@article {pmid42435764,
year = {2026},
author = {Zhang, C and Zhang, J and Wang, Y and Wang, Y and Lin, P and Wang, Y and Tang, Z and Yu, J and Zhou, Q and Cui, F},
title = {Neuron-Targeted Exosomal Delivery of siRNA Against RIPK3 Slows Neurodegenerative Progression in Alzheimer's Disease.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e76558},
pmid = {42435764},
issn = {2198-3844},
support = {2023YFA1801900//National Key R&D Program of China/ ; 82572678//National Natural Science Foundation of China/ ; JJ2024YX0560//Natural Science Foundation of Heilongjiang Province/ ; 2022CY CX0202//"Spring Goose" Talent Team Support Program of Heilongjiang Province/ ; 21032240006//Funding Program for Preferential Returned Scholars of Heilongjiang Province/ ; 20240NTJ 018//Young Elite Scientist Sponsorship Program of Heilongjiang Province/ ; },
abstract = {A major challenge in RNA therapeutics for central nervous system disorders is the lack of delivery systems capable of crossing the blood-brain barrier (BBB) while achieving cell-type-specific targeting. Herein, we develop an engineered exosomal siRNA delivery platform for systemic, neuron-targeted RNA transport to the brain. The platform leverages exosomes derived from an immortalized mouse hippocampal neuronal cell line as a biomimetic and functionally privileged material source, enhancing neuronal uptake and intracellular delivery efficiency. Through surface functionalization with a rabies virus glycoprotein-derived peptide, the system enables receptor-mediated BBB transcytosis and programmable siRNA loading. In human cortical organoids, the platform achieves efficient cytosolic delivery and robust gene silencing in neurons, demonstrating high delivery precision and bioavailability. As a proof of concept, targeting receptor-interacting protein kinase 3 (RIPK3) modulates necroptosis, a key pathway in inflammatory neurodegeneration. In transgenic mouse models, systemic administration suppresses RIPK3/MLKL signaling, reduces neuronal loss, and alleviates neuroinflammation and tau-associated pathology. Transcriptomic analyses further indicate stabilization of neuronal homeostasis across vulnerable brain regions. Collectively, the study establishes a modular and programmable exosomal RNA delivery platform and highlights age-defined, cell-derived biomaterials as a generalizable strategy for overcoming delivery barriers in neurological diseases.},
}

@article {pmid42435857,
year = {2026},
author = {Yagi, Y and Oda, S and Tatsumi, H},
title = {Cellular Basis of Medium Flow-Mediated Reduction of Aβ Neurotoxicity in Cultured Neurons.},
journal = {Neuroscience research},
volume = {},
number = {},
pages = {105090},
doi = {10.1016/j.neures.2026.105090},
pmid = {42435857},
issn = {1872-8111},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by elevated concentrations of amyloid β1-42 (Aβ1-42) in the brain, where it exerts neurotoxic effects. A recent study demonstrated that medium flow at approximately 10 μm/s reduces Aβ1-42 neurotoxicity in explant brain cultures containing neurons and beating ependymal cilia; however, the underlying mechanisms remain unclear. Neurons migrating from the explant and located within 300 μm of the beating cilia were exposed to cilia-generated medium flow, allowing analysis of Aβ1-42 toxicity under fluid flow conditions. Aβ1-42-containing putative EV-related extracellular particles (putative EV-related Eps), with diameters of 100-400nm were detected in the culture medium and exhibited neurotoxic effects. Pharmacological inhibition of EV release and endocytosis reduced intracellular accumulation of Aβ1-42 and attenuated neuronal toxicity. Under medium flow, fewer putative EV-related EPs bound to neurons, and their binding duration was significantly shortened. Rhodamine-conjugated concanavalin A staining revealed enhanced cell-surface glycan labeling in damaged neurons on the non-ciliated side compared with neurons on the ciliated side. These results suggest that shear stress reduces neuronal accumulation of Aβ1-42-containing putative EV-related EPs, likely through modulation of cell-surface glycosylation composition.},
}

@article {pmid42435996,
year = {2026},
author = {Shang, Y and Zhai, Z and Cong, L and Dong, X},
title = {Targeting the APOE4-driven peripheral-central immune axis: A new frontier for Alzheimer's disease therapy.},
journal = {Pharmacological research},
volume = {231},
number = {},
pages = {108339},
doi = {10.1016/j.phrs.2026.108339},
pmid = {42435996},
issn = {1096-1186},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder and a growing global health challenge. Despite decades of research dominated by the amyloid cascade hypothesis, single-target therapies aimed at Aβ or tau have largely failed, underscoring the need for a broader framework. Emerging evidence implicates neuroimmune dysfunction as a central driver of AD pathology, with the "peripheral-central immune axis" emerging as a critical node. The APOE4 allele, the strongest genetic risk factor for sporadic AD, plays a pivotal role in both central nervous system (CNS) lipid metabolism and peripheral immune homeostasis. This review synthesizes the association between APOE4 and peripheral immune dysregulation and its impact on neurodegeneration. We discuss APOE expression in CNS and peripheral immune cells, highlighting APOE4-associated alterations in monocyte/macrophage polarization, T cell subsets via IL-7/IL-7R downregulation, and gut microbiota composition. We delineate mechanisms by which APOE4 is associated with blood-brain barrier compromise, may promote conditions for immune cell trafficking, and contributes to neuroinflammation. Integrating preclinical and clinical evidence, we propose an "APOE4-associated peripheral-central immune infiltration cascade" as a unifying framework for understanding systemic AD pathogenesis. Finally, we review emerging therapeutic strategies targeting peripheral immunity and APOE, discussing multi-target approaches guided by APOE genotype and immune biomarkers, shifting from a CNS-centric toward a systemic immunomodulatory paradigm for precision medicine.},
}

@article {pmid42436002,
year = {2026},
author = {Han, J and Wu, S and Cui, X and Zhou, X and Yu, Q and Cheng, Q and Lu, Z and Zong, S},
title = {CAPNS1 restoration partially alleviates mitochondrial dysfunction and synaptic deficits in Alzheimer's disease through the Ca2[+]-CaMKIIβ-MAPK-PGC-1α axis.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.07.021},
pmid = {42436002},
issn = {1873-7544},
abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by brain atrophy and cognitive decline. While the amyloid cascade hypothesis remains the dominant framework, accumulating evidence indicates that mitochondrial dysfunction critically contributes to AD progression. Although improving mitochondrial function has been shown to rescue cognitive deficits in AD models, the underlying molecular mechanisms remain elusive. In this study, we identified a significant reduction in calpain small subunit 1 (CAPNS1) expression in both AD patient samples and male transgenic mouse models. Decreased CAPNS1 levels were strongly correlated with mitochondrial ultrastructural damage, reduced mitochondrial DNA (mtDNA) copy number, and progressive synaptic loss. Mechanistically, we found that CAPNS1 positively regulated mtDNA transcription and mitochondrial gene expression, and pharmacological data suggested the involvement of the Ca[2][+]-CaMKIIβ-MAPK-PGC-1α signaling axis, a master pathway governing mitochondrial biogenesis and respiratory capacity. This activation subsequently restored cellular ATP production and reduced mitochondrial reactive oxygen species accumulation. Importantly, neuronal-specific CAPNS1 upregulation in APP/PS1 transgenic mice markedly improved mitochondrial cristae integrity, reversed hippocampal long-term potentiation deficits, increased dendritic spine density, and partially alleviated spatial memory deficits in behavioral tests. We noted that loss-of-function experiments (e.g., CAPNS1 knockdown or knockout) were not performed in this study, and the proposed Ca[2][+]-CaMKIIβ-MAPK-PGC-1α axis should therefore be interpreted as a suggestive working model requiring further validation. Collectively, our findings indicate that CAPNS1 serves as a key regulator of mitochondrial function. By linking Ca[2][+] signaling to mitochondrial gene expression and synaptic integrity, CAPNS1 represents a promising therapeutic target for ameliorating synaptic loss and cognitive decline in AD.},
}

@article {pmid42436132,
year = {2026},
author = {Da Silva Oliveira, B and Innocenti, M and Granucci, F},
title = {Calcineurin/NFAT signaling in the temporal integration of Ca[2+] stress in neurodegeneration.},
journal = {Cell death discovery},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41420-026-03251-3},
pmid = {42436132},
issn = {2058-7716},
abstract = {The calcineurin (CaN)/nuclear factor of activated T cells (NFAT) signalling axis is a Ca[2+]-responsive pathway that translates intracellular Ca[2+] signals into long-term transcriptional programmes. Chronic disruption of intracellular Ca[2+] homoeostasis is a convergent feature of neurodegenerative disorders, particularly Alzheimer's disease (AD) and Parkinson's disease (PD). In these conditions, sustained or repetitive Ca[2+] elevations promote prolonged activation of the CaN/NFAT pathway, thereby linking Ca[2+] dysregulation to persistent cellular responses. In this review, we summarise the molecular organisation and regulation of the Ca[2+]/CaN/NFAT pathway and discuss its physiological roles in neurons and glial cells, including synaptic plasticity, neurodevelopment, neurogenesis, and neuroinflammatory responses. We critically examine experimental evidence linking CaN/NFAT signalling to AD and PD, distinguishing direct mechanistic roles from associative and model-dependent findings. Across disease contexts, the CaN/NFAT axis appears to function as a molecular node at which diverse insults, including amyloid-β and tau aggregates, α-synuclein toxicity, mitochondrial dysfunction, and chronic inflammatory cues, converge under conditions of sustained Ca[2+] dysregulation. We propose that the pathological relevance of CaN/NFAT lies less in pathway activation per se than in its capacity to convert chronic Ca[2+]-dependent stress signals into persistent transcriptional states affecting synaptic integrity, inflammatory tone, and cellular resilience. We conclude by discussing current therapeutic strategies targeting this pathway, their limitations, and the need for temporally and cell-type-specific modulation.},
}

@article {pmid42436138,
year = {2026},
author = {Li, CH and Cheng, TW and Lin, CH},
title = {Plasma pTau217 and pTau231 predict progression to dementia in Parkinson's disease: a prospective longitudinal study.},
journal = {NPJ Parkinson's disease},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41531-026-01469-7},
pmid = {42436138},
issn = {2373-8057},
support = {114-BIH019//National Taiwan University Hospital Hsinchu Branch/ ; 114-2314-B-002 -119 -MY3//National Science and Technology Council/ ; },
abstract = {This prospective study evaluated the prognostic utility of Alzheimer's disease-related plasma biomarkers (phosphorylated tau [pTau217 and pTau231], the amyloid-β [Aβ] 42/40 ratio) and neurofilament light chain (NfL) in 123 Parkinson's disease (PD) patients and 40 controls. Over a mean 5.1-year follow-up, 35 of 109 initially non-demented PD patients (32.1%) progressed to dementia. Plasma pTau217 and NfL levels were elevated, whereas the Aβ42/40 ratio was reduced, in cognitively impaired PD groups versus controls. Baseline pTau217 accurately differentiated dementia converters from non-converters (AUC = 0.877; 95% CI: 0.798-0.956). Patients with pTau217 ≥ 0.268 pg/mL had a higher risk of dementia progression (HR: 5.49; 95% CI: 2.37-12.74). This risk was further elevated in patients in the highest quartile (≥ 0.36 pg/mL; HR: 11.35; 95% CI: 2.60-49.59) versus the lowest quartile (< 0.20 pg/mL). Similarly, the pTau231 cut-off (≥ 2.575 pg/mL) predicted an increased risk of dementia (HR: 3.89; 95% CI: 1.67-9.03). Both pTau217 and pTau231 demonstrated high predictive performance in Cox models (C-index: 0.806 and 0.796, respectively). Plasma NfL exhibited longitudinal increases during follow-up. Baseline plasma pTau217 and pTau231 serve as surrogate markers for predicting dementia progression in PD. Further validation of these biomarker cut-off values is warranted.},
}

@article {pmid42436226,
year = {2026},
author = {Onishchenko, D and Mastrianni, JA and Chattopadhyay, I},
title = {Passive early screening for Alzheimer's disease and related dementias using EHR comorbidity patterns.},
journal = {NPJ digital medicine},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41746-026-02954-2},
pmid = {42436226},
issn = {2398-6352},
support = {852418/ALZ/Alzheimer's Association/United States ; P30 AG066619/AG/NIA NIH HHS/United States ; },
abstract = {Early identification of Alzheimer's disease and related dementias (ADRD) remains limited by specialized tests and late-stage diagnosis. The Zero-burden Risk Assessment (ZeBRA) is an AI-driven score that predicts incident ADRD up to a decade before diagnosis using only routine electronic health record (EHR) data, without laboratory tests, imaging, or questionnaires. Trained on 487,989 cases and 12,483,718 controls from nationwide U.S. insurance claims and validated on held-out National samples and two independent cohorts, ZeBRA achieved AUC = 0.93 and 0.83 in the 50+ cohort for 1-year and 10-year horizons, respectively, with positive likelihood ratios exceeding 10 in the National 50+ held-out cohort at 95% specificity and stable discrimination over time. Performance was consistent across age, sex, race, and ethnicity subgroups. In a prospective feasibility pilot, higher ZeBRA scores showed concordance with lower Montreal Cognitive Assessment (MoCA) scores, indicating greater cognitive impairment (R = -0.78, 95% CI: -0.94 to -0.37). Compared with prior EHR-based models, ZeBRA provides superior accuracy, cross-site generalizability, and noise-corrected interpretability via our novel Λ-OR attribution metric. Scalability and low burden suggest application in population-level early detection and presymptomatic trial enrichment.},
}

@article {pmid42436274,
year = {2026},
author = {Maserati, MS and Zama, F},
title = {Quantifying golden-ratio deviations in the tree drawing test to identify patients with Alzheimer's disease.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-61257-4},
pmid = {42436274},
issn = {2045-2322},
abstract = {The golden ratio ([Formula: see text]) exhibits unique autosimilarity properties that appear throughout biological systems, including human physiology and neural organization. The Tree Drawing Test (TDT), a simple cognitive assessment tool that mainly implies visuospatial, praxic and executive functions, may capture φ-based organizational principles that become disrupted in neurodegenerative conditions. This study examined the relationship between golden ratio proportions and cognitive impairment in tree drawings through quantitative analysis of a large cohort of cognitively impaired patients. We evaluated 613 Alzheimer's disease (AD) patients, 328 mild cognitive impairment (MCI) patients, and 438 healthy controls who completed the TDT. Five novel golden ratio-based deviation indices were developed to quantify proportional relationships between trunk and crown dimensions; among these, the trunk-based index [Formula: see text]showed the most consistent group separation (Distance-to-Diameter Ratio [Formula: see text]; Fisher Ratio [Formula: see text]), with all three pairwise diagnostic comparisons reaching [Formula: see text] (Mann-Whitney U, Bonferroni-corrected) in the full sample and across sex and education strata. Within a multinomial logistic regression framework with stratified 5-fold cross-validation, [Formula: see text]retained independent discriminative value after adjustment for age, education, and the established Space Occupation (SO) index, reaching a macro-averaged AUC of 0.834 (AD vs. rest: 0.855, 95% CI [Formula: see text]; CNTRL vs. rest: 0.911, 95% CI [Formula: see text]; MCI vs. rest: 0.736); the Likelihood Ratio Test confirmed that [Formula: see text]contributes information not captured by SO, age, and education combined ([Formula: see text], [Formula: see text]), and convergent results under two independent matched-subgroup strategies indicated that age and education differences do not explain this signal. Pre-specified operational cut-offs derived from the cohort yielded clinically interpretable sensitivity/specificity trade-offs, with AUC [Formula: see text] [0.894, 0.927] for healthy-control identification using the full multivariate model. As a secondary descriptive observation, group means of [Formula: see text]approximated the Fibonacci values F(5), F(7), F(9); a permutation-based null model (B [Formula: see text], [Formula: see text]) and a Fibonacci-vs-Lucas specificity comparison (100% vs. 0% confidence-interval containment) indicated that this alignment is unlikely to arise by chance and is specific to φ-convergent sequences, although the algebraic link between [Formula: see text]and φ implies that this finding should be regarded as a starting point for future studies rather than as proof of a biological mechanism. Within these limitations, golden-ratio-based TDT measures provide a quantitative complement, not a replacement, to traditional TDT indices for cognitive impairment assessment and require confirmation in independent multi-centre samples before clinical adoption.},
}

@article {pmid42436416,
year = {2026},
author = {Tang, L and Wu, N and Zhu, Y and Xu, H and Mo, Y},
title = {Bioinformatic analysis of differentially expressed mitochondrion-related genes, immune cell infiltration, and diagnostic value in Alzheimer's disease.},
journal = {BMC neurology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12883-026-05144-5},
pmid = {42436416},
issn = {1471-2377},
support = {2024Y12//2024 Ningbo Municipal Health Science and Technology Plan Project/ ; },
abstract = {BACKGROUND: Mitochondrial dysfunction and neuroinflammation are critically implicated in the pathogenesis of Alzheimer's disease (AD). However, a systematic exploration of key mitochondrion-related genes (MRGs) in AD, and their specific roles in reshaping the immune microenvironment and serving as diagnostic biomarkers, remains insufficient.

METHODS: To address this, we conducted an integrative bioinformatics analysis. Differentially expressed MRGs were identified from public AD transcriptomic datasets. Their biological functions were elucidated through enrichment analyses. The correlations between core MRGs and ssGSEA-derived immune-cell signature enrichment scores were quantified using transcriptome-based computational analysis. Finally, machine learning models were constructed and validated to assess the diagnostic potential of identified MRG signatures.

RESULTS: A robust set of dysregulated MRGs was identified in AD brains, showing predominant enrichment in pathways of oxidative phosphorylation and energy metabolism. Notably, the expression of key MRGs correlated significantly with altered infiltration abundances of specific immune cell types, including neutrophil-, eosinophil-, NK CD56bright cell-, and T follicular helper cell-related signatures. A diagnostic model constructed from a refined MRG signature exhibited promising predictive accuracy, with area under the curve (AUC) values reaching approximately 0.82 in the training cohort and around 0.74 in independent validation cohorts.

CONCLUSION: Our study defines a novel landscape of MRGs in AD, deciphers their tight crosstalk with the immune microenvironment, and establishes a promising MRG-based signature for AD diagnosis. These findings provide fresh insights into the potential molecular interplay between mitochondrial dysfunction and neuroinflammation in AD and nominate candidate mitochondrion-related biomarkers and regulatory mechanisms that warrant further experimental and clinical validation.},
}

@article {pmid42436528,
year = {2026},
author = {Abzhandadze, T and Hoang, MT and Bao, X and Åkerman, M and Norgren, J and García Pascual, B and Mo, M and Eriksdotter, M and Xu, H and Garcia-Ptacek, S},
title = {Thresholds for meaningful change in Mini-Mental State Examination scores in rare dementias.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02136-y},
pmid = {42436528},
issn = {1758-9193},
abstract = {BACKGROUND: We conceptualize the Real-World Reassessment Threshold (RWRT) as representing the smallest change that exceeds expected measurement variability while accounting for clinically expected cognitive decline over the assessment interval, whereas the minimum clinically important difference (MCID) indicates the smallest change likely to be clinically meaningful. To date, no study has empirically defined the RWRT or MCID for Mini-Mental State Examination (MMSE) scores in Lewy body dementia (LBD) or frontotemporal dementia (FTD), limiting the interpretation of longitudinal changes and clinical trial designs. We therefore aimed to estimate 12-month, diagnosis-specific MMSE thresholds for RWRT and MCID among individuals with LBD and FTD, and to evaluate the generalizability of these thresholds in an independent validation cohort.

METHODS: This registry-based cohort study included individuals diagnosed with LBD or FTD from the Swedish Registry for Cognitive/Dementia Disorders (SveDem, 2007-2022) with a 91-400-day MMSE follow-up, and an independent validation cohort from the U.S. National Alzheimer's Coordinating Center (NACC). The RWRT was estimated using distribution-based methods based on intraclass correlation coefficients (ICCs). MCID was estimated using both anchor-based and distribution-based (0.5 standard deviation) approaches.

RESULTS: We included 1,158 individuals from SveDem (873 LBD, 285 FTD) and 1,060 individuals from NACC (469 LBD, 591 FTD). Over the 91-400-day follow-up interval, MMSE scores demonstrated moderate to high reliability (ICC 0.70-0.90), corresponding to RWRT estimates ranged from 5 to 7 MMSE points. Anchor-based MCIDs differed by diagnosis, with a mean threshold of 0.7 points in LBD and 3.8 points in FTD in SveDem; similar diagnosis- and baseline severity-dependent patterns were observed in NACC. In contrast, distribution-based MCIDs were consistent across diagnoses, clustering around 2-3 MMSE points.

CONCLUSIONS: MMSE changes of less than five points over one year may reflect expected test variability combined with expected individual decline. However, average changes of 2-3 points may still be meaningful when combined with a clinical anchor of change, depending on diagnosis and disease stage. These results emphasize the importance of using both RWRT and MCID when evaluating MMSE change and selecting clinical trial endpoints.},
}

@article {pmid42436533,
year = {2026},
author = {Bentivenga, GM and Mammana, A and Baiardi, S and Vittoriosi, E and Mastrangelo, A and Ruggeri, E and Vargiu, CM and Polischi, B and Stanzani-Maserati, M and Rizzo, G and Pantieri, R and Raggi, A and Capellari, S and Parchi, P},
title = {Analytical and clinical validation of a novel proximity extension assay-based plasma biomarker panel in a cohort of prevalent neurodegenerative dementias.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02142-0},
pmid = {42436533},
issn = {1758-9193},
support = {Ricerca Corrente//Ministero della Salute/ ; },
abstract = {BACKGROUND: Blood-based biomarkers are increasingly recognized as promising tools for the diagnosis and monitoring of neurodegenerative diseases, offering a minimally invasive alternative to cerebrospinal fluid (CSF) testing. We evaluated the analytical performance and clinical utility of the Olink Target 48 Neurodegeneration panel, a novel multiplex proteomic platform based on the proximity extension assay (PEA) technology, in a large, clinically diverse dementia cohort.

METHODS: We retrospectively analyzed plasma samples from 238 patients with Alzheimer's disease (AD), dementia with Lewy bodies, frontotemporal dementia, progressive supranuclear palsy, and corticobasal degeneration, along with 65 healthy controls, quantifying 41 proteins in each sample. We assessed analytical performance using intra- and inter-assay coefficients of variation, evaluated diagnostic accuracy through receiver operating characteristic curve analysis, and investigated associations between biomarker levels, clinical severity measures, and pathology-specific CSF biomarkers for AD and Lewy body pathology (LBP) using general linear models.

RESULTS: The platform quantified 32 proteins with variable analytical performance; nine were excluded due to poor detectability. Strong correlations were observed between PEA-based measurements and established immunoassays for plasma pTau217, NEFL, and GFAP (all p < 0.001). Plasma pTau217 demonstrated superior diagnostic accuracy for AD, achieving an area under the curve (AUC) exceeding 0.91 against all comparison groups. Novel ratios combining NEFL with markers of immune function or synaptic integrity (NEFL/ITGB2, NEFL/ITGAM, NEFL/SCG2) achieved AUCs exceeding 0.93 for discriminating patients from controls, significantly outperforming NEFL alone (all p < 0.001). Thirteen proteins, spanning markers of neuroaxonal damage, myelin-associated processes, and immune function (i.e., Abeta40, Abeta42, BMP7, CLSTN3, ENO2, KLK8, MMP10, NEFL, NPTXR, OMG, RTN4R, SCG2, SDC4, all p < 0.01) showed significant independent associations with disease stage as measured by the Clinical Dementia Rating scale. Four proteins (i.e., pTau217, GFAP, SYT1, and SDC4) were significantly associated with AD pathology, while three (ENO2, ITGAM, and ITGB2) showed significant associations with LBP (all p < 0.05).

CONCLUSIONS: This multiplex platform provides multiplex biomarker measurements with potential utility for AD diagnosis and disease staging across neurodegenerative disorders. These findings support further validation studies for its implementation in clinical and research settings.},
}

@article {pmid42436578,
year = {2026},
author = {van Tol, BGJ and Groot, C and Vermeiren, MR and van de Giessen, E and Pijnenburg, YAL and Coomans, EM and Ossenkoppele, R},
title = {A probabilistic framework for clinicopathological Alzheimer's disease using tau-PET.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02133-1},
pmid = {42436578},
issn = {1758-9193},
abstract = {BACKGROUND: [[18]F]flortaucipir tau-PET detects neurofibrillary tangle (NFT) pathology in Alzheimer's disease (AD), one of the core pathological hallmarks of the disease. In clinical settings, tau-PET is usually interpreted qualitatively, and therefore quantitative estimates of how scan results alter the probability that AD explains a patient's symptoms are lacking. Here, we evaluate the probability of clinicopathological AD given a positive or negative tau-PET scan and examine how patient age and amyloid-PET status modulate this probability.

METHODS: We computed positive and negative predictive values (PPV/NPV) of tau-PET for clinicopathological AD, defined as mild cognitive impairment or dementia with AD as the primary etiology. To account for potential pathological and clinicopathological mismatches, PPV and NPV were modeled using literature-derived sensitivity and specificity estimates of [[18]F]flortaucipir PET for postmortem Braak V/VI NFT pathology, together with literature-derived age-dependent tau-PET positivity rates in cognitively unimpaired individuals. We also considered hypothetical clinician-estimated pre-PET AD probabilities. PPV and NPV were calculated for tau-PET and for sequential amyloid- and tau-PET scenarios.

RESULTS: Tau-PET PPV for clinicopathological AD was generally high, particularly in individuals with higher clinician-estimated pre-PET AD probabilities, and showed minor age-related declines (e.g., 84% at ages 50-55 vs. 75% at ages 85-90, at 50% pre-PET probability). Tau-PET NPV was consistently higher than PPV and showed negligible age-related decline (e.g., 92% at ages 50-55 vs. 90% at ages 85-90, at 50% pre-PET probability). A positive tau-PET following positive amyloid-PET substantially increased PPV, particularly in older individuals (e.g., PPV increased from 56% to 83% at ages 75-80 and 30% pre-PET probability), whereas the corresponding gain in NPV after tau-PET following amyloid-PET was smaller.

CONCLUSIONS: Tau-PET demonstrates high PPV and NPV for clinicopathological AD. A positive tau-PET following positive amyloid-PET further increases the probability of clinicopathological AD, particularly in older adults. This underscores tau-PET's clinical utility and highlights the effect of age and pre-PET certainty on post-PET AD probabilities.},
}

@article {pmid42436821,
year = {2026},
author = {Shan, G and Zhang, Y and Ding, AA},
title = {Statistical inference for saved time based on disease progression curves in Alzheimer's disease research.},
journal = {Contemporary clinical trials communications},
volume = {52},
number = {},
pages = {101664},
pmid = {42436821},
issn = {2451-8654},
abstract = {Saved time is an easy interpretation metric that provides information to patients on how long a new treatment can delay the disease progression in time as compared to the placebo. The frequently used projection approach for saved time estimation utilizes limited information from the available data. To address that limitation, the area above the disease progression curve was proposed to estimate saved time by using more information from data. However, it is a challenge to derive the closed-form statistical inference (e.g., confidence interval of saved time) as area above the curve is quadratic relative to visit time and saved time based on the curves is nonlinearly related to the area above the curve. In this article, we derived the closed-form variance of saved time based on the area above curve approach by using Taylor expansion. We then compared the performance of the closed-form method and the existing simulation-based method to construct the confidence interval for saved time based on the area above curve approach with regard to coverage probability and interval width under various scenarios. The simulation results indicate that the proposed closed-form method has similar performance as compared to the existing method, while the closed-form method can be computationally easy in practice without additional simulations in the existing method. Data from the completed phase 2 donanemab trial were used to illustrate the application of the proposed method.},
}

@article {pmid42436978,
year = {2026},
author = {Ishida-Takaku, T and Sohrabi, M and Pecoraro, HL and Combs, CK},
title = {Alzheimer's disease-related mutations in APP influence colorectal tumor formation in a sex-dependent manner.},
journal = {iScience},
volume = {29},
number = {7},
pages = {116645},
pmid = {42436978},
issn = {2589-0042},
abstract = {Cancer and Alzheimer's disease (AD) are age-associated diseases. Studies have indicated common mechanisms and interactions between these conditions. Epidemiological data demonstrate negative correlations between several cancers and AD. Despite this, few studies have explored their mutual influence on pathological outcomes. We utilized a human amyloid precursor protein (APP) mutant knock-in AD mouse model to investigate how familial mutations influence colorectal cancer development. Using a colitis-associated colorectal cancer (CAC) model, APP mutations promoted colon tumor formation in male mice but inhibited it in female mice. Correspondingly, inflammatory changes were reduced in the colons of female mice. Transcriptome analysis revealed differential expression, particularly in the enrichment of neuronal marker, steroid hormone, and immune cell signaling pathways. Additionally, distinct macrophage subtypes and neuronal profiles were observed in the colons of male and female APP mutant mice. These findings provide the first elucidation of the sex-dependent effects of APP mutations on colon cancer formation.},
}

@article {pmid42437010,
year = {2026},
author = {Igase, K and Igase, M and Matsuda, H and Hara, J and Bock, JR and Sadamoto, K and Shankle, WR},
title = {Relation between voxel-based specific regional analysis system for Alzheimer's disease (VSRAD) on 3-tesla MRI and cognitive performances: Practical application in clinical settings.},
journal = {IBRO neuroscience reports},
volume = {21},
number = {},
pages = {275-278},
pmid = {42437010},
issn = {2667-2421},
abstract = {BACKGROUND: Voxel-based specific regional analysis system for Alzheimer's disease (VSRAD) software using MRI scanner allows quantification of hippocampal and parahippocampal atrophy in the medial temporal structures by Z-score, and this score is widely used in clinical Alzheimer's disease (AD) diagnosis. However, it is unclear whether the Z-score is useful to discriminate normal aging from cognitive impairment (CI) or mild cognitive impairment (MCI). The present study examined the associations between VSRAD Z-score and cognitive performance quantified by Memory Performance Index (MPI) and determined a Z-score cut-off value.

METHOD: Three-tesla brain MRI was conducted in 100 outpatients without dementia, and all MRI data were analyzed using VSRAD. The target region of interest (ROI) mainly consisted of the para hippocampal gyrus. The degree of atrophy in the ROI was obtained from the averaged positive Z-score of the ROI. Cognitive performance was evaluated with the Japanese version of the MCI screen (MCIS). Patients were classified into normal (NL) and below normal (BNL) cognitive groups by MPI. The relation between MPI and VSRAD Z-score were assessed with logistic regression analysis, and the cut-off value for Z-score was determined by receiver operating characteristic curve analysis.

RESULTS: Sixty-two percent (62%) were identified as the BNL group by MPI. Univariate analyses found that the BNL group had a significantly higher age, shorter years of education, and higher Z-score in VSRAD compared to the NL group, but no statistically significant difference was observed between genders. Bivariate correlation found that MPI, which is adjusted for age, gender, and years of education, was significantly correlated with Z-score assessed by VSRAD (Pearson's r = -0.52, p < .001). A subsequent logistic regression of VSRAD Z-score on BNL classification was used to generate a receiver operating characteristic curve (AUC = 0.75). The Youden index was applied to identify a cut-off value of VSRAD Z-score of 1.14 (sensitivity = 62.9%; specificity = 84.2%) to classify MPI < 50.2 (BNL) with overall accuracy of 73.5%.

CONCLUSIONS: VSRAD Z-score using VSRAD software was one independent factor significantly associated with cognitive performance measured by MPI. The determination of a cut-off value for Z-score (1.14) that can help discriminate normal patients from those with MCI.},
}

@article {pmid42437499,
year = {2026},
author = {Brown, CA and Robinson, JL and Das, SR and McGrew, E and Suh, E and Van Deerlin, VM and Irwin, DJ and Nasrallah, IM and Mechanic-Hamilton, D and Yushkevich, PA and Wolk, DA and Lee, EB},
title = {Clinicopathologic Evaluation of Amyloid Clearance in Alzheimer Disease.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2026.13058},
pmid = {42437499},
issn = {1538-3598},
abstract = {IMPORTANCE: The long-term efficacy of amyloid-targeting therapies hinges on their ability to slow downstream neuropathologic change, but little is known about the influence of amyloid clearance on tau pathology and neurodegeneration.

OBJECTIVE: To determine the postmortem and in vivo association between amyloid levels and downstream neuropathology after treatment with aducanumab in a patient with patchy areas showing minimal residual amyloid levels.

This clinicopathologic case report from a single academic memory center includes a male carrier of the p.R47H TREM2 variant, which is associated with a higher risk of Alzheimer disease, who was in his 50s, had mild cognitive impairment, and received aducanumab while participating in a randomized clinical trial. Fourteen untreated controls, who were matched by age or presence of the TREM2 variant, also are included.

EXPOSURES: The male carrier of the p.R47H TREM2 variant had received 30 doses of aducanumab (cumulative dose of 280 mg/kg) over 4.5 years.

MAIN OUTCOMES AND MEASURES: Neuropathologic evaluation at autopsy, positron emission tomography to measure standardized uptake value ratio as a measure of amyloid and tau levels, and magnetic resonance imaging to determine longitudinal change in cortical thickness.

RESULTS: Four years after receiving the final dose of aducanumab, the patient died. An autopsy showed variable levels of amyloid pathology, including brain regions with very low levels of amyloid juxtaposed with brain regions that had typically high levels of amyloid in the deep cortical layers and only low levels of amyloid in the superficial cortical layers. Compared with the brain regions of the untreated controls, the brain regions of the patient after treatment with aducanumab showed low levels of amyloid that were preferentially found in the gyral crests, were associated with less tau pathology at autopsy, and were associated with slower longitudinal atrophy on in vivo magnetic resonance imaging (β = -0.50 [95% CI, -0.62 to -0.37]; t = -7.96 and P < .001). In contrast, the patient's brain regions with high amyloid burden were preferentially found in the sulcal depths and had similar levels of tau pathology as seen at autopsy in the untreated controls.

CONCLUSIONS AND RELEVANCE: In this case report, areas of extensive amyloid clearance after amyloid-targeting therapy were associated with less downstream neuropathologic change. In addition, amyloid clearance appears to preferentially occur in the gyral crests. Future studies should evaluate the differential mechanisms involved in amyloid clearance from superficial and deep cortical layers and in gyri and sulci because extensive amyloid clearance may be necessary to achieve downstream neuropathologic benefit after removal of amyloid.},
}

@article {pmid42437964,
year = {2026},
author = {Couch, E and Gantenberg, JR and Belanger, E},
title = {Adoption of Alzheimer's disease biomarkers by primary care clinicians: findings from the National Dementia Workforce Study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71665},
doi = {10.1002/alz.71665},
pmid = {42437964},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/diagnosis/diagnostic imaging ; *Biomarkers ; United States ; Cross-Sectional Studies ; *Primary Health Care/statistics & numerical data ; Female ; Male ; *Physicians, Primary Care/statistics & numerical data ; Magnetic Resonance Imaging ; Neuropsychological Tests/statistics & numerical data ; Medicare ; Positron-Emission Tomography ; },
abstract = {INTRODUCTION: Biomarkers for Alzheimer's disease (AD) are now available for clinical use; however, little is known about their use in primary care.

METHODS: Cross-sectional analysis of 2024 data from the National Dementia Workforce Study, a nationally representative survey of primary care providers (PCPs) who treat Medicare beneficiaries with dementia. We used survey weights to generate nationally representative estimates of self-reported biomarker use.

RESULTS: Among 2574 PCPs, computed tomography/magnetic resonance imaging (CT/MRI) (79%) and neuropsychological testing (71%) were most commonly used, followed by positron emission tomography (PET) (18%), plasma (16%), genetic (14%), and CSF testing (9%). PCPs confident in diagnosing dementia and from specialist settings were more likely to report ordering PET, plasma, genetic, and CSF testing.

DISCUSSION: This study describes patterns in the adoption of AD biomarkers in the year after Medicare expanded coverage for some biomarkers, providing a baseline for measuring changes in biomarker use. Guidelines are needed to inform PCP decision-making for biomarkers.},
}

Humans
*Alzheimer Disease/diagnosis/diagnostic imaging
*Biomarkers
United States
Cross-Sectional Studies
*Primary Health Care/statistics & numerical data
Female
Male
*Physicians, Primary Care/statistics & numerical data
Magnetic Resonance Imaging
Neuropsychological Tests/statistics & numerical data
Medicare
Positron-Emission Tomography

@article {pmid42437974,
year = {2026},
author = {Rutter, LA and Hamilton, LJ},
title = {Depressive symptom instability predicts incident mild cognitive impairment and dementia in older adults.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71672},
doi = {10.1002/alz.71672},
pmid = {42437974},
issn = {1552-5279},
support = {//NIH/ ; K01 AG086598/AG/NIA NIH HHS/United States ; R37AG057739-07/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Cognitive Dysfunction/epidemiology/diagnosis ; *Dementia/epidemiology/diagnosis ; *Depression/epidemiology ; Female ; Male ; Aged ; Longitudinal Studies ; Aged, 80 and over ; Incidence ; Risk Factors ; United States/epidemiology ; },
abstract = {INTRODUCTION: Neuropsychiatric symptoms frequently precede Alzheimer's disease and related dementias, yet risk prediction models typically rely on baseline depression severity or diagnostic status. We examined whether instability in depressive symptoms predicted incident mild cognitive impairment (MCI) or dementia.

METHODS: Data were drawn from 11,951 older adults enrolled across 42 US Alzheimer's Disease Research Centers and followed for up to 19 years. Depressive symptoms were assessed using the Geriatric Depression Scale and characterized using rule-based groupings and latent class trajectories. The Structured Life-Course Modeling Approach (SLCMA) was used to compare four competing temporal hypotheses of risk. Cox models adjusted for demographic factors and apolipoprotein E (APOE) ε4 status.

RESULTS: Fluctuating depressive symptom trajectories were associated with increased risk of incident cognitive impairment. Symptom instability showed the lowest prediction error in exploratory SLCMA analyses.

DISCUSSION: Instability in depressive symptoms may represent an early and clinically accessible risk marker for MCI and dementia.},
}

Humans
*Cognitive Dysfunction/epidemiology/diagnosis
*Dementia/epidemiology/diagnosis
*Depression/epidemiology
Female
Male
Aged
Longitudinal Studies
Aged, 80 and over
Incidence
Risk Factors
United States/epidemiology

@article {pmid42437975,
year = {2026},
author = {Thanou, E and Ganz, A and Pita-Illobre, D and Koopmans, F and Hoozemans, JJM and Rozemuller, A and Holstege, H and Smit, AB and Li, KW},
title = {Proteomics of post mortem brains in early- and late-onset Alzheimer's disease: Unraveling differential Aβ effects and potential AD biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71662},
doi = {10.1002/alz.71662},
pmid = {42437975},
issn = {1552-5279},
support = {765704//EU Marie Curie ITN EuroNeurotrophin/ ; OCENW.KLEIN.558//Dutch Research Council (NWO)/ ; //OPD-ZonMW via the MODEM consortium/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/metabolism ; Biomarkers/metabolism ; *Proteomics ; *Amyloid beta-Peptides/metabolism ; Female ; tau Proteins/metabolism ; Male ; Aged ; *Brain/metabolism/pathology ; Aged, 80 and over ; Age of Onset ; Proteome ; Autopsy ; Phosphorylation ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) occurs primarily as late‑onset (LOAD) and less frequently as early‑onset (EOAD). Its defining pathologies are hyperphosphorylated tau tangles and amyloid beta (Aβ) plaques.

METHODS: We analyzed the proteomes of 115 post mortem temporal lobe samples by mass spectrometry and searched with a dedicated AD spectral library including tau post‑translational modifications and Aβ isoforms to examine global protein changes in LOAD and EOAD.

RESULTS: AD tissues showed mitochondrial and synaptic pathway downregulation and immune and small‑molecule metabolic process upregulation, with EOAD exhibiting larger fold changes. AD biomarkers were elevated, and two multi‑phosphorylated tau peptides (p‑tau231/p-tau235 and p-tau231/p-tau235/p-tau237) were detected predominantly in AD. Aβ was present in 45% of cognitively unimpaired elderly controls, with subtle proteome changes resembling an early stage of neurodegeneration.

DISCUSSION: EOAD appears more aggressive. Tau p-tau231/p-tau235 and p-tau231/p-tau235/p-tau237 hold promise as novel AD biomarkers. Aβ's detection in cognitively unimpaired elderly controls precedes clinical AD symptoms.},
}

Humans
*Alzheimer Disease/pathology/metabolism
Biomarkers/metabolism
*Proteomics
*Amyloid beta-Peptides/metabolism
Female
tau Proteins/metabolism
Male
Aged
*Brain/metabolism/pathology
Aged, 80 and over
Age of Onset
Proteome
Autopsy
Phosphorylation

@article {pmid42438039,
year = {2026},
author = {Batool, M and Iqbal, J and Saif, H},
title = {Loneliness as an Interface Between Alzheimer's Disease and Suicidal Behaviour: A Methodological Concern.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {26},
number = {4},
pages = {e70194},
doi = {10.1111/psyg.70194},
pmid = {42438039},
issn = {1479-8301},
}

@article {pmid42438228,
year = {2026},
author = {Oh, JM and Jeong, WK and Son, HJ and Kim, SY and Oh, TW and Ji, M and Nam, JW and Baek, M and Park, JH and Shin, WH and Kim, HJ and Choi, B and Paik, MJ and Kim, H},
title = {Ameliorative Effects of a Naphthoquinone Derivative With β-Amyloid Aggregation Inhibitory Activity on Cognitive Impairment and Metabolite Analysis of the Blood and Brains of Mice.},
journal = {Drug development research},
volume = {87},
number = {5},
pages = {e70345},
doi = {10.1002/ddr.70345},
pmid = {42438228},
issn = {1098-2299},
support = {RS-2024-00347522//National Research Foundation of Korea (NRF)/ ; },
mesh = {Animals ; *Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; Mice ; Brain/metabolism/drug effects ; Male ; *Naphthoquinones/pharmacology/chemistry/therapeutic use ; Humans ; *Cognitive Dysfunction/drug therapy/metabolism ; Peptide Fragments/metabolism ; Alzheimer Disease/drug therapy/metabolism ; Scopolamine ; Madin Darby Canine Kidney Cells ; *Neuroprotective Agents/pharmacology ; Cognitive Enhancement ; },
abstract = {Accumulation of amyloid-β (Aβ) plaques is an important cause of Alzheimer's disease (AD) pathogenesis. In this study, we evaluated Aβ aggregation inhibitory activity of synthesized naphthoquinone derivatives as well as improvement in cognitive functions and metabolite profiling of brain tissues using scopolamine (SCO)-induced mice. Compound 888 (2-(4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)naphthalene-1,4-dione, [TPN]) showed the highest Aβ aggregation inhibitory activity (IC50 = 0.14 μM), and was more potent than the reference compound curcumin (IC50 = 1.63 μM). Compound TPN showed effective monoamine oxidase (MAO)-A, MAO-B, acetylcholinesterase, and butyrylcholinesterase inhibitions at 10 μM, likely as candidates for multitarget-directed ligands. TPN was permeable through the blood-brain barrier, and non-toxic to MDCK and SH-SY5Y cells. TPN displayed prolonged and stable interactions with Aβ42 during molecular dynamics simulations, in contrast to the short-lived contacts observed for curcumin. Cognitive impairment was significantly improved by TPN-treatment in behavioral tests. TPN treatment attenuated Aβ-related protein expression, inflammatory responses, oxidative stress-related changes, and apoptosis-related alterations, while preserving hippocampal pyramidal neurons and their typical morphology. In metabolite profiling, TPN modulated a narrower set of pathways mainly related to amino acid and kynurenine metabolism, whereas donepezil induced broader adjustments involving amino acid, mitochondrial/energy, and lipid-related pathways compared to those in the serum and cortex of the SCO group, in contrast to those in the hippocampus. Collectively, a potent Aβ aggregation inhibitor TPN showed significant cognitive improvement, accompanying by neuroprotective effects, decreasing inflammation, and retaining neuron structures, exhibiting changed metabolic profiles compared to the control treatments. These findings suggest that TPN has cognitive-protective and neuroprotective potential under scopolamine-induced impairment conditions and warrants further validation in AD-relevant models.},
}

Animals
*Amyloid beta-Peptides/metabolism/antagonists & inhibitors
Mice
Brain/metabolism/drug effects
Male
*Naphthoquinones/pharmacology/chemistry/therapeutic use
Humans
*Cognitive Dysfunction/drug therapy/metabolism
Peptide Fragments/metabolism
Alzheimer Disease/drug therapy/metabolism
Scopolamine
Madin Darby Canine Kidney Cells
*Neuroprotective Agents/pharmacology
Cognitive Enhancement

@article {pmid42438357,
year = {2026},
author = {Simrén, J and Benedet, AL and Di Molfetta, G and Pola, I and Tan, K and Cantoni, V and Libri, I and Rivolta, J and Ghidoni, R and Zetterberg, H and Borroni, B and Ashton, NJ},
title = {Plasma Proteomic Changes in GRN and C9orf72 Frontotemporal Dementia.},
journal = {European journal of neurology},
volume = {33},
number = {7},
pages = {e70704},
doi = {10.1111/ene.70704},
pmid = {42438357},
issn = {1468-1331},
support = {//Bluefield Project/ ; //Beiglers stiftelse/ ; //Stiftelsen för Gamla Tjänarinnor/ ; },
mesh = {Humans ; *C9orf72 Protein/genetics ; *Progranulins/genetics ; *Frontotemporal Dementia/blood/genetics ; Female ; Biomarkers/blood ; Male ; Proteomics ; Middle Aged ; Cross-Sectional Studies ; Aged ; Neurofilament Proteins/blood ; },
abstract = {BACKGROUND: Biomarkers reflecting the complex pathophysiology of genetic frontotemporal dementia (FTD) will be increasingly important with the advent of therapeutic trials aiming to slow or prevent the disease. In this study, we aimed to identify blood biomarker candidates using a multiplex panel of CNS-related proteins.

METHODS: We cross-sectionally evaluated 67 carriers (21 presymptomatic and 46 symptomatic) of pathogenic FTD-causing mutations in the GRN (n = 30 symptomatic) and C9orf72 (n = 16 symptomatic) genes and 42 matched non-carriers. Clinical severity was estimated using the CDR Dementia Staging Instrument with National Alzheimer Coordinating Centre Frontotemporal Lobar Degeneration component (CDR plus NACC FTLD). A total of 124 CNS-related proteins were measured in plasma using the NUcleic acid Linked Immuno-Sandwich Assay (NULISA) CNS panel. Group-level changes were then investigated using linear and non-linear regression models.

RESULTS: In GRN- and C9orf72-FTD, neurofilament light (NfL) was the most clearly altered protein compared with non-carriers (GRN: β [95% CI] = 4.0 standard deviations [3.6-4.4], C9orf72: β = 2.8 [2.2-3.4]), followed by neurofilament heavy (NfH; GRN: β = 0.83 [0.39-1.3], C9orf72: β = 1.4 [0.8-2.0]). Proteins exclusively altered in GRN-FTD included glial fibrillary acidic protein (GFAp; β = 0.50 [0.20-0.81]) and vascular cell adhesion protein 1 (VCAM1; Standardized β = -0.90 [-1.4 to -0.38]), changing with increasing disease severity. Neuronal pentraxin receptor (NPTXR; β = -0.94 [-1.5 to -0.4]) was selectively reduced in C9orf72-FTD. Nominally changed proteins in C9orf72-FTD included several inflammatory mediators.

CONCLUSIONS: Using this multiplex panel, established markers recapitulated previously established trends, while less-studied biomarker candidates were also identified. If validated in independent cohorts, these candidates could broaden the repertoire of blood biomarkers reflecting genetic FTD pathophysiology.},
}

Humans
*C9orf72 Protein/genetics
*Progranulins/genetics
*Frontotemporal Dementia/blood/genetics
Female
Biomarkers/blood
Male
Proteomics
Middle Aged
Cross-Sectional Studies
Aged
Neurofilament Proteins/blood

@article {pmid42438681,
year = {2026},
author = {Zuo, M and Zhu, H and Liu, Z and Zhang, Q and Song, S},
title = {TF-JointMAE: a self-supervised multi-representation EEG learning framework for Alzheimer's disease spectrum classification.},
journal = {Cognitive neurodynamics},
volume = {20},
number = {1},
pages = {133},
pmid = {42438681},
issn = {1871-4080},
abstract = {UNLABELLED: Accurate identification of Alzheimer's disease (AD) and its early stages, namely subjective cognitive decline (SCD) and mild cognitive impairment (MCI), is crucial for timely intervention. Electroencephalography (EEG) is widely used for AD assessment due to its non-invasiveness and high temporal resolution; however, its non-stationarity, noise interference, and individual variability make classification more difficult. To address this, this paper proposes a self-supervised learning framework, TF-JointMAE (Temporal-Frequency Joint Masked Autoencoder), that jointly models temporal and time-frequency representations of EEG and incorporates age information as a conditional physiological prior within a unified embedding space. By performing self-supervised masked autoencoder pre-training on multiple public EEG datasets, the model learns consistent and robust EEG representations, thereby improving AD-spectrum classification under limited-label conditions. On the publicly available CAUEEG dataset (Normal, SCD, MCI, Dementia) and the olfactory EEG dataset (Normal, MCI, Dementia), TF-JointMAE achieved test accuracies of 77.97% and 96.43%, respectively, and demonstrated higher discriminative stability in the MCI category. Further occlusion-sensitivity analysis revealed that the model showed varying sensitivity to EEG channels and time-frequency regions across cognitive states. These results demonstrate that TF-JointMAE effectively improves the robustness of EEG representations, providing potential auxiliary support for AD-spectrum classification and clinical decision-making. All source code is publicly available to support reproducibility (https://github.com/redpig-zhu/TF-JointMAE).

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11571-026-10501-8.},
}

@article {pmid42438728,
year = {2025},
author = {Moon, H and Du, JH and Lei, J and Roeder, K},
title = {AUGMENTED DOUBLY ROBUST POST-IMPUTATION INFERENCE FOR PROTEOMIC DATA.},
journal = {The annals of applied statistics},
volume = {19},
number = {2},
pages = {1006-1027},
pmid = {42438728},
issn = {1932-6157},
abstract = {Quantitative measurements produced by mass spectrometry proteomics experiments offer a direct way to explore the role of proteins in molecular mechanisms. However, analysis of such data is challenging due to the large proportion of missing values. A common strategy to address this issue is to utilize an imputed dataset, which often introduces systematic bias into downstream analyses if the imputation errors are ignored. In this paper we propose a statistical framework, inspired by doubly robust estimators, that offers valid and efficient inference for proteomic data. Our framework combines powerful machine learning tools, such as variational autoencoders, to augment the imputation quality with high-dimensional peptide data, and a parametric model to estimate the propensity score for debiasing imputed outcomes. Our estimator is compatible with the double machine learning framework and has provable properties. Simulation studies verify its empirical superiority over other existing procedures. In application to both single-cell proteomic data and bulk-cell Alzheimer's disease data our method utilizes the imputed data to gain additional, meaningful discoveries and yet maintains good control of false positives.},
}

@article {pmid42438861,
year = {2026},
author = {Liu, X and Lin, T and Jiang, Y and Luo, S and Chen, S and Chai, Y and Yang, Z and Wei, Y and Wang, H and Li, X and Xiang, YT and Sha, F and Tang, J},
title = {Antidepressant use and dementia, cognitive measures, and neuroimaging outcomes: A population-based cohort study.},
journal = {Psychological medicine},
volume = {56},
number = {},
pages = {e225},
doi = {10.1017/S0033291726104942},
pmid = {42438861},
issn = {1469-8978},
support = {82404371//National Natural Science Foundation of China/ ; 72304267//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Antidepressive Agents/therapeutic use/adverse effects ; Female ; Male ; *Dementia/epidemiology/diagnostic imaging ; Aged ; Neuroimaging ; Prospective Studies ; *Cognition/drug effects ; United Kingdom/epidemiology ; Middle Aged ; Magnetic Resonance Imaging ; Brain/diagnostic imaging ; Cohort Studies ; UK Biobank ; },
abstract = {BACKGROUND: Prior observational studies have reported conflicting results regarding whether antidepressant treatment reduces long-term dementia risk, likely due to confounding by indication and reverse causation. We aimed to investigate the association between baseline antidepressant use and incident dementia, incorporating cognitive and neuroimaging outcomes.

METHODS: We conducted a prospective cohort study using UK Biobank participants free of dementia at baseline. Antidepressant use was self-reported at baseline (2006-2010). Incident dementia was identified through linked electronic health records until December 19, 2022. Cox proportional hazards models estimated hazard ratios (HRs) for all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VD), adjusting for sociodemographic, lifestyle, health-related, antidepressant indication factors, and co-medication of other anticholinergics. In subsamples, cognitive performance (n = 57,330) and structural brain imaging (n = 42,276) were examined as intermediate outcomes.

RESULTS: Among 461,464 participants, 33,721 (7.3%) reported baseline antidepressant use. Over a mean follow-up of 13.4 years, 7,922 (1.7%) developed incident dementia. Baseline antidepressant use was associated with higher risks of all-cause dementia (adjusted HR: 1.47, 95% CI 1.36-1.60), AD (1.53, 1.36-1.73), and VD (1.44, 1.23-1.70). Users performed worse on fluid intelligence and prospective memory tasks and showed lower total and gray matter volume, regional reductions in the hippocampal gray matter and basal nucleus, and greater white matter hyperintensity volume.

CONCLUSIONS: Baseline antidepressant use was linked to a higher risk of dementia, poorer cognitive performance, and adverse brain structural changes. These findings underscore the importance of judicious prescribing, regular cognitive monitoring, and consideration of non-pharmacological approaches in clinical care.},
}

Humans
*Antidepressive Agents/therapeutic use/adverse effects
Female
Male
*Dementia/epidemiology/diagnostic imaging
Aged
Neuroimaging
Prospective Studies
*Cognition/drug effects
United Kingdom/epidemiology
Middle Aged
Magnetic Resonance Imaging
Brain/diagnostic imaging
Cohort Studies
UK Biobank

@article {pmid42438933,
year = {2026},
author = {Ke, Q and Xiong, Y and Cai, Z and Chen, F and Zhou, Z and Chen, Z and Huang, Y and Fang, S and Wu, P and Wang, S and Wang, HX},
title = {Peptide-Functionalized Hydroxypropyl Cellulose Mitigates Amyloid-β Protein Induced Endothelial Leakiness and Enhances Cognitive Function in Alzheimer's Disease.},
journal = {Angewandte Chemie (International ed. in English)},
volume = {},
number = {},
pages = {e1351374},
doi = {10.1002/anie.1351374},
pmid = {42438933},
issn = {1521-3773},
support = {21875060//National Natural Science Foundation of China/ ; 51402095//National Natural Science Foundation of China/ ; 51903076//National Natural Science Foundation of China/ ; 23JRRA0925//Natural Science Foundation of Gansu Province/ ; HKLB2410//Hubei Key Laboratory for Precision Synthesis of Small Molecule Pharmaceuticals/ ; HKLA2503//Hubei Key Laboratory for Precision Synthesis of Small Molecule Pharmaceuticals/ ; 2024DJC023//Department of Science and Technology of Hubei Province/ ; 2025CDB034//Department of Science and Technology of Hubei Province/ ; 2026AFB734//Department of Science and Technology of Hubei Province/ ; 2026AFB408//Department of Science and Technology of Hubei Province/ ; },
abstract = {Amyloid-β (Aβ) plays a central role in Alzheimer's disease (AD) pathogenesis by inducing endothelial leakiness and disrupting blood-brain barrier (BBB) integrity via direct binding to endothelial tight junction proteins. In this work, a peptide-functionalized cellulose derivative (HPC-pet) was synthesized by conjugating hydroxypropyl cellulose (HPC) with the Aβ-targeting KLVFFAED peptide (pet). Integrative experimental and theoretical investigations were performed to characterize the efficacy and underlying mechanism of HPC-pet in mitigating amyloid - β protein-induced endothelial leakage (APEL), as well as to profile its pharmacokinetic behavior. Benefiting from the synergistic effects between HPC matrix and pet moieties, HPC-pet is capable of suppressing Aβ aggregation progression and encapsulating formed Aβ oligomers. In vitro cellular assays suggested that HPC-pet interferes with the binding of Aβ to endothelial junction proteins and mitigates APEL. Computational modeling further analyzed the intermolecular binding patterns among Aβ, HPC, and VE-cadherin to elucidate the molecular interaction mechanism. Consistent with in vitro and computational results, HPC-pet can efficiently traverse the BBB and mitigate APEL. Following sustained in vivo delivery of HPC-pet to AD mice, reduced cerebral Aβ plaque burden and improved cognitive function were detected. This strategy safeguards endothelial function from Aβ oligomer-mediated damage, offering a promising candidate for intervening Aβ-driven AD progression.},
}

@article {pmid42439012,
year = {2026},
author = {Sachdeva, G and Kumar, G and Kumar, B},
title = {Systematic review- hormone replacement therapy in postmenopausal women with medical co-morbidities.},
journal = {Post reproductive health},
volume = {},
number = {},
pages = {1-12},
doi = {10.1080/20533691.2026.2690376},
pmid = {42439012},
issn = {2053-3705},
abstract = {BACKGROUND: Safety and efficacy of HRT in women with chronic medical conditions remain incompletely understood. As life expectancy rises and the use of HRT becomes more common, condition-specific recommendations are crucial to support clinical decisions.

OBJECTIVES: Systematic review on disease-specific effects of HRT in peri- and postmenopausal women with chronic medical disorders.

DATA SOURCES: Comprehensive search of PubMed, Embase, Cochrane Central Register of Controlled Trials, and Web of Science was conducted from inception to 31 August 2025. Cross reference was undertaken.

ELIGIBILITY CRITERIA: Systematic reviews, meta-analysis, Randomised controlled trials, cohort, and case-control studies examining oral, transdermal, or other HRT formulations in peri- or postmenopausal women with chronic diseases were included. Case reports, editorials, conference abstracts, and non-English publications were excluded.

METHODOLOGY: Titles, abstracts, and full-text articles were independently evaluated by three reviewers. Data extraction included study design, participant characteristics, HRT regimen, and outcomes.

RESULTS: Fifty-four studies met inclusion criteria, covering neurological (epilepsy, migraine, Alzheimer's, Parkinson's, multiple sclerosis, meningioma), metabolic, cardiovascular, autoimmune, renal, hepatic, and endocrine conditions. Oral estrogen formulations may increase risk whereas transdermal preparations may confer lower thrombotic and hepatic risk (limited evidence). Neurological benefits were observed in Parkinson's disease and multiple sclerosis, but evidence was limited for Alzheimer's disease and migraine. HRT was generally safe in stable autoimmune conditions. Cardiovascular safety is supported in women without pre-existing disease.

CONCLUSIONS: HRT should be individualised according to comorbidities, formulation, and route, with preference for transdermal or low-dose regimens in high-risk populations.

UNLABELLED: Registration: PROSPERO ID CRD420251233527.},
}

@article {pmid42439047,
year = {2026},
author = {Hicken, MT and DeAngelis, R and Rigby, D and Burnside, L and Adar, S and Burgard, S and Davis, BA and Donnelly, R and Finlay, JM and Hajat, A and Lee, J and Perry, BL and Thorpe, LE and Umberson, D},
title = {The social environment and cognitive aging over the life course: laying out critical concepts and research gaps.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71648},
doi = {10.1002/alz.71648},
pmid = {42439047},
issn = {1552-5279},
support = {R01AG060011/AG/NIA NIH HHS/United States ; R01AG065319/AG/NIA NIH HHS/United States ; R01AG076032/AG/NIA NIH HHS/United States ; R37AG57739/AG/NIA NIH HHS/United States ; P30AG066614/AG/NIA NIH HHS/United States ; U25AG088894/AG/NIA NIH HHS/United States ; R01MD013299/MD/NIMHD NIH HHS/United States ; },
mesh = {Humans ; *Social Environment ; *Cognitive Aging/psychology ; *Aging/psychology ; Residence Characteristics ; Alzheimer Disease ; },
abstract = {The social environment refers to our interpersonal relations, workplaces, and neighborhoods, towns, or cities in which we live. A growing literature indicates that social environments are related to cognitive aging and risk of Alzheimer's disease and related dementias (AD/ADRD). Still, relatively little is known about how social-environmental exposures affect cognitive function over the life course and into older ages. Addressing this limitation, our paper outlines key features of the social environment and recommends priority areas of research on the social environment and cognitive aging. We divide our discussion into three subdomains: social connections, residential context, and work context. We then identify important gaps in the conceptual and empirical literature before outlining avenues for future research to strengthen our understanding of how social-environmental exposures over the life course link with cognitive function and AD/ADRD risk in late life.},
}

Humans
*Social Environment
*Cognitive Aging/psychology
*Aging/psychology
Residence Characteristics
Alzheimer Disease

@article {pmid42439335,
year = {2026},
author = {Singh, S and Singh, S and Khandelwal, V and Bharti, U and Singh, PK},
title = {Gut Microbiota in Neuroinflammation, Neurodegenerative Disorders, and Neuropsychiatric Disorders: A Comprehensive Narrative Review.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273455874260702045636},
pmid = {42439335},
issn = {1996-3181},
abstract = {Neurodegenerative and neuropsychiatric illnesses are characterized by neuroinflammation, which is driven by microglial activation, cytokine production, and breakdown of the blood-brain barrier (BBB). It is currently known that the gut microbiota plays an important role in modulating neuroimmune signaling, which in turn may trigger anxiety-like behaviors and depressive phenotypes through the microbiota-gut-brain axis. This review aims to integrate the most recent mechanistic knowledge on treatment strategies targeting the gut microbiota to modulate neuroinflammation. This review article discusses preclinical and clinical studies that investigated microbial composition, metabolite profiles, and host-microbe interactions involved in neuroinflammatory processes. However, special attention was given to signaling via the vagus nerves and bile acids, as well as to tryptophankynurenine metabolism and short-chain fatty acids (SCFAs). To examine the potential connection between the two, researchers used animal models such as germ-free animals and antibiotic-injected mice for fecal microbiota transplantation (FMT). This article defines dysbiosis as amplifying neuroinflammatory responses by altering microglial phenotypes, disrupting the blood-brain barrier, and triggering the production of pro-inflammatory cytokines. In contrast, microbiome diversity rehabilitation through the use of probiotics, prebiotics, synbiotics, and dietary modifications reduces neuroinflammatory markers and enhances cognitive and behavioral status. Clinical trials have shown considerable promise in diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), autism spectrum disorder (ASD), and depression. However, variability in treatment protocols, treatment resistance, and host-specific factors continue to pose significant challenges. This narrative review integrates mechanistic insights into microglial activation, cytokine signaling, blood-brain barrier regulation, vagal pathways, tryptophan metabolism, and short-chain fatty acids with emerging clinical evidence and therapeutic strategies, including probiotics, prebiotics, dietary modulation, and personalized microbiome-based interventions. Despite promising therapeutic potential, microbiome engineering faces important challenges, including safety concerns, lack of standardized intervention protocols, and substantial inter-individual variability in host-microbiome responses, which currently limit clinical translation. This review focuses on both neurodegenerative and neuropsychiatric disorders, examining shared neuroinflammatory mechanisms mediated by the gut-brain axis and evaluating microbiotatargeted therapeutic strategies across these disease categories. The review discusses both preventive strategies, including dietary modulation, prebiotics, and lifestyle-based microbiome interventions, as well as therapeutic approaches such as microbiota-targeted treatments aimed at mitigating neuroinflammation and disease progression.},
}

@article {pmid42439337,
year = {2026},
author = {Chavan, V and Jadhav, S and Jatrate, F and Jondhalkar, G and Jangme, C and Mhettar, P},
title = {Stimuli-responsive Lipid-based Nanoplatforms for Targeted Therapy of Brain Diseases: Current Challenges and Future Directions.},
journal = {Central nervous system agents in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715249462564260518110221},
pmid = {42439337},
issn = {1875-6166},
abstract = {The reported research revealed the peculiarity of stimuli-responsive lipidic nanocarriers for localised therapy in distinct brain diseases, as it is supremely challenging due to the complexity of the brain. The pitfalls of conventional carriers could be carefully addressed utilising these smart lipidic nanoparticles due to their versatile features. The meticulous depiction of cardinal strategies for boosting barrier penetration with a mechanism paves the roadmap for lipidic nanoparticles in targeting. The present review article offers viewpoints on the application of distinct endogenous stimuli, like pH, hypoxia, and enzymes, along with exogenous stimuli, such as temperature, magnetism, and light. Each stimulus elaborated their exploitation of pathophysiological changes during diseased conditions, and its mechanism of utilisation in treating the diseases protects healthy cells from damage. Importantly, the detailed emphasis on the role of lipidic nanocarriers and their key advantages, including biosafety, biocompatibility, and high payload, offers a new avenue for targeted therapies. The stimuli-responsive lipid-nanoparticle-mediated targeted therapy in conditions like neurodegenerative diseases (Alzheimer's and Parkinson's), tumours like glioblastoma multiforme (GBM), infectious conditions like meningitis, and traumatic conditions like intracerebral haemorrhage are discussed in this work. Despite advancements, fewer issues like nanotoxicity, controlled size, scalability, and distribution within the brain appear to have more solutions. In future multi-stimuli applications, biomolecule integration and clinical translation could resolve many of the drawbacks of the present situation. Concisely, in the future, stimuli-responsive lipid nanoparticles will serve as an intriguing approach for targeted therapy in brain diseases.},
}

@article {pmid42439488,
year = {2026},
author = {Kittle, K and Perales-Puchalt, J and Flatt, JD and VanKim, N and Anderson, JG},
title = {Exploring Psychosocial Factors and Health Measures Among Hispanic/Latino/a/e/x (H/L) and Non-H/L White LGBTQ+ Unpaid Caregivers of People Living With Dementia.},
journal = {Research on aging},
volume = {},
number = {},
pages = {1640275261469198},
doi = {10.1177/01640275261469198},
pmid = {42439488},
issn = {1552-7573},
abstract = {PurposeExamine differences in socioenvironmental factors, risk and protective factors, and health between Hispanic/Latino/a/e/x (H/L) and non-H/L White LGBTQ+ caregivers of individuals with Alzheimer's disease and related dementias (ADRD).MethodsUtilizing secondary survey data, we used unadjusted logistic regression and examined distributions of risk and protective factors and health between H/L and non-H/L White LGBTQ+ ADRD caregivers.ResultsH/L caregivers reported lower levels of perceived stress (15.1 vs. 19.3) and caregiver stigma (47.2 vs. 53.8). H/L caregivers reported fewer months of caregiving (22.8 vs. 28.7) and fewer used respite services (37.9% vs. 53.7%). Fewer H/L caregivers reported one or more chronic conditions (21.4% vs. 37.3%), but their self-rated global health was significantly lower (26.8 vs. 32.5). Transgender H/L caregivers reported the lowest use of respite services and lowest rates of chronic conditions.ConclusionDespite less risk, H/L caregivers reported poorer self-reported health, highlighting disparities possibly shaped by intersecting identities.},
}

@article {pmid42439628,
year = {2026},
author = {Chmiel, J and Gawełczyk, W and Soczyńska, J and Leszek, J},
title = {Lymphoid-like Suppressive Microglia in Alzheimer's Disease: A New Neuroimmune Regulatory Axis?.},
journal = {Cells},
volume = {15},
number = {13},
pages = {},
doi = {10.3390/cells15131151},
pmid = {42439628},
issn = {2073-4409},
mesh = {*Alzheimer Disease/immunology/pathology ; Humans ; *Microglia/immunology/pathology/metabolism ; Animals ; Proto-Oncogene Protein Spi-1 ; *Neuroimmunomodulation ; *Lymphocytes/immunology/pathology ; Trans-Activators/metabolism ; },
abstract = {Microglia are central regulators of Alzheimer's disease pathogenesis, but their roles cannot be reduced to a simple protective-versus-harmful dichotomy. Genetic, single-cell, and spatial studies have shown that Alzheimer 's-associated microglia occupy diverse disease-linked states shaped by amyloid plaques, tau pathology, lipid stress, complement activation, astrocyte signaling, aging, and immune genetic risk. Among the regulatory nodes controlling these states, SPI1, which encodes the myeloid transcription factor PU.1, has emerged as a key determinant of microglial identity and disease responsiveness. Human genetic studies suggest that reduced SPI1 expression may be protective, whereas experimental data indicate that excessive PU.1 suppression can impair essential microglial functions. This review examines the emerging concept that partial, plaque-associated reduction in PU.1 may enable a distinct lymphoid-like immunoregulatory microglial program marked by CD28 expression. Recent evidence suggests that PU.1-low CD28-positive microglia may restrain neuroinflammation and amyloid pathology, raising the possibility that Alzheimer's plaques induce not only inflammatory and phagocytic microglial responses, but also endogenous suppressive programs that limit tissue damage. We discuss this proposed PU.1/CD28 regulatory axis in relation to disease-associated microglia, TREM2-APOE signaling, complement-mediated synapse loss, antigen-presentation pathways, plaque-niche biology, and therapeutic microglial reprogramming. We also highlight major unresolved questions, including whether PU.1-low CD28-positive microglia are present and functional in human Alzheimer's disease, whether they are specific to amyloid-rich niches or extend to tau and mixed pathologies, and how such states could be safely manipulated without disrupting essential immune surveillance. We propose that lymphoid-like suppressive microglia represent a promising but still unproven framework for understanding protective neuroimmune regulation in Alzheimer's disease and for developing state-specific microglial therapies.},
}

*Alzheimer Disease/immunology/pathology
Humans
*Microglia/immunology/pathology/metabolism
Animals
Proto-Oncogene Protein Spi-1
*Neuroimmunomodulation
*Lymphocytes/immunology/pathology
Trans-Activators/metabolism

@article {pmid42439636,
year = {2026},
author = {Baldo, KAT and Gozlan, E and Chidebe, EO and Awogbindin, I and Ocaña Prieto, M and Dalmacio, LM and Ben-Azu, B and Frenkel, D and Tremblay, MÈ},
title = {Human Microglial Molecular Alterations in Aging and Alzheimer's Disease.},
journal = {Cells},
volume = {15},
number = {13},
pages = {},
doi = {10.3390/cells15131159},
pmid = {42439636},
issn = {2073-4409},
support = {52867-59420//Joint Canada-Israel Research Program, Canadian Institutes of Health Research (CIHR), the International Development Research Center (IDRC), the Israel Science Foundation (ISF), and the Azrieli Foundation/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/metabolism/genetics ; *Microglia/metabolism/pathology ; *Aging/pathology/metabolism/genetics ; Oxidative Stress ; Cellular Senescence ; Animals ; Brain/pathology ; },
abstract = {Microglia, the resident innate immune cells of the central nervous system, are central players in brain development, healthy aging, and degenerative pathology, including Alzheimer's disease (AD). Aging is a major risk factor for AD, and various studies have identified alterations in microglial molecular signatures and morphological patterns that overlap with microglial states during aging. However, the mechanisms underlying the divergence of aging trajectories toward disease remain unclear. Thus, understanding the molecular changes in microglia during aging and AD pathology is crucial to elucidating the mechanisms that drive disease progression. In this review, we examine current advances in understanding the phenotypic alterations in human microglia, highlighting gene signatures and morphological changes that may aid in defining microglia's molecular and functional programs in healthy aging and over the course of AD. We further explore the roles of oxidative stress and cellular senescence in driving the development of a chronic reactive state in microglia during aging, which may also contribute to the complex process underlying the onset and progression of AD pathology. This review highlights the advancements in therapeutic strategies focused on targeting pertinent pathological microglial changes during aging and in disease to mitigate the AD neurodegenerative process.},
}

Humans
*Alzheimer Disease/pathology/metabolism/genetics
*Microglia/metabolism/pathology
*Aging/pathology/metabolism/genetics
Oxidative Stress
Cellular Senescence
Animals
Brain/pathology

@article {pmid42439654,
year = {2026},
author = {Wrasidlo, W and Masliah, E},
title = {Emerging New Pathways in Malignant Neoplasms and Neurodegenerative Disorders: Perspectives for Therapeutics.},
journal = {Cells},
volume = {15},
number = {13},
pages = {},
doi = {10.3390/cells15131177},
pmid = {42439654},
issn = {2073-4409},
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/therapy/pathology ; *Neoplasms/metabolism/therapy/pathology ; Signal Transduction ; Animals ; Aging ; Proteotoxic Stress ; },
abstract = {Neurodegenerative disorders such as Alzheimer's disease (AD) and malignant neoplasms are among the most prevalent age-associated diseases worldwide. Although cancer is characterized by uncontrolled proliferation, resistance to apoptosis, and metabolic reprogramming, AD and other neurodegenerative disorders such as Lewy body disease (LBD) including Parkinson's Disease (PD) and fronto-temporal lobar degeneration (FTLD) are defined by synaptic dysfunction, neuronal loss, neuroinflammation, and impaired proteostasis with misfolded protein aggregates. Despite these contrasting phenotypes, converging epidemiological and molecular data support an inverse relationship between cancer and neurodegenerative disorders, whereby a history of cancer is associated with reduced AD risk, whereas AD is linked to a lower incidence of multiple malignancies. These observations suggest that oncogenesis and neurodegeneration may represent divergent outcomes of shared biological processes dysregulated during aging. This conundrum likely reflects differential regulation of core cellular pathways governing cell survival, stress responses, metabolism, and genomic integrity but could also reflect the differential influence of aging pathways and secreted growth factors. Pro-survival and proliferative signaling pathways commonly activated in cancer, including PI3K-AKT-mTOR signaling, altered p53 function, enhanced DNA damage tolerance, and anabolic metabolism, are often impaired in AD, LBD and FTLD, where neurons exhibit heightened vulnerability to stress, mitochondrial dysfunction, defective autophagy, and activation of pro-apoptotic cascades. Conversely, tumor-suppressive mechanisms that restrain proliferation may protect against malignancy but increase susceptibility to degeneration in post-mitotic neurons. Aging-related processes such as cellular senescence, immune dysregulation, and loss of proteostasis may further exert divergent effects in oncogenesis and neurodegeneration. This review aims to clarify associations between specific cancer types and neurodegenerative disorders, examine shared and opposing selected molecular mechanisms linking specific cancers and neurodegeneration, and contextualize these relationships within broader aging pathways (e.g., cell senescence, proteostasis). By integrating epidemiological, mechanistic, and therapeutic perspectives, we highlight unifying biological principles and translational opportunities at the intersection of cancer, neurodegeneration, and aging.},
}

Humans
*Neurodegenerative Diseases/metabolism/therapy/pathology
*Neoplasms/metabolism/therapy/pathology
Signal Transduction
Animals
Aging
Proteotoxic Stress

@article {pmid42439669,
year = {2026},
author = {Robert, J},
title = {What Are the Potential Therapeutic Benefits of Targeting Blood-Borne Lipoproteins in the Treatment of Alzheimer's Disease?.},
journal = {Cells},
volume = {15},
number = {13},
pages = {},
doi = {10.3390/cells15131191},
pmid = {42439669},
issn = {2073-4409},
mesh = {Humans ; *Alzheimer Disease/drug therapy/blood/therapy ; *Lipoproteins/blood/metabolism ; Animals ; Amyloid beta-Peptides/metabolism ; Lipoproteins, HDL ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, the deposition of amyloid-β (Aβ) plaques, the formation of neurofibrillary tangles, and cerebrovascular dysfunction. Evidence suggests that blood-borne lipoproteins play a role in the disease's pathophysiology by influencing the cerebrovasculature and amyloid metabolism. Low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL) can contribute to oxidative stress, endothelial dysfunction, vascular dysfunction, and the accumulation of amyloidogenic peptides, thereby exacerbating neurodegeneration. The role of lipoprotein(a) (Lp(a)) remains unclear, whereas high-density lipoprotein (HDL) is recognized for its cerebroprotective properties, including anti-inflammatory and vasoreactive functions. These properties help to maintain neuronal homeostasis and facilitate the clearance of Aβ from the brain. This review summarizes the current evidence regarding the role of lipoproteins in AD and discusses how therapeutic strategies targeting lipoprotein pathways, such as lipid-lowering agents and HDL mimetics developed for cardiovascular diseases, may benefit patients with AD.},
}

Humans
*Alzheimer Disease/drug therapy/blood/therapy
*Lipoproteins/blood/metabolism
Animals
Amyloid beta-Peptides/metabolism
Lipoproteins, HDL

@article {pmid42439681,
year = {2026},
author = {Li, X and Wang, X and Dou, J and Wang, J and Xue, F},
title = {Rethinking Anti-Inflammatory Therapy in Alzheimer's Disease: From Broad Suppression to Stage-State-Space Neuroimmune Reprogramming.},
journal = {Cells},
volume = {15},
number = {13},
pages = {},
doi = {10.3390/cells15131208},
pmid = {42439681},
issn = {2073-4409},
support = {20231023//Ministry of Industry and Information Technology/ ; DZS2026009//Zhejiang Wanli University/ ; SC1032511980070//Zhejiang Wanli University/ ; JT2680100001//Zhejiang Wanli University/ ; },
mesh = {*Alzheimer Disease/immunology/drug therapy/pathology/therapy ; Humans ; Animals ; *Anti-Inflammatory Agents/therapeutic use/pharmacology ; Microglia/metabolism ; Inflammation ; *Neuroimmunomodulation ; Astrocytes ; Neuroinflammatory Diseases ; },
abstract = {Alzheimer's Disease (AD) is now understood as a biologically diverse condition, with amyloid and tau pathology evolving within dynamic neuroimmune networks. This challenges the traditional view that AD-related inflammation can be broadly suppressed therapeutically. We review evidence showing that neuroinflammation in AD is stage-dependent, cell-state-specific, spatially organized, and functionally complex. Microglia and astrocytes can aid in plaque containment, debris clearance, synaptic balance, metabolic adaptation, and tissue repair, but may also exacerbate injury through type-I interferon, inflammasome, complement, tumor necrosis factor, and lipid pathways. Many failed anti-inflammatory trials likely stem from mismatches in targets, timing, spatial considerations, pathway redundancy, and biomarker selection, rather than invalidating neuroinflammation as a therapeutic target. Recent single-cell and spatial transcriptomic, proteomic, metabolomic, and network-medicine studies offer a framework for precision intervention by identifying inflammatory endotypes, anatomical niches, and pathway modules. We propose the Stage-State-Space Neuroimmune Reprogramming Model (S3-NRM), aligning AD immunotherapy with disease stage, glial/endotype state, and spatial inflammatory niche, guided by fluid, imaging, and omics biomarkers. Future therapies should selectively suppress harmful immune responses while preserving beneficial glial functions.},
}

*Alzheimer Disease/immunology/drug therapy/pathology/therapy
Humans
Animals
*Anti-Inflammatory Agents/therapeutic use/pharmacology
Microglia/metabolism
Inflammation
*Neuroimmunomodulation
Astrocytes
Neuroinflammatory Diseases

@article {pmid42439701,
year = {2026},
author = {Delgado, AM and Greer, BD and Maul, RW and Gearhart, PJ},
title = {Hunting for an Antigen: Humoral Immunity in Alzheimer's Disease.},
journal = {Cells},
volume = {15},
number = {13},
pages = {},
doi = {10.3390/cells15131227},
pmid = {42439701},
issn = {2073-4409},
support = {AG000777//National Institute on Aging, NIH/ ; },
mesh = {Humans ; *Alzheimer Disease/immunology/pathology ; *Immunity, Humoral/immunology ; Animals ; Blood-Brain Barrier/immunology/pathology ; *Antigens/immunology ; B-Lymphocytes/immunology ; },
abstract = {Alzheimer's disease (AD) is the leading cause of dementia, affecting millions of individuals on a global scale. A fatal and incurable neurodegenerative disease, AD is defined by various molecular and cellular abnormalities, such as the formation of intracellular neurofibrillary tangles and extracellular amyloid plaque deposition, leading to increased neuroinflammation, parenchymal tissue breakdown, and cognitive deficiencies. These pathological conditions are associated with the disruption of the blood-brain barrier (BBB), which is the protective network of cells responsible for maintaining homeostasis at the borders of the central nervous system (CNS). The breakdown of the BBB results in a dysregulation of the neuroimmune axis. The induction of inflammatory and autoimmune responses has been a key topic of study in AD, particularly surrounding innate immune cell activation. Recent discoveries focusing on the adaptive immune branch in the diseased CNS show evidence of effector and memory T cell activation and expansion, highlighting the complex relationship of the neuroimmune axis. It is speculated that humoral immunity might play a significant role in pathology through the production of autoantibodies. However, the contribution of B cells and plasma cells is unclear. We aim to review the literature addressing the following questions: are B cells protective or pathogenic in the CNS during AD, and do their antibodies have specific antigenic targets within this niche? The characterization of humoral contributions to immune dysregulation in AD is critical to the development of novel therapeutic strategies to slow or prevent neurodegeneration and cognitive impairment.},
}

Humans
*Alzheimer Disease/immunology/pathology
*Immunity, Humoral/immunology
Animals
Blood-Brain Barrier/immunology/pathology
*Antigens/immunology
B-Lymphocytes/immunology

@article {pmid42439703,
year = {2026},
author = {Clemente, E and Sivasubramanian, R and Kordes, S and Bhatia, P and Hans, R and Vogel, S and Baumann, M and Klebl, B and Sterneckert, J},
title = {Reducing PI4KIIIα Levels or Activity Limits Tau Seed Internalization and Assembly in Human Cortical Neurons.},
journal = {Cells},
volume = {15},
number = {13},
pages = {},
doi = {10.3390/cells15131228},
pmid = {42439703},
issn = {2073-4409},
support = {01EK1606A//Federal Ministry of Research, Technology and Space/ ; core funding//TUD Dresden University of Technology/ ; },
mesh = {Humans ; *tau Proteins/metabolism/genetics ; *Neurons/metabolism/pathology ; *Cerebral Cortex/pathology/metabolism ; Induced Pluripotent Stem Cells/metabolism ; *Phosphotransferases (Alcohol Group Acceptor)/metabolism ; Minor Histocompatibility Antigens ; },
abstract = {Tau protein aggregation and spreading are central features of neurodegenerative diseases such as Alzheimer's disease and frontotemporal dementia. Here, we investigated the role of phosphatidylinositol 4-kinase type IIIα (PI4KIIIα) in regulating tau propagation. We first used tau biosensor cells to demonstrate that both pharmacological inhibition and genetic reduction in PI4KIIIα effectively reduce the seeding of tau aggregation by extracellular seeds. To extend these findings to a more physiologically relevant system, we generated induced pluripotent stem (iPS) cell-derived cortical neurons carrying pathogenic MAPT mutations. These neurons rapidly acquired tauopathy-associated features, including expression of disease-relevant isoforms such as 4R tau, thereby enabling in vitro modeling of tau pathology. Using this model, we established phenotypic assays to monitor tau propagation and aggregation and applied them to test candidate small molecules. Notably, inhibition of PI4KIIIα consistently reduced seeding of tau assemblies in human neurons, highlighting this kinase as an important player in the seeding of tau pathology. Collectively, our work identifies PI4KIIIα as a regulator of tau pathology and provides new experimental platforms to dissect the molecular mechanisms of tau propagation. These findings open potential avenues for the development of strategies to slow or prevent tau-mediated neurodegeneration in the central nervous system.},
}

Humans
*tau Proteins/metabolism/genetics
*Neurons/metabolism/pathology
*Cerebral Cortex/pathology/metabolism
Induced Pluripotent Stem Cells/metabolism
*Phosphotransferases (Alcohol Group Acceptor)/metabolism
Minor Histocompatibility Antigens

@article {pmid42439783,
year = {2026},
author = {Ono, RMS and Lima, JEBF and Lira, JASP and Sanches, FCA and Piassi, LO and Coelho, LBV and Moreira, NCS and Sakamoto-Hojo, ET},
title = {Molecular and cellular processes connecting type 2 diabetes to Alzheimer's disease, focusing on oxidative stress, metabolic dysfunction, and neurodegeneration.},
journal = {Genetics and molecular biology},
volume = {49Suppl 1},
number = {Suppl 1},
pages = {e20250233},
doi = {10.1590/1678-4685-GMB-2025-0233},
pmid = {42439783},
issn = {1415-4757},
abstract = {Advancing age has been associated with an imbalance between a gradual increase in reactive oxygen species (ROS) production and a decline in the efficiency of antioxidant defense mechanisms. Due to the fact that organisms are constantly exposed to endogenous and exogenous ROS sources, this condition of oxidative stress promotes a systemic pro-oxidant state that, in conjunction with many other risk factors, progressively worsens throughout life, triggering the development of chronic diseases, such as type 2 diabetes (T2D) and Alzheimer's disease (AD). These diseases have emerged as closely interconnected conditions that share some common molecular and cellular mechanisms. In this review, on the light of literature data, we explore the interconnection between several pathological processes implicated in both diseases, focusing on a series of cellular and molecular alterations, from metabolic dysfunction to neurodegeneration (including insulin resistance, oxidative stress, mitochondrial and endoplasmic reticulum dysfunction, among others). We highlight how the connection between those processes may culminate in the development of neurodegeneration and disease progression. Furthermore, we discuss the challenges and limitations to model those diseases, emphasizing some aspects of the current knowledge in terms of providing new perspectives to the development of multi-target therapeutic approaches.},
}

@article {pmid42439854,
year = {2026},
author = {Assafa, TE and Dzikovski, B and Lai, AL and Freed, JH and Srivastava, M},
title = {Detergent-like Toxicity Mechanism of Amyloid Cylindrins Revealed by Cross-Link Spin Labeling Electron Spin Resonance.},
journal = {Journal of the American Chemical Society},
volume = {},
number = {},
pages = {},
doi = {10.1021/jacs.6c03827},
pmid = {42439854},
issn = {1520-5126},
abstract = {Amyloid oligomers are considered to be the most toxic species in neurodegenerative diseases, such as Alzheimer's, and Parkinson's, among others. A major challenge in studying amyloid oligomers has been their heterogeneous character, coupled with a lack of methods that can probe targeted, localized structural information. In this paper, we show that in detergent micelles, the oligomeric state of amyloid cylindrin peptide K11 V increases from a hexamer to an octamer. This reveals a detergent-like toxicity mechanism of the K11 V peptide, in which the octamer-form extracts lipids from biological membranes. The findings are confirmed by Alphafold simulations, showing that the octamer has a β-barrel structure, with a pore stabilized by using the unbranched hydrophobic tails of the detergent molecules. The experimental results are obtained by a unique electron spin resonance (ESR)-based methodology that can be applied to amyloidogenic proteins to uncover inaccessible amyloid oligomer structures. The process involves (1) stabilization of the minimal amyloid oligomer domain, using a cross-linking bifunctional nitroxide spin label, combined with (2) an oligomer stabilizing mutation, (3) DEER spectroscopy, which can be performed in a native environment, and (4) T1-edited DEER measurements, which can validate structure in samples with heterogeneous populations, combined with (5) a model-free distance reconstruction approach that can analyze distance distributions with inverted distance components, ideal for analysis of T1-edited DEER.},
}

@article {pmid42440180,
year = {2026},
author = {Mohamadpour, M and Amandadi, M and Javan, M and Hosseinkhani, S},
title = {A Combination of Artemisinin, N-acetylcysteine, Resveratrol, and Hesperidin Ameliorates Hippocampal Damage and Pathological Features in an Experimental Model of Alzheimer's Disease.},
journal = {Neurochemical research},
volume = {51},
number = {4},
pages = {},
pmid = {42440180},
issn = {1573-6903},
mesh = {Animals ; *Resveratrol/therapeutic use/administration & dosage ; *Alzheimer Disease/drug therapy/pathology/chemically induced/metabolism ; *Hippocampus/drug effects/pathology/metabolism ; *Hesperidin/therapeutic use/administration & dosage ; *Acetylcysteine/therapeutic use/administration & dosage ; Male ; *Artemisinins/therapeutic use/administration & dosage ; *Neuroprotective Agents/therapeutic use/administration & dosage ; Rats ; Disease Models, Animal ; Drug Therapy, Combination ; Streptozocin ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; Maze Learning/drug effects ; Rats, Sprague-Dawley ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive impairment and pathological accumulation of amyloid-β and tau proteins. This study investigated the potential neuroprotective effects of a combined treatment consisting of artemisinin, N-acetylcysteine, resveratrol, and hesperidin in a streptozotocin (STZ)-induced intracerebroventricular (ICV) rat model of AD. Twenty 8-week-old rats were divided into four groups: control, SHAM, STZ-ICV, and STZ-ICV receiving oral administration of the compound combination for 30 days. Cognitive performance was evaluated using the Morris water maze and passive avoidance tests. Neurodegenerative and molecular changes were assessed through Western blot analysis of phosphorylated tau, amyloid-β-related markers, and apoptosis- and inflammation-associated proteins. Histological analyses included Nissl staining and immunofluorescence for amyloid deposition and caspase-3 expression. Results demonstrated that STZ-ICV administration induced significant cognitive impairment, neuronal loss, and increased amyloid-β and phosphorylated tau levels. Treatment with the combined compounds partially improved behavioral performance and was associated with reductions in amyloid-β deposition, tau phosphorylation, and caspase-3 expression, along with improved neuronal preservation in the hippocampus. These findings suggest that the combined administration of artemisinin, N-acetylcysteine, resveratrol, and hesperidin exerts multi-target neuroprotective effects in an experimental AD model, potentially through modulation of oxidative stress, neuroinflammation, and apoptotic pathways. However, further studies are required to evaluate pharmacokinetics, safety, and translational relevance before clinical application.},
}

Animals
*Resveratrol/therapeutic use/administration & dosage
*Alzheimer Disease/drug therapy/pathology/chemically induced/metabolism
*Hippocampus/drug effects/pathology/metabolism
*Hesperidin/therapeutic use/administration & dosage
*Acetylcysteine/therapeutic use/administration & dosage
Male
*Artemisinins/therapeutic use/administration & dosage
*Neuroprotective Agents/therapeutic use/administration & dosage
Rats
Disease Models, Animal
Drug Therapy, Combination
Streptozocin
Amyloid beta-Peptides/metabolism
tau Proteins/metabolism
Maze Learning/drug effects
Rats, Sprague-Dawley

@article {pmid42440182,
year = {2026},
author = {Chijioke, BS and Ben-Azu, B and Esuku, DT and Nekabari, MK and Usin, SG and Friday, FB and Iwhiwhu, P and Moses, AS and Chidebe, EO and Nwawuba, S},
title = {Silymarin attenuates senescence-exacerbated amyloidogenesis, neuroinflammation, and oxidative stress in lipopolysaccharide-induced memory impairment in aging mice.},
journal = {Biogerontology},
volume = {27},
number = {4},
pages = {},
pmid = {42440182},
issn = {1573-6768},
mesh = {Animals ; *Oxidative Stress/drug effects ; *Silymarin/pharmacology ; Lipopolysaccharides ; Female ; *Memory Disorders/chemically induced/drug therapy/metabolism ; *Aging/drug effects/metabolism ; Mice ; Antioxidants/pharmacology ; *Neuroinflammatory Diseases/metabolism/drug therapy ; Doxycycline ; },
abstract = {Accelerated cellular perturbations such as cellular senescence, neuroinflammation and oxidative stress are hallmarks of Alzheimer's disease, a neurodegenerative disease associated with memory decline. However, the senolytic effects of silymarin, a flavonolignan with known antioxidant and anti-inflammatory properties, on memory decline remain unknown. Hence, we investigated the effect of silymarin on doxycycline-mediated senescence and exacerbated neuroinflammation in lipopolysaccharide-induced memory-impaired mice. Five groups of adult Swiss female mice (n = 10) were exposed to doxycycline-induced accelerated senescence for 21 days, followed by lipopolysaccharide-induced neuroinflammation from days 15-21, and silymarin (50 and 100 mg/kg, p.o.) or donepezil (1 mg/kg, p.o.) treatments. Spatial and non-spatial memory, and social and motor function tests in mice were assessed. Biochemical assays were performed on the prefrontal cortex and hippocampus to assess senescence-associated secretory phenotypes (SASPs), including SA-β-galactosidase activity, cytokines (TNF-α, IL-6, IL-10), amyloid-beta levels, acetylcholinesterase activity, oxidative stress markers, and molybdoenzymes. Doxycycline-lipopolysaccharide-exacerbated memory impairments were reversed by silymarin, accompanied by reduced molybdoenzymes, malondialdehyde, nitrite, and elevated antioxidants (glutathione, superoxide-dismutase, catalase) in the prefrontal cortex and hippocampus. Additionally, silymarin reverses doxycycline-exacerbated lipopolysaccharide-induced increases in IL-6 and TNF-α release and myeloperoxidase activity while also reducing IL-10 levels. Similar to donepezil, silymarin reduced heightened acetylcholinesterase activity associated with doxycycline-enhanced lipopolysaccharide-induced accumulation of cortical SA-β-galactosidase and amyloid-β levels, relative to the doxycycline-lipopolysaccharide group. These findings suggest that silymarin ameliorates doxycycline-lipopolysaccharide-exacerbated memory impairment and modulates senescence and neuroinflammation by reducing oxidative stress, SASP marker levels, and amyloid-beta concentrations in the prefrontal cortex and hippocampus of mouse brains.},
}

Animals
*Oxidative Stress/drug effects
*Silymarin/pharmacology
Lipopolysaccharides
Female
*Memory Disorders/chemically induced/drug therapy/metabolism
*Aging/drug effects/metabolism
Mice
Antioxidants/pharmacology
*Neuroinflammatory Diseases/metabolism/drug therapy
Doxycycline

@article {pmid42440193,
year = {2026},
author = {Adiniaev, Y and Omar, M and Daniel, O and Timor, TM and Barash, Y and Brook, OR and Klang, E and Gorenshtein, A},
title = {Generative large language models in the clinical management of Alzheimer's disease and mild cognitive impairment.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {8},
pages = {},
pmid = {42440193},
issn = {1590-3478},
mesh = {Humans ; *Alzheimer Disease/therapy/diagnosis ; *Cognitive Dysfunction/therapy/diagnosis ; *Large Language Models ; Generative Artificial Intelligence ; },
abstract = {BACKGROUND: Dementia affects over 55 million people worldwide. Mild cognitive impairment (MCI) often precedes Alzheimer's disease (AD). Clinical management requires integrating uncertain evidence from neuropsychological testing, neuroimaging, and biomarkers. Large language models (LLMs) also generate probabilistic outputs, but whether they can reliably support diagnostic, therapeutic, or educational tasks in AD and MCI has not been systematically examined.

METHODS: We searched PubMed, Scopus, and PubMed Central (January 2023 to April 2026) for studies evaluating generative LLMs on clinical tasks in Alzheimer's disease (AD) or mild cognitive impairment (MCI). Risk of bias was assessed using QUADAS-AI and AXIS. Narrative synthesis followed the SWiM guideline.

PROSPERO: CRD420261372436.

RESULTS: Eleven studies were included: diagnosis (n = 3), treatment guidance (n = 2), and patient/caregiver education (n = 8); two studies contributed to multiple domains. Diagnostic models achieved high internal accuracy (0.94-0.97) but declined on external validation; three-way classification accuracy dropped approximately 7% points, and MMSE-prediction R² collapsed from 0.90 to 0.25 on an external dataset. Treatment guidance approached but did not match structured clinical guidelines. Educational outputs were rated moderate to high quality but lacked source attribution and exceeded recommended reading levels; retrieval augmentation improved usability without improving accuracy. Hallucination was quantified in only 2 of 11 studies, and no study evaluated prospective clinical use.

CONCLUSIONS: Current evidence does not support the use of LLMs for diagnosis, treatment selection, or patient education in AD/MCI without clinician oversight. These findings reflect the specific model versions, prompting strategies, and evaluation conditions in place at the time of each study, and are further limited by small heterogeneous evaluations, sparse hallucination measurement, and absence of prospective clinical validation.},
}

Humans
*Alzheimer Disease/therapy/diagnosis
*Cognitive Dysfunction/therapy/diagnosis
*Large Language Models
Generative Artificial Intelligence

@article {pmid42440235,
year = {2026},
author = {Arruda, JE and Dundon, NM and Jefferson, A and Jester, H and Ortega, A and Folk, E and Ibrahim, S and Mrahi, N and Wade, A},
title = {Improving the Reliability of the Flash Visual Evoked Potential P2 (FVEP-P2).},
journal = {Applied psychophysiology and biofeedback},
volume = {},
number = {},
pages = {},
pmid = {42440235},
issn = {1573-3270},
abstract = {Unlike the pattern-reversal visual evoked potential, the flash visual evoked potential (FVEP) has had limited clinical use because of lower reproducibility and higher inter- and intra-individual variability. One potential explanation involves the time-locked nature of FVEP recordings, where activity such as unintentional suppression of eyes-closed alpha can lead to overlapping potentials that might obscure the FVEP-P2. The present investigation evaluated the reliability of the FVEP-P2 in young healthy controls across five sessions after applying narrow-band filtering (1-7 Hz) and additional notch filtering to remove alpha and beta activity. It was hypothesized that spectral entrainment would occur within the alpha and that correction for this entrainment would significantly improve the reliability of FVEP-P2. 27 younger, healthy participants aged 18-39 years (M = 24.48, SD = 5.26; 17 females) took part in the study, all reporting no history of photosensitivity or seizures, neurological disorders, or color deficiency. Each participant experienced five sessions of 100 strobe flashes with their eyes closed. The FVEP-P2 associated with each trial was identified using an automated algorithm. Narrow-band filtering (1-7 Hz) significantly improved FVEP-P2 latency reliability compared to the uncorrected condition. Notch filters targeting alpha and beta separately did not produce significant improvements, suggesting additive or overlapping contributions. FVEP-P2 amplitude reliability also improved with filtering, primarily because of attenuating alpha-band interference. Narrow-band and notch filtering mitigated alpha- and beta-band interference, enhancing the test-retest reliability of the FVEP-P2. These findings establish a clearer physiological basis for FVEP unreliability and demonstrate that spectral correction can elevate the FVEP-P2 to clinically acceptable reliability levels, supporting the continued clinical utility of the FVEP, particularly in patients for whom pattern-reversal stimuli are unsuitable (e.g., infants, comatose, or uncooperative individuals) and as a candidate biomarker in mild cognitive impairment and Alzheimer's disease (Arruda et al., 2020; Fix et al., 2014).},
}

@article {pmid42440317,
year = {2026},
author = {Miner, AE and Zetterberg, H and Blennow, K and Groh, JR and Singh, A and Dieckhoff, K and Tripodis, Y and Adler, CH and Balcer, LJ and Bernick, C and Peskind, E and Asken, BM and Tanner, JA and Rabinovici, GD and Banks, SJ and Barr, WB and Wethe, JV and Cantu, RC and Dodick, DW and Mez, J and Palmisano, JN and Martin, B and Stein, TD and McKee, AC and Cummings, JL and Shenton, ME and Reiman, EM and Stern, RA and Ashton, NJ and Alosco, ML and , },
title = {Plasma Phosphorylated Tau 217 in Participants at Risk for Chronic Traumatic Encephalopathy.},
journal = {JAMA network open},
volume = {9},
number = {7},
pages = {e2622966},
doi = {10.1001/jamanetworkopen.2026.22966},
pmid = {42440317},
issn = {2574-3805},
mesh = {Humans ; Male ; *Chronic Traumatic Encephalopathy/blood/diagnosis ; *tau Proteins/blood ; Biomarkers/blood ; Case-Control Studies ; Middle Aged ; Longitudinal Studies ; Phosphorylation ; Amyloid beta-Peptides/blood ; Aged ; Adult ; },
abstract = {IMPORTANCE: In vivo biomarkers for detecting neuropathologies from repetitive head impacts (RHI), including chronic traumatic encephalopathy (CTE), are needed.

OBJECTIVE: To evaluate the utility of plasma phosphorylated tau 217 (p-tau217), assess its performance as a beta-amyloid (Aβ) biomarker in participants with RHI exposure at risk for CTE, and explore concordance with CTE neuropathology in a postmortem subsample.

This longitudinal, multicenter, case-control study used data from the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of CTE (DIAGNOSE CTE) Research Project, collected from September 2016 to October 2023. Participants were former American football players (case participants) and asymptomatic men unexposed to RHI (control participants). A subsample had available neuropathologic data.

EXPOSURES: RHI, traumatic encephalopathy syndrome (TES) diagnoses, and levels of CTE certainty.

MAIN OUTCOMES AND MEASURES: Plasma p-tau217 (classified as positive [≥0.63 pg/mL], intermediate [0.40-0.62 pg/mL], and negative [<0.40 pg/mL]), Aβ-positron emission tomography (PET; 18F-florbetapir; with Aβ-positive defined as a standardized uptake value ratio [SUVR] ≥1.10), and tau-PET (18F-flortaucipir). TES diagnoses were assigned by multidisciplinary consensus conference. Analyses of postmortem brains controlled for age, race, and APOE ε4 status.

RESULTS: Among 231 participants (mean [SD] age, 57.75 [8.25] years), 177 were former football players (117 professional and 60 college) and 54 were unexposed participants. Former football players had higher baseline mean (SD) p-tau217 concentrations than unexposed participants (0.35 [0.26] pg/mL vs 0.27 [0.14] pg/mL; P = .008), although this was driven by a higher proportion of Aβ-PET-positive participants among former players. Plasma p-tau217 increased over time across the sample (B = 0.207 [95% CI, 0.117-0.298]; P < .001), with no significant time × exposure group interactions. Among football players, p-tau217 showed no time × group interactions with TES diagnosis, TES-CTE certainty, or RHI metrics. Higher p-tau217 concentration correlated with higher global Aβ-PET SUVR (B = 0.058 [95% CI, 0.053-3.501; P = .01), with a few discordant cases (5 participants were p-tau217-negative and Aβ-PET-positive; 7 participants were p-tau217-positive and Aβ-PET-negative). P-tau217 had similar areas under the curve for projecting Aβ-PET positivity as cerebrospinal fluid (CSF) p-tau181/Aβ42 and CSF Aβ40/42 measures (p-tau217: AUC, 0.88 [95% CI, 0.80-0.96]; CSF p-tau181/Aβ42: AUC, 0.89 [95% CI, 0.79-1.00]; CSF Aβ40/42: AUC, 0.85 [95% CI, 0.72-0.98]). Among 9 brain donors, 6 had CTE (stages II-IV; none with Alzheimer disease). Seven had negative or intermediate p-tau217, concordant with Aβ-PET. Two p-tau217 outliers with stage III CTE had normal concentrations upon additional testing.

CONCLUSIONS AND RELEVANCE: The findings of this study suggest that plasma p-tau217 concentration is unlikely to be useful for the detection of CTE, but it does show utility for ruling out Aβ pathology in participants at risk for CTE.},
}

Humans
Male
*Chronic Traumatic Encephalopathy/blood/diagnosis
*tau Proteins/blood
Biomarkers/blood
Case-Control Studies
Middle Aged
Longitudinal Studies
Phosphorylation
Amyloid beta-Peptides/blood
Aged
Adult

@article {pmid42440519,
year = {2026},
author = {Lee, CC and Calegari, F},
title = {Enhancing adult neurogenesis attenuates hippocampal-related behavioral deficits in an Alzheimer's mouse model.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1833016},
doi = {10.3389/fnins.2026.1833016},
pmid = {42440519},
issn = {1662-4548},
abstract = {Alzheimer's disease (AD) is the most prevalent form of dementia, characterized by progressive memory loss, cognitive decline, and emotional dysregulation. Adult hippocampal neurogenesis (AHN) critically contributes to cognition and mood but undergoes precipitous decline during AD progression. Here, we investigated whether enhancing AHN through genetic expansion of endogenous neural stem cells (NSC) ameliorates AD-related phenotypes. Using lentiviral overexpression of the cell cycle regulators Cdk4 and CyclinD1 in the dentate gyrus of 3xTg-AD mice, we show that enhancing AHN is accompanied by partial improvements in selected behavioral measures associated with hippocampal function, including in the open-field test and Morris water maze. These findings indicate that the AD-compromised neurogenic niche remains responsive to NSC-targeted stimulation and support the use of AHN as a potential additional avenue for multi-modal therapeutic strategies for AD.},
}

@article {pmid42440553,
year = {2026},
author = {Dhivyabharathi, VR and Suresh Kumar, S},
title = {Hybridization of fuzzy logic based relevance vector and multi kernel image enhancement for Alzheimer's disease diagnosis.},
journal = {Health information science and systems},
volume = {14},
number = {1},
pages = {72},
doi = {10.1007/s13755-026-00465-8},
pmid = {42440553},
issn = {2047-2501},
abstract = {Alzheimer's disease (AD) is a progressive neurological disorder impacting a significant segment of the global population. Magnetic resonance imaging (MRI) is used to visualize brain structures and detect changes associated with AD. Early detection remains a major challenge, particularly for multiclass classification of disease severity. This paper presents an integrated hybrid framework for AD diagnosis combining Variational Mode Decomposition, fuzzy clustering, and multi-kernel learning. The proposed method comprises: (i) Variational Mode and Non-convex Optimized pre-processing for noise removal, (ii) Fuzzy Relevance Vector Machine-based segmentation to identify regions of interest, and (iii) Multi-Kernel SVM based clustering for classifying mild, moderate, and non-demented cases. The framework is validated on the Alzheimer's Disease Multiclass Images Dataset. Performance is evaluated using peak signal-to-noise ratio (PSNR), segmentation accuracy, training time, and precision. The results demonstrate that systematic integration of these established techniques achieves competitive performance, with average PSNR of 28.45 dB, segmentation accuracy of 91%, and precision of 90.6%.},
}

@article {pmid42440589,
year = {2026},
author = {Huang, X and Xu, G and Zhou, Y and Wang, D and Ai, L and Liu, H and Fan, A and Wang, L and Zhang, P},
title = {P2-engineered exosomes encapsulating curcumin alleviate cognitive decline in AD-like mice by improving microglia-related neuropathology.},
journal = {Materials today. Bio},
volume = {39},
number = {},
pages = {103388},
doi = {10.1016/j.mtbio.2026.103388},
pmid = {42440589},
issn = {2590-0064},
abstract = {Natural exosomes, as drug carriers, can deliver anti-inflammatory agents across the blood-brain barrier (BBB) to lesion sites in the brain, thereby demonstrating immense potential in the treatment of brain inflammation-related diseases. However, the application of natural exosomes is constrained by their poor targeting ability. Herein, we report a novel drug delivery system (P2-Exo-Cur) constructed by engineering exosomes to display the P2 peptide on their surface, thereby enabling targeted delivery of curcumin to microglia. Our results revealed that P2-Exo-Cur possesses a nanoscale membrane structure and can efficiently deliver curcumin to microglia both in vitro and in vivo. This technology provides a microglia-targeted delivery approach for anti-inflammatory agents such as curcumin, while overcoming the undesirable off-target effects that limit their efficacy. Furthermore, treatment of lipopolysaccharide (LPS)-induced inflammatory BV2 cell models with P2-Exo-Cur significantly suppressed the polarization of BV2 cells toward the M1 phenotype, as well as the secretion of pro-inflammatory cytokines. Finally, we also validated the excellent therapeutic potential of this technology in the 5xFAD mouse model. In conclusion, in this study, we for the first time constructed engineered exosomes that can specifically bind to the NCAM protein on microglia to achieve precise delivery of curcumin by expressing the P2 peptide on their surface, exerting beneficial effects in AD treatment without causing significant adverse effects. This strategy may offer a non-invasive and innovative therapeutic method for the management of brain inflammation-related diseases.},
}

@article {pmid42440665,
year = {2026},
author = {Han, J and Sun, Y and Song, Y and Wu, Y and Wang, X},
title = {The latest research progress of ligustilide in the prevention and treatment of central nervous system disorders.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1843537},
doi = {10.3389/fphar.2026.1843537},
pmid = {42440665},
issn = {1663-9812},
abstract = {BACKGROUND: Ligustilide (LIG), a natural phthalide compound mainly isolated from Angelica sinensis and Ligusticum chuanxiong, has attracted increasing attention because of its diverse pharmacological activities, including anti-inflammatory, antioxidant, anti-apoptotic, and neuroprotective effects. Emerging studies suggest that LIG may have therapeutic relevance in central nervous system (CNS) disorders.

PURPOSE: This review systematically summarizes the pharmacological effects, molecular mechanisms, pharmacokinetic characteristics, metabolism, safety profile, and therapeutic potential of LIG in CNS disorders.

METHODS: Relevant studies published up to 26 October 2025 were retrieved from PubMed, Web of Science, and Scopus using keywords related to ligustilide, central nervous system disorders, pharmacokinetics, metabolism, and toxicity. After removing duplicate records and excluding reviews, editorials, and irrelevant articles, 55 eligible original studies were included in this review.

RESULTS: Current evidence indicates that LIG exerts neuroprotective effects in multiple CNS disorders, including ischemic stroke, cerebral ischemia-reperfusion injury, vascular dementia, Alzheimer's disease, Parkinson's disease, traumatic brain injury, and anxiety disorders. Its mechanisms mainly involve modulation of PI3K/Akt, MAPK, NF-κB, Nrf2/ARE, AMPK, and other signaling pathways, leading to reduced oxidative stress, inflammation, apoptosis, and mitochondrial dysfunction. In addition, available studies suggest that LIG can cross the blood-brain barrier and shows relatively favorable safety in preclinical models.

CONCLUSION: LIG demonstrates broad neuroprotective potential in preclinical studies and may represent a promising candidate for CNS disease intervention. However, its poor chemical stability, low oral bioavailability, limited toxicity evaluation, and lack of clinical evidence remain major challenges for translational application. Further studies are required to optimize delivery strategies and validate its efficacy and safety in clinical settings.},
}

@article {pmid42440686,
year = {2026},
author = {Feng, X and Bi, S and Shi, C and Chang, Q and Zhang, J and Zhuang, Y},
title = {Comparison of safety of lecanemab and donanemab: a real-world disproportionality analysis using the FDA adverse event reporting system.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1868789},
doi = {10.3389/fphar.2026.1868789},
pmid = {42440686},
issn = {1663-9812},
abstract = {BACKGROUND: Lecanemab and donanemab are anti-amyloid-β (Aβ) monoclonal antibodies recently approved for the treatment of Alzheimer's disease (AD). Although both agents have demonstrated therapeutic potential, their post-marketing adverse event reporting profiles remain insufficiently characterized and compared in spontaneous reporting systems. This study aimed to systematically compare adverse event signals associated with these two drugs using the FDA Adverse Event Reporting System database, with sex-stratified and sensitivity analyses performed to support the main findings.

METHODS: FAERS reports up to the fourth quarter of 2025 were retrospectively analyzed. Reports in which lecanemab or donanemab was recorded as the primary suspect drug were included. AEs were classified by system organ classes (SOCs) and preferred terms (PTs) according to the Medical Dictionary for Regulatory Activities (MedDRA). Signal detection was performed using four algorithms: reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS). Sex-stratified analysis, sensitivity analysis after excluding reports involving concomitant medications, and time-to-onset (TTO) analysis based on the Weibull shape parameter model were also conducted. False discovery rate (FDR) correction was applied to analyses involving multiple P values.

RESULTS: A total of 3,640 AE reports were identified, including 2,602 for lecanemab and 1,038 for donanemab. Nervous system disorders was the most frequently reported SOC and the only SOC meeting the positivity criteria across all four algorithms for both drugs. At the PT level, the frequently reported events for both drugs were mainly concentrated in amyloid-related imaging abnormality (ARIA)-related events, including ARIA with oedema/effusion (ARIA-E) and ARIA with microhaemorrhages/haemosiderin deposition (ARIA-H), headache, and infusion-related reactions. The strongest disproportionality reporting signals were mainly observed for ARIA-related preferred terms and cerebral microhaemorrhage. In separate FAERS-based disproportionality analyses, lecanemab showed stronger disproportionality reporting signals for ARIA-H, whereas donanemab showed stronger disproportionality reporting signals for ARIA-E. In addition, drug-specific PT signal distributions differed between the two agents. Several potential novel PT signals were also identified. Sex-stratified analysis suggested differences in the distribution of certain PT signals between female and male reports. Sensitivity analysis supported the stability of most core signals. The median TTO was 46 days for lecanemab and 31 days for donanemab, and Weibull analysis suggested different temporal patterns of AE occurrence.

CONCLUSION: Using four signal detection algorithms, this study compared real-world adverse event reporting profiles associated with lecanemab and donanemab. The two drugs showed both shared and distinct adverse event reporting profiles, particularly in ARIA subtype-related disproportionality signals, drug-specific PT signals, potential novel reporting signals, sex-stratified reporting patterns, and TTO characteristics. These findings provide pharmacovigilance evidence for targeted safety monitoring and hypothesis generation, but should not be interpreted as causal associations or true incidence estimates.},
}

@article {pmid42440728,
year = {2026},
author = {Badesso, S and Espelosín, M and Alonso, C and Montilla, A and Collantes, M and Cuadrado-Tejedor, M and García-Osta, A},
title = {Reprogramming lipid metabolism for cognitive restoration in Alzheimer's via PLA2G4E.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70285},
doi = {10.1002/trc2.70285},
pmid = {42440728},
issn = {2352-8737},
abstract = {INTRODUCTION: Growing evidence implicates dysregulated brain lipid metabolism in Alzheimer's disease (AD) pathogenesis, influencing membrane integrity, neuroinflammation, and amyloid beta and tau pathology, thereby representing a promising therapeutic target. However, therapeutic strategies targeting lipid pathways remain largely unexplored.

METHODS: The therapeutic potential of PLA2G4E, previously identified in our earlier work, was validated in the APP[NL-G-F] AD mouse model using a translational gene-delivery approach with a blood-brain barrier-penetrant adeno-associated vector (AAV) (AAVP31) to achieve widespread brain expression. Brain lipidomics was performed to investigate the molecular mechanisms underlying treatment effects.

RESULTS: PLA2G4E expression rescued memory deficits, reduced tau phosphorylation, and improved brain glucose metabolism and cognitive performance in AD models and aged wild-type mice. These effects were accompanied by partial normalization of disease-associated lipid metabolic alterations.

DISCUSSION: These findings support PLA2G4E as a promising therapeutic target in AD and provide mechanistic evidence linking modulation of lipid metabolic pathways to synaptic and cognitive rescue.},
}

@article {pmid42440762,
year = {2026},
author = {Xing, X and Wang, K and Feng, Y and Wu, C and Jia, L and Li, H and Wen, Z and Tang, Y and Wang, Z and Zhang, X and Li, X and Hua, Y and Zhang, L and Dong, X},
title = {Post-marketing safety of lecanemab: a real-world study based on FAERS database, multicenter cohort and network pharmacology.},
journal = {Frontiers in psychiatry},
volume = {17},
number = {},
pages = {1822543},
doi = {10.3389/fpsyt.2026.1822543},
pmid = {42440762},
issn = {1664-0640},
abstract = {INTRODUCTION: Lecanemab is a monoclonal antibody targeting amyloid-beta (Aβ) approved for treating Alzheimer's disease (AD) with mild cognitive impairment or mild dementia. Continuous monitoring of its real-world safety profile remains essential. This study aimed to analyze lecanemab-related adverse events (AEs) using the FDA Adverse Event Reporting System (FAERS) database and a multicenter cohort, and explored mechanisms via network pharmacology.

METHODS: We conducted an updated disproportionality analysis of FAERS data from 2023 to 2024 to identify disproportionate reporting signals (SDRs). A multicenter retrospective cohort study was performed, including lecanemab users from June 2024 to February 2025. Data were collected from electronic medical records of five tertiary hospitals. AEs were identified and influencing factors of AE occurrence were analyzed. Additionally, a drug-gene interaction network was constructed to explore potential mechanisms.

RESULTS: In the FAERS analysis of 2,764 AEs from 1,389 lecanemab users, 12 of 41 positive SDRs were prioritized, with 75% (9/12) being nervous system disorders, primarily amyloid-related imaging abnormalities (ARIA). In the cohort study, 29.05% (43/148) of patients experienced AEs, with infusion-related reactions being most common. Age was identified as a risk factor for AE occurrence [OR (95% CI): 1.109 (1.011-1.215), P = 0.028], while pre-treatment significantly reduced AE incidence. Gene enrichment analysis suggested potential links between lecanemab-related genes and AEs.

DISCUSSION: This study provides real-world evidence on the risk profile of lecanemab, highlighting the importance of continued safety monitoring. These findings may inform discussions about the risks associated with anti-amyloid treatments and warrant further confirmation in large-scale prospective studies.},
}

@article {pmid42440891,
year = {2026},
author = {Lautenbacher, S and Schreiber, V and Grupp, C and Carbon, CC and Kellner, H and Kunz, M},
title = {Pain differences in cognitive impairment appear only during active motor tasks.},
journal = {Frontiers in pain research (Lausanne, Switzerland)},
volume = {7},
number = {},
pages = {1849507},
doi = {10.3389/fpain.2026.1849507},
pmid = {42440891},
issn = {2673-561X},
abstract = {Cognitive impairment in older adults has been associated with altered pain processing and potentially increased pain vulnerability, although findings are inconsistent. We hypothesized that cognitive impairment has a stronger impact on movement-related pain in everyday contexts than on pain sensitivity assessed in passive laboratory settings. Thirty-eight cognitively healthy and 38 cognitively impaired older adults (50% women; groups age- and sex-matched), classified using the CERAD scale (Consortium to Establish a Registry for Alzheimer's Disease), completed standardized motor tasks (walking, bed mobility, lifting tasks) and experimental pressure and heat pain assessments. Pain intensity (NRS) was recorded for all tasks. Perceived exertion was assessed during motor tasks, and clinical pain status was determined via a structured interview. Groups did not differ in baseline clinical pain or experimental pain sensitivity. However, cognitively impaired participants reported significantly higher movement-related pain during motor tasks. In a blockwise regression model, movement-related pain was significantly predicted by clinical pain and experimental pain sensitivity; however cognitive status (CERAD) explained additional variance to a similar amount. In conclusion, reduced cognitive functioning significantly predicted increased pain during active, everyday motor tasks. This may reflect diminished capacities for recall, planning, and execution of pain-minimizing movement strategies. These findings underscore the importance of assessing pain in behaviorally relevant contexts where movement provokes pain, to better understand pain mechanisms in cognitively impaired older adults.},
}

@article {pmid42440956,
year = {2025},
author = {Alcina, J and Munera, D and Martinez, L and Giudicessi, A and Bonillas Félix, NA and Medrano, R and Martinez, JE and Solis, I and Tristão-Pereira, C and Malotaux, V and He, B and Ribas, A and Ramirez, NJ and Ramirez-Gomez, LA and Vila-Castelar, C and Gonzalez Catalan, M and Saldana, DG and Gatchel, JR and Quiroz, YT},
title = {Mild behavioral impairment and its relationship to cognition in community-dwelling older adults from the Boston Latino Aging Study.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {2},
pages = {e70121},
doi = {10.1002/dad2.70121},
pmid = {42440956},
issn = {2352-8729},
abstract = {BACKGROUND: Mild behavioral impairment (MBI) is associated with cognitive decline and dementia risk. This study assessed the relationship between MBI severity and cognition in community-dwelling older Latino adults.

METHODS: The cognitive function index (CFI) assessed subjective cognition, and the MBI-Checklist (MBI-C; self-report) measured MBI symptoms in 168 older Latinos (134 cognitively unimpaired, 34 with mild cognitive impairment). The Mini-Mental State Examination (MMSE) and NEUROPSI Delayed Word List Recall measured cognitive function. Linear regressions examined the impact of MBI-C symptoms on cognition, controlling for age, sex, and education.

RESULTS: The MBI domain of decreased motivation predicted subjective cognition and delayed verbal recall performance. The mood dysregulation domain predicted only subjective cognition. Neither domain predicted total MMSE scores.

DISCUSSION: MBI symptoms of decreased motivation and mood dysregulation influenced poorer subjective and objective cognition in Latinos, potentially signaling prodromal Alzheimer's related changes. These findings highlight the need to assess neuropsychiatric symptoms in this population.

HIGHLIGHTS: Decreased motivation predicted worse subjective cognition and verbal memory.Mood dysregulation only predicted worse subjective cognition.These findings were adjusted for age, sex, and education in Latino older adults.},
}

@article {pmid42441284,
year = {2026},
author = {Schlein, ML and Stephen, CA and Caldwell, GA and Ciesla, L and Caldwell, KA},
title = {An Alzheimer's disease-associated mutant of C. elegans displays mechanosensory sensitivity following exposure to lavender extracts.},
journal = {microPublication biology},
volume = {2026},
number = {},
pages = {},
doi = {10.17912/micropub.biology.002220},
pmid = {42441284},
issn = {2578-9430},
abstract = {Lavandula angustifolia (lavender) extract displayed antioxidant properties in mammalian studies and has been promoted as a candidate neurotherapeutic for Alzheimer's disease (AD). To better inform its clinical utility, we exposed wildtype (N2) and spr-4 mutant strains of C. elegans to extracts from this lavender species and examined animals for neurobehavioral changes in a mechanosensory phenotype. Importantly, spr-4 encodes the worm ortholog of repressor element 1-silencing transcription factor (REST), an established genetic modifier of AD. While low concentrations of lavender did not alter behavioral responses, spr-4 mutants selectively displayed neuronal vulnerability at the highest concentration tested, thereby revealing dose-responsive, lavender-associated neurotoxicity.},
}

@article {pmid42441387,
year = {2026},
author = {},
title = {Ceperognastat in Early Symptomatic Alzheimer Disease: Research Summary.},
journal = {JAMA},
volume = {},
number = {},
pages = {e2612911},
doi = {10.1001/jama.2026.12911},
pmid = {42441387},
issn = {1538-3598},
}

@article {pmid42441390,
year = {2026},
author = {Blazhenets, G and Soleimani-Meigooni, DN and Chiotis, K and Allen, IE and Rabinovici, GD and La Joie, R and , and Apostolova, LG and Asken, BM and Bejanin, A and Benzinger, TLS and Betthauser, TJ and Bluma, M and Bombois, S and Bourgeat, P and Bouteloup, V and Braskie, MN and Brendel, M and Brickman, AM and Bryant, N and Bullich, S and Carrillo, MC and Casaletto, K and Cash, DM and Chang, CC and Chang, HI and Chao, Y and Chêne, G and Chételat, G and Coath, W and Collij, LE and Colmant, L and Corrada, MM and Craft, S and Dickerson, BC and Dubois, B and Dufouil, C and Fajardo, A and Farrar, G and Fortea, J and Frings, L and Frisoni, GB and Gardner, RC and Garibotto, V and Gnörich, JS and Gordon, BA and Gu, Y and Guan, Y and Guo, T and Hanseeuw, BJ and Hansson, O and Harrison, TM and Huang, Q and Huang, SH and Iaccarino, L and Ishii, K and Ishi, K and Jagust, WJ and Johnson, SC and Kato, T and Katsumi, Y and Kaye, J and Koeppe, RA and Kolinger, GD and Kramer, JH and Landau, SM and Landeau, B and Lao, PJ and Lee, S and Lleó, A and Lopresti, BJ and Lowe, VJ and Luchsinger, JA and Malpetti, M and Mao, X and March, A and Masters, CL and Meyer, PT and Mezenge, F and Mormino, EC and Franquesa-Mullerat, M and Nakamura, A and Nordberg, A and O'Brien, JT and O'Bryant, SE and Pappas, I and Peretti, DE and Quenon, L and Rowe, CC and Rowe, JB and Rudolph, MD and Salvadó, G and Schott, JM and Schwartz, DL and Schwarz, CG and Seo, SW and Shekari, M and Silbert, LC and Smith, R and Snyder, HM and Sokolowski, A and Sperling, RA and Sun, P and Taggett, JZ and Toga, AW and Touroutoglou, A and Vaillancourt, DE and van de Giessen, E and Vijverberg, J and Vemuri, P and Villain, N and Villemagne, VL and Villeneuve, S and Wang, WE and Weiner, M and Woodworth, D and Xiao, C and Xie, F and Yoon, Y and Young, CB and Yun, M and , },
title = {Amyloid PET Quantitation and Centiloid Thresholds in the Diagnosis of Alzheimer Disease: An Individual Participant Data Meta-Analysis.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2026.13116},
pmid = {42441390},
issn = {1538-3598},
abstract = {IMPORTANCE: Amyloid positron emission tomography (PET) is increasingly used in research and clinical settings to determine the etiology of cognitive decline and eligibility for amyloid-targeting therapies. To assist with amyloid PET evaluation and to guide clinical decision-making, images can be quantified in a standardized unit called Centiloid, the interpretation of which can vary according to the method and threshold used.

OBJECTIVE: To collect Centiloid values from available studies and determine robust positivity cutoffs using data-driven methods and correspondence with visual reads.

DATA SOURCES: PubMed search (October 2024) identified studies with Centiloid values. Corresponding authors were invited to share individual participant data. Additional data were obtained through access-controlled repositories and conference outreach (July 2024-July 2025).

STUDY SELECTION: Studies were included if they provided Centiloids, radiotracer, age, and sex.

DATA EXTRACTION AND SYNTHESIS: Each study was analyzed using a unified statistical pipeline; study estimates were pooled using random-effects meta-analysis.

MAIN OUTCOMES AND MEASURES: Gaussian mixture models (GMMs) were fitted to Centiloid values for each study. In studies with a bimodal distribution (per integrated completed likelihood), single cutoffs for positivity were set as mean plus 2 SDs of the lower gaussian component. Using GMMs, a double-cutoff approach defined a lower certainty range using a 90% posterior probability cutoff for assignment to the low (amyloid-negative) vs high (amyloid-positive) component. An alternative Centiloid cutoff was derived from maximizing the correspondence (Cohen κ) with the binary visual reads when available.

RESULTS: This meta-analysis included cross-sectional amyloid PET scans acquired with 5 radiotracers from 49 227 participants across 53 studies from 15 countries (mean age, 71 years; 54% female, 62% cognitively impaired). The data-driven GMM approach identified a bimodal distribution in 51 studies (n = 48 786), resulting in a single cutoff for positivity of 18 Centiloids (95% CI,16-19; I2 = 97%). The double-cutoff approach revealed high confidence for interpreting scans as negative when Centiloid values were lower than 11 (95% CI, 9-13; I2 = 95%) and interpreting scans as positive if Centiloid values were higher than 26 (95% CI, 24-28; I2 = 95%). In analyses of correspondence with binary (positive or negative) visual reads of amyloid PET scans (n = 35 045; 36 studies), Centiloids were highly predictive of visual positivity (Cohen κ, 0.86; 95% CI, 0.83-0.89; I2 = 96%) with a cutoff of 27 Centiloids (95% CI, 24-30; I2 = 80%).

CONCLUSIONS AND RELEVANCE: In this individual participant data meta-analysis, positivity cutoffs converged around 18 Centiloids (data-driven) and 27 Centiloids (visual reads). Findings from a double-cutoff analysis suggest that scans in the 11 to 26 Centiloid range should be interpreted with caution depending on the context of use.},
}

@article {pmid42441396,
year = {2026},
author = {Fleisher, AS and Munsie, L and Mancini, M and Cheng, YJ and Guo, J and Nuthall, H and Otero, DS and Kotari, V and Kielbasa, W and Hutton, M and Brys, M and Mergott, DJ and Mintun, M and Hansson, O},
title = {Ceperognastat in Early Symptomatic Alzheimer Disease: A Randomized Clinical Trial.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2026.12768},
pmid = {42441396},
issn = {1538-3598},
abstract = {IMPORTANCE: Inhibiting O-linked N-acetylglucosaminidase (OGA) is hypothesized to slow accumulation of aggregated, hyperphosphorylated tau and neurofibrillary tangle formation.

OBJECTIVE: To evaluate the efficacy and safety of the potent oral OGA inhibitor ceperognastat in early symptomatic Alzheimer disease (AD).

This double-blind, randomized, placebo-controlled phase 2 study was conducted at 72 sites in 5 countries from September 2021 to August 2024, with a posttreatment observational extension period through May 2025. The primary outcome population comprised participants with early symptomatic AD and biomarker evidence of tau pathology, including low to medium baseline tau levels (excluding individuals with high levels), as measured by positron emission tomography (PET) with flortaucipir F18.

INTERVENTION: Participants were randomized 1:1:1 to receive once-daily, oral ceperognastat at doses of 0.75 mg (n = 110) or 3 mg (n = 108) or placebo (n = 108).

MAIN OUTCOMES AND MEASURES: The primary outcome was change in Integrated AD Rating Scale (iADRS) score. The success criterion was a 60% or greater probability of achieving greater than or equal to 25% slower progression vs placebo using a bayesian probabilistic disease progression model. The 6 secondary outcomes were Alzheimer's Disease Assessment Scale-Cognitive Subscale, 13-item version; Alzheimer's Disease Cooperative Study-Activities of Daily Living scale; Clinical Dementia Rating-Sum of Boxes; Mini-Mental State Examination; tau PET; and volumetric magnetic resonance imaging.

RESULTS: Of the 327 randomized participants (mean age, 73.4 years; 201 [61.5%] females), 259 (87 receiving ceperognastat 0.75 mg, 86 receiving ceperognastat 3 mg, and 86 receiving placebo) with low to medium baseline tau levels were included in the primary outcome population (mean age, 74.3 years; 161 [62.2%] females). In this population, no clinically meaningful benefit vs placebo was observed for the primary end point (iADRS score) at 100 weeks: posterior mean change from baseline was -8.39 with ceperognastat 0.75 mg, -13.27 with ceperognastat 3 mg, and -10.07 with placebo. The disease progression ratio relative to placebo was 0.84 (95% credible interval [CrI], 0.66-1.04) for the ceperognastat 0.75 mg group and 1.32 (CrI, 1.10-1.58) for the ceperognastat 3 mg group, corresponding to 16% less and 32% greater progression, respectively. No benefits were demonstrated for secondary clinical end points. From baseline to 76 weeks, least-squares mean change in standardized uptake value ratio on PET showed a statistically significantly smaller increase (P = .04) vs placebo only for the ceperognastat 3 mg group in the lateral temporal lobe. Volumetric magnetic resonance imaging showed less whole brain volume loss in participants treated with ceperognastat vs placebo (43.2% [ceperognastat 0.75 mg] and 49.5% [ceperognastat 3 mg] less vs placebo; both P < .001). The ceperognastat 3 mg group had more serious (ceperognastat 0.75 mg: n = 13 [12.0%]; ceperognastat 3 mg: n = 29 [26.4%]; placebo: n = 17 [15.7%]) and severe (ceperognastat 0.75 mg: n = 7 [6.5%]; ceperognastat 3 mg: n = 15 [13.6%]; placebo: n = 7 [6.5%]) treatment-emergent adverse events.

CONCLUSIONS AND RELEVANCE: Ceperognastat did not slow disease progression of early symptomatic AD.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05063539.},
}

@article {pmid42441398,
year = {2026},
author = {Rabinovici, GD and Grill, JD},
title = {Ceperognastat in Alzheimer Disease: Lessons From a Negative Clinical Trial.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2026.12323},
pmid = {42441398},
issn = {1538-3598},
}

@article {pmid42441402,
year = {2026},
author = {Vetere, LM and Galas, AM and Vaughan, N and Kohler, C and Feng, Y and Christenson Wick, Z and Philipsberg, PA and Liobimova, O and Gordon, KE and Fernandez-Ruiz, A and Cai, DJ and Shuman, T},
title = {Medial entorhinal-hippocampal desynchronization parallels the emergence of memory impairment in a mouse model of Alzheimer's disease pathology.},
journal = {Cell reports},
volume = {45},
number = {7},
pages = {117646},
doi = {10.1016/j.celrep.2026.117646},
pmid = {42441402},
issn = {2211-1247},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive impairments in episodic and spatial memory, as well as circuit and network-level dysfunction. While functional impairments in medial entorhinal cortex (MEC) and hippocampus (HPC) have been observed in patients and rodent models of AD, it remains unclear how communication between these regions breaks down in disease, and what specific physiological changes are associated with the onset of memory impairment. Here, we use silicon probes to simultaneously record neural activity in MEC and HPC before or after the onset of spatial memory impairment in the 3xTg mouse model of AD pathology. We find that reduced hippocampal theta power, reduced MEC-CA1 theta coherence, and altered phase locking of MEC and hippocampal neurons all coincide with the emergence of spatial memory impairment in 3xTg mice. Together, these findings suggest that disrupted temporal coordination of neural activity in the MEC-hippocampal system parallels the emergence of memory impairment in a model of AD pathology.},
}

@article {pmid42441421,
year = {2026},
author = {Wang, L and Cai, Q and Yang, Y and Zhou, Y and Liu, Y and Wu, P and Liu, J and Liu, Y},
title = {A Multitarget Nanosystem Loaded with Donepezil for Alzheimer's Disease Treatment by Activating Mitophagy and Reshaping the Inflammatory Microenvironment.},
journal = {ACS applied materials & interfaces},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsami.6c05393},
pmid = {42441421},
issn = {1944-8252},
abstract = {A paradigm shift from single-target interventions toward multitarget synergistic actions is increasingly recognized as a promising therapeutic approach for Alzheimer's disease (AD). Given this, an oxidative stress-responsive nanocomposite, RuO2-TPP/Don@BSA (RDB), was developed to enable effective AD therapy via a "cocktail strategy". Utilizing bovine serum albumin (BSA), the system crosses the blood-brain barrier (BBB) through gp60 receptor-mediated endocytosis. Within the AD brain microenvironment, RDB undergoes disulfide bond cleavage in response to elevated H2O2 levels, thereby releasing donepezil (Don) and RuO2-TPP in a stimuli-responsive manner. Meanwhile, RuO2-TPP escapes from lysosomes, targets mitochondria, and interrupts the oxidative stress cascade, further repairing mitochondrial dysfunction and activating mitophagy. Moreover, RDB promotes the polarization of microglia from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, thereby reshaping the inflammatory microenvironment of AD. Finally, RDB demonstrated significant efficacy in APP/PS1 transgenic AD mice, markedly reducing hippocampal expression of GFAP and Iba-1, concomitant with a notable improvement in cognitive dysfunction. In summary, these findings establish RDB as a multitarget synergistic therapeutic system that offers a promising strategy for the treatment of AD.},
}

@article {pmid42441515,
year = {2026},
author = {Xu, S and Zhang, J and Mao, R and Yang, S and Zhao, D and Yang, W},
title = {Evaluating Triptolide Effects on Hippocampal Gephyrin, Collybistin, and Autophagy in an Aβ1-42 Mouse Model.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {232},
pages = {},
doi = {10.3791/70397},
pmid = {42441515},
issn = {1940-087X},
mesh = {Animals ; *Amyloid beta-Peptides/administration & dosage ; *Hippocampus/drug effects/metabolism/pathology ; Mice ; *Diterpenes/pharmacology ; *Phenanthrenes/pharmacology ; *Alzheimer Disease/metabolism/drug therapy ; Mice, Inbred C57BL ; Disease Models, Animal ; *Membrane Proteins/metabolism/biosynthesis ; *Peptide Fragments/administration & dosage ; Epoxy Compounds/pharmacology ; *Carrier Proteins/metabolism/biosynthesis ; *Autophagy/drug effects ; Male ; },
abstract = {Alzheimer's disease is associated with synaptic dysfunction, but standardized procedures for evaluating how Aβ-induced pathology affects inhibitory synapse-associated proteins and autophagy-related signaling after candidate intervention remain limited. This protocol describes a workflow for establishing an Aβ1-42-induced Alzheimer's disease-like mouse model and assessing the effects of triptolide on hippocampal Gephyrin, Collybistin, PI3K/Akt/GSK-3β signaling, and autophagy-related markers. Adult C57BL/6J mice receive bilateral intracerebroventricular injection of Aβ1-42 prepared under aggregation-inducing conditions, followed by daily intraperitoneal administration of triptolide with or without the PI3K inhibitor LY294002. Spatial learning and memory are evaluated using Morris water maze testing. Hippocampal neuronal injury and Aβ deposition are assessed by hematoxylin and eosin staining and Aβ immunohistochemistry, and hippocampal lysates are analyzed by Western blotting to quantify Gephyrin, phosphorylated Gephyrin, Collybistin, PI3K/Akt/GSK-3β signaling proteins, LC3-II/I, and p62. Key procedural considerations include standardized Aβ1-42 preparation, accurate stereotaxic injection, consistent behavioral testing conditions, blinded region-of-interest selection, and standardized image and densitometry analysis. Using this workflow, Aβ1-42 administration produced spatial learning and memory deficits, hippocampal neuronal injury, Aβ deposition, reduced Gephyrin and Collybistin expression, altered PI3K/Akt/GSK-3β signaling, and increased LC3-II/I and p62 accumulation. Triptolide partially reversed these behavioral, histological, and molecular changes, whereas LY294002 attenuated its effects. This protocol can be used to evaluate Aβ-induced hippocampal molecular alterations and candidate interventions, while recognizing that this model does not reproduce the chronic, multifactorial progression of human Alzheimer's disease.},
}

Animals
*Amyloid beta-Peptides/administration & dosage
*Hippocampus/drug effects/metabolism/pathology
Mice
*Diterpenes/pharmacology
*Phenanthrenes/pharmacology
*Alzheimer Disease/metabolism/drug therapy
Mice, Inbred C57BL
Disease Models, Animal
*Membrane Proteins/metabolism/biosynthesis
*Peptide Fragments/administration & dosage
Epoxy Compounds/pharmacology
*Carrier Proteins/metabolism/biosynthesis
*Autophagy/drug effects
Male

@article {pmid42441681,
year = {2026},
author = {Carrasco-Vega, S and Millavil-Cofré, C and Soto-Labbé, M and Julio-Ramos, T and Godoy-Díaz, Á and Toloza-Ramirez, D},
title = {[Social Cognition and Theory of Mind as a Differential Marker Between Alzheimer's Disease and Behavioral Variant Frontotemporal Dementia].},
journal = {Revista medica de Chile},
volume = {154},
number = {4},
pages = {577-590},
doi = {10.4067/s0034-98872026000400577},
pmid = {42441681},
issn = {0717-6163},
mesh = {Humans ; *Theory of Mind/physiology ; *Alzheimer Disease/diagnosis/psychology/physiopathology ; *Frontotemporal Dementia/diagnosis/psychology/physiopathology ; *Social Cognition ; Diagnosis, Differential ; Neuropsychological Tests ; Biomarkers ; },
abstract = {UNLABELLED: While language, memory, and executive function have been proposed as differential markers between Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD), recent studies emphasize the role of Social Cognition (SC) and Theory of Mind (ToM) in distinguishing between these conditions.

AIM: To characterize SC and ToM performance in patients with AD and bvFTD.

METHODOLOGY: This review followed PRISMA guidelines and included studies published between January 2015 and March 2024 from PubMed, Scopus, and Web of Science.

RESULTS: Fourteen studies were critically analyzed. Findings suggest that SC and ToM are impaired in both disorders. In AD, the main deficits involve emotional recognition and perception, and social behavior. In bvFTD, common impairments include decision-making, emotion recognition, social behavior, and empathy loss.

CONCLUSIONS: SC and ToM may support the differential diagnosis between AD and bvFTD, particularly in early stages. Further research is needed to develop standardized assessments for clinical use to detect and classify the severity of SC and ToM decline.},
}

Humans
*Theory of Mind/physiology
*Alzheimer Disease/diagnosis/psychology/physiopathology
*Frontotemporal Dementia/diagnosis/psychology/physiopathology
*Social Cognition
Diagnosis, Differential
Neuropsychological Tests
Biomarkers

@article {pmid42441749,
year = {2026},
author = {Wolff, T and Joblin, C and Banner, K and Murawski, A and Janulis, P and Ramirez-Zohfeld, V and Olvera, C and Lindquist, L and Birkett, M},
title = {Caregiver Networks of Older Adults With Alzheimer Disease: Design and Protocol for a Multisite Study Using Network Canvas.},
journal = {JMIR research protocols},
volume = {15},
number = {},
pages = {e98270},
doi = {10.2196/98270},
pmid = {42441749},
issn = {1929-0748},
mesh = {Humans ; *Caregivers/psychology ; *Alzheimer Disease/psychology/complications ; Aged ; *Social Support ; Female ; Male ; Research Design ; Social Networking ; },
abstract = {BACKGROUND: Patients with Alzheimer disease commonly rely on family caregivers for daily functioning. Research shows that relationships between caregivers and persons with memory loss have important effects on the health and well-being of both caregivers and persons with memory loss. However, most studies rely on a single caregiver-person with memory loss dyad as the unit of analysis, thereby neglecting the broader network of caregivers who collectively shape care experiences and outcomes.

OBJECTIVE: This study develops a conceptual and methodological framework for studying caregiver networks and investigates how the properties of caregiver networks relate to health and well-being outcomes for both persons with memory loss and caregivers. It measures and maps the social networks of caregivers of persons with memory loss while examining population heterogeneity in caregiver relationships and identifying network-based predictors of well-being for both caregivers and persons with memory loss.

METHODS: Our team is conducting a large multilocation (Illinois, Indiana, and Hawaii) study comprising 200 caregiver networks of persons with memory loss, supported by data from persons with memory loss and their caregivers. Networks will be collected using cutting-edge Network Canvas software tools, developed by members of our team within the Complex Data Collective, and analyzed using both quantitative and mixed methods.

RESULTS: This study was funded in August 2023 by the National Institutes of Health (R01AG083034), with an expected end date of July 2028. This study protocol was approved by the institutional review board of Northwestern University (STU00219675) and was piloted internally before participant recruitment began in January 2025. As of March 2026, a total of 155 participants have been enrolled. Enrollment is planned to end by April 2027, with results expected between August 2027 and November 2027.

CONCLUSIONS: This study advances research on caregivers of persons with memory loss by operationalizing a scalable and replicable approach to measuring caregiver networks. The ability to easily measure and identify structural features of caregiver systems helps in identifying predictors of caregiver experiences and outcomes and provides large benefits for the caregiver-person with memory loss research community.},
}

Humans
*Caregivers/psychology
*Alzheimer Disease/psychology/complications
Aged
*Social Support
Female
Male
Research Design
Social Networking

@article {pmid42441927,
year = {2026},
author = {Coysh, T and Laban, R and Veleva, E and Heslegrave, AJ and Darwent, L and Holm-Mercer, L and Mok, TH and Hart, MS and Lunn, MP and Keshavan, A and Schott, JM and Jaunmuktane, Z and Brandner, S and Gonzalez-Ortiz, F and Blennow, K and Zetterberg, H and Collinge, J and Mead, S},
title = {Performance of Alzheimer Disease Plasma Biomarkers in Patients With Prion Diseases.},
journal = {Neurology},
volume = {107},
number = {3},
pages = {e214712},
doi = {10.1212/WNL.0000000000214712},
pmid = {42441927},
issn = {1526-632X},
abstract = {BACKGROUND AND OBJECTIVES: Prion diseases can mimic Alzheimer disease (AD) at presentation. Alzheimer's Association AD diagnostic criteria suggest that a single abnormal highly specific plasma biomarker (including p-tau217) is sufficient for a biological diagnosis. We investigated the performance of AD plasma biomarkers in distinguishing AD and prion diseases.

METHODS: We examined plasma biomarker data from patients with prion disease from a prospective cohort study recruited through the UK National Prion Clinic. Prion diseases were diagnosed clinically or with autopsy confirmation, and AD was diagnosed clinically with CSF biomarker confirmation. Plasma p-tau217, p-tau181, Aβ42/40 ratio, brain-derived tau (BD-tau), neurofilament light chain (NfL), and glial fibrillary acid protein (GFAP) were measured using Simoa. Median biomarker values in different groups were compared with Kruskal-Wallis test, and area under the receiver operating characteristic curve was used to compare accuracy in distinguishing prion diseases from sporadic AD (sAD). Lumipulse p-tau217 and NfL were measured in a validation study in a different laboratory.

RESULTS: In the main study, we analyzed 345 samples from 278 individuals (mean age 58 [SD 13.5], 48.2% female), including 204 with prion diseases (121 sporadic Creutzfeldt-Jakob disease [CJD], 11 iatrogenic CJD, 9 variant CJD, 47 slow-progressing inherited prion disease (IPD) and 16 fast-progressing IPD), 33 with AD, and 41 healthy controls. For discriminating prion disease without AD copathology from sAD, none of p-tau217 (area under the curve [AUC] [95% CI] 0.605 [0.486-0.724]), p-tau181 (AUC 0.554 [0.446-0.661]), or GFAP (AUC 0.514 [0.389-0.640]) performed well. Aβ42/40 discriminated moderately (AUC 0.770 [0.684-0.856]). NfL/p-tau217 ratio (AUC 0.996 [0.987-1.000]), NfL (AUC 0.988 [0.974-1.000]), BD-tau/p-tau217 ratio (AUC 0.963 [0.929-0.996]), and BD-tau (AUC 0.934 [0.890-0.978]) discriminated very well. In an independent validation study, consecutive samples were analyzed from 32 patients with sAD and 35 patients with sporadic Creutzfeldt-Jakob disease (mean age 65.0 [SD 6.4], 56.7% female). NfL/p-tau217 again discriminated almost perfectly (AUC 0.986 [95% CI 0.966-1.000]).

DISCUSSION: Plasma p-tau217 and p-tau181 are increased in both AD and prion diseases (regardless of burden of AD copathology). Diagnosing AD with a single abnormal p-tau plasma biomarker risks misdiagnosing prion diseases as AD. Plasma NfL/p-tau217 discriminates near-perfectly and could act as a flag to suspect prion diseases where this is a diagnostic possibility.

CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that plasma NfL/p-tau217 discriminates patients with CJD from those with AD.},
}

@article {pmid42441928,
year = {2026},
author = {Bellomo, G and Gaetani, L},
title = {Plasma P-Tau217: A Powerful Alzheimer Disease Biomarker in the Right Clinical Context.},
journal = {Neurology},
volume = {107},
number = {3},
pages = {e214821},
doi = {10.1212/WNL.0000000000214821},
pmid = {42441928},
issn = {1526-632X},
}

@article {pmid42442024,
year = {2026},
author = {Andreeva, T and Tuparev, N and Taneva, SG},
title = {Multimodal biophysical markers of neurodegeneration: Morphology, mechanics, and thermodynamics.},
journal = {Current opinion in structural biology},
volume = {100},
number = {},
pages = {103330},
doi = {10.1016/j.sbi.2026.103330},
pmid = {42442024},
issn = {1879-033X},
abstract = {The identification of novel noninvasive biomarkers remains a major challenge in the diagnosis of neurodegenerative diseases. Significant efforts focus on fluid biomarkers, including proteins, peptides, and miRNAs, detectable in blood plasma and peripheral blood cells. Here, we review recent findings on blood plasma and peripheral blood cells physical parameters in Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis emphasizing atomic force microscopy and calorimetry assay. Alterations in morphology, nanostructure, and stiffness of red blood cells and platelets, together with thermodynamic signatures of red blood cells and plasma, provide sensitive indicators of disease-related changes. These integrated biophysical parameters not only distinguish neurodegeneration from healthy states but also enable discrimination among different neurodegenerative disorders, highlighting their potential as minimally invasive diagnostic markers.},
}

@article {pmid42442298,
year = {2026},
author = {Akca, S and Ilkar Erdagi, S and Sari, S and Ozbagci, DI},
title = {Eugenol-derived carbamates as sub-nanomolar dual cholinesterase inhibitors with neuroprotective activity against Alzheimer's disease: Structure-activity relationships and molecular dynamics insights.},
journal = {Bioorganic chemistry},
volume = {180},
number = {},
pages = {110233},
doi = {10.1016/j.bioorg.2026.110233},
pmid = {42442298},
issn = {1090-2120},
abstract = {Carbamate-based cholinesterase inhibitors represent a clinically validated therapeutic strategy for Alzheimer's disease (AD); however, sub-nanomolar AChE inhibitory activity within natural phenol-derived scaffolds has not been previously reported. To address this gap, a series of eleven eugenol-based carbamate derivatives (E1-E11) was rationally designed, synthesized, and evaluated as multifunctional anti-AD agents. Systematic variation of the carbamate N-substituent enabled fine modulation of inhibitory potency and isoform selectivity, revealing well-defined structure-activity relationships. Among the synthesized compounds, E11 emerged as the most potent AChE inhibitor (IC50 = 0.62 nM), surpassing rivastigmine (0.80 nM), the only clinically approved carbamate-based inhibitor, while displaying a markedly AChE-selective profile (SI = 24.0). To our knowledge, this represents the most potent AChE inhibitory activity reported for a carbamate within a natural phenol-derived framework. E10 established a genuine dual inhibitory profile (AChE IC50 = 4.25 nM; BChE IC50 = 3.20 nM), relevant to multitarget therapy across AD disease stages. Enzyme kinetic studies confirmed mixed-type inhibition for both lead compounds, with nanomolar Ki values indicating simultaneous engagement of the catalytic and peripheral anionic sites. These findings were corroborated by 200 ns molecular dynamics simulations and MM-PBSA binding free energy analyses, which revealed stable dual-site binding modes consistent with the kinetic data. Although DPPH radical scavenging was attenuated by carbamate masking of the phenolic hydroxyl group, CUPRAC analysis revealed significant electron transfer-based antioxidant capacity for E10 and E11. Importantly, both lead compounds demonstrated significant neuroprotective effects in H2O2-challenged HT-22 mouse hippocampal neuronal cells, a well-established oxidative stress model relevant to AD neurodegeneration, with acceptable cytotoxicity profiles. In silico ADME profiling predicted favorable gastrointestinal absorption, blood-brain barrier permeability, and absence of P-glycoprotein efflux liability for all compounds. Collectively, these findings establish eugenol-based carbamates as a pharmacologically competitive and structurally accessible multifunctional scaffold for AD, with E10 and E11 identified as priority candidates for further preclinical investigation; however, the present study is limited to in vitro and in silico evaluation, and in vivo pharmacological assessment and detailed metabolic profiling, particularly regarding the predicted mild CYP450 liability of the aryl-substituted derivatives, are warranted in future studies.},
}

@article {pmid42442374,
year = {2026},
author = {Crivelli, L and Suemoto, CK and Sosa, AL and Lopera, F and Aguillón, D and Allegri, RF and Nitrini, R and Calandri, IL and Velilla-Jiménez, L and Yassuda, MS and Acosta-Baena, N and Salinas, RM and Charamelo, A and Derio, CD and Acosta, DM and León-Salas, JM and Duque-Peñailillo, L and Cusicanqui, MI and Custodio, N and Anchia-Alfaro, A and Núñez-Herrera, A and Rubens, A and Leites, A and Vigil-Martínez, A and Damian, A and Flores-Blanco, BM and Custodio, B and Laforcada, C and Márquez, C and Friedlaender, CV and Espinoza-Cruz, CG and Cañadas, C and Peixoto, C and Muñoz, DH and Slezak, DF and Felix, E and Aguirre-Salvador, E and Surace, EI and Mariani, F and De La Torre, GR and Verástegui, G and Keller, G and Peixoto, GH and Morilla, HA and Jiménez-Velázquez, IZ and More, JY and Rodríguez, JF and Tosatti, JAG and de Faria Rocha, JV and Saldarriaga-Hernández, J and Huilca, JC and García-Molina, JT and Martínez-Galindo, JG and Duran, JC and Rodriguez, JG and Gomes, KB and César-Freitas, KG and Agüero, K and Mora-Villalobos, L and Asprilla, LO and de Souza, LC and Soto, L and Cortabarría, L and Baldeón, L and Carreira, LL and Marin-Buitrago, L and Moreno, MC and Barbosa, MT and Torheim, M and Magalhães, MAZ and da Graça Morais Martin, M and Martin, ME and Torres, MF and Menéndez, M and Hernandez, MA and Granizo, MS and Gutiérrez, M and Corvalán, N and Mora, PJ and Peguero, P and Ramírez-Santos, R and Fernández, RS and Montesinos, R and Ospina-Henao, S and Montes, SY and Santero, S and Brucki, SMD and Josephy-Hernandez, S and Vazquez, TC and Bérgamo, Y and Bocanegra, Y and Muñoz, YA and Vicuña, Y and Lora, ZDC and Kivipelto, M and Raman, R and Espeland, MA and Baker, LD and Snyder, HM and Sevlever, GE and Carrillo, MC and Caramelli, P and , },
title = {Multidomain lifestyle intervention for the prevention of cognitive decline in at-risk older adults in Latin America (LatAm-FINGERS): a single-blind, multicentre, randomised controlled trial.},
journal = {Lancet (London, England)},
volume = {},
number = {},
pages = {},
doi = {10.1016/S0140-6736(26)01278-X},
pmid = {42442374},
issn = {1474-547X},
abstract = {BACKGROUND: Latin America faces a high dementia burden, with increased prevalence of factors associated with cognitive decline. Multidomain lifestyle interventions might delay cognitive decline, but populations from Latin America remain under-represented in dementia prevention trials. We aimed to investigate the feasibility of a culturally adapted, multidomain, systematic lifestyle intervention and investigate its effects on global cognitive function in at-risk older adults (aged 60-77 years).

METHODS: The LatAm-FINGERS Initiative for Cognitive Change (hereafter referred to as LatAm-FINGERS) was a single-blind, multicentre, randomised clinical trial conducted in 11 Latin American countries (Argentina, Bolivia, Brazil, Chile, Colombia, Costa Rica, Dominican Republic, Ecuador, Mexico, Peru, and Uruguay). Individuals aged 60-77 years with high risk of dementia (cardiovascular risk factors, ageing, and dementia risk score ≥6), and suboptimal cognitive performance were randomly assigned (1:1) to receive either a 2-year systematic lifestyle intervention (SLI group) or a flexible lifestyle intervention (FLI group). Randomisation was stratified by the study centre to ensure balance and implemented using permuted blocks of eight. Participants and intervention staff were not masked to group assignment, but individuals who assessed outcomes were masked throughout the trial. The SLI provided structured multidomain lifestyle interventions with supervised support and monitoring; FLI offered health advice. Primary outcomes were trial feasibility (evaluated using selected RE-AIM measures: Reach, Implementation, and Maintenance) and the intervention's effects on global cognitive composite trajectories over 2 years (change in the global cognitive composite score over 2 years). This trial is registered at ClinicalTrials.gov (NCT06492967) and has been completed.

FINDINGS: Participants were enrolled between Oct 27, 2021, and July 7, 2023; the last participant completed follow-up on Nov 7, 2025. Among 1719 assessed, 1065 participants included in the analytic sample were randomly assigned to the SLI group (n=539) or the FLI group (n=526). Mean age was 67·5 years (SD 4·7), 795 (75%) of 1065 participants were women, and 270 (25%) were men. Self-reported race and ethnicity were: 624 (59%) Mestizo, 288 (27%) White, 72 (7%) Mulatto, 25 (2%) Mixed or other, 18 (2%) Black, 14 (1%) Indigenous, and 24 (2%) did not report race or ethnicity. 877 (82·3%) of 1065 completed the 2-year follow-up. Recruitment effectiveness (Reach) was 62·0%; mean adherence to the SLI group (Implementation) was 71·6% over the entire trial; and frequencies of complete cognitive outcomes data (Maintenance) were 87·9% at 6 months, 85·3% at 12 months, 81·4% at 18 months, and 84·8% at 24 months in the SLI group compared with 86·3% at 6 months, 78·9% at 12 months, 73·4% at 18 months, and 79·8% at 24 months in the FLI group. Dropouts were higher in the FLI group than in the SLI group (20·2% vs 15·2%; p=0·042). Global cognitive composite scores increased over time in both groups, with a mean annual change of 0·31 SD (95% CI 0·28-0·34) per year in the SLI group and 0·20 SD (0·17-0·23) per year in the FLI group (mean between-group difference of 0·11 SD per year [0·06-0·15; p<0·0001]). Overall, 478 adverse events were reported (412 in the SLI group and 66 in the FLI group). The most common adverse events were musculoskeletal symptoms (113 [21%] in the SLI group, 13 [2%] in the FLI group), upper respiratory infections (50 [9%] in the SLI group, one [<1%] in the FLI group), and COVID-19 infection (31 [6%] events in the SLI group). Serious adverse events occurred in 50 (9%) participants in the SLI group and 24 (5%) participants in the FLI group; none were related to the intervention. There were eight deaths (three in the SLI group and five in the FLI group), and none were related to the intervention.

INTERPRETATION: A culturally adapted multidomain lifestyle intervention was feasible across Latin America and resulted in greater cognitive improvements than a flexible health-advice intervention in older adults at risk of cognitive decline. These findings extend the evidence base for multidomain lifestyle interventions to populations historically under-represented in dementia research, supporting their feasibility and scalability as strategies to reduce cognitive decline risk amid the rapidly growing burden of dementia in low-income and middle-income countries.

FUNDING: Alzheimer's Association.

TRANSLATIONS: For the Spanish and Portuguese translations of the abstract see Supplementary Materials section.},
}

@article {pmid42442404,
year = {2026},
author = {Marsden, M and McLaren, JE and Bevan, RJ and Penn-Ripley, D and Somerville, M and Lauder, SN and Jones, MH and Maros, LB and McGurk, MR and Gallimore, A and Price, DA and Miners, KL and Ladell, K and Siebzehnrubl, FA and Hughes, TR and Humphreys, IR and Clement, M},
title = {Cytomegalovirus-induced T cell responses accelerate Alzheimer's disease progression in mice.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag043},
pmid = {42442404},
issn = {1460-2156},
support = {//Jane Hodge Foundation/ ; MR/X00922X/1/MRC_/Medical Research Council/United Kingdom ; 207503/Z/17/Z/WT_/Wellcome Trust/United Kingdom ; //Brain Tumour Charity/ ; MR/V000489/1//MRC/ ; MR/S07709/1//MRC/ ; MR/X018318/1//MRC/ ; },
abstract = {Infections have long been implicated as causative factors in Alzheimer's disease (AD). Multiple studies have further suggested a key role for herpesviruses, such as cytomegalovirus (CMV). Using transgenic 3xTg-AD mice, we demonstrate that systemic infection with the β-herpesvirus murine CMV (MCMV) accelerates the development of cognitive decline, tauopathy and synaptic loss in the hippocampus, all of which are key features of AD. Accelerated disease progression after infection was associated with substantial lymphocyte infiltration into the brain, dominated by MCMV-specific effector memory CD8+ T cells expressing CXCR3. T cell receptor analyses revealed that clonally diverse virus-specific CD8+ T cells were selectively recruited into the brain during the development of AD. T cell depletion or treatment with the antiviral drug valganciclovir during chronic infection reduced lymphocytic infiltrates in the brain and reversed cognitive decline. These data provide a mechanistic link between chronic viral infections and the development of AD.},
}

@article {pmid42442566,
year = {2026},
author = {Coccurello, R},
title = {Sleep-Related Alzheimer's Disease Vulnerability in Aging: A Muscle-Metabolic Perspective.},
journal = {Neuroscience and biobehavioral reviews},
volume = {},
number = {},
pages = {106869},
doi = {10.1016/j.neubiorev.2026.106869},
pmid = {42442566},
issn = {1873-7528},
abstract = {Sleep disruption is a hallmark of aging and a plausible driver of Alzheimer's disease vulnerability. Reduced slow-wave sleep, increased fragmentation, and circadian instability may facilitate amyloid-β accumulation, tau propagation, neuroinflammation, oxidative stress, and impaired glymphatic clearance. Yet the physiological factors that predispose older adults to unstable sleep remain insufficiently integrated into models of brain aging. This Review advances a sleep-muscle-brain framework in which sarcopenia, sarcopenic obesity, and insulin resistance are conceptualized as modifiable muscle-metabolic conditions that may bias sleep continuity and shape the biological impact of sleep disruption. We examine irisin/FNDC5-BDNF signaling as a hypothesis-generating candidate modifier of metabolic regulation, neurotrophic support, and brain resilience, while emphasizing that direct evidence for a causal role in human sleep regulation remains insufficient. Irisin-related pathways intersect with insulin sensitivity, inflammatory control, and BDNF-dependent synaptic plasticity, all of which are relevant to the physiological context in which sleep disruption may influence Alzheimer's disease pathophysiology. We propose that age-related attenuation of muscle endocrine signaling, together with insulin resistance and low-grade inflammation, may lower the threshold at which sleep fragmentation translates into amyloid/tau dyshomeostasis, glial activation, and network dysfunction. Rather than treating sleep disturbance as an isolated brain-centered risk factor, this framework positions sleep as a biobehavioral hub through which peripheral aging processes can modulate neurodegenerative resilience. The Review integrates evidence from sleep neuroscience, geroscience, metabolism, and neurodegeneration, and identifies experimentally testable predictions. A sleep-muscle-brain perspective may help refine risk stratification and guide multimodal interventions combining sleep optimization, resistance exercise, metabolic targeting, and Alzheimer's disease biomarker monitoring.},
}

@article {pmid42442677,
year = {2026},
author = {Shu, XD and Liu, HF and Liao, YQ and Pu, WJ and Zhao, T and Pan, WD and Zhang, N and Li, JY},
title = {Saebias A-G, eudesmane sesquiterpenes from Salvia plebeia with potential for Alzheimer's disease prevention via anti-neuroinflammatory and neuroprotective effects.},
journal = {Phytochemistry},
volume = {},
number = {},
pages = {115024},
doi = {10.1016/j.phytochem.2026.115024},
pmid = {42442677},
issn = {1873-3700},
abstract = {Saebias A-G (1-7), seven previously undescribed eudesmane sesquiterpenoids compounds and seventeen known compounds were isolated from Salvia plebeia R.Br. Among them, compound 1 is a unique C16-type eudesmane sesquiterpenoid featuring a 6/6/5-membered scaffold, 2-3 are nor-eudesmane sesquiterpenoids and 5 contains a rare 6/6/3/5 tetracyclic skeleton. Their structures including absolute configurations were elucidated by extensive spectroscopic methods, single-crystal X-ray crystallographic and ECD calculation. All compounds were evaluated for their inhibitory effect on nitric oxide (NO) production induced by lipopolysaccharide (LPS) in BV-2 cells and neuroprotective effect induced by H2O2 in PC12 cells. The results showed that four compounds exhibited significant NO inhibitory effects, with IC50 values ranging from 0.76 to 3.72 μM. Among them, compound 2 showed significant inhibitory effect, which significantly suppressed the production of IL-6, IL-1β, and iNOS in a concentration-dependent manner. The PC12 cells damage induced by H2O2 was attenuated by compounds 2, 10, 11, 13, 15, and 23. Moreover, compounds 2 and 11 delayed H2O2 induced damage, stabilized reactive oxygen species (ROS), mitochondrial membrane potential (MMP) and apoptosis expression levels. Notably, compound 2 exerted dual anti-neuroinflammatory and neuroprotective activities, and its multi-target pharmacological profile makes it a promising candidate for the prevention and treatment of Alzheimer's disease. These studies provide new potential neuroprotective agents for the prevention and treatment of neurodegenerative diseases.},
}

@article {pmid42442754,
year = {2026},
author = {Sonnenberg, A and Bakis, LK and Kohen, R},
title = {Gastrointestinal Diagnoses and Symptoms in Medicare Patients With Neuropsychiatric Diseases.},
journal = {Journal of clinical gastroenterology},
volume = {},
number = {},
pages = {},
doi = {10.1097/MCG.0000000000002422},
pmid = {42442754},
issn = {1539-2031},
abstract = {BACKGROUND AND AIMS: Many patients with psychiatric and neurological diseases suffer from gastrointestinal symptoms. Our study aimed to analyze the frequency of gastrointestinal disease in patients with underlying neuropsychiatric diagnoses.

METHODS: The study utilized the 2018 Inpatient Standard Analytic File of the Centers for Medicare and Medicaid Services (CMS), which contains the electronic health records of 6,462,321 unique patients. The concurrence of 2 diagnoses was assessed by calculating odds ratios (OR) with their 95% CIs, adjusted for the confounding influences of demographic characteristics (age, sex, ethnicity).

RESULTS: Dementia was most strongly associated with dysphagia (2.85, 2.83 to 2.88). Schizophrenia was associated with functional GI disorders (1.62, 1.60 to 1.64), constipation (1.67, 1.65 to 1.69), and dyspepsia (2.02, 1.88 to 2.17). Bipolar disorder was most significantly associated with irritable bowel syndrome (1.83, 1.79 to 1.87) and dyspepsia (1.88, 1.77 to 2.01). Depression was significantly associated with all types of upper and lower GI symptoms with significant ORs ranging from 1.33 to 2.14. Amyotrophic lateral sclerosis was strongly associated with complaints of functional GI disorder (2.32, 2.18 to 2.46), constipation (2.37, 2.23 to 2.51), dysphagia (11.77, 11.19 to 12.39), flatulence and bloating (2.75, 2.14 to 3.54). Parkinson disease was mostly associated with constipation (1.79, 1.77 to 1.82) and dysphagia (2.96, 2.92 to 3.00). In Alzheimer disease, only symptoms of dysphagia (2.15, 2.12 to 2.17) stood out. Multiple sclerosis was associated with most GI diagnoses (OR ranging from 1.32 to 2.06), except for abdominal pain and reflux symptoms.

CONCLUSIONS: Concurrence of gastrointestinal and neuropsychiatric diagnoses is common. Caring for patients with neuropsychiatric diseases, physicians need to be aware of and proactively search for the presence of concurrent gastrointestinal disease.},
}

@article {pmid42428106,
year = {2026},
author = {Kleiman, MJ and O'Shea, D and Rader, K and Baig, M and Camacho, S and Salcedo, A and Galvin, JE},
title = {The Puppy Escape Narrative: Validation of an Openly Available Recall Task for MCI Detection.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
pmid = {42428106},
abstract = {INTRODUCTION: Narrative recall is widely used to detect cognitive impairment, but dominant instruments carry proprietary restrictions. The Craft Story 21 (CS), the non-proprietary NACC UDS4 standard, is not available standalone. Here, we validate the freely available Puppy Escape (PE).

METHODS: 346 participants (153 cognitively normal, 106 subjective cognitive impairment, 87 mild cognitive impairment) completed PE and CS. Analyses evaluated convergent and criterion validity, MCI-vs-control discrimination, and incremental validity.

RESULTS: PE and CS converged (r=.43-.47) and were equivalent on 10/12 neuropsychological measures. PE Delayed discriminated MCI from controls (d=1.03; ROC-AUC equal to CS, DeLong p=.510) and added variance beyond CS (ΔR[2]=+.054, p<.001). Automated subscores revealed MCI deficits in location, action, and name content. PE-18 short form retained discrimination (d=1.02) with 18 items.

DISCUSSION: PE matched CS across all validation domains and captured complementary diagnostic information. PE and PE-18 are available via online registration explicitly permitting industry-sponsored research and fee-for-service clinical use.},
}

@article {pmid42435542,
year = {2026},
author = {Zhou, S and Chen, H and Wang, F and Jiang, JH},
title = {Near-infrared phenothiazine-fused rhodol with large Stokes shift for fluorogenic imaging of butyrylcholinesterase in vivo.},
journal = {Talanta},
volume = {311},
number = {},
pages = {130248},
doi = {10.1016/j.talanta.2026.130248},
pmid = {42435542},
issn = {1873-3573},
abstract = {Butyrylcholinesterase (BChE) is a serine hydrolase that plays diverse roles in physiological and pathological processes, and imaging BChE activity is of great importance for disease diagnosis and drug development. Here we develop a new activatable near-infrared (NIR) fluorescent probe, DR760, for high contrast imaging of BChE activities in vivo. A new NIR fluorophore with a large Stokes shift is engineered by fusing phenothiazine with rhodol. We further develop a fluorogenic probe for BChE by caging the hydroxyl group with a cyclopropyl ester moiety. It is shown that BChE-mediated release of the caging group results in a fluorescence enhancement of 81-fold at 760 nm. The probe is further explored to image BChE activity and monitor changes in BChE activity in a drug-treated Alzheimer's disease (AD) cellular model. The capability of the probe for imaging BChE activity in vivo is demonstrated using a tumor-bearing mice model. Collectively, this study shows that DR760 affords a new molecular tool for detecting BChE activity in vitro and in vivo.},
}

@article {pmid42435584,
year = {2026},
author = {Arranz, J and Lantero-Rodríguez, J and Braun-Wohlfahrt, LS and Vaqué-Alcázar, L and Rodríguez-Baz, Í and Kac, PR and Arslan, B and Maure-Blesa, L and Pertierra, L and Videla, L and Carmona-Iragui, M and Benejam, B and Del Hoyo Soriano, L and Barroeta, I and Fernández, S and Bejanin, A and Lleó, A and Ashton, NJ and Zetterberg, H and Fortea, J and Alcolea, D and Montoliu-Gaya, L},
title = {CSF and plasma tau biomarkers in the Down syndrome-Alzheimer's disease continuum.},
journal = {EBioMedicine},
volume = {130},
number = {},
pages = {106370},
doi = {10.1016/j.ebiom.2026.106370},
pmid = {42435584},
issn = {2352-3964},
abstract = {BACKGROUND: Nearly all individuals with Down syndrome (DS) develop Alzheimer's disease (AD) dementia, primarily due to overexpression of the APP gene. Although specific cerebrospinal fluid (CSF) and plasma tau biomarkers have been investigated in DS-AD, how different tau species change in the DS-AD continuum in comparison to sporadic AD remains uncertain.

METHODS: In this cross-sectional study, we analysed CSF and plasma tau biomarkers in 461 samples from the DABNI and SPIN cohorts, including individuals with DS, cognitively normal euploid participants, and patients with sporadic AD. Biomarker differences were assessed using linear regression with Tukey post hoc comparisons. LOESS modelling was applied to estimate the age at which tau biomarkers became abnormal.

FINDINGS: We analysed 461 participants from the DABNI and SPIN cohorts. Both CSF and plasma tau biomarkers increased during the asymptomatic stages of DS and in euploid controls, coinciding with Aβ positivity; across the DS clinical spectrum the largest increases were observed for CSF NTA-tau (fold-change [fc] = 6.46-6.94), CSF p-tau217 (fc = 6.43-6.74) and plasma p-tau217 (fc = 4.63-6.54) (linear regression adjusted for age, sex and APOE-ε4 with Tukey post-hoc tests; all p < 0.001). During the dementia stages, CSF tau biomarkers showed only modest further increases (no CSF biomarker differed between pDS and dDS; all p ≥ 0.268), whereas plasma tau biomarkers retained a broader dynamic range across symptomatic phases (pDS vs dDS: plasma p-tau217 p = 0.001, p-tau181 p = 0.002, p-tau231 p = 0.004). Plasma p-tau217 showed the highest diagnostic accuracy, with areas under the curve (AUC) of 0.91-0.97 for biological categorisations and numerically higher values than CSF in symptomatic stages (pDS vs dDS: plasma p-tau217 AUC = 0.69 [95% CI 0.58-0.80] vs CSF p-tau217 AUC = 0.53 [95% CI 0.41-0.65]; DeLong test p = 0.019). In LOESS analyses, tau biomarkers diverged from age-matched controls in the late 30s to early 40s (e.g., plasma p-tau217 ≈ 37.3 years, CSF p-tau181 ≈ 38.1 years) and reached abnormality (+2 SD) over an approximately 20-year span between the fourth and sixth decades, outlining differential but temporally compressed increases. Finally, during symptomatic stages, tau biomarker levels remained stable in DS-AD, in contrast to sporadic AD, where levels declined with advancing age.

INTERPRETATION: These findings highlight the complementary roles of CSF and plasma tau biomarkers in tracking disease progression: CSF biomarkers capture early pathological changes, whereas plasma biomarkers more effectively reflect disease progression within symptomatic stages. Furthermore, tau biomarkers might support disease staging and monitor clinical progression in DS-AD, but with the need to adapt biomarker frameworks to this specific population.

FUNDING: La Caixa Foundation, Instituto de Salud Carlos III, Generalitat de Catalunya, National Institute on Ageing, Wellcome Trust, Jérôme Lejeune Foundation, Medical Research Council, Alzheimer's Association, National Institute for Health Research, EU Joint Programme-Neurodegenerative Disease Research, Alzheimer's Society.},
}

@article {pmid42435587,
year = {2026},
author = {Domínguez-García, A and Delgado-Uriarte, JC and Cervantes-Arriaga, A},
title = {Precision therapeutics and innovative clinical trial design in neurodegenerative diseases.},
journal = {Revista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion},
volume = {78},
number = {4},
pages = {100050},
doi = {10.1016/j.ric.2026.100050},
pmid = {42435587},
issn = {2564-8896},
abstract = {Neurodegenerative diseases are biologically heterogeneous disorders characterized by progressive neuronal dysfunction, overlapping molecular pathologies, and limited disease-modifying therapies. Advances in biomarker development, molecular staging, and precision medicine are reshaping therapeutic strategies and clinical trial design across Parkinson's disease, Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, Huntington's disease, and related disorders. This review summarizes emerging therapeutic approaches, including monoclonal antibodies targeting protein aggregation, immune-modulating and metabolic interventions, antisense oligonucleotides, gene replacement and genome-editing strategies, stem cell-based therapies, and neurosurgical delivery platforms and neuromodulation technologies. It also examines evolving clinical trial methodologies such as biomarker-enriched recruitment, adaptive and delayed-start designs, platform trials, decentralized models, and master protocols. Additional emphasis is placed on diagnostic biomarkers, multimodal artificial-intelligence pipelines, systems-biology perspectives, network-based therapeutic strategies, and the reproducibility and interpretability requirements for computational tools. Despite recent progress, major challenges remain, including biological heterogeneity, limited translatability of preclinical models, delivery barriers, long-term safety concerns, and inequities in access to biomarker-based care and trial participation. Future directions will require combination therapies, integrated biomarker pipelines, preventive strategies, and pragmatic trial systems capable of translating biological advances into durable and equitable clinical benefit.},
}

@article {pmid42435662,
year = {2026},
author = {Kim, KY and Ham, H and Yoon, EJ and Kim, E and Kim, YK and Lee, JY and , },
title = {Relative importance of blood-based biomarkers for Alzheimer's disease-specific neurodegeneration and cognitive decline.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {9},
pages = {100644},
doi = {10.1016/j.tjpad.2026.100644},
pmid = {42435662},
issn = {2426-0266},
abstract = {BACKGROUND: Although blood-based biomarkers are now available for diagnosing Alzheimer's disease (AD), the best biomarker for AD-specific neurodegeneration and cognitive decline remains unclear. This study aimed to determine the relative importance of four plasma biomarkers-phosphorylated tau (p-tau) 217, p-tau181, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP)-in AD-specific neurodegeneration and cognition.

METHODS: We analyzed cross-sectional data from two independent, ethnically distinct cohorts spanning the clinical spectrum from cognitively unimpaired to dementia: 150 participants from the SAMD cohort (100% Asian) and 284 participants from the ADNI cohort (94.0% White). Plasma biomarker levels were quantified using Single-Molecule Array (Simoa) assays. We employed dominance analysis to determine the hierarchical contributions of these biomarkers to AD signature regions of interest (ROI) thickness (entorhinal, inferior temporal, middle temporal, and fusiform regions), total cognition, and memory, stratified by amyloid-PET status. Three sensitivity analyses were further conducted to validate the findings across these cohorts, mitigating potential biases arising from differences in demographic characteristics and clinical severity. All analyses were adjusted for age, sex, education, and APOE ε4 status.

RESULTS: The dominance hierarchy differed markedly according to the amyloid status. Plasma GFAP and p-tau217 emerged as the dominant predictors for AD signature ROI thickness and cognitive impairment in amyloid-positive participants. Specifically, GFAP demonstrated superior dominance in explaining cortical atrophy within the SAMD cohort, whereas p-tau217 was the dominant predictor in the ADNI cohort. P-tau217 generally outperformed the others in explaining total cognition and memory in the amyloid (+) group. In contrast, among amyloid (-) participants, plasma NfL showed greater explanatory power than GFAP for both neurodegeneration and cognitive decline across both cohorts.

CONCLUSION: The efficacy of plasma biomarkers in reflecting AD-related neurodegeneration varies significantly depending on the presence of amyloid pathology. While GFAP and p-tau217 are robust indicators of AD-associated changes linked to plaque pathology, NfL better reflects non-specific neurodegeneration involving axonal damage. Consequently, a stratified approach based on amyloid status is essential for the optimal application of blood-based biomarkers in monitoring disease progression and evaluating therapeutic efficacy in future clinical trials and precision medicine.},
}

@article {pmid42435702,
year = {2026},
author = {González-Rodríguez, VM and Martín-López, E},
title = {[In response to 'Advances and controversies in the treatments of Alzheimer's disease'].},
journal = {Atencion primaria},
volume = {58},
number = {8},
pages = {103570},
doi = {10.1016/j.aprim.2026.103570},
pmid = {42435702},
issn = {1578-1275},
}

@article {pmid42435703,
year = {2026},
author = {Ghose, A and Paidesetty, SK and Prusty, SK and Satapathy, BS and Panda, PK and Pakeeraiah, K and Mishra, A and Dandela, R},
title = {Rationally designed phytochemical-derived carbamate hybrids unveiling potent inhibition of cholinesterase and amyloid-β peptides.},
journal = {Bioorganic chemistry},
volume = {180},
number = {},
pages = {110242},
doi = {10.1016/j.bioorg.2026.110242},
pmid = {42435703},
issn = {1090-2120},
abstract = {Alzheimer's disease (AD) is most likely to be caused by the accumulation of Aβ and dysfunction of the cholinergic pathology. Oxidative damage, alterations of brain glucose metabolism, and cognitive impairment are all demonstrated in the STZ models. In order to overcome such effects, a new set of phenolic-carbamate conjugates (5a-5h) was synthesized, and their structures were elucidated using FTIR, UV, and NMR spectroscopy. The in silico studies confirmed excellent binding capabilities against AChE and Aβ targets. In vitro antioxidant assays depicted a significant free radical scavenging ability, with compound 5c exhibiting the enhanced effect. Cell line study with SH-SY5Y and PC12 cells showed greater % cell viability. AChE activity demonstrated compound 5c has significant effectiveness (IC50 = 1.98 uM). Neurobehavioral activity showed an improvement in learning and memory during behavioural assessments. In vivo antioxidant study showed greater scavenging activity (SOD, CAT, GSH), reduced of oxidative stress (MDA, NO), and the improvement in total antioxidant activity. Overall, the compound 5c has demonstrated significant results comprising decreased cholinesterase and Aβ inhibition deciphering enhanced cholinergic restoration. Hippocampal integrity was preserved, as it was confirmed by histopathological examination. It concludes that bromo-vanillyl carbamate derivative 5c (30 mg/kg) has potent antioxidant, anti-amyloid, and neuroprotective characteristics, rendering it a promising multitarget lead that warrants further investigation for the treatment of AD.},
}

@article {pmid42428693,
year = {2026},
author = {Li, J and Zhu, Q and Qin, J and Xue, H},
title = {Oral Microbiota and Alzheimer's Disease: A Bidirectional Mendelian Randomization Study Based on East Asian Ethnicity.},
journal = {Health science reports},
volume = {9},
number = {7},
pages = {e72632},
pmid = {42428693},
issn = {2398-8835},
abstract = {BACKGROUND AND AIMS: The "oral-microbiota-brain axis" has been hypothesized to contribute to Alzheimer's disease (AD) pathogenesis, but causal evidence remains limited. We performed a bidirectional Mendelian randomization (MR) study to investigate potential genetic causality between oral microbiota and AD in East Asians.

METHODS: Two-sample MR integrated genome-wide data from 2984 Chinese participants (saliva/tongue dorsum microbiomes) and 7036 Japanese participants (3962 AD cases/4074 controls). Genetic instruments were selected using pragmatically moderated significance thresholds (forward: p < 5 × 10[-4]; reverse: p < 5 × 10[-5]), with causality assessed via inverse-variance weighted (IVW) regression and four Supporting methods. Sensitivity analyses validated robustness. We examined 3117 microbial taxa-AD pairs, followed by exploratory Gene Ontology (GO) enrichment analysis.

RESULTS: Forward MR identified 12 candidate causal taxa: five with risk-increasing associations (e.g., Prevotella sp. MGS2526, OR = 1.32 [1.14-1.52], p = 1.4 × 10[-4]) and seven with protective associations (e.g., Streptococcus mitis MGS519, OR = 0.81 [0.69-0.94], p = 7.9 × 10[-3]). Reverse MR suggested AD may influence the abundance of three microbial species (e.g., Streptococcus sanguinis MGS515, OR = 1.04 [1.01-1.07], p = 3.6 × 10[-3]). Exploratory GO analysis highlighted enrichment in pathways related to synaptic transmission and nutrient metabolism.

CONCLUSION: This study provides genetic evidence consistent with a bidirectional relationship between oral microbiota and AD in East Asians, nominating 15 microbial taxa as candidates for further investigation. The implicated biological pathways offer hypotheses for mechanistic links via the oral-microbiota-brain axis. These findings advance the etiological understanding of AD and highlight priority targets for future experimental and clinical validation.},
}

@article {pmid42428696,
year = {2026},
author = {O'Kelly, M and Lanata, SC and Kleen, JK},
title = {Mapping the space of dementia with EEG in stained glass.},
journal = {Frontiers in dementia},
volume = {5},
number = {},
pages = {1820301},
pmid = {42428696},
issn = {2813-3919},
abstract = {Dementia conditions, including Alzheimer's disease, are progressive disorders for which effective treatments remain under development. Accordingly, interventions that improve quality of life are an important focus of patients, caregivers, and providers, including traditional art forms like painting and sculpture. In this Perspective article, we discuss the use light as a unique form of art to create transformative spaces that stimulate the senses and potentially support wellbeing. We outline an art-science collaborative initiative in which the patients themselves contribute, including through the recording and conversion their EEG brainwave activity to 2D time-frequency spectrogram representations. These representations are transferred to the ancient art of stained glass and installed into the patient's own home. This intervention creates a novel dynamic environment of illumination and colour saturation, derived from the patient and in sync with ever-changing solar and climate influences. Details of the approach and options for meaningful patient-centred customization are described, with illustrations of the procedures and resulting installations, along with thoughts for future improvements.},
}

@article {pmid42428835,
year = {2026},
author = {Hua, OH and Tran Thai, H and Hoang Son, NL and Le Ha, V and Huyen Tran, T and Phung Nguyen, V and Van Anh, TT and Le Thi, H and Duc Cuong, N and Van Tat, P},
title = {Development of Novel Inhibitors for Alzheimer's Disease from Erythrina variegata L. Extract-Derived Clusters Using Molecular Docking, QSAR Modeling, Quantum Chemical Calculations, and Molecular Dynamics Simulations.},
journal = {ACS omega},
volume = {11},
number = {26},
pages = {39390-39416},
pmid = {42428835},
issn = {2470-1343},
abstract = {The objective of this investigation is to identify and enhance compounds from the medicinal plant Erythrina variegata L. that possess potential inhibitory activity against acetylcholinesterase (AChE). Consequently, this investigation will contribute to the pursuit of supportive therapeutic agents for Alzheimer's disease. The initial research matrix was composed of nanocluster materials that were derived from the crude extract. The identification of 13 compounds was achieved by utilizing an ultraperformance liquid chromatography system in conjunction with quadrupole time-of-flight mass spectrometry for structural elucidation. Compound VN62 was chosen due to its favorable binding energy (ES = -8.038 kcal/mol) and RMSD = 1.388 Å, as evidenced by molecular docking simulations and analytical results with the AChE protein (PDB ID: 1EVE). The pIC50 values were predicted using reliable QSAR models, such as QSARGA‑MLR, QSARGA‑ANN, and QSARKPLS‑LF, which were constructed on this basis. Five novel derivatives (VN62N1-VN62N5) were designed from VN62, subsequently semisynthesized, and structurally confirmed using spectroscopic methods, guided by QSAR and docking results. The AChE inhibitory activity was assessed in vitro, and VN62 demonstrated an IC50 of 1.34 μg/mL (pIC50 = 5.498). Conversely, the newly designed derivatives demonstrated a trend toward enhanced activity. Furthermore, a multicriteria evaluation model integrating QSAR, docking, ADMET, and quantum descriptors identified VN62N4 as the top-ranked candidate overall. Molecular dynamics simulations over 400 ns confirmed the structural stability of the VN62N4-AChE complex, as evidenced by stable RMSD, low RMSF in active-site residues, and persistent hydrogen bonding and hydrophobic interactions. The findings verify the efficacy of a comprehensive, multimethod in silico screening strategy in directing the development of AChE inhibitors.},
}

@article {pmid42428879,
year = {2026},
author = {Hermosillo-Abundis, C and Arias-Carrion, O and Contreras-Ibáñez, C and Mendez-Rojas, MA},
title = {From Air to Brain: Environmental Nanoparticles as Modifiable Risk Factors for Neurodevelopmental, Neurodegenerative, and Mental Disorders.},
journal = {ACS omega},
volume = {11},
number = {26},
pages = {38267-38287},
pmid = {42428879},
issn = {2470-1343},
abstract = {Ultrafine particles (≤100 nm) and other environmental nanoparticles have emerged as biologically active pollutants that can cross biological barriers, including the blood-brain barrier and the placenta. Growing evidence implicates ultrafine particles in a wide range of neuropsychiatric conditions, yet their effects remain poorly integrated into clinical and public health frameworks. In this review, we distinguish between size-defined ultrafine particles (UFPs, ≤100 nm), composition-defined environmental nanoparticles originating from combustion and secondary formation processes, and engineered nanomaterials (ENPs), which differ in physicochemical properties, exposure scenarios, and regulatory status. This narrative systematic review synthesizes findings from human and experimental studies on the neuropsychiatric and neurodevelopmental effects of environmental nanopollutants. A structured search was conducted in PubMed, Web of Science, Scopus, and Google Scholar up to November 2025, following explicit inclusion and exclusion criteria. Eligible studies included peer-reviewed human and animal research assessing mental health or neurological outcomes of nanopollutant exposure. Epidemiological studies(?)primarily involving traffic-related air pollution and mixed combustion-derived ultrafine particle exposures(?)suggest associations with increased risk of cognitive impairment, autism spectrum disorder, depression, schizophrenia, and neurodegenerative diseases, including Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis. Prenatal and early life exposures were linked to cortical thinning, altered neurodevelopmental trajectories, and early proteinopathies. Underlying mechanisms include neuroinflammation, oxidative stress, and protein aggregation. Despite methodological heterogeneity, the evidence supports the urgent need for regulation and prevention. Environmental nanopollutants constitute an under-recognized, modifiable risk factor for neuropsychiatric and neurodegenerative conditions. A paradigm shift is needed to incorporate environmental exposure history into mental health research, risk assessment, and prevention strategies. Regulatory action targeting nanopollutant emission and exposure, particularly in vulnerable populations, is critical to mitigating long-term neurological consequences.},
}

@article {pmid42429089,
year = {2026},
author = {Zhang, Z and Li, D and Liu, J and Lu, L and Cai, W and Yu, G},
title = {[Mechanism of Bushen Yijing Formula in improving cognitive function in Alzheimer's disease model mice].},
journal = {Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences},
volume = {},
number = {},
pages = {1-12},
doi = {10.3724/zdxbyxb-2025-0747},
pmid = {42429089},
issn = {1008-9292},
abstract = {OBJECTIVES: To explore the mechanism of Bushen Yijing Formula (BSYJF) in the treatment of Alzheimer's disease (AD) through an integrated approach combining transcriptomics, network pharmacology, and molecular docking.

METHODS: Twelve amyloid precursor protein/presenilin-1 (APP/PS1) transgenic mice were randomly divided into normal control, model, and BSYJF groups. The treated group received daily intragastric administration of BSYJF for 12 consecutive weeks. Cognitive function and hippocampal amyloid β-protein (Aβ) deposition were assessed using behavioral tests and immunohisto-chemistry. Hippocampal tissues were subjected to transcriptomic sequencing to identify differentially expressed genes (DEGs). Functional enrichment analyses were performed using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA). In parallel, active compounds of BSYJF were screened via the TCMSP and PubChem databases, and AD-related targets were retrieved from GeneCards and other disease databases. Core targets were identified by intersecting these targets with transcriptomic DEGs. Molecular docking and molecular dynamics simulations were employed to evaluate binding affinity between active compounds and core targets, and qPCR was used to validate expression changes of core target genes.

RESULTS: BSYJF treatment improved cognitive function and reduced hippocampal Aβ deposition in APP/PS1 mice. Transcriptomic analysis revealed 73 DEGs between the model and BSYJF groups. GO analysis identified enrichment in 281 biological processes, 104 cellular components, and 120 molecular functions. KEGG analysis highlighted 110 pathways, and GSEA supplemented 322 enriched gene sets, many related to the immune system, neurodegenerative diseases, and signaling pathways such as Th17 cell differentiation and NF-κB. Integrated analysis with network pharmacology prioritized 10 core targets. Molecular docking and molecular dynamics simulations indicated strong structural stability and binding affinity of BSYJF bioactive constituents to these core targets. qPCR results confirmed that BSYJF downregulated the expression of Aurkb, Nr1i3, and Ttk, while upregulating Apob and Ces1d, consistent with the transcriptomic findings.

CONCLUSIONS: Transcriptomics, bioinformatics analysis, and animal experiments suggest that BSYJF may regulate immune-inflammatory responses and alleviate neuronal damage through a multi-component, multi-target, and multi-pathway approach, thereby improving cognitive function in AD model mice.},
}

@article {pmid42429097,
year = {2026},
author = {Lu, Y and Li, D and Hu, Y and Lu, L and Yu, G},
title = {[Bushen Yijing formula attenuates amyloid β-protein deposition and oxidative damage in Caenorhabditis elegans].},
journal = {Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences},
volume = {},
number = {},
pages = {1-13},
doi = {10.3724/zdxbyxb-2025-0419},
pmid = {42429097},
issn = {1008-9292},
abstract = {OBJECTIVES: To investigate the protective effects of Chinese medicine Bushen Yijing formula against amyloid β-protein (Aβ) deposition and oxidative damage using an in vitro culture model of Caenorhabditis elegans.

METHODS: An in vitro culture system of C. elegans (strains N2, CL4176, TJ356, and LG333) was employed. The herbal components of the formula were water‑extracted, freeze‑dried into lyophilized powder, and added to the culture medium at different concentrations. Oxidative stress was induced by paraquat exposure. Evaluated parameters included lifespan; time to paralysis and pharyngeal Aβ deposition in CL4176; levels of total antioxidant capacity, superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), malondialdehyde (MDA), and reactive oxygen species (ROS) measured by commercial kits; apoptosis detected by acridine orange staining; nuclear translocation of DAF‑16::GFP in TJ356 nematodes and SKN-1::GFP in LG333 nematodes observed under fluorescence microscopy. Molecular docking and dynamics simulations were further performed to assess the binding stability of the active components catalpol and tetrahydroalstonine (THA) with the core targets FOXO and Nrf2. All experiments were performed in triplicate and independently repeated three times.

RESULTS: Compared with the normal control group, Bushen Yijing formula significantly extended the lifespan of N2 nematodes under both oxidative stress and normal conditions (all P<0.01), compared with the control group of the AD model, prolonged the time to paralysis and reduced pharyngeal Aβ deposition in CL4176 (all P<0.01). Compared with the control group in the paraquat-induced oxidative stress model in N2, Bushen Yijing formula elevated total antioxidant capacity, SOD, CAT, and GSH levels (all P<0.01), decreased MDA and ROS levels (all P<0.05), and attenuated apoptosis. Moreover, the formula promoted nuclear translocation of DAF‑16 and SKN‑1 (all P<0.01). Molecular docking revealed that binding energies of catalpol and THA with FOXO and Nrf2 were all below －7.00 kcal/mol, and dynamics simulations confirmed high stability and favorable affinity for the FOXO-catalpol, Nrf2-catalpol, and Nrf2-THA complexes.

CONCLUSIONS: Bushen Yijing formula alleviates Aβ deposition and its neurotoxicity, enhances antioxidant capacity, and attenuates oxidative stress injury in model nematodes, likely through stable binding and regulation of the FOXO/Nrf2 signaling pathway.},
}

@article {pmid42429220,
year = {2026},
author = {Feter, N and Nanda, A and Hourihan, S and Aslan, D and Feter, J and Sayre, MK and Bharadwaj, PK and Ally, M and Song, H and Arora, A and Maltagliati, S and Lai, MHC and Wilcox, RR and Klimentidis, YC and Alexander, GE and Raichlen, DA},
title = {Associations of distinct sedentary behaviors with cortical, subcortical, and white matter hyperintensity volumes: Evidence from the ARIC study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71582},
pmid = {42429220},
issn = {1552-5279},
support = {P30AG019610/NH/NIH HHS/United States ; R56AG067200/NH/NIH HHS/United States ; R01AG064587/NH/NIH HHS/United States ; R01AG072445/NH/NIH HHS/United States ; //Arizona Department of Health Services/ ; //McKnight Brain Research Foundation/ ; 75N92022D00001/HL/NHLBI NIH HHS/United States ; 75N92022D00002/HL/NHLBI NIH HHS/United States ; 75N92022D00003/HL/NHLBI NIH HHS/United States ; 75N92022D00004/HL/NHLBI NIH HHS/United States ; 75N92022D00005/HL/NHLBI NIH HHS/United States ; U01HL096812//ARIC Neurocognitive Study/ ; U01HL096814//ARIC Neurocognitive Study/ ; U01HL096814//ARIC Neurocognitive Study/ ; U01HL096899//ARIC Neurocognitive Study/ ; U01HL096902//ARIC Neurocognitive Study/ ; U01HL096917//ARIC Neurocognitive Study/ ; /NS/NINDS NIH HHS/United States ; /AG/NIA NIH HHS/United States ; /DC/NIDCD NIH HHS/United States ; //National Instituteon Aging's Intramural Research Program/ ; //National Institute of Neurological Disease and Stroke Intramural Research Program/ ; },
mesh = {Humans ; Female ; *Sedentary Behavior ; *White Matter/diagnostic imaging/pathology ; Magnetic Resonance Imaging ; Male ; Middle Aged ; *Brain/diagnostic imaging/pathology ; Longitudinal Studies ; Aged ; },
abstract = {INTRODUCTION: Longitudinal studies linking sedentary behavior (SB) in different contexts to brain structure and white matter hyperintensity (WMH) volume remain limited.

METHODS: We analyzed data from the Atherosclerosis Risk in Communities (ARIC) study (n = 1,712). Self-reported SB was assessed at visit 1 (1987-1989), with neuroimaging (3T magnetic resonance imaging [MRI]) at visit 5 (2011-2013). Participants were non-demented adults (57% women; 53[5.2] years) who reported frequency of TV watching and occupational sitting. Outcomes included cortical, subcortical, and Alzheimer's disease-signature regions (ADSR), and total WMH brain volumes.

RESULTS: Frequent TV watching was associated with increased WMH volume and reduced frontal, occipital, and ADSR volumes. Sitting during work, which is more cognitively active, was linked to lower WMH and larger frontal (males only), occipital, and parietal volumes. Results remained consistent when adjusted for physical activity.

DISCUSSION: SB is associated with structural brain and WMH volumes. Cognitively active SB may preserve brain structure and cerebrovascular health.},
}

Humans
Female
*Sedentary Behavior
*White Matter/diagnostic imaging/pathology
Magnetic Resonance Imaging
Male
Middle Aged
*Brain/diagnostic imaging/pathology
Longitudinal Studies
Aged

@article {pmid42429357,
year = {2026},
author = {Jin, Z and Peng, Y and Sheng, M and Zheng, Y and Wang, Q and Chen, Y and Zhang, T and Li, Z and Huang, Y and Huang, J and Yang, X},
title = {Interface Self-Assembly of Au10 Nanoclusters for Enhanced Electrochemiluminescence and Alzheimer's Disease Biomarker Detection.},
journal = {Small (Weinheim an der Bergstrasse, Germany)},
volume = {},
number = {},
pages = {e74501},
doi = {10.1002/smll.74501},
pmid = {42429357},
issn = {1613-6829},
support = {22393930//National Natural Science Foundation of China/ ; 22034006//National Natural Science Foundation of China/ ; SKL202302029//Science and Technology Development Plan Project of Jilin Province, China/ ; },
abstract = {Atomically precise metal nanoclusters (NCs), as ultrasmall materials with well-defined composition and structure, exceptional biocompatibility, and unique optical properties, position them as strong candidates in the field of electrochemiluminescence (ECL). However, the ECL efficiency of NCs is relatively low, which dramatically constrained their applications due to the demands of detection sensitivity and brightness. In this study, we report the interface self-assembly of Au10 nanoclusters for the first time, and ultimately formed a fibrous structure with a high aspect ratio, Au10-Fiber, which is an innovative approach that significantly enhances the ECL activity of Au10 NCs. By employing time-dependent and in situ spectroscopic techniques, we visually monitored the dynamic assembly process, and elucidated the interface self-assembly mechanism mediated by aurophilic interaction and π-π stacking. The increase in local electronic density, enhanced conductivity of the ordered structure, and accelerated electron transfer within the π-conjugated system collectively contributed to the significant enhancement of the ECL performance, thereby revealing the key structural factors responsible for ECL enhancement. As a proof of concept, we successfully constructed an ECL immunosensor based on Au10-Fiber for the detection of Alzheimer's disease biomarker Aβ1-42, achieving a detection limit below 3.33 fg/mL.},
}

@article {pmid42429480,
year = {2026},
author = {Ng, CA and Lim, MJH and Chong, EJY and Colombo, G and Schinazi, VR and Venketasubramanian, N and Chen, CL},
title = {A comparison of the Quick Dementia Rating System and Montreal Cognitive Assessment for detecting mild cognitive impairment and dementia assessed by the Clinical Dementia Rating Scale.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261467344},
doi = {10.1177/13872877261467344},
pmid = {42429480},
issn = {1875-8908},
abstract = {BackgroundThe Clinical Dementia Rating (CDR) scale is widely used for staging mild cognitive impairment (MCI) and dementia but suffers from lengthy administration time (45-60 min). The Montreal Cognitive Assessment (MoCA; 10-15 min) and Quick Dementia Rating System (QDRS; 3-5 min) are promising brief alternatives, although it remains unclear which tool performs better in discriminating between cognitive and functional impairment stages.ObjectiveTo compare the performance of the QDRS and MoCA in identifying MCI, dementia, and individuals eligible for disease modifying therapies and clinical trials (DMTT).Methods376 older adults (34.8% NCI, 33.0% MCI, 32.2% dementia) recruited from the memory clinic (n = 284, 75.5%) and community (n = 92, 24.5%) in Singapore completed the QDRS, MoCA, and CDR. No cognitive impairment (NCI), MCI, and dementia were staged as CDR-Global Scores (CDR-GS) of 0, 0.5, and ≥1, respectively. The DMTT subgroup was defined as CDR-GS of 0.5-1. Discriminative performance was determined by area under the curve (AUC) and compared using DeLong's test. Agreement with CDR classifications was determined on McNemar's test.ResultsBoth QDRS and MoCA demonstrated fair-to-excellent discrimination across CDR-staged groups (MCI: AUC 0.79-0.84; Dementia: AUC 0.92-0.97; DMTT: AUC 0.85-0.91), with no significant differences in discrimination observed. The QDRS correctly identified a greater proportion of MCI (55.6% versus 19.4%; p < 0.001) and DMTT (58.9% versus 41.7%; p < 0.001) versus the MoCA.ConclusionsThe QDRS and MoCA are practical brief alternatives to the CDR. The QDRS was advantageous for identifying MCI and DMTT, whereas both were effective screening tools for dementia.},
}

@article {pmid42429504,
year = {2026},
author = {Lu, K and Lu, Y and Tang, R and Dong, X and Zhuang, P and Gao, Y and Cheng, M and Wang, Y and Wang, Y},
title = {Mechanisms of autophagy-lysosome pathway impairment in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261460879},
doi = {10.1177/13872877261460879},
pmid = {42429504},
issn = {1875-8908},
abstract = {The autophagy-lysosomal pathway is key for the removal of harmful substances in cells. This article integrates evidence that highlights the role of lysosomal function and the autophagy-lysosomal pathway in maintaining intracellular homeostasis and the effects of their dysfunction on protein secretion and metabolic disorders, leading to the pathogenesis of Alzheimer's disease (AD) and other tau diseases. Dysfunction of the autophagy-lysosomal pathway is believed to be the main factor leading to the accumulation of amyloid-β and tau proteins, which are also pathological features of AD. This article also discusses why autophagy is indispensable in the early to mature stages of neuronal development and how damage to the function of autophagy can cause neurodevelopmental abnormalities and neurodegenerative diseases. We also summarized the potential role of oligodendrocytes. We believe that its relationship with lysosomes can provide a new perspective and research direction for future research on neurodegenerative diseases. Autophagy-lysosomal pathway damage is considered to be a key factor in the pathology and diagnosis of multiple sclerosis, but we believe that the challenge associated with its transformation into clinical treatment is enormous. These findings suggest that enhancing or improving autophagy function may be an effective treatment method to alleviate the condition of AD patients, which can provide new strategies for clinical treatment and intervention of AD in the future.},
}

@article {pmid42429744,
year = {2026},
author = {Wu, Y and Xiang, F and Li, M and Zhang, H and Wu, M and Zhang, Y and Pu, X and Guo, Y and Li, K},
title = {SMDNet: A Self-Training-Aware and Multi-Modal-Adaptive Deep Learning Network for Low-Data Aβ42 Probe Design and Optimization.},
journal = {Journal of medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jmedchem.6c01102},
pmid = {42429744},
issn = {1520-4804},
abstract = {Amyloid-β (Aβ) plaque accumulation is a crucial hallmark of Alzheimer's disease, and fluorescence imaging can support disease diagnosis and monitoring. However, Aβ42 probe development is often hindered by trial-and-error experiments due to subtle structure-property effects. Here, we developed SMDNet, a self-training-aware and multimodal-adaptive deep learning (DL) framework for low-data Aβ42 probe design and optimization. SMDNet combines iterative self-training with confidence-aware and distribution-aware sampling to improve data quality, while integrating molecular graphs, fingerprints and protein descriptors through cross-attention and protein-conditional adaptive layer normalization. Ablation studies, external validation and generalization analyses confirmed the strong predictive ability of SMDNet. Interpretability analyses further highlighted chemically meaningful substructures associated with model predictions. As a proof of concept, SMDNet guided the rational design of five ThT-derived probe candidates, with TA3 showing favorable binding affinity and high-contrast imaging performance. Additional validation on coumarin- and naphthalimide-based candidates further supported useful predictive discrimination across distinct fluorescent scaffold classes.},
}

@article {pmid42429753,
year = {2026},
author = {Banerjee, G and van Veluw, SJ},
title = {Untangling the web of APOE, cerebral amyloid angiopathy and Alzheimer's disease.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag243},
pmid = {42429753},
issn = {1460-2156},
}

@article {pmid42430015,
year = {2026},
author = {Khodaei, M and Bidabad, B and Shiri, ME and Sedaghat, MK},
title = {Ricci Flow-Based Approach for Early Diagnosis of Alzheimer's Disease.},
journal = {Neuroinformatics},
volume = {24},
number = {3},
pages = {},
pmid = {42430015},
issn = {1559-0089},
mesh = {*Alzheimer Disease/diagnostic imaging ; Humans ; *Magnetic Resonance Imaging/methods ; Early Diagnosis ; *Hippocampus/diagnostic imaging/pathology ; Female ; Aged ; Male ; Discriminant Analysis ; *Image Interpretation, Computer-Assisted/methods ; Aged, 80 and over ; Imaging, Three-Dimensional/methods ; },
abstract = {Early diagnosis of Alzheimer's disease (AD) is increasingly important due to its rising prevalence and significant impact on individuals, families, and healthcare systems. Hippocampal atrophy is a well-established and significant biomarker for AD. Advanced techniques like MRI imaging and surface parameterization have shown considerable promise in improving the accuracy and speed of AD diagnosis. This study aims to utilize the Ricci flow method to map the 3D hippocampal surface to a 2D sphere and extract relevant features for early AD detection. The process involves several key steps: inputting an MRI scan and preprocessing to isolate the hippocampal surface, applying the Ricci flow to map this surface to a sphere, constructing a feature vector using Linear Discriminant Analysis (LDA) and Kernel LDA, and employing various classifiers to diagnose AD, with model evaluation based on the ADNI dataset. Experimental results reveal that combining Ricci flow-based feature extraction with Kernel LDA significantly improves diagnostic accuracy. The model achieves classification accuracies of 97.28% (NC/AD), 96.14% (NC/EMCI), 96.45% (NC/MCI), 94.83% (EMCI/LMCI), 95.84% (MCI/AD), and 95.37% (LMCI/AD). Additionally, it attains 93.65% and 92.30% accuracy in three-way and four-way classification tasks, respectively. These results outperform most reviewed studies and are comparable to others. This research highlights the potential of merging advanced 3D imaging techniques with mathematical models to enhance diagnostic precision, emphasizing the critical role of early detection in the effective treatment and management of Alzheimer's disease.},
}

*Alzheimer Disease/diagnostic imaging
Humans
*Magnetic Resonance Imaging/methods
Early Diagnosis
*Hippocampus/diagnostic imaging/pathology
Female
Aged
Male
Discriminant Analysis
*Image Interpretation, Computer-Assisted/methods
Aged, 80 and over
Imaging, Three-Dimensional/methods

@article {pmid42430052,
year = {2026},
author = {Castagna, A and Cotroneo, AM and Mosele, M and Sapone, P and Martinelli, E and Rahmati, M and Smith, L and Veronese, N},
title = {Hyperhomocysteinemia, a risk factor for various health conditions: an umbrella review of systematic reviews with meta-analysis.},
journal = {Aging clinical and experimental research},
volume = {},
number = {},
pages = {},
doi = {10.1007/s40520-026-03433-0},
pmid = {42430052},
issn = {1720-8319},
abstract = {BACKGROUND: Hyperhomocysteinemia, an elevation of plasma homocysteine levels, has been implicated in multiple diseases, yet its causal role remains debated. This umbrella review systematically evaluated and graded the evidence from published systematic reviews and meta-analyses on associations between hyperhomocysteinemia and diverse health outcomes.

METHODS: We searched Medline, Embase, and Web of Science up to March 5, 2025. Eligible studies were systematic reviews and meta-analyses of observational studies reporting associations between hyperhomocysteinemia and any health outcome. Methodological quality was assessed using AMSTAR-2, and the certainty of evidence was graded using GRADE.

RESULTS: A total of 104 meta-analyses including 2,110 studies and 953,793 participants were analyzed, covering 126 outcomes. Eighty-three percent of outcomes showed significant associations with hyperhomocysteinemia. Nine outcomes were supported by high, 18 by moderate, 73 by low, and 26 by very low certainty of evidence. High-certainty evidence supported associations between hyperhomocysteinemia and increased risks of stroke, intracerebral haemorrhage, fracture (hip and total), and chronic kidney disease. Moderate-certainty evidence linked hyperhomocysteinemia to dementia, Alzheimer's disease, mortality, and selected cardiovascular and pregnancy outcomes. Most meta-analyses were of low or critically low methodological quality.

CONCLUSIONS: Across nearly one million participants, hyperhomocysteinemia was consistently associated with adverse health outcomes, particularly vascular, neurological, skeletal, and renal conditions. While causality cannot be inferred, the evidence supports hyperhomocysteinemia as a potentially modifiable risk factor meriting targeted preventive and interventional research.

PROTOCOL REGISTRATION: https://osf.io/dezms.},
}

@article {pmid42430077,
year = {2026},
author = {Li, L and Wang, S and Duan, L and Zhang, L and Yan, H and Zhu, Y and Tao, L and Gao, Y},
title = {Targeting IL-33 in Precision Neuroimmunology: Cellular Mechanisms and Therapeutic Strategies for CNS Disorders.},
journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology},
volume = {21},
number = {1},
pages = {},
pmid = {42430077},
issn = {1557-1904},
support = {SYS2019027//Suzhou Municipal Science and Technology Bureau/ ; 82471418, 82001382//National Natural Science Foundation of China/ ; SBK2020040785//Jiangsu Provincial Natural Science Foundation of China/ ; KJXW2019018//a project of invigorating healthcare through science, technology, and education/ ; },
mesh = {*Interleukin-33/immunology/antagonists & inhibitors/metabolism ; Humans ; Animals ; *Central Nervous System Diseases/immunology/drug therapy/metabolism ; *Neuroimmunomodulation/drug effects/physiology/immunology ; *Precision Medicine/methods/trends ; },
abstract = {Interleukin-33 (IL-33), an alarmin cytokine of the IL-1 family, has emerged as a pivotal regulator of neuroimmune interactions in the central nervous system (CNS). Acting through its receptor ST2, IL-33 orchestrates diverse immune responses by modulating microglial polarization, shaping T cell differentiation, activating type 2 innate lymphoid cells (ILC2s), and engaging mast cell-macrophage regulatory circuits. Across distinct neurological disorders, including epilepsy, stroke, traumatic brain injury (TBI), Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), cerebral malaria, and glioma, IL-33 exerts both protective and pathogenic effects in a context-dependent manner. In epilepsy, IL-33 modulates neuroinflammation and neuronal excitability; in stroke, it attenuates acute neurovascular injury while influencing post-stroke remodeling; in AD, it enhances amyloid-β clearance and mitigates chronic neuroinflammation; in MS, it regulates autoimmune demyelination via T cell and innate immune pathways. These shared yet disease-specific mechanisms underscore IL-33's central role in neuroimmune homeostasis and its potential as a precision therapeutic target. Future research integrating multi-disease models, temporal disease staging, and single-cell multi-omics will be essential to define the conditions under which IL-33 modulation yields maximal therapeutic benefit.},
}

*Interleukin-33/immunology/antagonists & inhibitors/metabolism
Humans
Animals
*Central Nervous System Diseases/immunology/drug therapy/metabolism
*Neuroimmunomodulation/drug effects/physiology/immunology
*Precision Medicine/methods/trends

@article {pmid42430091,
year = {2026},
author = {You, Y and Duan, D and Xiang, Q},
title = {The Role of PGC-1α in Neurodegenerative Diseases: Molecular Mechanisms, Translational Challenges, and Therapeutic Potential.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42430091},
issn = {1559-1182},
mesh = {Humans ; *Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism ; *Neurodegenerative Diseases/metabolism/therapy ; Animals ; Mitochondria/metabolism ; *Translational Research, Biomedical ; *Translational Science, Biomedical ; },
abstract = {Neurodegenerative diseases (NDDs) are progressive disorders in which mitochondrial dysfunction, oxidative stress, proteostasis failure, neuroinflammation, and synaptic damage progressively interact to drive neuronal vulnerability. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) links metabolic adaptation to stress-response pathways that are repeatedly disrupted in Alzheimer's disease, Parkinson's disease, Huntington's disease, polyglutamine (PolyQ) disorders, and amyotrophic lateral sclerosis. Rather than providing only an updated catalogue of studies, this review organizes the evidence into a cross-disease rheostat framework that explains why PGC-1α modulation is protective in some settings but incomplete or maladaptive in others. Current findings indicate that PGC-1α supports mitochondrial biogenesis, oxidative phosphorylation, antioxidant defense, mitophagy, autophagy, protein quality control, and inflammatory balance. However, its effects are highly context dependent. In several models, restoration of PGC-1α-related signaling improves mitochondrial function and reduces neuronal injury, whereas broad, sustained, or cell-inappropriate activation may produce limited benefit or undesirable outcomes. These observations suggest that PGC-1α is not a simple neuroprotective switch, but a flexible regulatory hub whose therapeutic value depends on cell type, isoform profile, disease stage, and activation level. Emerging strategies, including small-molecule modulators, gene delivery, antisense-based approaches, nanoparticle systems, and exercise-related interventions, remain largely preclinical and face major barriers related to CNS delivery, pathway selectivity, dose and cell-type control, peripheral safety, and validated target-engagement biomarkers. Nevertheless, clinical translation requires stronger causal validation, reliable target-engagement biomarkers, selective delivery methods, and long-term safety assessment. Future research should focus on precision-based modulation of PGC-1α to determine when and how this pathway can be safely used for disease modification. Such a careful approach may help transform PGC-1α from a broad experimental target into a clinically relevant strategy for well-defined neurodegenerative phenotypes.},
}

Humans
*Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism
*Neurodegenerative Diseases/metabolism/therapy
Animals
Mitochondria/metabolism
*Translational Research, Biomedical
*Translational Science, Biomedical

@article {pmid42430332,
year = {2026},
author = {Sánchez-Escudero, JP and Díaz González, DC and Aguillón-Niño, DF and Garcia-Barrera, MA and Aguirre-Acevedo, DC and Trujillo-Orrego, N},
title = {NavegApp, a serious game for assessing spatial cognition: Diagnostic accuracy in preclinical and prodromal Alzheimer's disease.},
journal = {PLOS digital health},
volume = {5},
number = {7},
pages = {e0001521},
pmid = {42430332},
issn = {2767-3170},
abstract = {Alzheimer's Disease (AD) is the leading cause of dementia worldwide, yet early detection remains challenging due to limited access to biomarker-based diagnostic tools, especially in low- and middle-income countries. This study aims to evaluate the diagnostic accuracy of NavegApp, a serious game developed to assess Spatial Cognition (SC), in distinguishing individuals at various stages of AD, including asymptomatic and symptomatic PSEN1-E280A mutation carriers. A cross-sectional sample of 226 participants underwent neurological and neuropsychological evaluations alongside NavegApp targeting allocentric navigation, mental rotation, and visuospatial memory. Results showed excellent diagnostic accuracy for distinguishing symptomatic PSEN1-E280A carriers from asymptomatic carriers and healthy controls, particularly in allocentric navigation metrics (AUC-ROC = 0.94-0.97). However, in asymptomatic participants, diagnostic performance was modest (AUC ≈ 0.57-0.60), indicating limited discriminative capacity at the preclinical stage. Cross-sectional comparisons detected prodromal-stage deficits in visuospatial and mental rotation tasks, whereas diagnostic accuracy for distinguishing sporadic MCI from health controls was moderate to low. These findings demonstrate the feasibility of NavegApp as a digital tool for cognitive assessment, with potential applicability in cognitive screening for underserved communities. Further research must validate its use across diverse settings and establish its integration into clinical practice for early AD detection.},
}

@article {pmid42430835,
year = {2026},
author = {Kalra, P and Grewal, AK},
title = {Glymphatic dysfunction in neurodegeneration: From impaired clearance to mechanism-driven therapeutic innovation.},
journal = {Current opinion in pharmacology},
volume = {89},
number = {},
pages = {102647},
doi = {10.1016/j.coph.2026.102647},
pmid = {42430835},
issn = {1471-4973},
abstract = {Glymphatic system refers to a system that involves perivascular clearance mechanisms within the brain, which are crucial for the elimination of neurotoxic proteins such as amyloid-β (Aβ) and tau proteins in Alzheimer's disease (AD), α-synuclein in Parkinson's disease (PD), and mutant huntingtin (mHTT) in Huntington's disease (HD). There is mounting evidence suggesting that glymphatic dysfunction is an important cause of neurodegenerative diseases, characterized by failure of cerebrospinal fluid-interstitial fluid (CSF-ISF) exchange due to abnormal clearance. Mechanistically, this dysfunction is affected by aging, astroglial aquaporin-4 (AQP4) depolarization, vascular impairment, sleep abnormalities, oxidative damage, and neuroinflammation. Additionally, aberrant glymphatic flow acts as a crucial link between peripheral and central pathologies, amplifying neurodegeneration via altered solute transport and inflammation signaling. Glymphatic dysfunction has been found to be involved in diseases such as AD, PD and HD, thus indicating the widespread significance of glymphatic pathology. Therapeutically, targeting glymphatic function through modulation of AQP4 polarization, improving sleep-dependent clearance, and decreasing oxidative and inflammatory mechanisms may provide promising strategy for disease modification. This review provides a comparative and mechanistic overview of glymphatic dysfunction across AD, PD, and HD, highlighting peripheral-central interactions, biomarkers, imaging approaches, and therapeutic strategies, while addressing unresolved issues related to transport mechanisms, causality versus epiphenomenon, and translational limitations.},
}

@article {pmid42430935,
year = {2026},
author = {Esmaeeli, S},
title = {IL-10 and β-endorphin: A paradoxical loop of microglial clearance in Alzheimer's disease.},
journal = {Revista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion},
volume = {78},
number = {4},
pages = {100049},
doi = {10.1016/j.ric.2026.100049},
pmid = {42430935},
issn = {2564-8896},
}

@article {pmid42430964,
year = {2026},
author = {Daffner, KR and Riera, K and Ghorayeb, GR and McFeeley, BM and Weizenbaum, E and Willment, K and Gale, SA},
title = {Suboptimal adherence to brain health recommendations in patients pursuing anti-amyloid antibody therapy for Alzheimer's disease: Report from the Brain Health Vital Signs project.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {8},
pages = {100640},
doi = {10.1016/j.tjpad.2026.100640},
pmid = {42430964},
issn = {2426-0266},
abstract = {BACKGROUND: Consensus is consolidating around a set of lifestyle and medical factors that can promote brain health and reduce the risk of dementia for older adults and further decline for those with early Alzheimer's disease (AD) and related disorders. Little is known about the degree to which recommended brain-healthy behaviors have been adopted by patients with early AD pursuing anti-amyloid antibody therapy (AAT), a proactive group interested in doing what is under their control to help preserve cognitive and functional status. Here, initial results of a clinically relevant quality improvement study are reported.

OBJECTIVE: To determine the extent to which patients pursuing AAT for AD adhere to consensus-based brain health recommendations.

PARTICIPANTS: One hundred fifty patients with mild cognitive impairment (MCI) or mild dementia due to AD seeking AAT were studied and compared to a group of 117 patients with MCI or mild dementia who were not pursuing AAT.

MEASUREMENTS: Using a clinical survey tool developed for the project, patients were assessed on 15 modifiable risk factors for cognitive decline and dementia, including 11 via e-survey (diet, physical activity, cognitive activity, sleep, social engagement, smoking status, alcohol consumption, hearing, vision, mood/stress, and purpose in life) and 4 via electronic medical record (EMR) (blood pressure, BMI, LDL cholesterol level, and HbA1c). For each factor, the percentage of each of the two patient groups that was not optimally adhering to brain health-related guidelines was calculated. For each individual, the total number of factors not optimally being followed was determined.

RESULTS: Less than 3% of patients with early AD pursuing AAT were following or had anthropometric measures/lab values in line with all 15 brain health recommendations. The five factors with the lowest adherence rates involved physical activity, mood/stress, HbA1c, blood pressure, and BMI, with 44-63% of the AAT group suboptimally following consensus-based guidelines. For 11 of 15 factors, >25% of the group were not adhering to guidelines. No robust differences in degree or pattern of adherence to guidelines were observed between patients pursuing and not pursuing AAT. There were no data in the EMR for HbA1c in >42% of patients and for LDL in >23% of patients in either group.

CONCLUSIONS: Suboptimal adherence to brain health recommendations may be common among patients with early AD, whether they are pursuing AAT or not. These results suggest that healthcare systems may need to develop more effective strategies and individualized interventions for addressing modifiable risk factors for cognitive decline and dementia, and more efficacious procedures for ensuring that relevant, actionable data associated with brain health are updated in the EMR.},
}