Alzheimer's & Dementia最新文献

{"title":"Impact of kidney function on biomarkers of neurodegeneration, white matter hyperintensities, and cognition in older adults","authors":"Anisa Dhana,&nbsp;Charles S. DeCarli,&nbsp;Klodian Dhana,&nbsp;Pankaja Desai,&nbsp;Kristin Krueger,&nbsp;Kyle Dennis,&nbsp;Ted K. S. Ng,&nbsp;Denis Evans,&nbsp;Kumar B. Rajan","doi":"10.1002/alz.70397","DOIUrl":"10.1002/alz.70397","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> BACKGROUND</h3>\u0000 \u0000 <p>We evaluated the association between kidney function, neurodegenerative biomarkers (i.e., neurofilament light chain [NfL], total tau [t-tau], and glial fibrillary acidic protein [GFAP]), white matter hyperintensities, and global cognition.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>The study consisted of 1207 participants living on the south side of Chicago, Illinois, enrolled in the Chicago Health and Aging Project, a population-based cohort since 1993. Kidney function was assessed using the estimated glomerular filtration rate (eGFRcr), calculated according to the 2021 Chronic Kidney Disease Epidemiology (CKD-EPI) based on age, sex, and serum creatinine levels.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>In a multivariable-adjusted model, lower levels of eGFRcr were associated with higher levels of biomarkers of neurodegeneration. Specifically, for a 1-SD decrease of eGFRcr, there was a 22% increase in NfL levels in serum. eGFRcr levels were not associated with white matter hyperintensities or global cognition.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>Kidney function may be considered when interpreting NfL, GFAP, and t-tau levels for risk stratification in research and clinical applications.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Kidney function is associated with higher neurfilament light chain (NfL), total tau (t-tau), and glial fibrillary acidic protein (GFAP) serum concentrations, while there was no association with white matter hyperintensities or global cognition.</li>\u0000 \u0000 <li>Individuals with severely impaired kidney function had 146.7% higher serum concentrations of NfL when compared to people with normal kidney function.</li>\u0000 \u0000 <li>This study suggests assessing kidney function in older adults when interpreting NfL, GFAP, and t-tau levels in the serum for risk stratification.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 10","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://alz-journals.onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70397","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145282795","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":"Impact of cerebral small vessel disease on cognitive outcomes in early age at onset MCI and dementia: Findings from the DIASPORA study","authors":"Jonathan Naftali,&nbsp;Amir Glik,&nbsp;Ruth Eliahou,&nbsp;Gil D Rabninovici,&nbsp;Howar J Rosen,&nbsp;Fanny Elahi,&nbsp;Felix Benninger,&nbsp;Ilan Goldberg,&nbsp;Eitan Auriel,&nbsp;Ophir Keret","doi":"10.1002/alz.70773","DOIUrl":"10.1002/alz.70773","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> BACKGROUND</h3>\u0000 \u0000 <p>This study assessed the impact of cerebral small vessel disease (CSVD) on cognition in individuals with early-onset (EO; &lt;65 years) and late-onset (LO; ≥65 years) cognitive complaints.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>Participants underwent prospective evaluations including cognitive testing, hyperphosphorylated tau-217 (p-tau217) and neurofilament-light-chain (NfL), and magnetic resonance imaging (MRI). Each CSVD marker was modeled for interaction with group age on results on cognitive outcomes: Montreal Cognitive Assessment (MoCA), Mini-Mental State Examination (MMSE), Neuropsychiatric Inventory Questionnaire (NPI-Q), and Clinical Dementia Rating (CDR) scale plus National Alzheimer's Coordinating Center–Frontotemporal Lobar Degeneration module (NACC-FTLD).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Altogether, 168 patients (91 EO) were included. white matter hyperintensity (WMH) volume was associated with worse CDR+NACC-FTLD in EO (<i>β </i>= 17.8, <i>p </i>= 0.013), remaining significant after adjusting for p-tau217 and NfL, but not gray matter atrophy. Lacunes were associated with worse CDR plus NACC-FTLD in EO (<i>β </i>= 4.3, <i>p </i>= 0.011), with age-dependent associations with MoCA, MMSE, CDR + NACC-FTLD, and NPI-Q (<i>p</i> &lt; 0.01).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>CSVD markers, although less prevalent in EO, had greater clinical impact. These findings highlight an increased vulnerability to vascular pathology in EO patients and the importance of early detection.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Cerebral small vessel disease (CSVD) markers were more impactful in early-onset than late-onset dementia.</li>\u0000 \u0000 <li>White matter hyperintensity (WMH) volume predicted functional decline in early onset, independent of neurodegeneration.</li>\u0000 \u0000 <li>Lacunes showed age-dependent effects on multiple cognitive outcomes.</li>\u0000 \u0000 <li>Findings support early detection of CSVD in younger individuals with dementia.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 10","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12519510/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145285470","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":"Cerebrospinal fluid proteomic associations of APOE genotypes reveal distinct protective and risk mechanisms for Alzheimer's disease","authors":"Eleonora M. Vromen,&nbsp;Senne B. Lageman,&nbsp;Johan Gobom,&nbsp;Rik van der Kant,&nbsp;Valerija Dobricic,&nbsp;Lars Bertram,&nbsp;Johannes Streffer,&nbsp;Simon Lovestone,&nbsp;Stephanie J. B. Vos,&nbsp;Mikel Tainta,&nbsp;Yvonne Freund-Levi,&nbsp;Lutz Frölich,&nbsp;Julius Popp,&nbsp;Gwendoline Peyratout,&nbsp;Magda Tsolaki,&nbsp;Frans Verhey,&nbsp;Rik Vandenberghe,&nbsp;Jolien Schaeverbeke,&nbsp;Kaj Blennow,&nbsp;Sven J. van der Lee,&nbsp;Philip Scheltens,&nbsp;Yolande A. L. Pijnenburg,&nbsp;Wiesje M. van der Flier,&nbsp;Charlotte E. Teunissen,&nbsp;Henrik Zetterberg,&nbsp;Pieter Jelle Visser,&nbsp;Betty Tijms","doi":"10.1002/alz.70738","DOIUrl":"10.1002/alz.70738","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> BACKGROUND</h3>\u0000 \u0000 <p>The apolipoprotein E (<i>APOE</i>) gene includes the strongest protective (ε2) and risk (ε4) variants for sporadic Alzheimer's disease (AD), but underlying mechanisms remain unclear. We studied <i>APOE</i> genotype effects on the cerebrospinal fluid (CSF) proteome.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>Using untargeted tandem mass tag mass spectrometry, we analyzed CSF from 227 cognitively normal (CN) controls (A–T–), 165 CN A+, and 177 individuals with mild cognitive impairment (MCI A+) from two large cohorts. We compared protein levels across <i>APOE</i> genotypes using linear regression and characterized biological pathways.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Five hundred forty-nine of 978 proteins (56%) differed between ε2/ε3 (<i>n</i> = 32 individuals) or ε4 carriers (<i>n</i> = 181 individuals) and ε3/ε3 controls. ε2/ε3 controls showed the most differences, with higher levels of 280 proteins enriched for neuronal plasticity. ε4 carrier controls showed increased proteins linked to blood–brain barrier dysfunction, and A+ ε4 carriers were related to glucose metabolism.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>Combining two cohorts enabled analysis of the rare <i>APOE</i> ε2 genotype, suggesting protective effects may occur through improved neuronal plasticity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Apolipoprotein E (<i>APOE</i>) genotypes show distinct cerebrospinal fluid proteomic mechanisms in early Alzheimer's disease (AD).</li>\u0000 \u0000 <li>Combining cohorts enabled analysis of rare <i>APOE</i> ε2–associated protection in AD.</li>\u0000 \u0000 <li>The rare ε2 genotype may confer protection through improved neuronal plasticity.</li>\u0000 \u0000 <li><i>APOE</i> ε4 carriers show increased blood–brain barrier dysfunction and glucose metabolism.</li>\u0000 \u0000 <li>These findings offer new insights into genotype-specific mechanisms in early AD.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 10","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://alz-journals.onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70738","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145282747","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":"Blood-based pre-screening in the SKYLINE secondary prevention Ph3 gantenerumab study","authors":"Alina Bauer,&nbsp;Christina Rabe,&nbsp;Courtney Schiffman,&nbsp;Fiona Rose,&nbsp;Gesine Respondek,&nbsp;Fabiana Gullotta,&nbsp;Laura Schlieker,&nbsp;Alexander Jethwa,&nbsp;Isabelle Schrurs,&nbsp;Ekaterina Manuilova,&nbsp;Susanne Ostrowitzki,&nbsp;Tobias Bittner","doi":"10.1002/alz.70676","DOIUrl":"10.1002/alz.70676","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>SKYLINE was a secondary prevention study that used blood-based biomarker (BBBM) pre-screening to screen out participants with a low likelihood of amyloid positivity by positron emission tomography (PET) or cerebrospinal fluid (CSF) testing.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>This retrospective analysis used data from SKYLINE (ClinicalTrials.gov: NCT05256134; terminated prematurely) and the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study to compare predicted and actual clinical performance characteristics of various biomarker combinations using prototype Elecsys^® plasma immunoassays (Roche Diagnostics International Ltd, Rotkreuz, Switzerland).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>In &gt;3500 participants screened in SKYLINE, tau phosphorylated at threonine 181 (pTau181) and apolipoprotein E4 protein (ApoE4p) was the highest-performing BBBM combination. Actual clinical performance of the BBBM pre-screening in SKYLINE was similar to predictions based on A4 in terms of screen-out rate, positive predictive value, and 1-negative predictive value.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>BBBM pre-screening in SKYLINE using prototype plasma pTau181 and ApoE4p immunoassays effectively alleviated participant burden by avoiding unnecessary PET or CSF testing.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>We compared blood-based biomarker (BBBM) performance in SKYLINE and Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4).</li>\u0000 \u0000 <li>Pre-screening improved amyloid positivity (defined by positron emission tomography/cerebrospinal fluid) screen failure rate.</li>\u0000 \u0000 <li>Tau phosphorylated at threonine 181 (pTau181) and apolipoprotein E4 protein was the highest-performing combination among BBBMs tested.</li>\u0000 \u0000 <li>Pre-screening eased participant burden by reducing subsequent screening procedures.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 10","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12519518/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145285480","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":"Culturally sensitive CLEAR guidelines on disclosing and communicating a diagnosis of dementia","authors":"Zahinoor Ismail,&nbsp;Saskia Sivananthan,&nbsp;Sarah Main,&nbsp;Alixe Ménard,&nbsp;Jhnelle McLaren-Beato,&nbsp;Larry W. Chambers,&nbsp;Vivian Welch,&nbsp;Isabelle Vedel,&nbsp;Eric E. Smith,&nbsp;Vivian Ewa,&nbsp;Sid Feldman","doi":"10.1002/alz.70744","DOIUrl":"10.1002/alz.70744","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Providing a dementia diagnosis is challenging, especially in primary care and considering diverse patient backgrounds. The Alzheimer Society of Canada (ASC), the College of Family Physicians of Canada, and the Canadian Consensus Conference on the Diagnosis and Treatment of Dementia (CCCDTD) guideline group partnered with patients, care partners, and clinicians to generate contemporaneous guidance for primary care practitioners. While relevant to all communities, Black and Chinese Canadians were formally represented in working groups. A literature review identified needs areas. Informed by Guidelines International Network (GIN) principles and through iterative group meetings with all partners, these needs were explored and incorporated into guidance. The Compassionate Language and Empathetic Approaches for Respectful Dementia Disclosure (CLEAR) offers recommendations on: holistic engagement, fostering hope, acknowledging care partners, identifying disclosing clinicians, appointment structure and environment, person-centered communication, specific discussion topics, and emotional supports, all through a cultural competence lens. These guidelines address communication challenges in disclosing a dementia diagnosis and enhancing care and support for persons living with dementia and their care partners.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Healthcare practitioners (HCPs) struggle with disclosing and communicating dementia diagnoses.</li>\u0000 \u0000 <li>Guidance is limited in primary care and different patient ethnocultural groups.</li>\u0000 \u0000 <li>We developed culturally sensitive guidelines with scripts and practical materials.</li>\u0000 \u0000 <li>Appropriate communication techniques and terminology are recommended in Compassionate Language and Empathetic Approaches for Respectful Dementia Disclosure (CLEAR).</li>\u0000 \u0000 <li>Patient-centered and holistic approaches for the patient and care partner are emphasized.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 10","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://alz-journals.onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70744","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145282793","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":"GRPa-PRS: A risk stratification method to identify genetically-regulated pathways in polygenic diseases","authors":"Xiaoyang Li,&nbsp;Brisa S. Fernandes,&nbsp;Andi Liu,&nbsp;Jingchun Chen,&nbsp;Xiangning Chen,&nbsp;Zhongming Zhao,&nbsp;Yulin Dai","doi":"10.1002/alz.70779","DOIUrl":"10.1002/alz.70779","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Polygenic risk score (PRS) assesses genetic risk for diseases, yet some high-risk individuals avoid illness while low-risk individuals develop it. We hypothesize that unknown counterfactors may reverse PRS predictions, offering insights into disease mechanisms and interventions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>We developed a novel framework to identify genetically-regulated pathways (GRPas) using PRS-based stratification in Alzheimer's disease (AD) and schizophrenia (SCZ) cohorts. We calculated PRS models, stratified individuals by risk and diagnosis, and analyzed differential GRPas. For AD, analyses were further conducted with and without apolipoprotein E (<i>APOE)</i> effects, and across <i>APOE</i> haplotype.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>In AD, we identified several well-known AD-related pathways, including amyloid-beta clearance, tau protein binding, and resilience-related calcium signaling pathway, and divalent inorganic cation homeostasis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>Our method offers flexibility for exploring GRPas among PRS-stratified subgroups using summary statistics or individual-level data. Fewer GRPas identified in the no-APOE AD model and SCZ suggest a more polygenic architecture, necessitating larger samples to detect significant GRPas.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Characterize genetically-regulated expression (GReX) among groups stratified by polygenic risk score (PRS)</li>\u0000 \u0000 <li>Leverage GReX and PRS to explore the resilience and susceptibility at the pathway level</li>\u0000 \u0000 <li>Highlight calcium signaling and cation homeostasis functions linked to resilience</li>\u0000 \u0000 <li>Enable personalized prevention by reinforcing the different resilience factors present or absent in each individual</li>\u0000 \u0000 <li>Our genetically-regulated pathway (GRPa) -PRS framework can be further expanded to other complex polygenic traits</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 10","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://alz-journals.onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70779","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145282800","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":"TREM2-apoE3 interactions and Alzheimer's disease: Molecular and structural insights and effects of TREM2 R47H and apoE4 variants","authors":"Rory A. Greer,&nbsp;Ryan A. Tuckey,&nbsp;Hunter B. Dean,&nbsp;Thomas J. Brett,&nbsp;Erik D. Roberson,&nbsp;Yuhua Song","doi":"10.1002/alz.70729","DOIUrl":"10.1002/alz.70729","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Triggering receptor expressed on myeloid cells 2 (TREM2) and apolipoprotein E (apoE) are among the strongest Alzheimer's disease (AD) genetic risk factors. TREM2 and apoE3 direct interaction has been established; however, molecular and structural insight into TREM2–apoE3 interactions and effects of AD-associated variants on TREM2–apoE3 interactions are not fully understood.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>We used consensus protein–protein docking and molecular dynamics simulations to determine an experimentally consistent TREM2–apoE3 complex structure and examine AD-associated TREM2 R47H, and apoE4 variants effects.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Our experimentally consistent TREM2–apoE3 complex structure identified new potential TREM2–apoE3 interactions alongside the known interactions. TREM2–apoE3 interactions impacted TREM2 and apoE3 structures and conformations. AD-associated TREM2 R47H and apoE4 variants altered TREM2–apoE binding mode and conformational stability.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>This study determined an experimentally consistent TREM2–apoE3 complex structure and revealed a potential mechanism that AD-associated TREM2 R47H variant alters TREM2–apoE3 binding mode. Understanding TREM2–apoE interactions is important for developing therapeutics that regulate this interaction and prevent lost binding in AD-associated variants.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Triggering receptor expressed on myeloid cells 2 (<i>TREM2</i>) and apolipoprotein E (<i>APOE</i>) are two strong genetic risk factors for Alzheimer's disease (AD).</li>\u0000 \u0000 <li>An experimentally consistent TREM2–apoE3 complex structure was determined.</li>\u0000 \u0000 <li>New potential interaction interfaces between TREM2 and apoE3 were identified.</li>\u0000 \u0000 <li>TREM2–apoE3 interactions altered TREM2 and apoE3 conformation.</li>\u0000 \u0000 <li>AD-associated TREM2 R47H variant shifted apoE3 binding TREM2 into multimerization site. ApoE4 destabilized TREM2 and apoE conformations in TREM2–apoE complexes.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 10","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://alz-journals.onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70729","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145282746","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":"Employment, volunteering, and health-related resource use in pre-symptomatic AD: Results from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study","authors":"Carolyn W. Zhu,&nbsp;Charlene Flournoy,&nbsp;Rema Raman,&nbsp;Mary Sano","doi":"10.1002/alz.70641","DOIUrl":"10.1002/alz.70641","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;Little is known about productive time use and health-related resource use during “pre-symptomatic” AD, defined by the presence of brain amyloid in the absence of cognitive symptoms. We compared changes in resource use and participation in paid employment and/or volunteering in cognitively unimpaired older adults with amyloid accumulation (Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease [A4] study, &lt;i&gt;N&lt;/i&gt; = 1165) to otherwise matched participants without amyloid accumulation (Longitudinal Evaluation of Amyloid Risk and Neurodegeneration [LEARN] study, &lt;i&gt;N&lt;/i&gt; = 507).&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;Health-related resource use was self-reported using the Resource Use Inventory (RUI). Longitudinal analyses examined effect on RUI from study (A4 vs LEARN), time, and their interaction, controlling for Alzheimer's Disease Cooperative Study-Preclinical Alzheimer's Cognitive Composite (ADCS-PACC) and the Clinical Dementia Rating (CDR) scale, and their change scores from baseline.&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;Over time, paid employment and volunteering decreased, and unpaid help and hospitalization increased. Results showed clear associations between ADCS-PACC and CDR with RUI.&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;Little detectable impact of amyloid levels on RUI was found in pre-symptomatic AD that has been identified as an ideal stage to target for dementia prevention.&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;Using data from a cohort of cognitively unimpaired older adults with evidence of amyloid accumulation enrolled in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study and otherwise matched participants who did not meet subthreshold levels of amyloid accumulation enrolled in the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study, this study showed clear associations between clinical variables and resource use and participation in paid employment and volunteering but suggested little detectable impact of amyloid levels on rate of change during the preclinical stage.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Our results suggest that economic benefits from currently available treatment that effectively removes amyloid may not be immediately or concurrently observed during the short timeline of clinical trials.&lt;/li&gt;\u0000 ","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 10","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://alz-journals.onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70641","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145282796","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":"Complementary utility of plasma biomarkers and Aβ-PET for diagnosis, risk-stratification, and treatment monitoring in Alzheimer's disease","authors":"Lyduine E. Collij,&nbsp;Niklas Mattsson-Carlgren,&nbsp;Shorena Janelidze,&nbsp;Rik Ossenkoppele,&nbsp;Oskar Hansson","doi":"10.1002/alz.70763","DOIUrl":"10.1002/alz.70763","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>With the rapid development of blood biomarkers (BBMs) related to amyloid-β (Aβ) pathology in Alzheimer's disease (AD), the question arises whether these can replace the accepted reference standard, positron emission tomography (PET), for assessing Aβ burden. BBMs can differentiate Aβ status reliably in cognitively impaired patients, but two-threshold strategies to further improve their performance demonstrate the need for pathological confirmation by Aβ-PET in a non-negligible portion of individuals (∼10%–40%), especially in early-stage disease where BBM performance declines due to lower AD prevalence, reducing the test's positive predictive value (PPV) and increasing the risk for false-positives. This may be increasingly relevant in the future, considering the development of (very) early interventions against AD. Further, BBMs do not accurately reflect the actual Aβ load or change after immunotherapy. Consequently, there are clear remaining needs for Aβ-PET in several clinically important settings as (i) a confirmatory test and (ii) to determine treatment response.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>When used as stand-alone tests, blood biomarkers (BBMs) demonstrate good sensitivity and specificity (84%–90%) relative to amyloid-β positron emission tomography (Aβ-PET).</li>\u0000 \u0000 <li>Two-threshold strategies improve BBM performance but require confirmatory testing by, for example, Aβ-PET in a non-negligible portion of patients that fall in an intermediate range or “gray-zone” (∼10%–40%).</li>\u0000 \u0000 <li>In early/preclinical populations, BBM performance declines due to lower AD prevalence, reducing the test's positive predictive value (PPV) and increases the gray-zone population.</li>\u0000 \u0000 <li>Currently available BBMs cannot reliably estimate Aβ-PET burden or track Aβ-plaque removal post-immunotherapy.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 10","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://alz-journals.onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70763","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145288303","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":"Anticholinergics, executive function, and cognitive/behavioral changes in Down syndrome","authors":"Nancy Raitano Lee,&nbsp;Goldie A. McQuaid,&nbsp;Haila Jiddou,&nbsp;Jessica McNulty,&nbsp;Hannah E. Grosman,&nbsp;Kamaria T. Tucker,&nbsp;Meghan O'Brien,&nbsp;Gregory L. Wallace","doi":"10.1002/alz.70649","DOIUrl":"10.1002/alz.70649","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Anticholinergic (AC) medication use is considered a risk factor for cognitive impairment and deterioration in the general population; yet, this has not been examined in Down syndrome (DS), a disorder with high dementia rates.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>Family members of 108 young adults with DS (18–39 years) reported on their loved one's medication use, executive function, and changes in cognition and behavior using a dementia screener. Medications were coded for their AC potency using the CRIDECO Anticholinergic Load Scale (CALS).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Forty percent of the sample was taking at least one medication with a CALS AC potency of ≥1. These individuals were reported to have greater executive function difficulties and more changes in cognition/behavior relative to those not taking AC medications.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>AC medication use may represent a modifiable risk factor for cognitive deterioration in adults with DS; more research on this topic, particularly with older adults with DS, is needed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Identifying modifiable risk factors for dementia in Down syndrome (DS) is critical.</li>\u0000 \u0000 <li>A risk factor studied in the general population is anticholinergic (AC) medication.</li>\u0000 \u0000 <li>This risk factor has not been studied in DS, a high-risk group.</li>\u0000 \u0000 <li>AC medication use was associated with everyday cognitive challenges in young adults with DS.</li>\u0000 \u0000 <li>Longitudinal studies across adulthood, including older adults with DS, are needed.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 10","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12516352/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145278881","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}