ConProject-001

与高加索人相比，阿尔茨海默病（AD）在AA人群中的患病率是两倍，在LA人群中是1.5倍。 尽管如此，非高加索人在AD研究中的代表性大大不足，包括临床试验和遗传学研究。 问题研究此外，迄今为止还没有在不同人群中进行多组学研究。基于以下理由， 多组学研究可以确定疾病相关的途径和治疗靶点，AMP-AD靶点发现 并启动了临床前验证项目。这项工作导致了RNA测序的产生和分析， 基于RNAseq的转录组、全基因组序列（WGS）、蛋白质组、代谢组和 来自患有AD和非AD神经病理学的高加索人患者的> 2，500个脑样品的表观基因组数据， 以及未受影响的对照。这些大量的数据已经提供给研究界。 这些数据还被用于识别或验证AD和其他疾病的潜在风险机制。 神经退行性疾病，并导致数据驱动的识别和提名超过500个关键驱动因素 AD的基因/候选靶标。尽管高加索人取得了这些进展， AD、非AD和对照大脑未知。对不同群体的多组学分析对于 发现对所有人群都有用的疾病相关治疗靶点的全谱 受AD影响。在本补充中，我们建议从3个大脑区域生成和分析RNAseq数据 331例AA或LA患者，代表AD和相关疾病谱。的目的 我们的建议是在这些不同的队列中确定AD的途径、分子和潜在的治疗靶点 利用大脑转录组和其他现有数据。将对调查结果进行比较研究 从这个提议和那些从高加索队列内AMP-AD。预计这些比较将 确定共享和人群特异性AD途径和分子，并最终告知 在人群中的AD治疗靶点的效用。该提案是'铲准备'与可用的样品 和数据我们将利用现有的基础设施、协议和分析管道， 为AMP-AD的大规模多组学研究而建立。因此，拟议的研究有望成功 填补少数人群对AD的疾病途径和治疗靶点的知识空白。具体 目的是：1）在AD谱的不同人群中生成大脑转录组图谱：我们 将在3个大脑区域（993个大脑样本）中进行大脑RNAseq，以生成详细的大脑转录组 在这些不同的人群中。2)在不同人群中鉴定AD的分子靶点：使用 从目标1的数据，我们将发现差异表达的基因和网络在AD，他们的行为跨越 多个大脑区域和多种病理，并指定治疗靶点列表。如果获得资助，这项研究 将提高这些不同群体的目标发现潜力，并为这些目标的发现奠定基础。 开创了在少数民族人群中进行多组学研究的先河。

Alzheimer’s disease (AD) is twice as prevalent in AA and 1.5 times in LA populations compared to Caucasians. Despite this, non-Caucasians are vastly under-represented in AD research including clinical trials and genetic studies. Further, there are no multi-omics studies to date in diverse populations. Based on the rationale that multi-omics studies can identify disease-relevant pathways and therapeutic targets, AMP-AD Target Discovery and Preclinical Validation Project was launched. This effort led to the generation and analysis of RNAsequencing (RNAseq) based transcriptome, whole genome sequence (WGS), proteome, metabolome and epigenome data on >2,500 brain samples from Caucasian patients with AD and non-AD neuropathologies, as well as unaffected controls. This vast amount of data has been made available to the research community. These data have also been utilized to identify or validate potential risk mechanisms in AD and other neurodegenerative diseases and led to the data-driven identification and nomination of over 500 key driver genes/candidate targets for AD. Despite these advances for Caucasians, the multi-omic landscape of diverse AD, non-AD and control brains are unknown. Multi-omics profiling of diverse cohorts is essential for the discovery of the full spectrum of disease-relevant therapeutic targets that will be of utility to all populations affected with AD. In this supplement, we propose to generate and analyze RNAseq data from 3 brain regions of 331 AA or LA patients that represent the spectrum of AD and related disorders. The objective of this proposal is to identify pathways, molecules and potential therapeutic targets of AD in these diverse cohorts utilizing brain transcriptome and other existing data. Comparative studies will be conducted between findings from this proposal and those from the Caucasian cohorts within AMP-AD. These comparisons are expected to identify both shared and population-specific AD pathways and molecules and can ultimately inform the extent of utility for AD therapeutic targets across populations. The proposal is ‘shovel-ready’ with available samples and data. We will leverage existing infrastructure, protocols, analytic pipelines that we and others already established for large-scale multi-omics studies in AMP-AD. Thus, the proposed study is poised to successfully fill the knowledge gap for disease pathways and therapeutic targets of AD for minority populations. The specific aims are: 1) To generate a brain transcriptome map in diverse populations across the AD spectrum: We will perform brain RNAseq in 3 brain regions (993 brain samples) to generate a detailed brain transcriptome map in these diverse populations. 2) To identify molecular targets for AD in diverse populations: Using data from Aim 1, we will discover differentially expressed genes and networks in AD, their behavior across multiple brain regions and multiple pathologies and nominate a list of therapeutic targets. If funded, this study will enhance the target discovery potential of these diverse cohorts and establish the groundwork for these pioneering multi-omics studies in minority populations.