2009;400,000), adjusting for device and demographics which can affect performance. Principal Component Analysis (PCA) was used to derive domain-specific and total composite scores. We compared clinical groups and correlated performance with standard assessments.<br><br>RESULTS: Uptake was ~70%. PCA identified components across memory, processing speed, language, and executive functions. AD showed memory and language impairments compared with the norms and other groups. iNPH had greater executive and processing speed deficits, consistent with a subcortical impairment profile. TBI showed milder deficits in memory, working memory, and language. Cognitron total composite was associated with standard supervised tests (ADAS-Cog: &#x3b2;&#x2009;=&#x2009;-0.76, p&#x2009;<&#x2009;0.001 and ACE-III: &#x3b2;&#x2009;=&#x2009;0.69, p&#x2009;<&#x2009;0.001). In iNPH, Cognitron composite predicted walking speed (estimate&#x2009;=&#x2009;1.10, p&#x2009;<&#x2009;0.001), a core clinical feature of the disease which is difficult to evaluate remotely. We selected five tasks with high completion rates, discriminability between conditions, and broad cognitive coverage. The derived short composite showed very high accuracy in separating AD (AUC&#x2009;=&#x2009;0.94) and iNPH (AUC&#x2009;=&#x2009;0.90) from age-matched norms; performance was weaker for TBI (AUC&#x2009;=&#x2009;0.66).<br><br>INTERPRETATION: Online assessment in older clinical populations is feasible and sensitive to subtle disease-specific cognitive deficits. A demographically adjusted, 15-min battery offers a scalable adjunct to standard testing, with potential to reduce burden on patients and healthcare systems.},
}
@article {pmid42433215,
year = {2026},
author = {Cai, L and Zhao, X and Liao, C and Liu, Q and Hu, S and Huang, M},
title = {Efficacy and predictors of cognitive stimulation therapy combined with pharmacotherapy for mild-to-moderate Alzheimer's disease: a randomized controlled trial.},
journal = {Frontiers in psychiatry},
volume = {17},
number = {},
pages = {1840039},
pmid = {42433215},
issn = {1664-0640},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is associated with progressive cognitive decline, functional impairment, and reduced quality of life. Although pharmacological treatments such as cholinesterase inhibitors and memantine are commonly used, their clinical benefits remain limited and heterogeneous. Cognitive stimulation therapy (CST) may provide additional benefits when combined with standard pharmacotherapy. This randomized controlled trial (RCT) aimed to evaluate the clinical efficacy of modified CST combined with standard drug therapy on cognitive function, activities of daily living, and quality of life in patients with mild-to-moderate AD and to explore key predictors of CST efficacy using a multivariate regression model.<br><br>METHODS: This evaluator-blinded randomized controlled trial enrolled 80 patients with mild-to-moderate Alzheimer's disease (AD), who were randomly assigned in a 1:1 ratio to either the modified CST plus standard pharmacotherapy group (study group, n = 40) or the standard pharmacotherapy-alone group (control group, n = 40).The modified CST program comprised 14 weekly 45-minute sessions. The primary endpoint was the change in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) score from baseline to post-intervention. Secondary measures included the Activities of Daily Living (ADL) scale and the Quality of Life in Alzheimer's disease (QOL-AD) questionnaire. Data were analyzed using an intention-to-treat (ITT) approach. Independent predictors of treatment efficacy were identified using a two-stage screening strategy (univariate screening and stepwise regression).<br><br>RESULTS: A total of 75 patients completed the study, and 80 were included in the ITT analysis. After 14 weeks of intervention, baseline-adjusted ANCOVA showed that the study group had significantly better post-intervention ADAS-Cog scores than the control group. The adjusted mean difference in ADAS-Cog score was -3.28 points (95% CI: -3.72 to -2.83; P < 0.001), favoring the study group. Significant baseline-adjusted between-group differences were also observed for ADL (adjusted mean difference = -4.93, 95% CI: -8.39 to -1.47; P&#xa0;=&#xa0;0.006) and QOL-AD (adjusted mean difference = 2.69, 95% CI: 1.01 to 4.37; P&#xa0;=&#xa0;0.002), both favoring the study group. Higher years of education (&#x3b2; = -0.54, P < 0.001), regular physical activity (&#x3b2; = -0.28, P&#xa0;=&#xa0;0.003), higher baseline Mini-Mental State Examination (MMSE) scores (&#x3b2; = -0.22, P&#xa0;=&#xa0;0.001), and active hobbies (&#x3b2; = -0.20, P&#xa0;=&#xa0;0.002) were significant independent predictors of CST efficacy.<br><br>DISCUSSION: Modified CST combined with medication significantly delays cognitive decline and improves QOL-AD in patients with mild-to-moderate AD. Educational attainment, lifestyle factors, and cognitive reserve are key determinants of CST efficacy. Relevant institutions should develop targeted enhancement protocols for patients with lower educational levels or insufficient cognitive reserves when implementing CST.<br><br>TRIAL REGISTRATION: Chinese Clinical Trial Registry, identifier ChiCTR2600118654, https://www.chictr.org.cn.},
}
@article {pmid42433292,
year = {2026},
author = {Chen, C and Gu, P and Ren, J},
title = {High-throughput whole-brain scattering imaging resolves amyloid plaques through clearing-assisted contrast modulation.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.28.735093},
pmid = {42433292},
issn = {2692-8205},
abstract = {Label-free scattering imaging is widely used in pathology because it enables sensitive tissue assessment without exogenous contrast agents. Yet its limited optical penetration has prevented scattering-based methods from being applied to whole-organ pathology mapping. Here we present clearing-assisted scattering tomography (CAST), a high-throughput, label-free whole-brain mesoscope enabled by selective lipid clearance for scattering enhancement (SELiC). SELiC modulates endogenous refractive-index heterogeneity in cleared tissue, providing whole-brain optical penetration while retaining strong scattering contrast from amyloid plaques and white-matter fibre bundles. CAST enables volumetric imaging of intact mouse brains and brain-wide mapping of amyloid plaque pathology across anatomical regions. This platform establishes a scalable route for label-free, system-level analysis of amyloid pathology and tissue architecture in Alzheimer's disease (AD) models.},
}
@article {pmid42433433,
year = {2026},
author = {Jategaonkar, MS and Miller, NH and Zur, SE and Geula, C and Penzes, P and Zaccard, CR},
title = {Nanotubular networks in the aging brain: from neuroprotection to neurodegeneration.},
journal = {Frontiers in human neuroscience},
volume = {20},
number = {},
pages = {1864090},
pmid = {42433433},
issn = {1662-5161},
abstract = {Intercellular communication in the central nervous system extends far beyond classical synaptic transmission. Contemporary studies utilizing in vivo, super-resolution, and ultrastructural microscopy approaches have revealed dynamic nanotubular networks capable of direct protein, organelle, and Ca[2+] signal exchange between cells. Microglial tunneling nanotubes (TNTs) support cooperative α-synuclein aggregate clearance and mitochondrial rescue, whereas dendritic nanotubes (DNTs) mediate neuron-to-neuron connectivity that may contribute to amyloid-β redistribution or accumulation before plaque formation. Emerging evidence further suggests that nanotubular functions are dependent on cell type and structure. Microglial TNTs have typically been associated with aggregate handling, clearance, and cellular rescue, whereas neuronal TNTs and recently described DNTs provide distinct examples of disease-relevant cargo redistribution. A central unresolved question is not simply whether nanotubular networks mediate clearance and rescue or facilitate pathological spread, but how their regulation changes during development, adulthood, aging, and neurodegenerative disease. Existing studies emphasize disruption or collapse of TNT and DNT networks as important features of disease progression. Here, we propose that aging may contribute to intermediate states of nanotubular dysfunction before overt collapse, altering the efficiency, directionality, or consequences of intercellular exchange in a cell-type-specific manner. Mapping the cellular and regional dynamics of nanotubular networks in the brain, particularly during aging and Alzheimer's disease, will be essential for determining when nanotubular connectivity supports resilience, becomes dysfunctional, or contributes to pathological protein redistribution. These efforts may reveal therapeutic strategies for preserving nanotubular integrity and function before the development of late-stage neurodegenerative disease.},
}
@article {pmid42433479,
year = {2026},
author = {Magnani, A and Pierobon, A and Torlaschi, V and Fundarò, C and Maffoni, M},
title = {Why some minds bend, not break: an exploratory study of cognitive and psychological performance across levels of cognitive reserve in subjective cognitive decline.},
journal = {Frontiers in psychology},
volume = {17},
number = {},
pages = {1808150},
pmid = {42433479},
issn = {1664-1078},
abstract = {INTRODUCTION: Subjective Cognitive Decline (SCD) is a heterogeneous at-risk condition along the Alzheimer's disease continuum, characterized by cognitive complaints despite preserved neuropsychological performance. Cognitive reserve (CR) may help explain individual differences in resilience to early cognitive and psychological vulnerability. This exploratory cross-sectional study examined whether global and domain-specific CR-education, occupational activity, and leisure time - were associated with differences in cognitive and psychological functioning in individuals with SCD.<br><br>METHODS: Fifty-one older adults with SCD underwent a comprehensive neuropsychological assessment and self-report measures of subjective complaints, depressive symptoms, and anxiety. Non-parametric analyses compared performance across low, medium, and high CR levels.<br><br>RESULTS: Cognitive performance was globally preserved, while depressive symptoms were clinically relevant in a substantial proportion of participants. Selective CR-related differences emerged: higher global CR was associated with better visuospatial-constructive performance; lower leisure-time CR was associated with faster performance on attentional and executive tasks; and occupational CR showed a non-monotonic association with depressive symptoms, with lower scores in the medium CR group. No differences emerged in other cognitive domains.<br><br>DISCUSSION: These findings support a multidimensional and domain-specific conceptualization of CR in SCD and highlight the clinical value of integrating CR into early cognitive aging assessment.},
}
@article {pmid42434322,
year = {2026},
author = {Boateng, S and Nguefang, GL and Mapouka, M and Lawal, R and Gyabaah, S and Nwatamole, B and Kasar, A and Adatsi, S and Njei, B},
title = {Increased Risk of Alzheimer Disease-Associated Mortality in Nonobese vs Obese Metabolic Dysfunction-Associated Steatotic Liver Disease: A 30-Year National Cohort Study.},
journal = {Gastro hep advances},
volume = {5},
number = {9},
pages = {101030},
pmid = {42434322},
issn = {2772-5723},
abstract = {BACKGROUND AND AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized for its extrahepatic consequences, including emerging links to neurodegenerative disorders such as Alzheimer disease (AD). Whether AD mortality risk differs across MASLD phenotypes, remains unclear.<br><br>METHODS: We analyzed adults from the Third National Health and Nutrition Examination Survey (1988-1994) with mortality follow-up through 2019 via the National Death Index. Participants were followed for AD mortality. Cumulative incidence was estimated using Kaplan-Meier methods. Cox proportional hazards models evaluated MASLD phenotypes and AD mortality, adjusting for age, sex, race/ethnicity, poverty-income ratio, body mass index, and smoking status.<br><br>RESULTS: Among 7125 adults, 1033 had nonobese MASLD and 817 had obese MASLD. At baseline, nonobese MASLD participants were older (mean age 60 &#xb1; 12 years), more likely male (59%), and more frequently White (46%) compared with obese MASLD (mean age 56 &#xb1; 13 years, 46% male, 37% White; P < .001). Age-standardized cumulative incidence of AD mortality was highest in nonobese MASLD (1.98%), followed by non-MASLD (1.81%) and obese MASLD (0.78%). In adjusted models, MASLD was not significantly associated with AD mortality overall. However, nonobese MASLD was independently associated with higher AD mortality compared with obese MASLD (adjusted hazard ratio 3.76; 95% confidence interval 1.19, 11.90; P = .024) and with the overall population (adjusted hazard ratio 1.49; 95% confidence interval 1.03, 2.16; P = .034).<br><br>CONCLUSION: Nonobese MASLD emerged as distinct high-risk metabolic phenotype associated with significantly higher AD mortality, independent of demographic, socioeconomic, and behavioral factors. These findings suggest that nonobese MASLD may reflect unique neuro-metabolic vulnerability and warrant further mechanistic investigation into pathways such as differential adiposity patterns, inflammation, and metabolic signaling. Targeted screening, improved risk stratification, and prospective studies are needed to better define and mitigate long-term cognitive risks in this understudied subgroup.},
}
@article {pmid42434351,
year = {2026},
author = {Jaberi, KR and Alashti, SK and Hooshmandi, S and Vatankhah, P and Haghighi, MR and Savardashtaki, A and Aligholi, H and Jaberi, AR},
title = {Region-specific Transcriptomic Signatures in Alzheimer's Disease: A Meta-analysis of Vulnerable Brain Regions Reveals MicroRNA-hub Gene Regulatory Networks.},
journal = {Journal of medical signals and sensors},
volume = {16},
number = {},
pages = {14},
pmid = {42434351},
issn = {2228-7477},
abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by progressive neurodegeneration in regionally vulnerable brain areas, yet molecular insights into early pathogenic mechanisms remain limited.<br><br>METHODS: We conducted a meta-analysis of transcriptomic datasets from brain regions affected in early-to-moderate AD - including entorhinal cortex, CA1 hippocampus, angular gyrus, and frontal cortex synaptoneurosomes - using data from seven mRNA and one microRNA (miRNA) microarray studies (GSE16759, GSE110226, GSE37264, GSE26972, GSE36980, GSE37263, GSE39420, and GSE157239). Preprocessing included background correction, log2 transformation, quantile normalization, and batch correction via ComBat. Differentially expressed features were defined as false discovery rate <0.05 and | logFC| &#x2265; 1.23 (genes) or &#x2265; 2 (miRNAs).<br><br>RESULTS: We identified 172 differentially expressed genes (122 upregulated and 50 downregulated) and 82 significant miRNAs. Hub genes included Inositol-trisphosphate 3-kinase B (ITPKB), Synaptotagmin 1, Dystrobrevin alpha (DTNA), X Inactive Specific Transcript, and Regulator of G protein signaling 4 (RGS4). Functional enrichment highlighted calcium signaling, synaptic failure, and neuroinflammation. Notably, hsa-miR-30d-5p was predicted to target both ITPKB and DTNA, suggesting a regulatory axis linking miRNA dysregulation to calcium dyshomeostasis. Receiver operating characteristic analysis revealed that only RGS4 showed moderate discriminative capacity (area under the curve [AUC] =0.70), while other hub genes (e.g., ITPKB, AUC = 0.40) exhibited below-chance performance, underscoring the limitations of single-gene classifiers in postmortem tissue.<br><br>CONCLUSION: This study provides mechanistic hypotheses - rather than diagnostic biomarkers - by uncovering region-specific, miRNA-mediated regulatory networks in AD-affected brain tissues. Future validation in accessible biofluids is essential before clinical translation.},
}
@article {pmid42434375,
year = {2026},
author = {Diggin, S and Rueda-Delgado, L and Buick, A and Dyer, JF and Alexander-Sefre, A and Barbey, F and Rowe, JB and Muhammed, K and Harel, BT and Hansen, BJ and Tunbridge, E and Lai, R and Hawellek, DJ and Hake, AM and Marston, H and Oswal, A and Coulthard, E and Pattan, V and Evans, V and Gibson, S and Kipps, C and Kozak, R and Mannering, N and Moss, M and Nguyen, V and Ruddock, K and Shinobu, LA and Toniolo, S and Murphy, B},
title = {A real-world feasibility study: at home longitudinal use of the Cumulus NeuLogiq® platform for electrophysiological and neurocognitive measures in patients with mild Alzheimer's Disease dementia.},
journal = {Frontiers in digital health},
volume = {8},
number = {},
pages = {1840966},
pmid = {42434375},
issn = {2673-253X},
abstract = {INTRODUCTION: Dementias, including those caused by Alzheimer's Disease (AD), are a leading global cause of death, necessitating improvements in early detection and development of more effective disease-modifying therapies. Well-validated pen-and-paper measures serve as the primary method used for cognitive assessment in research and clinical trials in AD. However, these suffer from rater error, infrequent "snapshot" bias, and have limited sensitivity to early-stage pathology, which presents challenges for measuring efficacy in prevention trials. Recent technological advances offer the potential to measure subtle cognitive changes and account for day-to-day variability through real-world data collection. The Cumulus Neuroscience NeuLogiq® platform ("the platform"), is comprised of a wireless electroencephalography (EEG) headset, tablet-based cognitive tasks based on well-established paradigms which were designed to be user-friendly based on patient panel inputs, third party integrations (mood, speech and sleep assessments) and cloud-based analytics. This platform has demonstrated utility in healthy populations and may enable objective, frequent, and patient-centered disease tracking in AD and other CNS disorders.<br><br>METHODS: This paper presents findings from a 52-week study involving individuals with mild AD dementia and healthy controls. Analyses focus on usability (e.g., ease of use ratings and reported technical issues) and feasibility (e.g., adherence; withdrawal rates) of using the platform, unsupervised, in the real-world at home setting and exploring how baseline cognitive status and demographic factors impact platform usability.<br><br>RESULTS: Longitudinal study data after 12 months offer valuable insights into the feasibility of the platform for patients with mild AD enrolled in long-term studies, such as clinical trials. The participants' high adherence to the protocol underscores the practicality of utilizing the platform in this context. Although participants with dementia reported lower confidence levels (31.6%, N = 18) and encountered some minor technical challenges during the initial home setup (accounting for 16.1% of issues reported in Stage 1), they nonetheless demonstrated strong engagement, achieving an overall adherence rate of 77% across the 52-week study protocol.<br><br>DISCUSSION: This demonstrates that even participants with dementia remain able and willing to use the EEG headset and complete tablet-based cognitive tasks over a year, from the comfort of their homes.},
}
@article {pmid42434591,
year = {2026},
author = {Zeng, H and Li, Z and Jiang, S and Wu, J and Ren, Z and Leng, Y and Zhao, Q and Zhou, P and Gao, P and Wang, P and Zou, X},
title = {Mechanisms and disease associations of oxidative stress-mediated brain-bone axis dysregulation: a knowledge mapping and trend analysis based on Bibliometrics.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1755503},
pmid = {42434591},
issn = {1663-4365},
abstract = {BACKGROUND: Oxidative stress, characterized by the systemic imbalance between reactive oxygen species and antioxidant defenses, is increasingly recognized as a central pathological nexus driving the dysregulation of the brain-bone axis. Despite the accumulation of empirical evidence, a systematic characterization of the field's intellectual structure and thematic progression remains absent. This study employs a multi-database bibliometric approach to map the research landscape of oxidative stress-mediated neuro-skeletal crosstalk and identify emerging research frontiers.<br><br>METHODS: A systematic search was performed across the Web of Science Core Collection, Scopus, and PubMed databases from their inception to April 30, 2025. Following a rigorous screening process based on predefined criteria, 717 relevant publications were included. Bibliometric mapping and network analyses were conducted using CiteSpace, VOSviewer, and the Bibliometrix R-package to evaluate collaboration patterns, co-citation structures, and keyword evolution.<br><br>RESULTS: The analysis reveals a steady increase in research output since 2009, marked by distinct developmental phases. Early investigations primarily focused on fundamental oxidative damage mechanisms, while subsequent research transitioned toward systemic disease associations (e.g., Alzheimer's disease and osteoporosis) and targeted intervention strategies, including mesenchymal stem cell therapy and melatonin. Recent trends indicate a methodological and thematic shift toward high-resolution translational themes, such as neuroimmune regulation and the "gut-brain-bone" axis. Notably, "gut microbiota" and "extracellular vesicles" have emerged as high-centrality nodes, reflecting an increasing focus on inter-organ communication and systemic redox modulation.<br><br>CONCLUSION: This study provides the first comprehensive mapping of the research trajectories within the oxidative stress-mediated brain-bone axis field. The findings delineate a clear progression from isolated mechanistic studies toward integrated, multi-system frameworks, underscoring the shift toward precision medicine and translational applications. By identifying current research gaps and emerging hotspots, this analysis offers a systematic reference for future interdisciplinary investigations and the development of targeted therapeutic strategies for neuro-skeletal comorbidities.},
}
@article {pmid42434592,
year = {2026},
author = {Long, X and Rong, M and Long, S and Wen, S and Mo, L and Xu, M and Zhang, Z and Nie, Q},
title = {Trajectories and timing of accelerated decline in specific memory domains preceding Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1868433},
pmid = {42434592},
issn = {1663-4365},
abstract = {INTRODUCTION: Memory impairment is a hallmark feature of Alzheimer's disease (AD) and may emerge years before clinical diagnosis. However, the temporal sequence and acceleration patterns of decline across specific memory domains during the preclinical stage remain incompletely understood. This study aimed to characterize the longitudinal dynamics of four distinct memory processes in individuals progressing to clinical AD, and to identify the temporal sequence of continually accelerated decline.<br><br>METHODS: We analyzed longitudinal data from 382 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) who converted from cognitively normal or mild cognitive impairment to AD. Generalized additive mixed models (GAMMs) were employed to characterize the nonlinear trajectories of four Rey Auditory Verbal Learning Test (RAVLT) derived scores over time prior to AD diagnosis, adjusting for key demographics and genetic factors. The finite difference method was applied to identify time points of continually accelerated decline from the fitted curves. Sensitivity analyses additionally adjusted for stroke and emotional incontinence, replicating all steps.<br><br>RESULTS: Our analysis revealed distinct nonlinear progression patterns across memory domains. All trajectories significantly deviated from linearity (Edf > 1, p < 0.001). Learning memory demonstrated the earliest continually accelerated decline, beginning 8.5 years before AD onset. APOE-&#x3b5;4 allele carriage exhibited a dose-dependent effect, significantly associated with RAVLT_learning (&#x3b2; = -0.389 for one allele, -0.530 for two alleles) and RAVLT_forgetting (&#x3b2; = -0.449 for one allele, -0.508 for two alleles), but not with RAVLT_immediate performance. Females exhibited better immediate memory function than males, which was positively associated with years of education.<br><br>CONCLUSION: The decline in four memory tests among individuals with preclinical AD followed nonlinear trajectories, with learning memory exhibiting the earliest continuously accelerated decline. Higher education was associated with better immediate memory performance, while the APOE-&#x3b5;4 genotype specifically exacerbated impairments in learning memory and retention loss.},
}
@article {pmid42434607,
year = {2026},
author = {Wilson, D and Copeland, K and Mette, L and Khare, M and Polak, M and Signes, JM and Skelton, T},
title = {Comparison of a multi-analyte algorithmic immunoassay blood test with immunoprecipitation mass spectrometry for the detection of amyloid pathology.},
journal = {Alzheimer's &amp; dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70420},
pmid = {42434607},
issn = {2352-8729},
abstract = {INTRODUCTION: Alzheimer's blood-based biomarker (BBM) tests using single biomarkers or ratios are well characterized, but head-to-head comparisons of multi-analyte algorithmic tests on shared cohorts are lacking. We compared a five-biomarker algorithmic immunoassay (LucentAD Complete) with an algorithmic immunoprecipitation mass-spectrometry (IP-MS) benchmark on a shared plasma cohort.<br><br>METHODS: Symptomatic individuals (n&#xa0;=&#xa0;192) with longitudinal samples from Alzheimer's Disease Neuroimaging Initiative (ADNI) were analyzed versus amyloid positron emission tomography (PET). Cross-sectional (n&#xa0;=&#xa0;115) and longitudinal (n&#xa0;=&#xa0;179; 12-year span) cohorts representing disease progression were used.<br><br>RESULTS: The immunoassay amyloid risk score demonstrated a 0.94 area under the curve (AUC) and 92%-93% accuracy, achieving performance parity with IP-MS metrics on shared samples. The two-cutoff design yielded an intermediate zone of 10.4%-12.8%.<br><br>DISCUSSION: These results establish diagnostic parity between algorithmic immunoassay and algorithmic IP-MS assay. In addition, providing individual biomarker results alongside a validated risk score offers a more granular foundation for comprehensive management than amyloid status alone, supporting premium reimbursement for multi-analyte algorithmic BBMs in clinical practice.},
}
@article {pmid42434808,
year = {2026},
author = {Baker, B and Emerson, S and Tran, T and Mohapatra, N and Wang, D and Zaw, T and Doshi, A and Lopez, JM and Hassan, D and Kumar, P and Farmer, D and Wang, A},
title = {Brain targeting and trafficking of extracellular vesicles in central nervous system diseases: a therapeutic roadmap.},
journal = {Nanomedicine (London, England)},
volume = {},
number = {},
pages = {1-19},
doi = {10.1080/17435889.2026.2698782},
pmid = {42434808},
issn = {1748-6963},
abstract = {Extracellular vesicles (EVs) mediate intercellular signaling in the central nervous system (CNS) by transferring lipids, proteins, and nucleic acids among neurons, glia, endothelium, and immune cells. Brain targeting depends on a linked sequence: EV ligands and adsorbed protein coronas engage receptor modules, select endocytic routes, determine intracellular fate, and define the therapeutic readouts. These fates include lysosomal degradation, recycling, rare cytosolic delivery, or transport across the blood-brain barrier (BBB). In disease, the same pathways can disseminate proteopathic seeds and amplify neuroinflammation. Heparan sulfate proteoglycans (HSPGs) and LDL receptor family members, including low-density lipoprotein receptor-related protein 1 (LRP1), regulate tau, α-synuclein, and amyloid-β handling. Phosphatidylserine readers and complement shape myeloid sink capture and inflammatory output. Integrin, tetraspanin, and ICAM-1 nanoclusters influence avidity, organotropism, and immune suppression. At the BBB, endothelial HSPGs, LRP1, and transferrin receptor (TfR) support receptor-mediated uptake, motivating engineered ligands such as rabies virus glycoprotein-derived peptides, Angiopep-2, and TfR binders. However, endosomal escape remains a major kinetic barrier to nucleic acid delivery. We synthesize these principles across Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, glioblastoma, and demyelinating disease, and outline design and assay standards needed to translate EV biology into safe, manufacturable CNS therapeutics.},
}
@article {pmid42434876,
year = {2026},
author = {Shea, YF and Wong, YL and Chan, PL and Yam, KK and Wong, FCK and Wong, TK and Chan, KPF and Cheung, YWE and Mak, HKF and Ip, SMM and Chan, WC and Chan, KH and Chiu, PKC and Lam, CW},
title = {Application of plasma phosphorylated tau 217 in a memory clinic focusing on Chinese patients.},
journal = {Singapore medical journal},
volume = {},
number = {},
pages = {},
doi = {10.4103/singaporemedj.SMJ-2025-225},
pmid = {42434876},
issn = {2737-5935},
abstract = {INTRODUCTION: Plasma phosphorylated tau (P-tau) 217 has not been extensively studied in the Chinese population in a real-world memory clinic for detecting Alzheimer's disease (AD). This study aimed to determine a local cut-off for plasma P-tau 217 in a Chinese population and apply it to a similar cohort of patients in our memory clinic, evaluating its impact on diagnostic outcomes in a real-world setting.<br><br>METHODS: Ninety-eight patients were offered measurement of plasma P-tau 217 using S-PLEX&#xae;. The validation cohort, consisting of 48 patients who underwent amyloid positron emission tomography (PET), was used to determine the cut-offs for plasma P-tau 217 and posttest probabilities through receiver operating curve analysis. Unsupervised clustering analysis was also used to derive the cut-off. These cut-offs were applied to an application cohort (n = 50) without amyloid PET to study the clinical impact.<br><br>RESULTS: The sensitivity and specificity of the test, using a single cut-off of plasma P-tau 217 >10.08 pg/mL, were 86.67% and 88.89%, respectively. Unsupervised clustering analysis generated a cut-off of >11.69 pg/mL. After applying the two determined cut-offs in the application cohort, 50% of patients clinically diagnosed with AD were reclassified as non-AD, while 16.7% of patients initially diagnosed as non-AD were reclassified as AD. Using a post-test probability cut-off of >39.41%, the classification of AD and non-AD patients had a sensitivity of 93.33% and a specificity of 88.89%.<br><br>CONCLUSION: Plasma P-tau 217 is useful in diagnosing AD among Chinese patients in a memory clinic with diverse underlying aetiologies of cognitive impairment.},
}
@article {pmid42434897,
year = {2026},
author = {Sharma, A and Suresh, V and Kola, PR and Raj, R and Javairia, F and Nithyanandam, A and Kaur, A and Arora, H and Uwishema, O and Gorty, D and Beriwal, N and Verma, A and Qidwai, K and Singh Malhotra, H and Kumar Garg, R},
title = {Comparative risk of amyloid-related imaging abnormalities with anti-amyloid-β monoclonal antibodies: A systematic review and penalized likelihood network meta-analysis of randomized trials.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261466097},
doi = {10.1177/13872877261466097},
pmid = {42434897},
issn = {1875-8908},
abstract = {BackgroundAnti-amyloid-β monoclonal antibodies represent a new class of disease-modifying therapies for Alzheimer's disease (AD). Their clinical adoption is complicated by amyloid-related imaging abnormalities (ARIA), encompassing vasogenic edema (ARIA-E) and hemorrhagic changes (ARIA-H). The comparative ARIA risk across agents and the influence of genetic factors remain incompletely characterized.ObjectiveTo quantify the pooled incidence of ARIA-E and ARIA-H associated with anti-amyloid-β immunotherapies and to compare relative risks across agents using network meta-analytic modeling.MethodsFollowing PRISMA guidelines (PROSPERO: CRD420250653157), we searched PubMed, EMBASE, Scopus, Web of Science, and Ovid through January 2026 for Phase II/III randomized controlled trials of anti-amyloid-β immunotherapies in AD. Random-effects models estimated pooled prevalence and odds ratios (ORs). A penalized likelihood network meta-analysis addressed sparse events. APOE ε4-stratified analyses and Bayesian sensitivity models were also performed.ResultsTwenty-two trials (up to 23,120 participants) were included. Pooled ARIA-E prevalence was 6.8% and ARIA-H was 15.8%, with substantial heterogeneity. Anti-amyloid-β therapy significantly increased odds of ARIA-E (OR 7.93; 95% CI 4.50-13.98) and ARIA-H (OR 1.87; 95% CI 1.28-2.72) versus placebo. The highest ARIA-E risk was seen with donanemab and aducanumab, followed by gantenerumab and lecanemab. APOE ε4 carriage significantly elevated ARIA-E (OR 2.28) and ARIA-H (OR 2.07) risk, with a clear gene-dose effect in homozygotes.ConclusionsARIA risk varies substantially across anti-amyloid-β therapies and is strongly modulated by APOE ε4 status. These findings support genotype-informed risk stratification and individualized MRI monitoring to optimize the benefit-risk balance of disease-modifying therapies in AD.},
}
@article {pmid42434900,
year = {2026},
author = {Vinters, HV and Magaki, S},
title = {Amyloid-related imaging abnormalities after immunotherapy: How might brain microvascular basement membrane components be involved?.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261467705},
doi = {10.1177/13872877261467705},
pmid = {42434900},
issn = {1875-8908},
abstract = {Basement membrane components are integral to the physiologic function of cerebral microvessels. Immunotherapy (including by the use of lecanemab) in Alzheimer's disease patients may result in vascular complications identified by neuroimaging (ARIA-E and ARIA-H). This pilot study (on a relatively small number of human brain specimens) suggests one mechanism might be through the effects of lecanemab on a collagen component of said microvessel walls. It utilizes microvessels isolated from human brains (of Alzheimer's disease patients) and maintained in a viable state, to examine this mechanism using novel biochemical and molecular approaches. These yield preliminary evidence of how lecanemab may influence a specific component of the cerebral microvasculature and suggest other studies that may be used to address this important question.},
}
@article {pmid42434902,
year = {2026},
author = {Meng, G and Cai, L and Mo, Z and An, S and Sun, W and Shen, P and Xie, Y},
title = {Mitophagy deficiency and calcium dyshomeostasis underlying the pathogenesis and progression of Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261465779},
doi = {10.1177/13872877261465779},
pmid = {42434902},
issn = {1875-8908},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder defined by three pathological hallmarks: amyloid-β (Aβ) deposition, tau hyperphosphorylation leading to neurofibrillary tangles formation, and neuronal loss. Mounting evidence over the past decade has underscored that mitophagy deficiency and calcium dyshomeostasis play pivotal regulatory roles in AD pathological progression, with these two abnormalities persisting throughout the entire course of disease onset and development. Mitophagy impairment can result in the accumulation of dysfunctional mitochondria, thereby further exacerbating calcium dyshomeostasis which can suppress autophagic flux in turn. This reciprocal interaction establishes a vicious cycle that can synergistically accelerate Aβ plaque and neurofibrillary tangle formation, impair synaptic structure and function, and ultimately elicit neuronal programmed cell death and cognitive decline. This review systematically summarizes the biological basis of mitophagy and calcium homeostasis, as well as their mutual regulatory networks. It places particular emphasis on deciphering the pathological mechanisms through which concurrent impairments of these two pathways synergistically drive AD pathogenesis and progression. Furthermore, we propose intervention strategies targeting to modulate mitophagy deficiency and calcium dyshomeostasis, which hold great promise for providing novel insights and potential therapeutic targets for the clinical management of AD.},
}
@article {pmid42434908,
year = {2026},
author = {Doganyigit, B and Schurr, T and Hofer, A and Schütz, S and Defrancesco, M},
title = {Multidomain cognitive impairment, along with comorbidities and psychiatric hospitalizations, shorten survival time of patients with Alzheimer's disease dementia: A long term, naturalistic follow-up study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261468789},
doi = {10.1177/13872877261468789},
pmid = {42434908},
issn = {1875-8908},
abstract = {BackgroundThe survival time following an initial Alzheimer's disease dementia (ADD) diagnosis is influenced by various demographic, cognitive and clinical factors. Cognitive clusters are more detailed than individual cognitive measures, but they are rarely used as predictors in survival analyses.ObjectiveWe conducted a long-term retrospective study following patients from the time of their initial ADD diagnosis until their death. Cognitive clusters as well as clinical data were assessed as predictors of survival time.MethodsWe used hierarchical clustering to identify cognitive clusters based on the results of neuropsychological examinations (CERAD-Plus). We fitted a Cox regression model with cognitive clusters and clinical covariates (e.g., age, sex, Mini-Mental State Examination [MMSE] score, annual rate of hospitalizations, and pre-existing diseases) to predict survival time.ResultsData from 202 patients (mean age = 77.79 ± 5.35 years; mean survival time 74.04 ± 41.03 months) were analyzed. Two cognitive clusters were identified: the amnestic cluster (AC, N = 89) and the mixed cluster (MC, N = 80). The Cox regression models identified the following variables as most predictive of shorter survival times: higher age (HR = 1.04) and lower MMSE score at baseline (HR = 0.92), pre-diagnosed atrial fibrillation (HR = 2.06) and delirium (HR = 3.13), and a higher annual rate of psychiatric (HR = 4.84) and somatic (HR = 1.67) hospitalizations. Patients in the MC had a shorter survival time than those in the AC group (HR = 1.45).ConclusionsThis study provides evidence that a detailed analysis of neuropsychological profiles at the time of ADD diagnosis can predict disease progression. Preventing psychiatric hospitalizations, especially, could positively influence the survival of ADD patients.},
}
@article {pmid42434915,
year = {2026},
author = {Akbar, N and Lin, D and Cheung, YHC and Mohamed, A and Chowdhury, M and Damouras, S},
title = {Low body mass index is associated with higher rates of mild cognitive impairment and worse memory performance among older Canadian adults: An analysis of the Canadian Longitudinal Study on Aging (CLSA) database.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261464179},
doi = {10.1177/13872877261464179},
pmid = {42434915},
issn = {1875-8908},
abstract = {BackgroundBoth low and high body mass index (BMI) have been identified as risk factors for dementia, though the association between the range of BMI classifications and presence of mild cognitive impairment (MCI) and memory performance warrants further investigation.ObjectiveThis study aimed to investigate the association between the range of BMI classifications and presence of MCI, as well as overall memory performance, among a large Canadian sample of older adults.MethodsThis study utilized data from 40,232 participants from the Canadian Longitudinal Study on Aging (CLSA). The association between BMI and cognitive function was examined at baseline and first follow-up (3 years). Linear regression was used to model the relationship between BMI and memory performance, while logistic regression was used to assess the association between BMI and the odds of meeting criteria for MCI.ResultsIn the final regression model, a weak (partial eta-squared=0.8%, 95% CI [0.63%, 0.97%]) inverted-U relationship between BMI and REYII memory performance was demonstrated, with normal BMI showing the best performance. In the final logistic regression model, being underweight was associated with 3.22 times greater odds (95% CI [1.63, 6.39]) of meeting criteria for MCI compared to normal BMI. No association was demonstrated between change in BMI and change in cognitive performance between baseline and 3-year follow-up.ConclusionsBeing underweight is linked to higher odds of MCI, suggesting the importance of adequate nutrition in preserving cognitive health among older adults.},
}
@article {pmid42434956,
year = {2026},
author = {Kalainilavan, K and Kota, L and Karuppusamy, V and Sakthivel, P and Ilangovan, A},
title = {Blue Light Irradiated, Para Site-Selective C-H/C-H Cross-Dehydrogenative Coupling of Electron-Rich Arenes with Quinones.},
journal = {The Journal of organic chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.joc.6c00669},
pmid = {42434956},
issn = {1520-6904},
abstract = {A metal-free, regioselective C-H/C-H dehydrogenative arylation of electron-rich arenes with quinones has been developed. Utilizing Eosin-Y as a photocatalyst and K2S2O8 as the terminal oxidant, this protocol enables the para selective quinonylation of phenols and anisoles under mild, open flask conditions. The reaction is promoted by trifluoroacetic acid (TFA) and visible light, providing a sustainable route to biologically active arylated quinone derivatives, including those with potential therapeutic applications for Alzheimer's disease. The methodology is scalable to gram level synthesis and tolerates a broad range of functional groups, delivering the desired cross-coupled products in moderate to high yields.},
}
@article {pmid42435043,
year = {2026},
author = {Dabas, A and Yadav, P and Singh, R},
title = {Exploring thiazole conjugates as cholinesterase inhibitors for Alzheimer's disease treatment.},
journal = {Future medicinal chemistry},
volume = {},
number = {},
pages = {1-15},
doi = {10.1080/17568919.2026.2699679},
pmid = {42435043},
issn = {1756-8927},
abstract = {Alzheimer's Disease (AD), a major global health concern, is marked by memory loss and cognitive decline, especially in the elderly. Cholinergic hypothesis is one of the leading hypotheses toward the treatment of AD, prompting the development of cholinesterase (ChE) inhibitors. Acetylcholinesterase (AChE) remains a vital therapeutic target due to its role in enhancing acetylcholine levels and neural function. The natural products, synthetic analogs, and hybrid molecules have been evaluated as inhibitors of ChEs. Recent studies highlight thiazole-fused heterocyclic scaffolds and their derivatives as promising ChE inhibitors with neuroprotective potential. This article covers the synthesis of conjugates of thiazole with piperazine, benzimidazole, pyrazole, and other heterocyclic compounds, along with their potential as ChE inhibitors. This article will be useful to medicinal chemists and pharmaceutical industries to design and synthesize library of thiazole conjugates.},
}
@article {pmid42424747,
year = {2026},
author = {Galler, JA and Yang, L and Wu, CY and Young, C and Guzmán-Vélez, E and Cropp, KW and Bannon, AW and Dodge, HH and Gerber, JA and Arnold, SE},
title = {MIND GamePack: A novel digital health technology for assessment of participants with and without cognitive impairment.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {8},
pages = {100642},
doi = {10.1016/j.tjpad.2026.100642},
pmid = {42424747},
issn = {2426-0266},
abstract = {BACKGROUND: Digital biomarkers offer promising avenues for enhancing the identification, prognosis, and phenotyping of Alzheimer's Disease (AD). This study evaluates the feasibility and utility of the MIND GamePack©, a digital game platform designed to measure leisure cognitive activity over time.<br><br>METHODS: Gameplay data were collected from 60 participants across two cohorts over 3-6 months: Cohort I (no cognitive complaints) and Cohort II (subjective complaints, mild cognitive impairment, mild dementia). Analyses focused on compliance, correlation with validated neuropsychological instruments (Montreal Cognitive Assessment [MoCA], Repeatable Battery for the Assessment of Neuropsychological Status [RBANS], and Trail Making Test [TMT]), test-retest reliability, and known groups comparison.<br><br>RESULTS: The MIND GamePack&#xa9; displayed high compliance and excellent test-retest reliability within 1 week (ICC=0.81-0.95) for most selected features. Several game features displayed moderate to strong correlations with standardized neuropsychological test performance. Features related to memory tasks across select games (Normalized Accuracy and Normalized Redundant Move Variability of Memory Match and Word Repetition Rate of Word Scramble) exhibited significant associations with RBANS Sum of Index Score, TMT Part A, and MoCA, respectively. Participants without cognitive impairment exhibited improvement in features over 3 months compared to those with cognitive impairment. Baseline game features differentiated cognitively normal [CN] from cognitively impaired [CI] participants across nearly all domains after controlling for age, sex, and education (p<.01).<br><br>CONCLUSIONS: The MIND GamePack&#xa9; offers a sensitive, engaging approach to cognitive monitoring and screening, with potential use for dense tracking in longitudinal research and interventional clinical trials.},
}
@article {pmid42424917,
year = {2026},
author = {Lapmanee, S and Thonapan, N and Sriwong, S and Bhubhanil, S and Wongchitrat, P and Charoenphon, N and Ngernsutivorakul, T and Hooncharoen, K and Bunwatcharaphansakun, P and Khongkow, M and Namdee, K},
title = {RGD-functionalized cannabidiol lipid nanoparticles improve brain delivery and alleviate cognitive and metabolic dysfunction via gut-brain axis modulation in an Alzheimer's disease model.},
journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie},
volume = {201},
number = {},
pages = {119724},
doi = {10.1016/j.biopha.2026.119724},
pmid = {42424917},
issn = {1950-6007},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and neuronal loss. Evidence links gut-brain axis dysfunction and metabolic disturbances to AD. Although cannabidiol (CBD) has neuroprotective effects, its use is limited by poor bioavailability and brain delivery.<br><br>METHODS: Arginylglycylaspartic acid (RGD)-functionalized, CBD-loaded lipid nanoparticles (CBD/LNP-RGD) were developed to enhance targeted delivery across the blood-brain barrier (BBB) via integrin &#x3b1;v&#x3b2;3-mediated transcytosis. Cellular uptake and BBB permeability were evaluated in vitro. Anti-inflammatory and antioxidant effects were assessed in A&#x3b2;/LPS-induced models. In vivo efficacy was examined using cognitive-behavioral tests, including the novel object recognition and the Morris water maze. Metabolic parameters, histopathology, synaptic protein expression, and gut barrier integrity were also evaluated.<br><br>RESULTS: CBD/LNP-RGD demonstrated a 3-fold increase in cellular uptake and a 65% enhancement in BBB transport compared to non-targeted formulations. Treatment significantly reduced pro-inflammatory cytokines (i.e., IL-6 and TNF-&#x3b1;, p&#x202f;<&#x202f;0.001) and intracellular reactive oxygen species (p&#x202f;<&#x202f;0.001). In vivo, CBD/LNP-RGD improved cognitive performance comparable to Donepezil (p&#x202f;<&#x202f;0.001). Additionally, it normalized glycemic control, insulin resistance, and triglyceride levels without hepatic or renal toxicity. At the tissue level, CBD/LNP-RGD reduced A&#x3b2; and tau pathology, restored short-chain fatty acids, preserved hippocampal neuronal integrity, and upregulated synaptophysin and PSD-95 proteins. Enhanced intestinal barrier function was evidenced by increased expression of tight junction proteins ZO-1 and occludin.<br><br>CONCLUSIONS: CBD/LNP-RGD represents a multifunctional nanotherapeutic platform that improves brain delivery and exerts neuroprotective, anti-inflammatory, antioxidant, and metabolic regulatory effects. Its ability to modulate both central pathology and the gut-brain axis highlights its potential as a disease-modifying strategy for Alzheimer's disease.},
}
@article {pmid42425064,
year = {2026},
author = {Rudman, MD and Ulrich, JD and Holtzman, DM},
title = {Recent advances in Alzheimer's disease: From molecular mechanisms to therapeutic strategies.},
journal = {Cell},
volume = {189},
number = {14},
pages = {4193-4224},
doi = {10.1016/j.cell.2026.06.006},
pmid = {42425064},
issn = {1097-4172},
mesh = {*Alzheimer Disease/therapy/pathology/drug therapy/metabolism/immunology ; Humans ; Animals ; Apolipoproteins E/metabolism/genetics ; Plaque, Amyloid/pathology ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) remains the leading cause of dementia worldwide and an escalating global health crisis. The hallmark amyloid plaques and neurofibrillary tangles (NFT) are now known to be accompanied by a complex array of pathologies that culminate in neurodegeneration and cognitive decline. New disease-modifying therapies for AD can now slow cognitive decline through the removal of amyloid plaques from the brain, but treatments to stop or prevent cognitive impairment remain elusive. In this review, we summarize the most recent updates in AD research on pathologic disease mechanisms and therapeutic strategies, highlighting advancements in apolipoprotein E (APOE) biology, neuroimmunology, biomarker discovery, and initial experience with new disease-modifying therapies. These important discoveries are revolutionizing AD diagnosis and treatment and provide hope for a future where AD is not only treatable but also preventable.},
}
@article {pmid42425116,
year = {2026},
author = {Janbek, J and Laursen, TM and Jørgensen, K and Jensen, MM and Eliasen, MH and Christensen, AI and Walsh, S and Sommerlad, A and Brayne, C and Waldemar, G},
title = {Mapping dementia risk factors and their interactions in Denmark: a nationwide cohort study.},
journal = {The Lancet. Public health},
volume = {},
number = {},
pages = {},
doi = {10.1016/S2468-2667(26)00124-6},
pmid = {42425116},
issn = {2468-2667},
abstract = {BACKGROUND: Although global estimates for dementia risk reduction are available, risk profiles might differ in a high-income, welfare-state setting. Few studies have been conducted that simultaneously estimate the prevalence of dementia risk factors and their associated risk of dementia within the same nationwide population. We aimed to estimate the relative risk of dementia and the population attributable fractions (PAFs) for 16 potentially modifiable risk factors, their combinations, and their interactions based on routinely collected health registry and survey data.<br><br>METHODS: We conducted a nationwide cohort study based on data from Danish registries and the Danish National Health Survey (DNHS). The whole population, which included individuals born in or before 1957 who were alive, living in Denmark, and dementia-free at the start of follow-up, was followed up from age 65 years, or Jan 1, 2010 (whichever came last); individuals with additional data from the DNHS formed a subpopulation. Follow-up ended at death, emigration, dementia diagnosis, or on Dec 31, 2022 (whichever came first). The primary outcome was incident all-cause late-onset dementia diagnosis (age &#x2265;65 years). We calculated dementia hazard ratios and PAFs for 16 risk factors (depression, traumatic brain injury, hospital-diagnosed infections, vision impairment, cardiovascular disease, sleep disorders, diabetes, hearing loss, hypercholesterolaemia, low education, hypertension, physical inactivity, social isolation, smoking, alcohol consumption, and obesity), as well as their combinations, and interactions between risk factors. Analyses were stratified by sex, birth cohorts, and educational level. Sensitivity analysis included accounting for reverse causation by splitting the risk time into less than 5 years and more than 5 years since exposure.<br><br>FINDINGS: The whole population comprised 1&#x2008;753&#x2008;515 individuals, of whom 194&#x2008;368 had additional DNHS data. The overall PAF for dementia in Denmark was 37&#xb7;8% (95% CI 35&#xb7;6-40&#xb7;0) for the assessed risk factors. PAF for individual risk factors was highest for hospital-diagnosed infections (9&#xb7;4% [9&#xb7;3-9&#xb7;4]), depression (8&#xb7;7% [8&#xb7;6-8&#xb7;8]), and cardiovascular disease (CVD; 7&#xb7;6% [7&#xb7;6-7&#xb7;7]). After accounting for reverse causation, the PAF for hospital-diagnosed infections was 7&#xb7;0% (95% CI 6&#xb7;9-7&#xb7;0), and 5&#xb7;7% (5&#xb7;7-5&#xb7;8) for depression. The apparently protective effect of obesity on dementia was also shown to be driven by reverse causation. The overall PAF was higher in males, 1948-57 birth cohorts, and individuals with low education. Risk factor profiles varied by sex and birth cohorts. Risk factor combinations involving depression, hospital-diagnosed infections, or CVD showed the strongest superadditive effects. Interactions between some risk factors were seen in only some of the studied subgroups (eg, in the 1948-57 birth cohorts and individuals with low education).<br><br>INTERPRETATION: These findings reinforce the need for tailored dementia interventions building on country-specific evidence. Our findings on interactions between different risk factors are important for generating novel hypotheses on the mechanisms underlying dementia disorders and highlighting at-risk population groups for whom targeting of one risk factor could reduce the risk associated with the co-occurring factor.<br><br>FUNDING: The Alzheimer-forskningsfonden, the KID foundation, and the Danish Ministry of Health.},
}
@article {pmid42425184,
year = {2026},
author = {Taher, RF and Abd Elkarim, AS and El-Fadaly, AA and Abdelhameed, MF and Eid, MM and Essa, AF and El-Kashak, WA and Son, NT and Ahmed, YH and Elshamy, AI},
title = {UPLC-ESI-qTOF-MS metabolomic characterization and in vivo neuroprotective activity of Diplotaxis harra ethanolic extract through antioxidant, anti-cholinesterase, and anti-amyloid mechanisms.},
journal = {Fitoterapia},
volume = {},
number = {},
pages = {107380},
doi = {10.1016/j.fitote.2026.107380},
pmid = {42425184},
issn = {1873-6971},
abstract = {Aluminum chloride (AlCl3)-induced neurotoxicity is a widely used model of Alzheimer's disease, featuring oxidative stress, cholinergic dysfunction, amyloid deposition, and cognitive deficits. This study investigated the neuroprotective effects of Diplotaxis harra ethanolic extract (DH-EtOH) in AlCl3-treated rats and linked them to its phytochemical profile. UPLC-ESI-qTOF-MS analysis revealed a chemically rich extract dominated by phenolic acids, flavonol glycosides (~40% of metabolites), glucosinolates, amino acid derivatives, phospholipids, and oxidized fatty acids, supporting a multitarget mode of action. Oral DH-EtOH (75-150 mg/kg) improved spatial memory in T-maze tests, with the higher dose restoring near-normal performance. Biochemically, hippocampal acetylcholinesterase activity was significantly inhibited, glutathione levels were restored, and malondialdehyde levels decreased by ~35% versus AlCl3 controls. Histology showed preserved hippocampal architecture and reduced GFAP immunoreactivity, indicating attenuation of astrocyte activation. Pathological markers Tau and Aβ1-42 were also significantly diminished in a dose-dependent manner. These results demonstrate that DH-EtOH exerts multitarget neuroprotection through synergistic actions of diverse metabolite classes. Its chemical complexity underpins efficacy in restoring cognitive function, reducing oxidative stress, and mitigating Alzheimer-like pathology, highlighting the potential of this medicinal plant as a natural, multifaceted cognitive enhancer.},
}
@article {pmid42425228,
year = {2026},
author = {Avila-Gutierrez, K and de Sauvage, M&#xc1;C and Depret, N and Oudart, M and Thompson, R and Alvear-Perez, R and Poulot-Becq-Giraudon, Y and Kozlowski, E and Monnet, H and Mailly, P and Garcia, V and Jourdren, L and Lucas, A and Bemelmans, A and Hirbec, H and Escartin, C and Cohen-Salmon, M},
title = {Local translation controls early reactive changes in perisynaptic astrocyte processes at pre-symptomatic stages of Alzheimer's disease.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107528},
doi = {10.1016/j.nbd.2026.107528},
pmid = {42425228},
issn = {1095-953X},
abstract = {Early synaptic dysfunction is a hallmark of Alzheimer's disease (AD), yet the astrocytic mechanisms underlying these alterations remain poorly defined. Here, we identify astrocyte perisynaptic processes (PAPs) as subcellular hotspots of early translational dysregulation in AD. Soluble Aβ1-42 rapidly enhanced global and local protein synthesis in primary astrocytes. In 5.5-month-old APP/PS1-dE9 (APP) mice, translating ribosome affinity purification (TRAP) revealed widespread remodeling of the PAP translatome, while whole-astrocyte translation remained largely unchanged. Dysregulated mRNAs were linked to neuroinflammation, synaptic remodeling, and endoplasmic reticulum stress, and alterations emerged prior to amyloid plaque deposition. Among them, Serpina3n encoding α1-antichymotrypsin exhibited increased mRNA abundance in PAPs, uncovering spatially restricted translational control. Mechanistically, early Serpina3n upregulation was partially driven by JAK-STAT3 signaling, with preferential effects in astrocyte processes. These findings provide a conceptual advance by demonstrating that local translation in astrocyte PAPs is an early and compartment-specific mechanism that may contribute to synaptic dysfunction and disease initiation in AD.},
}
@article {pmid42425257,
year = {2026},
author = {Houmam, S and Siodlak, D and Seshadri, M and Hallum, GB and Pezant, NP and Stanford, DR and Salinas-Salinas, C and Thomason, YM and Santín-Márquez, R and Stout, MB and Freeman, WM and Montgomery, CG and Rice, HC},
title = {Cell-specific expression of APP and GABABR1 isoforms in wild-type and the APP NL-G-F mouse model of Alzheimer's disease.},
journal = {Brain research},
volume = {},
number = {},
pages = {150463},
doi = {10.1016/j.brainres.2026.150463},
pmid = {42425257},
issn = {1872-6240},
abstract = {Amyloid precursor protein (APP) is a type I transmembrane protein that undergoes proteolytic processing to generate amyloid-β, the main component of amyloid plaques found in brains with Alzheimer's disease (AD). APP proteolytic processing also generates soluble APP alpha (sAPPα) which modulates synaptic transmission and neurite outgrowth through the γ-aminobutyric acid type B receptor (GABABR). sAPPα specifically binds the 1a isoform of GABABR subunit 1 (R1a) which contains two sushi domains absent in R1b. Here, we define the cell type-specific expression patterns of APP and GABABR1a in the brain and assess their alterations in the APP NL-G-F model of AD. We determined relative RNA levels of R1a and R1b isoforms in oligodendrocytes, microglia, endothelial cells, astrocytes, and neurons in adult mice using two approaches. We developed an isoform-specific RNAseq analysis workflow to probe publicly available datasets. We also isolated these cell types from a single mouse brain and performed RT-qPCR with isoform-specific primers. APP and GABABR1 isoforms were differentially expressed among cell types. APP and GABABR1a expression were highest in oligodendrocytes. In contrast, GABABR1b expression was highest in astrocytes. While microglia expressed relatively low levels of GABABR, they showed the greatest change in GABABR expression in the APP NL-G-F mouse model, with alterations that were both sex- and age-specific. Together, our findings identify candidate cell types in which future studies may investigate the potential role of APP-GABABR signaling in health and AD.},
}
@article {pmid42425281,
year = {2026},
author = {Mierzwa, N and Wężyk, M},
title = {Synaptic Dysfunction as a Major Driver in Alzheimer's Disease: Beyond the Amyloid Paradigm.},
journal = {Neuroscience and biobehavioral reviews},
volume = {},
number = {},
pages = {106858},
doi = {10.1016/j.neubiorev.2026.106858},
pmid = {42425281},
issn = {1873-7528},
abstract = {While β-amyloid (Aβ) peptides have dominated Alzheimer's disease (AD) research for decades, the unexpected failure of several anti-amyloid therapies has underscored critical gaps in our understanding of the early pathogenic mechanisms of AD. This review presents a fundamental re-evaluation of the causal chain in AD pathogenesis: the previously dominant amyloid-centric model may need to be shifted toward synaptic dysfunction coupled with glutamate excitotoxicity and neurometabolic failure as potential major drivers of cognitive decline in AD. We gather emerging evidence demonstrating that neuronal hyperactivity and glutamate excitotoxicity-both potentially independent of amyloid deposition-can contribute to synaptic damage at preclinical stages of AD. We propose that the chronic neuronal burden of metabolic overload, rather than amyloid toxicity alone, may trigger a cascade of synaptic deterioration and neuronal death. This metabolic-energetic framework introduces a new biological economy to neurodegeneration, in which neurons are compromised by unbalanced energy demands that are only later amplified by protein toxicity. By integrating recent findings on glutamate dysregulation with amyloid and tau pathology, we present a multifactorial model that emphasizes the temporal primacy and mechanistic interplay of excitotoxicity in early synaptic dysfunction, rather than treating these pathways as parallel or independent events. This model offers an explanation for why amyloid removal so often fails: intervening at the level of downstream synaptic damage is likely too late. This reframing carries profound therapeutic implications: targeting synaptic health and glutamate homeostasis before the onset of irreversible amyloid-driven damage may yield more effective preventive strategies than current approaches that predominantly focus on amyloid removal. This synapse-focused perspective prioritizes synaptic health and repositions amyloid as one contributing factor within a broader, integrated model of AD.},
}
@article {pmid42425385,
year = {2026},
author = {Thakkar, A and Mote, C and Gadade, A and Dighe, V and Kaur, G and Vora, A},
title = {Longifolene mitigates amyloid beta induced neurotoxicity by acting on PI3K/AKT/NFκB pathway: Comprehensive in vitro, in vivo pharmacokinetics and pharmacodynamic studies for Alzheimer's disease.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {179119},
doi = {10.1016/j.ejphar.2026.179119},
pmid = {42425385},
issn = {1879-0712},
abstract = {Alzheimer's disease (AD) is a multifactorial disease characterized with deposition of Amyloid-β peptide leading to oxidative stress and neuroinflammation. Terpenes are a broad class of natural compounds known to possess anti-oxidant and anti-inflammatory effects. Longifolene (LNF), a major constituent of pine resin is a non -polar sesquiterpene possessing promising anti-oxidant and anti-inflammatory activity. Oxidative stress and neuroinflammation are pathological drivers of AD. The current work is focused on evaluating the neuroprotective potential of LNF using in vitro cell line-based and in vivo animal-based model for AD. Pre-treatment with LNF at 1, 10 and 100 μM displayed significant neuroprotective potential in Aβ1-42 induced neurotoxicity in SH-SY5Y cell-line. Additionally, 0.5 and 1μM of LNF significantly prevented ROS generation, mitochondrial dysfunction and apoptosis in SH-SY5Y cell-line. Pharmacokinetic studies in rats showed that LNF achieved the therapeutic concentrations in brain. Further, in pharmacodynamic studies, 20 days pre-treatment and 30 days post-treatment with LNF at 10, 50 and 100 mg/kg resulted in dose-dependent improvements in behavioral, biochemical and histopathological parameters in Aβ1-42 induced AD in rats. Functional assays demonstrated that LNF brought about significant reduction in levels of AChE, TNF-α and IL-6 levels and elevation in BDNF in the rat brain. Histopathological examination of the cortex and hippocampus showed that LNF at doses of 50 and 100 mg/kg markedly attenuated neuronal swelling and cortical atrophic changes, while preserving the pyramidal layer thickness in the hippocampus. Protein expression studies using western blot analysis showed that LNF displays anti-AD activity by acting on PI3K/AKT/NFκB pathway. These findings highlight LNF as a potential neuroprotective agent for AD intervention.},
}
@article {pmid42425476,
year = {2026},
author = {Qian, Z and Hu, Z and Li, Y and Zuo, D and He, R and Ye, K},
title = {Targeting the pathological tau N368 fragment: A pharmacological perspective on a novel immunotherapy for Alzheimer's disease.},
journal = {Pharmacological research},
volume = {231},
number = {},
pages = {108337},
doi = {10.1016/j.phrs.2026.108337},
pmid = {42425476},
issn = {1096-1186},
abstract = {Alzheimer's disease (AD) is the most prevalent dementia, and while anti-Aβ immunotherapies have recently been approved, their modest clinical benefits underscore an urgent need for strategies targeting tau pathology, which correlates more closely with cognitive decline. Asparagine endopeptidase (AEP) generates a pathological tau fragment by cleaving tau at N368 residue (Tau N368). This fragment drives neurodegeneration through dual mechanisms: it promotes toxic aggregation and directly antagonizes BDNF/TrkB neurotrophic signaling. Clinically, the cerebrospinal fluid (CSF) Tau N368/total-tau ratio has emerged as a promising biomarker that appears to accurately reflects neocortical tau burden and cognitive impairment, though prospective validation is needed. From a pharmacological perspective, a Tau N368-specific monoclonal antibody has demonstrated robust preclinical efficacy in mouse models, substantially reducing tau pathology, restoring neurotrophic signaling, and improving cognitive deficits in two AD mouse models. This review provides a comprehensive pharmacological analysis of the AEP-Tau N368 axis. We examine its molecular mechanisms, critically evaluate its role as a candidate biomarker with potential pharmacodynamic utility, and assess the preclinical proof-of-concept for targeted immunotherapy while acknowledging the need for independent replication and addressing translational challenges. By situating this approach within the broader landscape of failed tau-targeted trials, we discuss remaining opportunities and translational challenges, including brain penetration, patient stratification, and combination strategies that position Tau N368 as a candidate for further pharmacological development in AD and related tauopathies.},
}
@article {pmid42426112,
year = {2026},
author = {Kim, Y and Choudhary, A and Kim, H and Teale, P and McConnell, B and Al Borno, M},
title = {Comparing vibrotactile stimulation to combined visual and auditory stimulation for 40 Hz gamma entrainment.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-60911-1},
pmid = {42426112},
issn = {2045-2322},
abstract = {There is significant interest in combined visual and auditory stimulation to entrain 40 Hz gamma oscillations for the treatment of Alzheimer's disease and other neurological conditions such as stroke and insomnia. In this work, we compared another sensory modality-vibrotactile stimulation delivered with a glove-to visual and auditory stimulation in 15 healthy participants in terms of electroencephalogram (EEG) responses and subjective experience. We found that vibrotactile stimulation from the glove could evoke 40 Hz EEG responses in the central, frontal and, to a lesser extent, occipital cortices. We also observed distinct patterns of functional connectivity between the two stimulation modalities. Participants preferred the vibrotactile stimulation over the visual and auditory stimulation. Our study supports future investigations on vibrotactile stimulation for the treatment of neurological conditions.},
}
@article {pmid42426158,
year = {2026},
author = {Vöglein, J and Levin, J and Stögmann, E and Haass, C and Höglinger, GU and Frölich, L and Jessen, F},
title = {Attitudes of specialist memory-clinic patients with early symptomatic Alzheimer's disease towards lecanemab: results from a multicenter survey in Europe.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {42426158},
issn = {2045-2322},
mesh = {Humans ; *Alzheimer Disease/drug therapy/psychology/genetics ; Female ; Male ; Aged ; Europe ; Surveys and Questionnaires ; Cross-Sectional Studies ; Middle Aged ; Aged, 80 and over ; Memory ; },
abstract = {Lecanemab approval in the European Union (EU) was granted after a delay. This delay resulted in concerns from many stakeholders, but attitudes of patients with early symptomatic Alzheimer's disease receiving specialist memory-clinic care remained insufficiently assessed. Therefore, we evaluated attitudes of specialist memory-clinic patients with early symptomatic Alzheimer's disease towards lecanemab in Europe. In this anonymous, international, multicentre, cross-sectional survey conducted from October 14, 2024 to February 18, 2025, a standardized, expert-developed questionnaire assessed attitudes towards lecanemab treatment and EU approval. Before answering four binary questions, participants received brief explanatory information on expected clinical benefit, amyloid-related imaging abnormalities (ARIA), and the increased ARIA risk associated with APOE ε4 homozygosity. The survey was conducted in specialist memory clinics within the European Alzheimer's Disease Consortium (EADC), the German memory clinic network (DNG), and Austrian memory centers. Available recruitment-flow data were limited to completed questionnaires because the survey was anonymous and distributed locally. 281 patients with early symptomatic Alzheimer's disease completed the survey. Network-level sample sizes were EADC n = 202, DNG n = 60, and Austria n = 19; country-specific sample sizes within the EADC and response rates were not available. Endorsement was high for both individual treatment with lecanemab (81.9%, 95% confidence interval [CI] 76.8-86.2) and general EU approval (91.8%, 95% CI 87.9-94.7). Endorsement remained substantial, but was lower, in the context of APOE ε4 homozygosity (treatment: 61.2%, 95% CI 55.2-66.9; approval: 76.5%, 95% CI 71.1-81.3). Approval-related questions received higher endorsement than treatment-related questions (84% vs. 72%; p < 0.001). Support for approval for APOE ε4 homozygotes declined after regulatory recommendations excluded this group (from 87% to 73%; p = 0.025); this comparison reflects independent respondents completing the anonymous survey before versus after November 14, 2024. Network-level comparisons were descriptive and underpowered for geographic inference. High endorsement within this specialist memory-clinic sample suggests perceived value of access to lecanemab. Greater endorsement for approval than for individual treatment may reflect support for treatment access beyond personal treatment choice, but alternative explanations such as social desirability, acquiescence, misunderstanding, or effects of the survey information cannot be excluded. The findings should not be generalized beyond specialist memory-clinic patients and should be interpreted in view of potential selection and response biases, absent response-rate data, and the brief, non-validated binary questionnaire.},
}
@article {pmid42426263,
year = {2026},
author = {Mondejar-Duran, J and Díaz-Quintana, A and Ganfornina, MD and Sanchez, D},
title = {Apolipoprotein D acts as a chaperone of Aβ peptide delaying its assembly into amyloid aggregates.},
journal = {Cellular and molecular life sciences : CMLS},
volume = {},
number = {},
pages = {},
doi = {10.1007/s00018-026-06339-2},
pmid = {42426263},
issn = {1420-9071},
abstract = {The accumulation of amyloid-β (Aβ) peptides is at the root of Alzheimer's disease (AD), where oligomeric forms of Aβ disrupt brain physiology before any sign of dementia. Intense research has been directed to extrinsic molecules that modulate Aβ aggregation. However, more knowledge is needed about endogenous mechanisms maintaining Aβ homeostasis in a healthy brain. The Lipocalin Apolipoprotein D (ApoD) displays neuroprotective functions, many of which rely on managing lipids in cell membranes or lipoprotein particles. ApoD is upregulated in the aging brain and AD and is present in amyloid-β plaques. However, the functional relationship of ApoD with Aβ peptides aggregation needs to be studied. Using aggregation and ligand binding assays guided by molecular dynamics modeling, in this work we demonstrate that human ApoD is able to interact with Aβ, both in monomeric or aggregated states. Multiple binding sites in ApoD, including its hydrophobic ligand-binding pocket, are demonstrated between ApoD and Aβ by fluorescence titration, and these diverse interactions delay the aggregation process and reduce the number of large aggregates. Modeling the dynamics of interactions in sub-stoichiometric ApoD/Aβ ratios predicts that ApoD decreases the probability of switching to the β-stranded structure required for Aβ oligomerization. Our findings reveal Aβ as a novel ligand category for ApoD and therefore place this Lipocalin as an important element of the endogenous control of Aβ. ApoD is able to chaperon Aβ monomers from their origin in cellular membranes, preventing their progression towards amyloid plaques.},
}
@article {pmid42426288,
year = {2026},
author = {Medina, F and Bellizzi, A},
title = {The emerging role of circular RNAs in neurodegenerative diseases and viral infections.},
journal = {Journal of neurovirology},
volume = {32},
number = {4},
pages = {},
pmid = {42426288},
issn = {1538-2443},
support = {R21 AG092247/GF/NIH HHS/United States ; },
mesh = {Humans ; *RNA, Circular/genetics/metabolism ; *Virus Diseases/genetics/metabolism/virology/pathology/immunology ; *Neurodegenerative Diseases/genetics/virology/metabolism ; MicroRNAs/genetics/metabolism ; RNA, Competitive Endogenous ; Animals ; *Alzheimer Disease/genetics/virology/pathology/metabolism/immunology ; Virus Replication/genetics ; *Parkinson Disease/genetics/virology/pathology/metabolism/immunology ; Brain/virology/metabolism/pathology ; },
abstract = {Circular RNAs (circRNAs) represent a class of highly stable, covalently closed RNA molecules increasingly recognized as important regulators of brain aging and neurodegenerative disease. Growing evidence also implies circRNAs in viral infection, suggesting a potential intersection between viral neuropathogenesis and neurodegeneration. However, no studies have yet directly integrated circRNAs, neurotropic viral infections, and neurodegenerative disorders within a single mechanistic framework. To date, specific circRNAs have been linked to the progression of Alzheimer's disease and Parkinson's disease, where they regulate central pathological processes including amyloid-β clearance, neuroinflammation, synaptic plasticity, neuronal apoptosis, and oxidative stress. Moreover, it has been established that both host cells and viruses produce circRNAs during infection. Virus-derived circRNAs can enhance viral replication, promote immune evasion, and support latency. In contrast, host circRNAs contribute to antiviral defense by acting as microRNA sponges, interacting with viral proteins, or encoding peptides with antiviral activity, mechanisms particularly explored in viral oncogenesis. In this review, we will evaluate the most updated research evidence on the role of circRNAs in major neurodegenerative diseases and neurotropic viral infections. Considering the growing concern regarding the long-term neurological consequences of viral infections, including chronic neuroinflammation, viral reactivation, and post-viral syndromes, dysregulated circRNAs may represent a mechanistic link between viral infection and associated neurodegenerative processes. Finally, we will discuss future directions for identifying circRNAs-based biomarkers and developing circRNAs-targeted therapeutic strategies for age-related and virus-associated neurological disorders.},
}
@article {pmid42426293,
year = {2026},
author = {Suhadolc, A and Horvat, S and Kos, J and Pišlar, A},
title = {Glial Cysteine Cathepsins: From Homeostasis to Neurodegeneration.},
journal = {Cellular and molecular neurobiology},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10571-026-01776-w},
pmid = {42426293},
issn = {1573-6830},
support = {P4-0127//The Slovenian Research and Innovation Agency/ ; },
abstract = {Glial cells, namely microglia, astrocytes, and oligodendrocytes, play crucial roles in maintaining homeostasis in the central nervous system and orchestrating responses to injury, infection, and disease. Among the molecular regulators of glial function, cysteine cathepsins have emerged as key modulators of both physiological and pathological processes. These lysosomal peptidases are traditionally known for their housekeeping roles in protein degradation; however, accumulating evidence highlights their broader involvement in antigen presentation, microglial and astrocyte reactivity, inflammatory signalling, apoptosis, and myelination. Under normal conditions, cysteine cathepsins support essential functions in the central nervous system, including immune surveillance and tissue remodelling. Conversely, their dysregulation, characterized by overexpression, increased enzymatic activity, or mislocalization, can promote neuroinflammation and neurodegeneration, contributing to the pathogenesis of disorders such as Alzheimer's disease and multiple sclerosis. This review provides a comprehensive synthesis specifically focused on the diverse roles of cysteine cathepsins across major glial cell types, systematically summarizing current knowledge in microglia, astrocytes, and oligodendrocytes. We emphasize their cell type-specific, context-dependent, protective, and deleterious functions. Furthermore, we discuss mechanistic links between cysteine cathepsin activity and neurodegenerative processes and evaluate the therapeutic potential and current limitations of selectively targeting glial cysteine cathepsins. A deeper understanding of the context-dependent dual roles of these enzymes in brain physiology and pathology is critical for designing targeted interventions that could mitigate neuroinflammation and neurodegeneration.},
}
@article {pmid42426326,
year = {2026},
author = {Wu, Q and Fan, D and Ren, J and Xing, Y and Chen, Z and Jin, H and Lu, Y and Wang, X and Zheng, H},
title = {SUMOylation in Mitochondrial Quality Control: Mechanisms and Implications for Neurodegenerative Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42426326},
issn = {1559-1182},
mesh = {*Sumoylation/physiology ; *Neurodegenerative Diseases/metabolism/pathology ; Humans ; *Mitochondria/metabolism/pathology ; Animals ; Mitophagy ; },
abstract = {Mitochondria, as the primary energy-generating organelles in neurons, play a pivotal role in regulating cellular metabolism. Given the post-mitotic nature and long lifespan of neurons, they are particularly vulnerable to the cumulative burden of mitochondrial damage. In response to various physiological and stress signals, a sophisticated mitochondrial quality control (MQC) system has evolved, which encompasses mitochondrial biogenesis, dynamics (fission and fusion), and mitophagy. This coordinated network acts as a critical surveillance mechanism to eliminate damaged components and maintain a healthy mitochondrial pool. The small ubiquitin-like modifier (SUMO) pathway, involving reversible SUMOylation and deSUMOylation, has emerged as a key regulator of MQC by directly modifying its core components. Dysregulation of the SUMO pathway disrupts mitochondrial homeostasis, and the resulting mitochondrial dysfunction is increasingly recognized as a central pathogenic mechanism in neurodegenerative diseases. This review systematically examines the role of the SUMO pathway in regulating MQC and its implications in the pathogenesis of Alzheimer's disease, Parkinson's disease, and Huntington's disease. Finally, we discuss the therapeutic potential and translational challenges of targeting the SUMO pathway for the treatment of neurodegenerative diseases.},
}
@article {pmid42426404,
year = {2026},
author = {Wang, Z and Zou, Q and Lin, S and Li, S and Cui, Y and Zhang, D and Han, C and Li, Y and Li, J and Zhao, Y and Gao, R and Song, J and Yuan, Z},
title = {NicheTrans: spatial-aware cross-omics translation.},
journal = {Nature methods},
volume = {},
number = {},
pages = {},
pmid = {42426404},
issn = {1548-7105},
abstract = {While spatial multiomics offers insights into complex biological systems, its widespread adoption is hindered by technical challenges, specialized requirements and limited accessibility. Here we present NicheTrans, a spatially aware cross-omics translation method and a flexible Transformer-based multimodal framework. Unlike existing single-cell translation methods, NicheTrans incorporates both cellular microenvironment information and multimodal data. We validated the advantage of NicheTrans across diverse biological cases. Through NicheTrans, we uncovered spatial multiomics domains that were not detectable through single-omics analysis alone. Model interpretation revealed key molecular relationships, including gene programs associated with dopamine metabolism and amyloid β-associated cell states. In addition, using translated protein markers as spatial landmarks, we quantified the spatial organization of key glial cell subtypes in the Alzheimer's disease brain. NicheTrans represents a powerful tool for generating comprehensive spatial multiomics insights from more accessible single-omics measurements, making multiomics analysis more feasible for the broader research community.},
}
@article {pmid42426435,
year = {2026},
author = {Singh, D and Panda, S and Singal, CMS and Pandey, HS and Seth, P and Sharma, SK},
title = {Safranal protects neurons against amyloid beta-induced toxicity.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42426435},
issn = {1568-5608},
abstract = {Amyloid beta is critically involved in the initiation and progression of Alzheimer's disease (AD). This peptide is neurotoxic. It can cause cell death by acting on neurons. It can also cause neuronal cell death by acting on glial cells, resulting in the production of toxic and inflammatory molecules, which eventually cause neurotoxicity. In this study, we show that safranal, a compound present in the spice saffron, reduces reactive oxygen species (ROS) and nitric oxide (NO) levels from hippocampal neuronal cells, HT22, treated with oligomeric amyloid beta. It reduces alteration in mitochondrial membrane potential induced by amyloid beta. Safranal shows protective effects against amyloid beta-induced toxicity not only to HT22 cells but also to human neurons. Furthermore, we show that safranal reduces ROS, NO and inflammatory molecule levels from amyloid beta-treated astrocytic cells. Importantly, it provides protection to human neurons from the toxic effects of conditioned medium derived from human astrocytes treated with amyloid beta. Thus, safranal protects neurons against amyloid beta-induced direct and indirect toxicity, suggesting that it could be beneficial in the fight against AD.},
}
@article {pmid42426493,
year = {2026},
author = {Seemikeri, CC and Mailankody, P and Rajeswarie, RT and Chanda, B and Mahale, RR and Padmanabha, H},
title = {Peripheral neuropathy as a presenting feature of familial early onset Alzheimer's disease: a rare clinical association.},
journal = {Acta neurologica Belgica},
volume = {},
number = {},
pages = {},
pmid = {42426493},
issn = {2240-2993},
abstract = {We describe a patient with genetically confirmed familial early-onset Alzheimer's disease in whom sensory peripheral neuropathy preceded cognitive decline by almost a decade. A 40- year- old man presented with clinical and electrophysiological features of sensory neuropathy, and 9 years later developed memory disturbances. Genetic testing revealed a heterozygous PSEN1 c.349 C > T (p. Pro117Ser) mutation in exon 5. To the best of our knowledge, peripheral neuropathy as an initial manifestation of familial early-onset Alzheimer's disease has never been reported before and could be a possible manifestation of the underlying degenerative process. With this report, we highlight the rarity of this association and underscore the importance of a comprehensive clinical and electrophysiological evaluation in patients with familial early-onset Alzheimer's disease who present with sensory symptoms, gait disturbances, skin or trophic changes, or other clinical features suggestive of peripheral neuropathy.},
}
@article {pmid42426644,
year = {2026},
author = {Kasuga, K and Shimizu, S and Kimura, N and Kasanuki, K and Sakurai, S and Serisawa, S and Masuda, T and Ataka, T and Tadokoro, M and Hashimoto, C and Shiina, H and Nakamura, Y},
title = {Diagnostic delay in early-onset Alzheimer's disease in Japan: a retrospective study.},
journal = {BMC neurology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12883-026-05121-y},
pmid = {42426644},
issn = {1471-2377},
support = {Not applicable//Eisai/ ; Not applicable//Eisai/ ; Not applicable//Eisai/ ; Not applicable//Eisai/ ; Not applicable//Eisai/ ; Not applicable//Eisai/ ; Not applicable//Eisai/ ; Not applicable//Eisai/ ; Not applicable//Eisai/ ; Not applicable//Eisai/ ; },
abstract = {BACKGROUND: Diagnosing early-onset Alzheimer's disease (EOAD) has unique challenges compared with late-onset AD (LOAD), but the diagnostic journey in Japan is unknown. The objectives of this study were to evaluate the time from symptom onset to diagnosis of EOAD compared with LOAD in Japan, and to investigate factors affecting the time to diagnosis.<br><br>METHODS: Patients aged between 18 and 79 years who were diagnosed between April 2011 and March 2023 at participating facilities across Japan with "probable AD dementia", "mild cognitive impairment due to AD", or an equivalent diagnosis were included. Patients were categorized by age of onset as EOAD (<&#x2009;65 years) or LOAD (&#x2265;&#x2009;65 years). Eligible EOAD and time-matched LOAD patients were enrolled. This retrospective observational study was registered in the UMIN Clinical Trials Registry on 28 November 2023 (UMIN000052928).<br><br>RESULTS: The mean (standard deviation) time from symptom onset to diagnosis (primary endpoint) was 138.3 (91.0) weeks for EOAD (n&#x2009;=&#x2009;79) and 99.6 (81.5) weeks for LOAD (n&#x2009;=&#x2009;59) (p&#x2009;=&#x2009;0.011). Time from symptom onset to first medical visit was 89.0 (74.2) weeks (EOAD) and 57.6 (71.5) weeks (LOAD) (p&#x2009;=&#x2009;0.024). No difference between EOAD and LOAD was found in the time after the first medical visit to diagnosis.<br><br>CONCLUSIONS: In Japan, patients with EOAD experienced a longer time to diagnosis than patients with LOAD. Symptoms, regional differences, and access to medical care may have influenced the time to diagnosis. Therefore, it is important to raise awareness of the disease and the need for early consultation, even among non-elderly individuals.<br><br>TRIAL REGISTRATION: UMIN000052928.},
}
@article {pmid42426853,
year = {2026},
author = {Zhang, Q and Schultz, JL and Simmering, JE and Kirkpatrick, BQ and Weber, MA and Skuodas, S and Hicks, T and Pierce, G and Laughlin, M and George, B and Bertolli, AX and Larson, T and Thangavel, R and Oya, M and Meyerholz, DK and Aldridge, G and Fassler, J and Narayanan, NS},
title = {Glycolysis-enhancing α1-adrenergic antagonists have therapeutic potential in Alzheimer's disease.},
journal = {Alzheimer's research &amp; therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02135-z},
pmid = {42426853},
issn = {1758-9193},
support = {R03 AG078787/NH/NIH HHS/United States ; R01 NS129711/NH/NIH HHS/United States ; R01 NS120987/NH/NIH HHS/United States ; Cannon-Williams Faculty Fellowship//University of Iowa/ ; },
abstract = {BACKGROUND: Terazosin (TZ) is widely prescribed for hypertension and benign prostatic hyperplasia. Recent studies suggest that TZ enhances glycolysis and may protect against neurodegenerative diseases.<br><br>METHODS: We tested the hypothesis that TZ is neuroprotective in Alzheimer's disease (AD) in a yeast model, a mouse model, and two human datasets.<br><br>RESULTS: We report four main results. First, TZ increased ATP levels in a Saccharomyces cerevisiae mutant with impaired metabolism, and reduced Amyloid-beta42 (A&#x3b2;42) aggregation. Second, in 5xFAD mice, TZ attenuated amyloid pathology and rescued cognitive impairments in spatial memory and interval timing. Third, in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, AD patients taking glycolysis-enhancing drugs had a slower progression of both cognitive dysfunction and metabolic neuroimaging biomarkers (18&#xa0;F-fluorodeoxyglucose positron emission tomography (FDG-PET)). Finally, in the Merative Marketscan dataset, patients taking glycolysis-enhancing drugs had lower risks of developing AD.<br><br>CONCLUSION: These data provide preliminary evidence that glycolysis-enhancing drugs have therapeutic potential in AD.},
}
@article {pmid42426901,
year = {2026},
author = {Tang, Q and Xu, M and Xiao, X and Cao, J and Yang, W},
title = {Emerging mechanisms and targeted therapy of PANoptosis in neurological diseases.},
journal = {Reviews in the neurosciences},
volume = {},
number = {},
pages = {},
pmid = {42426901},
issn = {2191-0200},
abstract = {PANoptosis is a distinct inflammatory and lytic cell death pathway, orchestrated by the PANoptosome and executed through caspases and receptor-interacting protein kinases (RIPKs). Unlike other forms of programmed cell death, PANoptosis integrates components from multiple death signaling cascades. To date, several PANoptosome complexes - such as those nucleated by ZBP1, AIM2, RIPK1, and NLRP12 - have been characterized. These supramolecular assemblies form via domain-domain interactions upon detection of pathogen-associated or damage-associated signals. By eliminating infected and compromised cells, this coordinated pathway helps maintain tissue homeostasis, while its synchronized release of inflammatory cytokines and damage-associated molecular patterns (DAMPs) enhances innate immune responses, resulting in more effective pathogen clearance compared to any single cell death mechanism. Growing evidence underscores the relevance of PANoptosis across a spectrum of pathological conditions, including neurological disorders, infections, inflammatory diseases, cancer, and homeostatic imbalances, often mediated by PANoptosis-associated proteins. In neurological contexts - such as stroke, Parkinson's disease, Alzheimer's disease, and traumatic brain injury - PANoptosis activation correlates with disease progression and prognosis, highlighting its potential as a therapeutic target. In this review, we systematically outline the molecular foundations of PANoptosis, examine its role in neurological diseases, and summarize current pharmacological and methodological strategies for its modulation. A deeper understanding of PANoptosis may inform the identification of novel therapeutic targets for neurological disorders.},
}
@article {pmid42426931,
year = {2026},
author = {Doser, RL and LaRocca, TJ},
title = {Transcriptomic Evidence of Mitochondrial Double-Stranded RNA Accumulation in Brain Aging and Alzheimer's Disease.},
journal = {Aging cell},
volume = {25},
number = {7},
pages = {e70616},
doi = {10.1111/acel.70616},
pmid = {42426931},
issn = {1474-9726},
support = {F32AG087636/AG/NIA NIH HHS/United States ; R01AG078859/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/genetics/pathology/metabolism ; *Brain/metabolism/pathology ; *RNA, Double-Stranded/metabolism/genetics ; *Aging/genetics ; *Transcriptome/genetics ; *Mitochondria/metabolism/genetics ; *RNA, Mitochondrial/metabolism/genetics ; Female ; },
abstract = {Mitochondria and inflammation are tightly linked in aging and Alzheimer's disease (AD), and recent evidence implicates mitochondrial double-stranded RNA (mt-dsRNA) as a potential trigger of inflammation. We examined mt-dsRNA accumulation and dsRNA signaling in brain aging and AD using complementary human brain tissue and in vitro transcriptomic datasets by quantifying mitochondrial transcripts, dsRNA editing, and related gene expression patterns. We found that mt-dsRNA signatures increased after midlife and coincided with reduced expression of mitochondrial RNA processing and translation machinery, along with increased expression of dsRNA antiviral signaling proteins, consistent with cytoplasmic mt-dsRNA-driven inflammation. In AD brains, mt-dsRNA signatures were further increased and correlated with cognitive impairment, neuropathological severity, and AD risk genotypes. Genes associated with these measures reflected altered ubiquitin-dependent regulation of antiviral signaling, potentially indicating altered sensitivity to mt-dsRNA. Together, these findings highlight mitochondrial RNA homeostasis as an unrecognized contributor to age- and AD-related neurodegeneration and identify mt-dsRNA as a potential driver of chronic inflammation in the brain.},
}
@article {pmid42427159,
year = {2026},
author = {Bevins, EA and Léger, GC and Herman, MA and Ringman, JM and Roy, S and Shtrahman, M and Pa, J and Feldman, HH},
title = {Safety considerations of gene-based therapies for Alzheimer's disease.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71515},
doi = {10.1002/alz.71515},
pmid = {42427159},
issn = {1552-5279},
support = {//Epstein Family Alzheimer's Research Collaboration (EFARC)/ ; },
mesh = {Humans ; *Alzheimer Disease/therapy/genetics ; *Genetic Therapy/adverse effects/methods ; Gene Therapy Agents ; Animals ; Dependovirus/genetics ; Oligonucleotides, Antisense/therapeutic use ; },
abstract = {Gene-based therapies show increasing promise for the treatment of neurologic disease. In 2016, nusinersen, an RNA-based therapy, was approved for children with spinal muscular atrophy (SMA). Over 200 clinical trials have utilized gene therapy approaches for a host of neurodegenerative and neuromuscular disorders, including Alzheimer's disease (AD).[1] Delivering gene-based therapies to the central nervous system (CNS) has raised safety concerns. As clinical trials utilizing gene therapy paradigms are undertaken and as approved therapies translate into clinics, a better understanding of safety issues and monitoring parameters is needed. We describe current therapeutic approaches for AD using gene-based therapies such as adeno-associated virus gene therapy and RNA interference by antisense oligonucleotides (ASOs) and undertake a review of medical safety considerations for existing AD gene therapy trials. We identify challenges in analyzing medical safety data currently available and provide guidelines for making this information more accessible and interpretable for the future.},
}
@article {pmid42427161,
year = {2026},
author = {Yang, Y and Lorenz, A and Sathe, A and Schilling, KG and Gaynor, LS and Choi, SE and Lee, ML and Scollard, P and Trittschuh, EH and Mukherjee, S and Mez, J and Dumitrescu, LC and Landman, BA and Crane, PK and Cuccaro, ML and Hohman, TJ and Archer, DB},
title = {Genetically linked brain imaging markers of memory decline in aging and Alzheimer's disease.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71663},
doi = {10.1002/alz.71663},
pmid = {42427161},
issn = {1552-5279},
support = {U24 AG074855/AG/NIA NIH HHS/United States ; U01 AG068057/AG/NIA NIH HHS/United States ; R01 AG059716/AG/NIA NIH HHS/United States ; K01-EB032898/AG/NIA NIH HHS/United States ; R01-EB017230/AG/NIA NIH HHS/United States ; K01-AG073584/AG/NIA NIH HHS/United States ; 75N95D22P00141/AG/NIA NIH HHS/United States ; R01-AG059716/AG/NIA NIH HHS/United States ; UL1-TR000445/AG/NIA NIH HHS/United States ; UL1-TR002243/AG/NIA NIH HHS/United States ; S10-OD023680//Vanderbilt Clinical Translational Science Award/ ; //Vanderbilt's High-Performance Computer Cluster for Biomedical Research/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/diagnostic imaging ; *Aging/genetics ; Female ; Genome-Wide Association Study ; Male ; *Brain/diagnostic imaging/pathology ; Aged ; *Memory Disorders/genetics/diagnostic imaging ; Aged, 80 and over ; Middle Aged ; Magnetic Resonance Imaging ; Apolipoproteins E/genetics ; Neuroimaging ; Memory ; },
abstract = {INTRODUCTION: Memory is a strong endophenotype for Alzheimer's disease (AD) but is typically detectable only after substantial brain change. Genetically linking late-life memory with mid-life brain traits may identify early markers of AD-related cognitive decline.<br><br>METHODS: We leveraged GeNetic cOVariance Analyzer (GNOVA) to estimate genetic covariance between genome-wide association studies (GWASs) of memory performance (MEM) and decline (memslopes) and 3935 UK Biobank (UKB) imaging-derived phenotypes (IDPs) across diffusion, structural, and functional modalities, stratifying by cognitive status and apolipoprotein E (APOE) inclusion. Memory GWASs included 24,216 non-Hispanic White older adults (mean&#xa0;=&#xa0;74.46 years); IDP GWASs included 33,224 European-ancestry mid-life participants (45.1 to 81.8 years, mean&#xa0;=&#xa0;64.28).<br><br>RESULTS: Diffusion and structural IDPs in medial temporal and frontal regions showed the strongest genetic covariance with memory, with additional shared genetic architecture in default mode network functional connectivity.<br><br>DISCUSSION: Mid-life brain traits genetically linked to late-life memory map to AD-vulnerable regions, suggesting biologically relevant risk pathways and potential drug targets for cognitive decline.},
}
@article {pmid42427263,
year = {2026},
author = {Raza, AR and Tariq, S and Gondal, HY and Chotana, GA and Rehman, MFU and Akhter, S},
title = {Design, Synthesis, and Evaluation of Halogenated Indoles Amines as Acetylcholinesterase Inhibitors: Integrated In-Vitro and In-Silico Approaches.},
journal = {Chemistry &amp; biodiversity},
volume = {23},
number = {7},
pages = {e03327},
doi = {10.1002/cbdv.202503327},
pmid = {42427263},
issn = {1612-1880},
support = {HEC-20-3873//Higher Education Commission/ ; },
mesh = {*Cholinesterase Inhibitors/chemical synthesis/chemistry/pharmacology ; *Acetylcholinesterase/metabolism ; *Indoles/chemistry/pharmacology/chemical synthesis ; Structure-Activity Relationship ; *Drug Design ; Molecular Docking Simulation ; *Amines/chemistry/pharmacology/chemical synthesis ; Molecular Dynamics Simulation ; Humans ; Halogenation ; Molecular Structure ; Animals ; },
abstract = {Alzheimer's disease is a neurodegenerative disease with limited therapeutic options and is most prevalent in the elderly. According to the cholinergic hypothesis, disease progression can be mitigated by inhibiting acetylcholinesterase (AChE). Herein, a series of substituted indole amines 19-42 was designed, synthesized via a Chiron-guided approach to generate structurally diverse 2,3-diphenyl-substituted indole derivatives, and characterized by UV-vis, FT-IR, NMR, and MS. In silico studies, such as molecular docking, molecular dynamics simulations, and ADMET analyses, were performed to evaluate binding interactions, stability, and drug-likeness, followed by in vitro cholinesterase inhibition assays. The compounds exhibited moderate inhibitory activity, with IC50 values ranging from 4.28 to 12.70 µM. Among them, compound 25 showed the highest activity (IC50 = 4.28 µM), comparable to galantamine (IC50 = 4.71 µM). Docking studies revealed strong binding affinities for halogenated derivatives, particularly compound 27 (-11.93 kcal/mol), while MD simulations confirmed a stable protein-ligand complex. Structure-activity relationships indicated that phenyl and halogen substitution patterns influence binding and activity; however, biological potency did not strictly correlate with docking scores. ADMET analysis indicated several limitations, including poor solubility and limited BBB permeability, suggesting that these compounds should be considered preliminary lead scaffolds for further optimization.},
}
@article {pmid42427279,
year = {2026},
author = {Mori, F and D'Antonio, F and Zazzaro, G and Conti, D and Mitolo, M and Cagnin, A and Venneri, A},
title = {Neuropsychological Tests for Detecting Prodromal DLB: A Systematic Review.},
journal = {European journal of neurology},
volume = {33},
number = {7},
pages = {e70681},
doi = {10.1111/ene.70681},
pmid = {42427279},
issn = {1468-1331},
support = {PE0000006//European Union-NextGenerationEU/ ; },
mesh = {Humans ; *Prodromal Symptoms ; *Neuropsychological Tests ; *Lewy Body Disease/diagnosis/psychology ; *Cognitive Dysfunction/diagnosis ; },
abstract = {BACKGROUND: The prodromal phase of Dementia with Lewy bodies (DLB) remains unexplored and poorly defined. This systematic review scrutinised studies on the earliest cognitive DLB deficits, focusing on the most useful neuropsychological tests.<br><br>METHODS: From an initial pool of 2307 articles, 37 articles met inclusion criteria including either a prodromal DLB population or DLB cohorts comprehensive of individuals in prodromal or Mild Cognitive Impairment (MCI) due to Lewy Bodies pathology. These studies included comparisons with healthy controls, MCI due to Alzheimer's Disease (MCI-AD), or other aetiologies, and patients with established dementia.<br><br>RESULTS: Mild impairments were found in attention, executive functions, visual perception, and working memory in prodromal DLB patients. Prodromal DLB exhibited worse performance in memory and language than healthy controls, while showing better memory but worse performance in visual perception, attention, and executive tasks than MCI-AD. Comparisons in some articles with MCI of other aetiologies confirmed the distinctiveness for prodromal DLB of this pattern of impairment. The most used tests to detect prodromal DLB included the Frontal Assessment Battery (FAB), Digit Symbol Substitution Test (DSST), Stroop test, AX continuous performance test (AX-CPT), digit span backward, Rey-Osterrieth Complex Figure copy, pareidolia test, and Visual Object and Space Perception battery (VOSP).<br><br>CONCLUSIONS: Prodromal DLB can be detected using test batteries focused on specific cognitive domains and facilitating early diagnosis. It is possible to standardise a targeted test battery centred on specific visuoperceptual and attention domains for early detection of subtle cognitive decline due to Lewy body pathology.},
}
@article {pmid42427416,
year = {2026},
author = {Cvek, B},
title = {Comment on "Disulfiram as an anti-inflammatory agent: mechanisms, nano-delivery strategies, and applications in non-oncologic diseases" by Q. Jiang, M. Jiang, Y. Lv, X. Zhang, S. Wang and J. Zhao, RSC Adv., 2025, 15, 36344.},
journal = {RSC advances},
volume = {},
number = {},
pages = {},
pmid = {42427416},
issn = {2046-2069},
abstract = {The referenced article reviews the purported anti-inflammatory properties of disulfiram, an anti-alcohol drug also known as Antabuse. However, the anti-inflammatory properties of disulfiram should be considered alongside a wealth of scientific research demonstrating its potential to treat various conditions, including cancers, Alzheimer's disease, sepsis, tuberculosis, blindness and heart conditions. I argue that almost all these results are unreliable using basic chemical knowledge. Most importantly, disulfiram has never been shown to be an active molecule in vivo. The authors of the referenced article did not address this fact at all. Testing disulfiram in vitro yields misleading and dangerous pseudoscientific "results", suggesting that it could be a potential treatment for an ever-growing list of diseases.},
}
@article {pmid42427517,
year = {2026},
author = {Chen, Y and Zhang, S},
title = {AART enables fast and accurate cross-platform proteomic translation.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.29.735313},
pmid = {42427517},
issn = {2692-8205},
abstract = {Plasma proteomic profiling has been widely used for biomarker discovery, disease prediction and diagnosis, and patient stratification. However, technical differences across assay platforms often result in low-to-moderate agreement, limiting study reproducibility, data integration, and model transferability. Here we present AART, a cross-platform proteomic translation framework that integrates matched-protein ridge regression with proteome-wide residual learning. We benchmarked AART spanning three independent cohorts profiled using three major platforms, including Olink, SomaScan, and mass spectrometry. Across all six translation directions, AART achieved the best performance compared with baseline methods for both overlapping and non-overlapping protein translations, with a relative improvement of 92.0% on average over direct mapping and by up to 31.6% over cpiVAE, the strongest baseline. Proteins that were accurately translated and improved by AART were enriched for extracellular, vesicle-associated, and tissue-restricted plasma biology. In downstream applications, AART improved the reproducibility of proteomic association analyses relative to direct cross-platform comparison by 75.5% for type 2 diabetes and 370.6% for Alzheimer's disease. AART-enabled cohort integration enhanced diagnostic accuracy for amyotrophic lateral sclerosis by 92.6% compared with non-integration analysis. AART was overall one to three orders of magnitude faster than cpiVAE, facilitating biobank-scale applications. Together, these results establish AART as a fast, accurate, and scalable framework for cross-platform proteomic translation, enabling more reproducible, transferable, and integrated proteomic research.},
}
@article {pmid42427537,
year = {2026},
author = {Ngo, JC and Xu, Y and Olah, M and Sher, F},
title = {Dense CRISPR Mapping of the WAVE Complex Identifies Pharmacological Modulators of AD-Linked Myeloid Migration.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.30.735672},
pmid = {42427537},
issn = {2692-8205},
abstract = {Although genetic risk for Alzheimer's disease (AD) strongly converges on microglial pathways, the druggable functional protein regions that control disease-relevant microglial behaviors remain largely unknown. Here, we applied dense CRISPR-Cas9 mutagenesis and CRISPRtile-based functional mapping to the WAVE regulatory complex (WRC), a central regulator of actin remodeling and cell migration. In a pooled CCL2-directed migration assay in human THP-1 myeloid cells, perturbation of NCKAP1L , CYFIP1 , and BRK1 impaired migration and revealed divergent effects among WRC paralogs. Residue-level analysis mapped discrete migration-associated functional regions within CYFIP1 and NCKAP1L, including a CYFIP1 regulatory hotspot and a prioritized NCKAP1L region nominated for pharmacological targeting. Human single-nucleus datasets identified NCKAP1L as a microglia-enriched WRC component expressed across diverse microglial states. Machine-learning-guided compound prediction nominated Montelukast sodium and Piperacetazine, which we experimentally validated as negative and positive modulators of chemokine-directed migration, respectively. These findings establish WRC-dependent migration as a pharmacologically tunable myeloid process relevant to AD.},
}
@article {pmid42427539,
year = {2026},
author = {Fuchs, U and Schröder, S and Pena, T and Krüger, DM and Burkhardt, S and Schütz, AL and Hempel, N and Gisa, V and Taghavi, T and Cortes, J and Gertig, M and Delalle, I and Sananbenesi, F and Fischer, A},
title = {Loss of the lncRNA SOX1-OT promotes p53-dependent cell-cycle arrest in astrocytes.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.03.736275},
pmid = {42427539},
issn = {2692-8205},
abstract = {Long non-coding RNAs (lncRNAs) are increasingly recognized as regulators of brain cell function, but their roles in astrocyte biology and neurodegeneration remain poorly understood. Here, we identify Sox1ot/SOX1-OT as a conserved, brain-enriched lncRNA that is downregulated in Alzheimer's disease and in reactive astrocyte states. Antisense oligonucleotide-mediated depletion of Sox1ot in astrocytes revealed a transcriptional program marked by activation of p53 target genes selectively associated with cell-cycle inhibitory pathways. Consistent with this, Sox1ot depletion enhanced p53 occupancy at target promoters such as Cdkn1a , increased Cdkn1a expression and levels of its protein product p21, and thereby induced G1 arrest and reduced astrocyte proliferation. In contrast, other canonical p53 outputs, including apoptosis and senescence, were not affected, indicating that Sox1ot selectively modulates distinct branches of p53 signaling. Notably, loss of Sox1ot/SOX1-OT was accompanied by impaired glutamate uptake, reduced lactate secretion, and altered astrocyte support functions, suggesting that these deficits arise as downstream consequences of the p53-dependent transcriptional shift rather than direct primary effects of Sox1ot loss. Together, these findings identify SOX1-OT as an astrocyte-enriched regulatory layer that constrains a p53-dependent cell-cycle program and highlight its role in shaping astrocyte state transitions in Alzheimer's disease.},
}
@article {pmid42427577,
year = {2026},
author = {Sheets, DEG and Ruff, DA and Srinath, R and Allen, KS and Morrison, JH and Cohen, MR},
title = {Progressive loss of independence in neuronal representations predicts cognitive decline.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.28.734833},
pmid = {42427577},
issn = {2692-8205},
abstract = {Intelligent behavior depends on the brain's ability to represent multiple features of the environment simultaneously while keeping those representations independent [1,2] . Patients with Alzheimer's disease often mix up objects, people, and events [3-7] , raising the possibility that disease mixes up the way that information is represented in the brain. Here we show that the independence of visual representations progressively breaks down during early stages of disease progression in a rhesus macaque model of Alzheimer's disease and related dementias [8-10] . In visual area V4, representations of different visual features become progressively less independent, such that the representation of one feature is increasingly influenced by the value of another. We term this loss of independence neuronal feature confusion. This neuronal change predicts a specific behavioral consequence: because feature representations become less independent, preferences associated with one visual feature increasingly influence visually guided choices associated with other, independent features. Using an analogous image-selection task, we found the same behavioral signature in people with mild cognitive impairment, distinguishing them from age-matched controls. These results identify a specific and measurable alteration in neuronal population representations that predicts a behavioral change observed across species. More broadly, these findings demonstrate that neuronal population representations can guide the development of sensitive, non-invasive behavioral methods for early detection of functional changes associated with Alzheimer's disease.},
}
@article {pmid42427581,
year = {2026},
author = {Denos, A and Jones, B and Moran, N and Smith, E and Brown, K and Earls, N and Burlette, R and Garrard, C and Clark, E and Coleman, E and Elison, J and Wells, J and Matute, J and Brown, J and Sorensen, M and Poulson, M and Paymard, N and Nielsen, C and Tolley, D and Vickers, E and Daouahi, W and Price, JC},
title = {Ontological Analysis of Brain Proteostasis Highlights the Sex-Dependent Trajectory of ApoE Isoform-Specific Regulation.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.29.735293},
pmid = {42427581},
issn = {2692-8205},
abstract = {Apolipoprotein E (ApoE) is the strongest genetic predictor of Alzheimers disease (AD) risk, with ApoE4 increasing and ApoE2 decreasing risk relative to ApoE3. Using a global LC-MS proteomic approach, we integrated protein abundance and kinetics in Human-APOE knock-in mice for young (3-month) and aged (18-month) cohorts to quantify the changes in steady-state proteostasis. By mapping 6,052 identified proteins and 3,986 associated turnover rates into ontological groups, we observed that vesicle trafficking and mitochondrial dysregulation occur as early as 3 months in ApoE4 mice accompanied by hyperactive metabolism that eventually reduces with age. In contrast, young and old ApoE2 mice retain similar signatures to ApoE3 mice in metabolic, mitochondrial, cellular regulation, and membrane trafficking ontologies. We found that females had more isoform-induced ontological changes relative to ApoE3, providing insight into sex-dependent vulnerabilities. Our global proteomic approach for ApoE proteostasis crucially unifies independent literature observations while providing turnover kinetics to uncover the underlying mechanism behind abundance changes. Data are available via ProteomeXchange with identifier PXD079261.},
}
@article {pmid42427583,
year = {2026},
author = {Plaska, CR and Jacobs, T and Bruno, D and Lee, SH and Imbimbo, BP and Osorio, RS and Benedet, AL and Ashton, NJ and Zetterberg, H and Pomara, N and , },
title = {Sex-specific associations between astrocytic reactivity and cognitive decline in unimpaired elderly.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.30.702902},
pmid = {42427583},
issn = {2692-8205},
abstract = {INTRODUCTION: Astrocyte reactivity may contribute to increased Alzheimer's disease (AD) risk in women. Although higher plasma glial fibrillary acidic protein (GFAP) levels have been reported in women, few studies have investigated sex-specific relationships with other plasma AD biomarkers and cognition.<br><br>METHODS: Participants were enrolled in the Memory Education and Research Initiative, a longitudinal community-based cohort, and underwent evaluation including blood biomarker sampling. The Alzheimer's Disease Neuroimaging Initiative (ADNI) was included as a replication cohort.<br><br>RESULTS: Unimpaired women exhibited higher plasma GFAP levels than men (N=584). Higher baseline GFAP was associated with worse longitudinal episodic memory, exclusively in women. In addition, both higher baseline and increasing GFAP levels over time were associated with lower longitudinal plasma A&#x3b2;42/40 ratio. The key results were replicated in the ADNI cohort.<br><br>DISCUSSION: These findings suggest that astrocytic reactivity is more pronounced in women and may contribute to sex-specific vulnerability to AD-related pathology and cognitive decline.},
}
@article {pmid42427625,
year = {2026},
author = {Berthoux, C and Rodenas-Ruano, A and Bist, L and Nasrallah, K and Castillo, M and Shelkar, GP and Dravid, SM and Swanger, SA and Castillo, PE},
title = {GluN2D-containing NMDA receptors support dentate granule cell excitability, synaptic plasticity, and memory.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.06.710109},
pmid = {42427625},
issn = {2692-8205},
abstract = {UNLABELLED: N-Methyl-D-aspartate ionotropic glutamate receptors (NMDARs) are crucial for synaptic transmission, long-term plasticity, neuronal activity, and cognition. Consistent with these functions, NMDAR dysfunction is linked to several brain disorders, including Alzheimer's disease, autism, schizophrenia, and depression. NMDARs are tetrameric complexes composed of two essential GluN1 subunits and two distinct GluN2 subunits (GluN2A-D) that define their functional characteristics. Although the roles of GluN2A and GluN2B, which are highly expressed in the brain, have been extensively studied, much less is known about GluN2D in brain function. Using selective GluN2D antagonists in the mature rodent brain and a conditional GluN2D knockout model, we assessed the role of GluN2D-containing NMDARs in dentate granule cells (GCs). We found that these receptors are tonically active, primarily extrasynaptic, and facilitate GC action-potential firing. Additionally, physiologically relevant presynaptic and postsynaptic activity patterns induced strong long-term potentiation of NMDAR-mediated transmission at medial perforant path synaptic inputs. This plasticity was likely driven by lateral diffusion of GluN2D and supported by non-canonical glutamate delta-1 (GluD1) receptors. Finally, removing GluN2D from excitatory cells in the dentate gyrus impaired spatial memory. Overall, our findings demonstrate that GluN2D-containing NMDARs are vital for hippocampal function, likely by modulating GC activity and mediating NMDAR synaptic plasticity.<br><br>TEASER: GluN2D-containing NMDA receptors control dentate gyrus function by regulating neuronal firing and synaptic plasticity.},
}
@article {pmid42427630,
year = {2026},
author = {Forster, PM and Bracko, O and Rust, R},
title = {Shared and disease-specific human brain vascular signatures in Alzheimer's disease, frontotemporal dementia, and Huntington's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.01.735865},
pmid = {42427630},
issn = {2692-8205},
abstract = {The blood-brain barrier (BBB) plays a central role in brain function and is increasingly implicated in neurodegenerative disease. Major neurodegenerative disorders, including Alzheimer's disease (AD), frontotemporal dementia (FTD), and Huntington's disease (HD), share overlapping pathological features. Yet, the extent to which these diseases converge or diverge at the level of BBB-associated cell types remains poorly understood. Here, we performed a comparative analysis of vessel-enriched human brain transcriptomic datasets across AD, FTD, and HD to define shared and disease-specific neurovascular alterations. We identify a partially conserved transcriptional signature of vascular dysfunction across all three diseases, alongside disease-specific changes in endothelial, pericyte, and perivascular cell populations. Endothelial remodeling was most prominent in capillary and venous segments, highlighting segment-specific vulnerability along the arteriovenous axis. Notably, we identified two molecularly distinct human pericyte subtypes across all three datasets and found a consistent reduction in the matrix-type pericytes (M-peri) fraction, suggesting a selective decline. Cell-cell communication analysis further revealed reorganized endothelial-pericyte signaling networks, with prominent alterations in extracellular matrix-associated pathways, including LAMININ, COLLAGEN, FN1, and NCAM, together with changes in contact-dependent and vascular signaling pathways such as NOTCH and VEGF. Together, our findings define shared and disease-specific neurovascular mechanisms across major neurodegenerative disorders and highlight BBB-associated pathways as central features of neurodegeneration, providing a framework for future diagnostic and therapeutic strategies.},
}
@article {pmid42427640,
year = {2026},
author = {Du, JT and Chartrand, T and Jayadev, S and Prater, KE and Lin, KZ},
title = {Integrating morphology and gene expression of neural cells in unpaired single-cell data using GeoAdvAE.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.19.689368},
pmid = {42427640},
issn = {2692-8205},
abstract = {BACKGROUND: Cellular morphological transitions are observed across many diseases, yet their functional role remains unclear because few technologies profile form and function in the same cell. Linking single-cell morphology to transcriptomics is difficult: the two modalities share no feature correspondence and are typically measured in different cells.<br><br>METHODS: We present GeoAdvAE, a geometry-aware adversarial autoencoder for diagonal (unpaired) integration of single-cell morphology and single-cell RNA sequencing. GeoAdvAE couples modality-specific variational autoencoders with a Gromov-Wasserstein regularizer and an adversarial discriminator to embed unpaired morphologies and transcriptomes into a shared latent space that preserves both reconstruction fidelity and cross-modal geometry.<br><br>RESULTS: Using patch-seq neurons with joint morphology-RNA measurements as ground truth, GeoAdvAE attains the best cross-modal cell-type matching accuracy among diagonal integration methods, outperforming optimal-transport, latent-alignment, and adversarial baselines. Applied to 98 CAJAL-quantified microglial morphologies and 31,948 single-cell transcriptomes from the 5xFAD Alzheimer's disease model, GeoAdvAE recovers a one-dimensional axis that aligns the two modalities. Integrated-gradient attribution highlights transcriptomic shifts (DNA repair in ramified microglia; cell killing in amoeboid microglia), nominates gene markers (Ms4a6b ; Ftl1 / Fth1), and reveals disease-associated microglia signatures that are decoupled from morphology.<br><br>CONCLUSIONS: GeoAd-vAE provides a scalable and interpretable approach to connecting cellular "form" and "function" when joint profiling of morphology and transcriptomics is impractical. Our method is publicly available at https://github.com/turbodu222/GeoAdVAE .},
}
@article {pmid42427663,
year = {2026},
author = {Poirier, EL and Stainton, A and Simon, O and Mittal, SS and Varona Ortiz, AB and Kim, SA and Rauch, JN},
title = {Zinc Differentially Modulates Tau Aggregation, Fibril Morphology, and Prion-like Seeding in a Construct-Dependent Manner.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.01.735859},
pmid = {42427663},
issn = {2692-8205},
abstract = {The role of tau fibril structure in seeding and propagation of aggregation remains a central unresolved question in tauopathy biology. While non-proteinaceous cofactors are increasingly observed in patient-derived tau filaments, whether they actively determine fibril structure and function is not well understood. Here, we show that zinc, a divalent cation dysregulated in Alzheimer's disease (AD), can drive fundamentally different aggregation and seeding outcomes depending on tau sequence context. Using heparin-free conditions, we compared full-length 2N4R tau (residues 1-441) with an AD-tau fragment (residues 304-380) corresponding to the ordered fibril core. Strikingly, Zn [2+] exerted opposite effects on these constructs: it accelerated aggregation, increased fibril length, and enhanced cellular seeding for AD-tau, while slowing aggregation, shortening fibrils, and suppressing seeding for full-length tau. These findings demonstrate that cofactor effects are not intrinsic properties of the cofactor itself, but emerge from its interplay with tau sequence and conformational constraints. More broadly, our results support a model in which small-molecule cofactors act as active architects of fibril structure and function, suggesting that chemically distinct environments could generate structurally and biologically distinct tau strains in disease.},
}
@article {pmid42427668,
year = {2026},
author = {Pallerla, AV and Lucido, CC and Saito, K and Nolt, GL and Arbones-Mainar, JM and Funnell, JL and Satish, D and Smith, LM and Stephens, IO and Goulding, D and MacLean, SM and Olmsted, SM and Adreon, D and Hernandez, G and Golden, LR and Persohn, S and Macauley, SL and Territo, PR and Morganti, J and Johnson, LA},
title = {Anti-amyloid immunotherapy drives APOE4 specific increases in glial reactivity, perivascular immune activation, and ARIA-like events.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.26.734793},
pmid = {42427668},
issn = {2692-8205},
abstract = {Anti-amyloid antibodies represent the first disease modifying therapeutics for Alzheimers disease (AD). Adoption of these novel treatments has been slowed by the occurrence of amyloid related imaging abnormalities (ARIA) - treatment-associated edema (ARIA-E) or microhemorrhages (ARIA-H) that disproportionately affect carriers of the E4 allele of apolipoprotein E (APOE). With E4 carriers comprising nearly 70% of the AD population, there is a critical need to understand the unique vulnerability of E4 carriers to these events. To address this gap, we utilized the EFAD mouse model - which expresses human APOE isoforms on the 5xFAD background of amyloidosis - to directly compare the effects of anti-amyloid therapy across APOE genotypes. 9-month-old E2, E3, and E4FAD mice received weekly injections of chimeric Aducanumab (chAdu) or IgG control for 12 weeks, to assess APOE isoform-specific effects on amyloid dynamics, ARIA-H-like microhemorrhages, and underlying cellular and transcriptomic responses. E4FAD mice demonstrated plaque reductions with accompanying increases in microhemorrhages (measured on both MRI and histology), and increases in microglial and astrocyte reactivity - especially in the perivascular compartment. Additionally, vascular branching analysis and parallel single cell and spatial transcriptomics revealed a loss of vascular plasticity and increased inflammatory and immune signaling in the neurovascular units of E4FAD mice. Together, these findings suggest the cerebrovasculature of E4s is uniquely susceptible to antibody mediated vascular damage and provide immunological targets for the assessment or mitigation of ARIA risk in this highest need population.},
}
@article {pmid42427702,
year = {2026},
author = {Sloane, A and Kattunga, VM and Andersen, JK},
title = {Mitochondrial Hsp60/10 Client Protein Decline Reveals Braak/Tau- and Cognition-Linked Proteostasis Vulnerabilities in Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.25.734545},
pmid = {42427702},
issn = {2692-8205},
abstract = {BACKGROUND: Alzheimer's disease (AD) is classically defined by amyloid and tau pathology and is accompanied by broad disruptions in proteostasis. Heat shock proteins (HSPs) help maintain proteostasis, yet mitochondrial chaperone systems remain comparatively underexplored in AD. Hsp60 and Hsp10 form a mitochondrial chaperonin complex that folds dozens of AD-implicated mitochondrial proteins, but this client network has not been evaluated as an integrated proteostasis axis in AD. It remains unknown whether Hsp60/10 client proteins are selectively vulnerable across AD severity.<br><br>METHODS: We analyzed transcriptomic, proteomic, neuropathological, and cognitive data from the Religious Order Study and Memory and Aging Project (ROSMAP) to evaluate Hsp60/10 client proteins in AD. We compared Hsp60/10 clients with abundance-matched non-client mitochondrial proteins and tested differences across AD diagnostic groups and associations with Braak/tau burden, cognitive outcomes, and network centrality. These evidence layers were integrated into a candidate prioritization framework.<br><br>RESULTS: Hsp60/10 client abundance declined more strongly at the protein level than at the RNA level in late-stage AD. Compared with abundance-matched non-client mitochondrial proteins, Hsp60/10 clients showed stronger late-stage protein abundance decline. Greater late-stage client decline was associated with higher Hsp60/10 network centrality, defining a selectively vulnerable client subnetwork. Lower client abundance was associated with greater Braak/tau burden and greater cognitive impairment. Integrated prioritization nominated mitochondrial translation and TCA/pyruvate/redox clients as high-priority candidates for mechanistic follow-up.<br><br>CONCLUSIONS: Together, these findings identify an Hsp60/10 client-centered mitochondrial proteostasis axis spanning mitochondrial translation and TCA/pyruvate/redox metabolism that is associated with AD severity. These findings identify a novel potential axis warranting further investigation as a mechanistic link between mitochondrial dysfunction, proteostasis, and AD.},
}
@article {pmid42427719,
year = {2026},
author = {Sharma, S and Comandante-Lou, N and Ma, Y and Fujita, M and Bennett, DA and Zammit, AR and De Jager, PL},
title = {Neuroticism is linked to cognitive decline and increased risk of Alzheimer's disease through dysregulation of excitatory neurons.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.27.735015},
pmid = {42427719},
issn = {2692-8205},
abstract = {INTRODUCTION: Neuroticism is an established risk factor for Alzheimer's disease (AD), yet the molecular mechanisms linking this personality trait to neurodegeneration remain poorly understood.<br><br>METHODS: We leveraged single-nucleus RNA-sequencing data from longitudinal cohort studies of cognitive aging (n = 655) to investigate the mechanisms mediating the association between neuroticism and AD.<br><br>RESULTS: We identified two genes associated with neuroticism, both of which are downregulated in excitatory neurons: ADRA1B and LY6E-DT . In addition, we found that neuroticism is associated with enrichment of a specific excitatory neuron subpopulation: Exc.12. Further analysis revealed that Exc.12 partially mediates the relationship between neuroticism and AD, accounting for 12.2% of the total effect.<br><br>DISCUSSION: The dysregulation of excitatory neurons may represent a key cellular change that links neuroticism to AD.},
}
@article {pmid42427721,
year = {2026},
author = {Subbulakshmi, S and Park, J and Rathmann-Bloch, J and Ward, T and Cheng, GL and Miller, DS and Schwartz, ST and Sheng, J and Tran, TT and Sha, SJ and Deutsch, G and Trelle, AN and Mormino, EC and Wagner, AD},
title = {Dissociable structural and molecular pathways of age-related change in sustained attention.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {42427721},
issn = {2692-8205},
abstract = {Sustained attention, the capacity to maintain goal-directed attention over extended periods, declines with age but with substantial individual variability across cognitively unimpaired (CU) older adults. The neurobiological mechanisms driving both the decline and its variability across CU remain poorly understood. Two candidate processes may contribute: microstructural deterioration of the superior longitudinal fasciculus (SLF), the principal white-matter tract coupling prefrontal and parietal nodes of the dorsal attention network, and subclinical accumulation of Alzheimer's disease (AD)-related pathology, which may erode attentional function through disruption of neuromodulatory systems and progressive involvement of frontoparietal cortical substrates. We combined (a) diffusion MRI tractography, quantifying SLF fractional anisotropy (FA) and mean diffusivity (MD) alongside two control tracts, the corticospinal tract (CST) and cingulum (CGC), with (b) a plasma panel indexing AD-related pathology (pTau-181, pTau-217), neuroaxonal injury (NfL), and astrocytic reactivity (GFAP) in 162 CU older adults drawn from two Stanford cohorts (plasma subsample N = 146). Sustained attention was assessed using the gradual-onset Continuous Performance Task (gradCPT) and indexed by a composite score (Att-Z) derived from discriminability (d') and response-time variability (RTV). Parallel mediation and commonality analyses were used to test whether structural and molecular pathways contribute independently to age-related attentional decline. Older age was associated with lower Att-Z (β = -0.315, p < 0.001). In simultaneous three-tract regression models, only SLF microstructure uniquely predicted Att-Z (FA: β = +0.275, p < 0.001; MD: β = -0.320, p < 0.001). SLF microstructure mediated the age-attention relationship. At the molecular level, plasma pTau-181 (β = -0.212, pFDR < 0.03) and pTau-217 (β = -0.163, pFDR < 0.05) predicted Att-Z and each mediated age-related attentional decline. Yet, neither pTau isoform predicted SLF microstructure, indicating that the molecular pathway operates independently of white-matter integrity. NfL also reached FDR-corrected significance for Att-Z (β = -0.156, pFDR < 0.05) but attenuated to non-significance when modelled jointly with pTau-181 or pTau-217, suggesting that the attentionally relevant component of molecular ageing is specific to AD-related pathology rather than NfL-related neuroaxonal damage. GFAP showed no association with sustained attention in any model. In parallel mediation models, SLF microstructure and plasma pTau carried significant independent indirect effects with negligible shared variance, and both pathways retained significance when modelled jointly. These findings reveal a multi-pathway architecture of attentional ageing in which structural disconnection of the dorsal attention network and accumulation of AD-related pathology operate as dissociable and additive mediators of individual differences in attention and of age-related attentional decline, detectable before clinical impairment. Their mechanistic independence identifies two separable biological targets for preserving attentional capacity in CU older adults, including those in the preclinical phase of AD.},
}
@article {pmid42427742,
year = {2026},
author = {Rossitto, LM and Lu, T and Ma, Y and Kaila Sharma, P and Burghi, V and Gonzalez, CC and Bruystens, J and Maurya, S and Wu, J and Lona, A and Kufareva, I and Gutkind, JS and Gonzalez, DJ and Chen, X and Taylor, SS},
title = {Selective knockout of PKA regulatory subunits reveal opposite catalytic and metabolic consequences with implications for Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.26.734839},
pmid = {42427742},
issn = {2692-8205},
abstract = {cAMP-dependent Protein Kinase A (PKA) is a master regulator of cell signaling involved in energy metabolism, synaptic plasticity, and stress response. Dysregulated PKA signaling is implicated in diseases including neurodegeneration and cancer. PKA catalytic activity is regulated by two nonredundant regulatory subunits, Type I (RIα/RIβ) and Type II (RIIα/RIIβ), whose divergent functions are not fully understood. We generated double-knockout (KO) cell lines of RIα/RIβ and RIIα/RIIβ subunits and performed multiplexed MS-based proteomic and phosphoproteomic profiling under basal and glucose-perturbed conditions. We found that RI and RII loss drives distinct, and often opposite, remodeling of the cellular proteome and phosphoproteome. While both mutants blunted metabolic flexibility to glycolytic stressors and stimuli, RI and RII KO cells exhibited elevated and depressed glycolytic signaling, respectively. Interestingly, RI KO increased the abundance and kinase activity of the PKA catalytic subunit Cα isoform, leading to an increase in PKA substrate phosphorylation, whereas RII KO decreased the abundance, kinase activity, and substrate phosphorylation by the catalytic subunit Cβ isoform. Notably, one of the most differentially affected PKA sites between RI and RII KOs maps to Tau, whose hyperphosphorylation is a hallmark of Alzheimer's disease. Loss of RI increased Tau phosphorylation, which was not only caused by increased PKA catalytic activity, but also a higher binding affinity of Tau to RII subunits on the negatively-charged flexible linker region. Overall, the present study demonstrates that PKA RI and RII subunits play nonredundant roles in modulating PKA activity, metabolic flexibility, and phospho-regulation of key disease-associated substrates such as Tau.},
}
@article {pmid42427748,
year = {2026},
author = {Katsuki, F and McNally, JM and Gerashchenko, D and Uygun, DS and Tyler, A and McCoy, JG and McKenna, JT and Brown, RE},
title = {Early Loss of Deep Restorative Sleep and Auditory Stimulus Evoked 40-Hz activity of Hippocampal Parvalbumin Neurons in the APP/PS1 Mouse Model of Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.26.725476},
pmid = {42427748},
issn = {2692-8205},
abstract = {Sleep abnormalities and dysfunction of gamma band (30-80 Hz) activity generated by parvalbumin (PV) interneurons are early characteristics of Alzheimer's disease (AD) which correlate with the severity of amyloid-β deposition (Aβ) and cognitive impairment. However, the timing of these alterations in vivo with respect to disease progression is unclear. Here, in longitudinal recordings from APP/PS1/PV-cre (AD mice) from 3-6 months, we found reduced sleep slow-wave power (0.5-4 Hz) in hippocampus and medial prefrontal cortex in AD mice as young as 3 months old, compared to non-AD (PV-cre) mice, well before overt pathology. This finding was primarily due to reductions in the NREM delta range (1.5-4 Hz), a hallmark of restorative functions of sleep. In contrast, beta (15-30 Hz) power linked to insomnia was significantly higher across all sleep-wake states. Loss of deep NREM sleep was not compensated by an increase in NREM sleep time, instead NREM sleep during the dark (active) phase was slightly but significantly lower in AD mice. 40-Hz auditory steady-state responses and associated evoked calcium responses of hippocampal PV neurons recorded using fiber photometry were also impaired by 3 months old. However, Y-maze performance in 3- and 6-month-old AD mice was not significantly different from non-AD mice. These results reveal reduced deep sleep and PV-associated 40-Hz activity as very early changes amenable to early intervention occurring prior to cognitive deficits. Furthermore, they establish APP/PS1 mice as a good model to causally test the relationship between sleep, PV neuronal activity and amyloid-mediated pathology.},
}
@article {pmid42427763,
year = {2026},
author = {Nielsen, CO and Denton, RL and Quilling, CR and Virgin, KL and Cutler, KJ and Gates, SS and Sorensen, MD and Poulson, MF and Hilton, TC and Driggs, BK and Hernandez, Z and Snedaker, PM and Naylor, BC and Transtrum, MK and Price, JC},
title = {Kinetic Lipidomics: Quantifying in vivo changes in lipid metabolism using metabolic labeling.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.29.735310},
pmid = {42427763},
issn = {2692-8205},
abstract = {Lipid metabolism reflects the dynamic balance between metabolic turnover and concentration. Kinetic mass spectrometry (MS) enables direct quantification of molecular turnover in vivo. Previous work has shown that MS-based kinetic proteomics has provided powerful insights into proteome regulation. Analogous lipidome-wide kinetic measurements remain limited by challenges in defining molecule-specific labeling behavior. Here, we extend kinetic MS to untargeted lipidomics. Isotope labeling with deuterated water ([2] H 2 O) is commonly used for monitoring turnover of palmitate and other select lipids by measuring labeling of stable C-H positions with deuterium ([2] H). Here, we extend the deuterium-incorporation model underlying these targeted lipid turnover assays to support untargeted analysis of all detectable lipids. This allows us to empirically quantify the effective fraction of endogenous synthesis (A syn) and the turnover rate (k) across hundreds of lipid species simultaneously. One central barrier to lipidome-wide kinetic modeling is determining the endogenous number of deuterium-labeling sites for each molecule (n L) which is required to estimate A syn and k accurately. The n L value is an essential component of biological kinetic assays. In kinetic proteomics, curated amino acid n L libraries enable peptide-level modeling by summing sequence-specific labeling-site values, but comparable resources are lacking for lipids and may not generalize across metabolic states or non-mammalian systems. Yet, gaps remain for lipids and for amino acids in modified metabolic conditions or non-mammalian biologies. Here, we empirically determine lipid n L values and validate the process with peptides against an n L library. To evaluate this strategy in a biologically relevant setting, we applied it to brain tissue from transgenic mice expressing human ApoE isoforms, where altered lipid transport and metabolism are implicated in Alzheimer's disease risk. These data validate the method in a clinically relevant context and suggest that genotype-dependent metabolism can alter empirically determined lipid n L values.},
}
@article {pmid42427771,
year = {2026},
author = {Zemke, JE and Huang, G and Starr, E and Broder, M and Marsh, J and Renganathan, A and Phillips, B and Marsh, TW and Minaya, M and Cruchaga, C and Iyer, AK and , and Karch, CM},
title = {The NORAD -pumilio regulatory axis links lncRNA dysregulation to tau propagation-associated phenotypes.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.30.735697},
pmid = {42427771},
issn = {2692-8205},
abstract = {Long non-coding RNAs (lncRNAs) are increasingly implicated in neurodegenerative disease, yet their roles in tauopathy remain poorly understood. Here, we defined the lncRNA landscape across iPSC-derived neurons, astrocytes, and microglia harboring the frontotemporal dementia-associated MAPT IVS10+16 mutation and investigated how lncRNA dysregulation interfaces with tau pathology. Transcriptomic analyses revealed extensive cell-type specific lncRNA expression changes, with neurons exhibiting the greatest degree of mutation-associated remodeling. Comparative analyses with MAPT IVS10+16 patient brain tissue identified NORAD and MIR22HG as lncRNAs significantly dysregulated across all three cell types and human brains. NORAD was also altered in Alzheimer's disease and Parkinson's disease brains, suggesting a broader role in neurodegenerative disease. Mechanistically, NORAD -associated protein networks converged on pathways related to RNA regulation, cytoskeletal organization, proteostasis, and tau interaction networks. Given the established role of NORAD in regulating PUM1 and PUM2 RNA-binding (pumilio) proteins, we examined the NORAD -pumilio axis and identified enrichment of pumilio-associated pathways linked to autophagy, endocytosis, proteostasis, and cytoskeletal regulation. NORAD depletion reduced tau seeding and uptake, whereas functional depletion of PUM1 or PUM2 increased both processes, supporting an antagonistic relationship between NORAD and pumilio signaling in modulation of tau aggregation. Together, these findings identify widespread lncRNA dysregulation across neural cell types in the setting of a MAPT mutation and nominate the NORAD -pumilio axis as a regulatory pathway linking RNA homeostasis and tau propagation biology.},
}
@article {pmid42427864,
year = {2026},
author = {Cushing, BJ and Shahidehpour, RK and Abner, EL and Jicha, GA and Neltner, JM and Breig, MK and Teodorescu, KL and Neltner, AM and Coskun, EP and Kovacs, GG and Nelson, PT},
title = {Prevalent versus incident progressive supranuclear palsy: An analysis of the frequencies of neuropathological and clinical features at U.S. Alzheimer's Disease Research Centers indicate a relatively common tauopathy of aging.},
journal = {Research square},
volume = {},
number = {},
pages = {},
pmid = {42427864},
issn = {2693-5015},
abstract = {Progressive supranuclear palsy (PSP) is a neurodegenerative disease diagnosed according to its histopathologic pattern of tau proteinopathy ("tauopathy"). It is increasingly appreciated that PSP is heterogeneous in both clinical and pathological presentations. However, the prevalence of PSP subtypes, in comparison to other tauopathies, remain incompletely characterized. Here we analyzed NACC Neuropathology Data Set data aggregated from 37 U.S. Alzheimer's Disease Research Centers (ADRCs). Clinical and gold-standard neuropathologic features of autopsied participants were compared, stratifying on cognitive status at recruitment into the study. The final sample comprised 6994 individuals who were followed approximately annually for 4.0 years on average before autopsy. Among those with dementia at recruitment (n=4309), 2.9% had autopsy-confirmed corticobasal degeneration (CBD), 2.6% Pick's disease, and 4.6% PSP. By contrast, among those recruited while cognitively normal (n=1452), 0.7% had CBD, 0.1% Pick's disease, and, remarkably, 3.3% were diagnosed with PSP pathology. The relatively high frequency of PSP pathology detected among individuals recruited while cognitively normal suggests there is a subtype of PSP that is unexpectedly common in the broader population. In comparing between incident (recruited normal) and prevalent (recruited with dementia) autopsy-confirmed PSP, those with incident PSP died older (89.6 years versus 76.2 years on average). Furthermore, incident PSP pathology cases were less likely to manifest stereotypical PSP clinical features, but more likely to have parkinsonism, compared to prevalent PSP pathology cases. In a convenience sample of autopsy-confirmed PSP from the University of Kentucky ADRC (n=23), digital pathology analyses using HALO software and AI-based analytic modules revealed that PSP tau pathology was more severe in prevalent PSP, but in the putamen, incident cases had a higher proportion of tufted astrocytes and lower proportion of NFTs. In summary, incident PSP pathology is a relatively common tauopathy in older ADRC participants, often differing clinically and pathologically from prevalent PSP.},
}
@article {pmid42427890,
year = {2026},
author = {Lin, F and Teng, Y},
title = {Magnolol mitigates neuroinflammation via NF-κB/IL-6/IL-1β pathways in AlCl3-induced Alzheimer's disease: insights from in-vivo and in-silico investigations.},
journal = {3 Biotech},
volume = {16},
number = {8},
pages = {314},
pmid = {42427890},
issn = {2190-572X},
abstract = {The neuroprotective effectiveness of natural substances against neuroinflammatory pathways linked to Alzheimer's disease (AD) is still not well understood. In this study, we used both in vivo and in silico methods to assess the therapeutic potential of magnolol at dosages of 25 and 50 mg/kg body weight in a rat model of AD produced by aluminium chloride (AlCl3). Significant cognitive impairments, elevated levels of malondialdehyde (MDA), and increased expression of important neuroinflammatory mediators, including nuclear factor kappa-B (NF-κB), interleukin (IL-6), and interleukin-1β (IL-1β), were all brought on by exposure to AlCl3. Magnolol treatment markedly reduced the levels of pro-inflammatory cytokines, lactate dehydrogenase (LDH), and nitric oxide (NO), improved cognitive function, and strengthened antioxidant defence systems as shown by increased glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD) activities. Histopathological examination further validated Magnolol's neuroprotective properties, showing decreased neuronal degeneration. Magnolol has substantial binding affinities for NF-κB, IL-6, and IL-1β, according to molecular docking and dynamic modelling studies, indicating that it can directly influence neuroinflammatory signalling pathways. Overall, these results show that magnolol has important neuroprotective effects by reducing oxidative stress and inhibiting important inflammatory mediators, underscoring its potential as an effective treatment option for AD.},
}
@article {pmid42428004,
year = {2026},
author = {Mohanraj, S and Radhakrishnan, S},
title = {FuzzyFed-CNN: secure and explainable multimodal federated learning for early Alzheimer's diagnosis.},
journal = {Frontiers in artificial intelligence},
volume = {9},
number = {},
pages = {1852196},
pmid = {42428004},
issn = {2624-8212},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative condition that has a great effect on cognitive impairment and quality of life. Timely intervention requires the early and reliable diagnosis of the patient, but current diagnostic systems are frequently troubled with the limitations of data privacy, their lack of interpretability, and the fusion of heterogeneous clinical and imaging data.<br><br>OBJECTIVE: The proposed study suggests FuzzyFed-CNN, an explainable and privacy-oriented multimodal FL system that incorporates CNNs as well as fuzzy inference systems to enhance the early detection of AD and model interpretability and data privacy.<br><br>METHODS: The suggested framework involves CNN-based extractions of features using the T1-weighted MRI structural scans, and the use of the fuzzy-rule-based reasoning with the demographic and neuropsychological features, such as age, MMSE scores, and hippocampal volume. Experiments were done using a subset of the ADNI and OASIS-3 datasets. The training was conducted in a FL setting using the FedAvg algorithm. The metrics of accuracy, sensitivity, specificity, F1-score, and AUC were used to evaluate model performance.<br><br>RESULTS: Experiments that FuzzyFed-CNN with its accuracy, sensitivity, and specificity measure 97.7, 98.0, 99.0, and F1-score of 98.0. The suggested framework was better at performing compared to baseline models such as MobileNet and ResNet., DenseNet, EfficientNet. Grad-CAM visualizations also supported that the model paid attention to clinically significant brain regions, including the hippocampus and the cortical areas.<br><br>CONCLUSION: The results demonstrate that combining multimodal learning, fuzzy reasoning, and federated training can be used to achieve considerable improvements in the diagnosis of AD without damaging patient privacy and improving the interpretability of the models.},
}
@article {pmid42428045,
year = {2026},
author = {Aggarwal, K and Ramu, V and Padmanaban, K and Hemalatha, B},
title = {Diagnosis of Alzheimer's disease from neuroimages using steerable quantum probabilistic hamiltonian generative modeling with adaptive chaotic satin bowerbird optimization.},
journal = {Cognitive neurodynamics},
volume = {20},
number = {1},
pages = {129},
pmid = {42428045},
issn = {1871-4080},
abstract = {Alzheimer's Disease (AD) is a disease of the brain that lowers quality of life due to cognitive impairment. A correct diagnosis is therefore essential for timely interventions and follow-up care for executives. However, existing deep learning methodologies for neuroimage-based diagnosis seriously lack reliability due to decreased accuracy and increased false positive rates, both of which can lead to misdiagnosis and suboptimal care planning. This study proposed an innovative Steerable Quantum Probabilistic Hamiltonian Generative Modeling with Adaptive Chaotic Satin Bowerbird Optimization (SQPHGM-ACSBO) framework for diagnosing AD using neuroimages within the ADNI dataset. A total of 5,154 neuroimages from the ADNI dataset were utilized in this study, comprising 2,590 MCI, 1,124 AD, and 1,440 cognitively normal (CN) samples. The process begins with image enhancement via an Adaptive Self-Guided Loop Filter, followed by precise brain region segmentation with GoogLeNet Inception-v3, and advanced feature extraction using a new Discrete Cosine-Krawtchouk-Tchebichef Transform (DCKTT). Classification is performed using the SQPHGM model, which combines the strengths of Steerable Transformers and Quantum-Probabilistic Hamiltonian Learning to model complex neuroimaging patterns, while the Adaptive Chaotic Satin Bowerbird Optimization (ACSBO) algorithm optimizes classification performance. With 99.9% accuracy and 99.8% precision, the suggested method outperforms current methods and provides a dependable, high-performance solution for AD diagnosis from neuroimaging data, according to experimental results. The main innovation of this work is the all-in-one optimization of steerable transformer-based directional feature learning, quantum-probabilistic Hamilton generator modeling, and adaptive-chaotic satin bowerbird optimization integrated within a single diagnostic pipeline, which allows for representing the complicated neuroimaging patterns better, and the convergence stability is also increased, compared to the previous deep learning-based Alzheimer diagnosis models.},
}
@article {pmid42428048,
year = {2026},
author = {Azizpour Lindi, H and Shalbaf, R and Shalbaf, A and Sadatshahabi, M and Abharian, P},
title = {Interpretable feature-transformer framework for cross-subject MCI detection using nonlinear dynamical and graph-theoretic EEG features.},
journal = {Cognitive neurodynamics},
volume = {20},
number = {1},
pages = {132},
pmid = {42428048},
issn = {1871-4080},
abstract = {Early and accurate detection of Mild Cognitive Impairment (MCI) is essential for preventing progression toward Alzheimer's disease (AD). In this cross-subject study, we investigate the effectiveness of entropy- and graph-based EEG features for distinguishing MCI from healthy controls (HC), using two modeling approaches: (1) a Transformer network applied to the engineered feature set, and (2) an EEGNet model trained on the same feature representation for comparison. The dataset consists of resting-state, eyes-closed EEG recordings from 183 participants (127 HC, 56 MCI), collected using a 20-channel STAT[™] X24 wireless system and segmented into 3-second epochs. EEG data underwent standard preprocessing, including band-pass filtering, downsampling, normalization, and class-balancing augmentation applied to the minority class. From each channel, nonlinear dynamical measures (e.g., sample and fuzzy entropy, Higuchi fractal dimension, Lyapunov exponent) and graph-theoretic connectivity descriptors derived from coherence matrices across five frequency bands were extracted, yielding a structured 19[Formula: see text]77 feature representation. The feature-based Transformer achieved the best performance (97.04% ± 0.72), outperforming the feature-based EEGNet baseline and highlighting the benefits of combining rich handcrafted features with attention-based modeling. SHAP (SHapley Additive exPlanations) analysis provided global and local interpretability, revealing the most influential nonlinear and connectivity features as well as the EEG channels contributing most to classification. Overall, these results demonstrate the effectiveness of feature-Transformer integration and support the potential of interpretable feature-driven deep learning models for early MCI detection.},
}
@article {pmid42428054,
year = {2026},
author = {Ghisays, V and Denkinger, MN and Singh, A and Marques, TM and Malek-Ahmadi, M and Jensen, KV and Protas, HD and Sohankar, J and Goradia, DD and Devadas, V and Chen, Y and Li, S and Langbaum, JB and Weiner, MW and Reiman, EM and Su, Y and Ashton, NJ and , },
title = {Prognostic value of plasma brain-derived pTau.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
pmid = {42428054},
abstract = {BACKGROUND: Plasma brain-derived pTau217 (BD-pTau217) may provide a Alzheimer's disease-specific plasma tau measure than total pTau217, but its prognostic value is unclear. We compared BD-pTau217 and total plasma pTau217 for predicting clinical and amyloid PET progression in cognitively unimpaired (CU) ADNI participants.<br><br>METHODS: Plasma NULISAseq biomarkers were measured in 1,427 ADNI participants, including 529 CU individuals. Amyloid PET progression was assessed in baseline CU amyloid-negative participants (Centiloid &#x2265;24.1) with longitudinal PET imaging; clinical progression was assessed in all baseline CU participants. Associations were evaluated using Cox models and time-dependent AUC.<br><br>RESULTS: BD-pTau217 did not clearly outperform total pTau217 for predicting progression to mild cognitive impairment or dementia. However, among baseline amyloid-negative participants (N=175), BD-pTau217 better predicted amyloid PET positivity at 2.5 years (tdAUC 0.82 vs 0.69; HR=10.54, p=0.00015) and 4 years (tdAUC 0.77 vs 0.64; HR=7.03, p=0.00055).<br><br>CONCLUSION: BD-pTau217 improved prediction of near-term amyloid PET progression, with less clear advantage for clinical progression.<br><br>HIGHLIGHTS: BD-pTau217 predicted amyloid PET progression in CU ADNI participants.BD-pTau217 outperformed total pTau217 at the CL &#x2265;24.1 threshold.BD-pTau217 and total pTau217 performed similarly for clinical progression.Prognostic performance varied across amyloid PET thresholds.BD-pTau217 may support risk stratification in prevention trials.<br><br>RESEARCH IN CONTEXT: Systematic review: Plasma pTau217 biomarkers show strong cross-sectional associations with amyloid and tau pathology and are increasingly used to support Alzheimer's disease diagnosis and trial screening. Recent assay designs selectively measuring brain-derived pTau217 may reduce peripheral contributions to total pTau217 measurements, but their longitudinal prognostic value relative to total pTau217 remains less well established.Interpretation: In cognitively unimpaired ADNI participants, plasma BD-pTau217 showed stronger prognostic performance than total pTau217 for progression from amyloid PET negative to amyloid PET positive status, particularly at the primary CL &#x2265;24.1 threshold. In contrast, BD-pTau217 and total pTau217 showed more similar performance for predicting clinical progression to MCI or dementia.Future directions: These findings support further evaluation of BD-pTau217 for biological risk stratification and prevention trial enrichment. Validation is needed in more diverse cohorts, longer follow-up intervals, and across clinical-grade assay platforms.},
}
@article {pmid42428055,
year = {2026},
author = {Hoehne, CL and Salinas, V and Shirani, A and Stuve, O and Stopschinski, BE},
title = {NSAID use is associated with lower dementia and Alzheimer's disease prevalence and slower cognitive decline: A retrospective longitudinal analysis of the NACC cohort.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
pmid = {42428055},
abstract = {INTRODUCTION: Dementia, particularly Alzheimer's disease (AD), is a major global health challenge, with prevalence projected to reach 150 million cases by 2050. AD is characterized by progressive cognitive decline linked to neuroinflammation and neurodegeneration. Non-steroidal anti-inflammatory drugs (NSAIDs) have been explored as potential neuroprotective agents, particularly diclofenac, which has been proposed to modulate microglial inflammasome signaling. However, prior studies investigating NSAIDs in AD have yielded inconsistent findings. We therefore reexamined the relationship between selected NSAIDs and dementia outcomes in a large longitudinal cohort from the National Alzheimer's Coordinating Center (NACC).<br><br>METHODS: We analyzed cross-sectional and longitudinal data from the NACC database collected between 2005 and 2022. Associations between NSAID exposure and dementia, AD, and cognitive trajectories were examined. Propensity score matching was performed to compare NSAID users with matched non-users while adjusting for demographic and clinical confounders. Longitudinal mixed-effects models were used to assess cognitive decline based on Montreal Cognitive Assessment (MoCA) scores.<br><br>RESULTS: Among 47,165 participants, diclofenac and naproxen use were associated with a lower prevalence of dementia and AD compared with matched non-users, whereas etodolac showed no significant associations. Diclofenac users demonstrated reduced odds of dementia and AD. Naproxen showed similar cross-sectional associations. In longitudinal modeling, diclofenac users had a significantly slower rate of cognitive decline than non-users.<br><br>DISCUSSION: These findings suggest a compound-specific association between NSAID use and AD, with diclofenac potentially modulating disease progression through anti-inflammatory mechanisms. The observed modulation of longitudinal cognitive decline supports further investigation of inflammatory pathways, including microglial and inflammasome signaling, as therapeutic targets in biomarker-defined AD populations.},
}
@article {pmid42428058,
year = {2026},
author = {Zhang, Y and Chen, B and Sun, H and Shi, R and Li, Y and Du, J and Horimoto, ARVR},
title = {Retinal Transcriptome-Wide Association Study Identifies Novel Alzheimer's Disease Risk Genes.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.01.26357036},
pmid = {42428058},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is the leading cause of dementia worldwide. The retina shares molecular pathways with the brain, yet no study has systematically linked retinal gene expression to AD risk.<br><br>METHODS: We performed transcriptome-wide association studies (TWAS) using two independent retinal eQTL panels (Strunz et al., n = 311; EyeGEx, n = 406) and a large meta-analyzed AD genome-wide association study (GWAS) (Bellenguez et al., 111,326 cases, 677,663 controls). Genes were further validated with GWAS in the independent Alzheimer's Disease Sequencing Project (ADSP) using a matched eQTL-panel strategy.<br><br>RESULTS: We identified 62 AD-associated genes across the two eQTL panels using Bellenguez et al. as the discovery cohort. Of these, 31 were replicated in the ADSP cohort. The findings highlight shared complement-mediated immune dysregulation (CD55 , CD46, TREM2) and provide functional transcriptomic evidence to prioritize novel causal drivers of AD pathogenesis, including STYX and the LRRC37 gene family.<br><br>DISCUSSION: Retinal data capture core AD genetic architecture and reveal novel risk genes, highlighting the retina as a molecularly informative tissue for dementia research.},
}
@article {pmid42428079,
year = {2026},
author = {Baumeister, H and Lüsebrink, F and Kleineidam, L and Hansen, N and Schmid, M and Moscoso, A and Leuzy, A and Mastenbroek, SE and Groot, C and Brosseron, F and Ramirez, A and Preis, L and Gref, D and Spruth, EJ and Gemenetzi, M and Altenstein, S and Fliessbach, K and Kimmich, O and Schott, BH and Rostamzadeh, A and Glanz, W and Incesoy, EI and Butryn, M and Janowitz, D and Rauchmann, BS and Mladinov, M and Grazia, A and Sodenkamp, S and Stöcker, T and Hetzer, S and Dechent, P and Stoecklein, S and , and , and , and Peters, O and Hellmann-Regen, J and Priller, J and Schneider, A and Wiltfang, J and Buerger, K and Perneczky, R and Teipel, S and Laske, C and Spottke, A and Wagner, M and Jessen, F and Düzel, E and Berron, D},
title = {Subtyping and staging of Alzheimer's disease from routine structural MRI with PHASE-AD.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.26.26356678},
pmid = {42428079},
abstract = {Structural MRI is routinely acquired in the clinical assessment of Alzheimer's disease, yet quantitative morphometric indices derived from these scans remain largely confined to research settings. Here we present PHASE-AD - a framework that translates such indices into clinically interpretable classifications of atrophy subtype and stage that jointly capture atrophy progression while accounting for inter-individual atrophy heterogeneity. PHASE-AD is trained on MRI scans from 8,415 participants and robustly captures limbic-predominant and hippocampal-sparing atrophy subtypes that were identified across seven independent datasets. Two cross-validation schemes revealed high robustness across different field strength and scanner manufacturer configurations. Atrophy classifications were associated with diverging clinical profiles and tau accumulation patterns. In prospective designs mirroring contemporary AD trials, they stratified longitudinal cognitive trajectories and outperformed semi-quantitative visual MRI assessments as a clinically established comparator. These findings support the integration of automated atrophy subtyping and staging into clinical practice and pharmacological trials.},
}
@article {pmid42428094,
year = {2026},
author = {Zhu, Y and Pettigrew, C and Soldan, A and Moghekar, A and Albert, M and Bandeen-Roche, K and Wang, MC},
title = {The countdown paradox: time-varying analysis of biomarker-clock age and symptom onset.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.19.26355994},
pmid = {42428094},
abstract = {Research focused on Alzheimer's disease (AD) 'biomarker clocks' seeks to identify ages at which AD pathological landmarks occur (e.g., initiation of amyloid accumulation) and are meaningfully related to disease outcomes (e.g., symptom onset). However, the statistical approach for assessing the association between age at biomarker-clock event and remaining time to clinical symptom onset can create a structural artifact. We term it here the 'countdown paradox', because the remaining time to symptom onset shrinks as the age at biomarker-clock event increases, which may result in inaccurate associations between age at biomarker-clock event and the remaining time. We conducted analyses to examine this issue with simulation studies and theoretical results, and also examined it empirically using five biomarkers in two longitudinal AD-related cohorts (BIOCARD and ADNI): (1) CSF Abeta42/Abeta40, (2) CSF p-tau181, (3) plasma p-tau181, (4) amyloid PET, and (5) plasma p-tau217. As an alternative analytic approach to the standard approach, we used a time-varying effect analysis that evaluates the association between biomarker-clock events and symptom onset on the 'age' time scale, avoiding the structural coupling between predictor and outcome. This analytic approach generates clinically relevant insights on the prognostic value of biomarker-clock events. Under simulated null scenarios in which the biomarker was generated independent of symptom onset, the standard analysis produced false-positive rates up to 100% and hazard ratios above 1, regardless of the true effect direction, whereas the time-varying analysis maintained type I error near the nominal 5%. Moreover, in analyses of both the BIOCARD and ADNI cohorts, the standard analysis produced uniformly significant associations for ages at biomarker-clock events, based on all five biomarkers (hazard ratios 1.94-3.34, all P < 0.01), comparable to the pattern predicted by the countdown paradox and reported in the literature. The time-varying analysis showed a different pattern for the effect of age at biomarker-clock events: for all biomarkers investigated, a younger age at biomarker-clock events is associated with a higher hazard for symptom onset on the age scale, conveying the opposite prognostic message implied by the standard analysis. These findings suggest that the standard biomarker-clock analysis may generate inaccurate associations and even reverse the apparent direction of the age effect, inverting the resulting prognostic message. A time-varying effect analysis avoids this by relating the age at a biomarker-clock event to clinical onset, with important implications for interpreting prior biomarker-clock studies.},
}
@article {pmid42312459,
year = {2026},
author = {Banik, A and Pal, S and Pal, A and Pal, M and Dutta, I and Roy, D and Chattopadhyay, A and Benito-Leon, J},
title = {Qualitative clock-drawing errors across dementia etiologies and mild cognitive impairment: a clinically interpretable six-class framework.},
journal = {CNS spectrums},
volume = {31},
number = {1},
pages = {e20},
doi = {10.1017/S1092852926101072},
pmid = {42312459},
issn = {2165-6509},
abstract = {OBJECTIVE: To characterize qualitative Clock Drawing Test (CDT) error profiles across dementia etiologies and mild cognitive impairment (MCI), and to propose a clinically interpretable six-class framework.<br><br>METHODS: In a hospital-based study in Kolkata, India, consecutive adults with cognitive impairment completed a free-drawn "ten past ten" CDT. Errors were coded using classical qualitative categories and clock components (face, numbers, hands), then collapsed into six classes: conceptual, stimulus-bound/perseveration, spatial, planning, number-related, and graphic-conceptual. For nonexclusive domains, omnibus Pearson &#x3c7;&#xb2; tests summarized error distributions across diagnoses; Cram&#xe9;r's V quantified effect size.<br><br>RESULTS: Participants included Alzheimer's disease (AD; n = 36), vascular dementia (VaD; n = 16), behavioral variant frontotemporal dementia (bvFTD; n = 9), MCI (n = 19), and other conditions (n = 22). Although 50.0% drew a normal clock face, only 11.8% achieved perfect numbering and 12.7% set the hands correctly. Conceptual errors were most frequent (70.6%), followed by spatial errors (47.1%); neglect and counterclockwise numbering were rare (3.9% each). Error distributions differed by diagnosis for face, numbers, and hands (all p < 0.001; V = 0.4-0.5). The six-class scheme retained a significant distributional association with diagnosis (&#x3c7;&#xb2; = 43.365, p = 0.002; V = 0.3): bvFTD showed prominent conceptual and graphic-conceptual failures, AD combined conceptual and spatial errors, MCI emphasized spatial and number-related errors, and VaD was heterogeneous.<br><br>CONCLUSIONS: Qualitative CDT profiles vary meaningfully across cognitive disorders. This concise six-class framework captures clinically salient patterns, especially in severely degraded drawings, and may complement brief memory screening and digital CDT metrics.},
}
@article {pmid42418471,
year = {2026},
author = {Hirsch, F and Frontzkowski, L and Steward, A and Roemer-Cassiano, SN and Biel, D and Zhu, Z and Palleis, C and Gnörich, J and Klonowski, M and Höglinger, G and Brendel, M and Franzmeier, N},
title = {Modular brain networks shape amyloid-driven tau spread and cognitive decline.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71617},
pmid = {42418471},
issn = {1552-5279},
support = {A2021026S//BrightFocus Foundation/ ; AARG-22-973496/ALZ/Alzheimer's Association/United States ; EXC21452SyNergy-ID390857198//Deutsche Forschungsgemeinschaft/ ; //Gerhard und Ilse Schick Stiftung/ ; },
mesh = {Humans ; *tau Proteins/metabolism ; Positron-Emission Tomography ; *Cognitive Dysfunction/metabolism/diagnostic imaging/pathology ; *Brain/metabolism/diagnostic imaging/pathology ; *Amyloid beta-Peptides/metabolism ; Female ; *Alzheimer Disease/metabolism/diagnostic imaging/pathology ; Male ; Aged ; Connectome ; *Nerve Net/diagnostic imaging/metabolism ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Alzheimer's disease involves trans-synaptic spread of tau pathology from temporal lobe epicenters, driven by amyloid beta (Aβ) deposition. How modular brain network architecture shapes this process and the ensuing cognitive decline remains incompletely understood. We tested whether the efficiency with which tau epicenters access cross-network communication pathways modulates Aβ-driven tau propagation.<br><br>METHODS: We combined baseline/longitudinal amyloid/tau positron emission tomography (PET) data across two independent AD cohorts (N&#xa0;=&#xa0;490) with multimodal connectomics data. We quantified epicenter broadcast capacity (EBC), capturing whether tau epicenters preferentially access regions supporting cross-network communication or within-network communication.<br><br>RESULTS: Higher EBC was associated with faster A&#x3b2;-related global tau accumulation, greater spatial tau spread, and steeper cognitive decline. Effects were driven by stronger epicenter communication with cross-network connectors, whereas preferential within-network routing was associated with relative containment of tau spread.<br><br>DISCUSSION: We identify a mechanism through which epicenter connectivity biases A&#x3b2;-driven tau propagation toward brain-wide broadcast or regional containment, helping explain heterogeneity in disease progression.},
}
@article {pmid42418485,
year = {2026},
author = {Bahri, S and Palani, RS and Silvers, R and Michael, B and Lattanzi, V and André, I and Linse, S and Griffin, RG},
title = {High-resolution structure of monomorphic Aβ1-40 fibrils.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {123},
number = {28},
pages = {e2603575123},
doi = {10.1073/pnas.2603575123},
pmid = {42418485},
issn = {1091-6490},
support = {AG058504//HHS | NIH | National Institute on Aging (NIA)/ ; GM132997//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; VR2015-00143//Swedish Research Council/ ; },
mesh = {*Amyloid beta-Peptides/chemistry/ultrastructure/genetics ; *Peptide Fragments/chemistry/ultrastructure/genetics ; *Amyloid/chemistry/ultrastructure ; Humans ; Models, Molecular ; Alzheimer Disease/metabolism ; Magnetic Resonance Spectroscopy ; Protein Conformation ; Nuclear Magnetic Resonance, Biomolecular ; },
abstract = {Amyloid-β (Aβ) fibrils primarily composed of Aβ1-40 and Aβ1-42 form the core of senile plaques in Alzheimer's disease. Aβ1-40 fibrils may exhibit significant polymorphism influenced by sample preparation conditions, complicating atomic resolution structural characterization. To establish a reliable structural baseline, we developed a protocol for expressing and purifying recombinant Aβ1-40 that forms monomorphic fibrils under physiological conditions (pH 7.4). We present a high-resolution structure of these unseeded, monomorphic Aβ1-40 fibrils obtained using magic-angle spinning NMR spectroscopy (PDB ID 12GB). We obtained unambiguous chemical shift assignments for approximately 90% of the residues and measured over 500 distance and torsion angle restraints. The resolved structure, with a backbone RMSD of 0.63 ± 0.06 Å, shows two monomers per filament plane, with two distinct β-sheets (residues E11-E22 and K28-V39, respectively) running along the fibril axis with H-bonding between each plane, and the two strands linked by a flexible loop region. This structure reveals three continuous hydrophobic cores inside each filament which bury 24 hydrophobic side chains per filament plane: those of L17, F19, A21, V24, A30, I32, M35, V40 between the two β-strands within each monomer and I31, L34, V36, V39 between the two monomers. Small angle X-ray scattering reveals the size and geometry of the fibril cross-section, which is compatible with a two-filament arrangement with a total of 4 monomers per fibril plane.},
}
@article {pmid42418497,
year = {2026},
author = {Zhang, Y and Lee, JH and Yu, Z and Tao, Y and Rimal, S and He, Y and Lv, L and Lu, B and Ping, Y},
title = {Dopamine-driven mitochondrial reverse electron transport in immune cells mediates gut-brain ROS signaling during sleep deprivation.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {123},
number = {28},
pages = {e2530907123},
doi = {10.1073/pnas.2530907123},
pmid = {42418497},
issn = {1091-6490},
support = {R01AG089752 R01NS084412 and R37NS083417//Foundation for the National Institutes of Health (FNIH)/ ; 25X010301278//Shanghai Jiao Tong University (SJTU)/ ; 25ZR1401188//Science and Technology Commission of Shanghai Municipality (STCSM)/ ; },
mesh = {Animals ; *Reactive Oxygen Species/metabolism ; *Mitochondria/metabolism ; Signal Transduction ; *Dopamine/metabolism ; *Brain/metabolism ; *Sleep Deprivation/metabolism/immunology ; Electron Transport ; Drosophila melanogaster/metabolism ; Hemocytes/metabolism/immunology ; Drosophila Proteins/metabolism/genetics ; Oxidative Stress ; },
abstract = {Sleep deprivation (SD), together with inevitable stress inherent to conventional SD protocols, can induce oxidative stress and inflammation, thereby increasing the risk of premature death. However, the source and signaling pathways underlying reactive oxygen species (ROS) generation remain unclear. Here, we demonstrate that both mechanical and thermogenetic SD, along with possible stress induced by both protocols, lead to initial ROS accumulation in Drosophila gut subregions, including the proventriculus (PV) and PV-resident hemocytes, via upregulation of dopamine (DA) biosynthesis. Intriguingly, DA acts unconventionally by activating mitochondrial reverse electron transfer (RET), presumably through modifying interactions between the respiratory complex I proteins NDUFV1 and NDUFS3. RET-ROS elicits hemolymphatic IMD/Relish-mediated antibacterial defense. However, during chronic SD, downregulation of the Drosophila APOE/D ortholog Neural Lazarillo promotes the recruitment of hemocytes to the central brain and, together with this process, leads to widespread neuronal ROS accumulation in an Alzheimer's disease (AD) fly model. Inhibiting RET or hemocytic DA levels extends the survival of animals under chronic SD. Our work reveals DA-driven RET-ROS in innate immune cells during SD, highlights the pivotal role of a gut-innate immune-brain crosstalk in mediating the effect of SD manipulation on aging and AD pathogenesis, and suggests ways to lessen the consequence of SD, a profound health issue in modern society.},
}
@article {pmid42418504,
year = {2026},
author = {Cai, Y and Wang, Y and Huang, W and Su, Y and Lei, M and Jia, R and Wu, C and Zhang, T and Sun, L and Peng, B and Cheng, J and Yu, J and Chen, X and Ye, Q and Yu, J and Xin, J},
title = {Lecanemab treatment improves B cell subpopulation immune homeostasis in patients with Alzheimer's disease.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71655},
pmid = {42418504},
issn = {1552-5279},
support = {82571602//National Natural Science Foundation of China/ ; 82371188//National Natural Science Foundation of China/ ; 2022ZD0211603//Brain Science and Brain-like Intelligence Technology-National Science and Technology Major Project/ ; ADB510200//Lingang Laboratory/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/immunology ; *Homeostasis/drug effects ; Female ; Male ; *B-Lymphocyte Subsets/drug effects/immunology ; Aged ; *Antibodies, Monoclonal/therapeutic use/pharmacology ; *B-Lymphocytes/drug effects/immunology ; Leukocytes, Mononuclear/drug effects ; },
abstract = {INTRODUCTION: Lecanemab, the first disease-modifying therapy for Alzheimer's disease (AD), mitigates pathology primarily by clearing amyloid plaques, but its impact on peripheral immunity remains unclear.<br><br>METHODS: To assess Lecanemab's immunological effects, we performed antibody array analysis of serum and single-cell RNA sequencing of peripheral blood mononuclear cells collected from healthy controls and patients with AD at baseline, 3, and 6 months post-treatment.<br><br>RESULTS: Lecanemab restored multiple serum chemokines to healthy levels in patients with AD. Compared to controls, baseline samples from patients with AD showed altered frequencies and functions of na&#xef;ve and unswitched memory (UswM) B cells. Lecanemab treatment corrected the abnormal na&#xef;ve and UswM B cell proportions and rebuilt their functional homeostasis by alleviating chronic inflammation and reversing the dysregulation of key pathways including immune response, NF-&#x3ba;B, RAGE, and cell adhesion.<br><br>DISCUSSION: These findings uncover a novel peripheral immunomodulatory mechanism of Lecanemab, offering new insights into AD therapeutics.},
}
@article {pmid42418748,
year = {2026},
author = {Kivisild, A and Aaltonen, M and Aho, K and Heikkinen, SV and Lehtonen, A and Leppänen, L and Rinnankoski, I and Tervonen, L and Soppela, H and Haapasalo, A and Martikainen, J and Hartikainen, PH and Katisko, K and Krüger, J and Solje, E},
title = {Long-Term Income and Productivity Losses in Individuals With Early-Onset Dementia: Evidence From 15 Years Preceding the Diagnosis.},
journal = {Neurology},
volume = {107},
number = {3},
pages = {e218268},
doi = {10.1212/WNL.0000000000218268},
pmid = {42418748},
issn = {1526-632X},
mesh = {Humans ; Female ; *Income/statistics &amp; numerical data ; Finland/epidemiology ; Male ; Retrospective Studies ; Longitudinal Studies ; Middle Aged ; *Dementia/economics/epidemiology/diagnosis ; *Cost of Illness ; Age of Onset ; *Efficiency ; Aged ; Alzheimer Disease/economics ; Frontotemporal Dementia/economics ; },
abstract = {BACKGROUND AND OBJECTIVES: Early-onset dementia (EOD), affecting individuals younger than 65 years, imposes a substantial socioeconomic burden. However, evidence on long-term income trajectories and productivity loss across EOD subtypes remains limited. The aim of this study was to evaluate income trajectories and societal productivity loss in individuals with different EOD subtypes.<br><br>METHODS: This retrospective, population-based longitudinal cohort study included all patients with EOD from Kuopio University Hospital and Oulu University Hospital referral area between January 2010 and December 2021. Diagnoses were re-validated through clinical data review. For each study case, 10 randomly selected matched controls were used. Demographics, education, and comorbidities were obtained from national registers. Annual gross income was retrieved from Statistics Finland tax records. The Human Capital Approach was used to calculate productivity losses, in effect by estimating the annual income difference relative to controls using a generalized estimating equation regression model, with panel data spanning 15 years before diagnosis and the year of diagnosis.<br><br>RESULTS: The EOD cohort comprised 793 patients (50.4% women; mean age 59.6 years): 421 with Alzheimer disease (AD), 179 with frontotemporal dementia (FTD) spectrum disorders, 46 with &#x3b1;-synucleinopathies (&#x3b1;-SYNUs), and 147 with other EOD etiologies. Compared with 7,926 age-matched and sex-matched controls, patients with EOD showed substantial and progressively increasing productivity loss up to 15 years before diagnosis, with cumulative losses of &#x20ac;74,577 (46,423-102,732) per patient. In the AD group, productivity loss emerged 6 years before diagnosis (&#x20ac;2,767; 95% CI 18-5,515; p = 0.024) and reached &#x20ac;11,431 at diagnosis (95% CI 8,676-14,184; p < 0.001). In the FTD group, loss appeared 11 years before diagnosis (&#x20ac;4,799; 95% CI 433-9,166; p = 0.031) and increased to &#x20ac;16,116 at diagnosis (95% CI 11,671-20,561; p < 0.001). In the &#x3b1;-SYNU group, differences were variable and significant only at diagnosis (&#x20ac;11,284; 95% CI 2,574-19,993; p < 0.011). In the "other EOD" group (predominantly vascular and mixed dementias), productivity loss remained consistently high across the follow-up (e.g., &#x20ac;8,744 at diagnosis; p < 0.001).<br><br>DISCUSSION: This large-scale longitudinal study demonstrates significant productivity loss up to 15 years before EOD diagnosis, with variation across dementia subtypes. Earlier recognition and targeted interventions are needed in the future to mitigate the substantial socioeconomic burden of EOD.<br><br>This study is part of DEGE-RWD-research project (protocol registered to ClinicalTrials.gov: NCT06209515), coordinated by Neurocenter Finland.},
}
@article {pmid42418847,
year = {2026},
author = {de La Seiglière, H and Letourneur, &#xc6; and Ichas, F and De Giorgi, F},
title = {Phase separation and protein aggregation in neurodegenerative diseases.},
journal = {Biophysical chemistry},
volume = {338},
number = {},
pages = {107678},
doi = {10.1016/j.bpc.2026.107678},
pmid = {42418847},
issn = {1873-4200},
abstract = {Neurodegenerative diseases such as Alzheimer's, Parkinson's, frontotemporal dementia, and ALS are characterized by amyloid protein aggregation involving intrinsically disordered proteins that are also capable of liquid-liquid phase separation (LLPS). LLPS, known to drive the formation of dynamic membraneless organelles essential for cellular functions, can play a role in limiting fibrillation process or aberrantly transition into solid aggregates under pathological conditions. Here we review how mutations, post-translational modifications, and environmental factors can modulate LLPS of proteins like Tau, TDP-43, FUS, and α-synuclein, potentially regulating amyloid aggregation. We also examine the interplay of these proteins exploring how LLPS and condensate maturation could impinge on the emergence of co-pathologies contributing to disease progression. Finally we discuss emerging therapeutic strategies, aimed at modulating phase separation dynamics.},
}
@article {pmid42419155,
year = {2026},
author = {Pegoraro, G and MacBean, LF and Smith, AR and Soanes, DM and Smith, RG and Imm, J and Harvey, J and Kouhsar, M and Laroche, V and Weymouth, L and Castanho, I and Hide, W and Palmer, L and Lett, DJ and Robinson, AC and Woodman, N and McDade, K and Boche, D and Pishva, E and Lunnon, K},
title = {Systemic infections alter cortical transcriptional signatures in Alzheimer's disease.},
journal = {Neurobiology of aging},
volume = {167},
number = {},
pages = {155-167},
doi = {10.1016/j.neurobiolaging.2026.06.010},
pmid = {42419155},
issn = {1558-1497},
abstract = {Alzheimer's disease (AD) is characterized by neuroinflammation, yet the impact of concurrent systemic infections on the AD brain remains poorly understood. We investigated the molecular mechanisms underlying the central nervous system response to systemic infections in AD by analyzing RNA sequencing data generated in the prefrontal cortex from 202 post-mortem donors (113 AD, 89 controls), where we stratified by the presence of a respiratory infection at the time of death. We identified 763 significant differentially expressed genes (DEGs) between AD and controls without infection, which were enriched for oxidative phosphorylation and neurodegenerative pathways. In contrast, 122 DEGs distinguished AD from controls during infection, with 57 genes uniquely altered in AD in the presence of infection, including MAPK4, VAV3, and POU3F4, implicating infection-dependent mechanisms of vascular and immune regulation. Pathway activity analysis revealed that infection in AD suppresses some immune and vascular pathways, while enhancing transcriptional and developmental programs. Weighted gene co-expression network analysis uncovered three key modules: one module strongly associated with AD, enriched for aging and signal transduction; one module linked to both AD and infection, highlighting cytoskeletal remodeling and host-pathogen interactions; and one module specific to infection, enriched in astrocytes, pericytes, and endothelial cells, implicating blood-brain barrier dysfunction. These findings suggest that systemic respiratory infections reshape transcriptional programs in the AD brain, dampening immune effector pathways and engaging vascular and host-pathogen processes in blood-brain-barrier-associated cell types. Our results highlight the complex interplay between systemic infection, neuroinflammation, and vascular responses in AD.},
}
@article {pmid42419161,
year = {2026},
author = {Jiang, W and Lin, Y and Guo, Q and Miao, Y},
title = {Dietary patterns and Alzheimer's disease: East-west perspectives and future intervention strategies.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {8},
pages = {100636},
doi = {10.1016/j.tjpad.2026.100636},
pmid = {42419161},
issn = {2426-0266},
abstract = {Among various modifiable risk factors, dietary patterns (DPs), as a holistic lifestyle intervention, have become a focus of current research due to their protective effects on cognitive health. Classic Western DPs, such as the Mediterranean diet (MedDiet), have been widely confirmed to effectively improve cognitive function, thereby reducing the risk of Alzheimer's disease (AD). However, existing evidence mainly concentrates on Western populations and their DPs, including the MODERN (Machine learning-assisted Optimizing Dietary intERvention against demeNtia risk) diet optimized using machine learning. Given the significant differences in food types, dietary habits, and cooking methods among Asian populations, research on localized DPs optimized for cognitive health in Asian populations remains insufficient. In this context, the team at the Department of Geriatrics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine has taken the lead in systematically defining the Shanghai Cognitive Diet Pattern (SCDP). This review aims to comprehensively outline the core features and potential biological mechanisms relevant to AD in both classic Western DPs and the emerging East Asian DP. Subsequently, this review will systematically compare Eastern and Western DPs. In conclusion, this review proposes shifting dietary strategies from population-level adaptation to individual precision, in conjunction with multimodal lifestyle management, and offers novel strategies for the prevention and management of AD.},
}
@article {pmid42419451,
year = {2026},
author = {Raadani, A and Hamdi, A and Yangui, I and Jiménez-Araujo, A and Rodríguez-Arcos, R and Moreno, JMM and Ruiz, MJM and Messaoud, C and Ali, IBE and Guillén-Bejarano, R},
title = {Novel oligomeric caffeoyl derivatives and acylated flavone glycosides from Satureja nervosa Desf.: Chemical characterisation, structure-activity relationships, and multi-target bioactivity in Caenorhabditis elegans disease models.},
journal = {Fitoterapia},
volume = {},
number = {},
pages = {107377},
doi = {10.1016/j.fitote.2026.107377},
pmid = {42419451},
issn = {1873-6971},
abstract = {Satureja nervosa Desf. (Lamiaceae) contains structurally complex phenolic compounds, yet comprehensive chemical characterisation and mechanisms of bioactivity remain unexplored. This investigation identified and characterized bioactive constituents from eighteen wild Tunisian populations using water and ethanol extraction, established structure-activity relationships through systematic correlation analysis, and validated multi-target biological activities using in vivo disease models. HPLC-DAD-MS analysis with authentication against 13 commercial standards identified 49 phenolic compounds, including eleven previously unreported hydroxycinnamic acid-acylated flavone O-glycosides representing the first comprehensive report of such structures in Satureja, alongside multiple bioactive oligomeric caffeoyl derivatives (lithospermic acids, salvianolic acids, clinopodic acids). Water extracts demonstrated superior chemical diversity (31 vs 25 compounds) and phenolic content (97-1843 vs 2-161 mg/100 g DW) compared to ethanol extracts. Structure-activity correlation analysis identified specific oligomeric depsides as principal bioactive constituents: lithospermic acid-2 (R = 0.682, P < 0.01) for acetylcholinesterase inhibition and clinopodic acid K (R = 0.624, P < 0.01) for α-amylase inhibition. Elite water extracts demonstrated exceptional in vivo efficacy at 4 mg/mL in three Caenorhabditis elegans disease models: 63-64% increased survival against juglone-induced oxidative stress (wild-type N2), 75-78% metabolic rescue in daf-2(e1370) insulin-signalling mutants, and 62-75% neuroprotection against amyloid-β paralysis in the GMC101 Alzheimer's model, significantly outperforming ethanol extracts. The superior bioactivity of structurally complex oligomeric and acylated compounds compared to simple phenolic acids (rosmarinic acid constituting 58-83% of ethanol extracts) demonstrates multi-mechanistic effects beyond predictable phenolic antioxidant activity, establishing S. nervosa oligomeric phenolic derivatives as pharmacologically distinct bioactive natural products with validated multi-target therapeutic potential in vivo disease-relevant models.},
}
@article {pmid42419491,
year = {2026},
author = {Ellappan, S and Kujur, PP and Mondal, AC},
title = {The Autophagy-Senescence-Inflammasome Axis: A Novel Triad in Neurodegenerative Diseases?.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103248},
doi = {10.1016/j.arr.2026.103248},
pmid = {42419491},
issn = {1872-9649},
abstract = {Chronic neuroinflammation is a defining feature of brain ageing and neurodegenerative disorders, yet the molecular mechanisms responsible for its persistence remain incompletely understood. Although autophagy dysfunction, glial senescence, and inflammasome activation are well-established contributors to progressive neurodegeneration, these processes are often analysed independently or through pairwise interactions, leaving their collective contribution to persistent neuroinflammation and disease progression insufficiently defined. Here, we synthesise emerging evidence supporting an integrated 'Autophagy-Senescence-Inflammasome (ASI) axis', in which reciprocal interactions among impaired autophagy, senescent glia, and inflammasome signalling establish a self-sustaining cycle of neuroinflammation. We discuss how defective autophagy promotes mitochondrial dysfunction, oxidative stress, and danger signalling, while senescent astrocytes and microglia amplify inflammatory responses through the senescence-associated secretory phenotype (SASP). These intertwined processes converge on chronic inflammasome activation, with mitochondrial dysfunction emerging as a central mechanistic hub. Evidence across Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, stroke, and chronic neuropathic pain highlight the broad relevance of this pathological network. We further analyse current therapeutic strategies targeting autophagy, senescence, and inflammasome pathways, emphasising the limitations of single-target approaches and the potential of multi-target interventions. By integrating these processes into a unified framework, this review provides new insights into the possible molecular mechanisms underlying neuroinflammaging and identifies the 'ASI axis' as a promising target for neurodegenerative disease-modifying therapies.},
}
@article {pmid42419611,
year = {2026},
author = {Bolon, M and Barbereau, A and Aimard, M and Monge, C and Bouvet, P and Meissirel, C and Richard, S},
title = {Nose-to-brain delivery of an amyloid beta blocking peptide using polylactic acid-poloxamer 188 nanocarriers.},
journal = {Nanomedicine : nanotechnology, biology, and medicine},
volume = {75},
number = {},
pages = {102987},
doi = {10.1016/j.nano.2026.102987},
pmid = {42419611},
issn = {1549-9642},
abstract = {BACKGROUND: Alzheimer's disease, characterized by a progressive cognitive decline, represents a major global health challenge. A novel blocking peptide (seq: KRKKSRYKSWSVYVG) which binds with high affinity for toxic amyloid beta oligomers implicated in the early stages of the disease pathogenesis, has shown promising therapeutic potential. To overcome the challenges of brain drug delivery, nanoparticles combined with a nose-to-brain delivery approach were used to enhance brain biodistribution and drug delivery efficiency. In this study, we evaluated the feasibility of using these nanoparticles to deliver the blocking peptide to the brain.<br><br>RESULTS: Nanoparticles composed of polylactic acid and poloxamer P188 were synthesized and successfully functionalised with surface-adsorbed blocking peptide, exhibiting physicochemical characteristics suitable for nose-to-brain delivery. The nanoparticles preserved the blocking peptide therapeutic activity against amyloid beta aggregation and, in addition, protected it from enzymatic degradation. Functional cellular evaluation showed biocompatibility of the nanoparticle-blocking peptide compound and potential internalization by neuronal cells. Importantly, in vivo experiments demonstrated the successful delivery of the nanoparticles from the nasal cavity to the brain, representing a significant step forward in targeted brain delivery.<br><br>CONCLUSION: Nanoparticles functionalised with an anti-amyloid beta aggregation peptide successfully reached the brain following intranasal administration, suggesting their potential as a therapeutic strategy against the Alzheimer's disease.},
}
@article {pmid42419633,
year = {2026},
author = {Cauzzi, E and Ficchì, S and De Paolis, ML and Saba, L and Montanari, M and Loffredo, G and La Barbera, L and Krashia, P and Nobili, A and D'Amelio, M},
title = {Midbrain dopamine loss drives parvalbumin interneuron vulnerability through tissue plasminogen activator-linked perineuronal-net breakdown and hippocampal disinhibition.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107527},
doi = {10.1016/j.nbd.2026.107527},
pmid = {42419633},
issn = {1095-953X},
abstract = {Midbrain dopaminergic degeneration is an early feature of Alzheimer's Disease (AD), dementia with Lewy bodies (DLB), and AD-Parkinson's disease overlap (AD-PD). However, its direct contribution to the failure of hippocampal inhibitory-circuits, a pathological feature shared across these conditions, remains unresolved. Parvalbumin-positive interneurons (PV-INs) regulate hippocampal excitation-inhibition balance and are directly modulated by dopamine (DA). These neurons are protected by perineuronal nets (PNNs), extracellular-matrix structures supporting fast GABAergic signaling and neuronal resilience. We tested whether midbrain-derived DA loss is sufficient to destabilize hippocampal PV-IN function, potentially promoting their vulnerability or affecting PNN integrity. Through stereotaxic unilateral 6-hydroxy-dopamine lesion of the Ventral Tegmental Area/Substantia Nigra pars compacta in C57BL/6 N mice, we reduced the hippocampal DA tone and midbrain-derived synaptic input onto PV-INs. At 1-month post-lesion, PV-IN numbers were preserved, but the PNN integrity was reduced, accompanied by increased expression of tissue plasminogen activator (tPA), a PNN-remodeling protease. In CA1 pyramidal neurons, spontaneous inhibitory postsynaptic currents showed reduced frequency with faster decay, and bicuculline unmasked heightened population-spike excitability. By 6-months post-lesion, PV-IN numbers declined significantly, especially in CA1, demonstrating progressive vulnerability. D2/D3 receptor (D2/D3R) activation with quinpirole normalized tPA levels in PV-INs ex vivo, restored PNN integrity after sub-chronic treatment in vivo and increased inhibitory postsynaptic-event frequency, indicating functional recovery of GABAergic drive. These findings support the involvement of a DA-D2/D3R-tPA axis contributing to PV-IN extracellular-matrix integrity and hippocampal inhibitory tone. They also demonstrate that DA depletion is sufficient to trigger PNN breakdown, reduce GABAergic inhibition, network hyperexcitability, and cause progressive PV-IN loss independently of canonical protein aggregates like Aβ, tau or α-synuclein, characteristic of AD, DLB or AD-PD. This mechanism links midbrain degeneration to hippocampal circuit failure, highlighting D2/D3R signaling and extracellular proteolysis as actionable targets for early circuit stabilization across AD, DLB, and AD-PD.},
}
@article {pmid42420047,
year = {2026},
author = {Li, L and Gu, Y and Luo, X and Wang, J and Jia, Y and Yan, T},
title = {Corrigendum to "Chrysin reprograms microglial metabolism and function via targeting SYK to alleviate the symptoms of Alzheimer's disease" [J. Ethnopharmacol. (2026) 122056].},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {122169},
doi = {10.1016/j.jep.2026.122169},
pmid = {42420047},
issn = {1872-7573},
}
@article {pmid42420075,
year = {2026},
author = {Chew, V},
title = {Exercise-induced liver-to-brain communication in aging and Alzheimer's disease.},
journal = {Journal of hepatology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jhep.2026.06.003},
pmid = {42420075},
issn = {1600-0641},
}
@article {pmid42420092,
year = {2026},
author = {Newberg, AB and Hua, Y and Ayubcha, C and Monti, DA},
title = {Fluorodeoxyglucose PET Scans in the Integrative Medicine Setting.},
journal = {PET clinics},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.cpet.2026.06.001},
pmid = {42420092},
issn = {1879-9809},
abstract = {Functional imaging with fluorodeoxyglucose (FDG) PET has substantially advanced our understanding of the biological processes underlying a wide range of neurologic and systemic disorders. In particular, brain FDG PET enables the visualization of regional metabolic activity associated with different mental states and neuropsychiatric conditions. By assessing patterns of cerebral glucose metabolism, FDG PET can provide insight into an individual's current brain function, including age-related metabolic changes and early alterations suggestive of neurodegenerative disorders such as Alzheimer's disease. This article reviews potential indications for FDG PET scanning in integrative medicine practice and situates it within the broader landscape of functional imaging modalities.},
}
@article {pmid42420222,
year = {2026},
author = {Sobol, KV},
title = {Effects of Metabolites of Lactic Acid Bacteria on Nerve Cells of the Microbiota-Gut-Brain Axis.},
journal = {Biochemistry. Biokhimiia},
volume = {91},
number = {6},
pages = {867-892},
doi = {10.1134/S0006297926600377},
pmid = {42420222},
issn = {1608-3040},
mesh = {Humans ; Animals ; *Brain/metabolism ; *Lactobacillales/metabolism ; *Neurons/metabolism ; *Gastrointestinal Microbiome ; Probiotics ; },
abstract = {This review examines the key pathways of bidirectional communication between the gut and brain along the microbiota-gut-brain axis, with particular emphasis on the effects of metabolites of lactic acid bacteria (metLABs) on neurons of the enteric and central nervous systems. Special attention is given to the role of metLABs in intracellular signaling. The review further explores the direct effects of metLABs on mitochondrial function in nervous tissue, neuronal plasticity, and neuritogenesis. Potential mechanisms for the release of neurotrophic factors in both cells and host organism following exposure to metLABs or probiotic products are analyzed. Although clinical evidence remains limited, existing studies suggest that regular consumption of metLAB-containing fermented foods may positively influence brain functions through modulation of the microbiota-gut-brain axis. At least two ongoing clinical trials currently investigate whether normalization of the gut microbiota through probiotic interventions can slow the progression of Alzheimer's disease. As this field continues to advance rapidly, further studies are expected to provide important insights into the therapeutic potential of microbiota-targeted strategies for neurological health.},
}
@article {pmid42420230,
year = {2026},
author = {Blagova, AV and Perepelitsa, ES and Satish, A and Lifanov, DA and Zhdankina, VI and Kopylova, AA and Guk, PV and Salmina, AB and Illarioshkin, SN},
title = {Development of Metabolic Stress in Vascular Organoids under Normal Conditions and with AD/PD-Associated Genetic Backgrounds.},
journal = {Biochemistry. Biokhimiia},
volume = {91},
number = {6},
pages = {992-1005},
doi = {10.1134/S0006297926600286},
pmid = {42420230},
issn = {1608-3040},
mesh = {Humans ; *Organoids/metabolism/pathology ; *Parkinson Disease/metabolism/genetics/pathology ; Induced Pluripotent Stem Cells/metabolism/cytology ; *Alzheimer Disease/metabolism/genetics/pathology ; Mitochondria/metabolism ; Oxidative Stress ; Connexin 43/metabolism ; Endothelial Cells/metabolism ; *Stress, Physiological ; NAD/metabolism ; },
abstract = {Vascular organoids derived from human induced pluripotent stem cells (iPSCs) are promising models for studying vascular pathology, including neurodegenerative diseases. In this study, we investigated signs of mitochondrial dysfunction in the vascular organoids derived from the iPSCs of a healthy donor, as well as patients with Alzheimer's disease (AD) and Parkinson's disease (PD). In the conditioned medium of vascular organoids from the PD patient-derived cells, but not from the AD patient-derived cells, a trend toward a disrupted NAD[+]/NADH balance was observed, accompanied by the reduced expression of the connexin 43 (Cx43) protein. A sign of metabolic vulnerability of endothelial cells in the vascular organoids from the PD patient-derived cells, but not from normal or AD patient-derived organoids, manifested as reduced expression of c-Myc was observed. Changes in the membrane potential were detected in the vascular organoids from the AD and PD patient-derived, as well as increase in the mitochondrial superoxide anion production were observed, which may indicate development of oxidative stress in the microvessel cells during neurodegeneration.},
}
@article {pmid42420256,
year = {2026},
author = {He, CY and Wang, XY and Fan, J and Wang, YN and Masters, CL and Wang, YJ},
title = {Could the cognitive benefits of amyloid-beta clearance grow in time for Alzheimer's disease?.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-04188-y},
pmid = {42420256},
issn = {2158-3188},
support = {82588301//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82120108010//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82401695//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Alzheimer's disease (AD) is characterized histologically by amyloid-β (Aβ) deposition in the brain. Immunotherapies targeting Aβ clearance have become a leading treatment strategy. Although these therapies effectively reduce cerebral Aβ burden, their cognitive benefits remain modest during the trial period. This review systematically assesses the extent of Aβ clearance by immunotherapies and its related cognitive outcomes, focusing on whether cognitive benefits increase over time. We refine a model of the "lag effect" between plaque clearance and cognitive benefit, which is potentially influenced by clearance rate, treatment duration, disease stage, genetic factors, and aging. We also discuss the underlying biological mechanisms and potential neuroprotective targets. Future research should prioritize long-term studies, early intervention, personalized therapies, and combination approaches addressing multiple pathological pathways. Given limited short-term cognitive gains, optimizing outcomes will require tailoring treatments to individual patient factors-including genetics, disease progression, and aging-to minimize side effects and enhance long-term cognitive function.},
}
@article {pmid42420546,
year = {2026},
author = {Nour, H and Mounadi, N and Samadi, A and Chtita, S},
title = {Stylopine as multi-target anti-Alzheimer agent.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-61364-2},
pmid = {42420546},
issn = {2045-2322},
support = {#12R282//Zayed Bin Sultan Center for Health Sciences, United Arab Emirates University/ ; },
abstract = {Alzheimer's disease is a complex neurodegenerative disorder involving multiple enzymes, such as acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), monoamine oxidase B (MAO-B), and β-secretase (BACE-1). Currently available treatments are limited to acetylcholinesterase inhibitors, which offer purely symptomatic relief and do not halt disease progression. Consequently, the development of multi-target ligands represents a promising therapeutic approach. In this study, Alkaloids were evaluated using in silico approaches. Predictions of biological activity performed using the PASS software revealed stylopine as a promising candidate with potential anti-Alzheimer activity. Furthermore, this compound demonstrated strong binding affinity for key targets (Torpedo AChE, BuChE, and BACE-1), as well as a promising pharmacokinetic profile. Molecular dynamics simulations and MM-GBSA calculations have demonstrated the stability of stylopine-target interactions. Taken together, these studies suggest that stylopine could be a promising multitarget agent for the treatment of Alzheimer's disease, although further experimental data are needed to confirm its efficacy.},
}
@article {pmid42420985,
year = {2026},
author = {Liu, Z and Ao, WL and Luo, AD and Guan, SQ and Wang, J and Yu, CY and Xu, ZC and Xu, P and Huang, H},
title = {Microglia-mediated synaptic pruning in neural circuit remodeling: multidimensional control in homeostasis and neuropathology.},
journal = {BMC medicine},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12916-026-05016-2},
pmid = {42420985},
issn = {1741-7015},
support = {Qiankehe Foundation - ZSYS(2025)030//the Key Laboratory of Brain Function and Brain Disease Prevention and Treatment of Guizhou Province/ ; CXTD[2022]013//the Guizhou Basic and Clinical Research Scientific and Technological Innovation Talent Team Project/ ; GCC-2022-038-1//the Guizhou Provincial "Hundred" Level Innovative Talents Fund/ ; },
abstract = {BACKGROUND: Microglia, the resident immune cells of the central nervous system, are key regulators of synaptic plasticity and neural circuit homeostasis.<br><br>MAIN BODY: This review summarizes the mechanisms by which microglia shape synaptic structure and function, including dynamic synaptic interactions, selective pruning, epigenetic regulation, extracellular matrix remodeling, metabolic adaptation, and communication with other glial cells. Under physiological conditions, these processes support circuit refinement, synaptic stability, and cognition, which are modulated by circadian rhythms and the microbiota-gut-brain axis. In Alzheimer's disease, schizophrenia, and related disorders, microglial dysfunction can shift synaptic pruning from a controlled homeostatic process to pathological synapse loss. Excessive complement-mediated pruning, disrupted excitation-inhibition balance, neuroinflammation, and metabolic dysregulation may jointly impair synaptic integrity and circuit function.<br><br>CONCLUSION: This review highlights microglial heterogeneity, state transitions, and targeted modulation as important directions for understanding synaptic remodeling and developing therapeutic strategies for neurological diseases.},
}
@article {pmid42421081,
year = {2026},
author = {Watkins, MM and Xhafkollari, G and Zhao, N and Ross, OA},
title = {Understanding the genetic imperfections of Lewy body dementia.},
journal = {Molecular neurodegeneration},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13024-026-00961-1},
pmid = {42421081},
issn = {1750-1326},
support = {AG087165/NH/NIH HHS/United States ; U54-NS110435/NH/NIH HHS/United States ; NA//American Brain Foundation/ ; NA/ALZ/Alzheimer's Association/United States ; NA//Michael J. Fox Foundation for Parkinson's Research/ ; NA//American Parkinson Disease Association/ ; NA//Lewy Body Dementia Association/ ; },
abstract = {Lewy body dementia (LBD) is a clinically and pathologically complex neurodegenerative disease. Its etiology remains poorly understood and, as such, it is likely underdiagnosed in clinical practice. Clinically, LBD is defined by fluctuations in cognition, visual hallucinations, rapid eye movement (REM) sleep behavior disorder (RBD), and motor dysfunction. The disease is pathologically defined by the presence of Lewy bodies in the brain, which are protein aggregates made up of misfolded α-synuclein; however, co-pathologies are often present and greatly complicate both symptom presentation and research interpretation. This heterogeneous pathology paired with overlapping clinical features of Alzheimer's disease and Parkinson's disease hinder diagnostic clarity. With no specific biological biomarkers currently identified, it is the hope that genetics can help with diagnosis and to clarify the pathomechanistic nature of this multifaceted disorder. Through rare familial studies, SNCA, the gene which encodes α-synuclein, was implicated in disease risk and development, underscoring its central role in α-synucleinopathies. Shortly after this discovery, a genome wide association study (GWAS) confirmed this risk, and identified two other major genes, APOE and GBA, to be associated with LBD. The APOE ε4 allele, which is a well-established risk factor for AD, is also associated with an increased risk for LBD. This common association demonstrates that APOE is implicated in a broader role in neurodegenerative disease pathogenesis. Meanwhile, GBA mutations, which are associated with lysosomal dysfunction and are also a known risk factor for PD, are linked to a more severe cognitive decline and earlier disease onset. However, even with these advances, our understanding of LBD's genetic architecture remains incomplete. Overcoming these limitations will require larger, more diverse study cohorts, comprehensive analyses, technological advances, and improved phenotyping upon clinical presentation of disease. Current clinical diagnostic strategies often struggle to capture the full spectrum of LBD symptoms and commonly lead to misdiagnosis/misclassification. By combining genetic data with improved phenotyping and the latest novel technologies, we can greatly improve our mechanistic understanding of LBD. These insights will not only improve diagnostic accuracy but will also lead to the development of disease modifying treatments specifically designed to best treat each individual patient.},
}
@article {pmid42421403,
year = {2026},
author = {Lim, EY and Han, K and Cho, AH},
title = {Role of Physical Activity in Protecting Against Dementia According to Menopausal Status.},
journal = {Journal of clinical neurology (Seoul, Korea)},
volume = {22},
number = {4},
pages = {427-436},
doi = {10.3988/jcn.2025.0615},
pmid = {42421403},
issn = {1738-6586},
support = {SC21ZISE0149/SSMH/Seoul St. Mary's Hospital, Catholic University of Korea/Korea ; },
abstract = {BACKGROUND AND PURPOSE: This study evaluated the impact of physical activity on dementia risk in females while considering their menopausal status and body mass index (BMI) as potential modifiers.<br><br>METHODS: This population-based retrospective cohort study utilized the Korean National Health Insurance Service database, and stratified 2,163,842 females aged &#x2265;40 years who underwent health examinations in 2009 into pre- and postmenopausal groups. Cox proportional-hazards models were used to estimate the adjusted hazard ratios (aHRs) for all-cause dementia, Alzheimer's dementia (AD), and vascular dementia (VaD) according to physical activity levels. Interaction terms were used to assess effect modification by BMI.<br><br>RESULTS: Regular physical activity was associated with a reduced risk of all-cause dementia and AD, but not VaD in premenopausal females (aHR=0.830, 95% confidence interval [CI]=0.739-0.931) and a reduced risk of all-cause dementia, AD, and VaD in postmenopausal females (e.g., aHR=0.884, 95% CI=0.868-0.900). The association between physical activity and dementia risk was largely consistent across BMI categories. However, a modest interaction was observed for light physical activity (LPA) (p=0.046), with a significant risk reduction in postmenopausal women with BMI &#x2265;25.0 kg/m&#xb2; (aHR=0.942, 95% CI=0.921-0.964).<br><br>CONCLUSIONS: Physical activity is associated with a lower risk of dementia in both pre- and postmenopausal females. Among postmenopausal females, even LPA such as walking may confer protective benefits, particularly in those with higher BMIs.},
}
@article {pmid42421594,
year = {2026},
author = {Medina, C and Fernández, RS and Krawczcyk, MC and Boccia, MM},
title = {Hippocampal prediction errors and claustral control at the perception-memory crossroads.},
journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences},
volume = {381},
number = {1954},
pages = {},
doi = {10.1098/rstb.2025.0253},
pmid = {42421594},
issn = {1471-2970},
support = {//Secretar&#xed;a de Ciencia y T&#xe9;cnica, Universidad de Buenos Aires/ ; },
mesh = {Animals ; *Hippocampus/physiology ; *Memory/physiology ; *Perception/physiology ; Humans ; *Claustrum/physiology ; Bayes Theorem ; Models, Neurological ; },
abstract = {Prediction errors (PEs)-the mismatches between what the brain expects and what it encounters-drive the continual alignment of perception with memory. Here, we review cross-species evidence showing that this cycle depends on hippocampal predictions that bridge sensory perception and declarative memory. The hippocampus generates probabilistic forecasts via pattern completion and separation, while the claustrum-a multisensory hub-constrains those forecasts with integrated perceptual evidence, jointly shaping the magnitude of the resulting PE signal. We combine two explanatory lenses: Bayesian inference, which prescribes how strongly a PE should update prior beliefs, and connectionist models, which reveal how local, neuromodulator-gated plasticity approximates that normative update in real circuits. Dopaminergic and cholinergic signals tune PE precision and experimental inactivation of the claustrum in mice impairs hippocampal-dependent memory reconsolidation, establishing causality in this perception-to-memory loop. We propose that aberrant PE calibration accounts for cognitive symptoms in Alzheimer's disease, schizophrenia and learning disorders. We also outline pharmacological and circuit-level strategies to normalize PEs, and a research agenda combining ultra-high-field imaging, causal manipulations and hybrid Bayesian-connectionist modelling. Clarifying how the hippocampus and claustrum cooperate to align perception with memory promises biomarkers and precision therapies for cognitive disorders. This article is part of the theme issue 'The role of hippocampal predictions in cognition: bridging perception and memory'.},
}
@article {pmid42421820,
year = {2026},
author = {Brosch, JR and Wang, S and Apostolova, LG and Agarwal, A and Allen, JW and Gutmann, L and Tobar, M and Gonzalez, L and Johnson, D and Treadway, L and Connolly, J and Tang, A and Lettich, E and Davies, S and Kuhn, N and Hammers, DB and Clark, D and Farlow, M and Willis, DR and Fowler, N and Wilcock, DM},
title = {The Indiana University Brain Health Program to deliver amyloid-targeted therapy to Alzheimer's disease patients.},
journal = {Alzheimer's &amp; dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70291},
pmid = {42421820},
issn = {2352-8737},
abstract = {INTRODUCTION: The Indiana University Brain Health Program was developed to support safe implementation of amyloid-targeting therapies (ATTs) for early Alzheimer's disease (AD).<br><br>METHODS: We established Neurology Brain Health Navigators (neuroBHNs) to extend our Brain Health Navigator model into specialty care. NeuroBHNs pre-screen patients for ATT eligibility, coordinate biomarker and imaging evaluation, provide structured education, and guide treatment initiation and monitoring. The program includes a dedicated social worker and insurance pre-authorization specialist to streamline infusion access. Blood pressure is monitored at each visit, and infusions are deferred if readings exceed 140/90&#xa0;mmHg.<br><br>RESULTS: Through December 16, 2025, 243 patients initiated lecanemab therapy. Apolipoprotein E (APOE) &#x3b5;4 homozygotes were not excluded; 74% of treated patients carried at least one Apo&#x3b5;4 allele. The ARIA rate was 13.2%, and 40% of patients experienced infusion-related reactions.<br><br>CONCLUSIONS: A navigator-centered model can efficiently deliver ATT while supporting structured education, screening, and safety monitoring, potentially contributing to favorable safety outcomes.},
}
@article {pmid42421969,
year = {2026},
author = {Xu, G and Cheng, Z and Zhou, Y and Guo, L and Zhu, H and Shen, Z},
title = {Osteoimmuno-brain axis: a bridge connecting osteoporosis and cognitive decline and its clinical significance in dementia and Alzheimer's disease.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1866071},
pmid = {42421969},
issn = {1664-3224},
mesh = {Humans ; *Alzheimer Disease/immunology/metabolism ; *Osteoporosis/immunology/metabolism ; *Brain/immunology/metabolism ; Animals ; *Cognitive Dysfunction/immunology/metabolism ; *Bone and Bones/immunology/metabolism ; *Dementia/immunology/metabolism ; Cytokines/metabolism ; },
abstract = {Osteoporosis and cognitive dysfunction, particularly Alzheimer's disease (AD), frequently co-occur in the elderly population, suggesting shared pathophysiological links. The emerging concept of the "osteoimmune-brain axis" provides a framework that emphasizes the immune system as the central mediator connecting skeletal and cerebral pathology. This review explores how the osteoimmune system-the dynamic interface between bone and immune interactions-influences brain function through pathways including systemic inflammation, cytokine release, and bone-derived hormones. We systematically synthesize evidence from basic mechanisms to clinical studies, with a critical appraisal of the strength and directionality of the evidence. Key questions addressed include: whether the observed associations are causal or merely associative; which bone-derived factors have human validation; and whether the axis primarily operates as a unidirectional driver, a bidirectional amplifier, or an epiphenomenon of shared aging processes. This review aims to provide a balanced theoretical foundation for future research and for developing prevention strategies targeting both skeletal and neurodegenerative diseases.},
}
@article {pmid42422091,
year = {2026},
author = {Herrera-Calderon, O and Calva, J and Guzmán-Flores, JM and Peña-Rojas, G and Andia-Ayme, V and Loyola-Gonzales, E and Pari-Olarte, JB and Almeida-Galindo, JS},
title = {Chemical and enantioselective GC-MS characterization of Minthostachys mollis (Benth.) Griseb. Essential oil from Peru and its acetylcholinesterase inhibitory activity.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1864128},
pmid = {42422091},
issn = {1663-9812},
abstract = {BACKGROUND: Minthostachys mollis (Benth.) Griseb., an aromatic medicinal plant widely used in traditional medicine in Peru, was investigated using an integrated chemical, enantioselective, and acetylcholinesterase (AChE) inhibitory approach.<br><br>AIM: To characterize the chemical and enantiomeric composition of M. mollis essential oil by GC-MS, evaluate its AChE inhibitory activity in vitro, and explore the molecular interactions of its volatile constituents with human AChE through molecular docking and molecular dynamics simulations.<br><br>METHODS: The essential oil (EO) collected from the leaves via steam distillation was analyzed using Gas Chromatography-Mass Spectrometry (GC-MS). Enantioselective GC-MS analysis was performed for the first time on this species. AChE inhibitory activity was evaluated in vitro using Ellman's assay, and molecular docking and molecular dynamics studies were performed on human AChE (PDB: 4EY7).<br><br>RESULTS: GC-MS analysis revealed 33 volatile compounds, of which 30 were structurally identified, accounting for 100% of the total EO composition. Oxygenated monoterpenes were the predominant chemical class (86.24%), with pulegone (63.82%) as the major constituent, followed by carvacrol (5.52%), 1,8-cineole (5.50%), and (E)-isocitral (4.98%). Enantioselective analysis revealed a marked stereochemical preference, including enantiomerically pure (S)-(-)-limonene and (1R,5R)-(+)-sabinene, as well as the predominance of (1S,5S)-(-)-&#x3b1;-pinene (92.54%, e.e. = 84.97%) and (1S,5S)-(-)-&#x3b2;-pinene (80.63%, e.e. = 61.86%). The AChE inhibitory activity showed a moderate inhibitory effect of the EO, with an IC50 value of 466.4 &#xb1; 1.01 &#x3bc;g/mL. Sesquiterpenes such as &#x3b3;-muurolene, &#x3b4;-amorphene, and &#x3b2;-bourbonene exhibited the most favorable binding affinities (&#x394;G values ranging from -7.3 to -7.0 kcal/mol), mainly mediated by hydrophobic interactions within the catalytic and peripheral anionic sites.<br><br>CONCLUSION: This study provides a comprehensive chemical and stereochemical characterization of M. mollis EO, supporting its relevance as a source of bioactive volatile compounds with moderate AChE inhibitory activity.},
}
@article {pmid42422111,
year = {2026},
author = {Wang, J and Fu, X and Liu, J and Yang, Y},
title = {Non-invasive brain stimulation in frontotemporal dementia: syndrome-specific signals and priorities for future trials.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1842455},
pmid = {42422111},
issn = {1663-4365},
abstract = {Frontotemporal dementia is the second most common cause of young-onset dementia after Alzheimer's disease and lacks disease-modifying treatment. This narrative review summarizes human studies of non-invasive brain stimulation, including repetitive transcranial magnetic stimulation and theta-burst stimulation, transcranial electrical stimulation, and transcranial photobiomodulation, in frontotemporal dementia and primary progressive aphasia. We review stimulation targets, protocols, outcomes, and safety, and organize the evidence by clinical subtype and modality. Current data remain preliminary, but recurrent signals support prefrontal and cerebellar repetitive transcranial magnetic stimulation/theta-burst stimulation and prefrontal or temporoparietal transcranial direct current stimulation, particularly in primary progressive aphasia. By contrast, controlled evidence in behavioral-variant frontotemporal dementia is limited and heterogeneous. Future trials should be sham-controlled, multicenter, and syndrome-stratified; combine stimulation with symptom-relevant cognitive or language therapy; and incorporate biomarker-informed targeting, target-engagement measures, and longer follow-up to determine durability and clinical relevance.},
}
@article {pmid42422112,
year = {2026},
author = {Ye, P and Li, Z and Cui, X and Wu, H and Jiang, H},
title = {ZBTB7A-mediated regulation of astrocytic glycolysis in neurodegenerative diseases: insights from literature review and bioinformatics prediction.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1852019},
pmid = {42422112},
issn = {1663-4365},
abstract = {The incidence of neurodegenerative diseases, including Alzheimer's disease (AD), continues to increase with the extension of human lifespan. However, their pathogenesis remains incompletely understood. Altered energy metabolism, particularly glucose metabolism involving glycolysis and oxidative phosphorylation, is widely recognized as an early pathological feature of neurodegenerative diseases. Astrocytes, the most numerous and widely distributed functional cells in the central nervous system (CNS), support neuronal energy demands through the astrocyte-neuronal lactate shuttle (ANLS). Glycolysis is a major pathway of astrocyte energy metabolism, and enhanced astrocytic glucose uptake and glycolytic flux may help attenuate the progression of neurodegenerative diseases such as AD. Zinc Finger and BTB Domain Containing 7A (ZBTB7A) is a POZ/BTB and Krüppel (POK) family transcription factor that has been implicated in the regulation of metabolic genes, including glycolysis-related genes, in several cellular contexts. However, its role in astrocyte glycolytic regulation under neurodegenerative conditions remains unclear. In this review, we summarize current knowledge of ZBTB7A biology, astrocyte glycolysis, and glial metabolic dysfunction in neurodegenerative diseases, and integrate published evidence with bioinformatics-based transcription factor binding prediction. Our analysis identified putative ZBTB7A-binding motifs in promoter regions of genes involved in glucose uptake, glycolytic flux, lactate production, and lactate transport. These findings suggest a potential association between ZBTB7A and the astrocytic glycolytic/lactate metabolic network. Therefore, this review provides a conceptual basis for future studies on ZBTB7A-associated transcriptional regulation in astrocyte metabolic remodeling and its potential relevance to neurodegenerative diseases.},
}
@article {pmid42422228,
year = {2026},
author = {Sukreet, S and Donohue, MC and Ngolab, J and Belsha, A and Salazar, J and Cohen, P and Jaiswal, S and Tan, V and Aggarwal, NT and Alber, J and Johnson, K and Jicha, GA and van Dyck, CH and Ramanan, S and Lah, JJ and Salloway, S and Verdooner, SR and Rafii, MS and Aisen, PS and Sperling, RA and Rissman, RA},
title = {Relationships between longitudinal retinal amyloid imaging and amyloid PET in the A4 Trial.},
journal = {Alzheimer's &amp; dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70422},
pmid = {42422228},
issn = {2352-8729},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is associated with retinal amyloid-related changes, which may help identify amyloid positron emission tomography (PET) positive (+) individuals. Previously, in a small cross-sectional study, we reported higher retinal spot counts (RSCs) in preclinical amyloid PET (+) individuals screened for the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial compared to control individuals enrolled in the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) trial before drug treatment.<br><br>METHODS: Eligible volunteers had retinal scans 48&#xa0;hours after consuming curcumin. Scans were processed and quantified via NeuroVision. Participants were grouped by amyloid status and treatment to assess the effect of solanezumab on RSC.<br><br>RESULTS: RSC did not differ significantly over time between groups and was not modified by treatment, diverging from the cross-sectional retinal amyloid findings observed in A4/LEARN.<br><br>DISCUSSION: Curcumin-based retinal amyloid labeling shows promise but needs standardized protocols and validation in larger cohorts to understand its relationship to amyloid PET.},
}
@article {pmid42422229,
year = {2026},
author = {Jarholm, JA and Tecelão, S and Kirsebom, BE and Ghazi, MM and Pålhaugen, L and Gísladóttir, B and Gonzalez-Ortiz, F and Akhavi, MS and Hopp, E and Fjell, AM and Timón-Reina, S and Nielsen, M and Blennow, K and Aarsland, D and Bjørnerud, A and Selnes, P and Fladby, T},
title = {Independent prognostic value of peak width of skeletonized mean diffusivity on clinical progression in Alzheimer's disease.},
journal = {Alzheimer's &amp; dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70416},
pmid = {42422229},
issn = {2352-8729},
abstract = {INTRODUCTION: Peak width of skeletonized mean diffusivity (PSMD) is a candidate magnetic resonance imaging marker for global white matter integrity. We investigated the value of PSMD in predicting clinical progression in amyloid-positive and amyloid-negative individuals.<br><br>METHODS: PSMD, cognition, and amyloid status were measured in 254 subjects from the Dementia Disease Initiation (DDI) cohort and 211 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Survival analysis was conducted on 166 DDI subjects and validated in 178 ADNI subjects using Clinical Dementia Rating scale.<br><br>RESULTS: High PSMD amyloid-positive individuals had an increased risk of clinical progression relative to those with low PSMD, driven by independent additive effects of amyloid pathology and PSMD. Higher PSMD was predominantly associated with slower processing speed and reduced executive function, but not with memory performance.<br><br>DISCUSSION: Combining PSMD with amyloid status may improve the prediction of clinical progression in Alzheimer's disease, particularly in relation to executive and processing speed domains.},
}
@article {pmid42422257,
year = {2026},
author = {Tian, C and Yang, S and Zhang, X and Yan, H},
title = {Ligand-specific duality of aryl hydrocarbon receptor signaling in cognitive health: from environmental neurotoxicity to microbiome-mediated neuroprotection.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1823961},
pmid = {42422257},
issn = {1662-4548},
abstract = {The aromatic hydrocarbon receptor (AhR) is a key molecular interface integrating environmental chemical signals with host-microbiome metabolism, with profound effects on brain function. This review systematically addresses the ligand-specific duality of AhR signaling in cognitive health, comparing the predominantly neurotoxic signaling driven by environmental polycyclic aromatic hydrocarbons (PAHs) with the predominantly neuroprotective signaling mediated by gut microbiota-derived tryptophan metabolites. However, this dichotomy is context-dependent rather than absolute. PAHs activate AhR in a sustained, high-affinity manner, engaging downstream NF-κB neuroinflammation, NLRP3 inflammasome activation, oxidative stress, synaptic dysfunction, and transgenerational epigenetic alterations. In contrast, microbiota-derived metabolites such as indole-3-propionic acid (IPA) and kynurenic acid (KYNA) elicit transient, low-affinity AhR activation that engages cell-type-specific programs promoting anti-inflammatory responses, neurogenesis, blood-brain barrier integrity, and neuronal homeostasis. Critically, the outcome of AhR activation is modulated by ligand pharmacokinetics, cell-type identity, temporal dynamics of receptor engagement, and tissue-specific co-factor availability. These contextual variables determine whether AhR functions as a driver of neurodegeneration or a guardian of cognitive resilience. We further examine the divergent roles of AhR in Alzheimer's and Parkinson's diseases, where the balance between detrimental and protective ligands determines disease progression. Finally, we discuss therapeutic strategies targeting the AhR-gut-brain axis, including dietary modulation, probiotic interventions, and selective AhR modulators. Understanding the context-dependent outcomes of AhR activation provides a framework for developing precision approaches to preserve cognitive function and prevent neurodegeneration.},
}
@article {pmid42422260,
year = {2026},
author = {Akhbari, M and Babaei, F and Navidi-Moghaddam, A and Ghafghazi, S and Khodabandehloo, F and Sarookhani, MR and Dargahi, L and Mohammadi, G and Nassiri-Asl, M},
title = {The effects of Saccharomyces boulardii on TLR4/NF-κB neuroinflammatory pathway in the hippocampus of LPS-induced rats.},
journal = {IBRO neuroscience reports},
volume = {21},
number = {},
pages = {199-206},
pmid = {42422260},
issn = {2667-2421},
abstract = {Saccharomyces boulardii (Sb), a probiotic yeast, is known for its positive effects on gastrointestinal and metabolic health. Recent research has explored its potential to influence neurological conditions by modulating neuroinflammatory responses via the gut-brain axis. Toll-like receptor 4 (TLR4) is recognized as a key molecular target in regulating neuroinflammation, particularly in disorders like Alzheimer's disease (AD). This study investigated whether Sb could alleviate downstream elements of the TLR4 neuroinflammatory pathway in a lipopolysaccharide (LPS)-induced rat model relevant to AD. Rats were randomly assigned to four groups: 1) control, 2) LPS, 3) Sb + LPS, and 4) Sb alone. All groups received either normal saline or Sb (a volume of 1 ml containing 10 [10] CFU) by oral gavage for four weeks. From day 14, LPS (250 μg/kg/day) or saline was administered intraperitoneally for nine days. Researchers assessed spatial memory, levels of TLR4 pathway-associated proteins in the hippocampus, pro-inflammatory cytokine expression, and neuronal survival using Nissl staining. The results showed that pre-treatment with Sb partially ameliorated spatial learning deficits, significantly reducing the LPS-induced elevation of nuclear factor kappa B (NF-κB) and interleukin-1β (IL-1β) in the hippocampus and protecting against neuronal loss in the hippocampal CA1 region. Sb mitigates LPS-induced neuroinflammation by modulating downstream elements of the TLR4 pathway-specifically NF-κB and IL-1β-rather than acting directly on the TLR4 receptor, likely through mechanisms involving the gut-brain axis.},
}
@article {pmid42422474,
year = {2026},
author = {Bosco, C and Shojaei, F and Theisz, AA and Nguyen, V and Song, H and Han, R and Torres, JO and Chheda, D and Lin, J and Peng, X and Waseem, NZ and Simpkins, C and Cureton, B and Himes, AK and Jessup, NM and Indiana, YL and Hendrie, HC and Barnes, PA and Hill, CV and Shih, PC},
title = {"I don't see anything specifically about Black/African Americans." Testing an Alzheimer-specific generative AI tool tailored for African American/Black communities.},
journal = {ACM transactions on computing for healthcare},
volume = {7},
number = {3},
pages = {},
pmid = {42422474},
issn = {2637-8051},
abstract = {Low levels of health literacy concerning Alzheimer's Disease and related dementias (ADRD) impact African American/Black communities access to appropriate ADRD care. Additionally, a legacy of mistrust in medical research due to systemic racism, has resulted in insufficient participation in ADRD clinical trials among African American/Black adults. This study explores the potential of generative AI to improve ADRD literacy and encourage participation in clinical trials among African American/Black older adults. We designed a mobile health intervention featuring AI-driven conversational agents - a chatbot and a voice assistant - specifically developed for this population. We tested the quality of the intervention using heuristics methodology adapted to the target population along with inputs from African American/ Black medical professionals and UX designers. Key findings highlight the unique needs of the African American/Black communities for culturally relevant content that is accessible to users with varying language levels and tailored to users' geographical location. Concerning the interaction, high levels of personalization and control over the interaction can promote the use of the tool, by minimizing complexity and maximizing accessibility. These findings show the novel contribution offered by our study in the domain of designing health technology with generative AI, particularly LLMS, for African American/Black communities.},
}
@article {pmid42422539,
year = {2026},
author = {Geron, C and Maquet, P},
title = {ABCA7 Mutation in Behavioral Variant of Frontotemporal Dementia: A Case Report.},
journal = {Case reports in neurology},
volume = {18},
number = {1},
pages = {317-324},
pmid = {42422539},
issn = {1662-680X},
abstract = {INTRODUCTION: Frontotemporal lobar degeneration (FTLD), a major cause of early-onset dementia, includes a heterogeneous group of neurodegenerative disorders with a strong genetic component. Mutations in MAPT, GRN, and C9orf72 are found in about 40% of patients with the behavioral variant (bvFTD). More recently, rarer pathogenic variants have been identified in other genes, such as ABCA7, initially linked to Alzheimer's disease but increasingly implicated in other neurodegenerative conditions. Here we describe a specific variant which has not previously been reported in the literature.<br><br>CASE PRESENTATION: We report the case of a 42-year-old woman who presented with progressive behavioral changes and executive dysfunction, consistent with a bvFTD. A whole-exome sequencing was conducted in a family trio, revealing a heterozygous nonsense variant in the ABCA7 gene (c.5260C>T, p.Arg1754*).<br><br>CONCLUSION: This case highlights support the hypothesis of an ABCA7 loss-of-function associated with early-onset bvFTD. It contributes to expand the genetic spectrum of frontotemporal dementia and underscores the importance of broad genetic testing.},
}
@article {pmid42422549,
year = {2026},
author = {Ruesga Mundo, S},
title = {Hierarchical-circular model of biological memory: a multilevel hypothesis for pathogenesis and allostatic integrity in Alzheimer's disease and related dementias.},
journal = {Frontiers in dementia},
volume = {5},
number = {},
pages = {1841647},
pmid = {42422549},
issn = {2813-3919},
abstract = {INTRODUCTION: Alzheimer's disease and related dementias remain largely resistant to disease-modifying therapies, despite decades of research focused on linear neuropathological pathways such as beta-amyloid and tau. Persistent paradoxes-including the dissociation between pathology burden and clinical expression, the impact of early-life stress, and the role of systemic factors-indicate the need for integrative theoretical frameworks. This article proposes a multilevel hypothesis conceptualizing dementias as disorders of biological memory and allostatic integrity rather than isolated brain pathologies.<br><br>HYPOTHESIS: The Hierarchical-Circular Model of Biological Memory posits that dementia emerges from progressive disruptions in a circular, multilevel system that encodes and stabilizes biological information across the lifespan. The model is organized around the unifying principle "Signal &#x2192; Plasticity &#x2192; Stable State" and integrates five interconnected levels: (1) morphogenetic programming and genetic architecture, (2) epigenetic molecular memory, (3) allostatic load and systemic physiological adaptation, (4) the Psychological-Neurological-Endocrine-Immunological (PNEI) network, and (5) interoceptive-neuronal integration. At any level, perturbation can propagate bidirectionally through the system, establishing maladaptive stable states that manifest clinically as dementia.<br><br>DEVELOPMENT OF THE HYPOTHESIS: Through a structured synthesis of longitudinal, mechanistic, and multisystem studies (2010-2025), the model specifies how gene-environment interactions, epigenetic modifications, cumulative allostatic load, neuroimmune dynamics, and altered interoceptive timescales jointly shape vulnerability and resilience. The concept of allostatic integrity is introduced as a dynamic systems-level property-distinct from allostatic load-that explains why similar neuropathological burdens may result in divergent clinical trajectories. Distinct dementia phenotypes are proposed to reflect different patterns of circular reinforcement across the five levels.<br><br>TESTABLE PREDICTIONS: This framework generates concrete, falsifiable predictions: (1) composite indices of allostatic integrity will outperform single biomarkers in predicting conversion from mild cognitive impairment to dementia; (2) multidomain interventions targeting more than one system level will have multiplicative, rather than additive, effects on slowing cognitive decline; (3) patients with similar amyloid/tau profiles but contrasting allostatic integrity will show markedly different trajectories of clinical progression; and (4) allostatic integrity moderates the protective effect of cognitive reserve, a pattern not predicted by reserve frameworks alone.<br><br>CONCLUSION: The Hierarchical-Circular Model of Biological Memory offers a unifying hypothesis for Alzheimer's disease and related dementias that bridges genetic, epigenetic, physiological, neuroimmune, and interoceptive processes across the lifespan. By reframing dementias as failures of biological memory and allostatic integrity, the model provides a conceptual roadmap for mechanistic research, multidomain prevention, and personalized treatment strategies.},
}
@article {pmid42422561,
year = {2026},
author = {Riccardi, N and Martin, A and Pytel, D and Newman-Norlund, S and Carroll, SL and Rorden, C and Fridriksson, J and Bonilha, L},
title = {Brain age gradients as intermediate phenotypes linking plasma p-tau217 to cognition in community-dwelling older adults.},
journal = {NPJ dementia},
volume = {2},
number = {1},
pages = {54},
pmid = {42422561},
issn = {3005-1940},
abstract = {Deep learning-based brain age models quantify regional deviations from normative aging and may capture structural changes relevant to dementia risk. Plasma phosphorylated tau-217 (p-tau217) is a scalable Alzheimer's disease biomarker, but its relationship to brain aging and cognition in cognitively unimpaired adults is unclear. In this cross-sectional study, we tested whether brain age patterns serve as indirect pathways linking plasma p-tau217 to cognition in the Aging Brain Cohort (ABC). Neuroimaging data from 518 adults (mean age = 43.7 years, 70.8% female) were analyzed using a validated deep learning brain age model, and decomposed via exploratory factor analysis into six gradients: frontal, dorsal, ventral, left frontotemporal, right frontotemporoparietal, and bilateral parietal. In a parallel mediation model including all six gradients as simultaneous mediators in adults aged ≥60 years (N = 71), a significant specific indirect effect of plasma p-tau217 on Montreal Cognitive Assessment (MoCA) scores was observed through accelerated right frontotemporoparietal aging (β = -0.111, 95% CI [-0.313, -0.010], p = 0.031). No other indirect pathways were significant, and neither the total nor direct effect was significant. These findings suggest a specific brain aging phenotype as a potential intermediate pathway linking tau-related pathology to cognition prior to clinical impairment.},
}
@article {pmid42422911,
year = {2026},
author = {Secco, GL and Qureshi, K and Shafeea, MS and Karpinski, PH and Wouters, K and Merlim da Silva, MC and Ganta, SR and von Quednow, E and Guzmán-Ríos, ED and Brice, KS and Dsouza, M and Fernandes, A and Noori, NN and Chaurasia, B and Yangi, K},
title = {Clinical, Radiological, and Immunohistological Distinctions Between Limbic-Predominant and Typical Alzheimer's Disease: A Systematic Review.},
journal = {Brain and behavior},
volume = {16},
number = {7},
pages = {e71586},
doi = {10.1002/brb3.71586},
pmid = {42422911},
issn = {2162-3279},
mesh = {Humans ; *Alzheimer Disease/pathology/diagnostic imaging/physiopathology/classification/metabolism ; *Limbic System/pathology/diagnostic imaging ; Atrophy ; Hippocampus/pathology/diagnostic imaging ; Temporal Lobe/pathology ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia worldwide and one of the leading causes of morbidity and mortality among elderly people. It is characterized by generalized brain atrophy, especially affecting the hippocampus and medial temporal lobe. In this context, new subtypes of AD have been documented, including a limbic-predominant subtype (LP), and the current literature is insufficient to clarify the similarities and differences between these subtypes and the typical presentation. Recently, new studies have proposed a clinical criterion for LP amnestic syndrome, separating it from AD. Therefore, this study aims to evaluate the clinical, radiological, and immunohistological distinctions between those two presentations.<br><br>METHODS: This study was conducted in accordance with the PRISMA guidelines. Notable databases were utilized for sources: PubMed, Embase, and Web of Science. Baseline characteristics, clinical, radiological, and immunohistological features, and follow-up times were recorded. Screening was performed using the Rayyan system, and quality assessment was conducted using appropriate tools.<br><br>RESULTS: After reviewing 211 articles, screening yielded 21 articles, totaling 11,315 patients. Among these, 1178 (15.7%) presented with LP and 4159 (36.7%) with AD. A total of 5378 (47.6%) had a different presentation, including hippocampal sparing only and the association of LP and typical AD. The weighted average for education in years was 24.31 for LP patients and 17.15 for typical AD patients. The weighted average for age at onset was 72.33 for typical AD patients and 77.36 for LP patients. For the duration of the disease, the weighted average for typical AD was 8.95, and it was 8.43 for LP. There were no differences in clinical presentation, with cognitive impairment and memory deficits being the most cited manifestations. MRI and FDG-PET are the most commonly used imaging techniques; in typical AD patients, different levels of hippocampal and medial, lateral parietal, and frontotemporal lobe atrophy are observed. In LP patients, imaging findings revealed lower hippocampal volume and higher metabolic rates than in typical AD patients. MRI R2 relaxometry in LP patients revealed lower R2 relaxation rates in the amygdala, hippocampus, and temporal lobe white matter compared with typical AD patients. Tau-PET imaging in typical AD patients demonstrated elevated standardized uptake value ratios in the parietal and posterior cingulate cortex. The immunohistological findings revealed a greater hippocampal tau burden than in cortical regions and a greater number of TDP-43 inclusions in LP patients than in typical AD patients. Typical AD patients had a weighted average of 20.06 and LP patients 17.7.<br><br>CONCLUSION: Our analysis of clinical, radiological, and immunohistological features revealed significant differences between LP and typical AD presentations. However, those findings alone cannot reliably determine accuracy, whether both presentations are stages of the same pathology or different diseases. More studies need to explore this field to further examine this topic.},
}
@article {pmid42423023,
year = {2026},
author = {Kim, S and Oda, H and Oyama, R and Makishi, R and Bade, S and Bade, S and Ally, I and Iijima, Y and Gibo, Y and Minami, K and Fukuzawa, F and Sanji, S and Inamine, K and Kishi, H and Huh, S and Tanifuji, T and Nagahiro, M and Watanabe, N},
title = {Efficacy, safety and policy implications of anti-amyloid monoclonal antibodies for Alzheimer's disease: protocol for a living systematic review and meta-analysis.},
journal = {BJPsych open},
volume = {12},
number = {4},
pages = {e182},
doi = {10.1192/bjo.2026.12044},
pmid = {42423023},
issn = {2056-4724},
abstract = {BACKGROUND: Dementia affects approximately 6-13% of adults aged 65 years and older, with Alzheimer's disease accounting for most cases. Established symptomatic therapies, including acetylcholinesterase inhibitors and memantine, provide limited benefit and do not modify disease progression. Multiple monoclonal antibodies (mABs) targeting different amyloid-β species have been developed as potential disease-modifying therapies; because some agents have entered clinical use whereas others remain investigational, a continuously updated synthesis of their efficacy and safety is needed.<br><br>AIMS: To evaluate the efficacy and safety of all anti-amyloid mABs for adults with Alzheimer's disease, using a living systematic review and meta-analysis.<br><br>METHOD: We will conduct a living systematic review and meta-analysis in accordance with the Cochrane Handbook, Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 and the PRISMA extension for living systematic reviews. Randomised controlled trials comparing any approved or investigational anti-amyloid mAB with placebo, standard care or active comparators will be included. Searches of Ovid MEDLINE, Embase, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov and WHO International Clinical Trials Registry Platform will be updated every 6 months. Meta-analyses will be conducted separately for each antibody molecule using random-effects models. Critical outcomes include global clinical change and disease severity, cognitive abilities, functional ability and dependency, and safety (serious adverse events, treatment discontinuation and amyloid-related imaging abnormalities). Important outcomes include neuropsychiatric symptoms, quality of life and health system outcomes. Certainty of evidence will be assessed using the methodology Grading of Recommendations, Assessment, Development and Evaluation.<br><br>RESULTS: This article describes a protocol; therefore, no review findings are available at this stage.<br><br>CONCLUSIONS: This living systematic review will provide an up-to-date synthesis of the benefits and harms of anti-amyloid monoclonal antibodies to inform clinical decision-making and health-system planning in Alzheimer's disease.},
}
@article {pmid42423068,
year = {2026},
author = {Lagartos-Donate, MJ and Escobar-Doncel, B and Zhang, CS and Fang, EF},
title = {NAD[+] modulates REST isoform expression and its downstream mitophagy in Alzheimer's disease.},
journal = {Autophagy},
volume = {},
number = {},
pages = {},
doi = {10.1080/15548627.2026.2701599},
pmid = {42423068},
issn = {1554-8635},
abstract = {Repressor Element 1-Silencing Transcription factor (REST) emerges as a metabolism-sensitive transcriptional hub that supports basal mitophagy, mitochondrial quality, and synaptic function in neurons. In Alzheimer's disease, REST becomes mislocalized and functionally impaired, coinciding with early defects in mitochondrial quality control. Activation of the NAD[+] -SIRT1 axis enhances REST nuclear activity, restores its mitochondrial and neuroprotective gene programs, and attenuates pathological and cognitive decline in experimental AD models. Our study highlights REST as a promising target to preserve mitochondrial and neuronal function.Abbreviations:Alzheimer's disease, AD; Repressor Element 1-Silencing Transcription factor, REST; Nicotinamide Adenine Dinucleotide, NAD[+].},
}
@article {pmid42423373,
year = {2026},
author = {Lang, J and Liu, Y},
title = {Unsupervised optimal deep transfer learning for classification under general conditional shift.},
journal = {Biometrics},
volume = {82},
number = {3},
pages = {},
doi = {10.1093/biomtc/ujag123},
pmid = {42423373},
issn = {1541-0420},
support = {JYB2025XDXM904//Ministry of Education of China/ ; 12571283//National Natural Science Foundation of China/ ; 12171157//National Natural Science Foundation of China/ ; },
mesh = {*Transfer Machine Learning ; Classification Algorithms ; Neural Networks, Computer ; *Deep Learning ; Humans ; Algorithms ; Likelihood Functions ; *Unsupervised Machine Learning ; },
abstract = {Classifiers trained on labeled source data may yield misleading results when applied to unlabeled target data drawn from a different distribution. Transfer learning can rectify this by transferring knowledge from source to target data, but its effectiveness frequently relies on stringent assumptions, such as label shift or strong separation conditions. We introduce a novel general conditional shift assumption, which encompasses label shift as a special case and facilitates the identifiability of both the target distribution and the shift function without requiring a separation condition. Our classifier is constructed by integrating deep neural networks (DNNs) and a pseudo-maximum likelihood approach. We establish asymptotic error bounds for our DNN-based classifier and estimators of the conditional probabilities ${ \boldsymbol{\eta }
_{P}
}
$ for source data and the target label distribution $\boldsymbol{\pi }
_{Q}
$, in terms of the intrinsic dimension of ${ \boldsymbol{\eta }
_{P}
}
$. Notably, the excess risk of the proposed classifier achieves the optimal minimax rate, up to a logarithmic factor. Our method not only eliminates the need to estimate the shift function, but also alleviates the curse of dimensionality when ${ \boldsymbol{\eta }
_{P}
}
$ exhibits a low-dimensional structure. Numerical simulations, along with an analysis of an Alzheimer's disease dataset, underscore its exceptional performance.},
}
@article {pmid42423483,
year = {2026},
author = {Solfrizzi, V and Imbimbo, BP},
title = {Frailty as an underrepresented dimension in clinical trials of Alzheimer's disease therapies.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261466693},
doi = {10.1177/13872877261466693},
pmid = {42423483},
issn = {1875-8908},
abstract = {Population aging is redefining the clinical reality of Alzheimer's disease and increasing the need for outcome measures that reflect the complexity of older adults. Although recent trials on putative disease-modifying drugs have moved beyond cognition-only endpoints and now include integrated cognitive-functional measures, frailty remains underrepresented in trial design. We discuss the demographic context of aging societies, the relevance of frailty to dementia expression, and the implications of recent amyloid-β-targeting antibody trials, which include substantial numbers of older adults. We propose that frailty can improve external validity, refine biomarker interpretation, and strengthen precision medicine approaches linking biological measures with functional outcomes.},
}
@article {pmid42423489,
year = {2026},
author = {},
title = {Jacob Labonte, BS, and Michael L Alosco, PhD, are the recipients of the 2026 Alzheimer Award.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261468905},
doi = {10.1177/13872877261468905},
pmid = {42423489},
issn = {1875-8908},
}
@article {pmid42423522,
year = {2026},
author = {Lohman, T and Kapoor, A and Engstrom, AC and Joyce, J and Quiring, M and Alitin, JPM and Gaubert, A and Nguyen, A and Head, E and Rodgers, KE and Bradford, D and Lashin, B and Han, SD and Mather, M and Nation, DA},
title = {Low frequency blood-oxygen-level-dependent oscillations, APOE4, and plasma pTau217.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261467275},
doi = {10.1177/13872877261467275},
pmid = {42423522},
issn = {1875-8908},
abstract = {BackgroundLow frequency oscillations in blood-oxygen-level-dependent signal (BOLD-LFOs) are generally considered nuisance signal in connectivity analysis and discarded. However, recent evidence suggests BOLD-LFOs shed light on cerebrovascular dysfunction and preclinical Alzheimer's disease, but the mechanisms remain unclear. No investigations have assessed the relationship between BOLD-LFOs and plasma pTau217, or how it differs in apolipoprotein ε4 (APOE4) carriers who are vulnerable to cerebrovascular dysfunction and genetically predisposed to AD.ObjectiveTo study the relationship between BOLD-LFOs and plasma p-Tau217 in APOE4 carriers compared to non-carriers.MethodsIndependently living older adults (N = 118) were recruited and underwent resting-state fMRI and venipuncture. BOLD-LFOs were quantified as signal power within the 0.01-0.10 Hz frequency range. Plasma pTau217 was assessed and linear regression quantified the interactive effect of APOE4 carrier status and BOLD-LFOs on plasma pTau217. 2×2 ANCOVA was used to compare BOLD-LFOs across APOE4 carrier and amyloid positivity statuses based on previously reported pTau217 cutoffs.ResultsThe interactive effect of APOE4 carrier status and BOLD-LFO power was significantly associated with plasma pTau217 (β = -0.78, p = 0.001). This relationship was driven by an inverse relationship between BOLD-LFOs and plasma pTau217 in APOE4 carriers (β = -0.57, p = 0.0007). Amyloid-β (+) APOE4 carriers displayed lower BOLD-LFOs than amyloid-β (-) APOE4 carriers (p = 0.008) and amyloid-β (+) non-carriers (p = 0.03). Models were adjusted for age, sex, vascular risk factors, and total intracranial volume.ConclusionsFindings suggests BOLD-LFOs are implicated in preclinical AD in an APOE4 dependent manner, adding support for the continued study of BOLD-LFOs in the context of cerebrovascular contributions to AD genetic risk.},
}
@article {pmid42423590,
year = {2026},
author = {Cai, W and Li, J and Chen, C and Mei, J and Liu, Y},
title = {Network toxicology screening of plastic-associated chemicals reveals candidates with structural mimicry to Alzheimer's disease-relevant molecules and predicted neurotoxicity.},
journal = {SAR and QSAR in environmental research},
volume = {},
number = {},
pages = {1-26},
doi = {10.1080/1062936X.2026.2697791},
pmid = {42423590},
issn = {1029-046X},
abstract = {Alzheimer's disease (AD) pathogenesis involves environmental factors, with plastic-associated chemicals emerging as potential neurotoxicants. This study employed a computational toxicology framework to screen plastic-associated chemicals for potential interference with AD-related pathways. From a compiled library of 12,751 plastic-associated chemicals, 2,315 compounds with high blood-brain barrier (BBB) permeability were identified. Using Morgan fingerprints and Tanimoto similarity (threshold ≥ 0.6), we pinpointed chemicals structurally analogous to known AD-active molecules, including 3,5-Dimethoxystilbene (similarity 0.731 to a resveratrol derivative) and Isoeugenol (similarity 0.710 to isorhapontigenin). Structural similarity alone does not imply toxicity; therefore, we further evaluated these candidates using target prediction, molecular docking, and in silico toxicity profiling. Target prediction and molecular docking indicated that several compounds may interact with core AD-related targets (e.g. AChE, MAOB, APP). Notably, ProTox-3.0 profiling revealed that both 3,5-Dimethoxystilbene and Isoeugenol exhibit a potential dual profile of concern: high predicted BBB penetrance (probability > 0.7) and predicted potential for neurotoxic effects (probability 0.54-0.68), although these moderate probability scores warrant cautious interpretation. High-affinity binding was validated for 3,5-Dimethoxystilbene with AChE (-9.1 kcal/mol), comparable to known AChE inhibitors in our docking validation. This study prioritizes plastic-associated chemicals with a 'brain-penetrating and potentially neurotoxic' profile based on integrated computational evidence, providing a data-driven foundation for experimental validation.},
}
@article {pmid42423628,
year = {2026},
author = {Luu, PV and Nguyen, CQ and Ton-Nu, HL and Phan, TT and Huynh, QT and Pham, NT and Le, HG and Chen, LY and Chang, YC and Su, JH and Peng, BR and Lai, KH},
title = {Xeniaphyllane-Type Diterpenoids from the Soft Coral Sclerophytum humesi: Resolving Absolute Configurations and Anti-Alzheimer's Potential.},
journal = {Journal of natural products},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jnatprod.6c00535},
pmid = {42423628},
issn = {1520-6025},
abstract = {A combined bioassay- and [1]H NMR-guided isolation strategy led to the discovery of four new terpenoids, including three xeniaphyllane-type diterpenoids, sclerohumins P-R (1-3), and a norcaryophyllene-type, sclerophyllene A (4), from the soft coral Sclerophytum humesi. The structures and absolute configurations of these compounds were elucidated by comprehensive spectroscopic analysis, including NMR, HRESIMS, SOR, TDDFT-ECD, and DP4+ probability analysis. The stereogenic centers at C-15 in related xeniaphyllanes were proposed for the first time based on comparative SOR analysis. Compounds 1 and 2 possess a tricyclic 4/9-fused carbocyclic framework featuring an epoxide moiety, whereas compounds 3 and 4 exhibit related bicyclic scaffolds. A plausible biogenetic pathway originating from geranylgeranyl pyrophosphate (GGPP) was proposed to account for their structural diversity. Compounds 1 and 2 showed potent AChE inhibitory activity (IC50 = 1.7 and 4.4 μM, respectively), while being inactive against BChE and noncytotoxic toward normal cell lines (HEK293 and Vero). Mechanistic studies combining enzyme kinetics and molecular docking revealed that 1 and 2 act as mixed-type AChE inhibitors, with Ki values of 1.02 and 1.87 μM, respectively. These findings represent the first report of xeniaphyllane-type diterpenoids with potential for neurotherapeutic development.},
}
@article {pmid42423667,
year = {2026},
author = {Huang, Q and Zuo, Y and Xie, Y and Liu, Z and Wang, L and Xu, H and Yu, M and Liu, C},
title = {A nose-to-brain drug delivery system targeting mitochondrial dysfunction: application potential and future prospects of chitosan nanogels in Alzheimer's disease.},
journal = {Biomaterials science},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6bm00624h},
pmid = {42423667},
issn = {2047-4849},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by neuronal degeneration and cognitive impairment. One of its core pathologies involves energy metabolism disruption and oxidative stress resulting from mitochondrial dysfunction. Traditional drugs struggle to effectively cross the blood-brain barrier (BBB), while the nasal-brain drug delivery system offers a novel approach for achieving direct brain access. Chitosan, a biodegradable natural polymer with strong mucosal adhesion properties, has been extensively utilized in recent years to construct nanogel carriers. This approach enhances drug retention and absorption in the nasal epithelium, enabling targeted delivery to the brain via the olfactory or trigeminal nerve pathways. This paper provides a systematic review of research progress on chitosan nanogel-based naso-cerebral drug delivery systems targeting mitochondrial dysfunction, focusing on their molecular mechanisms in improving mitochondrial energy metabolism, scavenging excess reactive oxygen species (ROS), suppressing neuroinflammation, and regulating apoptosis. Additionally, this paper analyzes the design principles of various modification strategies-such as triphenylphosphine (TPP) modification, pH/ROS responsiveness, and drug-loaded nanozyme complexes-along with their efficacy validation in AD models. It further explores the future development trends of chitosan nanogel-mediated multi-target intervention and smart-responsive nasal-brain delivery systems, offering new directions for precision treatment of AD.},
}
@article {pmid42423799,
year = {2026},
author = {Cui, H and Zhang, Y},
title = {Cistanoside A decreases Tau hyperphosphorylation and neuronal apoptosis through the AKT/GSK3β pathway in okadaic acid-induced in vivo and in vitro models of Alzheimer's disease.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42423799},
issn = {1573-4978},
support = {(2022YX085)//2022 Weifang Science and Technology Development Plan Project/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/drug therapy/chemically induced ; *tau Proteins/metabolism ; Apoptosis/drug effects ; Glycogen Synthase Kinase 3 beta/metabolism ; Rats ; Proto-Oncogene Proteins c-akt/metabolism ; Phosphorylation/drug effects ; Okadaic Acid/pharmacology ; Neurons/metabolism/drug effects ; Humans ; Signal Transduction/drug effects ; Disease Models, Animal ; Male ; Reactive Oxygen Species/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Cell Line, Tumor ; Rats, Sprague-Dawley ; Neuroprotective Agents/pharmacology ; },
abstract = {BACKGROUND: The multifactorial nature of Alzheimer's disease (AD) pathogenesis has driven the search for therapeutic agents with low toxicity that can act on multiple targets. Cistanoside A (Cis A), a bioactive compound derived from Cistanches Herba, exhibits anti-inflammatory, antioxidant, and antiapoptotic effects. Given that these processes are implicated in AD progression, we propose that Cis A may be a promising candidate for AD therapy.<br><br>METHODS: We employed an okadaic acid (OA)-induced rat model in vivo and SH-SY5Y cells in vitro. Cognitive function was assessed using the Morris water maze and novel object recognition tests. Hematoxylin and eosin and Nissl staining were performed to evaluate histopathological changes. Neuronal damage was assessed using the Cell Counting Kit-8 assay for cell viability, TUNEL staining for apoptosis, and western blotting for protein expression. Mitochondrial damage was examined using JC-1 and MitoSOX Red staining.<br><br>RESULTS: Cis A significantly improved cognitive deficits. It attenuated OA-induced apoptosis, restored mitochondrial membrane potential, and reduced reactive oxygen species levels in rats and SH-SY5Y cells by inhibiting hyperphosphorylation of Tau protein via the AKT/GSK3&#x3b2; pathway. Furthermore, the protective effect of Cis A was attenuated by MK-2206 and AKT knockdown in vitro.<br><br>CONCLUSION: Cis A significantly improves cognitive function and reduces AD-related pathology, highlighting its potential as a therapeutic candidate for AD.},
}
@article {pmid42423809,
year = {2026},
author = {Yousef, AI and El-Twab, SMA and Khadrawy, SM and Abdel-Moneim, A and Khalil, RG},
title = {Polydatin inhibits hippocampal neurodegeneration in diabetic rats via modulation of oxidative stress and NF-kB/COX-2/IL-6 inflammatory pathway.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42423809},
issn = {1573-7365},
mesh = {Animals ; *Oxidative Stress/drug effects ; *Glucosides/pharmacology/therapeutic use ; *Stilbenes/pharmacology/therapeutic use ; *Hippocampus/drug effects/metabolism/pathology ; Male ; Rats ; Cyclooxygenase 2/metabolism ; *Diabetes Mellitus, Experimental/metabolism/drug therapy ; *NF-kappa B/metabolism ; Interleukin-6/metabolism ; Neuroprotective Agents/pharmacology/therapeutic use ; Signal Transduction/drug effects ; Molecular Docking Simulation ; *Neurodegenerative Diseases/metabolism/drug therapy ; },
abstract = {Impaired insulin function and persistent hyperglycemia damage the brain of diabetics and raise the risk of Alzheimer's disease (AD). Although polydatin (PLD) possesses promising biological effects, no major study has yet explored its anti-neurodegenerative efficacy in the hippocampus. This study therefore aims to investigate the probable protective effects of PLD against hippocampal neurodegeneration in diabetic rats, as well as explore its in-silico inhibitory activity against two key enzymes implicated in the progression of AD. Experimental diabetes was induced in male albino rats then PLD was administered orally to the diabetic rats (50 mg/kg b.wt.) daily for four weeks. In silico molecular docking was used to predict the interactions of PLD against BACE1 and AChE. PLD treatment significantly improved diabetic parameters, lowering blood glucose and raising serum insulin. Excitingly, PLD markedly alleviated oxidative stress by reducing lipid peroxidation and nitric oxide levels while enhancing antioxidant defenses (elevated GPx activity and GSH content) in the hippocampus of diabetic rats. PLD also suppressed neuroinflammation by down-regulating NF-κB, COX-2, and IL-6 mRNA expression. Furthermore, PLD significantly elevated the protein level of IDE while lowered Aβ1-42 level. In silico, PLD revealed potent binding affinity for BACE1 (-8.6 Kcal/mol) and AChE (-10.5 Kcal/mol), interacting with key residues, indicating its inhibition potential. Overall, PLD effectively reduced neurodegeneration in the hippocampus of diabetic rats via inhibiting oxidative stress, inflammation, and Aβ1-42 accumulation. PLD may act as a promising multi-target anti-neurodegenerative candidate, capable of simultaneously modulating multiple pathways and more experimental validation are needed in the future.},
}
@article {pmid42423830,
year = {2026},
author = {Chen, P and Qiang, X and Zhao, Z and Wang, W and Zhen, H and Liu, Y},
title = {Inhibition of miR-25-3p Alleviates Neuroinflammation in Alzheimer's Disease By Targeting ADAM10.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42423830},
issn = {1559-1182},
mesh = {Humans ; *MicroRNAs/genetics/antagonists &amp; inhibitors/metabolism ; *Alzheimer Disease/genetics/metabolism/blood/pathology ; *ADAM10 Protein/metabolism/genetics ; *Amyloid Precursor Protein Secretases/metabolism/genetics ; Female ; Male ; *Membrane Proteins/metabolism/genetics ; Amyloid beta-Peptides/toxicity ; *Neuroinflammatory Diseases/genetics/metabolism/pathology/blood ; Cell Line, Tumor ; Apoptosis/drug effects/genetics ; Aged ; Cell Proliferation ; Up-Regulation/genetics ; Peptide Fragments/toxicity ; },
abstract = {As a neurodegenerative disorder, Alzheimer's disease (AD) is defined by progressive cognitive decline and involves intricate pathological mechanisms. This study aimed to investigate the clinical role and regulatory mechanism of miR-25-3p in AD. This investigation enrolled 115 AD patients and 110 healthy control subjects. Serum levels of miR-25-3p were quantified using quantitative real-time PCR (qRT-PCR), and the diagnostic performance of miR-25-3p for AD was assessed via receiver operating characteristic (ROC) analysis. In vitro, cellular models of AD were established by treating SH-SY5Y and HMC3 cells with amyloid-beta peptide 25-35 (Aβ25-35). Cellular proliferation and apoptosis were evaluated using the CCK-8 assay and flow cytometry, respectively. ELISA was employed to measure the concentrations of pro-inflammatory and anti-inflammatory cytokines. Furthermore, the direct targeting relationship between miR-25-3p and ADAM10 was confirmed through dual-luciferase reporter assays. miR-25-3p was significantly upregulated in the serum of AD patients and Aβ25-35-induced AD cell models, suggesting its potential diagnostic relevance for AD. Inhibition of miR-25-3p attenuated Aβ25-35-mediated neurotoxicity and neuroinflammation, whereas ADAM10 knockdown abrogated the neuroprotective effects of the miR-25-3p inhibitor in SH-SY5Y and HMC3 cells, which suggests that inhibition of miR-25-3p may alleviate the disease progression of AD by targeting ADAM10. Therefore, inhibition of miR-25-3p may alleviate the disease progression of AD by targeting ADAM10, providing a novel potential regulatory axis for AD intervention.},
}
@article {pmid42423842,
year = {2026},
author = {Liu, Y and Li, M and Yu, H and Liu, H and Xu, Q and Li, F},
title = {Regulatory Effects of the PDE8B Inhibitor PF-04957325 on Cognitive Impairment and Neuroinflammation in Aβ-Induced Alzheimer's Disease Mouse Models.},
journal = {Neurochemical research},
volume = {51},
number = {4},
pages = {},
pmid = {42423842},
issn = {1573-6903},
support = {No. 20250232//Medical Science Research Project of Hebei/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/chemically induced/metabolism ; *Amyloid beta-Peptides/toxicity ; Male ; Mice ; *Neuroinflammatory Diseases/drug therapy/metabolism/chemically induced ; Peptide Fragments/toxicity ; *Cognitive Dysfunction/drug therapy/metabolism/chemically induced ; Disease Models, Animal ; Hippocampus/drug effects/metabolism ; Signal Transduction/drug effects ; Mice, Inbred C57BL ; Maze Learning/drug effects ; Cyclic AMP Response Element-Binding Protein/metabolism ; Myeloid Differentiation Factor 88/metabolism ; Toll-Like Receptor 4/metabolism ; NF-kappa B/metabolism ; },
abstract = {Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) deposition, chronic neuroinflammation, and dysregulation of the cAMP/PKA/CREB pathway that impairs synaptic plasticity. PF-04957325 (PF), a selective PDE8B inhibitor, elevates intracellular cAMP; however, its systems-level effects and mechanisms in Aβ-driven AD are unclear. Here, we evaluate PF in an Aβ1-42 mouse model and delineate its modulation of cAMP/PKA/CREB and TLR4/MyD88/NF-κB signaling. An AD model was induced by intracerebroventricular injection of Aβ1-42, followed by oral PF administration (0.1 mg/kg/day). Cognitive performance was evaluated with the Morris water maze. Hippocampal pathology, Aβ burden, and apoptosis were assessed by H&amp;E, immunohistochemistry, and TUNEL assays. IL-1β and IL-6 were measured by ELISA in hippocampal tissue and BV2 supernatants. Western blotting quantified APP, p-tau, and pathway proteins. BV2 cells and si-PDE8B served to validate mechanisms in vitro. PF significantly shortened escape latency (p < 0.01) and increased both platform crossings and target-quadrant dwell time (p < 0.01). It alleviated hippocampal neuronal injury, reduced Aβ burden, and decreased TUNEL-positive cells. Molecularly, PF elevated cAMP and increased p-PKA/PKA and p-CREB/CREB ratios (p < 0.01), while decreasing TLR4, MyD88, and p-NF-κB p65/NF-κB p65 (p < 0.01). PF also lowered IL-1β and IL-6 levels in hippocampal tissue and BV2 supernatants (both p < 0.01). In vitro, 300 nM PF phenocopied PDE8B knockdown, restoring cAMP/PKA/CREB activity and suppressing TLR4/MyD88/NF-κB activation. PF exerts dual protective effects by activating cAMP/PKA/CREB to enhance synaptic plasticity and survival, while inhibiting TLR4/MyD88/NF-κB to mitigate neuroinflammation. These findings highlight PDE8B inhibition as a promising therapeutic strategy for AD.},
}
@article {pmid42423959,
year = {2026},
author = {Övüt, AR and Toyran, R and Bülbül, NG and Urhan, M},
title = {A real-world decision tree model based on [18]F-FDG PET/CT Z scores and Mini-Mental State Examination for differentiating mild cognitive impairment from clinically diagnosed Alzheimer disease.},
journal = {Annals of nuclear medicine},
volume = {},
number = {},
pages = {},
pmid = {42423959},
issn = {1864-6433},
abstract = {OBJECTIVE: To evaluate the ability of regional metabolic Z scores derived from [18]F-fluorodeoxyglucose positron emission tomography/computed tomography ([18]F-FDG PET/CT), medial temporal atrophy (MTA) scores, and Mini-Mental State Examination (MMSE) results to distinguish mild cognitive impairment (MCI) from clinically diagnosed Alzheimer disease (AD), and to develop an interpretable decision-tree model based on these parameters.<br><br>METHODS: This retrospective single-center study included 124 patients who underwent &#xb9;&#x2078;F-FDG PET/CT for suspected cognitive impairment between 2023 and 2025. Patients were classified as AD or MCI according to final clinical diagnoses established by experienced neurologists using National Institute on Aging-Alzheimer's Association criteria. Regional metabolic Z scores were generated with CortexID Suite by comparison with an age-matched healthy normative database. MTA was graded on structural magnetic resonance imaging using the Scheltens scale by two blinded nuclear medicine physicians. MMSE scores were retrieved from clinical records. A random forest algorithm was used to identify discriminative variables, which were then incorporated into a transparent decision-tree classifier. The dataset was divided into a training cohort (n&#x2009;=&#x2009;100) and a split-sample test cohort (n&#x2009;=&#x2009;24).<br><br>RESULTS: The final decision tree integrated regional metabolic Z scores and MMSE values in a hierarchical classification structure. In the split-sample test cohort, the model achieved an accuracy of 95.8% and a balanced accuracy of 96.4%, with 100% sensitivity and 92.9% specificity for AD classification. The area under the receiver operating characteristic curve was 0.964 (95% confidence interval, 0.894-1.000).<br><br>CONCLUSIONS: An interpretable decision-tree approach integrating quantitative &#xb9;&#x2078;F-FDG PET/CT metrics with cognitive assessment showed promising performance for distinguishing clinically diagnosed AD from MCI in a real-world clinical cohort.},
}
@article {pmid42423996,
year = {2026},
author = {Khaitin, AM and Lebedeva, AA and Kunitsyna, AE and Demyanenko, SV},
title = {The role of mitochondrial Na[+]/Ca[2+] exchanger in brain cell aging.},
journal = {Journal of bioenergetics and biomembranes},
volume = {58},
number = {1},
pages = {},
pmid = {42423996},
issn = {1573-6881},
support = {25-25-00452//Russian Science Foundation/ ; },
mesh = {Humans ; *Sodium-Calcium Exchanger/metabolism ; *Brain/metabolism/pathology ; *Mitochondria/metabolism/pathology ; Animals ; *Cellular Senescence ; Aging ; Neurons/metabolism ; },
abstract = {Considering the world's population aging and the importance of mitochondrial calcium regulation for all brain pathologies, researchers cannot neglect the role of mitochondrial sodium/calcium exchanger (NCLX) not only in pathologies like Alzheimer's and Parkinson's diseases, but in physiological "healthy" aging as well. Despite its critical role in mitochondrial metabolism upon neurodegeneration, the role of NCLX in physiological aging of CNS is almost unknown. NCLX interacts with regulatory partners like TMEM65 and signal pathways of PKA and HIF, connecting to broader metabolic networks of hypoxia, inflammation, oxidative stress, and autophagy. Understanding precise mechanisms of NCLX regulation and its cell-specific roles remains critical for developing targeted interventions to preserve brain function in aging. NCLX is functioning differently in neurons and glial cells, which should be investigated further and considered when studying brain aging. In this review we aim to encompass the current state and connections of this understudied topic and discuss the future prospects and implications.},
}
@article {pmid42424076,
year = {2026},
author = {Lyndon, S and Behlke, LM and Urizar, JC and Daffner, KR},
title = {Alzheimer Disease Biomarkers and Assisted Dying: When Diagnosis Becomes a Deadline.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2026.11317},
pmid = {42424076},
issn = {1538-3598},
}
@article {pmid42424084,
year = {2026},
author = {Zhang, Y and Yang, Y and Thunell, J and Miller, KEM},
title = {Days at Home Among Dually Eligible Medicare Beneficiaries With Alzheimer Disease and Related Dementias.},
journal = {JAMA network open},
volume = {9},
number = {7},
pages = {e2622670},
doi = {10.1001/jamanetworkopen.2026.22670},
pmid = {42424084},
issn = {2574-3805},
}
@article {pmid42424231,
year = {2026},
author = {Szyłak, E and Czarnowska, A and Kulczyńska-Przybik, A and Kopitelow, J and Mroczko, B and Kochanowicz, J and Kułakowska, A},
title = {Neurofilament Light Chain as a Biomarker in Neurology.},
journal = {European neurology},
volume = {},
number = {},
pages = {1-18},
doi = {10.1159/000552933},
pmid = {42424231},
issn = {1421-9913},
abstract = {Neurofilament light chain (NfL) has emerged as a highly sensitive biomarker of neuroaxonal injury across diverse neurological disorders. This review synthesizes current evidence regarding its diagnostic, prognostic, and therapeutic-monitoring utility, while outlining major clinical limitations and emphasizing the complementary role of glial fibrillary acidic protein (GFAP). NfL concentrations increase following axonal damage and correlate with inflammatory activity, lesion burden, and long-term disability progression in multiple sclerosis. Elevated levels also reflect neurodegeneration in Alzheimer's disease, predict disease severity and survival in amyotrophic lateral sclerosis, and are associated with motor and cognitive decline in Parkinson's disease and multiple system atrophy. In acute neurological conditions, including traumatic brain injury and stroke, NfL serves as a robust indicator of the extent of neuronal injury. Interpretation is constrained, however, by substantial physiological variability related to age, renal function, body mass index, and comorbidities, limiting the utility of absolute cut-off values. GFAP provides complementary information by capturing astrocytic damage, and the GFAP/NfL ratio may aid in differentiating multiple sclerosis from neuromyelitis optica spectrum disorder. Integration of NfL with multimodal biomarkers- such as GFAP, tau proteins, proteomic and metabolomic signatures, and advanced neuroimaging-may enhance diagnostic specificity and prognostic accuracy. Future research priorities include establishing age-adjusted reference intervals, validating longitudinal thresholds, and incorporating NfL into therapeutic monitoring frameworks. Advances in these areas are expected to improve diagnostic precision and support broader clinical implementation of NfL.},
}
@article {pmid42424238,
year = {2026},
author = {Tshimbombu, TN and Thurmann, KE and Decourt, B and Nyalundja, AD and Shardow, SB and Amoako, ME and Iragi, GM and Mwambali, JA and Sabbagh, MN},
title = {Autophagy in Alzheimer's disease: mechanisms, clinical trials, and horizons.},
journal = {Neuro-degenerative diseases},
volume = {},
number = {},
pages = {1-21},
doi = {10.1159/000553506},
pmid = {42424238},
issn = {1660-2862},
abstract = {BACKGROUND: Alzheimer's disease (AD) is an incurable progressive neurodegenerative disorder characterized by the pathological accumulation of amyloid beta (Aβ) plaques and neurofibrillary tangles in the brain. Recent findings have identified dysregulation of autophagy, a cellular mechanism for degradation and recycling, as a crucial contributor to the pathogenesis of AD. This narrative review examines the role of autophagy in the metabolism of Aβ and tau and evaluates current therapeutic strategies aimed at modulating autophagic pathways.<br><br>SUMMARY: Autophagy is governed by the key molecular regulators mammalian target of rapamycin, adenosine monophosphate-activated protein kinase, Beclin-1, and transcription factor EB, which collectively control the clearance of protein recycling, including aggregates, inside cells. Pharmacological agents such as rapamycin, resveratrol, and trehalose, alongside sigma-1 receptor agonists and gene therapy approaches, have demonstrated potential in modulating autophagy in preclinical and clinical studies. Despite these advances, significant challenges persist; namely, neuronal heterogeneity, optimal timing for therapeutic intervention, and the absence of reliable biomarkers to monitor autophagic activity and treatment efficacy.<br><br>KEY MESSAGES: Targeting autophagy offers a promising and potentially safe avenue for slowing AD progression. Future investigations should prioritize the development of selective autophagy modulators and personalized treatment strategies to restore autophagic flux and enhance clinical outcomes in patients with AD.},
}
@article {pmid42424274,
year = {2026},
author = {Nasir, AB and Kilani, Y and Aldiabat, M and Abdelghany, O and Hafez, Y and Desai, N and Madi, MY and Wade, FG and Qureshi, K and Frey, LJ and Farmer, AD and Syn, WK},
title = {Metabolic risk and metabolic dysfunction-associated steatotic liver disease and steatohepatitis in cognitive decline: A retrospective cohort study.},
journal = {PloS one},
volume = {21},
number = {7},
pages = {e0353160},
doi = {10.1371/journal.pone.0353160},
pmid = {42424274},
issn = {1932-6203},
mesh = {Humans ; Female ; Retrospective Studies ; Male ; Middle Aged ; *Cognitive Dysfunction/epidemiology/metabolism/complications ; Aged ; Risk Factors ; *Fatty Liver/complications/metabolism/epidemiology ; *Alzheimer Disease/epidemiology/metabolism ; *Dementia, Vascular/epidemiology/metabolism ; },
abstract = {OBJECTIVE: To determine whether metabolic risk factors (MRFs), metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are associated with incident mild cognitive impairment (MCI), vascular dementia (VD), and Alzheimer disease (AD).<br><br>DESIGN: Retrospective cohort study using TriNetX (2003-2023) with Propensity score matching.<br><br>SETTING: Multicenter, population-based sample from 69 U.S. healthcare organizations in the TriNetX electronic health record.<br><br>PARTICIPANTS: Adults aged &#x2265;50 years with &#x2265;1 outpatient visit and sufficient clinical/laboratory data. Individuals with prior diagnoses of cognitive impairment, cerebrovascular disease, advanced liver disease, malignancy, schizophrenia, or substance use disorders were excluded. Two matched cohorts were constructed: one with 3,546,833 individuals with MRFs and 3,546,833 healthy controls, and another with 525,844 individuals with MASLD/MASH and 525,844 with MRFs only. Matching was based on age, sex, race, and ethnicity.<br><br>Incident MCI, VD, and AD, identified using ICD-10 codes, assessed at 5-20-year intervals. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using logistic regression. Outcomes were prespecified.<br><br>RESULTS: Among 7,818,146 participants (mean [SD] age, 64.9 [8.8] years; 52.0% female), individuals with MRFs had higher odds of VD (OR, 1.65; 95% CI, 1.63-1.67), MCI (OR, 1.45; 95% CI, 1.42-1.48), and AD (OR, 1.21; 95% CI, 1.19-1.24) vs healthy controls. Compared to the MRF group, individuals with MASLD/MASH had lower odds of VD (OR, 0.86; 95% CI, 0.83-0.89) and AD (OR, 0.83; 95% CI, 0.78-0.88), but higher odds of MCI (OR, 1.37; 95% CI, 1.30-1.44); all p&#x2009;<&#x2009;.001.<br><br>CONCLUSIONS: In this large, propensity-matched retrospective cohort study, MRFs were independently associated with significantly increased long-term odds of MCI, VD, and AD. MASLD/MASH demonstrated a divergent cognitive risk profile relative to MRFs alone-characterized by higher odds of MCI but paradoxically lower odds of VD and AD, a pattern that warrants cautious interpretation given potential competing mortality risk, survivor bias, and residual confounding. These findings suggest that MASLD/MASH is associated with a distinct cognitive trajectory, highlighting the importance of early cognitive surveillance in this population.},
}
@article {pmid42424329,
year = {2026},
author = {O'Shea, DM and Chang, LC and Chowdhury, M and Cook, DJ and Cresswell, K and Minor, BD and Mitsova, D and Tourelle, MS and Galvin, JE and Besser, LM},
title = {The heat exposure, aging trajectories, and Alzheimer's disease (HEAT-AD) study protocol.},
journal = {PloS one},
volume = {21},
number = {7},
pages = {e0350611},
doi = {10.1371/journal.pone.0350611},
pmid = {42424329},
issn = {1932-6203},
mesh = {Humans ; *Alzheimer Disease/etiology/blood/epidemiology/physiopathology ; *Aging ; *Hot Temperature/adverse effects ; Aged ; Biomarkers/blood ; Male ; Female ; Middle Aged ; Risk Factors ; Cognitive Dysfunction ; Brain/diagnostic imaging ; Cognition ; Magnetic Resonance Imaging ; },
abstract = {Urban heat islands (UHIs) are areas of elevated surface temperature caused by limited vegetation and dense development. Extreme heat disproportionately affects older adults and may increase risk for Alzheimer's disease (AD) and related dementias (ADRD), but few studies have examined whether cumulative neighborhood-level heat exposure is associated with cognitive decline or ADRD biomarkers. This study will investigate whether recent UHI exposure is associated with cognitive function; determine whether cumulative UHI exposure is associated with cognitive decline, plasma ADRD biomarkers, and brain imaging biomarkers; and evaluate whether UHI exposure is associated with ADRD risk factors, including physical inactivity, social isolation, and inflammation, and whether tree canopy mitigates heat-ADRD associations. The study includes 500 adults aged ≥50 years from the Healthy Brain Initiative cohort in South Florida. Geocoded residential addresses will be linked to satellite-derived land surface temperature data to quantify recent exposure at the baseline cognitive visit and cumulative exposure during the month before, and 1 and 5 years before baseline. Participants complete annual clinical and neuropsychological assessments, brain MRI, and blood collection for ADRD biomarkers. A sub-sample of 200 participants will wear smartwatches during two 3-week periods to capture GPS-based heat exposure, physical activity, and daily cognitive testing. Analyses will be replicated using the nationally representative Health and Retirement Study. Primary outcomes include cognitive domain scores, brain imaging measures, and preclinical AD status determined from plasma biomarkers. This study will provide comprehensive data on cumulative UHI exposure and ADRD risk by integrating cognitive assessment, neuroimaging, and biomarkers. Findings will clarify whether neighborhood heat represents a modifiable ADRD risk factor and inform urban greening and brain health promotion strategies.},
}
@article {pmid42424440,
year = {2026},
author = {Dans, MG and Awalt, JK and Nguyen, N and Palandri, J and Ngo, A and Jarman, KE and Jeon, JH and Yeo, T and Park, H and Uhlemann, AC and Mao, EY and Gancheva, MR and Wilson, DW and Mukherjee, P and Chakraborty, A and Kristan, M and Stewart, L and Sutherland, CJ and Baud, D and Brand, S and Fidock, DA and Jackson, PF and Cowman, AF and Sleebs, BE},
title = {2-Amino-3,4-Dihydroquinazolines Exhibit Potent Antimalarial Activity by Targeting Plasmepsin X.},
journal = {ACS infectious diseases},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsinfecdis.6c00258},
pmid = {42424440},
issn = {2373-8227},
abstract = {The emergence of resistance to most clinically used antimalarials necessitates the discovery of new chemotypes. A phenotypic screen against asexual Plasmodium falciparum identified the 2-amino-3,4-dihydroquinazoline scaffold, previously developed as a β-secretase 1 inhibitor for Alzheimer's disease. Evaluation of hit analogues against malarial aspartyl proteases revealed potent inhibition of plasmepsin X. Structure-activity analysis showed that key motifs on the hit scaffold are required for driving biochemical and antimalarial but are associated with poor selectivity against human aspartyl proteases and low metabolic stability. Plasmepsin X was validated as the molecular target through forward genetics, activity against mutant parasites, and inhibition of plasmepsin X substrate processing. 2-Amino-3,4-dihydroquinazoline analogs exhibit moderate asexual killing rates, low-to-moderate resistance risk, no cross-resistance with multidrug-resistant strains, and transmission-blocking activity. Further optimization of potency and metabolic stability will be required to achieve in vivo efficacy and realize the potential of this antimalarial class.},
}
@article {pmid42424464,
year = {2026},
author = {Crowley, G and Kim, M and O'Neill, N and Turkes, E and Ghasemi, F and Giudice, L and De Schepper, S and Tan, BJY and Maffei, B and S S Ferreira, L and Rebejac, J and Rueda-Carrasco, J and Toneva, M and Fajardo, JC and Ge, JZ and Yang, ZG and Korhonen, P and Muckett, P and Bennett, D and Paoletti, C and Sow, TTM and Posner, DA and Sierksma, A and Sokolova, D and Konstantellos, V and Ali, L and Movahedi, K and MacAskill, AF and Tybulewicz, VLJ and Malm, T and Lignani, G and Clatworthy, MR and Hong, S},
title = {C1q and immunoglobulins mediate activity-dependent synapse loss in the adult brain.},
journal = {Science (New York, N.Y.)},
volume = {393},
number = {6807},
pages = {eadv1219},
doi = {10.1126/science.adv1219},
pmid = {42424464},
issn = {1095-9203},
mesh = {Animals ; *Complement C1q/metabolism/genetics/immunology/physiology ; *Synapses/pathology/immunology ; Mice ; *Alzheimer Disease/pathology/immunology ; Amyloid beta-Peptides/metabolism ; *Hippocampus/pathology/immunology ; Disease Models, Animal ; B-Lymphocytes/immunology ; *Immunoglobulins/metabolism ; Chemogenetics ; Neurons ; },
abstract = {Complement component 1q (C1q), the initiator of the classical complement cascade, mediates synaptic elimination in development and disease, yet the triggers for its deposition on synapses remain unclear. Using in vivo chemogenetics, we demonstrate that neuronal hyperactivity induces region-specific, C1q-dependent synapse loss in the adult hippocampus. Suppressing perforant pathway hyperactivity in a mouse model of Alzheimer's disease reduced local amyloid-β amounts and C1q deposition and partially rescued synapse loss. Combining spatial transcriptomics, live cell tracking, and super-resolution microscopy, we identified association of antibody-secreting B-lineage cells in the adult hippocampus with activity-dependent, C1q-mediated synapse loss under physiological conditions. Together, these findings link neuronal hyperactivity to C1q-mediated synapse loss in the adult brain and implicate immunoglobulins as players in this process.},
}
@article {pmid42411944,
year = {2026},
author = {Zhang, T and Ma, G and Wang, W and Huang, Q and Sun, S and Yang, H and Hong, X},
title = {Mortality trends and projections for type 2 diabetes with concomitant Parkinson's versus Alzheimer's disease among older United States adults, 1999-2023: A retrospective cohort study.},
journal = {Medicine},
volume = {105},
number = {27},
pages = {e49321},
pmid = {42411944},
issn = {1536-5964},
support = {ZKX18049//the Nanjing Municipal Medical Science and Technique Development Foundation, the Nanjing Key Medical Department (of Chronic NonCommunicable Disease Prevention and Control/ ; },
mesh = {Humans ; *Diabetes Mellitus, Type 2/mortality/epidemiology/complications ; United States/epidemiology ; *Alzheimer Disease/mortality/epidemiology/complications ; Retrospective Studies ; *Parkinson Disease/mortality/epidemiology/complications ; Aged ; Female ; Male ; Aged, 80 and over ; Comorbidity ; Mortality/trends ; },
abstract = {Although type 2 diabetes mellitus (T2DM) frequently co-occurs with Parkinson's disease (PD) and Alzheimer's disease (AD), a systematic comparison of their combined mortality burdens remains lacking. This study aimed to compare long-term mortality trends and project future burdens among older US adults with T2DM comorbid with either PD or AD. A retrospective cohort study was conducted using national mortality data (1999-2023) from the CDC WONDER database. Decedents were identified using ICD-10 codes for T2DM with PD (E11 + G20) or AD (E11 + G30). Temporal trends were analyzed to estimate annual percentage change (APC) and average annual percentage change (AAPC), and future age-adjusted mortality rates were projected through 2030. Both conditions exhibited sustained upward mortality trends from 1999 to 2023, with T2DM with PD showing higher relative growth (AAPCs) but lower absolute burden than T2DM with AD. The steepest increases in death counts occurred among Hispanic/Latino individuals and in the Western United States, while the highest AAPCs in age-adjusted mortality were seen among Hispanic/Latino adults with T2DM and AD and in the Western United States for both conditions. Males had higher age-adjusted mortality for T2DM with PD, whereas females had higher absolute death counts for T2DM with AD. Mortality for T2DM with PD peaked at ages 75 to 84, while for T2DM with AD it rose continuously with age. A marked shift from institutional to home-based deaths was observed. Projections indicate age-adjusted mortality will exceed 2023 levels by over 20% by 2030, reaching 6.66 (T2DM with PD) and 15.99 (T2DM with AD) per 1,00,000. Mortality associated with T2DM comorbid with PD or AD is escalating, characterized by distinct demographic and geographic disparities. These findings underscore the urgent need for integrated clinical screening, stratified prevention strategies, and strengthened community-based care to mitigate the growing burden of these complex multimorbidities.},
}
@article {pmid42411945,
year = {2026},
author = {Nakamura, Y and Tsushio, T and Tanahashi, M and Suganami, H and Omori, T and Nishiyama, K and Aoki, H and Nagakura, N},
title = {Post Hoc Subgroup Analysis by Disease Severity in a Non-Inferiority Trial of Donepezil 27.5 mg Transdermal Formulation in Japanese Patients With Mild-to-Moderate Alzheimer Disease.},
journal = {Alzheimer disease and associated disorders},
volume = {},
number = {},
pages = {},
doi = {10.1097/WAD.0000000000000738},
pmid = {42411945},
issn = {1546-4156},
support = {//Teikoku Seiyaku/ ; },
abstract = {BACKGROUND: The efficacy of cholinesterase inhibitors varies depending on the severity of Alzheimer disease. We examined the effects of the disease severity on the efficacy of donepezil 27.5 mg patches in Japanese patients with Alzheimer disease.<br><br>METHODS: A post hoc analysis of covariance using per-protocol set in a noninferiority study of donepezil 27.5&#xa0;mg patches with donepezil hydrochloride 5&#xa0;mg tablets (JapicCTI-194582) was conducted after imputation of missing data using multiple imputations.<br><br>RESULTS: No apparent imbalances in the extracted confounding factors were observed between the 2 treatment groups. The baseline value of the Alzheimer Disease Assessment Scale (Japanese version) cognitive subscale was adjusted using analysis of covariance. Least-squares mean of changes from baseline in the Alzheimer Disease Assessment Scale (Japanese version) cognitive subscale at week 24 for each group were -1.661 (-2.681 to -0.640) (donepezil patch) and 0.065 (-0.987 to 1.117) (donepezil hydrochloride tablet). The difference in the least-squares mean (95% CI) between 2 groups was -1.726 (-3.1913 to -0.2602, P=0.021).<br><br>CONCLUSIONS: A post hoc analysis of covariance using the per-protocol set suggested that donepezil patches may be more effective than donepezil tablets in slowing cognitive decline in patients with mild Alzheimer disease.},
}
@article {pmid42411987,
year = {2026},
author = {Ghaedrahmat, Z and Almasi, F and Shamsi Goushki, J and Moghiseh, Z},
title = {The role of organochlorine pesticides as environmental factors in Alzheimer's disease in human studies: A systematic review and meta-analysis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261465828},
doi = {10.1177/13872877261465828},
pmid = {42411987},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a prevalent neurodegenerative disorder among the elderly, influenced by both genetic and environmental factors. Organochlorine pesticides (OCPs) have recently been identified as potential environmental risk factors due to their bioaccumulation in adipose tissue and neurotoxic properties.ObjectiveThis systematic review aimed to examine the human evidence regarding exposure to OCPs and the risk of AD. The results of the meta-analysis showed that exposure to pesticides is significantly associated with an increased risk of AD.MethodsA comprehensive search was performed across major scientific databases, including PubMed/MEDLINE, Scopus, Web of Science, the Cochrane Library, and Embase.ResultsPooled estimates (random effects meta-analysis) of the four eligible studies showed a significant positive association between exposure to OCPs and the risk of AD (OR = 2.19; 95% CI: 1.40-3.42). These findings indicate that exposure to OCPs may significantly increase the risk of AD. The substantial heterogeneity among studies (I[2] = 84.58%) may partly reflect differences in exposure assessment approaches, such as biomonitoring-based measurements compared with occupational or geographically inferred exposure assessments.ConclusionsThese findings highlight the importance of controlling occupational and environmental exposures to pesticides in preventing neurodegenerative outcomes. The findings suggest that chronic exposure to lipophilic pesticides, particularly persistent chlorinated compounds, may contribute to neurodegenerative processes implicated in the pathophysiology of AD. Therefore, more studies with similar designs and more precise exposure measurements are needed to confirm the results and reduce the heterogeneity.},
}
@article {pmid42412004,
year = {2026},
author = {Zhang, J and Wang, Y and Lu, Z and Yang, Y and Wang, J and Zhao, L and Li, F and Miao, M and Chen, WM and Wu, SY and Sun, M},
title = {HbA1c trajectories after SGLT2 inhibitor initiation and the risk of dementia.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261462927},
doi = {10.1177/13872877261462927},
pmid = {42412004},
issn = {1875-8908},
abstract = {BackgroundType 2 diabetes mellitus (T2DM) is a major risk factor for dementia, yet the prognostic value of early dynamic glycemic changes following glucose-lowering therapy remains underinvestigated.ObjectiveTo determine whether early glycated hemoglobin (HbA1c) trajectories after initiating sodium-glucose cotransporter 2 inhibitors (SGLT2i) predict long-term dementia and mortality risks.MethodsThis retrospective new-user cohort study utilized electronic health records from the TriNetX Global Network. Adults with T2DM initiating their first SGLT2i were included. To mitigate immortal-time bias, a 1-year landmark design was applied. Patients were stratified by baseline HbA1c and classified into improved, stable, or worsened trajectories based on values 91-455 days post-initiation. Propensity-score matching was performed within strata. The primary outcome was all-cause dementia.ResultsAmong 172,050 matched patients, modest HbA1c worsening in those with Good baseline control (<7.0%) did not increase dementia risk (HR 0.93; 95% CI, 0.75-1.15). However, in patients with Fair baseline control (7.0-8.9%), worsening to Poor control significantly increased dementia (HR 1.39; 95% CI, 1.11-1.74) and mortality risks. Conversely, among those with Poor baseline control (≥9.0%), trajectory improvement conferred substantial neuroprotection, reducing the risk of dementia (HR 0.64; 95% CI, 0.51-0.79) and mortality (HR 0.71; 95% CI, 0.60-0.84). These findings provide clinically actionable evidence linking glycemic dynamics to neurodegenerative risk, particularly Alzheimer's disease and related dementias.ConclusionsDynamic HbA1c trajectories following SGLT2i initiation independently predict dementia risk. Integrating trajectory-based assessments into routine care provides an actionable, scalable biomarker to guide timely treatment intensification and mitigate diabetes-related neurocognitive decline.},
}
@article {pmid42412039,
year = {2026},
author = {Shi, Y and Ci, R and Geng, C and Zhang, X and Zheng, N and Qin, Y},
title = {Disruptions of the diffusion tensor image analysis along the perivascular space index and dynamic functional connectivity across the Alzheimer's disease spectrum: Implications for cognitive impairment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261465700},
doi = {10.1177/13872877261465700},
pmid = {42412039},
issn = {1875-8908},
abstract = {BackgroundAcross the Alzheimer's disease spectrum (ADS), spanning subjective cognitive decline (SCD), mild cognitive impairment (MCI), and Alzheimer's disease (AD) dementia, the interplay between alterations in diffusion tensor imaging (DTI) analysis along the perivascular space (ALPS), brain functional connectivity, and cognitive impairment (CI) remains poorly understood.ObjectiveTo evaluate DTI-ALPS index and brain network across clinical stages of ADS and assess whether brain network disruptions mediates the association between DTI-ALPS index and CI.MethodsA total of 188 ADS patients and 77 healthy controls (HC) were recruited. The DTI-ALPS index, dynamic functional connectivity (dFC) and network topology were estimated from MRI. Group differences were assessed using analysis of covariance. Mediation analyses examined whether disruptions in dFC or topology mediated the association between the DTI-ALPS index and CI.ResultsCompared with HC, SCD patients showed significantly reduced ALPS index in the left hemisphere, whereas MCI and AD patients showed significantly reduced ALPS index in both hemispheres. While topology showed no significant differences across ADS, dFC analysis revealed stage-specific alterations, with abnormalities in higher-order cognitive systems in the early stage and in primary processing systems in later stages. Mediation analysis indicated that dFC disruption, but not topology abnormalities, mediated the association between reduced DTI-ALPS index and CI in ADS patients.ConclusionsDecreased DTI-ALPS index and abnormalities in higher-order cognitive systems emerged as early as the SCD stage and exhibited stage-dependent differences across disease severity. Importantly, dFC disruption mediated the association between reduced DTI-ALPS index and CI, suggesting a potential underlying pathological mechanism.},
}
@article {pmid42412079,
year = {2026},
author = {Macoir, J and Hudon, C},
title = {The semantic association Test of Quebec (TASQ): a novel measure of semantic associative processing with normative data and preliminary clinical validation.},
journal = {Applied neuropsychology. Adult},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/23279095.2026.2699347},
pmid = {42412079},
issn = {2327-9109},
abstract = {The Semantic Association Test of Quebec (TASQ) was developed as a clinically practical measure of semantic associative processing within semantic memory. This study aimed to establish normative data and provide preliminary evidence of clinical validity in Quebec French-speaking middle-aged and older adults. The TASQ comprises 64 semantic association items assessing abstract concepts, natural concepts, manmade concepts, and famous people. Following pilot testing, normative data were collected from 255 cognitively healthy French-speaking adults aged 50-92 years. Exploratory clinical validation was also conducted in healthy controls (n = 24), individuals with Mild Cognitive Impairment (n = 12), and individuals with Alzheimer's disease (n = 12). Pilot testing confirmed the feasibility and clarity of the task. TASQ total score performance was significantly associated with age and education. Regression-based normative correction was retained for the total score, whereas percentile distributions were generated for the total score and semantic subscales. Participants with Alzheimer's disease performed significantly more poorly than healthy controls across all TASQ measures. TASQ total score was strongly associated with global cognitive functioning. The TASQ appears to be a time-efficient and clinically practical measure of semantic processing, supported by normative data and preliminary evidence of clinical validity in aging and neurodegenerative disease.},
}
@article {pmid42412289,
year = {2026},
author = {Sadhukhan, D and Mukherjee, A and Kamal, IM and Maitra, S and Vedeshachaitanya, BS and Bhattacharyya, B and Biswas, A and Chakrabarti, S and Biswas, A},
title = {Genetic and structural characterisation of alzheimer's disease associated variants in an Eastern Indian cohort.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42412289},
issn = {1573-7365},
support = {DST/CSRI-P/2017/22//Department of Science &amp; Technology, Govt. of India/ ; BT/NIDAN/01/05/2018//Department of Biotechnology, Ministry of Science and Technology, India/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics ; India/epidemiology ; Male ; Molecular Dynamics Simulation ; Female ; Amyloid beta-Protein Precursor/genetics ; Cohort Studies ; *Genetic Variation/genetics ; Middle Aged ; Aged ; Presenilin-1/genetics ; Exome Sequencing ; Membrane Transport Proteins/genetics ; Mutation ; LDL-Receptor Related Proteins/genetics ; ATP-Binding Cassette Transporters/genetics ; },
abstract = {Alzheimer's disease (AD) shows substantial clinical heterogeneity often caused by genetic variants contributing to both familial and early-onset forms. However, the genetic landscape of AD in the diverse Indian population remains further characterised. To identify probable pathogenic variants associated with AD, representing individuals from Eastern India and to assess their potential structural effects using molecular dynamics (MD) simulations. Whole-exome sequencing was performed in 29 radiologically confirmed AD patients. Variants identified were screened using standard in silico prediction tools and categorised according to their involvement in amyloid precursor protein (APP)-related and non-APP pathways. Molecular dynamics simulations of filtered variants in PSEN1, SORL1, and ABCA7 genes were conducted using GROMACS 2024 to assess conformational stability, flexibility (RMSD, RMSF), compactness (Rg), and solvent accessibility (SASA). Thirty-six variants across 18 genes were identified, including five pathogenic variants and 31 variants of uncertain significance. Frequently affected genes included ABCA7 (8 variants), SORL1 (3 variants), PSEN1 (two novel variants), and APP (London mutation, Val717Ile). Most patients (83.3%) had a positive family history, with a mean age at onset of 54.17 ± 11.74 years, presenting with typical AD, posterior cortical atrophy, or frontal variants. MD simulations revealed increased rigidity, altered electrostatic interactions, and disrupted ATP-binding dynamics in mutant proteins compared with wild type. This study identifies novel and known AD-associated variants in an Indian cohort and demonstrates their potential structural impact. Integrating genetic and structural analyses provides valuable insights into AD pathogenesis in underrepresented populations.},
}
@article {pmid42412302,
year = {2026},
author = {Zhang, C and Ma, Y and Shi, Z and He, X and Hu, J and Chen, S and Wu, H and Tian, M and Yan, C and Xing, M and He, L},
title = {Study on the Effects and Mechanisms of Resveratrol in Improving Cognitive Impairment in Aβ1-42-Induced Alzheimer's Disease Model Mice.},
journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology},
volume = {21},
number = {1},
pages = {},
pmid = {42412302},
issn = {1557-1904},
mesh = {Animals ; *Resveratrol/pharmacology/therapeutic use ; *Alzheimer Disease/chemically induced/drug therapy/metabolism ; *Amyloid beta-Peptides/toxicity ; Mice ; *Peptide Fragments/toxicity ; *Cognitive Dysfunction/drug therapy/chemically induced/metabolism ; Disease Models, Animal ; Male ; Autophagy/drug effects ; Mice, Inbred C57BL ; *Antioxidants/pharmacology/therapeutic use ; Oxidative Stress/drug effects ; },
abstract = {Aging is a major risk factor for neurodegenerative diseases, including Alzheimer's disease (AD). Targeting cellular senescence has therefore emerged as a promising therapeutic strategy. Resveratrol (RV), a natural polyphenolic compound, exhibits anti-aging properties through the regulation of autophagy and oxidative stress; however, its mechanisms in AD remain incompletely understood. In this study, we investigated the effects and underlying mechanisms of RV in an Aβ1-42-induced AD model. In vivo, RV administration significantly reduced the expression of aging-related markers and activated autophagy-associated signaling pathways. In vitro, RV treatment markedly attenuated Aβ1-42-induced cell viability loss and excessive reactive oxygen species (ROS) production. Further mechanistic analyses demonstrated that RV-induced autophagy activation was closely associated with the AMP-activated protein kinase/UNC-51-like kinase 1 (AMPK/ULK1) and silent information regulator 1/nuclear factor-kappaB (SIRT1/NF-κB) pathways. Collectively, these findings suggest that RV alleviates AD-related pathological processes by promoting autophagy and delaying cellular senescence, highlighting its potential as a therapeutic agent for age-related neurodegenerative diseases.},
}
@article {pmid42412505,
year = {2026},
author = {Nunkessore, O and Bonfils, F and Guedin, H and El Haj, M},
title = {[Autobiographical Memory in Alzheimer's Disease: Understanding to Better Support Patients].},
journal = {Geriatrie et psychologie neuropsychiatrie du vieillissement},
volume = {24},
number = {2},
pages = {207-219},
doi = {10.1684/pnv.2026.1290},
pmid = {42412505},
issn = {2115-7863},
mesh = {Humans ; *Alzheimer Disease/psychology/therapy ; *Memory, Episodic ; Aged ; Caregivers/psychology ; Self Concept ; Hippocampus/physiopathology ; },
abstract = {Autobiographical memory is central to the construction and maintenance of identity and psychosocial functioning. In Alzheimer's disease (AD), autobiographical memory progressively deteriorates, disrupting personal narratives and self-perception. This article provides an integrative review of current knowledge on autobiographical memory and its impairment in AD. Neuroanatomical correlates are discussed, highlighting the key role of the hippocampus and its interactions with the frontal and parietal cortices and the amygdala. Preserved cognitive resources and current supportive strategies, including multisensory stimulation, narrative reconstruction, and immersive approaches, are also examined. The role of family caregivers is emphasized, as mediators of memories, supporters of identity continuity, and contributors to shared memory processes. Future perspectives include the development of digital tools and integrative methodologies aimed at bridging experimental rigor and the lived experience of patients. Such approaches are essential for advancing our understanding of autobiographical memory decline in AD and for developing tailored interventions that support identity, autonomy, and psychosocial well-being.},
}
@article {pmid42412614,
year = {2026},
author = {Duan, W and Xing, Y and Liu, W},
title = {Protocol for generating multiplexed prime-edited monoclonal cell lines in porcine fetal fibroblasts.},
journal = {STAR protocols},
volume = {7},
number = {3},
pages = {104691},
doi = {10.1016/j.xpro.2026.104691},
pmid = {42412614},
issn = {2666-1667},
abstract = {Porcine fetal fibroblasts (PFFs) serve as standard donor cells for generating cloned pigs, and prime editing (PE) enables precise genome modification. Here, we describe a protocol for generating multiplexed prime-edited monoclonal cell lines in PFFs. We describe steps for pegRNA/ngRNA design and screening, plasmid electroporation, nocodazole treatment, puromycin selection, and monoclonal isolation and genotyping. Although demonstrated by introducing three Alzheimer's disease-associated pathogenic mutations, the pipeline can be readily adapted to multiplex PE of other endogenous loci in porcine cells. For complete details on the use and execution of this protocol, please refer to Liu et al.[1].},
}
@article {pmid42412645,
year = {2025},
author = {Hidasi, Z and Fullajtár, M},
title = {[Special aspects of the treatment of Alzheimer's disease (Anti-amyloid therapies and management of BPSD)].},
journal = {Psychiatria Hungarica : A Magyar Pszichiatriai Tarsasag tudomanyos folyoirata},
volume = {40},
number = {3-4},
pages = {274-281},
pmid = {42412645},
issn = {0237-7896},
mesh = {Humans ; *Alzheimer Disease/drug therapy/psychology/therapy ; *Amyloid beta-Peptides/immunology ; Antibodies, Monoclonal, Humanized/therapeutic use ; Immunization, Passive ; },
abstract = {Due to its diverse symptomatology, Alzheimer's disease requires a complex therapeutic approach. Among the disease-modifying pharmacotherapeutic options, significant progress has recently been made in the field of anti-amyloid antibody therapies. These are generally costly procedures in which passive immunization targets various components of the beta-amyloid cascade. The individual agents differ significantly in terms of efficacy and potential side effects/complications. Considering the questionable degree of cognitive effectiveness, and the associated risks, the exact evaluation of the practical applicability of these agents is currently not possible; long-term data analysis is needed. The symptom cluster of behavioral and psychological symptoms of dementia (BPSD) is in itself complex, encompassing a wide range of clinical phenomena. These symptoms, which frequently occur in everyday patient care and often have multifactorial origins and pathomechanisms, require a complex therapeutic approach. The therapeutic benefit of pharmacological treatments applicable to specific symptom clusters is often difficult to determine due to potential side effects; therefore, individualized treatment supplemented with non-pharmacological methods is warranted. Keywords: Alzheimer's disease; anti-amyloid therapies; behavioral and psychological symptoms of dementia (BPSD).},
}
@article {pmid42412728,
year = {2026},
author = {Rodgers, FE and Huntley, J and McWilliams, A and Sommerlad, A},
title = {Theory of mind deficits and awareness in Alzheimer's disease.},
journal = {Dementia and geriatric cognitive disorders},
volume = {},
number = {},
pages = {1-14},
doi = {10.1159/000553343},
pmid = {42412728},
issn = {1421-9824},
abstract = {INTRODUCTION: Social cognition (SC) is often impaired by dementia, contributing to difficulties with relationships and social isolation. Additionally, people with dementia frequently have impaired awareness of their impairments which may worsen distress for them, their family, and friends. We investigated SC in people with Alzheimer's disease (PwAD), awareness of SC, and whether PwAD overestimate SC abilities compared to healthy controls (HC).<br><br>METHODS: Participants completed the Interpersonal Reactivity Index perspective-taking subscale (IRI-PT), a self-report measure of SC, and The Awareness of Social Inference Test (short-form) (TASIT-S), a task-based measure of SC. Insight was evaluated by comparing self-assessment with TASIT-S performance. The Addenbrooke's Cognitive Examination (Version 3; ACE-III) measured general cognition.<br><br>RESULTS: We recruited 70 PwAD (mean age=78.13; mean ACE-III=71.80) and 17 HC (mean age=71.53; mean ACE-III=96.65). PwAD self-reported lower theory of mind (ToM) (IRI-PT=-2.16, 95% CI=-0.33-4.64, p=0.09) and performed worse on TASIT-S emotion recognition (-2.04, 95% CI=-2.89--1.20, p<0.001), sarcasm recognition (-0.91, 95% CI=-1.66--0.16, p=0.02), and ToM assessments (-1.42, 95% CI=-2.27--0.57, p=0.001). There was no significant relationship between IRI-PT and TASIT-S ToM in either group, nor in the participant group as a whole. We categorised 'under-estimators' (low IRI-PT, high TASIT-S ToM), 'over-estimators' (high IRI-PT, low TASIT-S ToM), and 'congruent-estimators', and found that lower ACE-III was associated with ToM over-estimation.<br><br>CONCLUSION: Differences in self-reported and task-assessed SC were observed between PwAD and HC, but self-estimated and task-assessed ToM were not associated, suggesting that SC self-estimation is unreliable in PwAD and possibly in healthy older adults.},
}
@article {pmid42413005,
year = {2026},
author = {Elmkvist, SB and Thygesen, CK and Jensen, P and Pihl, M and Freude, KK and Finsen, B and Larsen, MR},
title = {Proteomic and Phosphoproteomic Characterization of Disease-Associated Alterations in Nerve Terminals and Protein Inclusions of Alzheimer's Disease Patients.},
journal = {Journal of proteome research},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jproteome.5c01160},
pmid = {42413005},
issn = {1535-3907},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by synaptic dysfunction, protein aggregation, and widespread molecular alterations in the brain. In this study, we applied quantitative mass spectrometry-based proteomics and phosphoproteomics to characterize synaptosomes and sarkosyl-insoluble protein inclusions from the post-mortem frontal lobes of AD and control cases. We identified >3700 proteins across both fractions, revealing AD-associated changes in synaptic composition and phosphorylation patterns. Proteomic analyses indicated mitochondrial deficits and disruptions in vesicle trafficking within synapses, whereas insoluble protein inclusions showed an accumulation of spliceosomal components and glial activation markers as well as an enrichment of N-terminally truncated amyloid beta peptides in AD cases, suggesting involvement of postfibrillar processing events mediated by specific proteases in amyloid plaque pathology. Phosphoproteomic analysis revealed extensive alterations in pathways regulating vesicle trafficking, Golgi homeostasis, and synaptic function. We observed increased tau phosphorylation at AD-associated sites in insoluble inclusions and distinct phosphorylation changes in synaptic tau, particularly at S285 and S305, suggesting altered tau function and aggregation properties. These findings provide new molecular insights into AD-related nerve terminal composition and protein aggregation, advancing our understanding of disease-associated changes at the subcellular level.},
}
@article {pmid42413022,
year = {2026},
author = {Shan, H and Lu, G and Yuan, Y and Dong, Q and Fang, C and Yu, K and Chen, L and Wei, Z and Chen, H and Hu, L and Wu, T and Tao, S and Chen, Y and Luo, J and Qi, Y and Hu, J and Cheng, G and Fan, X and Yin, Y},
title = {Deep Plasma Proteomics-Based Diagnostic Panel for Early Detection of Amnestic Mild Cognitive Impairment.},
journal = {Journal of proteome research},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jproteome.6c00231},
pmid = {42413022},
issn = {1535-3907},
abstract = {Amnestic mild cognitive impairment (aMCI) is often considered an early clinical stage of Alzheimer's disease (AD), but its subtle presentation leads to infrequent neurological evaluations. Early plasma biomarker screening during routine check-ups in community hospitals could enhance aMCI detection rates. Advances in proteomics, particularly mass spectrometry, have enabled the detection of low-abundance plasma proteins, opening new possibilities for aMCI biomarker identification. This study included 84 participants from the STAR cohort. We utilized deep plasma proteomics to detect low-abundance proteins, enriched with nanoparticle magnetic beads. An early diagnostic model for aMCI was developed through bioinformatics and machine learning, with performance compared to the Simoa assay. We identified 4268 low-abundance plasma proteins and constructed a 12-protein diagnostic panel (AUC = 0.992 in the training set, AUC = 0.933 in the testing set), outperforming the Simoa assay (accuracy: 93.9% vs 24.4%). In conclusion, the 12-protein panel provides a cost-effective method for early aMCI detection, potentially improving screening efficacy.},
}
@article {pmid42413026,
year = {2026},
author = {Bai, Y and Peters, O and Freiesleben, SD and Fenski, F and Priller, J and Spruth, EJ and Schneider, A and Fliessbach, K and Wiltfang, J and Bartels, C and Rostamzadeh, A and Glanz, W and Teipel, S and Kilimann, I and Laske, C and Munk, MH and Spottke, A and Roy-Kluth, N and Brosseron, F and Wagner, M and Frommann, I and Lüsebrink, F and Ramirez, A and Dechent, P and Hetzer, S and Scheffler, K and Yakupov, R and Jessen, F and Düzel, E and Bainbridge, WA},
title = {Diagnostic Images for Mild Cognitive Impairment Are Sensitive to Alzheimer's Disease Biomarkers and Reveal Abnormal Scene Processing.},
journal = {Journal of cognitive neuroscience},
volume = {},
number = {},
pages = {1-13},
doi = {10.1162/JOCN.a.2636},
pmid = {42413026},
issn = {1530-8898},
abstract = {Research on visual episodic memory impairment in Alzheimer's disease often focuses on memory processes rather than the specific content of image being remembered. We previously showed that patients with mild cognitive impairment (MCI), a transitional stage that may precede Alzheimer's disease, can memorize certain images well, indicating that episodic memory is not uniformly impaired. Conversely, other specific images could not be memorized by MCI patients and were instead diagnostic for distinguishing MCI from healthy older adults. In this study, we investigate whether poor memory for these diagnostic images relates to impaired neural processing in specific brain regions and Alzheimer's biomarker pathology. We assessed 64 healthy controls and 48 MCI participants from the DZNE Longitudinal Cognitive Impairment and Dementia Study. Participants performed a visual scene memory task during fMRI and provided CSF biomarker data for amyloid and tau. Diagnostic images demonstrated significantly larger behavior-biomarker correlations (total tau, phospho-tau, Aβ42/Aβ40, and Aβ42/phospho-tau) compared with nondiagnostic images. This suggests memory for these specific diagnostic images is more affected by Alzheimer's disease pathology. The fMRI data revealed an interaction effect between group membership (healthy control/MCI) and image diagnosticity (diagnostic/nondiagnostic). MCI participants exhibited higher activation in specific scene-processing regions (parahippocampal place area, retrosplenial cortex, and occipital place area) for diagnostic compared with nondiagnostic images. Healthy controls, however, showed no processing differences between diagnostic and nondiagnostic images. These findings suggest MCI individuals may engage in inefficiently heightened encoding activation for diagnostic images. Our results show that special "diagnostic" images exist that can reliably reveal underlying amyloid and tau pathology alongside altered neural activity in scene regions.},
}
@article {pmid42413104,
year = {2026},
author = {Rahimi, S and Momeni, M and Khatooni, M},
title = {Communication Breakdown in Patients With Alzheimer Disease: An Evolutionary Concept Analysis.},
journal = {Professional case management},
volume = {},
number = {},
pages = {},
pmid = {42413104},
issn = {1932-8095},
support = {//Qazvin Univesity of Medical Sciences/ ; },
abstract = {BACKGROUND: Impaired communication is a common problem for many people with Alzheimer disease (AD), which results in behavioral disturbances and psychosocial distress. The current literature lacks a clear and unified conceptual definition of communication breakdown in AD, which limits its effective management.<br><br>AIM: This article aims to clarify the concept of communication breakdown in patients with AD by identifying its attributes, antecedents, and consequences to propose a new operational definition of the concept.<br><br>DATA SOURCES: A systematic search was conducted on the databases such as Cochrane Database of Systematic Reviews, PsycINFO, Scopus, Medline, Social Sciences Index, and EMBASE between the years 2010 and 2026.<br><br>DESIGN: Rodgers' evolutionary framework of concept analysis (2000) was used as a guide for analyzing the communication breakdown concept.<br><br>RESULTS/CONCLUSION: Four main attributes were extracted to describe and propose a coherent definition of communication breakdown in patients with AD that encompass cognitive and memory impairment, language impairment, failure of concentration and attention, and behavioral and emotional disorder.<br><br>This concept analysis provides an operational and new definition that will improve knowledge of issues related to communication breakdown in AD, which can be used by family caregivers, case managers, and health care providers when preventing and managing communication problems in patients with AD.},
}
@article {pmid42413114,
year = {2026},
author = {Dosanjh, A and Al-Jaf, S and Ye, E and Abdelrahman, KS},
title = {Impact of inhalational anesthetics on neurodegeneration in Alzheimer's disease: current evidence and potential implications.},
journal = {Canadian journal of physiology and pharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1139/cjpp-2025-0192},
pmid = {42413114},
issn = {1205-7541},
abstract = {Alzheimer's disease is the most common form of dementia, primarily affecting the elderly population. It is a progressive neurodegenerative disease with key pathogenesis hallmarks being amyloid-beta plaque accumulation, and neurofibrillary tangles of tau protein. With an increasingly aging population and rising numbers of surgical procedures, growing interest has been directed towards the potential impact of inhalational anesthetics, particularly isoflurane, sevoflurane and desflurane, in contributing to the neurodegenerative process. Evidence supporting anesthetic-related modulation of Alzheimer's disease pathways is derived predominantly from in vitro and animal models, with comparatively limited and heterogeneous human biomarker and clinical data. This review will explore the various mechanisms by which these volatile anesthetics contribute to the pathogenesis of neurodegeneration in the context of AD. This includes upregulation of beta-secretase 1 resulting in the formation of amyloid-beta oligomers and inhibition of tau dephosphorylation. While certain studies point towards a neuroprotective effect of these anesthetics, the evidence remains inconsistent. Collectively, these findings support perioperative strategies focused on maintenance of normothermia, optimization of oxygenation, and judicious anesthetic exposure as practical measures to mitigate vulnerability in at-risk populations.},
}
@article {pmid42413140,
year = {2026},
author = {Inoue, Y and Oguchi, T and Inoue, A and Tanaka, M and Sasaki, A and Saito, K and Ezure, H and Otsuka, N},
title = {From diabetic foot to dementia: A neurovascular continuum linking systemic diabetic vasculopathy, cerebral small vessel disease, and glymphatic dysfunction.},
journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie},
volume = {201},
number = {},
pages = {119681},
doi = {10.1016/j.biopha.2026.119681},
pmid = {42413140},
issn = {1950-6007},
abstract = {Diabetes mellitus, particularly type 2 diabetes mellitus (T2DM), is increasingly recognized as a major risk factor for cognitive decline and dementia. Epidemiological studies consistently demonstrate that individuals with diabetes exhibit a significantly elevated risk of both vascular cognitive impairment and Alzheimer's disease [1,2]. Beyond hyperglycemia, systemic vascular dysfunction has emerged as a central mechanism underlying diabetes-related brain injury. Diabetes induces widespread vascular alterations, including endothelial dysfunction, arterial stiffening, oxidative stress, and chronic low-grade inflammation [3,4]. These processes affect both peripheral and cerebral circulation and may contribute to the development of cerebral small vessel disease (CSVD), a major substrate of cognitive decline [10-12]. Increased arterial stiffness may impair the Windkessel effect and facilitate the transmission of excessive pulsatile energy into fragile cerebral perforating arteries, thereby promoting microvascular injury and white matter damage [13-17]. In addition, diabetes-associated disruption of the neurovascular unit (NVU) may lead to blood-brain barrier dysfunction, neuroinflammation, and neuronal injury [20-30]. Impairment of the glymphatic system responsible for the clearance of metabolic waste products such as amyloid-β and tau may further contribute to neurodegenerative processes [31-41]. In this review, we propose a "systemic vascular continuum" linking peripheral diabetic vasculopathy, cerebral small vessel disease, neurovascular unit dysfunction, and glymphatic impairment. Within this framework, diabetic foot ulcer (DFU) is presented as a clinically visible peripheral phenotype and surrogate marker of advanced systemic vascular injury rather than a direct causal factor [5-9]. This integrative model provides a conceptual framework for understanding diabetes-associated cognitive impairment and highlights vascular-targeted preventive and therapeutic strategies as promising approaches for risk stratification and intervention.},
}
@article {pmid42413147,
year = {2026},
author = {Fagla, BM and Zhao, G and Valencia-Olvera, AC and Weng, JM and Rosa, CD and Ticiani, E and Tai, LM and Veiga-Lopez, A and Buhimschi, IA},
title = {Exposure to oligomeric and fibrillar species of amyloid-β induces toxicity and impairs extravillous trophoblast cell function in vitro.},
journal = {Placenta},
volume = {182},
number = {},
pages = {257-266},
doi = {10.1016/j.placenta.2026.06.015},
pmid = {42413147},
issn = {1532-3102},
abstract = {BACKGROUND: Misfolding of proteins and their subsequent assembly into supramolecular aggregates are key pathophysiological mechanisms involved in neurodegenerative diseases, such as Alzheimer's disease (AD). These aggregates range from small prefibrillar oligomers to large fibrils of β-sheet-rich assemblies that can accumulate in tissues and disrupt normal physiological function. In AD, accumulation of amyloid-β (Aβ) oligomers (AβO) and fibrils (AβF) in the brain is a hallmark of disease. Critically, Aβ aggregates, among other proteins, are also detectable in the serum, urine, and placenta of women with preeclampsia (PE). However, the effects of misfolded protein buildup on placental function remain unclear. We hypothesized that accumulation of Aβ aggregates in placental tissue may disrupt key cellular processes, notably, extravillous trophoblast (EVT) cell survival, migration, and invasion.<br><br>METHODS: HTR-8/SVneo cells, an immortalized EVT cell line, were exposed to exogenous A&#x3b2;O or A&#x3b2;F preparations. Cytotoxicity, cell death mechanism, cell migration, and cell invasion were assessed using MTT, apoptosis/necrosis assays, scratch assays, and Transwell invasion assays, respectively.<br><br>RESULTS: While both A&#x3b2;O and A&#x3b2;F induced cytotoxicity via apoptosis in EVT cells, A&#x3b2;O had a more profound effect than A&#x3b2;F (p&#x202f;<&#x202f;0.001). Furthermore, scratch assays revealed that A&#x3b2;O decreased the rate of cell migration while A&#x3b2;F led to an increased rate compared to vehicle controls. Finally, both A&#x3b2;O and A&#x3b2;F inhibited epidermal growth factor-mediated cellular invasion when tested in a Transwell assay (p&#x202f;=&#x202f;0.017).<br><br>DISCUSSION: Our findings indicate that exposure to aggregated A&#x3b2; species alters trophoblast function in vitro in ways that may be relevant to placental mechanisms associated with preeclampsia.},
}
@article {pmid42413217,
year = {2026},
author = {Liu, Z and Tong, X and Li, X and Duan, X and Yang, Y and Chen, F and Liu, Y and Tao, X and Liu, W},
title = {Restoring the balance: Resistance exercise-induced insulin-like growth factor-1 restores PI3K/Akt and MAPK/ERK cross-talk to ameliorate Alzheimer's disease.},
journal = {Ageing research reviews},
volume = {121},
number = {},
pages = {103239},
doi = {10.1016/j.arr.2026.103239},
pmid = {42413217},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD) remains a progressive neurodegenerative disorder without effective disease-modifying therapies. Epidemiological evidence indicates that regular resistance exercise substantially reduces AD risk, an effect potentially mediated by insulin-like growth factor-1 (IGF-1). However, the complete mechanistic pathway from exercise-induced peripheral IGF-1 synthesis to its central neuroprotective actions has not been systematically integrated. This review provides a comprehensive framework linking resistance exercise to AD amelioration through IGF-1-dependent signaling. We first detail how resistance exercise stimulates IGF-1 secretion from the liver and skeletal muscle via both endocrine (GH-IGF-1 axis) and autocrine/paracrine (mechano-sensitive MGF induction) pathways. Subsequently, we delineate three complementary routes by which circulating IGF-1 enters the brain: (1) lipoprotein receptor-related protein-1(LRP-1)-mediated transcytosis across the blood-brain barrier (BBB) coupled with activity-dependent vasodilation, (2) lipoprotein receptor-related protein-2(LRP-2)-mediated transport across the blood-cerebrospinal fluid barrier (BCSFB) at the choroid plexus, and (3) passive diffusion through circumventricular organs (CVOs). Once within the central nervous system, we propose that IGF-1 exerts its therapeutic effects primarily by restoring the physiological cross-inhibitory balance between the phosphoinositide 3-kinase (PI3K)/ protein kinase B (Akt) and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathways. Specifically, by reactivating Akt, exercise-induced IGF-1 suppresses GSK-3β-driven tau hyperphosphorylation, while simultaneously tempering pathological MAPK/ERK overactivation, thereby reducing β-amyloid (Aβ) generation and neuroinflammation. This rebalancing action further promotes Aβ clearance, enhances synaptic plasticity, and counteracts neuronal apoptosis. Notably, we critically discuss the context-dependent "double-edged sword" nature of IGF-1 signaling, where excessive or mistimed activation may exacerbate late-stage pathology, underscoring the need for stage-specific interventions. In summary, this review integrates the peripheral synthesis, multi-route central delivery, and pathway-rebalancing mechanisms of exercise-induced IGF-1, providing a mechanistic rationale for personalized resistance exercise prescriptions as a non-pharmacological strategy to combat AD.},
}
@article {pmid42413317,
year = {2026},
author = {De León-Muñoz, A and Rubio-Arias, J&#xc1; and Ávila-Gandía, V and Andreu-Caravaca, L},
title = {Effects of physical exercise on neurofilament light chain in multiple sclerosis and other neurological disorders: A systematic review.},
journal = {Multiple sclerosis and related disorders},
volume = {113},
number = {},
pages = {107357},
doi = {10.1016/j.msard.2026.107357},
pmid = {42413317},
issn = {2211-0356},
abstract = {BACKGROUND: Neurofilament light chain (NfL) is a well-established biomarker of axonal damage and neurodegeneration, with critical relevance in multiple sclerosis (MS) and other neurological disorders. This systematic review primarily aims to assess the impact of physical exercise on circulating NfL concentrations in people with MS, while secondarily exploring its effects across other neurological conditions.<br><br>METHODS: Five databases (PubMed, Scopus, Web of Science, EBSCO, and Cochrane) were searched according to PRISMA guidelines (PROSPERO: CRD420261294977). The search was conducted from inception until February 27, 2026. Methodological quality was assessed using RoB 2.0, ROBINS-I, and the PEDro scale. Articles were graded for evidence and recommendation levels using the Oxford Centre for Evidence-Based Medicine (OCEBM) criteria.<br><br>RESULTS: Fifteen articles were analyzed, involving a total sample of 765 patients (484 women). The sample predominantly comprised patients with MS (n&#x202f;=&#x202f;368), followed by secondary groups with Alzheimer's disease (AD; n&#x202f;=&#x202f;305), vascular cognitive impairment (VCI; n&#x202f;=&#x202f;58), Huntington's disease (HD; n&#x202f;=&#x202f;31), and Parkinson's disease (PD; n&#x202f;=&#x202f;3). In MS, significant reductions in NfL were found following resistance training, Pilates, and high-intensity interval training (HIIT). Conversely, prolonged moderate-to-high intensity aerobic exercise yielded no significant effects on NfL in AD, VCI, HD, or MS. Findings for PD remain preliminary, though HIIT appears to induce acute, transient NfL reductions.<br><br>CONCLUSION: Physical exercise, specifically resistance training, Pilates, and HIIT, may be associated with reduced NfL concentrations in patients with MS, suggesting a potential neuroprotective role. In contrast, current evidence for other neurological disorders (AD, premanifest HD, PD, and VCI) remains preliminary or non-significant. Exercise modality and intensity appear to be key variables; notably, resistance-based programs also induced additional reductions in GFAP and tau protein.},
}
@article {pmid42413380,
year = {2026},
author = {Sivalingam, AM},
title = {β-sitosterol and next-generation neuroprotection for multi-target strategies and the gut-brain axis in neurodegenerative diseases.},
journal = {The Journal of steroid biochemistry and molecular biology},
volume = {264},
number = {},
pages = {107080},
doi = {10.1016/j.jsbmb.2026.107080},
pmid = {42413380},
issn = {1879-1220},
abstract = {Neurodegenerative disorders such as Alzheimer's and Parkinson's diseases arise from complex interactions among oxidative stress, neuroinflammation, metabolic dysfunction, and dysregulated signaling networks. This review aim of the synthesize mechanistic evidence on β-sitosterol as a multi-target phytochemical and clarify how its actions connect to gut-brain axis modulation in neurodegeneration. The integrated mechanistic framework linking β-sitosterol's effects on cholesterol homeostasis, neuroinflammation, mitochondrial function, cholinergic signaling, and microbiota-barrier integrity to cognitive outcomes. Scope: preclinical and early translational evidence on β-sitosterol alone and with complementary phytochemicals, including nano-delivery strategies. Increasing evidence highlights phytochemicals as promising multi-target therapeutic agents capable of modulating these interconnected pathological processes. β-Sitosterol exhibits broad activity by regulating cholesterol metabolism, suppressing neuroinflammation, restoring redox balance, preserving mitochondrial function, and inhibiting important Alzheimer's diseases targets, including acetylcholinesterase and butyrylcholinesterase. The mechanisms action of β-sitosterol may (i) dampen microglial activation via TLR4/NF-κB signaling, (ii) activate Nrf2-dependent antioxidant responses (Nrf2/HO-1), (iii) support mitochondrial function and reduce ROS, (iv) stabilize membrane cholesterol and modulate amyloidogenic processing, and (v) inhibit acetylcholinesterase/butyrylcholinesterase to restore cholinergic tone. Complementary showing a neuroprotective effect actions of other phytochemicals such as curcumin, resveratrol, sulforaphane, and sinapic acid further enhance neuroprotection by modulating pathways like Nrf2/HO-1, TLR4/NF-κB, PI3K/Akt, and autophagy. Collectively, preclinical studies demonstrate that diverse botanical extracts significantly improve cognitive performance, reduce amyloid burden, restore cholinergic function, and attenuate neuroinflammation and oxidative damage. Emerging preclinical evidence suggests in rodent models of amyloid pathology, β-sitosterol (5-50 mg/kg) has been reported to improve memory in behavioral tests and reduce markers of neuroinflammation and oxidative stress; gut-brain effects include microbiota remodeling and enhanced barrier integrity, which correlate with reduced neuroimmune activation. Advances in nano-delivery systems and functional food formulations substantially improve phytochemical stability, bioavailability, and brain targeting. Available evidence is chiefly preclinical; clinical translation will require standardized dosing, pharmacokinetic and blood-brain barrier penetration studies, and randomized trials with microbiome and cognitive endpoints. Collectively, these findings position phytochemicals as promising candidates for multi-target disease modification and the development of next-generation neurotherapeutic strategies.},
}
@article {pmid42413499,
year = {2026},
author = {Vear, A and Olsen, SA and Lange, ECH and Müller, MA and Svendsen, C and Clemmensen, C},
title = {Preventative semaglutide and tirzepatide treatment does not alter disease progression in the 5xFAD mouse model of Alzheimer's disease.},
journal = {Cell reports. Medicine},
volume = {},
number = {},
pages = {102906},
doi = {10.1016/j.xcrm.2026.102906},
pmid = {42413499},
issn = {2666-3791},
abstract = {There is growing evidence that long-acting mimetics of the gut-derived incretin hormones GLP-1 and GIP act as disease-modifying therapies for Alzheimer's disease (AD). Here, we temporally characterize the efficacy of the approved incretin receptor agonists semaglutide, a GLP-1R agonist, and tirzepatide, a GLP-1R/GIPR co-agonist, in preventing AD progression. In 5xFAD mice treated for 2 or 4 months, both incretin therapies lower body weight and improve glucose tolerance, yet neither compound produces measurable effects on memory or learning tasks, amyloid-β plaque deposition, or glial cell activation. In a non-amyloidogenic model, 3 days of incretin pre-treatment does not alter microglial activation or the expression of inflammatory markers following lipopolysaccharide (LPS) administration in mice. Our findings indicate that chronic semaglutide or tirzepatide treatment, even when initiated before overt pathology and delivered for a prolonged period, does not slow neuropathological progression in 5xFAD or LPS-treated mice.},
}
@article {pmid42413698,
year = {2026},
author = {Huynh, AL and Wrigley, S and Ward, D and Andrews, JS and Burrell, LM and Yates, PA},
title = {Assessing the relationships between frailty, sarcopenia and Alzheimer's disease biomarkers: a scoping review.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103246},
doi = {10.1016/j.arr.2026.103246},
pmid = {42413698},
issn = {1872-9649},
abstract = {INTRODUCTION: While both frailty and sarcopenia have been linked with the Alzheimer's disease (AD) clinical phenotype, their association with AD pathophysiology is unclear. This review aimed to identify current evidence of relationships between frailty, sarcopenia and AD biomarkers.<br><br>METHODS: Four databases (Ovid MEDLINE, Embase, PsycINFO, Web of Science) were searched for articles that explored relationships between frailty or sarcopenia and AD biomarkers. AD biomarkers (fluid, tissue, neuroimaging) were defined by the 2024 criteria for diagnosis and staging of AD: Alzheimer's Association Workgroup. Assessment of frailty and sarcopenia were by use of a method/tool defined by the authors of the study.<br><br>RESULTS: 8187 articles were screened, with 49 studies included (31 frailty, 22 sarcopenia, 4 both). For frailty, the main AD biomarkers evaluated were hippocampal volume (35%) and beta-amyloid [A&#x3b2;] positron electron tomography (PET) (29%). For sarcopenia, the most common AD biomarkers evaluated were hippocampal volume (36%) and A&#x3b2; PET (55%). The findings were limited by the heterogeneity of the available evidence, in particular, the variability in frailty/sarcopenia definitions, AD biomarker assessments and the predominance of cross-sectional studies. Potential associations were identified across some studies, but these associations were not consistent across all studies.<br><br>CONCLUSIONS: Conclusions are limited by substantial heterogeneity in the assessment of frailty, sarcopenia, AD biomarkers, and a lack of longitudinal data. Future studies are needed that include longitudinal analyses, consensus in AD biomarker, frailty and sarcopenia assessments, and incorporation of novel AD biomarkers, in particular tau and neuroinflammation, to help clarify these relationships.},
}
@article {pmid42413719,
year = {2026},
author = {Alameen, AAM and Al-Kuraishy, HM and Abdelaziz, AM and Al-Gareeb, AI and Albuhadily, AK and Batiha, GE},
title = {Targeting PARP1-dependent parthanatos in Alzheimer's disease: Mechanisms and therapeutic opportunities.},
journal = {Life sciences},
volume = {402},
number = {},
pages = {124578},
doi = {10.1016/j.lfs.2026.124578},
pmid = {42413719},
issn = {1879-0631},
abstract = {Alzheimer's disease (AD) is the predominant cause of dementia globally. This review clarifies the dual function of poly(ADP-ribose) polymerase 1 (PARP1) in AD pathogenesis, emphasizing its role in mediating parthanatos, a unique caspase-independent cell death mechanism. We analyze contemporary literature regarding PARP1 expression, parthanatos signaling, and pharmaceutical treatments in AD models. In addition, PARP1 exhibits context-dependent duality: its physiological nuclear expression in hippocampus neurons is essential for memory consolidation and decreases early in cognitive impairment, suggesting a correlative association with synaptic malfunction. In contrast, overactivity of PARP1 resulting from Aβ-induced oxidative stress and DNA damage induces neurodegeneration via multiple pathways, including NAD+/ATP exhaustion leading to metabolism collapse, creation of the AIF-MIF complex promoting parthanatos, NF-κB-induced neuroinflammation, dysregulation of mitophagy, and disruption of the neuroprotective SIRT1 signaling pathway. The overactivity contributes to a positive feedback loop, where PARP1 intensifies Aβ and tau protein accumulation while simultaneously disrupting the BBB. In preclinical models of AD, genetic knockout, pharmacologic agents such as PJ34 and MC2050, or precursors of NAD[+] such as nicotinamide and NMN attenuate Aβ deposition, normalize metabolism, and ameliorate cognitive decline. The PARP1/parthanatos pathway is at the center of the confluence of oxidative stress, DNA damage, metabolism disorder, and neuroinflammation in AD. Metformin and other PARP1 inhibitors offer intriguing treatment options. PARP1's cell-type- and intracellular location-dependent activity necessitates careful consideration of context, dose, and disease stage while developing therapies. The present understanding in this review could inform future research on PARP1 regulation in AD clinical practice.},
}
@article {pmid42413720,
year = {2026},
author = {Jiang, L and Zhang, Z and Luo, X and Wu, H and Huang, Z and Wu, W and Xu, S and Pan, J and Tan, Z},
title = {Steroidal alkaloid H89712 ameliorates neuroinflammation and memory deficits: Enhancing cerebral oxidative phosphorylation in APP/PS1 mice.},
journal = {Life sciences},
volume = {},
number = {},
pages = {124583},
doi = {10.1016/j.lfs.2026.124583},
pmid = {42413720},
issn = {1879-0631},
abstract = {AIMS: Alzheimer's disease (AD) poses a major health challenge with limited therapeutic options. This study aimed to investigate the anti-AD potential and underlying mechanism of a novel steroidal alkaloid, H89.<br><br>MATERIALS AND METHODS: In vitro, A&#x3b2;25-35-exposed HT-22 hippocampal neurons and LPS-stimulated BV2 microglia were used to assess H89 neuroprotection and anti-inflammatory activity. In vivo, 6-month-old APP/PS1 mice were orally administered H89 for 2&#x202f;months. Spatial memory was assessed by Y-maze (YM) and Morris water maze (MWM). Hippocampal morphology, neuronal apoptosis (TUNEL/NeuN), A&#x3b2; deposition (IHC), microglial activation (IBA-1), inflammatory cytokines (ELISA), and oxidative phosphorylation (RNA-seq, qRT-PCR, Western blot) were examined. Brain malondialdehyde (MDA), ATP, and cellular ROS were quantified.<br><br>KEY FINDINGS: H89 (10 and 50&#x202f;nM) significantly protected HT-22 cells against A&#x3b2;25-35-induced injury and attenuated LPS-induced TNF-&#x3b1;, IL-1&#x3b2;, and IL-6 secretion while elevating IL-10 in BV2 cells. In APP/PS1 mice, H89 increased novel arm exploration in the YM and target quadrant residence in the MWM, indicating improved spatial learning and memory. H89 ameliorated hippocampal neuronal morphology, reduced apoptosis, attenuated A&#x3b2; plaques and microglial activation (IBA-1), decreased TNF-&#x3b1;, IL-6 and MDA, and elevated IL-10 and cerebral ATP. Transcriptomic and molecular analyses confirmed that H89 upregulated oxidative phosphorylation-related genes and proteins (ATP5E, ATP5J2, NDUFA13, NDUFB3, COX7C, COX11). Cerebral ATP positively correlated with spatial memory but negatively correlated with neuroinflammation and oxidative stress.<br><br>SIGNIFICANCE: H89 exerts neuroprotective effects by enhancing mitochondrial oxidative phosphorylation and brain energy supply, concurrently suppressing neuroinflammation, oxidative stress, and neuronal apoptosis, suggesting its potential as a therapeutic candidate for AD.},
}
@article {pmid42413776,
year = {2026},
author = {Zafar, SA and Qin, W and Chengliang, L and Khan, AA and Faisal, MS},
title = {Thymus-derived myeloid programs track microglial tolerance states across human cohorts.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106221},
doi = {10.1016/j.neuint.2026.106221},
pmid = {42413776},
issn = {1872-9754},
abstract = {INTRODUCTION: Microglial functional positioning varies across individuals and disease contexts, yet conserved biological axes supporting reproducible cross-cohort inference remain poorly defined. Intrathymic T cell development offers a paradigm in which chemokines, extracellular matrix (ECM)/adhesion factors, and axon guidance cues jointly govern immune cell migration and selection. We asked whether thymus-derived transcriptional programs provide a transferable basis for quantifying microglial tolerance-like positioning across independent human cohorts.<br><br>METHODS: We applied consensus non-negative matrix factorization to Tabula Sapiens thymus single-cell transcriptomes to derive eight Myeloid Education Signatures (MES); under formal enrichment testing, two were significantly enriched for ECM/adhesion biology and the rest were treated as data-driven programs without a dominant axis. MES scores were projected into four independent microglia cohorts (SEA-AD, Olah, Tuddenham, multiple sclerosis; >100 donors) and related to a donor-level tolerance score (homeostatic minus activation gene-set activity). Glucocorticoid receptor (GR) activity, calibrated from an external perturbation dataset, was evaluated as a moderator. Cross-cohort synthesis used random-effects meta-analysis with sensitivity analyses and multiple testing control.<br><br>RESULTS: Seven of eight MES modules were inversely associated with tolerance positioning; the eighth (MES08, defined by CCL2/CXCL2 chemokine genes) showed the most heterogeneous coupling across cohorts. The association strengthened monotonically with microglial purity in three of four cohorts, was recapitulated in Visium spatial transcriptomics, and was robust to covariate adjustment, housekeeping-gene removal, and leave-one-dataset-out sensitivity. This coupling was preferential to thymus-derived modules: modules built identically from six other tissues (blood, spleen, liver, lung, bone marrow, lymph node) coupled 1.2 to 2.9 fold less strongly, across module-number and feature-selection choices. Under a formal per-module interaction model, GR activity did not moderate the association, a well-powered null reproduced with a canonical GR panel and an external cohort. Irisin pathway (five-gene FNDC5/PPARGC1A module) associations were modest and largely non-significant after correction.<br><br>CONCLUSIONS: Thymus-derived myeloid programs constitute a transferable, tissue-preferential axis inversely coupled to microglial tolerance-like positioning, without detectable glucocorticoid moderation.},
}
@article {pmid42413810,
year = {2026},
author = {Lv, Y and Jia, Y and Xu, B and Zhao, C and Fu, W and Zhang, Y and Li, B and Li, X},
title = {Atrazine induces Alzheimer's disease-like neurotoxicity by targeting SDHB and disrupting synaptic function: An integrated bioinformatic and in vivo study.},
journal = {Chemico-biological interactions},
volume = {437},
number = {},
pages = {112249},
doi = {10.1016/j.cbi.2026.112249},
pmid = {42413810},
issn = {1872-7786},
abstract = {Atrazine (ATR) is a globally prevalent herbicide linked to increased risks of cognitive impairment and neurodegeneration, but its molecular mechanism remains unclear. This study integrates bioinformatics, machine learning, and experimental validation to elucidate ATR induced Alzheimer's disease (AD)-like pathology. We combined predicted ATR targets with AD brain transcriptomics, identifying 32 shared genes enriched in neurodegeneration and synaptic signaling pathways. We constructed a diagnostic model using 14 machine learning algorithms; the ensemble model achieved an improved AUC of 0.891 in the training set, with external validation AUCs of 0.833, 0.869, and 0.900. SHAP interpretability analysis identified SDHB as the most important key risk factor. Molecular docking validated the stable binding between ATR and core target proteins, with binding energies ranging from -4.9 to -5.9 kcal/mol. Single-cell sequencing and in silico gene knockdown confirmed that SDHB deficiency primarily disrupts neuronal synaptic signaling pathways. In vivo experiments demonstrated that ATR exposure induces anxiety-like behavior and memory deficits, suppressed hippocampal SDHB, and elevated Aβ and p-tau levels. ATR also reduced synaptic markers PSD95 and SYP in a dose dependent manner, confirming SDHB suppression leads to synaptic damage. Based on these findings, we established the first standardized adverse outcome pathway (AOP) framework delineating the cascade of events from ATR-induced SDHB inhibition to cognitive impairment. This study demonstrates that ATR targets SDHB to induce synaptic dysfunction and AD-like neuropathology, offering a new mechanistic basis for environmental risk assessment.},
}
@article {pmid42413887,
year = {2026},
author = {Vallejo-Azar, MN and Freccero, P and Postillone, MB and Princich, JP and Solis, P and Medel, N and Lisso, J and Irureta, N and Morganti, S and Fernández, J and Collavini, S and Bendersky, M and Ramírez, A and Bernal, V and Kochen, S and Dalmasso, MC and Gonzalez, PN},
title = {GeNED.ar cohort: Neuroimaging Resource for Aging Studies in an Admixed Population from Argentina.},
journal = {NeuroImage},
volume = {},
number = {},
pages = {122117},
doi = {10.1016/j.neuroimage.2026.122117},
pmid = {42413887},
issn = {1095-9572},
abstract = {Well-characterized cohorts are essential for advancing neuroimaging biomarkers and refining models of brain aging and dementia across diverse populations. Despite growing neuroimaging research in Latin America, additional multimodal cohorts integrating imaging, genomic, and environmental data are needed to capture population diversity. We present GeNED.ar (Genetics and Neuroimaging of Aging and Dementia in Argentina), a multimodal cohort established in the Metropolitan Area of Buenos Aires to investigate brain aging in a population with genetic admixture and socioeconomic heterogeneity. The dataset combines two complementary recruitment strategies, community-based healthy participants and Memory Clinic attendees, including 3T MRI, genome-wide genotyping, and detailed sociodemographic data from 367 individuals aged 18-94 years. Participants comprise healthy individuals (n=235) and Memory Clinic attendees classified as cognitively unimpaired (n=65), mild cognitive impairment (n=37), Alzheimer's or mixed dementia (n=24), and vascular dementia (n=6). Genetic ancestry analysis (n=191) indicated a predominantly admixed population (65% European, 28.3% Native American) with significant differences across recruitment sources. Brain age gap (BAG), estimated from T1-weighted MRI, increased progressively along the clinical continuum, where people with dementia exhibited older-appearing brains relative to cognitively unimpaired participants, and intermediate values were observed in mild cognitive impairment. No independent associations were observed between BAG and individual genetic or environmental risk factors. By integrating multimodal MRI and genomic data across complementary recruitment settings, GeNED.ar provides a unique regional resource to evaluate neuroimaging biomarkers, facilitate cross-cohort validation, and strengthen the generalizability of aging and dementia models in genetically and socially diverse populations.},
}
@article {pmid42413935,
year = {2026},
author = {Lee, S and Kao, CY and Li, Z and Dan, T and Wu, G and Hao, W},
title = {Optimal control for anti-abeta treatment in Alzheimer's disease using a reaction-diffusion model.},
journal = {Journal of the Royal Society, Interface},
volume = {23},
number = {240},
pages = {},
doi = {10.1098/rsif.2025.1158},
pmid = {42413935},
issn = {1742-5662},
support = {1R35GM146894/GF/NIH HHS/United States ; DMS-2533995//NSF/ ; DMS 2208373//NSF/ ; DMS 2513176//NSF/ ; //Huck Chair in AI Mathematical Modeling from Penn State University's Huck Institutes of the Life Sciences/ ; },
mesh = {*Alzheimer Disease/diagnostic imaging/metabolism/drug therapy/therapy ; Humans ; *Amyloid beta-Peptides/metabolism/antagonists &amp; inhibitors ; *Models, Biological ; Positron-Emission Tomography ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder that severely impairs survival and quality of life. While anti-amyloid beta (Aβ) therapies can slow disease progression, their efficacy depends on personalized dosing that maximizes benefits and minimizes risks, such as amyloid-related imaging abnormalities (ARIA). Mathematical modelling offers a powerful tool for understanding AD dynamics and optimizing treatment, yet most models focus solely on temporal behaviour, overlooking spatial heterogeneity within the brain. In this study, we propose a spatially explicit reaction-diffusion model to describe Aβ plaque dynamics. We formulate an optimal control problem to minimize plaque concentration while balancing therapeutic efficacy and treatment risk. Under reasonable assumptions, we establish well-posedness and uniqueness of the optimal solution. A finite element method (FEM)-based numerical framework is developed to compute personalized treatment strategies. Our model is calibrated using longitudinal Aβ positron emission tomography (PET) data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), enabling estimation of patient-specific parameters, such as growth rate and effective diffusivity. Results show that optimized treatment strategies consistently outperform constant dosing regimens across patient groups, achieving substantial reductions in cumulative amyloid burden while minimizing side effects. This integrated, data-driven framework advances personalized, spatially informed therapeutic optimization for AD.},
}
@article {pmid42414168,
year = {2026},
author = {Lee, DR and Endo, AS and Kalbasi, TR and Turner, M and Jimenez, IA and Serrano, KS and Centeno, A and Reuben, DB},
title = {Psychiatric Hospitalization Precipitants and Outcomes in a Comprehensive Dementia Care Program.},
journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jagp.2026.06.002},
pmid = {42414168},
issn = {1545-7214},
abstract = {OBJECTIVES: Characterize the precipitants and outcomes of psychiatric hospitalizations among patients enrolled in a comprehensive dementia care program and identify factors associated with discharge to higher-level residential setting.<br><br>DESIGN: Retrospective cohort study.<br><br>SETTING: UCLA Alzheimer's and Dementia Care Program.<br><br>PARTICIPANTS: Patients hospitalized at the UCLA Resnick Neuropsychiatric Hospital (NPH).<br><br>MEASUREMENTS: Precipitating reasons for hospitalization, patient demographic and clinical characteristics, hospitalization-level characteristics, and caregiver relationship. Discharge to higher-level residential settings (e.g., assisted living, nursing home). Change in scheduled Central Nervous System (CNS)-active medications (antipsychotics, antidepressants, and sedative/hypnotics).<br><br>RESULTS: There were 180 psychiatric hospitalizations among 150 patients, with a median age of 79 years (IQR, 73-85) at admission and MMSE score of 17 (IQR, 12-24) at first hospitalization. Agitation was the most common precipitating reason for hospitalization (n = 127, 71%). Median length of stay was 14 days (IQR, 9-26); 54 (30%) resulted in discharge to a higher-level residential setting. Agitation as the precipitant for hospitalization (aOR, 4.7; 95% CI, 1.7-12.9, p = 0.003) and male sex (aOR, 2.3; 95% CI, 1.0-5.5, p = 0.049) were associated with higher odds of discharge to a higher-level setting. Most hospitalizations resulted in no change in the number of scheduled CNS-active medications (e.g., 69% had no change in the number of scheduled antipsychotics), while escalation occurred in 19%-28%, depending on medication class.<br><br>CONCLUSION: Psychiatric hospitalization precipitated by agitation or involving male patients was often followed by transition to higher-level residential care. Future studies should evaluate whether earlier outpatient psychiatry involvement and proactive placement planning can reduce hospitalization and subsequent placement changes.},
}
@article {pmid42414260,
year = {2026},
author = {Sulatsky, MI and Stepanenko, OV and Kayda, AA and Stepanenko, OV and Mikhailova, EV and Sulatskaya, AI},
title = {Spontaneous aging of mature amyloids alters structural stability, cytotoxicity, and susceptibility to biological clearance.},
journal = {Cell death discovery},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41420-026-03245-1},
pmid = {42414260},
issn = {2058-7716},
support = {23-74-10092//Russian Science Foundation (RSF)/ ; },
abstract = {Accumulation of amyloid fibrils is a key factor in the pathogenesis of progressive diseases, including neurodegenerative disorders such as Alzheimer's and Parkinson's disease, as well as systemic amyloidosis. Although amyloid deposits are known to persist in vivo for years or even decades, it remains unclear how the structure and biological properties of mature fibrils evolve during prolonged post-assembly residence. Here, we addressed this question using a simplified cell-free aqueous model designed to isolate the intrinsic time-dependent behavior of mature amyloid aggregates from the complexity of the biological milieu. Specifically, we investigated the long-term evolution of two polymorphs of lysozyme amyloid fibrils as model systems with distinct clustering propensities that mimic the diversity of amyloid deposits. We challenge the assumption of amyloid stability by demonstrating their spontaneous degradation over 16 months at physiological temperature, a process we define as amyloid "aging". This process is characterized by aggregate declustering, fibril shortening, and progressive depolymerization into monomeric subunits, accompanied by a pronounced reduction in intrinsic toxicity across multiple human cell lines. Notably, "aged" fibrils were disassembled and degraded more efficiently than freshly prepared aggregates by the molecular chaperone α-B-crystallin and immune-associated proteases, including matrix metalloproteinase-9 and cathepsins B and D. However, this enhanced degradation revealed a paradox: accelerated processing of "aged" amyloids did not always reduce cytotoxicity and, in some cases, even exacerbated it, consistent with the generation of biologically active fibril-derived species rather than their complete conversion into non-toxic monomers. We provide the first systematic evidence that mature amyloids are dynamic structures undergoing spontaneous degradation that fundamentally alters their cytotoxicity and susceptibility to biological clearance. Our results introduce amyloid aging as a previously underappreciated dimension of amyloid biology and emphasize the need to account for fibril "age" when evaluating pathogenic potential and developing anti-amyloid therapeutic strategies.Spontaneous "aging" of amyloid fibrils leads to suprastructural remodeling: declustering, fibril shortening, and attenuated cytotoxicity. While "aged" aggregates are degraded more efficiently by immune-associated proteases and α-B-crystallin than "fresh" fibrils, this enhanced degradation does not reduce cytotoxicity and, in some cases, exacerbates it, highlighting the complex interplay between aggregate maturity and biological outcomes.},
}
@article {pmid42414290,
year = {2026},
author = {Li, H and Pan, W and Rajendran, S and Zang, C and Wang, F},
title = {Empowering clinical trial design with agentic intelligence and real-world data.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {42414290},
issn = {2041-1723},
mesh = {Humans ; Electronic Health Records ; *Clinical Trials as Topic/methods ; *Research Design ; Machine Learning ; *Artificial Intelligence ; },
abstract = {Clinical trial design (CTD) is a time-consuming process that requires substantial domain expertise. Large-scale real-world data (RWD), such as electronic health records (EHR), encodes practice-based evidence that is of tremendous value to CTD. In recent years, many machine learning methods have been developed to extract such real-world evidence (RWE) from the RWD to inform CTD, but they still need to be communicated with the domain experts extensively in an iterative manner to be further refined and ultimately useful. In this paper, we introduce EmulatRx, an agentic framework that derives RWE for helping with CTD. Through the iterative conversation and analysis across agents with different roles, EmulatRx can autonomously refine trial protocols and finally generate a robust report containing insights that inform better CTD. We applied EmulatRx on the CTD process for both acute diseases (e.g., septic shock, acute heart failure, acute pulmonary edema, and acute kidney injury) using the MIMIC-IV data and chronic diseases (e.g., Alzheimer's disease and Parkinson's disease) using the INSIGHT Network across five New York City health systems. The results demonstrate EmulatRx's capabilities in facilitating and accelerating the CTD process.},
}
@article {pmid42414687,
year = {2026},
author = {Pearson, H},
title = {How to avoid dementia - what the science really says.},
journal = {Nature},
volume = {655},
number = {8122},
pages = {294-297},
pmid = {42414687},
issn = {1476-4687},
}
@article {pmid42414714,
year = {2026},
author = {Álvarez-Rodríguez, L and Vázquez, C and Cordón, B and Garcia-Martin, E and de Moura, J and Novo, J and Ortega, M},
title = {3D OCT-Based Retinal Biomarker Analysis for Automatic Regional-Wise Characterization of Neurodegenerative Diseases.},
journal = {Journal of imaging informatics in medicine},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10278-026-02098-5},
pmid = {42414714},
issn = {2948-2933},
support = {PI17/01726//Instituto de Salud Carlos III/ ; PI20/00437//Instituto de Salud Carlos III/ ; PI23/00935//Instituto de Salud Carlos III/ ; RD21/0007/0022//Instituto de Salud Carlos III/ ; FORT23/00010//Instituto de Salud Carlos III/ ; PID2023-148913OB-I00//Ministerio de Ciencia e Innovaci&#xf3;n/ ; ED431C 2024/33//Xunta de Galicia/ ; B23_23R//Gobierno de Arag&#xf3;n/ ; B50_24//Gobierno de Arag&#xf3;n/ ; },
abstract = {Neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD), essential tremor (ET), multiple sclerosis (MS), and Parkinson's disease (PD) are complex disorders that often exhibit overlapping symptoms, leading to diagnostic challenges. Given the increasing interest in retinal imaging as a non-invasive biomarker for neurodegeneration, this study proposes a fully automated machine learning pipeline for disease characterization using optical coherence tomography (OCT). We analyze macular thickness patterns across three key and relevant retinal elements: retinal nerve fibre layer (RNFL), ganglion cell layer to Bruch's membrane (GCL-BM), and the total retina. These are processed by two complementary regional layouts: the standard ETDRS scheme and a custom 3 × 3 quadrant grid. These measurements are used to train multiple classifiers to distinguish between healthy controls and NDDs either collectively or individually. The proposed method processes 34,375 OCT B-scans from 353 subjects and highlights disease-specific thickness patterns with a pathological distinction score ranging up to 0.71 depending on the retinal region, disease, and classifier. Sector-based grids generally outperform quadrant-based ones, revealing highly localized pathological signatures. Our findings demonstrate that each disease manifests distinct retinal alterations, aligning with current clinical literature while offering novel insights for ET and PD. The study reinforces the potential of grid-based OCT analysis as a discriminative and fully automatic screening tool, paving the way for improved early diagnosis and differential analysis of NDDs through retinal biomarkers.},
}
@article {pmid42415081,
year = {2026},
author = {Perez-Toro, PA and Almizel, M and Nöth, E and Maier, A and Arias-Vergara, T},
title = {Generating Alzheimer's narratives using large language models.},
journal = {BMC medical informatics and decision making},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12911-026-03653-4},
pmid = {42415081},
issn = {1472-6947},
abstract = {BACKGROUND: Analyzing semi-spontaneous speech is a promising direction for supporting Alzheimer's disease (AD) assessment, yet progress is limited by the scarcity of annotated clinical data. Large Language Models (LLMs) offer new opportunities to generate synthetic narratives that may resemble speech patterns of both patients with AD and healthy controls during cognitive evaluation tasks such as the Cookie Theft Picture description.<br><br>METHODS: This study evaluates whether models including GPT, T5/Flan-T5, LLaMA, Mistral, and Qwen can generate clinically plausible picture-description narratives under two configurations: Human-to-Bot, where an LLM responds directly to real interviewer prompts, and Bot-to-Bot, where two LLMs simulate both interviewer and participant roles. Models were fine-tuned on transcripts from the DementiaBank Pitt Corpus and assessed using lexical and semantic metrics, as well as human expert ratings. Generated narratives were further used to augment training data for an AD vs. healthy control classifier based on BERT embeddings and an MLP architecture.<br><br>RESULTS: LLMs differed substantially in their ability to reproduce clinically meaningful and semantically coherent narratives of patient-interviewer interactions. Mistral, LLaMA, and Qwen achieved the strongest automatic evaluation metrics, e.g., BERTScores above 0.90 in the Human-to-Bot condition-and produced narratives rated by human experts as fluent, plausible, and diagnostically informative. When combining real and synthetic narratives for classifier training, the highest F1-score reached 0.84, outperforming models trained on real data alone (F1&#x2009;=&#x2009;0.74). Synthetic data generated in Human-to-Bot settings contributed most to diagnostic improvements, whereas Bot-to-Bot interactions exhibited greater variability and reduced clinical realism.<br><br>CONCLUSION: LLMs can generate high-quality synthetic narratives that enhance downstream AD classification and show promising clinical plausibility in cognitive assessment contexts. Incorporating LLM-generated data provides a scalable strategy for mitigating data scarcity in dementia research. Future work should focus on improving fully synthetic dialogue quality, expanding multilingual capabilities, and refining evaluation frameworks to better capture clinically relevant linguistic features.},
}
@article {pmid42415114,
year = {2026},
author = {Strickland, MR and Holtzman, DM},
title = {ApoE lipoproteins in the central nervous system under homeostasis and role in Alzheimer's disease and related disorders.},
journal = {Molecular neurodegeneration},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13024-026-00970-0},
pmid = {42415114},
issn = {1750-1326},
support = {T32AG058518/NH/NIH HHS/United States ; RF1NS090934/NH/NIH HHS/United States ; },
abstract = {Apolipoprotein E (ApoE) is highly expressed in the central nervous system (CNS) where it plays a critical role in lipid homeostasis and in the etiology of Alzheimer's disease (AD) and related diseases. ApoE associates with lipids to form discoidal and spherical lipoproteins that carry lipid and protein cargo throughout the brain. In this review, we focus on the significance of ApoE as a lipoprotein and how this impacts the function of ApoE in homeostasis and disease. In the CNS, ApoE is primarily secreted by astrocytes, though other cells, including microglia, secrete ApoE under certain conditions. ApoE lipoproteins (LpE) secreted by different cell types carry unique lipids and proteins which alter its function. The lipidation state of ApoE alters its conformation and binding to different receptors and, consequently, its ultimate impact on AD pathology. Most dramatically, nonlipidated ApoE has minimal binding to the low density lipoprotein receptor (LDLR), while lipidation of ApoE restores high affinity binding to LDLR. Furthermore, the degree of ApoE lipidation also impacts ApoE receptor binding through changes in protein conformation and stoichiometry of ApoE molecules per lipoprotein. The lipidation state of ApoE also alters its interaction with amyloid-β and tau, the proteins involved in forming amyloid plaques and neurofibrillary tangles, the pathological hallmarks of AD. LpE also carry lipids and proteins that alter the function of ApoE. Understanding how the lipid and protein content of LpE interacts with the conformational changes that occur with lipidation and maturation are essential to mechanistically understanding the role of ApoE in homeostasis and disease pathogenesis. In this review, we highlight the current understanding of LpE biology in the CNS and delineate important areas of future research.},
}
@article {pmid42415176,
year = {2026},
author = {Eom, JW and Kim, KR and Kim, DH and Song, JG and Han, C and Kim, HW and Ha, S and Song, WJ and Kim, YH},
title = {Zinc-mediated lysosomal activation by 1H10 enhances autophagy and attenuates tau pathology in Alzheimer's disease models.},
journal = {Molecular brain},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13041-026-01328-9},
pmid = {42415176},
issn = {1756-6606},
support = {NRF-2020R1I1A1A01061724//National Research Foundation of Korea/ ; RS-2023-NF001356//National Research Foundation of Korea/ ; 2025-RISE-01-019-04//The seoul RISE centor/ ; },
abstract = {Impaired autophagic flux and lysosomal dysfunction contribute critically to the accumulation of pathological protein aggregates in Alzheimer's disease (AD). Emerging evidence suggests that intracellular zinc dynamics regulate lysosomal function by modulating processes such as acidification and lysosomal biogenesis. We previously identified 1H10 as an AMP-activated protein kinase (AMPK) inhibitor and subsequently demonstrated its zinc-binding capacity and ability to regulate intracellular zinc homeostasis. Building on our prior findings that intra-lysosomal zinc promotes acidification and activates transcription factor EB (TFEB), we investigated whether 1H10 enhances lysosomal function through zinc mobilization in neurons, thereby improving autophagy and reducing pathological protein accumulation. In primary cortical neurons, 1H10 increased lysosomal abundance and enhanced lysosomal degradative capacity in a zinc-dependent manner, as demonstrated by increased cathepsin B activity and DQ-BSA degradation. It alleviated lysosomal dysfunction induced by v-ATPase inhibition and promoted autophagic flux, leading to reduced accumulation of amyloid-β (Aβ) and tau in neuronal models. In 5XFAD mice, 1H10 treatment showed trends toward improved spatial learning in the Morris water maze, reduced tau phosphorylation at Thr205 and Ser214, normalized LC3-II levels, and restored autophagic-lysosomal homeostasis, without significant changes in extracellular amyloid plaque burden. These findings indicate that zinc-mediated lysosomal activation by 1H10 enhances the autophagy-lysosomal pathway and attenuates tau pathology in AD models, suggesting that targeting lysosomal function may represent a potential therapeutic strategy for neurodegenerative disorders characterized by impaired proteostasis.},
}
@article {pmid42415281,
year = {2026},
author = {Aldana, BI and Freude, K},
title = {Chemokines in Alzheimer's Disease: Early Defence, Late Damage and the Impact of Sex and Infection.},
journal = {Basic &amp; clinical pharmacology &amp; toxicology},
volume = {139},
number = {2},
pages = {e70273},
doi = {10.1111/bcpt.70273},
pmid = {42415281},
issn = {1742-7843},
support = {R434-2023-242//Lundbeck Foundation/ ; N/A//Alzheimersfonden/ ; },
mesh = {Humans ; *Alzheimer Disease/immunology/metabolism ; *Chemokines/metabolism/immunology ; Animals ; Female ; Male ; Sex Factors ; Signal Transduction ; Virus Diseases/immunology ; Neuroinflammatory Diseases/immunology ; COVID-19/immunology ; Receptors, Chemokine/metabolism ; Brain/immunology/metabolism ; Sex Characteristics ; },
abstract = {Chemokines constitute a versatile signalling network maintaining homeostasis and glia-neuron communication in the healthy brain but become progressively dysregulated during aging and Alzheimer's disease (AD). This review examines how chemokine systems transition from tightly regulated homeostatic signals to drivers of chronic neuroinflammation in AD. We describe the major chemokine families (CC, CXC, CX3C) and their dominant central nervous system (CNS) receptors (CCR2, CXCR3, CX3CR1), which activate canonical inflammatory pathways including NF-κB, JAK/STAT and PI3K-AKT. In AD, chemokine dysregulation occurs in a coordinated manner across multiple functional modules, including recruitment-associated (CCL2, CXCL1), interferon-inducible (CXCL10), loss-of-restraint (CX3CL1) and vascular-associated chemokines. These alterations shift the network from regulated immune communication to self-sustaining inflammatory circuits perpetuating chronic neuroinflammation. These networks reprogram microglia and astrocytes into disease-associated phenotypes, amplify peripheral immune cell infiltration and destabilise synaptic function. Biological sex profoundly influences neuroinflammatory trajectories, with females exhibiting enhanced microglial senescence and interferon signalling, while males show accelerated complement activation. Viral pathogens, particularly neurotropic viruses (HSV-1, HHV-6, VZV) and SARS-CoV-2, actively reprogram chemokine networks, linking infection to amyloid-β accumulation, tau pathology and neurodegeneration. Therapeutically, chemokine axes represent precision targets requiring stage-matched, sex-stratified interventions rather than broad anti-inflammatory approaches. Understanding chemokine network dynamics offers mechanistic insights into AD pathogenesis and could provide pointers for therapeutic strategies.},
}
@article {pmid42415306,
year = {2026},
author = {Gaetani, L and Nardi, G and Parnetti, L},
title = {Can the integration of blood-based biomarkers into Alzheimer's disease diagnosis revolutionize the field?.},
journal = {Expert review of neurotherapeutics},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/14737175.2026.2700246},
pmid = {42415306},
issn = {1744-8360},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a clinical-biological entity in which pathophysiological changes precede symptoms by years. Biomarkers are essential for early and accurate diagnosis, particularly in the era of disease-modifying therapies requiring biological confirmation. Cerebrospinal fluid (CSF) and amyloid positron emission tomography (amyloid-PET) are the reference standards, but increasing attention is devoted to blood-based biomarkers (BBMs) due to their scalability and cost-effectiveness.<br><br>AREAS COVERED: In this critical perspective, the authors critically appraise the current evidence supporting plasma phosphorylated tau at threonine 217 (p-tau217) as the leading BBM for AD. They also discuss its analytical performance, biological rationale, and diagnostic accuracy across the AD continuum, its relationship with established CSF, PET, and neuropathological biomarkers, its potential role in identifying patients eligible for disease-modifying therapies, and the main clinical and biological factors influencing its interpretation. Finally, they highlight current limitations, unresolved challenges, and give their future perspectives for the integration of plasma biomarkers into routine clinical practice.<br><br>EXPERT OPINION: BBMs are expected to reshape AD diagnostics. A stepwise approach, using plasma biomarkers as first-line tests followed by confirmatory CSF or PET, is currently the most feasible strategy. Ultimately, highly specific, brain-derived tau biomarkers may enable BBMs to replace CSF biomarkers.},
}
@article {pmid42415348,
year = {2026},
author = {Sohn, C and Pardo, S and Molleur, D and Paduri, SR and Lambert, M and Uttke, Z and Sohn, EJ and Thomas, MG and Weintraub, ST and Frost, B},
title = {Elevation of the mechanically-sensitive e protein emerin links nuclear mechanotransduction to tau-induced cytoskeletal remodeling in neurons.},
journal = {Nucleus (Austin, Tex.)},
volume = {17},
number = {1},
pages = {2697135},
doi = {10.1080/19491034.2026.2697135},
pmid = {42415348},
issn = {1949-1042},
mesh = {*Neurons/metabolism/pathology ; *Nuclear Proteins/metabolism/genetics ; Humans ; *Mechanotransduction, Cellular ; *tau Proteins/metabolism/genetics ; *Cytoskeleton/metabolism ; *Membrane Proteins/metabolism/genetics ; *Cell Nucleus/metabolism ; Animals ; Actins/metabolism ; },
abstract = {Neurodegenerative tauopathies, including Alzheimer's disease, are neuropathologically defined by pathological tau deposition. While tau drives neurotoxicity by disrupting cytoskeletal, nucleoskeletal, and genomic architecture, cellular mechanisms mediating tau-induced dysfunction of the cytoskeleton and nucleoskeleton are incompletely understood. Here, we identify proteins with differing abundance in a cellular tauopathy model, iTau. Building upon previous findings that pathogenic tau reduces nuclear tension, we find elevated levels of emerin, a central regulator of nuclear mechanotransduction, in iTau neurons and tau mutant iPSC-derived neurons. Neuronal emerin overexpression drives neurotoxicity, increases filamentous actin (F-actin), and induces nuclear invagination, mimicking cellular phenotypes of tauopathy. Alterations in emerin binding partners reflect its cytosolic relocalization in iTau neurons, suggesting that pathogenic tau may impact nuclear mechanotransduction by altering emerin levels and localization. Overall, we identify emerin as a potential mediator of cytoskeletal and nucleoskeletal remodeling in tauopathy and provide a foundation for future studies of emerin function in neurons.},
}
@article {pmid42415414,
year = {2026},
author = {Nguyen, DD and Paine, M and Lee, S and Fazlollahi, A and Wang, BB and O'Sullivan, JD and Nestor, PJ},
title = {Global Rather Than Vertical-Selective Saccadic Abnormalities in Progressive Supranuclear Palsy.},
journal = {Annals of clinical and translational neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/acn3.70480},
pmid = {42415414},
issn = {2328-9503},
support = {//Mater Foundation/ ; 2023/GNT2030157//NHMRC Ideas/ ; },
abstract = {OBJECTIVE: To test whether vertical saccades are preferentially affected in Progressive Supranuclear Palsy (PSP).<br><br>METHODS: PSP patients (n&#x2009;=&#x2009;24) were compared to age-matched controls (n&#x2009;=&#x2009;94) and two degenerative groups (Alzheimer's disease, n&#x2009;=&#x2009;20; Lewy body disease, n&#x2009;=&#x2009;50). Video-oculography (sampling rate: 1000&#x2009;Hz) was used to measure visually guided saccades (15.3&#xb0; amplitude) in vertical and horizontal planes. Traditional corrected velocity alongside novel metrics of velocity interruption, vacillation, and directional instability were compared across diagnostic groups.<br><br>RESULTS: Vertical saccades were slower than horizontal in all groups including controls. Velocities were significantly slowed in PSP; however, the magnitude of slowing was comparable in vertical and horizontal directions. Similarly, vertical and horizontal velocities were strongly correlated in PSP (r&#x2009;=&#x2009;0.77, p&#x2009;<&#x2009;0.001), as they were in all other groups. Likewise, velocity interruption, vacillation, and directional instability were more disordered in the vertical compared to the horizontal axis in both controls and PSP (p&#x2009;<&#x2009;0.05). Z-scores of all metrics in PSP were abnormal but with no predilection for vertical saccades. Vacillation was a predictor of saccade velocity.<br><br>INTERPRETATION: Contrary to conventional belief, vertical saccades were not selectively impaired in PSP. Instead, the findings indicated a more global disruption of the saccadic system. The clinical observation of impaired vertical saccades in PSP appears to be because vertical saccades are slower and more disordered than horizontal in the general population; thus, when abnormalities of saccades develop in all directions, it first reaches a threshold to be noticeable at the bedside in the vertical plane.},
}
@article {pmid42415688,
year = {2026},
author = {Hill, N and AlMuallim, HYO and Maddock, E and Hobbs, C and Clarke, E and Goncalves, MB and Corcoran, JPT},
title = {Treatment with KCL-286, a first-in-class retinoic acid receptor-β (RARβ) agonist, ameliorates neuronal DNA damage and inflammation in a mouse model of Alzheimer's disease.},
journal = {FEBS open bio},
volume = {},
number = {},
pages = {},
doi = {10.1002/2211-5463.70284},
pmid = {42415688},
issn = {2211-5463},
support = {110047/Z/15/Z/WT/WT_/Wellcome Trust/United Kingdom ; MR/R006466/1/MRC_/Medical Research Council/United Kingdom ; },
abstract = {Alzheimer's disease (AD) is a complex, multifactorial neurodegenerative disorder for which effective disease-modifying therapies remain limited. Accumulation of neuronal DNA double-strand breaks (DSBs) is an early pathological event that contributes to genomic instability and neuronal vulnerability in AD. Therapeutic strategies that enhance DNA repair may therefore be of considerable interest. Here, using the Tg2576 mouse model of AD, we show that treatment with KCL-286, a selective retinoic acid receptor-β (RARβ) agonist, reduces neuronal DNA damage. KCL-286 enhances DSB repair in neurons, in part through upregulation of the DNA repair factor BRCA1, while also attenuating neuroinflammatory activation. In addition, KCL-286 normalises microglial and astrocytic morphology, consistent with reduced pathological glial activation. Together, these findings demonstrate that selective RARβ activation ameliorates neuronal DNA damage and neuroinflammation in a mouse model of AD, supporting further investigation as a potential disease-modifying therapeutic strategy.},
}
@article {pmid42415907,
year = {2026},
author = {Li, J and Chen, B and Jiang, J and Feng, Y and Zhang, R and Li, D and Wang, R and Long, Z and Ge, L and Guo, Y and Zhou, Z and Zou, W and Zhong, C and Liao, L},
title = {Efficacy of antioxidants as a therapy for Alzheimer's disease: a meta-analysis.},
journal = {Frontiers in nutrition},
volume = {13},
number = {},
pages = {1878597},
pmid = {42415907},
issn = {2296-861X},
abstract = {BACKGROUND: Oxidative stress plays a central role in the pathogenesis of Alzheimer's disease (AD), contributing to neuronal damage, amyloid-beta aggregation, tau hyperphosphorylation, and neuroinflammation. Although antioxidants have been proposed as potential therapeutic agents, clinical trials have yielded inconsistent results.<br><br>OBJECTIVE: To systematically evaluate the efficacy of various antioxidants-including vitamins, polyphenols, and other antioxidant preparations-on cognitive function, oxidative stress biomarkers, neuropsychiatric symptoms, and disease progression in patients with AD.<br><br>METHODS: We conducted a systematic search of PubMed, Embase, and Web of Science from inception to October 2, 2025, for randomized controlled trials (RCTs) evaluating antioxidant interventions in AD patients. Study selection, data extraction, and quality assessment were performed independently by multiple reviewers. Meta-analyses were conducted using random-effects models where significant heterogeneity was present (I[2] > 50%). Outcomes included cognitive function scales (e.g., ADAS-Cog, MMSE), oxidative stress markers, neuropsychiatric symptoms, daily living abilities, neuroimaging measures, and fluid biomarkers.<br><br>RESULTS: A total of 23 RCTs comprising 10,537 participants were included. Antioxidants showed mixed effects across outcomes. While certain oxidative stress markers (urinary 8-iso-prostaglandin F2&#x3b1;: SMD 0.75, 95% CI 0.12-1.38) and neuropsychiatric symptoms (NPI: SMD -0.85, 95% CI -1.13 to -0.57) improved significantly, core cognitive endpoints such as ADAS-Cog (SMD 0.01, 95% CI -0.21 to 0.23) and MMSE (SMD 0.19, 95% CI -0.17 to 0.56) showed no significant benefit. Fluid biomarkers including A&#x3b2;42, p-tau, and t-tau remained unchanged. High heterogeneity was observed across multiple outcomes, reflecting variability in antioxidant types, dosages, and patient populations.<br><br>CONCLUSION: Antioxidants may improve certain oxidative stress markers and neuropsychiatric symptoms in AD patients but do not consistently enhance core cognitive function or alter AD-specific pathology. Current evidence does not support antioxidants as disease-modifying therapies, though they may serve as adjunctive interventions to improve quality of life and behavioral symptoms. Well-designed RCTs with longer follow-up and standardized protocols are warranted.<br><br>https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD420261321660, identifier: CRD420261321660.},
}
@article {pmid42415930,
year = {2026},
author = {Wang, PJ and Yang, XY and Ji, L and Shi, JJ and Cai, XM and Sun, P and Liu, HX and Jiang, F and Yang, F},
title = {Peripheral metabolomic profiling reveals lipid and amino acid alterations associated with immuno-inflammatory responses in treatment-naïve late-onset Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1858299},
pmid = {42415930},
issn = {1663-4365},
abstract = {BACKGROUND: Immuno-metabolic dysregulation contributes to Alzheimer's disease (AD) pathogenesis, yet the peripheral metabolic landscape and its interplay with neuroinflammation remain poorly characterized in treatment-naïve, late-stage patients. This study aimed to delineate plasma metabolic alterations and immuno-metabolic interactions in Chinese first-time outpatients with late-onset AD (CFTO-LOAD).<br><br>METHODS: Untargeted metabolomics and ELISA were applied to plasma from 35 CFTO-LOAD patients and 35 sex-matched cognitively healthy controls (CHCs) to quantify metabolites, cytokines (TNF-&#x3b1;, IL-17, IL-9), and soluble A&#x3b2;/Tau markers.<br><br>RESULTS: A total of 875 differentially abundant metabolites (DAMs) were identified in CFTO-LOAD, comprising 227 upregulated and 648 downregulated species (P < 0.05), predominantly lipids, fatty acids (e.g., dodecanoic acid, arachidonic acid), and amino acids (e.g., L-arginine, L-leucine). KEGG analysis revealed enrichment in fatty acid and amino acid metabolism, GABAergic synapse, and intestinal immune network pathways. CFTO-LOAD patients exhibited elevated pro-inflammatory cytokines TNF-&#x3b1; and IL-17 (P adj < 0.05), reduced IL-9 (P adj < 0.001), increased soluble p-Tau, p-Tau181, and p-Tau217 (P adj < 0.01), and decreased A&#x3b2;42/A&#x3b2;40 ratio (P adj < 0.001). Linear regression identified significant correlations between differential metabolites and immune/pathological markers, including positive associations of dodecanoic acid with TNF-&#x3b1; (r = 0.34, P adj < 0.05) and arachidonic acid with A&#x3b2;42/A&#x3b2;40 ratio (r = 0.30, P adj < 0.05), and negative associations of arachidonic acid with p-Tau217 (r = -0.43, P adj < 0.01) and sphinganine 1-phosphate with TNF-&#x3b1; (r = -0.28, P adj < 0.05).<br><br>CONCLUSION: These findings characterize the peripheral immuno-metabolic landscape in treatment-na&#xef;ve late-onset AD, identifying metabolic mediators that may mechanistically link neuroinflammation to A&#x3b2; and Tau pathology. This provides a foundation for biomarker development and therapeutic targeting in late-stage disease, pending independent validation.},
}
@article {pmid42415934,
year = {2026},
author = {Li, Q and Gu, M and Li, W},
title = {Exercise and neural circuit stability in early Alzheimer's disease: evidence across memory, executive, cholinergic, and circadian systems.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1863929},
pmid = {42415934},
issn = {1663-4365},
abstract = {Early Alzheimer's disease (AD) is increasingly understood as a phase in which neural circuit dysfunction emerges alongside molecular pathology and local neuronal injury. Although physical exercise has been linked to a deceleration in cognitive decline and beneficial cognitive and neural outcomes, most mechanistic explanations have predominantly focused on molecular or cellular pathways, with less emphasis on circuit-level interpretations. This narrative review integrates evidence from four neural systems that exhibit early vulnerability in AD and are pertinent to exercise-responsive cognitive or behavioral domains: the entorhinal cortex-dentate gyrus (EC-DG) circuit, the ventral hippocampus-medial prefrontal cortex (vHPC-mPFC) pathway, the medial septum/vertical diagonal band-hippocampal (MS/VDB-hippocampal) cholinergic circuit, and the suprachiasmatic nucleus-paraventricular nucleus (SCN-PVN) circadian axis. Across these systems, the evidence remains inconsistent. Direct circuit-level findings, including electrophysiological and functional-connectivity measurements, indicate circuit disruption in specific domains, whereas many exercise-related effects are inferred from molecular, structural, neurochemical, behavioral, or clinical-proxy outcomes. We therefore propose a multicircuit framework in which exercise may ameliorate AD-related cognitive and behavioral dysfunction through convergent but circuit-specific routes: EC-DG excitability and plasticity, vHPC-mPFC communication substrates, MS/VDB-hippocampal cholinergic modulation, and SCN-PVN circadian-neuroendocrine timing. This framework clarifies the evidence boundaries of exercise-related circuit modulation in early AD and identifies direct circuit-level measurements as a priority for future translational studies.},
}
@article {pmid42416049,
year = {2026},
author = {Yang, M and Liang, Z},
title = {GLP-1 receptor agonists in neurological diseases: mechanisms and therapeutic prospects from metabolism to neuroprotection.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1839620},
pmid = {42416049},
issn = {1664-3224},
mesh = {Humans ; *Glucagon-Like Peptide-1 Receptor Agonists ; Animals ; *Neuroprotective Agents/therapeutic use/pharmacology ; *Nervous System Diseases/drug therapy/metabolism ; Glucagon-Like Peptide-1 Receptor/metabolism ; *Neuroprotection/drug effects ; Oxidative Stress/drug effects ; },
abstract = {Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used metabolic therapies for type 2 diabetes and obesity, with well-established cardiovascular benefits. Beyond glycemic control, accumulating experimental and clinical evidence suggests that GLP-1RAs exert pleiotropic actions relevant to neurological diseases. Metabolic dysfunction, chronic inflammation, oxidative stress, mitochondrial impairment, and neurovascular injury represent convergent mechanisms that contribute to neurodegeneration, cerebrovascular pathology, and metabolism-related brain disorders. Notably, these processes overlap with pathways modulated by GLP-1 signaling across systemic and central compartments. GLP-1 receptors are expressed in neurons, glial cells, and components of the neurovascular unit, providing a biological basis for possible neurological effects. Preclinical studies suggest that GLP-1RAs can reduce neuroinflammation and oxidative stress, support mitochondrial function, and help maintain blood-brain barrier integrity. Clinical findings, however, remain inconsistent. Studies in Parkinson's disease have reported encouraging signals, but biomarker evidence for disease modification is still limited. In Alzheimer's disease, clinical trials have produced mixed or negative results. These differences may reflect disease stage, patient selection, drug-specific pharmacology, central nervous system exposure, endpoint sensitivity, and treatment duration. Overall, GLP-1RAs may influence neurological disease through metabolic, inflammatory, and vascular pathways, but their clinical role remains unsettled. Future studies should use biomarker-informed designs, prespecified neurological endpoints, appropriate drug selection, and sufficiently long follow-up to determine which patients and disease stages are most likely to benefit.},
}
@article {pmid42416144,
year = {2026},
author = {Huang, F and Guo, M and Yang, Y and Wang, Z},
title = {Aloe emodin attenuates Aβ1-42-Induced neurotoxicity in SH-SY5Y cells via downregulation of PPM1K.},
journal = {Open medicine (Warsaw, Poland)},
volume = {21},
number = {1},
pages = {20261473},
pmid = {42416144},
issn = {2391-5463},
abstract = {OBJECTIVES: To study the role and underlying mechanism of aloe emodin, a natural anthraquinone compound known for antioxidant, and anti-inflammatory activities, in Alzheimer's disease (AD).<br><br>METHODS: A&#x3b2;1-42-induced injury model was established using SH-SY5Y cells. A combination of CCK-8 assay, flow cytometry, ELISA, ROS fluorescence probe, RT-qPCR, and western blot assay was employed to systematically evaluate the effects of&#xa0;aloe emodin on cell viability, apoptosis, inflammation, and&#xa0;oxidative stress. Potential molecular targets were identified through bioinformatics analysis. The regulatory role of PPM1K in aloe emodin-mediated neuroprotection was further validated using PPM1K overexpression experiments.<br><br>RESULTS: Bioinformatics analysis revealed that PPM1K is significantly upregulated in AD and showed predicted in&#xa0;silico binding with aloe emodin. Aloe emodin markedly improved the viability of A&#x3b2;1-42-treated SH-SY5Y cells, suppressed apoptosis, reduced the release of pro-inflammatory cytokines, and attenuated ROS generation, accompanied by the downregulation of PPM1K expression. In contrast, overexpression of PPM1K significantly weakened the neuroprotective effects of aloe emodin, as evidenced by decreased cell viability and increased levels of apoptosis and oxidative stress.<br><br>CONCLUSIONS: Aloe emodin alleviates A&#x3b2;1-42-induced neuronal injury by targeting and downregulating PPM1K expression, suggesting that PPM1K is a critical mediator of the neuroprotective effects of aloe emodin.},
}
@article {pmid42416176,
year = {2026},
author = {Kim, DJ and Kim, YC and Jeong, BH},
title = {Association of SPHK1 polymorphisms with Alzheimer's disease susceptibility: Functional impact of the rs2247856 SNP on transcriptional efficiency.},
journal = {Alzheimer's &amp; dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70288},
pmid = {42416176},
issn = {2352-8737},
abstract = {INTRODUCTION: Sphingosine kinase 1 (SPHK1) has been implicated in the regulation of pro-resolving lipid mediators relevant to neuroinflammation in Alzheimer's disease (AD). However, no studies have evaluated the genetic association between SPHK1 polymorphisms and AD susceptibility.<br><br>METHODS: We analyzed genotype and allele frequencies of polymorphisms in the SPHK1 gene between patients with AD and healthy controls. In addition, transcription factor binding sites were evaluated. Furthermore, promoter activities associated with rs2247856 single nucleotide polymorphism (SNP) were assessed using a luciferase reporter assay.<br><br>RESULTS: Among the identified SNPs, the genotype distribution of rs2247856 showed a significant association with AD. Haplotype analysis revealed that haplotype 3 (CAGTACGG) was significantly more frequent in patients with AD than in controls. Profiler of Multi-Omics Data (PROMO) analysis suggested that the rs2247856 A allele disrupts the activating transcription factor 3 transcription factor binding site. Luciferase assays demonstrated significantly reduced promoter activity in constructs containing the A allele compared to the G allele (p < 0.001), indicating allele-specific regulation of SPHK1 transcription.<br><br>DISCUSSION: Our findings identify rs2247856 as a functional regulatory SNP in the SPHK1 gene associated with AD susceptibility. The reduced transcriptional activity of the A allele may impair SPHK1-mediated anti-inflammatory signaling, potentially contributing to AD pathogenesis.},
}
@article {pmid42416267,
year = {2026},
author = {de Leon, J and Allen, IE and Miller, Z and Dronkers, N and Henry, M and Gorno-Tempini, ML and Grasso, S},
title = {Reported symptoms and patterns of language impairment in bilingual speakers with primary progressive aphasia: a retrospective study.},
journal = {Aphasiology},
volume = {},
number = {},
pages = {},
pmid = {42416267},
issn = {0268-7038},
abstract = {BACKGROUND: The relative scarcity of studies of bilingual speakers with primary progressive aphasia (PPA) leads to knowledge gaps regarding their symptoms and patterns of language impairment. It is unknown if PPA symptoms in bilingual speakers differ from those of monolingual speakers. In addition, it remains unclear if one of a bilingual speaker's languages is more vulnerable to the onset of symptoms and/or is better preserved. Furthermore, bilingualism factors (e.g. order/age of language acquisition (L1/L2) and language dominance) may explain patterns of impairment both within and across the variants of PPA.<br><br>AIMS: To characterize the bilingualism factors, speech and language symptoms, and patterns of language impairment in a retrospective cohort of bilingual speakers with PPA.<br><br>METHODS: In a large cohort (N = 69) of bilingual speakers, we performed a chart review to extract information regarding self/caregiver-reported PPA symptoms, first language impacted by PPA at symptom onset, less preserved language at time of evaluation, and bilingual history factors (age/order of acquisition (L1/L2) and language dominance). We explored how emergence and presentation of symptoms associated with bilingualism factors.<br><br>RESULTS: The presenting symptoms were mostly consistent with current PPA diagnostic criteria, although symptoms unique to bilingual speakers were reported. The language reported to first be impacted by PPA, as well as the less preserved language at the time of evaluation, was generally reported to be the less dominant language, regardless of PPA variant. These measures did not associate as closely with age/order of acquisition (L1 versus L2).<br><br>CONCLUSION: Bilingual speakers with PPA may report additional symptoms that reflect their ability to speak more than one language. The less dominant language was most susceptible to the initial impact of PPA and also tended to the less preserved language at the time of evaluation. Future studies of bilingual speakers with neurodegenerative diseases should systematically consider bilingualism factors, which are likely to contribute to clinical presentation and disease progression.},
}
@article {pmid42416270,
year = {2026},
author = {Wang, A and Curel, T and Claeysen, S and Travers-Lesage, V and Cadot, M and Davis, A and Sopkova-de Oliveira Santos, J and Modeste, F and Brazzolotto, X and Nachon, F and Dallemagne, P and Since, M and Rochais, C},
title = {Combining β2-AR agonism with butyrylcholinesterase inhibition, a synergistic neuroprotective action against Alzheimer's disease.},
journal = {RSC medicinal chemistry},
volume = {},
number = {},
pages = {},
pmid = {42416270},
issn = {2632-8682},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder for which the current treatments remain largely symptomatic. Pleiotropic prodrug strategies offer a promising approach to address this complexity, combining complementary pharmacological mechanisms within a single molecular entity. In this study, we report the design, synthesis, and biological evaluation of novel carbamate-based pleiotropic prodrugs that combine butyrylcholinesterase (BuChE) inhibition and β2-adrenergic receptor (β2-AR) agonism. Seven salmeterol-derived carbamates were synthesized and evaluated for their cholinesterase inhibitory activity, β2-AR activity, and neuroprotective potential. Several derivatives exhibited potent and selective inhibition of human BuChE in the nanomolar range, revealing a clear structure-activity relationship driven by carbamate substitution and amine protection. Kinetics and LC-MS analyses demonstrated a pseudo-irreversible covalent inhibition mechanism associated with rapid enzyme reactivation, thereby enabling controlled salmeterol release. While carbamates behaved as inactive prodrugs at the β2-AR level, selected compounds displayed significant neuroprotective effects in a cellular model of amyloid-β-induced toxicity. Collectively, these findings validate salmeterol-derivated carbamates as innovative pleiotropic prodrugs and support the potential of combining BuChE inhibition and β2-AR agonism as a disease-modifying strategy for Alzheimer's disease.},
}
@article {pmid42416335,
year = {2026},
author = {Wang, XT and Wang, J and Zhao, XJ},
title = {Exercise training promotes neurogenesis in the adult hippocampus with a particular focus on cell cycle regulation.},
journal = {Frontiers in sports and active living},
volume = {8},
number = {},
pages = {1770350},
pmid = {42416335},
issn = {2624-9367},
abstract = {Adult neurogenesis is predominantly restricted to two neurogenic regions in the mammalian brain: the subventricular zone (SVZ) of the lateral ventricle and the subgranular zone (SGZ) of the dentate gyrus (DG) within the hippocampus. The hippocampus serves as a critical brain structure involved in learning and memory processes, and the continuous generation of new neurons contributes to enhanced synaptic plasticity. Accumulating evidence has demonstrated that impaired hippocampal neurogenesis is closely associated with various neuropsychiatric disorders, including Alzheimer's disease, epilepsy, and traumatic brain injury. Although the precise molecular and cellular mechanisms underlying adult neurogenesis remain incompletely elucidated, extensive research over the past several decades has identified numerous endogenous, exogenous, and environmental factors that modulate this process. Notably, exercise training, as a key exogenous stimulus, has been shown to promote adult hippocampal neurogenesis by influencing the neurochemical environment and functional integration of newly generated neurons. This review aims to summarize the relationship between cell cycle dynamics and adult hippocampal neurogenesis, with a particular emphasis on how physical exercise regulates the cell cycle to activate and promote the proliferation of neural stem cells (NSCs) in the DG, thereby facilitating the differentiation and lineage progression of neural progenitor cells. A deeper understanding of the regulatory mechanisms by which exercise enhances adult hippocampal neurogenesis may provide novel insights into the development of therapeutic strategies for neurological and psychiatric disorders.},
}
@article {pmid42416382,
year = {2026},
author = {Cabán, M and Abraído-Lanza, AF and Brown-Bradley, C and Meng, A and Tran, E and Lee, J and Wetmore, JB and Ottman, R and Siegel, K},
title = {The use of religion, prayer, and faith to cope with the receipt of Alzheimer's disease risk information in a research context: A qualitative study of Latinos in NYC.},
journal = {SSM. Qualitative research in health},
volume = {9},
number = {},
pages = {},
pmid = {42416382},
issn = {2667-3215},
abstract = {People commonly turn to religion when confronted with threatening events including illness. However, limited research has investigated the use of religious coping to manage distress associated with knowledge of one's risk for serious illnesses such as Alzheimer's disease (AD). To examine how they coped with receiving information about their risk for late-onset AD, semi-structured interviews were conducted with a sample of Latinos (ages 40-64) living in Northern Manhattan approximately 6 weeks, 9 and 15 months after receiving a numerical risk estimate (expressed as a percentage) of their chances of developing AD by age 85. Some also were told their APOE genotype, including whether it increased their susceptibility to late onset AD. Of 202 participants interviewed, 43 mentioned using religion to cope with the implications of receiving their AD risk information and the emotions it evoked and are the focus of this report. Five themes emerged from the data: 1) Praying to be protected from AD; 2) Praying to help manage emotions; 3) Giving control over to God; 4) Accepting AD as part of God's plan; and 5) Praying for the strength to accept one's fate and deal with whatever it brings. To our knowledge this is the first report describing how individuals use religion/spirituality to cope with the perceived implications of and the emotions elicited by receiving their AD risk information. This information can inform the development of culturally tailored support resources for those who choose to learn their risk status.},
}
@article {pmid42416856,
year = {2026},
author = {Ameenudeen, S and Srinivasan, H},
title = {Network pharmacology-based identification of hub genes targeted by ayurvedic formulation Triphala in controlling Alzheimer's disease by polypharmacological mechanisms.},
journal = {In silico pharmacology},
volume = {14},
number = {2},
pages = {186},
pmid = {42416856},
issn = {2193-9616},
abstract = {UNLABELLED: The multifactorial neurodegenerative disease known as Alzheimer's disease (AD) is typified by amyloid-β aggregation, tau hyperphosphorylation, neuroinflammation, and synaptic dysfunction, as well as progressive cognitive decline. Due to the limited effectiveness of conventional therapeutic approaches, multi-target agents must be investigated. A traditional Ayurvedic polyherbal formulation, Triphala contains a wide range of bioactive phytochemicals that have been shown to have neuroprotective effects. The molecular targets of Triphala phytocompounds related to AD pathology were clarified in the current study using a network pharmacology approach. BindingDB and SwissTargetPrediction were used to predict the putative protein targets of 18 phytocompounds, yielding 54 distinct targets. The STRING database was used to build a protein-protein interaction (PPI) network, which Cytoscape was then used to analyse. The following 7 important hub genes were identified using topological parameters (degree, betweenness, closeness centrality): BCL2, CASP3, MMP9, JUN, NFKB1, PTGS2, and ESR1. Potential mechanistic overlap was highlighted by the significant involvement of 20 genes in AD-related pathways and 30 genes in the lipid and atherosclerosis pathway, according to gene enrichment analysis using KEGG. Synaptic plasticity, oxidative stress response, neuroinflammatory signalling, and apoptosis regulation are the main functions of these genes. The integrative analysis highlights Triphala's polypharmacology mechanism and raises the possibility that it could be used as a multi-target therapeutic candidate for AD. This study offers a logical foundation for additional in vitro and in vivo validation of Triphala-derived neurotherapeutics as well as a systems-level framework for comprehending herb-compound-gene-disease interactions.<br><br>SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-026-00704-6.},
}
@article {pmid42416912,
year = {2026},
author = {Zou, Z and Liu, H and Lei, D and Jian, X and Li, X},
title = {Dynamic changes of gut microbiota during progression of three Alzheimer's disease mice models.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1849896},
pmid = {42416912},
issn = {1662-4548},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is an age-related and progressive neurodegenerative disorder characterized by cognitive impairment and irreversible neuronal degeneration, affecting approximately 55 million individuals worldwide. Despite extensive research efforts, the underlying pathogenic mechanisms of AD remain incompletely understood, and effective therapeutic strategies for preventing or delaying disease progression are still lacking. Increasing evidence suggests that the microbiota-gut-brain axis plays an important role in neurodegenerative diseases, including AD. However, the dynamic alterations of gut microbiota during AD progression across different transgenic mouse models remain poorly characterized.<br><br>METHODS: In the present study, we investigated age-dependent changes in gut microbiota composition in three commonly used AD mouse models, including APP/PS1, 3xTg, and 5xFAD mice, using 16S rRNA gene sequencing. Fecal samples were collected longitudinally at 2, 4, 6, and 8 months of age to evaluate microbial diversity, community structure, and differential bacterial taxa during aging and disease progression.<br><br>RESULTS: Our results demonstrated distinct and model-dependent alterations in gut microbiota composition across different stages of AD progression. Significant changes in microbial diversity and bacterial community structure were observed among the three AD mouse models and wild-type controls. In particular, dynamic alterations in Verrucomicrobiota, Proteobacteria, and Actinobacteriota were consistently identified during aging in AD mice. In addition, &#x3b2;-diversity, Linear discriminant analysis effect size (LEfSe), and correlation network analyses further revealed differential microbial signatures associated with different AD mouse models and age stages.<br><br>DISCUSSION: Overall, our findings provide additional evidence that gut microbiota composition undergoes dynamic alterations during aging in multiple AD mouse models and may be associated with AD-related progression. This study may contribute to a better understanding of microbiota-associated changes during AD development and provide a basis for future mechanistic studies targeting the microbiota-gutbrain axis in AD.},
}
@article {pmid42417039,
year = {2026},
author = {Feng, L and Jin, X and Li, X and Qu, T and Guo, H and Wang, Z and Quan, Y and Chen, L and Wang, L and Wang, Y},
title = {One-month early time-restricted eating enhances long-term memory by modulating brain fluid dynamics in males with metabolic syndrome: Evidence from perivascular diffusion and global blood-oxygen-level-dependent-cerebrospinal fluid coupling.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261465674},
doi = {10.1177/13872877261465674},
pmid = {42417039},
issn = {1875-8908},
abstract = {BackgroundMetabolic syndrome (MetS) serves as a precursor to Alzheimer's disease, a condition characterized by initial memory impairment and driven by dysregulated brain fluid dynamics. While time-restricted eating (TRE) improves memory in MetS, the mechanistic role of brain fluid dynamics in this process remains unclear.ObjectiveTo investigate whether a 1-month early TRE (eTRE) intervention enhances memory performance by improving brain fluid dynamics in individuals with MetS.MethodsTwenty-eight men with MetS and 30 matched healthy male controls underwent MRI scans. Brain fluid dynamics was assessed using the diffusion tensor image analysis along the perivascular space (DTI-ALPS) index and global blood-oxygen-level-dependent-cerebrospinal fluid (gBOLD-CSF) coupling. In the MetS group, metabolic risk factors, cognitive and psychological status, and memory performance were evaluated pre- and post-eTRE. Relationships between imaging indices and memory scores were examined by correlation analysis.ResultsAt baseline, men with MetS exhibited a lower DTI-ALPS index and higher gBOLD-CSF coupling than healthy controls (p < 0.05). After 1-month eTRE, the DTI-ALPS index increased (p < 0.001), while gBOLD-CSF coupling decreased (p = 0.027), approaching healthy control levels. Metabolic parameters and long-term memory performance also improved significantly (all p < 0.05). Changes in DTI-ALPS were positively correlated with delayed recall (r = 0.445, p < 0.05), whereas changes in gBOLD-CSF coupling were negatively correlated (r = -0.550, p < 0.05).ConclusionsA 1-month eTRE intervention improved long-term memory and brain fluid dynamics in males with MetS, providing a promising non-pharmacological strategy to counteract metabolic-driven neurodegenerative diseases.Trial registrationNational Medical Research Registration and Filing Information System (https://www.medicalresearch.org.cn/), MR-61-24-042065.},
}
@article {pmid42417046,
year = {2026},
author = {Weiss, JN and Eber, D and Cole, R},
title = {Dynamic light scattering spectroscopy and the Centiloid scale.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261467030},
doi = {10.1177/13872877261467030},
pmid = {42417046},
issn = {1875-8908},
abstract = {Dynamic light scattering (DLS) spectroscopy measures the Brownian movement of particles. Fifteen patients underwent DLS measurement and positron emission tomography amyloid imaging. The DLS measurement is noninvasive, quantitative, and inexpensive, with immediate results. We report a significant correlation between DLS measurements and Centiloid values.},
}
@article {pmid42417051,
year = {2026},
author = {Agüero-Rabes, P and Roa-Escobar, J and Téllez, R and Mañanes, V and Gómez-Tortosa, E},
title = {Eligibility for lecanemab therapy in a biomarker defined memory clinic cohort: A five-year analysis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261466695},
doi = {10.1177/13872877261466695},
pmid = {42417051},
issn = {1875-8908},
abstract = {We assessed cross-sectional lecanemab eligibility (January 2026) in 479 patients with mild cognitive impairment or dementia who underwent Alzheimer's disease (AD) biomarker testing at a tertiary memory clinic (2021-2025). Overall eligibility was 16%, with exclusions due to negative biomarkers (41%), advanced disease stage (31%), APOE ε4/ε4 homozygosity (6%), and other safety reasons (6%). In the 2025 subgroup (n = 100), eligibility increased to 32%, reflecting fewer exclusions for disease progression and a targeted evaluation of patients likely to meet criteria. These findings highlight a narrow post-diagnosis therapeutic window and suggest an upper eligibility limit under the current appropriate use recommendations for anti-amyloid therapies.},
}
@article {pmid42417056,
year = {2026},
author = {Dimas-Harms, LJ and Moser, VA},
title = {The arsenic-Alzheimer's disease link: Emerging evidence and unanswered questions.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261467042},
doi = {10.1177/13872877261467042},
pmid = {42417056},
issn = {1875-8908},
abstract = {Arsenic is a toxic heavy metal that reaches humans primarily through contaminated groundwater, presenting a persistent global public health concern. Chronic exposure, even at concentrations lower than current safety standards, disturbs brain development and function, raising concern that arsenic may contribute to Alzheimer's disease (AD). Wei et al. investigate early-life arsenic exposure and AD using Swedish national registries and geographic variation in groundwater arsenic. This work represents a critical step toward understanding whether historical environmental exposures in northern Europe have increased late-life neurodegenerative risk and underscores the importance of treating arsenic as a potentially modifiable environmental risk factor for AD.},
}
@article {pmid42417147,
year = {2026},
author = {Wang, Y and Nan, B and Gillen, DL and Corrada, MM},
title = {Statistical analysis of disease onset during lifespan with left truncation.},
journal = {Biometrics},
volume = {82},
number = {3},
pages = {},
doi = {10.1093/biomtc/ujag118},
pmid = {42417147},
issn = {1541-0420},
support = {R01 AG056764/NH/NIH HHS/United States ; RF1 AG075107/NH/NIH HHS/United States ; R01 AG021055/NH/NIH HHS/United States ; P30 AG066519/NH/NIH HHS/United States ; DMS 2412746//National Science Foundation/ ; },
mesh = {Computer Simulation ; Humans ; *Models, Statistical ; Data Interpretation, Statistical ; Dementia/mortality/epidemiology ; Alzheimer Disease/mortality ; *Age of Onset ; Statistics, Nonparametric ; },
abstract = {We consider a new nonparametric method for analyzing the onset of a chronic condition, e.g., dementia, when death occurs frequently in the study population. In contrast to the commonly used semi-competing risks or illness-death model, we study the distribution of the disease onset time conditional on the death time, which consists of two components that provide straightforward interpretations of the disease onset during the lifespan. Without imposing any model assumption, we propose a kernel-weighted product-limit estimator that properly handles the left-truncation, a common issue in aging studies. The estimator is asymptotically normal and its variance can be estimated by a Greenwood-type variance estimator. We use the integrated Brier score for the bandwidth selection and illustrate the proposed method with simulation studies, an analysis of The 90+ Study, and an analysis of the UC Health Data Warehouse.},
}
@article {pmid42417152,
year = {2026},
author = {Ben-Hayun, R and Zifman, N and Hadad, R and Fogel, H and Levy-Lamdan, O and Verhovski, N and Yarovinsky, N and Ayoub-Agbaria, R and Tanne, D},
title = {Towards a neurophysiological diagnostic marker of Alzheimer's disease using transcranial magnetic stimulation combined with electroencephalography.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261463653},
doi = {10.1177/13872877261463653},
pmid = {42417152},
issn = {1875-8908},
abstract = {BackgroundA scalable, objective measure of cortical function that differentiates Alzheimer's disease (AD) from other causes of cognitive impairment is still lacking. Transcranial magnetic stimulation combined with electroencephalography (TMS-EEG) enables direct assessment of cortical reactivity.ObjectiveTo test whether left primary motor cortex (M1L) P30 amplitude captures AD-related excitability changes, distinguishes biomarker-confirmed AD patients from controls (CN) and from other non-AD causes of cognitive impairment.MethodsNinety participants underwent M1L TMS-EEG with Delphi-MD: biomarker-confirmed AD (n = 22), other cognitively impaired (n = 27: vascular/mixed n = 12; frontotemporal dementia n = 4; unknown etiology n = 11), and CN (n = 41).ResultsP30 differed across biomarker-confirmed AD, other cognitively impaired, and CN (Quade F(2,80) = 4.989, p = 0.009, ηp[2] = 0.11). Pairwise tests showed higher P30 in biomarker-confirmed AD versus other cognitively impaired (t = 2.117, p = 0.037, d = 0.61) and versus CN (t = 3.14, p = 0.002, d = 0.80). Among 27 clinically suspected AD tested for biomarkers, P30 was higher in biomarker + (22/27) versus biomarker- (5/27) (p = 0.035, d = 0.98), had good discriminatory performance for biomarker-confirmed AD (ROC = 0.853 [95% CIboot 0.627-1.000], p < 0.001), and was not associated with cerebrovascular changes (p = 0.455, d = 0.24).ConclusionsP30 amplitude is elevated in biomarker-confirmed AD relative to CN and other causes of cognitive impairment, aligning with amyloid-associated cortical hyperexcitability. These findings support P30 as a promising, non-invasive physiological biomarker to aid differential diagnosis and, potentially, disease monitoring in AD.Trial registry name and URL: https://clinicaltrial.health.gov.il/clinicaltrials/?MOHResearchId=MOH_2022-04-13_010726.},
}
@article {pmid42417271,
year = {2026},
author = {Anagnostakis, F and O'Toole, CK and Erus, G and Srinivasan, D and Cui, Y and Kokkorakis, M and Ma, X and Reitz, C and Brickman, AM and Kontos, D and Gupta, A and Payabvash, S and Konofagou, EE and McIlvain, G and Cheng, F and Baldwin, MR and Shou, H and Davatzikos, C and Resnick, S and Wen, J},
title = {Association of sleep duration with Alzheimer's disease and cognition.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71528},
doi = {10.1002/alz.71528},
pmid = {42417271},
issn = {1552-5279},
support = {RF1AG092412/GF/NIH HHS/United States ; RF1AG054409/GF/NIH HHS/United States ; U24NS130411/GF/NIH HHS/United States ; },
mesh = {Humans ; *Sleep Duration ; *Alzheimer Disease/diagnostic imaging/pathology ; Female ; Magnetic Resonance Imaging ; Male ; Atrophy/pathology ; *Cognition/physiology ; Brain/pathology/diagnostic imaging ; Aged ; Neuropsychological Tests/statistics &amp; numerical data ; United Kingdom ; Sleep Initiation and Maintenance Disorders ; },
abstract = {INTRODUCTION: The association of sleep duration with Alzheimer's disease (AD) - related brain atrophy and cognition remains unclear.<br><br>METHODS: Among 38,816 participants in the UK Biobank, we examined the association between&#xa0;sleep duration and a validated machine-learning-derived magnetic resonance imaging (MRI) signature of AD-related atrophy (Spatial Pattern of Abnormality for Recognition of Early AD [SPARE-AD]) and three cognitive test scores using generalized additive models. Independently, electronic health records (EHR) from TriNetX were used to examine the 10-year AD risk associated with insomnia and hypersomnia.<br><br>RESULTS: Sleep duration exhibited a U-shaped association with SPARE-AD (p&#xa0;=&#xa0;0.001), Trail Making Tests A and B, and the Digit Symbol Substitution Test (all p&#xa0;<&#xa0;0.001).&#xa0;Short (5-6&#xa0;hours) and long (9-10&#xa0;hours) sleep duration were associated with poorer cognitive performance. Both insomnia and hypersomnia showed a high risk for Alzheimer's disease.<br><br>CONCLUSION: This study demonstrates a U-shaped association between sleep duration and AD-like atrophy and cognition.<br><br>DISCUSSION: These findings show that excessive or insufficient sleep is linked to worse brain health.},
}
@article {pmid42417429,
year = {2026},
author = {Pelkmans, W and Bikou, V and Salvadó, G},
title = {Timing the Alzheimer's disease pathological cascade.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag240},
pmid = {42417429},
issn = {1460-2156},
}
@article {pmid42417497,
year = {2026},
author = {Dubey, A and Chaurasia, A and Ansari, Z and Kushwaha, SK and Saraf, I and Kashaw, S and Swami, R and Kushwah, V},
title = {Targeting Autophagy in Alzheimer's Disease: Role of the AMPK/mTOR Pathway and Drug Repurposing.},
journal = {Drug development research},
volume = {87},
number = {5},
pages = {e70344},
doi = {10.1002/ddr.70344},
pmid = {42417497},
issn = {1098-2299},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Drug Repositioning ; *Autophagy/drug effects ; *TOR Serine-Threonine Kinases/metabolism ; Signal Transduction/drug effects ; *AMP-Activated Protein Kinases/metabolism ; Animals ; Neuroprotective Agents/pharmacology/therapeutic use ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) plaques and tau (τ) -related neurofibrillary tangles, often exacerbated by dysfunctional cellular clearance mechanisms. This manuscript explores the pivotal role of autophagy impairment in AD pathogenesis, with a specific focus on the AMPK/mTOR signaling axis as a primary regulatory pathway. Findings revealed that while mTOR overactivation suppresses autophagic flux and promotes the buildup of toxic protein aggregates, the activation of AMPK serves to restore homeostatic degradation processes. The review highlights that various pharmacological agent including rapamycin, metformin, trehalose, and curcumin, as well as repurposed drugs like lithium and statins can effectively enhance autophagy to ameliorate cognitive decline and neuroinflammation. Furthermore, herbal formulations such as Danggui Shaoyao San and phytoconstituents like Icariin demonstrate significant neuroprotective potential by modulating these same molecular pathways. Targeting autophagy represents a translationally viable approach for combating AD progression, with drug repurposing offering a time-efficient and cost-effective strategy. To advance these findings, future research should prioritize large-scale clinical trials to validate the efficacy of autophagy-inducing agents in human subjects. Additionally, investigating synergistic combinations of traditional bioactives with synthetic drugs and utilizing innovative delivery systems, such as intranasal nanotechnology-based platforms to bypass the blood-brain barrier, represents a promising frontier for developing effective, multi-targeted treatments against AD.},
}
@article {pmid42417611,
year = {2026},
author = {Heskett, MB and Vouzas, AE and Johnstone, B and Freese, KP and Yates, PA and Copenhaver, PF and Spellman, PT and Gilbert, DM and Thayer, MJ},
title = {Autosomal allelic inactivation at loci with variable replication timing and dosage sensitivity.},
journal = {eLife},
volume = {15},
number = {},
pages = {},
doi = {10.7554/eLife.109938},
pmid = {42417611},
issn = {2050-084X},
support = {R01GM130703/GM/NIGMS NIH HHS/United States ; RF1NS142814/NS/NINDS NIH HHS/United States ; R01GM083337/GM/NIGMS NIH HHS/United States ; 4K00CA245677-03/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; *Alleles ; Mice ; *DNA Replication Timing ; *Epigenesis, Genetic ; Humans ; *Gene Dosage ; *Genetic Loci ; *Gene Silencing ; },
abstract = {Autosomal monoallelic gene expression and asynchronous replication between alleles are established features of imprinted genes and genes regulated by allelic exclusion. Inactivation/Stability Centers (I/SCs) are recently described autosomal loci that exhibit epigenetic regulation of allelic expression and replication timing, with differences that can be comparable to those observed between the active and inactive X chromosomes . Here, we characterize >100 autosomal loci with allele-specific epigenetic regulation of replication timing and gene expression, defining them as I/SCs. I/SCs are approximately 1 Mbb in size and can contain both protein-coding and noncoding genes. In different single-cell derived clones, these genes may be expressed from a single allele, the opposite allele, both alleles, or not expressed at all. This stochastic, yet mitotically stable, pattern indicates that the choice of which allele is expressed is independent of parent of origin and independent of the expression status of the other allele. Similarly, alleles within I/SCs show varying replication timing, either earlier or later, that is also independent of the other allele. Additionally, we identify syntenic loci in the mouse genome that display epigenetic regulation of allelic replication timing, highlighting the genomic organization and conservation of I/SC-associated regulation between human and mouse genomes. The allele-restricted regulation described here creates extensive cellular mosaicism through a stable epigenetic mechanism. This mosaicism impacts numerous dosage-sensitive genes associated with human diseases such as Alzheimer, Parkinson, epilepsy, deafness, and impaired intellectual development.},
}
@article {pmid42417835,
year = {2026},
author = {Singh, A and Singh, L and Dalal, D},
title = {Pharmacological mechanisms of fisetin in neurodegenerative disorders: regulation of neuroinflammatory, oxidative, and autophagic pathways.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {42417835},
issn = {1432-1912},
abstract = {Neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and related progressive neurological conditions, are characterized by irreversible neuronal loss, cognitive impairment, and motor dysfunction. Accumulating evidence identifies chronic neuroinflammation as a critical contributor to disease initiation and progression. In particular, activation of the TLR-4/NF-κB signaling cascade in glial cells promotes excessive production of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6, together with induction of COX-2, iNOS, oxidative stress, and apoptosis, thereby exacerbating neuronal injury. Current pharmacotherapeutic strategies largely provide symptomatic benefit without effectively targeting the underlying pathogenic mechanisms. Fisetin, a naturally occurring flavonoid abundantly present in strawberries, apples, and persimmons, has recently attracted considerable attention owing to its pleiotropic neuroprotective properties. Experimental evidence indicates that fisetin suppresses TLR-4/NF-κB-mediated neuroinflammatory signaling, attenuates microglial activation, and enhances endogenous antioxidant defense through modulation of the Nrf2 pathway. Moreover, fisetin regulates apoptosis-associated mediators, thereby preserving neuronal integrity and survival. Notably, emerging studies demonstrate that fisetin-mediated inhibition of the TLR-4/Akt/mTOR signaling axis promotes autophagy-dependent α-syn clearance and neurogenesis, particularly in Parkinsonian models, highlighting its potential disease-modifying effects. These multifaceted pharmacological actions suggest that fisetin simultaneously targets interconnected inflammatory, oxidative, apoptotic, and proteostatic pathways implicated in neurodegeneration. Despite promising preclinical findings, additional investigations are required to elucidate its effects on inflammasome activation, glial cell crosstalk, pharmacokinetic behavior, and long-term clinical safety. Collectively, fisetin represents a promising multi-target therapeutic candidate for the management of inflammation-associated neurodegenerative disorders.},
}
@article {pmid42417851,
year = {2026},
author = {Talebnejad, MR and Zia, Z and Ostovan, VR and Nazarpour-Servak, M and Nowroozzadeh, MH},
title = {Retinal sublayer changes in cases with Alzheimer's disease and depression.},
journal = {Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie},
volume = {},
number = {},
pages = {},
pmid = {42417851},
issn = {1435-702X},
abstract = {PURPOSE: Alzheimer's disease (AD) and depression are two prevalent conditions in the elderly population, both of which may impact the structure or function of the visual pathway. This study simultaneously investigated the effects of AD and depression on optic nerve head and macular parameters using Optical Coherence Tomography (OCT) imaging.<br><br>METHODS: This cross-sectional study included two groups: 50 individuals with mild to moderate AD and 50 age-matched healthy controls (HCs). All participants underwent the Patient Health Questionnaire-9 (PHQ-9) and Mini-Mental State Examination (MMSE). Comprehensive ophthalmic examinations were performed, and individuals with significant refractive errors or ocular pathologies were excluded. Peripapillary RNFL (pRNFL) and macular layer imaging were conducted using Heidelberg OCT.<br><br>RESULTS: Compared to HCs, AD patients showed significant thinning of pRNFL in the supra temporal (HC: 136.38&#x2009;&#xb1;&#x2009;17.68&#xa0;&#x3bc;m vs. AD: 127.45&#x2009;&#xb1;&#x2009;16.08&#xa0;&#x3bc;m, P&#x2009;=&#x2009;0.010) and infra temporal (HC: 139.46&#x2009;&#xb1;&#x2009;20.88&#xa0;&#x3bc;m vs. AD: 127.99&#x2009;&#xb1;&#x2009;17.06&#xa0;&#x3bc;m, P&#x2009;=&#x2009;0.003) quadrants, while temporal and nasal sectors were not significantly different. Inner macular layers were also significantly reduced in the AD group: GCL volume (1.043&#x2009;&#xb1;&#x2009;0.073 vs. 0.981&#x2009;&#xb1;&#x2009;0.083&#xa0;mm&#xb3;, P&#x2009;<&#x2009;0.001), IPL volume (0.872&#x2009;&#xb1;&#x2009;0.061 vs. 0.834&#x2009;&#xb1;&#x2009;0.048&#xa0;mm&#xb3;, P&#x2009;=&#x2009;0.001), and GCC (2.832&#x2009;&#xb1;&#x2009;0.181 vs. 2.671&#x2009;&#xb1;&#x2009;0.192&#xa0;mm&#xb3;, P&#x2009;<&#x2009;0.001). Depression severity correlated negatively with GCL volume (&#x3c1; = -&#x2009;0.260, P&#x2009;=&#x2009;0.009). In stepwise regression analysis, MMSE score was more strongly associated with GCL volume than depression status and entered the model as the main predictor (&#x3b2;&#x2009;=&#x2009;0.489, P&#x2009;<&#x2009;0.001). The MMSE &#xd7; depression interaction term was also significant (&#x3b2; = -0.213, P&#x2009;=&#x2009;0.020), indicating that depression modified the association between cognitive impairment and GCL thinning.<br><br>CONCLUSIONS: AD and depression in the elderly can influence the thickness of inner retinal layers, with dementia appearing to have a more pronounced effect than depression. These retinal changes may have important implications not only for the early diagnosis and monitoring of AD, but also for the accuracy of OCT-based detection of early glaucoma in patients with coexisting neuropsychiatric disorders-particularly in those with AD, where reliable visual field testing may also be challenging.},
}
@article {pmid42417853,
year = {2026},
author = {Zheng, H and Yang, H and Ma, H and Zhu, L and Liu, A and Hou, X and Yang, C and Ye, W},
title = {Dietary sialic acid intake and incident dementia: evidence from a large prospective cohort study.},
journal = {European journal of nutrition},
volume = {65},
number = {5},
pages = {},
pmid = {42417853},
issn = {1436-6215},
support = {82204023//National Natural Science Foundation of China/ ; 2022ZD0211600//National Major Science and Technology Projects of China/ ; XRCZX2020019//Research Start-up Fund of Fujian Medical University/ ; No.2023QH1065//Research Start-up Fund of Fujian Medical University/ ; },
mesh = {Humans ; Prospective Studies ; *N-Acetylneuraminic Acid/administration &amp; dosage ; *Dementia/epidemiology/prevention &amp; control ; Male ; Female ; *Diet/methods/statistics &amp; numerical data ; Aged ; Middle Aged ; United Kingdom/epidemiology ; Risk Factors ; Incidence ; Proportional Hazards Models ; Alzheimer Disease/epidemiology ; Dementia, Vascular/epidemiology ; Follow-Up Studies ; },
abstract = {PURPOSE: Beneficial effects of sialic acid on cognition have been most often seen in cognitive development in infant models, whereas the relevant evidence from ageing population studies remains limited. We aimed to investigate the associations of dietary sialic acids and their subtypes (Neu5Ac and Neu5Gc) with the incident dementia in a large prospective study.<br><br>METHODS: A total of 210,796 middle-aged and older participants from UK Biobank were included in this study. Dietary sialic acids intake was estimated using repeated 24-h dietary recall questionnaires. Cox proportional hazards models were used to evaluate the association of sialic acid and its subtypes with dementia risk.<br><br>RESULTS: During a mean follow-up of 10.9&#xa0;years, 2469 incident all-cause dementia were recorded, of which 1077 were Alzheimer's disease (AD), and 454 were vascular dementia (VaD). Compared with participants in the lowest quartile (median intake: 25.12&#xa0;mg/d), participants in the third quartile of total sialic acids (median intake: 56.46&#xa0;mg/d) were associated with a 18% lower risk of all-cause dementia (HR 0.82; 95% CI 0.73-0.92) and a 31% lower risk of VaD (HR 0.69; 95%CI 0.53-0.91), respectively. Similar associations were observed for Neu5Ac and Neu5Gc, respectively. After mutual adjustment, the association of Neu5Gc with all-cause dementia or VaD risk remained unchanged, whereas the association of Neu5Ac with dementia risk became non-significant after adjusting for Neu5Gc.<br><br>CONCLUSION: Our findings suggest a potential non-linear protective association between total sialic acid and risk of all-cause dementia and VaD.},
}
@article {pmid42417935,
year = {2026},
author = {Gupta, A and Singh, S and Singh, TD},
title = {Regulation of NLRP3 inflammasome signaling in Alzheimer's disease: emerging neuroprotective role of phytochemicals.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42417935},
issn = {1568-5608},
abstract = {The Nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasome is a multiprotein complex that plays an important role in neuroinflammatory diseases, including Alzheimer's disease (AD). NLRP3 inflammasome activation involves upstream priming and activation signals, including amyloid-β aggregates, mitochondrial dysfunction, and oxidative stress, which promote inflammasome assembly and trigger downstream effector responses. This leads to caspase-1 activation and cleavage of GSDMD and the subsequent release of pro-inflammatory cytokines such as IL-1β and IL-18, thereby amplifying neuroinflammation and contributing to the neuronal damage characteristic of AD. Two known pathways of NLRP3 inflammasome activation are the canonical pathway, mediated by caspase-1, and the non-canonical pathway, mediated by caspase-11 (in mice) or caspase-4/5 (in humans). The use of phytochemicals to prevent NLRP3 inflammasome activation offers potential to reduce neuroinflammation and maintain neuronal integrity in AD. Phytochemicals such as resveratrol, ginkgolide B, and saffron, among others, have been shown to modulate the activity of the NLRP3 inflammasome through various mechanisms, including the inhibition of NLRP3 assembly, suppression of inflammasome priming signals, and regulation of downstream signaling pathways. Overall, phytochemicals that target NLRP3 inflammasome activation may offer potential benefits for AD management by attenuating neuroinflammation and protecting against neuronal damage.},
}
@article {pmid42418029,
year = {2026},
author = {Colitta, A and Mazzarone, T and Corsi, S and Petrozzi, L and Mengozzi, A and Del Chicca, M and Sessa, MR and Bacciardi, E and Virdis, A and Monzani, F and Baldacci, F and Turco, F and Siciliano, G},
title = {Plasma phosphorylated tau and cerebrovascular burden predict emergency department use in dependent older patients.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {8},
pages = {},
pmid = {42418029},
issn = {1590-3478},
support = {I53C22000780001//European Union - Next Generation EU/ ; },
mesh = {Humans ; *tau Proteins/blood ; Female ; Male ; *Emergency Service, Hospital/statistics &amp; numerical data ; Biomarkers/blood ; Aged ; Aged, 80 and over ; Prospective Studies ; *Cerebrovascular Disorders/blood ; *Cognitive Dysfunction/blood ; Phosphorylation ; *Frailty/blood ; Emergency Room Visits ; },
abstract = {BACKGROUND: Dependent older patients show high risk of adverse health outcomes when admitted to the emergency department (ED). The prompt identification of ED use risk factors in such population is hence needed. While frailty and cognitive impairment are a known clinical risk factors, biomarkers of most prevalent dementias have been scarcely investigated as possible ED use predictors. Within this framework, this prospective study explored whether plasma phospho-tau181 (ptau181) and cerebrovascular burden provide additional predictive value for 6-month ED use in elderly dependent patients, beyond frailty and age.<br><br>METHODS: We collected baseline clinical and laboratory data to validate a 32-item frailty index, while assessing cognitive impairment through the Mini-Mental State Examination. Biomarkers of cognitive impairment included plasma ptau181 and cerebrovascular burden, i.e., the Fazekas Scale. Binomial and Cox regression models tested the biomarkers of cognitive impairment as predictors of ED use, adjusting for frailty and age. The interaction between cognitive impairment biomarkers was explored.<br><br>RESULTS: Of the 102 recruited patients, 38 visited the ED. In the binomial models, the frailty index (OR&#x2009;=&#x2009;1.69, p&#x2009;=&#x2009;0.011) and the Fazekas Scale (OR&#x2009;=&#x2009;3.57, p&#x2009;=&#x2009;0.007) predicted ED use. At lower p-tau181 levels, ED admission risk increased only with higher cerebrovascular burden. Conversely, higher p-tau181 levels predicted ED use (OR&#x2009;=&#x2009;4.90, p&#x2009;=&#x2009;0.037) irrespective of cerebrovascular burden. No significant predictors of time to ED use emerged.<br><br>DISCUSSION: Beyond measures of clinical frailty, the routinary employment of cognitive impairment biomarkers may contribute identifying dependent older patients at short-term high risk of ED use, possibly reducing adverse health outcomes in such population.},
}
@article {pmid42418159,
year = {2026},
author = {Panisello, L and Millet-Sigalat, M and Novau-Ferré, N and Mateu-Fabregat, J and Carrasco, M and Ettcheto, M and Félix-Soriano, E and Camins, A and Bulló, M},
title = {Nut consumption as a therapeutic strategy to preserve brain function, attenuate neuropathology, and modulate cross-tissue microRNAs in a mouse model of Alzheimer's disease.},
journal = {Food &amp; function},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6fo00445h},
pmid = {42418159},
issn = {2042-650X},
abstract = {Nutritional modulation of brain metabolism is emerging as a key strategy for preventing Alzheimer's Disease (AD), with potential to influence key pathologies such as amyloid beta/β (Aβ) accumulation, tau phosphorylation, and neuroinflammation. However, the biological mechanisms linking diet, metabolism, and AD remain poorly understood. The aim of this study is to investigate the neuroprotective effects of a nut-enriched diet (NED) on AD-like pathology using APPswe/PS1dE9 (APP) transgenic mice, focusing on cognition, neuroinflammation, Aβ burden, and the potential regulatory role of circulating and brain-tissue specific microRNA (miRNA). APP and wild-type (WT) male mice were fed either a control diet (CD) or NED providing 10% of total energy from mixed nuts. Behavioral performance, Aβ deposition, glial activation, and synaptic integrity were assessed, alongside miRNA profiling in serum, cortex, and hippocampus. In APP mice, NED enhanced hippocampal-dependent memory, reduced microglia and astrocyte reactivity, decreased cortical and hippocampal Aβ plaque burden, and preserved dendritic spine density. Multi-compartment miRNA analyses revealed that NED modulated several AD-relevant miRNAs involved in insulin signaling, neuroinflammation, and synaptic function. These miRNA alterations correlated with improved cognitive outcomes and attenuated neuropathology, suggesting coordinated metabolic and molecular reprogramming in response to dietary intervention. A nut-enriched diet exerted significant neuroprotective effects in an AD mouse model, potentially mediated through coordinated miRNA regulation and related metabolic pathways. These findings support nut consumption as a feasible nutrition-based strategy for AD prevention and identify candidate miRNAs that may serve as biomarkers or mechanistic mediators at the intersection of diet, metabolism, and neurodegeneration.},
}
@article {pmid42418262,
year = {2026},
author = {Hopkins, WD and Achorn, A and Mulholland, MM and Magden, E and Schapiro, SJ and Fults, CL and Mangin, JF and Meguerditchian, A},
title = {A Comparative Study of Aging and Cortical Folding in Chimpanzees and Olive Baboons.},
journal = {American journal of primatology},
volume = {88},
number = {7},
pages = {e70190},
doi = {10.1002/ajp.70190},
pmid = {42418262},
issn = {1098-2345},
support = {2021711//National Science Foundation/ ; AG-067419/NH/NIH HHS/United States ; },
mesh = {Animals ; *Pan troglodytes/physiology/anatomy &amp; histology ; Female ; *Aging/physiology ; Male ; *Papio anubis/physiology/anatomy &amp; histology ; *Cerebral Cortex/anatomy &amp; histology/physiology ; Species Specificity ; Sex Factors ; Sex Characteristics ; Magnetic Resonance Imaging ; },
abstract = {In light of the evidence that nonhuman primates naturally develop Alzheimer's disease neuropathologies, there is a renewed interest in research on the comparative biology of aging, including neurological changes across the age groups in species with diverse lifespans. In this paper, we examined age-related differences in two measures of cortical folding, mean depth and fold opening, in a sample of chimpanzees (Pan troglodytes) and olive baboons (Papio anubis). We found significant species differences in the slope and pattern of age-related changes in cortical folding. As predicted, chimpanzees showed negative linear associations between age and mean depth and positive linear associations between age and fold opening, as we see in humans. However, contrary to our hypotheses, baboons showed positive quadratic associations between age and mean depth and negative quadratic associations between age and fold opening. Additionally, within the baboons but not the chimpanzees, significant sex differences were found in age-related differences in cortical folding. Here, male baboons showed significant linear associations between age, sulci depth, and fold opening, much like male and female chimpanzees. However, for female baboons, slopes of age-related differences in fold opening were flat or showed slight quadratic associations. It is possible that variation in primate social systems and/or reproductive aging may influence sex and species differences in brain aging. Longitudinal studies on primate brain aging, as well as comparative research with additional taxa, could shed light on the causes and implications of these differences.},
}
@article {pmid42418270,
year = {2026},
author = {Caselli, RJ and Geldmacher, DS and Schilling, TB},
title = {A Narrative Review of Amyloid-β Monoclonal Antibodies for Alzheimer Disease: How Amyloid Species Engagement May Affect Clinical Outcomes.},
journal = {The neurologist},
volume = {31},
number = {4},
pages = {129-135},
doi = {10.1097/NRL.0000000000000679},
pmid = {42418270},
issn = {2331-2637},
support = {//Eli Lilly and Company, Indianapolis, IN/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnostic imaging/metabolism ; *Amyloid beta-Peptides/immunology/metabolism ; *Antibodies, Monoclonal/therapeutic use ; Plaque, Amyloid/drug therapy ; Animals ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a leading cause of death worldwide, with growing prevalence as life expectancy increases. An important neurological hallmark of AD is the deposition of extracellular neuritic amyloid-β (Aβ) plaques that can disrupt synaptic transmission and cause neuronal death. More recent studies suggest that targeting Aβ species can slow the progression of cognitive decline in AD.<br><br>REVIEW SUMMARY: This narrative review examines the efficacy of monoclonal antibodies targeting the amyloid-&#x3b2; (A&#x3b2;) protein in the treatment of AD. It discusses the mechanisms by which these antibodies aim to mitigate amyloid pathology and explores their clinical outcomes in various trials. The review highlights the importance of amyloid plaque reduction to less than 25 Centiloids observed through amyloid positron emission tomography (PET) scans as a predictor of slowing cognitive decline. The findings suggest that targeting insoluble amyloid plaques is crucial for achieving clinical benefits in AD treatment. This review also discusses the phenomenon of amyloid-related imaging abnormalities (ARIA) that may be associated with monoclonal antibody therapy.<br><br>CONCLUSION: Monoclonal antibodies that target A&#x3b2; monomers, soluble oligomers and protofibrils, and insoluble fibrils/plaques were developed, and not all have provided clinical benefit. Emerging evidence suggests that it is important to reduce amyloid plaque burden to less than 25 Centiloids, consistent with a visually negative amyloid PET scan, in order to slow cognitive decline in early symptomatic AD.},
}
@article {pmid42418280,
year = {2026},
author = {Zhang, C and Chen, S and Zhao, H and Wang, Y and Zhou, L and Fan, H and Sun, Y},
title = {Phase Separation Drives Pathological Aggregation in Neurodegenerative Diseases: A 15-Year Bibliometric Landscape (2009-2024).},
journal = {Annals of the New York Academy of Sciences},
volume = {1561},
number = {1},
pages = {e70311},
doi = {10.1111/nyas.70311},
pmid = {42418280},
issn = {1749-6632},
support = {#82371153//National Natural Science Foundation of China/ ; #82571317//National Natural Science Foundation of China/ ; #ZR2022QH073//Natural Science Foundation of Shandong Province/ ; #ZR2025MS1188//Natural Science Foundation of Shandong Province/ ; #ZR2025LZ044//Natural Science Foundation of Yantai/ ; },
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; Phase Separation ; *Protein Aggregation, Pathological/metabolism/pathology ; *Bibliometrics ; Animals ; DNA-Binding Proteins/metabolism ; },
abstract = {Liquid-liquid phase separation (LLPS), a biophysical driver of membraneless organelle assembly, is central to pathological aggregation in neurodegenerative diseases. Initially linked to amyotrophic lateral sclerosis (ALS), LLPS dysregulation has now been implicated in Alzheimer's, Parkinson's, and frontotemporal dementia, where aberrant transitions convert dynamic condensates into insoluble fibrils. To systematically map this landscape, we employed CiteSpace-based bibliometrics to analyze 784 Web of Science articles from 2009 to 2024. Our analyses reveal dominant contributions from the United States, China, and Germany, with collaborative networks focusing on protein dynamics. Key hotspots include LLPS-driven aggregation of TARDBP (TDP-43), FUS, and α-synuclein, alongside stress granule dysfunction and nucleocytoplasmic transport defects. Emerging frontiers highlight therapeutic strategies targeting pathological condensates utilizing small-molecule chaperones and posttranslational modification modulators to restore cellular homeostasis. Our findings underscore LLPS as a critical axis bridging molecular pathology and translational innovation. The field is rapidly shifting from mechanistic exploration to therapeutic applications, emphasizing interventions to halt or reverse aggregation. By delineating global trends and changing priorities, our study highlights the transformative potential of phase-targeted interventions and provides a roadmap of groundbreaking interdisciplinary research into neurodegenerative disorders.},
}
@article {pmid42418295,
year = {2026},
author = {Gu, T and Guo, H and Guo, Z and Hua, S},
title = {Advances in the Core Role and Mechanisms of Mitochondrial Dysfunction in Alzheimer's Disease.},
journal = {Brain and behavior},
volume = {16},
number = {7},
pages = {e71418},
doi = {10.1002/brb3.71418},
pmid = {42418295},
issn = {2162-3279},
mesh = {*Alzheimer Disease/metabolism/pathology/physiopathology ; Humans ; *Mitochondria/metabolism/pathology ; Animals ; Mitophagy/physiology ; Oxidative Stress/physiology ; Mitochondrial Dynamics/physiology ; Energy Metabolism/physiology ; Mitochondria Associated Membranes ; Amyloid beta-Peptides/metabolism ; Brain/metabolism ; Brain-Gut Axis/physiology ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a complex neurodegenerative disorder whose pathogenesis involves multi-level pathological alterations. This review aims to systematically elucidate the central role and multifaceted molecular mechanisms of mitochondrial dysfunction in the progression of AD.<br><br>METHODS: A comprehensive analysis of the existing literature was conducted, synthesizing findings from studies investigating mitochondrial involvement in AD pathology. The review focused on key mechanistic pathways, including energy metabolism deficits, oxidative stress, synaptic damage, mitochondrial dynamics, mitochondria-associated membranes (MAMs), mitophagy, and the gut-brain axis.<br><br>RESULTS: The analysis revealed several critical mechanisms linking mitochondrial dysfunction to AD progression: (i) impaired mitochondrial energy metabolism, which establishes a causal relationship with oxidative stress and synaptic injury; (ii) dysregulation of mitochondrial fusion/fission dynamics, particularly the aberrant interactions of amyloid-beta (A&#x3b2;) and p-Tau with the fission protein Drp1 and the channel protein VDAC1; (iii) dysfunction of mitochondria-associated membranes (MAMs); (iv) defective mitophagy involving both the PINK1/Parkin pathway and receptor-mediated pathways; and (v) bidirectional crosstalk between mitochondria and the gut-brain axis. These interconnected pathways converge to amplify neuroinflammation and neuronal death.<br><br>CONCLUSION: Accumulated evidence positions mitochondrial dysfunction as a critical hub that integrates A&#x3b2;/Tau pathology, neuroinflammation, and neuronal loss, thereby perpetuating a self-sustaining vicious cycle in AD. Targeting mitochondrial bioenergetics, dynamics, quality control, and the mitochondria-inflammation axis offers substantial therapeutic promise. Emerging small molecules such as SS31 and DDQ have demonstrated protective effects in preclinical models. Future investigations should prioritize mechanistic dissection and translational research to facilitate the clinical development of mitochondria-targeted therapies for AD.},
}
@article {pmid42418307,
year = {2026},
author = {Özbek, Y and Yener, GG},
title = {Neurophysiological Differentiation of Conversion to Alzheimer's Disease: Longitudinal Changes in P300 Amplitude as an Indicator of Mild Cognitive Impairment Progression.},
journal = {Brain and behavior},
volume = {16},
number = {7},
pages = {e71555},
doi = {10.1002/brb3.71555},
pmid = {42418307},
issn = {2162-3279},
mesh = {Humans ; *Cognitive Dysfunction/physiopathology/diagnosis ; *Alzheimer Disease/physiopathology/diagnosis ; *Event-Related Potentials, P300/physiology ; Disease Progression ; Female ; Longitudinal Studies ; Male ; Electroencephalography/methods ; Aged ; Neuropsychological Tests ; },
abstract = {PURPOSE: This longitudinal study investigated whether P300 event-related potential (ERP) amplitude demonstrates group-level and longitudinal differences between stable and progressive mild cognitive impairment (MCI), and whether these electrophysiological changes may serve as preliminary markers associated with Alzheimer's disease (AD) progression.<br><br>METHOD: Fifty-four participants, including 27 cognitively unimpaired (CU) individuals and 27 individuals with multi-domain amnestic MCI, underwent EEG recording during a visual oddball task at baseline and follow-up assessment. Within 1 year, 14 MCI participants progressed to AD (pMCI), while 13 remained stable (sMCI). P300 amplitudes were compared across groups and over time, and exploratory receiver operating characteristic (ROC) analyses were conducted to evaluate discriminative performance. Correlations between P300 amplitudes and cognitive measures were also examined.<br><br>FINDINGS: Baseline analyses demonstrated significantly reduced P300 amplitudes in both MCI groups compared to CU participants (p < 0.001), consistent with early cortical dysfunction. Longitudinally, CU and sMCI groups exhibited amplitude decline over time, whereas the pMCI group showed persistently stable but markedly low amplitudes. Exploratory ROC analyses suggested potential group-level discriminative utility for differentiating pMCI from both CU and sMCI participants. In addition, lower P300 amplitudes were significantly associated with poorer global cognitive performance and memory scores.<br><br>CONCLUSION: These findings suggest that reduced P300 amplitude, particularly at central electrode locations, may represent a preliminary electrophysiological marker associated with progression from MCI to AD. The results support the potential relevance of P300 measures in future prognostic and longitudinal biomarker research in Alzheimer's disease.},
}
@article {pmid42418450,
year = {2026},
author = {Khandelwal, P and Duong, MT and Levorse, LM and Trotman, W and Bahena, A and Lim, SA and Denning, AE and Chung, E and Olm, CA and Radhakrishnan, H and Ittyerah, R and Prabhakaran, K and Mizsei, G and Schuck, T and Emrani, S and Vizcarra, JA and Robinson, J and Ohm, DT and Phillips, JS and Cohen, J and Wisse, LEM and Detre, JA and Nasrallah, IM and Brown, CA and Das, SR and Lee, EB and Tisdall, MD and Irwin, DJ and McMillan, CT and Wolk, DA and Yushkevich, PA},
title = {Postmortem brain MRI reveals differential associations of subcortical and limbic volumes with cortical thinning and neurodegenerative pathologies.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71649},
doi = {10.1002/alz.71649},
pmid = {42418450},
issn = {1552-5279},
support = {P30 AG072979/NH/NIH HHS/United States ; RF1 AG056014/NH/NIH HHS/United States ; R01 AG069474/NH/NIH HHS/United States ; R01 AG054519/NH/NIH HHS/United States ; P01 AG017586/NH/NIH HHS/United States ; U19 AG062418/NH/NIH HHS/United States ; R01 NS109260/NH/NIH HHS/United States ; F30 AG074524/NH/NIH HHS/United States ; P01 AG084497/NH/NIH HHS/United States ; P01 AG066597/NH/NIH HHS/United States ; },
mesh = {Humans ; Female ; *Magnetic Resonance Imaging ; Male ; Aged ; *Lewy Body Disease/pathology/diagnostic imaging ; Atrophy/pathology ; *Brain/pathology/diagnostic imaging ; Aged, 80 and over ; tau Proteins/metabolism ; *Alzheimer Disease/pathology/diagnostic imaging ; DNA-Binding Proteins/metabolism ; *Frontotemporal Lobar Degeneration/pathology/diagnostic imaging ; alpha-Synuclein/metabolism ; *Cerebral Cortical Thinning/pathology/diagnostic imaging ; *Neurodegenerative Diseases/pathology/diagnostic imaging ; *Limbic System/pathology/diagnostic imaging ; Middle Aged ; },
abstract = {INTRODUCTION: The impact of different neuropathologies on deep brain structures remains to be understood. We examine subcortical and limbic volumetry in neurodegenerative diseases involving phosphorylated tau (p-tau), α-synuclein, and transactive response DNA binding protein 43 (TDP-43).<br><br>METHODS: We acquired neuropathological measures and brain segmentations from postmortem analysis of 132 donors with Alzheimer's disease (AD), Lewy body disease (LBD), frontotemporal lobar degeneration with TDP-43 (FTLD-TDP), and FTLD-tau.<br><br>RESULTS: LBD had the least subcortical, limbic, and cortical atrophy compared to AD, FTLD-TDP, and FTLD-tau. In donors with both AD and LBD pathologies, primary LBD was associated with less atrophy than primary AD. While AD had cortico-subcortical and cortico-limbic morphometric associations, LBD had more limited parieto-occipital cortico-limbic associations. FTLD-TDP had cortico-subcortical while FTLD-tau had cortico-subcortical and cortico-limbic associations. In AD and FTLD-tau, hippocampal volumes correlated with p-tau burden, neuron loss, and gliosis. In LBD, thalamic &#x3b1;-synuclein severity was associated with subcortical/limbic volumes.<br><br>DISCUSSION: Postmortem neuroimaging reveals disease- and region-specific structure-pathology relationships.},
}
@article {pmid42418454,
year = {2026},
author = {Bréchet, L and Toussas, K and Marie, D and Unschuld, PG},
title = {The Hippocampus Links Episodic Memory and Bodily Awareness.},
journal = {Brain and behavior},
volume = {16},
number = {7},
pages = {e71570},
doi = {10.1002/brb3.71570},
pmid = {42418454},
issn = {2162-3279},
support = {2024-CAD03//Dementia Research Switzerland- Synapsis Foundation/ ; PZ00P1_208686/SNSF_/Swiss National Science Foundation/Switzerland ; },
mesh = {Humans ; *Memory, Episodic ; *Hippocampus/pathology/diagnostic imaging/physiopathology ; *Awareness/physiology ; Female ; Male ; Aged ; Magnetic Resonance Imaging ; *Cognitive Dysfunction/pathology/physiopathology/diagnostic imaging/psychology ; Middle Aged ; Atrophy/pathology ; },
abstract = {PURPOSE: Episodic autobiographical memory does not occur in isolation from the body: every remembered event was once encoded from a first-person perspective. Yet whether the hippocampus, long recognized as the canonical substrate of memory, also underpins the embodied self has remained unknown.<br><br>METHOD: We combined structural T1-weighted MRI with behavioral assessments of episodic memory (Logical Memory delayed recall) and bodily awareness (ARSQ 2.0 Somatic Awareness subscale) in patients with mild cognitive impairment (MCI) and healthy comparison groups to test whether hippocampal volume predicts both outcomes.<br><br>FINDING: We show that hippocampal volume predicts not only episodic memory performance but also bodily awareness in patients with MCI. Hippocampal volume explained substantial variance in both domains, whereas a control region did not, underscoring regional specificity. This effect was paralleled by a reduction of hippocampal volume in MCI patients compared to older and younger adults. Notably, both high- and low-cognition older adults showed larger volumes than in MCI.<br><br>CONCLUSION: These findings provide the first structural evidence that hippocampal atrophy is associated with reductions in both remembering and embodiment, positioning the hippocampus as a key node linking memory and bodily selfhood. Beyond revealing a novel dimension of hippocampal vulnerability, this work suggests translational opportunities. These findings open the possibility that bodily awareness may prove useful as an early marker in future longitudinal studies of Alzheimer's disease.},
}
@article {pmid42418465,
year = {2026},
author = {Moghekar, AR and Rock, JA and Mohs, RC and Hansson, O and Stomrud, E and Palmqvist, S and Mattsson-Carlgren, N and Johnson, SC and Zetterberg, H and Radwan, RR and Junfola, J and Miller, MC and Buitrago, L and De Simone, FI and Martin, K and Dickson, D and Benina, N and Hawkins, DM},
title = {Multicenter validation of plasma p-tau217/ amyloid beta 1-42 ratio in symptomatic Alzheimer's disease.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71644},
doi = {10.1002/alz.71644},
pmid = {42418465},
issn = {1552-5279},
support = {//National Institutes of Health (NIH)/ ; U19-AG033655/AG/NIA NIH HHS/United States ; P30-AG005146/AG/NIA NIH HHS/United States ; R01AG083740/AG/NIA NIH HHS/United States ; SG-23-1061717/ALZ/Alzheimer's Association/United States ; FO2024-0284//Swedish Brain Foundation/ ; 20243058//Kamprad Foundation/ ; FRS-0011//Family R&#xf6;nstr&#xf6;m/ ; FRS-0004//Family R&#xf6;nstr&#xf6;m/ ; AF-1011949//Swedish Alzheimer Foundation/ ; //Alzheimer's Drug Discovery Foundation (ADDF)/ ; AG027161//Wisconsin Registry for Alzheimer's Prevention (WRAP)/ ; AG021155//Wisconsin Registry for Alzheimer's Prevention (WRAP)/ ; //Wisconsin Alzheimer's Disease Research Center (WADRC)/ ; AG062715//Foundation for the National Institutes of Health/ ; //MultiPark at Lund University/ ; //Bundy Academy/ ; //Fujirebio US/ ; },
mesh = {Humans ; *Amyloid beta-Peptides/blood/cerebrospinal fluid ; *Alzheimer Disease/blood/diagnostic imaging/diagnosis/cerebrospinal fluid ; Female ; *tau Proteins/blood/cerebrospinal fluid ; *Peptide Fragments/blood/cerebrospinal fluid ; Male ; Positron-Emission Tomography ; Aged ; Biomarkers/blood/cerebrospinal fluid ; Middle Aged ; Sensitivity and Specificity ; Aged, 80 and over ; },
abstract = {INTRODUCTION: This study evaluated the diagnostic performance of the Lumipulse[®] G pTau 217/β-Amyloid 1-42 Plasma Ratio to detect amyloid positivity in patients with cognitive decline symptoms.<br><br>METHODS: The Lumipulse Plasma Ratio was evaluated using predetermined thresholds (&#x2264;0.00370 negative; &#x2265;0.00738 positive) against cerebrospinal fluid (CSF) biomarker ratios or amyloid positron emission tomography (PET) imaging as references in 499 adults (&#x2265;50 years old) enrolled in prospective studies conducted across academic memory clinics and research centers.<br><br>RESULTS: Amyloid status was determined by CSF in 347 patients (189 positive [54.5%]) and by PET imaging in 152 patients (66 positive [43.4%]). The Lumipulse Plasma Ratio was positive in 219 patients (43.9%), negative in 182 (36.5%), and indeterminate in 98 (19.6%). Positive and negative predictive values were 91.8% and 97.3%, with a sensitivity and specificity of 97.6% and 90.8%, respectively.<br><br>DISCUSSION: The US Food and Drug Administration-cleared Lumipulse Plasma Ratio demonstrated high accuracy in identifying amyloid pathology and offers an alternative to CSF testing and amyloid PET imaging.},
}
@article {pmid42406553,
year = {2026},
author = {Wen, S and Gao, J and Wang, Z and Ma, Q and Xu, XL and Chen, J},
title = {EphB1-Mediated Transient Blood-Brain Barrier Opening Facilitates a Ferritin-Based Nanotherapeutic for Alzheimer's Disease.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e76480},
doi = {10.1002/advs.76480},
pmid = {42406553},
issn = {2198-3844},
support = {ZKJC2203//Zhejiang Rehabilitation Medical Center/ ; ZKXK02//Zhejiang Rehabilitation Medical Center/ ; 2021C03050//Development Program of Zhejiang Province/ ; 82372109//National Natural Science Foundation of China/ ; },
abstract = {The treatment of Alzheimer's disease (AD) is severely hampered by the blood-brain barrier (BBB), which limits the delivery of therapeutic agents like donepezil (DPZ), an acetylcholinesterase inhibitor. While DPZ has multi-faceted benefits, its clinical efficacy is constrained by poor BBB penetration, requiring high doses that lead to significant side effects. To overcome this, we developed a brain-targeted nanotherapeutic utilizing apoferritin (AFn) nanoparticles loaded with DPZ (AFn-DPZ). We demonstrate that this platform, by binding to the EphB1 receptor on the blood-brain barrier, enables transient and reversible opening of the blood-brain barrier, thereby facilitating efficient and targeted drug delivery. Following intravenous administration in an AD mouse model, AFn-DPZ exhibited enhanced brain accumulation and sustained release of DPZ. This targeted delivery inhibited acetylcholinesterase activity, reduced amyloid plaque burden, alleviated neuroinflammation, attenuated oxidative damage, restored mitochondrial function, and upregulated the expression of brain-derived neurotrophic factor (BDNF). Consequently, AFn-DPZ treatment significantly improved cognitive performance compared to free DPZ. Our findings establish EphB1-mediated facilitation of BBB traversal as a promising strategy for enhancing nanotherapeutic delivery to the brain, offering a potent approach to address the complex pathology of AD.},
}
@article {pmid42406649,
year = {2026},
author = {Zawadzki, S and Okła, E and Michlewska, S and Bednarek, R and Ortega López, P and de la Mata, FJ and Jansons, J and Skrastina, D and Kreišmane, M and Piļipenko, V and Jansone, B and Ionov, M and Bryszewska, M and Miłowska, K},
title = {Tiered Evaluation of Carbosilane Dendrimer-siRNA Nanoplatform from Single-Cell Biocompatibility to Blood-Brain Barrier Model Dynamics and Murine Alzheimer Model Behavior Assessment.},
journal = {ACS applied materials &amp; interfaces},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsami.6c06099},
pmid = {42406649},
issn = {1944-8252},
abstract = {Blood-brain barrier (BBB) transport remains a primary constraint on achieving predictable central nervous system exposure for Alzheimer's disease (AD) therapeutics, motivating the evaluation of delivery platforms with barrier-resolved and functionally relevant end points. We assessed a carbosilane dendrimer (G3Si PEG6000) and its siRNA dendriplex using a tiered, upstream strategy spanning cell internalization, DNA damage screening, BBB model integrity and permeability, and in vivo AD-relevant murine model learning. At the cellular level, the dendrimer enhanced intracellular siRNA-associated signal with predominantly cytoplasmic localization, and siRNA complexation attenuated genotoxicity relative to the noncomplexed carrier. In a BBB triculture model, barrier function was preserved without sustained transendothelial electrical resistance (TEER) loss, and complementary tracer flux readouts showed time- and formulation-dependent, nonmonotonic changes, including TEER-permeability decoupling consistent with nonuniform perturbation and time-dependent changes in barrier-associated paracellular responses. In APOE4 knock-in mice, dendriplex treatment increased platform-zone crossings in the Morris Water Maze probe trial, whereas target-quadrant time showed only a modest, nonsignificant trend. Collectively, these integrated results indicate that siRNA complexation improves the BBB-relevant safety-performance balance of G3Si PEG6000 and supports further studies that directly link brain exposure and target engagement to cognitive outcomes.},
}
@article {pmid42406869,
year = {2026},
author = {Miao, L and Hou, F and Li, G},
title = {Key targets and mechanisms by which gut microbiota-derived metabolites regulate Alzheimer's disease through the immune - inflammatory pathway: Based on network pharmacology and molecular docking.},
journal = {PloS one},
volume = {21},
number = {7},
pages = {e0352999},
doi = {10.1371/journal.pone.0352999},
pmid = {42406869},
issn = {1932-6203},
mesh = {*Alzheimer Disease/metabolism/immunology/microbiology ; *Molecular Docking Simulation ; Humans ; *Gastrointestinal Microbiome/immunology ; Signal Transduction ; *Network Pharmacology ; Inflammation/metabolism/immunology ; Protein Interaction Maps ; },
abstract = {This study integrated network pharmacology, bioinformatics, and molecular docking to explore potential immune-inflammatory pathways associated with the relationship between gut microbiota-derived metabolites and Alzheimer's disease (AD). A total of 260 gut microbiota - derived metabolites were initially retrieved, and 196 common targets were identified by intersecting predicted metabolite-associated targets with AD-related targets. Further screening identified 14 key overlapping targets, including IL6, NFKB1, IL1B, PTGS2, TLR4, and PPARG. Protein-protein interaction (PPI) network analysis identified IL6, NFKB1, IL1B, CXCL8, PPARG, FOS, and JUN as central hub genes. Functional enrichment analyses indicated that these targets were mainly involved in immune-inflammatory responses, response to lipopolysaccharide, oxidative stress-related processes, and regulation of apoptosis. KEGG pathway analysis further suggested that the overlapping targets were associated with several inflammation-related signaling pathways, including the NOD-like receptor, TNF, NF-κB, and MAPK signaling pathways. In silico pharmacokinetic and toxicity evaluation showed that several representative metabolites exhibited heterogeneous but informative drug-likeness and pharmacokinetic/toxicity-related profiles relevant to gut-brain-axis hypothesis generation. Molecular docking was performed as an exploratory structural assessment and suggested that selected metabolites, including Enterodiol, Coumarin, and 3,9-dihydroxy-6H-benzo[c]chromen-6-one, showed top-ranked predicted docking poses in computationally identified surface-accessible pockets of representative hub proteins such as IL6 and NFKB1, with docking scores ranging from - 6.8 to - 8.1 kcal/mol. These docking scores were interpreted only as qualitative descriptors of predicted structural compatibility and were not used to infer quantitative biological activity, target inhibition, or therapeutic efficacy. Overall, this study prioritizes a potential multi-target immune-inflammatory network centered on IL6, NFKB1, and IL1B, providing a hypothesis-generating framework for understanding the possible role of gut microbiota-derived metabolites in AD-related neuroimmune regulation. Further experimental studies are required to validate the predicted metabolite-target associations and clarify their biological relevance.},
}
@article {pmid42407324,
year = {2026},
author = {Abdel-Rahman, SA and Gabr, MT},
title = {From DNA-encoded library (DEL) screening to in vivo validation: LILRB4 (ILT3)-targeted small molecules reprograms myeloid immune suppression.},
journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie},
volume = {201},
number = {},
pages = {119740},
doi = {10.1016/j.biopha.2026.119740},
pmid = {42407324},
issn = {1950-6007},
abstract = {Alzheimer's disease (AD) remains a major unmet clinical challenge, with limited therapeutic strategies capable of effectively modulating neuroimmune dysfunction. Leukocyte immunoglobulin-like receptor B4 (LILRB4/ILT3) has recently emerged as an inhibitory microglial immune checkpoint implicated in ApoE-mediated suppression of amyloid-β (Aβ) clearance and inflammatory signaling, supporting its potential as a therapeutic target in AD. Here, we applied DNA-encoded library (DEL) screening of approximately 3.6 billion compounds to identify small molecule binders of LILRB4. Biophysical validation identified APX1 as a direct LILRB4 ligand with submicromolar affinity, which was further confirmed by cellular thermal shift assay (CETSA). Docking-guided mutagenesis studies defined a discrete ligand-binding interface involving key hotspot residues required for stable target engagement. Functionally, APX1 disrupted the LILRB4-ApoE interaction in orthogonal ELISA and biolayer interferometry assays. In human iPSC-derived microglia, APX1 suppressed SHP1/2 phosphorylation, attenuated NF-κB activation and IL-1β secretion, and restored Aβ42 uptake under ApoE-driven inflammatory conditions. APX1 further demonstrated favorable in vitro developability, metabolic stability, and CNS exposure properties. In the 5xFAD mouse model of AD, oral administration of APX1 improved cognitive performance, reduced cortical and hippocampal Aβ42 burden, suppressed neuroinflammatory cytokines, and decreased activated microglial populations. Collectively, these findings establish APX1 as a promising small molecule modulator of the LILRB4-ApoE signaling axis and support pharmacological targeting of neuroimmune checkpoints as a therapeutic strategy for AD.},
}
@article {pmid42407430,
year = {2026},
author = {Ghanbarian, E and Khorsand, B and Zheng, L and Woodworth, DC and Glover, CM and Corrada, MM and Sajjadi, SA and Grill, JD and Ezzati, A and , },
title = {Hippocampal asymmetry captures non-amyloid-related risk of memory decline and clinical progression.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {8},
pages = {100638},
doi = {10.1016/j.tjpad.2026.100638},
pmid = {42407430},
issn = {2426-0266},
abstract = {BACKGROUND: Hippocampal atrophy is a key marker of Alzheimer's disease (AD)- related neurodegeneration; however, hippocampal volume alone may not fully capture heterogeneity in cognitive decline. Left-right hippocampal asymmetry may provide complementary information, but its prognostic value for long-term cognitive decline, particularly in relation to AD pathology, remains unclear.<br><br>OBJECTIVES: To determine whether hippocampal total volume and left-right hippocampal asymmetry provide complementary and independent information in capturing cognitive decline and clinical progression, and to examine their relationship to AD pathology.<br><br>DESIGN: Analysis of baseline MRI and longitudinal cognitive data over 10 years in four domains of memory, language, executive, and visuospatial function, using harmonized cognitive data from the Alzheimer's Disease Sequencing Project - Phenotype Harmonization Consortium (ADSP-PHC).<br><br>SETTING: Participants from ADNI 1, ADNI GO, ADNI 2, and ADNI 3 PARTICIPANTS: A total of 1,142 dementia-free participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with available baseline structural MRI, cerebrospinal fluid (CSF) amyloid-&#x3b2; (A&#x3b2;42) and phosphorylated tau (p-tau-181), and longitudinal cognitive follow-up.<br><br>MEASUREMENTS: Total hippocampal volume (left + right) and hemispheric asymmetry (absolute left-right volumetric difference) were modeled simultaneously. Linear mixed-effects models examined associations with baseline performance and longitudinal change across four cognitive domains. Cox proportional hazards models assessed risk of clinical progression to clinical dementia over up to 10 years of follow-up (median follow-up 4 years; median 5 visits per participant). All analyses adjusted for age, sex, education, APOE &#x3b5;4 status, and CSF biomarkers, with stratification by amyloid status.<br><br>RESULTS: The study cohort included 546 women (47.8%), with a mean age of 72.54 &#xb1; 6.98 years. Smaller total hippocampal volume was consistently associated with worse baseline performance and faster decline across all four cognitive domains, even after adjustment for amyloid and tau. In contrast, greater left-right hippocampal asymmetry was selectively associated with worse performance and faster decline in memory, independent of total hippocampal volume. In amyloid-stratified analyses, total hippocampal volume showed broad associations with cognitive performance across multiple domains in both amyloid-positive and amyloid-negative participants, whereas hippocampal left-right asymmetry demonstrated selective associations with memory performance, which were observed only among amyloid-negative individuals. With respect to clinical progression to dementia, smaller total hippocampal volume was associated with a higher risk of progression in the overall cohort and within both amyloid groups. In contrast, hippocampal asymmetry was associated with progression risk only among amyloid-negative individuals (hazard ratio per SD increase = 1.31, 95% CI: 1.03-1.65).<br><br>CONCLUSIONS: Hippocampal total volume and asymmetry capture distinct aspects of neurodegeneration, with asymmetry providing additional prognostic information for memory decline and clinical progression in the absence of detectable amyloid pathology.},
}
@article {pmid42409055,
year = {2026},
author = {Sigvard, CS and Franco-Valiente, JM and Mato, G},
title = {Adversarial attacks on a multimodal Alzheimer's disease detection system reveal complex interdependences between heterogeneous modalities.},
journal = {Biomedical physics &amp; engineering express},
volume = {},
number = {},
pages = {},
doi = {10.1088/2057-1976/ae866f},
pmid = {42409055},
issn = {2057-1976},
abstract = {Multi-modal models that fuse neuroimaging with clinical assessment data represent the current state of the art for automated Alzheimer's disease detection, yet their adversarial robustness remains poorly understood. We systematically investigated adversarial vulnerability in CogniNetMM, a model that fuses 3D structural MRI volumes with neuropsychological clinical variables, using the Fast Gradient Sign Method and DeepFool in three modality configurations: MRI only, clinical variables only, and both jointly. We further introduced a mean attack framework, in which the average perturbation vector across samples serves as a fixed-direction probe of the decision boundary, decoupling the contribution of attack direction from that of sample position.During training, we identified modality collapse, a training instability in which the fusion layer progressively suppresses the MRI pathway. Collapse probability decreased with larger batch sizes and was further reduced by stratified sampling on class-imbalanced data. Across all clinical variable configurations and both attack methods, the joint multi-modal attack achieved higher success than the average of the two unimodal attacks. For DeepFool, the advantage was strong enough that the joint attack outperformed each unimodal attack individually near the decision boundary. The mean attack replicated this result under a fixed perturbation direction, confirming that the advantage is a structural property of the fused decision boundary rather than an artifact of per-sample gradient alignment. These findings are consistent with a concave original-class region in the joint input space: non-linear modality coupling creates adversarially reachable regions that neither modality perturbation can access independently. Together, these results show that heterogeneous data fusion introduces emergent adversarial vulnerabilities beyond what unimodal analysis predicts, and that standard training practices on imbalanced medical datasets carry a risk of silent modality suppression.},
}
@article {pmid42409153,
year = {2026},
author = {Emam, M and Alatawi, FS and Alzamil, Y and Haj, N and Mahbub, AA and Ahmed, AM and Albadri, S and Alazzam, MB and , },
title = {Chemometric profiling reveals selective circulating bile acid remodeling in Alzheimer's disease.},
journal = {Clinica chimica acta; international journal of clinical chemistry},
volume = {},
number = {},
pages = {121218},
doi = {10.1016/j.cca.2026.121218},
pmid = {42409153},
issn = {1873-3492},
abstract = {Bile acids, cholesterol-derived metabolites, have been implicated in Alzheimer's disease (AD), but it remains unclear whether these changes reflect broad concentration differences or selective chemical remodeling of the circulating bile acid pool. This study examined whether circulating bile acid chemistry differs across cognitively normal (CN; n = 243), mild cognitive impairment (MCI; n = 325), and AD (n = 136) participants, with emphasis on conjugation status, primary-secondary transformation, hydrophobicity/polarity balance, sulfation-related chemistry, and chemometric profiles. Analyses were corrected for multiple comparisons using the FDR method. The results demonstrated that AD participants exhibited selective alterations in circulating bile acid chemistry. Specifically, the conjugated bile acids glycochenodeoxycholic acid (GCDCA), glycodeoxycholic acid (GDCA), and taurodeoxycholic acid (TDCA) were significantly elevated in AD, whereas unconjugated bile acids, glycoursodeoxycholic acid (GUDCA), and glycolithocholic acid sulfate (GLCAS) did not differ significantly after FDR correction. Chemistry-derived indices further indicated higher total conjugated bile acids, glycine- and taurine-conjugated bile acid indices, secondary-derived bile acid burden, conjugated/unconjugated ratio, secondary/primary ratio, and hydrophobic/hydrophilic ratio in AD. In contrast, the sulfated/hydrophobic ratio was lower, suggesting a relatively reduced contribution of sulfated bile acids compared with the hydrophobic component. Compositional log-ratio analyses supported a shift toward conjugated, secondary-derived, and hydrophobic bile acid chemistry, while chemical-chemical correlation analyses revealed stronger coupling among conjugation, secondary transformation, hydrophobicity, and sulfation-related indices in AD. Overall, AD was associated with structured bile acid remodeling, mainly involving conjugated, secondary-derived, and hydrophobic domains. Future mechanistic studies are needed to clarify the biological basis of these bile acid alterations.},
}
@article {pmid42409186,
year = {2026},
author = {Yang, X and Chen, S and Zhang, M and Fan, X and Wang, M and Fan, H},
title = {Global Research Trends and Mechanistic Insights of Sirtuins in Alzheimer's Disease: A Bibliometric and Translational Review.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {112029},
doi = {10.1016/j.brainresbull.2026.112029},
pmid = {42409186},
issn = {1873-2747},
abstract = {BACKGROUND: The sirtuin (SIRT) family of NAD[+]-dependent deacetylases has emerged as a central regulator in Alzheimer's disease (AD)-related pathophysiological pathways. However, the global publication landscape, research hotspots, and translational implications of SIRT-related AD research remain insufficiently integrated.<br><br>METHODS: Publications on sirtuins in AD was conducted in the Web of Science Core Collection database. Bibliometric analysis was performed using CiteSpace (version 6.4.1), VOSviewer (version 1.6.20), bibliometrix R package (https://www.bibliometrix.org), and Scimago Graphica (Version 1.0.46.0) to analyze trends, co-authorship, citation patterns, and research topics.<br><br>RESULTS: A total of 1,141 publications from 62 countries were identified, with 71% being original research articles. The field showed sustained growth with notable acceleration after 2015. China led in publication output (357 articles, 31.3%), while the United States ranked first in total citations (22,190). The University of Barcelona and the University of California System were the most productive institutions. Co-authorship analysis identified 6,019 authors with an average of 6.47 co-authors per document. Co-citation analysis emphasizes the central role of high-impact journals like Nature and PNAS. The thematic evolution in keyword analysis shows a shift from descriptive neurodegeneration studies toward mechanistic research, identifying oxidative stress, SIRT1/SIRT3 signaling, epigenetic regulation, amyloid-&#x3b2;, the mTOR pathway, autophagy, and neurogenesis as major hotspots. Biological interpretation of these hotspots suggests that SIRTs may contribute to AD pathophysiology through oxidative stress regulation, autophagy, epigenetic modulation, neurogenesis, and amyloid-&#x3b2;-related pathways, supporting their potential relevance to molecularly targeted strategies based on preclinical evidence. Citation burst analysis indicated emerging post-2015 interest in NAD&#x207a; metabolism and multi-target therapeutics, while persistent gaps remain in isoform-specific investigations, integrated multi-molecular studies, and robust clinical validation.<br><br>CONCLUSIONS: This study provides a comprehensive bibliometric and translational framework for SIRT-related AD research. Future research should prioritize mechanistic validation, address translational barriers including isoform selectivity and blood-brain barrier permeability, and expand investigation of under-studied SIRT isoforms.},
}
@article {pmid42409396,
year = {2026},
author = {Park, SM and Ko, AJ and Lim, JH and Park, EC},
title = {Income level and the risk of incident dementia among adults aged ≥50 with newly diagnosed type 2 diabetes: a population-based cohort study using the NHIS-Senior database in South Korea.},
journal = {BMJ open},
volume = {16},
number = {7},
pages = {e112641},
doi = {10.1136/bmjopen-2025-112641},
pmid = {42409396},
issn = {2044-6055},
mesh = {Humans ; *Diabetes Mellitus, Type 2/epidemiology/complications ; Republic of Korea/epidemiology ; Female ; Male ; Middle Aged ; *Dementia/epidemiology/etiology ; Aged ; *Income/statistics &amp; numerical data ; Retrospective Studies ; Risk Factors ; Incidence ; Databases, Factual ; Low Socioeconomic Status ; Socioeconomic Disparities in Health ; Sex Factors ; },
abstract = {INTRODUCTION: Type 2 diabetes mellitus (T2DM) is a well-established independent risk factor for dementia and is associated with dementia pathophysiology; however, the role of income level remains uninvestigated in this patient population. The aim of this study was to examine the association between income level and incident dementia risk among adults aged ≥50 years with newly diagnosed T2DM.<br><br>RESEARCH DESIGN AND METHODS: We conducted a retrospective population-based assessment of Korean National Health Insurance Service-Senior Cohort (2002-2019) data. Individuals aged &#x2265;50 years with a new primary or secondary diagnosis of T2DM from 2004 onward were included. Sex and income level were assessed. Subgroup analyses were performed to examine differences in dementia risk across income levels and assess whether associations between income levels and dementia risk varied by dementia subtype.<br><br>RESULTS: Among women with newly diagnosed type 2 diabetes, those in the low-income group showed a significantly higher risk of incident dementia compared with the high-income group (deciles 9-10) (HR=1.19, 95% CI 1.11 to 1.28). In men with newly diagnosed type 2 diabetes, a significant increase in dementia risk was observed only among Medical Aid recipients relative to the high-income group (HR=1.44, 95%&#x2009;CI 1.18 to 1.77). Similarly, women within this patient population showed significantly elevated risks among Medical Aid recipients (HR=1.33, 95%&#x2009;CI 1.11 to 1.61)&#x2009;and those in the first income decile. Subtype analyses further revealed that being a Medical Aid recipient was associated with an increased risk of vascular dementia in men, while lower income levels (including Medical Aid recipients and deciles 1 and 3) were associated with a higher risk of Alzheimer's disease in women all in comparison to their high-income counterparts.<br><br>CONCLUSIONS: Among middle-aged and older adults with newly diagnosed T2DM, having a lower income was significantly associated with elevated dementia risks, with the greatest risk observed among low-income women. The association between income level and dementia risk differed by dementia subtype, with vascular dementia and Alzheimer's disease being more prevalent among low-income men and low-income women, respectively. These findings highlight the need for sex-specific and income-specific dementia prevention strategies.},
}
@article {pmid42409639,
year = {2026},
author = {Zhang, X and Grigoryan, KA and Scherf, N and Wu, Q and Villringer, A and Schroeter, ML and Mueller, K},
title = {Mapping the Heart-Brain Continuum beyond Heart Failure: Why Neurology Matters.},
journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1523/JNEUROSCI.2274-25.2026},
pmid = {42409639},
issn = {1529-2401},
abstract = {To investigate whether cardiac dysfunction predicts further gray matter microstructural integrity and whether this integrity mediates the association with cognitive performance, we conducted a prospective observational cohort study of 73 patients (20 females and 53 males; mean age 54.8 years) from the Leipzig Heart Study. We performed baseline cardiac assessments followed by diffusion-weighted magnetic resonance imaging and cognitive testing after a follow-up of 3.5 years. Participants included patients with established heart failure and matched patients without heart failure presenting with suspected coronary artery disease. We assessed baseline cardiac biomarkers including left ventricular ejection fraction and N-terminal pro-B-type natriuretic peptide. The main outcomes were gray matter microstructural integrity (mean diffusivity) and cognitive performance. Mediation analysis evaluated whether regional mean diffusivity mediated the association between cardiac function and cognition. Across all 73 participants, a lower baseline ejection fraction predicted greater future gray matter mean diffusivity even in patients without clinical heart failure, acting as an early-stage indicator. Conversely, higher natriuretic peptide levels predicted extensive microstructural damage exclusively in the established heart failure group. Notably, increased mean diffusivity in Alzheimer's disease-vulnerable regions (specifically the cingulate and lingual gyri) significantly mediated the association between cardiac health and subsequent memory performance. In conclusion, cardiac dysfunction is associated with a predictable continuum of brain microstructural damage where conventional imaging previously failed. Crucially, this microstructural degradation mediates the link to memory decline, identifying brain microstructural integrity as a high-priority targets for upstream intervention aimed at preserving cognitive health.Significance Statement This study establishes a specific link between cardiac dysfunction and cognitive decline based on microstructural brain alterations. We identify a "heart-brain continuum" where routine cardiac biomarkers predict future brain microstructural damage. Crucially, this microstructural degradation targets Alzheimer's disease-vulnerable regions and acts as the mediator driving memory loss. By validating gray matter mean diffusivity as a sensitive tracker of this progression, our findings underscore that preserving brain microstructural integrity is a critical target in patients with cardiac dysfunction, offering a vital opportunity to intervene upstream before the onset of dementia.},
}
@article {pmid42409643,
year = {2026},
author = {Costa, RKM and Souza, FR and Silva, RDS and Rey, NA and Pimentel, AS},
title = {The Effect of Cu[2+] and Zn[2+] Ions' Nonbonded Interactions on the Aggregation of β-Amyloid 1-16 and 25-35 Fragments─A Molecular Dynamics Simulation Study.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00057},
pmid = {42409643},
issn = {1948-7193},
abstract = {Alzheimer's disease is linked to the formation and accumulation of extracellular β-amyloid aggregates, with toxicity primarily attributed to soluble oligomeric species, as proposed by the oligomeric hypothesis. Concurrently, the metal ion hypothesis suggests that transition metal ions, such as Cu[2+] and Zn[2+], directly modulate the aggregation process and the structural stability of β-amyloid (Aβ) fragments. In this study, molecular dynamics simulations were employed to produce collective variables to investigate the effects of these ions and their concentrations on the aggregation of the β-amyloid 1-16 and 25-35 fragments in aqueous solution for the first time. The free energy profile of aggregation indicates that the presence of Cu[2+] ions slightly decreases the energy associated with the aggregation of the β-amyloid 1-16 fragment, suggesting it acts as a modulator that partially stabilizes the oligomers. In contrast, we report for the first time that Zn[2+] ions do not reduce the energy barrier for the aggregation of the β-amyloid 1-16 fragment in aqueous solution. Zn[2+] displays a higher affinity for the acidic residues of Aβ1-16, establishing more frequent, yet less selective, contacts compared to those observed for Cu[2+] ions. The main finding is that Cu[2+] and Zn[2+] ions modulate the early aggregation pathway of β-amyloid. In particular, at high concentrations, Cu[2+] favors the formation of small, structurally ordered proto-oligomers enriched in antiparallel β-sheets, rather than simply increasing aggregate size, whereas Zn[2+] does not exhibit an analogous effect under the conditions studied. This metal-induced stabilization of β-sheet-rich low-order oligomers, particularly pronounced for Cu[2+], identifies early secondary structure transitions as the primary determinant of amyloid toxicity and a critical molecular event in Alzheimer's disease. The evidence presented in this study enhances our understanding of the oligomeric and metal ion hypotheses of Alzheimer's disease.},
}
@article {pmid42410071,
year = {2026},
author = {Suo, X and Wan, P and Yu, J and Zhu, X and Tian, C and Li, S and Sun, G and Liu, H and Liu, S and Geng, M and Tian, J and Yang, W and Zhang, Y},
title = {The Protective Effects of Small-Molecule Compound 0242 Against LPS-Induced Neuroinflammation and in P301S Tau Transgenic Mice.},
journal = {Neurochemical research},
volume = {51},
number = {4},
pages = {},
pmid = {42410071},
issn = {1573-6903},
support = {2024CXPT029, 2025CXPT011//Key R&amp;D Program of Shandong Province, China/ ; SYS202205//Shandong Laboratory Program/ ; ZR2024QH615//Shandong Provincial Natural Science Foundation/ ; },
mesh = {Animals ; Lipopolysaccharides/toxicity ; Mice, Transgenic ; *tau Proteins/genetics/metabolism ; Female ; *Neuroinflammatory Diseases/chemically induced/metabolism/drug therapy/prevention &amp; control ; Mice ; Microglia/drug effects/metabolism ; *Neuroprotective Agents/therapeutic use/pharmacology ; Alzheimer Disease/drug therapy/metabolism ; Hippocampus/drug effects/metabolism ; Mice, Inbred C57BL ; },
abstract = {Neuroinflammation and tau pathology are central drivers of Alzheimer's disease (AD) progression, necessitating multi-target therapeutic strategies. Here, we evaluated the efficacy and mechanisms of 0242, a novel small-molecule derivative optimized from the berberine scaffold. In lipopolysaccharide (LPS)-stimulated BV-2 microglia, 0242 treatment significantly inhibited cell activation and nitric oxide release without cytotoxicity, while downregulating the mRNA levels of pro-inflammatory cytokines IL-1β and TNF-α. Transcriptomic profiling revealed that 0242 modulated LPS-induced inflammatory gene signatures by enriched core signaling cascades, including NF-κB, TLR, and JAK-STAT and upregulating cytoprotective genes such as ceruloplasmin (Cp) and Bcl2a1b. In vivo, oral administration of 0242 attenuated hippocampal astrocyte and microglial activation in an LPS-induced acute neuroinflammatory mouse model. Furthermore, in female P301S tau transgenic mice, 0242 treatment significantly improved spontaneous locomotor activity and recognition memory. Histological and biochemical analyses confirmed that 0242 suppressed hippocampal glial activation and reduced total tau protein levels in the prefrontal cortex. Collectively, these findings suggest that 0242 may exert potent anti-neuroinflammatory effects by modulating multiple immune signaling cascades and uniquely alleviates tau pathology in AD.},
}
@article {pmid42410083,
year = {2026},
author = {Costello, H and Reeves, S and Glue, P and Young, AH and Howard, R},
title = {Depression in neurodegenerative disease: neurobiological mechanisms and emerging treatments.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42410083},
issn = {1476-5578},
abstract = {Depression is one of the most common and disabling neuropsychiatric complications of neurodegenerative diseases. In Alzheimer's disease (AD) and Parkinson's disease (PD), depressive syndromes affect more than one-third of patients and are associated with accelerated cognitive decline, reduced quality of life, and increased healthcare utilisation. Despite this burden, current antidepressant treatments show little or no efficacy in these populations, suggesting that depression arising in the context of neurodegeneration may reflect distinct underlying neurobiological mechanisms. Emerging evidence from molecular imaging, neuropathology, and cognitive neuroscience indicates disease-specific disruption of monoaminergic, glutamatergic, inflammatory, and reward-related circuits in AD and PD. These alterations may undermine the mechanisms of action of standard antidepressants and contribute to treatment resistance. Yet patients with cognitive impairment are routinely excluded from antidepressant trials, and few high-quality studies have evaluated novel therapies in neurodegenerative disease. In this narrative review, we synthesise current evidence on the neurobiological mechanisms underpinning depression in AD and PD and critically evaluate emerging pharmacological and neuromodulatory therapies targeting glutamatergic, serotonergic, dopaminergic, immune, and circuit-level dysfunction. Here, we highlight that depression in neurodegenerative disease offers a unique and underutilised model for mechanistically guided antidepressant development. We identify how interventions including glutamate modulators, dopaminergic agents, kappa opioid antagonists, immune-modulating therapies, and next-generation brain stimulation approaches may offer therapeutic promise. By aligning treatment development with disease-specific circuit and molecular pathology, this framework may improve outcomes for this neglected population while advancing precision psychiatry more broadly.},
}
@article {pmid42410123,
year = {2026},
author = {Wiseman, S},
title = {Glycosylation in Alzheimer's disease.},
journal = {Nature neuroscience},
volume = {29},
number = {7},
pages = {1528},
doi = {10.1038/s41593-026-02373-2},
pmid = {42410123},
issn = {1546-1726},
}
@article {pmid42410180,
year = {2026},
author = {Rudroff, T},
title = {The dual diversity crisis in alzheimer's disease research: why neuroimaging biomarkers and clinical trials keep failing.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42410180},
issn = {2509-2723},
abstract = {Alzheimer's disease clinical trials have failed at a rate exceeding 99% over two decades, and neuroimaging biomarkers developed in discovery cohorts have repeatedly disappointed in validation and clinical application. Standard explanations address symptoms rather than structural causes. I argue that Alzheimer's disease research is caught in a Dual Diversity Crisis: the simultaneous neglect of population diversity and individual neurobiological heterogeneity as compounding validity threats. The first dimension concerns the systematic over-reliance on Western, young, healthy, and university-affiliated (WYHU) research samples, from which biomarker normative standards are derived and then applied universally to a demographically distinct clinical population. The second concerns the erasure, through group-level analysis, of the substantial neurobiological heterogeneity that exists within any sample regardless of its demographic composition. The critical structural insight is that these two problems do not add; they multiply. A WYHU-derived group average is doubly unrepresentative: it misrepresents the target population demographically and conceals the individual variance that exists even within that already-unrepresentative sample. FDG-PET evidence demonstrates that biological sex accounts for approximately 30 times more metabolic variance than diagnostic category in patients with equivalent symptom profiles, directly challenging the construct validity of threshold-based trial inclusion. Correcting the Dual Diversity Crisis requires treating demographic diversity and individual neurobiological characterization as primary design parameters, not post-hoc corrections. Until this reconceptualization occurs, translational failure in Alzheimer's disease research remains the structurally expected outcome.},
}
@article {pmid42410183,
year = {2026},
author = {de Oliveira Portugal Couto, C and Hass das Eiras, ML and Juliao de Morais, JL and Leal Cordeiro Júnior, CW and Forlenza, OV and de Jesus Rodrigues de Paula, V},
title = {Chronic Lithium Exposure Reshapes PI3K-mTOR-linked Proteostatic Networks in the Hippocampus of an Alzheimer's Disease Mouse Model.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42410183},
issn = {1559-1182},
mesh = {Animals ; *Hippocampus/metabolism/drug effects/pathology ; *Alzheimer Disease/metabolism/drug therapy/pathology ; *Phosphatidylinositol 3-Kinases/metabolism ; Mice, Transgenic ; Disease Models, Animal ; *TOR Serine-Threonine Kinases/metabolism ; *Lithium/pharmacology/administration &amp; dosage/therapeutic use ; Signal Transduction/drug effects ; Protein Interaction Maps/drug effects ; Proteomics ; Mice ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β deposition, tau pathology, and alterations in signaling pathways involved in neuronal survival and protein homeostasis. Lithium has been suggested as a potential neuroprotective treatment, but the molecular mechanisms associated with its long-term effects are still not fully understood. In this study, we investigated the effects of chronic lithium treatment on hippocampal proteins associated with PI3K-related signaling in triple-transgenic Alzheimer's disease (3xTg-AD) mice. Wild-type and transgenic animals received either a lower or higher lithium dose for eight months. Hippocampal samples were analyzed by LC-MS/MS proteomics followed by protein interaction and functional enrichment analyses. From a total of 7768 identified proteins, bioinformatic analyses identified 157 proteins shared between APP-, MAPT-, and PI3K-associated datasets. Further network analyses identified 18 proteins related to PI3K signaling, including seven proteins shared among all three datasets: FKBP1A, HSPA1B, HSPA8, RAS-related proteins, RPL13, RPL19, and RPL24. These proteins are associated with protein folding, translation regulation, cellular stress responses, and signaling pathways. Chronic lithium treatment was associated with changes in the expression of these proteins in both wild-type and transgenic animals. The observed effects differed between the two lithium concentrations tested and did not follow a simple linear pattern. Our findings suggest that long-term lithium exposure is associated with changes in molecular networks related to proteostasis and translational regulation in the hippocampus. Although additional studies are needed to better understand the mechanisms involved, these results provide a proteomic framework for investigating lithium-sensitive pathways that may be relevant to Alzheimer's disease.},
}
@article {pmid42410250,
year = {2026},
author = {Rana, JK and Pinarbasi, ES and Fernandez, MG and Navratna, V and Conway, KS and Lieberman, AP and Barmada, SJ and Mosalaganti, S},
title = {CTE-type tau filaments in Alzheimer's disease with co-morbid LATE-NC.},
journal = {Acta neuropathologica},
volume = {152},
number = {1},
pages = {},
pmid = {42410250},
issn = {1432-0533},
support = {R01NS097542/NH/NIH HHS/United States ; 1DP2GM150019/NH/NIH HHS/United States ; },
}
@article {pmid42410282,
year = {2026},
author = {Festa, N and Alexovitz, K and Sifnugel, N and Cohen, I and Faustino, IV and Khasnavis, S and Young, J and Iscoe, M and Mecca, AP and Han, L and Hwang, U},
title = {Assigning Probable Dementia Status Using Routinely Collected Electronic Health Record Data.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70562},
pmid = {42410282},
issn = {1532-5415},
support = {KL2TR001862/NH/NIH HHS/United States ; P30AG021342/AG/NIA NIH HHS/United States ; P30AG073104/AG/NIA NIH HHS/United States ; R03AG088893/AG/NIA NIH HHS/United States ; R33AG069822/AG/NIA NIH HHS/United States ; },
abstract = {INTRODUCTION: More than half of older adults with Alzheimer's Disease and Related Dementias (ADRD) are undiagnosed, limiting timely access to person-centered care. Therefore, clinicians, researchers, and population health managers need scalable, reproducible approaches to monitor both prevalence and diagnostic gaps. We evaluated whether a decision-analytic modeling framework can translate a limited number of clinician-adjudicated cases of ADRD into a probabilistic computational phenotype for accurate, population-level assignments of probable ADRD in the emergency department (ED) setting using routinely collected electronic health record (EHR) data.<br><br>METHODS: Retrospective cohort study of 5000 adults aged &#x2265;&#x2009;65&#x2009;years from nine EDs within a large integrated health system (2014-2022). We randomly selected 500 individuals for clinician adjudication of dementia status (reference cohort), reserving the remaining 4500 as a phenotyping cohort. We developed the phenotype as a logistic regression model trained on adjudicated cases, embedding pattern-mixture multiple imputation to address information bias. We applied decision-curve analysis to evaluate clinical utility across probabilistic thresholds. We applied the phenotype to assign dementia status to 4500 unadjudicated patients and compared clinical characteristics to adjudicated cases.<br><br>RESULTS: The mean (SD) age was 77.4 (9.0) years; 55.4% were women; 102 individuals (20.4%) had clinician-adjudicated ADRD. The model demonstrated good discrimination (AUROC 0.87; 95% CI 0.82-0.91). Decision-curve analysis revealed net clinical benefit across examined thresholds (predicted probabilities 12%-32%), identifying an additional 16-18 probable ADRD cases per 100 older adults. Among those without ADRD-related diagnosis codes, net benefit ranged from 8 to 13 additional correct identifications per 100. Phenotype-assigned cases closely resembled clinician-adjudicated cases (standardized mean differences &#x2264;&#x2009;0.20).<br><br>CONCLUSIONS: A probabilistic computational phenotype derived from routinely collected EHR data accurately reproduced clinician-adjudicated ADRD status and demonstrated net clinical benefit, including among ED patients whose ADRD was not captured by diagnosis codes. Adoption of this replicable framework may enable healthcare organizations to strengthen ADRD surveillance and reduce underdiagnosis.},
}
@article {pmid42410293,
year = {2026},
author = {Kumar, RR and Kamaljeet, and Kosey, S},
title = {Neuroinflammation in neurodegenerative diseases: pathogenic pathways and emerging pharmacotherapeutic targets in Alzheimer's and Parkinson's disease.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42410293},
issn = {1568-5608},
abstract = {Neuroinflammation is now widely recognized as a key contributor to the initiation and progression of neurodegenerative diseases, particularly Alzheimer's disease (AD) and Parkinson's disease (PD). Chronic activation of brain-resident immune cells, including microglia and astrocytes, in response to misfolded protein aggregates such as amyloid-β and tau in AD and α-synuclein in PD, promotes maladaptive immune signaling, sustained cytokine release, and disruption of the blood-brain barrier (BBB). This chronic brain inflammation leads to synaptic dysfunction, neuronal loss and ultimately clinical deterioration. These processes are accompanied by disease-specific factors, such as inflammation of the gut-brain axis in PD and genetic modulators including APOE4, TREM2, and LRRK2. Furthermore, the development of fluid biomarkers together with neuroimaging techniques has improved early detection and monitoring of neuroinflammation leading to personalized therapeutic approaches. Clinical trials targeting microglial phenotypes, cytokine signaling, inflammasome activity, and genetic risk factors are emerging therapeutic strategies. Model limitations and heterogeneity of patients present challenges, but insights into neuroimmune interactions could provide a path forward for disease-modifying strategies. The present review aims to summarize new knowledge about the protective and detrimental aspects of neuroinflammation in AD and PD, providing an analysis on these developing prospects for targeted interventions toward slowing or stopping neurodegeneration.},
}
@article {pmid42410536,
year = {2026},
author = {Lim, CY and Sim, Y and Lee, YG and Ye, BS and Sohn, B},
title = {Comparative evaluation of automated MRI-based brain volumetry software for estimating cognitive domains in early Alzheimer's disease.},
journal = {BMC medical imaging},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12880-026-02535-5},
pmid = {42410536},
issn = {1471-2342},
support = {SMO124041//Samsung Medical Center/ ; RS-2023-00237618//National Research Foundation of Korea/ ; IIS-KR-0045//Bracco Imaging Korea/ ; },
abstract = {BACKGROUND: Brain volumetry software is widely accepted for assessment in Alzheimer's disease. However, direct comparisons for software-specific prediction capabilities across cognitive domains have not been reported. This study evaluates the performance of four brain volumetry software programs in predicting domain-specific cognitive scores in patients with early Alzheimer's disease (AD) using a consistent deep learning model.<br><br>METHODS: A total of 255 patients with amyloid PET-confirmed AD were retrospectively enrolled. Brain volumetric features were extracted from 3D T1-weighted MRI using four software programs (AQUA, DeepBrain, A-finder, and FreeSurfer). A multi-layer perceptron model incorporating seven clinical variables and software-specific volumetric features was trained to predict six cognitive outcomes: the Mini-Mental State Examination (MMSE) score and five Seoul Neuropsychological Screening Battery (SNSB) domain scores. Model performance was evaluated using mean squared error and Pearson's correlation coefficient (r).<br><br>RESULTS: The FreeSurfer-based model showed the numerically highest correlation for MMSE (r&#x2009;=&#x2009;0.56), language (r&#x2009;=&#x2009;0.38), visuospatial (r&#x2009;=&#x2009;0.21), and frontal/executive functions (r&#x2009;=&#x2009;0.32). The AQUA-based model showed the numerically highest correlation for attention (r&#x2009;=&#x2009;0.40), and DeepBrain for memory (r&#x2009;=&#x2009;0.38). MMSE scores were generally better predicted than domain-specific scores across all models.<br><br>CONCLUSION: Brain volumetry software showed modest, domain-dependent associations with cognitive scores in early AD, with the strongest signal for MMSE and no statistically significant prediction for visuospatial function. These findings support the potential of brain volumetry software to partially estimate domain-level cognitive profiles, while differences across software should be interpreted with caution rather than as evidence of intrinsic software superiority.},
}
@article {pmid42410640,
year = {2026},
author = {Gambacorta, N and Trisciuzzi, D and Mastrolorito, F and Leonetti, F and Altomare, CD and de Candia, M and Catto, M and Amoroso, N and Ciriaco, F and Nicolotti, O},
title = {MINERVA: a public XAI-powered platform advancing multi-target discovery in Alzheimer's disease.},
journal = {Journal of cheminformatics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13321-026-01253-y},
pmid = {42410640},
issn = {1758-2946},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder involving a complex interplay of interconnected pharmacological targets, a feature that limits the success of traditional single-target medicinal chemistry approaches. Here, we present MINERVA (Multi-target Interactive Network for Explainable Research and Visualization in Alzheimer's disease), a public web-based platform designed to support multi-target drug discovery assisted by eXplainable Artificial Intelligence (XAI) strategies. MINERVA integrates large-scale disease-focused high-quality data comprising as many as 70,960 small molecules annotated across 33 AD relevant targets, taken from ChEMBL and CADRO databases. To capture different levels of pharmacological relevance, four distinct pharmacological thresholds (i.e., 10 μM, 1 μM, 100 nM, and 10 nM) were set to enable the parallel exploration of weak to high-affinity ligand spaces. Independent Balanced Random Forest (BRF) classifiers were trained for each AD target threshold combination using an extended core-substituent fingerprint, which ensures robustness against class imbalance and chemical heterogeneity. MINERVA incorporates a probability binning based domain of applicability (DoA) to quantify prediction reliability and a SHAP-based explainability framework to fairly map fragment-level contributions directly onto chemical structures. MINERVA is freely accessible at https://prometheus.farmacia.uniba.it/minerva/.Scientific contributionHerein we introduce MINERVA, the first freely accessible platform that combines large-scale AD-related data curation, multi-target prediction, and multi-threshold bioactivity modeling within a fully explainable and user-friendly environment. By enabling transparent, ligand-based exploration of chemical space across multiple AD pathways, MINERVA provides a unique and practical resource for accelerating multi-target drug discovery in the neurodegenerative research area.},
}
@article {pmid42410680,
year = {2026},
author = {Stocks, J and Barbieri, E and Los, MA and Thompson, CK and Gefen, T and Geula, C and Mesulam, MM and Weintraub, S},
title = {Neuropathology-specific language features in primary progressive aphasia.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71633},
doi = {10.1002/alz.71633},
pmid = {42410680},
issn = {1552-5279},
support = {5R01AG077444/NH/NIH HHS/United States ; P30AG072977/NH/NIH HHS/United States ; P30AG013854/NH/NIH HHS/United States ; R01AG062566/NH/NIH HHS/United States ; //the Florane and Jerome Rosenstone Fellowship/ ; //the Karen Toffler Charitable Trust/ ; },
mesh = {Humans ; *Aphasia, Primary Progressive/pathology ; Male ; Aged ; Female ; Alzheimer Disease/pathology ; Aged, 80 and over ; Neuropsychological Tests ; Pick Disease of the Brain/pathology ; Supranuclear Palsy, Progressive/pathology ; Middle Aged ; Corticobasal Degeneration/pathology ; Tauopathies/pathology ; *Language ; Brain/pathology ; },
abstract = {INTRODUCTION: Primary Progressive Aphasia (PPA) clinical syndromes do not align consistently with underlying pathology. This study aimed to identify language markers for specific neuropathologies using both standard clinical tests and narrative speech analysis.<br><br>METHODS: We analyzed data from 82 autopsy-confirmed PPA cases, including Alzheimer's disease (AD), transactive DNA-binding protein 43 (TDP-43) type C (TDP-C), Pick's disease, and 4R-tauopathies (progressive supranuclear palsy/ cortico-basal degeneration (PSP/CBD). Linear mixed-effects regression was used to analyze performance on standardized aphasia tests and narrative speech variables.<br><br>RESULTS: TDP-C showed severe semantic deficits but high fluency, while AD was distinguished by impaired repetition. Narrative analysis differentiated 4R-Tauopathies: CBD patients demonstrated significantly poorer syntax and irregular verb inflection than PSP or Pick's, whereas PSP showed the lowest fluency.<br><br>DISCUSSION: While standard tests effectively capture lexical-semantic features in AD and TDP-C, narrative measures reveal subtle grammatical and fluency differences critical for distinguishing specific tauopathies. This study outlines a more robust approach for predicting underlying pathology in PPA.},
}
@article {pmid42410707,
year = {2026},
author = {Bindra, S and Pandian, R and Mathew, B and Anal, JMH},
title = {Quinoxaline-Based Monoamine Oxidase Inhibitors: Design Strategies, Synthesis, Structure-Activity Relationships, and Therapeutic Potential in Neurological Disorders: A Review From 1996 to 2026.},
journal = {ChemMedChem},
volume = {21},
number = {13},
pages = {e70330},
doi = {10.1002/cmdc.70330},
pmid = {42410707},
issn = {1860-7187},
mesh = {*Monoamine Oxidase Inhibitors/chemistry/chemical synthesis/pharmacology/therapeutic use ; *Quinoxalines/chemistry/pharmacology/chemical synthesis/therapeutic use ; Structure-Activity Relationship ; Humans ; *Monoamine Oxidase/metabolism ; *Drug Design ; *Nervous System Diseases/drug therapy/metabolism ; Molecular Structure ; Animals ; },
abstract = {Monoamine oxidases (MAOs) are key enzymes involved in the metabolism of neurotransmitters and play a significant role in the pathophysiology of neurological disorders such as depression, Parkinson's disease, and Alzheimer's disease. Inhibition of MAOs, particularly MAO-A and MAO-B, has emerged as a promising therapeutic strategy. Quinoxaline is an emerging scaffold with promising biological activities against various molecular targets, owing to its rich repertoire of bioactive molecules. Due to their favorable pharmacological profiles and structural versatility, quinoxaline derivatives have gained considerable attention among the various scaffolds explored. This review highlights rational design strategies for developing quinoxaline-based MAO inhibitors, focusing on structure-activity relationships (SARs) that govern their potency and selectivity. Modifications at specific positions of the quinoxaline ring system and the nature of substituents have demonstrated significant impacts on MAO-A versus MAO-B selectivity, metabolic stability, and blood-brain barrier permeability. This review primarily focuses on elucidating recent advancements in quinoxaline scaffolds targeting MAO inhibitors, including structural developments, structural-activity relationships (SAR), and potential therapeutic applications in neurological disorders, to help researchers develop a new generation of MAO inhibitors.},
}
@article {pmid42410730,
year = {2026},
author = {Lorenz, AS and Sathe, A and Yang, Y and Durant, A and Wu, Y and Kim, ME and Gao, C and Newlin, NR and Ramadass, K and Kanakaraj, P and Khairi, NM and Li, Z and Yao, T and Huo, Y and Dumitrescu, L and Shashikumar, N and Pechman, KR and Risacher, SL and Beason-Held, LL and An, Y and Arfanakis, K and Erus, G and Davatzikos, C and Habes, M and Wang, D and Tosun, D and Toga, AW and Thompson, PM and Mormino, EC and Zhang, P and Schilling, K and Albert, M and Kukull, W and Biber, SA and Landman, BA and Johnson, SC and Bendlin, B and Schneider, J and Bennett, DA and Jefferson, AL and Resnick, SM and Saykin, AJ and Below, JE and Hohman, TJ and Archer, DB and , and , and , },
title = {Genetic architecture of the limbic white matter microstructure in aging and Alzheimer's Disease.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71630},
doi = {10.1002/alz.71630},
pmid = {42410730},
issn = {1552-5279},
support = {K01-EB03289/NH/NIH HHS/United States ; R01-EB017230/NH/NIH HHS/United States ; R01-AG074339/NH/NIH HHS/United States ; P30-AG066515/NH/NIH HHS/United States ; K01-AG073584/NH/NIH HHS/United States ; U24-AG074855/NH/NIH HHS/United States ; 75N95D22P00141/NH/NIH HHS/United States ; R01-AG059716/NH/NIH HHS/United States ; UL1-TR000445/NH/NIH HHS/United States ; UL1-TR002243/NH/NIH HHS/United States ; R01-AG034962/NH/NIH HHS/United States ; R01-AG056534/NH/NIH HHS/United States ; U19-AG03655/NH/NIH HHS/United States ; NIAAG021155/NH/NIH HHS/United States ; NIAAG027161/NH/NIH HHS/United States ; NIAAG037639/NH/NIH HHS/United States ; NIAAG054047/NH/NIH HHS/United States ; U01AG024904/NH/NIH HHS/United States ; 26PRE1558066//American Heart Association/ ; IIRG-08-88733/ALZ/Alzheimer's Association/United States ; },
mesh = {Humans ; *Alzheimer Disease/genetics/pathology/diagnostic imaging ; *Aging/genetics/pathology ; *White Matter/pathology/diagnostic imaging ; Genome-Wide Association Study ; Female ; Male ; Aged ; *Limbic System/pathology/diagnostic imaging ; Polymorphism, Single Nucleotide ; Aged, 80 and over ; Diffusion Magnetic Resonance Imaging ; },
abstract = {INTRODUCTION: Limbic white matter (WM) abnormalities are prevalent in aging and Alzheimer's disease (AD), but genetic drivers are unclear.<br><br>METHODS: In 2614 older adults (mean age &#xb1; SD: 73.7 &#xb1; 9.8 years; 26% cognitively impaired) from seven harmonized cohorts enriched for cognitive impairment, we quantified free-water-corrected diffusion MRI (dMRI) metrics in seven limbic tracts. We estimated single nucleotide polymorphism (SNP) heritability, performed cohort genome-wide association studies (GWASs) with meta-analysis, evaluated shared genetic architecture and enriched pathways, and assessed AD relevance using brain RNA-seq data.<br><br>RESULTS: Limbic WM is heritable (h[2] = 0.26-0.60; pFDR < 0.05). Meta-GWAS identified six loci (p < 5 &#xd7; 10[-] [8]), including a signal implicating CDH19, an oligodendrocyte-enriched cell-adhesion gene. Additional loci were near the KC6, SENP5, RORA, FAM107B, and MIR548A1 genes. In brain tissue, RORA, FAM107B, and KC6 expression was associated with cognition and AD neuropathology. Results converged on insulin and immune biology and shared genetic architecture with lipid and cardiovascular traits.<br><br>DISCUSSION: Limbic WM microstructure is genetically influenced and links oligodendrocyte and vascular-inflammatory biology to AD-relevant outcomes.},
}
@article {pmid42411051,
year = {2026},
author = {Chen, HJ and Guo, Y and Huang, W and Hu, A and Liu, T and Chen, F},
title = {Glymphatic dysfunction associates with regional white matter hyperintensities and plasma amyloid-β burden across the Alzheimer's disease continuum.},
journal = {Psychological medicine},
volume = {56},
number = {},
pages = {e220},
doi = {10.1017/S0033291726105005},
pmid = {42411051},
issn = {1469-8978},
mesh = {Humans ; *Alzheimer Disease/blood/physiopathology/diagnostic imaging/pathology ; *Amyloid beta-Peptides/blood ; Female ; Male ; *White Matter/diagnostic imaging/pathology ; *Glymphatic System/physiopathology/diagnostic imaging ; Aged ; *Cognitive Dysfunction/blood/physiopathology/diagnostic imaging/pathology ; Diffusion Tensor Imaging ; *Cerebral Small Vessel Diseases/diagnostic imaging/physiopathology ; Biomarkers/blood ; Magnetic Resonance Imaging ; Prospective Studies ; Middle Aged ; },
abstract = {BACKGROUND: Glymphatic system dysfunction has been increasingly implicated in Alzheimer's disease (AD), yet its relationships with cerebral small vessel disease (CSVD), plasma biomarkers, and cognitive impairment across the AD remain incompletely understood.<br><br>METHODS: We prospectively recruited 216 participants from Hainan General Hospital, including healthy controls (HC), individuals with subjective cognitive decline (SCD), mild cognitive impairment (MCI), and AD dementia. All participants underwent brain magnetic resonance imaging, plasma biomarker testing, and neuropsychological assessments. White matter hyperintensity (WMH) volume from T2-weighted fluid-attenuated inversion recovery images served as a marker of CSVD. The diffusion tensor image analysis along the perivascular space (DTI-ALPS) index assessed glymphatic function. Plasma amyloid &#x3b2;-protein (A&#x3b2;) concentrations measured peripheral A&#x3b2; levels as a surrogate indicator of amyloid pathology.<br><br>RESULTS: The ALPS index was significantly lower in AD patients compared with HC, SCD, and MCI groups (all P&#xa0;<&#xa0;0.01) and tended to be lower in the MCI group relative to SCD. After controlling for demographics and APOE4 status, ALPS positively correlated with the plasma A&#x3b2;42/A&#x3b2;40 ratio (r&#xa0;=&#xa0;0.16, P&#xa0;=&#xa0;0.038). ALPS index showed significant negative correlations with log-transformed juxtaventricular and juxtacortical WMH volumes (r&#xa0;=&#xa0;-0.32, P&#xa0;<&#xa0;0.001; r&#xa0;=&#xa0;-0.19, P&#xa0;=&#xa0;0.010), with marginal correlation for periventricular WMH (r&#xa0;=&#xa0;-0.13, P&#xa0;=&#xa0;0.052).<br><br>CONCLUSION: Plasma A&#x3b2; levels and regional WMH burden are associated with glymphatic dysfunction as indicated by reduced ALPS. Impaired glymphatic clearance also correlates with cognitive impairment, providing theoretical support for novel pathophysiological hypotheses and potential therapeutic targets in AD pathogenesis.},
}
@article {pmid42411077,
year = {2026},
author = {Singh, P and Bhardwaj, S and Nagarajan, K},
title = {A Review on the Mechanisms of Neurodegeneration and the Potential of Plant Bioactives in Managing Neurological Conditions.},
journal = {Current aging science},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118746098388719251206111338},
pmid = {42411077},
issn = {1874-6128},
abstract = {Neurodegenerative disorders encompass a wide range of debilitating neurological conditions characterized by the progressive loss of specific neuronal populations in the central and/or peripheral nervous systems. This disease often leads to a gradual decline in cognitive, motor, and sensory abilities. This review explores the role of various lifestyle factors, such as age, sex, poor diet, depression, etc., which contribute to the onset and progression of NDDs. Various diseases are included in the neurodegenerative disorder, like Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, Multiple Sclerosis, and Lewy body disease, which are chronic conditions that significantly impact cognitive and motor functions. A literature search was conducted in the scientific database using the keywords "neurodegenerative disorders, phytoconstituents, and herbals". This review includes a collection of reports from ScienceDirect, Scholar Google, and PubMed, all searched up to 2024. The results were assessed, gathered, and reported in this paper. A total of 241 articles were included, with exponential growth in publication numbers from 1985 to 2024. Effective management and control of NDDs require addressing these risk factors, alongside exploring therapeutic interventions. Some plants and herbs used to treat neurodegenerative diseases, such as curcumin, ashwagandha, ginkgo biloba, epigallocatechin-3-gallate, quercetin, ginseng, and resveratrol, have shown potential to improve neuronal health and mitigate disease progression. This review highlights the dual role of natural compounds in promoting improvements and upregulating brain function while potentially reducing degradation. The phytopharmaceuticals show the potential for treating neurological conditions with better efficacy and safer profiles. The review suggested that future research should focus on integrating lifestyle modifications and natural therapies to enhance the quality of life for individuals at risk or suffering from neurodegenerative diseases.},
}
@article {pmid42411090,
year = {2026},
author = {Cabrera, J and Fuentealba, D and Montecinos, D and Caballero, J and Areche, C and Caballero, L and Melo, F and Cornejo, A},
title = {Barbatolic Acid Prevents Tau and Amylin Interaction and Stimulates the Growth of Acetylated Microtubules in Cell Culture.},
journal = {Current drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113894501474373260623073848},
pmid = {42411090},
issn = {1873-5592},
abstract = {INTRODUCTION: Neurodegenerative disorders, including Alzheimer's disease and related tauopathies, involve tau aggregates that correlate closely with cognitive decline. Clinical evidence indicates that patients with type 2 diabetes-characterized by amylin accumulation-experience exacerbated neurodegenerative symptoms, suggesting a cooperative pathologic effect between both proteins.<br><br>METHODS: Using isothermal titration calorimetry, fluorimetry, intrinsic fluorescence, molecular docking, cell culture, and confocal microscopy, we characterized the hydrophobic interactions driving the tau-amylin relationship and evaluated the efficacy of small molecules to inhibit these interactions and protect microtubule stability.<br><br>RESULTS: Tau and amylin co-assemble into morphologically distinct amyloid structures driven by hydrophobic interactions. Notably, barbatolic acid and divaricatic acid effectively disrupt this interprotein interaction. In Neuro2a (N2a) cell cultures, barbatolic acid promoted neuronal differentiation more effectively than retinoic acid. Furthermore, N2a cells exposed to tau aggregates pre-treated with barbatolic acid maintained intact acetylated microtubule networks, indicating a protective role in preserving cytoskeletal stability.<br><br>DISCUSSION: The tau-amylin interaction can be disrupted by barbatolic and divaricatic acid via interference with key lysine residues, offering a plausible therapeutic strategy to mitigate aggregate toxicity. Additionally, the unique ability of barbatolic acid to preserve and promote stable microtubule formation reveals a novel dual mechanism of action.<br><br>CONCLUSION: Because current treatments for neurodegenerative diseases remain palliative, developing multi-target compounds with these dual characteristics offers a promising path forward in pharmacophore design.},
}
@article {pmid42411093,
year = {2026},
author = {Afolabi, BL and Ajibola, AA and Adeyanju, AA and Akanji, MA and Adeyemi, OS},
title = {Revisiting Alzheimer's Disease Mechanisms: Amyloid Dynamics, and Emerging Insights.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050395410251029173713},
pmid = {42411093},
issn = {1875-5828},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by synaptic dysfunction, glial cell activation, and deterioration of neurons. Multiple pathways contribute to its pathophysiology, including β-amyloid (Aβ) plaque formation, intracellular neurofibrillary tangles, oxidative neuronal damage, and inflammatory responses. While Aβ deposition is considered an early trigger in the disease cascade, clinical symptom progression correlates more strongly with tau pathology and inflammatory responses. Recent concerns over data integrity in several high-profile AD studies have prompted critical re-evaluations of widely accepted hypotheses, emphasizing the urgent need for scientific transparency, reproducibility, and independent validation. In compiling this review, we prioritized findings supported by converging evidence from multiple experimental approaches and replication across independent cohorts. The hypothesis that an imbalance between Aβ42 synthesis and clearance is a central factor in AD has gained support from recent evidence, despite ongoing debate over the amyloid β-protein hypothesis. Dominant mutations associated with early-onset AD are primarily found in the amyloid precursor protein, which serves as the substrate for Aβ production, or in presenilin, the protease responsible for Aβ formation. The identification of presenilin as the catalytic site for β-secretase has provided crucial insights into AD pathogenesis. This review synthesizes current understanding of AD mechanisms, highlights emerging insights from multi-omics and spatial transcriptomic technologies, and discusses the evolving therapeutic landscape. Despite setbacks, the field continues to advance through methodological innovation and a revived interest in AD research integrity, offering hope for early diagnosis, more targeted treatments, and ultimately, disease-modifying therapies.},
}
@article {pmid42411214,
year = {2026},
author = {Ibrahim, MA and Baiomy, AAA and Khalil, HA and Anwar, MM and Mohamed, AS},
title = {Neuroprotective Role of Echinochrome in Aluminium Chloride-induced Alzheimer's Disease in Rats.},
journal = {Current neurovascular research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672026474798260627120211},
pmid = {42411214},
issn = {1875-5739},
abstract = {INTRODUCTION: Alzheimer's Disease (AD) is the foremost neurodegenerative disorder and a variant of dementia observed in clinical environments. Echinochrome is a potent antioxidant and a natural bioproduct derived from sea urchins. The current study investigates the neuroprotective efficacy of echinochrome against aluminium chloride-induced AD in rats.<br><br>METHODS: AD was induced using AlCl3 at a dosage of 200 mg/kg over a duration of four weeks, and the experimental design had four groups. The control group, AD group, and echinochrome were administered at 0.1 mg/kg and 1 mg/kg via intraperitoneal injection for 4 weeks.<br><br>RESULTS: The administration of echinochrome led to a decrease in escape latency time in the Morris maze, as well as reductions in malondialdehyde, nitric oxide, amyloid beta, tau protein, and acetylcholinesterase activity, while increasing levels of dopamine, serotonin, epinephrine, norepinephrine, glutathione, catalase, glutathione-S-transferase, and hippocampal histology. Moreover, echinochrome reinstates normal hippocampal histology, augmenting the number of pyramidal cells in the Cornuammonis area, as well as granular cells in the dentate gyrus region.<br><br>DISCUSSION: The administration of echinochrome to AD rats resulted in a reduction of escape latency time of the Morris maze, oxidative stress, amyloid beta, and Tau, while also restoring normal neurotransmitter levels and hippocampal histology.<br><br>CONCLUSION: Echinochrome exhibits neuroprotective properties against aluminium chloride-induced AD. The neuroprotective mechanisms of echinochrome include reducing oxidative stress, preventing the accumulation of amyloid beta and tau proteins, and suppressing acetylcholinesterase activity.},
}
@article {pmid42411221,
year = {2026},
author = {Sharma, A and Kaur, A and Khan, J and Pandey, H},
title = {Phyto-Nanotherapeutics for Alzheimer's Disease: Current Progress and Future Perspectives.},
journal = {Central nervous system agents in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715249455878260609100548},
pmid = {42411221},
issn = {1875-6166},
abstract = {Alzheimer's Disease (AD) is a prevalent neurodegenerative disorder characterized by progressive cognitive and behavioral impairment and represents a major cause of dementia worldwide. It primarily affects the elderly population. The disease is marked by progressive neuronal damage, leading to impairments in cognition, behavior, emotions, and communication. Although currently available therapies provide symptomatic relief, they fail to alter disease progression, necessitating the development of more effective therapeutic strategies. Phytoconstituents have gained considerable attention due to their neuroprotective properties and multitargeted mechanisms of action against pathways implicated in AD. However, their clinical application is limited by poor Blood-Brain Barrier (BBB) permeability, low bioavailability, and inadequate solubility. Nanotechnology offers a promising approach for brain-targeted drug delivery by enhancing the therapeutic efficacy of phytoconstituents through advanced nanocarrier systems. This review explores the synergistic potential of phytoconstituents and nanocarriers for the management of AD, aiming to improve therapeutic outcomes and overcome existing limitations. It further highlights the integration of medicinal plant-based compounds with nanotechnology as a novel strategy for AD treatment. The combination of nanocarriers and phytoconstituents may facilitate enhanced BBB penetration and improved neuroprotection. Notably, nanomedicine- based approaches, including phytoconstituent-loaded nanoparticles and liposomes, demonstrate significant potential to overcome delivery barriers and enable efficient drug transport to the brain.},
}
@article {pmid42411229,
year = {2026},
author = {Hu, Z and Su, Y and Xi, J and Li, J},
title = {Diagnostic Accuracy of Plasma p-tau181 Measured Using Automated Chemiluminescent Immunoassays for Alzheimer's Disease: A Systematic Review and Meta-Analysis.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050477953260623073513},
pmid = {42411229},
issn = {1875-5828},
abstract = {INTRODUCTION: To evaluate the diagnostic accuracy of plasma p-tau181 measured on fully automated immunoassay platforms for detecting Alzheimer's Disease (AD), and to determine how performance varies according to the reference standard used to define AD pathology.<br><br>MATERIALS AND METHODS: A systematic search was conducted across major databases for studies reporting the diagnostic accuracy of plasma p-tau181. Eligible studies enrolled adults across the Alzheimer's disease continuum and applied either CSF A&#x3b2;42/40, combined CSF A&#x3b2;42/40 and ptau181, or clinical diagnostic criteria as the reference standard. Data were synthesized using random- effects models. HSROC modeling was applied to estimate pooled sensitivity, specificity, and AUC.<br><br>RESULTS: A total of 19 studies involving 4266 participants were included. Most studies (18/19) used the Lumipulse platform, whereas only 1 study used Elecsys. Therefore, the pooled estimates mainly reflect Lumipulse-based evidence. Pooled sensitivity and specificity were 0.81 and 0.77 (AUC 0.84) when CSF A&#x3b2;42/40 defined amyloid pathology. When combined, CSF amyloid and tau positivity was required; sensitivity and specificity were 0.83 and 0.78 (AUC 0.86). Using clinical diagnostic criteria, pooled sensitivity reached 0.92, with a specificity of 0.78 (AUC 0.84). However, these subgroup estimates should be interpreted cautiously because substantial between-study heterogeneity remained, and some subgroups contained only a small number of datasets.<br><br>DISCUSSION: P-tau181 measured by automated chemiluminescent immunoassays showed promising diagnostic performance across reference standards, but the summary estimates are influenced by substantial heterogeneity and should not be interpreted as universally transferable measures of performance.<br><br>CONCLUSION: The results support plasma p-tau181 as a promising scalable biomarker for AD. However, because the available evidence is predominantly derived from Lumipulse-based studies, it remains insufficient to determine whether comparable performance extends to other automated CLIA platforms.},
}
@article {pmid42411439,
year = {2026},
author = {Zhu, J and Xie, H and Ouyang, Y and Zhu, T and Liu, Q and Liu, W and Xiong, S and Liu, M},
title = {Exploring the Microbiome-Kynurenine Axis in Mild Cognitive Impairment: From Gut to Brain.},
journal = {Journal of integrative neuroscience},
volume = {25},
number = {6},
pages = {48660},
doi = {10.31083/JIN48660},
pmid = {42411439},
issn = {0219-6352},
support = {2024JK2132//Projects of the science and technology innovation Program of Hunan Province/ ; 2024RC1061//Projects of the science and technology innovation Program of Hunan Province/ ; 20257637//Scientific Research Project of Hunan Provincial Health Commission/ ; [2022] 256//State Administration of Traditional Chinese Medicine 2022 Youth Qihuang Scholars Training Program (National Letter of Traditional Chinese Medicine Education)/ ; [2022] 357//Hunan Provincial Graduate Joint Cultivation Base for Acupuncture-Moxibustion and Tuina of Hunan University of Chinese Medicine (Hunan Provincial Department of Education Notice)/ ; [2021] 356//Acupuncture Bioinformation and Smart Wellness Innovation and Entrepreneurship Education Center of Hunan University of Chinese Medicine (Hunan Provincial Department of Education Notice)/ ; [2020] 19//Innovative Graduate Cultivation Base for Chinese Medicine Sub-health of Hunan University of Chinese Medicine (University Administrative Research Document)/ ; },
mesh = {Humans ; *Kynurenine/metabolism ; *Gastrointestinal Microbiome/physiology ; *Cognitive Dysfunction/metabolism/microbiology/immunology ; Animals ; *Brain/metabolism ; *Dysbiosis/metabolism/immunology ; },
abstract = {Mild cognitive impairment (MCI) represents a critical prodromal stage of Alzheimer's disease. This review synthesizes current evidence to present a coherent pathological cascade driving MCI progression: gut microbiota dysbiosis (e.g., enrichment of Prevotella and depletion of Akkermansia) triggers a butyrate deficit and compromise of intestinal integrity, leading to systemic inflammation. This inflammatory milieu upregulates indoleamine 2,3-dioxygenase 1 (IDO1), shifting tryptophan metabolism toward the kynurenine pathway and resulting in the dominance of neurotoxic branches (3-hydroxykynurenine [3-HK], quinolinic acid [QUIN]) over neuroprotective kynurenic acid (KYNA). This metabolic imbalance promotes N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity, oxidative stress, and neuroinflammation, which collectively precipitate synaptic dysfunction and cognitive decline. We explicitly highlight this "gut-immune-metabolic" vicious cycle as the core framework of MCI pathology. Targeting this cycle through a dual strategy-restoring microbial diversity and pharmacologically inhibiting the IDO1/kynurenine 3-monooxygenase (KMO) enzymes-represents a promising therapeutic approach to delay the transition from MCI to dementia.},
}
@article {pmid42411440,
year = {2026},
author = {Ye, T and Shuai, Y and Liu, Y and Liu, S and Tang, X and Tian, W and Zhang, Y and Kong, Y},
title = {Efficacy and Safety of Transcranial Direct Current Stimulation on Multiple Health Outcomes in Neurological Disorders: An Umbrella Review of Meta-Analyses of Randomized Controlled Trials.},
journal = {Journal of integrative neuroscience},
volume = {25},
number = {6},
pages = {47145},
doi = {10.31083/JIN47145},
pmid = {42411440},
issn = {0219-6352},
mesh = {*Transcranial Direct Current Stimulation ; Humans ; *Nervous System Diseases/therapy ; *Randomized Controlled Trials as Topic ; Meta-Analysis as Topic ; Systematic Reviews as Topic ; *Outcome Assessment, Health Care/statistics &amp; numerical data ; },
abstract = {BACKGROUND: Neurological disorders are a leading cause of disability worldwide. Transcranial direct current stimulation (tDCS) is a promising therapeutic tool for neurological disorders. However, a consensus on clinical recommendations for using tDCS in patients with neurological disorders is lacking. In this umbrella review, we aimed to establish evidence-based guidance for using tDCS to treat neurological disorders.<br><br>METHODS: This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines 2020. PubMed/MEDLINE, Embase, the Cochrane Library, the Web of Science, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) were systematically searched to identify and evaluate existing systematic reviews and meta-analyses on the use of tDCS for neurological disorders. Quality was assessed using the Measurement Tool to Assess Systematic Reviews 2 (AMSTAR 2) and the Grades of Recommendations, Assessment, Development, and Evaluation (GRADE) tool. The Hartung-Knapp-Sidik-Jonkman random effects model was employed for reanalysis.<br><br>RESULTS: A total of 17 systematic reviews and meta-analyses encompassing 358 randomized controlled trials and 7160 participants were analyzed. tDCS demonstrated efficacy across seven distinct health conditions, including stroke, Parkinson's disease, Alzheimer's disease, cerebellar ataxia, fibromyalgia, disorders of consciousness, and migraine. Adverse effects were rarely reported, with the exception of mood changes associated with fibromyalgia. Our results indicated that tDCS significantly improved 34 distinct health outcomes related to these conditions.<br><br>CONCLUSIONS: We found that tDCS may be a promising treatment for neurological disorders, with mild and infrequent adverse effects. Further studies are warranted to validate the therapeutic potential of tDCS in the reported neurological conditions, investigate additional neurological health outcomes, and explore the underlying mechanisms of tDCS effects. The PROSPERO Registration: CRD42024589432, https://www.crd.york.ac.uk/PROSPERO/view/CRD42024589432.},
}
@article {pmid42411493,
year = {2026},
author = {Stefano, GB},
title = {Beyond Amyloid: Evolutionary and Immune-Metabolic Perspectives on Alzheimer's Disease.},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {31},
number = {6},
pages = {53859},
doi = {10.31083/FBL53859},
pmid = {42411493},
issn = {2768-6698},
mesh = {Humans ; *Alzheimer Disease/metabolism/immunology/pathology ; Animals ; *Amyloid beta-Peptides/metabolism/immunology ; Immunity, Innate ; Brain/metabolism/immunology/pathology ; Mitochondria/metabolism ; Biological Evolution ; Gastrointestinal Microbiome ; },
abstract = {Alzheimer's disease (AD) is increasingly recognized as a multifactorial and systems-level disorder that extends beyond the classical amyloid cascade hypothesis. Rather than dismissing established concepts such as tau pathology, synaptic dysfunction, vascular compromise, mitochondrial abnormalities, and impaired proteostasis, emerging evidence suggests that these processes may interact dynamically with chronic immune activation, microbial signaling, and systemic metabolic stress. Recent studies examining the microbiome-gut-brain axis, chronic infection, innate immunity, and systemic immune-metabolic dysfunction have broadened the conceptual framework of AD pathogenesis. Importantly, amyloid-β (Aβ) is now understood to possess evolutionarily conserved antimicrobial and immunomodulatory properties, suggesting that amyloid deposition may initially represent a protective host-defense response rather than solely a toxic pathological event. This perspective does not overturn the amyloid cascade model but instead reframes amyloid biology within a broader adaptive evolutionary context in which chronic or dysregulated activation becomes maladaptive during aging. The present opinion article integrates these converging concepts into a unified framework in which AD emerges from the prolonged interaction among immune responses, microbial exposures, metabolic disturbances, mitochondrial dysfunction, vascular injury, and age-associated failures in proteostatic resilience. This integrative interpretation seeks to humanize the disease process by viewing neurodegeneration not simply as isolated protein accumulation, but as the gradual exhaustion of ancient host-defense and energy-regulatory systems that were originally evolutionarily advantageous for survival.},
}
@article {pmid42411865,
year = {2026},
author = {Wang, MT and Zhao, RC and Huang, M and Chen, J and Li, XP and Liu, YH and Wang, YJ},
title = {Plasma profiling of B lymphocyte-associated cytokines in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261464184},
doi = {10.1177/13872877261464184},
pmid = {42411865},
issn = {1875-8908},
abstract = {BackgroundImmunological dysregulation is a hallmark of Alzheimer's disease (AD), a neurodegenerative disorder characterized by amyloid-β (Aβ) plaque accumulation and hyperphosphorylated Tau protein pathology. AD is associated with altered humoral immunity, which may play a role in its pathogenesis.ObjectiveThis study aimed to investigate alterations in plasma levels of B lymphocyte-associated cytokines and their clinical relevance in AD.MethodsWe performed quantitative detections of 13 cytokines associated with B lymphocytes (TNF-β, IL-13, IFN-γ, TNF-α, IL-2, BAFF, IL-6, CD40L, IL-10, IL-12p70, IL-4, IL-17A, and IL-7) in plasma and analyzed their associations with cognitive functions and biomarkers of AD.ResultsWe found that plasma levels of CD40L, BAFF, TNF-β, IL-6 and IL-17A were increased in AD patients. However, the plasma IL-10 concentrations were decreased in Aβ-PET[+] subjects. Plasma levels of CD40L, BAFF, TNF-β, IL-6, IL-17A were negatively associated with the plasma Aβ42/40 ratio. Plasma levels of IL-10 were negatively associated with pTau181. Plasma levels of BAFF were negatively associated with MMSE scores.ConclusionsThese findings demonstrate an altered B lymphocyte-associated cytokine secretion profile in AD patients, which correlates with the clinical severity and biomarkers of the disease.},
}
@article {pmid42411930,
year = {2026},
author = {Verma, S and Ambatwar, R and Datusalia, AK and Khatik, GL},
title = {Kynurenic Acid, a Key Endogenous Neuroprotective Agent: Role of Its Derivatives in Therapeutics.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00081},
pmid = {42411930},
issn = {1948-7193},
abstract = {Kynurenic acid (KYNA) is an endogenous molecule that acts as a nonselective antagonist of ionotropic glutamate receptors and has been shown to have neuroprotective properties. Although KYNA has shown considerable therapeutic potential in neurodegenerative disorders, its limited permeability across the blood-brain barrier restricts its direct clinical application. To overcome this limitation, various ester and amide derivatives have been developed as prodrugs to enhance brain delivery and subsequently release KYNA within the central nervous system. Beyond serving as prodrugs, KYNA derivatives have attracted substantial interest in medicinal chemistry due to their ability to interact with multiple molecular targets. Additionally, these compounds exhibit a wide range of biological activities, including potential treatments for Alzheimer's disease, Parkinson's disease, Huntington's disease, and psychiatric disorders. Therefore, kynurenic acid-based scaffolds have prompted further research into their derivatives, leading to a range of structurally distinct products. Here, we discuss the neuroprotective role of KYNA and its derivatives, which exhibit diverse bioactivities.},
}
@article {pmid42411943,
year = {2026},
author = {McKay, TB and Kelly Graves, O and Mitchell, M and Mueller, A and Simon, C and Patel, P and Turco, I and Bertsch, J and Albanese, ML and Gleeson, E and Wint, A and Novak, A and Baker, S and Qu, JZ and Akeju, O},
title = {Intraoperative Lipoproteins Associated with Postoperative Delirium in a Prospective Observational Study of Older Adults Undergoing Cardiac Surgery.},
journal = {Journal of cardiothoracic and vascular anesthesia},
volume = {40},
number = {2},
pages = {571-582},
doi = {10.1053/j.jvca.2025.09.235},
pmid = {42411943},
issn = {1532-8422},
mesh = {Humans ; Prospective Studies ; Female ; Male ; *Cardiac Surgical Procedures/adverse effects/trends ; Aged ; Middle Aged ; *Delirium/blood/diagnosis/etiology ; Biomarkers/blood ; *Lipoproteins/blood ; *Postoperative Complications/blood/diagnosis ; Cohort Studies ; Cardiopulmonary Bypass/adverse effects ; },
abstract = {OBJECTIVE: To evaluate serum lipoproteins and other metabolites and their potential associations with the development of postoperative delirium.<br><br>DESIGN: Prospective observational cohort study.<br><br>SETTING: Single-site academic medical hospital.<br><br>PARTICIPANTS: Patients age 60 years and older scheduled for major cardiac surgery with cardiopulmonary bypass (CPB).<br><br>INTERVENTIONS: Delirium assessments were performed at baseline and twice daily up to postoperative day 3. The primary outcome evaluated serum collected before surgery, at the start and end of CPB, and on postoperative day 1.<br><br>MEASUREMENTS AND MAIN RESULTS: Sixty-five patients were recruited, with 18% of subjects developing postoperative delirium within 3 days of surgery (10 of 57 subjects with complete cognitive assessments). Metabolomic analysis of serum revealed an association between the abundance of cholesterol in large high-density lipoprotein (L-HDL-C%) at the start of CPB and the development of postoperative delirium (odds ratio per standard deviation increment in biomarker concentration, 0.23; 95% confidence interval [CI], 0.08-0.66). Serum neurofilament light chain was inversely correlated with L-HDL-C% levels at the same time point (Spearman &#x3c1;, -0.39; 95% CI, -0.59 to -0.15) and was significantly higher at the end of CPB in subjects who developed delirium compared to subjects who did not develop delirium (median, 20.4 [interquartile range (IQR),16.1-25.4] pg/mL vs 11.9 [IQR, 7.9-16.9] pg/mL).<br><br>CONCLUSION: Circulating blood biomarkers during surgery may provide insight into postoperative cognitive outcomes and should be evaluated in larger cohorts.},
}
@article {pmid42400072,
year = {2026},
author = {Keller-Norrell, PR and Casali, BT and Yost, LN and Reed, EG},
title = {Neonatal estradiol influences regional gene expression for early sex-specific inflammatory responses in the 5xFAD mouse model.},
journal = {Biology of sex differences},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13293-026-00948-z},
pmid = {42400072},
issn = {2042-6410},
support = {R01AG075897/AG/NIA NIH HHS/United States ; A2021036S//BrightFocus Foundation/ ; Institutional Funding//Northeast Ohio Medical University/ ; },
abstract = {BACKGROUND: Alzheimer's disease (AD), the most prevalent form of dementia, exhibits a strong sex bias, with women comprising two-thirds of all patients, for reasons that remain unclear. Microglia, as the brain's resident immune cell, are key players in AD pathogenesis and are increasingly understood as being sex-specific. However, the mechanisms underlying these differences, and how they may in turn contribute to distinct pathogenesis has not been well examined. Therefore, this study aimed to investigate the organizational role of neonatal estradiol (E2) in early-life sex-patterning of microglia for disease onset and progression.<br><br>METHODS: We assessed the effect of neonatal estradiol exposure on microglial and neuronal density, microgliosis, and gene expression related to microglial identity and responses using immunohistochemistry, qPCR, and ProteinSimple Jess on-capillary immunoblotting.<br><br>RESULTS: We find neonatal estradiol administration influences the expression of genes and proteins involved in inflammation and X chromosome inactivation, without affecting cellular composition of the cortex and hippocampus. Additionally, we observed genotype-dependent changes to the female reproductive cycle in E2 treated 5xFAD females.<br><br>CONCLUSIONS: Overall, the results of the present study provide novel insight into the role of steroid sex hormones in neonatal microglial programing, and how this programming may set the stage for further sex- and disease-linked alterations later in life.},
}
@article {pmid42400119,
year = {2026},
author = {Choudhary, HH and Yoshida, J and Islam, R and Wang, Z and Hanafy, KA},
title = {EXPRESS: Toll Like Receptor 4 (TLR4) in Neuroinflammation: From Acute Hemorrhagic Stroke to Chronic Neurodegeneration.},
journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism},
volume = {},
number = {},
pages = {271678X261468877},
doi = {10.1177/0271678X261468877},
pmid = {42400119},
issn = {1559-7016},
abstract = {Subarachnoid Hemorrhage (SAH) remains a leading cause of morbidity and mortality worldwide. While the primary injury is defined by mechanical tissue disruption, the progression of secondary brain injury is largely driven by robust neuroinflammatory cascades initiated by blood derived damage-associated molecular patterns (DAMPs). Among the key mediators of this response, Toll-like receptor 4 (TLR4) has emerged as a central regulator. TLR4 activation in microglia triggers downstream signaling through both MyD88 dependent and TRIF dependent pathways, driving the production of pro inflammatory cytokines and type I interferons. Additionally, non-canonical regulation of TLR4 by Lyn kinase introduces a critical modulatory mechanism that can shift microglial responses between inflammatory and phagocytic phenotypes in a sex dependent manner. Beyond hemorrhagic stroke, TLR4 mediated neuroinflammation also plays a significant role in the progression of Alzheimer's disease, where it influences amyloid-β recognition, clearance, and chronic glial activation. Emerging therapeutic strategies targeting TLR4 and its downstream signaling components including small molecules, natural compounds, aptamers, and TLR4-Lyn interaction modulators demonstrate promising potential in attenuating neuroinflammation and improving neurological outcomes. This review highlights the molecular mechanisms of TLR4 signaling in neuroinflammation and underscores its translational relevance as a therapeutic target in both acute and chronic neurodegenerative conditions.},
}
@article {pmid42400155,
year = {2026},
author = {Harriman, T and Harraz, OF},
title = {Tau protein differentially affects Piezo1 and Kir2.1 channels in brain capillary endothelial cells.},
journal = {Biophysical journal},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.bpj.2026.07.003},
pmid = {42400155},
issn = {1542-0086},
abstract = {Accumulation of amyloid-β (Aβ) peptides and Tau proteins in the brain is a hallmark of neurodegeneration. Such build-up forms Aβ plaques and Tau neurofibrillary tangles, both of which are associated with synaptic loss, cognitive decline, and reduced cerebral blood flow in Alzheimer's disease (AD). Two ion channels in brain capillary endothelial cells (ECs)-the inwardly rectifying potassium channel Kir2.1 and the mechanosensitive channel Piezo1-are critical regulators of cerebral blood flow, and both display impaired activity in AD. Whether Aβ and Tau affect these channels remains incompletely understood. Using patch-clamp electrophysiology and freshly isolated mouse brain capillary ECs, we examined whether Aβ1-40 or Tau-441 directly modulate Kir2.1 or Piezo1 function. Exogenously applied Aβ1-40 (10-100 nM) and Tau-441 (10-50 nM) had minimal effect on Kir2.1 current density, indicating that the Kir2.1 deficits observed in AD are less likely caused by direct interactions with Aβ or Tau. In contrast, we previously demonstrated that nanomolar Aβ1-40 enhanced Piezo1 function. We further show here that 50 nM Tau-441 significantly increased Piezo1 open probability, and this enhancement was abolished by the superoxide dismutase and catalase mimetic EUK-134. These data collectively suggest that altered Piezo1 function in neurodegenerative disease could involve a direct effect of Aβ peptides or Tau proteins and further suggest that acute exposure to these proteins minimally impacts Kir2.1 activity. These novel findings present a new pathway through which Tau proteins could impair neurovascular function during neurodegeneration.},
}
@article {pmid42400308,
year = {2026},
author = {Sousa, RAL and Costa, JMM and Pereira, RRS and Vieira, LCDR and Magalhães, CODE and Dias-Peixoto, MF},
title = {Exercise Snacking in Alzheimer's Disease: A Mechanistic Rationale Based on Repeated Exerkine Signaling.},
journal = {Journal of neurochemistry},
volume = {170},
number = {7},
pages = {e70517},
pmid = {42400308},
issn = {1471-4159},
support = {304455/2026-1//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; APQ-01160-26//FAPEMIG/ ; //Coordena&#xe7;&#xe3;o de Aperfei&#xe7;oamento de Pessoal de N&#xed;vel Superior/ ; },
abstract = {[Image: see text]},
}
@article {pmid42400646,
year = {2026},
author = {Jabli, MA and Mourad, M},
title = {Beyond complex architectures: a streamlined CNN pipeline for robust Alzheimer's disease classification from brain MRI.},
journal = {Neuroradiology},
volume = {},
number = {},
pages = {},
pmid = {42400646},
issn = {1432-1920},
abstract = {BACKGROUND AND PURPOSE: Alzheimer's disease, a common type of dementia, gradually steals memories and impacts daily life as brain cells deteriorate. We explored how Artificial Intelligence (AI) could help spot early signs of Alzheimer's using MRI brain scans.<br><br>MATERIALS AND METHODS: Our study focused on a deep learning approach, specifically a convolutional neural network (CNN), to distinguish between Alzheimer's, Mild Cognitive Impairment (MCI), and healthy individuals. We used two well-known datasets, OASIS and ADNI, for this work. After carefully preparing the ADNI data (which included 21,324 MRI images: 7,572 from MCI patients, 5,904 from healthy controls, and 7,848 from Alzheimer's patients) and the OASIS data (6,400 MRI images), our model performed exceptionally well.<br><br>RESULTS: The CNN Model achieved an accuracy of 99.67% with the ADNI images and 99.06% with the OASIS images. These encouraging results, which stand up well against other studies, show that our method can effectively analyze large amounts of data and accurately classify Alzheimer's.<br><br>CONCLUSIONS: Our main hope is that this kind of technology can give doctors and caregivers better tools to predict and detect the disease, ultimately saving time, reducing costs, and helping those affected by Alzheimer's.},
}
@article {pmid42400765,
year = {2026},
author = {Josephs, O and Dymerska, B and Graedel, NN and Balbastre, Y and Corbin, N and Callaghan, MF},
title = {Online image reconstruction via Multiple Orthogonal Reference Sensitivity Encoding (MORSE).},
journal = {Magma (New York, N.Y.)},
volume = {},
number = {},
pages = {},
pmid = {42400765},
issn = {1352-8661},
support = {203147/Z/16/Z/WT_/Wellcome Trust/United Kingdom ; 226793/Z/22/Z/WT_/Wellcome Trust/United Kingdom ; },
abstract = {OBJECTIVE: Parallel imaging is ubiquitous in MRI, enabling higher spatial and/or temporal resolution. However, successful unfolding is contingent on robust and accurate estimation of relative coil sensitivities, which often involves computation times that preclude online deployment. We present a computationally efficient method of robustly estimating coil sensitivities, and reconstructing under-sampled images using a data-driven regularised SENSE formalism that is commensurate with online deployment for Cartesian k-space acquisitions.<br><br>MATERIALS AND METHODS: The proposed image reconstruction method via Multiple Orthogonal Reference Sensitivity Encoding (MORSE) estimates multiple sensitivities per voxel to address issues, such as rapidly varying sensitivities, chemical shift artefact, or insufficient fields of view. It simultaneously provides a data-driven regularisation term for noise control providing inherent adaptability to diverse imaging contexts.<br><br>RESULTS: MORSE has been successfully deployed in multiple neuroimaging studies at both 3T and 7T, including functional studies of autobiographical memory processing, visual and auditory perception, and quantitative MRI studies of neurodegenerative diseases including Huntington's, Alzheimer's and Parkinson's. Exemplar image reconstructions are presented and compared with GRAPPA, ENLIVE, ESPIRiT and LORAKS. We also showcase application of MORSE outside of the brain via application in liver and knee imaging. MORSE consistently produced high-quality, artefact-free images with reconstruction times feasible for online deployment.<br><br>DISCUSSION: The proposed method of sensitivity estimation and unfolding regularisation is flexible and robust. It is made available to the community in open-source as a library of functions within the vendor-agnostic Gadgetron image reconstruction framework.},
}
@article {pmid42400785,
year = {2026},
author = {D'Souza, D and Sumbatian, D and Sever, B and Altman, I and Leykind, Y and Frenkel-Morgenstern, M},
title = {Detection of Chimeric RNAs from RNA-Seq Data with ChiTaRS 8.0: Insights for Liquid Biopsy and Drug Target Identification.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {3024},
number = {},
pages = {23-42},
pmid = {42400785},
issn = {1940-6029},
mesh = {Humans ; Liquid Biopsy/methods ; *RNA-Seq/methods ; Computational Biology/methods ; Software ; *Drug Discovery/methods ; Biomarkers, Tumor/genetics ; Leukocytes, Mononuclear/metabolism ; *RNA/genetics ; Neoplasms/genetics ; },
abstract = {Chimeric RNAs (chiRNAs), generated via genomic rearrangements or splicing events, are increasingly recognized as biomarkers and therapeutic targets in cancer and neurodegenerative disorders. This chapter introduces an integrative framework for high-confidence chiRNA identification leveraging the ChiTaRS 8.0 database and the ChiTaH pipeline. ChiTaRS 8.0 encompasses 47,445 human chiRNAs, 1,055 Hi-C breakpoints, and 1,598 drug targets, while ChiTaH facilitates disease-specific analysis of RNA-seq data from 250 peripheral blood mononuclear cell (PBMC) samples-including glioblastoma and oral squamous cell carcinoma-and 199 healthy controls. Our approach combines reference-based fusion detection, BLAT validation against GRCh38, gene-pair compatibility checks, and protein domain conservation analysis. Functional annotation and protein-protein interaction modeling uncovered oncogenic chiRNAs absent from existing databases, exhibiting tissue-specific patterns. In Alzheimer's disease, liquid biopsy analyses identified unique chimeras-such as ENO1-MCUR1 and APOE-APOE-in cerebrospinal fluid, linked to neurotransmitter pathways and amyloid processing, and absent in healthy samples, highlighting their potential as early biomarkers. We describe a scalable digital hospital framework integrating AI-driven fusion detection, relational databases, and clinical metadata for real-time diagnostics and patient monitoring. This system supports fusion-targeted drug discovery and patient stratification, bridging translational gaps in oncology and neurodegeneration. By coupling computational pipelines with multiomics data, our approach advances personalized medicine while addressing challenges in artifact filtering and functional validation. Ultimately, the ChiTaRS-ChiTaH platform offers a versatile tool for chiRNA discovery and annotation across diverse disease contexts, providing insights into molecular mechanisms and clinical applications.},
}
@article {pmid42401072,
year = {2026},
author = {Ma, L and Chen, S and Jia, Q and Tian, R and Zeng, Y and Luo, K and Meng, X and Yang, L},
title = {Therapeutic potential of scutellarin in central nervous system: A comprehensive review.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {159},
number = {},
pages = {158506},
doi = {10.1016/j.phymed.2026.158506},
pmid = {42401072},
issn = {1618-095X},
abstract = {BACKGROUND: Scutellarin (SCU) is a flavone glycoside mainly isolated from Erigeron breviscapus (Vant.) Hand. -Mazza, which is a type of medicinal herb broadly utilized in central nervous system (CNS) disorders. Although Scu possesses remarkable therapeutic actions on CNS disorders, the underlying mechanisms, pharmacokinetics, and safety issues are elusive. Meanwhile, the clinical trial and pharmaceutical study of SCU remain to be systematically delineated.<br><br>PURPOSE: The main purpose is to comprehensively summarize the updated information regarding the pharmacological actions, clinical studies, safety issues, pharmacokinetics and novel formulations of SCU used for CNS, to point out species of interest for further studies.<br><br>METHODS: The systematic search for SCU treatments for CNS disorders was performed considering all the articles published until November 2025 through multiple authoritative databases, including Web of Science, PubMed, Google Scholar, Chinese National Knowledge Infrastructure, and so on. The keywords included "scutellarin", "breviscapine", "central nervous system disorders", "ischemic stroke", "Alzheimer's disease", "pharmacokinetic", "clinical studies", and "novel preparation technology". All articles reporting the use of SCU to treat CNS disorders were retained for further analysis.<br><br>RESULTS: A total of 223 articles published between 2003 and 2026 were included, covering ten CNS diseases such as ischemic stroke, Alzheimer's disease, and Parkinson's disease. Regarding pharmacological mechanisms of SCU, 33 studies focused on oxidative stress, 48 on inflammatory responses, and 16 on mitochondrial function. Evidence from 23 clinical trials indicated that SCU has therapeutic potential for CNS diseases. Toxicity studies demonstrated good safety profile at therapeutic doses of SCU. Pharmacokinetic data revealed its rapid absorption, low bioavailability, and efficient systemic clearance (16 studies). Additionally, 22 studies indicated that novel formulations significantly improved the biological half-life and enhanced the bioavailability of SCU.<br><br>CONCLUSIONS: SCU is expected to become a pivotal phytochemical agent for the CNS protection. Extensive and intensive explorations on SCU are imperative to accelerate the utilization of SCU in the CNS disorders.},
}
@article {pmid42401161,
year = {2026},
author = {Prévot, V and Schwaninger, M and Nogueiras, R and Rasika, S},
title = {Tau-ing and fro-ing: the tanycytic shuttle in neurodegeneration.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {8},
pages = {100643},
doi = {10.1016/j.tjpad.2026.100643},
pmid = {42401161},
issn = {2426-0266},
abstract = {After more than a century since Alzheimer's disease (AD) was described and decades of research into β-amyloid and Tau proteins, mechanisms underlying pathogenic protein clearance from brain remain poorly understood. Recent research identifies tanycytes-specialized hypothalamic cells lining the third ventricle-as a previously unrecognized clearance system for brain Tau. These cells actively transport Tau from cerebrospinal fluid to blood via pituitary portal circulation but are dramatically fragmented in AD brains. Single-nucleus RNA sequencing reveals altered stress and transport gene expression in AD tanycytes, while functional studies show disrupted tanycytic transport reduces Tau efflux and exacerbates pathology. Beyond protein clearance, tanycytes maintain critical metabolic and neuroendocrine pathways influencing cognition. Their unique blood-brain interface position makes them attractive therapeutic targets. As transcriptomic evidence suggests tanycytes are hotspots for age-related changes, their dysfunction may herald "tanycytopathies" underlying multiple neurodegenerative disorders.},
}
@article {pmid42401529,
year = {2026},
author = {Song, J and Pelekanos, M and Richter-Stretton, G and Leinenga, G and Chicoteau, A and Lee, W and Odabaee, M and Nestor, PJ and Saifzadeh, S and Simon, C and de Las Heras, R and Götz, J},
title = {Multidimensional Safety Assessment of a Low-Intensity Scanning Ultrasound (SUS) Protocol in Sheep.},
journal = {Ultrasound in medicine &amp; biology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ultrasmedbio.2026.06.011},
pmid = {42401529},
issn = {1879-291X},
abstract = {OBJECTIVE: Preclinical studies in mouse models of Alzheimer's disease present low-intensity ultrasound in a scanning mode (SUS) as a promising neuromodulatory modality. However, given the significant differences in brain scale and complexity between mice and humans, we employed sheep as a large animal model to test a novel investigational device and assess safety as a necessary step before deploying SUS in clinical trials.<br><br>METHODS: Informed by functional assessments in mice, we used image-guided neuro-navigation to deliver a peak negative pressure of 2.6 MPa to four sheep using a scanning approach. Three sheep (#N1-3) underwent a non-recovery procedure followed by histological assessment, and one (#R1) received five repeated treatments spaced out 2-4 weeks over 12 weeks to assess long-term safety via magnetic resonance imaging (MRI) and behavioral observations.<br><br>RESULTS: In total, 631 sonications were performed, treating up to 50 individual spots per sheep. Evans blue extravasation, and hematoxylin and eosin and vanadium acid fuchsin-toluidine blue staining revealed no evidence of tissue damage or unintended blood-brain barrier (BBB) opening (given no microbubbles were used). Throughout the repeat treatments of sheep #R1, post-operative behavioral observations confirmed normal movement and no signs of pain or distress. MRI revealed no SUS-induced anatomical abnormalities, evidence of BBB opening, microhemorrhages and oedema, in agreement with the histological observations. Mild heating was observed at the inner skull surface following sonication, but no damage to skull or scalp tissue was detected.<br><br>CONCLUSION: Collectively, the acute and long-term safety assessment of the brain after SUS advocates translation to human studies.},
}
@article {pmid42401549,
year = {2026},
author = {Liu, C and Zhang, T and E, ED and Xu, TY and Yang, FR and Li, JW and Shang, Q and Zhang, ZY and Shen, HW and Zhang, XQ},
title = {Maraviroc attenuates inflammation-exacerbated cognitive and amyloid pathology in an early-stage Alzheimer's disease mouse model.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-04215-y},
pmid = {42401549},
issn = {2158-3188},
support = {32201322//National Natural Science Foundation of China (National Science Foundation of China)/ ; LY24H090001//Natural Science Foundation of Zhejiang Province (Zhejiang Provincial Natural Science Foundation)/ ; },
abstract = {Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by progressive cognitive decline, and increasing evidence indicates that systemic inflammation can accelerate disease progression. Maraviroc, a CCR5 antagonist approved for the treatment of human immunodeficiency virus (HIV) infection, has shown neuroprotective effects in several neurological contexts, but its role in AD-related pathology remains unclear. In this study, cognitive performance was assessed in 5 × FAD mice using the Y-maze, novel object recognition, novel location recognition, and social discrimination tests. Amyloid-related changes were evaluated by hippocampal APP/Aβ immunoblotting and plaque staining using 6E10 and Thioflavin S. Glial responses were examined by IBA1 and GFAP immunostaining, and inflammatory cytokines were quantified by ELISA. We found that 5 × FAD mice exhibited age-dependent cognitive impairments, with detectable deficits emerging at 3 months of age. Systemic administration of lipopolysaccharide (LPS) further exacerbated cognitive dysfunction, amyloid-related alterations, and neuroinflammatory responses in young 5 × FAD mice. Maraviroc treatment attenuated LPS-associated cognitive impairments, reduced amyloid-related measures, and dampened pro-inflammatory cytokine responses, with a trend toward reduced microglial cell density. Collectively, these findings demonstrate that systemic inflammation accelerates Alzheimer's-like pathology and cognitive decline, and suggest that pharmacological modulation of neuroinflammatory signaling by maraviroc may mitigate inflammation-driven disease exacerbation at early stages.Schematic diagram illustrating the effects of maraviroc on LPS-induced cognitive deficits in 3-month-old 5 × FAD mice. In this model, maraviroc is associated with modulation of glial inflammatory responses, reduced pro-inflammatory cytokine levels, and alleviation of amyloid pathology in the hippocampus, which together coincide with improved cognitive performance. Figure created with BioRender.com.},
}
@article {pmid42401584,
year = {2026},
author = {Menze, I and Bernal, J and Kievit, RA and Tripathi, KP and Kaleck, T and Yakupov, R and Altenstein, S and Bartels, C and Buerger, K and Butryn, M and Dechent, P and Ewers, M and Fliessbach, K and Frommann, I and Gemenetzi, M and Glanz, W and Gref, D and Hellmann-Regen, J and Hetzer, S and Incesoy, EI and Janowitz, D and Kiliman, I and Kleineidam, L and Kronmüller, MT and Laske, C and van Lent, DM and Lüsebrink, F and Perneczky, R and Peters, O and Preis, L and Priller, J and Rauchmann, BS and Rostamzadeh, A and Roeske, S and Scheffler, K and Schott, BH and Schneider, A and Sodenkamp, S and Spottke, A and Spruth, EJ and Stark, M and Teipel, S and Wagner, M and Wiltfang, J and Jessen, F and Ramirez, A and Schreiber, S and Düzel, E and Ziegler, G},
title = {Joint trajectories of brain atrophy, white matter hyperintensities and cognition quantify brain maintenance.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {42401584},
issn = {2041-1723},
mesh = {Humans ; *White Matter/pathology/diagnostic imaging ; Atrophy/pathology ; *Cognition/physiology ; *Brain/pathology/diagnostic imaging ; *Aging/pathology/physiology ; Magnetic Resonance Imaging ; Female ; Male ; Aged ; Aged, 80 and over ; Cognitive Dysfunction/pathology ; },
abstract = {Brain maintenance - the preservation of brain structure or function relevant to cognitive performance - remains challenging to quantify. Here, we propose a domain-general brain maintenance index derived by jointly modelling the longitudinal co-evolution of ageing-related atrophy (via medial temporal lobe to ventricle ratio, MTLV-ratio), white matter hyperintensities (WMH), and global cognition assessed by the preclinical Alzheimer's cognitive composite (PACC5) using latent growth curve modelling. We demonstrate its utility in 543 cognitively unimpaired older adults from the DELCODE cohort, followed annually over four years. We show that changes in MTLV-ratio and WMH additively predict cognitive change. We further show that higher neuroticism, depressive symptoms, lower openness, and faster biological ageing are related to unfavourable domain-specific trajectories and poorer brain maintenance. Our findings highlight the combined relevance of WMH and ageing-related atrophy dynamics for brain maintenance. Maintaining cerebrovascular and mental health alongside cognitive engagement could promote brain maintenance, delay cognitive decline and dementia.},
}
@article {pmid42401601,
year = {2026},
author = {Lam, J and Rodriguez-Cruces, R and Arafat, T and Royer, J and Chen, J and Dascal, A and Sahlas, E and Pana, R and Hopewell, R and Hsiao, CH and Massarweh, G and Soucy, JP and Rosa-Neto, P and Villeneuve, S and Caciagli, L and Koepp, M and Bernasconi, A and Bernasconi, N and Bernhardt, B},
title = {An open dataset of cerebral tau deposition in young healthy adults based on [[18]F]MK6240 positron emission tomography.},
journal = {Scientific data},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41597-026-07656-8},
pmid = {42401601},
issn = {2052-4463},
support = {FDN-154298, PJT-174995, PJT-191853//Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Sant&#xe9; du Canada)/ ; 14181//Brain Research Trust (BRT)/ ; NI17-039//Sick Kids Foundation/ ; RGPIN-2025-05932//Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada (Conseil de Recherches en Sciences Naturelles et en G&#xe9;nie du Canada)/ ; },
abstract = {Tauopathies are pathologies wherein phosphorylated insoluble tau aggregates in neurons, leading to dysfunction and degeneration. Positron emission tomography (PET) enables measurement of in vivo tau, with second-generation radiotracers such as [[18]F]MK6240 showing high tau affinity with minimal off-target binding. While tauopathies are commonly linked to age-related neurodegenerative diseases, notably Alzheimer's disease (AD), evidence suggests pathophysiological cascades may begin long before clinical onset. Increasingly, tau is recognized in pathologies affecting younger individuals, including autosomal dominant AD, Niemann-Pick disease type C, chronic traumatic encephalopathy, and epilepsy, thus highlighting the importance of normative data in non-geriatric populations. Here, we present a dataset of 33 young to middle-age healthy adults (mean age 34.0 ± 10.4 years, 12 female) with [[18]F]MK6240 PET data and T1w magnetic resonance imaging. Longitudinal data are also available in a subset of 9 participants with a minimum follow-up time of 1 year. Our dataset aims to support imaging biomarker studies on younger individuals potentially at risk for AD and to advance work in tauopathies affecting non-geriatric populations generally excluded from neurodegeneration studies.},
}
@article {pmid42401929,
year = {2026},
author = {Baghel, MS and Burns, GD and Tsapatsis, M and Peethambaran Mallika, A and Cruz, ALF and Cao, T and Chen, XK and De La Rosa, I and Marx, SR and Ye, Y and Sun, S and Li, T and Ling, JP and Wong, PC},
title = {TDP-43 dysfunction facilitates the pathological conversion of tau.},
journal = {Molecular neurodegeneration},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13024-026-00968-8},
pmid = {42401929},
issn = {1750-1326},
abstract = {TDP-43 proteinopathy coexists with tauopathy in a variety of neurodegenerative disorders, including Alzheimer's Disease (AD) and AD related dementia (ADRD). While such co-pathology of TDP-43 is strongly associated with worsened neurodegeneration, the pathogenic mechanism underlying the exacerbated neuron loss remains elusive. Loss of TDP-43 splicing repression occurring during the early stage of neurodegenerative disease suggests that such loss could facilitate the pathological conversion of tau. Here, we report that TDP-43 loss-of-function (LOF) in forebrain neurons (Tau4R; CaMKII-CreER; Tardbp[f/f] mice) exacerbates tauopathy-dependent brain atrophy is associated with vulnerable neurons sensitive to caspase 3-dependent cleavage of endogenous tau. We demonstrate that TDP-43 LOF in human iPSC-derived cortical neurons promotes TDP-43 dependent cryptic splicing which precedes caspase 3-mediated endoproteolysis of tau. Using a genetic approach to seed tauopathy in CaMKII-CreER; Tardbp[f/f] mice by expressing a four-repeat microtubule binding domain of human tau, we show that the amount of tau seed correlates with caspase 3-dependent tau cleavage, accelerated tauopathy and the loss of vulnerable neurons deficient in TDP-43. Together, these results strongly support the view that TDP-43 dysfunction exacerbates tauopathy-dependent brain atrophy by promoting caspase 3-dependent endoproteolysis of tau, disclosing novel mechanistic insights and therapeutic targets for human tauopathies harboring the co-pathology of TDP-43.},
}
@article {pmid42401978,
year = {2026},
author = {Alsina, R and Riba, M and Sartorio, M and Romera, C and Riu, J and Vilaplana, G and Aldecoa, I and Compta, Y and Sánchez-Valle, R and Del Valle, J and Pelegrí, C and Molina-Porcel, L and Vilaplana, J},
title = {Regional wasteosome accumulation across neurodegenerative diseases points to a shared underlying mechanism potentially related to glymphatic insufficiency.},
journal = {Acta neuropathologica communications},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40478-026-02362-3},
pmid = {42401978},
issn = {2051-5960},
support = {FPU//Ministerio de Ciencia, Innovaci&#xf3;n y Universidades/ ; Margarita Salas//Ministerio de Ciencia, Innovaci&#xf3;n y Universidades/ ; FPI//Ministerio de Ciencia, Innovaci&#xf3;n y Universidades/ ; PID2020-115475GB-I00//Ministerio de Ciencia, Innovaci&#xf3;n y Universidades/ ; 2021 SGR 00288 625//Generalitat de Catalunya/ ; },
abstract = {The glymphatic system plays a key role in clearing waste products from the brain and is essential for maintaining brain homeostasis. When dysfunctional, it appears to contribute to pathological changes that exacerbate brain disorders, including neurodegenerative diseases. Additionally, wasteosomes, also known as corpora amylacea, are structures that function as waste containers and are thought to increase in response to chronic glymphatic insufficiency. Hence, in this study, we evaluated whether the accumulation and distribution of wasteosomes are compatible with both the potential role of wasteosomes as a hallmark of the chronic glymphatic insufficiency and the presence of this insufficiency in certain neurodegenerative diseases. Accordingly, brain tissue from 185 donors was analysed, including cases of Alzheimer's disease, amyotrophic lateral sclerosis with TDP-43 proteinopathy, frontotemporal lobar degeneration with TDP-43 or tau proteinopathy, and non-diseased controls. Wasteosomes were examined across 28 brain regions comprised within 5 major brain areas, using region-specific scoring systems. Analysis was conducted through variance and covariance analyses, along with decision tree procedures. The findings reveal that wasteosomes are consistently found in specific critical regions, with a higher burden in donors with neurodegenerative diseases compared with controls. These regions are independent of the regional distribution of the underlying proteinopathy, and are potentially associated with glymphatic drainage pathways. From an integrated perspective, although further studies are required, the increased presence of wasteosomes in these critical regions across all diseased groups is consistent with the potential presence of chronic glymphatic insufficiency in these diseases.},
}
@article {pmid42402181,
year = {2026},
author = {Osmanovic Barilar, J and Vlahov, L and Krsnik, A and Mihalic, L and Babic Perhoc, A and Virag, D and Homolak, J and Salkovic-Petrisic, M and Knezovic, A},
title = {Time- and Region-Specific Effects of Intranasal Insulin on Oxidative Stress Parameters in the Rat Brain.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {40},
number = {13},
pages = {e72119},
doi = {10.1096/fj.202601712R},
pmid = {42402181},
issn = {1530-6860},
support = {HRZZ-2022-10-1895//Hrvatska Zaklada za Znanost (HRZZ)/ ; DOK-NPOO-2023-10-3354//Hrvatska Zaklada za Znanost (HRZZ)/ ; DOK-2025-02-5472//Hrvatska Zaklada za Znanost (HRZZ)/ ; 10106-24-1453//Medicinski Fakultet, Sveu&#x10d;ili&#x161;te u Zagrebu (University of Zagreb Medical School)/ ; },
mesh = {Animals ; *Oxidative Stress/drug effects ; *Insulin/administration &amp; dosage/pharmacology ; Male ; Rats, Wistar ; Administration, Intranasal ; *Brain/metabolism/drug effects ; Rats ; Oxidation-Reduction/drug effects ; Lipid Peroxidation/drug effects ; Sulfhydryl Compounds/metabolism ; Nasal Mucosa/metabolism/drug effects ; Superoxide Dismutase/metabolism ; },
abstract = {Understanding how intranasal insulin affects brain signaling and metabolism is essential for elucidating its therapeutic potential in neurodegenerative disorders with underlying metabolic dysfunction, such as Alzheimer's disease (AD). Oxidative stress, which increases with aging, has been observed in both AD and Type 2 diabetes, indicating a potential link between oxidative stress, brain insulin resistance and cognitive impairment. This study examined how intranasal insulin affects redox homeostasis across different brain regions and time points. Male Wistar rats received 2 IU of insulin intranasally and were sacrificed 3, 7.5, 15, 30, 60, and 120 min post-administration. Six animals served as intact controls. Redox homeostasis was assessed by measuring lipid peroxidation, total reductive capacity, thiol concentrations, and superoxide dismutase activity in plasma, nasal epithelia, and brain regions. The results were correlated with insulin signaling markers. Intranasal insulin induced rapid but regionally diverse redox responses. The most pronounced alterations occurred in nasal epithelia, where respiratory and olfactory regions exhibited distinct and opposing patterns. In the brain, significant alterations, particularly in thiol-related parameters, were observed across multiple regions including cortices, hippocampus, hypothalamus, olfactory bulb, and cerebellum. Plasma redox parameters remained largely unchanged, supporting the predominantly central action of intranasally delivered insulin. Correlation analyses revealed associations between oxidative stress markers and insulin signaling parameters, suggesting complex interactions between metabolic signaling pathways and redox regulation. These findings demonstrate that intranasal insulin modulates redox homeostasis in a rapid, region-specific, and time-dependent manner, highlighting the importance of spatial and temporal factors in insulin-mediated regulation of brain oxidative balance.},
}
@article {pmid42402306,
year = {2026},
author = {Chen, ML and Hao, LY and Zhang, ZH and Xu, HF and Li, HF and Wen, L and Zheng, GQ},
title = {Preclinical Evidence for Icariin in Alzheimer's Disease: Methodological Quality, Efficacy, and Mechanisms.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103228},
doi = {10.1016/j.arr.2026.103228},
pmid = {42402306},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD) currently lacks effective curative treatments. Icariin (ICA), a flavonoid from Epimedium, has been widely investigated in AD animal models with emerging neuroprotective potential. However, the methodological quality, reporting rigor, and translational reliability of this preclinical evidence have not yet been systematically evaluated. Studies investigating ICA in AD were retrieved from eight databases up to May 12, 2026. The reporting quality, risk of bias, and study quality were assessed using the ARRIVE 2.0 guidelines, the SYRCLE risk-of-bias tool, and the CAMARADES checklist, respectively. Meta-analyses were conducted to assess the therapeutic efficacy of ICA, and potential mechanisms were summarized. A total of 59 studies were included. The average reporting rate for ARRIVE 2.0 items was 56.12%, with major deficiencies in sample size calculation (0%), inclusion/exclusion criteria (0%), protocol registration (0%), randomization (5.08%), and blinding (11.86%). The SYRCLE assessment revealed that only a few domains were rated as low risk of bias. CAMARADES scores ranged from 2 to 5 (out of 10). Meta-analyses showed that ICA significantly improved cognitive performance in behavioral tests. In the Morris water maze, escape latency was reduced (SMD = -2.51, 95% CI -3.02 to -2.01), with similar improvements observed in the novel object recognition and Y-maze tests. ICA also significantly attenuated amyloid pathology, reducing hippocampal amyloid plaque number (SMD = -2.43, 95% CI -3.80 to -1.05), plaque area, and soluble Aβ1-42 levels. Preclinical evidence from AD animal models suggests that ICA improves cognitive performance and reduces amyloid burden through mechanisms involving neuroinflammation, amyloid and tau regulation, synaptic plasticity, mitochondrial and redox homeostasis. However, substantial methodological shortcomings-particularly in sample size calculation, randomization, blinding, and outcome pre-specification-limit confidence in the robustness and translational reliability of these findings. Strengthening methodological rigor and reporting transparency will be essential to support future clinical development.},
}
@article {pmid42402307,
year = {2026},
author = {Chen, Z and Yang, K and Lin, F and Tang, W and Shi, Y and Zhou, S and Liu, J and You, Y},
title = {White matter abnormalities in Alzheimer's disease: Implications for pathophysiology, diagnosis, and treatment.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103229},
doi = {10.1016/j.arr.2026.103229},
pmid = {42402307},
issn = {1872-9649},
abstract = {White matter (WM) abnormalities have emerged as a critical element in Alzheimer's disease (AD) pathogenesis, shifting from their former status as a passive consequence to an active contributor to disease progression. Notably, microstructural WM alterations, detectable early via advanced neuroimaging techniques such as diffusion tensor imaging, frequently precede overt gray matter atrophy and cognitive decline, highlighting their potential as early contributors to AD pathogenesis. The origins of WM pathology are multifactorial, involving a complex interplay among β-amyloid (Aβ) and tau aggregation, energy dysmetabolism, neuroinflammation, vascular dysfunction, and cellular senescence. Importantly, we emphasize a paradigm-shifting perspective: WM degeneration acts not merely as a downstream outcome but as a key driver of AD pathogenesis, capable of accelerating protein aggregation, amplifying neuroinflammation, and compromising neural plasticity. Given its early manifestation and close association with symptom onset, WM integrity has emerged as a sensitive and reliable biomarker for early AD detection and progression monitoring. Moving beyond diagnostics, the growing understanding of WM pathophysiology has unveiled a new frontier of therapeutic interventions aimed at myelin regeneration and WM protection. Despite persisting translational challenges, targeting WM integrity represents a pivotal avenue for developing disease-modifying therapies capable of slowing disease progression and improving clinical outcomes in patients with AD.},
}
@article {pmid42402621,
year = {2026},
author = {Calcagno, G and Mansuroglu, Z and Segrt, H and Conquet, L and Marin-Obando, JP and Bortolin, V and de Chaumont, F and Buée, L and Niedergang, F and Manet, C and Galas, MC and Montagutelli, X and Bonnefoy, E},
title = {Zika virus infection induces a persistent accumulation of Alzheimer's disease-like Tau phosphorylation in adult immunocompetent mice in association with memory and social behavior impairments.},
journal = {Acta neuropathologica communications},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40478-026-02368-x},
pmid = {42402621},
issn = {2051-5960},
support = {ANR-20-CE16-0017//Agence Nationale de la Recherche/ ; ANR-20-CE16-0017//Agence Nationale de la Recherche/ ; ANR-20-CE16-0017//Agence Nationale de la Recherche/ ; ANR-20-CE16-0017//Agence Nationale de la Recherche/ ; ANR-20-CE16-0017//Agence Nationale de la Recherche/ ; ANR-20-CE16-0017//Agence Nationale de la Recherche/ ; ANR-20-CE16-0017//Agence Nationale de la Recherche/ ; ANR-10-LABX-62-IBEID//French Government's Investissement d'Avenir program, Laboratoire d'Excellence/ ; ANR-10-LABX-62-IBEID//French Government's Investissement d'Avenir program, Laboratoire d'Excellence/ ; },
abstract = {Clinical and epidemiological data support the link between viral encephalitis and neurodegeneration but its causal mechanism remains mostly unknown. Zika virus (ZIKV) is an emerging, neurotropic flavivirus susceptible to induce cognitive impairments in infected adults. In this work we have analyzed the capacity of ZIKV to induce the accumulation of pathological phosphorylated Tau protein (pTau), a major driver of neurodegenerative disorders such as Alzheimer's disease, throughout the infection of adult immunocompetent mice. The capacity of ZIKV to induce pTau in vivo, was analyzed in the long term in three Collaborative Cross mouse strains displaying different responses to ZIKV. The establishment and propagation of pTau was quantified up to 60 days post-infection (dpi) in correlation with the level and localization of neuronal viral infection and of microglia activation using immunofluorescence, immunohistochemistry, wide field and confocal microscopy and gene expression analysis. Strength, coordination, memory and social behavior were evaluated before and following the establishment and progression of pTau. The role of microglia on ZIKV-induced pTau was investigated by partially depleting microglial cells using PLX3397 (PLX). ZIKV infection induced a significant accumulation of pTau starting at 15 that persisted at least until 60 dpi. At 15 dpi, pTau was observed in ZIKV-infected neurons in the CA2 and CA1 regions of the hippocampus and in non-infected cortical neurons in association with neuroinflammation and social behavior alterations. At 30 dpi, pTau progressed independently of infection and inflammation, positively correlated to PLX-susceptible Apoe gene expression in association with short-term memory defects. These results shed light on how brain viral infections, which are a major concern for public health, drive pTau accumulation and propagation in link with memory impairment and social behavior alterations laying the groundwork for potential new therapeutic treatments.},
}
@article {pmid42402880,
year = {2026},
author = {, },
title = {[Standard operating procedure for pre-analytical blood biomarker processing in Alzheimer's disease (2026 edition)].},
journal = {Zhonghua yi xue za zhi},
volume = {106},
number = {25},
pages = {2568-2578},
doi = {10.3760/cma.j.cn112137-20260202-00363},
pmid = {42402880},
issn = {0376-2491},
support = {2023YFC3605400//National Key Research and Development Program of China/ ; 82588301//Natural Science Foundation of China/ ; 2024GGXM003//Joint Project of the Chongqing Science and Technology Bureau and the Health Commission/ ; },
mesh = {*Alzheimer Disease/blood/diagnosis ; Humans ; *Biomarkers/blood ; Amyloid beta-Peptides/blood ; tau Proteins/blood ; },
abstract = {Alzheimer's disease (AD) is a major health threat to the elderly. With the clinical application of disease-modifying therapeutic drugs, early and accurate diagnosis of AD has become increasingly essential. Given the ease of collection, blood biomarker detection has emerged as a crucial method for early screening, clinical diagnosis, and disease monitoring of AD. In recent years, substantial progress has been achieved in the research of AD blood biomarkers, and some indicators have been introduced into clinical practice. However, the detection of AD blood biomarkers, such as β-amyloid protein and phosphorylated tau protein, are highly susceptible to pre-analysis factors, which reduces the reliability of their clinical application and restricts the comparability among different blood biomarker studies. Currently, in China, there is a growing trend in the scientific research, testing product development, and clinical application of AD blood biomarkers. Therefore, it is necessary to standardize the AD blood biomarker detection in China. Based on this background, Cognitive Impairment Working Group of the National Medical Quality Control Center for Neurological Diseases established the "Standard operating procedure for pre-analytical blood biomarker processing in Alzheimer's disease (2026 edition)". This standard is developed in line with international recommendations, incorporating the practical experience of blood biomarker research in China and taking into consideration both clinical and research needs. It formulates a standardized operating procedure for the pre-treatment of blood samples, providing a quality control reference for the research and clinical application of AD blood biomarkers in China.},
}
@article {pmid42402882,
year = {2026},
author = {Tian, C and Wang, ZY and Liu, SY and Kang, XX and Yu, ZW and Pan, DH and Guo, Z and Qiao, HW and Peng, GP and Zhang, W and Chen, B and Zhang, ZX and Zhang, J},
title = {[Consistency evaluation of the domestic Lifotronic platform and foreign luminescence platforms in detecting core cerebrospinal fluid biomarkers in Chinese Alzheimer disease patients].},
journal = {Zhonghua yi xue za zhi},
volume = {106},
number = {25},
pages = {2589-2600},
doi = {10.3760/cma.j.cn112137-20260414-01014},
pmid = {42402882},
issn = {0376-2491},
mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Alzheimer Disease/cerebrospinal fluid ; Amyloid beta-Peptides/cerebrospinal fluid ; *Biomarkers/cerebrospinal fluid ; Luminescent Measurements ; Retrospective Studies ; tau Proteins/cerebrospinal fluid ; East Asian People ; },
abstract = {Objective: To evaluate the consistency of measurement results and diagnostic agreement of core cerebrospinal fluid (CSF) biomarkers for Alzheimer disease (AD) in a Chinese population, which were measured across a domestically developed electrochemiluminescence platform (Lifotronic eCL8000), a Japanese chemiluminescence immunoassay platform (LUMIPULSE), and an American electrochemiluminescence platform (Meso Scale Discovery, MSD). Methods: CSF samples were retrospectively collected from 253 subjects recruited at Peking Union Medical College Hospital, Xuanwu Hospital Capital Medical University, and Beijing Tiantan Hospital between July 2013 and September 2019. The cohort was comprised of 132 males and 121 females, with the age of (62.4±13.3) years. All CSF samples were collected via standardized protocols and cryopreserved at -80 ℃. Inter-assay repeatability (coefficient of variation, CV) of the Lifotronic platform on different days was validated. Spearman's rank correlation analysis was used to evaluate the degree of correlation between the results of the Pumen platform and those of the LUMIPULSE and MSD platforms, with the correlation coefficient expressed as ρ. Subsequently, 4 core CSF biomarkers [β-amyloid 40 (Aβ40), β-amyloid 42 (Aβ42), phosphorylated tau (p-tau), and total tau (t-tau)] were quantitatively measured across the three platforms. The consistency of test results between platforms was evaluated using the Passing-Bablok regression model and Bland-Altman analysis. The 95% limits of agreement (LoA) were calculated by Bland-Altman analysis, with good agreement indicated when <5% of points fell outside the limits. Proportional and constant errors between the measurement systems were quantified by the Passing-Bablok regression model, utilizing a robust non-parametric method. [18]F-florbetapir positron emission tomography/positron emission tomography/computed tomography (PET/CT) imaging has been performed on 40 of the 253 subjects. With the PET/CT diagnostic results utilized as the gold standard, the diagnostic agreement between the CSF results from the 3 platforms and the PET/CT findings was compared by calculating Cohen's Kappa coefficient. Furthermore, AD diagnostic reference cut-off values for each platform were determined by employing receiver operating characteristic (ROC) curves. Results: The Lifotronic platform demonstrated good repeatability in CSF testing (CV<10%). Spearman's rank correlation analysis was used to evaluate the correlation between the Lifotronic platform and the LUMIPULSE and MSD platforms, with correlation coefficients denoted by ρ. In comparison with the LUMIPULSE platform, all correlation coefficients (ρ) were>0.85. The correlation coefficient (ρ) between the MSD and Lifotronic platforms was>0.80, with a Kappa value of 0.698 (P<0.05). Bland-Altman analysis and Passing-Bablok regression models showed that for t-tau, the mean bias between Lifotronic and LUMIPULSE was 214.95 (95%LoA:-1 490.59-1 920.50), with 99.60% (252/253) of the data points falling within the 95%LoA. In the detection of t-tau, the regression slope between the Lifotronic and LUMIPULSE platforms was 2.041 (Equation: Y=2.041X-75.184), and the regression slope with the MSD platform was 2.360 (Equation: Y=2.360X-87.503). Based on PET/CT imaging validation, the CSF diagnostic results of the Lifotronic platform were consistent with the PET/CT results (Kappa=0.885, P<0.05), as were those of the MSD platform (Kappa=0.714, P<0.05). The Lifotronic platform established AD diagnostic reference thresholds based on the t-tau/Aβ42 and p-tau-181/Aβ42 ratios (the cut-off value for t-tau/Aβ42 was 0.32, and for p-tau-181/Aβ42 was 0.035). The Kappa value between the Lifotronic and LUMIPULSE platforms was 0.928 (P<0.05), and the Kappa value between the Lifotronic and MSD platforms was 0.698 (P<0.05). Conclusion: This study systematically validated the reliability of domestically developed Lifotronic electrochemiluminescence platform and its corresponding assay kits in detecting AD CSF biomarkers, as well as their comparability with international platforms, demonstrating comparable capabilities in terms of accuracy, consistency, and cost control.},
}
@article {pmid42403010,
year = {2026},
author = {Erol Gunal, S and Teke Tuncel, S and Demir, &#x130; and Baysal, &#x130; and Telli, G and Sag Erdem, S and Ucar, G and Hanzlova, M and Musilek, K and Dogan, &#x130; and Gokhan Kelekci, N},
title = {Design, Synthesis, and Biological Evaluation of Chiral Urea and Thiourea Derivatives as Multitarget-Directed Anti-Alzheimer Agents.},
journal = {Drug development research},
volume = {87},
number = {5},
pages = {e70341},
doi = {10.1002/ddr.70341},
pmid = {42403010},
issn = {1098-2299},
support = {219Z128//Scientific and Technological Research Council of Turkey (T&#xdc;B&#x130;TAK)/ ; 18082//Bogazici University Research Fund (BAP)/ ; 2206-2025//University of Hradec Kralove/ ; },
mesh = {*Thiourea/pharmacology/chemistry/chemical synthesis/analogs &amp; derivatives ; *Alzheimer Disease/drug therapy ; Drug Design ; Humans ; *Urea/pharmacology/chemistry/analogs &amp; derivatives/chemical synthesis ; Stereoisomerism ; *Cholinesterase Inhibitors/pharmacology/chemistry/chemical synthesis ; Molecular Docking Simulation ; Structure-Activity Relationship ; Monoamine Oxidase/metabolism ; Acetylcholinesterase/metabolism ; Animals ; Amyloid beta-Peptides/metabolism ; },
abstract = {A series of novel chiral urea and thiourea compounds were designed as multitarget-directed ligands for Alzheimer's disease and evaluated against hAChE, hBChE, and hMAO-B, with exploratory assessment of HSD10. These chiral compounds were synthesized and fully characterized, and their enantiopurity was confirmed via HPLC. Biological screening revealed that several of the 38 single-enantiomer derivatives exhibited potent triple inhibition of hAChE, hBChE, and hMAO-B. Biological screening revealed that a significant number of the 38 synthesized single-enantiomer urea and thiourea derivatives potent inhibition across the primary target panel. Among them, compounds 14S (hAChE: 0.08 μM, hBChE: 0.93 μM, hMAO-B: 0.02 μM), 23R (hAChE: 0.06 μM, hBChE: 0.74 μM, hMAO-B: 0.08 μM), 6S (hAChE: 0.08 μM, hBChE: 0.65 μM, hMAO-B: 0.08 μM), and 30S (hAChE: 0.04 μM, hBChE: 0.74 μM, hMAO-B: 0.19 μM) showed the most promising multitarget profiles. Compounds 6S and 23R also displayed anti-Aβ aggregation activity, whereas 12S combined dual hMAO-B/hAChE inhibition with antioxidant activity. Compounds 3R and 11R were found to be highly active against hMAO-B (0.03 μM and 0.06 μM, respectively) and hBChE (0.68 and 0.72 μM). HSD10 inhibition was limited overall, with only compound 26S showing moderate activity (52.2%) at higher micromolar concentration. Molecular docking and molecular dynamics simulations supported the proposed ligand-target interactions for the most active compounds. In addition, selected derivatives showed no acute cytotoxicity under the tested conditions in HepG2 cells and high permeability potential in the PAMPA-BBB assay. Based on their in vitro profiles, seven compounds (3R, 6S, 11R, 12S, 14S, 23R, and 30S) were advanced to in vivo evaluation, and compounds 6S, 12S, and 23R, 30S produced significant improvements in the Morris Water Maze model. Collectively, these findings identify chiral urea and thiourea derivatives as promising lead structures for further anti-Alzheimer drug discovery.},
}
@article {pmid42403013,
year = {2026},
author = {Tung, TH and Babu, S and Tang, X and Sciutto, AL and Romer, M and Racha, P and Xu, R and Fiesler, V and Saha, A and Thai, T and Saito, T and Saido, TC and Zhao, Y and Grinspan, JB and Mathys, H and Kozai, TDY and Cambi, F},
title = {Fus-depleted oligodendrocytes reduce neuronal damage and Alzheimer's disease progression in the AppNL-G-F mouse.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag234},
pmid = {42403013},
issn = {1460-2156},
abstract = {Alzheimer's Disease (AD) is an age-dependent neurodegenerative disorder and represents the most common type of dementia, increasing in incidence at an alarming rate in the aging population. The hallmarks of the disease are amyloid plaque accumulation, microglia and astrocyte activation, and loss of presynaptic structure leading to cognitive decline. Recently, oligodendrocyte (OL) and myelin abnormalities have emerged as important contributors to the pathogenesis of AD. In normal brain homeostatic conditions, OL maintain neuronal health through myelin axon interactions and by supplying neurotrophic and metabolic support. How strengthening OL function may support neuronal health in AD neurodegeneration remains to be fully characterized and represents a gap in knowledge and a missed therapeutic opportunity. This study sought to examine how myelin and OL may improve neuronal deficits associated with AD. We have generated a novel mouse model (AD/cKO) by crossing the AppNL-G-F mouse, an established AD model, which carries three human AD mutations in the mouse App gene, with the FusOLcKO whose OL depleted of Fus (Fused in Sarcoma) produce thicker myelin associated with greater cholesterol biosynthesis. We evaluated spatial memory function with standardized cognitive testing. We evaluated microglia density and state, astrocytic activation and toxic phenotype, myelin density, cholesterol content, amyloid plaque burden, presynaptic structures, and neuronal hypoxic and oxidative damage in the hippocampus and cortex. We characterized the transcriptome of AD/cKO hippocampal OL compared to AD by using single-cell transcriptomic studies. Spatial working memory was fully preserved in the aged AD/cKO mouse relative to the AD mouse. This outcome was associated with reduced neuronal oxidative damage, preserved presynaptic structures at the amyloid plaque niches, and a shift in microglia state at the niches in both hippocampus and cortex. In contrast, amyloid plaque burden and microglia density were decreased in the hippocampus but not in cortex, uncoupling the neuronal and microglia effects from the amyloid burden. Fus dependent myelin increase was present in both hippocampus and cortex. Single-cell transcriptomics of AD/cKO hippocampal OL revealed upregulation of energy metabolism and antioxidant genes, suggesting a role of OL enhanced energy metabolism in mediating protection of neurons and affecting microglia state in AD pathology. This work provides new insight into how oligodendrocytes may protect neurons in AD, communicate with other glial cellular players, and point to potential targets for disease intervention aimed at slowing AD progression.},
}
@article {pmid42403484,
year = {2026},
author = {Yüksel Dal, D and Kilic, BA and Gamgam, G},
title = {Local brain connectome parameters across the spectrum of clinical cognitive decline.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1840382},
pmid = {42403484},
issn = {1662-4548},
abstract = {Neurological disorders such as Alzheimer's disease, Parkinson's disease, and autism disrupt the brain's structural and functional organization, particularly in specific regions, and ultimately lead to cognitive impairments. In Alzheimer's disease-related dementia, neuronal degeneration impairs structural connectivity between brain regions, which in turn leads to functional breakdowns. This phenomenon, referred to as disconnection syndrome, manifests as connectivity breakdowns in affected regions, with these localized changes indirectly influencing the entire brain network. As the disease progresses, patterns consistent with compensatory-type reorganization have been described in the literature, accompanied by structural and functional changes that have been hypothesized to transiently mitigate cognitive decline during early stages. This study examines the structural and functional reorganization of the brain across the clinical spectrum of Alzheimer's disease by analyzing local nodal changes using measures such as degree, strength, clustering coefficient, and betweenness centrality. Our findings show that early-stage nodal patterns are consistent with this hypothesized reorganization, whereas later-stage changes are dominated by progressive structural decline alongside persistent functional reorganization. Because the present study is cross-sectional and group-level, the compensatory interpretation should be regarded as a working hypothesis rather than a confirmed mechanism, and these exploratory patterns require validation in independent and longitudinal cohorts before clinical translation.},
}
@article {pmid42403668,
year = {2026},
author = {Alshanberi, AM and Nukaly, HY and Mousa, AH and Alhartani, MM and Nassar, JY and Ahmed, RA and Talmesany, TA and Shaikhomer, M and Imam, AA and Abo-Ali, EA and Hassan, FE and Ansari, SA},
title = {Assessment of Dementia Patients Caregivers' Home Safety Knowledge in the Outpatient Setting of Jeddah, Saudi Arabia.},
journal = {Risk management and healthcare policy},
volume = {19},
number = {},
pages = {604540},
pmid = {42403668},
issn = {1179-1594},
abstract = {BACKGROUND: Home safety is a major issue for individuals involved in caring for dementia patients due to a lack of practice and awareness, as it accounts for more than 90% of the needs of patients with dementia. Such caregivers face constant challenges in preventing accidents while trying to maintain the dementia patients' independence and quality of life.<br><br>OBJECTIVE: The objective of this unicentric study was to assess the correlates of dementia patients' caregivers' home safety practices.<br><br>METHODS: A cross-sectional study was conducted in an outpatient setting of a private hospital in Jeddah (Saudi Arabia) from November 2022 until January 2023 by assessing the possible correlation between the caregivers' demographics among 128 dementia patients' caregivers. It also evaluates their service experience including the type of care, assistance duration, duration of caregiving, average time spent with persons living with dementia, dementia care training experience and their home safety practice quality. A questionnaire utilizing selected items from the validated "Alzheimer's Association Home Safety Checklist" was employed to assess the caregivers' home safety practices. Besides, the caregivers' psychological well-being and depression were assessed through a validated "Patient Health Questionnaire-2.<br><br>RESULTS: Although 66% of caregivers showed good home safety practices, 29% of caregivers reported depressive symptoms. Caregivers with extended caregiving duration (more than 5 years) demonstrated significantly better home safety practices as compared to those with shorter duration (AOR: 5.68, 95% CI: 1.76-18.33, p = 0.004). Further, depressed caregivers provided poor service as compared to non-depressed caregivers (AOR: 2.94, 95% CI: 1.19-7.24, p = 0.019).<br><br>CONCLUSION: Short-term and long-term dementia training aligning with cultural values and traditions of Saudi Arabia are required to ensure the care of such persons living with dementia is achieved in an effective and respectful way. Moreover, trained caregivers can improve quality of life, delay institutionalization and reduce healthcare costs.},
}
@article {pmid42403700,
year = {2026},
author = {Coury, SM and Lopez, SD and Savoca, PW and Gaines, EM and Parenti, B and Razon, A and Dosanjh, KK and Labus, JS and Jacobs, JP and Eich, TS and Wong, MD and Callaghan, BL and Silvers, JA},
title = {Does sex moderate health and Alzheimer's disease risk tied to early educational experiences? The reducing inequities through social and educational change follow-up in early adulthood extension study protocol.},
journal = {Brain, behavior, &amp; immunity - health},
volume = {55},
number = {},
pages = {101294},
pmid = {42403700},
issn = {2666-3546},
abstract = {Alzheimer's disease (AD) -a progressive neurodegenerative disorder that is characterized by insidious cognitive decline and distinct neuropathological features- significantly impacts daily life functioning and behavior and is disproportionally prevalent in women compared to men. The reasons and risk factors for sex-based disparities in AD prevalence are still largely unclear, however early life exposures (e.g., education and stress) may be important contributing factors. Therefore, it is increasingly important to disentangle the complex interactions between known early environmental protective and risk factors and genetic susceptibility and uncover how these factors might impact and shape neurobiological processes. Moreover, it is critical to assess how these processes, in turn, influence later cognitive and brain health outcomes that may confer sex-specific pathways of risk for developing AD. In this paper we describe the rationale and study protocol for The Reducing Inequities through Social and Educational Change Follow-Up in Early Adulthood Extension (RISE-Up EA+; R01AG089426) study, a follow-up study of 300 participants aged 24-26 years old that leverages a natural quasi-experimental cohort to investigate how health outcomes tied to socioeconomic mobility opportunity may contribute to sex-specific vulnerability for developing AD later in life. To examine how sex-specific vulnerabilities related to early educational experiences may set the stage for later AD risk, we will assess self-report, cognitive, biological (e.g., inflammation and microbiome), and brain health measures. Results from this work provide the opportunity to better understand how adolescent mobility opportunities might contribute to later life health outcomes and influence sex-specific developmental pathways important for later AD risk.},
}
@article {pmid42403709,
year = {2026},
author = {Fontán-Baselga, T and Cañeque-Rufo, H and Rivera-Illades, E and Gramage, E and Zapico, JM and de Pascual-Teresa, B and Ramos-Álvarez, MDP and Vicente-Rodríguez, M and Herradón, G},
title = {Chronic inhibition of receptor protein tyrosine phosphatase β/ζ reduces amyloid plaque load and modulates pleiotrophin-expressing glial cells, glial-plaque interactions and genes related to amyloid beta clearance.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1839516},
pmid = {42403709},
issn = {1663-9812},
abstract = {Alzheimer's disease (AD) is the most common cause of dementia. Pleiotrophin (PTN) is a neurotrophic factor relevant for central nervous system repair, neuron differentiation and survival. It is upregulated in different neuroinflammatory conditions. PTN is an endogenous inhibitor of Receptor Protein Tyrosine Phosphatase (RPTP) β/ζ. In a previous study, we showed that a short treatment with the RPTPβ/ζ inhibitor MY10 reduced amyloid beta (Aβ) plaque formation and glial activation in old APP/PS1 mice. Nevertheless, these preliminary data required new studies to prove the disease-modifying potential of RPTPβ/ζ inhibition by using younger animals and a longer treatment with MY10. Thus, we have now treated for 3 months five- to seven-month-old wild type (WT) and APP/PS1 mice with MY10. This treatment decreased Aβ plaque formation and increased the number of microglial cells in the dorsal subiculum of APP/PS1 mice. In addition, MY10 reduced the number of GFAP+, not Iba1+, cells surrounding Aβ plaques. As expected, PTN expression was upregulated in the brain of APP/PS1 compared to WT mice and it was mainly found in Iba1+ and GFAP+ cells. Interestingly, treatment with MY10 significantly decreased the expression of PTN and the number of PTN-expressing Iba1+ and GFAP+ cells. MY10 induced a significant decrease of Mmp9 expression in the hippocampus of APP/PS1 mice, a key enzyme in AD progression. In summary, chronic inhibition of RPTPβ/ζ in APP/PS1 mice reduces Aβ plaque deposition, modulating glial-plaque interactions and the expression of specific genes including Ptn and its receptor.},
}
@article {pmid42403869,
year = {2026},
author = {Tuleubayeva, A},
title = {Cardiovascular Biomarkers as a Primary Care Gateway to Early Alzheimer's Disease Detection: The Case for an Integrated Screening Approach.},
journal = {Cureus},
volume = {18},
number = {6},
pages = {e110287},
pmid = {42403869},
issn = {2168-8184},
abstract = {Alzheimer's disease (AD) affects millions of Americans and represents one of the leading causes of disability and healthcare expenditure in the United States. The vast majority of patients are diagnosed at the symptomatic stage, when substantial neuronal loss has already occurred and the therapeutic window for disease-modifying treatment has closed. Recently approved disease-modifying therapies have created an urgent clinical need for pre-symptomatic patient identification. The cardiovascular risk factors most commonly managed in primary care -- hypertension, dyslipidemia, type 2 diabetes, atrial fibrillation, and chronic heart failure -- are among the most powerful modifiable antecedents of AD pathology, operating through systemic inflammation, cerebral small vessel disease, impaired glymphatic clearance, and tau hyperphosphorylation. The biomarkers used to monitor these conditions -- C-reactive protein, cardiac troponin, NT-proBNP, and homocysteine -- reflect active neurodegeneration risk processes already measured routinely in primary care. This clinical perspective proposes a three-stage integrated neuro-cardiological screening protocol linking cardiovascular biomarker assessment to plasma P-tau217 blood testing for AD confirmation. This framework addresses the implementation gap identified in recent United States primary care literature and represents a practical step toward closing the AD diagnostic gap.},
}
@article {pmid42403942,
year = {2026},
author = {Wang, W and He, Y and Xing, H and Zhang, H},
title = {Toward clinical translation of TMS-EEG: an integrative review of multidimensional neurophysiological measures.},
journal = {Frontiers in human neuroscience},
volume = {20},
number = {},
pages = {1804482},
pmid = {42403942},
issn = {1662-5161},
abstract = {Transcranial magnetic stimulation combined with electroencephalography (TMS-EEG) has emerged as a promising noninvasive approach for probing cortical reactivity and network dynamics with millisecond temporal resolution, with growing relevance for mechanistic and clinical neuroscience. However, despite rapid expansion of the field, TMS-EEG findings remain difficult to interpret because of substantial inter-individual variability and fragmentation across distinct analytical domains, including time-domain, spatially integrated, and time-frequency measures. These issues limit cross-study comparability and hinder clinical translation. In this review, we summarize the conceptual basis of TEPs, the physiological interpretation of canonical components (e.g., N15, P30), and commonly adopted analytical considerations. We further synthesize spatially integrated measures, including global and local mean field power (GMFP and LMFP), which quantify distributed cortical responses across multiple electrodes. Time-frequency indices, such as time-related spectral perturbation (TRSP) and inter-trial phase coherence (ITPC), are also reviewed to characterize TMS-induced oscillatory modulations. Drawing on the existing TMS-EEG literature in humans, we outline representative applications of these multidimensional metrics in neuropsychiatric and neurological conditions, including Alzheimer's disease, depression, epilepsy, and stroke. Finally, we discuss key methodological and translational challenges, such as stimulation-related artifacts, inter-individual variability, state-dependency of baseline oscillatory activity, and limited standardization, and highlight how these issues complicate the interpretation of TMS-EEG findings across studies and individuals. Together, this review aims to provide a structured reference framework for integrating and interpreting multidimensional TMS-EEG measures, thereby supporting more consistent understanding of the literature and informing future efforts toward harmonization and clinical translation.},
}
@article {pmid42403969,
year = {2026},
author = {Baquerizo-Burgos, J and Baquerizo-Burgos, E and Puga-Tejada, M and Baquerizo Y Flores, J},
title = {Normative Values for Prosaccade and Antisaccade Eye Movements in Adolescents Using a New Saccadometry Test.},
journal = {Journal of the American Academy of Audiology},
volume = {37},
number = {3},
pages = {197-208},
pmid = {42403969},
issn = {2157-3107},
mesh = {Humans ; *Saccades/physiology ; Adolescent ; Female ; Male ; Child ; Cross-Sectional Studies ; Reference Values ; },
abstract = {BACKGROUND: Saccadic eye movements (SEMs) are rapid, precise movements that reorient the visual fovea toward an object of interest. In clinical practice, assessing SEMs can help in differentiating and monitoring various neurologic, otoneurologic, and psychiatric conditions. Deviations from adequate saccadic patterns offer critical diagnostic information, enabling clinicians to more accurately identify related conditions such as schizophrenia, attention deficit hyperactivity disorder, Alzheimer's disease, and cognitive impairment in vestibular migraine, among others.<br><br>PURPOSE: Establish normative data for prosaccades (PSs) and antisaccades (ASs) in healthy adolescents aged 12-17&#x2009;years.<br><br>RESEARCH DESIGN: A cross-sectional, single-center study conducted between June and December 2023.<br><br>STUDY SAMPLE: Data were reported on 138 healthy participants aged 12 to 17&#x2009;years with no history of head trauma, neurologic, vestibular, behavioral, or psychiatric disorders, and use of medications affecting SEMs.<br><br>RESULTS: This study included 138 participants (mean age, 14.5 years; 44.2 percent female). A mean accuracy, latency, velocity, and directional error (DE) of 91.5 percent, 211 milliseconds (ms), 249.5 degrees per second (&#xb0;/s), and 0.8 percent in PSs and 117.0 percent, 304.7 ms, 249.8&#xb0;/s, and 11.8 percent for ASs were obtained, respectively. Significant reductions were found in horizontal random saccade velocity (p = 0.027), PS velocity (p = 0.001), AS latency (p < 0.001), and DE (p < 0.001) from younger to older adolescents. With age maturation, ASs' latency and DE showed a significant reduction. Compared with females, male participants have lower AS latencies (p < 0.041). Younger males (<15&#x2009;years) have higher PS velocities (p = 0.02). Young females and males have higher latencies (p = 0.031 and p < 0.01, respectively) and DE (p < 0.01 and p < 0.01, respectively) than the older participants (&#x2265;15&#x2009;years) in ASs.<br><br>CONCLUSIONS: This study established normative data for PSs and ASs for individuals aged 12-17 years using commercially available equipment. The findings indicate age-related variations, particularly in AS latency and DE.<br><br>CLINICAL RELEVANCE STATEMENT: The normative values obtained in this study could assist clinicians in the detection of cognitive control impairment or oculomotor dysfunction, and support complementary diagnostic tools in differentiating neurologic, vestibular, behavioral, or psychiatric disorders affecting adolescents.},
}
@article {pmid42404124,
year = {2026},
author = {Hu, G and Feng, L and He, L and Liu, N and Wang, H},
title = {Sequential [18]F-AV45/[18]F-AV1451 dual-tracer brain PET imaging in Alzheimer's disease: amyloid-tau deposition, diagnostic performance, cognitive associations, and modulation by APOE ε4.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1877217},
pmid = {42404124},
issn = {1664-2295},
abstract = {OBJECTIVE: Alzheimer's disease (AD) is neuropathologically defined by amyloid-β (Aβ) plaques and tau neurofibrillary tangles. The AT(N) framework underscores the importance of in vivo dual-pathology imaging, yet large-scale clinical data on sequential [18]F-AV45 (Aβ) and [18]F-AV1451 (tau) PET remain limited. This study aimed to characterize Aβ-tau deposition, evaluate the pathological discriminatory performance of dual-tracer PET for typical amnestic AD, investigate cognitive correlations, and examine the modulatory role of APOE ε4 in a large clinical cohort.<br><br>METHODS: We conducted a retrospective cross-sectional study of 438 participants, including 325&#x202f;AD patients, 68 mild cognitive impairment (MCI) patients, and 45 healthy controls (HC). All underwent sequential [18]F-AV45 and [18]F-AV1451 PET/CT. SUVRs were calculated in whole brain and 10 predefined regional ROIs, with the inferior cerebellar cortex as reference. Z-score normalization and binary logistic regression models were adopted to combine dual-tracer SUVR data for diagnostic performance assessment. Cognitive assessments included MMSE, MoCA, and ADAS-Cog. Statistical analyses comprised ANOVA, ROC (DeLong's test), Pearson correlation, and multivariable linear regression.<br><br>RESULTS: Whole-brain and regional SUVRs for both tracers were significantly higher in AD than in MCI and HC (all p&#x202f;<&#x202f;0.001), with peak uptake in the temporoparietal lobe. The dual-tracer strategy with standardized combination methods yielded superior pathological discriminatory efficacy for typical amnestic AD compared with single tracers, with an AUC of 0.97 for AD versus HC and 0.93 for AD versus MCI. Tau deposition showed stronger cognitive correlations than A&#x3b2;. Tau burden and APOE &#x3b5;4 were independent predictors of cognitive impairment. A&#x3b2; and tau SUVRs were strongly correlated (r&#x202f;=&#x202f;0.65-0.81), most prominently in the precuneus and inferior temporal gyrus. APOE &#x3b5;4 carriers exhibited significantly higher A&#x3b2; and tau deposition.<br><br>CONCLUSION: Sequential [18]F-AV45/[18]F-AV1451 dual-tracer PET enables accurate in vivo characterization of AD-related A&#x3b2;-tau pathology, and standardized combined analysis further improves its ability to distinguish typical sporadic amnestic AD from other groups. Tau is an independent driver of cognitive decline, while A&#x3b2; remains relevant for amyloid-targeted therapies. APOE &#x3b5;4 modulates A&#x3b2;-tau interactions. Dual-tracer PET is a robust tool for clinical AD evaluation, pathological staging, and therapeutic monitoring of typical amnestic AD.},
}
@article {pmid42404237,
year = {2026},
author = {Dobrushina, M and Krohn, F and Chandni, S and Dietrich, L and Glanz, W and Butryn, M and Hämmerer, D and Penalba-Sánchez, L},
title = {Behind the scenes of a 7T MRI clinical study in Alzheimer's disease: challenges and recommendations for future research.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1731961},
pmid = {42404237},
issn = {1663-4365},
abstract = {Combining pharmacological interventions with neuroimaging in Alzheimer's disease (AD) research presents logistical and methodological challengesparticularly during early study phases, such as recruitment and study visits. Yet, these challenges are rarely reported in detail. This perspective article shares early-phase experiences from a 7-tesla (7T) fMRI clinical study involving individuals with mild cognitive impairment due to AD (MCI-AD) and mild Alzheimer's disease dementia (mild ADD), highlighting recruitment hurdles and offering practical recommendations. From a pool of 1,001 patients, 476 had a clinical diagnosis of MCI-AD or mild ADD; after pre-selection and screening, only 48 participants (10%) met all inclusion criteria. Major exclusion factors included metal or tattoos (8%), missing surgical documentation (2%), beta-blocker use (27.5%), recent cancer/chemotherapy or brain radiation (1%), and lack of interest (20%). Effective communication, often requiring caregiver assistance, was essential for obtaining accurate medical histories and improving adherence. Internally, clear team coordination supported scheduling and protocol compliance. While strict eligibility criteria improve data quality, they can substantially limit recruitment and feasibility in pharmacological and high-field MRI drug studies. We propose strategies to optimize recruitment and screening, facilitate data collection, and balance scientific rigor with real-world clinical feasibility.},
}
@article {pmid42404238,
year = {2026},
author = {Li, N and Jiang, K and Peng, X and Yang, C and Xiong, W and Wang, W},
title = {Ershiwuwei Shanhu Pill ameliorates cognitive impairment in Alzheimer's disease mice by remodeling gut microbiota and host serum metabolites.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1820691},
pmid = {42404238},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD), with the most prominent pathological feature of the accumulation of amyloid-beta (Aβ) plaques and neurofibrillary tangles of hyperphosphorylated tau proteins (P-tau), is the foremost cause of dementia. Ershiwuwei Shanhu Pill (ESP) is commonly used in clinical practice in Tibetan areas to treat AD, and has been shown to alleviate cognitive impairment. However, whether ESP exerts its therapeutic effects by modulating the gut microbiota and serum metabolites remains unclear. In this study, APPswe/PSEN1dE9 transgenic (APP/PS1) mice (n = 11 per group) were treated with ESP (200 mg/kg, oral gavage) daily for 2 months and evaluated using the Morris Water Maze (MWM), brain histopathology, immunofluorescence, 16S rRNA sequencing, and untargeted serum metabolomics. ESP improved cognitive performance, reduced Aβ deposition and P-tau levels, and attenuated neuroinflammation. Concurrently, ESP significantly reshaped the gut microbiota (e.g., increasing Dubosiella and decreasing Bacteroides) and altered serum metabolites involved in tryptophan metabolism and glycolysis pathways (e.g., elevating Fructose 1,6-bisphosphate and reducing N-Acetylserotonin). In conclusion, these neuroprotective effects of ESP are associated with a remodeling of the gut microbiota and metabolic profile, providing a pharmacological basis for its clinical application and novel insights into AD intervention via the gut microbiota-metabolite-brain axis.},
}
@article {pmid42404289,
year = {2026},
author = {Larson, ST and Susman, JL},
title = {Navigating Alzheimer's Disease in Primary Care: Practical Strategies for Diagnosis and Management.},
journal = {International journal of general medicine},
volume = {19},
number = {},
pages = {603347},
pmid = {42404289},
issn = {1178-7074},
abstract = {Alzheimer's disease (AD), the most common form of dementia, is a neurodegenerative disorder that primarily affects older adults. Because the number of Americans 65 years of age and older living with AD is expected to increase and the availability of specialty physicians, such as neurologists and geriatricians, is limited, the role of primary care in diagnosing and managing patients with AD is expected to grow. Several guidelines for primary care providers are available for the evaluation, diagnosis, and treatment of patients with AD. However, there is no single concise and convenient reference tool for use in the primary care setting. In the primary care setting, clinicians are responsible for identifying patients at risk or demonstrating signs of cognitive impairment, administering cognitive tests, identifying appropriate referrals, and, in some cases, ordering blood-based biomarker testing. Although definitive testing and treatment identification may occur in the specialty care setting, in addition to serving as the hub to coordinate the multidisciplinary care team, primary care clinicians remain responsible for guiding patients and caregivers through shared decision-making regarding treatment, as well as the myriad responsibilities related to comorbidities, patient and caregiver psychological well-being, social support, and safety. This review aims to provide practical recommendations to primary care clinicians for the diagnosis, management, and long-term care of patients with AD.},
}
@article {pmid42404296,
year = {2026},
author = {You, X and Guo, Z},
title = {Multimodal Neuroimaging Mechanisms of Apathy in Alzheimer's Disease: A Narrative Review of Structural, Functional, and Molecular Evidence.},
journal = {International journal of general medicine},
volume = {19},
number = {},
pages = {622802},
pmid = {42404296},
issn = {1178-7074},
abstract = {Apathy is the most common neuropsychiatric symptom in Alzheimer's disease (AD) and is conceptualized as a pathological reduction of goal-directed motivation and behavior. It is currently believed that apathy has an independent neurobiological basis rather than merely accompanying cognitive decline. This narrative review synthesizes evidence from structural, functional, and molecular neuroimaging studies published up to 2025, identified through targeted PubMed searches and reference tracking, without applying formal systematic inclusion/exclusion criteria. Existing imaging evidence indicates that the core mechanism of apathy lies in the specific impairment of the prefrontal-basal ganglia motivational circuit: gray matter atrophy and hypometabolism in the anterior cingulate cortex (ACC) and orbitofrontal cortex are closely associated with impaired motivation integration and reward evaluation, whereas structural damage to the dorsolateral prefrontal cortex contributes to executive planning deficits. Functional network analysis further reveals suppression of the default mode network and ineffective compensation of the central executive network. Molecular imaging studies confirm that structural degeneration of the locus coeruleus, dopaminergic presynaptic transmission dysfunction, and synergistic pathological accumulation of amyloid-beta and Tau proteins in the motivational circuit collectively constitute the neurobiological basis of apathy. Furthermore, computational modeling has already been employed as an analytical framework to dissect these mechanisms, revealing altered effort-based decision-making and abnormal frontoparietal connectivity. Given the frequent impairment in self-awareness (anosognosia) regarding their own apathy in AD, informant-based assessments are essential for accurate clinical evaluation. Ultimately, integrating these multimodal biomarkers may facilitate early identification and stratified interventions, including dopaminergic and noradrenergic pharmacotherapies as well as non-invasive brain stimulation techniques such as transcranial magnetic stimulation (TMS).},
}
@article {pmid42404383,
year = {2026},
author = {Ramirez-Perez, N and Solis, I and Martinez, L and Bonillas Felix, N and Medrano, R and Ribas, A and Silva, GE and Martinez, JE and Giudicessi, A and Munera, D and Alcina, J and Vila-Castelar, C and Gonzalez Catalan, M and Ramirez-Gomez, LA and Saldana, D and Quiroz, YT},
title = {The Latin American Spanish PACC5 (LAS-PACC5): Advancing Cognitive Assessment in Latinos.},
journal = {Alzheimer's &amp; dementia (Amsterdam, Netherlands)},
volume = {18},
number = {1},
pages = {e70311},
pmid = {42404383},
issn = {2352-8729},
abstract = {INTRODUCTION: To address the need for validated Spanish-language cognitive assessments in Latino populations at risk for Alzheimer's disease (AD), we evaluated the psychometric performance of a Latin American Spanish adaptation of the Preclinical Alzheimer's Cognitive Composite-5 (LAS-PACC5).<br><br>METHODS: A total of 121 Spanish-speaking older adults from the Boston Latino Aging Study (BLAST; Mean age&#xa0;=&#xa0;64.98&#xa0;&#xb1;&#xa0;6.98 years; 69% female) were included. The LAS-PACC5 replaced literacy-dependent tasks with culturally and linguistically appropriate measures. Convergent validity was examined using measures validated in diverse Spanish-speaking populations.<br><br>RESULTS: LAS-PACC5 showed moderate associations with naming ability, episodic memory, and global cognition (all p's&#xa0;<&#xa0;0.001) and differentiated cognitively unimpaired (n&#xa0;=&#xa0;98) from impaired participants (n&#xa0;=&#xa0;23; p&#xa0;=&#xa0;0.005). Results were consistent across alternative cognitive classification approaches.<br><br>DISCUSSION: The LAS-PACC5 demonstrated convergent and discriminative validity, supporting its utility for early cognitive assessment in Spanish-speaking older adults and for improving Latino representation in AD Research.},
}
@article {pmid42404415,
year = {2025},
author = {Kazemi, S and Hesni Langroudi, N and Hasani Abharian, P and Tavakol, K and Joghataei, MT and Tavakol, S and Arbabi Bidgoli, S},
title = {Short-term Efficacy of Commercial Curcumin Nanomicelle on Cognition, Oxidative Stress and Choline Esterase in Alzheimer's Disease.},
journal = {Basic and clinical neuroscience},
volume = {16},
number = {3},
pages = {595-608},
pmid = {42404415},
issn = {2008-126X},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disease accompanied by cognitive dysfunction. Preclinical changes can precede the onset of clinical symptoms by decades, highlighting the need for preventative and therapeutic strategies to mitigate or delay disease progression. This pilot clinical trial aimed to investigate the effects of commercially available curcumin nanomicelles on oxidative stress pathways and serum cholinesterase levels in patients with AD.<br><br>METHODS: Fifteen volunteers with mild-to-severe AD and 15 age-matched healthy controls were enrolled. Participants with AD received 80 mg of thermodynamically stable 10 nm curcumin nanomicelles on alternate days for two months. Cognitive function, as assessed by the mini-mental state examination (MMSE), did not exhibit significant changes in patients with AD following curcumin nanomicelle administration (19.8 versus 20.6). Serum levels of oxidative stress biomarkers, including catalase (CAT), superoxide dismutase (SOD) inhibition, malondialdehyde (MDA) concentration, and cholinesterase activity, were evaluated before and after intervention.<br><br>RESULTS: The results showed no significant differences in cognition improvement, CAT activity, SOD inhibition, MOD concentration, or cholinesterase activity between patients with AD and healthy controls or before and after curcumin nanomicelle administration.<br><br>CONCLUSION: Although curcumin nanocarriers did not enhance antioxidant biomolecule levels, they did not provoke lipid peroxidation. Therefore, this study suggests that optimizing nanocarrier parameters, including concentration, particle size larger than 10 nm, and blood-brain barrier (BBB)targeting, warrants further investigation in a long-term study to explore their potential as supplemental therapies for AD.},
}
@article {pmid42404420,
year = {2025},
author = {Zhang, P and Xiao, H},
title = {Vitis Vinifera L. Flavones Preserve Mitophagy in the Amyloid-beta 1-42-induced Model of Alzheimer's Disease Neurodegeneration.},
journal = {Basic and clinical neuroscience},
volume = {16},
number = {3},
pages = {641-656},
pmid = {42404420},
issn = {2008-126X},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by amyloid-beta (Aβ) accumulation, leading to inflammation, oxidative stress, and impaired synaptic function. This study aimed to investigate the neuroprotective mechanisms of Vitis vinifera L. flavones (VTF) against Aβ-induced neurodegeneration and their potential as AD therapeutics.<br><br>METHODS: In an in vitro analysis, A&#x3b2;1-42 oligomers were used to induce mitophagy in SHSY5Y neuroblastoma cells. Cells were treated with VTF alone and in combination with chloroquine (CQ), a lysosomal inhibitor, to assess A&#x3b2;1-42-induced mitophagy. Transmission electron microscopy (TEM) and immunofluorescence (IFC) were used to investigate the effects of A&#x3b2;1-42 on autophagosomes and deposition. Cellular protection against A&#x3b2;-induced damage was assessed using the Cell Counting Kit-8 (CCK-8) assay. Western blotting (WB) was used to determine the expression of autophagy-lysosomal pathway proteins (Beclin-1, Atg7, p62, and BACE1) and the LC3-II/LC3-I ratio, which serves as a marker of autophagy.<br><br>RESULTS: CQ and VTF demonstrated significant neuroprotection against A&#x3b2;1-42-induced neurodegeneration (P<0.05). VTF, alone or with CQ, increased viable cell count (~1.2-fold; P<0.05), indicating reparative capabilities. TEM and IFC showed robust protection by VTF and CQ against A&#x3b2; protein deposition, as well as preservation of mitochondrial and autophagosomal structures. VTF and CQ treatments reduced Beclin-1, Atg7, and BACE1 levels, indicating the modulation of mitophagy and autophagy-lysosomal suppression. VTF+CQ maintained LC3-II/LC3-I balance, confirming VTF's role in preserving autophagy (P<0.01).<br><br>CONCLUSION: This study reveals the novel neuroprotective role of VTF, emphasizing its potential as an AD therapeutic. Future research should extend investigations to in vivo models and clinical settings to enhance our understanding of VTF's neuroprotective efficacy.},
}
@article {pmid42404421,
year = {2025},
author = {Mansouri, Z and Motamedi, F and Khodagholi, F and Zahmatkesh, M},
title = {Histone Deacetylase Class IIb Inhibition Improves Amyloid-β-induced Learning and Memory Deficits in Male Rats.},
journal = {Basic and clinical neuroscience},
volume = {16},
number = {3},
pages = {583-594},
pmid = {42404421},
issn = {2008-126X},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a neurodegenerative disease associated with progressive impairment of cognitive function. The primary pathological features of AD include aggregation of amyloid-β (Aβ) and hyperphosphorylation of the tau protein. Histone deacetylases (HDACs) play a crucial role in the pathophysiology of neurodegenerative diseases. This study aimed to investigate the potential neuroprotective effects of HDAC6 and HDAC10 inhibition in a rodent model of AD.<br><br>METHODS: Learning and memory deficits were induced by bilateral intra-hippocampal A&#x3b2; injections in male Wistar rats. Tubacin (HDAC6 inhibitor) and bufexamac (HDAC6 and 10 inhibitors) were microinjected 30 minutes after A&#x3b2; injection. The possible molecular changes in the hippocampus following A&#x3b2; injection were also assessed by western blotting analysis of pCREB/CREB and Pp70/P70 ratios.<br><br>RESULTS: Our results revealed that bufexamac significantly recovered learning and memory impairments induced by A&#x3b2; in the Morris water maze (MWM) task. Tubacin improved memory decline without affecting learning. Bilateral intra-hippocampal injection of each of the HDAC inhibitors significantly increased the pCREB/CREB and Pp70/p70 ratios compared to the A&#x3b2; group, which was concurrent with behavioral alterations.<br><br>CONCLUSION: HDAC IIb treatment may be a promising strategy for improving learning and memory impairments in an animal model of AD, suggesting that HDAC targeting is a valuable strategy for further investigation.},
}
@article {pmid42404434,
year = {2026},
author = {Lao, PJ and Lee, S and Talmasov, D and Dass, D and Chikwem, N and Johnson, A and Smith, A and Guzman, D and Okafor, A and Houlihan, H and Heuer, L and Sanchez, T and Maldonado, A and Palacios, C and Rossano, S and Andrews, H and Reitz, C and Kreisl, WC and Noble, JM and Qureshi, YH and Small, SA},
title = {Inflammatory alterations mediate tau-associated neurodegeneration.},
journal = {Brain communications},
volume = {8},
number = {4},
pages = {fcag242},
pmid = {42404434},
issn = {2632-1297},
abstract = {Microglia monitor and respond to the brain's microenvironment to maintain homeostasis. However, in Alzheimer's disease and related dementias, chronically pro-inflammatory microglia may contribute to pathology. We hypothesized that inflammatory alterations, measured as microglia density via 18 kDa translocator PET, would be elevated with a topography similar to tau, be most strongly associated with tau compared to amyloid and neurodegeneration, and mediate pathways among amyloid, tau and neurodegeneration. Participants (21 cognitively unimpaired, 25 cognitively impaired) from the Longitudinal Imaging of Microglial Activation in Different Clinical Variants of Alzheimer's Disease study underwent baseline amyloid PET (Florbetaben standard uptake value ratio), tau PET (MK6240 standard uptake value ratio), 18 kDa translocator PET (ER176 standard uptake value ratio) and structural MRI (grey matter volume). Biomarkers were quantified in 13 a priori regions of interest. Cognitive assessments and consensus diagnoses were performed at the Columbia Alzheimer's Disease Research Center with biomarker information when available to define cognitive impairment. We evaluated cross-sectional regional colocalization of microglia density and amyloid, tau and neurodegeneration biomarker elevations in cognitively impaired individuals compared to amyloid-negative cognitively unimpaired individuals, microglia density associations with amyloid, tau and neurodegeneration biomarkers and microglia density mediation pathways among amyloid, tau and neurodegeneration. Exploratory analyses were stratified by amyloid positivity. Across all cognitively impaired individuals with different underlying brain microenvironments to which microglia are sensitive, higher microglia density colocalized with greater tau (10 regions) more often than with amyloid (8 regions) and neurodegeneration (4 regions), was associated with greater tau (β = 0.29-0.67 in cingulate, lingual and parietal regions) and neurodegeneration (β = -3.6 to -0.14 in limbic and medial temporal regions), and mediated tau-associated neurodegeneration (β = -0.44 to -0.26 in limbic, temporal and parietal regions). In the context of amyloid-positivity, microglia may also mediate amyloid-associated tau (β = 0.24-0.25 in parietal regions) and tau spreading (β = 0.09-0.12 across progressive Braak stage regions), whereas amyloid may not be necessary for tau-associated neurodegeneration, particularly in limbic regions (β = -0.46 to -0.37 in amyloid-negative individuals with cognitive impairment alone). Glia may represent a promising target for intervening on tau-associated neurodegeneration across individuals with cognitive impairment.},
}
@article {pmid42404763,
year = {2026},
author = {Wang, X and Piao, Y and Xia, B and Chu, W and Yao, X and Li, W},
title = {Diet, gut microbiota, and the gut-brain axis: mechanistic interactions and therapeutic implications in neuropsychiatric disorders.},
journal = {Frontiers in cellular and infection microbiology},
volume = {16},
number = {},
pages = {1834069},
pmid = {42404763},
issn = {2235-2988},
mesh = {Humans ; *Diet ; *Gastrointestinal Microbiome/physiology ; *Mental Disorders/therapy/microbiology ; *Brain ; Animals ; Dysbiosis ; *Brain-Gut Axis/physiology ; Probiotics/therapeutic use ; Fecal Microbiota Transplantation ; },
abstract = {The gut microbiota is a dynamic trans-kingdom ecosystem that contributes to host immunological, metabolic, and neuroendocrine homeostasis through the microbiota-gut-brain axis (MGBA). Diet is one of the major environmental factors shaping this axis, as it influences microbial composition, microbial production of neuroactive metabolites, and intestinal barrier integrity. Dysbiosis has been increasingly associated with neurological, psychiatric, and neurodevelopmental disorders, including Alzheimer's disease, Parkinson's disease, depression, autism spectrum disorder, and attention-deficit/hyperactivity disorder. Experimental studies have identified several potential mechanisms linking gut microbiota to brain function, including immune modulation, vagus nerve signaling, microbial metabolite production, and blood-brain barrier regulation. However, translating these findings into clinical practice remains challenging because human studies are affected by genetic heterogeneity, dietary variation, medication use, lifestyle factors, and disease-specific confounders. In this review, we summarize current evidence on the interactions among diet, gut microbiota, and brain function, with particular emphasis on microbial metabolites, immune mediators, and barrier-related mechanisms. We also critically discuss microbiota-targeted interventions, including precision nutrition, probiotics, and fecal microbiota transplantation, highlighting both their therapeutic potential and their current limitations. A more cautious and mechanistically integrated understanding of the MGBA may support the development of personalized strategies for neuropsychiatric disease prevention and management.},
}
@article {pmid42404899,
year = {2026},
author = {Oh, SJ and Shin, OS and Hur, JY},
title = {From infection to dysfunction: viral triggers and antiviral immune factors in Alzheimer's disease pathology.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1839357},
pmid = {42404899},
issn = {1664-3224},
mesh = {Humans ; *Alzheimer Disease/immunology/pathology/virology ; Animals ; *Virus Diseases/immunology ; Brain/immunology/virology/pathology ; Host-Pathogen Interactions/immunology ; SARS-CoV-2/immunology ; },
abstract = {Neurodegenerative diseases and neurocognitive disorders increasingly appear to share a common and underappreciated contributor: the viral-immune axis in the brain. This review presents current evidence linking neurotropic viruses and host antiviral immunity to the onset and progression of neurodegeneration and neurocognitive dysfunction. We explore how viral infections, particularly by Herpesviruses, Severe Acute Respiratory Syndrome Coronavirus 2, and Human Immunodeficiency Virus, disrupt neural homeostasis through neuroinflammation, amyloidosis, tauopathy, and autophagy dysregulation in neurodegeneration including Alzheimer's disease (AD). Simultaneously, host antiviral mechanisms, including type I interferons and interferon regulatory factors, often amplify neuronal damage when dysregulated. By examining viral and immune interactions within the neurodegenerative diseases, this review aims to broaden our understanding of the viral-immune axis in the brain and inspire novel approaches to prevention and treatment.},
}
@article {pmid42404903,
year = {2026},
author = {Guo, H and Yang, Z and Cheng, L},
title = {Cholinergic regulation of neuroinflammation: linking microglia, immunometabolism, and neuromodulation.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1837643},
pmid = {42404903},
issn = {1664-3224},
mesh = {Humans ; *Microglia/metabolism/immunology ; Animals ; *Neuroinflammatory Diseases/metabolism/immunology ; *Neuroimmunomodulation ; Signal Transduction ; Receptors, Cholinergic/metabolism ; },
abstract = {Neuroinflammation is increasingly recognized as a core pathological process in various neurological diseases, including neurodegenerative disorders, stroke, autoimmune demyelinating diseases, and acute brain dysfunction associated with systemic inflammation. Among its regulatory mechanisms, the cholinergic anti-inflammatory pathway links neural activity with immune regulation. However, its neurological relevance extends beyond the classical peripheral vagus nerve-mediated inflammatory reflex. Within the central nervous system, cholinergic signaling interacts with resident immune cells, particularly microglia, and influences inflammatory tone, neuronal vulnerability, and tissue repair. Recent advances in immunometabolism further suggest that metabolic reprogramming may bridge cholinergic signaling and microglial inflammatory phenotypes. In this review, we discuss the role of cholinergic regulation of neuroinflammation from three interrelated perspectives: microglia as the hub of core cells, immune metabolism as the basis of mechanism, and neural regulation as the frontier of transformation. We first reviewed the cholinergic system and its role in neuroimmune communication, then discussed how cholinergic signals shape microglial state and metabolic process, and finally evaluated its disease-specific evidence in Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis and acute inflammatory brain dysfunction. We will also discuss pharmacological and bioelectronic methods, including targeting cholinergic receptors and vagus nerve stimulation, as emerging therapeutic strategies. By integrating cholinergic biology, microglial heterogeneity, and metabolic reprogramming, this review proposes an updated framework for understanding neuroinflammation in neurology, and highlights the future opportunities for precise neuroimmune intervention.},
}
@article {pmid42404994,
year = {2026},
author = {Gunasekaran, TI and Meena, D and Lee, AJ and Wu, S and Dumitrescu, L and Sperling, R and Hohman, TJ and Huang, J and , and , and Dehghan, A and Tzoulaki, I and Mayeux, R and Vardarajan, B},
title = {Common and rare variant analyses implicate JARID2 in cerebral tau deposition.},
journal = {NPJ dementia},
volume = {2},
number = {1},
pages = {52},
pmid = {42404994},
issn = {3005-1940},
abstract = {Genetic research on Alzheimer's disease (AD) has primarily focused on amyloid-β (Aβ), with fewer studies exploring tau pathology. We performed common variant GWAS on tau-PET SUVRs from A4 (n = 311 preclinical AD) and ADNI (n = 375 across diagnostic groups) cohorts. We complemented this with locus-specific rare variant analyses in 1561 individuals across five cohorts. Genetic findings were evaluated using circulating plasma proteins from the UK Biobank Pharma Proteomics Project (n = 54,129). Polygenic risk scores (PRS) for tau and amyloid-SUVR were tested for association with AD. GWAS identified two loci: rs78636169 (P = 5.76 × 10[-10]) in JARID2 and rs7292124 (P = 2.20 × 10[-8]) near ISX. Rare-variant analysis in JARID2 revealed chr6:15257832:A:G (P = 7.08 × 10[-05]) in harmonized analysis and chr6:15492808:C:T (P = 1.65 × 10[-09]) in rare-variant meta-analysis. Pleiotropy analyses suggested limited overlap between tau- and amyloid-related genetic signals. Gene-based analysis highlighted JARID2, a component of the PRC2 multi-protein complex. Mendelian randomization analysis identified LRRFIP1, a protein that binds with PRC2, as potentially causally linked to tau pathology. Amyloid-PRS, but not tau-PRS, was associated with AD clinical status, with age-dependent effects in APOE-ε4 carriers. Leveraging both GWAS and a large rare-variant cohort, we identified JARID2 as a candidate gene associated with tau pathology and observed patterns consistent with partially distinct roles of Aβ and tau in AD progression.},
}
@article {pmid42405563,
year = {2026},
author = {Riccioppo Rodrigues, G},
title = {Diluting the signal: Class-level pooling and the ecological fallacy in meta-analyses of anti-amyloid monoclonal antibodies.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261467048},
doi = {10.1177/13872877261467048},
pmid = {42405563},
issn = {1875-8908},
abstract = {The recent Cochrane review of amyloid-β-targeting monoclonal antibodies concludes that future research on disease-modifying treatments for Alzheimer's disease should focus on alternative mechanisms. This conclusion rests on class-level pooling of nine pharmacologically heterogeneous agents, only three of which received FDA approval. This analytical decision commits an ecological fallacy at the drug level, diluting the signal of the agents that have modified clinical practice. This commentary situates the review within the broader literature, discusses the methodological origins of the error, and argues for stratified approaches that preserve clinical and regulatory relevance in syntheses of heterogeneous drug classes.},
}
@article {pmid42405963,
year = {2026},
author = {Williams, J},
title = {Correction: Are we fully exploiting genetic discoveries to understand and treat Alzheimer's disease?.},
journal = {Mammalian genome : official journal of the International Mammalian Genome Society},
volume = {37},
number = {1},
pages = {},
doi = {10.1007/s00335-026-10247-y},
pmid = {42405963},
issn = {1432-1777},
}
@article {pmid42406171,
year = {2026},
author = {Wu, H and Xia, J and Shi, Z and Zhang, C and Chen, S and Dai, L and He, L},
title = {Vorinostat Rescues Cognitive Deficits in a Neuroinflammatory Mouse Model: A Study of Sex Differences and the Underlying TLR4/NF-κB Mechanism.},
journal = {Neurochemical research},
volume = {51},
number = {4},
pages = {},
pmid = {42406171},
issn = {1573-6903},
mesh = {Animals ; *Toll-Like Receptor 4/metabolism ; Male ; *Vorinostat/therapeutic use/pharmacology ; Female ; *NF-kappa B/metabolism ; Mice, Inbred C57BL ; Mice ; *Neuroinflammatory Diseases/drug therapy/metabolism/chemically induced ; Lipopolysaccharides ; *Sex Characteristics ; *Cognitive Dysfunction/drug therapy/metabolism/chemically induced ; Signal Transduction/drug effects ; Microglia/drug effects/metabolism ; Neuroprotective Agents/therapeutic use/pharmacology ; Disease Models, Animal ; Hippocampus/drug effects/metabolism ; Histone Deacetylase Inhibitors/therapeutic use/pharmacology ; },
abstract = {With the acceleration of global aging, Alzheimer's disease (AD) poses a significant public health challenge, and effective treatments are still lacking. Neuroinflammation, particularly microglia-mediated inflammation, plays a central role in AD pathogenesis, with the Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) signaling pathway being a key regulator. The histone deacetylase inhibitor (HDACi) Vorinostat (SAHA) has shown anti-inflammatory and neuroprotective potential in preclinical studies. Given the significant sex differences in AD incidence, pathology, and treatment response, this study aimed to systematically investigate the effects of SAHA on lipopolysaccharide (LPS)-induced neuroinflammation and cognitive dysfunction, analyzing its sex-specific effects and underlying mechanisms. An LPS-induced neuroinflammation model was established in male and female C57BL/6 mice via intraperitoneal injection (1 mg/kg) for 7 consecutive days, followed by SAHA (50 mg/kg) gavage intervention for 23 days. Cognitive function was assessed using Y-maze, novel object recognition, and passive avoidance tests. Hippocampal pathology was analyzed via hematoxylin-eosin (HE) staining and Nissl staining. Western blot and quantitative PCR (qPCR) were used to detect hippocampal expression of the TLR4/TRAF6/IKKα/NF-κB pathway, inflammatory factors (IL-6, IL-1β, TNF-α, iNOS), and neuroplasticity-related proteins (BDNF, p-CREB). In vitro experiments using LPS-stimulated BV2 microglia validated SAHA's anti-inflammatory mechanisms via CCK-8, Griess assay, qPCR, and Western blot. Results showed that LPS treatment significantly activated the TLR4/TRAF6/IKKα/NF-κB pathway, upregulated hippocampal pro-inflammatory factors, caused neuronal damage, and impaired learning and memory; these effects appeared more pronounced in female mice, though this observation is exploratory and requires cautious interpretation. SAHA treatment markedly alleviated LPS-induced inflammation, neuropathology, and cognitive deficits. Notably, SAHA appeared to produce differential effects across sexes: female mice showed potentially stronger and more comprehensive improvements in cognitive recovery, downregulation of inflammatory factors, and upregulation of BDNF and p-CREB compared to males, suggesting a possible sexually dimorphic response. In vitro experiments further confirmed that SAHA significantly reduced inflammation in LPS-stimulated BV2 microglia by inhibiting the TLR4/TRAF6/IKKα/NF-κB pathway. In conclusion, this study demonstrates that SAHA exerts neuroprotective effects by inhibiting the TLR4/NF-κB pathway, thereby improving cognitive impairment, and may have a more pronounced protective effect in females. These findings suggest SAHA is a promising drug for treating neuroinflammation-induced cognitive dysfunction and highlight the importance of considering sex as a biological variable in epigenetic therapy for precision medicine.},
}
@article {pmid42406197,
year = {2026},
author = {Saikat, SN and Siam, NH},
title = {Translational potential of medicinal plants for Alzheimer's disease: integrated evidence from molecular mechanisms to preclinical and clinical findings.},
journal = {Natural products and bioprospecting},
volume = {16},
number = {1},
pages = {},
pmid = {42406197},
issn = {2192-2195},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder driven by amyloid-β accumulation, tau hyperphosphorylation, oxidative stress, neuroinflammation, mitochondrial dysfunction, and cholinergic deficits. Despite extensive research, current FDA-approved therapies provide only modest symptomatic relief, underscoring the urgent need for safe and multi-targeted alternatives. This comprehensive review synthesizes evidence from in vitro, in vivo, and clinical studies on 15 medicinal plants and their 21 active compounds with therapeutic relevance to AD. Studies were included based on defined screening criteria: reported neuroprotective activity in at least one AD-related pathway, mechanistic evidence from preclinical or clinical investigations, and publication between 2015 and 2025. Analysis demonstrates that numerous plant extracts and isolated compounds including those from Allium sativum, Bacopa monnieri, Centella asiatica, Crocus sativus, Curcuma longa, Ginkgo biloba, Hericium erinaceus, Melissa officinalis, Nigella sativa, Salvia miltiorrhiza, Vitis vinifera, and others exert neuroprotective actions through convergent mechanisms. These include attenuation of oxidative and inflammatory pathways, inhibition of acetylcholinesterase and BACE-1, suppression of amyloid and tau pathology, enhancement of synaptic plasticity, mitochondrial support, and activation of neurotrophic signaling such as BDNF, TrkB and NRF2. Several compounds, including crocin, crocetin, curcumin, bilobalide, tanshinone IIA, bacosides, thymoquinone, and salvianolic acid B, demonstrate strong mechanistic activity across multiple AD-related pathways. Clinical trials further validate translational potential, with improvements reported in cognitive performance, behavioral symptoms, biomarker regulation, and daily functioning in individuals with mild cognitive impairment, AD, or age-related cognitive decline. Together, the evidence highlights medicinal plants as promising complementary or alternative strategies for modifying disease-relevant mechanisms and supporting cognitive health. Continued high-quality clinical investigations and optimized formulations are essential to advance these candidates toward therapeutic application.},
}
@article {pmid42406259,
year = {2026},
author = {Nguyen, TH and Nguyen, HNT and Pham, MQ and Phung, HTT},
title = {Tetrapeptide inhibitors of BACE-1 revealed by combined data-driven screening and physics-based free-energy refinement.},
journal = {Molecular diversity},
volume = {},
number = {},
pages = {},
pmid = {42406259},
issn = {1573-501X},
abstract = {Alzheimer's disease remains a major global health challenge, and β-site amyloid precursor protein cleaving enzyme 1 (BACE-1) represents a critical therapeutic target as it catalyzes the rate-limiting step in amyloid-β production. While computational studies have extensively explored small-molecule BACE-1 inhibitors, large-scale screening combined with physics-based refinement has rarely been applied to peptide scaffolds. Here, we report an integrated machine learning (ML)-to- free energy perturbation (FEP) pipeline, combining XGBoost-based screening, molecular docking, replicate explicit-solvent molecular dynamics (MD), and absolute FEP calculations, as a multi-stage alternative to single-scoring approaches for tetrapeptide lead discovery against BACE-1. Screening a library of 16,000 tetrapeptides with an XGBoost model prioritized four candidates (HWRE, HWER, WHRR, and HWRQ) for structure-based evaluation. Molecular docking confirmed favorable positioning within the catalytic cleft, while replicate MD simulations revealed multivalent binding through hydrogen bonds, salt bridges to the catalytic dyad (Asp32/Asp228), and hydrophobic contacts with conserved pocket residues; interaction-fingerprint and hotspot analyses provided residue-level guidance for optimization. FEP calculations delivered quantitative thermodynamic ranking, separating three strong predicted binders (HWRE, WHRR, HWRQ; ΔGFEP = - 29.45 to - 32.00 kcal mol[-1]) from the weaker candidate HWER (ΔGFEP = - 14.78 kcal mol[-1]). The three high-affinity peptides share a conserved H/W/R motif with persistent dyad anchoring and dense hydrogen-bond networks, a compact scaffold amenable to peptidomimetic optimization, with HWRE as the top lead across all computational stages. This study delivers experimentally testable tetrapeptide candidate inhibitors and establishes a scalable framework for peptide-based ligand discovery against BACE-1 and related aspartyl proteases.},
}
@article {pmid42406414,
year = {2026},
author = {Zhang, S and Qin, RZ and Ajisafe, MP and Qin, HL},
title = {Sulfonamides: a decade of development in synthetic methods and biological activity studies.},
journal = {Organic &amp; biomolecular chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6ob00639f},
pmid = {42406414},
issn = {1477-0539},
abstract = {Sulfonamides are privileged structural motifs widely found in bioactive molecules and pharmaceuticals, and their derivatives exhibit excellent structural diversity, a feature proven useful for discovering novel therapeutic agents. The development of novel sulfonamide-containing compounds with reduced toxicity, low production costs, and high potency constitutes a research focus in medicinal chemistry. Recent advances in sulfur dioxide insertion, reactions of sulfinate salts, transformation of thiols/disulfides, and sulfonyl precursor coupling have enabled efficient, green, and functional-group-tolerant synthesis of diverse sulfonamides. Moreover, the biological applications and structure-activity relationships of sulfonamides are comprehensively reviewed, including anti-diabetic, antimicrobial, anti-inflammatory, carbonic anhydrase inhibitory, anticancer, and anti-Alzheimer's disease activities, highlighting their critical roles in medicinal chemistry and drug development. In addition, FDA-approved drugs bearing the sulfonamide moiety over the past 50 years are also summarized. It is anticipated that this review will provide medicinal chemists with clear insights for the structural design and development of low-toxicity, high-potency sulfonamide-based drugs targeting numerous life-threatening diseases.},
}
@article {pmid42406507,
year = {2026},
author = {Rachmian-Cooper, N and Shmulevich, R and Akiva, H and Pokorna, S and Dassa, B and Cherqui, U and Malitsky, S and Itkin, M and Kliger, BA and Goliand, I and Salame, TM and Krizhanovsky, V},
title = {Senescent cells accumulate lipid droplets.},
journal = {Aging},
volume = {18},
number = {1},
pages = {768-786},
doi = {10.18632/aging.206390},
pmid = {42406507},
issn = {1945-4589},
mesh = {*Lipid Droplets/metabolism ; Animals ; Humans ; Microglia/metabolism ; *Cellular Senescence/physiology ; *Alzheimer Disease/metabolism/pathology ; Mice ; Fibroblasts/metabolism ; Lipid Metabolism ; Brain/metabolism/pathology ; Senescence-Associated Secretory Phenotype ; Disease Models, Animal ; },
abstract = {Senescent cells (SnCs) are growth-arrested yet remain metabolically active and undergo extensive reprogramming to support their survival and the Senescence-Associated Secretory Phenotype (SASP). SnCs undergo key metabolic changes, including increased glycolysis, altered mitochondrial function and dysregulated lipid metabolism. While these metabolic changes are increasingly recognized, a comprehensive understanding of how they contribute to the pathophysiological effects of SnCs is still lacking. Here, through metabolic profiling, we identified elevated levels of glycolytic metabolites in SnCs, which coincided with an increased presence of lipid metabolites, specifically triacylglycerol derivatives, the precursors of lipid droplets (LDs). We show that SnCs accumulate LDs in a classical primary human fibroblast model, and that senescent microglia upregulate LDs markers in a mouse model of Alzheimer's disease (AD), where they play a pathological role. Single-nucleus analysis of brains from AD patients further revealed an elevated levels of LDs markers in senescent brain cells, including microglia. Previous studies implicated both lipid droplet-containing microglia and senescent microglia in AD pathology. Our findings provide evidence that these may represent the same cell population, in which the co-occurrence of LDs accumulation and the senescent state jointly contribute to their disease-promoting properties.},
}
@article {pmid42399802,
year = {2026},
author = {Kong, L and Zhu, F and Zhang, L and Yang, Q},
title = {Scoping review on orofacial pain management in older adults with dementia.},
journal = {BMC geriatrics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12877-026-07953-2},
pmid = {42399802},
issn = {1471-2318},
abstract = {BACKGROUND/OBJECTIVES: Orofacial pain in older adults with dementia is often overlooked due to cognitive decline and impaired communication, impairing patients' quality of life and exacerbating neuropsychiatric behavioural symptoms. This scoping review aimed to map available evidence regarding prevalence, assessment tools, clinical management strategies and research gaps, with the aim of informing clinical practice and guiding future research.<br><br>METHODS: Systematic literature searches were performed in PubMed, Web of Science, Embase and Cochrane Library from database inception to December 2025. Two independent reviewers performed literature screening and data extraction, and any disagreements were resolved via consensus discussion. Narrative synthesis was adopted to summarise findings, and the review strictly followed PRISMA-ScR guidelines. This review was retrospectively registered on the Open Science Framework on 5 March 2026 (OSF: https://osf.io/qmg64). The literature search was completed prior to registration.<br><br>RESULTS: Twenty one studies were included. Orofacial pain prevalence varied: 7.4%-21.7% in community-dwelling older adults; 11.9% (rest) and 21.9% (mastication) in hospitalised patients; up to 48.8% in nursing home residents with severe dementia. A meta-analysis (n&#x2009;=&#x2009;6115) reported a pooled prevalence of 19.0%. Nearly half (50.3%) of patients without self-reported pain had underlying oral pathological lesions. Based on limited validation studies, the OPS-NVI demonstrates relatively stronger psychometric properties compared to other available tools, though evidence remains preliminary and head-to-head comparisons are lacking, while the OHAT-NL may be suitable for community screening by caregivers. Paracetamol is frequently recommended as a first-line option for mild to moderate pain based on general geriatric pain guidelines, but direct evidence for orofacial pain in dementia is limited. Multidimensional non-pharmacological strategies, including staged oral care, caregiver training and multidisciplinary collaboration, are generally suggested. Major systemic barriers include limited dental service access, insufficient caregiver training, and information fragmentation.<br><br>CONCLUSIONS: Orofacial pain represents a substantial underrecognised burden among older adults with dementia. Immediate priorities include integrating oral health assessment into routine care, promoting scenario-specific use of validated tools, and strengthening caregiver education. Future research should prioritise subtype-specific investigations and translate existing evidence into implementable clinical protocols.},
}
@article {pmid42399884,
year = {2026},
author = {Noppert, GA and Stebbins, RC and Zhang, KP and Kobayashi, L and Langa, KM and Levin, B and Li, C and Aiello, AE},
title = {Associations between immunosenescence and domain-specific cognition in the Health and Retirement Study Harmonized Cognitive Assessment Protocol.},
journal = {BMC biology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12915-026-02679-4},
pmid = {42399884},
issn = {1741-7007},
support = {R01AG075719/NH/NIH HHS/United States ; R01 AG070953/NH/NIH HHS/United States ; },
abstract = {BACKGROUND: Alzheimer's disease and related dementias (ADRD) pose a critical challenge for the aging U.S. population, yet many biological pathways remain unclear. Recent work has focused on whether peripheral immunosenescence contributes to cognitive aging. Using the Health and Retirement Study (HRS), we examined associations between peripheral immunosenescence and domain-specific cognitive function.<br><br>RESULTS: Immune function was associated with general and domain-specific cognition, with variation by sex and immune marker. The CD4&#x2009;+&#x2009;EMRA:Na&#xef;ve T Cell Ratio, CD4&#x2009;+&#x2009;Na&#xef;ve:CD8&#x2009;+&#x2009;EMRA Ratio, and CMV IgG showed the most consistent associations, particularly with general and executive function. A one-SD increase in CMV IgG was associated with 0.06 SD lower executive function (95% CI: -0.07, -0.05), persisting after adjustment for confounders.<br><br>CONCLUSIONS: Associations with peripheral immune markers suggest a potential role for peripheral immunosenescence in cognitive aging. The immune system may be an early contributor to cognitive vulnerability, underscoring the need to integrate immune aging into ADRD research.},
}
@article {pmid42399965,
year = {2026},
author = {Bell, TR and Franz, CE and Fennema-Notestine, C and Sundermann, EE and Hughes, SB and Panizzon, MS and Lerman, I and Elman, JA and Kremen, WS},
title = {Chronic pain as a risk factor for Alzheimer's disease pathology: a longitudinal ADNI study.},
journal = {Alzheimer's research &amp; therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02137-x},
pmid = {42399965},
issn = {1758-9193},
support = {K01AG081559/AG/NIA NIH HHS/United States ; K01AG063805/AG/NIA NIH HHS/United States ; R01AG050595/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: Growing evidence supports chronic pain (CP) as a risk factor for Alzheimer's disease and Alzheimer's disease-related dementias (AD/ADRD). We examined whether CP is associated with longitudinal worsening of AD-related biomarkers, brain structure, and cognition, and whether effects differ by APOE-ε4 status.<br><br>METHODS: Data were drawn from 1,493 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) without baseline dementia (mean age&#x2009;=&#x2009;72.4&#x2009;&#xb1;&#x2009;7.19 years; 48% female). Linear mixed-effects models tested longitudinal change in cerebrospinal fluid (CSF) and positron emission tomography (PET) amyloid-&#x3b2; (A&#x3b2;) and phosphorylated tau (p-tau181), structural MRI indices (AD-related cortical signature, hippocampal and entorhinal volumes, precuneus thickness), and cognitive outcomes (episodic memory, executive function, Mini-Mental State Examination [MMSE]). Models included fixed effects of CP status, APOE-&#x3b5;4 status, time (years since baseline), and their two-way and three-way interactions, adjusting for age, sex, education, baseline A&#x3b2; positivity status, and time-varying depressive symptoms.<br><br>RESULTS: At baseline, 30% of participants (n&#x2009;=&#x2009;452) reported CP and 45% (n&#x2009;=&#x2009;666) were APOE-&#x3b5;4 carriers. CP and APOE-&#x3b5;4 status did not independently predict baseline CSF A&#x3b2;42/A&#x3b2;40, PET A&#x3b2; burden, or CSF p-tau181. Longitudinally, the CP+/&#x3b5;4&#x2009;+&#x2009;group showed greater AD-like changes in CSF A&#x3b2;42/A&#x3b2;40 and CSF p-tau181, thinning of the precuneus (&#x3b2;=-0.09, p<.001) and faster decline in episodic memory (&#x3b2;=-0.08, p<.001), compared to all other groups. Many of these associations remained when excluding participants with MCI or restricting to A&#x3b2;-negative participants.<br><br>CONCLUSIONS: The combination of CP and APOE-&#x3b5;4 carriership was associated with greater longitudinal worsening of brain structure and cognitive function, even among individuals who were A&#x3b2;-negative at baseline. These findings provide in vivo evidence that CP is associated with greater AD-related worsening over time in the context of genetic susceptibility. As evidence accumulates, CP may warrant recognition as a risk factor in dementia prevention frameworks, though causal inferences require further study.},
}
@article {pmid42399983,
year = {2026},
author = {Bavarsad, MS and Pereira, FL and Reinhardt, MM and Satpati, A and Spina, S and Seeley, WW and Jagust, W and Rabinovici, GD and Green, A and Grinberg, LT},
title = {Regional mapping of CSF1R-positive microglia in neurodegenerative diseases and progressive MS, with exploratory presynaptic marker analyses.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-026-03945-6},
pmid = {42399983},
issn = {1742-2094},
abstract = {BACKGROUND: Microglial colony-stimulating factor-1 receptor (CSF1R) is a therapeutic and imaging target, yet the regional, disease-specific distribution of CSF1R-positive microglia in the human brain remains incompletely defined, limiting interpretation of emerging CSF1R-PET signals. We sought to build a cross-disease, multi-region, quantitative map of CSF1R-positive microglia in neurodegenerative conditions and progressive multiple sclerosis (MS) lesions, with an exploratory comparison to presynaptic marker burden.<br><br>METHODS: CSF1R mRNA&#x2011;positive microglia were quantified by RNAscope across six cortical regions (MFG, IFG, ITG, AG, CA1, EC) in early&#x2011;onset Alzheimer's disease (EOAD), late&#x2011;onset AD (LOAD), progressive supranuclear palsy (PSP), and frontotemporal lobar degeneration with TDP-43 inclusions due to progranulin mutation (FTLD&#x2011;GRN), and in primary and secondary progressive MS (PPMS, SPMS) within cortical gray&#x2011;matter plaques, plaque-adjacent gray matter and white matter. Positivity was defined a priori as&#x2009;&#x2265;&#x2009;3 puncta with housekeeping&#x2011;probe pass and negative&#x2011;control verification, counting blinded, and densities were cortical&#x2011;thickness corrected. Iba-1 immunolabeling verified microglial identity. Western blot provided protein&#x2011;level verification. We explored ROI&#x2011;level associations of CSF1R with SV2A and synaptophysin previously measured in the same regions/cases.<br><br>RESULTS: In neurodegeneration, increases were smaller and region&#x2011;specific (e.g., EOAD-ITG/CA1; LOAD-AG; PSP-AG; FTLD&#x2011;GRN-IFG/ITG/AG/EC), with minimal white&#x2011;matter change. In progressive MS, gray-matter CSF1R-positive microglia densities did not differ from controls, whereas SPMS white matter was increased. Exploratory analysis showed that CSF1R and SV2A were positively associated across ROIs in neurodegenerative diseases (e.g., PSP approximately &#x3c1;&#x2009;=&#x2009;0.66), and weakest in LOAD; synaptophysin showed similar patterns, suggesting that regions with higher CSF1R-positive microglia density can coincide with relative preservation of presynaptic markers.<br><br>CONCLUSIONS: A cross&#x2011;disease, region&#x2011;resolved map reveals region&#x2011;specific changes in CSF1R&#x2009;+&#x2009;cell density in neurodegeneration, but only white matter in MS. These findings provide the histological context needed to interpret future CSF1R&#x2011;PET. Prospective studies pairing CSF1R&#x2011;PET with SV2A&#x2011;PET and multiplex tissue profiling are warranted to define microglial states and synaptic outcomes in vivo.},
}
@article {pmid42398567,
year = {2026},
author = {Quach, B and Salehi, S and Roufegarinejad, R and Guleria, VS and Mante, M and Florio, J and Rissman, RA and Winston, CN},
title = {Neuropathological and functional impact of astrocyte-derived extracellular vesicles in an aged model of Alzheimer's disease.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115893},
doi = {10.1016/j.expneurol.2026.115893},
pmid = {42398567},
issn = {1090-2430},
abstract = {Extracellular vesicles (EVs) are lipid-bound particles that transfer cargos between cells. While plasma neuronal-derived EVs (NEVs) from individuals with mild cognitive impairment (MCI) and Alzheimer's disease (AD) have been reported to exhibit high pathogenic potential, this study examined the impact of astrocyte-derived EVs (AEVs) in an aged AD mouse model. Plasma AEVs were isolated from cognitively normal control (CNC), MCI, and AD individuals using GLAST-based immunocapture and AEV size, purity, and tetraspanin were validated by flow cytometry, nanoparticle tracking, and super-resolution microscopy. AEVs pooled by clinical cohort were injected into the hippocampus of 6-month-old female PSAPP mice. Behavioral, biochemical, and neuropathological outcomes were assessed 6 months later. Rotarod assessment revealed significant impairment in motor coordination (p < 0.0001) in mice receiving MCI- and AD-AEVs compared with those receiving CNC-AEVs. While Morris water maze (MWM) also demonstrated that CNC-AEVs injected mice exhibited a trend toward increased target quadrant entries and faster escape latencies, these measures did not reach did not reach statistical significance. No overt changes were observed in the staining of amyloid plaque burden (6E10), and astrogliosis (GFAP). Immunoblotting of 82E1 and 22C11 confirmed Aβ/AAP levels remained similar across all injected mice, whereas increased cortical tau accumulation was observed in MCI- and AD-AEV injected mice. Cerebellar synaptic density (SY-38) remained unchanged. These findings suggest that while human-derived AEVs can precipitate early tau-related changes and motor coordination deficits, they do not significantly alter overall amyloidosis or astrocyte-reactivity at this time point. Further investigation is required to determine the viability of AEVs as biomarkers or therapeutic targets given the subtle nature of the observed structural pathology.},
}
@article {pmid42398608,
year = {2026},
author = {Chen, L and Kang, X and Deng, W and Zhang, Y and Zhao, Y and Song, C and Yang, Z},
title = {Structural characterization of a branched α-glucan from Pseudostellaria heterophylla and its neuroprotective effect against Alzheimer's disease via regulating the microbiota-gut-brain axis.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {153352},
doi = {10.1016/j.ijbiomac.2026.153352},
pmid = {42398608},
issn = {1879-0003},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited therapeutic options. Emerging evidence highlights the gut-brain axis as a promising target, and natural polysaccharides offer multi-target advantages. Here, we isolated and structurally characterized PF30-3, a homogeneous branched α-D-glucan (69.91 kDa) from Pseudostellaria heterophylla, featuring a (1 → 4)-α-d-glucopyranosyl backbone with (1 → 4,6)-α-d-glucopyranosyl branching points. In LPS-stimulated RAW264.7 macrophages, 200 μg/mL PF30-3 significantly inhibited nitric oxide release, restored cell viability, and rebalanced inflammatory cytokines. The in vivo efficacy was first validated in an Aβ1-42-induced zebrafish AD-like model, where 20 mg/kg PF30-3 effectively rescued spatial memory and learning impairments. These findings were further translated to 5 × FAD mice, in which oral administration of 50 mg/kg PF30-3 for 24 consecutive days significantly improved the recognition and spatial memory without observable acute toxicity. Mechanistically, PF30-3 reduced cerebral Aβ deposition in vivo, an effect not attributable to direct aggregation inhibition as shown by ThT and CD assays. Instead, PF30-3 exerted its effects through multiple indirect pathways, including inhibition of glial cell hyperactivation, repair of intestinal barrier integrity, rebalancing of serum inflammatory cytokines, and remodeling of gut microbiota composition, characterized by a decreased Firmicutes/Bacteroidota ratio and enrichment of beneficial genera such as Muribaculum, Bacteroides, and Prevotellaceae_UCG-001. Correlation analyses linked these microbial shifts to improved cognitive outcomes and reduced neuroinflammation. Collectively, these findings demonstrate that PF30-3 exerts neuroprotective effects through modulation of the microbiota-gut-brain axis, highlighting it as a promising natural polysaccharide-based candidate for AD therapy.},
}
@article {pmid42398643,
year = {2026},
author = {Başoğlu, H and Göçmen, AY and Yiğit, E and Aydin-Abidin, S and Uydu, HA and Öztürk, H and Keser, H and Abidin, &#x130;},
title = {Cortical Cholesterol Deficit and Reduced Network Excitability in ApoE-Deficient Mice.},
journal = {Archives of biochemistry and biophysics},
volume = {},
number = {},
pages = {110921},
doi = {10.1016/j.abb.2026.110921},
pmid = {42398643},
issn = {1096-0384},
abstract = {Apolipoprotein E (ApoE) is a key regulator of cholesterol transport in both the periphery and the central nervous system and is the major genetic risk factor for late-onset Alzheimer's disease. Although ApoE deficiency is known to elevate circulating cholesterol levels, its consequences for brain cholesterol homeostasis, synaptic integrity, and cortical network excitability remain incompletely understood. In the present study, ApoE knockout (ApoE[-]/[-]) and wild-type (WT) mice were used to evaluate systemic and brain cholesterol levels, synaptic protein expression, and cortical electrophysiological activity. ApoE deficiency resulted in significantly elevated serum cholesterol levels compared with wild-type mice. In contrast, cortical cholesterol levels were significantly reduced in ApoE[-]/[-] mice, whereas hippocampal cholesterol levels remained unchanged. Consistent with altered cortical lipid homeostasis, synaptophysin (SYP) and postsynaptic density protein-95 (PSD-95) levels were significantly decreased in ApoE-deficient animals. At the functional level, ApoE deficiency was associated with reduced basal cortical network activity, reflected by lower electrocorticographic (ECoG) power. Moreover, pharmacological excitation with 4-aminopyridine (4-AP) produced a markedly attenuated increase in cortical excitability in ApoE-deficient mice. Inflammatory markers, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), showed no differences between WT and ApoE[-]/[-] mice. Similarly, oxidative stress markers measured in cortex and hippocampus did not indicate a consistent increase in oxidative damage. These findings demonstrate that ApoE deficiency is associated with a multilevel disruption characterized by elevated peripheral cholesterol, reduced cortical cholesterol availability, synaptic protein loss, and diminished cortical network excitability under both basal and hyperexcitable conditions. The results highlight a potential link between impaired brain cholesterol homeostasis and altered synaptic network function in the cortex of ApoE-deficient mice.},
}
@article {pmid42398685,
year = {2026},
author = {Tang, Y and Huang, L and Li, W and Gao, T and Shi, N and Zhu, Y and Wang, Y and Nan, J and Zhu, Y and Li, J and Ma, Y},
title = {Efficacy of Non-Invasive Brain Stimulation in Alzheimer's Disease: An Umbrella Review of Meta-Analyses.},
journal = {Neuroscience and biobehavioral reviews},
volume = {},
number = {},
pages = {106844},
doi = {10.1016/j.neubiorev.2026.106844},
pmid = {42398685},
issn = {1873-7528},
abstract = {This umbrella review integrates systematic reviews and meta-analyses to evaluate the efficacy of non-invasive brain stimulation (NIBS) in Alzheimer's disease (AD). We searched seven databases from inception to 20 June 2025 for relevant literature. Effect sizes and 95% confidence intervals were extracted using a structured approach and visualized through effect size heatmaps and evidence mapping. Methodological quality and evidence certainty were assessed using AMSTAR 2 and GRADE, respectively. A total of 42 publications, encompassing 130 primary studies and 5,771 patients, were included. NIBS yielded significant immediate improvements in global cognition, daily living, neuropsychiatric symptoms, memory, language, executive function, global impression, visuospatial function, and cholinergic transmission. Among 119 outcome associations, 57.1% were statistically significant (p < 0.05). Long-term benefits were sustained only in global cognition. Moreover, these techniques exhibited modality-specific effects on cognitive and clinical outcomes. Subgroup analysis identified repetitive transcranial magnetic stimulation (rTMS) as the most effective technique, supported by 16 moderate- to high-quality associations. Transcranial direct current stimulation (tDCS) showed inconsistent results with only three moderate-quality associations, while transcranial alternating current stimulation (tACS) demonstrated potential but limited evidence. Intermittent theta burst stimulation (iTBS) showed no significant cognitive benefits in the limited available evidence. Available safety evidence, though limited, suggests generally mild and transient adverse effects. NIBS, particularly rTMS, shows therapeutic potential for AD, though this is based on preliminary evidence. Future multicenter long-term studies and standardized protocols are needed to facilitate the precise application of NIBS in AD treatment.},
}
@article {pmid42398763,
year = {2026},
author = {Busse, PJ and Brown, ES and Wisnivesky, J and Federman, A and Busse, WW},
title = {Impact of cognitive impairment and depression on asthma in older patients.},
journal = {The journal of allergy and clinical immunology. In practice},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jaip.2026.06.037},
pmid = {42398763},
issn = {2213-2201},
abstract = {Depression and cognitive decline in older adults with asthma are associated with poorer disease control, increased risks for exacerbations, higher healthcare utilization, and greater mortality risk. In this age group, depression and cognitive impairment also negatively impact self-management behaviors and alter perception of asthma symptoms. Conversely, data suggest that in some individuals, asthma can induce depression and cognitive deficits, increasing the risk of dementia, including Alzheimer's disease. Because there is a bidirectional communication between the lungs and brain, asthma, particularly in the aged, may result in functional and structural changes of the central nervous system. Identifying and addressing depression and cognitive decline in older patients is often insufficiently integrated into clinical practice. Asthma in the aged is a distinctive phenotype and is complicated by increased risks for depression and loss of cognition, which collectively compromise management.},
}
@article {pmid42398801,
year = {2026},
author = {Zhang, W and Wang, Y and Tocci, D and Wang, C and Zhang, C},
title = {HDAC11 as a potential therapeutic target for Alzheimer's disease.},
journal = {Drug discovery today},
volume = {},
number = {},
pages = {104730},
doi = {10.1016/j.drudis.2026.104730},
pmid = {42398801},
issn = {1878-5832},
abstract = {Alzheimer's disease (AD) is the leading cause of dementia. It is characterized by amyloid and tau pathological hallmarks, accompanied by synaptic dysfunction, neuroinflammation, and progressive neuronal loss. Although amyloid-reducing antibodies have recently expanded the disease-modifying therapeutic options, no disease-modifying small-molecule therapeutics are currently available for AD. Epigenetic regulators, particularly histone deacetylases (HDACs), have attracted increasing attention as potential therapeutic targets. Among them, HDAC2, 3 and 6 are supported by broad AD-related evidence, whereas HDAC11 has emerged as a mechanistically distinct potential target. As the sole class IV HDAC and a relatively brain-enriched but not brain-specific lysine defatty-acylase, HDAC11 connects lipid metabolism, innate immunity, microglial function, neuroinflammation, and AD-associated pathology. We discuss advances in HDAC11 biology and AD-related pathology, position HDAC11 among other established AD-relevant HDAC isoforms, and discuss progress relating to HDAC11-selective inhibitors. We pay particular attention to target druggability, chemical probe development, blood-brain barrier penetration, pharmacokinetics, safety and off-target liabilities, and translational promise. In summary, HDAC11 is an emerging therapeutic target in AD, but future studies are needed for chemical optimization, for pathological validation using other disease models, and to show safety and efficacy in the AD context.},
}
@article {pmid42398843,
year = {2026},
author = {Guan, L and Lin, M and Zhang, R and Shao, X and Chen, B and Yang, J and Zhao, Z and Huang, P},
title = {Segmentation of the parasagittal dura mater on multi-center 3D-FLAIR MRI.},
journal = {NeuroImage},
volume = {},
number = {},
pages = {122099},
doi = {10.1016/j.neuroimage.2026.122099},
pmid = {42398843},
issn = {1095-9572},
abstract = {The parasagittal dura (PSD), located bilaterally alongside the superior sagittal sinus (SSS), has been increasingly implicated in cerebrospinal fluid-meningeal lymphatic communication, contributing to CSF waste clearance and immune surveillance. We assembled a training set of 55 3D-Fluid-Attenuated Inversion Recovery (3D-FLAIR) scans from Alzheimer's Disease Neuroimaging Initiative(ADNI) and local datasets to train an nnU-Net-based model for automated PSD segmentation (mcPSD-Net). Segmentation performance was assessed against manual ground truth in an independent test set (N=25) containing images acquired from various scanners. Three voxel overlap metrics (DICE, Precision and Recall) and three surface distance metrics (HD, HD95, ASSD) were used to evaluate the accuracy of the mcPSD-Net. Multiple linear regression models were performed to evaluate the associations of PSD volume (normalized by intracranial volume) with age, and sex in the whole ADNI3 dataset and a local community dataset. In the testing dataset, mcPSD-Net achieved good performance (Dice coefficient=0.76; precision=0.84; recall=0.73; HD=21.42mm; HD95=4.00mm; ASSD=0.53mm). Regression analyses demonstrated that PSD volume increased significantly with age in both the ADNI3 (standardized β = 0. 390, p<0.001) and local community dataset (standardized β = 0. 307, p<0.001). Compared to females, males had a significantly larger PSD volume in both datasets (p<0.001 for all). Furthermore, including scanner vendor as a covariate did not improve model fitting in the ADNI3 dataset. In summary, we developed a deep learning model that segments PSD from 3D-FLAIR images acquired using different vendors and imaging protocols, providing a tool for related clinical imaging studies.},
}
@article {pmid42398884,
year = {2026},
author = {Turkelson, A and Ng, YT and Garabedian, R and Gonzalez, R and Benson, L and Birditt, KS},
title = {Your Heart Beats Next To Mine: Daily Physiological Synchrony Among Black And White ADRD Caregiver-Care Recipient Dyads.},
journal = {Biological psychology},
volume = {},
number = {},
pages = {109341},
doi = {10.1016/j.biopsycho.2026.109341},
pmid = {42398884},
issn = {1873-6246},
abstract = {Close relationships are often physiologically synchronous, showing correlated changes in cardiovascular reactivity that vary by relationship quality and predict well-being. Little is known about physiological synchrony among dementia caregiver-care recipient dyads, which may be impacted by the chronic strain of caregiving and functional declines due to dementia. The present study examined physiological synchrony among caregivers and care recipients in daily life using heart rate data and whether synchrony varied by interpersonal tensions, relationship type, and race. A total of 148 Alzheimer's disease and related dementia (ADRD) caregivers (ages 22 to 86; 27% Black; 79% female; 63% spousal caregivers) and their care recipients participated in a 5-day ecological momentary assessment study in which caregivers completed mobile phone surveys every three hours, six times per day, and both caregivers and care recipients wore mobile heart rate monitors 24hours per day. Stability and influence models revealed that caregivers and care recipients were physiologically synchronous in daily life (i.e., past moment heart rate of one dyad member was associated with current moment heart rate of the other dyad member). Physiological synchrony was stronger for spousal and White caregiver dyads, particularly during periods of higher interpersonal tension, whereas Black caregiver dyads exhibited physiological synchrony during periods of lower interpersonal tension. This study adds to the growing literature on physiological synchrony by examining an understudied interpersonal context of dementia caregiving in a diverse sample. Implications of these findings for interventions among ADRD caregiving dyads are discussed.},
}
@article {pmid42398889,
year = {2026},
author = {Musaeus, CS and Waldemar, G and Kjær, TW and Andersen, BB and Høgh, P and Kidmose, P and Fabricius, M and Hribljan, MC and Hemmsen, MC and Rank, ML and Frederiksen, KS},
title = {Epileptiform discharges are associated with increased theta activity over time in patients with Lewy body dementia.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.06.040},
pmid = {42398889},
issn = {1873-7544},
abstract = {Electroencephalography (EEG) slowing and reduced functional connectivity are markers of Alzheimer's disease (AD) and Lewy body dementia (DLB), but the significance of epileptiform discharges to these changes remains unknown. To investigate whether epileptiform discharges are associated with EEG slowing or decreased functional connectivity over time. In this longitudinal observational exploratory study, we included a total of 15 healthy controls, 25 patients with AD, and 10 patients with DLB. The patients underwent conventional resting-state EEG up to three times over 6 months. A baseline ear-EEG recording was used to quantify the number of epileptiform discharges per 24 h. We found that compared to healthy controls, DLB and AD patient groups showed a pattern of slowing and decreased alpha coherence. Epileptiform discharges were not associated with slowing or coherence at baseline. In longitudinal analyses, patients with DLB and epileptiform discharges demonstrated an increase in relative theta power over six months compared with patients with DLB without epileptiform discharges. No significant longitudinal theta-power changes were observed in patients with AD. These findings suggest that while EEG slowing is a characteristic feature of neurodegenerative diseases, epileptiform discharges are not directly associated with baseline EEG theta activity but may be linked to a distinct longitudinal trajectory of theta activity in DLB. Given the small group sizes and unbalanced subgroups analysis, these observations should be considered exploratory and require confirmation in larger longitudinal studies.},
}
@article {pmid42399261,
year = {2026},
author = {Bergendorf, A and Park, JH and Ball, BK and Brubaker, DK},
title = {Modeling single nucleus microglia across species identifies immune pathways and therapeutic candidates in Alzheimer's disease.},
journal = {NPJ systems biology and applications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41540-026-00775-3},
pmid = {42399261},
issn = {2056-7189},
support = {DGE-1842166//National Science Foundation Graduate Research Fellowship Program/ ; NIH T32 predoctoral fellowship T32DK101001/DK/NIDDK NIH HHS/United States ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by memory loss and behavioral changes. A pivotal influence on AD pathology is the dysregulation of microglia in the brain. Despite promising findings in mouse models, there are limitations to the translatable biological information across species due to differences in the physiology, timeline of disease, and human heterogeneity. To address these interspecies discrepancies, we developed a novel implementation of the Translatable Components Regression (TransComp-R) framework, which integrated microglial single-nucleus transcriptomic data to identify biological pathways in mice AD models predictive of human AD. We compared model variations with sparse and traditional principal component analysis (PCA), finding that standard PCA encoded more interpretable mouse PCs compared to sPCA despite limited differences in technical performance. Mouse PCs significantly differentiated human AD from control microglial cells in the BA41/42, BA6/8, hippocampus and entorhinal cortex brain regions. However, these PCs had limited separation of human AD from control microglia in the prefrontal cortex. Additionally, we identified gene signatures from FDA-approved drugs that correlated with significant mouse component loadings, including valproic-acid and calcifediol. This computational framework may support the discovery of cross-species disease similarities, including the identification of candidate pharmacological solutions that may translate across species.},
}
@article {pmid42399299,
year = {2026},
author = {Kang, EH and Choi, SR and Shin, A and Han, M and Lee, EB},
title = {Anemia and risk of dementia in the general population: a propensity-score based cohort study.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-57471-9},
pmid = {42399299},
issn = {2045-2322},
support = {#18-2022-0005//Seoul National University Graduate School of Convergence Science and Technology/ ; RS-2025-02215880//Korea Health Industry Development Institute/Republic of Korea ; },
abstract = {An elevated risk of dementia among anemic population has been reported in previous studies. However, measurement on the risk of individual subtypes of dementia has been limited. We aimed to quantify risk of dementia and its subtypes in the general population with anemia, using Korean National Health Insurance Service data linked to biennial national health check-ups. We conducted a cohort study on propensity-score fine-stratification (PSS)-weighted 50,008 anemic and 992,497 non-anemic participants aged ≥ 60 years who underwent three consecutive check-ups during 2006-2011. Anemia was defined as hemoglobin levels (Hb) <12 g/dL (females) or < 13 g/dL (males) and non-anemia as levels above the cut-offs at all three check-ups, requiring chronicity of low Hb. The primary outcome was incident dementia. Secondary outcomes included Alzheimer's disease (AD) and vascular dementia (VD). We estimated PSS-weighted hazard ratios (HRs) and 95% confidence intervals (CIs) using Cox models. Dose-responsive (Hb ≥ 10 g/dL as mild, < 10 g/dL as moderate-to-severe) and subgroup (age, sex, income, diabetes, and cardiovascular disease at baseline) analyses were done. Over 11.8 years on average, 430,161 dementia cases developed with a HR (95% CI) of 1.09 (1.08-1.11) for dementia, 1.10 (1.08-1.11) for AD, and 1.04 (1.01-1.07) for VD. The risk of dementia was higher for moderate-to-severe anemia (HR 1.20, 95% CI 1.15-1.26) than mild anemia (HR 1.09, 95% CI 1.08 - 1.10) versus non-anemia. The association was consistent across subgroups, being greater in males than females (p for interaction < 0.05, HR 1.14, 95% CI 1.12-1.17 in males, HR 1.07, 95% CI 1.05-1.09 in females). This large population-based cohort study shows that the risk of dementia associated with persistent anemia was greater for AD than VD, of which association was dose-responsive and affected by sex.},
}
@article {pmid42399403,
year = {2026},
author = {Endrizzi, W and Ragni, F and Bovo, S and Chandra, A and Moroni, M and Jurman, G and Osmani, V},
title = {The landscape of artificial intelligence in neurodegenerative diseases: a systematic review.},
journal = {Communications medicine},
volume = {},
number = {},
pages = {},
doi = {10.1038/s43856-026-01669-5},
pmid = {42399403},
issn = {2730-664X},
abstract = {BACKGROUND: The rising global burden of neurodegenerative diseases underscores an urgent need for advanced research in diagnosis, prognosis, and treatment. Artificial Intelligence (AI) methods, particularly when applied to multimodal data, offer a powerful tool to address these challenges. However, a comprehensive overview and critique of the current landscape of AI methods is lacking.<br><br>METHODS: 4,685 records of peer-reviewed, primary research articles were screened and 1,956 articles reviewed in full text, yielding 1,186 included studies. For each included study, clinical objectives, disease focus, data modalities, modelling approach, evaluation strategy, and reporting practices were extracted.<br><br>RESULTS: Fewer than 5% of studies integrated pharmacological treatments into their predictive models, limiting the extent to which models can directly inform clinical decision-making. Neuroimaging was the predominant input modality, while integration of other clinically relevant data types was relatively rare. Reproducibility rates remain critically low at 35%, and external validation practices fail to use geographically and demographically diverse datasets.<br><br>CONCLUSIONS: Overall, AI research in neurodegenerative diseases suffers from significant limitations in reproducibility, data inclusivity, and clinical translatability. We provide a set of recommendations that can be adopted to address these issues and improve reliability and downstream clinical utility.},
}
@article {pmid42399414,
year = {2026},
author = {Du, JN and Tio, ES and Bennett, DA and Schneider, JA and Sevim Bayrak, C and Alexander-Bloch, A and Zhang, B and Felsky, D},
title = {Copy number variant scores are associated with cerebrovascular pathology in aging.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42399414},
issn = {1476-5578},
support = {P30AG10161//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; P30AG72975//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG15819//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG17917//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U01AG46152//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U01AG61356//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01MH133843//U.S. Department of Health &amp; Human Services | NIH | National Institute of Mental Health (NIMH)/ ; R01MH132934//U.S. Department of Health &amp; Human Services | NIH | National Institute of Mental Health (NIMH)/ ; R01MH134896//U.S. Department of Health &amp; Human Services | NIH | National Institute of Mental Health (NIMH)/ ; },
abstract = {Late-onset Alzheimer's disease (LOAD) is the most common cause of dementia in older adults, with specific genomic copy number variants (CNVs) implicated in its pathology. However, the aggregate burden of genome-wide CNVs in dementia and age-related neuropathologies is uncharacterized. This study investigated the association between genome-wide CNV scores (CNV-S) and dementia, as well as LOAD-related neuropathologies, in 1011 elderly participants (mean age 88.06) from two ongoing US-based longitudinal clinical-pathological cohort studies who were initially dementia-free and consented to brain donation upon death. Participants exhibited varying cognitive statuses at death (429 dementia, 258 mild cognitive impairment, 324 cognitively normal). We evaluated effects of (1) eight individual-level CNV-S based on gene loss intolerance and dosage sensitivity; (2) a single nucleotide polymorphism (SNP)-based LOAD polygenic score (PGS-LOAD) calculated using Bayesian continuous shrinkage; and (3) covariates (age, sex, and education). Outcomes included cognitive scores across 19 tests, clinical diagnoses of Alzheimer's disease or mild cognitive impairment, and four LOAD-related neuropathologies assessed postmortem. Analyses identified 4867 CNVs (3918 deletions, 949 duplications) mapped to 3211 genes. Higher deletion CNV-S were significantly associated with increased cerebrovascular pathologies (pLI: β = 0.14, 95% CI [0.08, 0.21]; LOEUF: β = 0.14, 95% CI [0.08, 0.20]; pHI: β = 0.15, 95% CI [0.08, 0.21]; binarized pHI: β = 0.14, 95% CI [0.08, 0.21]). Models predicting cerebral atherosclerosis that included deletion CNV-S significantly outperformed models based on only PGS-LOAD (R[2] increase: 0.02). These findings suggest that genome-wide CNV burden, particularly deletions in dosage-sensitive genes, contributes to cerebrovascular pathology in aging. CNV-S may augment existing LOAD genetic risk models by capturing vascular pathways distinct from traditional SNP-based risk.},
}
@article {pmid42399591,
year = {2026},
author = {Song, Y and Guo, Y and Wang, Y and Zhou, J},
title = {Rethinking Alzheimer's Origins: Antimicrobial Amyloid and Tau Point to Potential Upstream Immune Triggers.},
journal = {Neuroscience bulletin},
volume = {},
number = {},
pages = {},
pmid = {42399591},
issn = {1995-8218},
}
@article {pmid42399717,
year = {2026},
author = {Chédotal, H and Povlsen, K and Narayanan, D and Gotfredsen, CH and Gajhede, M and Bach, A and Clausen, MH},
title = {Discovery of Ligands for the TNFR1 Extracellular Domain Using Fragment-Based Drug Discovery.},
journal = {ChemMedChem},
volume = {21},
number = {13},
pages = {e70365},
doi = {10.1002/cmdc.70365},
pmid = {42399717},
issn = {1860-7187},
support = {1032-00084B//Danmarks Frie Forskningsfond/ ; //Villum Fonden/ ; NNF19OC0055818//Novo Nordisk Fonden/ ; CF19-0072//Carlsbergfondet/ ; 2018-07152//Vetenskapsr&#xe5;det/ ; 2018-04969//VINNOVA/ ; 2019-02496//Svenska Forskningsr&#xe5;det Formas/ ; },
mesh = {*Receptors, Tumor Necrosis Factor, Type I/antagonists &amp; inhibitors/metabolism/chemistry ; Ligands ; Humans ; Crystallography, X-Ray ; *Drug Discovery ; Surface Plasmon Resonance ; *Small Molecule Libraries/chemistry/pharmacology/chemical synthesis ; Structure-Activity Relationship ; Protein Domains ; Molecular Structure ; Models, Molecular ; Dose-Response Relationship, Drug ; },
abstract = {Tumor necrosis factor receptor 1 (TNFR1) plays a major role in immunoregulation. It is involved in inflammatory and autoimmune diseases like rheumatoid arthritis, psoriasis, Alzheimer's disease, and multiple sclerosis. However, few small-molecule inhibitors of TNFR1 have been reported, even though they constitute a good alternative to already existing antibody therapies targeting the TNF pathway. Here, we report the discovery of a new class of molecules for the extracellular domain of TNFR1 using a fragment-based approach through primary screening by NMR spectroscopy, followed by orthogonal validation by surface plasmon resonance (SPR) and X-ray crystallography. Guided by these results, we have synthesized 46 analogs with micromolar potency showing up to ∼10-fold improved affinity toward TNFR1 compared to the fragment hits. These results can provide a structural basis for the discovery of novel TNFR1 inhibitors in the future.},
}
@article {pmid42343639,
year = {2026},
author = {Watzlawik, JO and Bustillos, BA and Rodriguez Martinez, C and Dickson, DW and Wszolek, ZK and Ross, OA and Springer, W and Fiesel, FC},
title = {Robust and sensitive ELISA detection of total and activated PRKN.},
journal = {Autophagy},
volume = {},
number = {},
pages = {1-16},
doi = {10.1080/15548627.2026.2694658},
pmid = {42343639},
issn = {1554-8635},
abstract = {Parkinson disease (PD) is closely linked to disruptions in mitochondrial quality control, a process regulated by the ubiquitin kinase PINK1 and the E3 ubiquitin ligase PRKN/parkin. Upon mitochondrial damage, PINK1 phosphorylates ubiquitin, which in turn recruits and activates PRKN. Full activation of PRKN is mediated by PINK1-dependent phosphorylation of PRKN at serine 65, which leads to widespread ubiquitination of mitochondrial substrates and amplifies the mitophagy response. Disruption of this pathway results in mitochondrial accumulation, oxidative stress, and neuronal death, all key mechanisms of PD pathogenesis. Genetic studies have shown biallelic loss-of-function mutations in PRKN are the most common cause of early-onset PD. Although the role of haploinsufficiency remains under investigation, PRKN protein becomes insoluble and inactive with aging or post-translational modifications, indicating that functional protein levels are a key determinant of disease risk. Reliable quantification of total and activated PRKN in samples has not been feasible, limiting research and clinical assessment. To address this, we developed and validated knockout (KO)-verified sandwich ELISA assays that quantify both total PRKN and PINK1-phosphorylated p-S65-PRKN. These assays provide absolute quantification of PRKN, improving functional diagnosis, and patient stratification in PD. Application of these methods established the concentration of PRKN in cells and in brain and revealed significant effects of a common genetic PRKN variant, further highlighting the importance of determining functional PRKN protein levels. The developed immunoassays complement previously established PINK1 and p-S65-Ub measurements, enhancing mechanistic insight into mitophagy and enabling effective monitoring of PD therapies and other neurodegenerative diseases.Abbreviations: AD: Alzheimer disease; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; ECL: electrochemiluminescence; ELISA: enzyme-linked immunosorbent assay; IBR: In-between-RING; iPSC: induced pluripotent stem cell; KO: knockout; LoB: limit of blank; LoD: limit of detection; LoQ: limit of quantification; MSD: Meso Scale Discovery; PD: Parkinson disease; p-S65-PRKN: serine 65 phosphorylated PRKN; p-S65-Ub: serine 65 phosphorylated ubiquitin; REP: repressor element of PRKN; RING: really interesting new gene; Ub: ubiquitin; UBL: ubiquitin-like domain; VCL: vinculin; WT: wild-type.},
}
@article {pmid42392003,
year = {2026},
author = {Serra, L and Mancini, M and Bonarota, S and Caruso, G and Di Domenico, C and Rizzuti, M and Di Lorenzo, F and Mencarelli, L and Koch, G and Caltagirone, C and Giove, F and Bozzali, M and Gelfo, F},
title = {Hippocampal-cortical structural networks in the progression of cognitive impairment: A source-based morphometry analysis in individuals with subjective cognitive decline, mild cognitive impairment and Alzheimer's disease.},
journal = {Neurobiology of aging},
volume = {167},
number = {},
pages = {129-145},
doi = {10.1016/j.neurobiolaging.2026.06.009},
pmid = {42392003},
issn = {1558-1497},
abstract = {Neural plasticity and memory mechanisms progressively change during pathological aging. This study aimed to identify patterns of structural covariance across Alzheimer's disease (AD) stages and their relationship with episodic memory performance. Fifty-nine AD patients, 59 patients with amnestic Mild Cognitive Impairment (a-MCI), 46 individuals with Subjective Cognitive Decline (SCD), and 49 Healthy Controls (HC) underwent neuropsychological assessment, including verbal episodic memory tests (15-Word List and Short Story) and 3 T Magnetic Resonance Imaging (MRI). T1-weighted images were processed using the Source-Based Morphometry (SBM) pipeline to extract structural covariance networks. Group differences were assessed using ANCOVA, and correlations with memory performance were examined using Pearson's coefficients. Three hippocampal-cortical networks were identified: the hippocampal-diencephalic network (HDN), hippocampal-anterior cingulate-occipital network (HACON), and mesiotemporal-orbitofrontal network (MTON). AD patients showed marked reductions in grey matter connectivity across all networks, while a-MCI patients exhibited intermediate values, particularly in HDN and MTON. Network-memory correlations showed distinct patterns across groups: in HC, HDN and HACON correlated with recall and recognition, whereas MTON connectivity correlated with memory performance in SCD, a-MCI, and AD. These findings indicate a stage-dependent disruption of hippocampal-cortical networks and suggest that MTON integrity supports long-term memory, with progressive disconnection contributing to severe impairment in AD.},
}
@article {pmid42392133,
year = {2026},
author = {Liu, T and Liu, Y and Liu, X and Li, Y and Yuan, J and Wang, S and Lin, X and Guo, Q},
title = {CausalTCC: causal temporal contrastive learning for automated Alzheimer's disease biomarker discovery with bio-electrical signals.},
journal = {Journal of neural engineering},
volume = {},
number = {},
pages = {},
doi = {10.1088/1741-2552/ae8578},
pmid = {42392133},
issn = {1741-2552},
abstract = {OBJECTIVE: Learning robust representations from scarce labeled bio-electrical time-series data remains a critical challenge in clinical diagnosis. While contrastive learning has shown promise, existing approaches often overlook the intrinsic causal dynamics inherent in physiological signals, leading to over-smoothed representations. This study presents CausalTCC, an end-to-end framework for causal temporal contrastive learning of bio-electrical signals toward Alzheimer's disease (AD) biomarker discovery.<br><br>APPROACH: CausalTCC is developed through three modules: (1) asymmetrical augmentation: distinct weak and strong augmentation strategies generate diverse views while respecting physiological characteristics; (2) causal temporal contrasting: a Transformer-based autoregressive backbone with causal masking integrates intra-view causal loss to capture intrinsic temporal dependencies; and (3) causal contextual contrasting: a symmetric InfoNCE loss leverages instance-level discrimination to learn domain-invariant causal representations, reducing reliance on labeled examples.<br><br>MAIN RESULTS: Extensive experiments compared CausalTCC to six state-of-the-art counterparts (e.g., EEGNet and EEG-SSL) on four datasets (HAR, AD_A, AD_FTD, and Brain_Lat): (1) CausalTCC achieves the best average F1-scores of 60.1%, 71.0%, and 76.9% under 1%, 5%, and 10% labeled data, outperforming the second-best method by up to 7.2%; (2) under extreme data scarcity (1% labels), it demonstrates substantial improvements on AD_A (Acc: 70.0%, F1: 67.9%); and (3) the causal self-supervision makes CausalTCC far superior to conventional supervised methods.<br><br>SIGNIFICANCE: Overall, CausalTCC presents a physiologically grounded and relatively parameter-efficient framework that maintains competitive inference efficiency while balancing model complexity and predictive performance for EEG-based clinical decision support.},
}
@article {pmid42392137,
year = {2026},
author = {Chen, Y and Yan, F and Xiao, P and Li, X and Yu, L and Dong, S and Yao, C},
title = {Non-invasive nanosecond transcranial pulsed electric fields: a deep-penetrating, high-field stimulation that suppresses hippocampal β-amyloid and improves cognitive deficits in Alzheimer's disease model.},
journal = {Journal of neural engineering},
volume = {},
number = {},
pages = {},
doi = {10.1088/1741-2552/ae8579},
pmid = {42392137},
issn = {1741-2552},
abstract = {OBJECTIVE: Hippocampal β-amyloid (Aβ) pathology may induce early circuit dysfunction and memory impairment in Alzheimer's disease (AD), making it a key target for slowing disease progression. However, existing transcranial electrical stimulation approaches, while remaining within safety limits, are insufficient to non-invasively generate sufficiently strong electric fields in deep brain regions. Here, we investigated whether nanosecond transcranial pulsed electric field stimulation (ns-tPFS) could provide a non-invasive deep-target strategy for modulating hippocampal Aβ pathology in an AD model.<br><br>APPROACH: The 10-month-old 5xFAD mice were selected for delivering repeated ns-tPFS (500 ns, 500 V, 1 Hz). The intracranial electric field exposure was estimated using finite-element modeling (FEM). Treatment effects were evaluated using the Morris water maze, Y-maze, immunofluorescence of A&#x3b2; deposition in the hippocampus and cortex, and western blotting of A&#x3b2;-related proteins. In addition, the structural responses of A&#x3b2; oligomers to pulsed electric fields were examined by employing molecular dynamics simulations, and structural brain safety was assessed by 9.4 T small-animal MRI.<br><br>MAIN RESULTS: ns-tPFS generated transient hippocampal electric fields on the order of 104 V/m. It reduced the hippocampal A&#x3b2; burden and was associated with coordinated changes in A&#x3b2;-related pathways, including decreased amyloidogenic processing and modulated A&#x3b2; transport-related receptors. Molecular dynamics simulations further suggested that A&#x3b2; oligomers are structurally sensitive to nanosecond-scale electric field transients within the hippocampal field range estimated by FEM. These changes were accompanied by improved spatial and working memory in 5xFAD mice. In contrast, under the present stimulation regimen, healthy mice were observed with no detectable cognitive impairment, or macroscopic MRI abnormalities.<br><br>SIGNIFICANCE: ns-tPFS may be a promising non-invasive deep-target electric-field strategy for mitigating hippocampal A&#x3b2; pathology and improving cognitive performance in an AD mouse model.},
}
@article {pmid42392247,
year = {2026},
author = {Kumar, R and Sinha, S and Babu, MA},
title = {Interactions-Guided Blueprint of Acetylcholinesterase Binding: A Review on Structural and Molecular Determinants.},
journal = {Chemico-biological interactions},
volume = {},
number = {},
pages = {112224},
doi = {10.1016/j.cbi.2026.112224},
pmid = {42392247},
issn = {1872-7786},
abstract = {Acetylcholinesterase (AChE) remains one of the most extensively studied enzymatic targets in neuropharmacology due to its central role in cholinergic neurotransmission and its relevance in symptomatic cognitive disorders, toxicology, and neuromodulation. AChE terminates cholinergic neurotransmission by hydrolysing acetylcholine, and its inhibition provides clinically established symptomatic relief in cholinergic dysfunction-associated pathological conditions. For any newly discovered ligand, the precise target binding mode often remains challenging, and unfortunately, the binding patterns of most reported compounds have not been experimentally resolved. However, with recent advances in structural biology, particularly biomolecular crystallographic structures deposited in the Protein Data Bank, have significantly enriched our understanding of the active site of AChE and its interactions with diverse chemical classes of ligands. To this end, this article presents a comprehensive systematic analysis of 202 AChE-ligand complexes (1993-2025) since the first breakthrough, categorizing ligands by their core scaffolds or functional groups, including decamethonium, huprine, galanthamine, quinoline, huperzine, tacrine, pyridinium, sulphonamide, and quaternary amine derivatives. Crucial interactions with core residues of the binding pocket, such as hydrogen bonding, cation-π, carbon-π, π-π stacking, and van der Waals forces, primarily associated with the stabilization of AChE-ligand complexes, are discussed involving organisms like Tetronarce californica, Homo sapiens, and Mus musculus, emphasizing their role in inhibitory potency. All ligands are further evaluated using Lipinski's Rule of Five filters to assess drug-likeness and identify optimization strategies for improved bioavailability and pharmacokinetics. By integrating structural insights with ligand features, this article provides a comprehensive framework for the rational design and optimization of next-generation AChE modulators across neurological and toxicological conditions.},
}
@article {pmid42392306,
year = {2026},
author = {Zhang, Y and Pu, J and Shen, Z and Ye, Z and Liu, J and Zhang, D and Deng, K and Yao, Y},
title = {Global Trends and Evolving Frontiers in Intranasal Delivery for CNS Diseases (2000-2025): A Bibliometric Analysis and Systematic Review.},
journal = {World neurosurgery},
volume = {},
number = {},
pages = {125172},
doi = {10.1016/j.wneu.2026.125172},
pmid = {42392306},
issn = {1878-8769},
abstract = {BACKGROUND: Intranasal administration (nose-to-brain delivery) has emerged as a pivotal non-invasive strategy to bypass the blood-brain barrier (BBB) for treating central nervous system (CNS) disorders. However, the exponential growth of literature in this domain presents challenges in grasping the holistic research trajectory and identifying emerging hotspots.<br><br>METHODS: This study conducted a comprehensive bibliometric analysis of 4,009 publications retrieved from the Web of Science Core Collection (WoSCC) spanning from 2000 to 2025. Tools including VOSviewer, CiteSpace, and R-bibliometrix were employed to map spatiotemporal trends, collaborative networks, and keyword evolution.<br><br>RESULTS: The analysis reveals a robust upward trend in global research output, predominantly driven by China and the United States. Keyword clustering identified five major research sub-domains: Alzheimer's disease, Oxytocin (behavioral/psychiatric applications), Stroke and Neuroinflammation, Brain Tumors, and Nanoparticles. Burst detection analysis elucidates a distinct paradigm shift in scientific focus: early investigations prioritized mucosal absorption mechanisms and tolerance; the focus subsequently transitioned to specific therapeutic agents (e.g., insulin, oxytocin); and most recently, the field has been dominated by the optimization of delivery vectors, specifically lipid-based nanoparticles and exosomes.<br><br>CONCLUSION: While nanotechnology has become the current technological frontier for enhancing brain targeting, a critical gap remains between promising preclinical results and clinical translation. Future research must prioritize the development of biomimetic delivery systems and highly predictive translational models to bridge the divide between bench and bedside. This review provides a strategic roadmap for researchers to navigate current trends and address the barriers hindering clinical application.},
}
@article {pmid42392339,
year = {2026},
author = {Salman, Y and Denning, AE and Schaeverbeke, JM and Tomé, SO and Joudiou, N and Khandelwal, P and Yushkevich, PA and Vandenberghe, R and Gallez, B and Wisse, LE and Hanseeuw, BJ},
title = {Volumetric postmortem MRI of the medial temporal lobe in Alzheimer's disease and related disorders: methodological advances and implications for in vivo biomarker development.},
journal = {NeuroImage},
volume = {},
number = {},
pages = {122098},
doi = {10.1016/j.neuroimage.2026.122098},
pmid = {42392339},
issn = {1095-9572},
abstract = {Magnetic resonance imaging (MRI) is central to the study and diagnosis of neurodegenerative diseases. Yet, no MRI biomarker is currently specific to a given neurodegenerative disease. This may result from the limited resolution of conventional MRI, which restricts detailed investigation of medial temporal lobe (MTL) subregions, a crucial hub for many neuropathologies. Moreover, in vivo MRI cannot be directly compared with neuropathological data, the gold standard for disease definition. Even when antemortem MRI and postmortem analyses are combined, the time gap between imaging and neuropathological examination allows pathogenic processes to progress, reducing the accuracy of these correlations. Over the past two decades, postmortem MRI has gained increasing interest because it enables long, motion-free acquisitions and the use of specialized coils and preclinical scanners, providing ultra-high spatial resolution. Additionally, it allows direct correspondence between imaging and neuropathological measures. Consequently, volumetric postmortem MRI, particularly investigations of the MTL, has become an increasingly common approach in Alzheimer's disease and related disorders (ADRD). This narrative review specifically focuses on volumetric postmortem MRI of the MTL and summarizes the main methodologies for anatomical postmortem MTL imaging in ADRD and recent advances in the characterization of neurodegenerative changes, from brain preparation to MRI acquisition. It also highlights the translational potential of volumetric postmortem MRI for developing in vivo biomarkers, optimizing imaging protocols and segmentation methods, and assessing the impact of proteinopathies. Finally, it outlines current limitations, technical challenges, and perspectives for future research.},
}
@article {pmid42392383,
year = {2026},
author = {Dhar, I and Gupta, S and Mishra, R and Dadhich, A},
title = {Gingipains as macromolecular mediators at the periodontal-brain interface: Mechanistic, diagnostic, and therapeutic evidence in Alzheimer's and Parkinson's diseases.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {153320},
doi = {10.1016/j.ijbiomac.2026.153320},
pmid = {42392383},
issn = {1879-0003},
abstract = {Chronic periodontitis, driven by Porphyromonas gingivalis, has emerged as a modifiable risk factor for Alzheimer's disease (AD) and Parkinson's disease (PD) the two most prevalent and socioeconomically burdensome neurodegenerative disorders through systemic dissemination of its signature cysteine proteases, gingipains (RgpA, RgpB, Kgp). This narrative critical review is explicitly scoped to AD and PD, the only neurodegenerative conditions for which postmortem detection of gingipains in affected brain regions, mechanistic evidence from cellular and animal models, and clinical epidemiological data currently exist in sufficient depth to support an integrated synthesis. Robust meta-analyses confirm that periodontitis is associated with elevated AD/PD risk (OR/HR 1.2-3.5), while gingipains have been detected in a high proportion (>85-90%) of postmortem AD/PD brains, correlating with tau/α-synuclein pathology, neuroinflammation, and neuronal loss. Mechanistic studies in cellular and animal models demonstrate that gingipains can disrupt blood-brain barrier integrity via tight-junction cleavage, trigger NF-κB/NLRP3-driven glial activation, catalyse amyloid-β/α-synuclein seeding, induce tau truncation/hyperphosphorylation, and precipitate mitochondrial oxidative damage, thereby generating self-amplifying neurotoxic cascades. Salivary gingipain activity offers a non-invasive, high-sensitivity biomarker candidate for early risk stratification that may outperform conventional fluid markers in prodromal cohorts. Therapeutically, small-molecule gingipain inhibitors have shown neuroprotective effects in preclinical models (e.g., atuzaginstat/COR388 failed primary endpoints in the Phase 2/3 GAIN trial but demonstrated subgroup benefits in P. gingivalis-positive participants; the next-generation inhibitor LHP588 is advancing in the Phase 2 SPRING trial). Emerging approaches including nanotechnology, CRISPR-based virulence gene disruption, and targeted delivery platforms aim to improve brain exposure and specificity. This review provides an integrated, isoform-resolved framework linking gingipain structure-function to neurodegeneration. While associative and mechanistic evidence is compelling, definitive causation in humans and disease-modifying efficacy require further validation through biomarker-guided clinical trials. Precision inhibition of gingipains represents a promising upstream strategy for addressing a potentially modifiable microbial contributor at the oral-brain interface.},
}
@article {pmid42392515,
year = {2026},
author = {Pandey, JK and Verma, SK and Kumar, J and Perwej, Y and Jha, DSK and Panchal, BY and Ferdouse, R and V, S and Banerjee, S and Tiwari, M and Badal, R and Mandal, P and Baghel, JS},
title = {Transformative Role of Advanced Neural Computation in Clinical Image Diagnostics: A Review of Key Concepts and Applications.},
journal = {Seminars in ultrasound, CT, and MR},
volume = {},
number = {},
pages = {},
doi = {10.1053/j.sult.2026.06.010},
pmid = {42392515},
issn = {1558-5034},
abstract = {Medical imaging plays a crucial role in modern diagnostic practices, but traditional techniques often face limitations in accuracy, efficiency, and scalability. The emergence of deep learning (DL) has led to significant improvements that are transforming this field. This review discusses how DL algorithms are enhancing diagnostic imaging by improving accuracy, enabling automated analysis, and supporting personalized treatment plans. It focuses on key deep learning (DL) frameworks, including convolutional neural networks (CNNs), recurrent neural networks (RNNs), and generative adversarial networks (GANs). The review examines their applications in important medical imaging tasks such as image classification, segmentation, reconstruction, and disease prediction. It also considers how DL techniques are integrated with tools like radiomics, data augmentation strategies, and predictive analytics models. DL methods have shown superior performance in detecting and classifying diseases like pneumonia, tuberculosis, and Alzheimer's. They also improve the quality and speed of imaging modalities such as MRI, CT, and ultrasound. Despite these advances, challenges remain in data availability, model interpretability, clinical validation, and ethical issues related to bias and privacy. Addressing these challenges is essential for the successful clinical use of DL in medical imaging. This review ends with suggestions for future directions and best practices for ethically and practically integrating DL technologies into routine healthcare.},
}
@article {pmid42392701,
year = {2026},
author = {Li, JY and Wang, XX and Wan, SF and Feng, TT and Guo, AJ and Liu, JY and Feng, K},
title = {[Research progress on role of PINK1/Parkin-mediated mitophagy in Alzheimer's disease and TCM interventions].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {51},
number = {8},
pages = {2143-2152},
doi = {10.19540/j.cnki.cjcmm.20260113.701},
pmid = {42392701},
issn = {1001-5302},
mesh = {Humans ; PTEN-Induced Putative Kinase ; *Protein Kinases/metabolism/genetics ; *Alzheimer Disease/drug therapy/metabolism/genetics/physiopathology ; *Ubiquitin-Protein Ligases/metabolism/genetics ; *Mitophagy/drug effects ; Animals ; *Drugs, Chinese Herbal/administration &amp; dosage ; Mitochondria/metabolism/drug effects ; },
abstract = {Alzheimer's disease(AD) is a neurodegenerative disorder characterized by progressive cognitive decline. Current treatment strategies mainly focus on symptomatic regulation of the neurotransmitter system, but their intervention effects on key pathological processes such as amyloid β(Aβ) deposition and abnormal phosphorylation of Tau protein remain limited. Therefore, it is urgent to explore new intervention targets from the perspective of the key mechanisms underlying the disease's occurrence and development. In recent years, mitochondrial dysfunction and imbalanced mitophagy have been recognized as closely related to the onset and progression of AD. The PTEN-induced putative kinase 1(PINK1)/E3 ubiquitin-protein ligase parkin(Parkin) pathway is a classic mechanism for the recognition, ubiquitination marking, and autophagic clearance of damaged mitochondria. Multiple studies have shown that under AD pathological conditions, the expression of this pathway is blocked, or its activity is reduced, leading to restricted mitophagy flux and obstacle clearance, which in turn exacerbate oxidative stress, energy metabolism disorders, and synaptic function damage, accelerating neuronal degeneration. Based on this, intervention strategies targeting PINK1/Parkin-mediated mitophagy have gradually attracted attention. Existing research indicates that single components and formulas of TCM, as well as some bioactive molecules, can reduce Aβ deposition, inhibit abnormal phosphorylation of Tau protein, and enhance synaptic plasticity by regulating PINK1/Parkin-mediated mitophagy, thereby exerting neuroprotective effects and improving cognitive function. However, the current evidence mainly comes from experimental studies, and the blood-brain barrier permeability, long-term safety, and clinical reproducibility of these interventions still need further verification. This article systematically reviewed the molecular mechanisms and upstream regulatory networks of PINK1/Parkin-mediated mitophagy, elaborated on the research evidence of its role in the pathological process of AD, and focused on summarizing the research progress of TCM interventions targeting this pathway, aiming to provide references for subsequent mechanism verification, evidence-based research design, and exploration of comprehensive intervention strategies.},
}
@article {pmid42392719,
year = {2026},
author = {Yuan, CB and Ju, YT and Liu, YM and Wang, BS and Zhang, L and Yu, CY and Yang, YL and Chen, WY and Leng, YJ and Cheng, MJ and Min, DY},
title = {[Quercetin improves cognitive impairment in mice with Alzheimer's disease by inhibiting inflammatory response and activating cAMP/PKA/CREB signaling pathway].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {51},
number = {8},
pages = {2323-2334},
doi = {10.19540/j.cnki.cjcmm.20251210.801},
pmid = {42392719},
issn = {1001-5302},
mesh = {Animals ; *Alzheimer Disease/drug therapy/genetics/immunology/psychology/metabolism ; Male ; *Quercetin/administration &amp; dosage ; Signal Transduction/drug effects ; Mice ; *Cyclic AMP Response Element-Binding Protein/genetics/metabolism ; Humans ; *Cyclic AMP/metabolism/genetics/immunology ; *Cyclic AMP-Dependent Protein Kinases/genetics/metabolism ; Mice, Inbred C57BL ; *Cognitive Dysfunction/drug therapy/genetics ; Mice, Transgenic ; Disease Models, Animal ; Hippocampus/drug effects ; },
abstract = {This study aimed to investigate the effects of quercetin on cognitive dysfunction in a mouse model of Alzheimer's disease(AD) and to explore its potential mechanisms. Network pharmacology was used to construct a "drug-core component-key target-pathways-disease" network to identify potential targets and related pathways associated with drug efficacy. Thirty 3-month-old male APP/PS1 transgenic mice were randomly divided into a model group, a quercetin group(100 mg·kg~(-1)), and a donepezil hydrochloride group(0.5 mg·kg~(-1)), while age-matched C57BL/6J mice from the same litter served as the control group. Each group consisted of 10 mice, and the treatment groups received the corresponding drug interventions for 24 weeks. The Morris water maze(MWM) test was used to assess memory performance, and the nest-building test was applied to evaluate daily living ability. hematoxylin-eosin(HE) staining, Nissl staining, and immunohistochemistry were used to assess pathological changes in hippocampal neurons. Western blot analysis was used to detect the expression levels of tau, phosphorylated(p)-tau, interleukin-1β(IL-1β), tumor necrosis factor-α(TNF-α), brain-derived neurotrophic factor(BDNF), cyclic adenosine monophosphate(cAMP), protein kinase A(PKA), p-PKA, cAMP response element-binding protein(CREB), and p-CREB-related signaling proteins in hippocampal tissue. Network pharmacology analysis identified 165 quercetin-related active component targets and 4 324 learning-and memory-related targets. Intersection analysis yielded 71 AD-related core genes. Protein-protein interaction(PPI) network analysis identified protein kinase B(Akt1), estrogen receptor 1(ESR1), epidermal growth factor receptor(EGFR), and non-receptor tyrosine kinase(SRC) as core target genes. Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway analysis indicated that quercetin may regulate AD progression through the PI3K/Akt signaling pathway, cAMP signaling pathway, TNF signaling pathway, and EGFR tyrosine kinase inhibitor resistance-related pathways. Animal experiments showed that, compared with the control group, the model group exhibited significantly reduced nesting scores, prolonged escape latency(P<0.05), and fewer platform crossings(P<0.05). The number of neurons in the cortex and hippocampus was significantly decreased, and extracellular amyloid β(Aβ) deposition was significantly increased(P<0.01). In addition, the expression levels of p-tau/tau, IL-1β, TNF-α, cAMP, p-PKA/PKA, and p-CREB/CREB in hippocampal tissue were significantly elevated(P<0.01), whereas BDNF protein expression was significantly reduced(P<0.01). Compared with the model group, the quercetin and donepezil hydrochloride groups showed significantly increased nesting scores, shortened escape latency(P<0.05), and increased numbers of platform crossings(P<0.05). The number of neurons in the hippocampal CA1 region was significantly increased(P<0.01), and the expression levels of p-tau/tau, IL-1β, TNF-α, cAMP, p-PKA/PKA, and p-CREB/CREB in hippocampal tissue were significantly decreased(P<0.05, P<0.01). These results indicate that quercetin can significantly improve cognitive impairment in APP/PS1 transgenic mice, and its mechanism may be associated with activation of the cAMP/PKA/CREB signaling pathway and reversal of the upregulation of pro-inflammatory cytokines, including TNF-α and IL-1β.},
}
@article {pmid42392731,
year = {2026},
author = {Lyu, SY and Wang, XZ and Chen, XY and Guo, R},
title = {[Exploring mechanism of "treating different diseases with the same method" for depression and Alzheimer's disease based on "liver-spleen-kidney" axis and advances in traditional Chinese medicine intervention].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {51},
number = {10},
pages = {2726-2738},
doi = {10.19540/j.cnki.cjcmm.20260108.302},
pmid = {42392731},
issn = {1001-5302},
mesh = {Humans ; *Alzheimer Disease/drug therapy/physiopathology/metabolism ; *Drugs, Chinese Herbal/administration &amp; dosage/therapeutic use ; *Spleen/drug effects/physiopathology ; *Kidney/drug effects/physiopathology ; *Liver/drug effects/physiopathology ; Animals ; *Medicine, Chinese Traditional ; *Depression/drug therapy/physiopathology ; },
abstract = {Depression(major depressive disorder, MDD) and Alzheimer's disease(AD) are two highly prevalent neuropsychiatric disorders. With the aging population, their comorbidity rate continues to rise. The pathogenesis of MDD and AD is complex, and modern medicine still lacks strategies that can simultaneously intervene in the core processes of both diseases. The theory of "treating different diseases with the same method" in traditional Chinese medicine(TCM) is an important therapeutic principle, which means that different diseases showing identical syndromes during their development can be treated with the same approach. This provides a TCM perspective for the diagnosis and treatment of their comorbidity. Based on the theory of the "liver-spleen-kidney" axis, this study identified that MDD and AD shared common pathogenesis: liver dysfunction in free coursing, spleen dysfunction in transportation, and kidney essence deficiency. It further connected this pathogenesis with the dysregulation of the neuroendocrine-immune(NEI) network in modern medicine, revealing common pathological mechanisms in neuroinflammation, dysfunction of the "hypothalamic-pituitary-adrenal"(HPA) axis, and gut microbiota dysbiosis. Meanwhile, it also reviewed specific mechanisms of TCM herbs such as Bupleuri Radix(Chaihu), Paeoniae Radix Alba(Baishao), and Astragali Radix(Huangqi), as well as their active components, in treating MDD and AD by regulating the NEI network through multiple targets and pathways. This may provide evidence for the application of the "treating different diseases with the same method" theory and broaden the perspective for the treatment of MDD and AD.},
}
@article {pmid42392749,
year = {2026},
author = {Liu, MY and Zhong, XQ and Zhang, H and Huang, MT and Liang, YS and Ren, YK and Huang, LP and Deng, MZ},
title = {[Mechanism of Ding-Zhi-Xiao-Wan on sphingolipid metabolism disorders in Alzheimer's disease based on network pharmacology, molecular docking, and animal experiments].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {51},
number = {10},
pages = {2906-2917},
doi = {10.19540/j.cnki.cjcmm.20260104.801},
pmid = {42392749},
issn = {1001-5302},
mesh = {Animals ; *Alzheimer Disease/metabolism/drug therapy/genetics ; Mice ; *Sphingolipids/metabolism ; Network Pharmacology ; Molecular Docking Simulation ; Humans ; *Drugs, Chinese Herbal/administration &amp; dosage/chemistry ; Male ; Disease Models, Animal ; Signal Transduction/drug effects ; Oxidative Stress/drug effects ; Apoptosis/drug effects ; },
abstract = {Exploring the mechanism of Ding-Zhi-Xiao-Wan(DZXW) on disorders of sphingolipid metabolism in Alzheimer's disease(AD) through network pharmacology, molecular docking and animal experiments. The chemical constituents of DZXW were obtained via the TCMSP, with target prediction conducted using the SwissTargetPrediction database; the GeneCards database was consulted to identify targets associated with AD and sphingolipid metabolism disorders. The intersecting targets from these three databases underwent GO and KEGG enrichment analyses. Cytoscape was employed to construct networks and screen core components and targets for molecular docking validation. Animal experiments employed AD model mice, utilising the water maze, ELISA, qPCR, LC-MS, and Western blot to evaluate the effects of DZXW on behavioural, oxidative stress, inflammatory, apoptotic, and sphingolipid metabolism-related indicators. Network pharmacology identified 51 common targets, with enrichment analysis indicating their involvement in multiple pathways including signal transduction, apoptosis, and the phosphatidylinositol 3kinase/protein kinase B(PI3K/Akt) pathway. Molecular docking revealed that multiple components within DZXW(such as cerevisterol and isorhamnetin) interacted with targets including caspase 3(CASP3), mitogen-activated protein kinase 14(MAPK14), estrogen receptor 1(ESR1), and silent information regulator factor 2 related enzyme 1(SIRT1), with SIRT1 being particularly crucial. Animal studies indicate that DZXW enhances learning and memory capacity in AD mice, reduces ceramide levels, and inhibits oxidation factors [4-hydroxynonenal(4-HNE), 8-hydroxy-2'-deoxyguanosine(8-OHdG), nicotinamide adenine dinucleotide phosphate oxidase 4(NOX4)] and inflammatory factors [tumour necrosis factor-α(TNF-α), interleukin(IL)-1β], downregulates CASP3, MAPK14, sphingomyelin phosphodiesterase 1-3(SMPD1-3), B cell chronic lymphocytic leukaemia/lymphoma-2(Bcl-2)-associated X protein(Bax), and increases IL-10, ESR1, mammalian target of rapamycin(mTOR), SIRT1, PI3K phosphorylation, Akt phosphorylation, and Bcl-2. In conclusion, DZXW may improve sphingolipid metabolism disorders in AD by inhibiting neuronal apoptosis and mitigating oxidative and inflammatory responses through the SIRT1/PI3K/Akt pathway.},
}
@article {pmid42392863,
year = {2026},
author = {Jiménez-Huete, A and Rognoni, T and Montoya, G and Borda, MG and Riverol, M and , },
title = {Diagnostic accuracy of a two-cut-off approach using the FAQ/MMSE ratio and FAQ for clinical preselection of patients for anti-amyloid therapy.},
journal = {Journal of neurology, neurosurgery, and psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1136/jnnp-2026-338997},
pmid = {42392863},
issn = {1468-330X},
abstract = {BACKGROUND: Anti-amyloid therapies for Alzheimer's disease (AD) require efficient patient selection. The Clinical Dementia Rating (CDR) scale is the reference standard for staging, but it is time-consuming to administer. Simple tools to distinguish early-stage cognitive impairment (CDR 0.5-1) from more advanced stages (CDR 2-3) would therefore be of substantial clinical value.<br><br>METHODS: Participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohorts 1-3 with CDR &#x2265;0.5 were analysed. Three logistic regression models using Mini-Mental State Examination (MMSE), Functional Assessment Questionnaire (FAQ) or the FAQ/MMSE ratio as predictors were developed. Two cut-offs per model were selected to ensure minimum sensitivity and specificity of 0.99, defining rule-out, rule-in and intermediate (uncertain) zones. Performance was assessed using discrimination, calibration and decision curve analysis.<br><br>RESULTS: Among 1533 ADNI participants with CDR &#x2265;0.5, two-thirds (n=1022) were assigned to the training set and one-third (n=511) to the test set. FAQ/MMSE and FAQ showed excellent discrimination (area under the curve, AUC 0.97-0.98), outperforming MMSE (AUC 0.94-0.95). FAQ/MMSE demonstrated the best overall performance, although differences compared with FAQ were small and not statistically significant. Dual cut-offs for FAQ/MMSE (0.67 and 1.44) and FAQ (12 and 27) enabled clinically meaningful stratification, with 80% and 70% of participants classified into high-confidence zones, respectively. Results were consistent across the training and test sets.<br><br>CONCLUSIONS: The FAQ/MMSE ratio and FAQ score show high accuracy in distinguishing early-stage (CDR 0.5-1) from more advanced cognitive impairment (CDR 2-3). These simple measures may support the clinical preselection of patients for further evaluation in the context of anti-amyloid therapy.},
}
@article {pmid42392958,
year = {2026},
author = {Zhao, H and King, KY and Wong, ST},
title = {Clonal hematopoiesis in Alzheimer's brain: Protective, pathogenic, and context-dependent?.},
journal = {Trends in molecular medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.molmed.2026.06.009},
pmid = {42392958},
issn = {1471-499X},
abstract = {Clonal hematopoiesis is emerging as a surprising modifier of Alzheimer's disease. Recent findings suggest that mutant myeloid cells may enter or expand within the brain, adopting either inflammatory or reparative states. We propose that their effects depend on the mutation, timing, clone size, brain niche, and disease stage.},
}
@article {pmid42392996,
year = {2026},
author = {Zhang, Y and Zhu, F and Wu, X and Li, Z and Huang, P and Gao, Y and Zeng, L},
title = {[Epigenetic regulator DOT1L controls neuronal amyloid pre-cursor protein expression via the p38 mediated mitochondrial fission-fusion homeostasis axis].},
journal = {Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences},
volume = {},
number = {},
pages = {1-13},
doi = {10.3724/zdxbyxb-2025-0706},
pmid = {42392996},
issn = {1008-9292},
abstract = {OBJECTIVES: To investigate the regulatory role of epigenetic regulator disruptor of telomeric silencing 1-like (DOT1L) and its mediated histone H3 lysine 79 (H3K79) methylation in modulating neuronal amyloid precursor protein (APP) expression, and to elucidate the underlying mechanisms involving mitochondrial homeostasis and the upstream p38 kinase.<br><br>METHODS: Alzheimer's disease (AD) models were established using APP/presenilin-1 (APP/PS1) double-transgenic mice and N2a cells overexpressing the human Swedish mutant APP (N2a-APPswe). Immunofluorescence staining was employed to assess DOT1L expression and localization in mouse brain tissues. N2a-APPswe cells were treated with the DOT1L-specific inhibitor EPZ5676 and divided into four groups: blank control, solvent control, DOT1L inhibitor, and DOT1L inhibitor plus p38 agonist (Gynostemma pentaphyllum extract). Western blotting was performed to measure the phosphorylation levels of DRP1 at Ser616 and Ser637 (key mitochondrial fission regulators), the levels of autophagy-related proteins p62 and the LC3-&#x2161;/LC3-&#x2160; ratio, the phosphorylation level of p38, as well as the expression of APP and APP-processing proteins BACE1 and PS1. Real-time quantitative polymerase chain reaction was used to detect mRNA levels of APP and genes involved in mitochondrial fission and fusion. Proteomics data were systematically analyzed through Gene Ontology analysis, WikiPathways enrichment analysis, and STRING protein-protein interaction network analysis to identify key signaling pathways. Mitochondrial morphology was evaluated by Mito-Tracker fluore-scence staining to measure average branch length.<br><br>RESULTS: DOT1L expression was signifi-cantly reduced in neurons of APP/PS1 mice compared to wild-type controls. DOT1L inhibition led to decreased H3K79me2 levels (P<0.01), accompanied by a marked increase in APP protein expression (P<0.01), although APP mRNA levels were reduced (P<0.01). Proteomics analysis revealed that differentially expressed proteins were highly enriched in the mitochondrial electron transport chain. Compared with the solvent control, the DOT1L inhibitor group showed inhibited mitochondrial fission, as evidenced by decreased p-DRP1 (Ser616), increased p-DRP1 (Ser637), downregulated MIEF1 mRNA, upregulated MFN1 mRNA (all P<0.05), and increased average mitochondrial branch length (P<0.05), along with reduced p-p38 levels (P<0.05). Co-administration of the p38 agonist significantly reversed these mitochondrial dynamics abnormalities (all P<0.05) and attenuated the abnormally elevated protein levels of APP, BACE1, and PS1 (P<0.05) compared to the DOT1L inhibitor group.<br><br>CONCLUSIONS: DOT1L maintains normal mito-chondrial fission and functional homeostasis through regulation of the p38 signaling pathway, thereby modulating APP expression.},
}
@article {pmid42393071,
year = {2026},
author = {Feng, LR},
title = {The cancer Alzheimer's disease paradox.},
journal = {npj aging},
volume = {12},
number = {1},
pages = {},
pmid = {42393071},
issn = {2731-6068},
}
@article {pmid42393277,
year = {2026},
author = {Weinberg, MS and Kodali, MC and Li, Z and Galler, JA and Tidball, AR and Reynolds, WC and Young, C and Devitte-McKee, K and Fatima, HA and Kivisäkk, P and Chatterjee, M and Kulkarni, A and Billingsly, JM and Bartlett, AL and Sui, SH and Kühtreiber, WM and Gerber, J and McManus, AJ and Tanzi, RE and Das, S and Faustman, DL and Arnold, SE},
title = {Bacillus Calmette-Guérin (BCG) immunotherapy reprograms CNS immunity and alters Alzheimer's biomarkers: results from two open-label clinical trials.},
journal = {Communications medicine},
volume = {6},
number = {1},
pages = {},
pmid = {42393277},
issn = {2730-664X},
support = {T32-MH112485//U.S. Department of Health &amp; Human Services | NIH | Office of Extramural Research, National Institutes of Health (OER)/ ; UL3AG067696//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; P30AG062421//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; UL1TR002541//U.S. Department of Health &amp; Human Services | NIH | National Center for Advancing Translational Sciences (NCATS)/ ; UM1TR004408//U.S. Department of Health &amp; Human Services | NIH | National Center for Advancing Translational Sciences (NCATS)/ ; AACSF-22-970716/ALZ/Alzheimer's Association/United States ; PTC REG-20-653582/ALZ/Alzheimer's Association/United States ; },
abstract = {BACKGROUND: Immune aging may contribute to Alzheimer's disease. Bacillus Calmette-Guérin (BCG), a vaccine known to induce trained immunity, has been linked to reduced Alzheimer's risk in prior studies. However, whether trained immunity can be observed in the human central nervous system remains unclear. We assessed whether BCG induces trained immunity-like responses in adults with and without Alzheimer's-related changes.<br><br>METHODS: We conducted two related one-year, open-label clinical trials in adults aged 55 years or older (n&#x2009;=&#x2009;12 without Alzheimer's-related pathology; n&#x2009;=&#x2009;11 with Alzheimer's-related pathology) recruited at a single center. Participants received two intradermal BCG vaccinations one month apart. Protocol-defined objectives included safety, neurocognitive outcomes, and longitudinal immune and Alzheimer's biomarker changes in blood and cerebrospinal fluid. Immune responses were assessed using cytokine assays and single-cell profiling. All enrolled participants were included where data were available; longitudinal changes were analyzed using mixed-effects models.<br><br>RESULTS: Here we show that BCG induces persistent, trained immunity-like changes in immune cells in cerebrospinal fluid, including enhanced innate responsiveness and associated transcriptional programs. These responses differ from blood, suggesting compartment-specific immune imprinting. In participants without Alzheimer's-related changes, these immune shifts are accompanied by decreased amyloid-&#x3b2; levels in cerebrospinal fluid and increased levels in blood. BCG was well tolerated, with no unexpected safety signals observed.<br><br>CONCLUSIONS: These findings suggest trained immunity-like responses in the central nervous system that may influence Alzheimer's-relevant pathways. This approach may represent an early neurodegenerative intervention strategy, although larger controlled studies are needed to confirm these observations.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov NCT04507126 (June 23, 2020) and NCT05004688 (August 6, 2021).},
}
@article {pmid42393306,
year = {2026},
author = {Benussi, A and Bozzali, M},
title = {Mixing apples and antibodies: when the Cochrane average obscures the evidence in Alzheimer's disease.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {7},
pages = {},
pmid = {42393306},
issn = {1590-3478},
}
@article {pmid42393367,
year = {2026},
author = {Vostrý, M and Binter, J and Kovářová, K and Posel, Z and Kubová, N and Cmorej, PC and Kroufek, R},
title = {Feasibility and preliminary effects of outdoor versus indoor cognitive-motor therapy in women with Alzheimer's disease: A randomized single-blind pilot study.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-60446-5},
pmid = {42393367},
issn = {2045-2322},
support = {CZ.02.01.01/00/23_021/0010653//Programme Johannes Amos Comenius/ ; },
abstract = {Alzheimer's disease is associated with progressive cognitive, functional and social decline. Non-pharmacological interventions that combine cognitive and motor stimulation are increasingly used in long-term care, but less is known about the feasibility and preliminary effects of delivering such programmes in outdoor rather than indoor settings. This exploratory randomized single-blind pilot study compared outdoor and indoor cognitive-motor therapy in institutionalized older women with Alzheimer's disease, focusing on global cognitive performance, selected functional outcomes, attendance and practical implementation. Fifty women aged 66.1-70.2 years with late-onset Alzheimer's disease were randomized to a seven-month outdoor cognitive-motor programme (n = 25) or an indoor cognitive-motor programme (n = 25). Sessions were delivered five times weekly for 45 min. Outcome assessors and data analysts were blinded to group allocation; therapists and participants could not be blinded because of the intervention setting. Global cognition was assessed with the Mini-Mental State Examination (MMSE). Functional outcomes were assessed using modified FIM-based indicators for daily tasks, mobility and social adaptability. Attendance and adverse events were recorded as feasibility outcomes. All randomized participants completed the study. Mean attendance was 91% in the outdoor group and 89% in the indoor group, and no intervention-related adverse events were recorded. Both groups improved on the MMSE, with a median increase of approximately two points. The outdoor group showed statistically significant within-group improvements in all three FIM-based indicators (daily tasks, mobility and social adaptability), whereas the indoor group did not show statistically significant functional change. However, these broader gains were observed in the context of baseline functional imbalance, including lower outdoor-group mobility and social-adaptability scores, and the small female-only sample and partial non-equivalence of intervention content limit between-group causal interpretation. A seven-month cognitive-motor programme was feasible in participating long-term care facilities. The findings suggest that outdoor delivery may be associated with broader functional gains than indoor delivery, but the results should be interpreted as preliminary and in light of the baseline functional imbalance. A fully powered, prospectively registered trial with more equivalent intervention arms, repeated measurement points, standardized functional outcomes and detailed monitoring of comorbidities and medication changes is warranted.},
}
@article {pmid42393497,
year = {2026},
author = {Ramesh, A and Reddy, R and Patel, AB},
title = {Quantitative Assessment of Neurometabolism by Deuterium and Proton NMR Spectroscopy Using [6,6'-[2]H2]Glucose.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00030},
pmid = {42393497},
issn = {1948-7193},
abstract = {Neurometabolic analysis is routinely performed using [13]C NMR/MRS in conjunction with the administration of [13]C-labeled tracers. Despite its widespread use, the low sensitivity of [13]C NMR necessitates long acquisition times. To address this limitation, the present study introduces an indirect approach that uses a single [1]H NMR acquisition to measure deuterium labeling by exploiting labeling at specific sites, thereby providing a novel and more efficient strategy for assessing neurometabolism. In this study, male SD rats were infused with [6,6'-[2]H2]glucose for 10-90 min, and the [2]H labeling of cortical metabolites was measured ex vivo using [2]H NMR spectroscopy. After 90 min of [6,6'-[2]H2]glucose infusion, resonances corresponding to [3-[2]H2]lactate, [4-[2]Hx]glutamate, [4-[2]Hx]glutamine, and [3-[2]H]aspartate (∼2.60 ppm) were detected. In contrast, signals corresponding to [2-[2]H]aspartate (∼3.90 ppm), [2-[2]H]glutamate (∼3.76 ppm), and [3-[2]H]glutamate (∼2.09 ppm) were not detected, even after prolonged infusion, suggesting complete loss of the [2]H label during the second turn of the tricarboxylic acid cycle. The cerebral metabolic rate of glucose oxidation, estimated by fitting an exponentially saturating curve to the pooled labeling of [4-[2]Hx]glutamate, [4-[2]Hx]glutamine, and [3-[2]H]aspartate, was 0.389 ± 0.031 μmol/g/min. The [4-[2]Hx]glutamate levels were also derived by subtracting the [4-[1]H2]glutamate resonance intensity from total [4-[1]H2]glutamate intensity estimated using the [3-[1]H2]glutamate intensity in unedited [1]H NMR spectra. The concentrations of [4-[2]Hx]glutamate determined from [1]H NMR spectra were comparable to those determined from [2]H NMR. Moreover, when applied to 5xFAD mice (2.53 ± 0.43 μmol/g, n = 7), a model of Alzheimer's disease, this indirect approach revealed significantly reduced (p = 0.028) [4-[2]Hx]glutamate levels compared with controls (2.99 ± 0.15 μmol/g, n = 7). This decrease was comparable to that observed with the direct [2]H NMR measurements and was consistent with findings from [13]C tracer-based studies.},
}
@article {pmid42393517,
year = {2026},
author = {Wen, Y and Dong, H},
title = {Generalizable Protein Folding Pathway Exploration with DA2-GRASP: Extending Beyond Miniproteins.},
journal = {Journal of chemical theory and computation},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jctc.6c00480},
pmid = {42393517},
issn = {1549-9626},
abstract = {Elucidating protein dynamics is crucial for deciphering fundamental biological processes, from enzyme catalysis to cellular signaling, as its dysregulation directly causes protein misfolding diseases such as Alzheimer's and Parkinson's. While artificial intelligence has revolutionized static protein structure prediction, capturing the high-dimensional dynamics of protein folding remains a formidable challenge that limits our ability to fully understand these vital biological phenomena. Here we present DA2-GRASP, a computational framework that overcomes this barrier by integrating deep learning with advanced sampling techniques to map protein folding pathways with unprecedented efficiency and accuracy. DA2-GRASP learns low-dimensional latent representations of protein conformations via a variational autoencoder and combines multidirectional generative sampling guided by local potential energy gradients to efficiently steer conformational transitions along energetically favorable paths, enabling accurate and efficient reconstruction of folding pathways. Our method achieves sublinear computational scaling with sequence length, contrasting the quadratical scaling of molecular dynamics-based conventional approaches, enabling tractable simulations. It maintains high precision in quantifying mutation-induced perturbations to folding thermodynamics, crucial for understanding disease mutations. It also enables atomistic characterization of the folding process of medium-sized proteins such as ubiquitin and small ubiquitin-like modifier (SUMO, ∼80 residues) on standard workstations, a task typically requiring specialized supercomputing platforms such as Anton. Analysis of these proteins provides new mechanistic insights into how structurally similar folds with low sequence identity navigate divergent folding pathways. DA2-GRASP thus establishes a versatile and powerful framework for exploring protein-folding dynamics and their functional consequences.},
}
@article {pmid42393750,
year = {2026},
author = {Zhang, J and Yang, N and Zou, P and Zong, X},
title = {Microglial checkpoint collapse in Alzheimer's disease: a tri-axial framework for biomarker-informed neuroimmune therapy.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-026-03924-x},
pmid = {42393750},
issn = {1742-2094},
support = {24CDA1269588//American Heart Association/ ; },
abstract = {BACKGROUND: Anti-amyloid antibodies have validated amyloid-β (Aβ) as a disease-relevant target in Alzheimer's disease (AD), but their modest clinical effect, efficacy largely restricted to early disease, and amyloid-related imaging abnormalities (ARIA) indicate that Aβ removal alone does not resolve the glial, lipid, and inflammatory programmes that sustain neurodegeneration. Microglia sit at the centre of this therapeutic gap. Single-nucleus and spatial profiling has resolved several AD-associated microglial states, yet state labels remain descriptive and do not explain why adaptive engagement becomes maladaptive.<br><br>MAIN BODY: We frame AD-relevant microglial dysfunction as checkpoint collapse: progressive failure of regulatory nodes that coordinate lipid sensing, lysosomal competence, neuronal restraint, and inflammatory threshold control. The central nodes are TREM2-mediated lipid and apolipoprotein sensing, progranulin-associated lysosomal regulation, CX3CR1-dependent neuron-microglia restraint, and CD33/Siglec-3 inhibitory tone. When these controls destabilise, downstream pathology can be organised around three coupled effector axes: a lipid axis centred on APOE-biased cholesterol trafficking, ACSL1/DGAT2-driven lipid-droplet accumulation, and impaired lysosomal flux; an iron/ferroptosis axis involving labile iron, phospholipid peroxidation, and insufficient GPX4/FSP1 defences; and an inflammation/complement axis linking NLRP3 activation, type-I interferon signalling, and C1q/C3-dependent synaptic engulfment to tau pathology and synapse loss. White-matter injury, astrocyte-microglia crosstalk, and cGAS-STING-linked senescence are integrated as cross-axis amplifiers.<br><br>CONCLUSIONS: This framework is proposed as a hypothesis-generating scaffold for biomarker-informed translational studies, rather than as a validated clinical stratification system. It may help organise stage-aware therapeutic hypotheses, including regulatory-node preservation in early disease, lipid-handling restoration and ferroptosis control at intermediate stages, and complement- or senescence-directed modulation in later disease. Current glial, iron, inflammatory, and imaging biomarkers remain insufficiently specific to assign individual patients reliably to discrete pathological axes in clinical practice.},
}
@article {pmid42393875,
year = {2026},
author = {Behera, A and Chandrasekaran, Y and Dhonthi Shekar, N and Saravanan, S and Manickam Dakshinamoorthi, B and Srinivasan, GP and Dharmalingam Jothinathan, MK},
title = {Genetic Approaches in Zebrafish Neurology: Genetic, Drug and Therapy Insights.},
journal = {Current drug research reviews},
volume = {},
number = {},
pages = {},
doi = {10.2174/0125899775470368260619041554},
pmid = {42393875},
issn = {2589-9783},
abstract = {Zebrafish (Danio rerio) has emerged as a valuable vertebrate model organism widely used in biological and biomedical research due to its rapid embryonic development, optical transparency, high fecundity, and genetic similarity to humans. These characteristics have made zebrafish an important experimental model in developmental biology, toxicology, cancer research, and particularly in the investigation of neurodegenerative diseases. A significant proportion of human genes have functional counterparts in zebrafish, allowing researchers to explore disease mechanisms and genetic pathways relevant to human neurological disorders. Advances in genetic technologies, including CRISPR-Cas9 genome editing, transgenic approaches, and mutagenesis screening, have further strengthened the use of zebrafish in neuroscience research. These tools enable precise manipulation of genes involved in neuronal development, degeneration, and disease progression. Zebrafish models have been successfully employed to study major neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. In addition, the model provides an efficient platform for drug screening, neurotoxicity studies, and therapeutic evaluation. This review highlights the role of zebrafish in genetic approaches to neurological research, emphasizing its contributions to disease modeling, drug discovery, and the development of potential therapeutic strategies for complex neurodegenerative disorders.},
}
@article {pmid42393905,
year = {2026},
author = {Zelek, MC and Walker Ii, JQ and Crocker-Sabbagh, I},
title = {Real-World Cognitive Stabilization via CDSS-Guided Multidomain Interventions in MCI and Older Adults with Cognitive Concerns.},
journal = {Current aging science},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118746098476197260627055743},
pmid = {42393905},
issn = {1874-6128},
abstract = {INTRODUCTION: Randomized multidomain trials have established that cognitive decline requires coordinated action across modifiable contributors, but routine care lacks delivery infrastructure. We evaluated real-world cognitive trajectories in older adults receiving uMETHOD Health clinical decision support system (CDSS)-guided care plans and assessed whether this multidomain approach could be operationalized in routine care.<br><br>METHODS: This retrospective, nonrandomized implementation-and-outcomes study analyzed the complete eligible paired cohort: individuals with CDSS-guided care plans and two valid sameinstrument cognitive assessments &#x2265;6 months apart. No additional selection was made by outcome, adherence, or trajectory. The CDSS integrates EHR-derived diagnoses, medications, biomarkers, vital signs, genomics, and lifestyle factors through expert clinical rules with constrained AI support to generate individualized clinician-, patient-, and caregiver-facing plans.<br><br>RESULTS: Favorable cognitive trajectories were observed in 294 of 345 matched assessment pairs (85.2%) over a mean follow-up of 14.1 months. Assessments used seven validated instruments; mean age was 74.6 years, and baseline medication use was 11.7 medications/patient. Favorable trajectories included 83.5% stable, improved, or minor decline without diagnostic progression and 1.7% slower-than-expected decline on benchmarked instruments (MoCA, MMSE, or SAGE).<br><br>DISCUSSION: The CDSS served as an implementation layer, translating multidomain evidence into prioritized, patient-specific next-best actions within ordinary clinical workflows. This positions multidomain cognitive management as a scalable, routine-care activity rather than a researchonly protocol.<br><br>CONCLUSION: Multidomain cognitive management was made executable in routine practice, with favorable trajectories observed in 85.2% of paired assessments. The practical implication is immediate: evidence-based cognitive management can be operationalized now at the point of care.},
}
@article {pmid42394082,
year = {2026},
author = {Khan, A and Kabir, H},
title = {Evaluating the User Experience and Therapeutic Efficacy of Humanoid Socially Assistive Robots in Alzheimer's Disease and Related Dementias (ADRD) Care.},
journal = {Studies in health technology and informatics},
volume = {338},
number = {},
pages = {626-630},
doi = {10.3233/SHTI260920},
pmid = {42394082},
issn = {1879-8365},
mesh = {Humans ; *Alzheimer Disease/therapy/psychology ; Female ; *Robotics ; Male ; *Self-Help Devices ; Aged ; *Dementia/therapy/psychology ; Aged, 80 and over ; Intelligent Systems ; Treatment Outcome ; },
abstract = {BACKGROUND: Addressing neuropsychiatric symptoms in Alzheimer's Disease and Related Dementias (ADRD) requires scalable, non-pharmacological interventions. This study evaluated the user experience and clinical efficacy of a humanoid Socially Assistive Robot (SAR) in an ADRD care setting.<br><br>METHODS: A randomized, 8-week, baseline-controlled intervention was conducted (N=19), utilizing each participant's pre-intervention status as the control. Outcomes included acute mood change, sustained depressive symptoms via the Geriatric Depression Scale (GDS), and user acceptance via the User Experience Questionnaire (UEQ).<br><br>RESULTS: The SAR achieved "Excellent" UEQ ratings (x > 2.0) across all dimensions, indicating high accessibility and engagement. Analysis revealed a significant acute positive mood boost (p < 0.001) and a sustained reduction in GDS scores over 8 weeks compared to baseline. A strong correlation existed between robotic stimulation and clinical GDS improvement (p < 0.01).<br><br>CONCLUSION: Humanoid SARs are highly accepted and efficacious adjunctive tools for improving emotional health in ADRD populations, supporting their integration into formal dementia care protocols.},
}
@article {pmid42394100,
year = {2026},
author = {Yoon, S and Patterson, M and Sun, F and Broadwell, P and Crupi, R and Kim, M and Davis, N},
title = {Leveraging the J48 Algorithm to Inform Community-Based AI Solutions for African American Dementia Caregiving.},
journal = {Studies in health technology and informatics},
volume = {338},
number = {},
pages = {713-717},
doi = {10.3233/SHTI260938},
pmid = {42394100},
issn = {1879-8365},
mesh = {Humans ; *Black or African American ; *Caregivers/psychology ; *Artificial Intelligence ; *Dementia/ethnology/nursing ; *Algorithms ; Adult ; Female ; Male ; Middle Aged ; United States ; Adolescent ; Young Adult ; Alzheimer Disease ; },
abstract = {We applied the J48 machine learning algorithm to build models that identify demographic and caregiving factors associated with perceived risks and benefits of community-based AI solutions for African American family caregiving. 572 diverse family members of a person with Alzheimer's disease and related dementias (ADRD) participated in this online survey in the U.S. The J48 algorithm (C4.5) identified race as the primary predictor for AI support, with African Americans favoring AI-enabled hospital-based diagnostic testing and faith-based apps regardless of their demographic or caregiving factors. Conversely, risk perceptions were heightened among highly educated White family members (aged 25-34) for clinical AI and among younger family members (ages 18-34) for community-based meal-related apps. Overall, model's F-measures (0.83) and PRC areas (0.74) confirm that community-based AI preference is driven more by cultural context and specific use cases than by general caregiving circumstances. While African Americans are willing to support the development of AI applications, enthusiasm does not extend uniformly across all community settings. While scientists should prioritize AI in clinical and faith-based settings, they must exercise caution in the nutritional domain where algorithms may perpetuate bias.},
}
@article {pmid42394275,
year = {2026},
author = {Hernandez-Kapila, YL and Weisenberger, DJ},
title = {Of mice and men-The emerging oral-gut-brain axis of health and disease.},
journal = {Periodontology 2000},
volume = {},
number = {},
pages = {},
doi = {10.1111/prd.70064},
pmid = {42394275},
issn = {1600-0757},
support = {U54AG089335/NH/NIH HHS/United States ; },
abstract = {OBJECTIVES: Oral health's inextricable links to systemic health are highlighted by the emerging oral-gut-brain axis and other well-known axes. There is growing evidence of a complex oral-gut-brain axis linking mouth and gut microbiomes with the central nervous system. Axis disruptions, characterized as oral and gut dysbiosis or microbial imbalances, can trigger oral and systemic inflammation and neuroinflammation, contributing to diseases such as Alzheimer's disease and Parkinson's disease.<br><br>MATERIALS AND METHODS: We summarize the oral-gut-brain axis mechanistic pathways, key evidence from human clinical and animal studies, and how the oral microbiome modulates human health and disease.<br><br>RESULTS: Periodontal disease (PD) is associated with increased oral pathogen presence in diseased tissues throughout the human body. Preclinical models recapitulate these findings. Experimental periodontal infection induces dysbiosis that is linked to activation of inflammatory pathways that promote diseased phenotypes. Novel therapeutic approaches, including the probiotic fbacteriocin nisin, are increasingly recognized for targeted microbiome therapy at multiple inflection points across the axis. Nisin restores microbial balance, reduces inflammation, inhibits end-organ pathology, prevents periodontal bone loss, and reduces brain amyloid/tau accumulation and cytokine expression.<br><br>CONCLUSIONS: These findings highlight the complexity of the oral-gut-brain axis and the ability to modulate the axis using bacteriocin-based approaches.<br><br>CLINICAL RELEVANCE: Future probiotic or antimicrobial strategies aimed at ameliorating neuroinflammatory and metabolic diseases via microbiome-targeted therapy hold clinical promise.},
}
@article {pmid42394367,
year = {2026},
author = {Kreiselmaier, S and Keller, M and Nardi, L and Mueller, C and von Wiegen, N and Bickenbach, K and Gröbner, L and Abukhalaf, M and Tholey, A and Mueller, MM and Körschgen, H and Schmeisser, MJ and Becker-Pauly, C and Pietrzik, CU},
title = {The Role of Meprins on the Brain Extracellular Matrix and Perineuronal Nets.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {40},
number = {13},
pages = {e72097},
doi = {10.1096/fj.202601333R},
pmid = {42394367},
issn = {1530-6860},
support = {CRC 1080 A15//Deutsche Forschungsgemeinschaft (DFG)/ ; CRC 1080 Z2//Deutsche Forschungsgemeinschaft (DFG)/ ; },
mesh = {Animals ; *Perineuronal Nets/metabolism ; *Extracellular Matrix/metabolism ; Mice ; Brevican/metabolism ; *Metalloendopeptidases/metabolism/genetics ; *Brain/metabolism ; Mice, Transgenic ; Synapses/metabolism ; Long-Term Potentiation/physiology ; Male ; Neurocan/metabolism ; Alzheimer Disease/metabolism ; Humans ; },
abstract = {Meprin α and meprin β are zinc metalloproteases that are strongly expressed in intestinal and renal tissues and are expressed as homo- and heterodimers. In the kidney and intestine, they are involved in extracellular matrix assembly and modulation of inflammatory responses. However, meprin β has recently attracted attention because it generates Alzheimer's Disease (AD)-specific Aβ peptides and cleaves brevican, a major component of the perineuronal nets (PNNs) in the brain. PNNs stabilize synapses, thereby regulating plasticity and memory formation. Brevican cleavage correlated with impaired spatial memory formation and impaired CA1 long-term potentiation (LTP) in meprin β transgenic mice. Furthermore, numerous studies have shown the dysregulation of PNN components in AD. Still, the physiological and pathological functions of proteolytic PNN remodeling remain elusive. This study identified an essential role of meprin α in brevican cleavage. It enhanced meprin β's catalytic activity on brevican in co-expression. Moreover, an N-terminomics analysis identified novel meprin β substrates, neurocan, and receptor-type tyrosine-protein phosphatase zeta (RPTPζ) in the brain. Both are key components of PNNs. RPTPζ cleavage by meprin α and meprin β was confirmed in vitro. To assess the functional impact of meprin-mediated proteolysis on the brain extracellular matrix, PNNs and synaptic organization were investigated in vivo using immunofluorescence and electron microscopy. Meprin-mediated proteolysis disrupted PNN structure and decreased synapse density in the hippocampal CA1 region of meprin β transgenic mice. This identifies meprin-dependent PNN remodeling as a novel mechanism contributing to synaptic dysfunction.},
}
@article {pmid42394391,
year = {2026},
author = {Rabichow, BE and Nixon, L and Tallant, LE and Gibson, KA and Nascari, DG and Barnett, JH and Massa, N and Fryer, JD},
title = {Amyloid exacerbates tau and alpha-synuclein pathologies, behavioral impairments, and neuroinflammation in a mixed dementia model.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71639},
doi = {10.1002/alz.71639},
pmid = {42394391},
issn = {1552-5279},
support = {NS110435//NINDS Lewy Body Dementia Center Without Walls/ ; //Translational Genomics Research Institute (TGen) Foundation/ ; NS084974/GF/NIH HHS/United States ; AG062556/GF/NIH HHS/United States ; AG062110/GF/NIH HHS/United States ; NS094137/GF/NIH HHS/United States ; AG057997/GF/NIH HHS/United States ; AG062077/GF/NIH HHS/United States ; AG047327/GF/NIH HHS/United States ; AG049992/GF/NIH HHS/United States ; NS110435/GF/NIH HHS/United States ; },
mesh = {Animals ; *alpha-Synuclein/metabolism/genetics ; *tau Proteins/metabolism/genetics ; Disease Models, Animal ; Mice ; *Neuroinflammatory Diseases/pathology/metabolism ; *Mixed Dementias/pathology ; *Amyloid beta-Peptides/metabolism ; Brain/pathology/metabolism ; Mice, Transgenic ; Plaque, Amyloid/pathology ; Phosphorylation ; },
abstract = {INTRODUCTION: Neurodegenerative diseases often involve overlapping alpha-synuclein (asyn), amyloid beta, and tau proteinopathies, yet the mechanisms, impact, and directionality of their interactions remain unclear.<br><br>METHODS: We induced brain-wide neuronal asyn/tau pathologies via viral expression of wild-type asyn, mutant asyn[E46K], mutant tau[A152T], or both asyn[E46K]/tau[A152T] in adult amyloidosis knock-in mice and controls, either post-plaque deposition (6 months old) or pre-plaque (3 months old). Open-field behavior was assessed baseline and 3 and 6 months post-transduction, followed by neuropathology and neuroinflammation analyses.<br><br>RESULTS: Post-plaque induction in amyloid mice increased asyn/tau total and phosphorylated levels and exacerbated amyloid-related hyperlocomotion/anxiety. Pre-plaque induction produced robust phosphorylated pathologies irrespective of amyloid, while causing similar amyloid-dependent behavioral synergy. Tau pathology drove LGALS3[+] inflammatory glial responses in white-matter fibers.<br><br>DISCUSSION: Amyloid context gates vulnerability, with certain synergies manifesting across stages. White-matter gliosis is a novel mechanism of tau[A152T] risk. Together, our data argue for the development of stage-aware, multitarget interventions and biomarkers.},
}
@article {pmid42394394,
year = {2026},
author = {Prados, M and Acosta, C and Mattke, S},
title = {Estimated labor market outcomes of people progressing from preclinical to early-stage Alzheimer's disease in the United States.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71628},
doi = {10.1002/alz.71628},
pmid = {42394394},
issn = {1552-5279},
support = {//Research contract from Biogen to USC/ ; },
mesh = {Humans ; *Alzheimer Disease/economics/epidemiology ; United States/epidemiology ; Female ; Male ; *Employment/statistics &amp; numerical data ; Aged ; Middle Aged ; Disease Progression ; *Cognitive Dysfunction/epidemiology/economics ; *Income/statistics &amp; numerical data ; },
abstract = {INTRODUCTION: Secondary prevention treatments for Alzheimer's disease (AD) that are currently in late-stage clinical trials may preserve productivity and workforce participation.<br><br>METHODS: Using the nationally representative Health and Retirement Study waves from 1996 to 2020, we estimated changes in labor force participation, annual earnings, and social assistance payments between incident cases of cognitively impaired and statistically matched cognitively normal individuals.<br><br>RESULTS: Among 20,717 respondents (aged 50 to 79), 5232 developed mild cognitive impairment or mild dementia. Disease onset was associated with a five-percentage-point (p.p.) reduction in workforce participation, annual earnings losses of US$8233 (23%) and US$5616 (18%) for men and women who remained in the labor force, respectively, and an increase of 3.5. p.p. male and 5.6 p.p. female social assistance beneficiaries.<br><br>DISCUSSION: Onset of cognitive impairment was associated with statistically significant and meaningful reduction in workforce participation and earnings and increased participation in social assistance programs.},
}
@article {pmid42394416,
year = {2026},
author = {Ceron, C and Casquero-Veiga, M and Lamanna-Rama, N and Fernández-Nueda, I and Fernández-Pena, A and Olazagoitia, N and Sobrino, G and Herraiz, A and González, MI and Muñoz-Hernando, M and Ruperti-Repilado, A and Romero-Sanz, E and Morcillo, M&#xc1; and Pérez-Medina, C and Moro, MA and Villaverde, G and Rubio, J and Fernandez-Ferro, J and Desco, M and Herranz, F and Salinas, B and Fuster, V and Cortes-Canteli, M},
title = {Unveiling the procoagulant state in Alzheimer's disease: A novel PET imaging strategy.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71652},
doi = {10.1002/alz.71652},
pmid = {42394416},
issn = {1552-5279},
support = {CPII21/00007//Instituto de Salud Carlos III/ ; AC20/00091//Instituto de Salud Carlos III/ ; AC20/00077//Instituto de Salud Carlos III/ ; A2023012F//BrightFocus Foundation/ ; JDC2022-048922-I//Ministerio de Ciencia e Innovaci&#xf3;n (MCIN/AEI/10.13039/501100011033)/ ; RED2022-134299-T//Ministerio de Ciencia e Innovaci&#xf3;n (MCIN/AEI/10.13039/501100011033)/ ; JDC2022-048922-I//European Union NextGenerationEU/PRTR/ ; ICT2021-006950//European Union NextGenerationEU/PRTR/ ; PID2024-157521OB-I00//European Union NextGenerationEU/PRTR/ ; CNS2023-144316//European Union NextGenerationEU/PRTR/ ; PID2022-140616OB-I00//European Union NextGenerationEU/PRTR/ ; PDC2022-133493-100//European Union NextGenerationEU/PRTR/ ; ref.202180E048//Nanomedicine CSIC Hub/ ; S2022/BMD-7403//Comunidad de Madrid/ ; //PTI-NEUROAGING CSIC/ ; JPND2020-568-025//EU Joint Programme - Neurodegenerative Disease Research/ ; RYC2023-043741-I//Ministerio de Ciencia, Innovaci&#xf3;n y Universidades (ES, MICIU/AEI/10.13039/501100011033)/ ; ICT2021-006950//Ministerio de Ciencia, Innovaci&#xf3;n y Universidades (ES, MICIU/AEI/10.13039/501100011033)/ ; PID2024-157521OB-I00//Ministerio de Ciencia, Innovaci&#xf3;n y Universidades (ES, MICIU/AEI/10.13039/501100011033)/ ; CNS2023-144316//Ministerio de Ciencia, Innovaci&#xf3;n y Universidades (ES, MICIU/AEI/10.13039/501100011033)/ ; PID2022-140616OB-I00//Ministerio de Ciencia, Innovaci&#xf3;n y Universidades (ES, MICIU/AEI/10.13039/501100011033)/ ; PDC2022-133493-100//Ministerio de Ciencia, Innovaci&#xf3;n y Universidades (ES, MICIU/AEI/10.13039/501100011033)/ ; CEX2020-001041-S//Ministerio de Ciencia, Innovaci&#xf3;n y Universidades (ES, MICIU/AEI/10.13039/501100011033)/ ; },
mesh = {Animals ; *Alzheimer Disease/diagnostic imaging ; *Positron-Emission Tomography/methods ; Humans ; Mice ; Mice, Transgenic ; *Brain/diagnostic imaging/pathology/metabolism ; Fibrin/metabolism ; Female ; Male ; Aged, 80 and over ; Gallium Radioisotopes ; Zirconium ; Disease Models, Animal ; Blood Platelets ; },
abstract = {INTRODUCTION: A subset of Alzheimer's disease (AD) patients exhibits a procoagulant state that remains undiagnosed despite available treatments. We developed positron emission tomography (PET) strategies to in vivo detect cerebral microthrombi in TgCRND8 mice.<br><br>METHODS: PET was performed with a fibrin-binding probe (FBP) in TgCRND8 and wild-type mice using a zirconium-89-radiolabeled and a click-chemistry pre-targeted gallium-68 radiotracer. Platelet content was assessed in post mortem brain tissue from AD patients and TgCRND8 mice, and evaluated by PET using a CD41 pre-targeted gallium-68 nanoradiotracer.<br><br>RESULTS: Cerebral FBP uptake differentiated TgCRND8 from wild-type mice, particularly ex vivo and with advancing age. Cerebral fibrin burden correlated with platelet content in AD patients, and elevated cerebral platelet burden in TgCRND8 mice was confirmed in post mortem tissue and in vivo by PET.<br><br>DISCUSSION: Our findings support PET-based detection of AD-associated cerebral microthrombi and the development of imaging biomarkers to stratify AD patients by procoagulant status and inform personalized therapies.},
}
@article {pmid42394922,
year = {2026},
author = {Zhang, D and Zhang, J and Liu, B and Liu, M and Chen, W and Du, G},
title = {HDFT-MViT: a progressive core-enhanced mix framework for Alzheimer's disease classification using MRI images.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1860368},
pmid = {42394922},
issn = {1664-2295},
abstract = {BACKGROUND: Early and accurate diagnosis of Alzheimer's disease (AD) is critical. In MRI-based computer-aided diagnosis, convolutional neural networks (CNNs) excel at extracting local features but struggle to model long-range dependencies, while Vision Transformers (ViTs) offer strong global modeling capabilities but suffer from high computational complexity, limiting their deployment in resource-constrained settings.<br><br>NEW METHODS: This paper proposes HDFT-MViT, a lightweight hybrid architecture based on MobileViT that integrates a hierarchical dynamic filter with a lightweight Transformer. The model adopts a progressive Core-Enhanced Mix design: Shallow layers employ MobileNetV2 inverted residual blocks for efficient local feature extraction; intermediate and deep layers incorporate a dual-branch module that integrates a dynamic filter for frequency-domain global modulation and a lightweight Transformer for spatial long-range dependency modeling, followed by hierarchical fusion via learnable weights. A channel attention mechanism is further introduced to enhance feature discriminability.<br><br>RESULTS: Evaluations on the public ADNI-1 (3-class) and ADNI-2 (4-class) MRI datasets show that HDFT-MViT achieves state-of-the-art classification accuracies of 98.85&#x202f;&#xb1;&#x202f;0.27% and 98.07&#x202f;&#xb1;&#x202f;0.54%, respectively, while maintaining a lightweight profile with only 3.46 M parameters, confirming its effectiveness and efficiency.<br><br>CONCLUSION: HDFT-MViT achieves an optimal balance between local detail perception and global semantic understanding within a computationally efficient framework, offering a promising tool for clinical AD diagnosis. Code will be released upon acceptance.},
}
@article {pmid42394931,
year = {2026},
author = {Jeon, YH and Kim, JA and Kang, DY and Lee, S and Choi, NK and Park, JY},
title = {Ginkgo biloba extract for dizziness-related symptoms in central neurological disorders: a systematic review and meta-analysis.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1860538},
pmid = {42394931},
issn = {1664-2295},
abstract = {BACKGROUND AND PURPOSE: Dizziness associated with central neurological disorders-broadly defined as dizziness or vertigo attributable to central nervous system pathology affecting central vestibular processing-is a clinically challenging and heterogeneous condition with limited treatment options. Ginkgo biloba extract-through its microcirculatory, neuroprotective, and anti-inflammatory mechanisms-represents a biologically plausible intervention. However, its efficacy in this setting has not been comprehensively established. We evaluated the efficacy and safety of Ginkgo biloba extract through a systematic review and meta-analysis of randomized controlled trials (RCTs).<br><br>METHODS: Nine international and Korean databases were searched from January 1974 through November 2025. Studies were eligible if they were RCTs enrolling adults aged 18&#x202f;years or older with cerebrovascular disease, neurodegenerative disease, or central vestibular dysfunction who had dizziness, vertigo, or balance-related symptoms or relevant outcome assessments. Cochrane RoB 2.0 tool and certainty of evidence was rated using the Assessment, Development and Evaluations (GRADE) approach. Prespecified subgroup analyses by underlying etiology and intervention type, together with leave-one-out sensitivity analyses, were performed to explore heterogeneity.<br><br>RESULTS: Nine RCTs (N&#x202f;=&#x202f;2,394) were included; participants were predominantly drawn from dementia populations (71.6%), with smaller contributions from cerebral arteriosclerosis (23.0%) and vertebrobasilar or posterior circulation disorders (5.4%). Ginkgo biloba significantly reduced dizziness/vertigo severity on the 11-point box scale (MD&#x202f;-&#x202f;0.76, 95% CI&#x202f;-&#x202f;1.35 to -0.18; p&#x202f;=&#x202f;0.01) and VAS (SMD&#x202f;-&#x202f;0.38, 95% CI&#x202f;-&#x202f;0.58 to -0.19; p&#x202f;=&#x202f;0.0001). Moderate-certainty evidence suggested improvements in functional outcomes and quality of life, including the Alzheimer's Disease Activities of Daily Living International Scale (MD&#x202f;=&#x202f;-0.17, 95% CI: -0.22 to -0.13) and the Dementia Quality of Life - Proxy (MD&#x202f;=&#x202f;2.00, 95% CI: 0.85 to 3.15). The intervention was generally well tolerated, with significantly lower risks of angina pectoris (OR 0.51, 95% CI 0.31 to 0.85) and tinnitus (OR 0.37, 95% CI 0.22 to 0.63) and no significant increase in other adverse events.<br><br>CONCLUSION: Ginkgo biloba extract may reduce dizziness severity and improve daily functioning in patients with central neurological disorders accompanied by dizziness or vertigo, with a favorable safety profile. However, given the small number of eligible trials, substantial clinical and statistical heterogeneity, and the predominance of dementia-derived data, these findings should be interpreted with caution. Well-designed RCTs in clearly defined central vestibular populations, ideally confirmed by neuroimaging or vestibular testing, are needed to confirm these results.<br><br>https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD420251229692, PROSPERO: CRD420251229692.},
}
@article {pmid42394935,
year = {2026},
author = {Leone, L and Kiernan, TJ and Kuwabara, S and Barnett, M and Devenney, E and Ahmed, RM and Lin, CS},
title = {A convergence of global epidemics: diabetes as a modulator of neurodegenerative and neuro-inflammatory disorders.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1824840},
pmid = {42394935},
issn = {1664-2295},
abstract = {Diabetes mellitus (DM) and neurological disorders are rapidly converging global health burdens, driven by population ageing, the growing prevalence of metabolic syndrome, and limited early detection and disease-modifying therapies for many neurological syndromes. Beyond its established role in diabetes-related peripheral neuropathy, DM is increasingly implicated as a modifier of risk, phenotype, and prognosis across a wide range of central and peripheral nervous system diseases. In this narrative review, we synthesize current epidemiological, clinical, genetic, and mechanistic evidence examining the relationship between DM and 10 clinically important neurological disorders: Alzheimer's disease (AD), vascular dementia (VaD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), multiple sclerosis (MS), myasthenia gravis (MG), and neuromyelitis optica spectrum disorder (NMOSD). Across these conditions, DM acts as a context-dependent disease modifier, increasing risk in some disorders, appearing protective or delaying onset in others, and influencing disease phenotype, progression, and treatment response. We highlight potential areas of mechanistic convergence, such as insulin resistance, inflammation, disrupted energy homeostasis, and genetic predisposition, alongside important divergences shaped by disease-specific pathology. We also discuss the clinical and translational implications of this interface, including diagnostic challenges, opportunities for improved risk stratification, and growing interest in repurposing antidiabetic therapies, particularly metformin, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter-2 inhibitors, for neurological benefit. As the global burden of diabetes and neurological disease escalates, it is crucial to better understand the interplay between metabolic dysfunction, neurodegeneration, and neuro-immune pathways. The integration of insights across diseases may inform prevention strategies and support the development of therapeutic interventions at the metabolic-neurological interface.},
}
@article {pmid42395011,
year = {2026},
author = {Lee, MY and Jeon, SJ and Kim, HJ and Kim, M},
title = {Red ginseng-mediated modulation of the NLRP3 Inflammasome in neuroinflammatory-related cognitive impairments.},
journal = {Journal of ginseng research},
volume = {50},
number = {4},
pages = {101022},
pmid = {42395011},
issn = {1226-8453},
abstract = {The NLRP3 inflammasome is a key immune regulator involved in the pathophysiology of neuroinflammation and various neurodegenerative diseases. Recent studies have shown that both activation and inhibition of the NLRP3 inflammasome can influence disease progression and symptoms in models of cognitive impairment, including Alzheimer's disease (AD). Red ginseng (RG), a traditional medicinal plant, possesses anti-inflammatory properties and shows potential for modulating the NLRP3 inflammasome pathway. This review highlights the effects of RG on the NLRP3 inflammasome, with a particular focus on its therapeutic potential in AD and related cognitive impairments. The structure and activation mechanism of the NLRP3 inflammasome are first described, followed by a discussion of its role in neurodegenerative diseases and neuroinflammation. We then explore how RG and its major components regulate the priming and activation phase of the NLRP3 inflammasome, and discuss their therapeutic potential based on findings from the neuroinflammatory-related cognitive impairment model. Furthermore, we identify supporting evidence for the application of the RG-NLRP3 mechanism in other central nervous system disorders (CNS) disorders, such as cerebral ischemia and vascular dementia. Overall, RG emerges as a promising therapeutic candidate for mitigating neuroinflammation and enhancing cognitive function in neuroinflammatory-related cognitive disorders through NLRP3 inflammasome regulation. Future studies using various neurodegenerative disease (NDD) models and clinical trials are necessary to further validate the therapeutic potential of the RG-NLRP3 pathway.},
}
@article {pmid42395049,
year = {2026},
author = {Hofmann, A and Perneczky, R},
title = {Obstacles and solutions for implementing amyloid-targeting treatments in Europe.},
journal = {Alzheimer's &amp; dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70367},
pmid = {42395049},
issn = {2352-8729},
abstract = {Recent approvals of disease-modifying therapies by the European Medicines Agency mark a historic shift in the treatment landscape of Alzheimer's disease (AD) within the European Union that will challenge national health-care systems and require major adaptations and modernization. This Perspective article provides an overview of the major obstacles in Europe concerning successful implementation of amyloid-targeting treatments and offers potential solutions to overcome them. Major hurdles include a lack of recognition regarding the critical importance of an early, biomarker-based AD diagnosis; low acceptance of blood tests and digital cognitive screening tools; insufficient investment in magnetic resonance imaging capacities; and a fragmented infrastructure for clinical registries. We call on European clinicians, research institutions, and policy makers for a bold and coordinated action to urgently modernize diagnostic pathways and monitoring infrastructure to deliver novel AD treatments in a timely, safe, and equitable manner to all patients who may benefit.},
}
@article {pmid42395104,
year = {2026},
author = {Li, J and Zhou, FL and Chen, JJ and Lin, ZJ and Shi, X and Zhang, GG and Yang, HJ and Dong, MJ and Yi, L and Hu, J and Chen, XH},
title = {Novel PSEN1 (Q223 L) mutation causes early-onset Alzheimer's disease: A case report.},
journal = {World journal of radiology},
volume = {18},
number = {6},
pages = {116652},
pmid = {42395104},
issn = {1949-8470},
abstract = {BACKGROUND: Mutations in the PSEN1, PSEN2, and APP genes are known to cause Alzheimer's disease (AD). Among these, PSEN1 mutations are the most frequent causes of autosomal dominant early-onset AD (EOAD). Patients harboring pathogenic mutations often exhibit considerable clinical heterogeneity. Identifying novel mutations and analyzing their associations with clinical cases is crucial for advancing our understanding of the pathogenesis of AD.<br><br>CASE SUMMARY: This report describes the clinical presentation of a family with EOAD. The proband was a 43-year-old Chinese female who presented with a three-year history of cognitive decline for 3 years. Magnetic resonance imaging demonstrated diffuse cerebral cortical atrophy. Next-generation sequencing identified a novel heterozygous c.668A>T mutation in PSEN1, which resulted in a p.Gln223 Leu. cerebrospinal fluid biomarker analysis revealed abnormal levels of amyloid and tau, indicative of underlying Alzheimer's pathology. Furthermore, [18]F-flortaucipir (AV-1451) positron emission topography and [18]F-florbetapir (AV-45) positron emission topography imaging demonstrated extensive cerebral amyloid beta and tau deposition.<br><br>CONCLUSION: We report a novel pathogenic PSEN1 mutation, Q223 L, identified for the first time in a Chinese family with EOAD.},
}
@article {pmid42395191,
year = {2026},
author = {Zhang, K and Sha, L and Sun, X},
title = {Editorial: Association of diabetes mellitus with cognitive impairment and neurological disorders, volume II.},
journal = {Frontiers in endocrinology},
volume = {17},
number = {},
pages = {1900873},
pmid = {42395191},
issn = {1664-2392},
}
@article {pmid42395342,
year = {2026},
author = {Barrantes, FJ},
title = {Correction: Cognitive synaptopathy: synaptic and dendritic spine dysfunction in age-related cognitive disorders.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1845297},
doi = {10.3389/fnagi.2026.1845297},
pmid = {42395342},
issn = {1663-4365},
abstract = {[This corrects the article DOI: 10.3389/fnagi.2024.1476909.].},
}
@article {pmid42395343,
year = {2026},
author = {Terman, E},
title = {Biomarkers, diagnosis, and the meaning of disease: evaluating competing frameworks for Alzheimer's disease classification.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1841695},
pmid = {42395343},
issn = {1663-4365},
}
@article {pmid42395345,
year = {2026},
author = {Zhao, B and Zhou, R and Liu, P and Li, Q and Yan, Y and Du, J and Zhao, K and Liu, J and Wang, J and Qu, Q},
title = {FLOT1 and EEF1D: ac4C-related genes bridging Alzheimer's disease and sleep deprivation.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1825164},
pmid = {42395345},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's disease (AD) and sleep deprivation (SD), two common conditions in the elderly, share complex molecular connections and may mutually influence each other's pathogenesis. Current drugs only relieve symptoms with limited efficacy, making it urgent to explore the shared pathological mechanisms and potential intervention targets of the two conditions. This study used bioinformatics: first screening AD-related genes associated with SD and N4-acetylcytidine (ac4C) from relevant data; then identifying key genes via Mendelian randomization (MR) analysis and machine learning; finally screening AD-related key cells with single-cell RNA sequencing (scRNA-seq) data, to provide a basis for revealing the molecular and cellular regulatory mechanisms of AD-SD comorbidity.<br><br>METHODS: This study integrated bulk RNA sequencing (RNA-Seq) and scRNA-seq data from the Gene Expression Omnibus (GEO) database to identify AD-related key genes associated with SD and ac4C. Machine learning algorithms, including MR, were applied to screen these key genes. Additionally, gene set enrichment analysis (GSEA) was conducted to explore the pathways associated with the key genes, while ssGSEA was used to assess differences in immune cell infiltration. For the scRNA-seq data, key cells involved in AD pathology were further identified. Subsequently, the differential expression of the two key genes was validated using peripheral blood samples collected from AD and SD patients.<br><br>RESULTS: Through MR analysis, machine learning algorithms, and other analytical approaches, FLOT1 and EEF1D were identified as key genes. GSEA revealed that these key genes were enriched in multiple pathways, including the lysosome pathway, chemokine signaling pathway, and leukocyte transendothelial migration. Immune cell infiltration analysis suggested that myeloid-derived suppressor cells (MDSCs) might serve as key immune cells. Additionally, scRNA-seq analysis identified microglia, CD4&#x202f;+&#x202f;T cells, CD8&#x202f;+&#x202f;T cells, and natural killer (NK) cells as key cell types involved in AD pathogenesis. Critically, these key genes were successfully validated in peripheral blood samples from AD and SD patients, aligning with the above analysis.<br><br>CONCLUSION: Overall, FLOT1 and EEF1D were identified as key genes associated with SD and ac4C in AD. This finding provided new grounds for the clinical diagnosis and treatment of AD.},
}
@article {pmid42395347,
year = {2026},
author = {Tang, Y and Ruan, Y and Zheng, D and Huang, Y and Qi, W and Yuan, Q and Xue, C and Xiao, C},
title = {Striatal functional connectivity alterations in mild cognitive impairment subtypes defined by CSF A/T biomarkers.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1831310},
pmid = {42395347},
issn = {1663-4365},
abstract = {BACKGROUND: Mild cognitive impairment (MCI) is the prodromal stage of Alzheimer's disease (AD), the primary cause of dementia. In addition to supporting motor and higher-order cognitive activities, the basal ganglia, particularly the caudate nucleus and putamen, may exhibit early AD-related network changes. This study investigated differences in striatal functional connectivity (FC) across MCI subtypes marked by cerebrospinal fluid (CSF) amyloid-β (Aβ42) and phosphorylated tau (p-tau) (A/T) biomarkers (A+/A- and T+/T-), along with associations among altered FC, AD pathology, and cognitive performance.<br><br>METHODS: From the ADNI database, 212 individuals with MCI were stratified into three groups: A-T- (n = 54), A+T- (n = 28), and A+T+ (n = 52). Group differences in putamen and caudate connectivity were investigated using seed-based FC analyses. Changes in FC, CSF biomarkers, and cognitive function were evaluated using partial correlation analyses. The discriminative value of FC changes was assessed using univariate and multivariate logistic regression analyses.<br><br>RESULTS: Compared with the A-T- and A+T- groups, the A+T+ group was older and showed lower episodic memory (EM) scores. The left caudate and bilateral cerebellar anterior lobes, between the right caudate and bilateral medial frontal gyrus (MFG), and between the left putamen and left MFG all had higher FC in the A+T+ group. In the A+T+ group, right caudate-MFG connectivity was positively correlated with CSF p-tau levels (r = 0.424, p = 0.012) and negatively correlated with EM scores (r = -0.38, p = 0.018). Compared with single-region models, multivariate logistic regression demonstrated superior classification performance.<br><br>CONCLUSION: Patients with MCI and coexisting CSF A&#x3b2; and tau pathologies (A+T+) exhibit increased FC in striatal-cortical circuits, which is strongly associated with tau pathology and episodic memory impairment. These findings provide neuroimaging evidence that striatal network alterations are linked to tau-related pathology in prodromal AD. Changes in striatal FC may serve as an early neurobiological indicator of AD-related MCI.},
}
@article {pmid42395350,
year = {2026},
author = {Van Skike, CE and Hernandez, SF and Hussong, SA and Miller, LR and Makhlouf, H and Muppala, AC and DeRosa, N and Jahrling, JB and Dineley, KT and Galvan, V},
title = {mTOR drives cerebrovascular dysfunction and blood-brain barrier breakdown in a model of Alzheimer's disease with cerebral amyloid angiopathy.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.23.733858},
pmid = {42395350},
issn = {2692-8205},
abstract = {Cerebral amyloid angiopathy (CAA) is characterized by the deposition of amyloid β fibrils (Aβ) within walls of the cerebrovasculature and contributes to intracerebral hemorrhage, ischemic stroke, and cognitive dysfunction in patients with Alzheimer's disease (AD) and in non-pathological aging. Previous studies have shown that mTOR drives cerebrovascular dysfunction and cognitive impairment observed in AD, vascular cognitive impairment, and normative aging. However, the mechanisms by which mTOR contributes to CAA are unknown. Here, we show that mTOR drives the accumulation of fibrillar vascular Aβ lesions in the Tg2576 Model of AD with CAA (using equal numbers of female and male mice), which directly impair endothelium-dependent cerebrovascular reactivity. Additionally, we found that blood-brain barrier (BBB) breakdown and remodeling of tight junction proteins, dependent on mTOR, are associated with increased cerebral microhemorrhages. Finally, we show that mTOR contributes to neurovascular uncoupling in Tg2576 AD mice through nNOS dysfunction and inhibition of non-nitric oxide synthase-dependent contributions to neurovascular coupling (NVC). Contextual memory impairments were ameliorated by the mTOR inhibitor rapamycin. Improvements in memory were associated with reduced cerebrovascular Aβ fibril accumulation, enhanced endothelium-dependent vasodilation, reduced fibrillar Aβ load, restoration of BBB integrity, attenuation of intracerebral microhemorrhage, and restoration of NVC. These data indicate that mTOR drives vascular accumulation of fibrillar Aβ, including those associated with brain vasculature, and mediates cerebrovascular dysfunction in a model of AD with CAA. Thus, mTOR inhibitors represent a promising treatment option for patients with CAA and AD.},
}
@article {pmid42395371,
year = {2026},
author = {Aladeokin, AC and Jeltsch, M and Davtyan, H and Blurton-Jones, M and Koistinaho, J},
title = {Composition and activity of the proteasome in human iPSC-derived neuronal model of early-stage sporadic Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.23.734021},
pmid = {42395371},
issn = {2692-8205},
abstract = {INTRODUCTION: The proteasome is a critical cellular degradative machinery impaired in late-stage Alzheimer's disease (AD). However, the status and activity of the proteasome in early-stage sporadic AD (sAD) is unknown.<br><br>METHODS: A cellular model of human early-stage sAD was generated from sAD patient iPSC-derived cortical neurons by dual-SMAD inhibition. The iPSCs, neuroprogenitors, and cortical neurons were validated by the expressions of key markers. The level of total intraneuronal A&#x3b2; was measured by ELISA. Composition and native proteolytic activities of the proteasome in control and sAD cortical neurons were measured using complementary fluorogenic probes.<br><br>RESULTS: Control and sAD patients iPSCs expressed pluripotent markers OCT4, NANOG, and SSEA4 which induced into neuroprogenitors expressing NESTIN and PAX6. The neuroprogenitors terminally differentiated into cortical neurons expressing neuronal markers MAP2 and TUJ1, and cortical layer marker TBR1. The level of intraneuronal A&#x3b2; in the sAD cortical neurons was significantly higher compared to control. Control and sAD cortical neurons expressed native 30S, 26S, and 20S proteasome assemblies with the sAD cortical neurons displaying higher 20S assemblies. Increased active 20S assemblies was associated with higher &#x3b2;1, &#x3b2;2, and &#x3b2;5 proteolytic sites activities.<br><br>DISCUSSION: The significant elevation in the proteolytic activities of the &#x3b2;1, &#x3b2;2, and &#x3b2;5 subunits of 20S proteasome in sAD cortical neurons suggests that this may be a possible compensatory response to elevated intraneuronal A&#x3b2;.},
}
@article {pmid42395377,
year = {2026},
author = {Qiu, J and Bosch, MA and Wolfe, M and Korac, K and Rizzo, S and Stincic, TL and Farley, SE and Fitzgerald, W and Rajendran, M and Laguerre, A and Stein, F and Copenhaver, PF and Rønnekleiv, OK and Rønnekleiv-Kelly, SM and Rostovtseva, TK and Bezrukov, SM and Schultz, C and Kelly, MJ},
title = {Identifying Novel Estrogenic Mitochondrial Targets in Hypothalamic Proopiomelanocortin Neurons by Chemoproteomics.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.17.732817},
pmid = {42395377},
issn = {2692-8205},
abstract = {Loss of estrogens at menopause is linked to impaired brain metabolism and increased risk of Alzheimer's disease (AD). However, estrogen replacement therapies are limited due to the deleterious effects of estrogen on peripheral organs and increased risk of vascular dementia. We have developed a non-steroidal estrogenic compound, STX, which does not bind to the classical estrogen receptors α and β, but mimics estrogenic signaling in the central nervous system (CNS) without the peripheral reproductive actions. STX is protective against neurodegeneration in stroke and AD models, but its molecular targets are unknown. Here, we identified and validated STX neural targets using chemoproteomic, molecular biological, electrophysiological and metabolic assays of hypothalamic proopiomelanocortin (POMC) neurons. Chemoproteomic profiling identified voltage dependent anion channels (VDAC1-3) as major intracellular binding partners in mHypo43 (POMC) cells. Based on quantitative single-cell PCR, Vdac2 was identified as the dominant isoform in female hypothalamic POMC neurons. Seahorse metabolic flux analyses showed that STX potently increased glycolysis, oxidative respiration and mitochondrial ATP production in mHypo43 cells. Nanomolar concentrations of STX enhanced VDAC2 voltage-dependent gating in reconstituted lipid membranes and shifted the low-conductance states toward anion selectivity, consistent with increased ATP flux. Together, these findings reveal a mechanism for the neuroprotective effects of STX through enhancing mitochondrial bioenergetics and modulating VDAC channel properties, potentially increasing cellular energy stores. Therefore, this work identifies previously unrecognized estrogenic mitochondrial targets and provides a mechanistic basis for the neuroprotective actions of STX relevant to menopause-associated brain vulnerability.},
}
@article {pmid42395379,
year = {2026},
author = {Estrella, LD and Dasgupta, S and Gundavelli, A and Li, H and Yang, HS and Chancellor, S and Pastika, T and Abdourahman, A and Tamm, J and Yanamandra, K and Romanul, N and Liao, F and Zhao, K and Lin, G and Srinivasa, PP and Wang, X and Martin, A and Asque, E and Doering, A and Ried, JS and Talanian, RV and Kwon, T and Woodbury, ME and Grinberg, YY and Agastra, E and Oakley, DH and Hyman, BT and Serrano-Pozo, A and Zwang, T and Das, S and Bennett, RE},
title = {Cerebrovascular Single-Nucleus RNA-Seq Reveals Heat Shock Activation and Vascular Remodeling in Alzheimer's Disease and Primary Tauopathies.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.26.734052},
pmid = {42395379},
issn = {2692-8205},
abstract = {Cerebrovascular alterations are widely observed in both Alzheimer's Disease (AD) and primary tauopathies. Here, we hypothesized that mechanisms of cerebrovascular alterations are shared between AD and primary tauopathies. We performed single-nucleus RNA sequencing of postmortem human inferior temporal gyrus to characterize transcriptomic changes across cerebrovascular cell types in AD and primary tauopathies (Corticobasal Degeneration, Pick's disease, and Progressive Supranuclear Palsy). Differential gene expression analyses revealed disease-specific transcriptional programs across vascular cell populations. However, genes involved in the heat-shock response were consistently upregulated across all diseases, suggesting a conserved cerebrovascular stress response during neurodegeneration. We further identified marked cerebrovascular remodeling in AD relative to primary tauopathies, along with dysregulation of genes mapping to AD risk loci in endothelial cells. Transcriptomic findings were validated using tissue clearing, light-sheet microscopy, and immunofluorescence quantification of vascular markers. These results define a conserved vascular stress program alongside AD-specific remodeling, highlighting the vasculature as a therapeutic target in neurodegeneration.},
}
@article {pmid42395391,
year = {2026},
author = {Sharma, MS and Agarwal, R and Tiwari, N and Sharma, M and Kaushik, A and , },
title = {Alzheimer's Disease Selectively Perturbs Age-Sensitive Brain Radiomic Features Across the Disease Continuum.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.17.732875},
pmid = {42395391},
issn = {2692-8205},
abstract = {Normal brain aging and Alzheimer's disease both involve progressive structural brain alterations, making it challenging to distinguish pathological neurodegeneration from normative aging-related atrophy. This study investigated whether Alzheimer's disease exhibits radiomic patterns that mimic, diverge from, or selectively perturb age-associated structural brain changes. T1-weighted magnetic resonance imaging scans from the Alzheimer's Disease Neuroimaging Initiative were analyzed using a region-wise radiomics framework across 10 anatomically defined brain regions. Radiomic features were extracted following automated segmentation, bias field correction, and intensity normalization. Age-associated radiomic patterns were first identified in cognitively normal subjects using Spearman correlation analysis. Features demonstrating significant age sensitivity were subsequently compared between cognitively normal and Alzheimer's disease cohorts across age bins using Welch's two-sample t-tests with permutation-based significance estimation and false discovery rate correction. Medial temporal and limbic regions, particularly the hippocampus, entorhinal cortex, and cingulum, demonstrated consistent age-aligned radiomic trajectories with systematic, statistically significant disease-related shifts across all age bins, supported by large effect sizes and bootstrap-validated confidence intervals. In contrast, several other regions demonstrated more heterogeneous and less stable patterns of group separation across age bins. Secondary analysis using late mild cognitive impairment subjects demonstrated that these radiomic divergences are detectable at the transition from normal cognition to mild cognitive impairment, with statistically significant CN-LMCI separation but no significant LMCI-AD separation, positioning the identified markers as early-stage rather than late-stage indicators of neurodegeneration. These findings indicate that Alzheimer's disease does not uniformly mimic normal aging across the brain but instead selectively perturbs radiomic features associated with normative aging trajectories. The identified markers represent promising candidates for age-adjusted radiomic biomarkers, warranting validation in independent cohorts to establish their generalisability. The fully automated nature of the analytical pipeline - spanning segmentation, feature extraction, and statistical comparison without manual annotation - may facilitate scalable validation of these biomarkers in larger neuroimaging cohorts.},
}
@article {pmid42395402,
year = {2026},
author = {Hossain, MS and Praticò, D},
title = {Temporal and Regional Circular RNA profiling in a Tauopathy Mouse Model: Implications for Tau Pathology and Neurodegeneration.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.18.733253},
pmid = {42395402},
issn = {2692-8205},
abstract = {MicroRNAs (miRNA), are non-coding RNA that act as post-transcriptional regulators of gene expression in various organs including the brain where they play an important role in neurodegeneration. Circular RNAs are single-stranded, covalently closed loop RNA molecules recognized as upstream regulators of miRNA. Previous studies have shown that circRNAs are dysregulated in Alzheimer's and other neurodegenerative diseases. However, a systematic, age-and region-specific circRNA atlas in primary tauopathy is lacking. To this end, we performed comprehensive circRNA sequencing of hippocampal and cortical tissues from a model of human tauopathy, h-Tau mice, at 3, 6, and 12 months of age. We identified circRNA-miRNA sponging networks that target and regulate key tau disease-associated pathways, including kinases, phosphatases, histone deacetylase, glutamatergic and GABAergic synapse, and microglial efferocytosis. Our study demonstrates an age- and region-specific circRNA landscape in the brain of a model of human tauopathy and identify candidate circRNA-miRNA-mRNA regulatory axes converging on core tau pathological processes. These findings support the novel hypothesis that specific circRNAs have the potential to be used as biomarkers and therapeutic targets against tau-driven neurodegeneration.},
}
@article {pmid42395404,
year = {2026},
author = {Giorgio, J and Blazhenets, G and Landau, SM and Pezzoli, S and Yokoyama, JS and Soleimani-Meigooni, DN and Carrillo, MC and Grinberg, LT and Seeley, WW and Spina, S and Nudelman, KN and Apostolova, LG and Dickerson, BC and Jagust, WJ and Rabinovici, GD and Joie, R and , and , },
title = {Characterisation of Posterior Predominant Amyloid PET Binding Across Multiple Cohorts.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.17.733031},
pmid = {42395404},
issn = {2692-8205},
abstract = {The standard approach to quantify amyloid (Aβ) PET averages uptake within a single cortical mask that assumes no clinically relevant spatial heterogeneity in uptake patterns. Here, in a sample of 12,379 clinically impaired participants taken from four phenotypically diverse cohorts we use data-driven approaches to discover heterogeneous patterns of Aβ-PET binding, uncovering a reproducible and clinically relevant pattern of posterior predominant Aβ-PET binding. In particular, Aβ-PET positive participants who have posterior predominant binding are less likely to be APOE -ε4 carriers, more severely impaired, have thinner cortex in posterior regions, and greater posterior tau PET burden. Furthermore, in a subsample of participants with neuropathological assessment, participants with posterior predominant Aβ binding have a higher likelihood of having cerebral amyloid angiopathy at autopsy. These findings suggest that Aβ-PET accumulates along two orthogonal axes with biological and clinical relevance, indicating that the standard approach to assess Aβ-PET is insufficient to capture meaningful signal from Aβ-PET imaging. This work has implications for the diagnosis and treatment of Alzheimer's disease and extends our understanding of the mechanisms governing variable Aβ-PET distribution and its downstream effects.},
}
@article {pmid42395416,
year = {2026},
author = {Wang, X and Walker, AC and Reeves, MM and Bejarano, JG and Song, Y and Dunmore, J and Yue, M and Rawlinson, B and Engelberg-Cook, E and DeTure, M and Tome, RB and Narayan, A and Bartfield, J and Graff-Radford, NR and Boeve, BF and Peterson, RC and Knopman, DS and Oskarsson, B and Day, GS and Murray, ME and Dickson, DW and Cook, C and Zhang, Y and Petrucelli, L and Josephs, KA and Prudencio, M},
title = {TDP-43 subtypes shape transcriptomic signatures in Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.22.733827},
pmid = {42395416},
issn = {2692-8205},
abstract = {TAR DNA-binding protein 43 (TDP-43) pathology frequently co-occurs with Tau neurofibrillary tangles (NFTs) and amyloid β plaques in Alzheimer's disease (AD), driving significant clinical heterogeneity. Whether TDP-43 engages autonomous molecular programs or instead amplifies Tau-driven neurodegeneration remains difficult to resolve, largely because these pathologies often co-occur. To separate these overlapping signatures, we generated regionally resolved transcriptomic profiles from cognitively normal controls (Controls), neuropathologically defined cohorts of AD, AD with limbic-predominant age-related TDP-43 encephalopathy (AD/LATE), and frontotemporal lobar degeneration (FTLD-TDP), categorizing them by their distinct TDP-43 subtypes (types α and β for AD/LATE; types A and B for FTLD-TDP). By integrating transcriptomic profiles with quantitative measures of phosphorylated TDP-43 (pTDP-43) and Tau (pTau), we separated pathology-associated signals within mixed disease contexts. We found that TDP-43 is linked to distinct transcriptomic programs in AD/LATE that are largely uncoupled from Tau burden and diverge from those observed in FTLD-TDP. These signatures showed regional specificity, with transcriptomic remodeling occurring in the amygdala across both diseases, whereas frontal cortex alterations were largely restricted to FTLD-TDP. Furthermore, by stratifying cases by TDP-43 morphological subtype, we unmasked specific biological trajectories, from immune activation to unique cellular vulnerabilities, that are not apparent in unstratified cohorts. Together, our findings provide a framework for decoupling mixed proteinopathies and demonstrate that TDP-43 shapes autonomous, subtype-dependent transcriptional landscapes in AD.},
}
@article {pmid42395446,
year = {2026},
author = {Thomson, S and Li, XC and Walker, S and Tang, TCY and Graham, ME and Olechnowicz, SWZ and Bowden, R and , and Waugh, KA and Slawson, C and Burns, JM and Swerdlow, RH and Wilkins, HM and Shvetcov, A and Finney, CA},
title = {Patient cerebral organoids capture Alzheimer's disease proteomic biomarkers and drug targets.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.22.733874},
pmid = {42395446},
issn = {2692-8205},
abstract = {Patient iPSC-derived cerebral organoids are a leading human model of Alzheimer's disease, yet their proteome has never been benchmarked against human disease. Clinical cohorts now nominate thousands of biomarkers and drug targets across three proteomic platforms, and whether patient organoids capture these candidates is unknown. Here, we profile AD and control cerebral organoids containing neurons, astrocytes, and microglia on the three platforms driving clinical discovery, mass spectrometry, SomaScan, and Olink, in both conditioned media and lysate. Benchmarked against 121 studies and clinical cohorts of over 17,000 plasma, CSF, and cortex samples, patient organoids detect almost every nominated candidate and reproduce the disease-associated change in roughly one in four of the most reproducible. This convergence spans plasma, CSF, and cortex, and extends to synaptic, mitochondrial, and proteostatic biology. We provide the first multi-platform reference proteome of a patient-derived AD model, establishing it as a translationally relevant system for studying AD.},
}
@article {pmid42395472,
year = {2026},
author = {Wang, C and Ma, CT and Crotty, C and Zeng, FY and Bobkov, A and Covel, JA and Rivera, EK and Sergienko, E and Kosik, KS and Olson, SH and Jackson, MR and Rauch, JN},
title = {High-Throughput Screening Identifies Small-Molecule Inhibitors of the Tau-LRP1 Interaction.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.24.733881},
pmid = {42395472},
issn = {2692-8205},
abstract = {The cellular uptake and propagation of tau are central features of tauopathies, including Alzheimer's disease, and are mediated by the endocytic receptor low-density lipoprotein receptor-related protein 1 (LRP1). While prior studies have implicated LRP1 in tau binding and internalization, the biochemical features of this interaction and its suitability for therapeutic targeting remain incompletely defined. Here, we establish a quantitative and scalable framework to interrogate the tau-LRP1 interaction and identify small-molecule modulators. We engineered and purified the LRP1 ligand-binding domain 4 (BD4), a key region mediating tau interaction, and developed multiple orthogonal assays, including fluorescence polarization, split luciferase complementation, and time-resolved FRET, to measure LRP1-BD4 interactions with tau and a known peptide ligand. Across assay formats, we observe consistent binding affinities in the nanomolar range and demonstrate competitive displacement by tau, receptor-associated protein (RAP), and a peptide ligand, supporting overlapping binding interfaces. Leveraging these platforms, we performed small molecule high-throughput screening and identified a set of candidate inhibitors of the LRP1-BD4-tau interaction. Selected compounds reduced tau uptake in a cellular assay, phenocopying competitive inhibition by tau and a peptide ligand. Together, these studies define the LRP1-BD4-tau interaction as a biochemically tractable and druggable interface and establish an integrated discovery pipeline linking mechanistic characterization to functional cellular outcomes. This work provides a foundation for the development of therapeutic strategies targeting LRP1-mediated tau uptake.},
}
@article {pmid42395483,
year = {2026},
author = {Zhang, W and Wang, L and Franzmann, EJ and Chen, XS},
title = {Multivariate Random Forests for Cross-Modal Multi-Omics Integration.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.17.732933},
pmid = {42395483},
issn = {2692-8205},
abstract = {Multi-omics studies are widely used across many areas of biomedical research. In many diseases, some signals are shared across data types, while others are strongest in a single omics layer. Current multi-omics clustering methods often either merge all data types into a single representation, which can blur biology that is strong in one layer, or rely on linear structure that may miss more complex relationships across data types. We introduce multiRF, a random-forest-based method that handles complex data types and separates shared and modality-specific structure for multi-omics data. multiRF learns sample similarities across omics layers from multivariate random forests, combines them across data types, and uses the resulting weights to estimate the part of each omics layer that is predictable from the others. The remaining residual is treated as modality-specific signal, allowing shared and modality-specific similarities to be clustered separately. In simulations, multiRF recovered shared clusters as well as or better than established integrative methods while more reliably separating modality-specific signal under nonlinear data structures. In TCGA head and neck squamous cell carcinoma, the shared component aligned with the main subtype structure across established reference classifications, while gene- and miRNA-specific components revealed additional immune and developmental biology. In the ADNI cohort with matched blood DNA methylation and structural MRI, the shared cross-modal aging signal was associated with future conversion to mild cognitive impairment or Alzheimer's disease, and a DNAm-specific residual signal showed exploratory additional information. These results show that multiRF can recover a common disease axis while retaining biologically meaningful signals specific to one data type. multiRF is available as an open-source R package at https://github.com/novawz/multiRF.},
}
@article {pmid42395514,
year = {2026},
author = {Wu, A},
title = {Discrete Cognitive Resolution in Alzheimer's Disease: Cross-Cohort Reanalysis of ADNI and NACC Longitudinal Data.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.18.733215},
pmid = {42395514},
issn = {2692-8205},
abstract = {INTRODUCTION: Do continuous cognitive totals capture patient-relevant transitions, or does decline have discrete structure?<br><br>METHODS: We formalize a discrete cognitive resolution (DCR) model in which decline is loss of binary discriminative coordinates, with deterministic emissions tying items to a shared low-dimensional mask. Using natively discrete item-level data (ADAS-Cog, 688 ADNI participants; MoCA sub-items, 13,323 NACC participants), we tested pre-specified signatures by out-of-sample log-loss against continuous-drift, per-item, and mixed-effects IRT competitors, with a coordinate-label permutation null (S2).<br><br>RESULTS: DCR beat both pre-specified baselines (ADNI 0.436 vs 0.965; NACC 0.566 vs 0.602). S2 was decisive in ADNI (AUC 0.782; null 0.529, P < .001); in NACC the signal concentrated in orientation (AUC 0.718). Mixed-effects IRT achieved lower log-loss than DCR.<br><br>DISCUSSION: Cognitive decline shows discrete coordinate structure when items are single-coordinate probes. The claim is structural, not predictive; encoding is decisive.},
}
@article {pmid42395537,
year = {2024},
author = {Wang, R and Maloney, B and Nho, K and Beck, J and Counts, SE and Lahiri, DK},
title = {Human microRNA-153-3p targets specific neuronal genes and is associated with the risk of Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.09.07.611728},
pmid = {42395537},
issn = {2692-8205},
abstract = {Alzheimers disease (AD) is a progressive degenerative disease characterized by a significant loss of neurons and synapses in cognitive brain regions and is the leading cause of dementia worldwide. AD pathology comprises extracellular amyloid plaques and intracellular neurofibrillary tangles. However, the triggers of this pathology are still poorly understood. Repressor element 1-silencing transcription/neuron-restrictive silencer factor (REST/NRSF), a transcription repressor of neuronal genes, is dysregulated during AD pathogenesis. How REST is dysregulated is still poorly understood, especially at the post-transcriptional level. MicroRNAs (miRNAs), a group of short non-coding RNAs, typically regulate protein expression by interacting with target mRNA transcript 3-untranslated region (UTR) and play essential roles in AD pathogenesis. Herein, we demonstrate that miR-153-3p reduces REST 3-UTR activities, mRNA, and protein levels in human cell lines, along with downregulating amyloid β precursor protein (APP) and α-synuclein (SNCA). We determine by mutational analyses that miR-153-3p interacts with specific targets via the seed sequence present within the respective mRNA 3-UTR. We show that miR-153-3p treatment alters the expression of these specific proteins in human neuronally differentiated cells and human induced pluripotent stem cells and that miR-153-3p is itself dysregulated in AD. We further find that single nucleotide polymorphisms (SNPs) within 5kb of the MIR153-1 and MIR153-2 genes are associated with AD-related endophenotypes. Elevation of miR-153-3p is associated with reduced AD probability, while elevated REST may associate with a greater AD probability. Our work suggests that a supplement of miR-153-3p would reduce levels of toxic protein aggregates by reducing APP, SNCA, and REST expression, all pointing towards a therapeutic and biomarker potential of miR-153-3p in AD and related dementias.},
}
@article {pmid42395556,
year = {2026},
author = {Fields, EA and Kim, CY and Nett, RS},
title = {Ancient origins of alkaloid biosynthesis in medicinal clubmosses.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.21.733354},
pmid = {42395556},
issn = {2692-8205},
abstract = {The plant kingdom is rich with medicinal natural products that are complex and difficult to access. Discovering how plants build these molecules can be challenging, especially for biosynthetic pathways that have unusual chemical transformations or require intricate coordination among cellular compartments. Here, we leveraged 300 million years of metabolic conservation to uncover how medicinal clubmosses organize extracellular and intracellular alkaloid biosynthesis to produce the Alzheimer's disease therapeutic huperzine A (HupA). We reveal not only scaffold-forming enzymes that form key precursors to hundreds of clubmoss alkaloids, but also an essential transporter that connects metabolism across the plasma membrane to enable complete HupA biosynthesis. Our results demonstrate how ancient evolutionary conservation can be used to identify cryptic biosynthetic components and unexpected cellular organization in plant specialized metabolism.},
}
@article {pmid42395576,
year = {2026},
author = {Taimouri, M and Ravindra, V},
title = {Normative brain-state trajectories reveal deviation from healthy aging in Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.19.733190},
pmid = {42395576},
issn = {2692-8205},
abstract = {Distinguishing healthy brain aging from early neurodegenerative disruption remains a major challenge in Alzheimer's disease. Here, we used resting-state fMRI from the Alzheimer's Disease Neuroimaging Initiative to model large-scale brain-state dynamics relative to a cognitively normal aging reference. A Hidden Markov Model trained exclusively on cognitively normal adults defined latent connectivity states, and a generalized additive model estimated an age-adjusted reference trajectory of transition entropy. Mild cognitive impairment and Alzheimer's disease showed progressively greater deviation from this reference, with the strongest disruption in Alzheimer's disease. A single absolute-deviation score retained much of the predictive information contained in higher-dimensional dynamic features, supporting its use as a compact and interpretable candidate biomarker of altered brain-state organization. These findings suggest that Alzheimer's disease is associated with measurable departure from healthy dynamic brain aging, providing an interpretable framework for future longitudinal and clinically validated studies.},
}
@article {pmid42395621,
year = {2026},
author = {Ferhat, A and Messaoudi, M and Guelifet, K and Amor, IB and Zahnit, W and Bendrihem, KA and Zeraib, A and Ouakouak, H and Benmohamed, M and Ferhat, MA and Larkem, I and Alsaeedi, H and Khan, AAP and Bechelany, M and Tian, F and Barhoum, A},
title = {Chemical profiling and in silico evaluation of a Matricaria chamomilla L. extract: exploring its antioxidant, antibacterial, antidiabetic, anti-inflammatory, and anticholinergic activities.},
journal = {Frontiers in nutrition},
volume = {13},
number = {},
pages = {1852820},
pmid = {42395621},
issn = {2296-861X},
abstract = {INTRODUCTION: This study aimed to investigate the phytochemical composition and multifunctional therapeutic potential of a hydroethanolic extract of Matricaria chamomilla L. collected from the semi-arid region of Algeria. The research focused on evaluating its antioxidant, antimicrobial, antidiabetic, anti-inflammatory, neuroprotective, and potential anticancer activities.<br><br>METHODS: Total polyphenol and flavonoid contents were determined using spectrophotometric methods. The phytochemical profile was characterized by Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS). Antioxidant activity was assessed using DPPH and galvinoxyl radical scavenging assays. Antimicrobial activity was evaluated against bacterial and fungal strains using inhibition zone measurements. Enzyme inhibitory activities against &#x3b1;-amylase, acetylcholinesterase, and butyrylcholinesterase were investigated in vitro. Anti-inflammatory activity was evaluated through protein denaturation inhibition and carrageenan-induced paw edema assays. Molecular docking studies were performed to assess the interactions of identified compounds with breast cancer targets ER&#x3b1; and HER2.<br><br>RESULTS: The extract contained high levels of total polyphenols (41.9 mg gallic acid equivalent/g extract) and flavonoids (17.1 mg rutin equivalent/g extract). LC-MS/MS analysis identified several bioactive compounds, including caffeic acid, gallocatechin gallate, and apigenin-7-O-glucoside. The extract exhibited moderate antioxidant activity, with IC50 values of 324.4 &#x3bc;g/mL and 22.7 &#x3bc;g/mL for DPPH and galvinoxyl assays, respectively. Strong antimicrobial effects were observed against Staphylococcus aureus (22 mm inhibition zone) and Candida albicans (18 mm inhibition zone). The extract also demonstrated potent inhibitory activities against &#x3b1;-amylase (IC50 = 440.6 &#x3bc;g/mL), acetylcholinesterase (IC50 = 3.11 &#x3bc;g/mL), and butyrylcholinesterase (IC50 = 28.7 &#x3bc;g/mL), surpassing standard inhibitors. In vitro anti-inflammatory activity reached 98.4% inhibition of protein denaturation at 2000 &#x3bc;g/mL, while in vivo edema inhibition reached 38.81%. Molecular docking revealed strong binding affinities of &#x3b1;-tocopherol and apigenin-7-O-glucoside toward ER&#x3b1; and HER2 receptors.<br><br>DISCUSSION: The findings demonstrate that Matricaria chamomilla L. possesses significant pharmacological potential due to its rich phytochemical composition and broad-spectrum biological activities. The observed antioxidant, antimicrobial, enzyme inhibitory, anti-inflammatory, and molecular docking results suggest that this plant could serve as a promising natural source for the development of therapeutic agents targeting diabetes, neurodegenerative disorders, microbial infections, and breast cancer. Further pharmacological and clinical investigations are warranted to validate these bioactivities and support future drug development applications.},
}
@article {pmid42395725,
year = {2026},
author = {Liu, HC and Lin, CY and Ho, CS and Chang, JF and Lee, KH and Yang, SY},
title = {Immunomagnetic reduction detects amyloid β 1-42, but neither x-42 nor 1-y.},
journal = {RSC advances},
volume = {},
number = {},
pages = {},
pmid = {42395725},
issn = {2046-2069},
abstract = {Amyloid β 1-42 peptide (Aβ1-42) is listed in the diagnostic guidelines as a plasma analyte for evaluating amyloid neuropathology in Alzheimer's disease. Owing to its ultralow concentrations in plasma, ultrasensitive analytical technologies have been developed for its accurate detection. Immunomagnetic reduction (IMR) is an ultrasensitive assay. In contrast to conventional immunoassays, which involve pairs of primary antibodies against the C-terminal and N-terminal domains of Aβ1-42 for achieving high specificity, IMR utilizes a single primary antibody against the C-terminal domain of Aβ1-42. Thus, IMR may be used to assay not only Aβ1-42 but also other Aβ peptides, such as Aβ x-42. In this work, the specificity of assaying Aβ1-42 using IMR was investigated. The binding specificities between the C-terminal antibody used in the IMR reagent and Aβ peptides were examined through western blot analysis. Furthermore, the interference effects of other Aβs on Aβ1-42 quantification using IMR were explored. The analytical performance, including the analytical curve, low limit of detection, high limit of detection, and storage stability of the reagents, was investigated. The C-terminal antibody only binds to Aβ1-42, and not to Aβ3-42, pyroglutamate-modulated Aβ3-42 (Aβp3-42), Aβ1-55, Aβ1-38, Aβ3-40, or Aβ1-40. The IMR Aβ1-42 assay developed using this antibody also demonstrated high selectivity for Aβ1-42. The lower and upper limits of detection for assaying Aβ1-42 were 17 fg mL[-1] and 30 000 pg mL[-1], respectively. Furthermore, the storage stability of the IMR Aβ1-42 reagent at 2-8 °C was at least 440 days. These results reveal that the IMR assay of Aβ1-42 exhibits high sensitivity and high specificity enabling precise measurement of Aβ1-42 concentrations in human plasma.},
}
@article {pmid42395838,
year = {2026},
author = {Moeller, S and Singsank, K and Goodwin, G and Lafont-Tanner, D and Lawrence, E and Renn, B and John, S},
title = {Multiracial participants in Alzheimer's research: scoping review and recommendations.},
journal = {Alzheimer's &amp; dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70276},
pmid = {42395838},
issn = {2352-8737},
abstract = {Evidence suggests that Alzheimer's disease (AD) presents differently across ethnoracial groups, producing disparate risk and resilience profiles that may be measured through neuropsychological data. Extant AD research primarily examines monoracial groups, despite the fact that Multiracial individuals make up more than 10% of the US population. Failure to incorporate data from Multiracial participants (those endorsing two or more racial identities) limits research and clinical efforts to address AD in minoritized communities. A scoping review examined the use of neuropsychological data from Multiracial participants within AD research. Three databases were searched (APA PsycInfo, Embase, and Web of Science) for studies containing ethnoracially minoritized groups. Two independent researchers reviewed articles and included studies that met the following criteria: published in 2000 (the year the US Census formally allowed self-identification of multiple races) or later, in English, US-based cohort (as race is a social construct), reported neuropsychological data, and the research was AD-related. Searches yielded 855 original articles. Following abstract review, 484 articles were screened in full, resulting in 19 articles that met the inclusion criteria. Most excluded articles (66.67%) contained vague racial descriptions (e.g., use of an undefined Other Race group), making it difficult to know whether Multiracial participants existed in the dataset. Roughly one-third (29.03%) of articles were excluded because they described only monoracial groups. Analysis of neuropsychological outcomes showed that most articles included Multiracial participant data in larger group-level analyses (e.g., normal cognition versus dementia) or grouped their data with other, less represented ethnic or racial groups (e.g., Other Races). This review demonstrates the paucity of research and need for intentional consideration of the inclusion of Multiracial participants in AD research. Recommendations to improve reporting of data from Multiracial participants are offered, including considerations for the anticipation and adaptation to changes in the social definitions of ethnicity and race.},
}
@article {pmid42395866,
year = {2026},
author = {Sidharth, A and Shin, D},
title = {The role of SUMOylation in regulating proteins that drive neuronal disease progression.},
journal = {Biochemistry and biophysics reports},
volume = {47},
number = {},
pages = {102687},
pmid = {42395866},
issn = {2405-5808},
abstract = {SUMOylation is a post-translational modification in which a Small Ubiquitin-like Modifier (SUMO) protein is reversibly attached to a lysine residue on a target protein in an ATP-dependent process. This modification can affect the function of target proteins by enhancing their stability or changing cellular translocation, thereby making SUMOylation a critical regulator in the pathogenesis of multiple diseases. The functional consequences of SUMOylation, however, are highly context dependent. In Alzheimer's disease, SUMOylation stabilizes proteins that drive disease progression and enhances neurotoxicity, thereby exacerbating these conditions. Similarly, in Progressive Supranuclear Palsy, SUMO-1 conjugation stabilizes truncated tau and blocks its ubiquitination, whereas SUMO-2/3 conjugation promotes Tau clearance and recovery from neuroinflammation, illustrating how distinct SUMO paralogues can exert opposing effects within the same disease. Conversely, increased SUMOylation can be neuroprotective in cerebral ischemia and Parkinson's disease by promoting autophagic clearance of pathogenic proteins. Beyond alterations in protein stability, aberrant SUMOylation can also lead to mis-localization of target proteins, which has been identified as a pathogenic mechanism in disorders such as Huntington's disease and Amyotrophic Lateral Sclerosis that results in impaired clearance and pathogenic buildup, which results in neuronal death. From a therapeutic standpoint, the SUMO inhibitor TAK-981 has shown promise in both Multiple Sclerosis and in pre-clinical glioblastoma models, underscoring the translational potential of targeting of this pathway. This review examines the multifaceted role of SUMOylation across diverse neurological conditions, evaluates the therapeutic potential of SUMO inhibitors and activators, and highlights the opportunities and challenges of modulating this pathway in currently incurable neurological disorders.},
}
@article {pmid42396039,
year = {2026},
author = {Yang, SY and Liu, HC and Chiu, MJ and Chang, JF and Ho, CS and Lee, KH},
title = {Changes in Plasma Amyloid β 1-42 Peptide and Total Tau Protein from Normal Cognition to Sever-Stage Alzheimer's Disease Using an Immunomagnetic Reduction Assay.},
journal = {ACS omega},
volume = {11},
number = {25},
pages = {36855-36865},
pmid = {42396039},
issn = {2470-1343},
abstract = {Measurements of plasma biomarkers are included in current guidelines for the diagnosis of Alzheimer's disease. Amyloid β 1-42 peptide (Aβ1-42) and tau protein are the key analytes. By using the ultrasensitive immunomagnetic reduction (IMR) assay, the combination of Aβ1-42 and total tau protein (T-Tau), i.e., Aβ1-42xT-Tau, effectively discriminates cognitively unimpaired (CU) individuals from patients with amnestic mild cognitive impairment (aMCI) and early-stage Alzheimer's disease dementia (eADD). However, the accuracy of plasma Aβ1-42xT-Tau in distinguishing mild/severe ADD (m-sADD) decreases. In this work, the dynamic changes in individual and combined plasma Aβ1-42 and T-Tau in CU, aMCI, eADD, and m-sADD individuals were investigated. One hundred thirty-nine individuals, including 66 CU, 24 aMCI, 26 eADD, and 23 m-sADD patients, were enrolled to investigate the distributions of plasma Aβ1-42 and T-Tau using IMR. In addition, 13 autopsies were performed to investigate the evolution of plasma Aβ1-42 and T-Tau with increasing Aβ plaque density in the brain. CU subjects had 249.8 ± 103.7 (pg/mL)[2] for plasma Aβ1-42xT-Tau. aMCI, eADD, and m-sADD patients had plasma Aβ1-42xT-Tau of 583.4 ± 139.2, 1061.1 ± 402.9, and 884.7 ± 488.9 (pg/mL)[2], respectively. Plasma Aβ1-42xT-Tau levels clearly increase from CU to aMCI to eADD patients. Similar changes in plasma Aβ1-42xT-Tau are correlated with high densities of Aβ plaques in the postmortem brain. Further analysis revealed that the dynamic changes in plasma Aβ1-42xT-Tau from CU to m-sADD patients are mainly attributed to T-Tau neuropathology. The results of the autopsy study suggest that the fibrillization of soluble tau proteins is accelerated at high Aβ plaque densities, possibly contributing to the dynamic change in plasma biomarkers from eADD to m-sADD. Measurements of individual or combined plasma Aβ1-42 and T-Tau using IMR show high sensitivity (>0.9) and high specificity (>0.9) for assessing aMCI and eADD patients. By using stepwise cutoff values, the prediction of staging CU, aMCI, or eADD is feasible in clinical practice.},
}
@article {pmid42396279,
year = {2026},
author = {Teo, MH and Taong, MRQ and Kan, CN and Tan, CH and , },
title = {Cognitive and Neuroimaging Biomarker Intra-Individual Variability in Alzheimer's Disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.21.26356195},
pmid = {42396279},
abstract = {BACKGROUND: Greater cognitive intra-individual variability (IIV) reflects increased heterogeneous performance across cognitive domains and has been linked to a higher risk of Alzheimer's disease (AD). However, it remains unclear whether cognitive IIV is linked to heterogeneous dispersion of regional AD pathology. Hence, we aimed to examine the association between cognitive IIV and AD neuroimaging biomarker IIV.<br><br>METHODS: This study included participants with normal cognition (CN) and mild cognitive impairment (MCI) from the Alzheimer's Disease Neuroimaging Initiative. Cognitive IIV was computed as the within-person standard deviation of five domain-specific neuropsychological test z-scores. Four neuroimaging biomarker IIV metrics were similarly derived using regional amyloid-&#x3b2; (n = 1,021), tau (n = 719), cortical thickness (n = 2,148), and combined amyloid-tau-neurodegeneration (ATN, n = 258). Associations between cognitive IIV and each biomarker IIV were evaluated using linear regression models, adjusted for relevant covariates.<br><br>RESULTS: Higher cognitive IIV was associated with greater biomarker IIV across amyloid-&#x3b2; (&#x3b2; = 0.039, SE = 0.014, p = .006), tau (&#x3b2; = 0.196, SE = 0.033, p < .001), cortical thinning (&#x3b2; = 0.036, SE = 0.008, p < .001), and ATN (&#x3b2; = 0.176, SE = 0.043, p < .001). Interaction analyses revealed that the associations of cognitive IIV with tau IIV, cortical thickness IIV, and ATN IIV were stronger in MCI than CN individuals. Significant interactions between cognitive IIV and biomarker positivity status showed that the effect with amyloid-&#x3b2; IIV was attenuated in A- (&#x3b2; = 0.004, SE = 0.014, p = .78) but that the effect with tau IIV remained robust even in T-individuals (&#x3b2; = 0.088, SE = 0.022, p < .001).<br><br>CONCLUSION: Elevated cognitive IIV is associated with greater heterogeneity in cortical dispersion of AD-related pathology, particularly in prodromal AD and in the presence of abnormal pathology. As a novel measure that captures variation in topographical scattering of AD pathological burden across the cortex, AD biomarker IIV may offer research and clinical utility beyond evaluating absolute biomarker load or thresholds.},
}
@article {pmid42396292,
year = {2026},
author = {Hernandez-Rasco, F and Ruiz, R and de Rojas, I and Puerta, R and Garcia-Mayor, C and Espinosa-Oliva, AM and García-Revilla, J and Bayon, P and Rivera-Ramos, A and Oualit, FR and Jiménez, S and Saez, ME and de Pablos, RM and Zhao, F and Olive, C and Sanz, P and Montalbán, X and Valero, S and Cano, A and Fernández, MV and Wells, AM and Cavazos, JE and Seshadri, S and Boada, M and Mañes, S and Heneka, MT and Vitorica, FJ and Ramirez, A and Venero, JL and Ruiz, A},
title = {Human IL-34 Deficiency Primes Microglia Toward Alzheimer's Disease-Associated States.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.21.26346696},
pmid = {42396292},
abstract = {BACKGROUND: Genome-wide association studies (GWAS), with independent replication in large European consortia, have identified a common nonsense variant in IL-34 (Y213X) as a genetic risk factor for late-onset Alzheimer's disease (AD). However, the biological consequences of this IL-34 mutation in humans, its prevalence in the population, and the mechanisms by which IL-34-Y213X alters microglial homeostasis, cerebrospinal fluid (CSF) proteomic networks, and amyloid pathology remain poorly understood.<br><br>METHODS: We combined human genetics, cerebrospinal fluid (CSF) and serum proteomics, transcriptomics, large-scale phenome-wide association analyses, and preclinical experimental models to define the impact of human IL-34 deficiency. IL-34 concentrations were first quantified in CSF and serum from deeply phenotyped AD cohorts stratified by the common IL-34-Y213X nonsense variant. IL-34 levels and IL-34-Y213X status were then integrated with unbiased CSF proteomic networks and AD biomarkers. Transcriptomic profiling of purified microglia from IL-34 knockout mice was performed to assess disease-associated microglial programs. Using APP/PS1 mice lacking IL-34, we examined the effects of IL-34 deficiency on microglial survival, tiling, and plaque encapsulation. Finally, we performed postmortem analyses of temporal cortex from AD patients carrying IL-34-Y213X to assess microglial density, spatial organization, and plaque-associated responses.<br><br>FINDINGS: IL-34-Y213X was a strong, dose-dependent loss-of-function (LOF) allele that reduced IL-34 levels by up to 2.5 standard deviations in CSF and serum and was common in multiple populations. IL-34 deficiency reshaped CSF proteomic networks, downregulating axon guidance and microglial support modules while upregulating inflammatory and extracellular matrix signatures, and showed pleiotropic associations with neurological, inflammatory, and metabolic traits. Transcriptomic analysis of sorted microglia from healthy 9-month-old IL-34KO compare to wild-type mice revealed a profound pro-inflammatory and disease-associated microglial transcriptional program enriched for disease-associated microglia (DAM) signatures, inflammatory pathways, and AD risk genes including APOE, CLU, and CASS4 . In APP/PS1 mice, genetic IL-34 deletion selectively depleted homeostatic gray-matter microglia, disrupted microglial tiling, and impaired plaque encapsulation, resulting in altered amyloid structure and enhancing neuritic injury. Concordantly, AD patients homozygous for IL-34-Y213X displayed markedly reduced cortical microglial density and increased microglial spatial dispersion, indicating a breakdown of the microglial network organization in the human brain.<br><br>INTERPRETATION: A common human IL-34 LOF variant creates a naturally occurring model of IL-34 deficiency that links microglial survival, CSF network signatures, and amyloid pathology in both mice and humans. Importantly, IL-34 deficiency alone is sufficient to induce inflammatory, AD-associated microglial states beyond simply reducing microglial number. These findings identify IL-34/CSF1R signaling as a critical determinant of microglial resilience and a potential upstream pathway linking human genetic variation to AD susceptibility, highlighting IL-34-dependent pathways as promising targets for disease modification.<br><br>FUNDING: This work was supported by grants from the Spanish Ministerio de Ciencia, Innovaci&#xf3;n y Universidades/FEDER/UE (PID2024-157400OB-I00) and FORTALECE program (FORT23/00008; Instituto de Salud Carlos III, Spain) to RRL and JLV, ISCIII of Spain co-financed by FEDER funds (European Union) through grants PI24/00308 (JV) and CIBERNED collaborative grant 2022/01 to JV, PID2023-147125OB-I00 and CEX2023-001386-S (Severo Ochoa Programme) to SMTBC. A.R. is supported by STAR Award. University of Texas System. Tx, United States, The South Texas ADRC. National Institute of Aging. National Institutes of Health. USA. (P30AG066546), the Keith M. Orme and Pat Vigeon Orme Endowed Chair in Alzheimer's and Neurodegenerative Diseases (2024-2025) and Patricia Ruth Frederick Distinguished Chair for Precision Therapeutics in Alzheimer's and Neurodegenerative Diseases (2025-2028). AR is also supported by the Agency for Innovation and Entrepreneurship (VLAIO) grant N&#xb0; PR067/21 for the HARPONE project and the ADAPTED project the EU/EFPIA Innovative Medicines Initiative Joint Undertaking Grant N&#xb0; 115975 and CIBERNED (ISCIII).},
}
@article {pmid42396302,
year = {2026},
author = {Mounié, A and Sato, K and Nakashima, S and Niimi, Y and Iwatsubo, T},
title = {Study partner profile effects on CDR-SB change in anti-amyloid therapy evaluation.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.22.26356066},
pmid = {42396302},
abstract = {INTRODUCTION: The Clinical Dementia Rating Sum of Boxes (CDR-SB), a primary outcome in anti-amyloid therapy (AAT) trials, integrates information from participants and study partners. CDR-SB scores may vary by study partner characteristics, but their impact on 18-month change interpretation remains unclear.<br><br>METHODS: Using the NACC Uniform Data Set, we fitted linear mixed-effects calibration models in an Alzheimer's disease (AD)-primary early symptomatic cohort and propagated study partner-associated coefficients through Monte Carlo simulations. We estimated components of 18-month CDR-SB change under observed profile changes, simulated follow-up imbalance in a common female living-with profile, and tipping-point scenarios. Analyses were repeated in amyloid-positive and trial-like cohorts.<br><br>RESULTS: The AD-primary cohort included 15,061 participants and 7,683 baseline-to-18-month pairs. Observed profile changes generated a negligible cohort-level component (mean 0.0014 points, 95% simulation interval 0.0006 to 0.0022). Simulated follow-up imbalance generated differences of 0.014 to 0.071 points across 10% to 50% reassignment. Under the primary calibration model, generating a 0.45-point difference, equal to the reported Clarity AD CDR-SB group difference, required median net imbalance >100% and was feasible in 48% of iterations. Amyloid-positive and trial-like cohorts had lower median tipping points but wider intervals, reflecting coefficient imprecision.<br><br>DISCUSSION: In the large AD-primary cohort, observed study partner profile changes and simulated follow-up imbalance generated CDR-SB differences that were small relative to the 0.45-point Clarity AD benchmark. Biomarker-confirmed estimates were less stable because of coefficient imprecision. These findings suggest limited impact under typical AD-primary conditions but support systematic study partner profile collection and sensitivity analyses in observational and external-comparator CDR-SB studies for AAT evaluation.},
}
@article {pmid42396303,
year = {2026},
author = {Lim, J and Islam, R and Raghavan, D and Omofojoye, B and Rodriguez, AD and Kiarashi, Y and Hershenberg, R and Clifford, GD and Kwon, H},
title = {Wearable sensing for quantifying cognitive and balance functions in naturalistic movements of older adults with mild cognitive impairment in therapeutic environments.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.18.26355980},
pmid = {42396303},
abstract = {UNLABELLED: Mild cognitive impairment (MCI) is a clinically important stage preceding Alzheimer's disease and related dementias, in which cognitive and balance functions are commonly evaluated using standard clinical assessments such as the Montreal Cognitive Assessment (MoCA) and Mini-Balance Evaluation Systems Test (Mini-BESTest). These assessments are administered episodically by clinicians and may miss functional changes during everyday movement. Recent studies and prior work in the Charlie and Harriet Shaffer Cognitive Empowerment Program (CEP), a therapeutic environment supporting lifestyle intervention and naturalistic social interaction, suggest that wearable and passive behavioral sensing can monitor movement patterns associated with cognitive and balance function in older adults with MCI. However, it remains unclear whether passive waist-mounted IMU data collected during naturalistic movement and social interaction can quantify clinician-rated cognitive and balance outcomes, particularly at the subdomain level, in an interpretable and demographically fair manner. To address this gap, we analyzed weekly IMU recordings collected over 6 months from 44 older adults with MCI in the CEP and trained tree-based ensemble regression models to estimate MoCA and Mini-BESTest total and subdomain scores, with interpretability and demographic fairness evaluation. Our models achieved RMSEs of 3.677 for MoCA and 3.672 for Mini-BESTest, benchmarked against Minimal Detectable Change and Minimal Clinically Important Difference thresholds. Feature importance analysis showed distinct movement signal properties across assessments, with general movement intensity features most informative for MoCA and temporal gait features led by cadence most informative for Mini-BESTest. Demographic bias analysis identified sex-related model bias, mitigated through post-processing while maintaining performance. This study supports the feasibility of wearable-based estimation of clinical assessment scores in older adults with MCI during naturalistic activity, with comparable performance between sexes after bias mitigation. This advances the validation of passive sensing for home monitoring to support clinical decision-making and personalized interventions.<br><br>AUTHOR SUMMARY: Mild cognitive impairment (MCI) is an early stage of cognitive decline that may precede Alzheimer's disease and related dementias. Cognitive and balance changes are usually evaluated during clinical visits, but clinical assessments may miss functional changes that occur during everyday movement. In this study, we examined whether waist-worn motion sensors could be used to estimate standard cognitive and balance assessment scores in older adults with MCI during naturalistic activity in a therapeutic program. We used machine learning models to analyze movement patterns collected over six months and evaluated whether the models could estimate total and subdomain scores from the Montreal Cognitive Assessment and Mini-Balance Evaluation Systems Test. We also examined which movement features were most informative, whether estimations differed by sex or race, and whether post-processing bias mitigation reduced these differences. Our findings suggest that passive wearable sensing may provide useful information about cognitive and balance function of older adults with MCI in naturalistic settings. With further validation, this approach could support future monitoring and triage tools by helping identify individuals with MCI who exhibit concerning movement or balance changes and may benefit from more detailed clinical evaluation.},
}
@article {pmid42396306,
year = {2026},
author = {Gomar, JJ and Gordon, ML and Christen, E and Giliberto, L and Keehlisen, L and Gong, M and Hoehn, N and Morley, E and O'Neil, A and Wuelfing, D and Malyavantham, K and Greenwald, B and Marambaud, P and Adrien, L and Jimenez, H and Davies, P and Koppel, J},
title = {Blood-Based Biomarkers Predict Differential Longitudinal Decline in Alzheimer's Disease Psychosis: Evidence from Two Cohorts.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.18.26355956},
pmid = {42396306},
abstract = {INTRODUCTION: Psychosis affects 40% of individuals with Alzheimer's disease (AD) and is associated with accelerated cognitive decline. Blood-based biomarkers, particularly plasma phosphorylated tau (ptau), have demonstrated utility in predicting cognitive decline in AD, with ptau217 showing superior performance in many studies. However, whether these biomarkers predict differential cognitive trajectories in AD with psychosis (ADP) remains unknown.<br><br>METHODS: Two independent cohorts were analyzed: Alzheimer's Disease Neuroimaging Initiative (ADNI; n=659: 172 cognitively unimpaired [CU], 406 AD, 81 ADP) and Litwin-Zucker Research Center (LZ; n=142: 68 CU, 57 AD, 17 ADP) with 6-year follow-up. Psychosis was defined by non-zero Neuropsychiatric Inventory delusions or hallucinations scores. In ADNI, plasma ptau181, ptau217, ptau231, amyloid-&#x3b2;42/40, GFAP, and NfL were quantified using NULISA. In LZ, ptau181, ptau205, ptau212, ptau217, amyloid-&#x3b2;42/40, GFAP, and NfL were quantified using Simoa. Linear mixed-effects models assessed prediction of cognitive decline across memory, language, visuospatial, and executive function domains.<br><br>RESULTS: In ADNI, baseline ptau181 predicted differential ADP decline in language (p<0.05), visuospatial (p<0.05), and executive function (p<0.05); ptau217 predicted language (p<0.05) and visuospatial (p<0.05) decline; GFAP predicted language (p<0.05) and visuospatial (p<0.05) decline; and NfL visuospatial decline (p=0.01). In LZ, ptau181 predicted decline in memory (p<0.05), language (p<0.0001), visuospatial (p<0.05), and executive function (p<0.05); ptau217 predicted memory (p<0.05) and visuospatial (p<0.05) decline; and GFAP predicted language decline (p<0.05). Johnson-Neyman analyses revealed ADP-AD divergence at low ptau181 thresholds in ADNI, while LZ showed crossover patterns with steeper ADP decline at low biomarker levels that attenuated at high levels where AD decline was steeper.<br><br>DISCUSSION: ADP exhibited accelerated cognitive decline across domains driven by a distinct biomarker landscape compared to non-psychotic AD. Plasma ptau181 demonstrated broader domain-specific associations with decline in ADP than other blood-based biomarkers and associated exclusively with executive function impairment, indicating its unique utility for predicting cognitive trajectories in this pathophysiological subtype.},
}
@article {pmid42396312,
year = {2026},
author = {Wang, Q and Jiang, M and Luna, A and Niu, X and Nan, Y and Sun, Q and Perrin, RJ and Franklin, E and Cruchaga, C and Flores, S and Benzinger, TLS and Wang, Y},
title = {Histologically validated diffusion MRI signatures of neuroinflammation and neurodegeneration in Alzheimer disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.11.26354743},
pmid = {42396312},
abstract = {UNLABELLED: Noninvasive neuroinflammation measurement remains a major barrier for Alzheimer disease (AD) therapeutics. We present generalized diffusion basis spectrum imaging (g-DBSI), a diffusion MRI framework that decomposes the tissue signal into biologically interpretable microstructural compartments. In postmortem Knight ADRC brains, g-DBSI-derived restricted isotropic fraction (RIF) and restricted anisotropic fraction (RAF) mapped cellularity and neurofilament density, while their ratio (RIF/RAF) tracked inflammatory cell density and peri-plaque amyloid-beta with higher specificity and regional consistency than RIF alone. In 112 living Knight ADRC participants stratified by PET amyloid, g-DBSI metrics showed amyloid-dependent trajectories: in low-amyloid individuals, RIF and RAF rose together with amyloid, consistent with early neuropil expansion and glial elaboration, whereas in high-amyloid individuals, RIF/RAF increased, and RAF declined, indicating established neuroinflammatory remodeling and neurofilament loss. CSF proteomics linked RIF/RAF to glia-enriched immune and vascular pathways, supporting g-DBSI as a clinically compatible MRI biomarker of neuroinflammation and neurodegeneration in AD.<br><br>TEASER: g-DBSI provides noninvasive MRI biomarkers of neuroinflammation and neurodegeneration in AD, validated by histopathology and CSF proteomics.},
}
@article {pmid42396323,
year = {2026},
author = {Vasiljevic, E and Schmitz, LL and Engelman, CD},
title = {Early-life nutritional environment is associated with late-life cognition in the Health and Retirement Study, a pellagra epidemic natural experiment.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.11.26355481},
pmid = {42396323},
abstract = {Early-life exposures are important to several late-life health outcomes. We sought to study the effect of an in utero nutritional environment and its interaction with Alzheimer's disease (AD) genetic risk on late-life cognitive function. We used a natural experiment created by the pellagra epidemic, a nutritional disease caused by a vitamin B 3 deficiency, to evaluate the association between in utero pellagra epidemic exposure and late-life cognitive function in the Health and Retirement Study (N = 18,285). We also evaluated whether the in utero exposure could modify the AD polygenic score's (PGS) effect on cognition. In utero pellagra epidemic exposure was significantly associated with cognition (β = -0.025). However, these effects were not isolated to the prenatal period as exposure during childhood periods also had an effect. The interaction between the in utero exposure and the AD PGS was significant, where the genetic effect on cognition was amplified with increasing (progressively worse) in utero exposure levels. These associations imply that the early-life nutritional environment affects late-life cognitive function and that these effects can modify genetic risk.},
}
@article {pmid42396324,
year = {2026},
author = {French, SR and Culwell, GC and Wiskoski, HE and Arias, JC and Zahra, S and Escareno, CE and Heitkamp, EN and Garcia, AR and Vidana, P and Quijada, JB and Kasparov, R and Vitali, F and Bedrick, EJ and Mushtaq, R and Alexander, GE and Weinkauf, CC},
title = {Reliable quantification of renal function from frozen blood samples.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.12.26355531},
pmid = {42396324},
abstract = {BACKGROUND: Differences in renal function may affect Alzheimer's disease (AD) blood biomarker levels independent of AD pathology. Although renal function was unaccounted for in foundational AD blood biomarker studies, there is potential to address this through quantification of estimated glomerular filtration rate (eGFR) from frozen serum and plasma samples. However, the validity of eGFR evaluation from long-term frozen blood samples is unknown.<br><br>METHODS: Adults aged 50-85 with &#x2265;2 vascular risk factors were recruited from vascular surgery or cardiology clinics in Tucson, Arizona from 2022-2025. Individuals with creatinine assessments in point-of-care whole blood (POC-WB) and frozen serum and plasma samples using the iSTAT (Abbott) were included. eGFR was calculated using the 2021 CKD-EPI creatinine equation without race. Agreement between POC-WB and frozen blood samples was assessed using Cohen's kappa with linear weights.<br><br>RESULTS: 134 participants (mean age: 72.6 &#xb1; 7.5 years, 39.6% female, 23.1% chronic kidney disease) had POC-WB eGFR available. Frozen serum and plasma samples had strong agreement with POC-WB for eGFR (Kw= 0.90-0.95, P<0.001). Pre-analytical factors had minimal effect on eGFR differences between POC-WB and frozen blood samples.<br><br>CONCLUSIONS: Renal function can be assessed from frozen blood samples with high consistency to POC-WB, which may be particularly relevant for interpretation of AD blood biomarkers in general aging and vascular populations who often have impaired renal function.},
}
@article {pmid42396326,
year = {2026},
author = {Ferreira-Atuesta, C and Schubert, KM and Noain, D and Draganski, B and Galovic, M and , },
title = {Association of antiseizure medication with lower amyloid and tau burden.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.22.26356204},
pmid = {42396326},
abstract = {Network hyperexcitability is increasingly implicated in prodromal Alzheimer's disease and may be suppressed by antiseizure medications (ASMs). ASMs are widely prescribed to older adults, yet whether their use relates to Alzheimer's-disease biomarkers at the population level is unknown. In 52,537 participants in the National Alzheimer's Coordinating Center (NACC) study, we compared cerebrospinal-fluid biomarkers, amyloid and tau positron emission tomography (PET) between ASM users and non-users using inverse-probability-of-treatment weighting with gradient-boosted propensity scores. ASM users showed directionally lower amyloid across multiple brain regions, amplifying markedly in APOE ε4 carriers (Centiloid β = -25.7, p = 0.007). All three temporal tau-PET composites were significantly lower in users (META-temporal β = -0.05, p = 0.01). The amyloid finding replicated independently in the the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset (Centiloid β = -8.6, p = 0.01), whereas four comparator drug classes showed no amyloid signal. These convergent observational findings provide a quantitative framework for evaluating ASMs as candidate disease-modifying agents in Alzheimer's disease.},
}
@article {pmid42396344,
year = {2026},
author = {Das, A and Lakhani, C and Mazeeva, VM and Raj, T and Knowles, DA},
title = {An empirical Bayes framework for burden and dispersion association tests helps prioritize rare variants associated with Alzheimer's disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.15.26354742},
pmid = {42396344},
abstract = {Rare genetic variants provide critical insight into the mechanisms underlying complex diseases, yet their study is limited by inherent statistical challenges, particularly in the noncoding genome where functional prioritization remains difficult. Here, we introduce parmigiano , an empirical Bayesian framework that systematically integrates functional annotations into existing rare variant association tests (RVATs), jointly learning annotation weights and a global variant filter threshold to enable trait-informed variant prioritization. We apply parmigiano to Alzheimer's disease (AD) whole-genome sequencing data (12,900 cases and 23,846 controls) and perform both coding and noncoding RVATs, leveraging AD-relevant cell-type-specific predictions of variant regulatory effect. Integrating parmigiano significantly increases association yield across five existing RVATs, uncovering 23 candidate AD genes - 19 uniquely detected by our framework -including SIGLEC10 and HUNK . Associations detected by parmigiano replicate more reliably in held-out data than those from the original RVATs and show higher overlap with known AD associations. parmigiano offers a unified, computationally efficient approach to variant prioritization, enabling scalable, interpretable rare variant analyses across coding and noncoding regions.},
}
@article {pmid42396347,
year = {2026},
author = {Gel, A and Phillips, E and Hausle, I and Thropp, P and Tosun, D and , },
title = {MCH-Guard: Multimodal Machine Learning Framework for Risk Stratification of Cerebral Microhemorrhage Risk in the Alzheimer's Disease Neuroimaging Initiative.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.18.26355972},
pmid = {42396347},
abstract = {BACKGROUND: Efficient cerebral microhemorrhage (MCH) monitoring is critical for anti-amyloid therapy safety due to ARIA-H risk. We developed MCH-Guard, a multimodal machine-learning framework, to stratify MCH risk using ADNI data (N=813).<br><br>METHODS: Nested models integrated clinical history, fluid biomarkers, and imaging to predict MCH presence, incidence, and stability.<br><br>RESULTS: The comprehensive model detected baseline MCH with high accuracy (AUC 0.86). Notably, the "minimal" model (M1), utilizing only demographics and clinical history, achieved robust performance (AUC 0.82). Longitudinal models predicted time-to-onset (R [2] =0.68) and stratified four-year risk. Furthermore, we identified a transient vascular instability phenotype-where MCH status fluctuates- which was strongly predicted by hepatic factors.<br><br>CONCLUSIONS: MCH-Guard offers a flexible clinical decision-support tool for optimizing spontaneous MCH &amp; ARIA surveillance. The strong performance of the clinical-only M1 model supports equitable risk assessment in resource-limited settings, while the characterization of vascular instability addresses a critical confounder in safety monitoring.},
}
@article {pmid42396431,
year = {2025},
author = {Ganitidis, T and Vlontzou, ME and Athanasiou, M and Nikita, KS and Davatzikos, C},
title = {Source-Free Active Learning for Adapting Alzheimer's Diagnostic Deep Learning Models Across Neuroimaging Cohorts.},
journal = {... IEEE-EMBS International Conference on Biomedical and Health Informatics. IEEE-EMBS International Conference on Biomedical and Health Informatics},
volume = {2025},
number = {},
pages = {},
pmid = {42396431},
issn = {2641-3590},
abstract = {Alzheimer's Disease (AD) classification across multiple neuroimaging sites faces significant challenges due to domain shifts arising from variations in data acquisition protocols, imaging devices, and population demographics. While large-scale multi-site datasets offer unprecedented opportunities for developing robust diagnostic models, the heterogeneity between sites often leads to poor model generalization. This work proposes an uncertainty-informed active learning framework for Source-Free (SF) Domain Adaptation (DA) to classify cognitively normal individuals and AD patients across different neuroimaging studies. The proposed approach leverages Monte Carlo dropout to estimate prediction uncertainty and guide the selection of the most informative samples from the target domain for model adaptation, eliminating the need for source domain data during deployment. The framework was evaluated on a large-scale dataset comprising 3,177 participants from five neuroimaging studies (ADNI-1, ADNI-2/3, PENN, AIBL, and OASIS) with 145 regional brain volume measurements. The uncertainty-based active learning approach achieved the highest median AUC of 91.4% across all source-target combinations, outperforming baseline models (89.7%) and demonstrating superior performance compared to other SF and Source-Aware (SA) DA methods. Additionally, the distribution shifts between studies were quantified using maximum mean discrepancy to evaluate the effectiveness under variable inter-site shift. The results demonstrate that SF methods can achieve comparable or superior performance to SA approaches while addressing privacy constraints inherent in medical imaging applications.},
}
@article {pmid42396515,
year = {2026},
author = {Hwang, E and Shim, HS and Kim, SC and Nam, MH and Hyeon, SJ and Kim, HJ and Kim, JE and Park, HJ and Woo, J and Hwang, EM and Stein, T and Lee, J and Choi, JH and Ryu, H},
title = {Basal forebrain parvalbumin neuron dysfunction links network oscillation deficits to hippocampal pathology in Alzheimer's disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10027900/v1},
pmid = {42396515},
issn = {2693-5015},
abstract = {Background Basal forebrain (BF) degeneration is a key pathological feature of Alzheimer's disease (AD) and is closely associated with cognitive decline. Although parvalbumin (PV)-expressing neurons are abundant in the BF and are important regulators of cortical network activity, their contribution to AD pathogenesis remains poorly understood. Methods To investigate the role of BF-PV neurons in AD, we examined the effects of PV knockdown in the BF of APP/PS1 mice. Electrophysiological recordings, behavioral analyses, retrograde tracing, hippocampal transcriptome profiling, and integrative computational analyses, including meta-correlation analysis and artificial neural network (ANN) modeling, were performed to assess the impact of BF-PV loss on neural network activity, hippocampal pathology, and cognitive function. Results BF-PV knockdown disrupted theta oscillations and theta-gamma coupling in the parietal cortex and impaired hippocampal synaptic activity and memory-related behaviors in mice. Retrograde tracing demonstrated that BF neuronal circuits project directly to the hippocampus. Transcriptome analysis revealed that BF-PV knockdown increased amyloidosis- and microvessel-associated gene signatures while reducing synaptic plasticity-related gene expression in the hippocampus. Furthermore, meta-correlation analyses and ANN modeling indicated that BF-PV dysfunction strongly predicts hippocampal pathology, disrupted EEG coupling, and behavioral abnormalities in AD mice. Conclusions These findings identify BF-PV neuronal dysfunction as an important contributor to hippocampal pathology, neural network dysregulation, and cognitive impairment in AD, highlighting BF-PV neurons as a potential mechanistic link between BF degeneration and AD progression.},
}
@article {pmid42396669,
year = {2026},
author = {Wu, M and Li, Y},
title = {Exercise and fluoxetine in Alzheimer's disease: Molecular mechanisms of synergistic and antagonistic effects (Review).},
journal = {International journal of molecular medicine},
volume = {58},
number = {3},
pages = {},
doi = {10.3892/ijmm.2026.5908},
pmid = {42396669},
issn = {1791-244X},
mesh = {*Alzheimer Disease/drug therapy/metabolism/therapy/pathology ; Humans ; *Fluoxetine/therapeutic use/pharmacology ; Animals ; *Exercise/physiology ; Oxidative Stress/drug effects ; Mitochondria/metabolism/drug effects ; Selective Serotonin Reuptake Inhibitors/therapeutic use ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid‑β deposition, tau pathology, synaptic dysfunction, neuronal loss and neuroinflammation. Regular physical activity is a key non‑pharmacological strategy that can ameliorate cognitive impairment and multiple AD‑related pathological features across experimental models by improving mitochondrial function and quality control, strengthening antioxidant defenses, suppressing neuroinflammation and supporting synaptic plasticity. These effects are closely linked to enhanced neurotrophic signaling and cerebrovascular regulation, both of which contribute to resilience against AD‑associated cognitive decline. Fluoxetine, a selective serotonin reuptake inhibitor widely prescribed for depression, has also shown potential benefits in AD models, including modulation of mitochondrial and redox homeostasis, inflammatory signaling and neuroplasticity. The present review integrates evidence on the convergent and divergent molecular targets of exercise and fluoxetine within core AD pathways, highlighting scenarios in which combined interventions may produce synergistic effects, as well as conditions that could lead to antagonistic effects. By mapping shared nodes and potential points of interference, the present review aims to clarify mechanistic hypotheses and inform the design of optimized, clinically translatable strategies that integrate lifestyle and pharmacological approaches for AD.},
}
@article {pmid42397410,
year = {2026},
author = {Zhang, Y and Zhang, J and Xu, S},
title = {Correction to: Multiscale characterization and classification of Alzheimer's disease via integration of brain fingerprint radiomics and graph‑theoretical network metrics.},
journal = {Neuroradiology},
volume = {},
number = {},
pages = {},
doi = {10.1007/s00234-026-04102-9},
pmid = {42397410},
issn = {1432-1920},
}
@article {pmid42397523,
year = {2026},
author = {Chakole, VR and Sen, P},
title = {Overexpression of human interleukin 6 in NaCl inducible bacterial system and its characterization.},
journal = {Applied biochemistry and biotechnology},
volume = {},
number = {},
pages = {},
pmid = {42397523},
issn = {1559-0291},
support = {RGEMS seed fund 2025-26//Vellore Institute of Technology, Vellore/ ; },
abstract = {Human Interleukin-6 (hIL6) is a multifunctional cytokine that plays a central role in host defence system due to its wide range of immune and hematopoietic activities. hIL-6 stimulates the inflammatory and autoimmune processes in many diseases such as multiple sclerosis, diabetes, atherosclerosis, Alzheimer's disease, systemic lupus erythematous, multiple myeloma, prostate cancer &amp; rheumatoid arthritis. Due to its clinical and research relevance, production of recombinant hIL-6 in biologically active state is considerably important. In this study, we reported successful cloning, transformation, expression, purification and characterization of hIL-6 by using salt inducible expression system i.e. GJ1158. The hIL6 was subcloned from pcDNA3.1 into the prokaryotic expression vector pRSET-B and transformed in GJ1158. Recombinant expression of protein was done by NaCl at mid-log phase. Cobalt-NTA affinity chromatography (IMAC) and S-200 size exclusion chromatography (SEC) were used to obtain approx. 95% purified hIL6 protein (1.5 mg; 18.8% overall recovery). The recombinant hIL-6 was confirmed by western blotting and MALDI-TOF MSMS while functional validation was done by ELISA and MTT assay. The study establishes a cost effective and environmentally favourable strategy for producing recombinant hIL-6 in a prokaryotic host without compromising structural and functional properties. This expression system can used to produce hIL-6 for research, diagnostic and potential therapeutic applications.},
}
@article {pmid42397646,
year = {2026},
author = {Ardah, MT and Yaseen, BM and Malathi, H and Ray, S and Thyagarajan, R and Shankhyan, A and Eshmetov, R and Ataullaev, Z and Mishra, MK},
title = {Targeted nanomedicine strategies for Alzheimer's disease therapy.},
journal = {Discover nano},
volume = {21},
number = {1},
pages = {},
pmid = {42397646},
issn = {2731-9229},
abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and is characterized by amyloid-beta deposition, tau pathology, synaptic dysfunction, and progressive cognitive decline. Currently approved symptomatic therapies, including acetylcholinesterase inhibitors and the NMDA receptor antagonist memantine, provide modest and time-limited benefit and do not directly modify upstream disease drivers. This review synthesizes recent nanomedicine strategies that aim to bridge this gap by integrating biomarker-oriented nanosensors and imaging probes for earlier detection with targeted nanocarriers designed to overcome delivery barriers, particularly the blood-brain barrier, while improving pharmacokinetics and limiting off-target exposure. We highlight converging design principles, including stimulus-responsive release, receptor- and ligand-guided targeting, biomimetic coatings, and organelle-focused delivery to mitochondria and lysosome-autophagy pathways. Beyond repackaging existing agents, nano-enabled approaches are discussed in relation to amyloid and tau clearance or neutralization, redox and mitochondrial rescue, microglia-centered immunomodulation, and regenerative support for neuronal and neurovascular repair. To move beyond a descriptive overview, this review presents a stage-informed and pathology-guided framework for matching nanomedicine design to amyloid-predominant, tau-dominant, neuroinflammatory, mitochondrial, and advanced neurovascular phenotypes. We also evaluate translational constraints, including long-term safety, biodistribution, reproducibility, immunogenicity, scalable manufacturing, regulatory characterization requirements, and the trade-off between biological sophistication and clinical manufacturability. Finally, we distinguish platforms with nearer-term translational potential, such as selected lipid, polymeric, and extracellular vesicle-based systems, from exploratory multifunctional inorganic or highly complex biomimetic designs. This balanced framing clarifies where nanomedicine may realistically advance disease-modifying therapy while identifying evidence gaps that still limit translation.},
}
@article {pmid42397694,
year = {2026},
author = {Liu, X and Li, M and Wei, Z and Shang, T and Zou, W},
title = {Border-Associated Macrophages in CNS Health and Disease: A Comprehensive Review of Ontogeny, Heterogeneity, and Functional Plasticity at Neural Interfaces.},
journal = {ASN neuro},
volume = {18},
number = {1},
pages = {2687503},
doi = {10.1080/17590914.2026.2687503},
pmid = {42397694},
issn = {1759-0914},
mesh = {Animals ; *Macrophages/immunology/metabolism/physiology ; Humans ; *Central Nervous System/immunology/metabolism ; *Neuronal Plasticity/physiology ; *Central Nervous System Diseases/immunology/pathology ; },
abstract = {Border-associated macrophages (BAMs) represent a specialized population of tissue-resident immune cells strategically positioned at the critical interfaces between the central nervous system (CNS) and peripheral circulation, including the meninges, choroid plexus, and perivascular spaces. As frontline sentinels of the neuroimmune system, BAMs perform essential functions in immune surveillance, barrier integrity maintenance, and homeostatic regulation, yet their unique biology and disease-associated roles remain incompletely characterized compared to parenchymal microglia. This review aims to synthesize current knowledge on BAM ontogenetic origins, compartment-specific heterogeneity, transcriptional programs, and functional outputs in both health and neurological disorders. We conducted a comprehensive literature analysis integrating findings from lineage tracing studies, single-cell RNA sequencing, spatial transcriptomics, and functional interrogation in animal models of disease. The results reveal that BAMs exhibit remarkable cellular diversity shaped by distinct ontogenetic origins-primarily yolk sac-derived erythro-myeloid progenitors with variable contributions from fetal liver and postnatal monocytes depending on anatomical compartment. Compartment-specific marker combinations (CD206, LYVE1, CD163, MHCII) define functionally distinct subsets, and core transcriptional regulators including PU.1 and IRF8 maintain BAM identity while CSF-1/IL-34-CSF1R signaling governs survival and renewal. In neurological disorders including ischemic stroke, Alzheimer's disease, multiple sclerosis, and brain tumors, BAMs display pronounced double-edged roles, transitioning from protective homeostatic guardians to pathogenic drivers depending on disease stage and microenvironmental context. This comprehensive analysis establishes a unified framework for understanding BAM biology and identifies critical opportunities for developing subset-specific therapeutic strategies targeting these interface macrophages in neurological diseases.},
}
@article {pmid42397748,
year = {2026},
author = {Barata, MA and Guimas Almeida, C},
title = {Protocol for semi-automatic quantitative bioimaging analysis of synapse loss.},
journal = {STAR protocols},
volume = {7},
number = {3},
pages = {104675},
doi = {10.1016/j.xpro.2026.104675},
pmid = {42397748},
issn = {2666-1667},
abstract = {Synapse loss correlates with cognitive decline in neurodegenerative diseases like late-onset Alzheimer's disease. We developed a semi-automated workflow to quantify synapse loss in primary mouse neurons. The protocol includes culturing neurons on coverslips, using short hairpin RNA (shRNA)-expressing lentivirus, maintaining cultures, and labeling excitatory and inhibitory presynaptic markers by immunofluorescence. Image acquisition and analysis using Fiji/ComDet macros enable region of interest selection, neurite length measurement, puncta detection, and quantification of synapse density, size, and intensity following Bin1 knockdown. For complete details on the use and execution of this protocol, please refer to Barata et al.[1].},
}
@article {pmid42398025,
year = {2026},
author = {Zhai, W and Zhou, D and Yuan, Z and Ji, J},
title = {PLNFGL: Joint Estimation of Multi-Condition Gene Networks from Single-cell RNA-seq Data.},
journal = {Bioinformatics (Oxford, England)},
volume = {},
number = {},
pages = {},
doi = {10.1093/bioinformatics/btag485},
pmid = {42398025},
issn = {1367-4811},
abstract = {MOTIVATION: Graphical models have been widely used in bioinformatics to infer the conditional dependence structure among random variables, but traditional Gaussian graphical models (GGMs) are suboptimal for single-cell RNA sequencing (scRNA-seq) due to dropout events and distributional mismatch. Moreover, most existing methods estimate networks under a single condition, limiting their utility in multi-condition studies.<br><br>RESULTS: We propose PLNFGL (Poisson Log-Normal Fused Graphical Lasso), a joint network estimation framework for scRNA-seq data. PLNFGL uses a multivariate Poisson log-normal model to accommodate dropout effects and estimates the covariance via moment methods. A joint graphical model is then employed to infer condition-specific precision matrices. Simulations show improved estimation accuracy. Applications to scRNA-seq data of Alzheimer's disease and spatial transcriptomics of lung cancer reveal cell-type-specific interaction networks. Edge set enrichment enables pathway analysis, validating known interactions and highlighting novel disease-related targets. This work provides a powerful tool for the integrative analysis of scRNA-seq data.<br><br>The R implementation of PLNFGL is available at https://github.com/jijiadong/PLNFGL, and an archival version is available on Zenodo at https://doi.org/10.5281/zenodo.20744172.<br><br>SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.},
}
@article {pmid42398038,
year = {2026},
author = {Hoang, MN and Kim, L and Fisher, L and DuBose, L and Ory, MG and Lee, S and Falohun, T and Fan, Q},
title = {Exploring Informal Caregivers' Perception of the Olera Digital Caregiving Assistance Platform for Dementia Care: Mixed Methods Evaluation Study.},
journal = {JMIR formative research},
volume = {10},
number = {},
pages = {e92967},
doi = {10.2196/92967},
pmid = {42398038},
issn = {2561-326X},
mesh = {Humans ; *Caregivers/psychology/statistics &amp; numerical data ; *Dementia/psychology/therapy/nursing/complications ; Female ; Middle Aged ; Male ; Aged ; *Perception ; Surveys and Questionnaires ; Qualitative Research ; Adult ; Digital Health ; Aged, 80 and over ; Digital Media ; Mobile Applications/standards ; Internet ; },
abstract = {BACKGROUND: Informal caregivers of people living with dementia often experience high rates of caregiver burnout while providing care. Although there are many websites and mobile apps available to help caregivers, many do not use digital tools. The Olera platform was developed to be an easily adoptable web-based support tool, connecting caregivers with long-term services and supports, financial assistance, and educational resources. The platform was developed based on the Build-Measure-Learn framework with input from caregiver needs assessments and usability studies.<br><br>OBJECTIVE: This study aims to evaluate the quantitative and qualitative feedback of informal caregivers of people living with dementia on the second iteration of the Olera platform. The primary objective was to assess caregivers' acceptance of this caregiving platform. The secondary objective was to use qualitative methods to explore (1) the study cohort's challenges in daily caregiving to determine and compare them with prior literature, (2) their experience when using the Olera platform, and (3) their attitudes toward integrating artificial intelligence in caregiver services for future studies and platform development.<br><br>METHODS: Caregivers were recruited through various sources and screened for eligibility through an initial survey. Participants used the platform for 4 weeks and completed a survey with an adapted Technology Acceptance Survey (TAS) and qualitative open-ended questions at the end of the testing period. TAS responses were summarized with descriptive statistics, while ANOVAs, t tests, and linear regressions were used to compare the differences in the overall TAS scores by caregiver characteristics. Qualitative feedback data on the platform's usefulness were analyzed via a thematic analysis framework approach.<br><br>RESULTS: A total of 65 caregivers in the United States completed the study, with a mean age of 59.9 (SD 9.8) years. The majority were female (61/65, 95.3%), non-Hispanic or Latino White (45/65, 69.2%), and the adult child of their care recipient (42/65, 64.6%). Evaluation of the Olera platform showed a high acceptance rate, with each TAS item scoring above 5.0 and an overall TAS score of 5.83 (SD 0.85) out of 7. Higher platform use frequency was associated with higher TAS ratings in technology acceptance (F3,61=7.88, P<.001). Thematic analyses elicited the caregiving challenges, evaluation of the Olera platform, and feedback on artificial intelligence-assisted support.<br><br>CONCLUSIONS: The Olera platform is an example of a beneficial web-based tool, though key features were requested to be included in the next iteration. Additionally, data supported prior findings regarding informal caregiver challenges and the insufficiency of conventional support mechanisms, indicating a need for more innovative digital solutions. Future research and development efforts using the Build-Measure-Learn approach are necessary to further iterate the platform's key features, enhance the tool, involve more informal caregivers in its improvements, and serve as a model for customizable, person-centered online care support.},
}
@article {pmid42398039,
year = {2026},
author = {McKenna, M and Torous, J and Rozenblit, E and Flathers, M and Ryan, S and Byun, AJS and Lim, C},
title = {Real-Time Smartphone Monitoring Assessments as a Cognitive Biomarker of Alzheimer Disease: Protocol for a Development Study.},
journal = {JMIR research protocols},
volume = {15},
number = {},
pages = {e93259},
doi = {10.2196/93259},
pmid = {42398039},
issn = {1929-0748},
mesh = {Humans ; *Alzheimer Disease/diagnosis/psychology ; *Smartphone ; Pilot Projects ; Biomarkers/analysis ; *Cognitive Dysfunction/diagnosis ; Neuropsychological Tests ; Female ; Cognition ; },
abstract = {BACKGROUND: The diagnosis and monitoring of Alzheimer disease (AD) currently rely on clinician-administered, in-person, and cross-sectional pen-and-paper cognitive assessments. While clinically validated, these measures are time-intensive, infrequently administered, and limited in their ability to detect early, subtle, or short-term cognitive changes. Thus, more frequent, ecologically valid assessments are critical to improving sensitivity to early cognitive impairment and disease progression.<br><br>OBJECTIVE: This study aims to develop and pilot a smartphone-based assessment battery that combines active cognitive assessments with passive smartphone sensor data (eg, steps, sleep) and survey data to identify and longitudinally characterize cognitive impairment associated with AD.<br><br>METHODS: We developed a suite of digitized versions of standard cognitive tests alongside novel, game-based cognitive tests within the mindLAMP platform. Uniquely, these tests integrate into the platform's mobile survey and digital phenotyping capabilities to produce a comprehensive assessment tool capable of simultaneously tracking self-reported, behavioral, and cognitive symptoms in real time. These tools were unified within the Smartphone Monitoring Assessment in Real Time-Alzheimer's framework. Across a 6-month pilot study involving individuals with mild cognitive impairment or mild AD, we will examine the feasibility, acceptability, and longitudinal adherence to these assessments. We will compare digital cognitive and passive data streams against standard clinical assessments to evaluate their usefulness in detecting cognitive impairment and change over time.<br><br>RESULTS: Recruitment began in April of 2025. As of February 2026, 13 participants with mild cognitive impairment or AD (mean age 72.8, SD 6.5 y, 8 male) and 12 controls (mean age 71.6, SD 7.8 y, 6 male) have been enrolled; recruitment is ongoing. Preliminary analyses on participant compliance, passive data, and variations in game scores are in progress. Data analysis is expected to be completed by mid-2026, and we anticipate results to be published in 2027. This study is funded by the a2 Pilot Awards, a subaward of funding given to the Trustees of the University of Pennsylvania under the a2 Collective, beginning in April 2024.<br><br>CONCLUSIONS: Smartphone-based cognitive assessments, when combined with digital phenotyping, offer a scalable and ecologically valid approach to detecting and monitoring AD in real-world settings. This framework has the potential to enhance early detection, enable continuous monitoring, and support future machine learning-based automated identification of cognitive impairment, ultimately facilitating earlier and more personalized care.},
}
@article {pmid42398140,
year = {2026},
author = {Zhu, Q and Ye, N and Huang, L and Wang, H and Zhao, Q and Ma, L and She, G and Mu, L and Shi, W},
title = {A nanowire-based fluorescent sensor for detecting hydrogen peroxide (H2O2) dyshomeostasis in cell body and synapse of Alzheimer's disease (AD) cell model.},
journal = {Talanta},
volume = {311},
number = {},
pages = {130250},
doi = {10.1016/j.talanta.2026.130250},
pmid = {42398140},
issn = {1873-3573},
abstract = {Revealing the levels of hydrogen peroxide (H2O2) in neuron's cell body and synapse with high spatial resolution is very important not only for clarifying the pathways between the fluctuation of H2O2 and neurotoxicity of amyloid-β oligomers (AβOs), but also for further understanding the pathogenesis of Alzheimer's disease (AD). Herein, a single nanowire-based H2O2 fluorescent sensor has been designed and developed by covalently modifying H2O2-responsive molecules onto the surface of silicon nanowires (SiNWs). The sensor features high spatial resolution, excellent selectivity and high sensitivity. By positioning SiNW sensors into both cellular compartments, respectively, the AβOs-induced alterations of H2O2 levels in cell body and synapse of neurons are detected. It is found that H2O2 levels in cell body and synapse are gradually elevated with prolonging AβOs exposure. Moreover, the elevation of H2O2 in synapse occurs prior to the increase in cell body. It is demonstrated that the clathrin-mediated endocytosis serves as a prime pathway mode for transporting exogenous AβOs into the cells, and plays a critical role in preferentially elevating H2O2 levels in synapse. The method developed in this work for monitoring H2O2 with high spatial resolution will be beneficial for exploring the critical role of H2O2 in AD pathogenesis.},
}
@article {pmid42398193,
year = {2026},
author = {Saumur, TM and Ashraf, H and Mathers, KE and Wagner, B},
title = {Pharmacotherapy for Alzheimer's Disease and Dementias in Long-Term Care: A Real-World EHR Study.},
journal = {Journal of the American Medical Directors Association},
volume = {27},
number = {9},
pages = {106293},
doi = {10.1016/j.jamda.2026.106293},
pmid = {42398193},
issn = {1538-9375},
abstract = {OBJECTIVES: To characterize contemporary pharmacologic medication order patterns for Alzheimer's disease (AD) and related dementias (ADRD) among US long-term care (LTC) residents and to examine facility- and resident-level factors associated with treatment.<br><br>DESIGN: Retrospective and observational study.<br><br>SETTING AND PARTICIPANTS: Electronic health record data from 1,675,873 LTC residents in the PointClickCare Life Sciences clinical database included 295,946 with a documented ADRD diagnosis in skilled nursing facilities in the United States who remained in facility at the end of the study window (January-April 2025).<br><br>METHODS: Residents were classified as treated/untreated based on the presence of &#x2265;1 ADRD medication order as outlined by the Alzheimer's Association. Analyses incorporated demographics, comorbidities, medication burden, and facility characteristics. Multivariate logistic regression estimated the odds of having an ADRD medication order.<br><br>RESULTS: Overall, 82.0% of residents with ADRD had &#x2265;1 order for ADRD medication. Treatment was most common among residents with Lewy body dementia (91.1%) and early onset AD (90.3%) and least frequent among Asian (72.3%), Native Hawaiian, or Other Pacific Islander (74.6%) and short-stay residents (75.6%). Treated residents exhibited a higher medication burden (mean, 8.6 vs 6.3). Diagnoses for other chronic conditions as well as specific ADRD subtypes strongly impacted probability of treatment; diabetes was associated with lower odds of treatment, whereas ADRD subtypes strongly predicted treatment.<br><br>CONCLUSIONS AND IMPLICATIONS: Approximately one-fifth of residents with ADRD did not have an ADRD medication order, and treatment varied significantly by nonclinical predictors. These findings underscore the need to investigate and understand possible treatment disparities, optimize polypharmacy management, and discover new ADRD treatments, and develop safer and more effective ADRD therapies.},
}
@article {pmid42398284,
year = {2026},
author = {Basu, R and Polsky, DE and Van Houtven, CC},
title = {Patient-Driven Grouping Model and Home Health Use Among Traditional Medicare Beneficiaries.},
journal = {Journal of the American Medical Directors Association},
volume = {27},
number = {8},
pages = {106327},
doi = {10.1016/j.jamda.2026.106327},
pmid = {42398284},
issn = {1538-9375},
abstract = {OBJECTIVES: In January 2020, the Centers for Medicare &amp; Medicaid Services implemented the Patient-Driven Groupings Model (PDGM), the most substantial revision to Medicare's home health (HH) prospective payment system since its introduction in 2000. PDGM shortened the payment period from 60 to 30 days and eliminated therapy visit thresholds from payment calculations. Because Medicare's HH payment policies have historically shaped patterns of service use, payment changes under PDGM were expected to influence service intensity and episode length. The aim of this study is to examine whether PDGM influences HH utilization among Medicare beneficiaries, particularly those with Alzheimer's disease and related dementias (ADRD).<br><br>DESIGN: Cross-sectional cohort study.<br><br>SETTINGS AND PARTICIPANTS: A 20% random sample of traditional Medicare beneficiaries who used HH services in 2019 (pre-PDGM) and 2021 (post-PDGM).<br><br>METHODS: We compared total HH visits and length of stay (LOS) during a standardized 60-day episode in the pre- and post-PDGM periods. Generalized linear models were used to estimate changes in visit volume and LOS following PDGM implementation, comparing beneficiaries with ADRD and without ADRD.<br><br>RESULTS: Beneficiaries with ADRD experienced a steeper decline in total visits (from 22.4 to 17.9) compared with those without ADRD (from 18.2 to 15.4), driven by reductions in therapy visits, which fell from 12.9 to 9.9 among beneficiaries with ADRD and from 9.8 to 8.3 among those without ADRD. The average LOS within a 60-day episode also decreased after PDGM implementation. Adjusting for patient-level characteristics, beneficiaries with ADRD in the post-PDGM period received 2.04 fewer total visits, including 1.4 fewer therapy visits, than those without ADRD. These patterns differed by the severity of ADRD.<br><br>CONCLUSIONS AND IMPLICATIONS: PDGM's reimbursement changes and the shortening of the payment period may disproportionately affect Medicare beneficiaries with ADRD, underscoring the need to assess the implications for patient outcomes and future refinements of the payment policy.},
}
@article {pmid42398294,
year = {2026},
author = {Jyothi, GD and Kumar, CM and Kottala, RK},
title = {Combined transformer encoder-CNN architecture with texture features for MRI-based Alzheimer's disease detection.},
journal = {Psychiatry research. Neuroimaging},
volume = {362},
number = {},
pages = {112277},
doi = {10.1016/j.pscychresns.2026.112277},
pmid = {42398294},
issn = {1872-7506},
abstract = {Alzheimer's disease (AD) develops long before clinical symptoms appear, which highlights the need for early diagnostic tools. Current diagnostic techniques often miss the subtle structural brain changes in the early stages of AD, creating a critical gap in timely medical intervention. This paper proposes a combined modified Transformer Encoder-Convolutional Neural Network (CNN) architecture for AD detection using Magnetic Resonance Imaging (MRI). Data augmentation techniques, including rotation, zooming, brightness adjustment and flipping, are applied to increase the number of training images. Images are processed using a Modified Gaussian Filtering technique (modGFT) that implements a spatially adaptive variance to suppress noise while preserving critical anatomical edges and structural details. Relevant features, including shape features, Improved Median Robust Extended Local Binary Pattern (ImpMRELBP) and Pyramid Histogram of Oriented Gradients (PHOG) features, are extracted. The ImpMRELBP descriptor highlights boundaries and captures meaningful texture variations. These features are input into a hybrid modTransEncd-CNN detection model. The model incorporates batch normalization and an enhanced attention module, improving training speed, stability and generalization. The results from both models are merged using soft voting for AD classification. Experimental results demonstrate that the proposed modTransEncd-CNN method outperforms traditional models, achieving 96% accuracy.},
}
@article {pmid42398379,
year = {2026},
author = {Mosquera Losada, ME and Martín, JP and Mariño, AO and Gómez-Conesa, A},
title = {Aetiological diagnosis of cognitive impairment in older adults: The role of geriatric nursing and factors associated with its detection.},
journal = {Geriatric nursing (New York, N.Y.)},
volume = {72},
number = {},
pages = {104157},
doi = {10.1016/j.gerinurse.2026.104157},
pmid = {42398379},
issn = {1528-3984},
abstract = {AIMS: To quantify the proportion of residents with cognitive impairment who receive an aetiological diagnosis during their stay in nursing homes, to identify associated sociodemographic and stay-related factors, and to evaluate the association between geriatric specialist availability and aetiological diagnosis METHODS: Retrospective observational cohort study with up to 24 months of follow-up across eight nursing homes in Pontevedra, Spain. Participants were aged ≥60 years, had cognitive impairment at admission and no prior aetiological diagnosis (n = 98). The primary outcome was receipt of an aetiological diagnosis during the stay.<br><br>RESULTS: An aetiological diagnosis was recorded in 26/98 residents (26.5%). Among those diagnosed, dementia accounted for 69.2%; vascular dementia predominated (55.5%), followed by Alzheimer's disease (22.2%); in 22.2% the subtype was not recorded. Median length of stay was longer in residents who received a diagnosis (24 vs 5.5 months; p < 0.01). In bivariate analyses, the presence of a geriatric nurse and a geriatrician was associated with a greater likelihood of receiving an aetiological diagnosis.<br><br>CONCLUSIONS: Only one quarter of residents with cognitive impairment received an aetiological diagnosis during their stay, indicating considerable scope for improvement. Longer length of stay and the presence of healthcare professionals specialised in geriatrics were associated with higher diagnostic rates.},
}
@article {pmid42398400,
year = {2026},
author = {Xin, Z and Tan, H and Xu, Y and He, P and Wang, Z and Bu, X and Wu, H},
title = {Design, synthesis and evaluation of dual modulators targeting glutaminyl cyclase and cannabinoid CB2 receptor.},
journal = {European journal of medicinal chemistry},
volume = {317},
number = {},
pages = {119115},
doi = {10.1016/j.ejmech.2026.119115},
pmid = {42398400},
issn = {1768-3254},
abstract = {Alzheimer's disease (AD) is the major cause of dementia and one of the most common chronic diseases affecting aging populations. As such, novel and effective therapeutic agents are urgently needed to address this growing public health challenge. Given the involvement of glutaminyl cyclase (QC) and cannabinoid type 2 receptor (CB2R) dysregulation in AD progression, we designed, synthesized, and evaluated a series of biphenyl carboxamide derivatives as dual modulators targeting QC and CB2R. In vitro assays showed that most of the 35 compounds exhibited notable QC inhibitory and CB2R agonistic activity; for example, compound 18 demonstrated potent activity against both targets (QC, IC50 = 0.65 ± 0.07 μM; CB2R, EC50 = 0.32 ± 0.04 μM). Structure-activity relationship analysis indicated that the amide-linked motif (R[1]) is critical for CB2R agonistic potency, while the introduction of a methoxy group (R[2]) on the biphenyl scaffold enhances activity against both targets. Molecular docking further supported the interactions between these compounds and their respective protein targets. Taken together, these dual modulators targeting QC and CB2R warrant further investigation as potential therapeutic candidates for AD.},
}
@article {pmid42121377,
year = {2026},
author = {Shieu, B and Neidre, DB and Song, L and Delgado, RE and Cary Reid, M and Gaugler, JE and White, CL},
title = {Latino family caregivers: "it's what we do-we take care of our own".},
journal = {The journals of gerontology. Series B, Psychological sciences and social sciences},
volume = {81},
number = {8},
pages = {},
doi = {10.1093/geronb/gbag086},
pmid = {42121377},
issn = {1758-5368},
support = {#2021318//RRF Foundation for Aging/ ; },
mesh = {Humans ; *Caregivers/psychology ; *Hispanic or Latino/psychology ; *Dementia/nursing/ethnology ; Female ; Aged ; Community-Based Participatory Research ; Male ; Qualitative Research ; Middle Aged ; Texas/ethnology ; Aged, 80 and over ; Adult ; },
abstract = {OBJECTIVES: To better understand the interplay of culture and family caregiving among Latinos, we explored the perceptions of caregivers of persons living with dementia on how their culture informs the care they provide.<br><br>METHODS: This study used a descriptive qualitative design to explore the perceptions of Latino family caregivers of persons living with dementia. A Community-Based Participatory Research (CBPR) approach underpinned the study design and execution, with a Latino Caregiver Advisory Council (LCAC) engaged in study design, recruitment, and interpretation. Individual semi-structured interviews were conducted via Zoom with Latino family caregivers of persons living with dementia from South Central Texas, in either English or Spanish. The interview guide consisted of questions about participants' perceptions of caregiving and culture. Content analysis was used to analyze the transcripts.<br><br>RESULTS: Among 13 caregivers, we identified two overarching themes, "The Influence of Culture on Caregiving" and "Barriers to Care," that together illustrate how cultural values serve as a profound source of both resilience and distress. We identified key subthemes related to the influence of culture (i.e., motivations for providing care, who provides this care, and where it is provided) and barriers to care (i.e., cultural beliefs about dementia, structural barriers to accessing resources, and systemic financial challenges).<br><br>DISCUSSION: Our findings indicate that culture can be a source of strength and a source of stress for Latino family caregivers. These results highlight the need for tailored caregiver support intervention programs that recognize the cultural influence shaping how families give and receive care.},
}
@article {pmid42385702,
year = {2026},
author = {Zhou, Z and Luquette, LJ and Dong, G and Kim, J and Ku, J and Kim, K and Ramesh, N and Bae, M and Caplin, A and Shao, DD and Sahile, B and Essuman, K and Goodman, E and Miller, MB and Huang, AY and Nathan, WJ and Nussenzweig, A and Park, PJ and Lagier-Tourenne, C and Lee, EA and Walsh, CA},
title = {Recurrent patterns of TOP1-mediated neuronal genomic damage shared by major neurodegenerative disorders.},
journal = {Cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.cell.2026.06.013},
pmid = {42385702},
issn = {1097-4172},
abstract = {Amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD) represent two major categories of neurodegenerative disorders-TAR DNA-binding protein 43 (TDP-43) and tau proteinopathies-for which the mechanisms driving neuronal death remain unclear. Single-cell whole-genome sequencing of 469 neurons from C9ORF72 ALS, C9ORF72 FTD, AD, and control brains revealed increased somatic single-nucleotide variants (sSNVs) and insertions/deletions (sIndels) in all three diseases. Mutational signature analysis identified a disease-associated sSNV signature consistent with oxidative damage and an sIndel process affecting 22% of ALS, 76% of FTD, and 61% of AD neurons-but only 2% of control neurons-resembling signature ID4, previously linked to topoisomerase 1 (TOP1)-mediated mutagenesis. Rapid approach to DNA adduct recovery (RADAR) assays confirmed increased TOP1-DNA covalent complexes, and duplex sequencing confirmed the increased sIndels and identified single-strand events as likely precursor lesions. TOP1-associated sIndel mutagenesis and genome instability thus represent a mechanism shared by both TDP-43 and tau neurodegeneration.},
}
@article {pmid42385975,
year = {2026},
author = {Abhishek, and Singh, S},
title = {ARBUTIN AS A THERAPEUTIC CANDIDATE FOR AUTISM: CURRENT EVIDENCE AND MECHANISTIC INSIGHTS INTO PI3K/Akt/mTOR and Nrf2 PATHWAYS.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {179103},
doi = {10.1016/j.ejphar.2026.179103},
pmid = {42385975},
issn = {1879-0712},
abstract = {Arbutin is a natural glycoside that protects neurons and is useful in a variety of neurological conditions. There is a need to further explore its scientific properties as arbutin regulates mitochondrial function, control apoptotic proteins, lowers oxidative stress, enhance behavioral and cognitive outcomes and thus may be considered a potential target for Parkinson's, Alzheimer's, neuroinflammation, epilepsy and Huntington's disease. Arbutin via PI3K/Akt/mTOR and Nrf2 signaling pathways, helps to balance redox equilibrium, mitochondrial integrity and neuronal survival, plays a major role in mediating these effects. Autism Spectrum Disorder (ASD) is closely associated with dysfunction of these pathways, which cause oxidative2 stress, synaptic deficits and neuroinflammation. While reducing NF-κB mediated pro-inflammatory cytokines including TNF-α, IL-1β and IL-6, arbutin increases Akt phosphorylation and Nrf2 nuclear translocation, activating antioxidant enzymes like SOD, GSH, HO-1 and NQO1. These coordinated molecular processes may help preserve neuronal homeostasis, inhibit apoptosis and decrease ROS induced neuronal damage. Arbutin may enhance synaptic plasticity and potentially modulate the pathogenic pathways underlying ASD and other neurodevelopmental disorders by concurrently regulating oxidative stress, mitochondrial dysfunction and neuroinflammation. Taken together these finding suggest arbutin may act as a promising therapeutic candidate capable of restoring neuronal homeostasis and translating mechanistic understanding into potential therapeutic applications. Arbutin is a promising phytochemical with potential relevance for autism and associated neurological diseases due to its combined molecular actions. However, direct experiment and clinical evidence supporting the role of arbutin in ASD remains limited.},
}
@article {pmid42385986,
year = {2026},
author = {Millhauser, GL and Singewald, K and Smart, A and Pavlovici, F},
title = {Isotope-Edited ESEEM: A New Method for Probing Copper Binding Sites in Neurodegenerative Proteins.},
journal = {The Journal of biological chemistry},
volume = {},
number = {},
pages = {113310},
doi = {10.1016/j.jbc.2026.113310},
pmid = {42385986},
issn = {1083-351X},
abstract = {The interactions between intrinsically disordered domains in neurodegenerative proteins are often stabilized by the inclusion of physiologic metal ions such as copper or zinc. Characterizing the metal ion coordination environment in such cases is critical for assessing the stability and organization of these relevant protein-protein interactions but is challenging given the lack of regular molecular order of the relevant protein domains. We recently developed a new pulsed Electron Paramagnetic Resonance (EPR) approach that takes advantage of Electron Spin Echo Envelope Modulation (ESEEM) with selective [15]N isotope labeling. Histidine side chains with [14]N or [15]N coordinated to Cu[2+] give distinct, fully resolvable signals in both ESEEM and its two-dimensional companion method HYSCORE. The approach was applied to the cellular prion protein, PrP[C], to investigate how its otherwise neurotoxic, disordered N-terminal domain is regulated through a Cu[2+] linkage to its globular C-terminal domain. Sortase-mediated ligation created an expressed murine prion protein with segmental [15]N-labeling exclusive to the N-terminal domain. Isotope-edited ESEEM identifies the specific His residues from both domains that participate in this essential regulatory process. Extending this approach to hetero-protein complexes focused on how Cu[2+] may facilitate the interaction between PrP[C] and the Aβ peptide, a dominant component of senile plaques in Alzheimer's disease. Combining [15]N-labeled PrP[C] with unlabeled Aβ, shows that both proteins simultaneously coordinate Cu[2+] with Aβ contributing a single His side chain. Collectively, this review highlights isotope-edited ESEEM as an effective method for achieving residue-specific insights into metal coordination within structured and disordered protein complexes.},
}
@article {pmid42386071,
year = {2026},
author = {Del Castillo, IL and Garcia-Martin, J and Gutierrez, A and Moreno-Gonzalez, I},
title = {Amylin at the crossroads of type 2 diabetes and neurodegenerative diseases.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103226},
doi = {10.1016/j.arr.2026.103226},
pmid = {42386071},
issn = {1872-9649},
abstract = {Type 2 diabetes (T2D) is traditionally viewed as a metabolic disease centered on insulin resistance and β-cell failure. However, growing evidence supports its reclassification as a systemic proteinopathy, in which the aggregation of amylin (islet amyloid polypeptide, IAPP) emerges as a key pathogenic event. In this review, we examine the shift toward an IAPP-centric model of disease, highlighting how IAPP misfolding and aggregation drive β-cell dysfunction independently of, and in parallel with, metabolic stress. We integrate recent advances in the structural biology of IAPP to provide a mechanistic framework for its cytotoxicity. IAPP aggregation disrupts cellular homeostasis through membrane damage, proteostasis imbalance, mitochondrial dysfunction, oxidative and ER stress, and inflammation, ultimately leading to progressive β-cell loss. Beyond the pancreas, we position IAPP as a molecular bridge between peripheral metabolic stress and neurodegeneration. Through prion-like cross-seeding, IAPP interacts with Aβ, tau, α-synuclein, and PrP, linking T2D as a major risk factor for neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. We review emerging therapeutic strategies, including long-acting non-fibrillating analogues that suppress endogenous secretion, cross-amyloid inhibitors, conformation-specific immunotherapies, and synthetic chaperones. Finally, we discuss structure-based and AI-driven diffusion models as tools to design binders that selectively mask the amyloidogenic core while preserving the homeostatic function of IAPP. Given the projected magnitude of T2D, targeting the IAPP-neurodegeneration axis through early detection and midlife intervention is essential to mitigating the impending socioeconomic impact of combined metabolic and cognitive decline.},
}
@article {pmid42386101,
year = {2026},
author = {Kitagawa, T and Kamagata, K and Uchida, W and Takabayashi, K and Andica, C and Rui, Z and Ozawa, T and Hagiwara, A and Akashi, T and Sano, K and Wada, A and Tanaka, Y and Hosoi, R and Kanzawa, J and Aoki, S and , },
title = {Investigating tau-related white matter degeneration in Alzheimer's disease using fixel-based analysis.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107518},
doi = {10.1016/j.nbd.2026.107518},
pmid = {42386101},
issn = {1095-953X},
abstract = {Alzheimer's disease involves the accumulation of amyloid-β and tau proteins, with tau-related white matter degeneration potentially contributing to cognitive impairment. This study investigated the relationship between regional tau deposition and white matter degeneration using fixel-based analysis and examined whether white matter changes mediate tau-related cognitive decline. We analyzed data from 285 participants in the Alzheimer's Disease Neuroimaging Initiative, classified based on amyloid and tau biomarker status into four groups: 141 amyloid-negative tau-negative cognitively unimpaired (A - T - CU), 58 amyloid-positive tau-negative cognitively unimpaired (A + T - CU), 49 amyloid-positive tau-positive mild cognitive impairment (A + T + MCI), and 37 amyloid-positive tau-positive dementia (A + T + Dementia). Fixel-based analysis metrics included fiber density, log-transformed fiber-bundle cross-section, and their combined measure derived from diffusion MRI. These were evaluated in relation to [18]F-flortaucipir tau PET standardized uptake value ratios and multiple cognitive assessments. Results showed that A + T + MCI and A + T + Dementia participants exhibited significantly reduced fixel-based metrics in subcortical white matter adjacent to cortical regions with high tau deposition, particularly in temporal and frontal areas (FDR-corrected p < 0.05), with more widespread reductions in A + T + Dementia. Mediation analysis revealed that white matter degeneration across multiple subcortical white matter regions adjacent to temporal, insular, and parietal cortices significantly and partially mediated the relationship between regional tau deposition and cognitive decline, accounting for 6.3-19.7% of the total effect. These findings suggest that tau-related white matter degeneration in regions adjacent to heavily affected cortical areas partially contributes to cognitive impairment in Alzheimer's disease.},
}
@article {pmid42386501,
year = {2026},
author = {Karlovich, E and Priemer, DS and Rhodes, CH and Perl, DP and Tanji, K and Goldman, JE},
title = {Non-Alzheimer Aβ deposits in the human CNS: Implications with hypoxia and related conditions.},
journal = {Brain pathology (Zurich, Switzerland)},
volume = {},
number = {},
pages = {e70120},
doi = {10.1111/bpa.70120},
pmid = {42386501},
issn = {1750-3639},
support = {//Thompson Family Foundation/ ; HU00012120007//Uniformed Services University of the Health Sciences/ ; 312159-1.00-66531//Henry M. Jackson Foundation/ ; //Department of Defense Uniformed Services University Brain Tissue Repository and Neuropathology Program/ ; },
abstract = {We recently reported the deposition of Aβ in the frontal cortex of individuals who died of acute coronavirus disease 2019 (COVID-19), or who did not have COVID-19 but had respiratory distress, or infants with severe cardiac malformations. These Aβ deposits were not the senile, neuritic core "plaques" of Alzheimer's disease (AD) and did not stain for Thioflavin-S or with antibodies to phosphorylated tau protein. Here, we examined multiple sections of the brains of such individuals, finding these non-Alzheimer Aβ deposits (NADAs) predominantly in the isocortex, including frontal, temporal, insular, and occipital, but also in subcortical structures such as the diencephalon, cerebellum, brainstem, and spinal cord, albeit many fewer. NADAs also appeared around blood vessels and within blood vessel walls, but did not incite an inflammatory response. We also examined brains of individuals with metabolic and mitochondrial diseases that lead to hypoxic damage and one individual with severe hyperthermia. All had NADAs identical to the ones we previously reported. These Aβ deposits somewhat resemble the amorphous or diffuse plaques or deposits that have been thought to be associated with early stages of AD, but they are morphologically distinguishable and appear in brains of young individuals who have no Alzheimer pathology. We suggest that the deposits are associated with hypoxia or related mechanisms of injury.},
}
@article {pmid42386668,
year = {2026},
author = {Mascioli, D and Mancini, M and Conti, M and Bissacco, J and Buttarazzi, V and Simonetta, C and Avvento, F and Veltri, F and Nesci, V and Bernardini, S and Sancesario, GM and Centonze, D and Stefani, A and Pierantozzi, M and Schirinzi, T},
title = {Alzheimer's Disease Cerebrospinal Fluid Biomarkers Predict Survival in Progressive Supranuclear Palsy.},
journal = {Movement disorders : official journal of the Movement Disorder Society},
volume = {},
number = {},
pages = {},
doi = {10.1002/mds.70418},
pmid = {42386668},
issn = {1531-8257},
support = {PNRR-M4C2-I1.3 Project PE_00000019 "Heal Italia"//Italian Ministry of University and Research (MIUR)/ ; PRIN Bando 2022 Prot. 20222FYK9R//Italian Ministry of University and Research (MIUR)/ ; },
abstract = {BACKGROUND: Alzheimer's disease (AD)-related pathology may co-occur in progressive supranuclear palsy (PSP), although its clinical and prognostic impact is unclear.<br><br>OBJECTIVES: To assess whether cerebrospinal fluid (CSF) AD biomarker profiles at diagnosis predict severity and survival in PSP.<br><br>METHODS: CSF amyloid-&#x3b2;42 (A&#x3b2;42), total and phosphorylated tau (t-tau, p-tau) levels from 85 newly-diagnosed PSP patients and 59 controls were assessed by the amyloid/tau/neurodegeneration (AT[N]) framework, and the p-tau/A&#x3b2;42 ratio (AD+ if &#x2265;0.08), and implemented in a survival analysis through Kaplan-Meier, Cox regression, and LASSO-Cox modeling.<br><br>RESULTS: AD CSF signature was identified in 5.9% and 18.8% of PSP patients, according to AT(N) and ratio, respectively. It was unrelated to phenotype or severity but strongly predicted survival, with AD+ patients showing markedly shorter survival. The p-tau/A&#x3b2;42 ratio was the strongest independent predictor of mortality, together with phenotype and smoking.<br><br>CONCLUSIONS: AD-related CSF signature defines a biological PSP subgroup with shortened survival. The p-tau/A&#x3b2;42 ratio offers a pragmatic prognostic tool for patient stratification. &#xa9; 2026 International Parkinson and Movement Disorder Society.},
}
@article {pmid42386678,
year = {2026},
author = {Walton, AM and Moss, D and Chai, HW and Stephan, AT and Gamaldo, AA and Ross, LA and Phillips, CB},
title = {The moderating role of personality in the associations between delay discounting and technology use among older adults.},
journal = {The journals of gerontology. Series B, Psychological sciences and social sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/geronb/gbag123},
pmid = {42386678},
issn = {1758-5368},
abstract = {OBJECTIVES: Delay discount rate (DDR), or the devaluation of a future reward as the delay to its receipt increases, often leads individuals to favor smaller, immediate rewards over larger, delayed ones. Older adults' technology use may reflect delay discounting, with short-term ease favored over long-term benefits, and personality traits such as openness or neuroticism further modifying these associations. However, these relationships in older adults' decision-making remain unexplored. Therefore, this study examined (1) associations of DDR with social media and mobile application use, and (2) whether the relationships were moderated by personality traits in a sample of community-dwelling adults aged 55+ years (N = 119, Mage=68.63).<br><br>METHODS: Measures included the Monetary Choice Questionnaire, Mobile Application Use Questionnaire, one item from The Australian National University Alzheimer's Disease Risk Index to assess social media use, and the Big Five Personality Inventory.<br><br>RESULTS: Linear regression analyses revealed that greater DDR was associated with higher social media and mobile app use (p&#x2009;<&#x2009;0.001). Neuroticism and openness significantly moderated the relationship between DDR and mobile app (p&#x2009;=&#x2009;.017) and social media use (p = .008), respectively.<br><br>DISCUSSION: Results suggest a greater delay discount rate is associated with more frequent technology use among participants with lower levels of neuroticism and openness. This study contributes to an initial understanding of the combined effects of stable and alterable factors that can impact older adults' willingness to use technology, allowing for the development of more refined strategies to promote healthy engagement.},
}
@article {pmid42386680,
year = {2026},
author = {Guleria, VS and Winston, CN},
title = {Primary cilia-extracellular vesicle crosstalk in Alzheimer's disease: Emerging mechanisms and biomarker potential.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71645},
doi = {10.1002/alz.71645},
pmid = {42386680},
issn = {1552-5279},
support = {R00AG0703900/NH/NIH HHS/United States ; U19AG074879/NH/NIH HHS/United States ; U19AG024904/NH/NIH HHS/United States ; },
mesh = {*Alzheimer Disease/metabolism/pathology ; Humans ; *Cilia/metabolism/pathology ; *Extracellular Vesicles/metabolism ; Biomarkers/metabolism ; Animals ; Signal Transduction/physiology ; Brain/metabolism ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative condition marked by cognitive decline and synaptic issues. Recent studies show primary cilia (PCs), sensory organelles present on the surface of most mammalian cells, act as a critical regulators of brain homeostasis and signaling. PCs act as a signaling hubs for pathways like G protein-coupled receptor, Hedgehog, Wnt, and neuroinflammation. When PCs are depleted or dysfunctional, they impair the processing of amyloid precursor protein, tau phosphorylation, synaptic signaling, and neuron-glia communication, leading to tau tangles, neuroinflammation, and amyloid beta plaques that drive AD progression. Beyond their role in signal transduction, PCs also regulate the biogenesis, release, and cargo selection of extracellular vesicles (EVs), and dysfunctional EV-PC crosstalk may contribute to AD progression. Examining PC-derived EVs offers pathway-specific insights into early ciliary and neuroinflammatory issues. This review consolidates evidence on PCs' multifaceted role in AD pathogenesis and suggests their potential as an early biomarker.},
}
@article {pmid42386684,
year = {2026},
author = {Hazan, J and Liu, KY and Howard, R},
title = {What should convince a clinician of disease modification in Alzheimer's disease clinical trials?.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71643},
doi = {10.1002/alz.71643},
pmid = {42386684},
issn = {1552-5279},
support = {//The Blood Biomarker Challenge (UCL ADAPT study)/ ; //University College London&#xa0;Hospitals Biomedical Research Centre/ ; CRTF2023B-003//Alzheimer's Research UK/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/therapy ; *Clinical Trials as Topic ; },
abstract = {The recent publication of extension data from post-regulatory trials of amyloid-lowering antibody therapies, such as donanemab and lecanemab, requires clinicians to critically appraise trial designs and analyses in order to evaluate claims made by authors and sponsors of disease modification. This Perspective outlines the challenges with assessing claims of disease course modification, provides a framework for their evaluation, reviews the different trial designs and analytical approaches used to test or support them, and proposes a practical appraisal checklist for evaluating studies.},
}
@article {pmid42386726,
year = {2026},
author = {Pola, I and Akinyemi, T and Tan, K and Olalusi, O and Traichel, W and Giacomucci, G and Yaria, J and Rahmouni, N and Ogunde, G and Oguntiloye, O and Macedo, AC and Fagbemi, A and Cadmus, E and Therriault, J and Popoola, F and Paddick, SM and Dotchin, C and Kisoli, A and Walker, R and Ogunronbi, M and Olujobi, D and Famuyiwa, O and Akinyemi, J and Owolabi, M and Udeh-Momoh, CT and Ladokun, O and Griswold, A and Romero-Ortuno, R and Pericak-Vance, M and Ogunniyi, A and Debette, S and Lawlor, B and Ashton, NJ and Kalaria, R and Zetterberg, H and Rosa-Neto, P and Akinyemi, RO and Benedet, AL},
title = {Plasma proteomic profiles of Alzheimer's disease and neurodegeneration in African cohorts.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-026-74971-4},
pmid = {42386726},
issn = {2041-1723},
abstract = {Alzheimer's disease and related dementia (ADRD) represents a growing public health burden, especially in low- and middle-income countries. Yet, most studies focus on Non-Hispanic white (NHW) populations from high-income countries. This study investigates plasma proteomic signatures associated with amyloid pathology in African populations. Nigerian older adults from the VALIANT study and participants from a Tanzanian study, with available biomarker quantification in plasma are employed. For proteomic comparison, participants from the Canadian TRIAD cohort are included, capturing a distinct population. Here, we show that multiple proteins are differentially abundant in the plasma of p-tau217-positive individuals and in the different cognitive groups, with findings largely consistent amongst African cohorts. Comorbidities are significantly associated with protein levels and differences in plasma biomarkers levels are found between sexes. Lastly, VALIANT and TRIAD show both shared and unique protein profiles in relation to amyloid-pathology. These findings support the utility of fluid biomarkers in ADRD in African populations.},
}
@article {pmid42386756,
year = {2026},
author = {Park, SY and Park, S and Park, HJ and Park, H and Lee, BJ and Kim, S and Chun, YS},
title = {Time-averaged simulated microgravity ameliorates tau-induced deficit in Drosophila melanogaster.},
journal = {NPJ microgravity},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41526-026-00626-9},
pmid = {42386756},
issn = {2373-8065},
support = {2021R1I1A1A01044744//Ministry of Education/ ; RS-2024-00460066//Ministry of Science and ICT, South Korea/ ; RS-2024-00458826//Ministry of Science and ICT, South Korea/ ; RS-2024-00344706//Ministry of Science and ICT, South Korea/ ; },
abstract = {Space exploration presents environmental challenges, including microgravity, high-energy radiation, and extreme temperature changes. Accelerated aging in space provides a unique opportunity to study age-related neurodegenerative diseases. Tauopathies, such as Alzheimer's disease, are characterized by neurofibrillary tangles of hyperphosphorylated tau protein in the brain. We studied how time-averaged simulated microgravity (taSMG), which replicates space conditions, affects tauR406W-induced neurotoxicity in transgenic flies. Applying taSMG at an early stage of neurodegeneration reduced severe locomotion impairment in tauR406W-expressing flies. This protective effect was sustained, specific to the tau mutation, and dependent on the timing, duration, and severity of tau expression. Transcriptomic analysis revealed that taSMG normalizes gene expression related to the extracellular environment, innate immune response, and olfactory function. These results underscore gravity's role in modulating tauopathy and suggest that microgravity may potentially offer new therapeutic insights for neurodegenerative diseases.},
}
@article {pmid42386783,
year = {2026},
author = {Grimaldi, S and Singh, K and García-Gomar, MG and Koley, S and Hannanu, FF and Stefani, A and Bilgic, B and Videnovic, A and Bianciardi, M},
title = {CSF turnover dysfunction: a hidden early biomarker in iRBD?.},
journal = {NPJ Parkinson's disease},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41531-026-01444-2},
pmid = {42386783},
issn = {2373-8057},
abstract = {Evidence in Alzheimer's disease and other dementias shows that changes in cerebrospinal fluid (CSF) turnover and perivascular spaces (PVS) volume are associated with disease progression through impairment of waste-clearance glymphatic pathways. Volume of CSF, PVS, and drainage structures such as venous sinus are mostly excluded in current MRI studies of premanifest synucleinopathy. Here, we used 7 Tesla MRI to investigate whether modifications in CSF, PVS, and venous sinus volumes occur in 18 prodromal synucleinopathy patients (namely isolated rapid-eye-movement sleep behavior disorder, iRBD) compared to 20 healthy young and 18 elderly controls. Our results demonstrated increased CSF and PVS volumes in iRBD without a matching increase in drainage venous structures, as observed in elderly controls. This suggests increased CSF and PVS fluid stasis, possibly due to impaired CSF filtration, a mechanism that could reduce glymphatic function and exacerbate the neurodegenerative process in iRBD.},
}
@article {pmid42386905,
year = {2026},
author = {Chun, H and Youn, W and Lim, H and Harada, R and Ko, HY and Yoon, J and Oh, SJ and Seemann, P and Pepe, JG and Shoichet, BK and Lee, HW and Furumoto, S and Okamura, N and Yun, M and Lee, CJ},
title = {In-depth multimodal validation of [18]F-THK5351 for imaging monoamine oxidase-B-mediated reactive astrogliosis in Alzheimer's and related neurodegenerative diseases.},
journal = {Experimental &amp; molecular medicine},
volume = {},
number = {},
pages = {},
pmid = {42386905},
issn = {2092-6413},
support = {RS-2025-16071448//National Research Foundation of Korea (NRF)/ ; RS-2022-00144475//National Research Foundation of Korea (NRF)/ ; RS-2025-00520546//National Research Foundation of Korea (NRF)/ ; RS-2022-00144475//National Research Foundation of Korea (NRF)/ ; RS-2024-00403076//Korea Basic Science Institute (KBSI)/ ; },
abstract = {[18]F-THK5351, initially developed as a positron-emission tomography (PET) tracer for tau pathology, was later shown to display high affinity for monoamine oxidase-B (MAO-B), raising uncertainty about the biological origin of its brain signals in neurodegenerative diseases. To resolve this ambiguity, we implemented a multi-scale validation framework integrating enzyme activity inhibition assays, molecular docking, biolayer interferometry, autoradiography, multiple transgenic and viral animal models, and human PET imaging. THK5351 selectively inhibited MAO-B while sparing MAO-A and exhibited reversible binding kinetics to recombinant MAO-B. Computational modelling localized THK5351 near the MAO-B substrate funnel, revealing moderate binding energy and weaker π-π stacking interactions compared with selective tau tracers. Autoradiographic analysis of human cortical tissue demonstrated that tracer binding was dominated by MAO-B-related signals, with a smaller contribution from tau aggregates, a difference insufficient to produce visually distinguishable patterns in clinical imaging. In APP/PS1 mice, [18]F-THK5351 uptake colocalized with regions of reactive astrogliosis and was abolished by MAO-B inhibition, whereas overexpression of P301L-hTau induced extensive tau deposition without affecting tracer retention. MAO-B knockout reduced both tracer binding and tau phosphorylation, and viral induction of astrogliosis elevated tracer uptake that was reversed by selective MAO-B blockade. In a patient with corticobasal syndrome, tracer signals decreased during selegiline treatment and reappeared after drug withdrawal, mirroring preclinical pharmacological responses. Collectively, these findings demonstrate that [18]F-THK5351 uptake primarily reflects MAO-B-mediated reactive astrogliosis rather than tau pathology, providing mechanistic insight into its signal origin and underscoring the value of cross-scale, multimodal validation in PET tracer development for neurodegenerative disease research.},
}
@article {pmid42386951,
year = {2026},
author = {Zhou, Y and Li, WL and Liu, ZQ and Ai, WQ and Kou, JX and Fan, HW and Han, ZT and Hu, YZ and Zhang, HH and Jia, JJ and Zeng, Y and Guo, ZY and Man, HY and Lu, YM and Liu, D and Zhu, LQ},
title = {Author Correction: Spinal cord Tau pathology induces tactile deficits and cognitive impairment in Alzheimer's disease via dysregulation of CCK neurons.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41593-026-02356-3},
pmid = {42386951},
issn = {1546-1726},
}
@article {pmid42387039,
year = {2026},
author = {Koshenov, Z and Postic, S and Schoiswohl, G and van Amsterdam, S and Hois-Zelinka, V and Oflaz, FE and Rost, R and Tiapko, O and Gottschalk, B and Hirtl, M and Bachkoenig, OG and Koshenova, A and Erdogan, YC and Sagintayev, A and Krnjic, A and Pfabe, JU and Sarikas, S and Hochreiter, B and Gindlhuber, J and Schittmayer, M and Tadic, J and Ehall, B and Madeo, F and Madl, T and Malli, R and Birner-Gruenberger, R and Pieber, T and Eisenberg, T and Slak Rupnik, M and Graier, WF},
title = {Presenilin-1 controls glycolysis and identity of pancreatic beta cells.},
journal = {Communications biology},
volume = {},
number = {},
pages = {},
doi = {10.1038/s42003-026-10581-6},
pmid = {42387039},
issn = {2399-3642},
support = {10.55776/W1226//Austrian Science Fund (Fonds zur F&#xf6;rderung der Wissenschaftlichen Forschung)/ ; },
abstract = {Presenilin-1 (PS1) is an endoplasmic reticulum protein, most known for its role in pathogenesis of familial Alzheimer's Disease (AD). PS1 has been attributed roles in intracellular calcium homeostasis in the brain, as well as in the pancreatic beta cells, where it has been shown to be fundamental for the initial phase of glucose-induced insulin secretion. To gain mechanistic insight into beta cell autonomous function of PS1, we have examined various beta cell models and found that PS1 controls glycolytic flux of pancreatic beta cells by regulating sub-mitochondrial Ca[2+] homeostasis. Transient knock down of PS1 yielded a glycolytic bottleneck at the step catalyzed by glyceraldehyde-3-phosphate dehydrogenase, resulting in defective glucose responsiveness. Moreover, we show that PS1 is needed for the preservation of beta cell identity, likely due to its role in glycolysis. Finally, we show that mouse islets from an in vivo model of AD mimic the defective glucose responsiveness seen in beta cells with transient PS1 knock down, while the identity loss and whole-body glucose homeostasis are not severely impacted, suggesting an adaptive response. Thus, the current work highlights beta cell autonomous role of PS1 and adds a layer of complexity in its impact on whole body metabolism.},
}
@article {pmid42387103,
year = {2026},
author = {Chen, Y and Cheng, L and Wang, Q and Liu, Q and Li, W and Wang, C and Lv, L and Yue, W},
title = {Shared genetic architecture of schizophrenia and Alzheimer's disease and related dementias implicates 16p11.2 and lifespan brain vulnerability.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42387103},
issn = {1476-5578},
support = {82330042//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82441005//National Natural Science Foundation of China (National Science Foundation of China)/ ; U22A20304//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Epidemiological and clinical observations linking schizophrenia (SCZ) to increased dementia risk, together with the occurrence of psychosis in Alzheimer's disease and related dementias (ADRD), suggest that shared genetic liabilities may contribute to their co-occurrence. Leveraging large-scale genome-wide association study summary statistics for SCZ (53,386 cases and 77,258 controls) and ADRD (111,326 cases and 677,663 controls), we systematically investigated their shared genetic architecture and potential biological mechanisms. We identified three significant local genetic correlations (P < 2.0 × 10[-5]) and cross-trait polygenic enrichment between SCZ and ADRD, with 39 genomic loci jointly associated at conjunctional false discovery rate (conjFDR) < 0.05. Fifteen high-confidence genes (CNIH4, CD302, PCGF3, TFR2, EPHX2, SNX32, EFEMP2, CTSW, ASPHD1, TAOK2, INO80E, DOC2A, MAPK3, KANSL1, and XPNPEP3) were consistently prioritized across positional, expression quantitative trait locus, and chromatin-interaction mapping. Tissue- and cell-type enrichment analyses highlighted cerebellar tissues and ependymal-cell-related signals, while pathway analyses implicated synaptic signaling, axonal growth, and presynaptic structural organization. At the locus level, colocalization and transcriptome-wide association analyses converged on 16p11.2, prioritizing INO80E, YPEL3, SLX1B, and TMEM219. Developmental trajectory modeling further revealed region- and stage-specific expression divergence of prioritized 16p11.2 genes, with prominent differences spanning childhood and adulthood. Brain-wide association analysis linked the 16p11.2 lead variant rs9932702 to cortical gray-white contrast (β = -0.062, P = 7.5 × 10[-15]), a neuroimaging phenotype related to gray-white boundary microstructure and myelination. Finally, bidirectional Mendelian randomization supported a modest directional association between genetic liability to SCZ and increased ADRD risk, but not the reverse direction. Collectively, these findings provide convergent genetic, regulatory, transcriptomic, developmental, and imaging evidence for partial shared liability between SCZ and ADRD, highlighting 16p11.2 and biological processes related to neurodevelopment, synaptic and axonal organization, myelination-related microstructure, and later-life brain vulnerability.},
}
@article {pmid42387181,
year = {2026},
author = {Hernáez, &#xc1; and Hernando-Redondo, J and Chillarón, JJ and Ros, E and Martínez-González, M&#xc1; and Corella, D and Salas-Salvadó, J and Estruch, R and Timiraos, J and Hernández, MH and Cueto-Galán, R and Fiol, M and Lapetra, J and Majem, LS and Fanlo-Maresma, M and Pérez-Vega, KA and Sala-Vila, A and Toledo, E and Asensio, EM and Paz-Graniel, I and Castañer, O},
title = {Adipokines and satiety hormones and incidence of Alzheimer's disease and dementia in older adults: a nested case-control study.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42387181},
issn = {2509-2723},
support = {PI17/00214//Instituto de Salud Carlos III/ ; PI20/00012//Instituto de Salud Carlos III/ ; CP21/00097//Instituto de Salud Carlos III/ ; CB06/03//Instituto de Salud Carlos III/ ; CB06/03/0028//Instituto de Salud Carlos III/ ; CB16/11/00229//Instituto de Salud Carlos III/ ; CB06/02/0029//Instituto de Salud Carlos III/ ; 101201060//HORIZON EUROPE Marie Sklodowska-Curie Actions/ ; 2021 SGR 00144//Ag&#xe8;ncia de Gesti&#xf3; d'Ajuts Universitaris i de Recerca/ ; ICREA Academia//Ag&#xe8;ncia de Gesti&#xf3; d'Ajuts Universitaris i de Recerca/ ; PROMETEO-17/2017//Generalitat Valenciana/ ; },
abstract = {Obesity is known to have an intricate relationship with the development of Alzheimer's disease and dementia (mid-life obesity increases risk, whereas late-life adiposity may also have an effect). In this context, adipokines and satiety signals are suggested to play a role in late life, but their association with the incidence of these outcomes remains unclear. Our study aimed to assess whether five selected plasma adipokines and satiety hormones (leptin, ghrelin, resistin, adipsin, and fibroblast growth factor-21) were associated with incident Alzheimer's disease and dementia in older adults at high cardiovascular risk in a nested case-control study within the PREDIMED trial (90 dementia cases [73 of which were Alzheimer's disease], 156 controls). Participants were at high cardiovascular disease risk but free from dementia at baseline. Associations with biomarkers were assessed using multivariable conditional logistic regression. Higher resistin levels were associated with higher incidence of Alzheimer's disease in the multivariable-adjusted model (per one SD increase: OR 1.56, 95% CI 1.02 to 2.38); additional adjustment for body mass index slightly attenuated the association (OR 1.52, 95% CI 0.99 to 2.34). Our findings should be replicated in larger prospective studies but suggest that, despite the complex association between anthropometric measures and the incidence of dementia, high levels of resistin were tentatively associated with greater odds of incident Alzheimer's disease in older adults at high cardiovascular risk.},
}
@article {pmid42387213,
year = {2026},
author = {Phillips, B and Sanford, J and Janve, VA and Liu, M and Johnson, M and Gong, K and Bergmann, K and Lowery, J and Flynn, A and Brock, W and Montejo, BS and Sykora, N and Budde, J and Mellios, N and Papageorgiou, G and Sperling, RA and Buckley, RF and Seto, M and Morris, JC and Perlmutter, JS and Kotzbauer, PT and Perrin, RJ and Hohman, TJ and Ibanez, L and Cruchaga, C},
title = {Blood-based circular RNAs for early diagnosis of Alzheimer's disease.},
journal = {Nature medicine},
volume = {},
number = {},
pages = {},
pmid = {42387213},
issn = {1546-170X},
support = {R01AG044546//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
abstract = {Detection of Alzheimer's disease (AD) before the development of clinical symptoms is critical for enabling the use of new treatments. Circular RNAs (circRNAs) are highly stable non-coding RNAs enriched in the brain that can cross the blood-brain barrier. Here, analyzing blood data from 1,221 individuals with AD and healthy individuals, we identified 34 circRNAs associated with AD status. A predictive model including these 34 circRNAs was comparable to plasma phosphorylated Tau-217 (pTau217) in classifying AD based on biomarker-confirmed (amyloid-β and Tau) status and replicated in independent samples from the Knight-Alzheimer Disease Research Center (n = 551: 76 AD, 475 cognitively unimpaired) and preclinical A4 (n = 1,767) cohorts. Classification of biomarker-confirmed status by blood circRNAs (area under the curve (AUC) = 0.945) had a higher predictive ability than plasma pTau217 (AUC = 0.877) and was further improved in the integrated model (circRNA+pTau217 AUC = 0.977). This model showed high AD specificity with low predictive power for Parkinson's disease, frontotemporal dementia, and other neurodegenerative diseases. In the Knight-Alzheimer Disease Research Center discovery cohort, these circRNAs (hazard ratio = 2.92) outperformed pTau217 (hazard ratio = 1.81) and amyloid-positron emission tomography when predicting progression to symptomatic AD. Although prospective validation in larger cohorts is needed, these results propose blood circRNAs as potential biomarkers for AD diagnosis and disease progression.},
}
@article {pmid42387273,
year = {2026},
author = {Bangerter, LR and Kim, K and Liu, Y and Lapid, MI and Radford, JG and Griffin, JM},
title = {Caregiver Reports of Lucid Episodes in Alzheimer's Dementia and Lewy Body Dementias.},
journal = {Journal of geriatric psychiatry and neurology},
volume = {},
number = {},
pages = {8919887261464594},
doi = {10.1177/08919887261464594},
pmid = {42387273},
issn = {1552-5708},
abstract = {Purpose of ResearchLucidity is the transient recovery of abilities and communication that were seemingly lost among people living with dementia (PLWD). This study describes lucid episodes reported by Alzheimer's dementia (AD) and Lewy Body Dementias (LBD) caregivers. We analyzed survey data from 212 current AD (n = 191) and LBD caregivers who reported the frequency, duration, and characteristics of 653 lucid episodes witnessed in the past month.Major FindingsMost AD caregivers (67%) and LBD caregivers (81%) witnessed a lucid episode within the past month. LBD caregivers reported lucid episodes with greater changes in awareness and communication, compared to AD caregivers. LBD caregivers reported longer lucid episodes and that the PLWD knew about their change in lucidity, compared to AD caregivers.ConclusionsFindings suggest that differences in lucid episode intensity, timing, and meta-awareness between AD and LBD are possible and may inform care strategies for PLWD.},
}
@article {pmid42387430,
year = {2026},
author = {Xu, X and Li, J and Pan, H and Zhao, B and Wang, D},
title = {Insulin resistance and the risk of dementia: a systematic review and meta-analysis of prospective cohort studies.},
journal = {BMC neurology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12883-026-05079-x},
pmid = {42387430},
issn = {1471-2377},
abstract = {BACKGROUND: Mechanistic and cross-sectional studies have indicated a correlation between insulin resistance and dementia; however, further evidence from prospective studies is needed to elucidate the relationship between insulin resistance and the risk of developing dementia.<br><br>METHODS: A systematic review and meta-analysis were conducted. Searches were performed in PubMed, EMBASE, and the Cochrane Library for relevant articles published up to December 20th, 2025. Cohort studies investigating the risk of dementia onset associated with insulin resistance were included.<br><br>RESULTS: A total of ten studies were included in the meta-analysis. Insulin resistance was associated with an increased risk of all-cause dementia (HR&#x2009;=&#x2009;1.11, 95% CI 1.03-1.21, 9 studies included) and Alzheimer's disease (HR&#x2009;=&#x2009;1.23, 95% CI 1.01-1.50, 7 studies included). A similar association was observed between insulin resistance and the risk of vascular dementia (HR&#x2009;=&#x2009;1.04, 95% CI 1.01-1.07, 4 studies included).<br><br>CONCLUSION: The available evidence suggested that insulin resistance might be associated with an increased risk of all-cause dementia, Alzheimer's disease, and vascular dementia. Further well-designed prospective studies are warranted to clarify the causal relationship between insulin resistance and dementia.<br><br>TRIAL REGISTRATION: The study was registered with PROSPERO under the registration number CRD42024550842 on June 5th, 2024.},
}
@article {pmid42387631,
year = {2026},
author = {Murphy, EK and Hatch, K and Wise, SY and Fatanmi, OO and Petrus, SA and Bhomia, M and Lecca, D and Knollmann-Ritschel, BEC and Perl, DP and Singh, VK and Iacono, D},
title = {γ-radiation reduces phosphorylated-tau in rhesus macaque brains: potential implications for Alzheimer's disease and other tauopathies.},
journal = {Alzheimer's research &amp; therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02128-y},
pmid = {42387631},
issn = {1758-9193},
support = {PAT-74-10982//Uniformed Services University of the Health Sciences/ ; DM178016//Joint Program Committee-7/Radiation Health Effects Research Program/ ; p51 RR013986/RR/NCRR NIH HHS/United States ; P51 OD011133/CD/ODCDC CDC HHS/United States ; },
abstract = {BACKGROUND: Studies on the effects of γ-radiation on nonhuman primate (NHP) brains are limited, despite the critical need to understand the impact of radiation exposure on the brain from various sources like radiotherapy equipment, space travel, and potential nuclear events.<br><br>METHODS: We investigated molecular and neuropathological changes in rhesus macaque brains after a single 5.8&#xa0;Gy total-body &#x3b3;-radiation exposure. We analyzed samples dissected from frontal cortex (FCtx), hippocampus (Hippo), and cerebellum (CRB) of irradiated (RAD) vs. unirradiated/control (CTRL) animals. Western blotting and digital PCR (dPCR) analyses were used to measure different phosphorylated-Tau (pTau) forms and neurodegeneration markers (i.e., amyloid protein precursor [APP], neurofilament-light chain [NFL], glial fibrillary acidic protein [GFAP], ionized calcium-binding adapter molecule 1 [IBA1/AIF1], and myelin basic protein [MBP]).<br><br>RESULTS: We detected lower levels of different forms of soluble pTau species (pTau181, and pTau217, among others) in RAD vs. CTRL animals across all three examined brain regions. While APP and GFAP levels were unchanged in the FCtx, increased IBA1 and NFL levels were detected alongside decreased MBP levels. Moreover, dPCR data identified decreased expression of GFAP and MBP in the FCtx. Importantly, the molecular changes observed were not accompanied by overt signs of neurodegeneration or cellular abnormalities upon neuropathological assessment.<br><br>CONCLUSIONS: These findings in irradiated NHPs' brains are novel and indicate that a single total-body &#x3b3;-radiation exposure significantly alters soluble pTau levels after a few weeks from irradiation without causing obvious neurohistological damage. These results open intriguing new possibilities of exploring &#x3b3;-radiation-based strategies to modulate the progression of tauopathies, including Alzheimer's disease.},
}
@article {pmid42387651,
year = {2026},
author = {Nxele, Z and Ndlovu, S and Ngubane, C and Hewer, R and Delport, A},
title = {Tagged and untagged amyloid precursor protein E2 domain have comparable thermal stability and metal-ion binding propensity.},
journal = {BMC research notes},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13104-026-07938-9},
pmid = {42387651},
issn = {1756-0500},
abstract = {OBJECTIVE: The amyloid precursor protein, central to the pathology of several disease including Alzheimer's disease, cancer and obesity, represents a therapeutic target. Being able to screen amyloid precursor protein, and its domains, in rapid high-throughput assays could advance drug discovery efforts. The purpose of this study was to determine if removal of a C-terminal tag from the amyloid precursor protein E2 domain was necessary for ligand screening using differential scanning fluorometry. To this end, we assessed both the thermal stability and metal-ion binding propensity in both the tagged and untagged protein.<br><br>RESULTS: The C-terminal myc-6xHis-tag does not impact the amyloid precursor protein E2 domain thermal stability with comparable melting temperatures of 59.4&#xa0;&#xb0;C and 59.1&#xa0;&#xb0;C in sodium phosphate buffer, for tagged and untagged protein, respectively. Additionally, the tag had no influence on the ability of the metal-ions, Zn[2+] and Cu[2+], to shift the thermal stability of the E2 domain indicating that metal-ion binding is not influenced by the tag. We therefore suggest that it is not necessary to remove the C-terminal tag from the E2 domain for ligand screening using differential scanning fluorometry.},
}
@article {pmid42387856,
year = {2026},
author = {Miles, N and McNamee, B and Zadikoff, C and Boiser, J and Shebley, M and Boinpally, R},
title = {Comparison of ABBV-552 Safety and Pharmacokinetics in Healthy Asian and Western Adults.},
journal = {Clinical pharmacology in drug development},
volume = {15},
number = {7},
pages = {e70072},
doi = {10.1002/cpdd.70072},
pmid = {42387856},
issn = {2160-7648},
support = {//AbbVie/ ; },
mesh = {Adult ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; Administration, Oral ; *Alzheimer Disease/drug therapy/physiopathology ; Asian People ; Dose-Response Relationship, Drug ; Healthy Volunteers ; *Membrane Glycoproteins/agonists ; *Nerve Tissue Proteins/agonists ; White People ; },
abstract = {ABBV-552, a positive modulator of synaptic vesicle glycoprotein 2A (SV2A), was under investigation as a treatment for cognitive impairment related to Alzheimer's disease. This Phase 1, multicenter, open-label, parallel cohort study (NCT05686980) was conducted to examine the pharmacokinetics (PK), safety, and tolerability of ABBV-552 in healthy adult Japanese and Han Chinese participants and to compare PK and safety findings with healthy adult Western participants from previous studies. Japanese participants in Cohort 1 (N = 10) received three ascending single oral doses (5, 15, and 40 mg) of ABBV-552 with a washout of 7 days between doses. Han Chinese participants in Cohort 2 (N = 7) received a single oral dose of 40 mg ABBV-552. After a single oral dose of 40 mg ABBV-552, PK was comparable between both cohorts. Additionally, the range of individual ABBV-552 concentrations and mean 24-h profiles were comparable with historical data in healthy adult Western participants. In this small study population, single doses of ABBV-552 were well tolerated at all tested doses. Common adverse events reported were dizziness (39%), somnolence (11%), and fatigue (11%). No unique safety signals following single dose ABBV-552 administration were observed in the Japanese or Han Chinese populations examined compared with the previously examined Western population.},
}
@article {pmid42388101,
year = {2026},
author = {Lai, HY and Meng, LC and Ye, YJ and Chen, HM and Chen, LK and Hsiao, FY},
title = {Comparative risk of ventricular arrhythmia and sudden cardiac death among acetylcholinesterase inhibitors in dementia: A population-based cohort study.},
journal = {British journal of clinical pharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1002/bcp.70656},
pmid = {42388101},
issn = {1365-2125},
support = {MOST 110-2634-F-010-001//Taiwan Ministry of Science and Technology/ ; NSTC111-2622-8-A49-019-IE//Taiwan National Science and Technology Council/ ; NSTC112-2923-B-A49-002-MY2//Taiwan National Science and Technology Council/ ; //Interdisciplinary Research Center for Healthy Longevity of National Yang Ming Chiao Tung University/ ; },
abstract = {BACKGROUND: Previous studies have suggested that acetylcholinesterase inhibitors (AChEIs) may be associated with an increased risk of ventricular arrhythmia or sudden cardiac death, potentially related to QTc prolongation. However, evidence comparing the real-world risk of severe cardiac conduction outcomes among the three AChEIs-donepezil, galantamine and rivastigmine-remains limited.<br><br>OBJECTIVE: This study aimed to compare the risk of ventricular arrhythmia or sudden cardiac death associated with the use of different AChEIs in older adults with dementia.<br><br>METHODS: We conducted a retrospective cohort study using Taiwan's National Health Insurance database. Older adults diagnosed with dementia who initiated AChEI therapy between 2010 and 2019 were identified and categorized according to the AChEI prescribed. Participants were followed until the end of 2020. Stabilized inverse probability of treatment weighting was applied to balance baseline characteristics, with rivastigmine serving as the reference group. Cox proportional hazards models were used to estimate hazard ratios for ventricular arrhythmia or sudden cardiac death.<br><br>RESULTS: A total of 66&#x2009;589 older adults with dementia initiating AChEI therapy were included. Donepezil was the most frequently prescribed AChEI (64.8%), followed by rivastigmine (33.0%) and galantamine (2.3%). Compared with rivastigmine, IPTW-weighted analyses showed no significant association between donepezil use (HR 0.95, 95% CI, 0.82-1.09) or galantamine use (HR 1.40, 95% CI, 0.90-2.18) and the risk of ventricular arrhythmia or sudden cardiac death.<br><br>CONCLUSIONS: The risk of ventricular arrhythmia or sudden cardiac death was comparable among donepezil, galantamine and rivastigmine in older patients with dementia.},
}
@article {pmid42388121,
year = {2026},
author = {Schwartz, NU and Dietz, CD and Lin, Z and Tammewar, G and Bui, N and La Joie, R and Wang, Y and Sreekrishnan, A and Suhami, D and VandeVrede, L and Ljubenkov, PA and Rojas, JC},
title = {Reduced diffusion associated with amyloid-related imaging abnormalities in three patients treated with donanemab.},
journal = {Neurocase},
volume = {},
number = {},
pages = {1-6},
doi = {10.1080/13554794.2026.2695021},
pmid = {42388121},
issn = {1465-3656},
abstract = {Amyloid-related imaging abnormalities (ARIA) with edema (ARIA-E) and with hemorrhage (ARIA-H) are common adverse effects of amyloid-targeting therapies (ATT), characterized on MRI by T2/fluid-attenuated inversion recovery (FLAIR) hyperintensities and susceptibility-sensitive hypointensities, respectively. ARIA resulting from ATT is not commonly associated with reduced diffusion or acute infarcts. In this case series, we describe three patients with mild cognitive impairment due to Alzheimer's disease (AD) - a 75-year-old woman, a 74-year-old woman, and an 80-year-old man (APOE ε3/ε3, ε4/ε4, and ε3/ε4, respectively) - who developed ARIA accompanied by transient foci of reduced diffusion within the first six months of donanemab treatment, without permanent T2/FLAIR correlates. The diffusion-restricting lesions may represent ischemic infarcts, although the lack of permanent T2/FLAIR correlate is atypical. Clinicians should be aware that reduced diffusion may accompany ARIA. The course can be highly dynamic, and both the clinical presentation and management implications may vary.},
}
@article {pmid42388234,
year = {2026},
author = {Varmazyar, T and Heidariyeh, N and Ababzadeh, S},
title = {Effects of metformin and exercise on Alzheimer's model induced by D-galactose in the rats: A behavioral, histological and BDNF gene study.},
journal = {Biochemistry and biophysics reports},
volume = {47},
number = {},
pages = {102668},
pmid = {42388234},
issn = {2405-5808},
abstract = {The objective of the current research is to investigate the cognitive performance of male Alzheimer's disease rats in the context of the combined effects of exercise and metformin. The rats were divided into eight different groups. The Morris water maze (MWM) and the open field test (OFT) were employed to assess the cognitive functionality and motor activity of rats, respectively. The hippocampus of rats was subjected to histological evaluation, and expression of brain-derived neurotrophic factor (BDNF) was measured using the real-time polymerase chain reaction (RT-PCR) method. On concluding day of training, the d-gal-met100-exe group (D-galactose plus optimized 100mg/kg of metformin along with exercise) exhibited a diminished duration in the target quadrant (P < 0.0001) and covered a shorter distance to find the platform (P = 0.0004). On the day of the test, the distance covered in the target quadrant decreased in the d-gal group that received 120mg/kg of D-galactose (P = 0.0186) and significantly increased in the d-gal-met100-exe group compared to the d-gal group (P = 0.0002). The OFT indicated no substantial variations in distance or overall speed across the groups, suggesting that metformin did not affect motor activity. Based on the histology findings, in the d-gal-met100-exe group, fewer pyramidal cells led to less neuronal damage (P < 0.0001). In contrast, the BDNF gene in the hippocampus of the aforementioned group rose considerably as compared to the d-gal group (P = 0.0002). In general, the combined administration of metformin and exercise had a greater effect on enhancing memory and learning in Alzheimer's rats.},
}
@article {pmid42388323,
year = {2026},
author = {Almeida, S and Song, Y and Marques, F and Sharma, N},
title = {Editorial: Emerging mechanisms in neurodegenerative disease pathogenesis: vertebrate and invertebrate model organisms.},
journal = {Frontiers in molecular neuroscience},
volume = {19},
number = {},
pages = {1891031},
doi = {10.3389/fnmol.2026.1891031},
pmid = {42388323},
issn = {1662-5099},
}
@article {pmid42388392,
year = {2026},
author = {Zhao, J and Fan, Y and Yang, K and Gao, H},
title = {Fecal microbiota transplantation: from empirical remedy to precision medicine.},
journal = {Frontiers in microbiomes},
volume = {5},
number = {},
pages = {1863308},
pmid = {42388392},
issn = {2813-4338},
abstract = {Fecal microbiota transplantation (FMT) has evolved from an empirical remedy for recurrent Clostridioides difficile infection (rCDI) into a foundational platform for precision microbiome-based therapeutics. This comprehensive review details FMT's journey, analyzing its multifaceted mechanisms of action-including restoration of colonization resistance, metabolic reprogramming via short-chain fatty acids and bile acids, and profound immunomodulation-which extend far beyond simple microbial replacement. We critically evaluate its established, high efficacy in rCDI and its expanding, albeit more variable, applications across a wide spectrum of gastrointestinal diseases (such as inflammatory bowel disease, irritable bowel syndrome, and constipation), neurological disorders (including Parkinson's and Alzheimer's disease), metabolic conditions, autoimmune diseases, and oncology (particularly in modulating response to immune checkpoint inhibitors and treating graft-versus-host disease). The review further discusses the critical challenges of donor-recipient variability, safety, and the lack of standardized protocols that have driven the field's technical evolution. This progression encompasses refined processing methods like washed microbiota transplantation (WMT), diverse delivery routes including oral capsules, and the exploration of non-bacterial components like bacteriophages through fecal filtrate transplantation (FVT). Ultimately, we highlight the field's trajectory toward next-generation, defined live biotherapeutic products (LBPs) and engineered microbial consortia, aiming to transition from the complex "black box" of whole stool to safer, more consistent, and rationally designed precision therapies that target the specific dysbiotic networks underlying diverse human diseases.},
}
@article {pmid42388533,
year = {2026},
author = {Di Donna, MG and Bagnato, MR and Bonomi, CG and Motta, C and Centonze, D and Martorana, A and Diomedi, M},
title = {Cerebrovascular reactivity and plasma p-tau181 in Alzheimer's disease: Insights into APOE-related vascular phenotypes.},
journal = {Alzheimer's &amp; dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70250},
pmid = {42388533},
issn = {2352-8737},
abstract = {INTRODUCTION: Vascular dysfunction is increasingly recognized as a key contributor to Alzheimer's disease (AD). This study explored cerebrovascular reactivity (CVR), measured by the breath-holding index (BHI) via Transcranial Doppler (TCD), in relation to plasma AD biomarkers, metabolic dysfunction, cardiovascular burden, and apolipoprotein E (APOE) genotype.<br><br>METHODS: We enrolled 64 patients with cerebrospinal fluid (CSF)-confirmed AD (30 APOE &#x3b5;3, 34 APOE &#x3b5;4) and 28 age-matched healthy controls in a cross-sectional blinded study. All participants underwent TCD to assess middle cerebral artery flow velocity and BHI. AD patients were further evaluated for insulin resistance (TyG index), magnetic resonance imaging markers of small vessel disease (SVD), and plasma biomarkers (phosphorylated tau 181 [p-tau181], amyloid beta [A&#x3b2;]42/A&#x3b2;40 ratio - AmyR). Multivariate regressions examined associations between BHI and AD-related parameters, stratified by APOE genotype.<br><br>RESULTS: BHI was significantly reduced in both AD groups compared to controls (p&#xa0;<&#xa0;0.001), with no difference between &#x3b5;3 and &#x3b5;4 carriers. In &#x3b5;3 patients, lower BHI was independently associated with higher plasma p-tau181. In the MRI subgroup analysis, &#x3b5;3 patients showed a negative correlation between BHI and both TyG and mCSVD while showing a positive correlation with AmyR. None of these associations were observed in &#x3b5;4 carriers.<br><br>DISCUSSION: Our findings indicate that CVR impairment is present across AD genotypes but more strongly linked to AD pathology and vascular-metabolic dysfunction in APOE &#x3b5;3 carriers. CVR may represent a non-invasive biomarker of early vascular contributions to cognitive decline in AD.},
}
@article {pmid42388534,
year = {2026},
author = {Alshami, J and Wu, G and Garduño, BM and Silva, AC and Rizzo, SJS and Cogram, P and Xu, X},
title = {Meeting report for the Second International Conference on Unconventional Animal Models of Alzheimer's Disease and Aging (UAMAA 2026).},
journal = {Alzheimer's &amp; dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70281},
pmid = {42388534},
issn = {2352-8737},
abstract = {The Second International Conference on Unconventional Animal Models of Alzheimer's Disease and Aging (UAMAA 2026) was held February 9 through 11, 2026, in Irvine, California. Building upon the inaugural meeting in Santiago, Chile (2023), this conference expanded an international effort to develop, characterize, and rigorously evaluate non-traditional animal models with enhanced translational relevance for Alzheimer's disease (AD) and aging research. The meeting convened leading investigators across genomics, systems neuroscience, comparative biology, and pathology to discuss naturally occurring and engineered models including degu (Octodon degus), dog (Canis lupus familiaris), marmoset (Callithrix jacchus), rhesus macaque (Macaca mulatta), naked mole-rat (Heterocephalus glaber), and emerging large animal species including elephants and whales. A central theme was the need for cross-species integration of multimodal and multi-scale approaches to interrogate cellular vulnerability, gene regulatory programs, and age-associated neuropathology and circuit alterations across species. UAMAA 2026 emphasized cross-species comparison, human brain atlas integration, and translational alignment with National Institutes of Health priorities. The conference highlighted growing momentum toward a diversified model ecosystem aimed at accelerating mechanistic insight and therapeutic discovery in AD and aging research. A special journal issue associated with the conference has been announced to extend these themes into peer-reviewed scientific discourse.},
}
@article {pmid42388673,
year = {2026},
author = {Le Bihan, D},
title = {Synaptic micromechanics and brain softening as a mechanobiological hypothesis for Alzheimer's disease.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1858655},
pmid = {42388673},
issn = {1662-4548},
abstract = {Alzheimer's disease (AD) is usually framed as a proteinopathy and network disorder, but this view may be incomplete. We propose a mechanobiological hypothesis in which synaptic micromechanics, regional brain softening, vascular pulsatility, and glymphatic transport are parts of a coupled fluid-solid system whose failure contributes to AD progression. In this framework, early synaptic and glial mechanical fragility reduces the capacity of vulnerable circuits to maintain stable structure, efficient signaling, and waste clearance, while age-related tissue softening and impaired perivascular transport amplify amyloid and tau accumulation, network dysfunction, and cognitive decline. This framework integrates converging evidence from dendritic spine to glymphatic system biology, concordant results obtained with diffusion MRI and magnetic resonance elastography, and treats altered tissue mechanics not merely as a correlate of degeneration but as a potentially active multicomponent of disease expression. It further predicts that biomechanical alterations should be detectable before gross atrophy, should covary with glymphatic impairment, and may help explain why molecular pathology and clinical symptoms are often only partly aligned. By positioning brain mechanics as an interface between protein aggregation, synaptic dysfunction, and impaired clearance, this framework identifies testable imaging biomarkers and suggests potential early-stage intervention strategies aimed at preserving tissue resilience as well as reducing pathological protein burden.},
}
@article {pmid42388698,
year = {2026},
author = {Jannati, A and Toro-Serey, C and Ciesla, M and Chen, E and Bates, D and Showalter, J and Tobyne, S and Pascual-Leone, A},
title = {Initial specialist validation of clinical decision support recommendations from a machine learning-enabled digital cognitive assessment.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1806000},
pmid = {42388698},
issn = {1664-2295},
abstract = {INTRODUCTION: Disease-modifying therapies for Alzheimer's disease (AD) heighten demand for scalable tools enabling primary care providers (PCPs) to detect cognitive impairment and triage patients for appropriate evaluation. The brief tablet-based Linus Health Core Cognitive Evaluation (CCE) integrates the Digital Clock and Recall (DCR) and Life and Health Questionnaire (LHQ) to generate clinical decision support (CDS) and decision-tree pathways.<br><br>METHODS: We conducted a retrospective specialist content-validity study (June 15-27, 2023) using a modified RAND/UCLA Appropriateness Method. Five board-certified cognitive/behavioral neurologists independently rated CDS recommendations and nine predefined pathway parts for patients aged &#x2265;55 across 21 de-identified reports. Items scored 1-9 were summarized as pooled medians with interquartile ranges; medians &#x2265;7 indicated appropriateness. Agreement among experts was quantified using ICC [2,k] and ICC [2,1].<br><br>RESULTS: All cognitive-impairment recommendations met the threshold. All seven borderline/impaired-DCR pathways were appropriate (median 7-8). Two pathways fell below threshold: cognitively unimpaired individuals with Green DCR scores (median 6) and a preliminary anti-amyloid treatment referral pathway (median 5). Agreement was moderate per patient [median ICC(2,k)&#x202f;=&#x202f;0.61] and lower for individual diagnostic-concern recommendations [median ICC(2,k)&#x202f;=&#x202f;0.25], reflecting specialist heterogeneity on borderline non-cognitive items and ceiling effects on high-rated items.<br><br>CONCLUSION: Cognitive neurologists judged CCE-derived CDS appropriate for PCP workup and referral decisions in older adults with suspected cognitive impairment. Findings support initial content validity of assessment-linked CDS, identify refinement priorities in low-risk and emerging-therapy pathways, and motivate planned PCP appropriateness and prospective implementation studies.},
}
@article {pmid42388814,
year = {2026},
author = {Shyong, J and Wang, J and Tran Huynh, QD and Fayzullina, M and Yuan, B and Lee, CK and Minehan, T and Seidler, PM and Wang, CCC},
title = {Correction: Discovery of penicillic acid as a chemical probe against tau aggregation in Alzheimer's disease.},
journal = {Chemical science},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6sc90134d},
pmid = {42388814},
issn = {2041-6520},
abstract = {[This corrects the article DOI: 10.1039/D4SC05469E.].},
}
@article {pmid42388895,
year = {2026},
author = {Fischer, DL and Spina, S and Miller, BL and Seeley, WW and Grinberg, LT},
title = {FTLD-TDP versus LATE-NC: Experience of a Brain Bank specializing in FTLD-TDP.},
journal = {Alzheimer's &amp; dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70411},
pmid = {42388895},
issn = {2352-8729},
abstract = {INTRODUCTION: Similarities between frontotemporal lobar degeneration with transactive response DNA-binding protein of 43 kDa (TDP-43) (FTLD-TDP) and limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) raise questions about whether they represent distinct entities or a single disease spectrum. The literature mostly examined series with disproportionate numbers of LATE-NC over FTLD-TDP.<br><br>METHODS: Leveraging a clinicopathological collection of FTLD-TDP (N&#xa0;=&#xa0;148) from the University of California, San Francisco, we compared demographic, clinical, genetic, and neuropathological features of FTLD-TDP, particularly FTLD-TDP type A (N&#xa0;=&#xa0;39), and LATE-NC (N&#xa0;=&#xa0;42).<br><br>RESULTS: FTLD-TDP type A cases were younger at onset and death, had shorter disease duration, and frequent genetic causes (GRN, C9ORF72) compared to LATE-NC, which were mostly sporadic and older. Blinded evaluation of middle frontal gyrus (MFG) TDP-43 immunostaining alone proved insufficient to reliably differentiate FTLD-TDP type A from LATE-NC stage 3. However, factoring in all neuropathologic features, FTLD type A and LATE-NC could be differentiated with&#xa0;>95% confidence.<br><br>DISCUSSION: These overall findings support distinct diagnostic entities for FTLD-TDP and LATE-NC.},
}
@article {pmid42388896,
year = {2026},
author = {Pignataro, P and Dicarlo, M and Urso, D and Zecca, C and Colaianni, G and Dell'Abate, MT and Vilella, D and Borlizzi, F and Suriano, C and Oranger, A and Colucci, S and Grano, M and Logroscino, G},
title = {Elevated sclerostin levels in cerebrospinal fluid are associated with cognitive impairment in the Alzheimer's disease continuum.},
journal = {Alzheimer's &amp; dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70417},
pmid = {42388896},
issn = {2352-8729},
abstract = {INTRODUCTION: Bone-derived sclerostin impairs cognitive function in both patients with Alzheimer's disease (AD) and mouse models of AD. For the first time, we explored the correlation of sclerostin with neurocognitive domains in the AD continuum.<br><br>METHODS: Sclerostin levels were measured in the cerebrospinal fluid (CSF) of a cohort of individuals with biological evidence of AD pathology, including patients with AD dementia, mild cognitive impairment due to AD (MCI), and subjective memory complaints (SMC). Correlations were examined between sclerostin and domain-specific cognitive scores.<br><br>RESULTS: CSF sclerostin correlated with overall cognitive function, as well as with all cognitive domains impaired in AD. Of note, MCI patients with high CSF sclerostin levels displayed a worse overall and domain-specific neurocognitive performance.<br><br>DISCUSSION: Our results evidenced the negative impact of sclerostin on all the cognitive domains predominantly in prodromal AD, suggesting its potential role as a biomarker of cognitive decline in the early stages of the disease.},
}
@article {pmid42388902,
year = {2026},
author = {Hao, Y and Yang, H and Zhong, J and Zhang, J and He, X and Dong, X},
title = {Examining of the mechanism by which Yin Huang Ge compound alleviates cognitive dysfunction in Alzheimer's disease mice through modulation of Aβ degrading enzymes and neurotrophic factors.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1821074},
pmid = {42388902},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's disease (AD) poses a significant threat to human health, and with the number of patients increasing annually, developing effective prevention and treatment strategies has become an urgent priority. Early intervention is a viable strategy for treating AD, as biomarker changes associated with β-amyloid (Aβ) can emerge 20 or more years before cognitive impairment becomes apparent. Traditional Chinese medicine (TCM) offers a potential avenue for treatment at this early stage.<br><br>OBJECTIVE: This study investigated the potential therapeutic effects of the Yin Huang Ge compound on cognitive function in a mouse model of AD and evaluated its efficacy in mitigating A&#x3b2; accumulation, a key pathological feature of AD.<br><br>METHODS: APP/PS1 mice were randomly assigned to the following groups: Controls (C57BL/6&#x202f;J mice) group, the Model group, YHG group, and donepezil (DNP) group. The YHG group and the DNP group were administered their respective drugs through gastric gavage, whereas the normal group and the Model group were supplied with saline. Administration sustained for a period of 30 consecutive days. We assessed mouse learning, memory, and spatial cognition using the Morris water maze, novel object recognition, Y-maze spontaneous alternation, and novel arm tests. Western blotting quantified the protein levels of &#x3b2;-amyloid 1-42 (A&#x3b2;1-42), insulin-degrading enzyme (IDE), neprilysin (NEP), matrix metalloproteinase-2 (MMP-2), and matrix metalloproteinase-9 (MMP-9). ELISA measured IDE and NEP enzymatic activity, while immunohistochemistry evaluated the expression of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3).<br><br>RESULTS: In contrast to the Control group, mice in the Model group exhibited significant impairments in learning, memory, and spatial cognition. The protein expression levels of A&#x3b2;1-42, MMP-2, and MMP-9 were markedly elevated (p&#x202f;<&#x202f;0.01), whereas the expression of IDE and NEP was significantly reduced (p&#x202f;<&#x202f;0.05, p&#x202f;<&#x202f;0.01). ELISA analysis further revealed a substantial decrease in IDE and NEP activity (p&#x202f;<&#x202f;0.01). A concomitant reduction in the expression of NT-3 and BDNF was also observed (p&#x202f;<&#x202f;0.01). Compared to the Model group, mice treated with YHG or DNP exhibited significantly improved learning, memory, and spatial cognition. The protein expression of A&#x3b2;1-42, MMP-2, and MMP-9 was reduced (p&#x202f;<&#x202f;0.05, p&#x202f;<&#x202f;0.01), whereas the expression of IDE and NEP was elevated (p&#x202f;<&#x202f;0.05). ELISA results confirmed the increased activity of IDE and NEP (p&#x202f;<&#x202f;0.05). These assays also revealed a marked upregulation in the expression of NT-3 and BDNF (p&#x202f;<&#x202f;0.01).<br><br>CONCLUSION: The YHG compound reduces cerebral A&#x3b2; deposition via a bidirectional regulatory mechanism, upregulating IDE and NEP to promote clearance while downregulating MMP-2 and MMP-9 to mitigate associated damage. It also elevates the expression of the neurotrophic factors BDNF and NT-3, which enhances endogenous neuroprotection and ameliorates core Alzheimer's disease pathology. Consequently, this treatment markedly improves cognitive function in APP/PS1 mice.},
}
@article {pmid42389205,
year = {2026},
author = {Fender, M and Leeman, J and Womack, J and Ulmer, C and Toles, M},
title = {Appalachian Home- and Community- Based Services for People Affected by Dementia.},
journal = {Online journal of rural nursing and health care : the official journal of the Rural Nurse Organization},
volume = {26},
number = {1},
pages = {38-52},
pmid = {42389205},
issn = {1539-3399},
abstract = {PURPOSE: Home- and community-based services (HCBS) have the potential to address the health needs of the rapidly growing population of people with ADRD in Appalachia and their informal caregivers. Little is known about the nature of HCBS and potential barriers to their use in Appalachia. The purpose of this qualitative study was to describe ADRD service providers' perceptions of the barriers and facilitators to providing high-quality HCBS for people with ADRD and their caregivers in the historically underserved region of Appalachia.<br><br>SAMPLE: A qualitative descriptive study was conducted 13 HCBS settings in Tennessee, West Virginia, Virginia, and North Carolina. A standardized, semi-structured guide was used to conduct telephone-based interviews with 13 leaders of HCBS programs.<br><br>METHODS: Using qualitative content analysis, two investigators coded interview transcripts, and the full study team used the coded data to identify themes related to HCBS barriers to providing ADRD services and strategies HCBS leaders used to address service delivery challenges.<br><br>FINDINGS: Participants held leadership positions in governmental (n=8), non-profit (n=3), and private (n=2) HCBS programs that provided education, service referrals, respite vouchers, support groups, and other services for people with ADRD and their families. Participants described service, cultural, geographic, and funding barriers to community-based ADRD care and strategies to address barriers, including community immersion, mobile HCBS vans, transportation services, and service advocacy.<br><br>CONCLUSIONS: The findings describe barriers to HCBS in Appalachia extending earlier research with evidence to frame future larger-scaled studies focused on increasing the reach of community-based ADRD care. Future studies are needed to describe larger cohorts of people with ADRD, access to HCBS services, and the relationship between service access and outcomes, such as hospital admission, control of comorbid health conditions, and caregiver self-efficacy. Implementation studies are necessary to examine adaptations of proven ADRD care models for future intervention research.},
}
@article {pmid42389265,
year = {2026},
author = {Temelli Goceroglu, R and Hacimuftuoglu, A},
title = {Advances in the treatment of Alzheimer's disease.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1819165},
pmid = {42389265},
issn = {1663-9812},
abstract = {Alzheimer's Disease (AD) is a progressive neurodegenerative disease for which disease-modifying therapies remain limited. Despite extensive efforts targeting amyloid-β and tau, these approaches have not translated into clear clinical benefit, underscoring the need for a more integrated understanding of AD pathogenesis. This narrative review summarizes recent advances in the molecular mechanisms underlying AD and evaluates current and emerging therapeutic strategies. A literature search was conducted using PubMed, Google Scholar, Web of Science and Scopus, focusing on preclinical and clinical studies addressing AD pathophysiology and treatment development. Conclusion: We summarize key pathogenic pathways, including Aβ aggregation, tau hyperphosphorylation, neuroinflammation, synaptic dysfunction, and metabolic dysregulation, and discuss how these interconnected processes have informed drug development efforts. Particular attention is given to limitations of single-target approaches and the growing interest in multi-target and combination therapies. In conclusion, a better understanding of the pathological mechanisms underlying AD may contribute to the development of more effective pharmacological therapies and integrated therapeutic approaches targeting the multifactorial nature of the disease.},
}
@article {pmid42389420,
year = {2026},
author = {Filippi, M and Cecchetti, G and Ghirelli, A and Spinelli, EG and Rugarli, G and Pisano, S and Samanes Gajate, AM and Chiti, A and Agosta, F},
title = {From Target Engagement to Treatment Governance: The Evolving Role of Amyloid PET in Anti-Amyloid Therapy.},
journal = {The Lancet regional health. Europe},
volume = {67},
number = {},
pages = {101757},
pmid = {42389420},
issn = {2666-7762},
abstract = {The introduction of anti-amyloid monoclonal antibodies has shifted Alzheimer's disease care from diagnostic clarification alone to the problem of treatment governance. While lecanemab and donanemab have demonstrated amyloid reduction at the group level, routine clinical care raises a different question: how should treatment exposure be managed in individual patients within constrained healthcare systems? We suggest that amyloid positron emission tomography (PET) may support this task by providing a quantitative baseline reference for target engagement and by informing decisions on treatment continuation, switching, or discontinuation during follow-up. However, amyloid reduction on PET should not be equated with proven individual-level clinical benefit, and the potential role of longitudinal PET must be considered alongside unresolved questions regarding safety, treatment burden, feasibility, and health-system capacity. Drawing on real-world experience from a high-volume European memory clinic, we argue that amyloid PET may have an increasingly relevant role within structured anti-amyloid treatment pathways.},
}
@article {pmid42389429,
year = {2026},
author = {Qin, Q and Xia, X and Zhang, X and Yang, S and Zhao, G and Su, C and Tang, Y},
title = {Development of a serum-based microRNA panel for Alzheimer's disease diagnosis.},
journal = {Journal of translational internal medicine},
volume = {14},
number = {3},
pages = {456-469},
pmid = {42389429},
issn = {2450-131X},
abstract = {BACKGROUND AND OBJECTIVES: MicroRNAs (miRNAs) are emerging as promising blood-based biomarkers for Alzheimer's disease (AD) because of their stability and regulatory roles in disease-related pathways. This study aimed to develop a serum-based miRNA panel for AD diagnosis.<br><br>METHODS: Serum samples from 550 participants were categorized into discovery (85 AD, 65 healthy controls [HCs]), training (73 AD, 53 HCs), and validation (99 AD, 99 HCs, 36 vascular cognitive impairment [VCI], 40 dementia with Lewy bodies [DLB]) cohorts. Through small RNA sequencing and qPCR validation, we identified key miRNAs and constructed a diagnostic panel via machine learning.<br><br>RESULTS: The 7-miRNA panel achieved area under the curve (AUC) values of 0.970 and 0.928 in the training and validation cohorts, respectively. The panel effectively differentiated AD from VCI (AUC = 0.951) and DLB (AUC = 0.851). Diagnostic performance remained robust across subgroups defined by age, gender, disease severity, and comorbidities (AUC 0.758-0.988). The risk score derived from the 7-miRNA panel was significantly associated with cognitive impairment (Mini-Mental State Examination [MMSE] score, r = -0.72) and plasma amyloid pathology biomarkers (A&#x3b2;42/40 ratio, r = -0.25; p-tau217, r = 0.36).<br><br>CONCLUSIONS: A serum-based 7-miRNA panel, which offers a minimally invasive and accessible approach, has strong diagnostic potential for AD.},
}
@article {pmid42389671,
year = {2026},
author = {Krishnan, L and Gunasekaran, G and Dhore, T and Lauinger, A and Kolachalama, V and Pappu, S},
title = {Leveraging artificial intelligence for analysis of the gut microbiome for dementia diagnosis: a scoping review and discussion.},
journal = {Frontiers in dementia},
volume = {5},
number = {},
pages = {1865441},
pmid = {42389671},
issn = {2813-3919},
abstract = {BACKGROUND: Dementia, a multifactorial disease with progressive cognitive decline, has been linked to imbalances in the gut-brain axis. Emerging artificial intelligence tools have augmented the identification of several gastrointestinal biomarkers for differential dementia detection and severity, but current literature lacks a comprehensive review.<br><br>AIMS: This study aims to better quantify the applications of AI in the exploration of the gut microbiome for diagnosis of specific subtypes of dementia.<br><br>METHODS: Primary articles (n&#x202f;=&#x202f;896) from any point in time through July 2025 were identified from PubMed, Web of Science, Scopus, and ScienceDirect. Title and abstract screenings filtered articles from 896 to 28 for critical appraisal and review for key bacteria, fungi, and metabolites. Methods adhered to the PRISMA extension for Scoping Reviews (PRISMA-ScR) guidelines.<br><br>RESULTS: Several studies utilized predictive models including random forests and neural networks to demonstrate alterations in the gut microbiota of Alzheimer's disease, an increasingly prevalent dementia subtype. These individuals have notably reduced levels of butyrate-producing bacteria, such as Butyrivibrio, Eubacterium, and Faecalibacterium, which contribute to anti-inflammation and gut-barrier maintenance. Increased levels of Odoribacter splanchnicus and Klebsiella pneumoniae, as well as bacteria from generas Bacteroides and Prevotella, which help generate short-chain fatty acids, have been implicated in neuroinflammation; Roseburia inulinivorans negatively correlates with functional ability. Interestingly, superagers also display unique microbiome profiles that seemingly have protective effects linked to superior cognitive resilience.<br><br>CONCLUSION: Distinct gut microbial compositions are associated with dementia. Furthermore, elucidating gut-brain interactions and their neurodegenerative implications can identify targets for earlier, synergistic diagnostics.<br><br>https://osf.io/yw2dc/overview.},
}
@article {pmid42389758,
year = {2026},
author = {Hussain, A and Alam, I and Agrawal, DK},
title = {Limitations of Current Therapies and Barriers in Alzheimer's Disease.},
journal = {Archives of internal medicine research},
volume = {9},
number = {2},
pages = {136-144},
pmid = {42389758},
issn = {2688-5654},
abstract = {Alzheimer's disease (AD) remains a major global health crisis due to its complex pathophysiology and limited therapeutic effectiveness. Despite advances in understanding key mechanisms such as amyloid-beta accumulation, tau pathology and neuroinflammation, current therapies provide limited clinical benefit. Multiple factors contribute to limitations and highlight the difficulty of translating scientific advancements into meaningful improvement in patient outcomes. This article provides a comprehensive and critical review of therapeutic, biological, clinical, and systemic barriers to effective Alzheimer's disease management as well as showcasing emerging strategies aimed to improve early detection, treatment approaches, and overall disease prevention.},
}
@article {pmid42389857,
year = {2026},
author = {Kashmoola, IO and Mohammad, SH and Alsaaty, MH},
title = {Adipokine dysregulation and oxidative stress in type 2 diabetes: Implications for neurodegeneration and neuroprotective eff ects of antidiabetic therapies.},
journal = {Neuropsychopharmacologia Hungarica : a Magyar Pszichofarmakologiai Egyesulet lapja = official journal of the Hungarian Association of Psychopharmacology},
volume = {28},
number = {2},
pages = {102-114},
pmid = {42389857},
issn = {1419-8711},
mesh = {Humans ; *Diabetes Mellitus, Type 2/drug therapy/complications/metabolism ; *Oxidative Stress/drug effects ; *Adipokines/metabolism ; *Hypoglycemic Agents/pharmacology/therapeutic use ; *Neuroprotective Agents/pharmacology/therapeutic use ; PPAR-gamma Agonists ; *Neurodegenerative Diseases/etiology/metabolism ; Animals ; Alzheimer Disease/metabolism ; },
abstract = {BACKGROUND: Neurodegeneration is accelerated by Type 2 diabetes mellitus through adipokine dysregulation, insulin resistance, oxidative stress, and neuroinfl ammation. This could link metabolic imbalance to Alzheimer's disease, Parkinson's disease, and cognitive decline. The aim of this review is to clarify the roles of adipokines in type 2 diabetes-induced neurodegeneration, their molecular pathways, and the possible neuroprotective potential of antidiabetic agents.<br><br>METHODS: Literature was searched in PubMed, Google Scholar, and Scopus for Englishlanguage articles published up to November 2025, using keywords like adipokines, diabetes mellitus, neurodegeneration, neuroinfl ammation, and antidiabetics.<br><br>RESULTS: Results highlight those elevated levels of pro-infl ammatory adipokines, such as TNF-&#x3b1;, IL-6, and resistin, together with reduced levels of neuroprotective adipokines, including adiponectin and leptin, may drive NF-kB activation, suppression of Nrf2 signaling, and amyloid and tau pathology. This is further exacerbated by oxidative stress and mitochondrial dysfunction. Antidiabetic agents like metformin, GLP-1 agonists, thiazolidinediones, and SGLT2 inhibitors restore adipokine balance, enhance AMPK/PPAR&#x3b3; signaling, and show cognitive benefi ts in mild cognitive impairment cohorts per clinical trials.<br><br>DISCUSSION: In conclusion, repurposing antidiabetics via biomarker-guided multiple therapies off ers disease-modifying promise for type 2 diabetes-linked neurodegeneration, necessitating large randomized controlled trials in prediabetic populations. (Neuropsychopharmacol Hung 2026; 28(2): 102-114) Keywords: Adipokines, Type 2 diabetes mellitus, Neurodegeneration, Neuroinfl ammation, Antidiabetic agents.},
}
@article {pmid42389895,
year = {2026},
author = {Pickett, D and Purvinsh, Y and Skrehot, JT and Warren, D and Kurouski, D},
title = {Nanoscale morphological and structural analysis of round and donut oligomers formed by C-terminal domain of TDP-43.},
journal = {Physical chemistry chemical physics : PCCP},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6cp01760f},
pmid = {42389895},
issn = {1463-9084},
abstract = {Amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD), limbic predominant age-related TDP-43 encephalopathy (LATE), and Parkinson's disease are associated with an abrupt aggregation of TAR DNA-binding protein 43 (TDP-43). Although molecular mechanisms of this pathological aggregation remain unclear, accumulated evidence suggests that the C-terminus domain (C-terminal domain (CTD)) is the trigger of TDP-43 self-assembly into toxic oligomers and fibrils. While the secondary structure and morphology of protein fibrils have been well documented, very little is known about TDP-43 oligomers. This is primarily because of the transient nature and low concentrations of these protein species. In the current study, we utilize nano-infrared spectroscopy, also known as atomic force microscopy-infrared (AFM-IR) spectroscopy, to investigate the morphology and secondary structure of CTD of TDP-43 oligomers formed at the early and middle stages of protein aggregation. This innovative technique allows us to resolve both morphology and secondary structure of individual protein aggregates. We found that at the early stage of protein aggregation, CTD of TDP-43 formed two morphologically different protein aggregates: donut-like (DO) and round (RO) oligomers. DO yielded fibrillar species, while RO persisted throughout the entire course of CTD TDP-43 self-assembly.},
}
@article {pmid42390354,
year = {2026},
author = {Brissach, DE and Berg, HH and Stensvold, D and Ingeström, EML and Walker, TL and Laukkanen, JA and Vasankari, T and Sando, SB and Tari, AR and Wisløff, U},
title = {Objectively Measured Cardiorespiratory Fitness as a Potential Biomarker for Alzheimer's Disease Risk in Older Adults: Evidence from the Generation 100 Study.},
journal = {Medicine and science in sports and exercise},
volume = {},
number = {},
pages = {},
doi = {10.1249/MSS.0000000000004064},
pmid = {42390354},
issn = {1530-0315},
abstract = {PURPOSE: Cardiorespiratory fitness is a modifiable physiological trait linked to dementia risk, but whether objectively measured peak oxygen uptake (VO2peak) and short-term changes fitness in older adults associates with Alzheimer's disease (AD) remains unknown. We examined whether baseline levels and one-year changes in VO2peak were associated with subsequent risk of AD in older adults.<br><br>METHODS: This prospective cohort study included participants from the Generation 100 Study. VO2peak was measured at baseline (2012-13) and 1-year follow-up. Participants were categorized as unfit (<80% of the sex-specific mean VO2peak), moderately fit (80-99%), or fit (&#x2265;100%). Incident AD was identified through national health registries, hospital records, and the Norwegian Prescribed Drug Registry. Cox proportional hazards models estimated associations between VO2peak and incident AD.<br><br>RESULTS: A total of 1491 participants free from dementia, aged 70-77 years were included. Mean VO2peak at baseline was 28.7&#x2009;mL/kg/min. During a median follow-up of 8.7 years, 77 developed AD. Compared with unfit, moderately fit (aHR 0.54, 95% CI 0.29-0.98) and fit (aHR 0.52, 95% CI 0.29-0.93) participants had a lower AD risk. Each 1&#x2009;mL/kg/min higher baseline VO2peak was associated with a 4% lower risk of AD (HR 0.96, 95% CI 0.92-1.00). Staying above 80% of sex-specific mean VO2peak (25.1&#x2009;mL/kg/min for men and 20.9&#x2009;mL/kg/min for women) was identified as a threshold of AD risk stratification of which below the risk increased substantially. Weaker associations were observed between one-year changes in VO2peak and subsequent AD risk.<br><br>CONCLUSIONS: Higher VO2peak in older adults was associated with a substantially lower risk of developing AD, whereas short-term changes in fitness did not confer additional benefit. These findings suggest that entering older age with fitness >80% of sex-specific mean may be more important for reducing late-life AD risk than achieving short-term improvements after the age of 70. CRF emerged as a clinically relevant biomarker for AD, that may help stratify risk and inform preventive strategies in ageing populations.},
}
@article {pmid42390364,
year = {2026},
author = {Liu, Y and Wang, X and Huang, W and Li, R and Zhang, H and Jiakesileke, S and Zhang, P and Petersen, JD and Cao, W},
title = {Gut microbiota alterations in Alzheimer's disease and mild cognitive impairment: A systematic review and meta-analysis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261465913},
doi = {10.1177/13872877261465913},
pmid = {42390364},
issn = {1875-8908},
abstract = {BackgroundAltered gut microbiota has been implicated in Alzheimer's disease (AD) and mild cognitive impairment (MCI), but findings across human studies are inconsistent.ObjectiveTo synthesize observational evidence on gut microbiota differences in older adults with AD or MCI compared with cognitively normal (CN) controls, and to assess the interpretive value of reported microbiome measures across disease stages.MethodsWe searched PubMed/MEDLINE, Embase, Scopus, Web of Science, and the Cochrane Library for observational studies published from 1 January 2012 to 10 December 2025 reporting fecal microbiota profiles in AD, MCI, and CN adults (mean age ≥60). Random-effects meta-analysis was used for α-diversity; β-diversity and taxonomic changes were summarized narratively.ResultsTwenty-three studies were included (AD = 698, MCI = 485, CN = 1060). In AD versus CN, pooled α-diversity estimates showed no robust statistically significant differences (Shannon SMD = - 0.23, 95% CI: - 0.57 to 0.11; Chao1 SMD = -0.36, 95% CI: -0.74 to 0.02; ACE SMD = -0.38, 95% CI: -0.88 to 0.11). In MCI versus CN, differences were small and non-significant (Shannon SMD = -0.01, 95% CI: -0.18 to 0.15; Chao1 SMD = -0.17, 95% CI: -0.37 to 0.02). β-diversity and taxonomic findings more often suggested community-structure disruption and altered microbial composition in AD, whereas MCI findings were less consistent.Conclusionsα-diversity is not supported as a useful biomarker for distinguishing AD or MCI from CN aging. Community-structure and taxonomic patterns may be more informative, but heterogeneity limits interpretation. Future studies should use standardized, function-oriented, and biomarker-informed approaches to clarify AD-continuum microbiome changes.},
}
@article {pmid42390578,
year = {2026},
author = {Petersen, CE and Damsgaard, L and Janbek, J and Laursen, TM and Vestergaard, K and Gottrup, H and Waldemar, G},
title = {Morbidity and medication use preceding a diagnosis of late-onset Alzheimer's disease: a Danish nationwide study.},
journal = {Journal of neurology},
volume = {273},
number = {8},
pages = {},
pmid = {42390578},
issn = {1432-1459},
mesh = {Humans ; *Alzheimer Disease/epidemiology/diagnosis/drug therapy ; Denmark/epidemiology ; Female ; Male ; Retrospective Studies ; *Prodromal Symptoms ; Aged ; Case-Control Studies ; Aged, 80 and over ; Morbidity ; },
abstract = {INTRODUCTION: Symptoms of Alzheimer's disease can emerge years before diagnosis, but detailed temporal mapping of morbidity and medication use in the prodromal period is lacking.<br><br>METHODS: We conducted a nationwide retrospective, incidence density-matched nested case-control study including individuals diagnosed with late-onset Alzheimer's disease in Danish memory clinics from 2016 to 2022 and cognitively healthy matched controls. Exposures were primary and secondary discharge diagnoses from hospital contacts, and redeemed prescriptions.<br><br>RESULTS: A total of 19,102 patients and 57,306 matched controls were included. At 10&#xa0;years before diagnosis, individuals who later developed late-onset Alzheimer's disease had more mental health and behavioral diagnoses and increased use of psychopharmaceuticals, as well as more injuries and hospital contacts for non-specific symptoms. During the five years and one-year preceding diagnosis, morbidity increased across multiple diagnostic categories, while most medication categories decreased.<br><br>CONCLUSION: Our findings suggest that prodromal late-onset Alzheimer's disease is characterized by gradual accumulation of morbidity, with injuries and neuropsychiatric symptoms as the most persistent. This knowledge can guide future hypothesis-driven studies towards better characterization of the prodromal phase that may improve early detection, reduce the burden of unexplained symptoms experienced by patients and their caregivers, and support clinicians facing diagnostic uncertainty.},
}
@article {pmid42390646,
year = {2026},
author = {Levine, CM and Caggiano, C and Anderson, T and Kelberman, MA and Weinshenker, D and Lail, HL and Wanders, D and Bangasser, DA and Kanoski, SE and Parent, MB},
title = {Hypothalamus Amyloid Levels Are Associated with Early Sex-Dependent Alterations in Peripheral Energy Homeostasis in TgF344-AD Rats.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42390646},
issn = {1559-1182},
mesh = {Animals ; Male ; *Hypothalamus/metabolism/pathology ; Female ; *Homeostasis/physiology ; *Energy Metabolism/physiology ; *Amyloid beta-Peptides/metabolism ; *Alzheimer Disease/metabolism/pathology ; *Sex Characteristics ; Uncoupling Protein 1/metabolism ; Adipose Tissue, Brown/metabolism/pathology ; Glucose/metabolism ; *Peptide Fragments/metabolism ; Rats, Transgenic ; },
abstract = {We reported previously that diet-induced obesity exacerbates early-stage Alzheimer's disease (AD)-like pathology in TgF344-AD rats. Those findings also suggested that they may be prone to weight gain during early AD development, raising the possibility of early hypothalamic dysfunction. In this study, we investigate this by determining whether hypothalamic soluble amyloid-β40 (Aβ40) and amyloid-β42 (Aβ42) are detectable during early AD development in TgF344-AD rats and whether their presence is associated with alterations in energy homeostasis. Energy intake, body composition, whole body glucose clearance, body temperature rhythms, interscapular brown adipose tissue (iBAT) mass, and iBAT expression of the thermogenic uncoupling protein 1 (UCP1) were assessed. The results demonstrate that Aβ40 and Aβ42 are detectable in the hypothalamus during the early stages of AD development and that hypothalamic but not cortical Aβ42 is associated with impaired glucose regulation in males and iBAT mass in females. Male TgF344-AD rats became heavier than wild-type (WT) littermates by 5 weeks of age, with a similar increase emerging later in females (~ 5 months). Female TgF344-AD rats consumed more chow and a high-fat high-sugar (HFHS) diet, gained more weight on that diet, and showed reduced UCP1, effects not seen in males. Both sexes exhibited elevated body temperatures. This increase was restricted to the dark phase in females, coinciding with excess caloric intake. Finally, HFHS feeding impaired glucose regulation in male but not female TgF344-AD rats. These findings suggest hypothalamic Aβ42 may contribute to sex-specific disruptions in peripheral energy homeostasis that may be an early symptom of AD development.},
}
@article {pmid42390689,
year = {2026},
author = {Chauhan, D and Goel, F and Rajput, MS},
title = {Ficus virens in neurotherapeutics: bridging ethnomedicinal evidence with Nrf2/Keap1 and neuroinflammatory mechanisms.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42390689},
issn = {1573-4978},
mesh = {Humans ; *NF-E2-Related Factor 2/metabolism ; *Kelch-Like ECH-Associated Protein 1/metabolism ; Animals ; Neuroprotective Agents/pharmacology ; Signal Transduction/drug effects ; *Ficus/chemistry/metabolism ; Antioxidants/pharmacology ; Oxidative Stress/drug effects ; Neurodegenerative Diseases/drug therapy/metabolism ; Plant Extracts/pharmacology/chemistry ; Anti-Inflammatory Agents/pharmacology ; *Neuroinflammatory Diseases/drug therapy/metabolism ; Medicine, Traditional/methods ; Phytochemicals/pharmacology ; },
abstract = {Neurodegenerative diseases include Alzheimer's and Parkinson's disease which are progressive loss of neurons due to oxidative stress, mitochondrial dysfunction and long-term neuroinflammation. The approach of attacking these intertwined pathological processes has emerged as a major approach in identifying effective neurotherapeutics. In that regard, the use of ethnomedicine has immense potential. Ficus virens is a medicinal plant that is traditionally used and has drawn attention because of its wide range of pharmacological activities and high phytochemical composition. This review is an overall summary of botanical properties, ethnomedicinal properties, phytochemical composition and pharmacological functions of Ficus virens, with special consideration to neuroprotective properties. Bioactive constituents found in abundance in the plant include flavonoids, phenolics, and terpenoids, and they help in its antioxidant and anti-inflammatory properties. Ficus virens has a neuroprotective effect, which is primarily mediated by the regulation of the Nrf2/Keap1 signaling pathway, which increases the expression of the endogenous antioxidant enzymes and redox homeostasis. Moreover, it inhibits neuroinflammatory responses by suppressing the major signaling pathways such as the NF-ĸB signaling pathway and inhibits production of pro-inflammatory cytokines and mediators. The review also cites the experimental results of both in vivo and in vitro studies which show that Ficus virens has the capacity to inhibit oxidative damages, mediate apoptotic mechanisms, and enhance neuronal survival. New methods, such as network pharmacology and advanced delivery systems based on nanotechnology are also mentioned as possible means of improving its therapeutic efficacy and bioavailability, especially to overcome the problem of the BBB.},
}
@article {pmid42390710,
year = {2026},
author = {Medeiros, EB and de Oliveira Monteiro, I and Kluwe-Schiavon, B and Possamai, OL and Fenilli, GP and Keller, GS and Lidio, AV and Casagrande, DD and Souza, CSM and de Bem Silveira, G and de Almeida, RCS and Vicente, HB and Magenis, ML and Luiz, GP and Damiani, AP and de Andrade, VM and Budni, J},
title = {Effect of Probiotic Supplementation in Older Individuals with Mild Cognitive Impairment and Alzheimer's Disease: A Randomized, Placebo-Controlled, Triple-Blind Clinical Trial.},
journal = {Probiotics and antimicrobial proteins},
volume = {},
number = {},
pages = {},
pmid = {42390710},
issn = {1867-1314},
abstract = {Alzheimer's disease (AD) is the most common type of dementia in older adults and often precedes mild cognitive impairment (MCI). These conditions are associated with biological alterations involving chronic inflammation, neuronal dysfunction, and genomic instability. In parallel, growing evidence has suggested a role for the gut-brain axis in cognitive aging, and probiotics have been investigated as a potential strategy to modulate inflammatory and neurotrophic pathways. This randomized, triple-blind, placebo-controlled clinical trial evaluated the effects of 12 weeks of supplementation with a probiotic blend containing Lactobacillus and Bifidobacterium strains in older adults classified as cognitively unimpaired (CU), MCI, or AD. The study examined DNA damage, inflammatory cytokines, neurotrophic factors, and stool consistency before and after the intervention. Overall, probiotic supplementation showed limited and heterogeneous effects across outcomes. DNA damage analyses did not indicate increased alkaline or oxidative DNA damage after probiotic supplementation, supporting the absence of detectable genotoxicity over the intervention period. Changes in inflammatory and neurotrophic biomarkers were more strongly related to time and diagnostic subgroups than to treatment allocation. Exploratory findings suggested a possible subgroup-specific effect on neurotrophic markers, particularly an increase in NGF in the MCI probiotic arm, but this pattern was not consistent across the broader biomarker panel. Stool consistency did not show reliable pre- to post-intervention changes. These findings suggest that the probiotic formulation was safe from a genotoxic perspective but did not produce a generalized biological effect across inflammatory, neurotrophic, or gastrointestinal outcomes. Larger studies incorporating dietary monitoring and microbiota profiling are needed to clarify whether specific probiotic strains can influence biological pathways relevant to cognitive aging.},
}
@article {pmid42390973,
year = {2026},
author = {Rubin, R},
title = {First Alzheimer Disease Blood Test May Produce Many False-Positive Results, Study Finds.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2026.12326},
pmid = {42390973},
issn = {1538-3598},
}
@article {pmid42391157,
year = {2026},
author = {Sekhon, H and Sukhu, A and Fallavollita, P and McLoone, S and Kumar, S and Mulsant, BH and Brooks, H and Khoury, B and Preston, AM and Vahia, I and Chabot, J and Nene, S and Wang, W and Noble, H and Rajji, TK and Brown, EE},
title = {Nature-based Virtual Reality for Depression in Alzheimer's Disease: Protocol of a Pilot Randomized Controlled Trial.},
journal = {Gerontology},
volume = {},
number = {},
pages = {1-18},
doi = {10.1159/000553254},
pmid = {42391157},
issn = {1423-0003},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is the most common form of dementia. Depression is common in AD, with limited evidence for efficacy of pharmacotherapy. Limited in-home non-pharmacological treatments for depression in AD underscore a need for novel in-home treatments. Virtual reality (VR) is an immersive audiovisual technology, which has been used in different clinical contexts. Exposure to nature can improve mental health, including the behavioural and psychological symptoms of dementia (BPSD). To our knowledge, in-home VR use has not been assessed in AD with depression (AD-D). This study aims to assess the feasibility of an in-home nature VR (N-VR) exposure versus an active non-immersive control intervention for individuals with AD-D.<br><br>METHODS: This is a pilot, parallel group, assessor-blinded, randomized controlled trial, assessing a N-VR for AD-D. Participants (n=50) with AD-D are randomized (1:1) to N-VR vs. an active control intervention of nature-based videos. All participants receive the intervention as 15-min sessions delivered twice a week, for 4 weeks. Assessments are conducted remotely by assessors (via WebEx) blinded to randomized assignment at baseline, after each session, and within 7 days of completing the 4-week course to assess tolerability, feasibility, and acceptability. Participants also have the option to participate in a focus group at the end of the study.<br><br>DATA ANALYSIS: Measures of feasibility, tolerability and acceptability, and preliminary clinical outcomes will be compared between the VR and control groups in intention-to-treat analyses. Qualitative data from the focus group is thematically analyzed. Relevant participant characteristics (e.g., age, sex, baseline clinical characteristics) will be described across groups and may be considered in exploratory or sensitivity analyses, recognizing the limited statistical power of this pilot study.<br><br>DISCUSSION: If successful, this study has the potential to establish feasibility of remote VR for individuals with AD-D.<br><br>CLINICAL TRIALS: NCT06732128 For the reporting of the RCT, the Consolidated Standards of Reporting Trials (CONSORT) has been used.},
}
@article {pmid42391257,
year = {2026},
author = {Sharif-Nia, H and Hosseini, L and She, L and Froelicher, ES},
title = {Hardiness and care-related stress in Iranian Alzheimer's caregivers: a cross-sectional study.},
journal = {British journal of community nursing},
volume = {31},
number = {7},
pages = {322-332},
doi = {10.12968/bjcn.2025.0136},
pmid = {42391257},
issn = {1462-4753},
mesh = {Humans ; Cross-Sectional Studies ; *Alzheimer Disease/nursing ; Iran ; *Caregivers/psychology ; Female ; *Stress, Psychological/psychology ; Middle Aged ; Male ; *Adaptation, Psychological ; Adult ; Surveys and Questionnaires ; Aged ; Coping Skills ; },
abstract = {BACKGROUND: Caring for individuals with Alzheimer's disease is widely recognised as a demanding and stressful responsibility. Caregivers' experiences largely depend on their ability to manage caregiving stress and cope effectively.<br><br>AIMS: This study examined the relationships between care stressors and care challenges with hardiness among family caregivers, considering the mediating role of care stress management.<br><br>METHODS: A cross-sectional study design was used. A total of 435 Iranian family caregivers completed an online survey between July and December 2021. Data were collected on demographics, hardiness, care challenges, care stressors and care stress management scales. Pearson's correlation and path analysis were used to examine associations and mediation effects between variables. In addition to significance testing, effect sizes were calculated for all correlations (Pearson's r) and path coefficients (b) to quantify the strength of associations.<br><br>RESULTS: The mean age of participants was 50.26 years (standard deviation=13.24). Care challenges showed a strong positive correlation with care stressors (r=0.798, P<0.001) and negative correlations with care stress management (r=-0.287, P<0.001) and hardiness (r=-0.392, P<0.001). Care stressors also negatively correlated with care stress management (r=-0.312, P<0.001) and hardiness (r=-0.304, P<0.001). In contrast, care stress management showed a positive correlation with hardiness (r=0.525, P< 0.001). Path analysis indicated that care stress management had a positive direct association with hardiness and mediated the indirect association between care challenges and hardiness.<br><br>CONCLUSIONS: Based on the results, approximately 85% of the variance in hardiness was explained by care stress management, care challenges and care stressors.<br><br>IMPLICATIONS FOR PRACTICE: The findings of this study may help nursing professionals to develop interventions that improve the hardiness of family caregivers and provide them with the necessary skills to manage the stressors associated with caregiving. This can lead to better health outcomes for both the caregivers and patients.},
}
@article {pmid42391577,
year = {2026},
author = {Bautista, JR and Goth, O and Anbari, AB and Powell, KR},
title = {Readability and Linguistic Characteristics of Alzheimer's Disease and Related Dementias Prevention, Symptom, and Treatment Information from Generative Artificial Intelligence Chatbots.},
journal = {Journal of gerontological nursing},
volume = {52},
number = {7},
pages = {7-11},
doi = {10.3928/00989134-20260608-03},
pmid = {42391577},
issn = {0098-9134},
mesh = {Humans ; *Alzheimer Disease/prevention &amp; control/therapy ; Generative Artificial Intelligence ; *Comprehension ; *Linguistics ; *Dementia/prevention &amp; control/therapy ; },
abstract = {PURPOSE: To examine the readability and linguistic characteristics of Alzheimer's disease and related dementias (ADRD) prevention, symptom, and treatment information from generative artificial intelligence (GenAI) chatbots.<br><br>METHOD: We analyzed 66 outputs from free-to-use GenAI chatbots. We extracted readability (word count, Fleisch Reading Ease, and Fleisch-Kincaid Grade Level) and linguistic scores (analytical thinking, clout, authenticity, and emotional tone) using Microsoft Word and the Linguistic Inquiry and Word Count software. Data were analyzed using descriptive statistics, t tests, analysis of variance, and multivariate analysis of variance.<br><br>RESULTS: ADRD information from GenAI chatbots, especially treatment information, had college-level readability. Linguistic analyses indicate a high analytical thinking score and low scores for clout, authenticity, and emotional tone.<br><br>CONCLUSION: Our sample of ADRD GenAI information exceeded recommended reading levels for patient education materials. Although the outputs exhibited logical thinking, they also included uncertain, inauthentic, and negative tones. ADRD caregivers should be aware of these characteristics when using GenAI chatbots for ADRD information-seeking.},
}
@article {pmid42391744,
year = {2026},
author = {Xin, Y and Sheng, J and Wang, L},
title = {A review of Alzheimer's disease diagnosis and prognosis models based on multimodal deep learning.},
journal = {Reviews in the neurosciences},
volume = {},
number = {},
pages = {},
pmid = {42391744},
issn = {2191-0200},
abstract = {Although some drugs have been approved for clinical treatment, early diagnosis and intervention remain the most effective strategies for managing Alzheimer's disease (AD) at present. With advances in deep learning and multimodal fusion, an increasing number of complex frameworks have been proposed. This paper systematically reviews multimodal deep learning-based models for AD diagnosis between 2020 and 2026. Beyond the technical survey, we explore how to deal with the heterogeneous modality integration and missing modality processing. From these experimental results, many models show impressive performance on public datasets. However, we have noticed a troubling problem that these "lab-perfect" results often falter when they face the chaos of the real-world. Because of the persistent black-box problem and the hidden traps of data leakage, the path to clinical use is still uphill. This work suggests that it is time to move beyond chasing tiny gains in accuracy and focus on building models that doctors can truly trust, understand, and use in real clinical settings.},
}
@article {pmid42391846,
year = {2026},
author = {Sun, Z and Peng, J and Feng, Z and Wang, X and Long, H and Qi, S and Li, L and Li, M and Yung, KKL and Cheung, KH and Zhang, Z},
title = {"Neurotoxic mechanisms of microplastic compounds in Alzheimer's and Parkinson's diseases: A network toxicology and molecular docking study".},
journal = {Ecotoxicology and environmental safety},
volume = {321},
number = {},
pages = {120437},
doi = {10.1016/j.ecoenv.2026.120437},
pmid = {42391846},
issn = {1090-2414},
abstract = {Microplastic compounds (MPCs), pervasive environmental pollutants, are increasingly implicated in human health risks. However, their neurotoxic mechanisms remain poorly understood. This study aims to investigate how MPCs contribute to neurodegenerative diseases, focusing on Alzheimer's (AD) and Parkinson's (PD) diseases as critical models. Using computational toxicology approaches, we screened 12 types of MPCs via SwissADME, identifying four representative MPCs with significant blood-brain barrier permeability and neurotoxic potential. Network toxicology (SwissTargetPrediction, ChEMBL) and protein interaction analysis (STRING, Cytoscape) revealed MPC-related AD/PD targets, including MAPK8 and SLC6A3, which were further validated through molecular docking (AutoDock). Key pathways-neuronal apoptosis and G protein-coupled receptor (GPCR) signaling-were disrupted by MPCs interactions, as evidenced by Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses. Notably, MPCs exhibited strong binding affinities to MAPK8 and SLC6A3, implicating these targets in neurodegeneration. Our findings establish a novel mechanistic link between environmental MPCs exposure and AD/PD pathogenesis, highlighting apoptosis dysregulation and GPCR signaling interference as central pathways. This work provides critical insights for policymakers and clinicians, underscoring the urgency of regulating MPCs to mitigate neurodegenerative risks and informing targeted therapeutic strategies.},
}
@article {pmid42391923,
year = {2026},
author = {Guo, H and Zheng, S and Shi, X and Wang, X and Ma, R and Li, G},
title = {VER155008 rescues cognitive impairment in P301S tauopathy mice by promoting HSPA8-mediated lipophagy.},
journal = {European journal of pharmacology},
volume = {1030},
number = {},
pages = {179107},
doi = {10.1016/j.ejphar.2026.179107},
pmid = {42391923},
issn = {1879-0712},
abstract = {Alzheimer's disease (AD) features tau accumulation and pathogenic lipid droplet (LD) buildup, driving neurodegeneration through oxidative stress and neuroinflammation. The chaperone heat shock protein family A member 8 (HSPA8) is upregulated in AD, which may have implications for impaired LD clearance via lipophagy. We investigated whether targeting HSPA8 with the small-molecule antagonist VER155008 alleviates tau pathology and cognitive deficits by activating lipophagy in P301S tauopathy models. P301S tau transgenic mice and HEK293T-P301S cells were utilized. Western blotting, immunohistochemistry, and immunofluorescence were performed to assess HSPA8 levels, lipophagy, tau proteins, and inflammatory markers. VER155008 or vehicle control was administered to P301S mice for four weeks, starting at seven months of age. Cognitive function was evaluated using the Morris water maze and novel object recognition tests. Synaptic density was assessed through Golgi staining and electron microscopy. HSPA8 was elevated in P301S mice, correlating with impaired lipophagy and suppressed AMP-activated protein kinase (AMPK) activity. VER155008 treatment restored cognitive function and synaptic density. Critically, it activated lipophagy and reduced hippocampal LDs and tau pathology. Moreover, HSPA8 overexpression suppressed lipophagy and increased both LD accumulation and tau pathology. Inhibition of HSPA8 by VER155008 activates AMPK-mediated lipophagy, concurrently reducing tau pathology, oxidative stress, and neuroinflammation in AD models. These beneficial effects were eliminated by treatment with the AMPK inhibitor Compound C. This identifies the HSPA8-lipophagy axis as a promising therapeutic target for tauopathies.},
}
@article {pmid42391929,
year = {2026},
author = {Wang, Y and Sang, J and Li, H and Ren, X and Chen, C and Zheng, N and Xiao, H and Wei, Y and Xu, L and Jiang, R and Zhang, W and Xu, Z and Ge, L and Zhu, J and Xiong, B and Chen, Y and Feng, F and Sun, H},
title = {Development of potent BChE/Nrf2 modulators for Alzheimer's disease treatment via dual suppression of ferroptosis.},
journal = {European journal of medicinal chemistry},
volume = {317},
number = {},
pages = {119093},
doi = {10.1016/j.ejmech.2026.119093},
pmid = {42391929},
issn = {1768-3254},
abstract = {Targeting multiple pathological mechanisms holds significant potential for Alzheimer's disease (AD) therapy. Here, we designed 50 hybrids combining the benzimidazole-aminofurazan scaffold of a BChE inhibitor (S06-1064) with the 1,2,4-oxadiazole moiety of an Nrf2 activator (6). After four optimization rounds, S27-1046 and S27-1047 emerged as potent, selective BChE inhibitors and Nrf2 activators (S27-1046: eqBChE IC50 = 2.51 ± 1.51 nM, hBChE IC50 = 128.30 ± 16.89 nM, FP IC50 = 188.20 ± 57.11 nM, 4.73-fold ARE induced fold at 20 μM; S27-1047: eqBChE IC50 = 7.16 ± 2.96 nM, hBChE IC50 = 296.10 ± 55.78 nM, FP IC50 = 36.87 ± 23.07 nM, 7.42-fold ARE induced fold at 20 μM). They directly bind Keap1, disrupt Keap1-Nrf2 interaction, enhance antioxidant enzyme expression, and activate the GSH-GPX4 axis to inhibit Aβ-induced ferroptosis. Both compounds also protect against oxidative stress and neuroinflammation. S27-1047 showed superior Nrf2 activation and Keap1 binding, thus was selected for in vivo evaluation. In an Aβ-induced AD mouse model, S27-1047 significantly improved cognition, outperforming mono- or combination therapies. It has 12.62% oral bioavailability and crosses the BBB. This work presents multi-target agents targeting BChE, Nrf2, and ferroptosis for effective AD therapy.},
}
@article {pmid42391971,
year = {2026},
author = {Ning, Y and Chen, M and Yang, H and Jia, J},
title = {Sotagliflozin improves cognitive deficits and attenuates neuroinflammation of Alzheimer's disease.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {23},
number = {4},
pages = {e00946},
doi = {10.1016/j.neurot.2026.e00946},
pmid = {42391971},
issn = {1878-7479},
abstract = {Effective treatments for Alzheimer's disease (AD) are limited. Due to shared pathological mechanisms between AD and diabetes, antidiabetic drugs like sodium-glucose cotransporter-2 inhibitors (SGLT2is) are potential therapeutic options. Although SGLT2is have shown cognitive benefits in diabetes models, their effects in AD models are not fully established. This study aimed to evaluate the therapeutic effects of sotagliflozin (Sota), an SGLT2i, in both in vivo and in vitro AD models. The network pharmacology analysis was used to predict the potential targets and pathways of Sota. And we selected 6-month-old APP/PS1 transgenic mice to investigate the effects of Sota. Cognitive function was assessed using the Morris water maze test. Immunohistochemistry and immunofluorescence were employed to quantify amyloid-beta (Aβ) plaque deposition in the hippocampal or cortex and analyze neuronal loss. Additionally, amyloid β oligomers induction and microglial cells were used to evaluate the effects of Sota on the release of pro-inflammatory mediators and to investigate the underlying mechanisms. In vivo, Sota treatment improved cognitive impairments, reduced pro-inflammatory cytokines, inhibited microglial activation, and promoted neuronal survival. In vitro, Sota mitigated Aß oligomer-induced toxicity in microglial cells by decreasing reactive oxygen species and pro-inflammatory cytokine release. Mechanistically, Sota treatment was associated with suppression of extracellular signal-regulated kinase (ERK) signaling. Our findings suggest that Sota improved cognitive impairment and attenuates neuroinflammation in AD. Sota may be a promising candidate for the treatment of AD.},
}
@article {pmid42079230,
year = {2026},
author = {Lai, HY and Yoo, Y and Tjaernberg, A and Li, R and He, Z and Travaglini, KJ and Qiao, Q and Agrawal, A and Kana, O and van Velthoven, C and Carroll, JB and Gillespie, M and Mukherjee, S and Fardo, DW and Li, XJ and Lein, E and Gabitto, MI},
title = {scVIP: personalized modeling of single-cell transcriptomes for developmental and disease phenotypes.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.20.717759},
pmid = {42079230},
issn = {2692-8205},
abstract = {Single-cell transcriptomics resolves cellular heterogeneity within individuals, but connecting molecular states to individual-level phenotypes requires frameworks that explicitly bridge these scales. We present scVIP, a generative model that links gene expression, cell-type composition, and phenotypic measurements within a single probabilistic model, which enables accurate phenotype prediction and interpretable trajectory inference. A cell-type-aware multi-instance learning architecture learns donor embeddings that capture progression while localizing phenotype-associated signals to specific cell populations. Applied across four settings, scVIP accurately predicts cortical developmental age (Pearson r = 0.95), characterizes Huntington's disease progression (concordance correlation coefficient = 0.90), integrates two Alzheimer's disease cohorts recovering disease-relevant microglial and astrocytic programs, and distinguishes healthy from ACPA-positive individuals and non-progressors from early RA individuals, identifying inflammatory T cell programs associated with disease. scVIP enables principled analysis of how cellular states collectively shape organism-level phenotypes across development and disease.},
}
@article {pmid42377782,
year = {2026},
author = {Zeenny, MN and Salame, I and Maatouk, L and Akoury, E},
title = {Neuroinflammation and Tauopathies.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42377782},
issn = {1573-4978},
mesh = {Humans ; *Tauopathies/metabolism/pathology ; Animals ; *Neuroinflammatory Diseases/metabolism/pathology ; tau Proteins/metabolism ; Signal Transduction ; Microglia/metabolism/pathology ; Alzheimer Disease/metabolism/pathology ; Inflammation/metabolism/pathology ; Phosphorylation ; Inflammasomes/metabolism ; Oxidative Stress ; Astrocytes/metabolism/pathology ; },
abstract = {Alzheimer's disease (AD) and related Tauopathies are neurodegenerative disorders characterized by the accumulation of hyperphosphorylated Tau protein in neurofibrillary tangles and frequently accompanied by amyloid-β (Aβ) pathology.[1] While Tau aggregation has long been considered a primary driver of neurodegeneration, growing evidence highlights neuroinflammation as a central and early contributor to disease onset and progression. This review combines current knowledge on the molecular and cellular mechanisms linking Tau pathology to chronic neuroinflammatory signaling, with a particular focus on microglia- and astrocyte-mediated responses. We discuss how dysregulated kinase-phosphatase balance, impaired proteostasis, and oxidative stress promote Tau hyperphosphorylation and aggregation, and how these processes are amplified by innate immune pathways, including TREM2-DAP12, toll-like receptors, GPCR signaling, the PI3K-Akt/PTEN axis, Wnt/β-catenin signaling, and the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome. Special emphasis is placed on the transition from early protective glial responses to chronic inflammation, which fosters prion-like propagation of Tau and accelerates synaptic dysfunction and neuronal loss. Finally, we evaluate emerging therapeutic strategies aimed at modulating neuroinflammatory pathways and restoring signaling homeostasis, highlighting their potential to slow or halt disease progression. Collectively, this review positions neuroinflammation as a critical mechanistic link between Tau pathology and neurodegeneration, underscoring its relevance as a therapeutic target in AD and other Tauopathies.},
}
@article {pmid42377826,
year = {2026},
author = {Lachhab, S and Elmoussaoui, S and Rafya, M and El Mansouri, AE and Mehdi, A and Ramalhosa, RR and Costa, AR and Carreiro, EP and Andrei, G and Snoeck, R and Benkhalti, F and Sanghvi, YS and Ali, MA and Lazrek, HB},
title = {Discovery of novel perillyl and myrtenyl nucleobase conjugates as dual anti-Alzheimer and antimicrobial agents.},
journal = {Molecular diversity},
volume = {},
number = {},
pages = {},
pmid = {42377826},
issn = {1573-501X},
abstract = {Recent studies suggest that Alzheimer's disease may be influenced by microbial infections and may involve multiple microbial pathogens contributing to its development and progression. Based on this hypothesis, dual antimicrobial and anti-Alzheimer's agents may provide advantages such as improved therapeutic effectiveness, treatment of infection-related Alzheimer disease, and reduced toxicity compared with single-target drugs. To discover novel therapeutic agents, a series of terpene-substituted pyrimidine derivatives were synthesized and evaluated for their antiviral, antibacterial, antifungal and anti-Alzheimer's activities. All compounds were characterized by spectroscopic methods to support their structures. Among all compounds screened for their biological activity, compounds 11 and 32 displayed excellent IC50 values of 10.1 and 9.9 µM, respectively, against eqBChE in comparison with Food and Drug Administration (FDA)-approved drugs galantamine (IC50 = 20.6 µM) and donepezil (IC50 = 4.1 µM) for the treatment of Alzheimer's disease (AD). Additionally, compound 32 exhibited promising antifungal activity against C. tropicalis (MIC = 0.83 µmol/ml and MFC = 1.69 µmol/ml), showing two-fold greater potency than fluconazole and three-fold greater potency than 5-fluorocytosine. Moreover, terpene derivative 32 showed moderate antibacterial activity against Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, and Enterococcus faecalis, with MIC and MBC values ranging from 3.35 to 6.71 µmol/ml. The docking studies of 32 with eqBChE supported the observed in vitro results. This study provides a promising lead compound with dual antimicrobial and anti-Alzheimer activity that may be further developed as a potential therapeutic agent for the treatment of Alzheimer's disease.},
}
@article {pmid42378088,
year = {2026},
author = {Yang, T and Xu, YR and Li, S and Bellier, JP and Tao, Y and Francis, AE and Stern, AM and Jin, S and Ostaszewski, BL and Lawton, TL and Pradier, L and Reczek, D and Lemere, CA and Walsh, DM and Selkoe, DJ},
title = {Immunotherapy with B28, an antibody to Aβ oligomers, potently decreases amyloid plaques, microgliosis, and memory decline in APP knock-in mice.},
journal = {Cell reports},
volume = {45},
number = {7},
pages = {117599},
doi = {10.1016/j.celrep.2026.117599},
pmid = {42378088},
issn = {2211-1247},
abstract = {Immunotherapy against amyloid β-protein (Aβ) for Alzheimer's disease (AD) has been widely approved. Breakthrough disease-modifying treatments such as lecanemab and donanemab are often followed by drugs with improved efficacy. By immunizing Trianni mice with aggregated synthetic Aβ, we obtained B28, a fully human antibody specifically selected for its neutralization of tau neuritic dystrophy induced by AD brain-derived oligomers. In a blinded trial in mutant human APP[NL-G-F] knock-in mice, weekly infusions of B28 for four months markedly reduced both amyloid plaques and Aβ oligomers, attenuated plaque-associated astrocytosis and microgliosis, preserved neurons, and lessened memory decline. Biochemical and histological analyses showed that B28 engaged both plaque-bound and diffusible Aβ, forming immune complexes and depleting free Aβ. In in vitro immunoassays, B28 had significantly higher affinity and captured more Aβ from AD brain extracts than did lecanemab. B28 is a potent, aggregate-preferring Aβ antibody that clears plaques and decreases gliosis, supporting its clinical development.},
}
@article {pmid42378151,
year = {2026},
author = {Espis, A and Marzi, C and Diciotti, S},
title = {NeuroBooster: a domain-informed self-supervised learning paradigm tailored for brain MRI analysis.},
journal = {IEEE journal of biomedical and health informatics},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/JBHI.2026.3708015},
pmid = {42378151},
issn = {2168-2208},
abstract = {Self-supervised learning (SSL) has demonstrated its potential to reduce reliance on labeled data and improve generalization to independent test sets compared to traditional supervised learning (SL). However, current SSL paradigms are predominantly designed as domain-agnostic and are often evaluated on benchmark datasets like ImageNet. As already shown in other studies, SSL paradigms tailored for the medical domain can outperform domain-agnostic SSL paradigms. This study introduces NeuroBooster, a paradigm tailored for brain MRI analysis. Its core idea is to leverage automated feature extraction tools to generate anatomical features, which are then used as targets in a regression pretext task. The paradigms were evaluated and compared on a regression task, i.e., age prediction, and a classification task, i.e., the discrimination between patients with Alzheimer's disease and cognitively normal subjects. Each pre-training and fine tuning experiment was repeated across 30 randomized seeds to estimate the uncertainty, while enabling full reproducibility. Our results revealed NeuroBooster's superiority across various scenarios. Notably, with only 1% of labeled data available, NeuroBooster achieved an average mean absolute error of 5.67 years smaller than SL. These findings demonstrate NeuroBooster's efficacy and highlight its potential within brain MRI analysis, suggesting a promising direction for developing specialized SSL paradigms in this domain.},
}
@article {pmid42378300,
year = {2026},
author = {Nihat, A and Arora, P and Schmidt, C and Rayner, MLD and Linehan, J and Brandner, S and Mead, S and Collinge, J and Jat, PS},
title = {A scalable, dividing cell model for the robust propagation and quantification of human sporadic Creutzfeldt-Jakob disease prions.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {123},
number = {27},
pages = {e2600341123},
doi = {10.1073/pnas.2600341123},
pmid = {42378300},
issn = {1091-6490},
support = {MR/P019862/1//UKRI | Medical Research Council (MRC)/ ; },
mesh = {Humans ; *Creutzfeldt-Jakob Syndrome/pathology/metabolism ; Animals ; Mice ; *Prions/metabolism ; Disease Models, Animal ; Brain/pathology/metabolism ; Biological Assay/methods ; Mice, Transgenic ; Models, Biological ; },
abstract = {Prion diseases represent a unique biological paradigm with mechanistic parallels to other neurodegenerative conditions like Alzheimer's and Parkinson's diseases. However, the study of human prion pathobiology and the development of effective therapeutics has been severely constrained by the inability to propagate human prions in dividing cells-forcing reliance on costly and slow animal bioassays. Here, we report the generation of EKV cells-a humanized cell model which supports the robust, indefinite propagation of sporadic Creutzfeldt-Jakob disease (sCJD) prions. We demonstrate that these cells replicate bona fide human prion infectivity in culture-cell lysates induce lethal neurodegeneration in humanized mice that is clinically and neuropathologically indistinguishable from inoculation with sCJD-infected brain tissue. We use EKV cells to develop the Human Prion Assay (HPA), which quantifies sCJD infectivity with sensitivity comparable to gold-standard mouse bioassay, while reducing the experimental timeline from years to weeks. Furthermore, we demonstrate that established sCJD infection can be cured by an anti-prion protein antibody, validating the system as a high-throughput platform for drug discovery. This model bridges a critical translational gap, offering a renewable alternative to animal bioassays, a paradigm to dissect the biology of human sCJD prion disease and screen for therapeutic agents.},
}
@article {pmid42378334,
year = {2026},
author = {Hafeez, AS and Mumtaz, S and Kumar, L and Amir, M and Maity, R and Ashraf, S and Khan, A and Hassan, M and Zaman, A and Asad, M and Singh, P and Faisal, AR and Dhali, A},
title = {Nationwide trends and forecasts in Alzheimer's and cerebrovascular disease-related mortality in the United States, 1999-2023: A CDC WONDER analysis.},
journal = {The Journal of international medical research},
volume = {54},
number = {6},
pages = {3000605261454837},
doi = {10.1177/03000605261454837},
pmid = {42378334},
issn = {1473-2300},
mesh = {*Alzheimer Disease/mortality ; Humans ; United States/epidemiology ; *Cerebrovascular Disorders/mortality ; Female ; Aged ; Male ; Retrospective Studies ; Aged, 80 and over ; Centers for Disease Control and Prevention, U.S. ; Forecasting ; Mortality/trends ; },
abstract = {ObjectiveTo describe nationwide mortality patterns related to Alzheimer's disease and cerebrovascular disease in United States adults aged ≥65 years and explore future trend projections.MethodsIn this retrospective study, we utilized the Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research database (ICD-10 G30, I60-I69) to calculate crude and age-adjusted mortality rates per 100,000 population. Temporal trends were modeled using Joinpoint regression, and 10-year forecasts were obtained using autoregressive integrated moving average models. Subgroup analyses were performed by sex, race/ethnicity, census region, urbanization, and place of death.ResultsWe identified 199,606 Alzheimer's disease-cardiovascular disease-related deaths. Overall, age-adjusted mortality rates peaked at 24.8 in 2002, reduced to 14.2 in 2013, and then rose to 18.7 in 2020 before dropping to 16.6 in 2023. Women exhibited higher age-adjusted mortality rates than men (20.1 vs. 16.0). Individuals of White and Black ethnicity bore the greatest burden, and the South and West recorded the highest regional age-adjusted mortality rates. These rates were consistently higher in non-metropolitan areas than in metropolitan areas. Exploratory projections estimate an overall age-adjusted mortality rate of 16.6 by 2033, with persistently higher rates in women, non-Hispanic Black populations, and among those residing in the West and non-metropolitan areas.ConclusionsDespite substantial decline since the early 2000s, Alzheimer's disease-cardiovascular disease mortality remains high and unevenly distributed. Exploratory projections suggest that the burden will remain substantial, underscoring the need for targeted prevention, vascular risk reduction, and equity-focused dementia care.},
}
@article {pmid42378690,
year = {2026},
author = {El Wahab, MMA and Saad, S and El-Enany, N and Sheribah, ZA},
title = {A Sustainable Spectrofluorimetric Quenching Approach for Determination of Pentoxifylline or Donepezil HCl via Complexation With Erythrosine B: Application to Tablets and Human Plasma.},
journal = {Luminescence : the journal of biological and chemical luminescence},
volume = {41},
number = {7},
pages = {e70542},
doi = {10.1002/bio.70542},
pmid = {42378690},
issn = {1522-7243},
support = {//The Science, Technology &amp; Innovation Funding Authority (STDF)/ ; //The Egyptian Knowledge Bank (EKB)/ ; },
mesh = {Spectrometry, Fluorescence/methods ; *Pentoxifylline/blood/analysis ; Humans ; Donepezil ; *Erythrosine/chemistry ; Tablets/analysis ; *Indans/blood/analysis ; *Piperidines/blood/analysis ; },
abstract = {This work introduces a novel, green switch on-off spectrofluorimetric quenching method using erythrosine B (EB) for nano-trace determination of pentoxifylline (PTX) or donepezil HCl (DPZ) in tablets and spiked plasma, enabling rapid clinical monitoring. The suggested approach relies on the quenching effect of either DPZ or PTX on the intrinsic fluorescence of EB, various experimental conditions influencing fluorescence quenching were investigated and optimized. An ion pair complex is formed between the cationic amino group in either drugs and the anionic phenolic group of EB at mild acidic conditions using Britton-Robinson buffer. After excitation at 528 nm, the fluorescence quenching intensities were measured linearly at 552 nm across the range (50-1000 ng/mL) for PTX with quantification limits of 16.76 ng/mL and over the range (20-500 ng/mL) for DPZ with limit of quantification 17.56 ng/mL for DPZ. The suggested method exhibited high % recoveries, confirming its reliable applicability in complicated matrices. The validation of the suggested methodology was further performed in accordance with the International Conference of Harmonization (ICH Q2R2) recommendations. Furthermore, the method's greenness, blueness and whiteness profiles was investigated, revealing its remarkable sustainability.},
}
@article {pmid42378963,
year = {2026},
author = {Li, C and Tambo, W and Powell, K and Giliberto, L and Sciubba, D},
title = {Endogenous neuroprotection in vascular cognitive impairment and dementia.},
journal = {EBioMedicine},
volume = {129},
number = {},
pages = {106357},
doi = {10.1016/j.ebiom.2026.106357},
pmid = {42378963},
issn = {2352-3964},
abstract = {Vascular cognitive impairment and dementia (VCID), affecting millions globally with 30% higher mortality than Alzheimer's disease, lacks effective pharmacotherapies. Microvascular dysfunction emerges decades before clinical symptoms, driving irreversible neurodegeneration once established. Clinical results show that nonpharmacologic interventions demonstrate greater effectiveness: three-fold greater cognitive improvement and five-fold enhanced functional outcomes versus pharmacotherapy, while avoiding adverse effects that affect 40% of patients receiving pharmacological treatments. These interventions orchestrate convergent mechanisms: vascular restoration (reversing vasoconstriction, augmenting perfusion), metabolic reprogramming (mitochondrial/glucose optimisation), neuroinflammation resolution, oxidative stress mitigation, and synaptic preservation. Exercise, neuromodulation, dietary modification, environmental enrichment and conditioning medicine activate multilevel endogenous repair mechanisms inaccessible to pharmacological targeting. This review presents a comprehensive mechanistic framework elucidating how nonpharmacologic strategies modulate interconnected vascular/non-vascular domains. It highlights emerging bioelectronic medicine as a promising disease-modifying therapy, establishing nonpharmacologic interventions as first-line strategies that reconceptualize VCID from intractable neurodegeneration to a preventable, potentially reversible, condition.},
}
@article {pmid42379016,
year = {2026},
author = {Yi, Z and Yao, Z and Wang, F and Xu, M and Deng, C and Yao, W and Chen, X and Shi, J and Liu, F and Dong, W and Wang, X},
title = {Ribavirin mitigates Alzheimer's disease model phenotypes by enhancing lysosomal function and suppressing ISR.},
journal = {Bioorganic chemistry},
volume = {180},
number = {},
pages = {110142},
doi = {10.1016/j.bioorg.2026.110142},
pmid = {42379016},
issn = {1090-2120},
abstract = {Alzheimer's disease (AD) is a debilitating neurodegenerative disorder for which effective therapies remain an urgent unmet need. This study investigated the therapeutic potential of the synthetic nucleoside analogue ribavirin in transgenic Caenorhabditis elegans (C. elegans) models of AD. We demonstrate that ribavirin specifically reduced the paralysis rate and improved short-term non-associative learning capacity of the Aβ AD models. These functional benefits were supported by a marked reduction in Aβ aggregation in vivo and a direct inhibition of Aβ structural transition from α-helix to β-sheet in vitro. Moreover, ribavirin could stably bind to the Aβ1-42 pentamer, disrupt the existing β-sheet networks, and increase the solvent exposure of hydrophobic residues. Mechanistically, ribavirin exerted its neuroprotective effects by enhancing lysosomal activity, attenuating Aβ-induced activation of the integrated stress response (ISR) in C. elegans models. Genetic studies further revealed that the efficacy of ribavirin was functionally dependent upon AMPK signalling, suggesting critical role of AMPK pathway. Crucially, ribavirin acted selectively, as it did not broadly activate other canonical stress responses. These findings establish a strong mechanistic rationale for repurposing ribavirin as a potential neuroprotective agent targeting AD.},
}
@article {pmid42379091,
year = {2026},
author = {Athira, ET and Satija, J},
title = {Exploring peroxidase substrates driven etching of gold nanorods towards indirect detection of amyloid beta1-42.},
journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy},
volume = {363},
number = {Pt 2},
pages = {128318},
doi = {10.1016/j.saa.2026.128318},
pmid = {42379091},
issn = {1873-3557},
abstract = {Plasmonic enzyme-linked immunosorbent assay (pELISA) leverages the localized surface plasmon resonance (LSPR) property of noble metal nanoparticles to achieve enhanced sensitivity compared to conventional immunoassays. The geometric alteration of plasmonic nanoparticles through oxidative moieties generates distinct colorimetric signals that can be employed to develop an ultrasensitive point-of-care pELISA. Advancing pELISA requires a systematic exploration of enzymatic reactions and nanomaterials, allowing for the precise detection of trace biomolecules. The study systematically investigates the etching efficiency of gold nanorods (AuNRs) using the products of five horseradish peroxidase (HRP) substrates, i.e., 3,3,5,5-tetramethylbenzidine (TMB), o-phenylene diamine dihydrochloride (OPD), 2,2-azino-bis-3-ethylbenzothiazoline-6-sulphonic acid (ABTS), 3-amino-9-ethylcarbazol (AEC), and 3,3'diaminobenzidine (DAB). Each substrate was evaluated under controlled conditions to determine its ability to induce aspect ratio-dependent spectral shifts in AuNRs, enabling quantitative colorimetric detection. UV-Vis spectroscopy reveals that only the oxidized product of TMB (TMBox2) significantly etches the AuNRs, producing a notable blue shift in the LSPR peak. The optimized etching approach was applied to develop an indirect competitive pELISA for detecting amyloid beta1-42 (Aβ1-42), a key biomarker for Alzheimer's disease. This method demonstrated a limit of detection of 0.37 pg/mL (≈83.14 fM), highlighting its potential for ultrasensitive and precise biomolecule quantification.},
}
@article {pmid42379112,
year = {2026},
author = {Surer, HK and Yaylagul, NK},
title = {Effectiveness of a structured caregiver support program for caregivers of people with Alzheimer's disease: A mixed methods study.},
journal = {Geriatric nursing (New York, N.Y.)},
volume = {72},
number = {},
pages = {104170},
doi = {10.1016/j.gerinurse.2026.104170},
pmid = {42379112},
issn = {1528-3984},
abstract = {The aim of this study was to evaluate the effect of the Structured Caregiver Support Program (SCSP) on caregiver burden, psychological well-being and psychological resilience of informal caregivers of people with Alzheimer's disease. A mixed-method research design, comprising both quantitative and qualitative research methods was used in this study. The quantitative part of the study was designed as a randomized controlled study with a pretest-posttest design. In the qualitative part of the study, a phenomenological approach was used and three focus group interviews were conducted. The quantitative findings of the study show that the SCSP produced a statistically significant difference in the intervention group compared to the control group in terms of reducing caregiver burden and improving psychological well-being and psychological resilience levels (p < 0.05). The effect sizes (Cohen's d) obtained from the post-test comparisons between groups ranged from 0.921 to 2.134, indicating a "large" effect size. In the qualitative findings of the study as a result of thematic analysis, three main themes emerged: "need for an intervention program", "changes brought about by the intervention program", and "evaluation of the intervention program". The SCSP is easy to implement and cost-effective. It can be used as a practical intervention program, especially for professionals working in health and care services.},
}
@article {pmid42379387,
year = {2026},
author = {Larrán, B and López-Alonso, M and Miranda, M and González-Martínez, &#xc1; and Rosado, B and García-Belenguer, S and Herrero-Latorre, C and Insua, D and Suárez, ML and Santamarina, G and Orjales, I},
title = {Brain mineral concentrations in canine cognitive dysfunction.},
journal = {Veterinary journal (London, England : 1997)},
volume = {},
number = {},
pages = {106766},
doi = {10.1016/j.tvjl.2026.106766},
pmid = {42379387},
issn = {1532-2971},
abstract = {Canine cognitive dysfunction (CCD) is a prevalent age-related neurodegenerative condition in dogs that shares several features with Alzheimer's disease (AD). Although mineral dyshomeostasis has been implicated in the pathogenesis of AD, its role in CCD remains largely unexplored. This retrospective study aimed to investigate regional brain mineral concentrations in 24 dogs with CCD and 15 dogs exhibiting successful cognitive aging (non-CCD). CCD diagnosis was based on the results of caregiver questionnaires, physical examination and laboratory analyses after ruling out any other intracranial disease. Four cortical regions with high β-amyloid pathology (prefrontal, parietal, temporal and occipital cortex) and one generally unaffected region (cerebellum) were analysed to determine the concentrations of 20 minerals by using plasma-based optical techniques and mass spectrometry. Compared to non-CCD dogs, CCD dogs had significantly lower concentrations of Ca, Fe, Mg, Mn and Zn, and higher levels of Cd, Mo, Ni and Pb in specific brain regions. The greatest number of significant differences were observed in the prefrontal cortex, the earliest and most consistently affected region in CCD, whereas the cerebellum remained largely unchanged. Principal component analysis distinguished CCD from non-CCD dogs and, within the CCD group, showed clustering of the cerebellum separately from cortical regions. The regional specificity of these alterations and their ability to distinguish CCD from non-CCD dogs support a link between disrupted mineral homeostasis and CCD. Notably, lower concentrations affected essential trace elements involved in antioxidant defence, neuronal signalling and neurotransmission, raising the possibility of functional implications that warrants further investigation.},
}
@article {pmid42379406,
year = {2026},
author = {Sp, D and Lee, M and Kim, J and Cho, YJ and Kim, SH and Yang, HJ},
title = {Neuro-Ocular Amyloid Characterization in Alzheimer's Disease via Cross-Site PET-MRI and Hierarchical Cross-Attention Driven Multimodal Representation Learning.},
journal = {NeuroImage},
volume = {},
number = {},
pages = {122081},
doi = {10.1016/j.neuroimage.2026.122081},
pmid = {42379406},
issn = {1095-9572},
abstract = {The eye is often described as a window to the brain and may offer a non-invasive opportunity for investigating neurodegenerative changes. Although cerebral amyloid-β (Aβ) accumulation is a well-established hallmark of Alzheimer's disease (AD), the potential of ocular regions to capture aspects of this pathology in positron emission tomography (PET) remains underexplored. Our primary objective is to conduct a radiomics-SUVR analysis to investigate the relationship between ocular regions of interest (ROI) extracted from PET imaging and regional SUVR values obtained from six brain PET regions. Our secondary objective is to address domain shifts arising from heterogeneous data distributions across imaging sites during ocular segmentation. This study included 228 participants from Chonnam National University Hospital (CNUH) and an external validation cohort of 50 participants from ADNI-4, all with paired [18]F-florbetaben PET and 3D T2-weighted MRI. For the segmentation task, we propose HCA-Net, a Hierarchical Cross-Attention Network that integrates co-registered PET and MRI using a multi-scale fusion strategy, allowing the model to better handle domain shifts in cross-site imaging conditions. For the radiomics-SUVR analysis, the segmented ocular ROI was classified into Aβ[+] and Aβ[-] groups using a CNN model. Radiomic features were then extracted and compared with corresponding regional brain SUVRs using statistical methods. While several features showed group differences at an uncorrected threshold, only one feature remained significant after correction for multiple comparisons highlighting the need for further validation. Correlation analyses identified modest associations between ocular radiomics and regional brain SUVRs, highlighting the influence of global amyloid burden on these relationships. Overall, our study presents a multimodal cross-site segmentation framework and provides preliminary evidence of neuro-ocular associations in AD through [18]F-FBB PET imaging, highlighting the need for further validation.},
}
@article {pmid42379471,
year = {2026},
author = {Yi, C and Chen, W and Shi, X and Lin, Y and Zheng, Y and Luo, G and Pei, Z and Zhang, X},
title = {DTI-ALPS Associations with Regional Amyloid Deposition and Glucose Metabolism in Mild Cognitive Impairment and Alzheimer's Disease.},
journal = {Journal of neuroradiology = Journal de neuroradiologie},
volume = {},
number = {},
pages = {101586},
doi = {10.1016/j.neurad.2026.101586},
pmid = {42379471},
issn = {0150-9861},
abstract = {OBJECTIVES: The DTI analysis along the perivascular space (DTI-ALPS) index is widely used to assess water diffusion alterations in Alzheimer's disease (AD), yet its biological interpretation remains debated. We investigated DTI-ALPS associations with regional amyloid-β (Aβ) deposition, glucose metabolism, and cognitive function in Chinese patients with AD and mild cognitive impairment (MCI), offering finer-grained imaging evidence for its pathophysiological interpretation.<br><br>METHODS: 34 AD dementia (ADD) patients, 40 MCI patients, and 52 cognitively normal controls (NCs) underwent MRI, [18]F-florbetapir ([18]F-AV45) (standardized uptake value ratio, SUVR; centiloid values, CL), and [18]F-FDG (SUVR) imaging. MRI volumetry and PET quantification used Neurophet SCALE PET software. Mediation analysis tested ALPS effects between pathology/metabolism and cognition.<br><br>RESULTS: ALPS differed significantly across groups (ADD:1.152&#xb1;0.113; MCI:1.247&#xb1;0.122; NC:1.302&#xb1;0.121; p<0.001). Adjusted for age, sex, education, and APOE4, ALPS correlated positively with MMSE (r=0.324, p<0.001) and MoCA (r=0.311, p<0.001) and negatively with CL (r=-0.415, p<0.001). The ALPS index showed negative correlations with [18]F-AV45 PET SUVR in nearly all brain regions, with the strongest negative associations observed in the posterior cingulate (r=-0.459), paracentral (r=-0.445), superior frontal (r=-0.441), and inferior temporal (r=-0.433) regions. For [18]F-FDG PET SUVR, the ALPS index demonstrated bidirectional correlations: positive in regions including the inferior parietal (r=0.396), isthmus of cingulate (r=0.376), and precuneus (r=0.369), but negative in the paracentral (r=-0.418), precentral (r=-0.406), and cerebellar white matter (r=-0.374) (all p<0.001). Mediation analysis revealed that the ALPS index mediates the relationships between glucose metabolism/A&#x3b2; accumulation and both abstract thinking and memory. Parietal/cingulate isthmus/precuneus FDG metabolism showed significant ALPS-mediated indirect effects across cognitive domains (p<0.05).<br><br>CONCLUSIONS: The ALPS index correlates with A&#x3b2; deposition and exhibits region-specific metabolic associations in AD, mediating amyloid-metabolism-cognition pathways and predicting cognitive decline. These findings provide a region-wise correlation map of perivascular water diffusion alterations in AD, informing future research directions, though underlying mechanisms require validation.},
}
@article {pmid42379954,
year = {2026},
author = {Broatch, JR and Saner, NJ and Jackson, ML and Syeda, W and Bishop, DJ and Brodtmann, A},
title = {Exercise as a regulator of glymphatic function.},
journal = {Trends in neurosciences},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tins.2026.06.002},
pmid = {42379954},
issn = {1878-108X},
abstract = {The glymphatic system is a brain-wide perivascular network hypothesized to facilitate the clearance of waste products that accumulate during normal brain activity, including neurotoxic proteins implicated in neurodegenerative diseases. Emerging evidence suggests that exercise may modulate glymphatic function, offering a potential mechanism to help explain the neuroprotective effects of exercise. In this review, we synthesize evidence from animal models and humans on the organization and regulation of the glymphatic system, examine its vulnerability to aging and neurodegenerative pathology, and discuss the potential roles of exercise in enhancing its function. We propose that the convergence between known regulators of glymphatic function and the physiological adaptations to exercise provides a mechanistic framework linking physical activity to glymphatic integrity and brain resilience.},
}
@article {pmid42380051,
year = {2026},
author = {Maia, M and Monteiro, AR and Martins, MS and Martinez-Gonzalez, L and Martínez, A and Remião, F and Silva, R and Sousa, E},
title = {Novel Xanthene Derivatives for Neuroprotection in Alzheimer's Disease-Synthesis and Biological Assessment.},
journal = {ChemMedChem},
volume = {21},
number = {13},
pages = {e70352},
doi = {10.1002/cmdc.70352},
pmid = {42380051},
issn = {1860-7187},
support = {UIDB/04423/2020//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e a Tecnologia/ ; UIDP/04423/2020//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e a Tecnologia/ ; SFRH/BD/146211/2019//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e a Tecnologia/ ; 10.54499/2021.05964.B//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e a Tecnologia/ ; UIDP/04378/2020//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e a Tecnologia/ ; UIDB/04378/2020//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e a Tecnologia/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Neuroprotective Agents/pharmacology/chemical synthesis/chemistry ; *Xanthenes/pharmacology/chemistry/chemical synthesis ; Amyloid beta-Peptides/metabolism/antagonists &amp; inhibitors ; Structure-Activity Relationship ; Cell Line, Tumor ; Cell Survival/drug effects ; ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism ; Molecular Structure ; Dose-Response Relationship, Drug ; Peptide Fragments ; },
abstract = {Alzheimer's disease (AD) is recognized by the World Health Organization as a global public health priority. There is an urgent need to develop disease-modifying therapies or treatments (DMT's) to prevent, delay, or slow the progression and target the primary AD pathophysiology mechanisms. Following previous works on the activity of tricyclic compounds in neuroprotection, this work focuses on the synthesis of novel xanthene derivatives. Eighteen compounds were obtained and assessed regarding their cytotoxicity, central nervous system (CNS) penetration, P-glycoprotein (P-gp) modulation, and neuroprotective effects against iron- and amyloid-beta (Aβ)-induced cytotoxicity. Generally, the derivatives were well tolerated by differentiated human neuroblastoma SH-SY5Y cells at concentrations up to 25 μM. Regarding their ability to activate P-gp, compounds 5, 7, 9, 11, 12, and 16 showed the most significant increases in P-gp activity. Neuroprotection assays demonstrated the ability of several xanthene derivatives to counteract iron (III)- and Aβ-induced cytotoxicity. It was clearly demonstrated the P-gp involvement in compound-mediated ability to reverse the cytotoxicity induced by the Aβ25-35 peptide. Additionally, parallel artificial membrane permeability assay (PAMPA) studies showed their potential to penetrate the blood-brain barrier (BBB) and reach the CNS, which is a crucial requirement for their potential biological activity in AD.},
}
@article {pmid42380069,
year = {2026},
author = {Zhang, Y and Qiao, H and Lv, Z and Guo, R and Li, D and Song, W and Wang, D},
title = {Transcranial 810 nm Pulsed Photobiomodulation Improves Learning and Reduces Aβ42 Burden in APP/PS1 Mouse Model of Alzheimer's Disease.},
journal = {Photobiomodulation, photomedicine, and laser surgery},
volume = {},
number = {},
pages = {25785478261465371},
doi = {10.1177/25785478261465371},
pmid = {42380069},
issn = {2578-5478},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a leading cause of dementia in older adults, and effective and widely applicable treatment options remain limited. Photobiomodulation (PBM) has shown promise for AD. However, reported estimates of the delivered dose after transcranial propagation vary widely, limiting translation from animal models to clinical settings.<br><br>OBJECTIVE: Building on our team's prior clinical findings, this study evaluated whether an 810 nm/10 Hz pulsed PBM regimen improves cognitive performance and reduces A&#x3b2;42 burden in APP/PS1 mice.<br><br>METHODS: APP/PS1 mice received PBM using an 810 nm LED pulsed at 10 Hz. Irradiation was delivered for 540 sec/day, 6 days/week, for 7 weeks, with a scalp-surface power density of 0.025 W/cm[2] and an energy density of 13.5 J/cm[2]. Cognitive function was evaluated using the Morris water maze, and A&#x3b2;42 burden was quantified by immunofluorescence.<br><br>RESULTS: Cortical and hippocampal A&#x3b2;42 plaque burden was reduced, p < 0.01. Exploratory correlation analyses suggested an association between hippocampal A&#x3b2;42 plaque number and reversal-learning performance in the histological subset, p = 0.02. The microglia-A&#x3b2;42 colocalization ratio increased by 7.53%, p = 0.03, indicating enhanced spatial association between microglia and A&#x3b2;42 after PBM.<br><br>CONCLUSIONS: These findings support further evaluation of this 810 nm/10 Hz pulsed PBM regimen in AD mouse models and highlight the value of standardized PBM parameter reporting in preclinical studies.},
}
@article {pmid42380191,
year = {2026},
author = {de Rojas, I and García-González, P and Olivé, C and Puerta, R and Montrreal, L and Alegret, M and Sotolongo-Grau, O and Cano, A and Marquié, M and Valero, S and Calero, M and Rábano, A and Pastor, AB and Del Ser, T and Quintela, I and Macías, J and Corma-Gómez, A and Pineda, JA and Franco-Macías, E and Buiza-Rueda, D and Bernal Sánchez-Arjona, M and Royo, JL and Mendoza, S and Lage, C and Antúnez, C and Corbatón-Anchuelo, A and Martínez-Larrad, MT and Diez-Fairen, M and Alvarez, I and Huerto Vilas, R and Arias Pastor, A and Menéndez-González, M and Martínez Rodríguez, C and Rosas Allende, I and García-Madrona, S and Frank-García, A and Martín-Montes, A and Baquero, M and , and , and Pérez-Tur, J and Bullido, MJ and Garcia-Ribas, G and Álvarez, V and Piñol-Ripoll, G and Pastor, P and Rodriguez-Rodriguez, E and García-Alberca, JM and Mir, P and Real, LM and Medina, M and Sáez, ME and Carracedo, &#xc1; and Heneka, MT and Tàrraga, L and Boada, M and Sánchez-Juan, P and Fernández, MV and van der Lee, SJ and Ruiz, A},
title = {Landscape of copy number variants in Spanish people with dementia.},
journal = {NPJ genomic medicine},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41525-026-00589-6},
pmid = {42380191},
issn = {2056-7944},
support = {FI20/00215//Instituto de Salud Carlos III/ ; CD22/00125//Instituto de Salud Carlos III/ ; PI17/01474, PI19/00335, PI22/01403 and PI22/00258//Instituto de Salud Carlos III/ ; CNV-304-PRF-866//Centro de Investigaci&#xf3;n Biom&#xe9;dica en Red sobre Enfermedades Neurodegenerativas/ ; CB06/05/2004 and CB18/05/00010//Centro de Investigaci&#xf3;n Biom&#xe9;dica en Red sobre Enfermedades Neurodegenerativas/ ; GR@ACE project//'la Caixa' Foundation/ ; GR@ACE project//Fundaci&#xf3;n ADEY/ ; GR@ACE project//Fundaci&#xf3;n Echevarne/ ; GR@ACE project//Grifols/ ; PID2021-122473OA-I00, PID2021-123462OB-I00 and PID2019-106625RB-I00//Spanish Ministry of Science and Innovation, Proyectos de Generaci&#xf3;n de Conocimiento/ ; PMP22/00022//NextGenerationEU/ ; N&#xba; PR067/21//Agency for Innovation and Entrepreneurship (VLAIO)/ ; N&#xba; 115975//EU/EFPIA Innovative Medicines Initiative Joint/ ; ADAPTED and HARPONE projects//Janssen Pharmaceutica/ ; N&#xba; AC19/00097//Joint Program for Neurodegenerative Diseases (JPND)/ ; DESCARTES project//German Research Foundation (DFG)/ ; STAR Award//University of Texas System/ ; },
abstract = {Recent studies suggest that copy number variants (CNVs) may contribute to the missing heritability of complex diseases such as Alzheimer's disease (AD) and related dementias (ADRD). We performed a CNV analysis using genotyping data (Axiom 815 K Spanish biobank array) from the GR@ACE/DEGESCO dementia dataset (n = 20,067) of the Spanish population. Applying PennCNV and extensive quality control, 8275 controls and 7818 dementia cases were selected for gene-level case/control associations. We identified 43,833 CNVs with deletions (47%) and duplications (53%). No genome-wide significant associations were found, but nominal associations were observed in PKP3-SIGIRR and FBRSL1 loci. CNVs in 2970 genes were exclusive to dementia cases and enriched in vascular-related pathways. Notable findings included 14q11.2 duplication and VPS13B deletions in ADRD cases, the latter confirmed by optical genome mapping. Our findings suggest potential novel genes associated with ADRD in the Spanish population. However, the limited resolution of array-based technologies in detecting CNVs warrants further investigation.},
}
@article {pmid42380200,
year = {2026},
author = {Kazmi, SA and Chandra, F and Wasney, M and Cheng, J and Lum, GR and Iyer, M and Di Blasi, D and Espinoza, AN and Lopez-Romero, A and Yang, X and Garud, N and Hsiao, EY},
title = {Select microbial metabolites promote tau aggregation in a murine tauopathy model.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-026-74775-6},
pmid = {42380200},
issn = {2041-1723},
support = {2018-191860//Silicon Valley Community Foundation (SVCF)/ ; },
abstract = {The gut microbiome is emerging as a modifier of risk for neurodegenerative diseases, but underlying mechanisms remain poorly understood. Here, we show that the hTau.P301S mouse model for progressive tauopathy develops alterations in the composition and function of the gut microbiome that are not recapitulated in amyloid-based 5xFAD or 3xTg models for Alzheimer's disease. Disrupting the gut microbiome via chronic antibiotic treatment exacerbates cognitive deficits and tau pathology in hTau.P301S mice, demonstrating a causal influence of the microbiome on tau-driven disease progression. This corresponds with widespread alterations in microbiome-dependent metabolites in the sera and brains of hTau.P301S mice, including subsets that correlate with the severity of tau pathology. By screening against tau biosensor cells, we identify select microbial metabolites-trimethylamine-N-oxide, 3-indoxyl sulfate, phenol sulfate, thymidine, and 2'deoxyuridine-that promote tau seeding and aggregation. Systemic administration of these metabolites worsens cognitive impairment and tau pathology in hTau.P301S mice. These findings establish a mechanistic link between the gut microbiome, serum and brain metabolites, as well as tau aggregation, suggesting that select microbial metabolites could potentially serve as therapeutic targets for tau-driven diseases.},
}
@article {pmid42380532,
year = {2026},
author = {Mazahir, I and Wali, B and Rehman, AS and Deep, G and Mangla, A and Jindal, G and Khan, H and Parvez, S and Raisuddin, S},
title = {Alpha Lipoic Acid Mitigates TBI-Induced Neuroinflammation by Regulating S100B/STIM Signaling via NF-ƙB Pathway.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42380532},
issn = {1559-1182},
mesh = {Animals ; Male ; *Brain Injuries, Traumatic/metabolism/complications/pathology/drug therapy ; Rats, Wistar ; *Signal Transduction/drug effects ; *Thioctic Acid/pharmacology/therapeutic use ; *S100 Calcium Binding Protein beta Subunit/metabolism ; *NF-kappa B/metabolism ; *Neuroinflammatory Diseases/drug therapy/metabolism/pathology/etiology ; Microglia/metabolism/drug effects/ultrastructure ; Neuroprotective Agents/pharmacology ; Maze Learning/drug effects ; },
abstract = {Alpha-lipoic acid (ALA) is a natural compound present in plants, animals, and humans. It provides neuroprotection through its antioxidant action, reducing oxidative stress and inflammation via pathways such as the Nrf-2 signalling pathway. It has shown protective effect against neuronal damage in Alzheimer's disease and Parkinson's disease. The traumatic brain injury (TBI) is a major cause of cognitive and motor impairments. TBI primarily initiates a series of secondary injury pathways, with glutamate excitotoxicity being a critical factor in neuronal degeneration. In this study, we investigated the protective effects of ALA on TBI induced by controlled cortical impact (CCI) in the cerebral cortex (CC) and hippocampus (HC) regions of the Wistar rats. TBI parameters were analysed using behavioural assays, including the Barnes maze test (BMT), beam balance test, grip strength, and Y-maze test (YMT). In addition, we measured brain water content, and analyzed histological alterations by light microscopy, microglial changes by the immunofluorescence technique, and ultrastructural changes by the transmission electron microscopy (TEM). Expression of markers of glutaminergic and calcium (Ca[2][+]) pathways was analysed by qRT-PCR and western blotting. ALA was administered following TBI induction in rats. It was shown that ALA downregulated S100B and the N-methyl-D-aspartate (NMDA) receptor subunit 2B (GRIN2B) mRNA expression. However, TBI-dependent alterations in excitatory amino acid transporter (EAAT) expression were downregulated in the CC region of adult rats with TBI. Protein expression of S100B, stromal interaction molecule (STIM), ubiquitin C-terminal hydrolase L1 (UCHL1), nuclear factor kappa (NF-ƙB), and glial fibrillary acidic protein (GFAP) was increased in the TBI group, as analysed by immunoblotting. Furthermore, expression of Iba1[+], a marker of microglial activation, was increased in TBI and mitigated by ALA. Overall, this study helps us understand the role of ALA as a mitigating compound in the TBI-induced rat model.},
}
@article {pmid42380654,
year = {2026},
author = {Saha, P and Chouhan, A},
title = {QUAD: a composite risk framework integrating uncertainty, applicability domain, and model disagreement for reliable QSAR predictions.},
journal = {Journal of computer-aided molecular design},
volume = {40},
number = {1},
pages = {},
pmid = {42380654},
issn = {1573-4951},
mesh = {*Quantitative Structure-Activity Relationship ; *Amyloid Precursor Protein Secretases/antagonists &amp; inhibitors/chemistry/metabolism ; *Aspartic Acid Endopeptidases/antagonists &amp; inhibitors/chemistry/metabolism ; *Glycogen Synthase Kinase 3 beta/antagonists &amp; inhibitors/chemistry/metabolism ; Uncertainty ; Humans ; *Alzheimer Disease/drug therapy ; Reproducibility of Results ; Random Forest ; Models, Molecular ; },
abstract = {Reliable prediction confidence estimation remains a major challenge in quantitative structure-activity relationship (QSAR) modeling, particularly when models are applied to structurally novel compounds or heterogeneous experimental datasets. Although several uncertainty quantification approaches have been proposed, the relative behavior of complementary reliability indicators under extrapolative validation conditions remains insufficiently characterized. In the present study, we introduce QUAD, a post-hoc reliability estimation framework integrating ensemble-based uncertainty, model disagreement, and applicability-domain (AD) risk into a unified molecule-level reliability score. The framework was evaluated using Random Forest regression and ECFP4 molecular fingerprints on two Alzheimer's disease-related benchmark datasets targeting β-site amyloid precursor protein cleaving enzyme 1 (BACE1) and glycogen synthase kinase-3β (GSK3β). Reliability behavior was systematically assessed under both conventional random train-test validation and more stringent Bemis-Murcko scaffold-based validation. In addition to evaluating the integrated QUAD framework, component-wise ablation analysis and reliability enrichment analysis were performed to investigate the relative contributions of uncertainty, disagreement, and applicability-domain information. Under conventional random-split evaluation, ensemble uncertainty demonstrated the strongest and most consistent correlation with prediction error across both datasets. For BACE1, uncertainty achieved Pearson and Spearman correlations of 0.366 and 0.338, respectively, while the integrated QUAD framework produced lower correlations (Pearson r = 0.303, Spearman ρ = 0.244). In contrast, GSK3β exhibited stronger overall reliability behavior, with QUAD retaining substantial correlation with prediction error (Pearson r = 0.439). Scaffold-based evaluation revealed pronounced dataset-dependent differences. Under scaffold extrapolation, QUAD performance deteriorated substantially in BACE1 (Pearson r = 0.071), whereas GSK3β retained comparatively robust reliability behavior (Pearson r = 0.363). Ablation analyses further demonstrated that ensemble uncertainty represented the most stable reliability indicator across validation regimes, while disagreement-based reliability estimation exhibited substantial sensitivity to structural extrapolation. Taken together, the present results indicate that integrated reliability estimation frameworks should not be interpreted as universally superior to individual uncertainty estimation approaches. Instead, the effectiveness of composite reliability estimation appears strongly dependent on dataset-specific relationships between constituent reliability indicators and validation conditions. The study further highlights the importance of scaffold-based evaluation for realistic assessment of molecule-level reliability estimation strategies in practical QSAR deployment scenarios.},
}
@article {pmid42380894,
year = {2026},
author = {Almeida-Meza, P and Dregan, A and Croak, B and Hettiaratchy, S and Fear, NT and Stevelink, SAM},
title = {Leveraging primary care data to understand military veteran health in England: feasibility study and matched-control comparison of recorded conditions.},
journal = {BMC medicine},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12916-026-05005-5},
pmid = {42380894},
issn = {1741-7015},
support = {FiMT21/1023KCL//Forces in Mind Trust/ ; },
abstract = {BACKGROUND: Evidence on the health needs of UK veterans accessing primary care is limited. Electronic health records (EHRs) offer an opportunity to address this evidence gap if veterans are correctly identified. This study validated the identification of veterans in the Clinical Practice Research Datalink (CPRD) and assessed its feasibility for examining their health compared with non-veterans.<br><br>METHODS: We conducted a matched cohort study in CPRD, the largest primary care database in the UK, identifying veterans using military-related codes in patients' EHRs. Each veteran was matched to one or two non-veterans on age, gender, practice, and index date. Validation was undertaken through general practitioner confirmation of veteran status. We compared demographics, risk factors and recorded health conditions using descriptive statistics. Poisson regressions assessed the association between veteran status and various physical and mental health conditions.<br><br>RESULTS: 122,484 veterans and 244,573 matched non-veterans were identified. 95% were captured using definite military terms, and validation showed substantial agreement with GP records. Veterans had higher recorded prevalence across all conditions. The largest differences were observed for PTSD (adjusted prevalence ratio [aPR] 16.43, 95% CI 14.89-18.13), followed by Alzheimer's disease (aPR 2.74, 95% CI 2.56-2.92), alcohol use disorder (aPR 2.23, 95% CI 2.09-2.39), hearing loss (aPR 2.09, 95% CI 2.02-2.15), and osteoarthritis (aPR 1.98, 95% CI 1.93-2.03). Recorded prevalence was also higher among veterans for COPD (aPR 1.83, 95% CI 1.77-1.89), depression (aPR 1.83, 95% CI 1.79-1.87), prostate cancer (aPR 1.83, 95% CI 1.73-1.94), coronary heart disease (aPR 1.78, 95% CI 1.72-1.84), lower back pain (aPR 1.73, 95% CI 1.70-1.77), and myocardial infarction (aPR 1.65, 95% CI 1.56-1.75). Differences for anxiety and breast cancer were modest.<br><br>CONCLUSIONS: This study establishes a foundation for UK veterans' health research using primary care data. Provided that identification and recording of veteran status improve in NHS records, CPRD offers considerable potential to monitor veteran health trends, identify needs, and evaluate interventions at scale.},
}
@article {pmid42381088,
year = {2026},
author = {Verberk, IMW and de Koning, LA and Coomans, EM and Trieu, C and Leeuwis, AE and Hunter, J and Honigberg, L and van der Flier, WM and Vijverberg, EGB and Ossenkoppele, R and van de Giessen, E and Teunissen, CE},
title = {The potential of key Alzheimer's plasma biomarkers to mimic tau PET MUBADA-based disease staging.},
journal = {Alzheimer's research &amp; therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02085-6},
pmid = {42381088},
issn = {1758-9193},
abstract = {BACKGROUND: Patients with Alzheimer's disease (AD) with a low to intermediate tau-PET burden might benefit most from anti-amyloid treatment. Staging tau burden with plasma biomarkers would offer a scalable alternative to staging with tau-PET. This study investigated whether key plasma biomarkers P-tau217, P-tau181, Aβ42/40, GFAP and NfL can be used to accurately stage amyloid status (A-/A+) and tau-PET burden, and evaluated the relation of such a plasma-based staging system with cognitive outcomes over time.<br><br>METHODS: We included 105 participants with subjective cognitive decline (n&#x2009;=&#x2009;27&#xa0;A-, n&#x2009;=&#x2009;18 A+), A+ mild cognitive impairment (n&#x2009;=&#x2009;10) or A&#x2009;+&#x2009;AD-dementia (n&#x2009;=&#x2009;50) from the Amsterdam Dementia Cohort who underwent [[18]F]flortaucipir PET-burden assessment (Tlow, Tintermediate or Thigh; based on MUBADA SUVr) and longitudinal cognitive assessment (average follow-up: 4.1&#x2009;&#xb1;&#x2009;3.5 years). AD-related plasma biomarkers were measured with Simoa. Discriminative performance (AUC) of each marker was compared using ROC analysis, and combined utility was assessed with logistic regression. Subsequently, cutoffs were established aiming for 90%-specificity, to regroup participants into a plasma-based staging scheme. Age-, sex- and education-adjusted linear mixed models (LMM) were performed to compare associations of plasma versus PET-based staging with longitudinal cognition.<br><br>RESULTS: 27 participants were A-TPET_low, 22&#xa0;A+TPET_low, 27&#xa0;A+TPET_int and 29&#xa0;A+TPET_high. To discriminate A-TPET_low participants from A+TPET_low/int participants, P-tau217 performed best among all measured markers P-tau217, P-tau181, A&#x3b2;42/40, GFAP and NfL (AUC&#x2009;=&#x2009;0.92 [95% CI: 0.856-0.985]). To discriminate A+TPET_high participants from A+TPET_low/int participants, also P-tau217 performed best among all markers (AUC&#x2009;=&#x2009;0.74 [95% CI: 0.618-0.862]). A combination of Wald's backward-selected plasma markers did not statistically improve discriminative performance (DeLong's p&#x2009;>&#x2009;0.05; two-marker combinations selected). Applying two cutoffs for P-tau217 as well as for the two-marker combinations, at 90% specificity to discriminate subsequent groups, we derived two plasma-based staging schemes. While the tau-PET staging scheme significantly and consistently associated with cognitive performance and decline across cognitive domains in LMMs, the plasma staging schemes did not.<br><br>CONCLUSIONS: Performance of plasma-based staging approaches developed in this study were high when discriminating individuals without amyloid pathology, while this was moderate when discriminating amyloid positive individuals with a high tau-PET burden. Our LMM findings visualize that tau staging in amyloid-positive individuals remains optimally performed with tau-PET scans.},
}
@article {pmid42381106,
year = {2026},
author = {Seok, JW and Kim, K and Kim, JU and Chun, JM},
title = {Association of inflammatory fluid biomarkers with the progression of Alzheimer's disease: a protocol for a systematic review and meta-analysis.},
journal = {Systematic reviews},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13643-026-03252-4},
pmid = {42381106},
issn = {2046-4053},
support = {NSN2512053//Ministry of Science and ICT, South Korea/ ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease that typically begins with mild cognitive impairment (MCI) and gradually worsens to mild, moderate, and severe dementia. There is increasing evidence that inflammatory responses in both peripheral and central compartments contribute to the pathophysiology of AD. However, meta-analyses that compare the changes in inflammatory biomarkers according to AD stages remain limited. This study aims to systematically evaluate the differences in inflammatory marker levels according to AD progression stages and to assess their potential utility as stage-specific biological indicators.<br><br>METHODS: This meta-analysis will be conducted according to the PRISMA-P guidelines. PubMed, Embase, Cochrane Library, and MEDLINE will be searched for studies involving elderly people aged 60&#xa0;years or older with MCI or AD diagnosed through June 30, 2025. According to the PECO framework, the primary comparison will be each AD-related clinical stage, including MCI, mild AD, moderate AD, and severe AD, versus cognitively normal older adults. Secondary analyses will examine between-stage comparisons when sufficient data are available. The primary outcomes will be inflammatory biomarker levels measured in blood-derived samples, including serum and plasma. Cerebrospinal fluid inflammatory biomarkers will be included as predefined secondary outcomes and analyzed separately. Biomarkers of interest include IL-6, CRP, TNF-&#x3b1;, IL-1&#x3b2;, YKL-40, complement C3, C5a, IL-2, IFN-&#x3b3;, GFAP, sTREM2, ferritin, and related inflammatory markers. Literature selection and data extraction will be performed independently by two reviewers. Statistical analysis will be performed using JASP to calculate the standardized mean differences (SMD) and 95% CI. A heterogeneity test, meta-regression, subgroup analysis, sensitivity analysis, and publication bias test will also be performed.<br><br>DISCUSSION: This study will systematically evaluate stage-specific changes in inflammatory biomarkers and identify potential response patterns and biological relevance of each marker in relation to AD progression. This review will examine whether some biomarkers follow nonlinear trajectories rather than linear changes, which may help explore their association with pathological mechanisms such as microglial activation and peripheral-central immune axis changes. This meta-analysis may provide foundational data for the development of inflammatory fluid biomarkers for early diagnosis and stage-specific prognosis in AD.<br><br>As this protocol is not eligible for registration in PROSPERO, a preliminary search has been performed to confirm that there are no duplicate systematic reviews.},
}
@article {pmid42381140,
year = {2026},
author = {Li, Y and Xie, K and Qian, S and Wang, Z and Zhang, H and Si, L},
title = {Quantifying Short-Term Functional Changes After Lecanemab Treatment in Early Alzheimer's Disease: An Exploratory 3-Month Follow-Up Case Report Using Eye Movement and Gait Analysis.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050471024260520113701},
pmid = {42381140},
issn = {1875-5828},
abstract = {INTRODUCTION: Lecanemab is a monoclonal antibody targeting amyloid-β (Aβ) and is currently used in clinical practice for the treatment of early Alzheimer's disease (AD). However, noninvasive biomarkers reflecting its early efficacy are still unclear. This exploratory case report aims to investigate the combination of eye movement and gait analysis to quantitatively monitor shortterm functional changes during lecanemab treatment.<br><br>CASE PRESENTATION: Two male patients, both diagnosed with mild Alzheimer's disease through amyloid- PET and both with the APOE &#x3b5;3/&#x3b5;3 genotype, received intravenous lecanemab (10 mg/kg, every two weeks) for three months. Cognitive assessments (Montreal Cognitive Assessment, Mini- Mental State Examination, Clinical Dementia Rating), eye movement tests (smooth pursuit, overlapping saccades, anti-saccades), and gait analysis under single-task and dual-task conditions were conducted at baseline and follow-up. Patient 1 (79 years old) showed stable cognitive function, significant improvement in multiple eye movement parameters, and partial improvement in gait under single-task conditions. Patient 2 (60 years old) did not follow up on cognitive function tests as scheduled and showed inconsistent changes in eye movement parameters, but improved selected gait measures under dual-task conditions, particularly a shorter turning time. Neither patient experienced Amyloid-Related Imaging Abnormalities or infusion-related adverse events during the infusion process.<br><br>CONCLUSION: This exploratory case report suggests that eye movement and gait analysis may be sensitive to short-term functional changes following lecanemab treatment, which were not consistently captured by traditional cognitive scales. These findings are hypothesis-generating and warrant further investigation in larger studies. Multimodal functional assessment may hold promise as a tool for monitoring early treatment effects in Alzheimer's disease.},
}
@article {pmid42381141,
year = {2026},
author = {Mehrabadi, S},
title = {The Role of Digital Health Technologies in Early Detection and Management of Alzheimer's Disease.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050415800251226061142},
pmid = {42381141},
issn = {1875-5828},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and functional impairment, posing significant challenges for early detection and management. In recent years, digital health technologies have emerged as promising tools to enhance the diagnosis, monitoring, and treatment of AD. This review paper explores the multifaceted role of digital health technologies in the early detection and management of Alzheimer's disease. We examine the use of wearable devices that monitor cognitive function and daily activities, as well as mobile health applications designed for cognitive training and symptom tracking. Additionally, we analyze the impact of telehealth services in providing remote care, particularly for underserved populations. The integration of artificial intelligence and machine learning for analyzing behavioral and cognitive data to support early diagnosis and risk assessment is also discussed. Furthermore, we explore the concept of digital biomarkers and their potential to complement traditional diagnostic methods. Ethical considerations surrounding privacy, data security, and informed consent are addressed to ensure responsible implementation of these technologies. Finally, we highlight gaps in current research and propose future directions for integrating digital health technologies into Alzheimer's care, emphasizing the potential for personalized interventions tailored to individual patient needs. This review underscores the transformative potential of digital health to reshape Alzheimer's disease management and improve patient outcomes.},
}
@article {pmid42381155,
year = {2026},
author = {Zhao, S and Huang, Q and Nie, B and Zhang, T and Zuo, C and Zhang, G and Mao, G and Shan, B},
title = {Decomposition-based harmonization for quantitative PET imaging across scanners and radiotracers.},
journal = {Medical physics},
volume = {53},
number = {7},
pages = {e70545},
doi = {10.1002/mp.70545},
pmid = {42381155},
issn = {2473-4209},
support = {12575380//National Natural Science Foundation of China/ ; 12205329//National Natural Science Foundation of China/ ; 11975249//National Natural Science Foundation of China/ ; 12175268//National Natural Science Foundation of China/ ; },
mesh = {*Positron-Emission Tomography/instrumentation ; *Image Processing, Computer-Assisted/methods ; Phantoms, Imaging ; Humans ; Radioactive Tracers ; },
abstract = {BACKGROUND: Quantitative positron emission tomography (PET) is widely applied in oncology, neuroscience, and clinical practice. However, its quantitative accuracy is often compromised by systematic variability arising from differences in scanners, acquisition protocols, and radiotracers, which limits the reliability of multicenter studies.<br><br>PURPOSE: To develop and validate PETHarmony, a novel voxel-level harmonization framework for minimizing inter-scanner and inter-tracer&#xa0;variability.<br><br>METHODS: PETHarmony utilizes a linear neural network to model covariates and singular value decomposition to isolate and remove variability in voxel space. Its performance was assessed in four scenarios: (i) using paired 18 F $^{18}
{\rm F}
$ -FBB PET/CT and PET/MR scans (N = 25, Huashan Hospital) to test the removal of scanner variability; (ii) using 20 repeated PET acquisitions of a NEMA NU-2 IQ phantom to validate absolute quantitative accuracy; (iii) using paired 18 F $^{18}
{\rm F}
$ -FBP and 11 C $^{11}
{\rm C}
$ -PiB scans from GAAIN (N = 46); and OASIS (N = 84) to evaluate cross-tracer consistency of cortical SUVR; and (iv) using unpaired multicenter data from ADNI (N = 471; 18 F $^{18}
{\rm F}
$ -FBP, 18 F $^{18}
{\rm F}
$ -FTP, 18 F $^{18}
{\rm F}
$ -FDG) to assess the impact on Alzheimer's disease (AD) classification. All harmonization procedures were conducted using leave-one-out cross-validation or by training on unpaired data and applying the learned transformations to paired&#xa0;data.<br><br>RESULTS: PETHarmony effectively eliminated voxel-level discrepancies between PET/CT and PET/MR images (P < 0.05 $P < 0.05$ reduced to n.s.). Phantom validation demonstrated that recovery coefficient curves were restored and closely aligned with the reference line, indicating improved quantitative accuracy. For cross-tracer consistency, linear regression between 18 F $^{18}
{\rm F}
$ -FBP and 11 C $^{11}
{\rm C}
$ -PiB was markedly improved toward the line of identity (y = x, R 2 $^{2}
$ = 1). Specifically, in the GAAIN cohort, the regression line improved from y = 0.52x + 0.52, R 2 ${\rm R}
^{2}
$ = 0.89 to y = 0.93x + 0.13, R 2 $^{2}
$ = 0.97. In the OASIS cohort, it improved from y = 0.51x + 0.55, R 2 ${\rm R}
^{2}
$ = 0.87 to y = 0.95x + 0.06, R 2 ${\rm R}
^{2}
$ = 0.95. Furthermore, PETHarmony improved multicenter AD classification accuracy by 15.3% (18 F $^{18}
{\rm F}
$ -FBP), 18.3% (18 F $^{18}
{\rm F}
$ -FTP), and 21.7% (18 F $^{18}
{\rm F}
$ -FDG).<br><br>CONCLUSIONS: PETHarmony achieves robust voxel-level harmonization of multicenter PET data, significantly improving cross-scanner and cross-tracer consistency and enhancing diagnostic accuracy. It provides a practical solution for standardizing quantitative PET in multicenter oncology, neuroscience, and other clinical&#xa0;trials.},
}
@article {pmid42381270,
year = {2025},
author = {Mirjalili, M and Brooks, H and Ma, C and Lee, A and Bikson, M and Voineskos, AN and Blumberger, DM and Fischer, CE and Flint, AJ and Herrmann, N and Kumar, S and Lanctôt, K and Mah, L and Mulsant, BH and Pollock, BG and Rajji, TK and , },
title = {Impact of Transcranial Direct Current Stimulation-Induced Electric Fields on Slowing Cognitive Decline in Older Adults With Mild Cognitive Impairment or Remitted Major Depressive Disorder: An Analysis of the PACt-MD Randomized Clinical Trial.},
journal = {Biological psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.biopsych.2025.09.020},
pmid = {42381270},
issn = {1873-2402},
abstract = {BACKGROUND: Mild cognitive impairment and remitted major depressive disorder increase the risk of dementia. The PACt-MD (Prevention of Alzheimer's Dementia With Cognitive Remediation Plus Transcranial Direct Current Stimulation in Mild Cognitive Impairment and Depression) trial (NCT02386670) has shown that combined cognitive remediation (CR) and transcranial direct current stimulation (tDCS) improve cognitive outcomes by targeting executive function and presumably leveraging neurophysiological mechanisms. Our study investigated whether the magnitude of electric fields (EFs) induced by tDCS in the dorsolateral prefrontal cortex (DLPFC) predicted cognitive response in PACt-MD participants.<br><br>METHODS: Data from the 143 PACt-MD participants (mean [SD] age = 71.8 [6.34] years) who received active CR+tDCS and had brain magnetic resonance imaging (MRI) were analyzed. EFs were estimated using individual MRI with tDCS electrode placement at Fz (anode) and Iz (cathode). Participants were split into high- and low-EF groups based on the median. We used linear mixed models to assess the effect of EF in the left and right DLPFC on global cognitive decline, the primary outcome of PACt-MD, over 72 months. The global cognitive decline is the average of z scores on all tests on the neuropsychological battery.<br><br>RESULTS: EF magnitude in the left DLPFC was associated with global cognitive decline (likelihood ratio test: p = .026). Participants with high EF showed slower cognitive decline than those with low EF, irrespective of diagnosis and APOE &#x3b5;4 status. No significant association was observed for the right DLPFC.<br><br>CONCLUSIONS: Our findings support that high EF in the DLPFC is associated with the efficacy of CR+tDCS. In future studies, tDCS dosing that results in a higher EF in the left DLPFC may improve the cognitive outcomes of CR+tDCS.},
}
@article {pmid42381275,
year = {2026},
author = {Yang, J and Mao, T and Gao, L},
title = {Role of incretins in Alzheimer's disease and their impact on behavioral aspects.},
journal = {Chinese medical journal},
volume = {},
number = {},
pages = {},
pmid = {42381275},
issn = {2542-5641},
abstract = {Recent studies highlight the therapeutic potential of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), two key incretin components, in neurodegenerative diseases, particularly Alzheimer's disease (AD). Although the incretin pathway may also affect other neurodegenerative conditions, this discussion focuses on AD. The therapeutic benefits are largely attributed to their role in enhancing energy metabolism. In vivo and in vitro studies have demonstrated that GLP-1 and GIP exert neuroprotective effects through the inhibition of oxidative stress, neuroinflammation, and neuronal apoptosis, while improving cellular metabolic function. Additionally, an emerging but often overlooked body of evidence suggests that incretin may influence human behaviors, such as eating habits, sleep patterns, physical activity, and vulnerability to substance addiction. These behavioral changes could, in turn, support neural regeneration through various molecular mechanisms. This article summarizes recent advancements in the understanding of incretin's influence on human behavior and its implications for AD.},
}
@article {pmid42381285,
year = {2026},
author = {Tan, H and Zhang, G and Du, C and Li, X and Bai, Y and Mao, L and Yang, F and Qi, Q and Zhao, N and Shi, W and Zhao, Y and Chang, M},
title = {The creation and verification of a detection model for mild cognitive impairment by employing eye-tracking and gait metrics.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261464176},
doi = {10.1177/13872877261464176},
pmid = {42381285},
issn = {1875-8908},
abstract = {BackgroundMild cognitive impairment is a prodromal stage of dementia, and early identification is crucial for prognosis.ObjectiveThis study aims to create and validate a machine learning model for diagnosing mild cognitive impairment (MCI) using eye movement and gait analysis data.MethodsTo facilitate model training and internal validation, a cohort of 235 patients was recruited from the Memory Clinic at Xi'an NO.3 Hospital between August 2024 and November 2025. In addition, data from 71 patients were randomly selected to form an independent test set. Feature selection was conducted using the Least Absolute Shrinkage and Selection Operator (LASSO) and multivariable logistic regression. Subsequently, various machine learning classifiers were compared. Model performance was assessed using metrics such as the area under the receiver operating characteristic curve (AUC) and decision curve analysis. To evaluate model interpretability, SHapley Additive exPlanations (SHAP) were employed.ResultsThe study involved 235 participants, divided into mild cognitive impairment (MCI) (n = 130) and healthy control (HC) (n = 105) groups. The final prediction model used four features: gait speed during a dual-task test, ground reaction force in a single-task test, antisaccade task accuracy, and noise rate in a saccade-to-pursuit task. The Gaussian Naive Bayes (GNB) classifier showed excellent performance with an AUC of 0.952 (95% CI: 0.923-0.981) in the validation group and 0.944 (95% CI: 0.912-0.967) in the test set.ConclusionsThe GNB model, combining eye movement and gait parameters, enables early MCI detection with high accuracy and practical clinical use.},
}
@article {pmid42381297,
year = {2026},
author = {Kim, JH and Lee, Y and Liao, Y and Schmid, CH and Kim, D and Trivedi, A and Meyers, DJ and Markides, K and Colon Vargas, M and Rosales, R and Crowe, M and Rivera-Hernandez, M},
title = {Diagnosis of Alzheimer's disease and related dementias and outmigration of older Puerto Rican Medicare Fee-for-service beneficiaries, 2012-2019.},
journal = {The journals of gerontology. Series B, Psychological sciences and social sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/geronb/gbag116},
pmid = {42381297},
issn = {1758-5368},
abstract = {OBJECTIVES: There is limited research on whether receiving a dementia diagnosis could prompt later-life migration, particularly among older Medicare beneficiaries in Puerto Rico. Prior research shows older Puerto Ricans are migrating to the mainland United States (U.S.), which may include those with an Alzheimer's Disease and Related Dementias (ADRD) diagnosis. This study examined yearly outmigration trends among older Puerto Ricans by exploring their movement patterns in 2011-2019.<br><br>METHODS: We used data from the Medicare Master Beneficiary Summary File and the Puerto Rican Community Survey and focused on Medicare Fee-for-Service enrollees aged 65 and older. The Chronic Conditions Warehouse algorithm was used to ascertain ADRD diagnosis, and migration was defined as the change of (end-of-year) residence from one year to the next. A linear probability model was used to calculate differences in the rate of outmigration between beneficiaries with and without ADRD.<br><br>RESULTS: Across the study period, the sample averaged 53,294 beneficiaries per year (43,819 [2019] to 66,625 [2012]), with 15% having a previous ADRD diagnosis each year. Overall, older Puerto Ricans previously diagnosed with ADRD were slightly more likely to move to the U.S. mainland compared to those without a diagnosis across the years (adjusted differences of b&#x2009;=&#x2009;0.14&#x223c;0.42%), though differences were statistically significant in some years. For example, outmigration spiked (over 2.5%) among all older adults in the year of Hurricane Maria, regardless of health status.<br><br>DISCUSSION: Our results suggest that older Puerto Ricans with ADRD are more likely to migrate as they face challenges in aging in place.},
}
@article {pmid42381348,
year = {2026},
author = {Cary, GA and Young, JE and Rose, SE and Frankowski, H and Wilkins, H and Amirtha Ganesh, SS and Draper, J and Darvas, M and Bothwell, M and Jayadev, S and Reid, AN and Greenwood, A and Levey, AI and Leal, K and Carter, GW and Wiley, JC},
title = {Kat5 cKO mouse replicates biological domain signatures associated with Alzheimer's disease.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71562},
doi = {10.1002/alz.71562},
pmid = {42381348},
issn = {1552-5279},
support = {//Emory-Sage-SGC-JAX TREAT-AD Center/ ; U54AG065187/AG/NIA NIH HHS/United States ; R01AG080585/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; *Alzheimer Disease/genetics/metabolism ; Humans ; *Lysine Acetyltransferase 5/genetics/metabolism ; Mice ; Mice, Knockout ; *Hippocampus/metabolism ; Neurons/metabolism ; Amyloid beta-Protein Precursor/metabolism/genetics ; Transcriptome ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) can be caused by autosomal-dominant familial Alzheimer's disease (FAD) mutations in amyloid precursor protein (APP) or presenilin-1 and 2, which form an enzyme substrate complex. KAT5 binds to the APP intracellular domain. Recent reports of decreased γ-secretase activity in FAD mutants support KAT5 membrane sequestration.<br><br>METHODS: We compare the hippocampal transcriptome profiles of the Kat5 brain-specific knockout (KO) mouse to multiple AD datasets through alignment with the TREAT-AD AD biological domains. We examine KAT5 subcellular localization in human wild-type and AD neurons.<br><br>RESULTS: The Kat5 KO mouse demonstrates downregulation of synaptic genes, metabolic pathways, and upregulation of DNA replication and repair, cell cycle, and immune response genes. We see similar profiles in Kat5 and comparative AD datasets. KAT5 is restricted to the cytosol in human AD neurons.<br><br>DISCUSSION: This analysis supports the hypothesis that KAT5 nuclear signaling downstream of APP cleavage plays a pivotal role in neuronal homeostasis.},
}
@article {pmid42381349,
year = {2026},
author = {Li, Y and Wang, D and Zhou, R and Yan, S and Wang, D and Wei, Y and Yao, H and Zhou, B and Lu, J and Wang, P and Liao, Z and Han, Y and Zhang, X and Zhang, Y and Liu, Y and Zhao, K and , },
title = {Human brain connectome profiles mediate the relationship between pathology burden and clinical phenotypes in Alzheimer's disease.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71638},
doi = {10.1002/alz.71638},
pmid = {42381349},
issn = {1552-5279},
support = {T2425027//National Natural Science Foundation of China/ ; 82401858//National Natural Science Foundation of China/ ; 62201091//National Natural Science Foundation of China/ ; 2025KYQD22//Research Initiation Project for Introduced Talents of BUPT/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/genetics ; *Connectome ; *Brain/pathology ; *Cognitive Dysfunction/pathology ; Phenotype ; Female ; Aged ; Male ; Disease Progression ; Magnetic Resonance Imaging ; },
abstract = {INTRODUCTION: Mild cognitive impairment (MCI), a prodromal stage of Alzheimer's disease (AD), shows pronounced clinical heterogeneity poorly explained by pathology burden, representing a gap complicating prognosis. As the brain operates as a complex network for information integration, we hypothesized that connectome architecture mediates the link between AD pathology and clinical expression.<br><br>METHODS: We developed a framework integrating structural and functional connectomes from multi-center cohorts, performing connectome-based subtyping in MCI, with analyses of upstream pathology, downstream phenotypes, and transcriptomic associations.<br><br>RESULTS: This approach identified an "MCI-compromised" (MCI-C) subgroup characterized by extensive structural-functional connectomic disruption and an "MCI-preserved" (MCI-P) subgroup with relatively preserved connectome integrity. Despite comparable pathology, MCI-C demonstrated more severe neurodegeneration, accelerated cognitive decline, and elevated progression risk. Multiscale analyses linked these patterns to transcriptomic profiles of mitochondrial, synaptic, and neuroimmune processes.<br><br>DISCUSSION: These findings demonstrate that the connectome acts as a critical mediator, rather than a passive endophenotype, shaping AD clinical expression.},
}
@article {pmid42381352,
year = {2026},
author = {Panteleienko, L and Banerjee, G and Mallon, D and Chan, E and Fandler-Höfler, S and Oliver, R and Harvey, V and Jaunmuktane, Z and Collinge, J and Werring, DJ},
title = {Evidence for progressive neurodegeneration in iatrogenic cerebral amyloid angiopathy.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71640},
doi = {10.1002/alz.71640},
pmid = {42381352},
issn = {1552-5279},
mesh = {Humans ; *Cerebral Amyloid Angiopathy/pathology/diagnostic imaging/etiology/complications ; Female ; Male ; Iatrogenic Disease ; Atrophy/pathology ; Magnetic Resonance Imaging ; Retrospective Studies ; Adult ; *Brain/pathology/diagnostic imaging ; Middle Aged ; Disease Progression ; Neuropsychological Tests ; Alzheimer Disease/pathology/etiology ; },
abstract = {INTRODUCTION: Iatrogenic transmission of amyloid beta can cause cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD), but the relationship between these phenotypes is unclear.<br><br>METHODS: We retrospectively analyzed standardized neuropsychological and neuroimaging data from 11 patients with iatrogenic CAA (iCAA). Brain MRI was assessed for medial temporal lobe atrophy (MTA), the posterior atrophy score for parietal atrophy, and global cortical atrophy (GCA).<br><br>RESULTS: All patients (mean age 42 &#xb1; 8.3 years) had childhood neurosurgery; 91% had confirmed cadaveric dura exposure. Six patients (55%) presented with intracerebral hemorrhage, and none showed MTA, parietal atrophy, or GCA at presentation. Over a median 5-year follow-up, 8/11 (73%) developed atrophy on at least one score, moderate to severe in three patients. Cognitive impairment was present in 9/11 (82%) at a median 3-year follow-up. AD was confirmed histopathologically in 2/4 (50%) examined cases.<br><br>DISCUSSION: Progressive brain atrophy and cognitive impairment are common in iCAA, suggesting frequent co-existing neurodegeneration and possible AD pathology. Vigilance for cognitive decline may enable earlier identification and management.},
}
@article {pmid42381490,
year = {2026},
author = {Turk, KW and Marin, A and Karaca, M and Price, AM and Palumbo, R and Budson, AE},
title = {Reaction time as a performance validity measure in older adults with and without early-stage Alzheimer's disease.},
journal = {Applied neuropsychology. Adult},
volume = {},
number = {},
pages = {1-12},
doi = {10.1080/23279095.2026.2692527},
pmid = {42381490},
issn = {2327-9109},
abstract = {INTRODUCTION: Performance validity assessment is important in evaluating older adults with and without cognitive impairment. Performance validity tests (PVTs) such as the Test of Memory Malingering (TOMM) may inaccurately classify Alzheimer's disease (AD) patients as testing invalid despite genuine effort. We explored an alternative PVT using reaction time (RT).<br><br>METHODS: Healthy older controls (OCs; N&#x2009;=&#x2009;20) and AD patients (N&#x2009;=&#x2009;20) completed an auditory oddball task and the TOMM. Over two counterbalanced sessions, OCs performed honestly and simulated dementia; AD patients completed one honest session.<br><br>RESULTS: RT differed between OC honest and simulating conditions and between AD and OCs in both conditions. Using a composite reflecting RT differences between true positives and false alarms, simulators took more time generating false alarms than true positives compared to AD patients (p&#x2009;=&#x2009;0.021; r&#x2009;=&#x2009;0.364). The composite did not differ between OC honest and AD groups. The RT composite showed comparable specificity to the TOMM in classifying AD patients (80% vs. 75% for TOMM Trial 2 and 65% for Trial 1).<br><br>DISCUSSION: The RT composite performed similarly to the TOMM without relying as heavily on episodic memory. It warrants investigation as a complement to memory-based PVTs. Future studies should replicate these findings in larger, education-matched samples.},
}
@article {pmid42381527,
year = {2026},
author = {Lee, HJ and Yoon, B and Hong, YJ and Jeong, JH and Kim, S and Wang, MJ and Choi, SH and Ryu, JS and Kang, S and Park, KH and Yang, DW},
title = {APOE Genotype Modifies the Predictive Performance of Plasma Biomarkers for Amyloid Plaque Burden in Subjective Cognitive Decline.},
journal = {Journal of Korean medical science},
volume = {41},
number = {25},
pages = {e184},
doi = {10.3346/jkms.2026.41.e184},
pmid = {42381527},
issn = {1598-6357},
support = {P0018061/KIAT/Korea Institute for Advancement of Technology/Korea ; HI18C0530/MOHW/Ministry of Health and Welfare/Korea ; },
mesh = {Humans ; *Biomarkers/blood ; Amyloid beta-Peptides/blood ; *Cognitive Dysfunction/diagnosis/pathology/genetics ; Positron-Emission Tomography ; Glial Fibrillary Acidic Protein/blood ; Female ; Neurofilament Proteins/blood ; tau Proteins/blood ; ROC Curve ; Male ; *Plaque, Amyloid/pathology ; Retrospective Studies ; Aged ; Genotype ; *Apolipoprotein E4/genetics ; Peptide Fragments/blood ; Area Under Curve ; *Apolipoproteins E/genetics ; Alzheimer Disease/diagnosis/genetics ; Middle Aged ; },
abstract = {BACKGROUND: Apolipoprotein E (APOE) ε4 is a well-known risk factor for Alzheimer's disease (AD), with ε4 carriers exhibiting distinct clinical and biological characteristics compared to non-carriers. This study investigated whether the predictive performance of plasma biomarkers for amyloid positron emission tomography (PET) outcomes varies by APOE ε4 carrier status in individuals with subjective cognitive decline (SCD).<br><br>METHODS: We retrospectively analyzed baseline data from the Cohort Study to Identify Predictors for the Clinical Progression to Mild Cognitive Impairment or Dementia from Subjective Cognitive Decline. Plasma levels of the amyloid beta (A&#x3b2;) 42/40 ratio, glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and phosphorylated tau (pTau) 181 were quantified using Single Molecule Array technology. We assessed predictive performance of plasma biomarkers for amyloid PET outcomes using receiver operating characteristic analysis and linear regression models.<br><br>RESULTS: The study included 104 participants, with 20 APOE &#x3b5;4 carriers and 84 non-carriers. Among &#x3b5;4 carriers, NfL (area under the curve [AUC] = 0.909), GFAP (AUC = 0.904), and pTau181 (AUC = 0.828) showed the highest predictive accuracy. For non-carriers, the most predictive biomarkers were pTau181/A&#x3b2;42 (AUC = 0.872), A&#x3b2;42/A&#x3b2;40 (AUC = 0.794), and pTau181 (AUC = 0.761). Significant interactions between APOE and biomarkers were noted for GFAP (P = 0.005) and NfL (P = 0.010) in predicting amyloid plaque burden.<br><br>CONCLUSION: Plasma biomarkers exhibit differential predictive performance for amyloid pathology based on APOE genotype, with GFAP and NfL showing interaction with APOE genotype. These findings suggest the importance of considering APOE genotype when interpreting plasma biomarker results for AD diagnosis in individuals with SCD.<br><br>TRIAL REGISTRATION: Clinical Research Information Service Identifier: KCT0003397.},
}
@article {pmid42381622,
year = {2026},
author = {Preeti, and Akanksha, and Khurana, N},
title = {Pongamol as a multitarget neuroprotective candidate: an integrative analysis of in silico predictions and biological evidence.},
journal = {Natural product research},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/14786419.2026.2694726},
pmid = {42381622},
issn = {1478-6427},
abstract = {Pongamol, a bioactive flavonoid derived from Pongamia pinnata (Fabaceae), has gained attention as a potential therapeutic agent for neurological disorders. Neurodegenerative and neuropsychiatric conditions such as Alzheimer's, Parkinson's, epilepsy, anxiety and depression are driven by oxidative stress, neuroinflammation, mitochondrial dysfunction, apoptosis and neurotransmitter imbalance, while current treatments remain largely symptomatic. This study evaluates the neuroprotective potential of pongamol using integrated in silico and experimental approaches. SwissADME analysis revealed favourable pharmacokinetic properties, including good oral bioavailability, high gastrointestinal absorption, blood-brain barrier permeability and non-substrate behaviour for P-glycoprotein. Prediction of activity spectra of substances predictions indicated antioxidant, anti-inflammatory, anti-Alzheimer's, antiparkinsonian, GABAergic, nootropic and cytoprotective activities. Target mapping identified interactions with potassium channels, melatonin receptors, phosphodiesterase-4D and kynurenine pathway enzymes. These findings were further supported by limited experimental studies suggesting possible attenuation of oxidative stress, suppression of neuroinflammation, inhibition of apoptosis and improvement in cognitive and behavioural outcomes in disease models, highlighting pongamol as a promising multitarget neuroprotective candidate.},
}
@article {pmid42381975,
year = {2026},
author = {Zhang, C and Fang, D and Zhang, L},
title = {Brain Endothelial Glycocalyx as a Blood-Facing Translational Interface in Alzheimer's Disease: Beyond "Leaky" Barriers Toward Repair-First Stratification.},
journal = {Drug design, development and therapy},
volume = {20},
number = {},
pages = {619901},
pmid = {42381975},
issn = {1177-8881},
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology/drug therapy ; *Glycocalyx/metabolism/pathology ; *Blood-Brain Barrier/metabolism/pathology ; Animals ; *Brain/metabolism/pathology ; },
abstract = {Alzheimer's disease (AD) pathogenesis is increasingly recognized as involving blood-brain barrier (BBB) and neurovascular unit (NVU) destabilization. The brain endothelial glycocalyx-a blood-facing glycan-rich interface-represents a critical but under-characterized determinant of BBB dysfunction in AD. In this review, we systematically reappraised glycocalyx abnormality mechanisms, distinguishing robust causal evidence from murine models from limited human observational data. We propose a four-dimensional interface-state framework (structural, glycosylation, transport, inflammatory) to stratify patients beyond binary "leaky versus intact" classifications. Glycocalyx deterioration in AD reflects compartmentalized remodeling (early mucin-domain depletion) rather than uniform shedding. A reversible therapeutic window exists in APOE4 carriers and mild cognitive impairment, but collapses with concurrent cerebral amyloid angiopathy (CAA) or amyloid-related imaging abnormalities (ARIA). Pathological glycocalyx disruption amplifies nonproductive vascular retention rather than parenchymal penetration. We advocate a hierarchical "repair-first, transport-engineering-second, exploitation-last" strategy. This repositions the glycocalyx as a decisive arbiter governing BBB-targeted interventions in AD, not merely a structural appendage.},
}
@article {pmid42382036,
year = {2026},
author = {Hofmann, A and Paczynski, M and Ponisio, MR and Saef, B and Roberts, JP and Powell, WJB and Gupta, A and Oh, I and Hofford, M and Posey, Z and Aldinger, M and Benzinger, TLS and Morris, JC and Snider, BJ and Schindler, SE},
title = {Performing multiple biomarker tests delays initiation of amyloid-targeting treatments.},
journal = {Alzheimer's &amp; dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70387},
pmid = {42382036},
issn = {2352-8729},
abstract = {INTRODUCTION: With the clinical availability of amyloid-targeting treatments (ATTs), accurate and timely biomarker-based diagnosis of Alzheimer's disease (AD) has become increasingly important. Three AD biomarker modalities are commonly available in clinical practice: amyloid positron emission tomography (PET), cerebrospinal fluid (CSF) tests, and blood tests.<br><br>METHODS: We investigated the use and agreement of different biomarker modalities in a memory clinic. Further, we calculated the time until ATT initiation for patients who underwent a single test versus multiple biomarker tests.<br><br>RESULTS: The blood test agreed with amyloid PET in nine of 11 patients and CSF tests in all 14 patients. The median time from first clinic visit to ATT initiation was 4.7 months in 209 patients who underwent a single test and 8.1 months in 12 patients who underwent multiple tests.<br><br>DISCUSSION: Performing multiple biomarker tests delays initiation of ATT and should be restricted to patients with uncertain amyloid status following the first biomarker test.},
}
@article {pmid42382037,
year = {2026},
author = {Haque, M and Brookes, KJ and Shao, B},
title = {Anti-amyloid therapy eligibility in a longitudinal brain-donor cohort with post mortem confirmation.},
journal = {Alzheimer's &amp; dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70400},
pmid = {42382037},
issn = {2352-8729},
abstract = {INTRODUCTION: Anti-amyloid therapies (AATs) for Alzheimer's disease (AD) demonstrate modest benefit in trials, but real-world eligibility remains uncertain. Requirements including biomarker confirmation and safety exclusions may limit access.<br><br>METHODS: Using the Brains for Dementia Research cohort, we linked longitudinal cognitive data with post mortem neuropathology to estimate trial-like AAT eligibility. Early stage was defined using harmonized cognitive thresholds. AD pathology required Thal amyloid phase &#x2265;3 and Braak stage &#x2265;IV. Exclusions were applied hierarchically: (1) vascular neuropathology, (2) anticoagulant use, and (3) apolipoprotein E (APOE)&#xa0;&#x3b5;4/&#x3b5;4&#xa0;homozygosity.<br><br>RESULTS: Of 1230 participants, 945 had sufficient data; 232 had early, pathology-confirmed AD. Vascular pathology excluded 70.7%, anticoagulant use 19.1%, and APOE &#x3b5;4/&#x3b5;4 homozygosity 3.6% of remaining cases. Overall, 53 individuals (4.3% of those screened) were eligible. Eligibility declined with age and was driven primarily by vascular comorbidity.<br><br>DISCUSSION: Using a conservative pathology-anchored framework, only a small proportion of this older brain-donor cohort met trial-like eligibility criteria.},
}
@article {pmid42382038,
year = {2026},
author = {Yang, Y and Xu, J and Hou, Y and Zhou, Y and Saykin, AJ and Cheng, F},
title = {Deep contrastive learning framework identifies cell-type-specific drug targets in Alzheimer's disease.},
journal = {Alzheimer's &amp; dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70406},
pmid = {42382038},
issn = {2352-8729},
abstract = {INTRODUCTION: Identifying disease-modifying drug targets is crucial for developing effective Alzheimer's disease (AD) treatments.<br><br>METHODS: We present a deep contrastive learning framework for cell type-specific AD-associated genes identification (alzCL). alzCL creates cell-type-specific representations of genes by integrating human brain single-nucleus RNA-sequencing data with the human protein-protein interactome, thereby capturing both genetic signatures and functional features.<br><br>RESULTS: By integrating human brain snRNA-seq data, alzCL outperforms the state-of-the-art models by 18% to 24% in area under the receiver operating characteristic curve. Via alzCL, we computationally identified 16, 164, and 221 AD-associated genes across astrocytes, microglia, and inhibitory neurons, respectively. Top prioritized genes (e.g., MAP3K5, P2RX4, and PRKD1) are significantly enriched in multiple AD-associated inflammatory and other pathobiological pathways. By integrating drug-target interaction data with alzCL-predicted AD-associated genes, we identified potential repurposable drugs for AD, including selonsertib and paroxetine.<br><br>DISCUSSION: AlzCL offers a deep contrastive learning framework for discovery of disease-associated genes and drug targets in AD.},
}
@article {pmid42382181,
year = {2026},
author = {DeDecker, K and Iroanyah, N and Morrison, A and Datta, J and Abejirinde, IO and Siu, CR and Stergiou-Dayment, C and Paron, S and Studzinski, CM},
title = {From community to policy: a frontline model for dementia assessment and brain health.},
journal = {Frontiers in dementia},
volume = {5},
number = {},
pages = {1821709},
pmid = {42382181},
issn = {2813-3919},
abstract = {Globally, dementia prevalence is projected to rise from approximately 55 million people in 2025 to 139 million by 2050. In Ontario, prevalence is estimated to reach 756,100 people by 2050-an increase of 202% since 2020-placing increasing strain on care partners, families, and health systems (Alzheimer Society of Canada, 2022). Throughout Ontario and Canada more broadly, existing pathways for cognitive screening, assessment, and diagnosis are constrained by limited primary care capacity, prolonged specialist wait times, and inequitable access, leaving many individuals without timely assessment or connection to supports. To help address these gaps, the Alzheimer Society of Ontario (ASO) and the Ontario Brain Institute (OBI) leveraged an existing community-delivered cognitive assessment process and enhanced it through the co-development of a provincial dementia registry-the first of its kind in Canada. This novel integrated approach embeds structured cognitive and functional assessment within community organizations, shares assessment results with primary care, and links standardized data to a provincial registry infrastructure. Together, this supports timely identification of cognitive concerns and enables the collection of a standardized minimum dataset-including cognitive, functional, demographic, and care-related information-across diverse populations. The dementia registry can serve as infrastructure to evaluate dementia-related innovations (including digital cognitive-screening tools) in real-world settings and support evidence generation to inform service planning and policy development, while strengthening earlier connection to supports and more coordinated care pathways for individuals and their care partners. This approach is aligned with emerging regulatory emphasis on real-world evidence (U.S. Food and Drug Administration, 2018; European Medicines Agency, 2021; Health Canada, 2019) and with Ontario's Improving Dementia Care in Ontario Act (2024), illustrating how co-designed, frontline-led approaches may bridge community needs and health system decision-making. Together, this work lays the groundwork for a scalable framework to advance equitable, person-centred dementia care in Ontario and beyond.},
}
@article {pmid42382525,
year = {2026},
author = {Bernhardt, AM and Höglinger, GU and Palleis, C},
title = {From clinical phenotypes to molecular stratification: early differential diagnosis of four-repeat tauopathies.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1801615},
pmid = {42382525},
issn = {1663-4365},
abstract = {Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are primary tauopathies defined by aggregation of four-repeat (4R) tau, yet early in vivo diagnosis remains limited by the dissociation between clinical phenotype and molecular pathology. Clinical presentations are heterogeneous, evolve over time, and frequently overlap with Alzheimer's disease, synucleinopathies, and mixed pathologies, particularly in corticobasal syndrome. As a result, clinical criteria provide structured phenotypic classification but have constrained specificity in early disease. This review synthesizes current evidence relevant to early diagnostic stratification in 4R tauopathies, integrating clinical criteria, supportive biomarkers of neurodegeneration, and emerging tau-directed molecular tools. The probabilistic value and limitations of contemporary criteria frameworks are discussed alongside the role of structural and functional imaging, dopaminergic imaging, and fluid markers as indicators of disease intensity and progression rather than molecular specificity. Advances in tau positron emission tomography and tau seed amplification assays are reviewed as biologically grounded approaches that directly interrogate aggregated and seed-competent tau species, with growing evidence for their potential contribution to individual-level stratification. Collectively, the literature supports a layered diagnostic approach in which clinical phenotype, supportive biomarkers, and tau-directed molecular measures are integrated to refine attribution of 4R tau pathology in vivo, a prerequisite for mechanism-based therapeutic development.},
}
@article {pmid42382677,
year = {2026},
author = {Siam, NH and Nasrin, N and Saiyara, S and Saha, H and Deb, DP and Islam, J},
title = {Medicinal Plants and Their Bioactive Phytochemicals as Emerging Therapeutic Strategies for Alzheimer's Disease: An Integrative Review of Preclinical and Clinical Evidence.},
journal = {Scientifica},
volume = {2026},
number = {},
pages = {6124916},
pmid = {42382677},
issn = {2090-908X},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by β-amyloid deposition, tau hyperphosphorylation, mitochondrial dysfunction, oxidative stress, neuroinflammation, and blood-brain barrier disruption, collectively leading to widespread cortical and subcortical atrophy. Current FDA-approved pharmacotherapies, including acetylcholinesterase inhibitors and memantine, provide only modest symptomatic relief and fail to halt disease progression, underscoring the urgent need for alternative therapeutic approaches. Growing evidence highlights medicinal plants and their bioactive phytoconstituents as promising candidates for AD prevention and treatment because of their multitarget mechanisms, favorable safety profiles, and long history of traditional use. This review synthesizes extensive in vitro, in vivo, and clinical studies demonstrating the neuroprotective potential of plant extracts and isolated compounds that exert antioxidant, anti-inflammatory, antiamyloidogenic, anti-tau, cholinesterase-inhibitory, and synaptic-modulating effects. Key medicinal species, including Abelmoschus esculentus, Brassica oleracea, Cannabis sativa, Citrus reticulata, Lantana camara, Launaea taraxacifolia, Lawsonia inermis, Marrubium vulgare, Markhamia lutea, Persicaria minor, Pithecellobium dulce, Salvia aristata, Trigonella foenum-graecum, and Withania somnifera, show significant cognitive and neuroprotective benefits in experimental AD models. Phytochemicals such as sulforaphane, nobiletin, trigonelline, diosgenin, verbascoside, withaferin A, and withanolides strongly modulate the amyloid, tau, oxidative, and inflammatory pathways. Clinical trials further support the therapeutic potential of several plant-derived interventions for mild cognitive impairment and AD-related dementia. Collectively, these findings highlight medicinal plants and their active constituents as compelling complementary or translational strategies for AD management, warranting further mechanistic and clinical validation. This review aims to evaluate the neuroprotective potential of medicinal plants and their bioactive compounds in preventing and managing AD by summarizing evidence from in vitro, in vivo, and clinical studies.},
}
@article {pmid42382756,
year = {2026},
author = {Xing, JF and Mu, K and Yan, X and Yang, X and Zhang, D and Gao, W and Zhang, T and Yang, S and Wang, R and Zhang, W and Zhu, Y},
title = {Calibrating microglia states in Alzheimer's disease: decoding immune-metabolic networks and nano-targeted multicomponent therapies.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1843978},
pmid = {42382756},
issn = {1664-3224},
mesh = {*Alzheimer Disease/metabolism/immunology/therapy/pathology ; Humans ; *Microglia/metabolism/immunology/pathology/drug effects ; Animals ; Amyloid beta-Peptides/metabolism ; Metabolic Networks and Pathways ; },
abstract = {Alzheimer's disease treatment is shifting from pathology removal to regulating the brain microenvironment. Anti-Aβ monoclonal antibodies, such as lecanemab and donanemab, provide statistically significant disease-modifying effects but offer only modest cognitive improvement and pose safety risks, including amyloid-related imaging abnormalities. These results show that amyloid clearance is clinically relevant but not sufficient for full restoration of neuroimmune, metabolic, synaptic, and neurovascular balance. Microglia are now seen as central to Alzheimer's disease susceptibility and progression, existing along dynamic, spatially organized, sex-influenced, and genetically determined continua beyond a simple pro- or anti-inflammatory state. This review calls out three key drivers of microglial dysfunction: the TREM2-APOE lipid-sensing axis, complement-mediated synaptic elimination, and immunometabolic reprogramming-including glycolysis, mitochondrial damage, autophagy failure, NAD+ depletion, and innate immune signaling. We examine natural bioactive compounds, metabolic modulators, and biomimetic nanodelivery as promising, yet currently unproven, strategies for adjusting microglial state. Future therapies should incorporate both pathology removal and microenvironment protection, tailored by disease stage, genetic profile, sex, vascular risk, and microglial state-associated biomarkers.},
}
@article {pmid42382939,
year = {2026},
author = {Tamondong-Lachica, DR and Villanueva, CAG and Roxas-Timonera, M and Palileo-Villanueva, LM and , },
title = {Philippine Clinical Practice Guidelines for Periodic Health Examination: Lifestyle Interventions for Adults and Adolescents.},
journal = {Acta medica Philippina},
volume = {60},
number = {10},
pages = {71-89},
pmid = {42382939},
issn = {2094-9278},
abstract = {BACKGROUND: Lifestyle has a considerable impact on the prevalence and prognosis of noncommunicable diseases, which continue to be the leading causes of morbidity and mortality in the country and around the world. Cardiovascular disease, cancer, chronic lung disease, and diabetes are universally recognized as being significantly related to modifiable behaviors such as tobacco smoking, physical inactivity, and poor diet. Alzheimer's disease, multiple sclerosis, depression, and anxiety disorders have also been linked to lifestyle factors. Interventions to encourage healthy lifestyles and discourage hazardous behaviors among individuals aim to lower the burden of noncommunicable illnesses, improve survival, and improve individuals' and communities' overall quality of life.<br><br>OBJECTIVE: This Philippine clinical practice guideline (CPG) was developed to provide recommendations on nonpharmacologic approaches to promote healthy lifestyles among adults and adolescents.<br><br>METHODS: The Periodic Health Examination 2 (PHEX2) Lifestyle Advice Task Force proceeded through the preparation and prioritization, CPG generation, CPG appraisal, and implementation based on the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to CPG development recommended by the Department of Health (DOH). Nonpharmacological interventions of interest for this guide-line were clinical interventions that pertain to strategies done or recommended by individual providers to patients, likely in a clinic setting. Evidence review experts systematically reviewed existing clinical practice guidelines, appraised, and summarized the evidence. For questions on specific advice on healthy diet and physical activity, the ADAPTE methodology was applied after appraising existing CPGs with the AGREE II instrument. A multisectoral panel formulated recommendations through a formal consensus based on the evidence summaries. The CPG was externally reviewed prior to publication. In addition to general questions on financial and intellectual conflicts of interest (COI), typically associated with the pharmaceutical industry, specific questions related to lifestyle, such as involvement with weight loss clinics or programs, wellness centers, tobacco, and e-cigarettes, were included.<br><br>RESULTS: Nineteen (19) recommendations were made by the consensus panel, including adopting the WHO guidelines on physical activity and diet. During the consensus panel meetings, the impact of lifestyle-focused interventions on disease prevention was primarily considered, as well as the effect of these interventions on the prognosis of established diseases.<br><br>CONCLUSIONS: The Philippine Guidelines on PHEX Phase 2 Lifestyle Advice CPG is a systematic synthesis of evidence to address lifestyle or nonpharmacologic interventions in preventing diseases and promoting better health. More evidence on the effectiveness and safety outcomes of lifestyle-related interventions, direct evidence for the prevention of internet addiction and internet gaming disorder, longer follow-ups for effects of electronic nicotine delivery systems (ENDS), and studies on cost-effectiveness, patients' preferences, and health equity impact assessments are needed to make more robust recommendations on a healthy lifestyle.},
}
@article {pmid42383056,
year = {2026},
author = {Liu, DZ and Cheng, GL and Hu, CF and Li, RY and Yang, CC and Chen, NC and Li, X and Jiang, DY and Chang, JY},
title = {Alternative splicing-based therapeutics for neurodegenerative diseases: a dual-database bibliometric and NLP-driven analysis (2000-2025).},
journal = {Frontiers in medicine},
volume = {13},
number = {},
pages = {1849726},
pmid = {42383056},
issn = {2296-858X},
abstract = {BACKGROUND: Neurodegenerative diseases (NDDs) are driven by complex molecular dysregulation, among which aberrant alternative splicing (AS) has emerged as a critical pathogenic mechanism. Despite the rapid development of splicing-targeted therapeutics, including antisense oligonucleotides (ASOs) and small molecules, comprehensive big-data syntheses mapping this translational landscape remain scarce. This study systematically analyzes the global research trends, conceptual frameworks, and clinical evolution of AS-based therapeutics for NDDs using an integrated bibliometric and natural language processing (NLP) approach.<br><br>METHODS: A dual-database retrieval strategy utilized the Web of Science Core Collection (WoSCC) and PubMed. The analysis targeted literature published between January 1, 2000, and December 31, 2025. A primary dataset of 620 records was extracted from WoSCC for comprehensive bibliometric mapping and Latent Dirichlet Allocation (LDA) topic modeling. A parallel analysis incorporated 10 targeted clinical trials and randomized controlled trials (RCTs) from PubMed using CLARA clustering to characterize high-evidence research. Bibliometric analyses, encompassing network topologies, citation bursts, and keyword evolution, were visualized using VOSviewer, CiteSpace, SCImago, and R.<br><br>RESULTS: Publication output exhibited sustained linear growth from 2000 to 2025. The United States and Western Europe emerged as the dominant collaborative hubs, while China exhibited high productivity but limited international integration. LDA topic modeling identified three core conceptual axes: molecular mechanisms, disease-specific pathological models (e.g., ALS, Alzheimer's, and SMA), and translational methodological frameworks. Keyword trajectories delineated a transition from fundamental in vitro exploration to in vivo models, culminating in clinical "drug discovery" and "RNA" therapeutics. CLARA clustering of clinical trials demonstrated a stark concentration of splicing-modifying interventions in pediatric spinal muscular atrophy (SMA), revealing a dual-track paradigm of supportive care and molecular interventions.<br><br>CONCLUSION: This multi-database bibliometric and NLP-driven study delineates the structural landscape of AS-based therapeutics for NDDs. It identifies a definitive paradigm shift from descriptive molecular biology to clinically actionable splicing interventions. These insights highlight the necessity to expand targeted RNA platforms beyond SMA into adult neurodegenerative populations, providing a strategic roadmap for future translational research.},
}
@article {pmid42383163,
year = {2026},
author = {van Alphen, JL and Pozzi, FE and Booij, J and Barkhof, F and Ten Kate, M and Teunissen, CE and van der Flier, WM and Lemstra, AW},
title = {Longitudinal biomarkers in dementia with Lewy bodies: A systematic review and meta-analysis.},
journal = {Clinical parkinsonism &amp; related disorders},
volume = {15},
number = {},
pages = {100470},
pmid = {42383163},
issn = {2590-1125},
abstract = {INTRODUCTION: Dementia with Lewy bodies (DLB) is the second most prevalent neurodegenerative dementia. It is clinically and biologically heterogeneous, yet longitudinal biomarker studies assessing different aspects of neuropathological processes in DLB are scarce. We systematically reviewed the literature to identify biomarkers suitable for tracking disease progression in DLB and to evaluate potential outcome measures for clinical trials by examining which biomarkers show longitudinal changes correlating with clinical progression.<br><br>METHODS: Following PRISMA guidelines, we searched CENTRAL, MEDLINE, Embase, Scopus, and Web of Science for longitudinal biomarker studies in DLB (sample size &#x2265;10, follow-up duration &#x2265;6&#xa0;months). We conducted meta-analysis of three structural MRI-studies assessing whole-brain atrophy.<br><br>RESULTS: Of 9162 titles screened, 17 studies met selection criteria including &#xb1;460 patients with MCI-LB/DLB. 15 studies included imaging biomarkers (MRI, SPECT, PET) and two studies included fluid biomarkers (plasma, CSF). Except for DAT-SPECT, most studies addressed non-DLB specific neurodegeneration or Alzheimer's disease (AD) pathology. Structural MRI-studies showed greater longitudinal atrophy in AD and mixed DLB&#xa0;+&#xa0;AD versus DLB and controls. Meta-analysis confirmed that DLB-patients were comparable to controls (p&#xa0;=&#xa0;0.37), but showed lower atrophy rates than AD (p&#xa0;=&#xa0;0.01). Amyloid-PET and biofluid studies suggested that amyloid accumulation follows typical progression, even in non-AD diagnoses. DAT-SPECT and FDG-PET demonstrated longitudinal changes correlating with clinical progression, showing promise as monitoring biomarkers.<br><br>CONCLUSION: No single biomarker currently suffices to track disease progression in DLB. DAT-SPECT and FDG-PET showed promise, but further research is warranted on these and alternative, more disease-specific, accessible and feasible modalities to improve disease monitoring in future clinical trials.},
}
@article {pmid42383392,
year = {2026},
author = {Sabouri, E and Shahmoradi, T and Keshvari, NZ and Khodaee, P and Saleki, K and Rezaei, N},
title = {Role of Toll-like receptors and oral-gut-brain axis in neurodegenerative and neuropsychiatric disorders.},
journal = {Reviews in the neurosciences},
volume = {},
number = {},
pages = {},
pmid = {42383392},
issn = {2191-0200},
abstract = {The oral-gut-brain axis is a path connecting the gastrointestinal tract and the central nervous system (CNS). The gut microbiota influences the immune system, metabolism, and nerve cells through the production of neurotransmitters and microbial metabolites that can cross the blood-brain barrier (BBB). The interplay between neuroinflammation and altered oral and gut microbiota is a bidirectional complex path modulated by inflammatory mediators. Recent studies suggest a potential role for Toll-like receptor (TLR) signaling pathways in the induction of neuroinflammation via the oral-gut-brain axis. As neuroinflammation is one of the key elements in the pathophysiology of neurodegenerative and neuropsychiatric disorders, this review was conducted to reflect on the pathophysiological pathways and clinical evidence on the role of TLR and inflammasome signaling pathways via oral-gut-brain axis in neurodegenerative diseases such as cognitive impairment, Alzheimer's disease, Multiple sclerosis, Parkinson's disease, Huntington's disease, and Amyotrophic lateral sclerosis, and psychiatric disorders such as major depressive disorder, anxiety disorders, schizophrenia, bipolar disorders, and Autism spectrum disorders. Because the contributing factors have not been fully understood yet, further studies could help provide novel therapeutic opportunities.},
}
@article {pmid42383593,
year = {2026},
author = {Kpetou, R and Raposo Pereira, F and Segobin, S and La Corte, V and Villain, N and Groussard, M and Jauny, G and Platel, H and Hinault, T and , },
title = {Multilayer brain connectivity and long-term cognitive changes in individuals at risk for Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261464453},
doi = {10.1177/13872877261464453},
pmid = {42383593},
issn = {1875-8908},
abstract = {BackgroundAmong aging individuals, some develop Alzheimer's disease (AD) while others remain cognitively stable. Understanding how structural and functional brain changes interact, could clarify this heterogeneity particularly among individuals at increased risk for AD.ObjectiveThis study aims to explore how structure-function connectivity changes relate to subsequent long-term cognitive trajectories in older adults with SMC and varying amyloid burden.MethodsWe analyzed data from the INSIGHT-preAD cohort, which includes older individuals with subjective cognitive complaints followed neuropsychologically over five years. Multiplex connectome integrating resting-state EEG functional connectivity and diffusion-weighted imaging-based structural connectivity was used to characterize brain network organization. We computed the multiplex participation coefficient (PC) as an index of structure-function similarity and examined its association with individual cognitive trajectories across the follow-up period.ResultsSignificant differences in multiplex connectivity were observed among amyloid positive participants who later progressed to AD compared to amyloid positive stable (e.g., non-progressors) and amyloid negative controls. Specifically, higher PC values in the delta band were observed in amyloid positive individuals who later developed AD. This pattern, particularly within the default mode network, was associated with subsequent cognitive decline suggesting that delta band structure-function similarity may represent a potential candidate marker of cognitive vulnerability and progression in AD.ConclusionsMost studies investigating AD have primarily examined functional or structural connectivity separately. By integrating both modalities using a multiplex approach, our study provides interesting preliminary evidence that structure-function connectivity may capture network-level changes associated with cognitive trajectories along AD continuum.},
}
@article {pmid42383821,
year = {2026},
author = {Zheng, Y and Kang, L and Yang, X and Zhou, R and Chen, H and Wang, W and Xu, X and Xu, W and Liu, J and Li, B and Deng, Y},
title = {Stage-dependent relationship between sleep duration and cortical tau deposition in cognitively impaired individuals: A cross-sectional study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261462419},
doi = {10.1177/13872877261462419},
pmid = {42383821},
issn = {1875-8908},
abstract = {BackgroundChanges in sleep characteristics are critical in the course of Alzheimer's disease (AD).ObjectiveWe aimed to explore the relationship between sleep duration and tau pathology progression in patients with AD and mild cognitive impairment (MCI).MethodsThis cross-sectional study included 172 patients (70 with MCI and 102 with AD). Sleep duration and disturbances were assessed through standardized questionnaires, while tau deposition and cerebrospinal fluid clearance were evaluated using tau-PET and diffusion tensor image analysis along the perivascular space (DTI-ALPS), along with comprehensive cognitive assessments. The data were adjusted for variables such as demographic factors, clinical symptoms, and medications.ResultsSleep duration showed a positive association with tau deposition in the MCI stage (total sleep: β = 0.18, p = 0.014; nighttime sleep: β = 0.20, p = 0.007) but negatively associated in the AD stage (total sleep: β = -0.18, p = 0.039; nighttime sleep: β = -0.20, p = 0.039). Patients with sleep disturbances demonstrated lower tau burdens (group difference = 0.62, p = 0.005). Mediation analysis revealed a significant indirect effect of depression in the sleep-tau relationship (total sleep: β = -0.26, p = 0.040; nighttime sleep: β = -0.24, p = 0.040).ConclusionsThis study first revealed the stage-dependent characteristics of sleep-tau relationships, highlighting the MCI stage as a critical research focus.Clinical TrialThe study was registered with ClinicalTrials.gov (NCT05623124). URL: https://clinicaltrials.gov/study/NCT05623124.},
}
@article {pmid42383918,
year = {2026},
author = {Chambliss, AB},
title = {The Emerging Role of Blood-Based Biomarkers in Predicting Alzheimer's Disease.},
journal = {The journal of applied laboratory medicine},
volume = {11},
number = {4},
pages = {997},
doi = {10.1093/jalm/jfag054},
pmid = {42383918},
issn = {2576-9456},
}
@article {pmid42383928,
year = {2026},
author = {Romero-Murillo, S and Cartas-Cejudo, P and De Miguel, M and Extramiana, L and Fernandez-Irigoyen, J and Santamaria, E},
title = {Unveiling the post translational modification code in Alzheimer's pathogenesis: crosstalk between phosphorylation and acetylation.},
journal = {Expert review of proteomics},
volume = {},
number = {},
pages = {},
doi = {10.1080/14789450.2026.2698463},
pmid = {42383928},
issn = {1744-8387},
}
@article {pmid42384085,
year = {2026},
author = {Sanchez, DL and Bennett, IJ},
title = {Normalization method for relative cerebral blood flow influences sex and cognitive status effects in nondemented older adults.},
journal = {Brain imaging and behavior},
volume = {20},
number = {4},
pages = {},
pmid = {42384085},
issn = {1931-7565},
mesh = {Humans ; Male ; Female ; *Cerebrovascular Circulation/physiology ; Aged ; *Cognitive Dysfunction/physiopathology/diagnostic imaging ; *Cognition/physiology ; Sex Characteristics ; Magnetic Resonance Imaging/methods ; Aged, 80 and over ; *Brain/diagnostic imaging/physiopathology ; Perfusion Magnetic Resonance Imaging ; Hippocampus/diagnostic imaging ; Neuropsychological Tests ; },
abstract = {Cerebral blood flow (CBF) is lower in males than females in cortical gray matter, but these sex effects are unknown in the hippocampus. Potential interactions between sex and cognitive status on CBF, which may contribute to the greater risk for females to develop mild cognitive impairment (MCI), are also understudied. Moreover, these effects may vary when regional CBF is normalized relative to individual differences in reference region CBF (residual rCBF) compared to more common difference scores (traditional rCBF). The current study examined effects of sex, cognitive status, and their interaction on residual and traditional rCBF in the cortical lobes and hippocampus in 111 cognitively unimpaired older adults (CU; 61.3%) and 49 older adults diagnosed with MCI (46.9% female) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with T1-weighted and perfusion-weighted magnetic resonance imaging data. As expected, rCBF was significantly lower in males than females in the occipital lobe, p = 0.010, but was unexpectedly significantly higher in males than females in the hippocampus, p < 0.001, with the sex effect being larger for traditional rCBF in the occipital lobe and residual rCBF in the hippocampus, ps < 0.024. Cognitive status significantly interacted with rCBF metric and region, ps < 0.014, but yielded no significant between group difference for any metric in any region, ps > 0.06. There were no significant interactions between sex and cognitive status, ps > 0.10. Taken together, these findings indicate that effects of sex on rCBF are region specific, independent of cognitive status, and vary with rCBF normalization method in non-demented older adults.},
}
@article {pmid42384109,
year = {2026},
author = {Spallazzi, M and Zilioli, A and Ruffini, L and Imbimbo, BP},
title = {Number needed to treat and harm for lecanemab and donanemab in early Alzheimer disease.},
journal = {Journal of neurology},
volume = {273},
number = {7},
pages = {},
pmid = {42384109},
issn = {1432-1459},
}
@article {pmid42384167,
year = {2026},
author = {Bi, Q and Zhang, L and Zhang, J and Wang, X and Zuo, C and Zhao, S and Wang, Z and Zhao, Z and Wan, H},
title = {Glucagon-like peptide-1 receptor agonists in neurodegenerative diseases: a bibliometric analysis of global research trends and research hotspots from 2006 to 2025.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {42384167},
issn = {1432-1912},
abstract = {This study aimed to systematically characterize the global research landscape, collaboration patterns, knowledge structure, and emerging hotspots of glucagon-like peptide-1 receptor agonists in neurodegenerative diseases using bibliometric methods. Publications related to glucagon-like peptide-1 receptor agonists and neurodegenerative diseases were retrieved from the Web of Science Core Collection from 2006 to 2025. Only English-language articles and reviews were included. Bibliometric analyses were performed using Bibliometrix, VOSviewer, and CiteSpace to evaluate annual publication trends, country and institutional contributions, author collaborations, journal distribution, citation structures, keyword co-occurrence, thematic evolution, and citation bursts. A Scopus-based sensitivity analysis was conducted to assess the robustness of the main bibliometric findings. A total of 1,202 publications were included, with annual output increasing from 2 in 2006 to 241 in 2025, particularly after 2020. China, the USA, and England were the leading contributors and major collaboration hubs. Shanxi Medical University, Lancaster University, and the National Institute on Aging were among the most productive institutions, while major journals included International Journal of Molecular Sciences, Neuropharmacology, European Journal of Pharmacology, Frontiers in Endocrinology, Frontiers in Pharmacology, and Journal of Alzheimer's Disease. Keyword and citation analyses indicated a thematic shift from exendin-4, Alzheimer's disease, Parkinson's disease, and neuroprotection toward semaglutide, neuroinflammation, cognitive impairment, clinical efficacy, evidence synthesis, and combination therapy. Research on glucagon-like peptide-1 receptor agonists in neurodegenerative diseases has expanded rapidly over the past two decades. Current bibliometric evidence suggests that this field has evolved from preclinical exploration toward broader translational and clinical research, with increasing attention to neuroinflammation, metabolic dysfunction, cognitive outcomes, and newer incretin-based therapies. However, the therapeutic implications of glucagon-like peptide-1 receptor agonists for neurodegenerative diseases remain to be further validated by high-quality mechanistic studies and well-designed clinical trials.},
}
@article {pmid42384283,
year = {2026},
author = {Mostafa, SS and Mohammed, RA and Abbas, AY and Othman, MA},
title = {The protective role of melatonin on the brain in a rat model of Alzheimer's disease.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42384283},
issn = {1573-7365},
mesh = {Animals ; *Melatonin/pharmacology/therapeutic use ; *Alzheimer Disease/chemically induced/drug therapy/metabolism/pathology/prevention &amp; control ; Male ; Rats ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Brain/drug effects/metabolism/pathology ; Disease Models, Animal ; Aluminum Chloride ; Maze Learning/drug effects ; Microglia/drug effects/metabolism ; Rats, Sprague-Dawley ; Tumor Necrosis Factor-alpha/metabolism ; },
abstract = {Alzheimer's disease is an age-related neurodegenerative disorder characterized by progressive cognitive decline and multiple biochemical and structural abnormalities in the brain. Accumulating evidence suggests that aluminum exposure may contribute to neurodegenerative process including those observed in AD and was linked to neuronal damage and cognitive impairment. Melatonin (Mel) is a neurohormone that regulates circadian rhythm and possesses antioxidant, anti-inflammatory and neuroprotective properties. The current study investigated the potential protective roles of Mel in a rat model of AD induced by aluminum chloride (AlCl3). Forty adult male rats were divided into 4 experimental groups: a control group, an AlCl3-treated group, an AlCl3+Mel-treated group, and a Mel-only group. AlCl3 was administered orally for four weeks. Cognitive performance and spatial learning were assessed using Morris water maze test. Plasma levels of the pro inflammatory cytokines; interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) were measured using enzyme linked immunosorbent assay. Histopathological examination of the frontal cortex was performed using hematoxylin and eosin staining, and immunohistochemistry was conducted using the neuronal marker NeuN, microglial marker Iba1, and inflammatory markers IL-6 and TNF-α. Mel treatment significantly improved learning and memory performance in the Morris water maze test. It also reduced plasma levels of IL-6 and TNF-α. Using immunohistochemistry, Mel increased NeuN expression, while reducing Iba1, IL-6 and TNF-α expression. These findings showed that Mel attenuated frontal cortical neurodegeneration and neuroinflammation in this model of AD, suggesting that Mel may represent a promising neuroprotective therapeutic strategy for AD.},
}
@article {pmid42384500,
year = {2026},
author = {Wang, Y and Jiao, CN and Gao, YL and Cui, XC and Zheng, CH and Liu, JX},
title = {Exploring Complex Genetic Mechanisms in Brain Imaging Genetics via a New Multi-task Learning Method.},
journal = {IEEE transactions on computational biology and bioinformatics},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/TCBBIO.2026.3709159},
pmid = {42384500},
issn = {2998-4165},
abstract = {Brain imaging genetics generally combines genotype data with brain structure and functional measures to investigate the genetic basis of neurological disorders. Multimodal brain imaging data carry different but complementary information, which can clearly measure the same brain. Multi-task sparse canonical correlation analysis (MTSCCA) is often used to analyze the bi-multivariate correlation between genotype data and multimodal imaging features; however, it lacks the capacity to identify class-specific biomarkers and to deeply capture complex genetic mechanisms. In this paper, a linear discrimination and decomposition method based on MTSCCA (LDMTSCCA) is proposed to solve above problems. Specifically, LDMTSCCA first extracts disease-related genetic information using sparse linear discriminant analysis, and then employs parameter decomposition to learn multi-level expression patterns of genetic loci. To better explore intricate genetic mechanisms, LDMTSCCA jointly incorporates disease states, parameter decomposition, and network connectivity constraints into the association analysis between multilocus genetic information and multimodal neuroimaging phenotypes. The proposed method is compared with the traditional single task, multi-task, multi-view, and deep learning-based canonical correlation analysis methods in Alzheimer's Disease Neuroimaging Initiative, which shows that LDMTSCCA not only achieves the highest canonical correlation coefficients but also identifies multi-level biomarkers.},
}
@article {pmid42384774,
year = {2026},
author = {Walker, KA and Blew, C and Duggan, MR and Joynes, C and Gomez, GT and Drouin, S and Cordon, J and Chen, J and Zhang, J and File, B and Nanasi, T and Lehallier, B and Oh, H and Surapaneni, A and Grams, ME and Palta, P and Sullivan, KJ and Pichet Binette, A and Wu, L and Zhu, J and Leonard, H and Singleton, AB and Fornage, M and Gottesman, RF and Mosley, TH and Chatterjee, N and Boerwinkle, E and Ferrucci, L and Coresh, J and Schlosser, P},
title = {Alzheimer's disease proteome-wide association study implicates adaptive immunity and identifies risk genes LILRB1 and SIRPA.},
journal = {Science translational medicine},
volume = {18},
number = {856},
pages = {eadx4852},
doi = {10.1126/scitranslmed.adx4852},
pmid = {42384774},
issn = {1946-6242},
mesh = {Humans ; *Alzheimer Disease/genetics/immunology ; *Genome-Wide Association Study ; *Genetic Predisposition to Disease ; Quantitative Trait Loci/genetics ; *Proteome/metabolism ; *Adaptive Immunity/genetics ; *Receptors, Immunologic/genetics ; Risk Factors ; *Antigens, CD/genetics ; },
abstract = {The rapid expansion of plasma proteomic data and protein quantitative trait loci (pQTLs) provides an opportunity to identify genes that confer disease risk through their effect on plasma protein abundance. We conducted an Alzheimer's disease (AD) proteome-wide association study (PWAS) integrating publicly available plasma cis-pQTL data (1348 European American and 1385 African American genetically determined protein models) with AD dementia GWAS summary statistics. Whereas the African American PWAS identified one candidate [apolipoprotein E (APOE)] and multiple suggestive genes, the European American PWAS identified 18 genes with putative causal relationships with AD through cis regulation of plasma protein abundance. Thirteen of these candidate genes were additionally supported by colocalization and complementary causal-inference analyses such as summary data-based Mendelian randomization. Four of these proteins were not previously detected in AD GWAS [complement decay-accelerating factor (CD55), leukocyte immunoglobulin-like receptor B1 (LILRB1), scavenger receptor class A member 5 (SCARA5), and signal regulatory protein alpha (SIRPA)]. A subset of candidate gene-associated proteins was associated with 8- and 20-year dementia risk, markers of AD pathology, and a CSF proteomic signature enriched for immune and metabolic processes. Putative causal proteins were enriched for adaptive (lymphocyte-mediated) immunity and, compared with GWAS candidates, showed less enrichment for synaptic and amyloid regulatory processes. LILRB1 and SIRPA, two immunoregulatory proteins not previously implicated in AD GWAS, showed the strongest mechanistic link to AD in the European American PWAS. These results shed additional light on AD etiology and enable the prioritization of potential AD therapeutic targets in peripheral circulation.},
}
@article {pmid42384796,
year = {2026},
author = {Hu, H and Guo, D and Pu, Y and Abuduaini, Y and Wang, X and Francks, C and Thompson, PM and Kong, XZ},
title = {Variations of global brain asymmetry are associated with aging and related diseases.},
journal = {Science advances},
volume = {12},
number = {27},
pages = {eadu9309},
doi = {10.1126/sciadv.adu9309},
pmid = {42384796},
issn = {2375-2548},
mesh = {Humans ; *Aging/pathology ; *Brain/physiopathology/pathology/diagnostic imaging ; Female ; *Functional Laterality ; *Alzheimer Disease/physiopathology/diagnostic imaging/genetics/pathology ; Male ; Magnetic Resonance Imaging ; *Parkinson Disease/physiopathology/diagnostic imaging/genetics/pathology ; Aged ; Cognition ; Machine Learning ; },
abstract = {Lateralization is a hallmark of brain organization, yet the structural basis underlying this phenomenon remains a critical, unresolved question in cognitive and systems neuroscience. In this study, we applied multivariate machine learning techniques to investigate variations of global brain asymmetry and their associations with cognitive functions, aging, and aging-related diseases, using large-scale datasets. Our findings revealed substantial and previously unknown structural differences between the hemispheres, and established key associations between structural asymmetries and lateralized functions. At the population level, we identified unique aging trajectories of hemispheric differences and uncovered diagnosis-specific variations in patients with Alzheimer's and Parkinson's disease, and in APOE ε4 carriers at genetic risk. Notably, we identified a "left hemi-aging" pattern that challenges the conventional "right hemi-aging" model. Together, these results advance our understanding of functional lateralization in the human brain and highlight the potential of global brain asymmetry as a biomarker for brain aging and related diseases.},
}
@article {pmid42385110,
year = {2026},
author = {Lichter, DG},
title = {Neuropathogenesis of Seizures in Patients With Alzheimer Disease and Lewy Body Dementia: Is There a Difference, and Does It Matter?.},
journal = {Neurology},
volume = {107},
number = {2},
pages = {e218344},
doi = {10.1212/WNL.0000000000218344},
pmid = {42385110},
issn = {1526-632X},
}
@article {pmid42385111,
year = {2026},
author = {Tort-Merino, A and Esteller-Gauxax, D and Pérez-Millan, A and Castellví, M and Bosch, B and Sánchez-Rodríguez, MM and Rigol, A and Rubio, G and Morante-Serra, C and Mir-Sala, L and Patricio, V and Juncà-Parella, J and Torres-Coll, J and Guillén, N and Martín-Sobrino, I and Massons, M and Canasto, P and Alcón, D and Fernández-Villullas, G and Puey, R and Comas-Albertí, A and Antonell, A and Borrego-Écija, S and Falgàs, N and Sánchez-Valle, R and Lladó, A and Balasa, M},
title = {Neuropsychological Profile and Cognitive Trajectories of Patients With Biomarker Evidence of Alzheimer Disease or Dementia With Lewy bodies.},
journal = {Neurology},
volume = {107},
number = {2},
pages = {e218201},
doi = {10.1212/WNL.0000000000218201},
pmid = {42385111},
issn = {1526-632X},
mesh = {Humans ; Female ; *Alzheimer Disease/psychology/blood/complications ; *Lewy Body Disease/psychology/blood/complications ; Male ; Aged ; Neuropsychological Tests ; Biomarkers/blood/cerebrospinal fluid ; Longitudinal Studies ; Retrospective Studies ; alpha-Synuclein/cerebrospinal fluid ; *Cognition ; tau Proteins/blood/cerebrospinal fluid ; Amyloid beta-Peptides/cerebrospinal fluid/blood ; Aged, 80 and over ; },
abstract = {BACKGROUND AND OBJECTIVES: Alzheimer disease (AD) and dementia with Lewy bodies (DLB) often coexist, yet the cognitive effect of mixed AD and α-synuclein pathology in vivo remains unclear. We aimed to (1) characterize baseline neuropsychological profiles, (2) assess plasma biomarker associations, and (3) examine longitudinal cognitive trajectories in patients with AD, DLB, and mixed pathology in a memory clinic cohort.<br><br>METHODS: This was a retrospective longitudinal study including participants from an academic memory clinic cohort with available CSF and blood samples at baseline who completed a comprehensive cognitive assessment. Baseline neuropsychological performance was compared between groups using analysis of covariance controlling for age, sex, and education. Associations between plasma biomarkers and cognition were examined using multiple linear regression models. Linear mixed-effects models examined longitudinal change across groups, with time from baseline, diagnosis, the diagnosis-by-time interaction, baseline age, sex, and years of education as fixed effects, and intercept as a random effect.<br><br>RESULTS: A total of 350 participants (mean age 70.1 &#xb1; 6.6 years; 48.6% female) were included: AD alone (n = 249), AD with &#x3b1;-synuclein pathology (n = 31), DLB alone (n = 33), and DLB with AD pathology (n = 37). At baseline, patients with AD showed greater impairment than those with DLB in memory and language (all p < 0.01). Compared with AD alone, patients with AD and &#x3b1;-synuclein pathology showed poorer performance in visual attention/processing speed (F[1,259] = 7.71, p < 0.01) and ideomotor apraxia (F[1,244] = 4.02, p < 0.05). Conversely, patients with DLB and AD pathology performed worse than those with isolated DLB in visual memory (F[1,38] = 5.38, p < 0.05), constructional praxis (F[1,59] = 6.26, p < 0.01), and executive function (F[1,40] = 5.68, p < 0.05). Memory (p < 0.01) and language (p < 0.05) best differentiated groups with mixed pathology. Plasma phosphorylated tau at threonine 217 was broadly associated with worse performance across cognitive domains in patients with AD (p < 0.05). Longitudinally, patients with AD showed steeper decline than those with DLB in memory (&#x3b2; = 0.184, SE = 0.069, p < 0.01) and language (&#x3b2; = 0.206, SE = 0.074, p < 0.01). Within AD, those with &#x3b1;-synuclein pathology exhibited steeper decline in encoding (&#x3b2; = -0.186, SE = 0.075, p < 0.05) and delayed total recall (&#x3b2; = -0.178, SE = 0.082, p < 0.05). Among mixed-pathology patients, those with primary AD diagnosis showed greater decline across memory (&#x3b2; = -0.324, SE = 0.104, p < 0.01), language (&#x3b2; = -0.359, SE = 0.109, p < 0.01), and visuospatial function (&#x3b2; = -0.356, SE = 0.175, p < 0.05).<br><br>DISCUSSION: Distinct neuropsychological profiles and trajectories emerge in AD and DLB depending on underlying pathology. Identifying mixed pathology in vivo is clinically relevant for accurate diagnosis and prognosis and has implications for outcome measures and patient stratification in clinical trials.},
}
@article {pmid42385113,
year = {2026},
author = {Ting, SKS and Saffari, SE and Zhan, SJ and Gosavi, TD and Hameed, S and Li, W and Mukesh Shah, J and Lin, SZZ and Sim, J and Chiew, HJ and Ng, KP and Ng, ASL},
title = {Neuropathologic Correlates of Seizures in Patients With Alzheimer Disease and Dementia With Lewy Bodies.},
journal = {Neurology},
volume = {107},
number = {2},
pages = {e218277},
doi = {10.1212/WNL.0000000000218277},
pmid = {42385113},
issn = {1526-632X},
mesh = {Humans ; Female ; Male ; *Lewy Body Disease/pathology/complications/epidemiology ; *Alzheimer Disease/pathology/complications/epidemiology ; *Seizures/pathology/epidemiology ; Retrospective Studies ; Aged ; Aged, 80 and over ; *Brain/pathology ; Cohort Studies ; Cerebral Amyloid Angiopathy/pathology ; },
abstract = {BACKGROUND AND OBJECTIVES: Seizures are a recognized comorbidity in dementia, with varying prevalence across Alzheimer disease (AD) and dementia with Lewy bodies (DLBs). Although previous studies have demonstrated an increased seizure risk in AD, the neuropathologic substrates underlying seizure susceptibility-particularly across dementia subtypes-remain incompletely understood. We aimed to identify distinct clinicopathologic correlates of clinically active seizures in AD and DLB using a large autopsy-confirmed cohort.<br><br>METHODS: We conducted a retrospective cohort study using data from the National Alzheimer's Coordinating Center (2005-December 2022). Autopsy-confirmed AD and DLB cases were included. Individuals with a history of stroke or traumatic brain injury were excluded. The primary outcome was clinically active seizures, defined as seizures occurring within 3 years before or after the diagnosis of dementia. Neuropathologic exposures included Braak stage, cerebral amyloid angiopathy (CAA), frontotemporal lobar degeneration, and vascular pathologies. Multivariable logistic regression models were used to examine associations between pathologic features and seizure occurrence, adjusting for relevant demographic covariates.<br><br>RESULTS: A total of 3,498 participants were included, comprising 3,040 with AD (mean age, 73.4 years; 48.5% female) and 458 with DLB (mean age, 75.1 years; 31.4% female). Active seizures were identified in 174 participants with AD (5.7%) and 13 with DLB (2.8%). In AD, Braak stage VI (vs V) was associated with higher odds of active seizures (adjusted odds ratio [OR], 1.81; 95% CI 1.20-2.82; p = 0.007), as was moderate to severe CAA (adjusted OR, 1.38; 95% CI 1.01-1.90; p = 0.045). In DLB, AD-related pathologic features were not associated with seizures. By contrast, vascular pathology was significantly associated with seizure occurrence, including microinfarcts (adjusted OR, 5.11; 95% CI 1.64-16.4; p = 0.005) and infarcts (adjusted OR, 4.11; 95% CI 1.27-12.9; p = 0.015).<br><br>DISCUSSION: In this autopsy-confirmed cohort, seizure susceptibility was associated with advanced tau pathology and CAA in AD. In DLB, exploratory analyses suggested a possible association between vascular pathology and seizures; however, these findings should be interpreted cautiously. Overall, the results support potentially distinct pathologic contributions to seizure susceptibility across dementia subtypes. Limitations include the use of advanced-stage pathologic samples, which may limit generalizability to earlier disease stages.},
}
@article {pmid42385118,
year = {2026},
author = {Morrill, VN and Pike, JR and Hu, J and Fornage, M and Surapaneni, A and Walker, KA and Knopman, DS and Mosley, TH and Coresh, J and Schneider, ALC and Smith, JR and Gottesman, RF},
title = {Genetic Risk for Alzheimer Disease, Midlife Hypertension, and Dementia: The ARIC Neurocognitive Study.},
journal = {Neurology},
volume = {107},
number = {2},
pages = {e218280},
doi = {10.1212/WNL.0000000000218280},
pmid = {42385118},
issn = {1526-632X},
mesh = {Humans ; *Hypertension/genetics/epidemiology ; Female ; *Alzheimer Disease/genetics/epidemiology ; *Dementia/genetics/epidemiology ; Male ; Middle Aged ; Genetic Risk Score ; *Genetic Predisposition to Disease ; Risk Factors ; Prospective Studies ; White People/genetics ; Black or African American/genetics ; United States/epidemiology ; Incidence ; },
abstract = {BACKGROUND AND OBJECTIVES: Genetics represent a nonmodifiable risk factor for Alzheimer disease (AD), with 60%-80% heritability. Midlife hypertension is a modifiable risk factor for both dementia and death. Our primary objective was to determine how genetic risk for AD modifies the association between hypertension and dementia.<br><br>METHODS: The Atherosclerosis Risk in Communities Study is an ongoing community-based prospective cohort study of 4 US centers. We analyzed White and Black participants free of dementia at age 55 years with genotypes and blood pressure measured at visit 1 (1987-1989). Three genetic risk groups (low, medium, high) were defined based on tertiles of a race-specific AD polygenic risk score. Dementia was ascertained through cognitive testing, informant interviews, hospitalization, codes and death records. Death was ascertained through the National Death Index. We examined the association of midlife hypertension with incident dementia within 3 genetic risk groups using Cox proportional-hazards and cumulative incidence function estimations. We used age 55 years as the time origin, with left truncation to allow entry at ages older than 55 years; age on December 31, 2022, was the administrative censoring date.<br><br>RESULTS: Among 8,931 White and 2,666 Black participants, the median follow up time was 26.6 and 23.8 years, the mean age was 54.0/53.5 years, and 53.0%/62.5% were female, respectively. After adjusting for demographics, midlife hypertension was significantly associated with dementia incidence across all genetic risk groups among White participants (low risk hazard ratio [HR] 1.29; 95% CI 1.07-1.55, medium risk HR 1.34; 95% CI 1.13-1.58, high risk HR 1.19; 95% CI 1.03-1.38) and among Black participants at high genetic risk (HR 1.31; 95% CI 1.04-1.66). Associations for low and medium genetic risk Black participants were consistent but not statistically significant. There were no significant differences in association of hypertension with dementia by AD genetic risk group. Individuals with hypertension had a 0%-2% higher probability of developing dementia by age 80 and a 6%-13% lower probability of dementia-free survival to age 80 years vs those without hypertension, across race and genetic risk groups.<br><br>DISCUSSION: Genetic risk for AD does not modify the association between hypertension and dementia. These data support the fact that all individuals with hypertension are likely to benefit from antihypertensive treatment.},
}
@article {pmid42385334,
year = {2026},
author = {Kim, W and Hwang, Y and Yang, Y and Kim, MG and Jang, H and Choi, SH and Seong, JK and Yoo, RE and Lee, WJ},
title = {Distinct spatial patterns of perivascular spaces enlargement for multiple and Co-existing pathologies of cognitive impairment.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {8},
pages = {100631},
doi = {10.1016/j.tjpad.2026.100631},
pmid = {42385334},
issn = {2426-0266},
abstract = {BACKGROUND: This study examines how amyloid-β and vascular pathology independently and jointly relate to regional perivascular space (PVS) burden on T2-weighted MRI.<br><br>METHODS: In 307 cognitively impaired participants retrospectively identified from the Seoul National University dementia cohort, PVS were automatically quantified in the basal ganglia (BG) and lobar white matter regions from 2D T2-weighted MRI. Amyloid-&#x3b2; and vascular pathology positivity were defined by [18F]Florbetaben PET and small vessel disease markers. Group differences among pathology-negative (n=36), vascular-only (n=106), amyloid-only (n=48), and mixed (n=117) subgroups, as well as amyloid-vascular interactions, were assessed using analysis of covariance and multivariable linear regression.<br><br>RESULTS: BG PVS were greater in participants with vascular burden than in pathology-negative participants (F=26.97, p<0.001; Cohen's d=1.28), independent of amyloid-&#x3b2;. Lobar PVS were higher in single-pathology than pathology-negative participants across the parietal, temporal, and occipital regions (F=8.25-18.04, Cohen's d=0.66-0.98, all p&#x2264;0.014), with no additional increase in the mixed group. Greater amyloid-&#x3b2; retention was associated with parietal, temporal, and occipital PVS in VB- participants (&#x3b2; [95% CI]=0.55 [0.19, 0.92], 0.69 [0.35, 1.02], 0.40 [0.16, 0.64], respectively). Among AB- participants, vascular burden was associated with BG PVS (&#x3b2; [95% CI]=0.65 [0.40, 0.89]). Multivariable regression demonstrated less-than-additive AB&#xd7;VB interactions in parietal, temporal, and occipital PVS (&#x3b2; [95% CI]=-0.65 [-1.08, -0.23], -0.74 [-1.13, -0.35], -0.42 [-0.70, -0.14], respectively).<br><br>CONCLUSIONS: Distinct regional PVS patterns reflect spatially selective and severity-dependent glymphatic-related structural alterations associated with amyloid-&#x3b2; and vascular pathologies, supporting PVS as a quantitative imaging biomarker for disentangling mixed pathways of cognitive impairment.},
}
@article {pmid42385487,
year = {2026},
author = {Oh, MJ and Lee, J and Jose, J and Bong, JH and Park, M},
title = {Construction of a bio-mimetic outer membrane layer via autodisplay of scFv onE. colifor SPR-based amyloid-β detection.},
journal = {Colloids and surfaces. B, Biointerfaces},
volume = {267},
number = {},
pages = {115947},
doi = {10.1016/j.colsurfb.2026.115947},
pmid = {42385487},
issn = {1873-4367},
abstract = {The development of highly sensitive biointerfaces is essential for the early diagnosis of Alzheimer's disease, characterized by the accumulation of amyloid-β(Aβ). In this study, a functionalized outer membrane layer using an scFv autodisplay system was constructed to enhance the performance of Surface Plasmon Resonance (SPR) biosensors. The single-chain variable fragment (scFv) against Aβ was genetically fused to an autotransporter and successfully expressed on the Escherichia coli outer membrane (OM). The biological activity and orientation of the autodisplayed scFv were validated via flow cytometry and fluorescence microscopy, showing a 35-fold higher binding affinity to Aβ compared to non-engineered controls. For the construction of the biointerface, isolated OM fractions were immobilized onto a gold substrate, forming a stable OM layer as confirmed by FT-IR spectroscopy. SPR analysis demonstrated that the scFv autodisplaying OM layer exhibited superior sensitivity with a limit of detection below 0.1 μg/mL and highly specific, concentration-dependent binding to Aβ. Crucially, the inherent physicochemical properties of the OM layer effectively minimized non-specific interactions, eliminating the need for additional blocking agents and ensuring structural stability even after washing steps. These findings establish the scFv autodisplay on an OM layer as a robust, scalable, and orientation-controlled platform for the label-free detection of biomarkers in complex biointerfaces.},
}
@article {pmid42385569,
year = {2026},
author = {Arruda Maciel, C and Oliveira da Silva, KG and Galbim de Paula, V and Alves Santana, V and Teles de Menezes, MCJ and Campos Gomes Pinto, F},
title = {Clinical response after cerebrospinal fluid shunting in complex versus pure idiopathic normal pressure hydrocephalus: A systematic review and meta-analysis.},
journal = {Clinical neurology and neurosurgery},
volume = {269},
number = {},
pages = {109557},
doi = {10.1016/j.clineuro.2026.109557},
pmid = {42385569},
issn = {1872-6968},
abstract = {BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) frequently coexists with neurodegenerative or vascular disease, but shunt outcomes in these complex presentations remain poorly synthesized.<br><br>METHODS: We performed a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 systematic review and meta-analysis of shunt outcomes in pure iNPH and complex iNPH. Binary outcomes were global shunt response and urinary improvement. Continuous outcomes were harmonized into cognition, gait, general function, and incontinence and summarized as standardized mean change with raw-score standardization (SMCR). Prespecified primary comparative estimates used random-effects models with Hartung-Knapp confidence intervals (CIs).<br><br>RESULTS: Nineteen unique analytical studies were included. In direct head-to-head binary comparisons, global shunt response was directionally lower in complex iNPH but did not reach statistical significance under the prespecified random-effects Hartung-Knapp model (odds ratio [OR] 0.31, 95% CI 0.09-1.10; k&#x202f;=&#x202f;3). Urinary improvement did not clearly differ between phenotypes (OR 0.85, 95% CI 0.58-1.25; k&#x202f;=&#x202f;3). Within complex iNPH, continuous pre-post estimates varied by domain and were imprecise: cognition was directionally positive, gait was near null with marked heterogeneity, and incontinence showed a small positive estimate. Direct continuous complex-minus-pure comparisons did not show a consistent deficit across domains. Exploratory time meta-regression suggested a phenotype-by-time interaction for incontinence, but this signal was based on sparse follow-up support and should be considered hypothesis-generating.<br><br>CONCLUSIONS: Low- to very-low-certainty evidence suggests that complex iNPH is associated with greater uncertainty and possibly lower global response than pure iNPH, but lower odds of response should not be interpreted as absence of response. Counseling should be phenotype-aware and domain-specific, particularly when Alzheimer-related biomarkers, parkinsonism, vascular burden, or other neurodegenerative features coexist with suspected iNPH.},
}
@article {pmid42385584,
year = {2026},
author = {Kiprov, DD and Green, AP and Boyinapalli, P},
title = {Technological advances in selective plasma adsorption: The MTx.100 column and the emergence of subtractive precision medicine.},
journal = {Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis},
volume = {65},
number = {4},
pages = {104484},
doi = {10.1016/j.transci.2026.104484},
pmid = {42385584},
issn = {1473-0502},
abstract = {Therapeutic plasma exchange (TPE) is well-established for autoimmune, hematological, and neurological disease but is intrinsically non-selective: protective immunoglobulins, coagulation factors, and albumin are depleted alongside pathogenic substances, and reliance on donor-derived replacement fluid carries logistical and immunological costs. The MTx.100 column (Marker Therapeutics AG) is a selective plasma adsorption device that addresses these limitations through hydrophobic-affinity adsorption. It targets pro-inflammatory cytokines, protein-bound metabolic waste, hydrophobic environmental contaminants, and microparticulates while preserving immunoglobulins, coagulation factors, electrolytes, and the patient's own signaling proteins. Plasma is treated and conserved, eliminating replacement-fluid dependency. Clinical experience encompasses approximately 1000 procedures globally. A prospective single-arm multicenter trial in 107 critically ill COVID-19 patients (424 procedures) demonstrated 28-day mortality of 37.4% against an FDA-agreed performance goal of 88.1% (p < 0.0001); propensity-matched analysis showed approximately three-fold higher survival odds versus standard of care (OR 3.0; 95% CI 1.56-5.85; p = 0.0008), with significant reductions in inflammatory and metabolic markers and no serious adverse events attributable to the column or procedure. Hospital case reports across polytrauma, post-LVAD implantation, and toxin-induced hepatitis demonstrated hemodynamic and electrolyte stability and favorable clinical trajectories. Across 114 elective outpatient procedures, vital signs and electrolytes remained stable throughout treatment, and third-party laboratory analyses confirmed measurable reduction of PFAS, microplastics, and persistent organic pollutants in treated patients. Within the emerging framework of subtractive precision medicine, selective plasma adsorption offers a complementary paradigm to additive pharmacotherapy for conditions characterized by inflammatory and toxic burden. A pilot trial in Alzheimer's disease is underway.},
}
@article {pmid42385586,
year = {2026},
author = {Khatri, BO},
title = {Therapeutic plasma exchange in Alzheimer's disease: From clinical trial to real-world evidence.},
journal = {Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis},
volume = {65},
number = {4},
pages = {104481},
doi = {10.1016/j.transci.2026.104481},
pmid = {42385586},
issn = {1473-0502},
abstract = {This article examines the expanding role of therapeutic plasma exchange (TPE) in Alzheimer's disease (AD), alongside recent developments in diagnostic approaches, disease mechanisms, and emerging disease-modifying treatments. Although AD has historically been considered a disorder defined by amyloid and tau pathology, contemporary models increasingly emphasize a multifactorial systems-biology framework that includes immune dysregulation, oxidative stress, vascular injury, impaired protein clearance, and synaptic dysfunction. Within this evolving model, TPE has emerged as a biologically rational, broadly acting therapeutic strategy that contrasts mechanistically with selective anti-amyloid monoclonal antibodies. This article reviews the global burden of AD and the need for safer disease-modifying therapies; current understanding of AD pathophysiology and biomarker-based diagnosis; available symptomatic and disease-modifying treatments; the AMBAR trial and the earlier pilot work that supported it; real-world cohort evidence; the author's clinical experience with TPE in AD; the mechanism of action of TPE in comparison with anti-amyloid monoclonal antibodies; the evolution of TPE from acute hospital-based therapy to chronic outpatient disease management; and future directions for TPE in neurodegenerative disease.},
}
@article {pmid42385644,
year = {2026},
author = {Luo, J and Rasmussen, IJ and Thomassen, JQ and Frikke-Schmidt, R},
title = {Causal insights of modifiable cardiovascular risk factors for dementia risk - potential for efficient prevention and improved brain health.},
journal = {Atherosclerosis},
volume = {419},
number = {},
pages = {120824},
doi = {10.1016/j.atherosclerosis.2026.120824},
pmid = {42385644},
issn = {1879-1484},
abstract = {BACKGROUND: The 2024 Lancet Commission report identifies 14 modifiable risk factors that may prevent half of dementia. The causal nature of these associations remains however unclear. We aimed to establish robust causal estimates for modifiable cardiovascular risk factors and dementia, offering tangible targets for effective dementia prevention.<br><br>METHODS: We selected independent variants from the largest genomic consortia to date (N&#x202f;=&#x202f;439,214 to 3,037,499) for each modifiable risk factor and generated polygenic risk scores for participants of European ancestry in the UK Biobank (N&#x202f;=&#x202f;408,788). We conducted univariable and multivariable linear Mendelian randomization, assessed genetic shapes by nonlinear approaches, and performed several sensitivity analyses, including sex stratification.<br><br>RESULTS: Genetic predisposition to high low-density-lipoprotein cholesterol (LDL-C) (1.12, 1.01-1.23), non-high-density-lipoprotein cholesterol (1.30, 1.26-1.35), triglycerides (1.19, 1.01-1.41), body mass index (1.04, 1.02-1.07), systolic (1.14, 1.09-1.20) and diastolic (1.10, 1.02-1.19) blood pressure, type 2 diabetes (1.04, 1.00-1.09) and smoking (1.18, 1.06-1.32), were associated with increased risk of all-cause dementia, while longer education was associated with a reduced risk (0.58, 0.33-0.99). Results for Alzheimer's disease and vascular dementia were directionally similar. Moreover, genetically predicted high physical activity level was associated with low risk of Alzheimer's disease (0.58, 0.33-0.99) only. Sensitivity analyses supported the main results, and no nonlinear shapes were detected.<br><br>CONCLUSION: These findings provide causal insights into modifiable cardiovascular risk factors for dementia and unfold a substantial potential for dementia prevention by timely treatment of high LDL-C, triglycerides, hypertension, and diabetes, alongside smoking cessation and maintenance of normal weight.},
}
@article {pmid42371968,
year = {2026},
author = {Cholerton, B and Godrich, D and Pasteris, J and Rivero, J and Martin, ER and Kunkle, BW and Naj, AC and Hamilton-Nelson, KL and Wang, H and Lee, WP and Dumitrescu, L and Hohman, TJ and Mayeux, R and Larson, EB and Crane, PK and Keene, CD and Latimer, CS and Mukherjee, S and Kofler, JK and Kamboh, MI and Bennett, DA and Molina-Porcel, L and Cuccaro, M and Pericak-Vance, MA and Rundek, T and Scott, WK and Kukull, W and Schellenberg, G and , and Beecham, GW and Montine, TJ},
title = {Genome wide association study meta-analysis of neuropathologic lesions of Alzheimer's disease and related dementias in a multi-site autopsy cohort.},
journal = {PLoS genetics},
volume = {22},
number = {6},
pages = {e1012170},
doi = {10.1371/journal.pgen.1012170},
pmid = {42371968},
issn = {1553-7404},
abstract = {Understanding the genetic foundations of dementia is critical to unraveling its complex molecular basis. Given that a clinical diagnosis of Alzheimer's disease (AD) dementia often results from interplay between multiple underlying neuropathologic co-morbidities, previous genome-wide association studies (GWAS) of clinically diagnosed AD are restricted in their ability to translate genetic associations to potential targeted therapeutics. The current study seeks to address these limitations by presenting the largest GWAS to date (n = 12,509) of neuropathologic hallmarks of AD and AD related dementias (ADRDs). We further performed a candidate-variant analysis using loci previously identified in GWAS of clinically diagnosed AD dementia and Parkinson's disease (PD). Finally, we conducted heritability and genetic correlation analyses using linkage disequilibrium (LD) score regression. We found broad genome-wide significant associations with APOE across AD and ADRDs but not cerebrovascular disease and vascular brain injury. We further identified 12 significant loci across 10 neuropathologic phenotypes, including 5 loci previously implicated in GWAS of clinical AD and ADRDs (variants on BIN1, PICALM/ EED, TMEM106B, GRN, and SNCA/ SNCA-AS1) and 7 novel genome-wide associations (variants on EPHA5, PSMG1, LINC00276, VAPA, LINC00290, DOCK4 and SLAIN2/ SLC10A4). Our analysis of AD and PD clinical candidate variants demonstrated several that were associated with AD neuropathologic change and Lewy body disease, as well as substantial overlap with neuropathologic lesions other than the primary neuropathologic hallmarks of these diseases. Heritability analyses demonstrated heritability that was high for amyloid plaques (78%) relative to prior clinical AD heritability analyses, intermediate for TDP-43 inclusions (41%), and low for remaining AD and ADRD pathologic features. This study underscores the importance of investigating the underlying neuropathologic hallmarks of AD and ADRDs as a step toward refining the translation of genetic associations to biomarker interpretation and development of targeted therapeutics.},
}
@article {pmid42372231,
year = {2026},
author = {Zhang, ZY and Wang, XM and Ma, X and Wang, Y and Wang, SD and Peng, YL and Cheng, K and Shen, YR and Tang, GZ and Wang, CW and Zhou, JN},
title = {Staging of Neuropil Morphological Alterations in Alzheimer's Disease.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.0213},
pmid = {42372231},
issn = {2152-5250},
abstract = {Alzheimer's disease (AD) involves the progressive fragmentation of neural connectivity. This study aims to investigate the morphological degeneration of neuropil fibers in AD and evaluate their utility as a marker for pathological severity. Post-mortem brain tissues from 92 cases across eight distinct regions were analyzed. We used Bielschowsky silver staining with automated quantitative morphometry to measure neuritic fiber length and curvature in the neuropil, and immunofluorescence to detect neurite cytoskeletal markers. Finally, a novel histological staging system for neuropil disruption was established to assess disease progression. Morphometric analysis revealed progressive reductions in neuritic fiber length and increased curvature tracking with disease severity, a significant negative correlation confirmed these are coupled degenerative manifestations. Immunofluorescence demonstrated extensive cytoskeletal fragmentation that corresponded to the pattern observed with silver staining. Based on morphometric analysis, a novel four-tier staging system was established, defined neuropil by homogeneous compactness (-), initial (+), extensive (++) disruption, and complete fragmentation (+++), which correlated preferentially with Phospho-Tau load. Crucially, subtle neuropil alterations were detectable in the entorhinal cortex, amygdala, and anterior hippocampus even in Braak 0 stage, suggesting a potential association between these early changes and the initial stages of tau pathogenesis. This study establishes a staging system for assessing neuropil degeneration, demonstrating that neuropil fragmentation and geometric distortion are candidate AD pathological markers. By systematically analyzing neuritic fiber morphology and proposing a neuropil disruption stage, this work provides critical insights into early AD pathogenesis, offering a foundation for future diagnostic strategies pending validation in independent cohorts with clinical correlations.},
}
@article {pmid42372237,
year = {2026},
author = {Marschner, RA and da Silva, FM and Crispim, D and Saraiva Gonçalves, CA},
title = {Muscle-Brain Crosstalk in Alzheimer's Disease: Exercise-Associated FNDC5/Irisin Pathways in Preclinical Models - A Systematic Review.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.0427},
pmid = {42372237},
issn = {2152-5250},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline, synaptic dysfunction, neuroinflammation, and altered amyloid-β processing. Growing evidence suggests that physical exercise exerts neuroprotective effects partly mediated by myokines released from skeletal muscle. Among these, irisin, a cleavage product of fibronectin type III domain-containing protein 5 (FNDC5), has emerged as a potential component of muscle-brain communication involved in neuroplasticity and memory-related pathways. This systematic review summarizes evidence from preclinical in vivo studies investigating exercise-induced FNDC5 expression and irisin-related signaling pathways in experimental models of AD. A literature search was conducted in PubMed and EMBASE following PRISMA guidelines to identify studies evaluating the effects of physical exercise on FNDC5 expression, irisin-related pathways, and cognitive outcomes in animal models of AD. Ten preclinical studies met the inclusion criteria and were included in the qualitative synthesis, encompassing both behavioral and mechanistic evidence. Overall, the evidence indicates that physical exercise was associated with increased FNDC5 expression, activation of irisin-related pathways, and downstream neuroprotective mechanisms including PPARGC1A, AMPK, SIRT1, and BDNF signaling. These molecular adaptations were associated with improvements in synaptic plasticity, reductions in neuroinflammation and oxidative stress, and attenuation of amyloid-related pathology. Behavioral assessments across multiple paradigms also demonstrated improvements in learning and memory following exercise interventions. Collectively, the available preclinical evidence suggests that FNDC5/irisin-related signaling is associated with neuroprotective effects of physical exercise in experimental models of AD as part of a broader exercise-induced response. Further studies are needed to clarify the underlying mechanisms and translational relevance of this pathway in AD.},
}
@article {pmid42372338,
year = {2026},
author = {Ersözlü, E and Preis, L and Aktuz, A and Droste, L and Erman, A and Gref, D and Strentz, KS and Hellmann-Regen, J and , },
title = {Drawing a line: Differentiating mild from moderate dementia using the functional activities questionnaire.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {8},
pages = {100630},
doi = {10.1016/j.tjpad.2026.100630},
pmid = {42372338},
issn = {2426-0266},
abstract = {BACKGROUND: Accurate differentiation between mild and moderate dementia is increasingly important, particularly as amyloid-targeting therapies are restricted to early disease stages. Functional impairment in instrumental activities of daily living is a hallmark of progression beyond mild dementia. The informant-based Functional Activities Questionnaire (FAQ) is widely used, but empirically validated cut-offs distinguishing mild from moderate dementia remain insufficiently defined.<br><br>METHODS: The optimal cut-off score was derived from the entire National Alzheimer's Coordinating Center (NACC) Uniform Data Set as a discovery cohort (n = 34,513) and validated in two independent multicentric cohorts (Alzheimer's Disease Neuroimaging Initiative (ADNI) n = 381 and Frontotemporal Lobar Degeneration Neuroimaging Initiative (FTLDNI) n = 74). The dementia staging was based on the Clinical Dementia Rating (CDR) global score. Functional impairment was assessed using the 10-item FAQ. Receiver operating characteristic analyses in NACC identified optimal thresholds, which were applied unchanged in validation cohorts. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated, and discordant cases were examined to identify factors associated with misclassification.<br><br>RESULTS: In NACC, the FAQ demonstrated excellent discrimination of moderate dementia (AUC=0.947, 95% CI 0.944-0.949). A cut-off value of &#x2265;18 maximized discrimination (sensitivity 96%, specificity 87%). A higher threshold of &#x2265;23 improved specificity (92%), while maintaining sensitivity (83%). In ADNI and FTLDNI, the sensitivity of &#x2265;18 threshold yielded 92% and 94%, respectively. Moreover, older age and lower cognitive performance were associated with higher odds of misclassification.<br><br>CONCLUSIONS: The FAQ robustly differentiates mild from moderate dementia across diverse cohorts. A threshold of &#x2265;18 prioritizes sensitivity, whereas &#x2265;23 favors specificity, supporting context-dependent functional staging in clinical and research settings. Individuals with FAQ scores between 18 and 22 may benefit from more detailed clinical staging.},
}
@article {pmid42372723,
year = {2026},
author = {Tyagi, M and de Hoog, E and Grega, M and Sullivan, KR and Walker, AC and Chadha, R and Northrop, A and Fábián, B and Hummer, G and Fuxreiter, M and Hyman, BT and Shepherd, JD},
title = {Arc mediates intercellular tau transmission via extracellular vesicles.},
journal = {Cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.cell.2026.06.008},
pmid = {42372723},
issn = {1097-4172},
abstract = {Tau pathology spreads cell to cell, but the mechanisms of intercellular tau transmission remain unclear. We find that the neuronal gene Arc is critical for the release of tau in neuronal extracellular vesicles (EVs) via a direct protein-protein interaction. Brain EVs purified from transgenic rTg4510 mutant tau mice (rTg[WT]) crossed with Arc knockout mice (rTg[Arc KO]) contain less tau and reduced tau seeding potential. Both Arc and tau are co-packaged in mouse and human brain-derived EVs. Moreover, Arc levels in brain-derived EVs isolated from human Alzheimer's disease (AD) brains show a strong positive correlation with phosphorylated EV-tau levels. rTg[Arc KO] mice have increased accumulation of intracellular tau and a modest increase in cell toxicity early in disease progression. Strikingly, intercellular tau transmission is almost absent in Arc KO mice. These results show that Arc is critical for the packaging of tau in EVs, which plays a significant role in intercellular tau transmission.},
}
@article {pmid42372923,
year = {2026},
author = {Lin, Z and Hu, L and Liu, Y and Ning, W and Wang, S and Fu, ZY and Guan, L},
title = {Rational design, synthesis, and biological evaluation of chalcone hybrids including benzoylpiperazin (phenylacetylpiperazin)-thiophene as anti- Alzheimer's agents.},
journal = {Bioorganic &amp; medicinal chemistry letters},
volume = {},
number = {},
pages = {130716},
doi = {10.1016/j.bmcl.2026.130716},
pmid = {42372923},
issn = {1464-3405},
abstract = {A series of chalcone hybrids including benzoylpiperazin (phenylacetylpiperazin)-thiophene were designed, synthesized and evaluated their inhibitory activities against cholinesterase (ChE). All compounds displayed good inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Among them, compound 2e displayed the most inhibitory activity against AChE, BChE and β-amyloid (Aβ42) with IC50 values 7.01, 5.39 and 4.47 μM, respectively. Meanwhile, 2e was found anti-Alzheimer's disease (AD) effect by significantly alleviating lipopolysaccharide (LPS)/Aβ-induced neurotoxicity, reducing the levels of reactive oxygen species (ROS), pro-inflammatory cytokines, and exert anti-inflammatory effects by regulating the NF-κB (Nuclear factor kappa-light-chain-enhancer of activated B cells) pathway. Furthermore, the molecular modeling studies showed that 2e target both catalytic active site as well as peripheral anionic site of AChE, BChE and Aβ42, and possess strong bind affinity. In addition, in silico ADMET and toxicity predictions demonstrated favorable oral absorption and potential blood-brain barrier (BBB) permeability for 2e. The rationale remains partly overstated. The novelty claim should more precisely distinguish this scaffold from previously reported chalcone, piperazine, thiophene, and multitarget ChE/Aβ inhibitors. The phrase "anti-Alzheimer's agents" should be softened, because the data are limited to enzyme assays, Aβ assays, BV-2 cellular models, docking, and computational predictions.},
}
@article {pmid42372976,
year = {2026},
author = {Price, TM and Tucker, AE and Funk, KE},
title = {Molecular and Environmental Drivers of Tau Post-Translational Modifications and Tau Pathology.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103223},
doi = {10.1016/j.arr.2026.103223},
pmid = {42372976},
issn = {1872-9649},
abstract = {Tau is an intrinsically disordered protein that functions to support cytoskeletal stability by binding microtubules in neuronal axons. While tau is involved in healthy neuronal function, it can become pathogenic by forming protein aggregates leading to neurologic diseases collectively known as tauopathies, which include Alzheimer's disease, frontotemporal dementia, and chronic traumatic encephalopathy. Post-translational modifications, including phosphorylation, O-GlcNAcylation, acetylation, methylation, ubiquitination, and protein truncation are molecular drivers that promote tau aggregation and subsequent disease development. There is a growing, but incomplete, understanding of the complex crosstalk that occurs among distinct modifications and how they orchestrate tau pathogenesis in concert. The drivers of tau post-translational modifications are not fully understood, but environmental factors, such as traumatic brain injuries, microbial infections, alcohol abuse, chronic stress, and heavy metal pollutants, increase risk of tau pathology formation. In this article we review the current literature describing the molecular changes that increase tau aggregation propensity, the environmental factors that promote those changes, and the multifactorial crosstalk that modulates tau pathogenesis. Our goal is to outline the biological pathways and molecular factors that drive tau pathogenesis in order to identify potential points of behavioral and/or therapeutic intervention for tauopathies.},
}
@article {pmid42373039,
year = {2026},
author = {Gao, K and Bao, J and Song, Y and Lin, CP and Iturria-Medina, Y and Biswal, BB and Wang, P},
title = {Beyond gray matter: unveiling the critical role of white matter in Alzheimer's disease.},
journal = {Progress in neuro-psychopharmacology &amp; biological psychiatry},
volume = {},
number = {},
pages = {111816},
doi = {10.1016/j.pnpbp.2026.111816},
pmid = {42373039},
issn = {1878-4216},
abstract = {Alzheimer's disease (AD) has traditionally been regarded as a disorder primarily affecting gray matter, while growing evidence highlights the significant role of white matter pathology in its progression. This review aims to assess the current state of knowledge regarding white matter abnormalities and elucidate the potential impact of white matter on the pathogenesis and progression of AD. White matter alterations, including inflammation, hyperintensities, structural and functional changes, often precede gray matter atrophy and cognitive decline during AD progression. Advanced imaging and histopathological studies suggest that white matter degeneration is not merely a downstream consequence of gray matter pathology; it may represent an independent, perhaps initiating, pathological pathway in AD progression. Moreover, white matter lesions in individuals with AD may be modifiable by both pharmacological and non-pharmacological interventions, supporting the potential for reducing white matter damage and improving cognitive functions.},
}
@article {pmid42373045,
year = {2026},
author = {Bulycheva, I and Watanabe, Y and Kitamura, K and Kabasawa, K and Saito, T and Takahashi, A and Kobayashi, R and Oshiki, R and Yamazaki, O and Watanabe, K and Takachi, R and Murai, U and Tsugane, S and Nakamura, K},
title = {Association between high dietary polyphenol intake and reduced risk of dementia: a 12-year cohort study.},
journal = {Clinical nutrition ESPEN},
volume = {},
number = {},
pages = {103438},
doi = {10.1016/j.clnesp.2026.103438},
pmid = {42373045},
issn = {2405-4577},
abstract = {BACKGROUND &amp; AIMS: Dietary polyphenols may play a modifiable role in reducing the risk of dementia; however, current evidence remains limited and inconclusive. This study aimed to investigate whether dietary polyphenol intake, taking caffeine intake into account, is associated with dementia risk in middle-aged and older people.<br><br>METHODS: Participants of this 12-year cohort study were 13,473 community-dwelling individuals aged 40-74 years (51.9% female). Dietary intake data were collected from 2011 to 2013 using a validated food frequency questionnaire. Polyphenol intake was adjusted for energy intake using the residual method. The outcome was incident dementia determined using Japan's long-term care insurance database. Multivariable Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs). Covariates included demographic factors, body size, lifestyle habits, and disease history (myocardial infarction, stroke, diabetes mellitus). An additional multivariable analysis was conducted, further adjusting for energy-adjusted caffeine intake.<br><br>RESULTS: The mean age of participants was 59.1 years. During follow-up, 337 males and 331 females developed dementia. Higher polyphenol intake was associated with a lower risk of dementia (multivariable-adjusted P for trend <0.0001), with the highest quintile (Q5) having a reduced risk of dementia (HR = 0.62, 95%CI: 0.49-0.78) compared to the lowest quintile (Q1, reference). After further adjusting for energy-adjusted caffeine intake, this association remained significant (P for trend = 0.0149), with Q5 having an HR of 0.70 (95%CI: 0.52-0.95). In males, higher polyphenol intake was associated with a lower hazard of dementia (multivariable-adjusted P for trend = 0.0002), with Q4 and Q5 having a lower hazard (Q4: HR = 0.59, 95% CI: 0.42-0.83; Q5: HR = 0.55, 95%CI: 0.40-0.76) compared to Q1. In females, higher polyphenol intake was associated with a lower hazard of dementia (multivariable-adjusted P for trend = 0.0106), with Q5 having a lower hazard (HR = 0.68, 95%CI: 0.49-0.96) compared to Q1.<br><br>CONCLUSION: High polyphenol intake is robustly associated with a decreased risk of dementia in middle-aged and older individuals, with the association remaining even after accounting for caffeine intake.},
}
@article {pmid42373097,
year = {2026},
author = {Chen, X and Wang, Z and Wang, J and Kong, D and Wang, X and Lu, L and Nelson, PT and Zhou, FM and Liao, FF},
title = {Distinctly altered TRPC3 and TRPC6 expression patterns in human Alzheimer's disease cortex and hippocampus.},
journal = {Brain pathology (Zurich, Switzerland)},
volume = {},
number = {},
pages = {e70118},
doi = {10.1111/bpa.70118},
pmid = {42373097},
issn = {1750-3639},
support = {R01-NS120327/NH/NIH HHS/United States ; R01-AG072703/NH/NIH HHS/United States ; P01&#x2009;AG078116/NH/NIH HHS/United States ; P30&#x2009;AG072946/NH/NIH HHS/United States ; 2023Y9286//Joint Funds for the Innovation of Science and Technology, Fujian province, China/ ; 2024J011004//Fujian Provincial Natural Science Foundation/ ; //Fujian Research and Training Grants for Young and Middle-aged Leaders in Healthcare, China/ ; },
abstract = {Calcium dysregulation is increasingly recognized as a convergent mechanism underlying neuronal vulnerability and glial overactivation in Alzheimer's disease (AD). Transient Receptor Potential Canonical (TRPC) channels are potential key modulators of Ca[2+] signaling in multiple cell types in central nervous system (CNS), mediating different pathophysiological roles. However, their cell type-specific remodeling and cellular origins of these changes in human AD tissue remain poorly defined. This study investigated their expression patterns with main focus on the two closely related members of TRPC3 and TRPC6 across human AD brains and two relevant mouse models. Formalin-fixed paraffin-embedded cortical and hippocampal tissues from AD patients and age-matched controls were examined using immunohistochemistry. Spatial relationships between TRPC3/TRPC6 and glial fibrillary acidic protein (GFAP)-positive astrocytes were assessed in adjacent serial sections. TRPC3 expression was markedly increased in AD cortex and hippocampus whereas TRPC6 was significantly reduced primarily in pyramidal neurons. TRPC3-positive regions showed close spatial correspondence with reactive astrocytes, particularly in the hippocampal and subcortical white matter regions, suggesting a partial astrocytic origin. TRPC6 exhibited negligible overlap with GFAP. These observations were reproduced in brain sections of both 5xFAD and PS19 transgenic (Tg) mice compared to their littermate controls. Our findings reveal a conserved pattern of divergent TRPC remodeling across human and mouse models with AD pathology. In addition, TRPC1 expression was significantly reduced in AD samples while TRPC4 and TRPC5 had no significant change in expression. Taken together, selected TRPC family members may undergo differential remodeling during AD pathogenesis, with TRPC3 and TRPC6 showing the most prominent and consistent alterations.},
}
@article {pmid42373113,
year = {2026},
author = {Weiss, SM and Watt, JA and Ewa, V and Straus, SE},
title = {Lecanemab use for early Alzheimer disease in Canada.},
journal = {CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne},
volume = {198},
number = {25},
pages = {E973-E976},
doi = {10.1503/cmaj.260193},
pmid = {42373113},
issn = {1488-2329},
}
@article {pmid42373496,
year = {2026},
author = {Wang, AM and Wang, YX and Ma, YH and Yang, XY and Guo, GY and Song, WC and Wang, SZ and Shi, FY},
title = {[Study on the risk factors of development for mild cognitive impairment to Alzheimer's disease based on the competitive risk joint model].},
journal = {Zhonghua liu xing bing xue za zhi = Zhonghua liuxingbingxue zazhi},
volume = {47},
number = {6},
pages = {1158-1164},
doi = {10.3760/cma.j.cn112338-20251013-00718},
pmid = {42373496},
issn = {0254-6450},
support = {81803337, 81872719//National Natural Science Foundation of China/ ; ZR2023MH313//Natural Science Foundation of Shandong Province/ ; 2019-10-156//Shandong Provincial Higher Education Youth Talent Introduction and Cultivation Program/ ; },
mesh = {*Alzheimer Disease ; Humans ; *Cognitive Dysfunction ; Risk Factors ; Boosting Machine Learning Algorithms ; Disease Progression ; Random Forest ; Female ; },
abstract = {Objective: To identify the risk factors for the progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD) using a competing risks joint model. Methods: This study was based on the Alzheimer's Disease Neuroimaging Initiative database. Three gradient boosting tree algorithm, namely CatBoost, XGBoost, and LightGBM, were employed to reduce the dimensionality of the high-dimensional lipoprotein and metabolite data (including 250 amino acids, lipids, and energy metabolism-related components, etc.). A random survival forest model (RSF) was used to screen out key demographic, cognitive function scores and metabolic variables. A competing risk joint model was constructed to identify the risk factors for the progression from MCI to AD. Results: A total of 8 lipoprotein and metabolite variables were identified by the three algorithms [creatinine, lactate, glycine, large high-density lipoprotein phospholipids percent (L_HDL_PL_PCT), acetic acid, tyrosine, β-hydroxybutyric acid and valine]. The RSF model identified 14 main variables, including cognitive function indicators [Functional Activities Questionnaire (FAQ), Alzheimer's Disease Assessment Scale-13 items (ADAS13), Alzheimer's Disease Assessment Scale word recognition item 4 (ADASQ4), and Alzheimer's Disease Assessment Scale-11 items (ADAS11)], lipoprotein and metabolites (acetic acid, L_HDL_PL_PCT, β-hydroxybutyrate, glycine, and creatinine), and baseline characteristics [age, years of education, marital status, retirement status, and apolipoprotein E ε4 allele (APOE-ε4)]. The univariate competing risk joint model showed that the longitudinal changes of ADAS11, ADAS13, ADASQ4, FAQ, and glycine, as well as baseline age, marital status, and APOE-ε4, were positively associated with the progression of MCI to AD (P<0.05). The results of the multivariate competing risk joint model further indicated that the longitudinal changes of ADAS13, ADASQ4, FAQ, and glycine, as well as baseline age, marital status, and APOE-ε4 were positively associated with AD incidence (P<0.05). Conclusions: Longitudinal increases in ADAS13, ADASQ4, FAQ, and glycine, as well as older age, unfavorable marital status, and APOE-ε4 carriage at baseline, were all risk factors for progression from MCI to AD.},
}
@article {pmid42373580,
year = {2026},
author = {Lee, J and Olafson, E and Toth, B and Casavant, E and Schauer, S and Bittner, T and Meyer, MR and Verghese, PB and Venkatesh, V and West, T and Braunstein, JB and Biever, A and Calderon, E and Mandl, M and Bayfield, A and Hoogenraad, CC and Teng, E and Monteiro, C and Anania, VG and Bohórquez, SMS and Yeh, FL},
title = {Evaluation of CSF and plasma tau species as fluid surrogate candidates for tau PET in prodromal to moderate Alzheimer's disease.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71604},
doi = {10.1002/alz.71604},
pmid = {42373580},
issn = {1552-5279},
support = {//Genentech Inc/ ; },
mesh = {Humans ; *tau Proteins/cerebrospinal fluid/blood/metabolism ; *Alzheimer Disease/diagnostic imaging/cerebrospinal fluid/blood/metabolism ; *Positron-Emission Tomography ; Female ; Biomarkers/cerebrospinal fluid/blood ; Male ; Aged ; Prodromal Symptoms ; Middle Aged ; Phosphorylation ; },
abstract = {INTRODUCTION: Positron emission tomography (PET) is a valuable tool for assessing tau pathology in Alzheimer's disease (AD), but it is not widely accessible. Clarifying the relationship between fluid tau species and tau PET in AD may allow for the identification of fluid biomarkers that could serve as more accessible surrogates for tau PET.<br><br>METHODS: Cerebrospinal fluid (CSF) and plasma tau species levels were assessed across prodromal to moderate AD subjects (CSF: n&#xa0;=&#xa0;53, plasma: n&#xa0;=&#xa0;181) via immunoassays and liquid chromatography-mass spectrometry. Fluid measures were correlated with [[18]F]GTP1 tau PET at baseline for head-to-head comparisons across analytes.<br><br>RESULTS: CSF C2N-eMTBR-tau243, tau phosphorylated at threonine 205 (p-tau205), p-tau217, and a peptide from the tau-441 microtubule-binding region (MTBR) (MTBR/243-254) exhibited the highest correlations with [[18]F]GTP1 standardized uptake value ratio. Plasma p-tau181 and p-tau217 demonstrated correlation rankings with tau PET similar to those observed with corresponding CSF analytes.<br><br>DISCUSSION: CSF C2N-eMTBR-tau243, MTBR/243-254, p-tau205, and p-tau217 demonstrated comparable strong correlations with tau PET. These findings may guide future development of plasma biomarker surrogates for tau PET.},
}
@article {pmid42373784,
year = {2026},
author = {Li, Y and Ulrich, JD and Holtzman, DM},
title = {Adaptive immunity in the pathogenesis of neurodegeneration.},
journal = {Nature immunology},
volume = {27},
number = {7},
pages = {1375-1389},
pmid = {42373784},
issn = {1529-2916},
support = {AG085374//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG069701//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG078106//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG083977//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; NS090934//U.S. Department of Health &amp; Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; },
mesh = {Humans ; *Adaptive Immunity/immunology ; *Neurodegenerative Diseases/immunology/pathology/therapy ; Animals ; Microglia/immunology ; *Central Nervous System/immunology/pathology ; Astrocytes/immunology ; Immunity, Innate ; },
abstract = {Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and others, are a group of neurological disorders characterized by progressive neuronal loss in the central nervous system (CNS) and the deterioration of CNS function. Multiple lines of evidence have highlighted activation of innate immune cells in the CNS, namely microglia and astrocytes, as hallmark pathological features in neurodegeneration and key drivers of disease progression. Advances in genetic, neuropathological and experimental studies also underscore the potential role of the adaptive immune system in disease pathogenesis. Here we summarize the current understanding of how adaptive immunity can shape the progression of neurodegenerative diseases and highlight cross-disease parallels and potentially shared mechanisms. We also examine cellular events leading to the recruitment of peripheral immune cells to the CNS, as well as candidate antigens driving the adaptive immune response. Last, we discuss potential therapeutic strategies to treat neurodegeneration via the manipulation of adaptive immune cells.},
}
@article {pmid42373786,
year = {2026},
author = {Guo, AX and Fisher, TM and Comandante-Lou, N and De Jager, PL and Liddelow, SA},
title = {Innate immune signaling and functions in astrocytes.},
journal = {Nature immunology},
volume = {27},
number = {7},
pages = {1364-1374},
pmid = {42373786},
issn = {1529-2916},
support = {AARF-24-1313800/ALZ/Alzheimer's Association/United States ; U01 AG061356/AG/NIA NIH HHS/United States ; },
mesh = {*Astrocytes/immunology/metabolism ; Humans ; *Immunity, Innate/immunology ; Animals ; *Signal Transduction/immunology ; Toll-Like Receptors/metabolism/immunology ; Innate Immunity Recognition ; Inflammasomes/metabolism/immunology ; },
abstract = {Astrocytes, long considered supportive cells of the central nervous system (CNS), have critical roles in innate immunity. This Review explores immune signaling pathways in astrocytes, including pattern recognition through Toll-like receptors, nucleic acid sensors and inflammasomes. These pathways enable the detection of danger signals and initiate protective responses and endogenous innate immune functions. Downstream signaling pathways, including the interferon, NF-κB and STAT3 pathways, mediate astrocyte reactivity and drive cytokine secretion, antiviral responses, phagocytosis and many other immune functions. While these responses are crucial for CNS health, their dysregulation can contribute to chronic inflammation and neurodegeneration in conditions such as Alzheimer's disease, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis. Additionally, astrocytes exhibit regional heterogeneity in their immune behaviors, which may influence disease trajectories. We highlight unresolved questions regarding the immune functions of astrocytes, their interplay with professional immune cells and their dual protective and pathological roles.},
}
@article {pmid42373968,
year = {2026},
author = {Gardner, KL and Lange, TE and Perna, MK and Wells, SI and Williams, MT and Vorhees, CV and Cox, M and Solomon, MB and Privette Vinnedge, LM},
title = {DEK Loss Induces Task-specific Deficits in Learning and Memory and Reprograms the Hippocampal Transcriptome in Mice.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42373968},
issn = {1559-1182},
mesh = {Animals ; *Hippocampus/metabolism ; Male ; *Poly-ADP-Ribose Binding Proteins/deficiency/metabolism/genetics ; *Chromosomal Proteins, Non-Histone/deficiency/metabolism/genetics ; Female ; *Oncogene Proteins/deficiency/metabolism/genetics ; *Transcriptome/genetics ; Mice, Knockout ; *Memory/physiology ; Mice, Inbred C57BL ; Mice ; Maze Learning ; Behavior, Animal ; DNA-Binding Proteins ; },
abstract = {DEK is an estrogen-responsive chromatin-remodeling protein broadly expressed in the murine and human brain, with high expression in memory-relevant regions such as the hippocampus. Prior work from our group and others has linked DEK loss to cellular features associated with Alzheimer's disease and Alzheimer's disease-related dementias. Notably, our group has demonstrated that DEK expression declines with increasing dementia severity in women, but not in age-matched men, suggesting a sex-specific relationship between DEK loss and cognitive vulnerability. Together, these findings support a potential neuroprotective role for DEK; however, functional consequences of DEK loss in vivo were unknown. Here, we examined behavioral and molecular consequences of Dek loss using male and female constitutive knockout (cKO) mice assessed across cognitive, sensorimotor, and affective domains. Across assays, Dek cKO mice of both sexes exhibited intact locomotor activity, anxiety-related behavior, sensorimotor gating, and fear-associated memory. In contrast, female Dek cKO mice displayed selective impairments in cognitive flexibility despite preserved spatial learning and memory, a phenotype not observed in males and indicative of female-specific vulnerability following DEK loss. This sex difference, observed during Morris water maze reversal learning, suggests disruption of hippocampal-prefrontal circuitry. Guided by known sex differences in hippocampal DEK expression, transcriptomic profiling of hippocampal tissue revealed shared and sex-specific consequences of Dek deficiency, including alterations in cytoskeletal organization, neuronal signaling, chromatin regulatory mechanisms, and cellular stress pathways. Collectively, these findings demonstrate sex- and cognitive-domain-specific effects of DEK loss and support further investigation of DEK in executive function and hippocampal-prefrontal cortex-mediated cognition.},
}
@article {pmid42374181,
year = {2026},
author = {Gong, R and Wang, H and Cao, L and Niu, H and Rominger, A and Luo, Z and Ni, R},
title = {Targeting the crosstalk between Alzheimer's disease and gastrointestinal cancers.},
journal = {Molecular medicine (Cambridge, Mass.)},
volume = {},
number = {},
pages = {},
doi = {10.1186/s10020-026-01545-x},
pmid = {42374181},
issn = {1528-3658},
abstract = {Epidemiological studies have revealed an inverse association between Alzheimer's disease and cancer. Here, we discuss the mechanisms involved in the relationship between Alzheimer's disease and gastrointestinal cancers, particularly pancreatic and gastric-colorectal cancers. The gut‒brain axis and pancreas‒brain axis connect the central nervous system with peripheral organs and form immune‒metabolic networks. We focus on bidirectional tumor-brain communication, involving cell-death pathways, apoptosis, metabolic dysregulation, microbiota, metabolic dysregulation, neuroinflammation, immune system and sensory-sympathetic circuits, and neural remodeling. Furthermore, we discuss potential integrated, multitarget therapeutic strategies, including metabolic regulation, microbiome interventions, and immune modulation. Prospective longitudinal cohorts incorporating prediagnostic exposures and molecular pathology are needed to establish temporality.},
}
@article {pmid42374285,
year = {2026},
author = {Pedersen, EK and Nielsen, A and Nicolaisdóttir, DR and Øksnebjerg, L and Tannebæk, K and Janbek, J and Waldemar, G and Nielsen, TR},
title = {Associations between a psychosocial intervention and quality of life and caregiver-related outcomes in family caregivers of people with dementia: the Danish DemTool trial.},
journal = {BMC geriatrics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12877-026-07835-7},
pmid = {42374285},
issn = {1471-2318},
abstract = {BACKGROUND: People with dementia often need comprehensive support, depending on the stage of the disease, from both family members and healthcare professionals. Caring for a person with dementia can be stressful and impact the caregiver's health and wellbeing. Studies show that family caregivers of people with dementia frequently experience stress, depression, and reduced quality of life. We aimed to assess the association between the psychosocial intervention (DemTool) and caregiver wellbeing and quality of life among family caregivers of people with dementia.<br><br>METHOD: DemTool trial was a pragmatic, cluster-controlled trial. The intervention was delivered by primary care dementia coordinators across 30 Danish municipalities from 2020 to 2023, with 15 serving as the intervention group and 15 as treatment as usual. The primary outcome measures were the Neuropsychiatric Inventory Caregiver Distress Scale (NPI-D) and the European Quality of Life Visual Analog Scale (EQ VAS). Both measures were completed at baseline and follow-up, alongside secondary quality of life outcomes. To estimate group differences in primary and secondary outcomes, we applied analysis of variance (ANOVA) and analysis of covariance (ANCOVA).<br><br>RESULTS: A total of 245 family caregivers were included in the study (181 in the intervention group and 64 in the treatment-as-usual group). Most participants were females caring for a spouse. Baseline scores for caregiver wellbeing and quality of life were similar across groups. The DemTool intervention was associated with a significant between-group difference in change from baseline in caregiver-related quality of life as measured by the Carer Experience Scale (CES), favoring the intervention. This was evident in the analysis adjusted for baseline scores (p&#x2009;=&#x2009;0.05) and remained significant when further adjusting for caregiver-related covariates (p&#x2009;=&#x2009;0.02). No statistically significant between-group differences were observed for the remaining wellbeing and quality-of-life outcomes.<br><br>CONCLUSION: No effects of DemTool were found on traditional health-related quality-of-life outcomes. However, a positive association was found between the intervention and the CES, underlining the importance of selecting outcomes that are directly related to the targeted effects of the intervention.<br><br>TRIAL REGISTRATION: The study protocol was registered in the ClinicalTrials.gov system, registration number: NCT07355829.},
}
@article {pmid42374489,
year = {2026},
author = {Saul, E and Chauveau, L and Landeau, B and Lasserve, J and Montagne, B and Foyard, E and Poisnel, G and Chételat, G and de Flores, R and , },
title = {Structural and molecular determinants of medial temporal lobe network vulnerability in aging and Alzheimer's disease.},
journal = {Alzheimer's research &amp; therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02125-1},
pmid = {42374489},
issn = {1758-9193},
support = {667696//European Union's Horizon 2020 Research and Innovation Program/ ; },
abstract = {BACKGROUND: The medial temporal lobe is organized into two memory-critical networks: the anterior-temporal and posterior-medial systems. While these systems show selective vulnerability to aging and Alzheimer's disease, the underlying structural and molecular determinants of this susceptibility remain unclear. We aimed to characterize the specific white matter pathways supporting these networks, investigate how amyloid-β and neuroinflammation interact to impact their integrity, and determine if structural changes relate to functional connectivity alterations.<br><br>METHODS: In 88 cognitively unimpaired (CU) older adults (&#x2265;&#x2009;65&#xa0;years) from the Age-Well cohort (NCT02977819), we combined longitudinal diffusion MRI tractography, resting-state fMRI, amyloid-&#x3b2; PET (Florbetapir), and plasma glial fibrillary acidic protein (GFAP). We reconstructed fiber pathways of the perirhinal (anterior-temporal system hub) and parahippocampal (posterior-medial system hub) cortices and quantified their microstructural integrity, network connectivity, and relationships to pathology.<br><br>RESULTS: The anterior-temporal and posterior-medial systems relied on partly distinct structural pathways. Both involved the inferior longitudinal and cingulum bundles, but the anterior-temporal system was specifically associated to their inferior portions, as well as thalamic radiations, and callosal fibers, whereas the posterior-medial system relied more on their superior portions and the inferior fronto-occipital fasciculus. We identified a non-linear, inverted U-shaped association between pathway integrity and amyloid-&#x3b2; burden, suggesting dynamic structural changes across early pathological stages. Crucially, plasma GFAP moderated this relationship for the posterior-medial pathway: the negative impact of amyloid-&#x3b2; on structural integrity was exacerbated in individuals with higher astroglial reactivity, highlighting a synergistic pathological effect. Finally, in high amyloid-&#x3b2; individuals, increased anterior-temporal functional connectivity correlated with lower anterior-temporal pathway integrity, suggesting that network higher FC may represent a maladaptive response to early amyloid-&#x3b2; deposition leading to white matter integrity loss.<br><br>CONCLUSIONS: Together, our findings reveal distinct mechanisms of vulnerability within medial temporal networks: while the posterior-medial system is primarily sensitive to the synergistic effects of amyloid-&#x3b2; and astroglial reactivity, the anterior-temporal system shows lower structural integrity linked to higher FC in the presence of amyloid. By providing a mechanistic framework for these early disruptions, this study advances the understanding of preclinical Alzheimer's disease and identifies specific structural-functional signatures that could serve as sensitive biomarkers for targeted interventions.},
}
@article {pmid42374501,
year = {2026},
author = {Bregman, N and de Barros, NP and Nathan, T and Levy, MH and Sima, D and Van Eyndhoven, S and Bar-David, A and Aizenstein, O and Niry, D and Atlan, L and Awad, AA and Ash, E and Omer, N and Shiner, T},
title = {Lecanemab in practice: AI-derived MRI predictors of benefit and Amyloid Related Imaging Abnormalities (ARIA).},
journal = {Alzheimer's research &amp; therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02127-z},
pmid = {42374501},
issn = {1758-9193},
abstract = {INTRODUCTION: Lecanemab, a monoclonal antibody targeting amyloid beta, has demonstrated meaningful clinical benefits in early Alzheimer's disease (AD), yet real-world data is needed to optimize patient selection and enhance safety monitoring, particularly with respect to amyloid-related imaging abnormalities (ARIA). Integration of quantitative and AI-derived MRI biomarkers may improve risk stratification and prediction of clinical trajectory.<br><br>METHODS: We conducted a retrospective real-world study of eighty-two patients with biomarker-confirmed early AD who initiated lecanemab at Tel Aviv Sourasky Medical Center between November 2023 and June 2025. Baseline MRI included volumetric T1-weighted imaging and susceptibility-weighted imaging (SWI). Automated whole-brain, regional cortical, and hippocampal volumes, and percentiles were extracted using FDA-cleared AI tools (icobrain by icometrix). Microhaemorrhage (MH) burden was assessed by both human and AI-assisted reads. Cognitive outcomes were evaluated using change in Mini-Mental State Examination (MMSE). Linear regression models assessed MRI predictors of cognitive response, and multivariable logistic regression identified predictors of ARIA.<br><br>RESULTS: Patients exhibited significantly lower cerebral volumes at treatment initiation. Mean whole brain percentile, mean gray-matter (GM) percentile, and mean white matter percentile were 11.45%, 8.6% and 38% respectively. Higher baseline GM volume predicted less MMSE decline at 12 months (&#x3b2; = 0.64, FDR-corrected p < 0.003). Hippocampal and white-matter volumes were not associated with cognitive outcomes. Seventeen patients (20.7%) developed ARIA. Baseline MH burden was the strongest predictor of ARIA (human rated OR=3.48 per MH, p=0.015, icobrain rated OR=3.25, p=0.01), while APOE &#x3b5;4 carriage showed a strong directional trend which did not reach significance. Aspirin use and hypertension were not associated with ARIA. Agreement between icobrain and experts for MH ratings was excellent with a single-measure intraclass correlation coefficient (ICC) of 0.89 (95% CI: 0.83-0.93).<br><br>CONCLUSIONS: AI-derived MRI markers, particularly GM volume and MH burden, provide valuable predictors of cognitive response and ARIA risk in patients treated with lecanemab. Integrating quantitative neuroimaging into clinical workflows may enhance personalized treatment decisions and improve real-world implementation of Amyloid-targeting therapies.},
}
@article {pmid42374538,
year = {2026},
author = {Moon, SH and Kim, MH and Ryoo, JH},
title = {Smoking cessation duration and risk of Alzheimer's disease: a nationwide cohort study in Korea.},
journal = {Alzheimer's research &amp; therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02132-2},
pmid = {42374538},
issn = {1758-9193},
support = {RS-2024-00509118//Ministry of Health and Welfare/ ; },
abstract = {BACKGROUND: Smoking is a modifiable risk factor for Alzheimer's disease, yet the temporal pattern of risk reduction following smoking cessation remains unclear. We investigated whether Alzheimer's disease risk declines according to the duration of sustained smoking cessation in a large nationwide cohort.<br><br>METHODS: Using the Korean National Health Insurance Service database (2002-2023), we identified 1,403,636 adults with stable longitudinal smoking patterns based on repeated biennial health examinations. Smoking status was classified as never smokers, current smokers, or sustained quitters, with cessation duration categorised into 2-year intervals (<&#x2009;2, 2-3, 4-5, 6-7, &#x2265;&#x2009;8 years). Incident Alzheimer's disease was defined as at least two separate NHIS insurance claims. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals, adjusting for demographic, lifestyle, and metabolic factors.<br><br>RESULTS: During a mean follow-up of 10.5 years, 58,519 incident Alzheimer's disease cases were identified. Compared with current smokers, sustained quitters exhibited progressively lower hazards of Alzheimer's disease with increasing duration of abstinence, demonstrating a dose-response pattern. Individuals who had quit for <&#x2009;2 years showed a risk reduction relative to current smokers (adjusted HR 0.899; 95% CI 0.819-0.986), while those with &#x2265;&#x2009;8 years of abstinence had substantially lower risk (adjusted HR 0.582; 95% CI 0.423-0.801). When referenced to never smokers, those with <&#x2009;2 years of abstinence retained excess risk, whereas cessation for &#x2265;&#x2009;2 years was associated with Alzheimer's disease risk approaching that of never smokers.<br><br>CONCLUSIONS: Sustained smoking cessation was associated with a graded reduction in Alzheimer's disease risk, with approximately 2 years of abstinence needed to approach never-smoker risk.},
}
@article {pmid42374761,
year = {2026},
author = {Xing, Z and Jiang, X and Yang, W and Wang, Y and Zhang, X and Zhao, C},
title = {Corrigendum to: Lithium Chloride Improves Electrophysiological and Memory Deficits in Rats with Streptozotocin-Induced Alzheimer's Disease.},
journal = {Current Alzheimer research},
volume = {23},
number = {1},
pages = {75},
doi = {10.2174/1567205023999260119152707},
pmid = {42374761},
issn = {1875-5828},
abstract = {In the published version of this article [1], the email address of the co-corresponding author, Zheng Xing, was missing from the corresponding address section. This has now been corrected. The original article can be found online at: https://www.eurekaselect.com/article/149786 Details of the error and the correction are provided below: Original: Address correspondence to this author at the Department of Pharmacy, The Second People's Hospital of Changzhou, The Third Affiliated Hospital of Nanjing Medical University, Changzhou, Jiangsu, 213004, P.R. China; E-mail: zhaochen3339@njmu.edu.cn (C.Z.); Corrected: Address correspondence to these authors at the Department of Pharmacy, The Second People's Hospital of Changzhou, The Third Affiliated Hospital of Nanjing Medical University, Changzhou, Jiangsu, 213004, P.R. China; E-mails: zhaochen3339@njmu.edu.cn (C.Z.); xingzheng@cczu.edu.cn (Z.X.).},
}
@article {pmid42374762,
year = {2026},
author = {Boudi, A and He, J and El Kader, IA and Liu, X and Mouhafid, M},
title = {Corrigendum to: Advancing Alzheimer's Disease Diagnosis Using VGG19 and XGBoost: A Neuroimaging-Based Method.},
journal = {Current Alzheimer research},
volume = {23},
number = {1},
pages = {76},
doi = {10.2174/1567205023999260119151250},
pmid = {42374762},
issn = {1875-5828},
abstract = {The publisher identified that references 42 and 43 were duplicated in the published version of this article [1]. The error has now been corrected. The original article can be found online at: https://www.benthamscience.com/article/150567 Details of the error and the correction are provided below: Original: [42] Muksimova S, Umirzakova S, Iskhakova N, Khaitov A, Cho YI. Advanced convolutional neural network with attention mechanism for Alzheimer's disease classification using MRI. Comput Biol Med 2025; 190, 110095. [43] Muksimova S, Umirzakova S, Iskhakova N, Khaitov A, Cho YI. Advanced convolutional neural network with attention mechanism for Alzheimer's disease classification using MRI. Comput Biol Med 2025; 190: 110095. http://dx.doi.org/10.1016/j.compbiomed.2025.110095 PMID: 40158456 Corrected: [42] Muksimova S, Umirzakova S, Iskhakova N, Khaitov A, Cho YI. Advanced convolutional neural network with attention mechanism for Alzheimer's disease classification using MRI. Comput Biol Med 2025; 190, 110095. http://dx.doi.org/10.1016/j.compbiomed.2025.110095 PMID: 40158456 [43] Olaimat MA, Bozdag S, Saeed F. TA-RNN: An attention-based time-aware recurrent neural network architecture to predict progression of Alzheimer's disease. Alzheimer's Dement 2024; 20(S1).},
}
@article {pmid42374773,
year = {2026},
author = {Kim, H and Liu, E and Kajiyama, B and Song, J and Paun, O and Han, SG and Gallagher-Thompson, D},
title = {Development of K-iCare: a culturally adapted stress management intervention for Korean American dementia family caregivers.},
journal = {Aging &amp; mental health},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/13607863.2026.2693238},
pmid = {42374773},
issn = {1364-6915},
abstract = {OBJECTIVES: We developed the Korean version of iCare (K-iCare), a cognitive behavioral therapy (CBT)-based stress management intervention for Korean American family caregivers of individuals with Alzheimer's disease and related dementias (ADRD).<br><br>METHODS: Using the Framework for Reporting Adaptations and Modifications-Enhanced (FRAME), K-iCare was developed through a five-stage process: (1) initial modifications by the research team; (2) feedback from two focus groups comprising former Korean American ADRD family caregivers and Korean American community service providers; (3) refinement of K-iCare; (4) validation by focus group participants and the original iCare developers; and (5) finalization for implementation.<br><br>RESULTS: Intervention materials were translated into Korean with systematic cultural and linguistic adaptations. The number of chapters was consolidated from nine to five, and caregiving scenarios were replaced with culturally relevant examples reflecting Korean American caregiving norms. The intervention format was revised from self-paced, asynchronous modules to synchronous weekly small-group sessions delivered in a hybrid format and led by a bilingual, bicultural, doctoral-level interventionist with expertise in ADRD care. Supporting materials (e.g. fidelity monitoring checklists) were developed to promote consistent intervention delivery.<br><br>CONCLUSION: The next phase will evaluate the feasibility and acceptability of K-iCare and generate preliminary estimates of intervention-associated change and outcome variability.},
}
@article {pmid42374809,
year = {2026},
author = {Jiang, B and Yan, Y and Xu, C and Zhao, X and Qi, F and Xu, S and Yang, W and Liu, X and Feng, L},
title = {Herpes zoster as a vaccine-preventable risk factor increases the risk of dementia: A nested case-control study in Chinese population.},
journal = {Human vaccines &amp; immunotherapeutics},
volume = {22},
number = {1},
pages = {2681253},
doi = {10.1080/21645515.2026.2681253},
pmid = {42374809},
issn = {2164-554X},
mesh = {Humans ; *Herpes Zoster/complications/prevention &amp; control/epidemiology ; Case-Control Studies ; Female ; China/epidemiology ; Risk Factors ; *Dementia/epidemiology/etiology ; Male ; Aged ; Middle Aged ; Aged, 80 and over ; East Asian People ; },
abstract = {Herpes zoster, a vaccine-preventable disease caused by the reactivation of varicella-zoster virus, has been linked to an increased risk of dementia in high-income countries. However, evidence from populations with low vaccination coverage remains limited. To address this gap, we conducted a nested case-control study using electronic health records from Yichang, China. A total of 51,843 incident dementia patients aged 50 y and older were matched with 338,877 controls by sex, age, and visit date. A documented clinical history of herpes zoster was significantly associated with an elevated risk of all-cause dementia (adjusted odds ratio [aOR] = 1.48; 95% confidence interval [CI]: 1.41-1.56), with the highest risk observed among individuals with herpes zoster involving the central nervous system (aOR = 1.59, 95%CI: 1.46-1.73). Among the dementia cases with prior HZ diagnosis, both Alzheimer's disease (aOR = 1.44, 95%CI: 1.14-1.79) and vascular dementia (aOR = 1.82, 95%CI: 1.49-2.21) showed increased risks following herpes zoster infection, with vascular dementia demonstrating a stronger association and more rapid progression (median time from first herpes zoster diagnosis to dementia onset: 1.5 y versus 2.2 y for Alzheimer's disease). The findings, derived from a population with minimal herpes zoster vaccination coverage, identify herpes zoster as a potentially modifiable risk factor for dementia. These also underscore the potential dual public health benefit of herpes zoster vaccination in preventing both acute infection and long-term cognitive decline.},
}
@article {pmid42375090,
year = {2026},
author = {Lee, HY and Hossain, MK and Jang, GH and Lee, H and Kim, YM and Chae, HJ},
title = {Behavioral and Biochemical Evaluation of a Curcumin-Loaded Nano-Liposomal Formulation in a Scopolamine-Induced Mouse Model of Cognitive Impairment.},
journal = {Biomolecules &amp; therapeutics},
volume = {34},
number = {4},
pages = {866-881},
doi = {10.4062/biomolther.2026.062},
pmid = {42375090},
issn = {1976-9148},
abstract = {Scopolamine-induced cognitive impairment in mice models acute cholinergic dysfunction associated with early functional features of Alzheimer's disease (AD). This study evaluated the neuroprotective potential of curcumin-loaded nanoliposomes (Cur-NL), a bioavailable curcumin formulation, using behavioral, molecular, and biochemical approaches. Male mice received oral Cur-NL (250, 500, or 1000 mg/kg) for 30 days, followed by a single intraperitoneal injection of scopolamine (2 mg/kg). Cognitive performance was assessed by the open field test and Barnes maze. Acetylcholinesterase (AChE) activity, acetylcholine (ACh) levels, hippocampal gene expression, and reactive oxygen species (ROS) accumulation were analyzed to investigate underlying mechanisms. Cur-NL significantly improved spatial learning and memory and restored cholinergic balance by normalizing AChE activity and ACh levels. Treatment also attenuated hippocampal neuroinflammation, oxidative stress, and ROS accumulation. Cur-NL modulated genes related to amyloid processing and synaptic plasticity, suppressing App and Bace1 and upregulating Adam10 and Bdnf. Network analyses supported the involvement of cholinergic, inflammatory, and synaptic signaling pathways. These findings indicate that Cur-NL confers multitarget neuroprotection in a scopolamine-induced model and may serve as a candidate for managing early cholinergic-related cognitive decline. Important limitations should be acknowledged: curcumin concentrations in plasma and brain were not quantified, and a free-curcumin comparator was not included. The findings should therefore be interpreted as evidence of efficacy of the tested Cur-NL preparation, not as a comparative demonstration of nano-liposomal superiority over free curcumin. Direct pharmacokinetic and head-to-head comparative studies are required to establish the formulation-specific contribution of nano-liposomal delivery.},
}
@article {pmid42375607,
year = {2026},
author = {Lee, N and Youn, K and Kwon, H and Kim, DH and Ho, CT and Jun, M},
title = {Fucoxanthin attenuates carbonyl stress and neuroinflammation by modulating MGO/RAGE/NF-κB axis in Aβ-induced models.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1811183},
pmid = {42375607},
issn = {1663-9812},
abstract = {INTRODUCTION: Amyloid-β (Aβ) accumulation is a central pathological feature of Alzheimer's disease (AD) and a major driver of disease progression. Recent evidence suggests that carbonyl stress associated with Aβ plays a critical role in AD pathology by promoting neuroinflammation and neuronal damage. In particular, methylglyoxal (MGO), a highly reactive carbonyl compound, contributes to activation of the receptor for advanced glycation end products (RAGE) and NF-κB-dependent inflammatory signaling, leading to synaptic dysfunction. The present study investigated whether fucoxanthin, a marine-derived carotenoid, attenuates Aβ-induced carbonyl stress and inflammatory responses associated with MGO/RAGE/NF-κB-related signaling.<br><br>METHODS: PC12 neuronal cells were pretreated with fucoxanthin (0.1-5&#xa0;&#x3bc;M) and exposed to aggregated A&#x3b2;25-35 (10&#xa0;&#x3bc;M) to assess its effects on carbonyl stress-associated inflammatory signaling. In parallel, an A&#x3b2;1-42 intracerebroventricular injection mouse model was used to validate the in vitro findings. Mice were orally administered fucoxanthin (100 or 200&#xa0;mg/kg/day) for 15 days and assessed for serum MGO levels, hippocampal RAGE/NF-&#x3ba;B activation, microglial activation, and synaptic marker expression.<br><br>RESULTS: Fucoxanthin significantly reduced the expression of pro-inflammatory mediators, including COX-2, iNOS, IL-1&#x3b2;, and TNF-&#x3b1; in A&#x3b2;-exposed neuronal cells. This anti-inflammatory effect was associated with inhibition of NF-&#x3ba;B nuclear translocation and downregulation of RAGE expression. Consistent with these in vitro findings, fucoxanthin treatment in A&#x3b2;1-42-injected mice alleviated systemic and hippocampal carbonyl stress, as evidenced by decreased serum MGO levels and suppression of hippocampal RAGE/NF-&#x3ba;B activation. These effects were accompanied by reduced microglial activation (Iba-1) across hippocampal subregions and significant restoration of both presynaptic and postsynaptic markers, indicating preservation of synaptic integrity.<br><br>CONCLUSION: These findings demonstrate the neuroprotective role of fucoxanthin in mitigating A&#x3b2;-induced carbonyl stress by targeting the MGO/RAGE/NF-&#x3ba;B axis, thereby suppressing neuroinflammation and preserving synaptic integrity in A&#x3b2;-induced cellular and mouse models. Fucoxanthin emerges as a promising pharmacological candidate targeting carbonyl stress-associated mechanisms in AD.},
}
@article {pmid42375805,
year = {2025},
author = {Castro-Fuentes, R and Socas-Pérez, R},
title = {Unveiling the significance of dog domestication in cognitive dysfunction: Are wolves protected?.},
journal = {Open veterinary journal},
volume = {15},
number = {2},
pages = {6126-6145},
pmid = {42375805},
issn = {2218-6050},
mesh = {Animals ; *Wolves ; Dogs ; *Domestication ; *Cognitive Dysfunction/etiology/epidemiology ; *Dog Diseases/etiology ; Risk Factors ; Aging ; },
abstract = {Over the course of their long coexistence with humans, dogs have developed a stronger bond with humans than with any other domestic species. This close relationship has promoted notable parallels in both genetics and lifestyle, thereby facilitating the development of comparable pathological conditions, including several central nervous system disorders. Canine cognitive dysfunction (CCD) is a spontaneous model of neurodegeneration that shares clinical features, neuropathological characteristics, and risk factors with human Alzheimer's disease (AD). However, the potential role of dog domestication in increasing CCD susceptibility remains poorly explored. In this sense, the gray wolf (Canis lupus), a direct ancestor of the domestic dog (Canis lupus familiaris), represents a comparative model of great interest, as the information available on its neuropathology and behavior associated with aging is very limited. To provide a preliminary framework for assessing how domestication may have shaped vulnerability to cognitive decline in canids, this study employed a database-driven analytical approach to evaluate the degree of impact of various risk factors shared by AD and CCD-including aging, oxidative stress, inflammation, sleep disturbances, and periodontal disease-in domestic dogs and gray wolves kept in captivity or semi-captivity. Our results indicate that domestic dogs have more pronounced key risk factors for CCD than captive or semi-captive gray wolves. This finding suggests that wolves may be less vulnerable to age-related cognitive dysfunction, possibly reflecting differences in evolutionary or domestication processes. Nevertheless, given the scarcity of neuropathological and behavioral data on aged wolves, these conclusions should be interpreted with caution, and further direct investigations are warranted. Domestication may have increased susceptibility to age-related cognitive dysfunction in dogs by enhancing exposure to key risk factors, as oxidative stress, inflammation, and lifestyle-related conditions. Recognizing these domestication-linked vulnerabilities highlights the need for preventive health strategies in dogs and provides a valuable comparative framework for understanding neurodegenerative processes across species within a One Health perspective.},
}
@article {pmid42375925,
year = {2026},
author = {Sujanthi, S and Ravishankkar, AM and Ponmaniraj, S and Nanthini, S},
title = {Magnetic resonance imaging-based Alzheimer's disease detection using an EfficientNet-CMSACCN framework.},
journal = {Cytotechnology},
volume = {78},
number = {4},
pages = {146},
pmid = {42375925},
issn = {0920-9069},
abstract = {Alzheimer's Disease (AD) is a degenerative neurological condition characterized by memory loss, cognitive deterioration, and brain tissue shrinkage. Detecting it at an early stage is difficult due to variations in disease progression and the restricted scope of single-modality neuroimaging methods. Magnetic Resonance Imaging (MRI)-based Alzheimer's diagnosis, such as magnetic resonance imaging, offers complementary structural and functional insights, but existing deep learning methods often struggle with data imbalance, high computational complexity, and limited generalization. To fill these research gaps, design an MRI-based EfficientNet feature extraction framework for Alzheimer's stage classification. EfficientNet, equipped with compound scaling, depthwise-separable layers, and squeeze-and-excitation components, enables precise characterization of cortical structures and whole-brain variations while preserving computational efficiency. Extracted features are classified using a Compression-based Multi-Scale Attention Convolutional Network (C-MSACCN), which integrates attention mechanisms and compression strategies to enhance accuracy and reduce model complexity. Furthermore, the Improved Cellular Neighbours Optimiser (ICNO) fine-tunes hyperparameters, striking a balance between exploration and exploitation for optimal convergence and robustness. With 99.9% accuracy, precision, recall, and F1-score on datasets, the model outperforms prior work. Validation confirms consistency, and visualisation methods highlight disease-relevant regions to provide clinical insight.},
}
@article {pmid42376002,
year = {2026},
author = {Paitel, ER and Pettigrew, C and Moghekar, A and Miller, MI and Faria, AV and Albert, M and Na, CH and Worley, P and Soldan, A},
title = {Associations of cerebrospinal fluid measures of synaptic function with white matter microstructure and cognition in older adults.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1851829},
pmid = {42376002},
issn = {1663-4365},
abstract = {INTRODUCTION: Lower levels of several synaptic proteins in cerebrospinal fluid (CSF) have been associated with greater cognitive decline among older adults, but there is limited understanding of their associations with brain structure. This study is among the first to examine the cross-sectional relationship between levels of three synaptic proteins (VGF, NPTX2, and GluA4) with magnetic resonance imaging (MRI) measures of white matter microstructure and volumes, and with cognitive performance. We also examined whether relationships between synaptic protein levels and white matter measures are influenced by CSF Alzheimer's disease (AD) biomarker levels [ratio of p-tau181/(Aβ42/Aβ40)].<br><br>METHODS: Participants included 151 middle-aged and older adults without dementia (132 cognitively unimpaired, 19 mild cognitive impairment, M age&#x202f;=&#x202f;69.3&#x202f;years). White matter volumes and microstructure [fractional anisotropy (FA), mean diffusivity (MD)], derived from MRI scans, were assessed in three regions: global cerebral, medial temporal lobe, and cerebellar peduncles.<br><br>RESULTS: In linear regression analyses, lower levels of NPTX2, VGF, and GluA4 were associated with lower FA and higher MD, even after accounting for CSF AD biomarker levels. Synaptic proteins were not associated with white matter volumes. Additionally, lower FA, higher MD, and lower VGF levels were associated with poorer executive function performance. An exploratory mediation analysis showed that cerebral white matter MD statistically mediated the relationship between VGF and executive performance.<br><br>DISCUSSION: These findings provide preliminary, cross-sectional support that VGF may act on cognition via white matter microstructure. Together the results suggest that white matter microstructure may represent one pathway linking synaptic proteins levels to cognitive performance among older adults. Future research is needed to advance understanding of the specific mechanisms driving these relationships.},
}
@article {pmid42376437,
year = {2026},
author = {Dominguez, LJ and Veronese, N and Ragusa, FS and Seminara, F and Baio, SM and Vernuccio, L and Catanese, G and Barbagallo, M},
title = {Prevention of cognitive decline and dementia: Current evidence on lifestyle factors and dietary patterns.},
journal = {EXCLI journal},
volume = {25},
number = {},
pages = {690-724},
pmid = {42376437},
issn = {1611-2156},
abstract = {Cognitive decline and dementia represent major and growing global health challenges, driven largely by population aging and increased longevity. Currently, more than 55 million people worldwide live with dementia, a figure projected to rise to approximately 153 million by 2050. Alzheimer's disease accounts for the majority of cases, and despite extensive research, effective disease-modifying therapies remain limited. Consequently, increasing attention has shifted toward prevention strategies targeting modifiable risk factors. Accumulating evidence indicates that dementia is not an inevitable consequence of aging and that up to 45 % of cases may be attributable to potentially modifiable lifestyle and environmental factors operating across the life course. Lifestyle behaviors-including diet, physical activity, smoking, alcohol consumption, sleep, and social and cognitive engagement-have emerged as key targets for intervention. In particular, adherence to healthy dietary patterns such as the Mediterranean, DASH, and MIND diets has been associated with better cognitive outcomes, while unhealthy dietary patterns may increase risk. However, findings across studies remain heterogeneous, and uncertainties persist regarding causality, optimal exposure timing, and specific lifestyle components. Recent large prospective cohorts, meta-analyses, umbrella reviews, and multidomain intervention trials have advanced understanding of these associations but have also highlighted important gaps, including limited randomized evidence and underrepresentation of diverse populations. This narrative review critically synthesizes current evidence on lifestyle factors and dietary patterns associated with cognitive decline and dementia risk, focusing on recent high-quality studies. By integrating findings across domains, it aims to clarify areas of consensus and uncertainty, inform prevention strategies, and identify priorities for future research and public health action. See also the graphical abstract(Fig. 1).},
}
@article {pmid42376440,
year = {2026},
author = {Shet, A and Sabahuddin, S and B, P and Jami, BNSSR and Alex, JSR and Lin, CY and Lung, CW},
title = {Early Alzheimer's risk detection via diffusion tensor imaging using a few-shot multichannel attention residual learning network.},
journal = {Frontiers in artificial intelligence},
volume = {9},
number = {},
pages = {1867451},
pmid = {42376440},
issn = {2624-8212},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is responsible for many dementia-related deaths worldwide, and Mild Cognitive Impairment (MCI) is often its earliest clinical manifestation. Early detection of MCI is essential to initiate timely interventions that can slow progression and improve the patient's quality of life. The emergence of diffusion tensor imaging (DTI) has made it a powerful neuroimaging modality for MCI detection, offering greater sensitivity to microstructural changes in white matter than basic structural imaging.<br><br>METHODS: A Multichannel Attention Residual Learning-DTI (MARL-DTI) architecture was designed with attention mechanisms and residual learning utilizing multiple DTI-derived diffusion metrics, including fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AxD). To overcome the scarcity of labelled neuroimaging data, the model was supplemented with a few-shot learning framework. The dataset comprised 239 DTI scans from ADNI was used to evaluate the model. Local Interpretable Model-Agnostic Explanations (LIME) assists in analysing the model's decision-making process behaviour.<br><br>RESULTS: The proposed MARL-DTI achieved a classification accuracy of 92.76%, outperforming baseline DenseNet variants, StatFusion-FCNN, and Matching Networks. Validation on an unseen dataset of 36 ADNI subjects yielded consistent accuracy (91.67%), confirming the model's reliability. LIME analysis was used to provide instance-level explanations, enabling qualitative assessment of the model's decision-making behaviour by highlighting feature contributions for individual predictions.<br><br>DISCUSSION: These results demonstrate that the proposed MARL-DTI framework surpasses traditional deep learning architectures in the early identification of MCI using DTI data. The model consistently achieved strong performance while maintaining transparency, using LIME as a validation tool to examine its decision-making behaviour. These findings highlight the potential of combining multi-channel volumetric DTI data with explainable deep learning approaches to support reliable and clinically relevant early detection of Alzheimer's disease.},
}
@article {pmid42376442,
year = {2026},
author = {Varmaa, GD and Sekar, A and Anshul, V and Reddy, GVK and Evangelin A, P},
title = {S [3]Net: a Synthesis-Segmentation-Spiking Network for Alzheimer's disease detection and segmentation.},
journal = {Frontiers in artificial intelligence},
volume = {9},
number = {},
pages = {1845114},
pmid = {42376442},
issn = {2624-8212},
abstract = {Early and accurate detection of Alzheimer's disease (AD) from Magnetic Resonance Imaging (MRI) scans is crucial for clinical intervention. A novel S [3]Net, a Synthesis-Segmentation-Spiking Network, is proposed for this purpose. It integrates synthetic MRI generation, pathology-aware segmentation, and spike-based classification. The Synthesis Network uses a generative adversarial network framework. In this stage, original MRIs are fused with lesion-only patches from disease-relevant regions. This fusion helps preserve high-frequency pathological structures. The generator is trained with adversarial, L2, and Structural Similarity Index Measure (SSIM) losses. These losses ensure that the synthetic images remain realistic and structurally accurate. The Segmentation Network follows an encoder-bottleneck-decoder design with skip connections. It incorporates latent features from both the generator and the discriminator. A hybrid Dice-Binary Cross-Entropy loss is used to enable precise lesion delineation, even in sparsely annotated regions. For classification, a spiking network is employed. It takes fused segmentation and discriminator features and propagates them through Leaky Integrate-and-Fire neurons. This process captures temporal spike dynamics and supports low-power, event-driven computation. On the Open Access Series of Imaging Studies (OASIS) dataset, S [3]Net achieves an Accuracy of 95.1%, an F1-score of 93.0%, and an IoU of 82.6%. The proposed S [3]Net model outperforms other state-of-the-art methods, demonstrating its effectiveness and clinical viability for automated AD diagnosis.},
}
@article {pmid42376449,
year = {2026},
author = {Vukmir, RB},
title = {Alzheimer's disease and related dementia: evaluation, diagnosis and acute care management.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1743770},
pmid = {42376449},
issn = {1664-2295},
abstract = {IMPORTANCE: The patient presenting with memory loss often requires a complex, extensive multidisciplinary specialty evaluation that may begin in the primary care, emergency department, or general neurology setting. The analysis begins with a suspicion or concern regarding cognitive performance raised by the patient, family, or provider. Ideally, a better understanding will empower the primary care and general neurology communities to screen for and appropriately diagnose, treat, or refer patients with dementia.<br><br>METHODS: The thematic focus of this narrative review is diagnosis, imaging, and treatment of Alzheimer's disease and related dementia (ADRD). Information was abstracted from the National Library of Medicine MEDLINE/PubMed database. Medical Subject Headings (MeSH) heading search terms included dementia and, more specifically, Alzheimer's disease. The search targeted primary research, preferentially compared to reviews, consensus statements, or case reports if feasible.<br><br>OBSERVATIONS: Delirium typically represents an acute or subacute fluctuating change in mental status, often temporally related to acute illness. While dementia is typically associated with a more chronic progressive presentation of cognitive change without the presence of concurrent illness. However, subacute or dementia presentations may be exacerbated in that setting as well.<br><br>CONCLUSION AND RELEVANCE: The diagnosis, management, and therapy of Alzheimer's disease and related dementia is undergoing rapid change in imaging and now the utility of blood-based biomarkers. As more amyloid-modifying therapy is administered, the acute care systems should be knowledgeable of the treatment course and potential for complications.},
}
@article {pmid42376832,
year = {2026},
author = {Gorriz, JM and Segovia, F and Jimenez-Mesa, C and Arco, JE and Martinez, FJ and Ramirez, J and Abulikemu, S and Suckling, J},
title = {Latent Space Projections and Atlases, a Cautionary Tale in Deep Neuroimaging using Autoencoders.},
journal = {International journal of neural systems},
volume = {},
number = {},
pages = {2650053},
doi = {10.1142/S012906572650053X},
pmid = {42376832},
issn = {1793-6462},
abstract = {This study introduces a deep learning framework for the inferential exploration of latent representations in 3D brain MRI, leveraging a simple convolutional autoencoder with a hierarchical encoder and a compact latent space. Trained on segmented gray matter images from the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset, the model learns latent representations that preserve neuroanatomical structure and reflect clinical variability across cognitive status. Dimensionality reduction techniques (PCA, t-SNE, PLS, UMAP) were applied to visualize and interpret the latent space, correlating it with anatomical regions defined by the AAL atlas. As a novel contribution, the Latent-Regional Correlation Profiling (LRCP) framework, which combines statistical association and supervised discriminability to identify brain regions that encode clinically relevant latent information is proposed. Our results show that even minimal architectures capture meaningful patterns associated with progression to Alzheimer's disease. Interpretability is assessed by applying SHAP-based regression to a post-hoc model that predicts reconstruction error from atlas-based regional gray matter intensities, thereby identifying anatomically meaningful regions involved in class-specific reconstruction strategies. These findings are further validated using statistical agnostic methods, highlighting the importance of rigorous evaluation in neuroimaging. This work demonstrates the potential of autoencoders as exploratory tools for biomarker discovery and hypothesis generation in clinical neuroscience.},
}
@article {pmid42376914,
year = {2026},
author = {Nguyen, HTM and Khajehali, E and Pham, V and Scott, JW and Dite, TA and Dagley, LF and Murphy, JM and Thompson, G and Tobin, AB and Thal, DM and Christopoulos, A and van der Westhuizen, ET and Valant, C},
title = {Low Agonism and Balanced Pathway Modulation Distinguish an M1 Muscarinic Receptor Positive Allosteric Modulator Lacking Cholinergic Adverse Effects.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00229},
pmid = {42376914},
issn = {1948-7193},
abstract = {Positive allosteric modulators (PAMs) of the M1 muscarinic acetylcholine receptor (mAChR) have progressed into clinical trials for cognitive disorders, such as Alzheimer's disease and schizophrenia. However, their successful translation has been limited by on-target cholinergic adverse effects. These limitations have been attributed to excessive allosteric agonism, however, the contribution of allosteric cooperativity, efficacy modulation and receptor regulatory mechanisms remains poorly defined. Here, we performed a comparative pharmacological analysis of five structurally distinct M1 PAMs (BQCA, MK-7622, PF-06767832, MIPS1780 and VU0486846) in HEK293A cells expressing the human M1 mAChR (hM1-WT) or a phosphorylation site-deficient human M1 mAChR (hM1-PD). Radioligand binding and functional assays were used to quantify binding affinity and cooperativity, as well as allosteric agonism and efficacy modulation on G protein-dependent and β-arrestin-associated pathways. Uniquely, VU0486846, previously reported to lack cholinergic adverse effects, displayed consistently low allosteric agonism, weaker binding and functional cooperativity but comparable efficacy modulation across all signaling pathways. In contrast, PAMs associated with cholinergic adverse effects had higher allosteric agonism, stronger cooperativity and preferential enhancement of β-arrestin-associated signaling. Removing the M1 mAChR phosphorylation sites uncoupled allosteric agonism from efficacy modulation for most M1 PAMs, with the loss of phosphorylation acting as a key regulator of allosteric signaling at the M1 mAChR. Together these results suggest that low allosteric agonism and balanced efficacy modulation may be essential for improved tolerability of M1 PAMs. This work provides a mechanistic framework for differentiating M1 PAM pharmacology beyond intrinsic agonism alone and may inform the design of safer M1-targeted therapeutics.},
}
@article {pmid42376965,
year = {2026},
author = {Akasaka, T and Watanabe, H and Ono, M},
title = {Bithiophene Scaffold for PET Imaging and Photosensitization as a Novel Theranostic Platform Targeting Amyloid-β Aggregates.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00047},
pmid = {42376965},
issn = {1948-7193},
abstract = {Amyloid β (Aβ) aggregates are primary targets for the diagnosis and curative treatment of Alzheimer's disease (AD). While various theranostic agents targeting Aβ aggregates have been developed, most rely on fluorescent imaging, which has limited clinical translation. In contrast, nuclear medicine imaging, particularly positron emission tomography (PET), offers high sensitivity and deep tissue permeability suitable for clinical settings. Moreover, photosensitization has emerged as a promising strategy to attenuate Aβ toxicity. In this study, we designed and synthesized novel bithiophene derivatives as PET/photosensitization theranostic agents. Western blotting analysis and MALDI-TOF MS spectrometry demonstrated that FABT-2 selectively oxidized Aβ aggregates under light irradiation, leading to a significant reduction in Aβ-induced cytotoxicity, as demonstrated by CCK8 and LDH assays. Furthermore, [18]F-labeled FABT-2 showed blood-brain barrier permeability in normal mice. These results suggest that FABT-2 may be a promising lead compound for the development of theranostic agents targeting Aβ aggregates.},
}
@article {pmid42377068,
year = {2026},
author = {Cantoni, V and Grassi, M and Premi, E and Cupidi, C and Zummo, E and Cotelli, MS and Benussi, A and Borroni, B},
title = {Long-term effects of multisession gamma transcranial alternating current stimulation in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261461248},
doi = {10.1177/13872877261461248},
pmid = {42377068},
issn = {1875-8908},
abstract = {This study investigated the long-term clinical effects of multisession gamma transcranial alternating current stimulation (tACS) over the precuneus in early-stage Alzheimer's disease. Forty-six patients from a previous randomized, double-blind, sham-controlled trial with an open-label extension underwent follow-up at 36 and 72 weeks. Participants received either 8 or 16 weeks of gamma tACS. Both treatment durations showed comparable long-term outcomes. Alzheimer's Disease Assessment Scale-Cognitive Subscale did not significantly worsen at 36 weeks, and Face-Name Association Test remained stable at both follow-up time points, whereas Clinical Dementia Rating-Sum of Boxes and Alzheimer's Disease Cooperative Study-Activities of Daily Living worsened over time. These findings suggest relative preservation of selected cognitive measures, despite worsening in broader clinical and functional outcomes.},
}
@article {pmid42377071,
year = {2026},
author = {Chung, MLK and Takeda, S and Ryu, J and Murayama, S and Koshimizu, U and Kondo, T},
title = {Carboxy terminal of ECRG4 is a potential initiator for amyloid pathology in Alzheimer's disease through interacting with APP intracellular domain.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261462890},
doi = {10.1177/13872877261462890},
pmid = {42377071},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) and the formation of neurofibrillary tangles. Although the amyloid cascade hypothesis underscores the centrality of Aβ accumulation, the precise initiators of this process remain unknown.ObjectiveIn this study, we investigate the potential role of Esophageal Cancer-Related Gene 4 (ECRG4) in AD. We hypothesized that ECRG4, which is associated with cognitive impairment and upregulated in AD, directly contributes to amyloid pathology.MethodsWe performed cell-based assays, co-immunoprecipitation, in vivo experiments using APP[NL-G-F/NL-G-F] knock-in mouse, and immunohistochemistry of human hippocampal sections.ResultsECRG4(133-148) associated with the amyloid precursor protein (APP) intracellular domain (AICD), leading to increased APP/Aβ accumulation. Furthermore, intracerebral injection of synthetic ECRG4(133-148) into AD model mice significantly augmented APP/Aβ deposition. Notably, the co-localization of ECRG4(133-148)-containing peptides with AICD-containing peptides increased with AD severity in human hippocampal tissue.ConclusionsOur findings establish that the carboxy-terminal fragment of ECRG4 acts as a potential initiator of amyloid pathology in AD through its interaction with AICD.},
}
@article {pmid42377087,
year = {2026},
author = {Rashid, MI and Abbas, M and Tahir, R and Alam, T and Noor, A and Ishrat, Z and Mudasir, M and Ahsan Sarfraz, M and Mehboob, U and Osman Abufatima, I},
title = {National trends and disparities in mortality among U.S. older adults, with coexisting Alzheimer's disease and hypertension, 1999-2023.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261461304},
doi = {10.1177/13872877261461304},
pmid = {42377087},
issn = {1875-8908},
abstract = {BackgroundHypertension (HTN) is a major modifiable risk factor associated with cognitive decline including Alzheimer's disease (AD), which continues to be the leading cause of dementia and death in the United States (U.S.). However, the national mortality burden of coexisting AD and HTN across demographic and geographic groups remains poorly defined.ObjectiveWe aimed to study these trends to provide insights for better prevention, management, and policy planning.MethodsA retrospective analysis was conducted using the CDC WONDER Multiple Cause-of-Death database (1999-2023), focusing on adults aged ≥65 years with AD and HTN. Temporal trends were assessed using Joinpoint regression to estimate annual percent changes. Mortality patterns were examined by sex, race, region, urban-rural status, state, and place of death.ResultsBetween 1999 and 2023, 504,360 deaths among U.S. adults aged ≥65 years listed both AD and HTN on death certificates, with age-adjusted mortality rates rising from 14.5 to 60.0 per 100,000. Women consistently experienced higher mortality than men (67.5 versus 48.1 per 100,000 in 2023). Non-Hispanic African American adults had the greatest overall burden (57.1) among races. Geographically, mortality was highest in non-metropolitan areas (48.7) and the West region (52.6), More than half of all deaths occurred in nursing homes or long-term care facilities.ConclusionsMortality for coexisting AD and HTN has quadrupled in the U.S. over the past two decades with substantial variations across groups, highlighting the substantial burden of deaths where AD and HTN coexist and the importance of effective HTN control and dementia care across the lifespan.},
}
@article {pmid42377089,
year = {2026},
author = {Chen, PY and Shieh, WY and Weng, LC and Tsai, HH and Wang, WX and Liu, CY},
title = {Process-level eye-movement dynamics enhance sensitivity to early Alzheimer's disease-related cognitive vulnerability.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261457344},
doi = {10.1177/13872877261457344},
pmid = {42377089},
issn = {1875-8908},
abstract = {BackgroundEarly Alzheimer's disease (AD)-related cognitive vulnerability is characterized by subtle disruptions in attentional and executive processing that may precede overt declines in global cognitive scores. Identifying process-sensitive behavioral markers capable of capturing these early alterations remains a major challenge in psychogeriatric assessment.ObjectiveTo examine whether eye-movement-derived process-level measures, particularly fixation-shift dynamics, are associated with early cognitive vulnerability in older adults and whether they provide incremental value beyond conventional cognitive screening scores in an AD-related context.MethodsThis cross-sectional study enrolled 109 adults aged ≥65 years, categorized as cognitively normal (CN, n = 33), mild cognitive impairment (MCI, n = 35), and dementia due to AD (ADD, n = 41). Participants completed a standardized online interactive cognitive task while eye movements were recorded using a non-head-fixed, desktop-based eye-tracking system. Cognitive-only, eye-movement-only, and combined multimodal models were compared using receiver operating characteristic (ROC) analysis and area under the curve (AUC).ResultsThe combined multimodal model consistently outperformed single-modality approaches. Discriminative performance was high for CN versus ADD (AUC = 0.925) and for CN versus cognitively impaired participants overall (AUC = 0.897). Fixation-shift dynamics emerged as a robust process-level marker, demonstrating particular sensitivity in distinguishing CN individuals from those with MCI.ConclusionsFixation-shift eye-movement dynamics capture early AD-related cognitive vulnerability beyond conventional total cognitive scores. This multimodal framework may support psychogeriatric screening and clinical triage by detecting subtle cognitive inefficiencies that precede measurable declines on standard cognitive tests.},
}
@article {pmid42377097,
year = {2026},
author = {Rennie, K and Tauskela, JS and Ménard, M and Aylsworth, A and Comas, R and Whitfield, J and Chakravarthy, B},
title = {The blood-brain barrier-penetrating fusion protein BBB-ABP selectively binds amyloid-β oligomers and prevents in vitro neurotoxicity.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261453068},
doi = {10.1177/13872877261453068},
pmid = {42377097},
issn = {1875-8908},
abstract = {BackgroundSoluble amyloid-β oligomers (Aβo) are considered the most neurotoxic species of Aβ and key drivers of Alzheimer's disease (AD) pathogenesis. Selective targeting of Aβo offers a promising therapeutic strategy. We previously identified an amyloid-binding peptide (ABP) that binds Aβo and engages Aβ deposits in AD mouse and human brain tissue. To facilitate brain penetration, ABP was fused to the blood-brain barrier (BBB) transporter FC5 and an Fc fragment, generating BBB-permeable constructs (mouse FC5-mFc2a-ABP and humanized FC5-hFc-ABP, referred to as BBB-ABP). Previous in vivo studies demonstrated the ability of BBB-enabled ABP to engage and clear Aβ from the central nervous system.ObjectiveThis study aimed to evaluate the in vitro functionality of BBB-ABP and its ability to prevent Aβo-induced neurotoxicity and synaptic dysfunction.MethodsBinding specificity was assessed using ELISA and western blot overlay assays. Functional assays were performed in SH-SY5Y cells and primary neurons to evaluate Aβo sequestration, protection against Aβo-induced toxicity, and effects on synaptic activity measured via multi-electrode arrays.ResultsBBB-ABP retained selective binding to Aβo and effectively prevented its interaction with neuronal proteins and its binding to dendritic spines in live primary neurons. BBB-ABP significantly reduced Aβo-induced toxicity in SH-SY5Y cells and primary neurons, including under conditions of NMDA-induced stress. Aβ exposure did not significantly alter spontaneous synaptic activity, precluding assessment of electrophysiological rescue by BBB-ABP.ConclusionsThese findings demonstrate that BBB-ABP maintains Aβo-selective binding and is capable of preventing the interaction of Aβo with neurons, thereby mitigating Aβo-induced toxicity in vitro, supporting its further development as a therapeutic candidate for AD.},
}
@article {pmid42377390,
year = {2026},
author = {Xu, L and Zhou, Y and Chen, H and Zhuang, J and Jiang, Y and Li, T and He, Z and Song, Z and Zhou, W},
title = {Porphyromonas gingivalis-Induced NETs Mediate Neuroinflammation via TLR4 Activation.},
journal = {Journal of dental research},
volume = {},
number = {},
pages = {220345261425925},
doi = {10.1177/00220345261425925},
pmid = {42377390},
issn = {1544-0591},
abstract = {Periodontitis, caused by periodontal pathogens such as Porphyromonas gingivalis, is a risk factor for Alzheimer's disease (AD) progression. Neutrophils, which are abundant in patients with periodontitis, release neutrophil extracellular traps (NETs) to resist microbial infection. We explored the mechanism and effects of P. gingivalis-induced NETs on the relationship between periodontitis and neuroinflammation. A murine periodontitis model was established via oral local application of P. gingivalis with or without tak242 (TLR4 inhibitor). Maxillary bones were evaluated via micro-computed tomography. The proportion of neutrophils was determined by flow cytometry. NET formation and morphology were analyzed via a cell-free DNA kit, a neutrophil elastase enzyme-linked immunosorbent assay (ELISA) and myeloperoxidase ELISA kit, reverse transcription polymerase chain reaction (RT-PCR), western blotting and immunofluorescence. Behavior tests were used to investigate cognitive ability. Neuroinflammation was assayed by immunohistochemistry (IHC) and RT-PCR. Amyloid precursor protein (APP) processing was measured by IHC. In vitro experiments explored the functional mechanism underlying the effects of P. gingivalis-induced NETs on the neuron-glia unit. We observed significant alveolar bone resorption with elevated neutrophil count and increased NET formation in mice with periodontitis. Cognitive abilities were impaired by periodontitis. Neuroinflammation manifested as glia activation and upregulated inflammatory cytokines, and APP processing was altered by the elevated expression of APP and PSEN1. These changes were specifically reversed by tak242. In vitro, P. gingivalis-induced NETs mediated M1 polarization in BV2 cells and changed APP processing in N2a cells, along with the activation of TLR4/Myd88/NF-κB and GSK3β/Akt, which is consistent with the in vivo findings. In conclusion, P. gingivalis-induced NETs play pivotal roles in the relationship between neuroinflammation and cognitive impairment. Furthermore, the effects of P. gingivalis-induced NETs on neuron-glia unit were related to TLR4 activation.},
}
@article {pmid42377424,
year = {2026},
author = {Jian, W and Sun, H and He, Y and Lan, X and Dong, L and Wang, Z and Jiang, S and Cai, Q and Li, H and Yao, D},
title = {Depressive-cognitive interactions modulate amygdala and hippocampus functional connectivity in mild cognitive impairment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261462932},
doi = {10.1177/13872877261462932},
pmid = {42377424},
issn = {1875-8908},
abstract = {BackgroundDepressive symptoms frequently co-occur with cognitive impairment in older adults. Although depression and cognition interact in brain activity, the underlying functional connectivity mechanisms in mild cognitive impairment (MCI) remains unclear.ObjectiveTo investigate how depressive symptoms modulate the relationship between cognition and amygdala/hippocampus functional connectivity in MCI.MethodsThis study included 138 participants (45 healthy controls and 93 MCI patients) who underwent resting state functional magnetic resonance imaging (rs-fMRI) and neuropsychological assessment using the Montreal Cognitive Assessment-Basic (MoCA-B) for cognitive function and Hamilton Depression Rating Scale (HAMD) for depressive symptoms. Seed-based functional connectivity analysis was performed using bilateral amygdala and hippocampus as seed regions to quantify the HAMD × MoCA-B non-monotonic interactions on whole-brain connectivity. Simple slopes analyses were conducted to characterize directionality changes across depression severity levels.ResultsWhole-brain analyses revealed significant HAMD × MoCA-B interaction effects (cluster p value < 0.05, voxel p value < 0.01, GRF corrected) demonstrating symptom-dependent reorganization of cognition-FC relationships. Amygdala connectivity decreased to anterior/middle cingulate and precuneus but increased to triangular part of inferior frontal gyrus (IFGtri), medial superior frontal gyrus, and cerebellar lobule IX. Hippocampal connectivity decreased to cuneus, insula, thalamus, and caudate but increased to opercular part of inferior frontal gyrus (IFGop), orbitofrontal cortex, and cerebellar lobule VIII.ConclusionDepressive symptoms alter amygdala and hippocampal FC relationships with cognition in MCI. Depression-dependent hippocampal/amygdala connectivity changes with the frontoparietal network (FPN-A)-particularly IFGop/IFGtri and cerebellum-suggest their role as critical hubs for emotional-cognitive integration, highlighting them as potential neuromodulation targets for cognitive and depressive symptoms in MCI.},
}
@article {pmid42377429,
year = {2026},
author = {Du, X and Wang, Y and Zhao, J and Liu, Y and Peng, D and , },
title = {APOE ε4-specific associations between agitation, cerebrospinal fluid biomarkers, and cognitive decline in cognitively impaired patients.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261464188},
doi = {10.1177/13872877261464188},
pmid = {42377429},
issn = {1875-8908},
abstract = {BackgroundThe associations between agitation, cerebrospinal fluid (CSF) biomarkers, and cognitive decline, and whether these relationships vary by APOE genotype, remain unclear in Alzheimer's disease (AD) and mild cognitive impairment (MCI).ObjectiveTo investigate the association between CSF biomarkers and agitation in cognitively impaired individuals, with a focus on the potential moderating role of APOE ε4 status.MethodsWe analyzed 491 cognitively impaired individuals (359 MCI and 132 AD) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with available CSF biomarker data. Neuropsychiatric symptoms were assessed using the Neuropsychiatric Inventory (NPI), focusing on agitation.ResultsAmong APOE ε4 carriers, agitation was significantly associated with higher CSF GAP-43 (OR = 1.584, 95% CI: 1.159-2.195, p = 0.005) and p-tau levels (OR = 1.49, 95% CI: 1.073-2.101, p = 0.02). These associations were not observed in non-carriers. In addition, APOE ε4 carriers with agitation showed a higher risk of progression to dementia compared with other groups (HR = 4.422, 95% CI: 2.542-7.692, p < 0.001).ConclusionsCSF GAP-43 and p-tau levels are associated with agitation in APOE ε4 carriers. Agitation in this subgroup is also associated with an increased risk of progression to dementia, suggesting that it may reflect underlying disease-related processes.},
}
@article {pmid42377442,
year = {2026},
author = {Abedin, MJ and Lee, YF and Zhang, M and Russ, AN and Gerashchenko, D and Bacskai, BJ and Kastanenka, KV},
title = {Compartment-specific analysis reveals disrupted astrocytic calcium transients in anesthetized Alzheimer's disease mice.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261464208},
doi = {10.1177/13872877261464208},
pmid = {42377442},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is characterized by presence of extracellular amyloid plaques, intracellular tau tangles, and extensive neuronal cell death. In addition to neurons, astrocytes modulate neuronal network activity through tripartite synapses. Also, astrocytes are increasingly recognized for their involvement in AD pathology. Aberrant astrocytic calcium signaling has been implicated in AD pathological processes, including disrupted synaptic transmission, dysregulated glutamate homeostasis, and impaired vascular function via astrocytic endfeet. Previous investigations have assessed compartment-specific astrocytic calcium transients, yet most employed a restricted range of metrics. Thus, comprehensive analyses of calcium dynamics within individual astrocytic compartments in mouse models of amyloidosis are lacking.ObjectiveTo analyze spontaneous calcium transients within distinct astrocytic compartments in APP/PS1 mice.MethodsUsing in vivo multiphoton imaging of Yellow Cameleon 3.6, a genetically encoded calcium indicator targeted to astrocytes in APP/PS1 mice, we analyzed spontaneous calcium transients in cortical astrocytes at 4-6 months of age. We quantified event rate, activity duration, area under the curve (AUC), and peak amplitude across four compartments: soma, processes, microdomains, and endfeet. Correlation analyses were used to assess astrocyte synchrony and distance-dependent activity relationships.ResultsIn APP/PS1 mice, somas exhibited increased activity duration and peak amplitude, while processes and microdomains showed reduced duration, AUC, and amplitude despite higher event rates. Endfeet showed reductions in all parameters. Correlation analyses revealed enhanced astrocyte synchrony in APP/PS1 mice, with distance-dependent correlation decay observed only in nontransgenic controls.ConclusionsThese findings highlight compartment-specific disruptions of astrocytic calcium activity caused by amyloidosis.},
}
@article {pmid42377581,
year = {2026},
author = {Terzioglu-Usak, S and Zaim, M and Beker, M and Isik, S and Elibol, B},
title = {Molecular links between reelin downregulation, topoisomerase IIβ alterations, and proteins involved in Alzheimer pathology in human SH-SY5Y neuroblastoma cell line.},
journal = {Experimental brain research},
volume = {244},
number = {8},
pages = {},
pmid = {42377581},
issn = {1432-1106},
support = {12.2016/7//Bezmialem Vak&#x131;f &#xdc;niversitesi/ ; },
mesh = {Reelin Protein ; Humans ; *Nerve Tissue Proteins/metabolism/genetics ; *Serine Endopeptidases/metabolism/genetics ; *Cell Adhesion Molecules, Neuronal/metabolism/genetics ; *Extracellular Matrix Proteins/metabolism/genetics ; Cell Line, Tumor ; *Down-Regulation/physiology ; *Alzheimer Disease/metabolism/pathology ; *DNA Topoisomerases, Type II/metabolism/genetics ; RNA, Small Interfering/metabolism/genetics ; tau Proteins/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; RNA, Messenger/metabolism ; Amyloid beta-Protein Precursor/metabolism ; Neuroblastoma/pathology ; Transfection ; Aspartic Acid Endopeptidases/metabolism ; Poly-ADP-Ribose Binding Proteins ; },
abstract = {Reelin signaling regulates multiple pathways in neurodegenerative conditions, including neuronal migration, synaptic plasticity, tau phosphorylation, and amyloidogenic processing of amyloid precursor protein (APP). This study aimed to investigate the impact of reelin downregulation on the expression of topoisomerase IIβ (topo IIβ), given its crucial role in neuronal differentiation and its established association with neurodegenerative disorders such as Alzheimer's disease (AD). Furthermore, we sought to elucidate the potential relationship between reelin downregulation and proteins implicated in the pathophysiology of AD. Firstly, the optimum concentration of small interfering RNAs (siRNA) targeting reelin was transfected into SH-SY5Y cells using Lipofectamine RNAiMAX reagent. The downregulation of reelin was confirmed at the mRNA level by real-time quantitative polymerase chain reaction (qRT-PCR). Reelin-mediated molecular alterations at both the mRNA and protein levels were analyzed by qRT-PCR and Western blotting. Reelin downregulation led to a decrease in the number of viable cells as determined by the MTT assay. Consistent with the downregulation of reelin gene expression, topo IIβ, Psen1, and BACE1 expressions were also reduced, whereas tau and APP expressions were upregulated. Although siRNA treatment effectively decreased reelin mRNA levels and the proteolytic fragment of reelin protein, no significant change was observed in total full-length reelin protein levels, suggesting the involvement of post-transcriptional regulatory mechanisms. Moreover, pTAU and APP protein expressions were increased, while Nurr1 protein was decreased in reelin-silenced cells. These findings suggest that downregulation of reelin gene expression may contribute to neurodegeneration through alterations in topo IIβ and nurr1 expression, in addition to changes in proteins associated with AD pathology.},
}
@article {pmid42377595,
year = {2026},
author = {Di Bari, MA and Bruno, R and Riccardi, G and Vanni, I and D'Agostino, C and Nonno, R and De Cecco, E and Burato, A and Legname, G and Cardone, F and Moda, F and Giaccone, G and Catania, M and Di Fede, G and Tagliavini, F and Agrimi, U},
title = {Prion-like transmission and propagation of human β-amyloid to the bank vole rodent model.},
journal = {Acta neuropathologica},
volume = {151},
number = {1},
pages = {},
pmid = {42377595},
issn = {1432-0533},
mesh = {Animals ; Arvicolinae ; Humans ; *Amyloid beta-Peptides/metabolism ; Disease Models, Animal ; *Brain/pathology/metabolism ; *Alzheimer Disease/pathology/metabolism/genetics ; *Prions/metabolism ; Female ; tau Proteins/metabolism ; Male ; Aged ; *Prion Diseases/pathology/metabolism ; },
abstract = {Over the past decades, growing experimental and observational evidence has suggested that Aβ and pTau, the hallmarks of Alzheimer's disease (AD), may spread through the nervous system via a prion-like mechanism. Here, we investigated the transmissibility of Aβ and pTau by inoculating bank voles, a wild-type rodent highly susceptible to prion diseases, with brain homogenates from four sporadic and five familial AD-affected patients. We observed that (i) neo-formed Aβ deposits and pTau inclusions were induced in recipient vole brains; (ii) Aβ pathology appeared to follow a specific neurotropic distribution; (iii) Aβ proteinopathy propagated through vole-to-vole inoculation. Our findings provide the first experimental evidence that human Aβ seeds are transmissible to a wild-type rodent model, further supporting the prion-like nature of Aβ. These results strongly support recent studies suggesting iatrogenic Aβ transmission, underscoring the need to evaluate the impact of Aβ seed exposure on human health.},
}
@article {pmid42377618,
year = {2026},
author = {Saini, D and Mujeeb, M and Akhtar, M and Haque, SE and Najmi, AK},
title = {PPAR-γ modulation restores the adiponectin-AMPK-AKT axis to attenuate metabolic stress-associated alzheimer's pathology.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42377618},
issn = {1573-4978},
mesh = {Animals ; *Alzheimer Disease/metabolism/drug therapy/pathology ; *PPAR gamma/metabolism ; Male ; Rats ; Proto-Oncogene Proteins c-akt/metabolism ; Rats, Wistar ; *AMP-Activated Protein Kinases/metabolism ; Signal Transduction/drug effects ; *Adiponectin/metabolism ; Telmisartan/pharmacology ; Disease Models, Animal ; Stress, Physiological/drug effects ; Insulin Resistance ; Neuroprotective Agents/pharmacology ; Lipopolysaccharides ; Isoflavones/pharmacology ; tau Proteins/metabolism ; },
abstract = {Background Increasing evidence links metabolic dysregulation, insulin resistance, and endotoxin-induced inflammation to sporadic AD. A disruption of the PPARγ-adiponectin-AMPK-insulin pathway leads to neuroinflammation, Aβ buildup, tau hyperphosphorylation, and cognitive impairments. This study examined the neuroprotective effects of telmisartan and formononetin alone and in combination in metabolically primed AD-like rats. Methodology A two-hit model was employed to simulate metabolic endotoxemia-related sporadic Alzheimer's disease in male wistar rats. The model utilised chronic HFD feeding and systemic administration of LPS (250 µg/kg, i.p.). The animals received telmisartan, formonoetin, their combination, or a PPARγ inhibitor/ blocker. We evaluated metabolic parameters, cognitive performance, insulin resistance, inflammatory cytokines, adiponectin concentrations, cholinergic function, histopathology, and immunohistochemical markers of Aβ, tau, IRS-1, AMPK, and AKT signalling. Results The outcomes of HFD + LPS encompass weight gain, insulin resistance, inflammation, cholinergic dysfunction, neurotoxicity, elevated Aβ and tau pathology, and cognitive impairment. The therapy with telmisartan and formononetin enhanced these alterations in a dose-dependent manner, with the combination regimen demonstrating greater efficacy. The treatment reinstated adiponectin levels, enhanced AdipoR1-AMPK-AKT signalling, diminished pathogenic IRS-1 serine phosphorylation, reduced pro-inflammatory cytokines, maintained neuronal structure, and augmented recognition memory. The co-administration of PPARγ inhibitor/blocker abolished these protective effects, showing mediation reliance on PPARγ. Conclusion Telmisartan and formononetin have significant metabolic and neuroprotective advantages against AD generated by HFD and LPS through the activation of the PPARγ-adiponectin-AMPK-IRS-1-AKT signalling pathway. Targeting metabolic-inflammatory pathways using natural PPARγ modulators may aid in delaying or preventing sporadic AD associated with obesity, insulin resistance, and endotoxemia.},
}
@article {pmid42377628,
year = {2026},
author = {Nasybullina, E and Akhmetzyanova, E and Rizvanov, A and Mukhamedshina, Y},
title = {Advances in neural organoids: structural organization, disease modeling, and applications in gene therapy.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42377628},
issn = {1573-4978},
support = {Kazan Federal University Strategic Academic Leadership Program (PRIORITY-2030)//Ministry of Science and Higher Education of the Russian Federation/ ; Kazan Federal University Strategic Academic Leadership Program (PRIORITY-2030)//Ministry of Science and Higher Education of the Russian Federation/ ; Kazan Federal University Strategic Academic Leadership Program (PRIORITY-2030)//Ministry of Science and Higher Education of the Russian Federation/ ; Kazan Federal University Strategic Academic Leadership Program (PRIORITY-2030)//Ministry of Science and Higher Education of the Russian Federation/ ; },
mesh = {Humans ; *Organoids/metabolism/pathology/cytology ; *Genetic Therapy/methods ; *Neurodegenerative Diseases/therapy/genetics/pathology ; Animals ; Genetic Vectors/genetics ; Neurons/metabolism ; Dependovirus/genetics ; Brain/metabolism ; Induced Pluripotent Stem Cells/metabolism/cytology ; Gene Transfer Techniques ; },
abstract = {Neural organoids and assembloids have emerged as advanced in vitro models that reproduce the cytoarchitecture and functional complexity of the human brain. This review focuses on recent applications of these three-dimensional systems for modeling neurodegenerative diseases and assessing the efficacy of gene therapy, particularly using adeno-associated viral vectors. The development of induced pluripotent stem cell technology enables the creation of patient-specific organoids that reflect individual genetic backgrounds and disease phenotypes. Neural organoids have been used to model Alzheimer's, Parkinson's, and Huntington's diseases, reproducing hallmark features such as protein aggregation, neuroinflammation, and synaptic dysfunction. They have also served as test systems for evaluating AAV-mediated gene delivery, revealing serotype-specific tropism and supporting optimization of vector design and gene expression. Further advances include integration of immune and vascular components and the construction of multi-regional assembloids that replicate inter-regional neuronal communication and complex network dynamics. Ongoing standardization and scalability of neural organoid systems, combined with bioengineering and analytical innovations, are expected to enhance reproducibility and translational relevance. The convergence of organoid models with gene therapy testing frameworks may accelerate preclinical validation and contribute to the development of precision approaches in neurology.},
}
@article {pmid42377668,
year = {2026},
author = {Zhang, J and Zhang, Q and Jordan, JD and Zong, X},
title = {Near‑Infrared Photobiomodulation in White‑Matter Disease: From Microglial States to Measurable Endpoints.},
journal = {Neuromolecular medicine},
volume = {28},
number = {1},
pages = {},
pmid = {42377668},
issn = {1559-1174},
support = {R01AG082207 and R01AG081874//National Institute on Aging of the National Institutes of Health under/ ; 149251504A//U.S. Department of Defense/ ; 24CDA1269588//American Heart Association Career Development/ ; },
mesh = {Humans ; *Microglia/radiation effects/physiology ; Animals ; *Low-Level Light Therapy/methods ; *Leukoencephalopathies/radiotherapy/diagnostic imaging/pathology ; *White Matter/radiation effects/injuries ; *Infrared Rays/therapeutic use ; Oligodendroglia/radiation effects ; Oxidative Stress ; Astrocytes/radiation effects ; Remyelination/radiation effects ; Axons/radiation effects ; },
abstract = {White-matter (WM) injury contributes to disability across multiple sclerosis, traumatic brain injury, Alzheimer's disease and related dementias, and small-vessel disease. We use microglial state programs as an organizing axis for WM injury-to-repair logic, while emphasizing that WM outcomes are multicellular and involve oligodendrocyte-lineage cells, astrocytes, axons/neurons, and vascular factors. Microglia span an injury-repair continuum, from inflammatory programs that increase oxidative stress and debris burden to repair-competent programs that support debris handling, remyelination, and axonal integrity. Near-infrared photobiomodulation (PBM; ~800-1100 nm) is most consistently associated with modulation of mitochondrial redox/bioenergetic pathways and inflammatory tone. CCO-centered mechanistic framing is best established near ~ 800-850 nm, whereas longer wavelengths (e.g., ~ 1064-1070 nm) may involve additional initiating mechanisms with downstream convergence on shared redox/bioenergetic and inflammatory pathways. Across demyelination and spinal cord injury models, appropriately dosed PBM has been reported to reduce inflammatory glial readouts and to associate with improved myelin/axon-related endpoints and functional measures, although mechanistic certainty varies across models. Human evidence remains early but broadly supports safety; a randomized trial in moderate traumatic brain injury reported treatment-related changes in diffusion-MRI WM metrics, while small dementia and chronic-injury studies report heterogeneous cognitive and physiological signals. Given dose dependence and depth-limited transcranial delivery, we synthesize mechanism-informed, dose-aware reporting guidance and WM-anchored outcome frameworks that pair diffusion MRI/DTI with interpretable biomarkers (e.g., NfL, GFAP, sTREM2) and thermally controlled sham designs. We also note potential indirect/systemic contributions that could help reconcile depth-dose constraints with deeper WM effects.},
}
@article {pmid42377735,
year = {2026},
author = {Das, K and Khatun, R and Begum, S and Bhattacharyya, K and Datta, M and Saha, D and Sarma, A and Mehta, P and Das, BK},
title = {The interplay between gut microbiota and Alzheimer's disease: mechanistic insights from dysbiosis to disease modulation.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42377735},
issn = {1573-7365},
mesh = {Humans ; *Alzheimer Disease/metabolism/microbiology ; *Gastrointestinal Microbiome/physiology ; *Dysbiosis/metabolism/microbiology ; Animals ; Brain/metabolism ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) is a chronic, progressive, neurodegenerative condition marked by memory loss and cognitive decline. It is characterized by neuropathological features such as amyloid plaque accumulation, neurofibrillary tangles of tau protein, and inflammatory changes in the brain. Recent research emphasizes how gut microbes influence the onset and progression of AD primarily through the gut-brain connection, a bidirectional communication system. The human gastrointestinal tract (GI) contains trillions of bacteria, primarily Bacteroidetes, Firmicutes, and Actinobacteria, which play vital roles in digestion, metabolic regulation, and immune modulation. However, factors such as diet, lifestyle, and environmental exposure can disrupt microbial balance, weaken intestinal barrier function, and initiate systemic inflammation. Such dysbiosis has been linked to defective regulation of the amyloid precursor protein (APP), leading to increased deposition of amyloidogenic peptides (Aβ). Moreover, the enteric nervous system, which expresses APP, may serve as an initial site of amyloid deposition, affecting gastrointestinal motility and inflammatory susceptibility. The gut microbiota also produces key bioactive compounds, including neurotransmitters such as serotonin, dopamine, acetylcholine, histamine, and gamma-aminobutyric acid (GABA), which influence the central nervous system (CNS) through neural, immune, and endocrine pathways. An imbalance in these neuroactive molecules may disrupt synaptic signaling and contribute to Alzheimer's-related cognitive dysfunction. Therefore, improving our understanding of gut-brain communication may advance knowledge of AD development and support the creation of new therapies. This review highlights the strong association between intestinal microbes and Alzheimer's pathogenesis, emphasizing microbiota modulation through probiotics, prebiotics, postbiotics, synbiotics, and antibiotics as potential therapeutic approaches, supported by emerging clinical trial evidence.},
}
@article {pmid42377771,
year = {2026},
author = {Kuznetsov, AV},
title = {Investigating a relation between amyloid beta plaque burden and accumulated neurotoxicity caused by amyloid beta oligomers.},
journal = {Medical &amp; biological engineering &amp; computing},
volume = {},
number = {},
pages = {},
pmid = {42377771},
issn = {1741-0444},
support = {DMS-2451660//Division of Mathematical Sciences/ ; },
abstract = {Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ), yet the specific link between plaque burden and cognitive decline remains a subject of intense investigation. This paper presents a mathematical model that simulates the coupled dynamics of Aβ monomers, soluble oligomers, and fibrillar species in the brain tissue. By modifying existing governing equations to include a dedicated conservation equation for Aβ monomers, the model explores how various microscopic processes, such as primary nucleation, surface-catalyzed secondary nucleation, fibril elongation, and fragmentation, contribute to macroscopic disease progression. Central to this study is the concept of "accumulated neurotoxicity" as a surrogate marker of biological age, defined as the time-integrated concentration of soluble Aβ oligomers. Unlike plaque burden, accumulated neurotoxicity cannot be reversed, and the harm it causes depends critically on the sequence of events that produced it. Numerical results demonstrate that while plaque burden and neurotoxicity both increase over time, their relationship is non-linear and highly sensitive to the efficiency of protein degradation machinery. Specifically, impaired degradation causes biological age, defined in terms of accumulated neurotoxicity, to advance considerably faster than calendar age. The model further identifies oligomer dissociation and fibril fragmentation as potential protective mechanisms that can counterintuitively reduce neurotoxic burden by diverting monomers away from the soluble oligomer pool. These findings provide a quantitative basis for understanding why individuals with similar plaque burdens may experience vastly different cognitive outcomes, underscoring the importance of targeting soluble oligomers early in therapeutic interventions.},
}
@article {pmid42261768,
year = {2026},
author = {Deng, R and Shargorodsky, A and Teopiz, K and Dri, CE and Wong, S and Le, GH and Zheng, YJ and McIntyre, RS},
title = {Lithium and long-term cognitive outcomes in bipolar disorder and early dementia: a systematic review.},
journal = {CNS spectrums},
volume = {31},
number = {1},
pages = {e18},
doi = {10.1017/S1092852926100996},
pmid = {42261768},
issn = {2165-6509},
mesh = {Humans ; *Bipolar Disorder/drug therapy/psychology ; *Lithium Compounds/therapeutic use ; *Cognitive Dysfunction/drug therapy ; *Antimanic Agents/therapeutic use ; *Dementia/drug therapy/psychology ; Randomized Controlled Trials as Topic ; *Alzheimer Disease/drug therapy/psychology ; Cognitive Enhancement ; },
abstract = {Cognitive impairment is a major determinant of disability in bipolar disorder (BD) and a defining feature of both mild cognitive impairment (MCI) and Alzheimer's disease (AD). Lithium, a first-line maintenance treatment for BD, is implicated in neuroprotective mechanisms including glycogen synthase kinase-3β inhibition, amyloid and tau modulation, and neurogenesis promotion. The overarching aim of this systematic review is to evaluate the long-term effects of lithium on cognition across BD, MCI, and early-to-moderate AD using randomized controlled trial (RCT) evidence. Online databases were searched from inception through May 2025 for RCTs reporting lithium's effect on cognitive outcomes in BD, MCI, or early-to-moderate AD with ≥8 weeks of follow-up. Risk of bias was assessed using the Cochrane RoB 2 tool. Eight RCTs met the inclusion criteria, ranging from 10 weeks to 3 years in duration. Across four BD trials, lithium did not exhibit consistent improvement or worsening on composite cognitive scores. Three of four MCI/AD trials reported attenuated global cognitive deterioration with low-dose lithium, especially when exposure was ≥12 months. Methodological limitations included small sample sizes, exploratory endpoints, and variable measures for cognitive function as well as lithium strategies. Lithium demonstrates preliminary signals of slower cognitive decline in MCI/AD. Available evidence suggests lithium has neutral effects on cognitive impairment in BD. Future adequately powered RCTs with cognition as a primary endpoint, functional measures, and biomarker outcomes are warranted to clarify lithium's role as a maintenance treatment in psychiatric disorders and its potential neuroprotective effects in neurodegenerative diseases.},
}
@article {pmid42364023,
year = {2026},
author = {Ebrahimbabaei, A and Hekmat, AS and Javanmardi, K},
title = {Neurotherapeutic roles of the protective arm of the renin-angiotensin system: from inflammation to cognitive rescue.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42364023},
issn = {1573-4978},
mesh = {Humans ; *Renin-Angiotensin System/drug effects/physiology ; Animals ; *Inflammation/metabolism ; Proto-Oncogene Mas ; Angiotensin-Converting Enzyme 2/metabolism ; Receptor, Angiotensin, Type 2/metabolism ; Receptors, G-Protein-Coupled/metabolism ; *Cognition/drug effects/physiology ; Signal Transduction ; Angiotensin I/metabolism ; Peptide Fragments/metabolism ; Peptidyl-Dipeptidase A/metabolism ; Neuroinflammatory Diseases/metabolism ; Proto-Oncogene Proteins/metabolism ; Blood-Brain Barrier/metabolism ; Brain/metabolism ; Oxidative Stress ; Oligopeptides ; },
abstract = {The renin-angiotensin system (RAS), traditionally recognized for its role in regulating blood pressure and fluid homeostasis, is increasingly understood to exert important effects across multiple organ systems, including the central nervous system (CNS). A local brain RAS contributes to neurovascular regulation, inflammation, oxidative stress, synaptic plasticity, and cognitive function. This review critically summarizes the neurotherapeutic relevance of the protective RAS arm, particularly the angiotensin-converting enzyme 2 (ACE2)-angiotensin-(1-7)-Mas receptor axis, the angiotensin II type 2 receptor (AT2R), and the alamandine/Mas-related G protein-coupled receptor D (MrgD) pathway. Experimental evidence suggests that these pathways may counterbalance angiotensin II type 1 receptor signaling by reducing neuroinflammation, oxidative injury, vascular dysfunction, and neuronal loss in models of ischemic stroke, Alzheimer's disease, Parkinson's disease, and multiple sclerosis. The strongest evidence remains preclinical, with most data derived from cell culture and animal models, whereas human evidence is still indirect and largely based on observational or early translational studies of RAS-modifying drugs. Important uncertainties remain regarding blood-brain barrier penetration, receptor-specific signaling, disease-stage dependency, systemic vascular effects, and reproducibility across models. Therefore, protective RAS signaling should be considered a promising but still exploratory therapeutic framework rather than an established treatment strategy for neurological disease. Future work should prioritize selective brain-penetrant agonists, validated biomarkers of central RAS activity, and rigorously designed clinical trials to determine whether modulation of ACE2-angiotensin-(1-7)-Mas, AT2R, or alamandine/MrgD signaling can produce clinically meaningful neuroprotection.},
}
@article {pmid42364272,
year = {2026},
author = {Cawthray, J},
title = {From PET to targeted radionuclide therapy in the Brain: The emerging role of radiometal-based platforms.},
journal = {Journal of inorganic biochemistry},
volume = {283},
number = {},
pages = {113397},
doi = {10.1016/j.jinorgbio.2026.113397},
pmid = {42364272},
issn = {1873-3344},
abstract = {Radiometal-based radiopharmaceuticals have become central to the advancement of molecular imaging and targeted radionuclide therapy, offering powerful tools for the diagnosis and treatment of diseases affecting the brain. The unique chemical versatility of radiometals - encompassing a broad range of coordination chemistries, physical half-lives, and emission properties - combined with an expanding repertoire of targeting biomolecules enables highly tunable and increasingly modular imaging and therapeutic platforms. In particular, positron emission tomography (PET) using radiometal-labelled tracers provides sensitive, quantitative, and non-invasive assessment of molecular processes in vivo, while radiometal-based therapeutic agents enable the selective delivery of cytotoxic radiation to diseased tissue. This review examines recent progress in the application of radiometal-based radiopharmaceuticals for brain disorders, with a focus on neuro-oncology - including primary brain tumours and brain metastases - as well as neurodegenerative diseases such as Alzheimer's disease and Parkinsons disease. Key challenges unique to brain applications are discussed, including the restrictive nature of the blood-brain barrier, heterogeneous target expression, and off-target biodistribution. Recent advances in chelator development, emerging antigen targets, alternative routes of administration, and strategies to improve brain delivery are highlighted. While imaging agents continue to lead therapeutic development in this space, reflecting the need for accurate disease characterisation, recent progress underscores the potential of radiometal-based therapies for brain disease. In particular, immunoPET has emerged as a powerful tool for evaluating target expression, biodistribution, and treatment response. Collectively, these developments position radiometal-based radiopharmaceuticals as a promising and evolving platform enabling personalised treatment strategies for neurological disorders.},
}
@article {pmid42364284,
year = {2026},
author = {Ramabharathi, TG and Subramaniam, K},
title = {Ternary pattern-driven feature extraction and self-attending GRU for clinical score prediction in Alzheimer's disease.},
journal = {Psychiatry research. Neuroimaging},
volume = {362},
number = {},
pages = {112269},
doi = {10.1016/j.pscychresns.2026.112269},
pmid = {42364284},
issn = {1872-7506},
abstract = {This article presents a unique deep learning technique to identify AD using data from magnetic resonance imaging (MRI). However, deep learning models' lack of interpretability prevents them from being used in clinical settings, where explainability is crucial for winning over medical personnel. In order to diagnose AD, this work proposes a self-attending bidirectional gated recurrent unit (SA-Bi-GRU) method based on explainable AI (XAI) that makes use of a deep learning model. Before the diagnosis process, an integrated Ternary pattern and Fourier-Bessel series expansion based empirical wavelet transform (TP-FBSE-EWT) method is used to extract features. Then, a hybrid binary teaching learning and Horse herd optimization (H-BTL-HHO) algorithm is presented to minimize the dimensions and screen properties of brain regions associated with AD. Additionally, by using the Gradient-weighted Class Activation Mapping (Grad-CAM) technique, the proposed structure seeks to improve the interpretability of deep learning models, giving clinicians important insights into disease diagnosis and an understanding of the decision-making process. The process is implemented using the MATLAB tool. The simulation findings reveal that the proposed CAD system for clinical score prediction outperforms prevailing systems by boosting accuracy, sensitivity, and specificity to 99.97%, 99.34%, and 98.89% for multi-class problems, respectively.},
}
@article {pmid42364425,
year = {2026},
author = {Rodrigues, EA and Dionizio, A and Rosa, CM and Campos, DHS and Damatto, FC and Reyes, DRA and Souza, LM and Santos, PP and Gatto, M and Borim, PA and Pagan, LU and Araújo, TT and Buzalaf, MAR and Cunha, TM and Okoshi, K and Okoshi, MP},
title = {Effects of SGLT2 inhibitor dapagliflozin on the heart of rats with long-standing Type 1 diabetes mellitus: Protein profile.},
journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie},
volume = {201},
number = {},
pages = {119719},
doi = {10.1016/j.biopha.2026.119719},
pmid = {42364425},
issn = {1950-6007},
abstract = {UNLABELLED: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have beneficial outcomes on the renal and cardiovascular system in diabetes mellitus (DM) patients. As most clinical trials were performed in Type 2 DM, the effects of SGLT2 inhibition in Type 1 DM are not completely clarified.<br><br>OBJECTIVE: To evaluate the effects of long-standing SGLT2 inhibitor dapagliflozin on the protein profile in rats with a Type 1 DM model.<br><br>METHODS: Male Wistar rats were divided into Control (C), DM, and DM treated with dapagliflozin (DM+DAPA) for 30 weeks. DM was induced by a single injection of streptozotocin (40&#x202f;mg/kg); dapagliflozin was added to chow (5&#x202f;mg/kg/day). Label-free mass spectrometry was used to assess left ventricular proteome. The bioinformatic tools used were STRING, Cytoscape, Cluster Marker, and ClueGO.<br><br>STATISTICAL ANALYSIS: ANOVA and Tukey or Kruskal-Wallis and Dunn.<br><br>RESULTS: Dapagliflozin attenuated body weight loss (C 574&#x202f;&#xb1;&#x202f;43; DM 339&#x202f;&#xb1;&#x202f;31*; DM+DAPA 413&#x202f;&#xb1;&#x202f;30*# g; p&#x202f;<&#x202f;0.05 * vs C; # vs DM) and reduced glycemia [C 108 (101-111); DM 554 (529-562)*; DM&#x202f;+&#x202f;DAPA 343 (237-416)*# mg/dL; p&#x202f;<&#x202f;0.05 * vs C; # vs DM]. Most proteins identified in the networks downregulated in DM vs C were upregulated in DM&#x202f;+&#x202f;DAPA vs DM. Proteins related to energy metabolism (CKm, Ak1, Atp5pf, Mdh1, Idh2), excitation-contraction coupling (Actc1, Casq2, Serca1, Serca2a), and oxidative stress (Sod1, Sod2) were upregulated in DM&#x202f;+&#x202f;DAPA. KEGG pathways enriched in DM vs Control included gap junction, necroptosis, and fatty acid degradation (upregulated), and Alzheimer's disease, cardiac contraction, and glycolysis/gluconeogenesis (downregulated). In DM&#x202f;+&#x202f;DAPA vs DM, upregulated pathways included Parkinson's disease, cardiac contraction, citrate cycle, necroptosis, and cyclic guanosine monophosphate-dependent protein kinase (PKG) signaling pathway; downregulated proteins were linked to ketone body metabolism.<br><br>CONCLUSION: Dapagliflozin modulates cardiac protein abundance by attenuating DM-induced changes in Type 1 DM rats.},
}
@article {pmid42364498,
year = {2026},
author = {Hu, H and Zhao, S and Xu, L and Ma, Z and Ma, R and Huang, F and Shi, L},
title = {Sequential targeting nanochaperone disrupts positive feedback loop of mitochondrial dysfunction for Alzheimer's disease therapy.},
journal = {Biomaterials},
volume = {335},
number = {},
pages = {124408},
doi = {10.1016/j.biomaterials.2026.124408},
pmid = {42364498},
issn = {1878-5905},
abstract = {Mitochondrial dysfunction is recognized as a key pathogenic mechanism of Alzheimer's disease (AD), involving a self-perpetuating feedback loop with three aspects: upstream β-amyloid protein (Aβ), downstream calcium ion (Ca[2+]) and reactive oxygen species (ROS). However, current therapeutic strategies only focus on one aspect and fail to address multiple factors within this cycle. Moreover, the lack of targeted approaches to the mitochondria within damaged neurons further limits their application. Herein, we developed a sequential targeting nanochaperone to selectively target damaged neuronal mitochondria and disrupt this vicious cycle for AD treatment. In this strategy, with the sequence mediation of damaged neuron-targeting and mitochondria-targeting peptides decorated on surface, the nanochaperone can first localize to the damaged neurons in AD brain and then translocate to mitochondria within them. Subsequently, this nanochaperone can effectively bind upstream Aβ proteins and inhibit their aggregation toxicity to mitochondria through the synergic effect of chaperone-mimicking microdomains and Aβ-targeting peptide on surface, thereby halting downstream mitochondrial Ca[2+] dyshomeostasis and ROS overload in the damaged neuron. Furthermore, the modified mitochondria-targeting peptide with antioxidant property can further scavenge overproduced ROS and regulate Ca[2+] homeostasis, which in turn contributes to reducing the Aβ-induced mitochondrial damage. Consequently, the nanochaperone efficiently restores the mitochondrial dysfunction by disrupting the self-amplifying feedback loop of "Aβ-Ca[2+]-ROS" in the AD mitochondrial microenvironment, resulting in the significant alleviation of neuronal damage and cognitive deficits in 5xFAD transgenic mice. Taken together, our work presents a novel therapeutic strategy against mitochondrial dysfunction for AD treatment.},
}
@article {pmid42364649,
year = {2026},
author = {Lamichhane, B and Niraula, A and Merindol, N and Gélinas, SE and Lagüe, P and Ricard, S and Germain, H and Desgagné-Penix, I},
title = {A Golgi-localized N-methyltransferase and reversible aldo-keto reductases coordinate dual terminal routes in galanthamine biosynthesis.},
journal = {The Plant journal : for cell and molecular biology},
volume = {126},
number = {6},
pages = {e70910},
pmid = {42364649},
issn = {1365-313X},
support = {CRC-2023-00353//Canada Research Chairs/ ; },
mesh = {*Galantamine/biosynthesis/metabolism ; *Methyltransferases/metabolism/genetics ; *Golgi Apparatus/metabolism/enzymology ; *Plant Proteins/metabolism/genetics ; *Alcohol Oxidoreductases/metabolism/genetics ; *Liliaceae/enzymology/metabolism/genetics ; *Amaryllidaceae/enzymology/metabolism/genetics ; },
abstract = {Galanthamine, a therapeutic Amaryllidaceae alkaloid produced exclusively by species within the Amaryllidoideae subfamily, is a key treatment for early-stage symptoms of Alzheimer's disease. Elucidating its biosynthetic pathway is essential for strategies aimed at enhancing production through metabolic engineering. Galanthamine derives from the metabolic precursor 4'-O-methylnorbelladine, which undergoes cytochrome P450-mediated para-ortho' C-C phenol coupling to yield nornarwedine. Two competing terminal routes have been proposed: (i) reduction of nornarwedine to norgalanthamine, followed by N-methylation, or (ii) N-methylation of nornarwedine to narwedine prior to reduction. Here, we identify three aldo-keto reductase (AKR) candidates (LaAKR1, LaAKR2, and LaAKR3) and three N-methyltransferase (NMT) candidates from Leucojum aestivum: LaNMT, homologous to coclaurine N-methyltransferase-like (NMT-like), and two γ-tocopherol methyltransferases (TMT) homologs, LaTMT1 and LaTMT2. Subcellular localization studies revealed distinct compartmentalization, with LaNMT targeted to the ER-cytosol, LaTMT1 to plastids, and LaTMT2 to the Golgi apparatus. In vitro, LaTMT2 methylated both nornarwedine and norgalanthamine, with a kinetic preference for nornarwedine. LaTMT1 methylated γ-tocopherol to α-tocopherol (vitamin E). All three AKRs catalyzed reversible interconversions between nornarwedine and norgalanthamine, and between narwedine and galanthamine, with LaAKR3 favoring the reduction reaction whereas LaAKR1 the oxidation reaction. These findings identify LaTMT2 and LaAKRs as key branch-enabling enzymes, reconcile long-standing models of galanthamine biosynthesis, and provide a strategic target for metabolic engineering strategies to enhance galanthamine production.},
}
@article {pmid42364669,
year = {2026},
author = {Qiu, X and Liu, Z and Wang, L and Yuan, Y and Tan, J and Han, Y and Li, Z and Meng, Y and Wang, W and Tan, Y},
title = {Time-dependent circulating metabolic changes and key regulatory pathways in Alzheimer's disease: A combined animal model and public database study.},
journal = {Experimental gerontology},
volume = {222},
number = {},
pages = {113216},
doi = {10.1016/j.exger.2026.113216},
pmid = {42364669},
issn = {1873-6815},
abstract = {Early diagnosis remains a major challenge in Alzheimer's disease (AD), as clinical symptoms often appear after irreversible pathological progression. This study aimed to identify early diagnostic biomarkers and clarify metabolic regulatory mechanisms in AD by integrating metabolomic profiling from a mouse model with validation using public human datasets. AD models were established in 42 C57BL/6J mice by intraperitoneal injection of D-galactose (120 mg/kg) combined with intragastric administration of aluminum chloride (20 mg/kg) for 8 weeks. Plasma samples were collected at weeks 0, 3, 6, and 8 for untargeted metabolomic profiling. Public plasma/cerebrospinal fluid metabolomic datasets and brain transcriptomic datasets from AD patients were further analyzed for validation. Time-dependent metabolic alterations were observed in AD mice, characterized by predominant metabolite depletion at weeks 3-6 and compensatory accumulation at week 8. The metabolic profile of AD mice was clearly separated from that of controls at week 8. Nicotinamide metabolism and sphingosine-related pathways showed dynamic dysregulation during AD progression. Notably, nicotinamide and sphingosine were persistently increased in AD mice and were also elevated in plasma samples from AD patients, whereas metabolites such as N,N-diethyl-m-toluamide were decreased. Transcriptomic analysis revealed abnormal expression of key genes involved in nicotinamide metabolism (NMNAT1 and SIRT1) and sphingosine metabolism (SPTSSA and SPHK1) in brain tissues from AD patients. In conclusion, AD is characterized by stage-dependent metabolic dysregulation, featuring early depletion followed by late compensation. Dysregulated nicotinamide and sphingosine metabolism may contribute to AD pathogenesis, and related metabolites and regulatory genes may serve as potential diagnostic biomarkers and therapeutic targets.},
}
@article {pmid42365084,
year = {2026},
author = {Kumar, D and Martin, AJ},
title = {Integrated machine learning, molecular docking, and molecular dynamics simulations for in silico identification of GSK3β inhibitors for Alzheimer's disease.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-59744-9},
pmid = {42365084},
issn = {2045-2322},
abstract = {Glycogen Synthase Kinase-3 Beta is a multifunctional serine/threonine kinase, involved in regulating multiple cellular processes. Its dysregulation plays a key role in progression of Alzheimer's disease and no FDA-approved GSK3β inhibitors for AD therapy are available, due to challenges in isoform selectivity, safety and pharmacokinetic limitations. Here, an OECD guideline-compliant, two-stage machine learning-based virtual screening framework is developed for GSK3β inhibitors. A chemically diverse dataset from different databases were pre-processed and used for model development and validation. A comparative study confirmed the superiority of this two-stage approach over standard multiclass models, by yielding significantly higher balanced accuracy on the internal test set (0.86 against 0.74) and specificity. The best predictive models were deployed as an open-access web tool and were used for screening ASINEX Synergy Library. In the structure-based approach, molecular docking with a validated docking protocol was performed and the best molecules were subjected to molecular dynamics simulation, binding free energy and per-residue decomposition analysis. Principal component analysis of trajectories confirmed global stability and consistent binding modes. Cross-screening against the homologous GSK3α isoform and the structurally distinct Cyclin-dependent kinase 2 (CDK2) by molecular docking revealed distinct mechanistic interaction profiles. Rather than exhibiting strict single-target exclusivity, the top hits showed binding affinity profiles consistent with potential CMGC family Multi-Target Directed Ligands (MTDLs), warranting experimental kinome validation. This presumed polypharmacological profile is advantageous for Alzheimer's therapeutics, positioning these compounds as robust candidates for simultaneously mitigating multiple kinase pathways that drive Tau hyperphosphorylation. Overall, this integrated ML model development, validation, screening, protein selection, molecular docking and molecular dynamics workflow provides a reproducible, interpretable, and high-confidence method for identification of GSK3β inhibitors for Alzheimer's disease.},
}
@article {pmid42365183,
year = {2026},
author = {Park, DK and Constant, AB and Honig, LS and Marder, KS and Provenzano, FA and , },
title = {Machine learning classification and regional differentiation of neuropathologically-confirmed Alzheimer's disease and comorbid Lewy body disease.},
journal = {Communications medicine},
volume = {},
number = {},
pages = {},
doi = {10.1038/s43856-026-01652-0},
pmid = {42365183},
issn = {2730-664X},
abstract = {BACKGROUND: Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) co-occur frequently, and growing evidence, including neuropathology, supports synergistic interplay between the diseases. We tested whether a single T1-weighted MRI scan may differentiate neuropathologically confirmed comorbid AD/DLB and AD controls using heterogeneously acquired neuroimaging.<br><br>METHODS: We obtained structural neuroimaging, on two groups, AD with and without DLB pathology. Convolutional neural networks are trained across dimensions. We introduce a triple-ensemble strategy consisting of majority voting schemes within a variety of plane permutations. In addition, we conduct voxel-wise statistical analyses.<br><br>RESULTS: Here we show convolutional neural networks record a classification accuracy of 0.820 and an f1 score of 0.79 in identifying comorbid DLB/AD from AD patients. Prediction accuracy is higher proximal to date of death, while the trained model largely outperforms clinical baseline diagnosis. The slice-level performance varies depending on the sampled brain location, with sensitivity highest in the temporal lobe and specificity highest in the occipital lobe. In DLB/AD, gray matter is relatively preserved though atrophy is observed in the occipital lobe, suggesting that the comorbidity differentially affects brain loss and may accelerate it in the occipital lobe.<br><br>CONCLUSIONS: This study demonstrates how machine learning approaches can address diverse neuroimaging data from clinical sources to differentiate neurodegenerative diseases using a true gold standard of neuropathological confirmation. The frameworks utilized here can be extended to other diseases that are frequently co-occurring and feasibly extend to single scan diagnostic clinical utility of scans already being acquired.},
}
@article {pmid42365239,
year = {2026},
author = {Novak, P and Katina, S and Brandoburova, P and Jezberova, M and Reznakova, V and Hanes, J and Jurcaga, F and Koson, P and Novak, M and Jönsson, L and Zilka, N},
title = {Which assessment tools best distinguish between mild cognitive impairment and dementia? Lessons from a Slovak memory clinic cohort.},
journal = {BMC geriatrics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12877-026-07801-3},
pmid = {42365239},
issn = {1471-2318},
support = {20-0447//Agent&#xfa;ra na Podporu V&#xfd;skumu a V&#xfd;voja/ ; 20-0447//Agent&#xfa;ra na Podporu V&#xfd;skumu a V&#xfd;voja/ ; 20-0447//Agent&#xfa;ra na Podporu V&#xfd;skumu a V&#xfd;voja/ ; 20-0447//Agent&#xfa;ra na Podporu V&#xfd;skumu a V&#xfd;voja/ ; 20-0447//Agent&#xfa;ra na Podporu V&#xfd;skumu a V&#xfd;voja/ ; ADDITION: Alzheimer's disease data-driven insights on individual outcomes of importance//EU Joint Programme - Neurodegenerative Disease Research/ ; ADDITION: Alzheimer's disease data-driven insights on individual outcomes of importance//EU Joint Programme - Neurodegenerative Disease Research/ ; ADDITION: Alzheimer's disease data-driven insights on individual outcomes of importance//EU Joint Programme - Neurodegenerative Disease Research/ ; ADDITION: Alzheimer's disease data-driven insights on individual outcomes of importance//EU Joint Programme - Neurodegenerative Disease Research/ ; },
abstract = {BACKGROUND: The utility of various cognitive assessment tools for distinguishing between mild impairment and dementia, as well as for determining cutoff values for specific populations, continues to be the subject of extensive research. Here, we assessed the utility and feasibility of these tools in the first Slovak memory clinic cohort.<br><br>METHODS: We enrolled a Slovak memory clinic cohort of patients with MCI and dementia (MCI, n&#x2009;=&#x2009;84; dementia, n&#x2009;=&#x2009;55). The participants were characterized using a range of cognitive assessment tools-Auditory Verbal Learning (AVLT), Category and Letter Fluency (CFT, LFT), Digit Span (DSF, DSB), Digit-Symbol Coding (DS-C), Frontal Assessment Battery (FAB), MMSE, MoCA, Rey Osterrieth Complex Figure (ROCF), and Trail Making Test (TMTA, TMTB); clinical assessments-Amsterdam Instrumental Activities of Daily Living (A-IADL) and 5-level EuroQol questionnaire with 5 dimensions (EQ-5D-5&#xa0;L); and scales for anxiety, dependency, depression, dignity, and MRI volumetry. The ability of the various assessments to distinguish between MCI and dementia was evaluated.<br><br>RESULTS: Over the course of three years, at a single memory clinic, it was feasible to enrol and evaluate a total of 150 participants, 139 of whom fulfilled the definition of either MCI or nonvascular dementia. Of the employed cognitive and clinical assessment tools, the best differentiation between MCI and dementia was observed for the AVLT and A-IADL. The DSF and DSB tests did not reveal differences between the populations. No differences were observed in education, vital signs, or anthropometric measurements. Participants with dementia had greater degrees of brain atrophy in the hippocampi and frontal, parietal, and temporal cortex; lower total brain volumes; and greater ventricular dilation.<br><br>CONCLUSIONS: This study confirms the utility of a range of cognitive assessment tools and scales for differentiating between MCI and dementia but reveals that some commonly employed tools, such as the DSF and DSB, may not be sensitive to these differences. This study highlights the importance of accurate assessment of the ability to perform activities of daily living and supports the development of objective, ecologically valid assessments of IADL.},
}
@article {pmid42365511,
year = {2026},
author = {Song, A and Zhao, Y and Wu, S and Xu, X},
title = {Frequency-specific effects of pulsed magnetic field on BV2 microglial cell function.},
journal = {Electromagnetic biology and medicine},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/15368378.2026.2694326},
pmid = {42365511},
issn = {1536-8386},
abstract = {The objective of this study was to investigate the effects of pulsed magnetic field (PMF) at different frequencies on phagocytosis, migration, and the expression of inflammatory factors in microglia. BV2 microglia were subjected to PMF at different frequencies for 3 d, twice daily. The changes of cell viability, phagocytosis and migration after magnetic stimulation were detected. The mRNA and protein levels of TNF-α and IL-1β were determined using RT-PCR and ELISA. The nuclear translocation of NF-κB P65 and intracellular Ca2+ level was detected through immunofluorescence. PMF at different frequencies did not affect microglial viability. Stimulation at all frequencies enhanced the ability of microglia to phagocytosis and migration. The mRNA expression level of IL-1β and TNF-α was significantly decreased by magnetic stimulation at 20 Hz and 40 Hz. However, only the protein level of IL-1β was significantly reduced by magnetic stimulation at 20 Hz, while TNF-α remained unaffected. Magnetic stimulation at 20 Hz and 40 Hz inhibited the nuclear translocation of NF-κB P65 and increased the intracellular Ca2+ level. Repetitive magnetic stimulation can modulate the secretion of inflammatory cytokines and enhance the phagocytosis and migration capacity of microglia in a frequency-dependent manner. This variation may be linked to differences in the activation of NF-κB and calcium in microglia.},
}
@article {pmid42366122,
year = {2026},
author = {Amado-Riveros, P and Riveros-Perez, E},
title = {Hormone Therapy is Associated with Better Cognitive Performance in Postmenopausal Women: Insights from the National Health and Nutrition Examination Survey (NHANES).},
journal = {Annals of geriatric medicine and research},
volume = {30},
number = {2},
pages = {236-245},
doi = {10.4235/agmr.25.0180},
pmid = {42366122},
issn = {2508-4909},
mesh = {Humans ; Female ; *Postmenopause/psychology/drug effects ; Cross-Sectional Studies ; *Cognition/drug effects ; Nutrition Surveys ; Aged ; Middle Aged ; *Estrogen Replacement Therapy ; United States/epidemiology ; Neuropsychological Tests ; },
abstract = {BACKGROUND: Alzheimer's disease is more prevalent among females. Estrogens influence brain metabolism and function, and low blood levels before, during, and after menopause may be associated with cognitive decline in later years. Here, we investigate the association between hormone therapy and reproductive lifespan with cognitive performance using a nationally representative sample from the National Health and Nutrition Examination Survey (NHANES) database.<br><br>METHODS: This cross-sectional study included 1,374 eligible women aged 60 years or older from the NHANES database. Cognitive performance was assessed using the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) word learning subtest, the Animal Fluency Test (AFT), and the Digit Symbol Substitution Test (DSST). Univariate analysis and multivariate logistic regression were employed to evaluate the association between hormone therapy, reproductive span, and cognitive performance. Restricted cubic spline curves were used to assess the relationship between age as a continuous variable and cognitive performance.<br><br>RESULTS: After adjusting for age, race, and educational level, hormone therapy was significantly associated with word recall, digit symbol, and animal fluency cognitive performance (p < 0.05). The reproductive span was associated with word recall performance (p = 0.027) but not with digit symbol or animal fluency. The age-related cognitive decline is attenuated by hormone therapy with maximum effect between 65 and 70 years for all dimensions.<br><br>CONCLUSION: There is a positive association between hormone therapy and cognitive performance in postmenopausal women, particularly in age groups with the steeper decline. In addition, there is no significant association between reproductive span and cognitive function.},
}
@article {pmid42366179,
year = {2026},
author = {Sim, SY and Kim, S and Kim, YS and Han, JS},
title = {Age-dependent Upregulation of Selenbp1 in 5XFAD Mice.},
journal = {Experimental neurobiology},
volume = {},
number = {},
pages = {},
doi = {10.5607/en26013},
pmid = {42366179},
issn = {1226-2560},
abstract = {Selenium-binding protein 1 (SELENBP1), previously implicated in several neurological and psychiatric disorders, was recently reported to be altered in the brains of individuals with Alzheimer's disease (AD). However, the cellular specificity of SELENBP1 in AD pathogenesis, including its role in amyloid-beta, remains unclear. Given the prominent role of microglia in amyloid-driven neuroinflammation and the hippocampal regional vulnerability in early AD, clarifying how SELENBP1 is regulated at both regional and cell-type-specific levels is essential. In this study, we examined age- and genotype-dependent changes in Selenbp1 expression in the hippocampus and prefrontal cortex of non-transgenic and 5XFAD mice at 1.5, 3, and 6 months of age by using western blot and immunofluorescence analyses. Western blot analyses revealed robust age-dependent increases in Selenbp1 expression in both regions, with no statistically significant genotype-dependent differences. However, immunofluorescence analyses showed that Selenbp1 levels were selectively increased in amyloid-vulnerable hippocampal subregions, including the dentate gyrus, dorsal subiculum, and retrosplenial cortex. Selenbp1 expression was expressed in microglia and was largely absent from neurons or astrocytes. These findings indicate that Selenbp1 elevation under AD-like conditions is region- and cell-type-specific, reflecting microglial responses detectable only through spatially resolved analysis. Therefore, Selenbp1 may represent a microglial molecular signature associated with early amyloid pathology.},
}
@article {pmid42366201,
year = {2026},
author = {Chen, Y and Gui, H and Ma, K and Zhang, Z and Zhao, T and Wang, M},
title = {Lifestyle-associated blood metabolic pathways and functional performance in cognitive aging.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-58782-7},
pmid = {42366201},
issn = {2045-2322},
abstract = {Functional decline is a major clinical feature of Alzheimer's disease (AD), yet the blood metabolic pathways associated with lifestyle factors and multidimensional functional performance across cognitive stages remain incompletely characterized. We applied a pathway-level blood metabolomics framework to harmonized, de-identified data from aging and dementia-related cohort resources spanning cognitively normal aging (CN), mild cognitive impairment (MCI), and AD. Metabolites were mapped to curated pathways and summarized into pathway activity scores across five domains: energy metabolism, amino acid metabolism, lipid metabolism, inflammation/oxidative stress, and microbiome-linked metabolism. We evaluated associations among physical activity, diet quality, pathway activity scores, and functional outcomes, including activities of daily living, gait speed, grip strength, global cognition, composite function, and frailty. To summarize pathway patterns jointly associated with physical activity and diet quality, we derived a lifestyle-modulated metabolic pathway score (LMPS) using elastic net regression with cross-validation, out-of-fold score estimation, and bootstrap stability assessment. Lifestyle-associated pathway activity showed coordinated patterns across metabolic domains and was associated with functional performance across cognitive groups. Higher LMPS values were associated with better physical and cognitive function and lower frailty, with graded differences observed across CN, MCI, and AD. Internal robustness analyses indicated greater stability at the pathway-domain level than at the individual-pathway coefficient level. Sensitivity analyses adjusting for cognitive group attenuated but did not eliminate the directionally consistent associations between LMPS and major functional outcomes. Convergent pathway patterns involved mitochondrial energy metabolism, lipid remodeling, inflammatory regulation, and microbiome-related metabolism. Pathway-level blood metabolomics identified lifestyle-associated metabolic patterns related to multidimensional functional outcomes across the cognitive aging spectrum. LMPS provides a data-driven summary of lifestyle-associated pathway variation in this cohort and may help generate hypotheses about metabolic correlates of functional performance. Independent and longitudinal validation will be required to determine its reproducibility, temporal relevance, and translational utility.},
}
@article {pmid42366234,
year = {2026},
author = {Rong, W and Xu, J and Li, B and Li, Y and Xu, Y},
title = {Correction: Single-cell atlas reveals the key role of pro-inflammatory IREB2[+] microglia subsets in the microenvironment of Alzheimer's disease.},
journal = {Clinical and experimental medicine},
volume = {26},
number = {1},
pages = {},
doi = {10.1007/s10238-026-02238-9},
pmid = {42366234},
issn = {1591-9528},
}
@article {pmid42366246,
year = {2026},
author = {Liao, K and Li, J and Jiao, F and Zhang, Z and Xu, L and Wang, Z and Li, W and Pang, H},
title = {Impact of reduced [18]F-MK6240 PET/MR acquisition duration on image quality and tau pathology assessment in patients with cognitive impairment.},
journal = {EJNMMI physics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40658-026-00914-z},
pmid = {42366246},
issn = {2197-7364},
support = {82472019//National Natural Science Foundation of China/ ; 82502406//National Natural Science Foundation of China/ ; },
abstract = {BACKGROUND: [18]F-MK6240 tau positron emission tomography (PET) is critical in Alzheimer's disease diagnosis and therapeutic monitoring. However, the standard 20-minute static acquisition poses challenges for cognitively impaired patients with limited tolerance for prolonged scans. This study evaluates the feasibility of reducing scan time while maintaining diagnostic accuracy through image quality and quantitative comparisons.<br><br>METHODS: 69 memory clinic patients (27 males and 42 females) who underwent [18]F-MK6240 PET examinations were retrospectively analyzed. All 20-minutes scans were acquired 90&#xa0;min post-injection of ~&#x2009;3.7 MBq/kg &#xb9;&#x2078;F-MK6240 and reconstructed mainly into 5-, 10-, 15-, and 20-minute datasets. Images were rated on a 5-point scale for overall quality, noise, and diagnostic confidence. Tau status (positive/negative) was the visually defined, and standardized uptake value ratios (SUVr) of Braak regions were calculated using cerebellar gray matter as reference. Agreement across durations was assessed via Bland-Altman analysis.<br><br>RESULTS: Among the 69 patients, 50 were classified as tau-positive and 19 as tau-negative. Diagnostic efficacy remained consistent across acquisition times compared to the 20-minute reference. The slight reduction in image quality for the 5-minute images relative to the other groups, but none of the images across any of the four durations were rated as poor (score&#x2009;<&#x2009;3). For 16 predefined regions used for visual assessment of regional tau involvement, both readers showed near-perfect agreement in scoring the extent of involvement (0%, 1-25%, 26-75%, or >&#x2009;75%) across the four scan durations, as evidenced by Kendall's W coefficients ranging from 0.984 to 1.000 (all p&#x2009;<&#x2009;0.001). Negative scans showed lower SUVr spread over Braak stages of four different time duration. Bland-Altman analysis demonstrated high agreement in Braak-stage SUVr values between the 20-minute images and the shortened acquisitions with mean differences close to zero across all comparisons.<br><br>CONCLUSION: Shortening &#xb9;&#x2078;F-MK6240 PET acquisition to 5&#xa0;min on a modern high-sensitivity PET/MR system results in a small, clinically acceptable decline in image quality. It does not compromise the reliability of visual reads or the stability of semi-quantitative measures compared to the standard 20-minute scan. These findings support the feasibility of 5-minute protocols, which offer practical benefits like reduced motion artifacts and improved patient throughput, as an operationally efficient alternative in clinical tau imaging.},
}
@article {pmid42366338,
year = {2026},
author = {Dey, AK and Al-Amin, MY and Ferdous, R and Alam, AHMK and Rahman, AA and Hossen, MB and Mollah, MNH and Sadik, MG},
title = {Isolation and identification of hasubanan alkaloids having anti-cholinesterase and antioxidant activity from the stem Stephania japonica.},
journal = {BMC complementary medicine and therapies},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12906-026-05447-7},
pmid = {42366338},
issn = {2662-7671},
support = {37-01-0000-073-04-012/2019//University Grants Commission of Bangladesh/ ; },
abstract = {BACKGROUND: A recent report showed that Stephania japonica chloroform fraction has potential anticholinesterase and antioxidant activities and is able to improve learning and memory in mice. Therefore, the aim of the present study was to isolate and identify compounds from the chloroform fraction with cholinesterase inhibitory and antioxidant activity that may be useful as new candidates for the treatment of AD.<br><br>METHODS: Chromatographic methods were used for isolation of compounds and the isolated compounds were analyzed by spectroscopic methods for structure elucidation. Acetyl- and butyryl-cholinesterase inhibitory activity were evaluated for by Ellman's method and the antioxidant activity by several in vitro models such as DPPH and hydroxyl radicals scavenging, reducing power, total antioxidant activity, and inhibition of brain lipid peroxidation. The interaction of cholinesterase enzymes and isolated compounds were examined by molecular docking studies.<br><br>RESULTS: Bioactivity guided approach led to the isolation of four compounds from the chloroform fraction and identified as aknadinine, aknadilactam, aknadicine and stephisoferuline on the basis of their [1]H-NMR and [13]C-NMR spectral data. All the compounds were of hasubanan type. They showed significant inhibition against acetylcholinesterase and butyrylcholinesterase, with at least two fold increased affinity for butyrylcholinesterase than acetylcholinesterase. The IC50 values of the alkaloids were in the range of 9.36-14.89&#xa0;&#xb5;g/mL against acetylcholinesterase and 3.97-6.66&#xa0;&#xb5;g/mL against butyrylcholinesterase. Kinetic analysis revealed that all the four compounds exhibited mixed type of inhibition against both acetylcholinesterase and butyrylcholinesterase. The interaction of compounds with several amino acids of enzymes was supported by molecular docking studies. All the hasubanan alkaloids showed antioxidant activity in all in vitro assays and inhibited peroxidation of brain lipid. The IC50 values of the compounds for scavenging of DPPH and hydroxyl radicals, and lipid peroxidation inhibition were found to be in the range of 5.1-40.91, 10.44-19.41, and 20.60-31.72&#xa0;&#xb5;g/mL, respectively.<br><br>CONCLUSION: The hasubabanan alkaloids isolated from S. japonica may represent a new class of anti-cholinesterase compounds. The multitargeted activity of hasubanan alkaloids may lead to new candidates for the treatment of AD.},
}
@article {pmid42366401,
year = {2026},
author = {Sun, W and Xing, R and Zhou, J and Li, Y and Xu, G},
title = {Facial phenotypes in Alzheimer's disease: from neurobiology to artificial intelligence.},
journal = {Alzheimer's research &amp; therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02129-x},
pmid = {42366401},
issn = {1758-9193},
support = {KYCX25_0823 to RX//Major Project of Philosophy and Social Science Research for Universities of Jiangsu Province/ ; 82171330//National Natural Science Foundation of China/ ; 4004013//Shenzhen Talent Introduction Fund/ ; 2023ZD0504800, 2023ZD0504801, 2023ZD0504802, 2023ZD0504803, 2023ZD0504804//Noncommunicable Chronic Diseases-National Science and Technology Major Project/ ; },
abstract = {Facial analysis is increasingly being explored as a source of scalable behavioral signals relevant to Alzheimer's disease (AD) and AD-related cognitive impairment. In this narrative review, informed by a structured literature search, we summarize current evidence on the biological and behavioral basis of facial alterations in AD, with particular emphasis on affective expressivity, neuropsychiatric manifestations, and dynamic facial behavior. We also review representative artificial intelligence-based facial analysis methods, including commonly used datasets, feature representations, and modeling strategies, ranging from facial landmarks and texture descriptors to spatiotemporal video models, multimodal fusion, and language-enhanced frameworks. Current evidence remains limited by small and largely single-center cohorts, heterogeneity in acquisition settings and outcome definitions, inadequate control of confounding factors, limited external validation, poor calibration reporting, and persistent concerns regarding interpretability and clinical specificity. Within the evolving biomarker-based diagnostic framework of AD, facial analysis is better viewed as a candidate, non-specific, and context-dependent tool for auxiliary risk stratification, triage support, and longitudinal monitoring rather than as stand-alone diagnostic tests. Future progress will depend on standardized data acquisition, integration with clinical and biomarker data, improved explainability, and prospective real-world validation.},
}
@article {pmid42366433,
year = {2026},
author = {Chen, Y and Yao, C and Yan, F and Xiao, P and Lu, X},
title = {[Finite-element simulation and experimental investigation of nanosecond transcranial pulsed electric field propagation and distribution in a three-dimensional brain model].},
journal = {Sheng wu yi xue gong cheng xue za zhi = Journal of biomedical engineering = Shengwu yixue gongchengxue zazhi},
volume = {43},
number = {3},
pages = {504-512},
pmid = {42366433},
issn = {1001-5515},
mesh = {Humans ; *Finite Element Analysis ; *Brain/physiology ; Computer Simulation ; Alzheimer Disease/therapy ; *Transcranial Direct Current Stimulation/methods ; Electromagnetic Fields ; Amyloid beta-Peptides/metabolism ; },
abstract = {Nanosecond pulsed electric field (nsPEF) exposure can disrupt and disaggregate amyloid-β, indicating its potential to improve symptoms of Alzheimer's disease. However, the propagation and distribution patterns of nsPEF within brain tissue remain insufficiently understood, making related simulation analysis necessary. In this study, a high-resolution three-dimensional human head model incorporating the scalp, skull, cerebrospinal fluid, gray matter, white matter, and hippocampus was constructed. Based on the spectral characteristics of nsPEF, the dielectric properties of human tissues at different frequency ranges were assigned, and a transient finite-element model of nsPEF exposure in the human brain was established. The simulation analysis identified two optimal electrode-pair positions and characterized the spatial distributions of intracranial electric field strength as well as current density. It further elucidated the dependence of the hippocampal electric field response and current density on pulse parameters. In addition, a physical human brain model was constructed to experimentally validate the finite-element simulation results. The results showed that transcranial nsPEF can reach deep brain regions with extremely narrow pulse widths, and pulsed electric fields with kilovolt-level amplitudes and nanosecond-scale pulse widths can generate electric field strengths of approximately 10 [3] V/m in the hippocampus. In summary, this work provides a theoretical basis and experimental support for optimizing the electrode configuration and stimulation parameters of transcranial nsPEF, thereby laying a foundation for future research on its application in non-invasive physical interventions for Alzheimer's disease.},
}
@article {pmid42366543,
year = {2026},
author = {Sui, Z and Feng, A and Gong, Y and Zha, S and Lv, Y and Zheng, Q and Li, L and Wang, Y},
title = {Predicting cognitive function in Alzheimer's clinical trials via amyloid β-protein biomarkers.},
journal = {British journal of clinical pharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1002/bcp.70665},
pmid = {42366543},
issn = {1365-2125},
support = {2025ZHYL037//Shanghai Municipal Health Commission Smart Healthcare Special Project/ ; 2024YFC3506600//National Key R&amp;D Program of China/ ; LSLSKL20240203//Open Research Program of the State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine/ ; },
abstract = {OBJECTIVES: This study investigates the association between amyloid-β (Aβ) biomarkers and clinical cognitive outcomes and quantitatively elucidates their relationship, providing robust evidence supporting the amyloid hypothesis and advancing the development of novel anti-amyloid therapeutics, such as aducanumab, lecanemab and donanemab.<br><br>METHODS: Placebo-controlled randomized clinical trials reporting A&#x3b2;-related biomarkers and cognitive function clinical outcomes were retrieved from PubMed, EMBASE and Cochrane Library. Pearson correlation analysis was first used to screen indices, and then a model-based meta-analysis (MBMA) using non-linear mixed-effect modelling was established to predict cognitive function based on biomarkers while examining relevant factors affecting the relationship.<br><br>RESULTS: Primary outcomes included changes in the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) and the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-COG-11). The analysis included 57 articles representing 93&#x2009;417 subjects, with a modelling subset of 18&#x2009;246 patients providing paired biomarker-endpoint data for Alzheimer's disease or mild cognitive impairment. Results showed significant correlations between the standard uptake value ratio (SUVR) of &#x3b2;-amyloid plaques and CDR-SB, centiloid and CDR-SB, and SUVR and ADAS-COG-11. Three prediction models of cognitive function scales based on imaging index of &#x3b2;-amyloid plaques were established and found to be significantly impacted by factors such as baseline CDR-SB, treatment duration and the proportion of patients receiving basic treatment.<br><br>CONCLUSIONS: This study clarified the correlation and established predictive models for CDR-SB and ADAS-COG-11 based on amyloid imaging. This research identifies potential biomarkers and model-derived benchmarks for future dose selection and decision-making in Alzheimer's drug development, potentially accelerating the development of new treatments.},
}
@article {pmid42366747,
year = {2026},
author = {Abed, H},
title = {Postoperative Experiences After Dental Treatment Under General Anesthesia in People Living With Alzheimer's Disease: A Descriptive Study With Caregiver and Staff Reports.},
journal = {Special care in dentistry : official publication of the American Association of Hospital Dentists, the Academy of Dentistry for the Handicapped, and the American Society for Geriatric Dentistry},
volume = {46},
number = {4},
pages = {e70201},
doi = {10.1111/scd.70201},
pmid = {42366747},
issn = {1754-4505},
mesh = {Humans ; *Anesthesia, General ; *Alzheimer Disease/complications ; Female ; Aged ; *Caregivers/psychology ; Male ; Aged, 80 and over ; *Anesthesia, Dental ; Postoperative Complications/epidemiology ; Middle Aged ; *Dental Care for Chronically Ill ; Anesthesia Recovery Period ; },
abstract = {AIMS: To describe the demographic and clinical characteristics of people living with Alzheimer's disease (AD) undergoing dental treatment under general anesthesia, to summarize peri-recovery challenges reported by healthcare staff, and to describe caregiver-reported postoperative experiences at three time points. The occurrence of postoperative delirium or hallucinations was also descriptively examined.<br><br>METHODS: In this single-center descriptive study, postoperative information was obtained through structured telephone contacts with caregivers and relevant clinical staff at three time points (immediate recovery, 2 days, and 2 weeks). Responses were analyzed using inductive content analysis and summarized descriptively.<br><br>RESULTS: Participants (n = 14) were elderly and predominantly in the moderate to late stages of AD, with substantial dependence on caregivers. Staff-reported observations indicated that agitation and behavioral disturbance during emergence and early recovery were the most prominent challenges. Resistance to care with monitoring devices was also noted. Caregivers reported increased pain, agitation, and care demands within the first 48 h following general anesthesia. By one week, most caregivers reported physical recovery and behavioral improvement. No documented cases of postoperative delirium or hallucinations were identified.<br><br>CONCLUSIONS: In this exploratory descriptive study, dental treatment under general anesthesia in people living with AD was followed by short-term postoperative behavioral and physical challenges that generally improved within one week. Given the small sample size and descriptive design, findings should be interpreted cautiously.},
}
@article {pmid42366768,
year = {2026},
author = {},
title = {Corrigendum to "Electromagnetic field induced activation of amyloid-β degrading enzyme, neprilysin, for accelerated Alzheimer's disease therapy".},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261463830},
doi = {10.1177/13872877261463830},
pmid = {42366768},
issn = {1875-8908},
}
@article {pmid42366949,
year = {2026},
author = {González, EG and Dicu, M and Villar, JR and Chira, C},
title = {Transformer-Based Anomaly Detection for Neurodegenerative Screening in MRI Images.},
journal = {International journal of neural systems},
volume = {},
number = {},
pages = {2650052},
doi = {10.1142/S0129065726500528},
pmid = {42366949},
issn = {1793-6462},
abstract = {The automatic detection of anomalies in medical images is a significant challenge in the assisted diagnosis of neurodegenerative diseases such as Alzheimer's. This paper presents an anomaly detection model based on Transformers for the analysis of brain magnetic resonance images. The proposed architecture combines a Vision Transformer as an encoder with a memory bank module that allows modeling the distribution of healthy brains and detecting deviations through reconstruction error. The model is trained using a one-class learning approach, using only images considered normal, with the aim of learning the representation of normality and automatically flagging atypical structural patterns. To adapt volumetric studies to the architecture, a preprocessing procedure is designed that transforms three-dimensional information into a two-dimensional representation compatible with the model. The results obtained demonstrate a solid ability to characterize normality and generate reliable predictions, confirming the viability of Transformer-based architectures for unsupervised anomaly detection in neuroimaging. This approach lays the foundation for future extensions in clinical settings and other medical imaging applications.},
}
@article {pmid42367034,
year = {2026},
author = {West, NR and Lindberg, MF and Dairou, J and MacGregor, S and Puthireddy, S and Meijer, L and Bhattacharyya, A},
title = {Leucettinib-21 decreases dosage effects of DYRK1A in human trisomy 21 induced pluripotent stem cell-derived neural cells.},
journal = {Disease models &amp; mechanisms},
volume = {19},
number = {6},
pages = {},
doi = {10.1242/dmm.052740},
pmid = {42367034},
issn = {1754-8411},
support = {//School of Medicine and Public Health, University of Wisconsin-Madison/ ; //Wisconsin Alumni Research Foundation/ ; P50HD105353//National Institute of Child Health and Human Development/ ; //Fondation J&#xe9;r&#xf4;me Lejeune/ ; //Agence Nationale de la Recherche/ ; //France 2030/ ; //Bpifrance/ ; 848077//HORIZON EUROPE Innovative Europe/ ; 190138295//HORIZON EUROPE European Innovation Council/ ; //University of Wisconsin-Madison/ ; },
mesh = {Humans ; Dyrk Kinases ; *Protein Serine-Threonine Kinases/metabolism/genetics/antagonists &amp; inhibitors ; *Protein-Tyrosine Kinases/metabolism/genetics ; *Down Syndrome/pathology/enzymology/genetics ; *Induced Pluripotent Stem Cells/drug effects/pathology/metabolism/enzymology ; *Neural Stem Cells/drug effects/pathology/metabolism/enzymology ; *Neurons/drug effects/pathology/metabolism/enzymology ; *Gene Dosage/drug effects ; Protein Kinase Inhibitors/pharmacology ; Cell Differentiation/drug effects ; Dioxoles ; Imidazoles ; },
abstract = {Dosage imbalance of dual specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) is a feature of several neurodevelopmental and neurodegenerative diseases, including Down syndrome, DYRK1A syndrome, autism spectrum disorders, Alzheimer's disease and Parkinson's disease. Thus, manipulating DYRK1A activity in the brain has emerged as a potential therapeutic target for neurological disorders. Several DYRK1A inhibitors have shown promise for improving cognition in rodent models of Down syndrome and Alzheimer's disease, for example, but the ability of these inhibitors to affect DYRK1A levels or activity in relevant human cells has not been established. We filled this gap by testing the effects of a new DYRK1A inhibitor on trisomy 21 induced pluripotent stem cell (iPSC)-derived neural progenitor cells and neurons, in which DYRK1A expression and activity are increased. Our results demonstrated that Leucettinib-21, a potent and selective low-molecular-mass pharmacological inhibitor of DYRK1A, decreases DYRK1A activity in human trisomy 21 iPSC-derived neural progenitor cells and cortical neurons. Leucettinib-21 reduces DYRK1A activity in a relevant human disease model, supporting future human trials.},
}
@article {pmid42367320,
year = {2026},
author = {Csikos, V and Thyfault, JP and Wilkins, HM},
title = {The impact of exercise on brain mitochondrial health and its relevance to Alzheimer's disease.},
journal = {Brain and environment},
volume = {5},
number = {},
pages = {},
pmid = {42367320},
issn = {3050-5917},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory loss, cognitive decline, and accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles in the brain. Mounting evidence implicates mitochondrial dysfunction as an upstream driver of AD pathogenesis, contributing to bioenergetic deficits, oxidative stress, impaired calcium homeostasis, and chronic neuroinflammation. Given the high energy demand of the brain, the preservation of mitochondrial function is critical for neuronal health. Physical exercise is recognized for its neuroprotective effects, with growing support that it may attenuate AD progression through enhancing mitochondrial quality control. This review explores how exercise influences key mitochondrial quality control processes in the brain-including mitochondrial-biogenesis, -dynamics, and mitophagy-and how these adaptations counteract AD-related pathologies. We further examine the dual role of reactive oxygen species, the impact of exercise-induced signaling molecules such as brain-derived neurotropic factor, irisin, and insulin-like growth factor 1, and the importance of cardiorespiratory fitness in fostering mitochondrial resilience. Finally, we highlight critical gaps in our understanding of how different exercise modalities uniquely affect brain mitochondria and AD pathology. Collectively, this underscores the potential of exercise as a non-pharmacological strategy to enhance brain mitochondrial health and promote cognitive resilience in aging and AD.},
}
@article {pmid42367372,
year = {2026},
author = {Cabán, M and Brown-Bradley, C and Wetmore, JB and Ottman, R and Siegel, K},
title = {Latinos' beliefs regarding the role played by nonmedical factors in the quality of Alzheimer's disease care: Findings from a NYC community-based sample.},
journal = {SSM. Qualitative research in health},
volume = {9},
number = {},
pages = {},
pmid = {42367372},
issn = {2667-3215},
abstract = {Latinos represent the fastest-growing subpopulation in the United States and are expected to experience the steepest increase in the coming decades in adults 65 and older living with Alzheimer's disease (AD). However, they also have a higher likelihood of delayed diagnosis, greater difficulty in accessing specialist referrals, treatments and support services and have fewer long-term and nursing care options than non-Latino Whites. A New York City community-based sample of Latinos completed qualitative interviews in English (63%) or Spanish (37%). We investigated participants' beliefs regarding Latinos' access to quality AD-related care. Data were coded by three team members using ATLAS.ti and thematic analysis was conducted by the senior qualitative team members. The results are organized along the care continuum from diagnosis through medical, supportive, and long-term care. The data revealed that participants (n = 155) believed a combination of nonmedical factors contributed to Latinos being diagnosed at a more advanced stage of AD and receiving poorer quality of care once diagnosed than non-Latino Whites. These included: limited financial assets, restricted health insurance coverage, cultural values and tendencies, limited availability of providers who understood their background and experiences or spoke Spanish, and to a lesser extent prejudice or discrimination. These findings are important because expectations of poor care may deter care seeking or once diagnosed may influence patients' level of engagement in care and treatment adherence. They have implications for enhancing patient-centered care for Latinos with AD as it emphasizes the incorporation of their perspectives when assessing the quality of care being delivered.},
}
@article {pmid42367689,
year = {2026},
author = {Liu, Y and Zhao, J and Shi, Z},
title = {Anti-Metabotropic Glutamate Receptor 5 Autoimmune Encephalitis with a Typical Alzheimer's Disease Biomarker Profile: A Case of Rapidly Progressive Dementia Unresponsive to Cholinesterase Inhibitors.},
journal = {Case reports in neurology},
volume = {18},
number = {1},
pages = {280-284},
pmid = {42367689},
issn = {1662-680X},
abstract = {INTRODUCTION: The distinction between neurodegenerative and autoimmune causes of rapidly progressive dementia can be challenging, particularly when atypical Alzheimer's disease (AD) biomarkers are present. We present a case of anti-metabotropic glutamate receptor 5 (mGluR5) autoimmune encephalitis (AE) initially misdiagnosed as AD due to concordant clinical, imaging, and biomarker findings.<br><br>CASE PRESENTATION: A 51-year-old woman developed progressive memory decline, apathy, and stereotyped paper-folding behavior over 2 years. She was diagnosed with rapidly progressive AD and treated with donepezil and memantine without improvement. Initial workup showed hippocampal neurodegeneration on magnetic resonance imaging/MRS and elevated plasma phosphorylated tau181, tau217, and GFAP - consistent with an AD biomarker profile. Neurological examination later revealed bilateral pyramidal signs. Re-evaluation identified serum anti-mGluR5 antibodies. Treatment with intravenous methylprednisolone and immunoglobulin led to marked improvement in cognition and behavior within 2 weeks.<br><br>CONCLUSION: This case demonstrates that anti-mGluR5 AE can manifest with a biomarker profile highly suggestive of AD, leading to prolonged misdiagnosis. It underscores the importance of considering AE in treatment-refractory or atypical dementia, even in the presence of supportive AD biomarkers, and highlights the potential for significant recovery with timely immunotherapy.},
}
@article {pmid42367849,
year = {2026},
author = {Gabal, E and Nguyen, TKO and Kovalenko, T and Gao, H and Rappaport, N and Funk, C and Baloni, P and Trushina, E},
title = {Mitochondrial Complex I Modulator Restores Network Resilience in Advanced Alzheimer's Disease Through Metabolic Reprogramming.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.14.732179},
pmid = {42367849},
issn = {2692-8205},
abstract = {Mitochondrial dysfunction and lipid dysregulation are among the earliest abnormalities in Alzheimer's disease (AD), yet their mechanistic interplay and therapeutic potential remain poorly understood. Here, we investigated whether restoration of mitochondrial function can reverse metabolic dysfunction and promote resilience in advanced-stage AD. Female APP/PS1 mice were treated with the brain-penetrant mitochondrial complex I (mtCI) modulator CP2 beginning at 19 months of age, when pathology and cognitive deficits were well established. To define the metabolic mechanisms underlying therapeutic response, we developed iMiceBrain , the first brain-specific genome-scale metabolic model of the mouse brain, and integrated transcriptomics, targeted metabolomics, lipidomics, and metabolic network analyses. CP2 treatment broadly reprogrammed AD-associated molecular signatures and restored pathways involved in mitochondrial function, glucose utilization, lipid metabolism, synaptic activity, and cellular stress responses. Metabolic modeling identified enhanced mitochondrial substrate flexibility, activation of fatty acid utilization, restoration of pyruvate dehydrogenase flux, and normalization of cholesterol metabolism as key features of the therapeutic response. Lipidomic analyses further demonstrated correction of disease-associated alterations in cholesteryl esters, phospholipids, and sphingolipids. Together, these findings demonstrate that mild mtCI modulation restores metabolic resilience by coordinating mitochondrial and lipid metabolism, establishing it as a disease-modifying therapeutic strategy for AD.},
}
@article {pmid42367894,
year = {2026},
author = {Morgan, GC and Gregory, A and Hanscom-Trofy, Y and Dong, R and Fan, F},
title = {Anatomical Identification and Pressure Myography of the Rat Middle Cerebral Artery: A Comprehensive Protocol for Diverse Genetic Models.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.12.718520},
pmid = {42367894},
issn = {2692-8205},
abstract = {The middle cerebral artery (MCA) is critical for cerebral blood flow autoregulation and a primary site of cerebrovascular pathology in stroke, Alzheimer's disease, and vascular dementia. Pressure myography enables precise ex vivo quantification of MCA structure and function, but requires accurate anatomical identification and careful vessel handling to ensure reproducibility across diverse rat genetic models. This chapter provides a comprehensive, step-by-step protocol for isolating and cannulating the rat MCA M2 segment for pressure myography. We detail precise anatomical landmarks to ensure consistent vessel selection across strains. The protocol includes optimized solutions, cannulation techniques, and pressure protocols validated across multiple rat models, including transgenic (TgF344-AD), diabetic (T2DN), consomic (SS.5 [BN] , FHH.1 [BN]), and genome-edited strains. Extensive troubleshooting notes address common technical challenges, including vessel viability assessment, pressure integrity, and strain-specific autoregulatory ranges. This methodology bridges molecular genetic findings with fundamental cerebrovascular physiology, enabling researchers to characterize myogenic reactivity, passive mechanical properties, and structural remodeling in rat models of cerebrovascular disease.},
}
@article {pmid42367902,
year = {2026},
author = {Huang, Y and Xie, X and Fernaine, M and Li, Z and Wang, X and Wang, J},
title = {Subregion-Specific Input Organization of Prefrontal-Projecting Basal Forebrain Cholinergic Neurons and Weakened Striatal-NBM Inhibitory Transmission in 5xFAD mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.11.731708},
pmid = {42367902},
issn = {2692-8205},
abstract = {UNLABELLED: Basal forebrain cholinergic neurons regulate cortical activity and cognition and are vulnerable in Alzheimer's disease (AD). However, the upstream circuits controlling projection-defined basal forebrain cholinergic populations remain incompletely understood. Here, we used projection-specific rabies-mediated monosynaptic tracing to map whole-brain inputs to medial prefrontal cortex (mPFC)-projecting cholinergic neurons in the nucleus basalis of Meynert (NBM) and horizontal limb of the diagonal band of Broca (HDB). mPFC-projecting NBM and HDB cholinergic neurons received broad but distinct input patterns. NBM cholinergic neurons received prominent striatal input, including input from D1-expressing medium spiny neurons, whereas HDB cholinergic neurons showed proportionally weaker striatal input and broader non-striatal contributions. Optogenetic electrophysiology confirmed that striatal inputs formed monosynaptic GABAergic inhibitory synapses onto NBM cholinergic neurons. This inhibitory transmission was weakened in 5xFAD mice, indicating impairment of a striatal-NBM inhibitory circuit in an AD mouse model. Together, these findings reveal subregion-specific input organization of mPFC-projecting basal forebrain cholinergic neurons and identify a vulnerable striatal-NBM circuit in AD.<br><br>HIGHLIGHTS: Whole-brain rabies tracing reveals input organization of mPFC-projecting BF cholinergic neurons.NBM and HDB cholinergic neurons projecting to mPFC show distinct monosynaptic input profiles.Striatal D1-MSNs are a major input source to mPFC-projecting NBM cholinergic neurons.Striatal-NBM inhibitory transmission is functionally impaired in 5xFAD mice.},
}
@article {pmid42367939,
year = {2026},
author = {Montenegro, P and Kim, R and Zedek, M and Chicas, M and Yeh, P and Yeh, H},
title = {Prenatal Alcohol Exposure Disrupts γ-Secretase Activity and Impairs Learning and Memory in Wild-Type and 3xTg-AD Mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.11.731622},
pmid = {42367939},
issn = {2692-8205},
abstract = {Although prenatal alcohol exposure (PAE) has been proposed as an early-life risk factor for Alzheimer's disease and related dementias (AD/ADRD), the mechanistic underpinnings are underexplored. Mutations in the Presenilin genes contribute to AD/ADRD, with Presenilin 1 acting as the catalytic subunit of the γ-secretase complex responsible for cleaving Notch and amyloid precursor protein (APP). We hypothesized that PAE disrupts γ-secretase activity during brain development, which persists and is associated with behavioral deficits later in life. Pregnant wild-type B6129 and 3xTg-AD mice were fed an ethanol-containing liquid diet during gestational days 13-15. From birth to adulthood, PAE increased APP C-terminal fragments and Notch intracellular domain (NICD) levels in cortical lysates. These changes were associated with impaired hippocampal-dependent learning and memory in wild-type mice at 3 and 6 months of age and exacerbated behavioral deficits in 4-month-old 3xTg-AD mice. Our findings provide the first mechanistic insight linking PAE to AD/ADRD vulnerability.},
}
@article {pmid42367943,
year = {2026},
author = {Ee, R and Amouzgar, M and Afaghani, J and Vijayaragavan, K and Cannon, BJ and Mrdjen, D and Tebaykin, D and Spence, A and Sant, C and Aley, D and Guo, Z and Sedov, K and Zafar, F and Montine, KS and Perna, A and Serrano, GE and Beach, TG and Angelo, M and Schüle, B and Corces, MR and Montine, TJ and Bendall, SC},
title = {APOE4 Drives Uniquely Dysfunctional Human Microglial States in Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.18.733295},
pmid = {42367943},
issn = {2692-8205},
abstract = {UNLABELLED: Variation in APOE, notably the ε4 allele, profoundly shapes risk and severity of late-onset Alzheimer's disease (AD), yet how it remodels human microglial states remains unresolved. We combine spatially resolved proteomic profiling with single-nuclear multiomic analyses to define microglial organization across APOE3/3 and APOE4/4 genotypes in AD. Quantifying condition-associated variation across the cellular manifold reveals a continuous landscape of microglial states. APOE4/4 shifts cells toward terminal states marked by loss of homeostatic identity, metabolic disruption, and incomplete acquisition of disease-associated programs. We identify an APOE4/4-enriched population in AD that exhibits inflammatory signaling without effective metabolic or phagocytic engagement, localizing to niches of gliosis and senescence, and coupled to chronic stress adaptation programs. Together with evidence that APOE4/4 potentiates the activation threshold of nascent microglia, these findings establish a unified framework for human microglial state change, linking genetic risk to spatial and molecular organization of immune responses in the AD brain.<br><br>GRAPHICAL ABSTRACT: APOE4/4 in Alzheimer's disease reshapes microglial fate along continuous trajectories characterized by proteomic, transcriptional, and epigenetic programs consistent with chronic stress adaptation, alongside distinct composite spatial niches comprised of astrocytic gliosis and cellular senescence.},
}
@article {pmid42367992,
year = {2026},
author = {Haynes, KA and Pandey, RS and Doud, EH and Cope, ZA and Little, GJ and Williams, SP and Nepali, U and Quinney, SK and Nagar, A and Charbe, NB and da Silva, L and Dage, JL and Duong, DM and Seyfried, NT and Sasner, M and Lamb, BT and Oblak, AL and Territo, PR and Carter, GW and Sukoff Rizzo, SJ},
title = {Molecular mechanisms underlying amyloid lowering by aducanumab: differential and comparative effects of sex and IgG reveal the post-treatment disease brain.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.16.731973},
pmid = {42367992},
issn = {2692-8205},
abstract = {INTRODUCTION: Improving the predictive validity of preclinical studies for Alzheimer's disease (AD) requires rigorous evaluation of therapeutic efficacy, safety, and sex-specific responses in translationally relevant models. As amyloid-targeting monoclonal antibodies continue to advance clinically, there is an urgent need to define the molecular milieu that persists after amyloid is reduced and disease progression continues. Leveraging the NIA-funded MODEL-AD Preclinical Testing Core, we investigated the biochemical, functional, and multi-omic signatures associated with chronic administration of murine chimeric aducanumab (chAdu) in 5XFAD mice, including the contribution of IgG-mediated effects.<br><br>METHODS: Male and female 5XFAD mice were treated weekly with chAdu beginning at 8 months of age and compared to age-and sex-matched murine IgG2a&#x3ba; isotype (IgG) and saline controls. Plasma and brain pharmacokinetics, amyloid-beta (A&#x3b2;), behavioral assessments, and treatment-emergent anti-drug antibodies (ADAs) were quantified. Post-treatment transcriptomic and proteomic analyses were performed to assess molecular pathways associated with chAdu and IgG exposure following 17-week treatment.<br><br>RESULTS: chAdu produced sex-dependent changes in A&#x3b2;, including increased plasma A&#x3b2;42:40 and reductions in brain A&#x3b2; which were associated with mild behavioral impairments in the absence of improvements in cognitive function. IgG control treatment produced similar reductions, indicating biologically active IgG-mediated processes independent of A&#x3b2;-targeted specificity. Treatment-emergent ADAs occurred in 10% of chAdu-treated mice and were associated with reduced drug exposure and efficacy. Multi-omics analyses confirmed sex-dependent and IgG-mediated effects at both the transcriptomic and proteome level revealing disease-associated genes and proteins not altered despite reductions in amyloid with treatment.<br><br>DISCUSSION: These findings demonstrate sex-dependent PK and pharmacodynamic responses to chAdu, identify biologically meaningful IgG-driven effects, and reveal molecular signatures that persist after amyloid reduction. This work provides biological insights into pathways that may remain insufficiently addressed following amyloid lowering; revealing novel targets for future drug discovery to prevent and treat disease.},
}
@article {pmid42368021,
year = {2026},
author = {Wang, R and Maloney, B and Nho, K and Beck, JS and Counts, SE and Lahiri, DK},
title = {MicroRNA-181 influences Alzheimer's risk by regulating neprilysin and microtubule-associated tau pathways, offering a novel target.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.11.731747},
pmid = {42368021},
issn = {2692-8205},
abstract = {UNLABELLED: Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) peptide plaques and neurofibrillary tangles from hyperphosphorylated tau, though factors linking amyloid and tau pathology remain unclear. We investigated whether microRNA-181d-5p (miR-181d) associates with AD-related brain changes and regulates neprilysin and tau. Modeling miR-181d across individuals with no cognitive impairment, mild cognitive impairment, and AD revealed region- and sex-specific associations. Higher miR-181d levels associated with greater AD probability in the temporal lobe and cerebellum, and lower probability in the posterior cingulate cortex of males; miR-181c attenuated these probabilities. SNPs near MIR181 associated with altered entorhinal cortical thickness. In cellular models, miR-181 reduced neprilysin 3'-UTR activity, mRNA, protein, and enzymatic activity, while increasing tau mRNA and protein. Neprilysin diminution impairs Aβ clearance and elevates tau, contributing to AD. RNA sequencing identified miR-181d-responsive neurodegenerative pathways. These findings identify miR-181 as a regulator of AD-relevant amyloid and tau pathways, providing novel targets.<br><br>TEASER: MiRNA-181 is a key regulator of Alzheimer's risk through its effects on neprilysin and tau proteins, a novel potential target.},
}
@article {pmid42368109,
year = {2026},
author = {Dorogan, M and Namballa, HK and Patra, S and Harding, WW},
title = {Recent Advances in Dopamine Receptor Ligands as Chemical Biology Tools.},
journal = {ACS omega},
volume = {11},
number = {24},
pages = {34870-34884},
pmid = {42368109},
issn = {2470-1343},
abstract = {Dopamine receptors (DRs) have been implicated in numerous disorders and diseases (e.g., Alzheimer's disease, Parkinson's disease, schizophrenia, and substance use disorders) and have served as attractive drug targets for these ailments. Despite their potential clinical utility, the development of selective DR ligands has been challenging due to difficulties in selectivity among the DR subtypes as well as other biogenic amine receptors and poor pharmacokinetic properties. The realization of their full potential necessitates continued advancements in DR ligands as investigative tools. This review aims to highlight the recent developments made in the chemical biology of DR ligands (e.g., bivalent ligands, photoactivatable ligands, photoswitchable probes, and fluorescent probes).},
}
@article {pmid42368154,
year = {2026},
author = {Sha, J and Geng, Z and Qi, S and Du, L and Hu, Q and Cai, M and Chen, D and Chen, Y and Liu, S and Song, H and Ling, T and Chang, C and Bai, B},
title = {Characterization of the Anti-Alzheimer Drug Lecanemab by Mass Spectrometry.},
journal = {ACS omega},
volume = {11},
number = {24},
pages = {35903-35912},
pmid = {42368154},
issn = {2470-1343},
abstract = {Lecanemab is a humanized mouse monoclonal antibody that is clinically approved for treating Alzheimer's disease by binding to amyloid oligom