Alzheimer's & Dementia最新文献

{"title":"A murine model of amyloid enhanced tauopathy: progressive changes in tau pathology and behavior","authors":"Dylan J. Finneran,&nbsp;Taylor Desjarlais,&nbsp;Brianna M. Jackman,&nbsp;David Morgan,&nbsp;Marcia N. Gordon","doi":"10.1002/alz.71839","DOIUrl":"10.1002/alz.71839","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> BACKGROUND</h3>\u0000 \u0000 <p>Our prior work demonstrated systemic P301L-tau injections in mice with mature amyloid resulted in several-fold enhancement of tauopathy compared to non-transgenic (NTg) littermates.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>APP+PS1 mice were injected intravenously with AAV.CAP-B10 expressing P301L tau (A/P+P301L). Mice were tested behaviorally and tissues collected for measurement of amyloid and tau pathology.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>A/P+P301L mice have greater spatial navigation memory impairments than control APP+PS1 mice, or AAV-tau injected NTg mice. Tau phosphorylation and deposition increased from 5 to 9 months after injection, culminating in numerous Gallyas-positive presumptive neurofibrillary tangles.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>In this model of amyloid-enhanced tauopathy, tau pathology acts synergistically with amyloidosis to exacerbate cognitive impairments compared to amyloid-only mice. The tauopathy is progressive, with more severe behavioral impairments and neurofibrillary deposits at longer survival times. The temporal staging of pathology in this model resembles that of Alzheimer's disease and may be useful for interrogating the linkage between amyloid and tau pathology.</p>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"22 10","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.71839","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149087407","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A murine model of amyloid‐enhanced tauopathy: Comparison of wild‐type and P301L‐tau","authors":"Dylan J. Finneran, Taylor Desjarlais, Brianna M. Jackman, Marcia N. Gordon, David Morgan","doi":"10.1002/alz.71788","DOIUrl":"https://doi.org/10.1002/alz.71788","url":null,"abstract":"INTRODUCTION To optimize a model of amyloid‐enhanced tauopathy we compared wild‐type (WT) tau with P301L‐tau in a mouse with mature amyloid. METHODS Mice transgenic for amyloid precursor protein and presenilin‐1 (APP+PS1, A/P) were injected intravenously with adeno‐associated virus with capsid B10 (AAV.CAP‐B10) expressing either WT or P301L human tau. Mice were behaviorally assessed 5 and 8 months and tissue collected 9 months after injection. RESULTS A/P+WT and A/P+P301L groups were equivalently impaired in spatial learning and memory. A/P+WT mice had significantly greater tau hyperphosphorylation than A/P+P301L mice. However, A/P+P301L mice had greater deposition of phospho‐tau and formation of Gallyas‐positive neurofibrillary tangles (NFTs). DISCUSSION These data demonstrate that WT‐tau is more highly phosphorylated than P301L‐tau in the presence of amyloid in mouse brain. Furthermore, despite the lack of NFT pathology in A/P+WT mice, WT‐tau still caused cognitive impairment. The use of WT‐tau in this model may make it more translatable for pre‐clinical assessments of potential therapeutics for AD.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"13 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149087524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Longitudinal untargeted metabolomics of cognitive impairment in Parkinson's disease","authors":"Yuyuan Lin,&nbsp;Yu Yu,&nbsp;Keren Zhang,&nbsp;Irish Del Rosario,&nbsp;Aline Duarte Folle,&nbsp;Elizabeth Rose Mayeda,&nbsp;Dean P. Jones,&nbsp;Douglas I. Walker,&nbsp;Jeff Bronstein,&nbsp;Adrienne M. Keener,&nbsp;Kimberly C. Paul,&nbsp;Beate Ritz","doi":"10.1002/alz.71890","DOIUrl":"10.1002/alz.71890","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Cognitive impairment is a common non-motor symptom of Parkinson's disease (PD), yet the mechanism remains unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>Longitudinal serum samples from PD patients in a community-based case–control study were profiled, with cognition assessed by the Mini-Mental State Examination at baseline and follow-up. We performed three metabolome-wide association studies: a baseline cross-sectional analysis (<i>n</i> = 632), a time-to-event analysis (<i>n</i> = 412), and a repeated measures analysis (<i>n</i> = 265), followed by “Mummichog” pathway analysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Of the 4762 metabolomic features, four reached statistical significance in the baseline analysis, 22 in the time-to-event analysis, and none in the repeated measures analysis. Dysregulated pathways included purine metabolism, the pentose phosphate pathway, fatty acid pathways, and C21-steroid hormone biosynthesis and metabolism.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>Disruptions in core metabolic pathways may contribute to PD-related cognitive impairments. Disturbances in pentose and purine pathways may occur before clinical cognitive decline is observed, suggesting early metabolic markers.</p>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"22 10","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.71890","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149087408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cell‐based polygenic risk scores predict clinical progression and prioritize network‐based therapeutic targets in Alzheimer's disease","authors":"Nathan Sahelijo, Priya Rajagopalan, Lu Qian, Rufuto Rahman, Daniel Goldstein, Sophia I. Thomopoulos, David A. Bennett, Lindsay A. Farrer, Thor D. Stein, Li Shen, Heng Huang, Kwangsik Nho, Andrew J. Saykin, Christos Davatzikos, Paul M. Thompson, Julia TCW, Gyungah R. Jun","doi":"10.1002/alz.71895","DOIUrl":"https://doi.org/10.1002/alz.71895","url":null,"abstract":"BACKGROUND Late‐onset Alzheimer's disease (AD) exhibits substantial biological heterogeneity. We developed a framework linking cell‐type–specific polygenic risk profiles to precision medicine in AD. METHODS Cell‐based polygenic risk scores (cbPRSs) derived from single‐nucleus RNA‐seq co‐expression networks were evaluated in Alzheimer's Disease Neuroimaging Initiative (ADNI) and Framingham Heart Study (FHS) cohorts. Network hubs were prioritized using a graph‐based PageRank algorithm and candidate drugs were validated in human‐induced pluripotent stem cell (hiPSC)–derived astrocytes. RESULTS Cell‐based PRS analysis identified two genetic risk axes independent of network cell‐type labels: an apolipoprotein E ( <jats:italic>APOE</jats:italic> )–concentrated axis (Ast‐M2/Oli‐M45) and an <jats:italic>APOE</jats:italic> ‐independent axis (Ast‐M10/Oli‐M50), which predicted accelerated progression to AD (hazard ratio: 1.25–2.02) and correlated with localized temporal lobe atrophy, reduced glucose metabolism, and global amyloid burden. High‐risk status specifically upregulated complement C4a protein expression in postmortem brains. PageRank network analysis identified four candidate drugs targeting the <jats:italic>APOE</jats:italic> ‐containing astrocyte network. Experimental treatment with estradiol and levetiracetam significantly reduced <jats:italic>APOE</jats:italic> and complement <jats:italic>C4</jats:italic> gene expression in hiPSC‐derived astrocytes. DISCUSSION By integrating cell‐based genetic risk with network‐level target prioritization, this framework enables robust patient stratification and experimental target validation.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"15 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149087409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cognitive impairment in Parkinson disease correlates with loss of cholinergic axon projections to cortex in an autopsy study","authors":"Rebecca Miller, Jennifer O'Shea, Laura M. Rosok, Sydney Lim, Erin E. Franklin, Richard J. Perrin, Helen Hwang, Dhruva Dhavale, Joel Perlmutter, Meghan C. Campbell, Paul Kotzbauer","doi":"10.1002/alz.71868","DOIUrl":"https://doi.org/10.1002/alz.71868","url":null,"abstract":"INTRODUCTION People with Parkinson's disease (PD) frequently develop dementia. We investigated the relationship between cognitive impairment and the loss of cholinergic axon projections from the nucleus basalis of Meynert to neocortical regions in PD. METHODS Levels of choline acetyltransferase (ChAT), the enzyme required for acetylcholine synthesis, were measured with a sandwich enzyme‐linked immunosorbent assay (ELISA) in eight brain regions from 37 PD autopsy cases. Analyses focused on relationships between measures of global cognitive impairment and average ChAT levels in four neocortical regions. RESULTS Mean neocortical ChAT levels positively correlated with the Mini‐Mental State Examination and a global cognition z‐score obtained by averaging performance in multiple cognitive domains. Mean neocortical ChAT levels also showed a trending inverse correlation with the Clinical Dementia Rating sum of boxes. DISCUSSION These results indicate a role for the loss of cholinergic projections to neocortical regions in the development of cognitive impairment in PD.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"405 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149087480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clusterin is enriched in plaque-associated astrocytes and localizes to synapses in Alzheimer's disease","authors":"Robert A. J. Byrne,&nbsp;Aurora Veteleanu,&nbsp;Hannah L. Cramp,&nbsp;Olivia G. Bacon,&nbsp;Kirsten L. Baillie,&nbsp;Matthew Bright,&nbsp;Rebekah S. Cooke,&nbsp;Gareth D. Fenn,&nbsp;Mariana Flores Castelán,&nbsp;Kok Yung Lee,&nbsp;Wioleta M. Zelek,&nbsp;B. Paul Morgan,&nbsp;Nikoleta Daskoulidou","doi":"10.1002/alz.71885","DOIUrl":"10.1002/alz.71885","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>The clusterin gene (<i>CLU</i>) is a top genome-wide association studies (GWAS) risk locus for Alzheimer's disease (AD) and elevated clusterin levels have been reported in AD biofluids and brain tissue. Despite growing interest in clusterin as a biomarker and therapeutic target, its cellular and subcellular localization in the human brain remains incompletely understood, in part due to a lack of well-characterized reagents.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>We generated and validated monoclonal antibodies (mAbs) that distinguish secreted and intracellular clusterin, and applied these tools to human biofluids, brain tissue, and induced pluripotent stem cell (iPSC) -derived astrocytes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>The mAbs enabled sensitive detection and quantification of clusterin in plasma, serum, cerebrospinal fluid, and brain tissue homogenates. Immunostaining demonstrated that clusterin is associated with amyloid plaques in AD brain and localizes to synapses in both healthy and AD tissue; the mAb detecting intracellular clusterin demonstrated specific expression in astrocytes, confirmed using astrocytoma lines and iPSC-derived astrocytes. Quantitative analysis demonstrated increased clusterin signal in plaque-associated astrocytes, particularly those surrounding larger plaques.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>The findings provide better understanding of clusterin expression in the healthy and AD brain, informing roles of clusterin in brain homeostasis and AD pathogenesis.</p>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"22 10","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.71885","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149087410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural compression and entorhinal vulnerability: Linking tentorial adjacency to tau burden and dementia progression","authors":"Luyue Zhang,&nbsp;Ana M. Franceschi,&nbsp;John F. Crary,&nbsp;Frank A. Provenzano,&nbsp;for the Alzheimer's Disease Neuroimaging Initiative","doi":"10.1002/alz.71827","DOIUrl":"10.1002/alz.71827","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Early neurofibrillary tau degeneration in the entorhinal cortex (EC) is a hallmark of Alzheimer's disease (AD) and aging. We propose a biomechanical cascade hypothesis, suggesting proximity to the tentorial incisura (TI) may render the EC susceptible to chronic mechanical stress, potentially contributing to tau pathology.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>We developed a neuroanatomical contact coefficient (NCC) to quantify EC–TI proximity using Alzheimer's Disease Neuroimaging Initiative multimodal imaging data (<i>n</i> = 47), stratifying participants into high and low adjacency groups.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Controlling for risk factors, EC tau positron emission tomography signal predicted conversion from mild cognitive impairment to AD only in the high-adjacency group (<i>P</i> = 0.036).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>Findings identify EC–TI proximity as a potential, novel, anatomically grounded biomarker of AD risk. These findings are consistent with a previously unrecognized biomechanical contribution to EC tau vulnerability in sporadic AD and aging, opening new avenues for early detection, risk stratification, and mechanistically targeted prevention strategies.</p>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"22 10","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.71827","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ApoE lipidation state directs immunometabolic reprogramming of human microglia.","authors":"Tsion G Shiferaw, Snigdha Sarkar, Katelyn M Baker, Rowan S Wooldridge, Hannah M Binfet, Victoria N Prozapas, Chinemerem P Ogbu, Athena A Schepmoes, Isaac K Attah, Christy S Niemeyer, Kayla G Sprenger, James E Hassell, Robert H Eckel, John T Melchior, Kimberley D Bruce","doi":"10.1002/alz.71882","DOIUrl":"10.1002/alz.71882","url":null,"abstract":"<p><strong>Introduction: </strong>ApoE ε4 is the strongest genetic risk factor for Alzheimer's disease (AD). Emerging evidence suggests that ApoE4 increases AD risk by disrupting microglial metabolism and function. However, whether ApoE lipidation state contributes to microglial dysfunction remains poorly understood.</p><p><strong>Methods: </strong>Human microglia were treated with lipid-free (LF) or lipid-bound ApoE3 or ApoE4. Label-free, live-cell holotomography and global proteomics were used to assess isoform- and lipidation-specific effects on lipid droplet (LD) dynamics, mitochondrial morphology, and microglial phenotype.</p><p><strong>Results: </strong>ApoE4 treatment resulted in fewer but enlarged LDs and increased mitochondrial fragmentation compared to ApoE3, effects that were enhanced by lipid-bound ApoE4. Proteomic analyses revealed a strong type I interferon response in cells exposed to LF-ApoE, which was exacerbated by LF-ApoE4.</p><p><strong>Discussion: </strong>These findings indicate that lipid-bound ApoE4 drives metabolic reprogramming, whereas LF-ApoE4 promotes inflammatory signaling, identifying ApoE lipidation as a critical modifier of ApoE4-associated AD risk.</p>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"22 10","pages":"e71882"},"PeriodicalIF":12.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13655218/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149163706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex-specific brain reserve and progression from mild cognitive impairment to Alzheimer's disease dementia.","authors":"Xulin Liu, Sterre C M de Boer, Maria Carmela Tartaglia","doi":"10.1002/alz.71913","DOIUrl":"10.1002/alz.71913","url":null,"abstract":"<p><strong>Introduction: </strong>Sex differences exist in Alzheimer's disease (AD) treatment response, but the role of sex in disease development and progression remains unclear.</p><p><strong>Methods: </strong>We performed multimodal analyses of AD biomarker-positive individuals with mild cognitive impairment (MCI) and AD from the Alzheimer's Disease Neuroimaging Initiative (ADNI; MCI n = 593, AD n = 270) and National Alzheimer's Coordinating Center (MCI n = 436, AD n = 174). Baseline gray matter volume (GMV) was compared by sex. In ADNI, tau positron emission tomography burden and cerebrospinal fluid growth-associated protein 43 (GAP-43) were assessed. Longitudinal analyses examined atrophy and conversion from MCI to dementia.</p><p><strong>Results: </strong>Females with MCI exhibited greater baseline GMV than males primarily in the thalamus, caudate, cerebellum, postcentral gyrus, and middle cingulate gyrus, with no differences at the AD stage. Despite this, females exhibited higher baseline GAP-43, greater tau burden in temporal and parietal regions, and more rapid annual hippocampal atrophy. Conversion rates were similar.</p><p><strong>Discussion: </strong>Findings suggest that females may tolerate greater pathology at early stages but experience faster neurodegeneration later, supporting sex-specific disease trajectories and highlighting the need for sex-informed biomarkers.</p>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"22 10","pages":"e71913"},"PeriodicalIF":12.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13661747/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149178810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tyrosine kinase inhibitor use and risk of neurodegenerative disease: A Swedish population-based cohort study.","authors":"Felix Wittström, Enoch Yi-Tung Chen, Iris Blotenberg, Torsten Dahlén","doi":"10.1002/alz.71916","DOIUrl":"10.1002/alz.71916","url":null,"abstract":"<p><strong>Introduction: </strong>Effective disease-modifying therapies remain unavailable for neurodegenerative diseases (NDDs). Tyrosine kinase inhibitors (TKIs) indicated for chronic myeloid leukemia (CML) have been hypothesized to modulate the pathological mechanisms underlying neurodegeneration. Therefore, we aimed to explore the association between initiation of six different TKIs and the subsequent risk of developing NDDs in Swedish nationwide registries (2005-2024).</p><p><strong>Methods: </strong>CML patients ≥50 years at diagnosis initiating TKI therapy were identified, alongside five comparators without CML matched on sex, age, and residence at diagnosis. CML cases and comparators were followed from the initiation date of the respective TKI and could contribute follow-up time to multiple TKI cohorts. A composite measure of NDD diagnosis or death due to NDD was the outcome. Hazard ratios (HRs) were estimated using Cox proportional hazards models, with adjustments for calendar year at follow-up initiation, and relevant comorbidities.</p><p><strong>Results: </strong>A total of 1322 CML cases were included in the study. 1188 initiated imatinib (of which 41 experienced an NDD event), 541 dasatinib (15 events), 390 nilotinib (five events), 174 bosutinib, 71 ponatinib, and 41 asciminib. Adjusted hazard ratios comparing each TKI group to their matched comparator populations were 0.98 (95% confidence interval [CI], 0.71 to 1.36) for imatinib users, 1.18 (95% CI, 0.68 to 2.03) for dasatinib users, and 0.37 (95% CI, 0.15 to 0.90) for nilotinib users. Bosutinib, ponatinib, and asciminib users were too few to conduct comparative analyses.</p><p><strong>Discussion: </strong>Initiation of nilotinib, but not imatinib or dasatinib, was associated with a significantly lower NDD incidence relative to general population comparators.</p>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"22 10","pages":"e71916"},"PeriodicalIF":12.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13655210/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149165095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}