Longitudinal Blood-based Transcriptomic Changes in AD: Relation to Clinical and Biomarker Data

摘要 阿尔茨海默病(AD)是一种导致痴呆症的进行性神经退行性疾病。尽管强度很大 在这方面的努力下，目前还没有证实可以阻止或延缓病程的疾病修饰疗法。无数临床试验 由于对病理生理学的不完全了解、患者的异质性以及缺乏精确度 基于阶段和其他特征的选择策略，对于这些特征，广泛可获得的预测生物标记将 有很大的影响。U19的总体目标是识别和验证中心链接的纵向 多民族人群阿尔茨海默病外周生物标志物(Clear-AD)纵向多组学研究 以及来自多个独立队列的多模式成像和流体内表型。项目2将进行 首次对特征良好的ADNI队列进行基于血液的多组学研究，包括4,120 生物量和最多7个时间点。ADNI是我们所知的唯一一项全基因组队列研究 测序、纵向DNA和RNA样本、DNA甲基化、代谢组学/脂质组学分析和 蛋白质组学，以及纵向多模式神经成像，以及同一参与者的液体AD生物标记物。 根据我们的初步结果，我们假设我们将能够确定 纵向分子特征改变和纵向“A/T/N/V”(淀粉样蛋白、tau蛋白、神经变性和 脑血管)生物标记物的变化，包括大脑连接性的网络改变。的首要目标是 项目2是识别可以作为候选的新的、非侵入性的、中心连接的分子签名 适用于早期检测和支持未来精确度的量身定制疗法设计的生物标志物 AD/ADRD的药物。三层方法将1)测试4条假设的生物路径(免疫、血管、 髓鞘形成、突触完整性)，2)评估另外20条ADRD途径，以及3)发现新的分子 使用无偏见搜索和人工智能(AI)策略的签名。目标1是识别分子 外周血液中的签名与认知状态的变化有关，无论是横断面还是 纵向的。AIM 2将确定血液中与A/T/N/V AD变化相关的分子特征 生物标志物，包括横截面和纵向。目标3将评估基于多组学的分子的能力 在基线和一段时间内分析以预测未来的疾病进展。AIM 4将复制和验证ADNI 使用基于血液和脑组织的数据(项目1)和来自多民族人口的数据的研究结果，包括 非洲裔和拉丁裔美国人血统(项目3)。项目2将采用综合翻译 U19核心支持的方法，结合纵向临床、多组学和AD生物标记物数据， 包括先进的神经成像，使人们能够更深入地了解阿尔茨海默病的分子基础，并 确定新的潜在治疗靶点和生物标记物策略。这些结果直接支持 NIA/NAPA AD/ADRD精准医学目标。

ABSTRACT Alzheimer’s disease (AD) is a progressive neurodegenerative condition leading to dementia. Despite intensive efforts, there are no disease modifying therapies proven to arrest or slow the course. Numerous clinical trials have failed due to incomplete understanding of pathophysiology, patient heterogeneity, and lack of precision in selection strategies based on stage and other features for which widely accessible predictive biomarkers would have a major impact. The overall goal of the U19 is to identify and validate Centrally-linked Longitudinal pEripheral biomARkers of AD (CLEAR-AD) in multi-ethnic populations by integrating longitudinal multi-omics and multimodal imaging and fluid endophenotypes from multiple independent cohorts. Project 2 will conduct the first longitudinal blood-based multi-omics study of the well-characterized ADNI cohort including 4,120 biospecimens and up to 7 time points. ADNI is the only cohort study to our knowledge with whole genome sequencing, longitudinal DNA and RNA samples, DNA methylation, metabolomics/lipidomics profiling and proteomics, along with longitudinal multimodal neuroimaging, and fluid AD biomarkers on the same participants. Based on our preliminary results, we hypothesize that we will be able to identify the relationship between longitudinal molecular signature changes and longitudinal “A/T/N/V” (amyloid, tau, neurodegeneration, and cerebrovascular) biomarker changes including network alterations in brain connectivity. The overarching goal of Project 2 is to identify novel, non-invasive, centrally-linked molecular signatures that can serve as candidate biomarkers suitable for early detection and design of tailored therapeutics supporting the future precision medicine of AD/ADRD. A 3-Tier approach will 1) test 4 hypothesized biological pathways (immune, vascular, myelination, synaptic integrity), 2) assess 20 additional ADRD pathways, and 3) discover novel molecular signatures using an unbiased search and Artificial Intelligence (AI) strategies. Aim 1 is to identify molecular signatures in peripheral blood associated with changes in cognitive status, both cross-sectionally and longitudinally. Aim 2 will identify molecular signatures in blood associated with changes in A/T/N/V AD biomarkers, both cross-sectionally and longitudinally. Aim 3 will assess the ability of multi-omics based molecular profiling at baseline and over time to predict future disease progression. Aim 4 will replicate and validate ADNI findings using blood- and brain tissue-based data (with Project 1) and data from multiethnic populations including African- and Latino- American ancestry (with Project 3). Project 2 will employ an integrative translational approach supported by the U19 Cores, combining longitudinal clinical, multi-omics, and AD biomarker data, including advanced neuroimaging, to enable deeper mechanistic insights into the molecular basis of AD and to identify new potential therapeutic targets and biomarker strategies. These outcomes directly support the NIA/NAPA goal of precision medicine for AD/ADRD.