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.

总结 尽管非裔美国人（AA）和拉丁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，这些人群在AD生物医学中的代表性仍然不足。 研究，特别是生物标志物研究和临床试验。U19项目3的总体目标是 利用现有的“试验就绪”AA和LA队列，进行纵向采血、临床、神经影像学检查， 认知数据，以确定中枢连锁的外周分子标记（CLPMS）， 新的血液生物标志物，将改善诊断和治疗的发展，在这些服务不足， 研究不足的人群。基于我们小组和其他人的初步数据，我们假设遗传学 AA和LA中易患痴呆风险的变异、转录组学和表观遗传学变化将揭示新的 与疾病相关的机制，以及与NHW中发现的机制的相似之处。项目3将利用 现有的AA和LA样本以及来自阿尔茨海默病神经影像学倡议（ADNI，66 AA 59）的数据 LA）和5个阿尔茨海默病研究中心（ADRC，564 AA，219 LA）：马约诊所，印第安纳州，1佛罗里达州， 密歇根州和骑士ADRC，加上额外的300 AA和LA预计参与者从这些ADRC。数据 从第六个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）确定AA和LA的血液多组学CLPMS，通过有效地提高AD诊断率， 以高特异性和敏感性区分临床诊断为AD的个体和 具有AD特征性的淀粉样蛋白、tau蛋白、神经变性和血管内表型变化， 神经影像学/CSF/血浆生物标志物数据，与没有这些内在表型变化的患者相比 AD的特征;（2）识别可以预测发展并跟踪进展的血液CLPMS 通过分析与临床、神经影像学、神经心理测量学 来自认知未受损、轻度认知障碍和AD患者的数据;（3）确定 这些群体的特定基因，基于可能影响这些群体的遗传变异、转录本或表观遗传变化， AD的发展，AA和LA与NHW血统的差异（与项目结果相比） （2）;（4）确定这些血液CLPMS是否在脑中表现出类似的模式（通过与来自脑组织的发现进行比较）。 项目1）;（5）通过使用来自以下的结果来确定参与AD的新途径、基因和遗传变体： 这些多组学特征在这个项目中得到了确认。使用三层方法来分析我们的研究结果， 翻译路线图为了优先考虑它们，我们希望以比较的方式确定AA和LA中的CLPMS 与NHWs合作，并将提高生物标志物研究的知识，从而在这些领域实现精准医学。 代表性不足的人群。这些研究将整合信息，预计也将导致更好地了解 为这些人群量身定制的治疗和可能的预防性干预措施的设计。