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

AD 中基于血液的纵向转录组变化：与临床和生物标志物数据的关系

• 批准号: 10555728
• 负责人: ANDREW J SAYKIN
• 金额: $ 78.05万
• 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/10555728
• 关键词: Acceleration; African; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease related dementia; Alzheimer’s disease biomarker; American; Amyloid; Artificial Intelligence; Biological; Biological Markers; Blood; Blood Vessels; Brain; Clinical; Clinical Trials; Cognition; Cognitive; Cohort Studies; Collaborations; Communities; Coupled; DNA; DNA Methylation; Data; Data Set; Dementia; Diagnostic; Disease; Disease Progression; Early Diagnosis; Epigenetic Process; Ethnic Population; Functional Magnetic Resonance Imaging; Functional disorder; Funding; Future; Genes; Genetic; Genetic Transcription; Goals; Heterogeneity; Immune; Immunity; Indiana; Latino; Length; Link; Liquid substance; Machine Learning; Magnetic Resonance Imaging; Modality; Modeling; Molecular; Molecular Profiling; Multimodal Imaging; Multiomic Data; Mus; Nerve Degeneration; Outcome; Participant; Pathway interactions; Patients; Peripheral; Population; Positron-Emission Tomography; Process; Proteomics; RNA; Research; Risk; Sampling; Site; Synapses; Testing; Therapeutic; Time; Transcript; Validation; Variant; biomarker identification; brain tissue; candidate marker; causal model; cerebrovascular; cognitive change; cognitive performance; cohort; design; differential expression; endophenotype; follow-up; genome sequencing; induced pluripotent stem cell; insight; lipidomics; longitudinal analysis; metabolomics; multi-ethnic; multimodal neuroimaging; multiple omics; myelination; neuroimaging; novel; open data; peripheral blood; polygenic risk score; precision medicine; predictive marker; predictive modeling; tau Proteins; telomere; therapeutic biomarker; therapeutic target; transcriptome sequencing; transcriptomics; translational approach; validation studies; whole genome

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.

抽象的 阿尔茨海默氏病（AD）是导致痴呆症的进行性神经退行性疾病。尽管很密集 努力，没有疾病修改疗法被证明可以逮捕或减慢课程。许多临床试验 由于对病理生理学，患者异质性不完全理解以及缺乏精度而失败 基于阶段和其他功能的选择策略，可广泛可访问的预测性生物标志物将 产生重大影响。 U19的总体目标是识别和验证集中纵向的纵向 通过整合纵向多摩学，在多种族种群中的AD（清除AD）的外围生物标志物 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 良好特征的ADNI队列的首次纵向血液多词研究包括4,120 生物测量和最多7个时间点。 ADNI是我们与整个基因组所知的唯一一项队列研究 测序，纵向DNA和RNA样品，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影像学和同一参与者的流体AD生物标志物。 根据我们的初步结果，我们假设我们将能够确定 纵向分子特征变化和纵向“ a/t/n/v”（淀粉样蛋白，tau，神经变性和 脑血管）生物标志物变化，包括大脑连通性的网络改变。总体目标 项目2是为了识别可以用作候选者的新型，无创的，中央链接的分子特征 适用于裁缝疗法的早期检测和设计的生物标志物支持未来的精度 AD/ADRD的医学。 3层方法将1）测试4个假设的生物学途径（免疫，血管， 髓鞘化，突触完整性），2）评估20额外的ADRD途径，3）发现新的分子 使用公正的搜索和人工智能（AI）策略的签名。目标1是识别分子 横截面和认知状况变化相关的外周血液的签名在横截面和 纵向。 AIM 2将识别与A/T/N/V AD变化有关的血液中的分子特征 生物标志物，无论是横截面还是纵向。 AIM 3将评估基于多矩的分子的能力 在基线和随着时间的时间进行分析，以预测未来的疾病进展。 AIM 4将复制并验证ADNI 使用基于血液和脑组织的数据（带有项目1）以及来自多种族种群的数据，包括 非洲和拉丁美洲人的血统（项目3）。项目2将采用集成的翻译 U19核心支持的方法，结合了纵向临床，多词和AD生物标志物数据， 包括高级神经影像学，以使对AD的分子基础的更深入的机理见解和 确定新的潜在治疗靶标和生物标志物策略。这些结果直接支持 NIA/NAPA的AD/ADRD精密医学目标。