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 生物医学领域的代表性仍然不足 研究，特别是生物标志物研究和临床试验 该 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、神经影像学和 认知数据，以识别中央关联的外周分子特征（CLPMS），该特征可以作为 新型血液生物标志物将改善这些服务不足和服务不足的地区的诊断和治疗方法的开发 根据我们小组和其他人的初步数据，我们对这一遗传进行了研究。 AA 和 LA 易患痴呆风险的变异、转录组和表观遗传变化将揭示新的 与疾病相关的机制以及与 NHW 项目 3 中确定的机制的相似之处将得到利用。 现有 AA 和 LA 样本以及来自阿尔茨海默氏病神经影像倡议 (ADNI, 66 AA 59 LA）和五个阿尔茨海默病研究中心（ADRC，564 AA，219 LA）：梅奥诊所，印第安纳州，1佛罗里达州， 密歇根州和奈特 ADRC，以及来自这些 ADRC 数据的另外 300 名 AA 和 LA 预计参与者。 从第六届 ADRC（埃默里大学）收集的另外 300 名 AA 参与者也将纳入该项目。 目的是：(1) 识别 AA 和 LA 中的血液多组学 CLPMS，这将通过有效地改善 AD 诊断 以高度特异性和敏感性区分临床诊断为 AD 的个体和患有 AD 的个体 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/脑脊液/血浆生物标志物数据，与那些没有这些内表型变化的人相比 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、神经心理测量相匹配的纵向血液多组学数据来诊断 AD 来自认知未受损、轻度认知障碍和 AD 患者的数据 (3) 确定血液 CLPMS； 针对这些人群，基于可能影响的遗传变异、转录本或表观遗传变化 AD 的发展，在 AA 和 LA 与 NHW 血统中存在差异（与项目的结果进行比较） 2); (4) 确定这些血液 CLPMS 是否在大脑中表现出相似的模式（通过与 项目 1); (5) 利用以下结果确定 AD 中涉及的新途径、基因和遗传变异 本项目中确定的这些多组学特征使用三层方法来分析我们的发现和结果。 翻译路线图以优先考虑它们，我们希望以比较的方式确定 AA 和 LA 中的 CLPMS 与 NHW 合作，将增强生物标志物研究知识，从而在这些领域实现精准医疗 这些研究将整合信息，预计也会带来更好的信息。 设计针对这些人群的治疗方法和可能的预防干预措施。