Alzheimer's & Dementia最新文献

{"title":"Plasma eMTBR‐tau243 as a disease biomarker across Alzheimer's disease clinical phenotypes","authors":"Jennifer L. Whitwell, Jerusha G. Bhaskaran, Ryota Satoh, Jonathan Graff‐Radford, Mary M. Machulda, Val J. Lowe, Michelle M. Mielke, Dennis W. Dickson, Shin‐Cheng Tzeng, John Bui, Philip B. Verghese, Tim West, Venky Venkatesh, Keith A. Josephs","doi":"10.1002/alz.71898","DOIUrl":"https://doi.org/10.1002/alz.71898","url":null,"abstract":"INTRODUCTION The concentration of endogenous tau microtubule‐binding region containing residue‐243 in plasma (eMTBR‐tau243) has been proposed to be a sensitive biomarker of tangle pathology in Alzheimer's disease (AD). We assessed eMTBR‐tau243 and phosphorylated tau217 (p‐tau217) with tau and Aβ‐positron emission tomography (PET) across different AD clinical phenotypes. METHODS Plasma eMTBR‐tau243, p‐tau217, and the ratio of non‐phosphorylated to phosphorylated tau217 (%p‐tau217) were measured in 20 Aβ‐PET positive AD patients representing four clinical phenotypes and 10 cognitively unimpaired controls. Plasma levels were correlated with PET, demographic and cognitive variables. RESULTS Plasma eMTBR‐tau243, p‐tau217, and %p‐tau217 levels were greater in AD than controls, with greatest levels observed in motor‐predominant AD. Plasma biomarker levels correlated with cortical flortaucipir‐PET uptake; eMTBR‐tau243 correlations were strongest. In AD, eMTBR‐tau243 levels were undetectable in patients with mild/focal flortaucipir‐PET uptake (45%). Only eMTBR‐tau243 correlated with cognition. DISCUSSION Plasma eMTBR‐tau243 may be an excellent biomarker for tau deposition and cognition in AD across different phenotypes.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"407 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149130519","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":"Associations between plasma biomarker levels and quantitative postmortem neuropathologic measures in Alzheimer's disease and related dementias","authors":"Celia R. Bianco, Neus Rabaneda‐Lombarte, Hadia Fatima, Johanna Celedon, Derek H. Oakley, Steven E. Arnold, Pia Kivisäkk, Alberto Serrano‐Pozo","doi":"10.1002/alz.71883","DOIUrl":"https://doi.org/10.1002/alz.71883","url":null,"abstract":"INTRODUCTION Validation of Alzheimer's disease blood‐based biomarkers (BBMs) has relied largely on amyloid beta (Aβ) and tau positron emission tomography (PET), with limited quantitative neuropathologic correlation studies. We examined associations between BBMs and quantitative postmortem neuropathology in 124 participants from the Massachusetts Alzheimer's Disease Research Center (MADRC) Longitudinal Cohort Study. METHODS Plasma phosphorylated tau 217 (p‐tau217), p‐tau181, total tau (t‐tau), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were measured using the Meso Scale Discovery platform and correlated with postmortem quantitative measures of Aβ plaques, AT8 <jats:sup>+</jats:sup> pTau neurons, cortical thickness, and GFAP <jats:sup>+</jats:sup> astrocytes across the temporal, frontal, and occipital lobes. RESULTS Plasma p‐tau217 strongly associated with Aβ plaques (especially neuritic) and AT8 <jats:sup>+</jats:sup> neurons. Associations were weaker for p‐tau181 and t‐tau. NfL associated only with lower cortical thickness. GFAP correlated with Aβ plaques, AT8 <jats:sup>+</jats:sup> neurons, and cortical and white matter GFAP <jats:sup>+</jats:sup> astrocytes. Plasma p‐tau217 and GFAP mediated the association between Aβ plaques and AT8 <jats:sup>+</jats:sup> neurons. DISCUSSION These findings support BBM biological specificity and utility for in vivo characterization of distinct neuropathologic processes.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"51 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149130521","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 associations of rapid eye movement (REM) sleep and slow‐wave sleep with plasma Alzheimer's disease biomarkers","authors":"Jeongyeon Hwang, Luisa F. Figueredo, Daphne I. Valencia, Thomas M. Tolbert, Eriko Hamada, Li Zhou, Joshua L. Gills, Joaquin Ruiz, Katarina R. Martillo, Sarah S. Chu, Ankita Kumar, Esther M. Blessing, Omonigho M. Bubu, Ankit Parekh, Korey Kam, Anna E. Mullins, David M. Rapoport, Indu Ayappa, Ricardo S. Osorio, Andrew W. Varga","doi":"10.1002/alz.71910","DOIUrl":"https://doi.org/10.1002/alz.71910","url":null,"abstract":"INTRODUCTION Data on how sleep architecture relates to progression of plasma Alzheimer's disease biomarkers remains limited. METHODS Sixty‐four cognitively unimpaired older adults (ages 55–90) underwent plasma collection twice 2.6 years apart and polysomnography proximate to the first plasma collection. Plasma amyloid beta (Aβ) 42 and 40 were measured via mass spectrometry. RESULTS Frontal slow‐wave activity (SWA) was inversely associated with plasma Aβ42/40 at cross‐section in bivariate analysis and in a covariate‐adjusted model. In comparison, low rapid eye movement (REM) sleep percentage was associated with a large longitudinal decline in annualized blood‐based Aβ42/40. In exploratory analyses, the association between low REM sleep percentage and faster decline in Aβ42/40 ratio was stronger in the amyloid‐positive group. DISCUSSION In cognitively unimpaired older adults, non‐REM SWA correlates with cross‐sectional amyloid load, whereas REM sleep may predict accelerated amyloid accumulation in preclinical stage, suggesting both may serve as early biomarkers and modifiable interventional targets.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"38 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149130516","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":"Proteomic dysregulation associated with cerebral amyloid angiopathy","authors":"Sang‐Won Han, Young Ho Park, Jung‐Min Pyun, Paula J. Bice, David A. Bennett, Shahram Oveisgharan, Andrew J. Saykin, SangYun Kim, Kwangsik Nho","doi":"10.1002/alz.71901","DOIUrl":"https://doi.org/10.1002/alz.71901","url":null,"abstract":"INTRODUCTION Cerebral amyloid angiopathy (CAA) is characterized by impaired vascular amyloid‐β clearance, distinct from Alzheimer's disease (AD), underscoring the need to clarify its molecular basis for predicting therapy‐related amyloid‐related imaging abnormalities. METHODS We analyzed <jats:italic>post‐mortem</jats:italic> brain proteomics from Religious Orders Study and Rush Memory and Aging Project (ROS/MAP) and cerebrospinal fluid (CSF) proteomics from Alzheimer's Disease Neuroimaging Initiative (ADNI) to identify CAA‐associated proteins and network modules, delineate their biological processes and cellular origins, and determine their diagnostic performance. RESULTS Proteomics analysis identified 30 proteins as associated with CAA severity, enriched in pathways distinct from AD pathology, with 11 replicated in ADNI. Two CAA‐associated modules were enriched for microglial vesicle transport and astrocytic potassium‐ion homeostasis. Pseudotime analysis demonstrated a molecular trajectory aligned with increasing CAA severity. Three proteins (RCSD1, FRZB, AKAP6) improved CAA classification beyond demographics and <jats:italic>APOE</jats:italic> ε4. DISCUSSION This integrative proteomics analysis identifies distinct, reproducible molecular signatures of CAA, revealing glia‐mediated pathways and promising biomarkers for CAA detection and therapy‐related risk assessment.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"8 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149130518","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":"Comorbidities and health-care use prior to early-onset Alzheimer's disease: A population-based case–control study","authors":"Laura Leppänen,&nbsp;Adolfina Lehtonen,&nbsp;Mikko Aaltonen,&nbsp;Kalle Aho,&nbsp;Ave Kivisild,&nbsp;Abbe Ullgren,&nbsp;Iina Rinnankoski,&nbsp;Helmi Soppela,&nbsp;Annakaisa Haapasalo,&nbsp;Anne M. Portaankorva,&nbsp;Päivi Hartikainen,&nbsp;Kasper Katisko,&nbsp;Eino Solje,&nbsp;Johanna Krüger","doi":"10.1002/alz.71831","DOIUrl":"10.1002/alz.71831","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>We examined whether comorbidities and health-care use differ between individuals later diagnosed with early-onset Alzheimer's disease (EOAD) and matched controls during the 15 years preceding diagnosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>This population-based case–control study included 407 EOAD patients diagnosed at two Finnish university hospitals (2010–2021), and 4035 age- and sex-matched controls. Prior diagnoses and health-care visits were obtained from nationwide registers.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>EOAD patients had higher prevalence of vertigo (5.9% vs. 2.1%, <i>p</i> &lt; 0.001), depression (5.7% vs. 2.3%, <i>p</i> &lt; 0.001), headache (4.9% vs. 1.6%, <i>p</i> &lt; 0.001), delirium (1.5% vs. 0.1%, <i>p</i> &lt; 0.001), brain injuries (2.9% vs. 0.9%, <i>p</i> = 0.002), thyroid disorders (2.5% vs. 0.8%, <i>p</i> = 0.008), alcohol-related disorders (3.4% vs. 1.4%, <i>p</i> = 0.009), epilepsy (2.2% vs. 0.7%, <i>p</i> = 0.009), strokes (4.4% vs. 2.0%, <i>p</i> = 0.008), and otorhinolaryngologic diseases (5.2% vs. 2.9%, <i>p</i> = 0.027) 1–5 years before diagnosis. Only otorhinolaryngologic diseases (4.7% vs. 2.1%, <i>p</i> = 0.036) differed 6 to 10 years prior, whereas no differences were seen 11 to 15 years before diagnosis. Hypertension and dyslipidemia showed no between-group differences. Health-care use increased markedly from year before EOAD diagnosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>EOAD is preceded by recognizable patterns of morbidity and increased health-care use, which may support earlier detection.</p>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"22 10","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.71831","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149123684","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":"Genetic evidence supports a cortical neuroprotective role of GLP-1 receptor activation in Alzheimer's disease: A drug-target Mendelian randomization study","authors":"Li Jiang,&nbsp;Xinyuan Chen,&nbsp;Jiangshun Qian,&nbsp;Kaiwen Fang,&nbsp;Chenyuan Dai,&nbsp;Dong Chang,&nbsp;Liang Jin,&nbsp;Wenjin Huang,&nbsp;Yuzheng Wang,&nbsp;Xiaomei Duan,&nbsp;Juan Wan,&nbsp;Mingqiang Li,&nbsp;Wendiao Zhang,&nbsp;Jinchen Li,&nbsp;Zijian Xiao,&nbsp;Heng Wu,&nbsp;Qingtuan Meng,&nbsp;Beisha Tang","doi":"10.1002/alz.71845","DOIUrl":"10.1002/alz.71845","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Whether glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) activation lowers Alzheimer's disease (AD) risk via peripheral metabolic improvement or direct neuroprotection remains unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>Using blood and brain-cortex <i>cis</i>-acting expression quantitative trait loci (<i>cis</i>-eQTLs) for <i>GLP-1R</i> as instruments, we performed <i>cis-</i>Mendelian randomization (<i>cis-</i>MR) for AD and seven biomarkers. Mendelian randomization Bayesian model averaging (MR-BMA), <i>cis-</i>multivariable Mendelian randomization (<i>cis</i>-MVMR), and two-step <i>cis-</i>MR assessed 11 metabolic and inflammatory mediators, and tissue-specific <i>cis-</i>MVMR identified the causal tissue.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p><i>GLP-1R</i> expression was associated with lower AD risk and cerebrospinal fluid phosphorylated tau (p-tau) levels. The <i>cis-</i>MVMR identified systolic blood pressure as the only independent mediator, whereas <i>GLP-1R</i> retained a direct protective effect on AD. Tissue-specific <i>cis-</i>MVMR attributed the effect predominantly to cortical (posterior inclusion probability [PIP] = 0.998) rather than blood <i>GLP-1R</i> expression (PIP = 0.002).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> CONCLUSION</h3>\u0000 \u0000 <p>Genetic evidence supports <i>GLP-1R</i> as a potential target in AD, with a protective effect not fully explained by peripheral metabolic improvement and possibly involving cortical neuroprotection, supporting further investigation of brain-penetrant agents at preclinical or prodromal stages.</p>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"22 10","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.71845","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088806","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: 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}