Alzheimer's & Dementia最新文献

{"title":"Synaptic and extrasynaptic distribution of NMDA receptors in the cortex of Alzheimer's disease patients","authors":"Sergio Escamilla, Raquel Badillos, Joan X. Comella, Montse Solé, Isabel Pérez‐Otaño, Jose V. Sánchez Mut, Javier Sáez‐Valero, Inmaculada Cuchillo‐Ibáñez","doi":"10.1002/alz.14125","DOIUrl":"https://doi.org/10.1002/alz.14125","url":null,"abstract":"BACKGROUNDSynaptic and extrasynaptic distribution of N‐methyl‐D‐aspartate receptors (NMDARs) has not been addressed in the brain from Alzheimer´s disease (AD) subjects, despite their contribution to neurodegeneration.METHODSWe have developed a protocol to isolate synaptic and extrasynaptic membranes from controls and AD frontal cortex. We characterized the distribution of the NMDAR subunits GluN2B, GluN2A, GluN1, and GluN3A, as well as post‐translational modifications, such as phosphorylation and glycosylation.RESULTSLower levels of synaptic GluN2B and GluN2A were found in AD fractions, while extrasynaptic GluN2B and GluN1 levels were significantly higher; GluN3A distribution remained unaffected in AD. We also identified different glycoforms of GluN2B and GluN2A in extrasynaptic membranes. Synaptic Tyr1472 GluN2B phosphorylation was significantly lower in AD fractions.DISCUSSIONReduction of synaptic NMDAR subunits, particularly for GluN2B, is likely to contribute to synaptic transmission failure in AD. Additionally, the increment of extrasynaptic NMDAR subunits could favor the activation of excitotoxicity in AD.Highlights<jats:list list-type=\"bullet\"> <jats:list-item>New protocol to isolate synaptic and extrasynaptic membranes from the human cortex.</jats:list-item> <jats:list-item>Low GluN2B and GluN2A levels in Alzheimer´s disease (AD) synaptic membranes.</jats:list-item> <jats:list-item>High GluN2B and GluN1 levels in AD extrasynaptic membranes.</jats:list-item> <jats:list-item>Specific glycoforms of extrasynaptic GluN2B and GluN2A.</jats:list-item> <jats:list-item>Low phosphorylation at Tyr1472 in synaptic GluN2B in AD.</jats:list-item> </jats:list>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":null,"pages":null},"PeriodicalIF":14.0,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Associations of semaglutide with first‐time diagnosis of Alzheimer's disease in patients with type 2 diabetes: Target trial emulation using nationwide real‐world data in the US","authors":"William Wang, QuangQiu Wang, Xin Qi, Mark Gurney, George Perry, Nora D. Volkow, Pamela B. Davis, David C. Kaelber, Rong Xu","doi":"10.1002/alz.14313","DOIUrl":"https://doi.org/10.1002/alz.14313","url":null,"abstract":"INTRODUCTIONEmerging preclinical evidence suggests that semaglutide, a glucagon‐like peptide receptor agonist (GLP‐1RA) for type 2 diabetes mellitus (T2DM) and obesity, protects against neurodegeneration and neuroinflammation. However, real‐world evidence for its ability to protect against Alzheimer's disease (AD) is lacking.METHODSWe conducted emulation target trials based on a nationwide database of electronic health records (EHRs) of 116 million US patients. Seven target trials were emulated among 1,094,761 eligible patients with T2DM who had no prior AD diagnosis by comparing semaglutide with seven other antidiabetic medications. First‐ever diagnosis of AD occurred within a 3‐year follow‐up period and was examined using Cox proportional hazards and Kaplan–Meier survival analyses.RESULTSSemaglutide was associated with significantly reduced risk for first‐time AD diagnosis, most strongly compared with insulin (hazard ratio [HR], 0.33 [95% CI: 0.21 to 0.51]) and most weakly compared with other GLP‐1RAs (HR, 0.59 [95% CI: 0.37 to 0.95]). Similar results were seen across obesity status, gender, and age groups.DISCUSSIONThese findings support further studies to assess semaglutide's potential in preventing AD.HIGHLIGHTS<jats:list list-type=\"bullet\"> <jats:list-item>Semaglutide was associated with 40% to 70% reduced risks of first‐time AD diagnosis in T2DM patients compared to other antidiabetic medications, including other GLP‐1RAs.</jats:list-item> <jats:list-item>Semaglutide was associated with significantly lower AD‐related medication prescriptions.</jats:list-item> <jats:list-item>Similar reductions were seen across obesity status, gender, and age groups.</jats:list-item> <jats:list-item>Our findings provide real‐world evidence supporting the potential clinical benefits of semaglutide in mitigating AD initiation and development in patients with T2DM.</jats:list-item> <jats:list-item>These findings support further clinical trials to assess semaglutide's potential in delaying or preventing AD.</jats:list-item> </jats:list>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":null,"pages":null},"PeriodicalIF":14.0,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142488803","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":"Pathway enrichment in genome-wide analysis of longitudinal Alzheimer's disease biomarker endophenotypes.","authors":"Thea J Rosewood,Kwangsik Nho,Shannon L Risacher,Shiwei Liu,Sujuan Gao,Li Shen,Tatiana Foroud,Andrew J Saykin,","doi":"10.1002/alz.14308","DOIUrl":"https://doi.org/10.1002/alz.14308","url":null,"abstract":"INTRODUCTIONThe genetic pathways that influence longitudinal heterogeneous changes in Alzheimer's disease (AD) may provide insight into disease mechanisms and potential therapeutic targets.METHODSLongitudinal endophenotypes from the Alzheimer's Disease Neuroimaging Initiative (ADNI) representing amyloid, tau, neurodegeneration (A/T/N), and cognition were selected. Genome-wide association analysis was performed using a linear mixed model (LMM) approach, followed by gene and pathway enrichment with significant and functionally relevant SNPs.RESULTSA total of 33 and 19 statistically significant pathways were identified associating with the intercept and longitudinal trajectory, respectively. The longitudinal intercept pathways represent eight groups: immune, metabolic, cell growth and survival, DNA maintenance, neuronal signaling, RAS/MAPK/ERK signaling pathways, vesicle and lysosomal transport, and transcription modification. Longitudinal trajectory pathways represented six groups: Immune, metabolic, cell signaling, cytoskeleton, and glycosylation.DISCUSSIONLongitudinal enrichment identified pathways that uniquely associate with trajectories of key AD biomarkers and cognition, providing new insight into AD course-related mechanisms and potential new therapeutic targets.HIGHLIGHTSA systematic genome-wide analysis with longitudinal AD biomarker endophenotypes was performed. Enriched pathways were identified with functionally derived SNP to gene analysis. Fifty-two pathways were associated with longitudinal trajectory and intercept. Many of the identified pathways are specific steps in larger pathways implicated in AD. The identified pathways may provide therapeutic targets and areas for further study.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":null,"pages":null},"PeriodicalIF":14.0,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142488292","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":"Enrichment for clinical trials of early AD: Combining genetic risk factors and plasma p-tau as screening instruments","authors":"Xin Wang, Xinran Wang, Steven D. Edland, Iris J. Broce, Anders M. Dale, Sarah J. Banks","doi":"10.1002/alz.14284","DOIUrl":"https://doi.org/10.1002/alz.14284","url":null,"abstract":"Identifying low-cost, minimally-invasive screening instruments for Alzheimer's disease (AD) trial enrichment will improve the efficiency of AD trials.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":null,"pages":null},"PeriodicalIF":14.0,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142487840","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":"Effectiveness of psychological therapies for depression and anxiety in atypical dementia","authors":"Celine El Baou, Rob Saunders, Joshua E. J. Buckman, Marcus Richards, Claudia Cooper, Natalie L. Marchant, Roopal Desai, Georgia Bell, Caroline Fearn, Stephen Pilling, Nikki Zimmermann, Val Mansfield, Sebastian Crutch, Emilie Brotherhood, Amber John, Joshua Stott","doi":"10.1002/alz.14332","DOIUrl":"https://doi.org/10.1002/alz.14332","url":null,"abstract":"People with dementia may benefit from psychological therapies for depression or anxiety, but evidence of their effectiveness in atypical dementia is limited.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":null,"pages":null},"PeriodicalIF":14.0,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142487838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Associations between AHA's Life's Essential 8 and cognition in midlife and older adults.","authors":"Lindsay Master,Yuqi Shen,Alexa C Allan,May A Beydoun,Alan B Zonderman,Michele K Evans,Orfeu M Buxton,Alyssa A Gamaldo","doi":"10.1002/alz.14294","DOIUrl":"https://doi.org/10.1002/alz.14294","url":null,"abstract":"INTRODUCTIONThis study evaluated the associations between Life's Essential 8 (LE8) and cognitive performance, and compared the strength of the relationships of Life's Simple 7 (LS7) and LE8 to cognition in midlife and older adults.METHODSParticipants (N = 1539) were from the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study. Cross-sectional multivariable regression examined the associations between LE8 and cognition. Secondary analyses compared model performance between LE8 and LS7 measures on cognition from the same available sample.RESULTSHigher LE8 scores were associated with better global cognitive performance, working memory, and attention. The LS7 model outperformed the LE8 model on global cognitive performance, but the LE8 model outperformed the LS7 model for the working memory domain.DISCUSSIONBetter cardiovascular health (CVH) was associated with better cognitive performance among US middle-aged and older adults. However, the association between CVH and specific cognitive domains varies when using LE8 versus LS7.HIGHLIGHTSCardiovascular health (CVH) is associated with cognitive performance. Life's Essential 8 (LE8) is a new construct to quantify CVH. Associations between LE8 and cognition were assessed. Higher LE8 was associated with better global cognitive performance. Higher LE8 was also associated with better working memory and attention.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":null,"pages":null},"PeriodicalIF":14.0,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489733","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 Alzheimer's Disease Neuroimaging Initiative-4 (ADNI-4) Engagement Core: A culturally informed, community-engaged research (CI-CER) model to advance brain health equity.","authors":"Mónica Rivera Mindt,Alyssa Arentoft,Amanda T Calcetas,Vanessa A Guzman,Hannatu Amaza,Adeyinka Ajayi,Miriam T Ashford,Omobolanle Ayo,Lisa L Barnes,Alicia Camuy,Catherine Conti,Adam Diaz,Bashir Easter,David J Gonzalez,Yolanda Graham Dotson,Isabella Hoang,Kaori Kubo Germano,Gladys E Maestre,Fabiola Magaña,Oanh L Meyer,Melanie J Miller,Rachel Nosheny,Van M Ta Park,Shaniya Parkins,Lisa Renier Thomas,Joe Strong,Sandra Talavera,Steven P Verney,Trinity Weisensel,Michael W Weiner,Ozioma C Okonkwo,","doi":"10.1002/alz.14242","DOIUrl":"https://doi.org/10.1002/alz.14242","url":null,"abstract":"INTRODUCTIONThe Alzheimer's Disease Neuroimaging Initiative-4 (ADNI-4) Engagement Core was launched to advance Alzheimer's disease (AD) and AD-related dementia (ADRD) health equity research in underrepresented populations (URPs). We describe our evidence-based, scalable culturally informed, community-engaged research (CI-CER) model and demonstrate its preliminary success in increasing URP enrollment.METHODSURPs include ethnoculturally minoritized, lower education (≤ 12 years), and rural populations. The CI-CER model includes: (1) culturally informed methodology (e.g., less restrictive inclusion/exclusion criteria, sociocultural measures, financial compensation, results disclosure, Spanish Language Capacity Workgroup) and (2) inclusive engagement methods (e.g., the Engagement Core team; Hub Sites; Community-Science Partnership Board).RESULTSAs of April 2024, 60% of ADNI-4 new in-clinic enrollees were from ethnoculturally or educationally URPs. This exceeds ADNI-4's ≥ 50% URP representation goal for new enrollees but may not represent final enrollment.DISCUSSIONFindings show a CI-CER model increases URP enrollment in AD/ADRD clinical research and has important implications for clinical trials to advance health equity.HIGHLIGHTSThe Alzheimer's Disease Neuroimaging Initiative-4 (ADNI-4) uses a culturally informed, community-engaged research (CI-CER) approach. The CI-CER approach is scalable and sustainable for broad, multisite implementation. ADNI-4 is currently exceeding its inclusion goals for underrepresented populations.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":null,"pages":null},"PeriodicalIF":14.0,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142488293","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":"Reductions in the white–gray functional connectome in preclinical Alzheimer's disease and their associations with amyloid and cognition","authors":"Lyuan Xu, Yu Zhao, Soyoung Choi, Muwei Li, Kurt G. Schilling, Zhongliang Zu, Baxter P. Rogers, Zhaohua Ding, Adam W. Anderson, Bennett A. Landman, John C. Gore, Yurui Gao","doi":"10.1002/alz.14334","DOIUrl":"https://doi.org/10.1002/alz.14334","url":null,"abstract":"The magnitudes and patterns of alterations of the white–gray matter (WM–GM) functional connectome in preclinical Alzheimer's disease (AD), and their associations with amyloid and cognition, remain unclear.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":null,"pages":null},"PeriodicalIF":14.0,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142487825","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":"Inhibiting mtDNA transcript translation alters Alzheimer's disease-associated biology","authors":"Alexander P. Gabrielli, Lesya Novikova, Amol Ranjan, Xiaowan Wang, Nicholas J. Ernst, Dhanushki Abeykoon, Anysja Roberts, Annie Kopp, Clayton Mansel, Linlan Qiao, Colton R. Lysaker, Ian W. Wiedling, Heather M. Wilkins, Russell H. Swerdlow","doi":"10.1002/alz.14275","DOIUrl":"https://doi.org/10.1002/alz.14275","url":null,"abstract":"Alzheimer's disease (AD) features changes in mitochondrial structure and function. Investigators debate where to position mitochondrial pathology within the chronology and context of other AD features.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":null,"pages":null},"PeriodicalIF":14.0,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142487839","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":"Comparative brain metabolomics reveals shared and distinct metabolic alterations in Alzheimer's disease and progressive supranuclear palsy","authors":"Richa Batra, Jan Krumsiek, Xue Wang, Mariet Allen, Colette Blach, Gabi Kastenmüller, Matthias Arnold, Nilüfer Ertekin-Taner, Rima Kaddurah-Daouk","doi":"10.1002/alz.14249","DOIUrl":"https://doi.org/10.1002/alz.14249","url":null,"abstract":"Metabolic dysregulation is a hallmark of neurodegenerative diseases, including Alzheimer's disease (AD) and progressive supranuclear palsy (PSP). Although metabolic dysregulation is a common link between these two tauopathies, a comprehensive brain metabolic comparison of the diseases has not yet been performed.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":null,"pages":null},"PeriodicalIF":14.0,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142487819","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}