Alzheimer's & Dementia最新文献

{"title":"Decoding adipose–brain crosstalk: Distinct lipid cargo in human adipose‐derived extracellular vesicles modulates amyloid aggregation in Alzheimer's disease","authors":"Li Yang, Michael Chan, Jianting Sheng, Shaohua Qi, Bill Chan, Dharti Shantaram, Xilal Y. Rima, Eduardo Reategui, Xianlin Han, Willa A. Hsueh, Stephen T. C. Wong","doi":"10.1002/alz.70603","DOIUrl":"https://doi.org/10.1002/alz.70603","url":null,"abstract":"INTRODUCTIONObesity is a major modifiable risk factor for Alzheimer's disease (AD), but the mechanistic link between peripheral metabolic dysfunction and AD progression remains unclear. Adipose‐derived extracellular vesicles (EVs) may penetrate the brain and alter lipid homeostasis, contributing to neurodegeneration.METHODSWe isolated exosome‐enriched EVs from subcutaneous and visceral fat of lean and obese individuals, followed by lipidomic profiling. An in vitro amyloid‐β (Aβ) aggregation assay using purified Aβ40 and Aβ42 peptides was performed under lipid environments mimicking physiological and pathological states.RESULTSObese‐derived EVs exhibited distinct lipid profiles, particularly in lysophosphatidylcholine (LPC) and sphingomyelin (SM) species. Functional assays demonstrated that lipid identity and concentration critically influenced Aβ aggregation kinetics.DISCUSSIONOur study reveals that obesity‐associated EV lipids modulate Aβ aggregation, linking adipose metabolism to AD pathology. These findings support lipid‐targeted strategies as potential therapeutics for neurodegenerative diseases.Highlights<jats:list list-type=\"bullet\"> <jats:list-item>Human adipose‐derived extracellular vesicles (EVs) from obese individuals exhibit distinct lipidomic profiles.</jats:list-item> <jats:list-item>EV lipids modulate amyloid‐β (Aβ) 40 and Aβ42 aggregation in a lipid‐type‐ and concentration‐dependent manner.</jats:list-item> <jats:list-item>Lysophosphatidylcholine (LPC) and sphingomyelin (SM) species from obese EVs significantly deregulate Aβ fibrillization in vitro.</jats:list-item> <jats:list-item>EV lipid cargo links peripheral metabolic state to amyloid pathology in Alzheimer's disease.</jats:list-item> </jats:list>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"100 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203250","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":"The PREVENT-AD cohort: Accelerating Alzheimer's disease research and treatment in Canada and beyond.","authors":"Sylvia Villeneuve, Judes Poirier, John C S Breitner, Jennifer Tremblay-Mercier, Jordana Remz, Jean-Michel Raoult, Yara Yakoub, Jonathan Gallego-Rudolf, Ting Qiu, Alfonso Fajardo Valdez, Bery Mohammediyan, Mohammadali Javanray, Amelie Metz, Safa Sanami, Valentin Ourry, Alfie Wearn, Alexandre Pastor-Bernier, Manon Edde, Julie Gonneaud, Cherie Strikwerda-Brown, Christine L Tardif, Claudine J Gauthier, Maxime Descoteaux, Mahsa Dadar, Étienne Vachon-Presseau, Andrée-Ann Baril, Simon Ducharme, Maxime Montembeault, Maiya R Geddes, Jean-Paul Soucy, Natasha Rajah, Robert Laforce, Christian Bocti, Christos Davatzikos, Lune Bellec, Pedro Rosa-Neto, Sylvain Baillet, Alan C Evans, D Louis Collins, M Mallar Chakravarty, Kaj Blennow, Henrik Zetterberg, R Nathan Spreng, Alexa Pichet Binette","doi":"10.1002/alz.70653","DOIUrl":"10.1002/alz.70653","url":null,"abstract":"<p><p>The PResymptomatic EValuation of Experimental or Novel Treatments for Alzheimer's Disease (PREVENT-AD) is an investigator-driven study that was created in 2011 and enrolled cognitively normal older adults with a family history of sporadic AD. Participants are deeply phenotyped and have now been followed annually for more than 12 years (median follow-up 8.0 years, SD 3.1). Multimodal magnetic resonance imaging (MRI), genetic, neurosensory, clinical, cerebrospinal fluid, and cognitive data collected until 2017 on 348 participants who agreed to open sharing with the neuroscience community were already available. We now share a new release including 6 years of additional follow-up cognitive data, and additional MRI follow-ups, clinical progression, new longitudinal behavioral and lifestyle measures (questionnaires, actigraphy), longitudinal AD plasma biomarkers, amyloid-beta and tau positron emission tomography (PET), magnetoencephalography, as well as neuroimaging analytic measures from all MRI modalities. We describe the PREVENT-AD study, the data shared with the global research community, as well as the model we created to sustain longitudinal follow-ups while also allowing new innovative data collection. HIGHLIGHTS: The PResymptomatic EValuation of Experimental or Novel Treatments for Alzheimer's Disease (PREVENT-AD) is a single-site longitudinal study that started in 2011 with annual follow-up data collection on individuals at risk of Alzheimer's disease who were all cognitively normal at enrolment. All 387 participants were enrolled between 2011 and 2017 and 306 (79%) of these participants were still in the study as of December 2023. While the PREVENT-AD dataset was not originally planned to be shared with the global research community, 348 participants retrospectively consented for their data to be shared with researchers worldwide. The first release of data was in 2019. We now share a second release that includes 6 years of additional follow-up visits, information on clinical progression and novel cognitive, behavioral, genetic, plasma and neuroimaging (amyloid and tau positron emission tomography [PET], magnetoencephalography [MEG], and new magnetic resonance imaging [MRI] sequences) data. It also includes analytic outputs for neuroimaging modalities.</p>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 10","pages":"e70653"},"PeriodicalIF":11.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12477627/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184425","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":"Recommendations for the development and use of technology to support people living with dementia and caregivers: A Delphi study.","authors":"Duygu Sezgin,Flora-Marie Hegerath-Segler,Hannah Christie,Jackie Poos,Kevin Cullen,Emer Meagher,Manuel Gonçalves-Pereira,Horst Christian Vollmar,Cíara O'Reilly,Aisling Mitchell,Salman Alabdulkder,David Neal,Sarah Janus","doi":"10.1002/alz.70755","DOIUrl":"https://doi.org/10.1002/alz.70755","url":null,"abstract":"INTRODUCTIONThis Delphi study, conducted by the INTERDEM Assistive Technology (AT) taskforce, explores existing and future challenges in the development, usability, cost-effectiveness, implementation, and ethics of AT for people living with dementia and caregivers. The study aims to identify key priorities and actions to address these challenges.METHODSA two-round modified electronic Delphi study was conducted with experts from health and social care, dementia research, technology development, people living with dementia, and caregivers.RESULTSConsensus was reached on 23 key statements highlighting the need for a user-centered approach to AT development. Priorities included integrating AT into care plans, enhancing accessibility, and ensuring collaboration between stakeholders. Ethical considerations, digital literacy, and equitable access were also emphasized.DISCUSSIONOur findings refine and update previous recommendations on AT development and use. This Delphi study contributes to guiding future research, policy, and practice to ensure AT effectively supports people living with dementia and caregivers.HIGHLIGHTSCo-designing technologies with users is crucial to ensure relevance and usability. Priorities in developing technology include improving access and affordability. Technology development should aim reducing disparities in digital access. Future research on technology should be inclusive and reflect real-life needs.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"155 1","pages":"e70755"},"PeriodicalIF":14.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182642","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":"Modeling presynaptic inhibition by the amyloid precursor protein demonstrates one potential mechanism for preventing runaway synaptic modification in Alzheimer's disease.","authors":"Dylan Barber,Michael E Hasselmo,Heather C Rice","doi":"10.1002/alz.70748","DOIUrl":"https://doi.org/10.1002/alz.70748","url":null,"abstract":"INTRODUCTIONPrevious simulations of Hebbian associative memory models inspired the malignant synaptic growth hypothesis of Alzheimer's disease (AD), which suggests that cognitive impairments arise due to runaway synaptic modification resulting from poor separation between encoding and retrieval.METHODSWe computationally model presynaptic inhibition by the recently identified interaction of soluble amyloid precursor protein alpha (sAPPα) with γ-aminobutyric acid type B receptor (GABABR) as one potential biological mechanism that can enhance separation between encoding and retrieval.RESULTSSimulations predict that the dual effect of sAPPα on long-term potentiation and presynaptic inhibition of glutamatergic synapses maintains effective associative memory function and prevents runaway synaptic modification. Moreover, computational modeling predicts that sAPPα, which interacts with the 1a isoform of GABABR, is more effective than the GABABR agonist baclofen at stabilizing associative memory.DISCUSSIONMolecular mechanisms that enhance presynaptic inhibition, such as sAPPα-GABABR1a signaling, are potential therapeutic targets for preventing cognitive impairments in AD.HIGHLIGHTSComputational modeling of Hebbian associative memory provides a framework for understanding the functional basis of Alzheimer's disease. Soluble amyloid precursor protein (sAPPα) presynaptic activation of γ-aminobutyric acid B (GABAB) receptors prevents runaway synaptic modification in associative memory models. sAPPα is more effective than baclofen at stabilizing associative memory.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"75 1","pages":"e70748"},"PeriodicalIF":14.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145189371","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":"Evidence-based standardized sample handling protocol for accurate blood-based Alzheimer's disease biomarker measurement: Results and consensus of the Global Biomarker Standardization Consortium.","authors":"Inge M W Verberk,Mariam Gouda,Daniel Antwi-Berko,Mardou van Leeuwenstijn,Bram Bongers,Isabel M Houtkamp,Wiesje M van der Flier,Shorena Janelidze,Oskar Hansson,Nathalie Le Bastard,Manu Vandijck,Jacob Hunter,Lee Honigberg,Kristopher M Kirmess,Philip B Verghese,Kaj Blennow,Henrik Zetterberg,Emily A Meyers,Rebecca M Edelmayer,Charlotte Teunissen","doi":"10.1002/alz.70752","DOIUrl":"https://doi.org/10.1002/alz.70752","url":null,"abstract":"INTRODUCTIONBlood-based biomarkers (BBMs) have revolutionized Alzheimer's disease diagnosis and monitoring. Their pre-analytical stability requires scrutiny. This study assessed pre-analytical effects to inform a standardized sample handling protocol.METHODSAssessed pre-analytical variations included collection tube type, hemolysis, centrifugation settings, centrifugation/storage delays, tube transfers, and freeze-thawing (n = 15/experiment). Phosphorylated tau (pTau) isoforms were measured with Simoa, Lumipulse, MesoScale Discovery, and immunoprecipitation-mass spectrometry. Amyloid-beta (Aβ42, Aβ40), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) protein were measured with Simoa.RESULTSAll assessed BBM levels varied by over 10% by collection tube type. Aβ peptides were the most sensitive, and their levels declined >by more than 10% under storage and centrifugation delays, more steeply at room temperature (RT) compared with 2°C to 8°C. NfL and GFAP levels increased by more than 10% upon RT/-20°C storage. pTau isoforms demonstrated stability across most pre-analytical variations.DISCUSSIONWe established an evidence-based handling protocol to ensure reliable sample handling for neurological BBMs upon adoption in clinics, trials, and research.HIGHLIGHTSSample handling protocols can mitigate pre-analytical effects on BBM results. We developed an evidence-based, expert-consensus plasma sample handling protocol. Primary collection tube and delays to centrifuging or freezing impact AD BBMs. Plasma pTau217 is highly resistant to pre-analytical sample handling variations. Plasma Aβ42 and Aβ40 were most sensitive to pre-analytical variations.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"23 1","pages":"e70752"},"PeriodicalIF":14.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145189483","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":"Plasma p-tau217, NfL, GFAP diagnostic performance and biomarker profiles in Alzheimer's disease, frontotemporal dementia, and psychiatric disorders, in a prospective unselected neuropsychiatry memory clinic.","authors":"Dhamidhu Eratne, Matthew Kang, Charles B Malpas, Christa Dang, Courtney Lewis, Oneil G Bhalala, Qiao-Xin Li, Steven Collins, Colin L Masters, Samantha M Loi, Alexander F Santillo, Kaj Blennow, Henrik Zetterberg, Dennis Velakoulis","doi":"10.1002/alz.70717","DOIUrl":"10.1002/alz.70717","url":null,"abstract":"<p><strong>Introduction: </strong>Plasma biomarkers offer promise for improving the diagnosis of Alzheimer's disease (AD) and differentiating AD and other neurodegenerative disorders (NDs) like frontotemporal dementia (FTD) from primary psychiatric disorders (PPDs), particularly in younger patients.</p><p><strong>Methods: </strong>In this prospective study, we investigated plasma phosphorylated tau 217 (p-tau217), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) in 341 unselected participants from a neuropsychiatry memory clinic, including AD (n = 40), behavioral variant FTD (bvFTD) (n = 15), PPD (n = 69), other NDs, and controls.</p><p><strong>Results: </strong>Plasma p-tau217 showed strong diagnostic performance for distinguishing AD from bvFTD (96% accuracy) and PPD (93% accuracy). NfL best distinguished all NDs from PPD, while GFAP did not bring additional value. Biomarker profiles using predefined cut-offs and age-adjusted z-scores further clarified group differences.</p><p><strong>Discussion: </strong>Plasma p-tau217 and NfL have strong diagnostic utility in real-world, diagnostically complex cohorts. These findings support implementation of scalable blood-based biomarkers to improve early and accurate diagnosis in memory clinical settings.</p><p><strong>Highlights: </strong>Plasma p-tau217 was significantly elevated in AD compared to other disorders. P-tau217 distinguished AD from bvFTD with high accuracy. P-tau217 distinguished AD from PPDs with high accuracy. NfL/p-tau217 ratio and GFAP added limited diagnostic value compared to p-tau217 and NfL. Findings support blood biomarkers in younger, real-world clinical cohorts.</p>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 10","pages":"e70717"},"PeriodicalIF":11.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12481210/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145190690","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":"Evaluation of hippocampal DLGAP2 overexpression on cognition, synaptic function, and dendritic spine structure in a translationally relevant AD mouse model.","authors":"Andrew Ouellette, Kristen O'Connell, Catherine Kaczorowski","doi":"10.1002/alz.70728","DOIUrl":"10.1002/alz.70728","url":null,"abstract":"<p><strong>Introduction: </strong>Developing effective therapeutics for Alzheimer's disease (AD) requires a better understanding of the molecular drivers of the disease. Our previous work nominated DLGAP2 as a modifier of age-related cognitive decline and risk for AD. We tested the hypothesis that overexpression of DLGAP2 in the hippocampus would protect against cognitive and synaptic deficits in a susceptible F1 5XFAD model.</p><p><strong>Methods: </strong>DLGAP2 was overexpressed in the hippocampus of F1 hybrid 5XFAD and non-transgenic littermates using a viral approach. Cognitive function, electrophysiological properties, and dendritic spine morphology were assessed at 6 and 14 months of age.</p><p><strong>Results: </strong>DLGAP2 overexpression impaired synaptic plasticity and exacerbated AD-related memory deficits but had minimal effect on spine structure or intrinsic neuronal properties.</p><p><strong>Discussion: </strong>We highlight the complex role of DLGAP2 in AD pathology. Targeted interventions involving postsynaptic proteins must consider potential adverse effects on synaptic integrity and cognitive performance, particularly in the context of AD.</p><p><strong>Highlights: </strong>DLGAP2 overexpression accelerates AD-related impairment of contextual fear acquisition and memory. DLGAP2 overexpression impairs synaptic plasticity prior to AD-related memory impairment, but not intrinsic excitability. Effect of DLGAP2 overexpression on thin spine density was blunted in AD mice from in vivo dendritic spine results that were replicated in cultured rodent neurons.</p>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 10","pages":"e70728"},"PeriodicalIF":11.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12481162/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145190719","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":"Calibration of multisite raters for prospective visual reads of amyloid PET scans.","authors":"David N Soleimani-Meigooni,Stefania Pezzoli,Ganna Blazhenets,Renaud La Joie,Zoe Lin,Carol L Soppe,Derek R Johnson,Mary Ellen I Koran,Jonathan E McConathy,Ilya M Nasrallah,Maria Rosana Ponisio,Jeremy A Tanner,Victor L Villemagne,Charles C Windon,Michael Zeineh,Sarah Biber,Walter A Kukull,Heather O'Connell,Daniel J Peterson,Elizabeth C Mormino,Sterling C Johnson,Gil D Rabinovici, , , ","doi":"10.1002/alz.70732","DOIUrl":"https://doi.org/10.1002/alz.70732","url":null,"abstract":"INTRODUCTIONIn multicenter Alzheimer's disease studies, amyloid positron emission tomography (PET) visual reads are typically performed centrally by a few experts. Incorporating a broader reader network enhances scalability and generalizability.METHODSTen neuroimaging experts from eight Alzheimer's Disease Research Centers (ADRCs) visually read 180 amyloid PET scans (30 scans and 15 duplicate scans for each of four tracers, imaged across a wide variety of scanners), using preferred reading software without anatomical imaging or quantitation. Scans were classified as elevated or non-elevated per tracer-specific criteria. Inter- and intra-rater agreement was assessed.RESULTSInter-rater agreement was substantial (Fleiss' κ = 0.78), with full consensus on 69% of scans. Inter-rater reliability was substantial to perfect across tracers (Fleiss' κ = 0.70-0.87). Intra-rater agreement was substantial to perfect (Cohen's κ = 0.79-1). Scans with intermediate (10-40 Centiloid) quantitation had lower reader agreement.DISCUSSIONA multicenter expert network achieved substantial agreement classifying amyloid PET scans. These scans provide a standard for reader training and reliability assurance in future studies.HIGHLIGHTSCalibration methods ensure reliable amyloid positron emission tomography (PET) visual reads across multiple raters. Substantial agreement is possible across readers using their preferred tools. Agreement is also substantial regardless of the amyloid PET tracer used. Scans with intermediate (10-40 Centiloid) quantitation have lower reader agreement. The calibration set will become a training tool for amyloid PET visual read studies.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"2 1","pages":"e70732"},"PeriodicalIF":14.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194519","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":"Defining the contributions of tau pathology in the amygdala to increasing depressive symptoms in aging.","authors":"Teodora Z Markova,Corrina S Fonseca,Claire J Ciampa,Alice Murphy,Susan Landau,Theresa M Harrison,Anne S Berry, ","doi":"10.1002/alz.70740","DOIUrl":"https://doi.org/10.1002/alz.70740","url":null,"abstract":"BACKGROUNDAmygdala tau accumulates in cognitively normal individuals and may contribute to neuropsychiatric changes.METHODSUsing data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), we investigated relationships among cross-sectional and longitudinal tau ([18F]Flortaucipir [FTP] positron emission tomography), changes in depressive symptoms and memory, and amyloid beta and apolipoprotein E (APOE) ε4 status. We report secondary analyses from the Berkeley Aging Cohort Study (BACS).RESULTSLongitudinal increases in depressive symptoms were associated with higher baseline FTP and increasing FTP in the amygdala. Relationships between FTP and depressive symptoms were strongest in APOE ε4 carriers, with moderation effects replicating in BACS. Entorhinal FTP did not show associations with depressive symptoms beyond variance explained by the amygdala but showed some specific associations with memory decline.DISCUSSIONOur findings indicate the strongest coupling between tau accumulation and depressive symptoms in APOE ε4 carriers and reinforce the importance of amygdala tau in understanding neuropsychiatric changes in older adults.HIGHLIGHTSThere is a lack of research focused on the role of tau in the amygdala in cognitively normal older adults. Amygdala tau is related to both worsening depressive symptoms and declining memory performance. APOE ε4 carriers seem to drive positive tau-depressive symptom associations. Focusing on the amygdala tau is useful for understanding neuropsychiatric trajectories in cognitively unimpaired older adults.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"46 1","pages":"e70740"},"PeriodicalIF":14.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194516","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":"Generational effects in Down syndrome: Enriched environment enhances functionality without reducing Alzheimer's disease risk.","authors":"Lídia Vaqué-Alcázar,Laura Videla,Bessy Benejam,Laura Del Hoyo Soriano,Isabel Barroeta,Susana Fernandez,Íñigo Rodríguez-Baz,José Enrique Arriola-Infante,Javier Arranz,Lucía Maure Blesa,Aida Sanjuan-Hernández,Alejandra O Morcillo-Nieto,Alexandre Bejanin,Eider M Arenaza-Urquijo,Alberto Lleó,David Bartrés-Faz,Maria Carmona-Iragui,Juan Fortea","doi":"10.1002/alz.70447","DOIUrl":"https://doi.org/10.1002/alz.70447","url":null,"abstract":"INTRODUCTIONDown syndrome (DS) is the leading cause of intellectual disability (ID) and a genetic form of Alzheimer's disease (AD). We wanted to assess whether generational changes have induced (1) milder ID with greater independence and (2) delayed AD diagnosis.METHODSWe analyzed 681 asymptomatic DS to test generational effects on ID, functionality, and cognition. In 353 DS individuals with AD, we compared clinical diagnosis age by ID using analysis of variance. In addition, dementia diagnosis age was examined through a published meta-analysis.RESULTSOur results indicate a generational shift toward a higher proportion of individuals with mild/moderate ID, greater intelligence, and autonomy. However, it was not paralleled by an ID-related delay in the age at AD onset in our cohort, or by generational delays reported over the past 35 years.DISCUSSIONThe findings highlight notable generational improvements in DS, but no effects on the age at AD dementia diagnosis.HIGHLIGHTSA generational effect has reduced the severity of intellectual disability in Down syndrome (DS). Individuals with DS have increased autonomy and improved intellectual milestones. The enriched environment has not delayed the age at Alzheimer's disease (AD) dementia in DS. Further studies should confirm if cognitive reserve might delay AD in DS.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"36 1","pages":"e70447"},"PeriodicalIF":14.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145209147","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}