Alzheimer's & Dementia最新文献

{"title":"Neuropathologic features of cognitively defined Alzheimer's disease subgroups in the Adult Changes in Thought study.","authors":"Caitlin S Latimer, Rod L Walker, Marika Bogdani, C Dirk Keene, Amber L Nolan, Daniel D Child, Shubhabrata Mukherjee, Seo-Eun Choi, Michael L Lee, Connie Nakano, Kelly Ehrlich, Linda K McEvoy, Paul K Crane","doi":"10.1002/alz.71938","DOIUrl":"https://doi.org/10.1002/alz.71938","url":null,"abstract":"<p><strong>Background: </strong>Individuals with Alzheimer's disease (AD) dementia can be subgrouped based on cognitive performance at diagnosis. We compared neuropathology across cognitively defined AD subgroups in the Adult Changes in Thought study.</p><p><strong>Methods: </strong>Scores for memory, executive functioning, language, and visuospatial abilities were derived from the Cognitive Abilities Screening Instrument and a neurocognitive battery. Subgroups were defined by relative performance within domains. Standardized neuropathologic evaluation was performed post mortem. Associations were estimated using ordinal logistic regression, with odds ratios (OR) and 95% confidence intervals (CIs) comparing neuropathology between the AD subgroups and relative to individuals without dementia.</p><p><strong>Results: </strong>Of 885 participants with post mortem neuropathology, 370 had AD dementia: 54% AD-no domain, 15% AD-memory, 15% AD-visuospatial, 8% AD-language, and 7% AD-executive. Among AD subgroups, associations were detected for limbic-predominant age-related transactive response DNA binding protein 43 kDa encephalopathy neuropathologic change (LATE-NC; P = 0.019) and hippocampal sclerosis (HS; P = 0.006), with highest levels in AD-language (LATE-NC OR 2.37, 95% CI 1.03-5.46 and HS OR 2.19, 95% CI 0.88-5.50) and AD-memory (LATE-NC OR 1.88, 95% CI 1.02-3.46 and HS OR 3.11, 95% CI 1.56-6.20) relative to AD-no domain, and lowest levels in AD-visuospatial. AD-visuospatial tended to have lowest estimated Alzheimer's disease neuropathologic change (ADNC) burden across AD subgroups. Relative to participants without dementia, all AD subgroups expectedly had higher ADNC burden, and several AD subgroups had higher odds of Lewy body pathology (P = 0.017) and gross infarcts (P = 0.004), with broadly similar estimates across multiple AD subgroups.</p><p><strong>Discussion: </strong>Neuropathologic patterns of ADNC and co-pathologies across AD dementia subgroups suggest cognitive phenotyping may inform clinicopathologic studies of AD dementia.</p>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"22 10","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149260425","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":"Vascular drivers of cerebrospinal fluid movement and enlarged perivascular spaces.","authors":"James D LeFevre, Yukti Vyas, Angela L Jefferson","doi":"10.1002/alz.71927","DOIUrl":"https://doi.org/10.1002/alz.71927","url":null,"abstract":"<p><p>Perivascular spaces (PVSs) facilitate cerebrospinal fluid flow and waste clearance, which are critical for maintaining brain homeostasis. Enlarged PVSs (ePVSs) are an emerging marker of cerebral small vessel disease and are implicated in protein accumulation, neurodegeneration, and cognitive decline. While prior reviews have described the anatomy and correlates of ePVSs, the vascular mechanisms that drive perivascular fluid dynamics, and how their dysfunction might lead to ePVSs, have not been reviewed. This review examines how vascular mechanisms drive perivascular fluid dynamics and discusses how their impairment may contribute to ePVS formation and their impact on cognition. We propose an integrated vascular-ePVS hypothesis in which early vascular dysfunction may contribute to impaired waste clearance and ePVS burden, potentially linking early-life vascular health with later proteinopathy and cognitive decline. Elucidating the vascular contributions to ePVSs is imperative to identify therapeutic targets to preserve cognition in Alzheimer's disease and related dementias.</p>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"22 10","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149260396","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":"Tau extent is associated with lower cognition in Down syndrome-related Alzheimer's disease.","authors":"Matthew D Zammit, Sigan L Hartley, Bradley T Christian, Michael S Rafii","doi":"10.1002/alz.71925","DOIUrl":"https://doi.org/10.1002/alz.71925","url":null,"abstract":"<p><strong>Introduction: </strong>¹⁸F-MK6240 is a second-generation tau positron emission tomography (PET) tracer with high dynamic range able to detect early tau pathology in Alzheimer's disease, however, its binding characteristics have not been evaluated in Down syndrome (DS), which is a population at high risk for early Alzheimer's disease onset. Past Down DS tau PET studies used ¹⁸F-Flortaucipir, which suffers from off-target binding in early-stage regions, limiting pathology confirmation. This study evaluates the binding of ¹⁸F-MK6240 in DS and examines the relationship between tau extent and cognition.</p><p><strong>Methods: </strong>Tau Extent was measured in participants from the Trial Ready Cohort-Down Syndrome using ¹⁸F-MK6240 and from the Alzheimer Alzheimer's Biomarker Consortium-Down Syndrome using ¹⁸F-Flortaucipir. Data were compared, harmonized, and explored in relationship to cognitive endpoints with consideration of age, sex, apolipoprotein E (APOE) ε4 status, and level of intellectual disability.</p><p><strong>Results: </strong>¹⁸F-MK6240 showed binding in the mesial temporal lobe shortly following the onset of beta-amyloid plaques, similar to our observations with ¹⁸F-Flortaucipir. Increased tau extent correlated with lower episodic memory and overall cognitive performance scores. Age, intellectual disability level, and sex also influenced cognitive scores.</p><p><strong>Discussion: </strong>This first evaluation of ¹⁸F-MK6240 in DS demonstrates its suitability as a sensitive biomarker for Alzheimer's disease tau pathology. Furthermore, the inverse associations between Tau Extent as measured by both ¹⁸F-MK6240 and ¹⁸F-Flortaucipir and cognitive outcomes highlight the potential of these biomarkers to evaluate signs of early cognitive change, underscoring the urgent need to include this population in early clinical interventions.</p>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"22 10","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149260403","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":"Vascular brain injury modifies the relationship between sleep duration, cognition, and white matter hyperintensity burden in the Alzheimer's disease continuum.","authors":"Soraya Lahlou, Zahinoor Ismail, Eric E Smith, Thien Thanh Dang-Vu, AmanPreet Badhwar","doi":"10.1002/alz.71838","DOIUrl":"10.1002/alz.71838","url":null,"abstract":"<p><strong>Introduction: </strong>Self-reported sleep duration is associated with dementia-risk and vascular brain injury markers, including white matter hyperintensities (WMHs), yet how additional cerebrovascular pathology alters these relationships remains unclear.</p><p><strong>Method: </strong>In a deeply phenotyped cohort (735) including healthy and Alzheimer's disease (AD) continuum individuals (subjective and mild cognitive impairment [MCI], dementia [AD], MCI and AD with high vascular burden [+V]), sleep was assessed using the Pittsburgh Sleep Quality Index. Individuals were classified as WMH-only or WMH+ (WMHs with microbleeds, infarcts, or cerebral amyloid angiopathy). Linear models tested interactions between sleep duration, WMH+ status, and diagnostic group on WMH burden and cognition.</p><p><strong>Results: </strong>In MCI+V and AD, WMH+ significantly amplified the association between shorter sleep and greater WMH burden. In AD, longer sleep related to better cognition in WMH+ but worse cognition in WMH-only (exploratory).</p><p><strong>Discussion: </strong>Additional vascular brain injury modifies how sleep relates to WMH burden and cognition across the AD continuum, highlighting the importance of moving beyond WMHs alone.</p>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"22 10","pages":"e71838"},"PeriodicalIF":12.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13656204/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149164013","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":"miR‐214‐3p and NCKAP1: A microglial functional dimension of Alzheimer's progression","authors":"Min‐Young Noh,Yeonsil Moon,Sungwoo Kang,Won‐Jin Moon,Hee‐Jin Kim,Sang Won Seo,Sugyeong Ahn,Mi‐Hyeon Kang,Yong Sung Kim,Hyunkee Kim,Jae‐sung Bae,Hee Kyung Jin,Hojin Choi,Seong‐Ho Koh,Kee Hyung Park,Gregory S. Day,Guojun Bu,Seung Hyun Kim","doi":"10.1002/alz.71903","DOIUrl":"https://doi.org/10.1002/alz.71903","url":null,"abstract":"Abstract INTRODUCTION Biological Alzheimer's disease (AD) pathology does not fully explain the marked heterogeneity in clinical severity or progression. We investigated whether patient‐derived induced microglia‐like cell (iMG) profiles capture a functional dimension of AD progression beyond conventional plasma biomarkers. METHODS We studied 114 participants comprising amyloid‐negative healthy controls ( n =  18) and amyloid‐positive AD‐continuum groups (cognitively unimpaired, n =  2; mild cognitive impairment, n =  18; AD dementia, n =  76). Plasma biomarkers, patient‐derived iMG phagocytic function, and molecular markers were measured from the same blood draw. Longitudinal clinical follow‐up was available in 102 participants, and paired baseline/follow‐up blood samples were analyzed in a longitudinal biomarker cohort ( n =  38). RESULTS iMG phagocytic capacity progressively declined across the AD continuum, accompanied by reduced NCK‐associated protein 1 (NCKAP1) expression and the strongest association with plasma glial fibrillary acidic protein (GFAP). Baseline NCKAP1 primarily reflected current cognitive impairment, whereas plasma miR‐214‐3p independently predicted faster cognitive decline beyond plasma tau phosphorylated at threonine 217 (p‐tau217), GFAP, neurofilament light chain (NfL), age, and baseline cognition. Within amyloid‐positive AD dementia, plasma miR‐214‐3p identified rapidly progressive disease and substantially improved prognostic discrimination beyond conventional plasma biomarkers. Longitudinally, declining NCKAP1 and increasing plasma miR‐214‐3p tracked the rate of cognitive deterioration, whereas plasma p‐tau217, GFAP, and NfL changed over time but did not track disease tempo. DISCUSSION Patient‐derived iMG profiling identifies microglial phagocytic dysfunction as a complementary functional dimension of AD progression beyond conventional plasma biomarkers. Longitudinal microglial dynamics tracked disease tempo more closely than conventional plasma pathology markers and may help interpret biological‐clinical discordance, supporting biologically informed staging, prognosis, and patient stratification in AD.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"32 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088827","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":"MIND diet-related plasma proteins are associated with Alzheimer's disease risk.","authors":"Shane Fernandez, Desarae A Dempsey, Soumilee Chaudhuri, Yen-Ning Huang, Tamina Park, Shiwei Liu, Frederick W Unverzagt, Sujuan Gao, Donna M Wilcock, Jiaqi Yang, Casey M Rebholz, Shannon L Risacher, Andrew J Saykin, Kwangsik Nho","doi":"10.1002/alz.71884","DOIUrl":"10.1002/alz.71884","url":null,"abstract":"<p><strong>Introduction: </strong>Adherence to the Mediterranean-Dietary Approaches to Stop Hypertension Intervention for Neurodegenerative Delay (MIND) diet is associated with reduced dementia risk, but underlying mechanisms remain unclear.</p><p><strong>Methods: </strong>Plasma proteomics (SomaScan 7k) from 206 Indiana Alzheimer's Disease Research Center participants were analyzed using network analysis to identify modules associated with MIND diet scores. Diet-related hub proteins were then investigated for associations with Alzheimer's disease (AD) phenotypes and as potential diet-AD outcome mediators. Validation analyses were conducted in the Atherosclerosis Risk in Communities study (n = 10,228) and Global Neurodegeneration Proteomics Consortium (n = 3,723) datasets.</p><p><strong>Results: </strong>Higher MIND diet scores were associated with lower AD odds (odds ratio = 0.75, p = 0.01) and lower plasma neurofilament light chain levels (β = -0.07, p = 0.02). Two proteins, MCTS1 and cytidylate kinase, were associated with MIND diet and AD risk, and may mediate their relationship (p[a × b < 0] ≥ 0.95). Validation analyses supported the MCTS1 finding.</p><p><strong>Discussion: </strong>Vascular-related biological mechanisms may underlie associations between diet and dementia risk.</p>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"22 10","pages":"e71884"},"PeriodicalIF":12.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13650594/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149134670","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":"Longitudinal clinical outcomes after amyloid clearance in aducanumab phase 3 studies","authors":"Menglan Pang,Holly M. Brothers,John O'Gorman,Jennifer Murphy,Yuval Zabar,Tyler Lasky,Changyu Shen,Ivana Rubino,David Knopman","doi":"10.1002/alz.71758","DOIUrl":"https://doi.org/10.1002/alz.71758","url":null,"abstract":"Abstract INTRODUCTION Anti‐amyloid antibody clinical trials with a high proportion of participants reaching treatment‐related amyloid clearance (TRAC) had positive clinical outcomes. We evaluated the aducanumab phase 3 program to determine whether TRAC during the double‐blind period was likewise associated with clinical benefit. METHODS We pooled ENGAGE and EMERGE (E/E) aducanumab‐treated participants in the amyloid positron emission tomography substudy who continued into the long‐term extension ≤ 134 weeks (continuously treated population) and/or returned to the EMBARK redosing study 0.7 to 2.5 years after termination of E/E (treatment gap population). Clinical outcomes were stratified by week 78 TRAC status. RESULTS TRAC participants had less clinical decline at week 78, week 134, and EMBARK baseline than non‐TRAC participants. Post‐TRAC, clinical decline was heterogeneous; approximately two thirds of TRAC participants had annualized decline of &lt; 1 point on Clinical Dementia Rating Sum of Boxes. DISCUSSION In these exploratory analyses, week 78 TRAC status was associated with better clinical outcomes. CLINICAL TRIAL REGISTRATION NCT02484547, NCT02477800, NCT04241068","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149092448","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":"Cross-cohort NULISAseq identifies tau-anchored CSF and plasma-specific signatures across the amyloid-positive Alzheimer's disease.","authors":"Lan Ding, Menghan Zheng, Simiao Wang, Wenying Liu, Yumei Liang, Siqi Xie, Ting Yang, Dandan Sheng, Shuheng Wang, Jianpeng Sheng, Jianping Jia","doi":"10.1002/alz.71915","DOIUrl":"10.1002/alz.71915","url":null,"abstract":"<p><strong>Introduction: </strong>ATN-stratified cerebrospinal fluid (CSF) proteomic signals may partly reflect classifier tau immunoassays; reproducible non-tau signals and CSF-plasma differences remain unclear.</p><p><strong>Methods: </strong>We profiled CSF from 60 A⁺ Beijing patients with Alzheimer's disease (AD) and 875 A⁺ Alzheimer's Disease Neuroimaging Initiative (ADNI) participants using the NULISAseq CNS Disease Panel. Differential expression was assessed using a false discovery rate (FDR) < 0.05 and |log₂FC|≥0.5 across three ATN contrasts. We also analyzed ADNI plasma, protein-cognition correlations, tau-adjusted associations, and nested models comparing non-tau proteins with tau biomarkers.</p><p><strong>Results: </strong>Eight CSF proteins met the cross-cohort criterion within at least one matched contrast: pTau-217, pTau-181, pTau-231, MAPT, SMOC1, MDH1, VSNL1, and FABP3. NULISA tau correlated with INNOTEST (ρ = 0.75-0.85) and Elecsys (ρ = 0.65-0.68). T and N classifications agreed for 94.6% of ADNI participants (κ = 0.880); after adjustment for CSF pTau-217, all 12 associations involving the four non-tau proteins retained their direction and FDR support. In CSF, Elecsys p-tau181 and NULISA tau-family analytes had the strongest cognitive correlations (mean |ρ| = 0.35 and 0.29-0.34, respectively), followed by FABP3 (0.24). Adding the four-protein block after tau increased cross-validated R² across all three cross-sectional outcomes in models without diagnosis (+0.0101 to +0.0265), most clearly for the Alzheimer's Disease Assessment Scale-Cognitive Subscale, 13-item version (ADAS-Cog13); diagnosis-conditioned models showed no stable increment beyond tau and clinical characteristics. In plasma, pTau-217 was the only analyte that met both thresholds in all three contrasts.</p><p><strong>Discussion: </strong>CSF NULISAseq identified a reproducible tau-associated signature across A⁺ cohorts that extended beyond the tau family. The four non-tau proteins extend the molecular profile associated with tau-defined disease state and merit further evaluation for biological stratification in independent cohorts.</p>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"22 10","pages":"e71915"},"PeriodicalIF":12.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13656197/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149163681","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":"Dementia with Lewy bodies and amyloid pathology: Eligible for anti-amyloid treatment or not?","authors":"Lieza G Exalto, Juliette L van Alphen, Frederik Barkhof, Charlotte Teunissen, Everard G B Vijverberg, Dag Aarsland, Afina W Lemstra","doi":"10.1002/alz.71907","DOIUrl":"10.1002/alz.71907","url":null,"abstract":"<p><p>In the future, treatment of dementia will be personalized, targeted to contributing pathologies, rather than the clinical syndrome. Anti-amyloid drugs for Alzheimer's disease are the first approved drugs; however, the impact of co‑pathology on the treatment effects remains incomplete. Currently, only patients with a clinical diagnosis of Alzheimer's disease are eligible for these new drugs, but could they also be beneficial when amyloid is present in other neurodegenerative diseases? For example, roughly 50% of patients with dementia with Lewy bodies are amyloid-positive. In this perspective, we discuss the theoretical benefits and challenges of anti-amyloid drugs in patients with a clinical diagnosis of dementia with Lewy bodies and concomitant Alzheimer's disease pathology. We show that a significant portion of newly diagnosed dementia with Lewy bodies patients could be eligible. We advocate for the systematic collection of efficacy and safety data using innovative strategies to achieve adequate statistical power.</p>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"22 10","pages":"e71907"},"PeriodicalIF":12.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13656199/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149164964","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":"H3K9me3 inhibition reverses Alzheimer's progression by restoring synaptic and immune proteostasis across the brain-retina axis.","authors":"Dieu-Trang Fuchs, Jean-Philippe Vit, Altan Rentsendorj, Yosef Koronyo, Julia Sheyn, Bhakta Prasad Gaire, Saba Shahin, Haoshen Shi, Oksana Chepurna, Miyah R Davis, Jered W Wilson, Stuart L Graham, Vivek K Gupta, Lon S Schneider, Michael T Kleinman, Tao Sun, Margaret Fahnestock, David A Horne, Mehdi Mirzaei, Keith L Black, Maya Koronyo-Hamaoui","doi":"10.1002/alz.71918","DOIUrl":"10.1002/alz.71918","url":null,"abstract":"<p><strong>Introduction: </strong>Epigenetic dysregulation is increasingly linked to aging and neurodegeneration, yet its contribution to retinal and brain pathology in Alzheimer's disease (AD) remains unclear.</p><p><strong>Methods: </strong>We quantified the repressive epigenetic mark histone H3 lysine 9 trimethylation (H3K9me3) in post mortem retinas and brains from donors spanning normal cognition, mild cognitive impairment, and AD dementia. Using a multi-enzyme methyltransferase panel, we characterized the in vitro inhibitory activity of ETP69, an epidithiodiketopiperazine, against suppressor of variegation 3-9 homologue 1 (SUV39H1) and other methyltransferases. In two transgenic AD mouse models (APPswe/PS1dE9 and APPswe/tauP301L/PS1^tm1Mpm), we assessed ETP69 effects on cerebral H3 methylation, behavior, AD-like pathology, synaptic integrity, and proteomic profiles.</p><p><strong>Results: </strong>H3K9me3 increased early across the AD continuum in both brain and retina, correlating with cognitive impairment and neuropathological burden. H3K9me3 levels were strongly correlated between matched brains and retinas (r = 0.72, p = 0.0002). ETP69 substantially inhibited SUV39H1 and several other methyltransferases in cell-free assays, while consistently reducing cerebral H3K9me3 in vivo relative to other histone marks assessed. In mice, pharmacological H3K9me3 reduction mitigated AD-like pathology, preserved synapses, and improved short- and long-term cognitive and visual performance. Proteomics revealed that H3K9me3 derepression re-established retinal and brain proteostasis and remodeled innate immune pathways and brain-derived neurotrophic factor/nerve growth factor-inducible protein (BDNF/VGF)-granin signaling.</p><p><strong>Discussion: </strong>This study identifies H3K9me3 accumulation as a shared, reversible epigenetic contributor to AD across the retina-brain axis; its reduction represents a promising disease-modifying strategy, and the retina may provide an accessible readout of brain epigenetic dysfunction.</p>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"22 10","pages":"e71918"},"PeriodicalIF":12.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13683561/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149226884","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}