Centrally-linked longitudinal peripheral biomarkers of AD in multi-ethnic populations

摘要（30行）： 现有脑脊液（CSF）和淀粉样蛋白β、tau和神经变性的神经影像学指标 （A，T，N）作为阿尔茨海默病（AD）的有用的诊断生物标志物，然而， AD中基于血液的生物标志物的需求未得到满足。首先，多组学研究发现了许多受干扰的生物 然而，AD中的生物学通路，对于捕获AD的这些不同生物学方面的生物标志物的系统研究， 是有限的。其次，AD是一种异质性疾病，但生物标志物可以区分生物学特征， 缺乏AD亚型。第三，核心AD神经病理学通常与其他神经病理学共存， 血管疾病（V）。在生物标志物发现中需要考虑这些共病和共病理。 第四，现有的生物标志物研究主要集中在非西班牙裔白人（NHW）。类似的研究， 代表性不足的人口（URP）。这个U19，汇集了来自13个国家的超过40名专家 机构，旨在弥合这些知识差距，以发现和验证中央链接的纵向 多种族人群中AD的外周生物标志物（CLEAR-AD）。CLEAR-AD U19基于 前提是AD是一种复杂的疾病，其中许多生物途径由于多组学而被破坏。 扰动，可以在脑中检测到并反映在血液中，即中枢连接的外周分子 签名（CLPMS）。CLEAR-AD U19的具体目标是：1）发现复合体的CLPMS， 异质性AD病理生理学及其共同病理学。2)识别纵向CLPMS， 预测动态神经影像学、流体生物标志物和AD谱的临床变化。3)表征 NHW、非洲裔美国人（AA）和拉丁裔美国人（LA）的CLPMS特征的差异和相似性 参与者发现多种族群体的生物标志物模式。4)为了使这些巨大的资源可以用于 科学界扩大和加速其影响。在这个由行政核心管理的U19中， 我们将利用NIH资助的ADNI、MCSA和ADRC队列（>3,700名多种族参与者）， > 20，000多组学测量（组学核心）将被处理并与> 48，000统一 AD认知、神经影像学和体液内表型（核心分析）。利用这些数据，我们将识别大脑 区域和细胞类型特异性CLPMS，其反映AD的生物亚型和疾病阶段（项目1）。我们 将发现CLPMS的纵向变化，预测认知和A/T/N/V进展（项目2）。我们将 定义URP中的纵向认知和A/T/N/V变化以及CLPMS，这些变化与NHW或 具体人口（项目3）。该U19将a）鉴定下一代AD生物标志物， 见解; B）建立精确的医学方法，用于严格的多组学生物标志物发现， c）发现可用作生物标志物和治疗靶点的分子; d）增强 在准备好试验的多种族人群中进行生物标志物研究;以及e）生成并共享一个广泛而协调的 NIH资助的队列中的内表型和多组学数据资源。

Summary Abstract (30 lines): Existing cerebrospinal fluid (CSF) and neuroimaging measures of amyloid ß, tau and neurodegeneration (A,T,N) serve as useful diagnostic biomarkers for Alzheimer’s disease (AD), however there remains an urgent, unmet need for blood based biomarkers in AD. First, multi-omic studies discovered many perturbed biological pathways in AD, however, systematic studies for biomarkers that capture these diverse biological facets of AD are limited. Second, AD is a heterogeneous disorder but biomarkers that can distinguish the biological subtypes of AD are lacking. Third, core AD neuropathology often co-exists with other neuropathologies such as vascular disease (V). These co-morbidities and co-pathologies need to be considered in biomarker discovery. Fourth, existing biomarker studies are heavily focused on non-Hispanic Whites (NHW). Similar studies in underrepresented populations (URP) are needed. This U19, bringing together >40 experts across 13 institutions, aims to bridge these knowledge gaps for discovery and validation of Centrally-linked Longitudinal pEripheral biomARkers of AD (CLEAR-AD) in multi-ethnic populations. CLEAR-AD U19 is based on the premise that AD is a complex disorder in which many biological pathways are disrupted due to multi-omic perturbations, which can be detected in brain and reflected in blood, i.e. centrally-linked peripheral molecular signatures (CLPMS). The specific aims of CLEAR-AD U19 are: 1) To discover CLPMS of the complex and heterogeneous AD pathophysiology and its co-pathologies. 2) To identify longitudinal CLPMS that detect and predict dynamic neuroimaging, fluid biomarker, and clinical changes across AD spectrum. 3) To characterize differences and similarities in CLPMS profiles across NHW, African American (AA) and Latino American (LA) participants to uncover biomarker patterns in multi-ethnic groups. 4) To make these vast resources available to the scientific community to amplify and accelerate its impact. In this U19 managed by the Administrative Core, we will leverage NIH-funded ADNI, MCSA and ADRC cohorts of >3,700 multi-ethnic participants to generate >20,000 multi-omics measures (Omics Core) that will be processed and integrated with >48,000 harmonized AD cognitive, neuroimaging and fluid endophenotypes (Analytic Core). Using these data, we will identify brain region and cell-type specific CLPMS, which reflect biological subtypes of AD and disease stage (Project 1). We will discover longitudinal changes in CLPMS that predict cognitive and A/T/N/V progression (Project 2). We will define longitudinal cognitive and A/T/N/V changes and CLPMS in URP that are either conserved with NHW or population-specific (Project 3). This U19 will a) Identify the next generation of AD biomarkers with mechanistic insights; b) Establish a precision medicine approach for rigorous multi-omics biomarker discovery and validation in AD; c) Discover molecules that can serve as biomarkers and therapeutic targets; d) Enhance biomarker research in trial-ready multi-ethnic populations; and e) Generate and share a vast and harmonized resource of endophenotype and multi-omics data in NIH-funded cohorts.