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.

概括 尽管非洲裔美国人（AA）和拉丁裔美国人患阿尔茨海默氏病（AD）的患病率更高 （LA）与非西班牙裔白人（NHW）相比，这些人群在AD生物医学中的代表性不足 研究，特别是在生物标志物研究和临床试验中。该U19项目3的总体目标是 利用现有的“准备就绪” AA和LA队列，并通过纵向血液收集，临床，神经影像和 认知数据是为了识别可以用作中心连接的外围分子特征（CLPM） 新型的血液生物标志物将改善这些服务不足的诊断和治疗的发展 研究的人口。基于我们小组和其他人的初步数据，我们假设该遗传 AA和LA中痴呆症风险的变异，转录组和表观遗传变化将揭示新型 与疾病相关的机制以及与NHW中发现的机制。项目3将利用 现有的AA和LA样品以及来自阿尔茨海默氏病神经成像倡议的数据（ADNI，66 AA 59 LA）和五个阿尔茨海默氏病研究中心（ADRCS，564 AA，219 LA）：梅奥诊所，印第安纳州，1florida，1florida， 密歇根州和骑士ADRC，再加上这些ADRC的300个AA和LA的参与者。数据 还将合并从另外300名AA参与者收集的第六次ADRC（Emory）。这个项目 目的是：（1）识别AA和LA中的血液多摩变CLPM，可以有效地改善AD诊断 以高特异性和敏感性区分临床诊断为AD的个体和谁 具有淀粉样蛋白，tau，神经变性和血管内表型会改变AD的特征。 神经影像学/CSF/等离子体生物标志物数据与没有这些内型变化的人 广告的特征； （2）确定可以预测发展的血液CLPM，并通过进展进行跟踪 AD，通过分析的纵向血液多摩学数据与临床，神经影像学匹配 来自认知单pir，轻度认知障碍和AD患者的数据； （3）确定血液CLPM 特定于这些人群，基于遗传变异，转录本或表观遗传变化，可能会影响 AD的开发，在AA和LA与NHW血统的开发不同（与项目的发现相比 2）; （4）确定这些血液CLPM是否暴露了大脑中的相似模式（与来自 项目1）; （5）通过使用来自 这些项目中确定的这些多摩尼克标志。使用三层方法分析我们的发现和 翻译以优先级的路线图，我们希望以比较方式识别AA和LA中的CLPM 使用NHWS，并将增强有关生物标志物研究的知识，从而在这些研究中实现精确医学 人口不足。这些研究将整合预期的信息，也会导致更好的知情 针对这些人群量身定制的疗法的设计和可能的预防干预措施。