Alzheimer's & Dementia最新文献

{"title":"Genome-wide association analyses identify candidate loci for amyloid imaging and plasma biomarkers in adults with Down syndrome","authors":"M. Muaaz Aslam,&nbsp;Lam-Ha T. Dang,&nbsp;Ruyu Shi,&nbsp;Kang-Hsien Fan,&nbsp;Asma Naseer Cheema,&nbsp;Laura Xicota,&nbsp;Danveet Minhas,&nbsp;Weiquan Luo,&nbsp;Narges Zafari,&nbsp;Vibha Acharya,&nbsp;Eleanor Feingold,&nbsp;Sharon Krinsky-McHale,&nbsp;Charles M. Laymon,&nbsp;Ann Cohen,&nbsp;Benjamin L. Handen,&nbsp;Bradley T. Christian,&nbsp;Elizabeth Head,&nbsp;Mark E. Mapstone,&nbsp;Alzheimer's Biomarker Consortium – Down Syndrome (ABC-DS),&nbsp;Joseph H. Lee,&nbsp;Carlos Cruchaga,&nbsp;M. Ilyas Kamboh","doi":"10.1002/alz.70358","DOIUrl":"https://doi.org/10.1002/alz.70358","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> BACKGROUND</h3>\u0000 \u0000 <p>People with Down syndrome (DS) overproduce amyloid-beta (Aβ) due to triplication of the amyloid precursor protein (<i>APP</i>) gene on chromosome 21, and consequently accumulate brain amyloid load at younger ages. We conducted genome-wide association (GWA) analyses on amyloid imaging and plasma biomarkers to discern the genetic architecture of amyloid burden in DS.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>GWA analyses were performed on amyloid positron emission tomography (PET) and plasma biomarkers (Aβ40, Aβ42, Aβ42/40 ratio) in participants from the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) and on plasma Aβ biomarkers available in an independent DS cohort, followed by meta-analysis of plasma Aβ biomarker data.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Meta-analysis on plasma biomarkers identified four novel loci: two for Aβ42 (<i>PFKFB3</i>/rs147647642, <i>p </i>= 2.83E-08; <i>DLX3-PICART1</i>/rs12952028, <i>p </i>= 9.31E-09) and two for Aβ40 (<i>LINC01941-GYPC</i>/rs78338676, <i>p </i>= 9.33E-09; <i>PDE4D</i>/rs146261781, <i>p </i>= 9.97E-08). Five genome-wide signals were observed for amyloid-PET in the ABC-DS cohort that need confirmation in an independent DS dataset.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>Despite the small sample, our findings highlight the unique genetic architecture of amyloid burden in DS.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Genetic markers for amyloid biomarkers in Down syndrome (DS) were identified.</li>\u0000 \u0000 <li>Meta-analyses identified four novel loci for plasma amyloid in two DS cohorts.</li>\u0000 \u0000 <li>Five loci associated with amyloid positron emission tomography levels were identified in the Alzheimer's Biomarker Consortium-Down Syndrome cohort.</li>\u0000 \u0000 <li>Multi-trait analysis revealed loci linking variants to amyloid biomarkers.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 7","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70358","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144635154","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":"Donanemab exposure-response in early symptomatic Alzheimer's disease","authors":"Ivelina Gueorguieva,&nbsp;Kay Chow,&nbsp;Laiyi Chua,&nbsp;Sergey Shcherbinin,&nbsp;Jennifer A. Zimmer,&nbsp;Cynthia D. Evans,&nbsp;Hong Wang,&nbsp;Emel Serap Monkul Nery,&nbsp;Dawn A. Brooks,&nbsp;John R. Sims","doi":"10.1002/alz.70491","DOIUrl":"https://doi.org/10.1002/alz.70491","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>These analyses aimed to identify factors impacting donanemab exposure, amyloid plaque, and clinical efficacy in early symptomatic Alzheimer's disease using a population pharmacokinetic/pharmacodynamic (PK/PD) approach.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>Analyses included donanemab trial participants (NCT02624778; NCT03367403; NCT04640077; NCT04437511). Dose- and exposure-response relationships were characterized relative to amyloid plaque lowering using indirect response PK/PD and disease progression models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Donanemab population PK was described by a biphasic distribution with an estimated terminal elimination half-life of approximately 12.1 days for a typical participant (72 kg body weight, 1:2560 maximum antidrug antibody [ADA] titer). Amyloid reduction was associated with maintaining median serum donanemab concentrations over 15 µg/mL (95% confidence interval: 8.54, 18.0). After completing active treatment, simulations showed an estimated plaque reaccumulation rate (median, 95% confidence interval) of 2.8 (2.16, 3.11) Centiloids/year. The donanemab disease progression model showed a clear treatment effect.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>These donanemab models can inform dosing strategies in future clinical trials.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Weight-based and flat dosing had similar exposure metrics; flat dosing was adopted.</li>\u0000 \u0000 <li>Donanemab exposure was influenced by weight and titer (not clinically relevant).</li>\u0000 \u0000 <li>2.8 Centiloids/year amyloid reaccumulation rate observed upon donanemab treatment completion.</li>\u0000 \u0000 <li>Around 30% reduction in disease progression rate on treatment for integrated Alzheimer's Disease Rating Scale (iADRS) and Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB).</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 7","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70491","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144635083","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":"Single-nucleus analysis reveals oxidative stress in Down syndrome basal forebrain neurons at birth","authors":"Nicole R. West,&nbsp;Kalpana Hanthanan Arachchilage,&nbsp;Sara Knaack,&nbsp;Shawn MacGregor,&nbsp;Masoumeh Hosseini,&nbsp;Ryan D. Risgaard,&nbsp;Pubudu Kumarage,&nbsp;Jose L. Martinez,&nbsp;Su-Chun Zhang,&nbsp;Daifeng Wang,&nbsp;Andre M. M. Sousa,&nbsp;Anita Bhattacharyya","doi":"10.1002/alz.70445","DOIUrl":"https://doi.org/10.1002/alz.70445","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Basal forebrain cholinergic neurons (BFCNs) are integral to learning, attention, and memory, and are prone to degeneration in Down syndrome (DS), Alzheimer's disease, and other neurodegenerative diseases. However, the mechanisms that lead to the degeneration of these neurons are not known.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>Single-nucleus gene expression and Assay for Transposase-Accessible Chromatin (ATAC) sequencing were performed on postmortem human basal forebrain from unaffected control and DS tissue samples at 0–2 years of age (<i>n</i> = 4 each).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Sequencing analysis of postmortem human basal forebrain identifies gene expression differences in DS early in life. Genes encoding proteins associated with energy metabolism pathways, specifically oxidative phosphorylation and glycolysis, and genes encoding antioxidant enzymes are upregulated in DS BFCNs.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>Multiomic analyses reveal that energy metabolism may be disrupted in DS BFCNs by birth. Increased oxidative phosphorylation and the accumulation of reactive oxygen species byproducts may be early contributors to DS BFCN neurodegeneration.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>First multiomic gene expression and ATAC analysis of human basal forebrain.</li>\u0000 \u0000 <li>Basal forebrain pathology in DS begins by birth.</li>\u0000 \u0000 <li>Cell type proportions are altered in early postnatal DS basal forebrain.</li>\u0000 \u0000 <li>Gene expression suggests dysregulated energy metabolism in DS BFCNs.</li>\u0000 \u0000 <li>Genes encoding oxidative phosphorylation subunits and glycolysis enzymes are dysregulated in DS BFCNs.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 7","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70445","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144635155","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":"Identifying subphenotypes of patients undergoing post-operative delirium assessment","authors":"Emily Margaret Louise Bowman,&nbsp;Daniel F. McAuley,&nbsp;Bernadette McGuinness,&nbsp;Anthony P. Passmore,&nbsp;David Beverland,&nbsp;Henrik Zetterberg,&nbsp;Jonathan M. Schott,&nbsp;Amanda Heslegrave,&nbsp;Elena Veleva,&nbsp;Rhiannon Laban,&nbsp;Aoife Sweeney,&nbsp;Emma L. Cunningham","doi":"10.1002/alz.70516","DOIUrl":"https://doi.org/10.1002/alz.70516","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Delirium has heterogeneous etiologies and clinical presentations and is often associated with poor outcomes. Its pathophysiological mechanisms remain largely hypothetical and without targeted pharmacological treatment. This work investigates subphenotypes of patients undergoing delirium assessment based on clinical features and fluid biomarkers.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>We performed latent class analysis of an observational cohort of older adults undergoing elective surgery.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Two classes were identified, both containing individuals experiencing delirium symptoms, with a higher number in Class 1 (<i>p</i> &lt; 0.001). Class 1 were older, less educated, and had more depression (<i>p</i> &lt; 0.001). They performed worse in all pre-operative cognitive assessments (<i>p</i> &lt; 0.001) and had more markers of central nervous system damage: cerebrospinal fluid glial fibrillary acidic protein, neurofilament light chain, and soluble triggering receptor expressed on myeloid cells 2 (<i>p</i> &lt; 0.001); plasma phosphorylated tau (<i>p</i> = 0.024); and amyloid beta 42/40 ratio (<i>p</i> &lt; 0.001). Class 2 experienced more pain (<i>p</i> = 0.006) and received more morphine equivalents (<i>p</i> = 0.018).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>Delirium and neighboring phenotypes should be investigated thoroughly in the newly dawning era of precision medicine, to establish novel treatments.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Latent class analysis identified two subphenotypes of patients.</li>\u0000 \u0000 <li>Both groups contained patients with delirium or its individual symptoms.</li>\u0000 \u0000 <li>Groups differed by age, education, depression, independent living, and pain levels.</li>\u0000 \u0000 <li>Groups differed by pre-operative and post-operative cognition.</li>\u0000 \u0000 <li>Groups differed by biomarker levels of neurodegeneration and neuronal injury.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 7","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70516","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144635099","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":"Baseline cognition and demographic, lifestyle, and cardiovascular risk factors in US POINTER","authors":"Kathryn V. Papp,&nbsp;Sarah Tomaszewski Farias,&nbsp;Marjorie Howard,&nbsp;Amber Thro,&nbsp;Tiia Ngandu,&nbsp;Brad Caudle,&nbsp;Bonnie C. Sachs,&nbsp;Michelle Chan,&nbsp;Kristin R. Krueger,&nbsp;Elizabeth R. T. Hartman,&nbsp;Athene Lee,&nbsp;Michele K. York,&nbsp;Marie T. Austin,&nbsp;Kathryn E. Demos,&nbsp;Thomas M. Holland,&nbsp;Xiaoyan Leng,&nbsp;Rema Raman,&nbsp;Heather M. Snyder,&nbsp;Maria C. Carrillo,&nbsp;Rachel A. Whitmer,&nbsp;Mark A. Espeland,&nbsp;Laura D. Baker,&nbsp;the US POINTER Study Group","doi":"10.1002/alz.70216","DOIUrl":"https://doi.org/10.1002/alz.70216","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Validation of the primary cognitive composite and baseline cognitive characteristics are presented for the US-Study-to-Protect-Brain-Health-Through-Lifestyle-Intervention-to-Reduce-Risk (US POINTER).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>US POINTER is a multicenter, randomized clinical trial of two lifestyle interventions testing cognitive benefit in older adults without significant cognitive impairment but at-risk for decline due to well-established factors. Cognition is measured using a global cognitive composite (US POINTER modified Neuropsychological Test Battery-PmNTB).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>The PmNTB is a valid cognitive composite, exhibiting good psychometric properties and tracking with other established outcomes. Among the 2111 enrolled participants (mean age = 68.2 years, 69% women, 31% from race and ethnic minoritized groups), demographic characteristics alone (age, sex, education, race, ethnicity) explained more variance in cognition measured using the PmNTB (25.94%) compared with cardiovascular and family history risk factors combined (added &lt; 3% explained variance).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>In a large diverse older adult cohort, demographic features rather than well-established risks for cognitive decline correlate with baseline global cognition.</p>\u0000 \u0000 <p>Clinical trial registration number: NCT03688126</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Demographic characteristics explain baseline cognition in at-risk older adults.</li>\u0000 \u0000 <li>The POINTER Modified Neuropsychological Test Battery (PmNTB) is a valid measure.</li>\u0000 \u0000 <li>Worse cognition tracks with E4+, high HbA1c, current smoking, Framingham heart risk.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 7","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70216","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144635084","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":"Genome-wide association of tau neuroimaging and plasma biomarkers in adults with Down syndrome","authors":"Kang-Hsien Fan,&nbsp;Ruyu Shi,&nbsp;Asma Naseer Cheema,&nbsp;Lam-Ha T. Dang,&nbsp;Laura Xicota,&nbsp;Sharon Krinsky-McHale,&nbsp;M. Muaaz Aslam,&nbsp;Narges Zafari,&nbsp;Vibha Acharya,&nbsp;Eleanor Feingold,&nbsp;Charles M. Laymon,&nbsp;Ann Cohen,&nbsp;Benjamin L. Handen,&nbsp;Bradley T. Christian,&nbsp;Elizabeth Head,&nbsp;Mark E. Mapstone,&nbsp;Alzheimer's Biomarker Consortium – Down Syndrome (ABC-DS),&nbsp;Carlos Cruchaga,&nbsp;Joseph H. Lee,&nbsp;M. Ilyas Kamboh","doi":"10.1002/alz.70398","DOIUrl":"https://doi.org/10.1002/alz.70398","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; INTRODUCTION&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Plasma biomarkers in Down syndrome (DS) accurately detect Alzheimer's disease (AD) pathology. This study aimed to identify genetic loci associated with plasma tau biomarkers (phosphorylated tau [p-tau]181, p-tau217, total tau [t-tau]) and tau positron emission tomography (PET) in DS.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; METHODS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We examined 375 people with DS from the Alzheimer's Biomarker Consortium–Down Syndrome (ABC-DS) with data on all four tau biomarkers, and 133 subjects from another study of DS with plasma t-tau. Single-trait and multi-trait genetic association analyses were conducted. AD polygenic risk scores (PRSs) were tested with tau biomarkers.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; RESULTS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Three genome-wide significant associations were identified for p-tau181: &lt;i&gt;TUBAP/&lt;/i&gt;rs76523946, &lt;i&gt;P &lt;/i&gt;= 2.21E-08; &lt;i&gt;CTNND2&lt;/i&gt;/rs142510573, &lt;i&gt;P &lt;/i&gt;= 3.04E-08; &lt;i&gt;CLSTN2/&lt;/i&gt;rs112448655, &lt;i&gt;P &lt;/i&gt;= 3.04E-08, and one for t-tau (&lt;i&gt;JHY/&lt;/i&gt;rs77264104, &lt;i&gt;P &lt;/i&gt;= 2.84E-08). AD PRS was associated with higher concentrations of tau PET (&lt;i&gt;β&lt;/i&gt; = 0.30, &lt;i&gt;P &lt;/i&gt;= 6.57E-04), p-tau217 &lt;i&gt;(β&lt;/i&gt; = 0.11, &lt;i&gt;P &lt;/i&gt;= 4.10E-02), and t-tau (&lt;i&gt;β&lt;/i&gt; = 0.12, &lt;i&gt;P &lt;/i&gt;= 3.60E-02).&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; DISCUSSION&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;These data indicate the presence of novel genetic loci in DS affecting plasma tau biomarkers and that AD risk PRS may modify tau neuroimaging and plasma biomarkers in DS.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Highlights&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;Four loci were linked to plasma total tau (t-tau) or phosphorylated tau (p-tau)181 with genome-wide significance.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;&lt;i&gt;JHY&lt;/i&gt;/rs77264104 stays genome-wide significant for plasma t-tau in a meta genome-wide association study (GWAS).&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Alzheimer's disease (AD) polygenic risk score is associated with tau positron emission tomography (PET), regardless of apolipoprotein E genotype and region.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Tau-PET genes in Down syndrome (DS) are enriched in the cerebrospinal fluid phosphorylated tau Alzheimer's disease dementia GWAS catalog.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;T-tau genes in DS are enriched in a verbal memory GWAS catalog within a mild cognitive impairment cohort.&lt;/li&gt;\u0000 &lt;/ul&gt;\u0000 &lt;/div&gt;\u0000 &lt;/section&gt;","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 7","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70398","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144635153","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":"Focused ultrasound-mediated APOE4 knockdown in mouse brain","authors":"Kaiyuan Zheng,&nbsp;Fotios N. Tsitsos,&nbsp;Alec J. Batts,&nbsp;Robin Ji,&nbsp;Tal Nuriel,&nbsp;Elisa E. Konofagou,&nbsp;Kam W. Leong","doi":"10.1002/alz.70464","DOIUrl":"https://doi.org/10.1002/alz.70464","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>The apolipoprotein E (<i>APOE</i>) ε4 allele is widely recognized as the strongest genetic risk factor for late-onset Alzheimer's disease. Therapeutic strategies to reduce apoE4 expression in <i>APOE</i> ε4 carriers hold promise to mitigate neuroinflammatory and neurodegenerative processes driving disease progression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>Focused ultrasound (FUS) was employed to transiently open the blood–brain barrier (BBB) for efficient knockdown of humanized <i>APOE</i> ε4 in the mouse brain via gene editing. The all-in-one clustered regularly interspaced short palindromic repeats (CRISPR)–based adeno-associated virus (AAV) vectors were administered intravenously at a dose of 1.5×10¹² vg per mouse to determine the gene-editing efficacy within the hippocampus.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>FUS-enhanced delivery of AAV resulted in a 12.6% knockdown of <i>APOE</i> ε4 gene expression in the targeted hippocampus, accompanied by an over 20% decrease in apoE4 protein levels and significant reductions in astrocyte and microglia levels.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>Our findings demonstrate a noninvasive, targeted approach for <i>APOE</i> ε4 knockdown, highlighting FUS-mediated brain-directed interventions as a promising therapeutic strategy for Alzheimer's disease.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Focused ultrasound (FUS) enables noninvasive, transient blood–brain barrier (BBB) opening for enhanced adeno-associated virus (AAV) delivery.</li>\u0000 \u0000 <li>FUS-mediated gene editing achieves a 12.6% knockdown in <i>APOE</i> ε4 expression within the hippocampus of mouse brain.</li>\u0000 \u0000 <li><i>APOE</i> ε4 knockdown significantly reduces apoE4 protein levels and astrocyte and microglia levels.</li>\u0000 \u0000 <li>No detectable gross toxicity was observed following the FUS-mediated gene editing.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 7","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70464","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144635070","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":"Genome-wide study links cardiometabolic factors to cognition via APOA4-APOA5-ZPR1-BUD13 and other loci in rural Indians","authors":"Shreya Chakraborty,&nbsp;Krithika Subramanian,&nbsp;Akkshaya Rajesh,&nbsp;Rupanwita Majumder,&nbsp;Khader Valli Rupanagudi,&nbsp;Abhishek Mensegere,&nbsp;TLSA study team,&nbsp;Thomas Gregor Issac,&nbsp;SANSCOG study team,&nbsp;Jonas Sundarakumar,&nbsp;Bratati Kahali","doi":"10.1002/alz.70429","DOIUrl":"https://doi.org/10.1002/alz.70429","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; INTRODUCTION&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Cardiometabolic risks affect cognition during aging, yet genetic basis for both remain understudied in Indians.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; METHODS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;This study constructs an ancestry-matched Indian haplotype reference panel for genotype imputation of 5111 rural Indians. Single-locus, gene-based, conditional genome-wide association analyses are performed on 20 cognitive and 10 cardiometabolic traits, with subsequent follow-up of identified associations through multimodal functional annotation. Furthermore, causal interrelationships between cardiometabolic and cognitive phenotypes by Mendelian randomization are investigated.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; RESULTS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;One novel memory-associated and 17 novel cardiometabolic phenotypes-associated (high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], triglycerides [TG], total cholesterol [TC], TG:HDL, and visceral adiposity index [VAI]) genome-wide significant loci, and multiple genes are identified. &lt;i&gt;AMIGO1&lt;/i&gt; (delayed-recall) and &lt;i&gt;ZPR1-APOA5&lt;/i&gt; (metabolic syndrome) exhibit distinct haplotype structure compared to other populations. Causal roles of cardiometabolic traits on various cognitive domains are identified via genetic instruments in &lt;i&gt;APOC3-APOA4-APOA5-ZPR1-BUD13&lt;/i&gt; among others.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; DISCUSSION&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;These findings illustrate the impact of cardiometabolic factors on cognition in a rural socioeconomically disadvantaged population, advancing efforts to address health disparities.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Highlights&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;Our newly constructed ancestry-matched haplotype reference panel gives better genotype imputation accuracy for the Indian population.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;One and 17 novel genome-wide significant single-loci were identified to be associated with cognitive and cardiometabolic traits, respectively. Several subgenome-wide hits for all phenotypes were identified.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Collapsing protein truncating variants (PTVs), there were two genes identified to be associated with cardiometabolic traits at a genome-wide level of significance, correcting for multiple phenotypes tested.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Haplotypic differences were identified compared to 1000 Genomes superpopulations f","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 7","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70429","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144635071","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":"Alzheimer's disease and its co-pathologies: Implications for hippocampal degeneration, cognitive decline, and the role of APOE ε4","authors":"Klara Gawor,&nbsp;Sam Verrept,&nbsp;Geethika Arekatla,&nbsp;David Wouters,&nbsp;Alicja Ronisz,&nbsp;Moritz Hecht,&nbsp;Celeste Laureyssen,&nbsp;Helena Ver Donck,&nbsp;Bas Lahaije,&nbsp;Simona Ospitalieri,&nbsp;Mathieu Vandenbulcke,&nbsp;Markus Otto,&nbsp;Christine A. F. von Arnim,&nbsp;Estifanos Ghebremedhin,&nbsp;Bernard Hanseeuw,&nbsp;Rik Vandenberghe,&nbsp;Matthew Blaschko,&nbsp;Alejandro Sifrim,&nbsp;Kristel Sleegers,&nbsp;Dietmar Rudolf Thal,&nbsp;Sandra O. Tomé","doi":"10.1002/alz.70483","DOIUrl":"https://doi.org/10.1002/alz.70483","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; INTRODUCTION&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;In neurodegenerative dementias, the co-occurrence and interaction of amyloid β peptide (Aβ), tau pathology, and other pathological lesions confound their individual contributions to neurodegeneration and their modulation by risk factors.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; METHODS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We analyzed 480 &lt;i&gt;post mortem&lt;/i&gt; human brains (ages 50–99) using regression and structural equation models to assess the relationships among Aβ, tau, limbic-predominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC), α-synuclein, other age-related lesions, and apolipoprotein E (&lt;i&gt;APOE&lt;/i&gt;) ε4, as well as their effects on CA1 neuronal density, brain weight, and cognitive status.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; RESULTS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Aβ, tau, LATE-NC, and amygdala-predominant α-synuclein pathology were mutually interdependent. Tau was the strongest predictor of global neurodegeneration, while LATE-NC primarily, but not exclusively, affected hippocampal neuron loss. Small vessel disease correlated with both LATE-NC and α-synuclein, while &lt;i&gt;APOE&lt;/i&gt; ε4 was mainly associated with extracellular parenchymal and capillary Aβ pathology.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; DISCUSSION&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Although Alzheimer's disease pathology plays a central role in brain degeneration, coexisting pathologies can both exacerbate and independently contribute to it. These factors should be considered in patient stratification.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Highlights&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;In aging individuals, amyloid β &lt;span&gt;peptide &lt;/span&gt;(Aβ), tau pathology, limbic-predominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC), and amygdala-predominant α-synuclein pathology were interrelated but contributed independently to neurodegeneration.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;LATE-NC was the &lt;span&gt;strongest&lt;/span&gt; driver of CA1 neuronal loss, while tau burden was the strongest predictor of global brain degeneration.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Apolipoprotein E ε4 was associated with both extracellular and capillary Aβ deposits, but not with tau burden.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Temporal lobe small vessel disease was associated with both LATE-NC and amygdala-predominant α-synuclein pathology.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Neural network models can reliably identify hippocampa","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 7","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70483","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144635073","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":"Pittsburgh plasma p-tau217: Classification accuracies for autosomal dominant and sporadic Alzheimer's disease in the community","authors":"Anuradha Sehrawat,&nbsp;Xuemei Zeng,&nbsp;Eric E. Abrahamson,&nbsp;Rebecca A. Deek,&nbsp;Alexandra Gogola,&nbsp;M. Ilyas Kamboh,&nbsp;Tharick A. Pascoal,&nbsp;Victor L. Villemagne,&nbsp;Oscar L. Lopez,&nbsp;Milos D. Ikonomovic,&nbsp;Beth E. Snitz,&nbsp;Ann D. Cohen,&nbsp;Thomas K. Karikari","doi":"10.1002/alz.70409","DOIUrl":"https://doi.org/10.1002/alz.70409","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Most available phosphorylated tau (p-tau)217 immunoassays have similar performance. It is unclear if this is due to the use of the same antibody (the “ALZpath antibody”). We established and evaluated a novel p-tau217 assay that uses an alternative antibody and benchmarked the results against ALZpath-p-tau217.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>After development and analytical validation of the University of Pittsburgh (“Pitt-p-tau217”) method, clinical verification was performed in three independent cohorts (<i>n</i> = 363).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Pitt-p-tau217 demonstrated high between-run stability, linearity, and specificity. Clinically, Pitt-p-tau217 differentiated neuropathologically confirmed <i>PSEN1</i> mutation carriers from controls with area under the curve (AUC) = 0.94, and amyloid beta (Aβ) positron emission tomography (PET)–positive from Aβ PET–negative cognitively normal older adults with AUC up to 0.84, equivalent to ALZpath-p-tau217 results. Both Pitt-p-tau217 and ALZpath-p-tau217 were slightly elevated in tau PET–positive versus tau PET–negative participants. Between-assay correlations were up to 0.93.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>The new Pitt-p-tau217 assay exhibits high and reproducible classification accuracies for identifying individuals with biological evidence of Alzheimer's disease, equivalent to the widely used ALZpath-p-tau217.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>We designed and developed an alternative assay to quantify plasma phosphorylated tau (p-tau)217, aiming to enhance accuracy and enable early detection of Alzheimer's disease (AD).</li>\u0000 \u0000 <li>Comprehensive analytical and clinical validation demonstrated that the new p-tau217 assay is a valuable and affordable resource for investigating AD pathophysiology.</li>\u0000 \u0000 <li>The new p-tau217 assay showed similar performance to the established ALZpath assay in staging and monitoring early AD.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 7","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70409","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144635075","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}