@article {pmid41866337,
year = {2026},
author = {Lindbohm, JV and Stražar, M and Lee, HM and Ashenberg, O and Mars, N and Sipilä, PN and Ripatti, S and Graham, D and Kivimäki, M and Xavier, RJ},
title = {Population and single-cell analyses reveal immune cell-specific expression profiles associated with Alzheimer's disease risk.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {3},
pages = {e71282},
doi = {10.1002/alz.71282},
pmid = {41866337},
issn = {1552-5279},
support = {339568//Research Council of Finland/ ; 350426//Research Council of Finland/ ; 331671//Research Council of Finland/ ; 355567//Research Council of Finland/ ; //Päivikki and Sakari Sohlberg foundation/ ; 221854/Z/20/Z/WT_/Wellcome Trust/United Kingdom ; R01AG056477/AG/NIA NIH HHS/United States ; MR/R024227/1/MRC_/Medical Research Council/United Kingdom ; MR/Y014154/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Humans ; *Alzheimer Disease/genetics/immunology ; Genome-Wide Association Study ; Single-Cell Analysis ; Brain/immunology/metabolism ; Mendelian Randomization Analysis ; Transcriptome ; Genetic Predisposition to Disease ; Quantitative Trait Loci ; },
abstract = {INTRODUCTION: Dysregulation of the peripheral immune system may increase Alzheimer's disease (AD) risk, but the underlying cell type-specific mechanisms remain unclear.

METHODS: We conducted Mendelian randomization and colocalization analyses of 4489 genes using single-cell expression quantitative trait locus data from unstimulated and stimulated peripheral immune cells, integrated with an AD genome-wide association study (N = 455,258). Spatial transcriptomics of brain tissue samples was used to identify brain-infiltrating immune cells.

RESULTS: Thirteen genes were associated with AD risk. Expression of BIN1, CTSW, CTSH, HLA-DRB1, TSTD1, PLEKHA1, and SCIMP increased AD risk, while EPHA1-AS1, FCER1G, FIBP, KAT8, STX4, and HLA-DQA1 reduced it. These associations were peripheral immune cell type and state specific. PLEKHA1 and TSTD1 were upregulated and FIBP downregulated in natural killer and T cells in AD brain tissue.

DISCUSSION: These findings link immune cell-specific gene expression to AD risk across activation states and within brain-infiltrating immune cells, highlighting potential targets for immune-based AD prevention and treatment.},
}

Humans
*Alzheimer Disease/genetics/immunology
Genome-Wide Association Study
Single-Cell Analysis
Brain/immunology/metabolism
Mendelian Randomization Analysis
Transcriptome
Genetic Predisposition to Disease
Quantitative Trait Loci

@article {pmid41866365,
year = {2026},
author = {Guo, G and Song, W and Wang, A and Cui, Q and Yang, X and Wang, Y and Ma, Y and Han, H and Li, Z and Zhang, Z and Meng, W and Wang, S and Shi, F},
title = {Sensitivity comparison of longitudinal cognitive function indicators of Alzheimer's disease after mild cognitive impairment: a prospective cohort study.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-44192-2},
pmid = {41866365},
issn = {2045-2322},
support = {81803337//National Natural Science Foundation of China/ ; 81803337//National Natural Science Foundation of China/ ; 81803337//National Natural Science Foundation of China/ ; 81803337//National Natural Science Foundation of China/ ; 81803337//National Natural Science Foundation of China/ ; 81803337//National Natural Science Foundation of China/ ; 81803337//National Natural Science Foundation of China/ ; 81803337//National Natural Science Foundation of China/ ; 81803337//National Natural Science Foundation of China/ ; 81803337//National Natural Science Foundation of China/ ; 81803337//National Natural Science Foundation of China/ ; 81872719//National Natural Science Foundation of China/ ; 81803337//National Natural Science Foundation of China/ ; 2019-6-156, Lu-Jiao//Shandong Provincial Youth Innovation Team Development Plan of Colleges and Universities/ ; 2019-6-156, Lu-Jiao//Shandong Provincial Youth Innovation Team Development Plan of Colleges and Universities/ ; 2019-6-156, Lu-Jiao//Shandong Provincial Youth Innovation Team Development Plan of Colleges and Universities/ ; 2019-6-156, Lu-Jiao//Shandong Provincial Youth Innovation Team Development Plan of Colleges and Universities/ ; 2019-6-156, Lu-Jiao//Shandong Provincial Youth Innovation Team Development Plan of Colleges and Universities/ ; 2019-6-156, Lu-Jiao//Shandong Provincial Youth Innovation Team Development Plan of Colleges and Universities/ ; 2019-6-156, Lu-Jiao//Shandong Provincial Youth Innovation Team Development Plan of Colleges and Universities/ ; 2019-6-156, Lu-Jiao//Shandong Provincial Youth Innovation Team Development Plan of Colleges and Universities/ ; 2019-6-156, Lu-Jiao//Shandong Provincial Youth Innovation Team Development Plan of Colleges and Universities/ ; 2019-6-156, Lu-Jiao//Shandong Provincial Youth Innovation Team Development Plan of Colleges and Universities/ ; 2019-6-156, Lu-Jiao//Shandong Provincial Youth Innovation Team Development Plan of Colleges and Universities/ ; 2019-6-156, Lu-Jiao//Shandong Provincial Youth Innovation Team Development Plan of Colleges and Universities/ ; ZR2023MH313//Shandong Provincial Natural Science Foundation/ ; ZR2023MH313//Shandong Provincial Natural Science Foundation/ ; ZR2023MH313//Shandong Provincial Natural Science Foundation/ ; ZR2023MH313//Shandong Provincial Natural Science Foundation/ ; ZR2023MH313//Shandong Provincial Natural Science Foundation/ ; ZR2023MH313//Shandong Provincial Natural Science Foundation/ ; ZR2023MH313//Shandong Provincial Natural Science Foundation/ ; ZR2023MH313//Shandong Provincial Natural Science Foundation/ ; ZR2023MH313//Shandong Provincial Natural Science Foundation/ ; ZR2023MH313//Shandong Provincial Natural Science Foundation/ ; ZR2023MH313//Shandong Provincial Natural Science Foundation/ ; ZR2023MH313//Shandong Provincial Natural Science Foundation/ ; },
abstract = {Accurate prediction of progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD) is critical for early intervention. Many existing models lack the ability to capture the nonlinear nature of cognitive decline and individual heterogeneity. This study employed a semi‑parametric joint model to analyze longitudinal cognitive trajectories and identify robust predictors of conversion. Data from 596 participants (184 AD converters, 412 stable MCI) were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Longitudinal assessments included ADAS‑Cog13, ADAS‑Cog11, CDR‑SB, FAQ, RAVLT‑IR, RAVLT‑L, and MMSE. A semi‑parametric joint model combining B‑splines for the longitudinal process with a Cox survival submodel was fitted for each cognitive measure. Model performance was evaluated using AIC, BIC, intraclass correlation coefficient (ICC), time‑dependent C‑index, dynamic AUC, and calibration curves. Subgroup analyses were conducted by APOE‑ε4 carrier status. In multivariable joint models, APOE‑ε4 carriage was a consistent risk factor (HR range: 1.38-1.77). Higher scores on ADAS‑Cog13 (HR = 3.71 per SD), ADAS‑Cog11 (HR = 2.71), CDR‑SB (HR = 3.79), and FAQ (HR = 2.85) increased the hazard of conversion, whereas higher scores on RAVLT‑IR (HR = 0.23), RAVLT‑L (HR = 0.14), and MMSE (HR = 0.53) were protective. All models showed high ICCs (0.94-0.98) and moderate‑to‑good predictive accuracy over 2, 5, and 8 year horizons (C‑index: 0.585-0.668). CDR‑SB and FAQ exhibited the strongest effect sizes and clearest dose‑dependent trajectories across APOE‑ε4 subgroups. Calibration curves demonstrated good agreement between predicted and observed survival. The semi‑parametric joint model effectively captures nonlinear cognitive‑functional decline and provides validated predictions of AD risk. APOE‑ε4 genotype combined with longitudinal monitoring of CDR‑SB and FAQ offers a robust framework for stratifying progression risk in clinical MCI management.},
}

@article {pmid41866449,
year = {2026},
author = {Wang, Z and He, F and Li, L and Wang, W and Zhang, L and Tang, J and Le, W},
title = {Sleep Disorders in Neurodegenerative Diseases: Pathological Correlations and Underlying Mechanisms.},
journal = {Neuroscience bulletin},
volume = {},
number = {},
pages = {},
pmid = {41866449},
issn = {1995-8218},
abstract = {Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), and others, represent an escalating public health burden in aging populations. NDDs are characterized by progressive neuronal loss and misfolded protein aggregation. Despite distinct clinical heterogeneity, these diseases universally present with debilitating non-motor symptoms, among which sleep-wake disorders are highly prevalent. Once considered secondary to neuronal damage, growing evidence now highlights a bidirectional interplay: sleep disruption is not only a consequence of neurodegeneration but also exacerbates its progression. This review synthesizes this complex interplay, outlining sleep phenotypes across major NDDs, dissecting key underlying mechanisms (impaired protein homeostasis, glymphatic dysfunction, chronic neuroinflammation, sleep-regulatory nucleus vulnerability, and circadian dysregulation), and summarizing current pharmacotherapeutic and non-pharmacological interventions. Attenuating sleep disorders may therefore provide symptomatic relief and disease‑modifying effects for NDDs.},
}

@article {pmid41866584,
year = {2026},
author = {Zhou, J and Zhang, X and Yin, S and Xue, S and He, Q and Chen, S and Xue, X},
title = {Molecular mechanisms of exercise-induced improvements in Alzheimer's disease: a focus on lipid homeostasis.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {41866584},
issn = {2047-9158},
support = {ZR2025QC303//Natural Science Foundation of Shandong Province/ ; 23TYJ03//Shandong Province Social Science Planning Research Project/ ; },
mesh = {*Alzheimer Disease/metabolism/therapy ; Humans ; *Lipid Metabolism/physiology ; *Exercise/physiology ; *Homeostasis/physiology ; Animals ; *Exercise Therapy/methods ; },
abstract = {Alzheimer's disease (AD) is the most prevalent type of dementia, and its pathophysiological mechanisms involve multiple factors, including genomic factors, metabolomic factors, and environmental factors. Lipid dysregulation occurs both centrally and peripherally in patients with AD, and the severity is closely associated with disease progression. Applied studies based on genome-wide association studies, genomic analyses, lipidomic analyses, mass spectrometry, and machine learning, have identified lipids as a key potential target for early diagnosis and intervention in AD. However, due to the complexity of AD pathogenesis and the considerable structural and functional diversities of lipids, pharmacological therapies that target lipid homeostasis have shown limited effectiveness in ameliorating AD pathology and are often accompanied by side effects. In contrast, exercise, a holistic intervention with multitarget effects, can modulate the levels of multiple lipids simultaneously and slow the progression of AD with minimal side effects. However, the mechanisms require further clarification. This review summarizes alterations and mechanisms of action of lipids-including fatty acids, triglycerides, glycerophospholipids, sphingolipids, and cholesterol-in AD and further outlines the possible molecular mechanisms through which exercise influences AD through modulation of lipid metabolism. We also review the recent clinical research on lipid-targeting drugs for AD, and propose a hypothesis that lipids may act as a mediator of the peripheral-central crosstalk between exercise and AD. Additionally, how different apolipoprotein E genotypes may affect the response to exercise in AD is explored. These insights provide a theoretical basis for nonpharmacological interventions for AD and offer an important reference for the development of lipid-related therapeutic targets.},
}

*Alzheimer Disease/metabolism/therapy
Humans
*Lipid Metabolism/physiology
*Exercise/physiology
*Homeostasis/physiology
Animals
*Exercise Therapy/methods

@article {pmid41866640,
year = {2026},
author = {Corrada, BR and Speth, RC},
title = {Is Alzheimer's an Autoimmune Disease?.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {41866640},
issn = {1559-1182},
support = {1R15AG091199-01/GF/NIH HHS/United States ; },
mesh = {*Alzheimer Disease/immunology/pathology/therapy ; Humans ; *Autoimmune Diseases/immunology/pathology ; Animals ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; },
abstract = {Alzheimer's disease is defined as a progressive neurodegenerative disorder characterized by a gradual decline in cognitive and functional abilities [1]. Although debate continues with respect to its exact pathology, several hypotheses have been proposed to explain its underlying mechanisms. The two primary pathological factors of Alzheimer's disease are the accumulation of amyloid-β plaques and neurofibrillary tangles composed of hyperphosphorylated tau and neurofilament protein [1, 2]. It should be noted that our use of the descriptor hyperphosphorylated tau is done to conform with current nomenclature; it should not be construed as indicating saturation of all the amino acids capable of being phosphorylated. Emerging clinical evidence proposes that some variants of Alzheimer's disease may be caused by an autoimmune process rather than a purely neurodegenerative one. The purpose of this paper is to review and evaluate evidence supporting and challenging the autoimmune hypothesis of Alzheimer's disease, as well as to explore its implications for future therapeutic strategies within the framework of the disease.},
}

*Alzheimer Disease/immunology/pathology/therapy
Humans
*Autoimmune Diseases/immunology/pathology
Animals
Amyloid beta-Peptides/metabolism
tau Proteins/metabolism

@article {pmid41866791,
year = {2026},
author = {Verma, K and Kumar, S},
title = {From autopsy to PET to cerebrospinal fluid to blood: Quantifying reference-standard dependence in Alzheimer's disease amyloid biomarker validation.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261430858},
doi = {10.1177/13872877261430858},
pmid = {41866791},
issn = {1875-8908},
abstract = {BackgroundBlood-based biomarkers are increasingly used as scalable front-line tools for Alzheimer's disease amyloid evaluation, but most are validated against amyloid positron emission tomography (PET) and/or cerebrospinal fluid (CSF) rather than neuropathology. In a chained validation cascade (neuropathology→PET→CSF→blood), reported performance may depend strongly on the comparator and on how "gray-zone" (indeterminate) results are handled.ObjectiveTo quantify benchmark dependence and gray-zone policy sensitivity in amyloid biomarker validation and characterize plasma-to-neuropathology performance inference from imperfect proxies.MethodsWe assembled a fully auditable evidence core spanning the amyloid cascade with reconstructable 2 × 2 tables. We recomputed positive percent agreement (PPA) and negative percent agreement (NPA) with 95% Wilson confidence intervals under a prespecified primary policy (exclude indeterminates) and two sensitivity policies (indeterminate→negative; indeterminate→positive). Reference-swap drift across benchmarks was summarized with Monte Carlo uncertainty intervals. For plasma-to-neuropathology inference, we combined plasma-PET agreement with tracer-specific PET-autopsy anchors and reported (i) chained-proxy point implications under conditional independence and (ii) partial-identification bounds without conditional independence across prevalence scenarios (π = 10-50%).ResultsUnder the primary policy, Lumipulse plasma pTau217/Aβ42 showed similar agreement across PET, CSF, and composite comparators (PPA 0.97-0.98; NPA ≈0.91), with drift intervals spanning zero. Indeterminates were frequent (∼19-20%) and dominated apparent shifts: indeterminate→negative reduced PPA by 0.13-0.21, whereas indeterminate→positive reduced NPA by 0.17-0.21. Chained-proxy implications for plasma versus neuropathology varied by PET tracer anchor (sensitivity 0.86-0.96; specificity 0.81-0.91), while bounds were wider (sensitivity 0.83-1.00; specificity 0.81-0.98).ConclusionsGray-zone policy is a first-order driver of reported blood-test performance, and proxy-to-proxy agreement does not uniquely identify plasma-to-neuropathology accuracy without explicit assumptions.},
}

@article {pmid41866837,
year = {2026},
author = {},
title = {Corrigendum to "Neuropsychiatric signs and symptoms clusters and regional amyloid on [18]F-FC119S PET in Alzheimer's disease".},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261423686},
doi = {10.1177/13872877261423686},
pmid = {41866837},
issn = {1875-8908},
}

@article {pmid41867027,
year = {2026},
author = {Weigand, AJ and Tsoy, E and Atkins, KJ and Jarrott, S and Farias, ST and Scheffler, AW and Brailow, T and Rankin, KP and Kramer, JH and Possin, KL},
title = {Classifying cognitive status with TabCAT Match and UDS executive function tests.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {3},
pages = {e71299},
doi = {10.1002/alz.71299},
pmid = {41867027},
issn = {1552-5279},
support = {P30 AG062422/AG/NIA NIH HHS/United States ; P30 AG072972/AG/NIA NIH HHS/United States ; R35 AG072362/AG/NIA NIH HHS/United States ; U01 NS128913/NS/NINDS NIH HHS/United States ; },
mesh = {Humans ; *Executive Function/physiology ; Male ; *Neuropsychological Tests ; Female ; Aged ; *Cognitive Dysfunction/diagnosis/classification ; Aged, 80 and over ; ROC Curve ; Alzheimer Disease/diagnosis ; },
abstract = {INTRODUCTION: Tablet-based Cognitive Assessment Tool (TabCAT) Match, a digital neuropsychological test, was compared to measures of executive function from the National Alzheimer's Coordinating Center's Uniform Dataset (UDS).

METHODS: TabCAT Match data were available for 1792 clinically diverse older adults. Receiver operating characteristic curves and analyses of covariance examined classification of Clinical Dementia Rating Scale (CDR) stages based on Match and UDS executive function scores. Sensitivity analyses were conducted across education level and testing language groups.

RESULTS: All measures had utility in differentiating CDR stages, with Match displaying the highest classification accuracy (AUC = 0.862) for cognitively unimpaired (CDR 0, clinically normal) versus cognitively impaired (CDR ≥ 0.5, mild cognitive impairment/dementia). The advantages of Match were especially apparent in non-English tested groups relative to UDS tests.

DISCUSSION: The identification of efficient neuropsychological measures, such as TabCAT Match, that are easily administered, sensitive to impairment, and appropriate across demographic groups is critical for optimizing diagnosis and clinical monitoring.},
}

Humans
*Executive Function/physiology
Male
*Neuropsychological Tests
Female
Aged
*Cognitive Dysfunction/diagnosis/classification
Aged, 80 and over
ROC Curve
Alzheimer Disease/diagnosis

@article {pmid41867029,
year = {2026},
author = {Chatila, ZK and Duggan, MR and Silberberg, E and Fernandez, J and Auber, LA and Bradshaw, EM and Schultek, NM},
title = {Can we refute a role for infections in Alzheimer's disease pathogenesis?.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {3},
pages = {e71288},
doi = {10.1002/alz.71288},
pmid = {41867029},
issn = {1552-5279},
support = {R01AG076018-05//US National Institutes of Health, National Institute on Aging/ ; F30AG074618//US National Institutes of Health, National Institute on Aging/ ; R01AG067581-05//US National Institutes of Health, National Institute on Aging/ ; },
mesh = {*Alzheimer Disease/microbiology/genetics/immunology/etiology ; Humans ; Gene-Environment Interaction ; *Infections/complications ; },
abstract = {While a growing body of literature suggests a role for infections in Alzheimer's disease (AD), microbial contributions to AD remains a contentious topic, in part due to challenges in reconciling the positive evidence with studies reporting null findings. Here, we examine the evidence that argues against a role for infections in AD, while offering mechanistic hypotheses that may account for both the negative and positive findings, including dysregulated host immunity and gene-environment interactions of AD-associated genes.},
}

*Alzheimer Disease/microbiology/genetics/immunology/etiology
Humans
Gene-Environment Interaction
*Infections/complications

@article {pmid41867189,
year = {2026},
author = {Solis-Urra, P and Olvera-Rojas, M and García-Rivero, Y and Zeng, X and Chen, Y and Sehrawat, A and Shekari, M and Oberlin, LE and Erickson, KI and Karikari, TK and Gómez-Río, M and Ortega, FB and Esteban-Cornejo, I},
title = {Effects of a 24-week resistance exercise program on brain amyloid and Alzheimer's disease blood-based biomarkers: the AGUEDA randomized controlled trial.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.02.26347392},
pmid = {41867189},
abstract = {We examined whether a 24-week resistance training program influenced brain amyloid-β (Aβ) and Alzheimer's Disease (AD)-related blood-based biomarkers. Ninety cognitively normal, physically inactive older adults aged 65-80 years were randomly allocated to a 24-week resistance training program (three ∼60-min supervised sessions/week) or a wait-list control group. Primary analyses assessed exercise-induced changes in brain Aβ (Centiloid values) and plasma ptau217/Aβ1-42 IPMS ratio. Secondary analyses examined ptau217/Aβ42 SIMOA ratio, ptau217, ptau181 and Aβ42/40, as well as potential interactions with sex, age, education, apolipoprotein ε4 (APOE4) status, amyloid PET-positivity, and comorbidities. The intervention produced no significant differences on brain Aβ or AD-related blood-based biomarkers (p>0.05) compared to the control group. However, the ptau217/Aβ1-42 IPMS ratio showed a small, non-significant increase in the control group (SMD = 0.162; 95% CI: -0.159 to 0.483) while remaining stable in the exercise group (SMD = 0.01; 95% CI: -0.291 to 0.310) with a similar trend for ptau217/Aβ42 SIMOA. Moderator analyses indicated differential responses by amyloid PET-positivity and APOE4 status on brain Aβ (p for interaction<0.05), with increases observed in APOE4 carriers and amyloid PET-positive individuals in the control group, whereas those allocated to the exercise intervention reduced their levels. The specificity observed within our subgroups suggests that resistance exercise may serve as a targeted intervention to modulate AD pathophysiology, raising new questions regarding its broader role in the delay of the disease in vulnerable populations.},
}

@article {pmid41867210,
year = {2026},
author = {Choi, JJ and Engelman, CD and Lu, T},
title = {Multi-Omics Integration of Transcriptomics and Metabolomics with Machine Learning Uncovers Novel Risk Factors for Alzheimer's disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.28.26347204},
pmid = {41867210},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder marked by cognitive decline, memory impairment, and functional deterioration. Its complex pathogenesis involves factors such as amyloid plaques, tau tangles, neuroinflammation, and synaptic dysfunction, but the precise mechanisms remain unclear, hindering effective treatment. Genetic, environmental, and lifestyle factors contribute to AD risk, yet their interactions are poorly understood. Recent advances in transcriptomics and metabolomics have shed light on the molecular underpinnings of AD, with gene expression alterations and metabolic disruptions implicated in disease progression. These multi-omics disruptions highlight the need for integrative analytical approaches to better characterize AD-relevant biology and advance biomarker discovery.

OBJECTIVES: To integrate genetically imputed whole blood transcriptomics and plasma metabolomics to predict cognitive performance (PACC3) and to identify risk genes and metabolites contributing to prediction, thereby characterizing molecular signatures associated with cognitive performance in AD.

METHODS: This study applies a machine learning algorithm to integrate genetically imputed whole blood transcriptomics and measured plasma metabolomics data to predict cognitive performance, as measured by PACC3 score, using data from the Wisconsin Registry for Alzheimer's Prevention (WRAP) cohort (N = 1,046). After training a machine learning model on WRAP, the predictive performance was evaluated using an independent dataset from the Wisconsin Alzheimer's Disease Research Center (ADRC) cohort (N = 85). Feature importance was assessed to identify genes and metabolites that may play a role as potential risk factors in AD.

RESULTS: The machine learning model achieved a normalized root mean squared error (NRMSE) of 0.743 ± 0.037 and an R² of 0.311 ± 0.016 across 5-fold holdout test folds in WRAP (p = 5.93 × 10 [-30]), and an NRMSE of 0.915 and an R² of 0.061 when applied to the Wisconsin ADRC cohort. Feature importance revealed transcriptomic biomarkers such as RIPK1 , IL6ST , and BIN1 whose higher imputed expression levels were associated with poorer cognitive performance whereas other potential biomarkers including UGP2 , NDUFB5 , and TMOD2 were associated with better cognitive performance, reflecting mitochondrial energy metabolism and molecular processes associated with cognitive resilience. Several predictive metabolites including benzoate, 3-phenylpropionate, and imidazolelactate also mapped to AD vulnerability signatures, while acyl-carnitine species such as hexanoylcarnitine (C6) and propionate-related metabolites aligned with metabolic resilience.

CONCLUSION: Integrated analysis of transcriptomics and metabolomics demonstrated potential utility for identifying candidate biomarkers associated with cognition in AD. Genes and metabolites reflecting inflammatory signaling, mitochondrial dysregulation, and lipid metabolism emerged consistently among the most influential contributors. These findings align with well-established AD vulnerability pathways and highlight convergent biology across two omics layers. Collectively, this supports the value of multi-omics integration for improving molecular characterization of AD and advancing biomarker prioritization for future mechanistic and translational studies.},
}

@article {pmid41867219,
year = {2026},
author = {Jannati, A and Toro-Serey, C and Ciesla, M and Chen, E and Showalter, J and Bates, D and Pascual-Leone, A and Tobyne, S},
title = {Streamlining Eligibility Assessment for Alzheimer's Disease-Modifying Therapies: Prediction of MMSE Scores Using the Digital Clock and Recall.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.03.26347542},
pmid = {41867219},
abstract = {INTRODUCTION: The eligibility of anti-amyloid disease-modifying therapies (DMTs) and their integration into clinical practice in some institutions requires a specific range of Mini-Mental State Examination (MMSE) scores. Reliance on this pencil-and-paper psychometric instrument imposes operational burdens and risks perpetuating health disparities due to the test's known educational and cultural biases. This study evaluates the efficacy of the Digital Clock and Recall (DCR™) - a rapid, FDA-listed digital cognitive assessment - to crosswalk to MMSE scores using machine learning, thereby offering a faster, scalable, and equitable mechanism for patient triage.

METHODS: We conducted a retrospective analysis using data from the multi-site Bio-Hermes-001 study (NCT04733989 , N=945). Participants were clinically classified as cognitively unimpaired, mild cognitive Impairment, or probable Alzheimer's dementia. We trained a Poisson elastic net regression model using age and multimodal digital features derived from the DCR (including drawing kinematics and voice acoustics) to predict MMSE scores. The model was tested for generalizability using an independent external validation cohort from the Apheleia study (NCT05364307 , N=238).

RESULTS: The machine learning model predicted MMSE scores with a root mean squared error (RMSE) of 2.31 in the training cohort. This error margin falls within the established test-retest reliability range of the manual MMSE itself (2-4 points), suggesting the prediction is statistically non-inferior to human administration. External validation in the Apheleia cohort demonstrated robust generalizability (RMSE = 2.62). Crucially, the model exhibited demographic fairness, maintaining consistent accuracy across Race (White RMSE = 2.34; Non-White RMSE = 2.14) and Ethnicity (Hispanic RMSE = 2.26; Non-Hispanic RMSE = 2.31).

DISCUSSION: Machine learning can leverage multimodal features from the DCR to accurately and equitably crosswalk to MMSE scores in support of current guidelines, transforming a time-intensive manual test into a rapid, automated assessment. By deploying this "digital triage" engine, where traditional assessments are still used for DMT eligibility, healthcare systems can streamline the identification of DMT-eligible patients, reduce specialist referral bottlenecks, and ensure that access to life-altering therapies is determined by pathology rather than demography.},
}

@article {pmid41867223,
year = {2026},
author = {Le Guen, Y and Peña-Tauber, A and Catoia Pulgrossi, R and Park, J and Orias, H and Greicius, MD},
title = {Population-scale burden analysis of rare damaging coding variants identifies novel risk genes for Alzheimer's disease and Parkinson's disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.03.26347540},
pmid = {41867223},
abstract = {Alzheimer's disease and related dementias (ADRD) [1] and Parkinson's disease and related disorders (PDRD) [2] have substantial genetic contributions, yet the role of rare damaging coding variants remains incompletely characterized at population scale [3-6] . We performed gene-based burden testing of rare loss-of-function and deleterious missense variants using whole-genome sequencing data from large population biobanks combined with disease-specific sequencing cohorts, leveraging proxy phenotypes to maximize statistical power for late-onset neurodegenerative diseases [7] . We confirmed rare variant burden in established ADRD genes (ABCA7, PSEN1, ADAM10, ATP8B4, GRN, SORL1, TREM2, SHARPIN) and PDRD genes (GBA1, LRRK2). We additionally identified novel associations in ADRD (IMPA2, PMM2, SYNE1, CHRNA4, FCGR1A) and PDRD (ANKRD27, CCL7, USP19, SKP1, KANSL3). The strongest signal was observed for ANKRD27 , where damaging variants clustered within domains mediating interactions with Rab GTPases and retromer components. Our results demonstrate the power of population-scale sequencing combined with proxy phenotypes to identify rare coding risk genes for neurodegenerative diseases.},
}

@article {pmid41867349,
year = {2026},
author = {Deng, Y and Zeng, D and Wang, Y},
title = {SEMIPARAMETRIC ANALYSIS OF INTERVAL-CENSORED DATA SUBJECT TO INACCURATE DIAGNOSES WITH A TERMINAL EVENT.},
journal = {The annals of applied statistics},
volume = {20},
number = {1},
pages = {623-640},
pmid = {41867349},
issn = {1932-6157},
abstract = {Interval-censoring frequently occurs in studies of chronic diseases where disease status is inferred from intermittently collected biomarkers. Although many methods have been developed to analyze such data, they typically assume perfect disease diagnosis, which often does not hold in practice due to the inherent imperfect clinical diagnosis of cognitive functions or measurement errors of biomarkers such as cerebrospinal fluid. In this work, we introduce a semiparametric modeling framework using the Cox proportional hazards model to address interval-censored data in the presence of inaccurate disease diagnosis. Our model incorporates sensitivity and specificity of the diagnosis to account for uncertainty in whether the interval truly contains the disease onset. Furthermore, the framework accommodates scenarios involving a terminal event and when diagnosis is accurate, such as through postmortem analysis. We propose a nonparametric maximum likelihood estimation method for inference and develop an efficient EM algorithm to ensure computational feasibility. The regression coefficient estimators are shown to be asymptotically normal, achieving semiparametric efficiency bounds. We further validate our approach through extensive simulation studies and an application assessing Alzheimer's disease (AD) risk. We find that amyloid-beta is significantly associated with AD, but Tau is predictive of both AD and mortality.},
}

@article {pmid41867350,
year = {2026},
author = {Cai, Z and Zeng, D and Marder, KS and Honig, LS and Wang, Y},
title = {DYNAMIC CLASSIFICATION OF LATENT DISEASE PROGRESSION WITH AUXILIARY SURROGATE LABELS.},
journal = {The annals of applied statistics},
volume = {20},
number = {1},
pages = {641-662},
pmid = {41867350},
issn = {1932-6157},
abstract = {Disease progression prediction based on patients' evolving health information is challenging when true disease states are unknown due to diagnostic capabilities or high costs. For example, the absence of gold-standard neurological diagnoses hinders distinguishing Alzheimer's disease (AD) from related conditions such as AD-related dementias (ADRDs), including Lewy body dementia (LBD). Combining temporally dependent surrogate labels and health markers may improve disease prediction. However, existing literature models informative surrogate labels and observed variables that reflect the underlying states using purely generative approaches, often posing unrealistic assumptions on the outcomes and suffering from misspecification thereof. We propose integrating the conventional hidden Markov model as a generative model with a time-varying discriminative classification model to simultaneously handle potentially misspecified surrogate labels and incorporate important markers of disease progression. We develop an adaptive forward-backward algorithm with subjective labels for estimation, and utilize the modified posterior and Viterbi algorithms to predict the progression of future states or new patients based on objective markers only. Importantly, the adaptation eliminates the need to model the marginal distribution of longitudinal markers, a requirement in traditional algorithms. Asymptotic properties are established, and significant improvements in finite samples are demonstrated via simulation studies. Analysis of the neuropathological dataset of the National Alzheimer's Coordinating Center (NACC) shows much improved accuracy in distinguishing LBD from AD.},
}

@article {pmid41867361,
year = {2026},
author = {Li, G and Yap, PT},
title = {A Large-scale Neural Model Inversion Framework for Effective Connectivity Estimation.},
journal = {Medical image computing and computer-assisted intervention : MICCAI ... International Conference on Medical Image Computing and Computer-Assisted Intervention},
volume = {15961},
number = {},
pages = {3-12},
pmid = {41867361},
abstract = {The development of a computational framework that can infer large-scale brain-wide effective connectivity (EC) based on resting-state functional MRI (rs-fMRI) represents a grand challenge to computational neuroimaging. Towards the goal of estimating full-scale, whole-brain EC, we developed a new computational framework termed Large-scale nEural Model Inversion (LEMI) by utilizing a linear neural mass model with an efficient Kalman-filter based gradient descent algorithm. Key advantages of LEMI include fast estimation of both intra-regional and inter-regional connection strengths for large-scale networks, allowing exploration of both intrinsic and external mechanisms in neuroscience problems. Using ground-truth simulations, we demonstrated that LEMI can accurately and efficiently recover model parameters in a large network (100 regions) within 90 minutes. We then applied the LEMI model to an empirical rs-fMRI dataset from the ADNI database and identified widespread reduced excitation-inhibition (E-I) ratio in patients with Alzheimer's disease (AD). Overall, LEMI provides an efficient and accurate computational framework to estimate large-scale EC and whole-brain E-I balance based on non-invasive neuroimaging data.},
}

@article {pmid41867506,
year = {2026},
author = {Mou, FS and Ahmed, T and Huda, MN and Nandi, AK},
title = {Artificial neural networks fighting real neural decline: a systematic review of AI in Alzheimer's research.},
journal = {Artificial intelligence review},
volume = {59},
number = {4},
pages = {124},
pmid = {41867506},
issn = {0269-2821},
abstract = {Alzheimer's disease (AD) is a major global health challenge, with Artificial Intelligence (AI) increasingly recognized as a transformative tool for early detection, disease progression modeling, and therapeutic discovery. This systematic review, conducted in accordance with PRISMA guidelines, analyzed 156 peer-reviewed studies published between 2010 and 2024, identified from four major databases (Scopus, PubMed, Web of Science, IEEE Xplore). A particular emphasis was placed on multimodal approaches that integrate neuroimaging, genetics, biomarkers, and clinical data to improve accuracy and translational value. To organize this fragmented field, we introduce a novel Layered Framework that categorizes AI applications into four domains: Early Detection, Disease Progression Modeling, Therapeutic Discovery, and Real-World Integration. In addition, we applied ARIMA-based forecasting to project research trajectories through 2030, which revealed generative models and transformer architectures as the fastest-growing and most promising methodologies. The review highlights substantial advances in early detection and multimodal fusion, particularly through deep learning, while also identifying persistent challenges such as limited model generalizability, ethical concerns, and underexplored clinical implementation. Addressing these barriers will require multi-cohort validation, interpretable AI, and equity-driven model development. By consolidating evidence and forecasting future directions, this review provides a roadmap for accelerating precision-driven innovations in Alzheimer's care.},
}

@article {pmid41867700,
year = {2026},
author = {Wu, C and Wu, C and Yin, X and Zhong, C},
title = {Serum Homocysteine as a Potential Dynamic Biomarker for Staging and Monitoring Progression in Alzheimer's Disease.},
journal = {Neuropsychiatric disease and treatment},
volume = {22},
number = {},
pages = {553269},
pmid = {41867700},
issn = {1176-6328},
abstract = {BACKGROUND: Reliable biomarkers are urgently needed for the early diagnosis and dynamic monitoring of Alzheimer's disease (AD). Serum homocysteine (Hcy) has been increasingly investigated but with inconsistent association to AD severity.

OBJECTIVE: To investigate the correlation between serum Hcy levels and AD severity/cognitive function, and to evaluate its clinical utility as a dynamic monitoring indicator for the disease.

METHODS: This retrospective study enrolled 80 AD patients (stratified by Mini-Mental State Examination [MMSE] score: 40 mild, 28 moderate, 12 severe) and 80 healthy controls from the Cerebrovascular Disease outpatient and inpatient departments of our hospital between January 2022 and December 2024. Fasting serum Hcy was measured via chemiluminescent immunoassay. Correlation with cognitive scores and severity discrimination were analyzed.

RESULTS: Serum Hcy levels were significantly higher in the AD group than controls (21.2 ± 6.6 vs 14.5 ± 4.8 μmol/L, p < 0.05), increasing with severity (mild: 16.8 ± 3.2, moderate: 21.2 ± 4.5, severe: 25.6 ± 5.8 μmol/L, p < 0.001). A strong inverse correlation with MoCA scores was observed (r = -0.76, p < 0.01). ROC analysis showed an AUC of 0.87 for discriminating AD severity, with an optimal cut-off of 17.5 μmol/L (sensitivity 78%, specificity 72%). After 6 months of B-vitamin intervention, Hcy decreased significantly with cognitive improvement.

CONCLUSION: Serum Hcy correlates strongly with AD severity and cognitive decline, supporting its potential as a dynamic biomarker for monitoring progression and treatment response.},
}

@article {pmid41867790,
year = {2026},
author = {Cho, S and Gabr, MT},
title = {Aβ-Overlapping Ectodomain Binding of the Clinical-Stage TREM2 Agonist VG-3927.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.02.709194},
pmid = {41867790},
issn = {2692-8205},
abstract = {Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial immune receptor genetically and functionally linked to Alzheimer's disease (AD). VG-3927, the first clinical-stage small-molecule TREM2 agonist, has been proposed to function as a transmembrane molecular glue and positive allosteric modulator (PAM). Whether it directly engages the extracellular ligand-recognition surface of TREM2 remains unknown. Here, we used a deep learning-based blind docking algorithm to map potential VG-3927 binding sites across TREM2 and identified a binding site within the ectodomain hydrophobic groove, a ligand-recognition surface previously implicated in Aβ and apoE binding. Microscale thermophoresis (MST) confirmed direct interaction of VG-3927 with TREM2 under optimized PEG-400 buffer conditions and independently demonstrated binding of Aβ [1-42] to the receptor. Co-incubation with Aβ reduced the VG-3927 thermophoretic response, consistent with interference at an overlapping ectodomain binding surface. Consistently, Aβ induced a rightward shift in the VG-3927 dose-response curve in a Jurkat TREM2-DAP12 NFAT reporter assay and attenuated VG-3927-induced phospho-SYK signaling. Together, these findings support the presence of a previously unrecognized ectodomain interaction mode for VG-3927 and suggest that amyloid-associated ligand occupancy may modulate TREM2 agonist activity within the AD microenvironment.},
}

@article {pmid41867823,
year = {2026},
author = {Rahim, A and Zhan, X and Han, Q and O'Donnell, A and Jeong, A and Madugundu, GS and Pujari, S and Kruk, M and Luo, X and Li, L and Wu, TP and Tretyakova, NY},
title = {DNA Adenine Methylation Clock in Brain Aging and Alzheimer's Disease Progression.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.05.709867},
pmid = {41867823},
issn = {2692-8205},
abstract = {N [6] -methyldeoxyadenosine (N [6] medA) is a recently identified endogenous DNA modification widely found in bacteria, plants, and eukaryotes. In mammals, N [6] medA has been implicated in brain function, immunity, and response to environmental stress, but its relevance to gene regulation and mammalian aging remains controversial due to its extremely low abundance (< 1 per 10 million adenines) and an uncertainty regarding its genomic origin. We have developed and validated an ultrasensitive isotope dilution nano liquid chromatography-nanospray ionization Orbitrap mass spectrometry methodology to quantify N [6] medA in genomic DNA. Applying this approach to human prefrontal cortex tissues, we found that genomic N [6] medA levels increase linearly with chronological age (Pearson correlation coefficient, 0.95). Individuals with mild cognitive impairment (MCI) and Alzheimer's disease (AD) exhibited a trend toward elevated cortical N [6] medA levels relative to age-matched controls. Genome-wide profiling of N [6] medA in human prefrontal cortex was conducted using two independent methods: NAME-Seq and MeDIP-Seq, which revealed age associated adenine methylation changes reminiscent of established epigenetic aging signatures such as the 5-methylcytosine clocks. N [6] medA mapping experiments identified a subset of genomic loci that were altered in MCI and AD. Pathway analysis of cross-validated adenine methylation sites revealed an enrichment of genes involved in neuronal function and age-related neurological processes, including glutamatergic synapse, axon guidance, and long-term depression. Finally, mass-spectrometry-based photoaffinity proteomics with synthetic DNA representing a region of the APP gene identified N [6] medA reader proteins with known roles in DNA repair, replication and transcription. Together, these findings identify N [6] medA as an age-associated DNA modification in the human brain and suggest that its accumulation and recognition by specific protein readers may contribute to molecular processes underlying brain aging and age-related neurodegeneration.},
}

@article {pmid41867862,
year = {2026},
author = {Bathini, P and Schilling, S and Rahfeld, JU and Holtzman, DM and Saido, TC and Lemere, CA},
title = {Early Binding of Anti-Amyloid Antibodies to CAA Drives Complement Activation, Inflammation and ARIA in Mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.04.709591},
pmid = {41867862},
issn = {2692-8205},
abstract = {Anti-amyloid antibody treatment for Alzheimer's disease is linked to Amyloid-Related Imaging Abnormalities (ARIA), including vasogenic edema (ARIA-E) and microhemorrhages (ARIA-H), especially in ApoE ε4/4 carriers. To investigate mechanisms underlying ARIA, we examined the binding and temporal vascular effects of immunization with 3D6, the precursor to the anti-amyloid antibody bapineuzumab, in two aged Alzheimer's disease amyloid mouse models. Acutely, 3D6 bound to cerebral amyloid angiopathy (CAA), resulting in C1q binding and classical complement activation. Weekly short-term immunization over 7 weeks resulted in elevated CAA- and plaque-associated complement deposition, red blood cell extravasation and microhemorrhages, and was accompanied by significant transcriptomic changes in genes related to complement, inflammation, vascular dysfunction, and endothelial lipid responses. Longer-term dosing over 13-15 weeks further increased complement deposition and was associated with blood-brain barrier disruption, MMP-9 upregulation, and microhemorrhages, accompanied by reduced amyloid burden and modest CAA clearance. C3 levels correlated with microhemorrhage severity. Perivascular macrophages co-localized with complement-decorated CAA in 3D6-treated mice. These findings implicate complement activation as an early key driver of ARIA and suggest that therapeutic targeting of complement may reduce ARIA risk.},
}

@article {pmid41867865,
year = {2026},
author = {Timinski, K and Neupane, K and Prince, A and Bhandari, N and Khan, MR and Sharma, S and Shiravand, Y and Traughber, CA and Raquepaw, Z and Gulshan, K},
title = {FDA-approved drug library screen identifies antidepressants, antimicrobials, anti-COPD, and anti-CVD agents as blockers of NLRP3 inflammasome and sepsis in a sex-dependent manner.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.05.709979},
pmid = {41867865},
issn = {2692-8205},
abstract = {The NLRP3 inflammasome pathway is central to host defense, but dysregulated activation of inflammasomes promotes diseases associated with metabolic syndrome (diabetes, obesity, CVD, MASLD), neurodegenerative diseases (Alzheimer's and Parkinson's), autoinflammatory conditions (CAPS, gout), and respiratory illnesses (asthma/COPD, and COVID-19). Therapeutic modulation of NLRP3 is challenging as it requires selective blockade of detrimental inflammasome activation without broadly suppressing innate immunity. Here, we used a phenotypic screen in THP-1 ASC-GFP monocytes to identify FDA-approved drugs that can block LPS-induced priming of NLRP3 inflammasome or inhibit NLRP3 assembly (ASC speck formation) without disrupting upstream priming. Various classes of drugs, such as antidepressants (Fluoxetine, Duloxetine), antihypertensives (Irbesartan, amlodipine, nebivolol), antidiabetics (Rosiglitazone), β-adrenergic agonists (Salmeterol), antimalarials (Mefloquine), antifungals (Azoles, ciclopirox), and antivirals (Saquinavir, Remdesivir), were identified as potent blockers of either priming or assembly of NLRP3 inflammasome. Hits were validated in several biochemical assays, including effect on release of proinflammatory cytokines, autophagy, lysosomal biogenesis, LPS binding, NF-kB nuclear localization, mitochondrial membrane potential, mitochondrial ROS, and biophysical properties of the cell membrane. A subset of identified drugs was tested in murine studies to probe effects on NLRP3 inflammasome assembly/activation and LPS-induced sepsis. Mice treated with ASC puncta blockers showed markedly reduced proinflammatory cytokines in peritoneal lavage and plasma. Mice treated with LPS-priming blockers showed a sex-specific increase in survival rate in the mouse model of LPS-induced mortality, validating the in vitro screen. Further studies in primary human cells and in vivo disease models are needed to assess the repurposing and therapeutic relevance of identified drugs.},
}

@article {pmid41867870,
year = {2026},
author = {Li, B and Hagy, KT and Safi, A and Beer, MA and Barrera, A and Geraghty, S and Rai, R and Pederson, AN and Reisman, SJ and Love, MI and Sullivan, PF and Eroglu, C and Crawford, GE and Gersbach, CA},
title = {Reprogramming of neuronal genome function and phenotype by astrocytes.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.07.710282},
pmid = {41867870},
issn = {2692-8205},
abstract = {UNLABELLED: Heterotypic cell-cell interactions are critical to governing cellular physiology, disease progression, and responses to the environment and pharmacologic interventions. For example, neurons and astrocytes engage in intricate interactions that are essential for brain development and function [1-3] . However, the transformation of these extracellular signals into epigenomic regulation that governs cell function is poorly understood. Here, we report that weeks of co-culture between human induced pluripotent stem cell (hiPSC)-derived neurons and mouse cortical astrocytes extensively reprograms gene expression and the chromatin accessibility landscape in neurons, affecting thousands of genes and putative gene regulatory elements (REs), including many transcription factors (TFs). These genes are enriched for functions implicated in neuronal differentiation and maturation, and tend to be impacted in schizophrenia, and autosomal dominant Alzheimer's disease. Through complementary CRISPR interference and activation screens, we recapitulated hundreds of astrocyte-induced transcriptional and chromatin remodeling events in mono-cultured neurons at both promoters and distal regulatory elements (REs) of TF genes. We discovered functional REs for ∼50 astrocyte-responsive TF genes, providing a map of gene regulatory network control. Astrocyte-responsive TF genes fall into groups that exert independent or counter-balancing transcriptional effects, highlighting the complex coordination of the neuronal response to astrocytes. Functional effects of specific TFs, including POU3F2 and TFAP2E, on neurite morphology and neuronal electrophysiology are consistent with transcriptional effects, demonstrating the capacity of direct epigenetic control to mimic heterotypic cellular signals. This work illuminates the regulation of neurodevelopment-and disease-relevant gene modules by neuron-astrocyte interactions, and provides a blueprint for applying modern functional genomics to uncover the links between cell microenvironment and epigenomic programming.

HIGHLIGHTS: Neuronal gene expression and chromatin accessibility landscape are profoundly remodeled by astrocytes over weeks of co-cultureAstrocyte-responsive neuronal gene modules and neuron-responsive astrocytic gene modules are enriched for genes associated with schizophrenia and familial Alzheimer's DiseaseSingle-cell CRISPR interference and activation screens of astrocyte-responsive gene regulatory elements identified dozens of functional regulatory elements of TF genes in neuronsSingle-cell CRISPR interference and activation screens of >200 astrocyte-responsive TF genes uncovered discrete functional clusters that promote neuronal maturity or stemnessAstrocyte-responsive TF genes reprogram neuronal electrophysiology and neurite morphology.},
}

@article {pmid41867871,
year = {2026},
author = {Ho, V and Tjondropurnomo, R and Nguyen, J and Balkó, E and Depew, S and Chen, X and Singh, R and Van Veen, JE and Rácz, B and Golshani, P},
title = {Single-Nucleus Transcriptomics Reveals Cell Type-Specific Remodeling and Epilepsy-Associated Microglia.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.04.709339},
pmid = {41867871},
issn = {2692-8205},
abstract = {Mesial temporal lobe epilepsy (TLE) is the most common form of acquired epilepsy involving the hippocampus and is a frequent sequelae of head trauma. TLE is associated with refractory seizures and significant cognitive deficits. Yet, the gene expression patterns and cell types driving epileptogenesis and the associated cognitive deficits are poorly understood. To address this, we performed single nucleus RNA sequencing on hippocampal tissue from mice at 3 and 6 weeks following pilocarpine-induced status epilepticus, a robust model of TLE. At these early timepoints, epilepsy samples showed reductions in specific Cck and Lamp5-Lhx6 interneuron subclusters, alongside increases in Cajal-Retzius cells, dentate granule (DG) cell precursors, and a mature DG cell subcluster. Among glia, an astrocyte subcluster and a markedly expanded microglia sublcuster were increased. We term this microglia population epilepsy-associated microglia (EAM). The transcriptomic profile of EAM partially overlaps with microglia described in models of Alzheimer's disease and traumatic brain injury, with enrichment of genes including Myo1e and Igf1 . EAM display amoeboid morphology, can be found in dense clumps around pyramidal and granule cell body layers, and exhibit enlarged vesicles and mitochondria on electron microscopy. Cell-cell interaction analysis predict that DG cells are the main interaction partners of EAM. This dataset recapitulates known cellular alterations in TLE while defining their underlying transcriptomic programs, enabling mechanistic dissection of the key processes driving epileptogenesis.},
}

@article {pmid41867873,
year = {2026},
author = {Graber, DJ and Sentman, ML and Cook, WJ and Sentman, CL},
title = {5xFAD-NSG mice: a preclinical Alzheimer model for human cell therapy studies.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.03.709048},
pmid = {41867873},
issn = {2692-8205},
abstract = {UNLABELLED: Cellular therapies are one class of medicine being developed to treat Alzheimer's disease (AD), a neurodegenerative disease with memory loss, aberrant protein accumulation in the brain, and neuroinflammation. One challenge for development of human cell therapeutics is to have preclinical animal models that allow the use of human cells without immune-mediated rejection of those cells. The 5xFAD transgenic mouse model is a robust disease model for AD that expresses human amyloid precursor protein and presenilin-1 with multiple familial AD mutations, develops microglia-mediated neuroinflammation, accumulates amyloid-beta (Aβ) in the brain, and shows behavior changes with age. To create a mouse model for AD that permits the transplantation of human cells without immune-mediated rejection, we bred the 5xFAD transgenes onto the NOD-SCID-IL-2Rγ-deficient (NSG) mouse model to create 5xFAD-NSG mice. We report that 5xFAD-NSG mice develop Aβ plaques in the brain, microgliosis, neuroinflammation, and behavior changes that increase with age. We demonstrate that injection of CAR engineered human T regulatory cells are detected in the cerebral cortex and spleen after eight days. This 5xFAD-NSG mouse model for AD will be helpful to develop human cell-based therapies for AD.

SIGNIFICANCE STATEMENT: 5xFAD transgenic NSG mice develop a progressive AD-like disease and are an in vivo model for testing human cell-based therapies for AD.},
}

@article {pmid41867897,
year = {2026},
author = {Halim, DO and Di Biase, E and Rajon, A and Jordi, L and Hallett, PJ and Isacson, O},
title = {APOE3 astrocytes can rescue lipid abnormalities and dystrophic neurites of APOE4 human neurons.},
journal = {PNAS nexus},
volume = {5},
number = {3},
pages = {pgag053},
pmid = {41867897},
issn = {2752-6542},
abstract = {Lipid abnormalities are emerging as key pathogenic mechanisms in neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and Lewy body dementia. Astrocytes in the brain provide apolipoprotein E (APOE) proteins and influence neuronal metabolism and health. Using live-cell imaging and objective neurite imaging techniques, we induced cellular lipid load (cholesterol and triglycerides) by inhibiting the lysosomal cholesterol transport protein NPC1 in human neuron-astrocyte cocultures and examined the effects of CRISPR-edited APOE3 and APOE4 human astrocytes on the rescue of dystrophic neurites, where axons and dendrites of nerve cells become disfigured. APOE3, but not APOE4 or APOE knockout, astrocytes prevented cholesterol- and lipid-induced neurite damage in APOE4 neurons. In the media of APOE3 neuron-astrocyte cocultures, high-density lipoprotein-like particles were larger and presumably more lipidated than those in equivalent APOE4 cocultures. This discovery highlights that living APOE3 astrocytes control key biological mechanisms by physiologically enhancing lipid cellular homeostasis and rescuing lipid-induced neurite structural abnormalities relevant to Alzheimer's disease and neurodegenerative diseases.},
}

@article {pmid41867912,
year = {2025},
author = {Noshin, K and Boland, MR and Hou, B and He, W and Lu, V and Shen, L and Zhang, A},
title = {Integrating Social Determinants of Health in a Multi-Modal Deep Clustering Survival Model for Injury-Risk in Alzheimer's and Related Dementia Patients.},
journal = {Proceedings of machine learning research},
volume = {281},
number = {},
pages = {155-164},
pmid = {41867912},
issn = {2640-3498},
abstract = {As our population ages, the prevalence of Alzheimer's Disease and Related Dementias (ADRD) and its associated burdens continue to rise. Social Determinants of Health (SDOH) significantly influence both ADRD development and progression. Using Electronic Health Records (EHR) from a quaternary care academic medical center in a diverse urban setting, we investigated SDOH's impact on multi-modal deep clustering survival machines. Our findings revealed that SDOH improved model performance across feature selection methods (DeepCox roll-out vs. SHAP DeepExplainer) and EHR clinical modalities (medication vs. laboratory). Additionally, Laboratory features proved more informative than medications for predicting injury-fall risk. Our results highlight SDOH's crucial role in ADRD progression, particularly regarding injury-fall risk. We found that feature importance varied by selection method when analyzing multi-modality EHR data, with education emerging as a key SDOH factor among our top 10 features, underscoring its significance in ADRD progression.},
}

@article {pmid41868131,
year = {2026},
author = {Liu, T and Ren, W and Geng, X and Liu, C},
title = {Uncaria rhynchophylla: an ethnopharmacological review integrating traditional Chinese medicine uses with phytochemical and pharmacological evidence.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1723499},
pmid = {41868131},
issn = {1663-9812},
abstract = {Uncaria rhynchophylla (Miq.) Jacks. (UR), a climbing shrub of the Rubiaceae family, has been a foundational remedy in traditional Chinese medicine for over 1,500 years, and has long been used to treat neurological disorders, hypertension, and inflammatory conditions associated with "Liver Wind" and "Liver Yang Rising." This review summarizes traditional ethnopharmacological knowledge by integrating it with scientific evidence related to UR's chemical composition, pharmacological mechanisms, and therapeutic potential. This systematic narrative review analyzed 78 studies from databases including PubMed, Web of Science, Scopus, CNKI, and Wanfang (2000-2025), focusing on peer-reviewed articles on UR's phytochemistry, pharmacology, and pharmacokinetics. The plant primarily contains monoterpenoid indole alkaloids, triterpenoids, flavonoids, and phenolics. Preclinical studies have demonstrated potential neuroprotective effects against Alzheimer's disease, Parkinson's disease, epilepsy, and depression, though these are largely limited to in vitro and rodent models with methodological flaws such as small sample sizes and lack of blinding. Its antihypertensive effects involve calcium channel antagonism and nitric oxide-mediated vasodilation, while its immunomodulatory, antiviral, and anti-inflammatory effects further extend its therapeutic scope. Pharmacokinetic studies show poor oral bioavailability due to first-pass metabolism via CYP3A4, as well as stereoselective elimination. Despite some evidence linking traditional applications to modern pharmacology, major challenges remain, including difficulties in standardization, poor bioavailability, and a lack of clinical validation. Prioritizing large-scale clinical studies, development of combined formulations, and identification of biomarkers will help advance UR into the realm of evidence-based therapeutics, addressing unmet needs in neurodegenerative and cardiovascular diseases.},
}

@article {pmid41868145,
year = {2026},
author = {Guo, J and Lin, K and Liang, R and Jiang, L and He, X and Chen, J and Zheng, M},
title = {Zebrafish study provides evidence for Porphyromonas gingivalis outer membrane vesicles eliciting Alzheimer's disease-like pathologies.},
journal = {Frontiers in cellular and infection microbiology},
volume = {16},
number = {},
pages = {1761068},
pmid = {41868145},
issn = {2235-2988},
mesh = {Animals ; Zebrafish ; *Alzheimer Disease/pathology/microbiology/etiology ; *Porphyromonas gingivalis/pathogenicity/metabolism ; Disease Models, Animal ; Amyloid beta-Peptides/metabolism ; Brain/pathology/metabolism ; Larva ; Proteomics ; Acetylcholinesterase/metabolism ; Periodontitis/microbiology ; *Bacterial Outer Membrane/metabolism ; Peptide Fragments ; },
abstract = {INTRODUCTION: Periodontitis has been epidemiologically linked to an increased risk of Alzheimer's disease (AD), yet the mechanistic contribution of periodontal pathogens remains insufficiently understood. Building on our previous findings that Porphyromonas gingivalis outer membrane vesicles (OMVs) induce cardiovascular dysfunction, this study investigates whether these vesicles also drive AD-related pathology using the zebrafish model.

METHODS: We microinjected P. gingivalis OMVs into the common cardinal vein of zebrafish larvae to evaluate locomotor behavior, brain injury, and neuroinflammatory responses. Integrated proteomic and transcriptomic analyses were performed to identify alterations in AD-associated pathways, and acetylcholinesterase activity along with Aβ1-42 plaque accumulation were quantified to validate hallmark AD phenotypes.

RESULTS: OMV exposure resulted in significant neurotoxicity, locomotor deficits, and robust neuroinflammation, accompanied by pronounced dysregulation of AD-related molecular pathways. Notably, OMVs markedly increased acetylcholinesterase activity and promoted Aβ1-42 deposition in larval brains.

DISCUSSION: These findings demonstrate that P. gingivalis OMVs act as potent inducers of neuronal damage and AD-like pathological features in vivo, providing mechanistic insight into how periodontal pathogens may contribute to neurodegenerative disease progression.},
}

Animals
Zebrafish
*Alzheimer Disease/pathology/microbiology/etiology
*Porphyromonas gingivalis/pathogenicity/metabolism
Disease Models, Animal
Amyloid beta-Peptides/metabolism
Brain/pathology/metabolism
Larva
Proteomics
Acetylcholinesterase/metabolism
Periodontitis/microbiology
*Bacterial Outer Membrane/metabolism
Peptide Fragments

@article {pmid41868184,
year = {2026},
author = {Liu, Z and Zhang, H and Wan, B and Yin, S and Yue, R},
title = {Advances and Therapeutic Potential of Anthraquinone Compounds in Neurodegenerative Diseases: A Comprehensive Review.},
journal = {Drug design, development and therapy},
volume = {20},
number = {},
pages = {580330},
pmid = {41868184},
issn = {1177-8881},
mesh = {Humans ; *Anthraquinones/pharmacology/chemistry/isolation & purification/therapeutic use ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Neuroprotective Agents/pharmacology/chemistry/isolation & purification ; Animals ; Rheum/chemistry ; },
abstract = {BACKGROUND: Rhubarb, traditionally used in China for neurological disorders, has recently attracted considerable scientific attention for its neuroprotective and cerebrovascular benefits. The main therapeutic components of rhubarb are anthraquinones, including emodin, aloe-emodin, chrysophanol, rhein, and physcion. Accumulating experimental evidence indicates that anthraquinones are of importance in neurodegenerative diseases (NDDs), such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis. However, as a promising candidate for drug development, the mechanisms by which anthraquinones treat NDDs have not been systematically reviewed. Therefore, this article outlines the anti-neurodegenerative effects of anthraquinones, focusing on their molecular mechanisms.

OBJECTIVE: This article reviews recent research progress of anthraquinones in NDDs, focusing on their potential targets and pathways to provide new ideas for the intervention and treatment of NDDs.

METHODS: A comprehensive search of PubMed, Web of Science, and Google Scholar was conducted for articles on the intervention of anthraquinones in NDDs in the past 20 years. The collected information was then summarized and analyzed.

RESULTS: Anthraquinones ameliorate NDDs through multiple mechanisms. They exhibit antioxidant and anti-inflammatory effects, protect mitochondria, and regulate microglial polarization. Furthermore, anthraquinones inhibit pyroptosis, apoptosis, tau phosphorylation, Aβ/α-synuclein aggregation, and acetylcholinesterase activity, while restoring metal homeostasis, activating estrogen receptors, modulating gut microbiota, increasing BDNF levels, and preserving blood-brain barrier permeability. More notably, these compounds play a neuroprotective role by mediating multiple signaling pathways and targets, including Nrf2, ERK1/2, PI3K/mTOR, ROS/TXNIP, SIRT1/PCG-1α, NLRP3, PI3K/Akt, MAPK, TLR4-NFκB, CaM/CaMKIV, and Ca[2+]/EGFR/PLCγ.

CONCLUSION: The pleiotropic actions of anthraquinones highlight their potential as therapeutic candidates for NDDs, yet clinical validation remains essential. Future studies should emphasize rigorously designed clinical trials and optimized brain-targeted delivery platforms. This review consolidates current evidence to support their translational development.},
}

Humans
*Anthraquinones/pharmacology/chemistry/isolation & purification/therapeutic use
*Neurodegenerative Diseases/drug therapy/metabolism
*Neuroprotective Agents/pharmacology/chemistry/isolation & purification
Animals
Rheum/chemistry

@article {pmid41868274,
year = {2024},
author = {Hasan, SA and James, AW and Fazili, FM and Tarabishi, S and Sheikh, NM and Shah, ZA},
title = {Endoplasmic Reticulum Stress in Neurodegenerative Diseases.},
journal = {Journal of dementia and alzheimer's disease},
volume = {1},
number = {2},
pages = {87-97},
pmid = {41868274},
issn = {3042-4518},
abstract = {Endoplasmic reticulum (ER) stress is a detrimental cellular phenomenon in the cells and is activated by the accumulation of unfolded or misfolded proteins in the ER. The unfolded protein accumulation activates the unfolded protein response (UPR), an adaptive mechanism designed to mitigate cellular stress by enhancing the ER's protein-folding capacity and protecting cells from apoptotic stimuli in neuroinflammation and neurodegenerative diseases. However, chronic ER stress and prolonged activation of the UPR can have adverse effects, including the activation of pro-apoptotic and inflammatory signaling pathways, which contribute to the development and progression of neurodegenerative disorders. Neurodegenerative diseases are complex and devastating conditions with underlying pathogenesis that are not fully understood. Genetic mutations leading to the accumulation of misfolded or phosphorylated tau proteins and amyloid-beta in the ER can induce ER stress, resulting in neuroinflammation and neuronal death. Several studies have reported the involvement of increased ER stress and UPR signaling proteins in the pathogenesis and progression of neurodegenerative diseases. Thus, inhibiting ER stress and neuroinflammation and targeting their associated signaling pathways represent a significant area of research interest. This review discusses the critical signaling molecules involved in ER stress, their mechanisms in the progression of neurodegenerative diseases, and the latest developments in the available ER stress inhibitors. Despite the extensive development of ER stress inhibitors over the years, only a limited number have been approved as pharmaceutical drugs. There remains a critical need for effective ER stress inhibitors to provide efficient treatments for neurodegenerative diseases, including Alzheimer's disease.},
}

@article {pmid41868350,
year = {2026},
author = {Xu, L and Kuang, J and Liu, A and Liao, L and Yu, L and Tian, C},
title = {EPR spectroscopy reveals different Cu(ii) coordination in APP142-172 and APP145-170 peptide fragments of amyloid precursor protein.},
journal = {RSC advances},
volume = {16},
number = {17},
pages = {15504-15509},
pmid = {41868350},
issn = {2046-2069},
abstract = {Amyloid precursor protein (APP) is central to Alzheimer's disease pathogenesis, yet the coordination chemistry and functional impact of core peptide fragments within its copper binding domain (CuBD) remain elusive. Here, we characterised the copper coordination environments and redox properties of two CuBD fragments APP142-172 and APP145-170 using electron paramagnetic resonance (EPR) and UV-Vis spectroscopy. At physiological pH, Cu(ii)-APP142-172 adopted a single N2O2 coordination, whereas Cu(ii)-APP145-170 existed in two distinct coordination modes identified by spectral simulation: the same N2O2 form (component I) as in Cu(ii)-APP142-172, and a nitrogen-rich 4N form (component II). Moreover, EPR-monitored pH titrations revealed that the 4N species predominated at alkaline pH and the N2O2 species at acidic pH. Although both Cu(ii)-APP complexes could promote Fe(ii) oxidation, only the N2O2 species (component I) exhibited ferroxidase activity, whereas the 4N species (component II) was redox-silent. These observations demonstrate that subtle changes in peptide length act as a structural switch for Cu(ii) coordination and redox activity, thereby affecting the copper-mediated regulation of neuronal redox processes.},
}

@article {pmid41868427,
year = {2026},
author = {Kim, S and Jeon, S and Cho, K and Kang, S and Bang, S and Ye, BS and Lee, JM},
title = {Deep learning for FDG-PET classification in patients with Alzheimer's disease, dementia with Lewy bodies and their mixed pathology: a solution for diagnostic heterogeneity.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1780858},
pmid = {41868427},
issn = {1663-4365},
abstract = {INTRODUCTION: Mixed pathology of Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) are frequently observed in patients with cognitive impairment, and complicate clinical diagnosis. We aimed to develop a classification model using [18]F-fluorodeoxyglucose (FDG) positron emission tomography (PET) to improve diagnostic accuracy for these challenging cases.

METHODS: We analyzed FDG-PET images from 277 participants who were categorized into AD, DLB, mixed disease, and healthy control (HC) groups. Deep learning-based classification models were trained on seven binary classification tasks and one multiclass classification task and subsequently integrated into an ensemble model to predict AD, DLB, mixed disease or HC groups.

RESULTS: The model achieved an AUROC of 0.73 (95% CI, 0.69-0.78) for AD, 0.90 (95% CI, 0.89-0.91) for DLB, 0.71 (95% CI, 0.66-0.75) for Mixed, and 0.87 (95% CI, 0.84-0.89) for HC.

DISCUSSION: The model represents the state-of-the-art in automatic FDG-PET-based classification of AD, DLB, Mixed, and HC. This study highlights the utility of FDG-PET as a biomarker for differentiating AD, DLB, Mixed, and HC groups, resolving diagnostic challenges caused by overlapping clinical features.},
}

@article {pmid41868495,
year = {2026},
author = {Chen, YJ and Xie, MR and Zhu, QQ and Zhou, SQ and Li, B and Yuan, H},
title = {Insulin-like growth factor 1 associated research in Alzheimer's disease: an exploratory trends analysis.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1709559},
pmid = {41868495},
issn = {1664-2295},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive impairment and behavioral deterioration. In recent years, the role of the insulin-like growth factor-1 (IGF-1) signaling pathway in the pathological process of AD has received increasing attention. This study provides a visual analysis of the current research status, development trends, collaboration networks, and research hotspots related to IGF-1 and AD.

METHODS: Publications were retrieved from the Web of Science and Scopus databases. CiteSpace, VOSviewer, and Bibliometrix software were used for visual analysis.

RESULTS: A total of 632 publications were included in the study. The annual publications related to IGF-1 and AD exhibited an overall upward trend. Research was concentrated in North America, Asia, and Europe. The United States holds a dominant position in terms of output, influence, and international influence. The Consejo Superior de Investigaciones Científicas was the most active institution. Journal of Alzheimer's Disease was the journal with the highest number of publications. Dr. Ignacio Torres-Aleman was the most prolific author. High-frequency keywords included IGF-1, AD, brain, insulin, controlled study, metabolism, oxidative stress, animals, signal transduction, amyloid beta protein, dementia, aging, and neuroprotection. Transgenic mouse, risk, depression, and cognitive impairment were the most powerful keywords that have emerged in recent years.

CONCLUSION: Research on IGF-1 and AD has continued to grow. Studies in this field have formed a tightly interconnected network, centered on the AD pathological core-IGF-1-related molecular mechanisms-downstream signaling pathways. The research focus is shifting from superficial correlations to investigations into underlying mechanisms and potential therapeutic targets. Depression and cognitive impairment are likely to become promising frontiers for future research.},
}

@article {pmid41868603,
year = {2025},
author = {Pan, S and Zhou, Y and Wang, X and Tong, J and Li, Y and Huang, J and Chen, S and Cui, Y and Wang, Z and Tan, YL},
title = {miRNA-associated gene networks reveal potential candidate markers for Alzheimer's disease.},
journal = {Frontiers in molecular biosciences},
volume = {12},
number = {},
pages = {1699404},
pmid = {41868603},
issn = {2296-889X},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory and cognitive decline. Recent studies highlight the significant role of microRNAs (miRNAs) in regulating genes related to AD. This research aims to develop miRNA-associated gene regulatory networks as candidate AD biomarkers.

METHODS: We recruited 85 AD patients and 74 healthy controls, conducting whole blood miRNA sequencing and applying machine learning to identify differentially expressed miRNAs, which were validated by quantitative reverse transcription polymerase chain reaction (qRT-PCR). We used bioinformatics databases to predict target genes for these miRNAs and obtained gene expression data from the Gene Expression Omnibus (GEO) database (GSE122063 and GSE18309). Using the ggplot2 package in R, we discovered the overlap between miRNA target genes and differentially expressed genes (DEGs) from the GSE datasets. Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses of the DEGs were then conducted using the Metascape database. Key hub genes were pinpointed by constructing a protein-protein interaction (PPI) network with the Retrieval of Interacting Genes (STRING) database and analyzing it with cytoHubba. Drug-gene interactions were predicted and examined using the Drug-Gene Interaction database (DGIdb) (http://www.dgidb.org/).

RESULTS: qRT-PCR was used to confirm the expression of the hub genes. The results showed that four miRNAs (miR-192-5p, miR-484, miR-21-5p, and miR-24-2-5p) were downregulated, while two target RNAs (SLC32A1 and GAD1) were upregulated.

DISCUSSION: This regulatory network, which is strongly linked to AD, has been initially identified as a candidate biomarker for AD. Our research provides new insights into the pathogenic mechanisms of AD, potentially improving the understanding of miRNAs' role in the disease.},
}

@article {pmid41868623,
year = {2026},
author = {Alcantara-Gonzalez, D and Santiago, E and Peña-Ortega, F},
title = {Amyloid-β acute exposition affects the CA1 hippocampal network activity and its topological organization, evaluated with multielectrode arrays.},
journal = {Frontiers in dementia},
volume = {5},
number = {},
pages = {1738954},
pmid = {41868623},
issn = {2813-3919},
abstract = {INTRODUCTION: Neuronal networks enable brain's information processing through a well-coordinated activity. Disruptions in this activity can impair key brain functions such as synaptic plasticity and long-term memory. Such dysfunctions are relevant to the cognitive deterioration in Alzheimer's disease (AD). Neuronal circuit alterations in AD are associated with amyloid-β (Aβ) extracellular accumulation across multiple brain regions involved in cognitive regulation. Although several studies have analyzed network topology and examined anatomical, functional, and effective connectivity to understand their role in AD, the direct contribution of Aβ to local neuronal network disturbances has not been investigated.

METHODS: We assessed the CA1 hippocampal network structure after acute exposure to Aβ1-42 (30 nM) using an in vitro multielectrode array approach. We analyzed neuronal spiking activity recordings, evaluated the frequency of spontaneous synchronized events, and assessed functional connectivity to elucidate the functional alterations in the network. We also elucidated the statistical features of network topology using Graph Theoretical analysis, small-world network properties, and network classification using the Estrada index approach.

RESULTS: CA1 hippocampal neurons showed an average reduced firing frequency. However, some putative pyramidal neurons and interneurons increased their activity. These differences in activity are cell-type-specific, being the interneurons the cells that mainly reduce their firing in presence of Aβ. The number and magnitude of their functional links within the network were not different, but a synchronized firing pattern of different neurons was observed. These changes were associated with alterations to the network's topological structure, indicating the generation of highly connected nodes in the presence of Aβ.

CONCLUSION: The main change in the reconfiguration of the CA1 hippocampal network induced by acute exposure to Aβ involved the differential change in firing of different neurons, where the average reduction in firing was found, but some neurons increased their firing. This may constitute an adaptive mechanisms that compensate for neuronal connectivity and help maintain the level of activity. This is the first time the Estrada index has been used to elucidate alterations in the topological neuronal network in an ex vivo brain preparation, highlighting its greater sensitivity for detecting changes compared to other topological network analysis approaches.},
}

@article {pmid41868751,
year = {2026},
author = {Zhang, Z and Zhang, R and Yang, W and Lv, K and Wu, M and Xu, L},
title = {AD diagnosis model based on fusion of heterogeneous brain imaging and genomic data.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1719390},
pmid = {41868751},
issn = {1662-4548},
abstract = {Alzheimer's disease (AD) is a common neurodegenerative disorder in the elderly population, and early screening can effectively delay the progression of the disease. Mild cognitive impairment (MCI) occurs prior to the onset of AD; however, the accuracy of existing MCI-to-AD prediction methods remains relatively low. Additionally, small sample sizes and high feature dimensions often lead to model overfitting, highlighting the need for effective early screening approaches. To address the aforementioned issues, this study integrated non-paired multi-modal features-including clinical indicators from the ADNI database, blood biomarkers, brain region volume features extracted from MRI, and genetic biomarkers from the GEO database-and proposed a gender-corrected random matching strategy. The Random Forest algorithm was adopted to evaluate this strategy, analyze feature importance, and compare the performance of 9 machine learning algorithms based on the top 40 ranked features. The predictive performance of multi-modal data was superior to that of single-modal data, and the proposed strategy achieved favorable results in early AD screening. 16 specific genetic features (e.g., IFI27, EDF1, RAP2A, KIF5C, SERPINA3, FBXW7, IFITM1, ISG15, PSMB3, APOE4, KCNB1, PSPH, HMGN2, S100A13, IFIT3, and CALM1) and 6 brain region volume features ranked high in terms of importance. When validated using paired datasets from ADNI across the 9 algorithms, ensemble learning models demonstrated significantly stronger fitting capabilities. The non-paired multi-modal fusion approach not only expands the sample size but also enhances the generalization ability and robustness of the model. This provides a theoretical basis for the application of this strategy in the field of small-sample medical research.},
}

@article {pmid41868828,
year = {2026},
author = {Falsitta, LV and Pikula, A},
title = {Plant-Based Dietary Patterns and Neuroimaging Biomarkers of Brain Health: A Scoping Review of Observational and Interventional Evidence.},
journal = {American journal of lifestyle medicine},
volume = {},
number = {},
pages = {15598276261434176},
pmid = {41868828},
issn = {1559-8284},
abstract = {Healthy dietary interventions are well established in cardiovascular disease prevention, but their effects on the brain remain underexplored. This scoping review aims to investigate how adherence to core components of a whole-food plant-based diet (WFPBD) may impact neuroimaging outcomes across different brain conditions. We searched PubMed and MEDLINE for studies published in the past 20 years evaluating the effects of a predominantly or exclusively WFPBD, alone or combined with other lifestyle factors, on neuroimaging biomarkers. Selected studies were grouped into three domains: (1) demyelinating disease, (2) dementia and Alzheimer's disease, (3) cognitive aging and cerebrovascular burden. The dataset comprised heterogeneous study designs and follow-up durations, including randomized-controlled trials (RCTs; n = 9; 14 days - 3 years), longitudinal observational studies (n = 7; 2-20 years), and cross-sectional studies (n = 6). Observational evidence suggests associations between plant-based dietary patterns and favorable neuroimaging outcomes, whereas RCTs have generally not confirmed these effects. Residual confounding and healthy user bias are potential limitations. Dietary patterns aligned with a WFPBD may be important components of broader lifestyle interventions supporting brain health. Confirming observational findings will require adequately powered randomized trials with standardized neuroimaging endpoints and well-designed dietary interventions.},
}

@article {pmid41869280,
year = {2026},
author = {Mitchell, K and Hebbern, C and Ferro, A and Olaniyan, T and Christidis, T and Cakmak, JD and Rouleau, M and Anastasopolos, AT and Popadic, I and Johnson, M and Zhao, N and Tjepkema, M and Cakmak, S},
title = {Sector-specific Long-term Associations Between Transportation, Industrial, and Residential Combustion Air Pollutant Mixtures (PM2.5, SO2, NO2, O3) and Neurological Disease-related Mortality in Canada.},
journal = {Environmental epidemiology (Philadelphia, Pa.)},
volume = {10},
number = {2},
pages = {e467},
pmid = {41869280},
issn = {2474-7882},
abstract = {BACKGROUND: Improving air quality requires addressing sector-specific air pollution (SSAP). This study examined the relationship between long-term SSAP and Alzheimer's disease and dementia mortality in Canada, and whether associations were modified by neighborhood greenness, educational attainment, and material deprivation.

METHODS: We used data from the 2006 Canadian Census Health and Environment Cohort with mortality follow-up through 2019, linked to the Canadian Vital Statistics-Death database. Annual exposures to ambient air pollutants (i.e., PM2.5, SO2, NO2, and O3) from multiple sectors were estimated using the Global Environmental Multiscale-Modelling Air Quality and Chemistry model (10 km resolution) with sector-specific contributions anchored to 2015 emissions profiles. Quantile g-computation models were used to estimate hazard ratios (HRs) for Alzheimer's disease and dementia per quartile increase in SSAP.

RESULTS: Alzheimer's disease mortality was most strongly associated with SSAP from residential fuel combustion (RES: HR = 1.29; 95% CI: 1.16, 1.43), and was also positively associated with emissions from on-road transportation (HR = 1.22; 95% CI: 1.12, 1.32), ore and mineral industries (ORE: HR = 1.17, 95% CI: 1.10, 1.24), air-marine-rail transportation (HR = 1.12; 95% CI: 1.06, 1.18), and manufacturing (MAN: HR = 1.06; 95% CI: 1.01, 1.11), while inverse associations were observed for the oil and gas sector (HR = 0.85; 95% CI: 0.81, 0.88). Dementia mortality was positively associated with oil and gas (HR = 1.06; 95% CI: 1.03, 1.09), and inversely associated with air-marine-rail transportation (HR = 0.88; 95% CI: 0.85, 0.92) and ORE (HR = 0.89; 95% CI: 0.85, 0.92). Associations were generally stronger in lower greenness areas and among individuals with lower educational attainment, although heterogeneity by sector was observed.

CONCLUSION: SSAP mixtures were associated with Alzheimer's disease and dementia mortality in Canada. The direction and magnitude of associations varied by sector and by environmental and sociodemographic context, supporting the value of targeted, sector-specific mitigation strategies to reduce neurodegenerative mortality risk.},
}

@article {pmid41869421,
year = {2026},
author = {Cai, Y and Dai, W and Liu, F and Li, Z and Liu, G},
title = {Causal Associations Between Chronic Inflammatory Skin Diseases and Alzheimer's Disease: A Bidirectional Two-Sample Mendelian Randomization Study.},
journal = {Clinical, cosmetic and investigational dermatology},
volume = {19},
number = {},
pages = {589176},
pmid = {41869421},
issn = {1178-7015},
abstract = {BACKGROUND: Inflammatory skin diseases (ISDs) and Alzheimer's disease (AD) share chronic immune activation, but their causal link remains unclear.

METHODS: We performed a bidirectional two-sample Mendelian randomization using GWAS summary data from Europeans. Instrumental SNPs were analyzed with inverse-variance weighted (IVW), weighted median, and MR-Egger methods, with sensitivity tests for pleiotropy and heterogeneity.

RESULTS: Forward MR revealed significant causal effects of ISDs on AD, including lichen planus (OR 1.318, p=0.005), psoriasis vulgaris (OR 1.126, p=0.004), psoriasis with arthropathy (OR 1.032, p=0.002), psoriatic arthritis (OR 1.053, p=0.016), psoriasis (OR 1.072, p=0.008), papulosquamous conditions (OR 1.046, p=0.007), and follicular cysts (OR 1.066, p=0.047). No heterogeneity or pleiotropy was detected. Reverse analysis showed no causal effect of AD on ISDs.

CONCLUSION: These findings support a potential causal role of chronic skin inflammation in AD risk, though effect sizes were modest and clinical implications remain exploratory. This suggests that neuroimmune mechanisms may represent potential targets for further investigation.},
}

@article {pmid41869564,
year = {2026},
author = {Chauhan, M and Singh, K and Sharma, P},
title = {Targeting of Itch by clomipramine or gene therapy improves cognitive defects related to Alzheimer's disease.},
journal = {iScience},
volume = {29},
number = {4},
pages = {115181},
pmid = {41869564},
issn = {2589-0042},
abstract = {We propose a therapeutic strategy against Alzheimer's disease (AD), which involves targeting E3 ubiquitin ligase AIP4 or Itch. Previous studies have shown that Itch is aberrantly activated in cortical neurons of a mouse model of AD and contributes to neuronal death. We used a two-pronged approach to target Itch in a mouse model for AD: (1) adeno-associated virus (AAV) expressing loss-of-function mutants of Itch and (2) clomipramine, a tricyclic antidepressant, which is an Itch inhibitor. Both treatments significantly improved learning and memory associated with AD mice. A reversal in neuronal apoptosis was observed in AD mouse brain, which explained the improvement in cognition. Clomipramine was able to inhibit Itch in neurons and prevent their apoptosis in response to Aβ42. Given that clomipramine is being used against psychiatric disorders, this drug may be repurposed for use against AD.},
}

@article {pmid41869698,
year = {2026},
author = {Koizia, LJ and Allott, VES and Harris, BHL},
title = {Unpacking uncertainty in polygenic risk scores: Playing "risk score roulette".},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261421230},
doi = {10.1177/13872877261421230},
pmid = {41869698},
issn = {1875-8908},
}

@article {pmid41870153,
year = {2026},
author = {Walker, E and Wu, F and Rundle, AG and Hua, S and Quinn, JW and Neckerman, KM and Afanasyeva, Y and Arslan, AA and Koenig, KL and Zeleniuch-Jacquotte, A and Chen, Y},
title = {The association between midlife neighbourhood walkability and Alzheimer's disease in women: a prospective nested case-control study.},
journal = {Age and ageing},
volume = {55},
number = {3},
pages = {},
doi = {10.1093/ageing/afag054},
pmid = {41870153},
issn = {1468-2834},
mesh = {Humans ; Female ; *Alzheimer Disease/epidemiology/prevention & control/psychology/diagnosis ; Middle Aged ; Case-Control Studies ; Aged ; Prospective Studies ; Adult ; Risk Factors ; *Walking ; *Neighborhood Characteristics ; Age Factors ; Women's Health ; },
abstract = {BACKGROUND: The role of modifiable environmental factors in Alzheimer's disease (AD) risk remains poorly understood. Built environment features such as neighbourhood walkability (NW) may influence long-term cognitive health among women.

METHODS: The New York University Women's Health Study recruited 14 273 cognitively healthy women aged 35-65 years between 1985 and 1991, with follow-up for over 30 years. We geocoded residential addresses for each participant to derive a validated four-item baseline NW measure and a two-item average annual NW index over the follow-up period. We conducted a nested case-control study of 1865 AD cases identified via linkage to Medicare claims during follow-up matched to 3730 controls on age, race/ethnicity and Medicare coverage using risk-set sampling. We used conditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals for AD in relation to tertiles of NW measures, adjusting for potential confounders. Subgroup analyses examined potential effect modification.

RESULTS: Compared with women living in areas with the lowest baseline NW, those in the middle and highest tertiles had lower odds of having a diagnosis of AD during follow-up, with an OR of 0.95 (0.82-1.11) and 0.83 (0.71-0.98), respectively (P-trend = .03). Results were similar when using average annual NW. The association did not differ appreciably by age, smoking status, education or body mass index.

CONCLUSIONS: Higher midlife NW was associated with reduced odds of AD later in life. These findings highlight the potential for built environment interventions to promote cognitive health and support healthy ageing in women.},
}

Humans
Female
*Alzheimer Disease/epidemiology/prevention & control/psychology/diagnosis
Middle Aged
Case-Control Studies
Aged
Prospective Studies
Adult
Risk Factors
*Walking
*Neighborhood Characteristics
Age Factors
Women's Health

@article {pmid41870255,
year = {2026},
author = {KamaliZonouzi, S and Amanollahi, M and Farshbafnadi, M and Dolatshahi, M and Raji, CA},
title = {Association between retinal neurodegeneration assessed by optical coherence tomography and PET-detected cerebral amyloid burden in Alzheimer's disease: A systematic review.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261433198},
doi = {10.1177/13872877261433198},
pmid = {41870255},
issn = {1875-8908},
abstract = {BackgroundRetinal imaging is proposed as a biomarker for Alzheimer's disease, but evidence linking retinal changes to cerebral amyloid remains inconsistent, particularly in preclinical populations.ObjectiveThis article evaluates whether retinal structural and microvascular changes measured by optical coherence tomography (OCT) and OCT-angiography (OCT-A) are associated with cerebral amyloid-β (Aβ) burden assessed by positron emission tomography (PET).MethodsPubMed, Embase, Scopus, and Web of Science were searched on November 10, 2025. Two reviewers independently did screening, extraction, and quality assessment. Extracted outcomes included macular and peripapillary retinal nerve fiber layer and ganglion cell-inner plexiform layer thickness, vessel density, foveal avascular zone size, and PET tracers.ResultsTwenty-two studies including 1616 participants met inclusion criteria. Fifteen assessed OCT, five OCT-A, and two both. Among cognitively normal individuals, seven studies compared retinal nerve fiber layer thickness by Aβ status, with only one reporting a significant difference. Overall, OCT metrics showed no consistent differences by Aβ status. OCT-A results were similarly inconsistent, with one study linking larger foveal avascular zone to Aβ positivity. Substantial heterogeneity in imaging devices, segmentation methods, and PET quantification was observed, and few studies adjusted for these factors.ConclusionsCurrent evidence does not demonstrate a consistent relationship between retinal OCT or OCT-A metrics and cerebral Aβ burden measured by PET. Methodological heterogeneity, small sample sizes, and limited statistical rigor contribute to inconclusive results. Standardized imaging protocols and longitudinal studies are required to determine whether retinal imaging can serve as a reliable non-invasive biomarker for early Alzheimer's disease.},
}

@article {pmid41870257,
year = {2026},
author = {Zhou, C and Ji, Y and Wang, Y and Liang, Y and Cao, Y and Lin, L and Wang, Y and Yang, Z and Liu, S and Chen, H},
title = {Meta-analysis of the efficacy of interventions for persons living with Alzheimer's disease: The role of music therapy.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261433196},
doi = {10.1177/13872877261433196},
pmid = {41870257},
issn = {1875-8908},
abstract = {BackgroundEmerging evidence supports the clinical utility of music therapy for Alzheimer's disease (AD), yet robust clinical evidence remains limited.ObjectiveThis study aimed to systematically evaluate the multidimensional effects of music therapy on individuals with AD and to identify optimal intervention parameters and cumulative duration thresholds to guide clinical implementation.MethodsWe conducted a systematic review using RevMan 5.4, analyzing 24 randomized controlled trials (n = 2316) from Chinese and English databases up to January 2025.ResultsCompared to controls, music therapy significantly improved cognition (MD = 2.14, 95%CI = 0.88∼3.41, p = 0.0009), reduced neuropsychiatric symptoms (SMD = -0.55, 95%CI = -0.99∼-0.12, p = 0.01) and anxiety (MD = -4.37, 95%CI = -6.68∼-2.06, p = 0.0002), enhanced quality of life (SMD = 0.51, 95%CI = 0.02∼1.01, p = 0.04), and alleviated caregiver burden (SMD = -0.75, 95%CI = -0.94∼-0.55, p < 0.00001). The optimal regimen involved: frequency >3 sessions/week (p = 0.002), duration <40 min/session (p = 0.03), and intervention period ≥12 weeks (p = 0.002). A staged care model progressing from individual to group-based approaches is recommended (all p < 0.05). Minimum cumulative intervention durations for symptom improvement were: ≥1440 min for quality of life, ≥1800 min for behavioral and psychological symptoms, and ≥3360 min for cognition (all p < 0.05).ConclusionsMusic therapy demonstrates multidimensional benefits for persons living with AD, with distinct cumulative dose thresholds required for improving specific clinical symptoms, providing valuable guidance for clinical practice.},
}

@article {pmid41870258,
year = {2026},
author = {Rissanen, JA and Kärkkäinen, S and Katisko, K and Vanninen, A and Luikku, AJ and Rauramaa, T and Musialowicz, T and Kokki, M and Julkunen, V and Portaankorva, AM and Haapasalo, A and Solje, E and Hartikainen, P and Leinonen, V and Kokkola, T and Herukka, SK},
title = {The performance of plasma pTau181 and pTau217 in distinguishing Alzheimer's disease from various neurodegenerative disorders, psychiatric disorders, and cognitively unimpaired controls.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261431800},
doi = {10.1177/13872877261431800},
pmid = {41870258},
issn = {1875-8908},
abstract = {BackgroundPlasma phosphorylated tau isoforms 181 (pTau181) and 217 (pTau217) are promising Alzheimer's disease (AD) biomarkers.ObjectiveWe evaluated the performance of pTau181 and pTau217 in the differential diagnostics between AD, other neurodegenerative diseases and non-neurodegenerative participants.MethodsWe included 104 patients with neurodegenerative diseases (37 with AD, 21 with synucleinopathies [SYNU], 24 with frontotemporal dementia [FTD] and 22 with idiopathic normal-pressure hydrocephalus [iNPH]) and 50 participants without neurodegenerative disorders (33 individuals undergoing knee arthroplasty and 17 with psychiatric diagnoses). pTau181 and pTau217 were measured via single-molecule array.ResultspTau181 differentiated AD patients from psychiatric patients with an area under the curve (AUC) of 0.879 and AD patients from all other participants with an AUC of 0.685. pTau181 was higher in patients with AD compared to FTD, iNPH, and non-neurodegenerative (ND) patients. pTau217 differentiated AD patients from psychiatric patients, with an AUC of 0.998, and AD patients from all other groups, with an AUC of 0.835. pTau217 was higher in AD patients compared to ND, FTD, and SYNU patients, but it did not differ between AD and iNPH patients without adjustment for age as a covariate.ConclusionsOur prospective cohort data indicate that pTau217 differentiates AD patients from psychiatric patients, with an excellent AUC value in receiver operating characteristic analysis. Our study supports the use of pTau217 rather than pTau181 as a minimally invasive tool to differentiate AD from non-neurodegenerative diseases (e.g., psychiatric disorders). Further studies are needed to determine the nature of pTau217 in iNPH.},
}

@article {pmid41870260,
year = {2026},
author = {Tallapragada, B and Markovic, SJ and Marston, KJ and Brown, BM and Galna, B and Shishegar, R and Gross, A and Lim, YY and Fripp, J and Doecke, JD and Hassenstab, J and Masters, CL and Maruff, P and Martins, RN and Sohrabi, HR},
title = {Composite scores to detect and monitor cognitive dysfunction in preclinical and prodromal Alzheimer's disease: A narrative review.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261433044},
doi = {10.1177/13872877261433044},
pmid = {41870260},
issn = {1875-8908},
abstract = {Cognitive composites combine scores from multiple neuropsychological tests and demonstrate greater sensitivity to Alzheimer's disease (AD) related cognitive changes than individual tests. This review examines the development, composition and validity of cognitive composites to detect AD-related cognitive changes. The included cognitive composites were evaluated using four criteria: cognitive domains assessed; neuropsychological tests used, the inclusion of non-neuropsychological measures (e.g., Mini-Mental State Examination) that produce a global score themselves; and statistical methods used to calculate the composite. Existing composites fall into two categories: domain-specific (e.g., episodic memory, executive function, attention) or general composites combining multiple cognitive domains while incorporating clinical and functional measures. Psychometric properties were not consistently reported across all the studies. Therefore, a standardized validation framework is proposed to address these inconsistencies. Future work should focus on systematically evaluating optimized weighting, including data from clinical and functional measures and consistent psychometric reporting for assessing and monitoring cognitive dysfunction in early AD.},
}

@article {pmid41870262,
year = {2026},
author = {Yoon, B and Lee, HJ and Chae, H and Oh, EJ and Hong, YJ and Jeong, JH and Park, KH and Kim, S and Wang, MJ and Choi, SH and Ryu, JS and Kang, S and Yang, DW},
title = {Plasma glial fibrillary acidic protein as a potential biomarker for differentiating amyloid-negative subjective cognitive decline and mild cognitive impairment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261427806},
doi = {10.1177/13872877261427806},
pmid = {41870262},
issn = {1875-8908},
abstract = {BackgroundDifferentiating subjective cognitive decline (SCD) from mild cognitive impairment (MCI) in amyloid-negative (A-) individuals is clinically relevant for early evaluation along the Alzheimer's disease (AD) pathway.ObjectiveTo assess whether plasma biomarkers discriminate between A-SCD and A-MCI and compare their performance.MethodsWe studied 114 amyloid PET-negative participants (93 A-SCD, 21 A-MCI) aged ≥60 years from multicenter cohorts. Plasma Aβ42/Aβ40 ratio, glial fibrillary acidic protein (GFAP), neurofilament light chain (NFL), and phosphorylated tau 181 (pTau181) were measured using Simoa. Associations with MCI were estimated with logistic regression; discrimination was assessed by ROC analysis with AUCs and pairwise AUC comparisons using 1000 bootstrap resamples.ResultsStandardized log (GFAP) was associated with MCI in univariate analysis (OR 2.32; 95% CI 1.35-4.00; p = 0.002) and after adjustment for age and sex (OR 2.45; 1.27-4.74; p = 0.008). GFAP showed moderate discrimination (AUC 0.71; 0.59-0.82), whereas Aβ42/Aβ40, NFL, and pTau181 did not. Pairwise AUC differences favored GFAP over Aβ42/Aβ40 (ΔAUC 0.34; p = 0.020), NFL (0.21; p = 0.032), and pTau181 (0.29; p = 0.005).ConclusionsIn this A- cohort, plasma GFAP was the most informative biomarker for distinguishing MCI from SCD, likely reflecting astrocytic activation. Given modest accuracy and limited disease specificity, GFAP may be most useful as part of a multimodal panel rather than a stand-alone test.},
}

@article {pmid41870302,
year = {2026},
author = {Stewart, PV and Boscarino, JJ},
title = {Non-linear demographic correction enhances the diagnostic utility of the Montreal Cognitive Assessment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261431359},
doi = {10.1177/13872877261431359},
pmid = {41870302},
issn = {1875-8908},
abstract = {BackgroundThe Montreal Cognitive Assessment (MoCA) is widely used for cognitive screening. Despite numerous studies showing that MoCA scores are affected by demographic variables including age, education, and race, the instrument is typically evaluated using a raw score or simple one-point education correction in clinical practice.ObjectiveIn this study, we comprehensively evaluate the diagnostic accuracy of the MoCA in a large cohort of individuals being evaluated for mild cognitive impairment or dementia.MethodsWe used data from the National Alzheimer's Coordinating Center (NACC) database to examine diagnostic accuracy of the MoCA, using both raw scores and Z-scores subject to non-linear demographic correction. We present comprehensive accuracy statistics, concordance with APOE ε4 status, and predictive validity of a mild cognitive impairment classification for the subsequent development of dementia.ResultsWe find that non-linear demographic correction modestly enhances diagnostic performance for individuals with mild cognitive impairment and dementia and results in classifying a higher proportion of APOE ε4 homozygous participants as individuals with dementia as compared to MoCA raw scores.ConclusionsNon-linear demographic correction may improve the diagnostic accuracy of the MoCA and increase concordance with a major known risk factor for Alzheimer's disease (i.e., APOE ε4 status).},
}

@article {pmid41870419,
year = {2026},
author = {Zhang, R and Vidoni, E and Vongpatanasin, W and Kerwin, DR and Cullum, CM and Rossetti, H and Stowe, AM and Billinger, SA and Gupta, A and Hall, T and Scheel, N and Zhu, DC and Hynan, LS and Burns, JM and Keller, JN and Binder, EF},
title = {Effects of Exercise and Intensive Vascular Risk Reduction on Cognitive Function in Older Adults: A Randomized Clinical Trial.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2026.0359},
pmid = {41870419},
issn = {2168-6157},
abstract = {IMPORTANCE: Physical inactivity, hypertension, and hyperlipidemia are modifiable cardiovascular risk factors for age-related cognitive decline and dementia. It remains unknown whether exercise training combined with intensive pharmacological reduction of cardiovascular risk factors (IRVR) would have greater benefits on cognitive function than those of exercise or IRVR alone.

OBJECTIVE: To determine the effects of exercise, IRVR, and exercise combined with IRVR on cognitive function in older adults.

This single-blind, multicenter randomized clinical trial with a 2 × 2 factorial design and duration of 24 months was conducted at 4 clinical sites in the US. Enrollment began on February 2, 2017; the final study visit was on January 31, 2022. After screening, older adults without dementia and with hypertension, family history of dementia, and/or self-reported subjective cognitive decline were randomized. Data were analyzed from December 2022 through October 2024.

INTERVENTIONS: Participants were randomized with a 1:1:1:1 ratio to aerobic exercise training, IRVR (lowering of systolic blood pressure to <130 mm Hg and serum low-density lipoprotein cholesterol with atorvastatin), IRVR + exercise, and usual care.

MAIN OUTCOMES AND MEASURES: The primary outcome was change in global cognitive function at 24 months from baseline, assessed with the Preclinical Alzheimer Cognitive Composite (PACC) score. Secondary outcomes were changes in the National Institutes of Health Toolbox Cognition Battery (NIHTB-CB) fluid composite score and individual test scores.

RESULTS: A total of 3290 individuals were screened, and 513 older adults (aged 60-85 years) without dementia and with hypertension, family history of dementia, and/or self-reported subjective cognitive decline were randomized. Among 513 randomized participants (mean [SD] age, 68.7 [6.0] years; 323 female participants [63.0%]), 443 completed 24-month visits, and 480 were included in the primary data analysis. For the primary outcome, there were no statistically significant interactions between intervention groups and time of visits (P = .13). At 24 months, PACC scores increased by 0.2 units in the no-exercise group (95% CI, 0.1-0.3) and by 0.3 units in the exercise group (95% CI, 0.2-0.4), with no significant group differences (0.1 units; 95% CI, -0.1 to 0.2; P = .37). PACC scores also increased by 0.3 units in the no-IRVR group (95% CI, 0.2-0.4) and by 0.2 units in the IRVR group (95% CI, 0.1-0.3), with no significant group differences (0.1 units; 95% CI, -0.3 to 0.03; P = .12). Increases in the NIHTB-CB composite score and individual test scores with exercise or IRVR showed similar results.

CONCLUSIONS AND RELEVANCE: In this multicenter randomized clinical trial among older adults with family history of dementia and/or self-reported subjective cognitive decline, exercise, IRVR, or both did not result in statistically significant differences in improvements in cognitive function over 24 months.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02913664.},
}

@article {pmid41870450,
year = {2026},
author = {Shah, D and Patel, A and Patel, A},
title = {Novel multitargeted Imidazo[1,2-a]pyridine-1,3,4-oxadiazole hybrids: design, synthesis and biological evaluation as anti-Alzheimer's agents.},
journal = {Future medicinal chemistry},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/17568919.2026.2649001},
pmid = {41870450},
issn = {1756-8927},
abstract = {AIMS: To design, synthesize, and evaluate novel imidazo[1,2-a]pyridine derivatives as dual acetylcholinesterase (AChE) and β-secretase (BACE1) inhibitors for potential Alzheimer's disease (AD) therapy.

MATERIALS AND METHODS: A series of imidazo[1,2-a]pyridine derivatives (DS1-DS15) were synthesized via cyclization using various aryl and heteroaryl acids and characterized by MP, TLC, FTIR, MS, and [1]H/[13]C NMR spectroscopy. Molecular docking studies were performed against AChE (PDB ID: 4EY7) and BACE1 (PDB ID: 4ACU). Pharmacokinetic properties were predicted using pkCSM, and molecular dynamics simulations were conducted for the lead compound. In vitro inhibitory activities were determined by IC50 values. In vivo anti-AD activity was evaluated in male Sprague Dawley rats using biochemical assays and histological analysis.

RESULTS: Compound DS7 showed the highest binding affinity toward both targets with stable protein-ligand interactions. It exhibited potent AChE inhibition (IC50 = 0.054 µM) and significant BACE1 inhibition (IC50 = 5.67 µM). In vivo studies demonstrated significant reversal of AD-associated biochemical and histopathological alterations at high dose.

CONCLUSION: DS7 emerged as a promising dual AChE/BACE1 inhibitor and a potential lead candidate for further optimization in AD drug development.},
}

@article {pmid41870451,
year = {2026},
author = {Stites, SD and Dedhia, M and Kuz, C},
title = {Predictors of extreme future time perspective change in persons who learn an Alzheimer's disease biomarker test result.},
journal = {Aging & mental health},
volume = {},
number = {},
pages = {1-17},
doi = {10.1080/13607863.2026.2643904},
pmid = {41870451},
issn = {1364-6915},
abstract = {OBJECTIVES: Future Time Perspective (FTP) refers to how individuals perceive their future. FTP can be impacted when people learn their Alzheimer's disease (AD) biomarker test result. This study aimed to understand what factors explain change in FTP after people learn their AD biomarker result and whether large FTP changes, after learning an AD biomarker test result, can be predicted by clinical and demographic characteristics.

METHOD: Cognitively unimpaired adults (N = 4,340) screening for an AD prevention trial, completed the 10-item FTP scale pre- and post- disclosure of their amyloid test result. We conducted bivariate and multivariable analyses. We calculated FTP change between pre- and post- result disclosure to estimate bivariate mean effects for covariates. We used a mixed-effects model to estimate time-varying effects and polytomous regression to estimate the relative risk ratio (RRR) of predictors of a large FTP increase (4th quartile) or decrease (1st quartile) compared to no change (2nd and 3rd quartiles).

RESULTS: In the mixed-effects model, the mean FTP score increased by 0.13 points from time 1 to time 2 (p < 0.001). Global cognition was a predictor of a large FTP increase post-disclosure (RRR = 0.95, p = 0.003 while elevated amyloid was a predictor of a large decrease (RRR = 1.25, p = 0.01). Women were more likely than men to experience a large FTP change, either increase (RRR = 1.45, p < 0.001) or decrease (RRR = 1.26, p = 0.005).

CONCLUSION: Disclosure processes may interact with reactions to specific test results, which has implications for the wider dissemination of these diagnostics. Assessable characteristics predict large FTP changes post-biomarker disclosure, which may help identify individuals with atypical outcomes.},
}

@article {pmid41870677,
year = {2026},
author = {Some, A and Naskar, N and Thomas, DM and Jeengar, MK and Nassar, A},
title = {Senescence as a Central Node in Alzheimer's Disease: Molecular Triggers, Cellular Effectors, and RNA-Based Interventions.},
journal = {Neurochemical research},
volume = {51},
number = {2},
pages = {},
pmid = {41870677},
issn = {1573-6903},
mesh = {*Alzheimer Disease/metabolism/pathology/therapy ; Humans ; Animals ; *Cellular Senescence/physiology ; Brain/metabolism/pathology ; Oxidative Stress/physiology ; },
abstract = {Alzheimer's disease (AD) is the most frequent neurodegenerative disorder. It is characterized by the buildup of amyloid-β (Aβ) plaques, as well as of tangles made out of tau that increasingly damage and kill neurons while also impairing memory and thinking. Recent findings indicate that cellular senescence is implicated in the pathogenesis of AD. Senescence occurs when cells irreversibly stop dividing under stress. In the brain, it can be induced by chronic activation of astrocytes and microglia, Aβ toxicity, tau hyperphosphorylation and oxidative stress. Senescent cells secrete proinflammatory factors, i.e., the senescence-associated secretory phenotype (SASP). These molecules promote inflammation, destroy mitochondria and interfere with synapses in ways that speed up the progress of the disease. Blocking those senescent cells may offer a new approach to treatment. Approaches including VEGFR-1 and SIRT5 interference, senolytics or senomorphs drugs, NLRP3 antagonist, PAI-1 inhibitors and small vessels inhibitors (including aspirin, curcumin derivatives and sildenafil) have been suggested to promisingly mitigate brain injury. RNA based therapy (miRNAs- and lncRNAs-targeted) and exosomal derived biomarkers are also an optimistic approach. A clearer understanding of how senescence is implicated in AD would have implications regarding the design and application of novel treatments aimed at delaying disease onset, slowing down progression or preserving brain function.},
}

*Alzheimer Disease/metabolism/pathology/therapy
Humans
Animals
*Cellular Senescence/physiology
Brain/metabolism/pathology
Oxidative Stress/physiology

@article {pmid41870774,
year = {2026},
author = {Mahmoud, MH and Mjery, Y and Fatani, SH and Jan, A and Taymour, S and Abdelsalam, K and Nasif, WA and Mukhtar, MH and Eldein, MMN},
title = {Protective effects of watercress (Nasturtium officinale) leaf methanolic extract against dextran sodium sulfate induced colon inflammation in rats.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {41870774},
issn = {1568-5608},
abstract = {Numerous factors can lead to inflammation and enlargement of the colon, posing a serious health risk. This study investigated the protective effects of watercress (Nasturtium officinale) leaf methanolic extract against dextran sodium sulfate (DSS)-induced colonic inflammation in rats. Phytochemical analysis showed high levels of polyphenols, flavonoids, and condensed tannins in the methanolic extract, which exhibited the strongest in vitro anti-diabetic (α-amylase and α-glucosidase enzymes; Inhib. % 72.61 and 62.36%, respectively), anti-Alzheimer (AChE; Inhib. % 65.86 ± 0.15%), and anti-arthritic activity (protein denaturation and the proteinase enzyme activity; Inhib. % 58.09 ± 0.14 and 55.39 ± 0.14%, respectively) and was therefore selected for the in vivo study. Oxidative stress and inflammatory responses in colon tissue were evaluated using biochemical tests, histopathological examination, and assessment of mRNA levels of inflammatory markers (NF-κB, IL-6, IL-1β) and antioxidant enzymes (SOD1, CAT, GPx1). Watercress extract treatment successfully reinstated antioxidant enzyme activity and decreased inflammatory indicators in both pre-treated and post-treated cohorts. Histopathological examinations demonstrated a significant enhancement in the architecture of colon tissue and a decrease in inflammatory lesions. Molecular assays confirmed normalization of mRNA expression of antioxidant enzymes and inflammatory markers disrupted by DSS administration (p ≤ 0.05). These findings indicate that the methanolic extract of watercress leaves exerts protective effects against DSS-induced colonic inflammation at biochemical, histological, and molecular levels, supporting its potential as a natural anti-inflammatory agent.},
}

@article {pmid41870777,
year = {2026},
author = {Mostafa, RE and Asaad, GF},
title = {Bridging the gaps in alzheimer's disease: a comprehensive review of current and emerging therapies.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {41870777},
issn = {1568-5608},
}

@article {pmid41870813,
year = {2026},
author = {Upadhayay, S},
title = {Role of Pentacyclic Triterpenes in the Management of Neurological Disorders: An Insight into Molecular Mechanisms and Therapeutic Approaches.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {41870813},
issn = {1559-1182},
mesh = {Humans ; Animals ; *Nervous System Diseases/drug therapy/metabolism ; *Pentacyclic Triterpenes/therapeutic use/pharmacology ; *Neuroprotective Agents/therapeutic use/pharmacology ; Signal Transduction/drug effects ; Oxidative Stress/drug effects ; },
abstract = {Neurological disorders represent major public health concerns globally, as they profoundly affect motor function, memory, and cognitive abilities, thus compromising patients' independence and quality of life. Despite extensive research, current treatment approaches predominantly offer palliative care, failing to hinder disease progression. The rising incidence of these disorders underscores an urgent necessity for more efficacious and disease-modifying therapies. According to findings, pentacyclic triterpenoids exhibit neuroprotective properties by inhibiting neuronal oxidative stress, neuroinflammation, apoptosis, and degeneration, making them promising candidates for targeting the underlying causes of neurodegeneration. Therefore, in this review, we explore natural and synthetic pentacyclic triterpenoids that exhibit neuroprotective effects by modulating signaling pathways, such as HMGB1, TLR4, NLRP3, NF-κB, Nrf2, PI3K, Akt, and CREB, which play crucial roles in regulating cell proliferation, differentiation, and neuronal plasticity. The present literature survey is performed by searching various keywords with several combinations: "pentacyclic triterpenes", "neurological disorders", Parkinson's Disease", "Huntington's Disease", "Alzheimer's Disease", "Multiple sclerosis", "Amyotrophic Lateral Sclerosis" "Epilepsy", "mitochondria dysfunction", "oxidative stress", "preclinical studies", "molecular mechanisms", and "clinical studies". Studies indicates that pentacyclic triterpenoids have a wide range of therapeutic potentials, current findings summarizes existing knowledge and examines the neuroprotective properties and potential molecular mechanisms of pentacyclic triterpenoids related with health benefits and neurological diseases. Available evidence suggests that pentacyclic triterpenoids possess the capacity to impede disease progression and may be beneficial in the treatment of neurological disorders. This review strengthens the understanding of pentacyclic triterpenoids and their molecular mechanisms, while also facilitating pharmaceutical discovery and development for neurodegenerative disorders.},
}

Humans
Animals
*Nervous System Diseases/drug therapy/metabolism
*Pentacyclic Triterpenes/therapeutic use/pharmacology
*Neuroprotective Agents/therapeutic use/pharmacology
Signal Transduction/drug effects
Oxidative Stress/drug effects

@article {pmid41870902,
year = {2026},
author = {Kang, J and Du, X and Zhang, X and Li, Y and Wang, C and Sun, S},
title = {METTL3-mediated TIGAR m6A modification and its role in microglia activation related to Alzheimer's disease.},
journal = {Neuroreport},
volume = {37},
number = {5},
pages = {195-203},
doi = {10.1097/WNR.0000000000002253},
pmid = {41870902},
issn = {1473-558X},
mesh = {Humans ; *Microglia/metabolism ; *Alzheimer Disease/metabolism ; *Methyltransferases/metabolism/genetics ; *Apoptosis Regulatory Proteins/metabolism ; *Adenosine/analogs & derivatives/metabolism ; Amyloid beta-Peptides/pharmacology ; Cell Line ; Phosphoric Monoester Hydrolases ; },
abstract = {OBJECTIVE: This study focused on clarifying whether methyltransferase3 (METTL3) participates in the polarization and activation of microglia in Alzheimer's disease (AD) by mediating the N6-methyladenosine (m6A) modification level of TP53-induced glycolysis and apoptosis regulator (TIGAR).

METHODS: Human microglia HMC3 cells were transfected with overexpression or knockdown lentivirus of METTL3, TIGAR, or TIGAR before being induced by Aβ treatment to establish an in-vitro AD cell model. The expression of TIGAR and METTL3 was measured by real-time quantitative PCR and western blot. Microglial polarization was assessed by detecting the expression of M1 microglia marker CD86 and M2 marker CD206 using immunofluorescence and measuring the protein expression of M1-associated iNOS and IL-1β, and M2-associated Arg-1 and IL-10 using western blot. PAR-CLIP was employed to examine the binding of METTL3 to TIGAR mRNA, and MeRIP was used to measure the m6A level of TIGAR mRNA. The stability of TIGAR mRNA was evaluated by an actinomycin D assay.

RESULTS: In Aβ-induced HMC3 cells, both METTL3 and TIGAR expressions were reduced. Aβ treatment in HMC3 cells increased M1 polarization and decreased M2 polarization. But this effect was partially reversed by overexpression of either METTL3 or TIGAR. METTL3 binds to TIGAR mRNA and increases its m6A level, thereby promoting TIGAR mRNA stability.

CONCLUSION: METTL3 modulates the balance of Aβ-induced polarization and microglia activation in HMC3 cells by upregulating TIGAR, promoting polarization toward an anti-inflammatory profile.},
}

Humans
*Microglia/metabolism
*Alzheimer Disease/metabolism
*Methyltransferases/metabolism/genetics
*Apoptosis Regulatory Proteins/metabolism
*Adenosine/analogs & derivatives/metabolism
Amyloid beta-Peptides/pharmacology
Cell Line
Phosphoric Monoester Hydrolases

@article {pmid41870994,
year = {2026},
author = {Pan, Z and Han, Y and Wang, G and Zhang, S and Lu, X and Su, X and Liu, Z},
title = {Dual-tracer PET/CT Imaging using 18F-AV-45 and 18F-AV-1451 for the Diagnosis of Alzheimer's Disease.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {229},
pages = {},
doi = {10.3791/69479},
pmid = {41870994},
issn = {1940-087X},
mesh = {*Alzheimer Disease/diagnostic imaging/metabolism ; *Carbolines/chemistry ; Humans ; *Positron Emission Tomography Computed Tomography/methods ; *Aniline Compounds/chemistry ; *Ethylene Glycols/chemistry ; *Radiopharmaceuticals/chemistry ; Fluorine Radioisotopes ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by an insidious onset and gradual deterioration. Clinically, it manifests as cognitive decline and behavioral changes rather than only as generalized dementia. Currently, the diagnostic accuracy of AD remains limited due to the nonspecific clinical manifestations and the low specificity of conventional examinations such as neuropsychological assessments, electroencephalography (EEG), computed tomography (CT), and magnetic resonance imaging (MRI). Positron emission tomography/computed tomography (PET/CT) provides detailed structural and functional information along with specific molecular distributions, making it increasingly valuable for the diagnosis and research of AD. We performed PET/CT scans using the radiotracers [18]F-AV-45 (florbetapir) and [18]F-AV-1451 (flortaucipir). The key distinction between these tracers lies in their molecular targets: [18]F-AV-45 binds to β-amyloid (Aβ), whereas [18]F-AV-1451 specifically targets tau protein. This study elaborates on the protocol for the combined use of both tracers in AD diagnosis, encompassing patient preparation procedures, image acquisition techniques, interpretation standards, and the clinical significance of their joint application. This dual-tracer protocol provides a sensitive, comprehensive, and non-invasive method for detecting both amyloid and tau pathology, enhancing early diagnosis, disease staging, and research on disease progression.},
}

*Alzheimer Disease/diagnostic imaging/metabolism
*Carbolines/chemistry
Humans
*Positron Emission Tomography Computed Tomography/methods
*Aniline Compounds/chemistry
*Ethylene Glycols/chemistry
*Radiopharmaceuticals/chemistry
Fluorine Radioisotopes
Amyloid beta-Peptides/metabolism
tau Proteins/metabolism

@article {pmid41871009,
year = {2026},
author = {Hallam, RD and Foran, G and Fletcher, NK and MacPherson, REK and Necakov, A},
title = {BDNF alters β-cleavage of APP and subcellular distribution of BACE1.},
journal = {American journal of physiology. Cell physiology},
volume = {},
number = {},
pages = {},
doi = {10.1152/ajpcell.00642.2025},
pmid = {41871009},
issn = {1522-1563},
support = {PGS-D//Natural Sciences and Engineering Research Council of Canada (NSERC)/ ; PGS-D//NSERC | RES'EAU-WaterNET/ ; RGPIN-2017-03904//NSERC | RES'EAU-WaterNET/ ; RGPIN-2018-06781//NSERC | RES'EAU-WaterNET/ ; },
abstract = {The accumulation and deposition of amyloid-beta (Aß) peptides is detrimental to neuronal networks and is driven by the cleavage of amyloid precursor protein (APP) by beta-secretase 1 (BACE1). The proteolytic processing of APP is tightly regulated by the opposing activities of BACE1 and ADAM10, with the latter producing a truncated, non-amyloidogenic fragment. Maintaining this balance is critical for normal physiological function, as complete inhibition of BACE1 has proven detrimental owing to the important physiological roles of its many substrates. Brain-derived neurotrophic factor (BDNF), an important mediator of neuronal function and survival, has recently been shown to reduce BACE1 activity in neural tissue, but the mechanism for this remains unknown. Previous research suggests that BACE1 cleavage of APP is favoured at acidic intracellular compartments, whereas non-amyloidogenic processing preferentially occurs at the plasma membrane. Hence, we hypothesized that BDNF alters the subcellular distribution of BACE1, reducing ß-cleavage of APP. Here, we show that acute BDNF treatment of differentiated neural cells (SH-SY5Y) reduced levels of sAPPß, a product of BACE1 cleavage of APP. Using confocal microscopy and quantitative image analysis, we found that this reduction in sAPPß levels is coincident with increased BACE1 localization to the plasma membrane, and a concomitant reduction of BACE1 localization to early endosomes. This effect appears to be independent of clathrin-mediated endocytosis (CME), as inhibition of CME by PitStop2 treatment increased a-cleavage of APP but did not reduce ß-cleavage independent of BDNF treatment. Hence, BDNF may reduce production of Aß by altering BACE1 distribution and decreasing upstream ß-cleavage.},
}

@article {pmid41871202,
year = {2026},
author = {Wu, S and Xie, J and Zhao, X and Zhao, H and Sánchez, OF and Yu, S and Rochet, JC and Freeman, JL and Yuan, C},
title = {Predifferentiation Neurotoxicity of GenX Exposure on hiPSC-Derived Cortical Neurons.},
journal = {Environmental science & technology},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.est.5c13193},
pmid = {41871202},
issn = {1520-5851},
abstract = {Hexafluoropropylene oxide dimer acid (HFPO-DA), commercially known as GenX, was introduced as a potentially safer substitute for an older type of per- and polyfluorinated substance (PFAS) named perfluorooctanoic acid (PFOA). Emerging evidence suggests that GenX may possess neurotoxicity comparable to or greater than that of PFOA, underscoring the need for evaluating its potential to induce adverse health effects on the central nervous system. Here, we performed a systematic evaluation of predifferentiation GenX exposure and its neurotoxic effects utilizing human induced pluripotent stem cell (hiPSC)-derived cortical neurons. Neurons exposed to 0.4 and 4 ppb GenX prior to differentiation possess altered neuronal characteristics including synaptic density and neural activity, accompanied by transcriptomic changes associated with neurodegeneration, including enriched differentially expressed genes (DEGs) in the Alzheimer's disease (AD) pathway and predicted dysregulation of amyloid processing. Consistent with the transcriptomic alterations, GenX exposure altered multiple APP processing readouts, including increased sAPPβ/sAPPα ratios and intracellular C99 accumulation, accompanied by reduced extracellular Aβ40 and Aβ42 levels. Hyperphosphorylation of tau was also observed along with lipid droplet accumulation and reduced global translational activity, indicating broader disruptions. Collectively, our findings suggest that GenX exposure prior to differentiation, mimicking developmental exposure, can lead to persistent molecular and functional alterations in human cortical neurons that resemble key features observed in neurodegenerative diseases.},
}

@article {pmid41871233,
year = {2025},
author = {Silva, A and Silva, S and Rodrigues, B and Simões, G and Dinis, I and Freitas, M and Resende, R and Bicker, J and Fortuna, A and Silva, MM and Santos, AE and Pinho, SA and Neves, B and Pereira, CF and Cruz, MT},
title = {Targeting NRF2 With Isoeugenol: A Promising Small Molecule for Neurodegenerative, Metabolic, and Chronic Inflammatory Disorders.},
journal = {Oxidative medicine and cellular longevity},
volume = {2025},
number = {1},
pages = {e7695056},
doi = {10.1155/omcl/7695056},
pmid = {41871233},
issn = {1942-0994},
support = {POCI-01-0145-FEDER-029369//COMPETE 2020-Operational Programme for Competitiveness and Internationalisation and Portuguese national funds via FCT - Fundação para a Ciência e a Tecnologia/ ; UIDB/04539/2020//COMPETE 2020-Operational Programme for Competitiveness and Internationalisation and Portuguese national funds via FCT - Fundação para a Ciência e a Tecnologia/ ; UIDP/04539/2020//COMPETE 2020-Operational Programme for Competitiveness and Internationalisation and Portuguese national funds via FCT - Fundação para a Ciência e a Tecnologia/ ; LA/P/0058/2020//COMPETE 2020-Operational Programme for Competitiveness and Internationalisation and Portuguese national funds via FCT - Fundação para a Ciência e a Tecnologia/ ; //COST Action CA20121, Bench to bedside transition for pharmacological regulation of NRF2 in noncommunicable diseases (BenBedPhar)/ ; 101080329//European Union/ ; },
mesh = {Humans ; *NF-E2-Related Factor 2/metabolism ; *Eugenol/analogs & derivatives/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; *Metabolic Diseases/drug therapy/metabolism ; *Inflammation/drug therapy/metabolism ; Chronic Disease ; Oxidative Stress/drug effects ; },
abstract = {Oxidative stress, driven by an imbalance between oxidants and antioxidants, disrupts redox homeostasis and contributes to the development of chronic diseases, including cancer, diabetes, neurodegenerative disorders, and aging. The NRF2-KEAP1 pathway is a pivotal cellular defense mechanism against oxidative stress, regulating the transcription of cytoprotective genes. Pharmacological NRF2 activation has emerged as a promising strategy to mitigate oxidative stress-related pathologies; however, challenges regarding target specificity, pharmacodynamics, efficacy, and safety remain unresolved. Isoeugenol, a phenylpropanoid found in essential oils, has traditionally been recognized as a skin allergen but is now gaining attention for its potential as an NRF2 activator. Emerging evidence suggests that isoeugenol exerts antioxidant, anti-inflammatory, and neuroprotective effects and modulates metabolic disorders such as diabetes mellitus. Despite its therapeutic potential, the direct correlation between isoeugenol's effects and NRF2 activation remains underexplored. Existing studies indicate that isoeugenol may activate NRF2 through multiple mechanisms, including covalent modification of KEAP1 cysteine residues, increased AKT activation and GSK3β inactivation, and glutathione depletion leading to reactive oxygen species (ROS) generation. Understanding these activation pathways is critical for leveraging isoeugenol as a therapeutic agent. This review provides a comprehensive analysis of isoeugenol's role in modulating NRF2 activity and its implications for treating oxidative stress-driven diseases. By integrating current findings, this review highlights new insights into the therapeutic potential of isoeugenol in translational medicine. We propose future research directions to optimize its application in clinical settings, paving the way for more targeted and effective NRF2-based interventions in chronic disease management.},
}

Humans
*NF-E2-Related Factor 2/metabolism
*Eugenol/analogs & derivatives/therapeutic use/pharmacology
*Neurodegenerative Diseases/drug therapy/metabolism
Animals
*Metabolic Diseases/drug therapy/metabolism
*Inflammation/drug therapy/metabolism
Chronic Disease
Oxidative Stress/drug effects

@article {pmid41871235,
year = {2026},
author = {Kapustin, D and Rashidi-Ranjbar, N and Wang, W and Binns, MA and McLaughlin, PM and Abrahao, A and Grimes, D and Lang, A and Marras, C and Masellis, M and Orange, JB and Rajji, TK and Roberts, A and Saposnik, G and Swartz, RH and Tang-Wai, DF and Tartaglia, MC and Troyer, A and Zinman, L and Fischer, CE and Kumar, S},
title = {Neuropsychiatric Symptom Clusters and Their Association With Brain Structure in Alzheimer Disease.},
journal = {The Journal of clinical psychiatry},
volume = {87},
number = {2},
pages = {},
doi = {10.4088/JCP.25m16192},
pmid = {41871235},
issn = {1555-2101},
mesh = {Humans ; *Alzheimer Disease/pathology/psychology/complications/physiopathology/diagnostic imaging ; Male ; Female ; Aged ; Magnetic Resonance Imaging ; *Brain/pathology/diagnostic imaging ; Aged, 80 and over ; Activities of Daily Living ; Longitudinal Studies ; },
abstract = {Objective: Neuropsychiatric symptoms (NPS) constitute a major challenge in Alzheimer disease (AD). We applied a component-based symptom paradigm by deriving Neuropsychiatric Inventory Questionnaire (NPI-Q) clusters and evaluating their longitudinal associations with regional brain volumes and functional outcomes (instrumental activities of daily living, activities of daily living [ADLs]). Methods: Participants with AD (N=111) were from the Ontario Neurodegenerative Disease Research Initiative. NPS were assessed using the NPI-Q. Symptom clusters were identified via principal components analysis at baseline. Magnetic resonance imaging-derived volumes for 34 cortical and 9 subcortical regions were obtained annually over 3 years. Longitudinal associations between NPS clusters and functional outcomes were examined using linear mixed-effects models adjusting for age, sex, Montreal Cognitive Assessment (MoCA), education, visit number, and cholinesterase inhibitor use. Results: Four clusters explained 62% of variance: hyperactivity (disinhibition, irritability, motor disturbance, agitation), psychosis (hallucinations, delusions, euphoria), neurovegetative (apathy, appetite), and affective (depression, anxiety, nighttime behavior). The hyperactivity cluster was associated with the left middle temporal (β=-0.24, P=.025) and right nucleus accumbens (β=-0.28, P=.007). The neurovegetative cluster was associated with the left middle temporal (β=-0.50, P<.001) and right nucleus accumbens (β=-0.55, P<.001). The affective cluster showed the strongest associations with the left rostral anterior cingulate (β=-0.42, P=.002) and right medial orbitofrontal cortex (β=-0.47, P=.001). All clusters predicted iADL outcomes; clusters 1, 3, and 4 also predicted ADL outcomes. Greater NPS burden, male sex, age, lower MoCA, and later visits predicted worse function. Conclusion: NPS in AD separate into hyperactivity, psychosis, neurovegetative, and affective clusters, supporting a cluster-based paradigm linking co-occurring behavioral symptoms with brain structure and functional decline.},
}

Humans
*Alzheimer Disease/pathology/psychology/complications/physiopathology/diagnostic imaging
Male
Female
Aged
Magnetic Resonance Imaging
*Brain/pathology/diagnostic imaging
Aged, 80 and over
Activities of Daily Living
Longitudinal Studies

@article {pmid41871655,
year = {2026},
author = {van der Heide, FCT and Zamoum, Y and Ounissi, M and Berendschot, TT and Cheung, CY and Koronyo-Hamaoui, M and Schmetterer, L and Chua, J and Peto, T and Lengyel, I and Csincsik, L and Creuzot, C and Arnould, L and Stalmans, I and Trucco, E and Macgillivray, T and Khawaja, AP and Zhu, LZ and Keane, PA and Wong, TY and Milea, D},
title = {Quantification of retinal microvascular imaging features from fundus photos in ocular and systemic disease: a framework for standardization.},
journal = {Progress in retinal and eye research},
volume = {},
number = {},
pages = {101461},
doi = {10.1016/j.preteyeres.2026.101461},
pmid = {41871655},
issn = {1873-1635},
abstract = {Microvascular dysfunction is increasingly recognized as an important contributor to ocular and systemic diseases, including diabetic retinopathy, cardiovascular disease, and Alzheimer's disease and related dementias. Elucidating how early microvascular injury contributes to disease pathobiology, and development of sensitive, quantifiable features of microvascular dysfunction, represents a critical frontier for improving risk stratification, enabling earlier diagnosis and guiding targeted interventions. In this context, retinal imaging has emerged as a powerful modality, enabling non-invasive, high-resolution visualization of the microvasculature with color and (ultra)widefield fundus imaging. Rapid technological advances have led to an array of, open-source tools for quantitative extraction of retinal microvascular features. However, progress in this field is hampered by poor comparability between tools, limiting reproducibility and cross-study integration. Differences between tools originate from variations in image processing steps, including vessel segmentation, arteriole-venule classification, optic disc detection, region-of-interest definition, and image quality assessment, and the algorithms for metric calculation. In this review we comprehensively compare existing analytical analysis tools for static vessel analyses and delineate how these methodological differences influence the vascular measure quantification. To advance robust, scalable biomarker development, we propose a methodological framework to standardize and harmonize retinal microvascular quantification. This framework can guide future studies in addressing key gaps in literature and in developing imaging biomarkers for clinical use. Critical open questions include whether and when retinal imaging features change during ocular and systemic disease, whether microvascular dysfunction is reversible, how microvascular dysfunction contributes to neurodegeneration, and how central and peripheral retinal microvascular dysfunction differ.},
}

@article {pmid41871661,
year = {2026},
author = {Sobhani, A and Sadr, NKS and Shahpasand, K and Mirnajafi-Zadeh, J and Behmanesh, M},
title = {Orphan G protein-coupled receptor 3 as a potential modulator of microglial inflammatory responses: implications for tau-associated neuroinflammation in Alzheimer's disease.},
journal = {Life sciences},
volume = {},
number = {},
pages = {124342},
doi = {10.1016/j.lfs.2026.124342},
pmid = {41871661},
issn = {1879-0631},
abstract = {INTRODUCTION: Neuroinflammation, driven largely by microglial activation, is a core pathological feature of Alzheimer's disease (AD). Pathological tau species represent one of the key drivers of inflammatory activation in AD; however, the upstream regulators governing microglial inflammatory responses remain incompletely understood. Orphan G protein-coupled receptors (GPCRs) are emerging neuroimmune modulators, yet their specific roles in tau-mediated neuroinflammation are not fully characterized. This study investigated selected orphan GPCRs as modulators of this response.

METHODS: Transcriptomic analyses of postmortem AD hippocampal tissue were performed to identify dysregulated orphan GPCRs, followed by functional network analysis. Key findings were validated in a cis P-tau-induced tauopathy mouse model and in cis P-tau-stimulated BV-2 microglial cultures using immunofluorescence, qPCR, Western blotting, and ELISA. Functional relevance was assessed using DNAzyme-mediated Gpr3 knockdown.

RESULTS: Transcriptomic profiling identified Gpr3, Gpr6, and Gpr12 as significantly upregulated orphan GPCRs in AD hippocampal tissue, with network analyses implicating them in inflammatory signaling pathways. In the cis P-tau model, hippocampal neuroinflammation was accompanied by microglial activation, increased inflammatory markers, and receptor upregulation. Immunofluorescence revealed a spatial association between increased GPR3 expression and microglial activation. In vitro, cis P-tau stimulation of BV-2 microglia induced Gpr3 expression, and its downregulation attenuated inflammatory outputs at both transcriptional and signaling levels, including reduced NF-κB protein level, modulation of AKT phosphorylation, and decreased TNF-α and IL-6 secretion.

CONCLUSION: These findings support a previously underexplored role for GPR3 in modulating microglial inflammatory responses under tau-associated pathological conditions in AD, highlighting its potential relevance as a therapeutic target for maladaptive neuroinflammation.},
}

@article {pmid41871753,
year = {2026},
author = {Suk, K},
title = {Disentangling causality in brain aging: The complex interplay between glial senescence, neuroinflammation, and neurodegeneration.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115737},
doi = {10.1016/j.expneurol.2026.115737},
pmid = {41871753},
issn = {1090-2430},
abstract = {The aging brain is characterized by accumulation of senescent glia, chronic neuroinflammation, and vulnerability to neurodegeneration. While their co-occurrence is established, causal relationships remain poorly understood-a critical gap for developing mechanism-based therapies rather than symptomatic treatments. This review examines evidence for causality among glial senescence, neuroinflammation, and neurodegeneration using Bradford Hill criteria, longitudinal studies, genetic approaches, and senolytic trials. Glial senescence in astrocytes and microglia initiates neuroinflammatory cascades through the senescence-associated secretory phenotype (SASP), creating self-perpetuating cycles driving neuronal dysfunction. However, neuroinflammation also emerges as a primary event triggered by peripheral signals, blood-brain barrier breakdown, or pathogens, subsequently inducing glial senescence. Neuronal damage generates inflammatory signals activating glia, indicating bidirectional causality. Disease-specific patterns are heterogeneous: in Alzheimer's disease, early microglial activation may precede amyloid pathology, while in Parkinson's disease, gut-brain inflammation may initiate central pathology. Common feed-forward loops amplify initial insults-senescence, inflammation, or protein aggregation-transcending linear causality. We propose a framework recognizing critical temporal windows and tipping points, distinguishing reversible from irreversible stages. Anti-inflammatory and senolytic interventions show promise preventively or early but limited efficacy in advanced disease, emphasizing intervention timing. Outstanding questions include identifying earliest causal events, determining points of no return, and understanding genetic-environmental modification of causal pathways. Addressing these requires longitudinal multi-omics studies and interventional trials. Establishing causation beyond correlation enables precision medicine targeting root causes, offering hope for preventing age-related cognitive decline and neurodegeneration.},
}

@article {pmid41871793,
year = {2026},
author = {Yang, SY and Jia, HL and Tuerhong, M and Liu, XY and Qin, GQ and Xu, Z and Zeng, Y and Xia, Q and Jiang, Y and Tu, PF},
title = {Anti-neuroinflammatory phenylpropanoids and phenolics from Astragalus membranaceus var. mongholicus.},
journal = {Fitoterapia},
volume = {},
number = {},
pages = {107190},
doi = {10.1016/j.fitote.2026.107190},
pmid = {41871793},
issn = {1873-6971},
abstract = {Astragalus membranaceus is used in traditional Chinese medicine for neuroinflammation-related conditions like ischemic stroke and Alzheimer's disease. A phytochemical investigation of its roots led to the isolation of three previously undescribed compounds, astragalusmonol A (1), astragalusmonosides A and B (2-3), along with seventeen known compounds (4-20). Their structures were confirmed by HRESIMS, NMR, IR, UV, electronic circular dichroism (ECD) calculations, X-ray crystallography, and chemical hydrolysis. All isolates were evaluated for anti-neuroinflammatory activity in lipopolysaccharide (LPS)-induced BV2 microglia. Fifteen of them exhibited significant activity, with compounds 12, 6, and 1 showing particularly potent effects (IC50 values of 3.74, 9.71, and 26.47 μM, respectively). The most active compound, 12, also significantly attenuated thrombus formation in a zebrafish cerebral thrombosis model. This study not only enriches the chemical diversity of Astragalus membranaceus but also highlights the active compounds, notably compound 12, as promising candidates for targeting neuroinflammatory disorders.},
}

@article {pmid41688968,
year = {2026},
author = {Liu, X and Zhang, ZS and Tao, QQ},
title = {Neuronal intranuclear inclusion disease: a diagnostic pitfall for MELAS.},
journal = {BMC neurology},
volume = {26},
number = {1},
pages = {},
pmid = {41688968},
issn = {1471-2377},
abstract = {BACKGROUND: Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disease characterized by eosinophilic hyaluronan inclusions in the nervous system and internal organs. Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) is the most common neurological mitochondrial disease involving multiple organs. The complex and overlapping clinical manifestations of both diseases pose a significant risk for misdiagnosis.

CASE PRESENTATION: We present a case of NIID that closely mimicked the phenotype of MELAS. A 60-year-old Chinese man presented with recurrent headaches and cognitive impairment. Upon the first clinical presentation, brain magnetic resonance imaging (MRI) revealed multiple lacunar infarction foci. During the second presentation, the cranial MRI indicated lesions in the left occipital and parietal cortex. Cerebrospinal fluid (CSF) analysis ruled out common infectious, autoimmune, and paraneoplastic etiologies. Screening for Alzheimer’s disease (AD) biomarkers was also unremarkable. Muscle biopsy pathology revealed ragged-red fibers (RRFs), a finding consistent with MELAS. Based on the muscle biopsy findings, a provisional diagnosis of MELAS was made, and the patient received a course of intravenous arginine therapy. However, genetic testing for the NOTCH2NLC gene via capillary electrophoresis identified a heterozygous CGG repeat expansion (15 and 97 repeats), confirming the diagnosis of NIID.

CONCLUSIONS: This case highlights the diagnostic challenge in distinguishing NIID from MELAS and underscores the necessity of genetic testing for NOTCH2NLC in patients with compatible phenotypes, even in the presence of MELAS-suggestive features like RRFs.},
}

@article {pmid41862740,
year = {2026},
author = {Blasco, D and McCain, S and Pal, S and Uhlmann, WR and Ferber, R and Sanghavi, K and Charnysh, E and Prince, AER and Lee, C and Roberts, JS and , },
title = {Views and experiences regarding workplace genetic testing: findings from a national survey of U.S. employees.},
journal = {Journal of community genetics},
volume = {17},
number = {2},
pages = {},
pmid = {41862740},
issn = {1868-310X},
abstract = {UNLABELLED: The emergence of voluntary health-related genetic testing in workplace wellness programs indicates a need to understand employees’ views and experiences regarding workplace genetic testing (wGT). A large, diverse national sample of employed adults (N=2000; median age=43 years; 51.1% female; 33% non-white) completed a web survey of their wGT views and experiences. Although 80% of participants indicated their employer did not offer wGT, 54.1% were interested in testing, especially (somewhat/very) for cancer (89.2%), heart disease (93.1%), and Alzheimer’s disease (85.3%). Characteristics associated with wGT interest included younger age (<55 years), Hispanic/Latino ethnicity, genetic testing experience or familiarity, and a positive family medical history (all p<0.05). Reasons for pursuing wGT (e.g., inform health behaviors) were endorsed more frequently than reasons for declining (e.g., insurance/employability concerns). Among participants offered wGT (20%), 60% indicated having undergone testing. Test uptake was associated with personal medical history, greater familiarity with genetic testing, and self-reported physical health (all p<0.05). A minority of employed adults surveyed reported being offered, or having had, wGT. Nevertheless, many employees are potentially interested in wGT, particularly for common diseases. Although employees have wGT concerns, many view it as beneficial to inform health behaviors and decisions.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12687-025-00856-6.},
}

@article {pmid41863136,
year = {2026},
author = {Takayama, T and Hirose, T and Goto, M and Daida, H and Nakajima, M and Nakanishi, A and Murakami, K and Motoi, Y},
title = {Utility of Regional Cerebral Blood Flow SPECT and MRI for Predicting Amyloid Deposition in Real-World Clinical Settings.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {26},
number = {3},
pages = {e70158},
doi = {10.1111/psyg.70158},
pmid = {41863136},
issn = {1479-8301},
support = {//PDRadiopharma/ ; //Toshiaki Ogasawara Memorial Foundation/ ; },
mesh = {Humans ; Male ; Female ; *Tomography, Emission-Computed, Single-Photon/methods ; *Alzheimer Disease/diagnostic imaging/metabolism ; Aged ; *Magnetic Resonance Imaging/methods ; Retrospective Studies ; *Cerebrovascular Circulation/physiology ; *Brain/diagnostic imaging/metabolism ; Japan ; Aged, 80 and over ; Middle Aged ; Positron-Emission Tomography ; *Amyloid/metabolism ; },
abstract = {BACKGROUND: With the advent of disease-modifying therapies for Alzheimer's disease, there is a growing demand for more cost-effective methods that predict amyloid PET positivity. In Japan, the combination of structural brain MRI and regional cerebral blood flow (rCBF) single-photon emission computed tomography (rCBF SPECT) is routinely used in clinical practice for neuroimaging. The present study investigated the utility of this imaging approach for amyloid PET positivity in real-world clinical settings.

METHODS: A retrospective analysis of 101 patients who visited the Memory Clinic at Juntendo University Hospital between April 2019 and September 2023 was performed. All patients had undergone amyloid PET imaging at their own expense, in addition to a neuropsychological assessment, structural brain MRI and rCBF SPECT. Among 58 cases that underwent a voxel-based specific regional analysis system for Alzheimer's disease (VSRAD), volumetric differences between the amyloid-positive and -negative groups were assessed using Statistical Parametric Mapping (SPM) version 12.

RESULTS: Among the 101 patients analysed, 68 were positive and 33 were negative for amyloid. Twenty-nine patients had a change in clinical diagnosis after amyloid PET imaging, which affected subsequent management. Using VSRAD, VOI severity (continuous value) was set to 0.95 based on Youden's index and AUC (95% CI) was 0.72 (0.572-0.867), with a sensitivity of 90%, specificity of 52% and accuracy of 78%. In the visual assessment, MRI and rCBF SPECT were combined, and AUC (95% CI) was 0.767 (0.629-0.905), with a sensitivity decrease to 21% and specificity increase to 95%. The SPM12 analysis revealed clusters in the right medial temporal lobe at an uncorrected threshold (p < 0.001). However, no voxels survived family-wise error (FWE) correction (p < 0.05).

CONCLUSION: A VSRAD analysis of brain MRI has moderate discriminatory ability as a screening tool for predicting amyloid PET positivity. The addition of SPECT to MRI was not associated with a statistically significant improvement compared with MRI alone. SPECT may contribute to the differential diagnosis of non-Alzheimer's disease. MRI alone could be considered an option to increase the pre-test probability of amyloid PET positivity.},
}

Humans
Male
Female
*Tomography, Emission-Computed, Single-Photon/methods
*Alzheimer Disease/diagnostic imaging/metabolism
Aged
*Magnetic Resonance Imaging/methods
Retrospective Studies
*Cerebrovascular Circulation/physiology
*Brain/diagnostic imaging/metabolism
Japan
Aged, 80 and over
Middle Aged
Positron-Emission Tomography
*Amyloid/metabolism

@article {pmid41863237,
year = {2026},
author = {Bansal, B and Gupta, M},
title = {Exploring the Therapeutic Potential of Sulfonamide-1,3,4-Thiadiazole Hybrids: Focus on Neurological and Infectious Diseases.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575427760260120203139},
pmid = {41863237},
issn = {1875-5607},
abstract = {The 1,3,4-thiadaizole is widely recognized in drug discovery for its favorable physicochemical characteristics and diverse range of biological activities. This heterocyclic compound contains a five-membered ring composed of nitrogen, carbon, sulfur, and oxygen atoms. The presence of sulfur in the thiadiazole ring enhances lipophilicity and membrane permeability, making these compounds attractive for medicinal development. Sulfonamides, which consist of a sulfonyl group (-SO2) attached to a benzene ring, exhibit numerous pharmacological activities, including antimicrobial and anti-infective effects. This review aims to provide a comprehensive examination of hybrid derivatives combining 1,3,4-thiadaizole and sulfonamide moieties, highlighting their potential for enhanced biological efficacy against a broad spectrum of diseases. When these structural moieties are linked, the resultant compounds often display increased potency, improved selectivity, and superior drug-like properties compared with either scaffold alone. Recent advances in the design of such hybrids were summarized, their synthesis and characterization were discussed, and in-vitro and in-vivo findings on their biological activities were presented, along with Structure-Activity Relationship (SAR) studies. The objective of this review is to emphasize the benefits and opportunities of these hybrids and thereby encourage further research and development of novel therapeutic agents.},
}

@article {pmid41863238,
year = {2026},
author = {Joshi, K and Prajapati, O and Mirza, S and Jamwal, P and Brambhat, M and Prajapati, D and Yadav, R and Barmade, MA and Yadav, MR and Murumkar, P},
title = {Research Progress on Pyrazine-based Medicinally Active Compounds: A Review.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575421765251128091319},
pmid = {41863238},
issn = {1875-5607},
abstract = {Medicinal chemists are highly interested in pyrazine-based compounds due to their diverse biological roles and potential therapeutic applications for various disorders. This research examines the expansion of pyrazine-derived compounds between the years 2014 and 2025. This review emphasizes their established efficacy against Cancer, Tuberculosis, Alzheimer's disease, microbial infections, inflammation, and viral pathogens. Pyrazines have shown significant prospects for drug discovery caused by their ability to target several biological processes. This paves the way for novel therapies. We have discussed significant discoveries of pyrazines, their complex mechanisms, and the necessary future actions to enhance the utility of pyrazine-based compounds as pharmaceuticals.},
}

@article {pmid41863240,
year = {2026},
author = {Negi, P and Arote, ND and Patravale, VB},
title = {Diamonds for the Mind: Exploring the Potential of Adamantane against Alzheimer's Disease.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575426460260130103605},
pmid = {41863240},
issn = {1875-5607},
abstract = {Alzheimer's disease (AD) is the predominant type of dementia, emerging as a major health issue globally due to its increasing incidence and the limited approved therapies that provide only symptomatic relief. Adamantane, a diamondoid hydrocarbon with a distinctive cage-like structure, has emerged as a promising scaffold in medicinal chemistry due to its high lipophilicity, leading to good central nervous system bioavailability. Notably, memantine, an NMDA (N-methyl-daspartate) receptor antagonist, is an adamantane derivative that is approved by the U.S. Food and Drug Administration (US FDA) to manage moderate-to-severe AD symptoms. This review analyses the structure-activity relationship (SAR) of several adamantane derivatives and their relevance to AD. Amino-substituted adamantanes, such as amantadine and memantine, display anti-Alzheimer potential due to improved NMDA receptor affinity and CNS permeability. Additional targets, such as voltage-gated sodium channels and retinoid receptors, are proposed as potential targets for adamantane derivatives developed to act against AD. While various adamantane compounds have been patented and studied, few have become clinically approved drugs. Structural changes, particularly at bridgehead carbon atoms, greatly influence pharmaceutical results. Adamantane's physicochemical features make it a preferred framework for future CNS-targeted therapies. Given the increasing need for more effective AD treatments, adamantane-based compounds present a viable option for new drug development.},
}

@article {pmid41863264,
year = {2026},
author = {Chen, N and Yu, L and Hua, Q and Li, B and Zheng, X and Shan, J and Guo, J and Lim, KX and Lee, TS and Ye, KX and Li, N},
title = {Ginseng for Cognitive Function in Elderly Adults with Mild Cognitive Impairment, Alzheimer's Disease, or Dementia: A Systematic Review and Meta-Analysis.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X415818251222083130},
pmid = {41863264},
issn = {1875-6190},
abstract = {INTRODUCTION: Cognitive decline and dementia are key features of brain aging that substantially affect individuals' health and quality of life. Existing treatments for dementia mainly focus on individuals with mild-to-moderate cognitive impairment. Ginseng, known for its anti-aging properties, has shown potential benefits for cognitive function. This study aimed to systematically review clinical evidence from randomized controlled trials (RCTs) regarding the potential of ginseng to prevent or slow cognitive decline and to explore the most effective dosing strategies.

METHODS: A comprehensive search was performed across 10 databases, including PubMed, Embase, Cochrane Library, Web of Science, Scopus, Ovid, CNKI, Wanfang Data, VIP database, and Chinese Biomedical Literature Database (CBM), covering studies from their inception to October 15, 2024. Two independent reviewers screened the studies for eligibility and assessed their quality. Data extraction and meta-analysis were conducted using Review Manager 5.4 and Stata 15.1, while Trial Sequential Analysis (TSA) was conducted using TSA 0.9.5.10 beta. The analysis focused on older adults diagnosed with mild cognitive impairment (MCI), Alzheimer's disease (AD), or other types of dementia.

RESULTS: Nine studies involving 617 patients were included. The results revealed that (1) compared with the control group, the ginseng group exhibited higher scores on the Mini-Mental State Examination (MMSE) (MD = 0.38, 95%CI (0.03, 0.74), P = 0.03) and lower scores on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) (MD = -2.21, 95%CI (-3.97, -0.44), P = 0.014), indicating improved cognitive function. (2) Subgroup analysis of MMSE outcomes indicated that a ginseng dose of 4.5g/d provided cognitive benefits. (3) TSA results confirmed the reliability of these meta-analysis results.

DISCUSSION: Ginseng may provide modest cognitive benefits for older adults with MCI, AD, or dementia. The observed effects are biologically plausible given ginseng's antioxidant and neuroprotective properties; however, the improvements did not reach the threshold for clinical significance. The limited number of included studies and moderate heterogeneity underscore the need for larger, high-quality RCTs to confirm these results and determine the most effective dosing strategies.

CONCLUSIONS: Current evidence indicates that ginseng can improve cognitive function in older adults with MCI, AD or dementia. However, the extent of improvement is modest and not statistically significant, and its clinical relevance remains uncertain. Nevertheless, ginseng could still be considered as a potential therapy for age-related cognitive decline.},
}

@article {pmid41863272,
year = {2026},
author = {Liang, Y and Li, M and Zhang, L and Zhu, R and He, X and Wei, Z},
title = {Akkermansia muciniphila in Central Nervous System Disorders: Mechanisms, Controversies, and Therapeutic Potential.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X419923251231071255},
pmid = {41863272},
issn = {1875-6190},
abstract = {Akkermansia muciniphila (A. muciniphila) is an intestinal mucus-dwelling mucindegrading bacterium that has recently attracted great interest due to its involvement in several metabolic diseases, including obesity, diabetes, and non-alcoholic fatty liver disease. Recent findings have indicated that A. muciniphila plays an important role in central nervous system (CNS) disorders via the microbiota-gut-brain axis (MGBA). This review highlights its dual roles in neuroprotection and pathogenesis, focusing on three key mechanisms, including immunomodulation, metabolic regulation, and barrier reinforcement. Although A. muciniphila has a beneficial role in the treatment of Alzheimer's disease, stroke, and depression, it is controversial for multiple sclerosis and Parkinson's disease because of context-dependent effects. We herein summarize recent progress in an understanding of the complex interplay between A. muciniphila and CNS disorders, highlighting that more work is needed to elucidate this relationship's causality and applicability toward treatment. Finally, we discuss the potential of A. muciniphila as a diagnostic biomarker and a target for nextgeneration probiotics in CNS disease management.},
}

@article {pmid41863273,
year = {2026},
author = {Singh, DD},
title = {PROTAC-Based Therapeutics: From Design to Clinical Potential in Neurodegenerative Disease.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X438970260115164001},
pmid = {41863273},
issn = {1875-6190},
abstract = {Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and ALS, are characterized by a progressive loss of neuronal function and a direct correlation between their progression and proteins with misfolded and aggregated structures. Although significant efforts have been made, and various therapies are available for their treatment, they show only a modest beneficial response to their progression. The main reasons for this phenomenon can be correlated with a loss of target specificity, low permeability in crossing the BBB, and their ineffectiveness in clearing proteins from neurons. Within this therapeutic paradigm, proteolysis-targeting chimaeras, or PROTACS, have been identified as a novel therapeutic strategy. Unlike traditional smallmolecule inhibitors, PROTACS take advantage of the natural ubiquitin proteasome system to specifically degrade target proteins. At a molecular level, PROTACS consist of a ligand that specifically recognizes a target protein, a linker, and an E3 ligand-recruiting ligand that specifically recruits an E3 ligase. At a therapeutic level, this offers the advantage of catalytic protein degradation that should allow for reduced dosing. Preclinical studies carried out using neurodegenerative disease models have shown the potential for selective targeting of major pathologic proteins, such as tau, α- synuclein, TDP-43, and mHTT, which are crucial for pathogenesis. In addition, developments in the formulation of brain-permeable PROTACS, understanding of E3 ligase expression levels in the central nervous system, and application of iPSC-derived neuronal systems have contributed to rapid developments in this area. Although pharmacokinetic modification and degradation-specific approaches are still required, evidence suggests a major therapeutic potential for PROTAC-based approaches for the treatment of neurodegenerative disorders.},
}

@article {pmid41863275,
year = {2026},
author = {Singh, AK and Kush, A and Bhushan, B and Dhanawat, M and Sharma, PK},
title = {Targeting Autophagy with Bioactive Compounds: Therapeutic Potential in Neurodegenerative Disorders.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X408653251130061347},
pmid = {41863275},
issn = {1875-6190},
abstract = {Neurodegenerative disorders (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), are characterized by the accumulation of misfolded proteins and impaired cellular clearance mechanisms. Autophagy, a critical lysosomedependent degradative pathway, plays a vital role in maintaining proteostasis and neuronal health. Dysregulation of autophagy has been implicated in the pathogenesis of multiple NDs, making it a promising therapeutic target. This review comprehensively examines the molecular mechanisms of autophagy and its dysfunction across major NDs. Furthermore, it highlights the potential of bioactive compounds such as flavonoids, alkaloids, polyphenols, and terpenoids to modulate autophagic flux, thereby promoting the clearance of toxic protein aggregates like amyloid-β, tau, and α- synuclein. Emerging strategies, including nanotechnology-based delivery systems, are also discussed for enhancing the bioavailability and efficacy of these compounds. The evidence suggests that pharmacological or natural induction of autophagy may alleviate neurodegenerative pathology, though context- and stage-specific modulation is essential. This work underscores the therapeutic promise of autophagy-enhancing bioactives and calls for further research into their clinical applications.},
}

@article {pmid41863277,
year = {2026},
author = {Ely Arman, NI and Makpol, S},
title = {The Link between Gut Microbiome, Amyloid-Beta Deposition, Brain Inflammation, and Alzheimer's Disease: A Review of Current Literature.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X416900251207210728},
pmid = {41863277},
issn = {1875-6190},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta (Aβ) plaques, neurofibrillary tangles, and cognitive decline. AD has gained increasing global attention. As the aging population continues to grow, the economic burden on individuals, families, and healthcare systems rises, emphasizing the urgent need for early detection and natural therapeutic approaches to address these challenges. The gut microbiota regulates essential physiological functions, including digestion, nutrient absorption, and inflammatory signaling. Dysbiosis, or changes in gut microbiome composition, is marked by the overgrowth of pathogenic bacteria and depletion of beneficial species. Gut dysbiosis is also linked to pathological features of AD, such as increased Aβ deposition, compromised intestinal and blood-brain barrier integrity, and neuroinflammation through the brain-gut microbiome axis (BGMA). However, the connection between the gut microbiome and AD pathological hallmarks remains unclear. This narrative review aims to explore current research on the relationship between gut dysbiosis and the pathological features of AD, with the goal of highlighting the role of the gut system in brain function and AD pathogenesis. Vitamin E, due to its antioxidative and anti-inflammatory properties, may serve as a promising natural option for modulating the gut microbiome while potentially delaying AD progression and promoting a balanced microbial composition.},
}

@article {pmid41863402,
year = {2026},
author = {van Rooij, JR and Vasilkovska, T and Van Spilbeeck, I and Van Audekerke, J and Kosten, L and Bertoglio, D and Verhoye, M},
title = {Resveratrol supplementation and caloric restriction exert sex-specific effects on cerebrovascular function in a rat model of Alzheimer's Disease.},
journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism},
volume = {},
number = {},
pages = {271678X261433498},
doi = {10.1177/0271678X261433498},
pmid = {41863402},
issn = {1559-7016},
abstract = {Cerebrovascular dysfunction, including reduced cerebral blood flow (CBF) and cerebrovascular reactivity (CVR), contributes to Alzheimer's disease (AD). Caloric restriction (CR) and resveratrol (Rsv) benefit vascular health, yet their impact on CBF and CVR in AD remains unclear. Here, we investigated the cerebrovascular effects of 40% CR or Rsv supplementation in WT and TgF344-AD rats. Using pseudo-continuous arterial spin labelling (pCASL) MRI, we observed that male Tg control (Ctrl) rats exhibited reduced relative CBF (rCBF) and absolute CBF (aCBF) in the caudate-putamen at baseline compared to WT Ctrl and Tg Rsv rats, while Rsv restored CBF to WT levels. Male Rsv rats also showed higher rCBF than CR rats in the somatosensory cortex, irrespective of genotype. In the cingulate cortex, male Tg rats had lower rCBF than WT, irrespective of treatment. During hypercapnia, Tg males displayed lower rCBF and aCBF across multiple regions, while Rsv increased rCBF in cingulate cortex and somatosensory cortex, regardless of genotype. In females, treatments did not affect baseline or hypercapnic CBF, although CR and Rsv reduced CVR compared to Ctrl. In summary, these findings suggest Rsv reverses AD-related hypoperfusion in males, whereas CR may impair cerebrovascular responsiveness in females, highlighting the need for sex-specific therapeutic strategies.},
}

@article {pmid41863463,
year = {2026},
author = {Mahavar, A and Patel, A and Patel, A},
title = {Corrigendum to: A Comprehensive Review on Deep Learning Techniques in Alzheimer's Disease Diagnosis.},
journal = {Current topics in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/1568026626999260319151953},
pmid = {41863463},
issn = {1873-4294},
abstract = {In the originally published article entitled "A Comprehensive Review on Deep Learning Techniques in Alzheimer's Disease Diagnosis", published in "Current Topics in Medicinal Chemistry" Vol: 25 Issue: 04 [1], certain phrases and expressions were unclear, which may have affected readability. These have now been revised to improve clarity and ensure that the intended meaning is accurately conveyed. The corrections do not affect the results, interpretations, or conclusions of the article. The original article can be found online at https://www.eurekaselect.com/article/140894 Details of the error and a correction are provided here: ORIGINAL Moreover, DBN is a graphical model that investigators use to obtain a deep hierarchical representation of training data and is frequently used for AD detection. An unsupervised probabilistic Deep Learning Technique is created by pre-training DBN models using the greedy learning approach. From bottom to top, layers of RBMs are stacked to create the DBN architecture. Each RBM layer includes both a visible and concealed layer. The top two levels of the DBN structure have an undirected or symmetric link, whereas the lowest layers have a direct connection. DBN building is comparable to RBM construction in that the first RBM is made through training, after which the weights are fixed, and the concealed layer is established as the RBM's next visible layer. The next RBMs go through this procedure iteratively [79]. CORRECTED Moreover, DBN is a graphical model that investigators use to obtain a deep hierarchical representation of training data and is frequently used for AD detection. An unsupervised probabilistic Deep Learning Technique is created by pre-training DBN models using the greedy learning approach. From bottom to top, layers of RBMs are stacked to create the DBN architecture. Each RBM layer includes both a visible and hidden layer. The top two levels of the DBN structure have an undirected or symmetric link, whereas the lowest layers have a direct connection. DBN building is comparable to RBM construction in that the first RBM is made through training, after which the weights are fixed, and the hidden layer is established as the RBM's next visible layer. The next RBMs go through this procedure iteratively [79]. The authors apologize for any inconvenience caused.},
}

@article {pmid41863469,
year = {2026},
author = {Qi, F and Chen, H and Li, S and Zhang, Y and Chen, X and Wang, A},
title = {From Mechanism to Therapy: Isoliquiritigenin as a Novel Anti-Inflammatory Agent for Inflammatory Disease Management.},
journal = {Endocrine, metabolic & immune disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715303395815250904075148},
pmid = {41863469},
issn = {2212-3873},
abstract = {INTRODUCTION: Accumulating evidence has multilaterally proved the indispensable contribution of inflammation in mediating various diseases over the last decade, including sepsis, obesity, diabetes, and neurological disorders. This established correlation between inflammation and disease progression has positioned anti-inflammatory intervention as a promising therapeutic strategy for disease prevention and treatment. Naturally occurring flavonoids have emerged as a subject of extensive investigation due to their well-documented anti-inflammatory properties and molecular mechanisms. The current review provides a comprehensive analysis of isoliquiritigenin (ISL), a bioactive flavonoid compound isolated from Glycyrrhiza glabra (licorice), with particular emphasis on its pharmacological activities and molecular mechanisms in modulating inflammation- associated disorders.

METHODS: A systematic literature review was executed across the PubMed and Google Scholar electronic databases spanning the period from January 2000 to December 2024, employing the following keyword combination: "isoliquiritigenin" (MeSH) AND "inflammation" (MeSH).

RESULTS: ISL was found to exhibit significant therapeutic potential in mitigating both acute and chronic inflammatory responses. Particular attention was devoted to elucidating ISL's multi-target regulatory mechanisms in acute organ injury models, including neurological, pulmonary, hepatic, and renal systems. Furthermore, the compound's therapeutic effects were found to extend to chronic inflammatory pathologies associated with metabolic and neurodegenerative disorders, notably diabetes mellitus, obesity-related complications, and Alzheimer's disease-associated tissue damage, particularly manifesting in ocular, pulmonary, and cardiovascular systems. Systematic characterization of ISL's molecular targets and associated signalling cascades, like MAPK, JAK/STAT3, Nrf2, and SIRT1 pathways, substantially enhanced our mechanistic understanding of its anti-inflammatory properties.

DISCUSSION: ISL demonstrated extensive protection in many inflammatory models. Its multi-target action implied broad therapeutic applicability. However, despite its excellent anti-inflammatory efficacy and safety profile, further study is required to investigate its effectiveness for clinical translation.

CONCLUSION: This comprehensive analysis has provided a pharmacological foundation for developing ISL-based therapeutic interventions against inflammation-driven human pathologies.},
}

@article {pmid41863516,
year = {2026},
author = {Chen, YC and Liu, Y and Chen, YJ},
title = {Multi-Omics Analysis for Identifying Glial Dysfunction-Associated Genes as Therapeutic Targets and Drug Candidates in Alzheimer's Disease.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {40},
number = {6},
pages = {e71684},
doi = {10.1096/fj.202504184R},
pmid = {41863516},
issn = {1530-6860},
support = {82402158//MOST|National Natural Science Foundation of China (NSFC)/ ; 2023GGA028//| Fujian Provincial Health Technology Project (Provincial Health Technology Project of Fujian Province)/ ; 2022YJRC3862//the Scientific Research Foundation for the Introduction of Talent of the First Affiliated Hospital of Fujian Medical University/ ; },
mesh = {*Alzheimer Disease/genetics/drug therapy/metabolism/pathology ; Humans ; *Neuroglia/metabolism/pathology ; Astrocytes/metabolism/pathology ; Transcriptome ; Machine Learning ; Genome-Wide Association Study ; Oligodendroglia/metabolism ; Multiomics ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, amyloid-β plaques, and neurofibrillary tangles. It's underlying mechanisms remain unclear and no disease-modifying therapies are currently available. Recent evidence has highlighted glial function as crucial factors in AD pathogenesis. Therefore, in this study, we aimed to find key AD-relevant cell populations and genes involved in glial function as well as potential therapeutic compounds. Single-cell transcriptomic data (GSE157827) and GWAS summary statistics (ieu-b-5067) were integrated using scPagwas to identify AD-associated cell subtypes and genes. Machine learning and ROC analyses were applied to refine and validate key genes, which were used to construct a diagnostic nomogram. Gene set enrichment, immune infiltration, and drug prediction analyses were performed, and the single-cell expression and pseudotime trajectories of key genes were further examined. Through scPagwas analysis, we identified oligodendrocytes and astrocytes as the major cell types associated with AD genetic risk, and revealed 27 candidate genes enriched in glial development and function, among which QKI and ZBTB20 ranked highest. Machine learning algorithms and validation across multiple independent datasets further identified QKI, ZBTB20, and C10orf90 as the key candidate genes. Single-cell analyses confirmed high expression of these genes in oligodendrocytes and astrocytes, and their dynamic, stage-associated expression patterns along glial differentiation trajectories. Drug-gene interaction and molecular docking analyses identified retinoic acid as a potential therapeutic compound targeting QKI and ZBTB20. Our findings highlighted that oligodendrocytes and astrocytes play a key role in the development of AD and provide new perspectives for future therapeutic strategies.},
}

*Alzheimer Disease/genetics/drug therapy/metabolism/pathology
Humans
*Neuroglia/metabolism/pathology
Astrocytes/metabolism/pathology
Transcriptome
Machine Learning
Genome-Wide Association Study
Oligodendroglia/metabolism
Multiomics

@article {pmid41863579,
year = {2026},
author = {Gupta, T and Kumar, S and Singh, TG and Singh, R},
title = {The metabolic roots of memory loss: interlinking the Diabetes-Alzheimer's hypothesis.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {41863579},
issn = {1573-7365},
}

@article {pmid41863580,
year = {2026},
author = {Shreya, and Singh, G and Hunjan, G and Aran, KR},
title = {Role of LncRNA NEAT1 in Alzheimer's Disease: Pathophysiological Insights and Therapeutic Approaches.},
journal = {Neurotoxicity research},
volume = {44},
number = {2},
pages = {},
pmid = {41863580},
issn = {1476-3524},
}

@article {pmid41863585,
year = {2026},
author = {Yeh, PY and Liao, RM and Chang, HY and Lin, WT and Chen, YZ and Lane, HY and Lin, CH},
title = {Gender-specific effects of sodium benzoate on cognitive improvement in individuals with dementia: a meta-analysis of randomized controlled trials.},
journal = {European archives of psychiatry and clinical neuroscience},
volume = {},
number = {},
pages = {},
pmid = {41863585},
issn = {1433-8491},
support = {NHRI-EX113-11133NI//National Health Insurance Administration/ ; NSTC 113-2622-B-039-003//National Science and Technology Council/ ; MOST 111-2314-B-182A-024 -MY3//National Science and Technology Council/ ; DMR-HHC-113-11 and DMR-113-211//China Medical University Hospital/ ; NHRI-EX111-10816NC//National Health Research Institutes/ ; CMRPG8M1311//Chang Gung Memorial Hospital/ ; },
abstract = {BACKGROUND: Previous double-blind randomized controlled trials (RCTs) have shown that sodium benzoate, a D-amino acid oxidase inhibitor enhancing D-serine availability and NMDA receptor-mediated function, is able to improve cognition in patients with cognitive decline. Accordingly, this study aimed to compare cognitive outcomes between patients receiving sodium benzoate and those receiving placebo.

METHODS: Following the PRISMA guidelines, this meta-analytic study utilized appropriate keyword strings to systematically search the PubMed, Embase, and Cochrane databases for RCTs published in all languages from inception to June 2024. Included criteria were: (1) patients aged 50 or older; (2) those diagnosed with dementia (probable Alzheimer's disease or vascular dementia) or those with mild cognitive impairment (MCI) having a clinical dementia rating score of 0.5; (3) RCTs comparing the effect of benzoate treatment with that of placebo controls; and (4) the use of cognitive tests as therapeutic effect outcomes.

RESULTS: Of 351 articles screened, five RCTs were included (246 sodium benzoate, 178 placebo; mean age 72.6 years; mean education 6.01 years; 62% female). The overall effect size for the therapeutic effect of sodium benzoate on cognitive improvement was significant (p = 0.02), with females outperforming males (p = 0.02). Additionally, regression analysis found the cognitive outcome generated from sodium benzoate was not influenced by the use of anti-dementia medication.

CONCLUSION: Our findings highlighted a better understanding of the effect of sodium benzoate on cognitive improvement, particularly in female patients with MCI and dementia.},
}

@article {pmid41863595,
year = {2026},
author = {Ji, J and Li, Z and Xing, A and Luo, G and Zhai, X and Xu, W and Li, J and Tan, T and Jia, R and Yan, Y and Zhang, X and Wang, L and Li, J and Li, K},
title = {Causal relationships between alzheimer's disease genetics and brain connectivity alterations: a multi-modal mendelian randomization study with transcriptomic validation of 191 rs-fMRI and 635 DTI neuroimaging traits.},
journal = {Brain imaging and behavior},
volume = {20},
number = {2},
pages = {},
pmid = {41863595},
issn = {1931-7565},
support = {2023XM016//Four "Batches" Innovation Project of Invigorating Medical through Science and Technology of Shanxi Province/ ; 0033/2023/RIB2//The Science and Technology Development Funds of Macao/ ; RP/FCA-14/2023//a Grant from Macao Polytechnic University/ ; },
}

@article {pmid41863628,
year = {2026},
author = {Mure, LS},
title = {Modern lights on neuropathology of Alzheimer's Disease.},
journal = {Sleep},
volume = {},
number = {},
pages = {},
doi = {10.1093/sleep/zsag080},
pmid = {41863628},
issn = {1550-9109},
}

@article {pmid41863703,
year = {2026},
author = {Al-Kuraishy, HM and Jabir, MS and Rafeeq, MF and Sulaiman, GM and Albuhadily, AK and Al-Gareeb, AI},
title = {Targeting of neuroinflammation, oxidative stress, and synaptic dysfunction by vinpocetine in alzheimer's disease: a comprehensive appraisal.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {41863703},
issn = {1573-7365},
}

@article {pmid41863761,
year = {2026},
author = {Bhardwaj, V and Goel, F and Rajput, MS},
title = {Targeting oxidative stress and neurodegeneration: the role of Putranjiva roxburghii in Alzheimer's.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {41863761},
issn = {1568-5608},
abstract = {AD is a complex neurodegenerative disease that leads to progressive memory loss, worsening cognitive abilities, and synaptic dysfunction. The pathophysiology of the disease is driven by oxidative stress and neuroinflammation, which cause neuronal damage and may facilitate amyloid-beta aggregation and tau hyperphosphorylation. Current treatment strategies provide symptomatic improvement but do not address the multifactorial causes of the disease; therefore, multi-targeted approaches are critical. Putranjiva roxburghii is a medicinal plant with a wealth of ethnomedicinal literature from India. It contains a variety of phytochemicals, including flavonoids, lignans, glycosides, and triterpenoids, that collectively exhibit antioxidant, anti-inflammatory, and neuroprotective effects. Preclinical studies suggest that it can scavenge ROS, decrease LPO, modulate cholinergic systems, and interfere with amyloid and tau pathology, supporting potential cognitive benefits. Notwithstanding the promising potential of these findings, challenges remain, including variable extraction methods, limited pharmacokinetic information, and the absence of clinical validation, which are obstacles to translation. This manuscript provides a limited examination of the phytochemical profile, neuroprotective mechanisms, and potential therapeutic applications in Alzheimer's disease (AD) attributed to P. roxburghii, and highlights the necessity for standardized formulations, molecular docking methodology, and rigorously designed clinical studies to determine its efficacy and safety in humans.},
}

@article {pmid41864041,
year = {2026},
author = {El Bakali, J and Ronco, C and Landry, V and Papavasileiou, KD and Papadourakis, M and Warenghem, S and Leroux, F and Charton, J and Dumont, J and Piveteau, C and Staels, B and Afantitis, A and Hennuyer, N and Deprez, B and Bosc, D and Deprez-Poulain, R},
title = {Discovery of pyrimidine-based small activators of insulin degrading enzyme.},
journal = {European journal of medicinal chemistry},
volume = {309},
number = {},
pages = {118740},
doi = {10.1016/j.ejmech.2026.118740},
pmid = {41864041},
issn = {1768-3254},
abstract = {Insulin-Degrading Enzyme IDE, a zinc metalloprotease that has been associated with Alzheimer 's disease, metabolic diseases and cancer, is an attractive target. Its complex structure, substrate preferences, non-catalytic activities require the development of modulators of this enzyme. While several potent inhibitors are now available, we still lack activators for both in vitro and in vivo explorations of IDE functions and potential application in Alzheimer 's disease. Here we describe the discovery of an original pyrimidine-based series of IDE activators by screening and its structure-activity relationships. Docking studies suggest that compounds may bind the IDE dimer interface, and sterically increase IDE catalytic activity. In vitro and in vivo activities of best activator are consistent with an increase in insulin hydrolysis by IDE in the presence of the activator BDM71230. This compound can serve as a pharmacological tool to explore this intriguing enzyme.},
}

@article {pmid41864079,
year = {2026},
author = {Grzelczyk, J and Pérez-Sánchez, H and Carmena-Bargueño, M and Gałązka-Czarnecka, I and Budryn, G and Hernik, D and Brenna, E and Boratyński, F},
title = {Acetylcholine-protective activity of chemo-enzymatically synthesized aryl vicinal diols and hydroxy ketones.},
journal = {Bioorganic chemistry},
volume = {175},
number = {},
pages = {109770},
doi = {10.1016/j.bioorg.2026.109770},
pmid = {41864079},
issn = {1090-2120},
abstract = {Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are the main enzymes responsible for the development and progression of Alzheimer's disease (AD). AChE and BChE hydrolyze acetylcholine (ACh), disrupting its management in neurotransmitters. In order to prevent and alleviate the symptoms of AD, the use of new compounds, chemo-enzymatically synthesized in environmentally friendly method from propenylbenzene derivatives as AChE and BChE inhibitors has been proposed. Molecular modeling and isothermal titration calorimetry were used to determine the AChE and BChE inhibition parameters. It has been observed that diols and hydroxy ketones have a significant inhibitory effect. In particular, 1-(4-hydroxy-3-methoxyphenyl)propane-1,2-diol showed inhibitory effects in both research models. The results indicate that diols and hydroxy ketones bind to AChE and BChE at the active site. This further suggests that these compounds could potentially be used in supplements or functional foods to prevent AD.},
}

@article {pmid41864176,
year = {2026},
author = {Li, J and Zhang, H and Zhou, X and Wang, Y and Wei, C and Yan, H and Wang, J},
title = {Molecular insights into SEN177 binding to human glutaminyl cyclase: a combined MD and DFT study.},
journal = {Journal of molecular graphics & modelling},
volume = {145},
number = {},
pages = {109372},
doi = {10.1016/j.jmgm.2026.109372},
pmid = {41864176},
issn = {1873-4243},
abstract = {Aberrant upregulation of human glutaminyl cyclase (hQC) is associated with the onset and progression of neurodegenerative disorders, notably Alzheimer's disease and Huntington's disease. Consequently, inhibition of hQC activity represents a potential avenue for treatment. SEN177, a potent small-molecule hQC inhibitor, has demonstrated notable preclinical efficacy but its binding mechanism remains incompletely understood. Herein, an integrated computational investigation was performed to elucidate the molecular basis of SEN177-hQC recognition. Notably, we implemented an integrated MD-energy decomposition-DFT scheme to rationalize the molecular mechanism of SEN177-hQC recognition. Molecular dynamics simulations indicated that SEN177 binding constrained the intrinsic conformational mobility of hQC, thereby stabilizing the protein-ligand complex. Energy decomposition analyses indicated that the P1 pharmacophore contributed significantly to binding affinity, with key interactions involving hotspot residues D159, E201, E202, W207, and L249. Complementary DFT analyses identified the frontier molecular orbitals and mapped electrophilic and nucleophilic regions that facilitated specific noncovalent contacts. Collectively, these results provide detailed mechanistic insight into the interaction landscape of SEN177 with hQC and provide a conceptual framework for designing more potent and selective hQC-targeting agents.},
}

@article {pmid41864190,
year = {2026},
author = {Tosun, S and Karalı, FS and Eskioğlu, Eİ and Çınar, N and Macoir, J},
title = {Linguistic vulnerabilities in mild cognitive impairment: Evidence from the DTLA-Tr screening battery.},
journal = {Cortex; a journal devoted to the study of the nervous system and behavior},
volume = {198},
number = {},
pages = {182-190},
doi = {10.1016/j.cortex.2026.03.007},
pmid = {41864190},
issn = {1973-8102},
abstract = {Mild Cognitive Impairment (MCI) represents a transitional stage between normal aging and dementia and is associated with an increased risk of progression to Alzheimer's disease. Conventional cognitive screening tools provide limited sensitivity for detecting subtle language impairments that may emerge in the earliest phases of neurodegeneration. This study aimed to evaluate the discriminative validity of the Turkish adaptation of the Detection Test for Language Impairments in Adults and the Aged (DTLA-Tr) in identifying language deficits in individuals with MCI. The sample comprised 110 participants, including 55 individuals with MCI and 55 age-, education-, and gender-matched healthy controls. All participants completed the Montreal Cognitive Assessment Turkish version (MoCA-Tr), Boston Naming Test Turkish Version (BNT-Tr), and DTLA-Tr following a fixed administration order. Group differences were analyzed using non-parametric tests and mixed-effects modelling. Discriminative performance of the DTLA-Tr Total Score was evaluated using ROC curve analysis. Individuals with MCI demonstrated significantly lower performance across multiple DTLA-Tr subtests, particularly in Repetition, Verbal Fluency, Alpha Span, Reading, and Semantic Matching. The DTLA-Tr Total Score showed fair discriminative accuracy for MCI (AUC = .69). The optimal cut-off (≤82) yielded a sensitivity of .44 and specificity of .85, indicating stronger specificity than sensitivity. The findings suggest that DTLA-Tr is a culturally appropriate and clinically useful tool for detecting language-related cognitive decline in MCI. Although its sensitivity remains modest, its multidimensional structure captures linguistic impairment.},
}

@article {pmid41864219,
year = {2026},
author = {Ashton, NJ},
title = {Biologically informed blood testing in Alzheimer's disease.},
journal = {The Lancet. Neurology},
volume = {25},
number = {4},
pages = {327-329},
doi = {10.1016/S1474-4422(26)00092-X},
pmid = {41864219},
issn = {1474-4465},
}

@article {pmid41864233,
year = {2026},
author = {Mattsson-Carlgren, N and Palmqvist, S and Horie, K and Barthélemy, N and Salvadó, G and Binette, AP and Tideman, P and Morris, JC and Benzinger, TL and Perrin, RJ and Janelidze, S and Collij, LE and Ossenkoppele, R and Schindler, SE and Stomrud, E and Bateman, RJ and Hansson, O},
title = {Integration of plasma eMTBR-tau243 and p-tau217 in the diagnosis and stratification of Alzheimer's disease: a prospective cohort study.},
journal = {The Lancet. Neurology},
volume = {25},
number = {4},
pages = {357-367},
doi = {10.1016/S1474-4422(26)00029-3},
pmid = {41864233},
issn = {1474-4465},
mesh = {Humans ; *tau Proteins/blood ; Female ; Male ; *Alzheimer Disease/blood/diagnosis ; Biomarkers/blood ; Aged ; Prospective Studies ; Middle Aged ; *Cognitive Dysfunction/blood/diagnosis ; Aged, 80 and over ; Cohort Studies ; },
abstract = {BACKGROUND: Alzheimer's disease pathology can be accurately identified with blood biomarkers (core 1 biomarkers), including plasma p-tau217 tests. Biomarkers that change longitudinally after diagnosis (core 2 biomarkers) can increase confidence that Alzheimer's disease pathology is contributing to cognitive symptoms. Plasma eMTBR-tau243 reflects tau tangle pathology and is a promising core 2 biomarker. We aimed to examine whether, among patients positive for plasma p-tau217, plasma eMTBR-tau243 improves classification of established Alzheimer's disease and predicts cognitive decline and tau tangle accumulation.

METHODS: In this prospective cohort study, we included adults aged 40 years or older with subjective cognitive decline, mild cognitive impairment, or dementia, based on cognitive test results and clinical assessments, consecutively recruited at two memory clinics in Sweden, as part of the Swedish BioFINDER-2 study. Data were collected prospectively specifically for the purposes of this study. We validated our findings in a cohort of patients from the Knight Alzheimer Disease Research Center (ARDC), which included individuals determined to be cognitively unimpaired or to have cognitive impairment. Using mass spectrometry techniques, plasma p-tau217 was measured as a ratio to a non-phosphorylated peptide (%p-tau217), and eMTBR-tau243 was measured as a concentration. A priori derived thresholds for positivity were used. The primary outcome was established Alzheimer's disease based on both Alzheimer's disease pathology-specific CSF or PET biomarkers and clinical assessment, in accordance with the International Working Group definition. This study was registered with ClinicalTrials.gov, NCT03174938.

FINDINGS: Between May 18, 2017, and Sept 8, 2023, we enrolled 572 patients with cognitive symptoms (142 with subjective cognitive decline, 259 with mild cognitive impairment, and 171 with dementia). 291 (51%) of 572 patients were female and 281 (49%) were male. All potentially eligible participants were included. Follow-up data collection was done until Sept 9, 2024. 350 (61%) of 572 patients had positive plasma %p-tau217. Among these, 341 (97%) were amyloid β (Aβ)-positive by CSF biomarkers or PET and 199 (57%) had established Alzheimer's disease (positive predictive value [PPV] 57%, 95% CI 51-61, for %p-tau217 alone). 194 (55%) of 350 %p-tau217-positive patients were also positive for eMTBR-tau243, with an accuracy of 81% (95% CI 76-84), PPV 84% (95% CI 78-88), negative predictive value (NPV) 77% (95% CI 68-82), and sensitivity 82% (95% CI 76-87) for established Alzheimer's disease, in cross-sectional analyses. Findings were similar in the validation cohort. Positive eMTBR-tau243 was associated with worse longitudinal cognitive decline and longitudinal tau tangle accumulation in %p-tau217 positive patients. Among %p-tau217 positive individuals, eMTBR-tau243 had an accuracy of 87%, PPV 76%, and NPV 90% in identifying individuals with high tau-PET load.

INTERPRETATION: Plasma %p-tau217 can confirm Aβ-positivity, while eMTBR-tau243 can confirm clinically symptomatic Alzheimer's disease. Initial testing with %p-tau217 followed by eMTBR-tau243 in %p-tau217-positive patients could help assess whether Alzheimer's disease pathology is causing symptoms. Plasma eMTBR-tau243 might also help in determining the severity of tau tangle burden, which could be useful in guiding therapeutic decisions.

FUNDING: National Institute of Aging, European Research Council, Alzheimer's Association, GHR Foundation, Swedish Research Council, ERA PerMed, Knut and Alice Wallenberg foundation, Strategic Research Area MultiPark at Lund University, Swedish Alzheimer Foundation, Swedish Brain Foundation, Parkinson foundation of Sweden, Cure Alzheimer's fund, Rönström Family Foundation, Berg Family Foundation, Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse, Skåne University Hospital Foundation, Michael J Fox Foundation, Lilly Research Award Program, Regionalt Forskningsstöd (Södra sjukvårdsregionen), Wallenberg AI; Autonomous Systems and Software Program and Data-Driven Life Science joint call for research projects, Greta and Johan Kock Foundation, and Swedish federal Government under the ALF agreement.},
}

Humans
*tau Proteins/blood
Female
Male
*Alzheimer Disease/blood/diagnosis
Biomarkers/blood
Aged
Prospective Studies
Middle Aged
*Cognitive Dysfunction/blood/diagnosis
Aged, 80 and over
Cohort Studies

@article {pmid41864298,
year = {2026},
author = {Olmsted, ZT and Sofroniew, MV},
title = {APP as an innate injury-response molecule.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107361},
doi = {10.1016/j.nbd.2026.107361},
pmid = {41864298},
issn = {1095-953X},
abstract = {Amyloid precursor protein (APP) is best known as the percussor for amyloid beta (Aβ), a hallmark of pathology in Alzheimer's disease and related disorders. Nevertheless, APP did not likely evolve to serve this purpose. This article reviews available evidence for functions of APP and its enzymatically generated proteolytic derivatives, sAPPα, CTFα, sAPPβ, CTFβ, p3 peptide, AICD, and Aβ. These functions include not only effects on the development and function of neurons in the central nervous system (CNS), but also innate roles in the response to diverse types of cell and tissue injury in multiple mammalian organ systems including the CNS. These responses include regulation or modulation of hemostasis, inflammation, glial cell functions, antimicrobial defense, and wound healing. We examine how dual, naturally occurring APP roles regarding both neuronal function and injury response, may relate to, and in some cases predispose to, APP-related effects in CNS neurodegenerative disorders.},
}

@article {pmid41864364,
year = {2026},
author = {Paidlewar, M and Kumari, S and Dhapola, R and Sharma, P and Vellingiri, B and Medhi, B and HariKrishnaReddy, D},
title = {PANoptosis in Alzheimer's disease: The expanding landscape of programmed cell death mechanisms and therapeutic interventions.},
journal = {Free radical biology & medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.freeradbiomed.2026.03.053},
pmid = {41864364},
issn = {1873-4596},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia in elderly people, marked by the accumulation of amyloid-β plaques and neurofibrillary tangles, resulting in neurodegeneration and cognitive decline. Emerging evidence identifies PANoptosis, a lytic form of programmed cell death that integrates pyroptosis, apoptosis and necroptosis as a central driver of AD progression. PANoptosis is orchestrated by multiprotein PANoptosome complexes such as RIPK1, AIM2, ZBP1 and NLRP12, which are activated by caspases, receptor- interacting protein kinases and innate immune stimuli including pathogen associated molecular pattern and damage associated molecular pattern. In AD, Aβ and tau aggregates activate inflammasomes, trigger mitochondrial dysfunction associated oxidative stress, and provoke chronic neuroinflammation, resulting in sustained PANoptotic cell death. Dysregulation of signalling pathways, including cGAS-STING, PI3K/ AKT, JAK/STAT/IRF1, and p38/ERK/JNK MAPK contribute to PANoptosis by enhancing inflammation, free radical generation, mitochondrial damage, synaptic impairment, and BBB disruption. Preclinical studies on compounds like celasterol, magnoflorin, calycosin, and liproxstatin-1, along with clinical trials on the drugs including nicotinamide riboside, barcitinib, dexmeditomidine, and semaglutide, suggest a neuroprotective potential by modulating PANoptotic pathways. This review underscores PANoptosis as a critical pathological mechanism in AD and highlights novel therapeutic avenues aimed at disrupting this cell death program to mitigate AD progression.},
}

@article {pmid41864514,
year = {2026},
author = {Wang, B and Cheng, K and Chen, Z and Chen, Y and Wang, Z and Ni, J},
title = {Transcranial Ultrasound Stimulation and Vagus Nerve Stimulation: Potential Therapeutic Strategies for Alzheimer's Disease.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111837},
doi = {10.1016/j.brainresbull.2026.111837},
pmid = {41864514},
issn = {1873-2747},
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder with limited efficacy from existing medications and conventional neuromodulation therapies. In recent years, emerging neuromodulation techniques have demonstrated promising therapeutic potential. This review focuses on exploring the therapeutic value of transcranial ultrasound stimulation (TUS) and vagus nerve stimulation (VNS) for AD. We systematically review the evidence for these techniques in AD basic research and clinical practice, elucidating their unique mechanisms of action. The review further contrasts the advantages of TUS and VNS over traditional AD therapies and explores their potential for synergistic application with conventional treatments. Finally, we propose future research directions, including combined VNS and TUS treatment strategies based on complementary mechanisms, aiming to provide theoretical foundations for developing multi-targeted, personalized AD therapies.},
}

@article {pmid41864543,
year = {2026},
author = {Wu, J and Ma, H and Niu, X and Zhang, Z and Guo, R and Shen, N and Tian, Y and Zhao, H and Yang, Y and Chen, Y},
title = {The p75NTR Signaling Axis: Bridging Neurodevelopmental Homeostasis, Pathological Mechanisms, and Therapeutic Strategies in Neurodegenerative Diseases.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103105},
doi = {10.1016/j.arr.2026.103105},
pmid = {41864543},
issn = {1872-9649},
abstract = {The neurotrophin receptor p75 (p75NTR) plays dual, context-dependent roles in the nervous system that are regulated by ligand binding, co-receptor interactions, and microenvironmental cues. During neurodevelopment, synaptic plasticity, and in neurodegenerative disorders, p75NTR orchestrates opposing cellular responses: it can support neuronal homeostasis through pro-survival pathways, while also initiating apoptotic and inflammatory cascades that exacerbate disease progression. In Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), activation of p75NTR drives pathological processes such as neuronal apoptosis and axonal degeneration, leading to impaired cognitive and motor function.Importantly, different structural domains of p75NTR have divergent effects. The extracellular domain (p75ECD) exhibits neuroprotective properties in AD models, in contrast with the pro-apoptotic activity associated with the full-length receptor. Therapeutic targeting of p75NTR with small-molecule ligands and ROCK inhibitors has shown efficacy in preclinical models, and some candidates have progressed to clinical trials. However, several challenges hinder clinical translation: (1) the mechanisms underlying p75NTR upregulation are not fully understood; (2) its downstream signaling network is highly complex; and (3) existing biomarker systems remain limited.A comprehensive understanding of p75NTR's role in neurodegeneration may clarify pathological mechanisms and reveal novel therapeutic targets. Achieving this will require multidisciplinary collaboration to bridge the gap between basic research and clinical applications.},
}

@article {pmid41864723,
year = {2026},
author = {Erkayıran, O and Çelik, D},
title = {Spirituality, culture, and family resilience in Alzheimer's care: A qualitative descriptive study in Türkiye.},
journal = {Archives of psychiatric nursing},
volume = {60},
number = {},
pages = {152050},
doi = {10.1016/j.apnu.2025.152050},
pmid = {41864723},
issn = {1532-8228},
mesh = {Humans ; *Alzheimer Disease/nursing ; *Spirituality ; *Caregivers/psychology ; Qualitative Research ; Female ; *Resilience, Psychological ; Turkey ; Middle Aged ; Aged ; Adaptation, Psychological ; *Family/psychology ; Interviews as Topic ; *Culture ; },
abstract = {BACKGROUND: Family caregivers of people with Alzheimer's disease face escalating practical and emotional demands. In collectivist settings, caregiving is also shaped by cultural values and spiritual meaning, yet these dimensions remain underexamined in psychiatric nursing contexts.

OBJECTIVE: To describe how spirituality, cultural norms, and personal meaning-making contribute to family resilience among Turkish female caregivers of relatives with Alzheimer's disease, and to outline implications for psychiatric and geriatric nursing practice.

METHODS: We conducted a qualitative descriptive study in Karaman, Türkiye, using purposive sampling in collaboration with the Provincial Directorate of Family and Social Services. Fourteen female family caregivers participated in audio-recorded, semi-structured, face-to-face interviews (30-90 min) conducted in Turkish in participants' homes. Data were transcribed verbatim and analyzed using reflexive thematic analysis. Reporting followed COREQ guidelines.

RESULTS: Analysis revealed six interrelated themes reflecting how Turkish caregivers sustain resilience in Alzheimer's care: collective adaptation within the family, spirituality as an emotional anchor, cultural expectations and moral meaning, personal growth and inner strength, endurance and emotional sacrifice, and hope and acceptance of uncertainty. Together, these themes illustrate a culturally embedded model of resilience in which caregiving is experienced not only as a demanding role but as a meaningful act of faith, moral duty, and emotional transformation.

CONCLUSIONS: Caregiving was experienced as a morally and spiritually meaningful family role that fostered resilience while also generating value tensions. Psychiatric and geriatric (geropsychiatry) nurses should incorporate spiritual assessment, culturally congruent care planning, and support for moral distress into routine caregiver care. These findings offer practice-ready guidance for tailoring caregiver support in culturally traditional contexts.},
}

Humans
*Alzheimer Disease/nursing
*Spirituality
*Caregivers/psychology
Qualitative Research
Female
*Resilience, Psychological
Turkey
Middle Aged
Aged
Adaptation, Psychological
*Family/psychology
Interviews as Topic
*Culture

@article {pmid41864794,
year = {2026},
author = {Fan, SP and Liu, PC and Wang, JZ and Win, NN and Lin, CH and Lin, HH},
title = {Epidemiological burden of Alzheimer's and Parkinson's diseases in East Asia: A comparative review of global burden of disease estimates and national registry data.},
journal = {Journal of the Formosan Medical Association = Taiwan yi zhi},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jfma.2026.03.072},
pmid = {41864794},
issn = {0929-6646},
abstract = {East Asia is navigating a period of unprecedented demographic aging, with neurodegenerative disorders like Alzheimer's disease and other dementias (ADODs) and Parkinson's disease (PD) emerging as primary public health challenges. Utilizing Global Burden of Disease (GBD) 2021 data, this review evaluates the longitudinal epidemiological trends in Taiwan compared to neighboring East Asian countries. We found that while ADODs remained relatively stable in most regions, Taiwan exhibited a recent increase in mortality and disability-adjusted life years (DALY). Notably, ADODs DALY trends are primarily driven by years of life lost (YLL) rather than years lived with disability (YLD), reflecting GBD's methodological emphasis on mortality at advanced ages. Conversely, PD showed an increasing trend on epidemiologic features across the region, with Taiwan exhibiting the highest health burden. Unlike ADODs, PD DALY in Taiwan are more closely aligned with YLD, suggesting that advancements in healthcare quality and prolonged life expectancy have extended the duration of lived disability. These divergent trajectories underscore the complex interplay between national health policies, socioeconomic factors, and environmental risks. We conclude that addressing the escalating burden of neurodegenerative disorders requires a transition toward data-driven, precision public health interventions and equitable resource allocation to ensure healthcare resilience in super-aged societies.},
}