@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.},
}

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

@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.},
}

Humans
*Alzheimer Disease/blood/diagnosis
*Biomarkers/blood
Primary Health Care

@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.

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.

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 (β = 0.44, 95% CI 0.16-0.73, p = 0.0025) and CSF (β = 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).

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.},
}

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

@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 & 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.

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)).

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.

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.

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.

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 São 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.

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.

DATA SOURCES: The search was carried out across Embase, PsycInfo, and Ovid Medline databases.

STUDY SELECTION: Of an initial return of 1,001 articles, 142 remained after title and abstract review, and 21 after full text review.

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.

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.

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 & 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 & dosage/toxicity ; Drosophila melanogaster ; Larva/drug effects ; Administration, Oral ; *Drosophila Proteins/administration & 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.},
}

Animals
*tau Proteins/administration & dosage/toxicity
Drosophila melanogaster
Larva/drug effects
Administration, Oral
*Drosophila Proteins/administration & dosage
Apoptosis/drug effects
Reactive Oxygen Species/metabolism
Pupa/drug effects

@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, Innovación 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.},
}

*Alzheimer Disease/genetics/pathology/metabolism
*Microglia/metabolism/pathology
Humans
Animals
*Aging/genetics
Mice
*DNA Transposable Elements/genetics
Aged, 80 and over
Mice, Transgenic
Female

@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.},
}

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

@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 & 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.},
}

Humans
*Alzheimer Disease/prevention & control/metabolism/therapy/physiopathology
*Homeostasis
*Brain/metabolism/physiopathology
*Exercise/physiology
Animals
Inflammation
*Regeneration
Aging

@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.},
}

*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

@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 & 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.},
}

Humans
*Alzheimer Disease/diet therapy/metabolism/prevention & control
*Oxidative Stress/physiology
Antioxidants
Gastrointestinal Microbiome
*Neuroprotection
Animals
Brain/metabolism
*Diet
Polyphenols
*Neuroprotective Agents

@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.},
}

Humans
*Alzheimer Disease/metabolism/drug therapy/blood
*Adiponectin/metabolism/blood
*Vitamin D/pharmacology
*Cysteine/pharmacology
Oxidative Stress/drug effects
Animals
Signal Transduction
Dietary Supplements

@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.},
}

*Alzheimer Disease/microbiology/metabolism
Humans
*Gastrointestinal Microbiome/physiology
Fatty Acids, Volatile/metabolism
Animals
Diet
Brain/metabolism

@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.},
}

*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

@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.},
}

*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

@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.},
}

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

@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 & 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.},
}

Humans
*Cholinesterase Inhibitors/pharmacology/chemistry/chemical synthesis
*Alzheimer Disease/drug therapy
Molecular Docking Simulation
Butyrylcholinesterase/metabolism/chemistry
*Cannabidiol/chemistry/pharmacology/analogs & 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

@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.},
}

*Alzheimer Disease/drug therapy/metabolism
*Kynurenine/metabolism
*Molecular Docking Simulation
Humans
Pilot Projects
Cholinesterase Inhibitors/chemistry/pharmacology
Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism/chemistry

@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.},
}

Humans
Oxidation-Reduction
*Neurodegenerative Diseases/metabolism/pathology
*Aging/metabolism
Animals
Oxidative Stress
Glutathione/metabolism
NAD/metabolism
NADP/metabolism
Mitochondria/metabolism

@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.},
}

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

@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.},
}

*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

@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.},
}

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

@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.},
}

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

@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.},
}

*Alzheimer Disease/drug therapy/metabolism/pathology
Humans
Computer Simulation
Amyloid beta-Peptides/metabolism
Donepezil/therapeutic use/pharmacokinetics
Memantine/therapeutic use/pharmacokinetics

@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.},
}

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

@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.},
}

Animals
Humans
*Cytochrome P-450 Enzyme System/metabolism
Holoenzymes/metabolism
Heme Oxygenase-1/metabolism
Heme/metabolism
*Nervous System Diseases/metabolism/pathology
Iron/metabolism

@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.},
}

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

@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.},
}

*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

@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 & 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.

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.

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-Aβ40 antibodies in CSF.

DISCUSSION: ABvac40 showed favorable long-term safety and durable immunogenicity, supporting further clinical development.

TRIAL REGISTRATION: ClinicalTrials.gov: NCT03461276, registered March 2, 2018. EudraCT: 2016-004352-30, registered March 10, 2017.},
}

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

@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.

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.

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 & 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).

METHODS: Subjects were divided into three groups: cognitively unimpaired (CU) (without subjective cognitive decline [SCD]) (n = 113), CU with SCD (n = 152), and mild cognitive impairment (MCI, n = 45). Plasma assays for amyloid beta (Aβ) 40, Aβ42, 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.

RESULTS: Biomarker levels were regressed by cognitive group, age, sex, race, and apolipoprotein E apoE ε4 status, yielded significant positive associations between age and numerous AD, neuroinflammation, cytokine, and BBB plasma markers.

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 & 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.

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.

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.

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 & 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.

METHODS: Exploratory (n = 470) and confirmatory factor analyses (n = 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 = 445) completed the Virtual Supermarket Test (VST) to assess convergent validity. Normative data were reported stratified by age and sex.

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.

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 & 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.

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.

RESULTS: Global gray-to-white matter CL best stratified amyloid status and BAPL scores, yielding CL thresholds of < 21 and > 38 and high diagnostic accuracy.

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.},
}

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

@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 & inhibitors/metabolism ; *Carbonic Anhydrase II/antagonists & 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.},
}

*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 & inhibitors/metabolism
*Carbonic Anhydrase II/antagonists & inhibitors/metabolism
*Carbonic Anhydrase Inhibitors/chemical synthesis/pharmacology/chemistry
Molecular Structure
Humans
Molecular Dynamics Simulation
*Biphenyl Compounds/chemistry/pharmacology/chemical synthesis
Animals

@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 & 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.

METHODS: We analyzed harmonized Global Neurodegeneration Proteomics Consortium (GNPC) plasma proteomics. Protected ε4 carriers (ε3/ε4 ≥75 years; ε4/ε4 ≥65 years; Clinical Dementia Rating [CDR] score = 0; n = 456) were compared with ε4 carriers with AD (n = 1096). Protein-wise models adjusted for age, sex, ε4 dosage, and plasma proteomic principal components. Top signals were integrated with loss-of-function burden testing and plasma/cerebrospinal fluid Mendelian randomization.

RESULTS: Protected ε4 status was associated with 721 protein measures. Integrated analyses prioritized LILRA5, DBI, BPNT1, PTEN, EPHA1, and PCDH10 as ε4-modified candidates and OMG, SELENOW, VAT1, and TPPP3 as broader AD-related signals. TREM2 and ACE were also identified.

DISCUSSION: This strategy highlights immune, synaptic, metabolic-stress, and myelin/axonal pathways that may delay AD onset.},
}

*Alzheimer Disease/genetics/blood
Humans
*Proteomics
*Apolipoprotein E4/genetics
Female
Male
Heterozygote
Aged
Age of Onset
Biomarkers/blood

@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 & 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 & 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.

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.

RESULTS: A total of 413 patients undergoing surgical treatment for HFs were included. The mean age of the patients was 80±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.

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.},
}

Humans
Female
*Hip Fractures/surgery/mortality/blood
Aged, 80 and over
Male
*Erythrocyte Indices
Aged
*Frailty/mortality
Intensive Care Units/statistics & numerical data
Hospital Mortality
Prognosis
Turkey

@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.

PURPOSE: To investigate the impact of DL-based enhancement applied to diagnostic quality structural MRI for Alzheimer's disease (AD) classification.

STUDY TYPE: Retrospective.

POPULATION: A total of 2293 brain MRI scans from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were split into training (n = 1605), validation (n = 229), and internal test (n = 459) sets. Two hundred and seventy scans from the National Alzheimer's Coordinating Center (NACC) served as an external test set.

FIELD STRENGTH/SEQUENCE: 1.5 T; 3D T1-weighted gradient-echo.

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%).

STATISTICAL TESTS: McNemar test for accuracy and DeLong test for macro-AUC in three-class one-versus-rest setting (p < 0.05).

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 = 0.18) and macro-AUC from 0.978 to 0.982 (p = 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).

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.

EVIDENCE LEVEL: 3.

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.

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.

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.

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},
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.

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.

CONCLUSION: A significant association was found between periodontitis and MCI, Alzheimer's disease and dementia with a "very low" evidence certainty.},
}

Humans
*Alzheimer Disease
*Cognitive Dysfunction/etiology/complications
*Periodontitis/complications
*Dementia/etiology
Risk Factors

@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 Investigación y Desarrollo/ ; FONDECYT Regular Grant No. 1241502//Agencia Nacional de Investigación y Desarrollo/ ; FONDECYT Regular Grants No. 1251980//Agencia Nacional de Investigación y Desarrollo/ ; FONDECYT Regular Grant No. 1261188//Agencia Nacional de Investigación 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.},
}

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

@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.},
}

Animals
*Receptors, G-Protein-Coupled/metabolism
Humans
*Neuroinflammatory Diseases/metabolism/drug therapy
*Molecular Targeted Therapy
Microglia/metabolism
*Inflammation/metabolism

@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.},
}

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

@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.

OBJECTIVE: To investigate associations of blood biomarkers of AD with global and domain-specific cognitive decline.

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.

MAIN OUTCOMES AND MEASURES: Baseline biomarkers, including amyloid β 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 ε4 status.

RESULTS: In the 2008 participants (mean [SD] age at baseline, 71.7 [10.1] years; 1215 female [60.5%]) included, associations with rate of change were observed across all cognitive domains for amyloid β 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 ε4 carriers vs noncarriers (β = -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-ε4 carriers (β = -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 (β = -0.023 [95% CI, -0.029 to -0.018] and -0.021 [95% CI, -0.028 to -0.015], respectively).

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.},
}

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

@article {pmid42593792,
year = {2026},
author = {Vigneswaran, S and Verberk, IMW and Boonkamp, L and In 't Veld, L and Koel-Simmelink, MJA and Antwi-Berko, D and van Unen, L and Rousset, R and Claessen, T and Zwan, MD and Ossenkoppele, R and Wilson, D and Lemstra, AW and Pijnenburg, YAL and van der Flier, WM and Muller, M and Mattace-Raso, F and Papma, JM and Seelaar, H and Teunissen, CE and van Harten, AC},
title = {Plasma Alzheimer Biomarkers and Diagnostic Decision-Making in Memory Clinics.},
journal = {JAMA network open},
volume = {9},
number = {8},
pages = {e2628864},
doi = {10.1001/jamanetworkopen.2026.28864},
pmid = {42593792},
issn = {2574-3805},
mesh = {Humans ; *Biomarkers/blood ; Female ; Male ; *Alzheimer Disease/diagnosis/blood ; Prospective Studies ; Glial Fibrillary Acidic Protein/blood ; Aged ; tau Proteins/blood ; Neurofilament Proteins/blood ; Netherlands ; Lewy Body Disease/diagnosis/blood ; Frontotemporal Lobar Degeneration/diagnosis/blood ; Middle Aged ; *Clinical Decision-Making ; },
abstract = {IMPORTANCE: Blood-based biomarkers (BBM) provide minimally invasive, scalable, lower-cost tools for identifying neurodegenerative diseases, but prospective data on their clinical validity in memory clinic settings are limited.

OBJECTIVE: To evaluate how a tailored plasma BBM panel (phosphorylated tau 181 [pTau181], glial fibrillary acidic protein [GFAP], and neurofilament light chain [NfL]) during multidisciplinary diagnostic meetings is associated with syndrome diagnosis, suspected etiology, and clinician confidence.

This prospective diagnostic study enrolled consecutive patients whose BBM were presented during weekly multidisciplinary meetings after standard workup (clinical assessment, neuropsychological testing, and brain magnetic resonance imaging) from September 2023 to October 2024 at 3 academic memory clinics in the Netherlands. When available, cerebrospinal fluid (CSF) and amyloid positron emission tomography (PET) results were subsequently shown. Findings were categorized as high, intermediate, or low probability for Alzheimer disease (AD), frontotemporal lobar degeneration (FTD), or dementia with Lewy bodies (DLB). Data were analyzed from December 2024 to July 2025.

EXPOSURES: BBM (pTau181, GFAP, and NfL) measured weekly and analyzed jointly as a diagnostic panel.

MAIN OUTCOMES AND MEASURES: Outcomes of interest were changes in suspected syndrome diagnoses, primary etiology, and clinician confidence before vs after BBM disclosure.

RESULTS: A total of 450 patients (mean [SD] age, 66 [10] years; 183 [41%] female; mean [SD] MMSE score, 25 [5]) were enrolled. Among 356 patients (79%) with AD as the primary suspected etiology, assessment of BBM classified 149 patients (42%) as high, 101 patients (28%) as intermediate, and 106 patients (30%) as low probability of AD. Median (IQR) diagnostic confidence in the total cohort increased from 80% (70%-90%) to 90% (70%-90%) after BBM disclosure (P < .001), increasing in 207 patients (46%), unchanged in 175 patients (39%), and decreasing in 68 patients (15%). Following BBM disclosure, syndrome diagnoses were revised in 6 patients (1%) and primary etiology was revealed in 23 patients (5%): 11 diagnoses (2%) shifted to AD, 3 diagnoses (1%) from AD to no neurodegeneration, 2 diagnoses (<1%) from AD to FTD, and 7 diagnoses (2%) became unclear. Among 450 patients, 234 (52%) had CSF and amyloid PET results. Using this as reference, BBM analyzed with an amyloid-positive vs amyloid-negative tool identified 76% amyloid positives and 85% amyloid negatives for high- and low-probability results, respectively; intermediate results occurred in 24% and 39%, respectively.

CONCLUSIONS AND RELEVANCE: In this prospective diagnostic study, a BBM panel was associated with altered etiologic diagnoses in a few patients and was associated with increased diagnostic confidence overall. These findings suggest that BBM may help refine the diagnostic process within specialized academic memory clinics.},
}

Humans
*Biomarkers/blood
Female
Male
*Alzheimer Disease/diagnosis/blood
Prospective Studies
Glial Fibrillary Acidic Protein/blood
Aged
tau Proteins/blood
Neurofilament Proteins/blood
Netherlands
Lewy Body Disease/diagnosis/blood
Frontotemporal Lobar Degeneration/diagnosis/blood
Middle Aged
*Clinical Decision-Making

@article {pmid42593973,
year = {2026},
author = {Brown, CK and Chen, EY and Chen, KH and Wells, JL and Scheffer, JA and Sturm, VE and Levenson, RW},
title = {Interpersonal emotion regulation in dementia: Diagnostic differences and associations with caregiver mental health.},
journal = {Emotion (Washington, D.C.)},
volume = {},
number = {},
pages = {},
doi = {10.1037/emo0001724},
pmid = {42593973},
issn = {1931-1516},
support = {/AG/NIA NIH HHS/United States ; },
abstract = {Close relational partners play a critical role in shaping each other's emotions during social interactions, a process known as interpersonal emotion regulation. We examined how different forms of dementia (i.e., Alzheimer's disease, behavioral variant frontotemporal dementia, primary progressive aphasia) affect interpersonal emotion regulation. We assessed how caregivers perceived their partners' prosocial regulatory efforts and tracked real-time changes in caregivers' affect during a dyadic interaction. We also investigated how these processes relate to caregivers' mental health. Informal caregivers (N = 62) reported on their own mental health symptoms (depression, anxiety) and how their care recipients, who had different forms of dementia, use prosocial interpersonal emotion regulation (i.e., efforts to make their partner feel better). Dyads then engaged in a 10-min unrehearsed discussion about a conflict in their relationship. Following this, caregivers viewed a video recording of the interaction and used a rating dial to provide continuous ratings of their own affective valence (negative-neutral-positive) during the conversation. Results revealed that among care recipients with Alzheimer's disease, primary progressive aphasia, and behavioral variant frontotemporal dementia, those with behavioral variant frontotemporal dementia showed the lowest use of prosocial interpersonal emotion regulation, and their caregivers experienced the greatest increases in negative affect during the interaction. Across diagnoses, greater increases in caregiver negativity during the interaction were associated with greater caregiver depression (but not anxiety). These findings provide new information about interpersonal emotion regulation in dementia and highlight how the emotional changes that occur during dyadic interactions are tied to caregiver depressive symptoms. (PsycInfo Database Record (c) 2026 APA, all rights reserved).},
}

@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.},
}

Humans
*Dementia/epidemiology
*Central Nervous System Sensitization/physiology
Sleep Wake Disorders/epidemiology
Risk Factors

@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.},
}

*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

@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&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.

DESIGN: Retrospective observational study.

SETTING AND PARTICIPANTS: Long-stay US NH residents.

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 ≥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 ≥1% difference in prevalence and ≥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.

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 ≥3 central nervous system-active drugs.

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.

METHODS: Participants who had structural magnetic resonance imaging and post-mortem pathology, with an interval of ≤ 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.

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.

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 & 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.

METHODS: We analyzed data from a community-based sample of Black adults aged ≥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.

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.

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.

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.

RESULTS: 238 caregivers (65.9% women; mean age 59.6 ± 12.4 years) and 238 care-recipients (153 women; mean age 77.5 ± 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.

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.},
}