Discovering Centrally Linked Peripheral Molecular Signatures of Alzheimer's Disease

摘要摘要 发现阿尔茨海默病(AD)生物标志物，用于早期诊断、跟踪疾病进展并及时 治疗性干预是一项重要的需求。尽管现有的神经成像和脑脊液 生物标记物，迫切需要开发具有成本效益的血液生物标记物，以便在 人口水平。大规模的多组学研究证实了阿尔茨海默病中的多种分子扰动。这些 这些发现支持了发现外周生物标记物的基本原理，这些标记物捕捉了中枢神经系统的全谱 这种疾病中发生的变化。我们的计划旨在利用血液和脑多组学的组合数据 识别反映中心分子的外围分子特征的特征良好的队列 在阿尔茨海默病患者的大脑中发生的扰动。我们假设血液分子特征可以作为中心- 连锁外周生物标记物(CLPBM)，因为血液中也可以观察到许多脑多组学变化 反之亦然。由于它们与大脑分子扰动有关，这种CLPBM可以提供机械性的 关于疾病及其进展的潜在驱动因素的信息。CLPBM也有望帮助患者 根据生物学亚型和疾病分期进行分层，最终为个性化铺平道路 医药。然而，目前还没有大规模的研究可以同时分析脑部和血液样本 发现可用作未来的中心连接的外周分子签名(CLPM)的相同个体 中心连锁外周生物标记物(CLPBM)。在项目1中，我们利用了三个具有互补性的研究 优点，梅奥诊所老龄化研究，阿尔茨海默病神经成像倡议和佛罗里达州梅奥诊所后 死亡的非洲裔美国人和拉美裔美国人，以实现我们的特定目标：1.发现大脑 通过分子图谱(转录组、基因组、甲基组、蛋白质组、 在多达5个脑区和匹配的血液样本中。2.确定特定单元格类型 通过对5个脑区和匹配的血液样本进行单核转录组分析，进行CLPMS。3. 通过对相同大脑区域的相同组学测量进行分析，在不同的人群中建立CLPMS 来自洛杉矶和AA参与者。4.发现反映生物亚型和时间进程的CLPM 通过使用先进的分子数据分析方法进行数据分析。我们希望识别大脑区域和 反映阿尔茨海默病异质性神经病理的细胞型特异性CLPM；与或驱动 阿尔茨海默病的生前临床、神经影像和认知进展及结局；定义生物学亚型 并预测多民族人群AD的分子分期。来自项目1的结果，以及来自 项目2和3，共同组成&gt；20,000多组学和&gt；48,000 AD表型，来自&gt；3,700多 将使用我们定义明确的翻译路线图方法对种族参与者进行分析，以确定优先顺序 用于翻译为AD的精确医学生物标志物的CLPMS。此外，数据、结果和知识 来自该项目的信息将被广泛分享，并为研究界提供前所未有的资源。

SUMMARY ABSTRACT Discovering Alzheimer’s disease (AD) biomarkers for early diagnosis, tracking of disease progression and timely therapeutic interventions is a significant need. Despite the utility of existing neuroimaging and cerebrospinal fluid biomarkers, there is an urgent need to develop cost-effective and blood-based biomarkers to apply at the population level. Large-scale multi-omics studies identified a multitude of molecular perturbations in AD. These discoveries support the rationale for discovery of peripheral biomarkers that capture the full spectrum of central changes that occur in this disease. Our proposal aims to leverage combined blood and brain multi-omics data in well-characterized cohorts to identify peripheral molecular signatures which reflect the central molecular perturbations that occur in AD brains. We hypothesize that blood molecular signatures can serve as centrally- linked peripheral biomarkers (CLPBM) since many brain multi-omics changes can also be observed in blood and vice versa. As they are linked with brain molecular perturbations, such CLPBM can provide mechanistic information on potential drivers of disease and its progression. CLPBM can also be expected to aid in patient stratification according to biological subtypes and disease stage, ultimately paving the way for personalized medicine. There are, however, no sizable studies that simultaneously analyze brain and blood samples from the same individuals to discover centrally-linked peripheral molecular signatures (CLPMS) that can serve as future centrally-linked peripheral biomarkers (CLPBM). In Project 1, we leverage three studies with complementary strengths, Mayo Clinic Study of Aging, Alzheimer’s Disease Neuroimaging Initiative and Mayo Clinic Florida post- mortem African American and Latino American cohorts, to accomplish our specific aims to: 1. Discover brain region-specific CLPMS through molecular profiling (transcriptome, genome, methylome, proteome, metabolome/lipidome) in up to 5 brain regions and in matched blood samples. 2. Identify cell-type specific CLPMS through single nucleus transcriptome profiling across 5 brain regions and in matched blood samples. 3. Establish CLPMS in diverse populations by profiling of same -omics measures across the same brain regions from LA and AA participants. 4. Discover CLPMS that reflect biological subtypes and temporal progression of AD through use of advanced analytics approaches of the molecular data. We expect to identify brain region and cell-type specific CLPMS, which reflect the heterogeneous neuropathology in AD; associate with or drive antemortem clinical, neuroimaging and cognitive progression and outcomes of AD; define biological subtypes and predict molecular stage of AD in multi-ethnic populations. Findings from Project 1, together with those from Projects 2 and 3, collectively comprising >20,000 multi-omics and >48,000 AD phenotypes from >3,700 multi- ethnic participants will be analyzed applying our well-defined Roadmap to Translation approach to prioritize CLPMS for translation to precision medicine biomarkers for AD. Further, the data, outcomes and knowledge from this Project will be shared broadly and serve as an unprecedented resource for the research community.