Peripheral and Central Biomarkers of Alzheimer's Disease in Diverse Cohorts

不同群体中阿尔茨海默病的外周和中枢生物标志物

• 批准号: 10555729
• 负责人: Minerva Maria Carrasquillo
• 金额: $ 58.04万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-15 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10555729
• 关键词: Address; African American population; Alcohol consumption; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease patient; Alzheimer' s disease risk; Alzheimer’s disease biomarker; American; Amyloid; Autopsy; Biological; Biological Markers; Biomedical Research; Blood; Blood Vessels; Blood specimen; Brain; California; Characteristics; Clinic; Clinical; Clinical Trials; Cognition; Cognitive; Cohort Analysis; Collection; Community Outreach; Data; Dementia; Development; Diabetes Mellitus; Diagnosis; Disease; Disease Progression; Disparity; Education; Epigenetic Process; Ethnic Population; Evaluation; Exhibits; Frequencies; Funding; Genes; Genetic; Genetic Risk; Genetic Variation; Genotype; Goals; High Prevalence; Hypertension; Impaired cognition; Incidence; Indiana; Individual; Institution; Knowledge; Latino; Link; Measures; Methylation; Michigan; Molecular; Molecular Profiling; Multiomic Data; Nerve Degeneration; Not Hispanic or Latino; Participant; Pathway interactions; Pattern; Peripheral; Phenotype; Plasma; Population; Preventive therapy; Prognostic Marker; Research; Resources; Sample Size; Sampling; Sensitivity and Specificity; Smoking; Subgroup; Testing; Time; Transcript; Translations; Underrepresented Populations; Universities; Validation; cerebrovascular; clinical diagnosis; cohort; comorbidity; comparative; data analysis pipeline; data archive; dementia risk; diagnostic biomarker; differential expression; endophenotype; genetic variant; genomic locus; image archival system; improved; lifestyle factors; longitudinal analysis; methylome; mild cognitive impairment; minimally invasive; multi-ethnic; multiple omics; neuroimaging; neuron loss; novel; outreach program; polygenic risk score; potential biomarker; precision medicine; predictive marker; preventive intervention; recruit; research study; risk variant; sample collection; tau Proteins; therapy design; therapy development; transcriptome; transcriptome sequencing; transcriptomics; trial readiness; whole genome

SUMMARY Despite a higher prevalence of Alzheimer’s disease (AD) among African Americans (AA) and Latino Americans (LA) compared to non-Hispanic whites (NHW), these populations remain underrepresented in AD biomedical research, particularly in biomarker studies and clinical trials. The overarching goal of Project 3 of this U19 is to leverage existing “trial-ready” AA and LA cohorts with longitudinal blood collections, clinical, neuroimaging and cognitive data in order to identify centrally-linked peripheral molecular signatures (CLPMS) that may serve as novel blood biomarkers that will improve diagnosis and the development of treatments in these underserved and understudied populations. Based on preliminary data from our group and others, we hypothesize that genetic variation, transcriptomic and epigenetic changes predisposing to dementia risk in AA and LA will reveal novel mechanisms associated with disease, as well as similarities with those identified in NHW. Project 3 will leverage existing AA and LA samples and data from the Alzheimer's Disease Neuroimaging Initiative (ADNI, 66 AA 59 LA) and five Alzheimer’s Disease research Centers (ADRCs, 564 AA, 219 LA): Mayo Clinic, Indiana, 1Florida, Michigan and Knight ADRCs, plus an additional 300 AA and LA projected participants from these ADRC. Data from a sixth ADRC (Emory) collected from another 300 AA participants will also be incorporated. This project aims to: (1) identify blood multi-omic CLPMS in AA and LA that will improve AD diagnosis by effectively discriminating, with high specificity and sensitivity, between individuals clinically diagnosed with AD and who have amyloid, tau, neurodegeneration and vascular endophenotype changes characteristic of AD based on neuroimaging/CSF/plasma biomarker data, versus those who do not have these endophenotype changes characteristic of AD; (2) identify blood CLPMS that can predict the development, and that track with progression of AD, by analyzing longitudinal blood multi-omics data-matched to clinical, neuroimaging, neuropsychometric data from cognitively unimpaired, mild cognitive impairment and AD patients; (3) identify blood CLPMS that are specific to these populations, based on genetic variants, transcripts or epigenetic changes that may impact the development of AD, differentially in AA and LA vs. those of NHW ancestry (by comparison to findings from Project 2); (4) to determine if these blood CLPMS exhibit similar patterns in the brain (by comparison to findings from Project 1); (5) to determine novel pathways, genes and genetic variants involved in AD by using results from these multi-omics signatures identified in this project. Using a 3-tiered approach to analyze our findings and Roadmap to Translation to prioritize them, we expect to identify CLPMS in AA and LA in a comparative fashion with NHWs and will enhance knowledge on biomarker research, thus enabling precision medicine in these underrepresented populations. These studies will integrate information expected to also lead to better informed designs for therapies and possibly preventive interventions that are tailored to these populations.

摘要 尽管非裔美国人(AA)和拉美裔美国人中阿尔茨海默病(AD)的患病率较高 (La)与非西班牙裔白人(Nhw)相比，这些群体在AD生物医学中的代表性仍然不足 研究，特别是在生物标志物研究和临床试验方面。本U19项目3的总体目标是 利用现有的可供试验的AA和LA队列，进行纵向血液采集、临床、神经成像和 认知数据，以识别中心连接的外周分子签名(CLPM)，其可用作 新的血液生物标志物将改善对这些服务不足和治疗的诊断和治疗的开发 未被充分研究的种群。根据我们小组和其他人的初步数据，我们假设基因 AA和LA易患痴呆症风险的变异、转录和表观遗传变化将揭示新的 与疾病相关的机制，以及与NHW中确定的那些相似之处。项目3将利用 现有的AA和LA样本和阿尔茨海默病神经成像倡议(ADNI，66 AA 59)的数据 洛杉矶)和五个阿尔茨海默病研究中心(ADRC，564个AA，219个洛杉矶)：印第安纳州梅奥诊所，佛罗里达州1 密歇根和奈特ADRC，外加来自这些ADRC的另外300名AA和LA预计参与者。数据 从第六次ADRC(埃默里)收集的另外300名AA参与者也将被纳入。这个项目 目的：(1)鉴定AA和LA的血液多组体CLPMS，有效地提高AD的诊断水平 区分临床诊断为阿尔茨海默病的人和世卫组织，具有高度的特异性和敏感性 阿尔茨海默病的淀粉样蛋白、tau蛋白、神经退行性变和血管内表型改变 神经影像/脑脊液/血浆生物标记物数据与那些没有这些内表型改变的人的对比 阿尔茨海默病的特征；(2)识别能预测发展的血液CLPMS，并跟踪进展 通过分析纵向血液多组学数据-与临床、神经成像、神经心理测量相匹配 来自认知正常、轻度认知障碍和AD患者的数据；(3)识别符合以下条件的血液CLPM 特定于这些群体，基于可能影响 阿尔茨海默病的发展，AA和LA与NHW血统的不同(与项目的结果比较 2)；(4)确定这些血液CLPM在大脑中是否表现出类似的模式(通过与 项目1)；(5)利用下列结果确定与阿尔茨海默病有关的新途径、基因和遗传变异 这些在本项目中确定的多重组学特征。使用三层方法分析我们的调查结果和 翻译路线图为确定优先顺序，我们希望以比较的方式确定AA和LA的CLPM 并将加强生物标记物研究的知识，从而使这些领域的精准医学成为可能 代表性不足的人群。这些研究将整合预计也将导致更多信息的信息 针对这些人群量身定做的治疗设计和可能的预防性干预措施。