Identification of the genetic and transcriptomic networks of cognitive and neuropathological resilience to Alzheimer’s disease associated viruses

识别阿尔茨海默病相关病毒的认知和神经病理恢复力的遗传和转录组网络

• 批准号: 10076393
• 负责人: Benjamin Readhead
• 金额: $ 7.45万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10076393
• 关键词: Address; Administrative Supplement; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Automobile Driving; Cerebral Amyloid Angiopathy; Cognitive; Data; Disease; Etiology; Genetic; Heterogeneity; Immunologic Markers; Lewy Bodies; Modeling; Molecular; Multiomic Data; Nerve Degeneration; Neuraxis; Pathway interactions; Peripheral; Phase; Risk; Risk Factors; Satellite Viruses; Tauopathies; Tissues; disease heterogeneity; genetic association; patient subsets; protein TDP-43; resilience; sex; synucleinopathy; tau Proteins; transcriptomics

Alzheimer’s is an incurable disease characterized by progressive accumulation of amyloid and tau neuropathology along with neurodegeneration. We do not fully understand the full spectrum of molecular pathways contributing to disease etiology in disease resident central nervous system tissue, specifically as a function of the temporal phases of disease. Furthermore, while genetic association studies have identified a myriad of loci associated with AD risk, it is still unclear how these risk factors modify risk for AD via cellular specific pathways at specific temporal phases of disease. Finally, there is increasing evidence for heterogeneity of disease presentation, including sex heterogeneity as well as neuropathological heterogeneity (e.g. amyloid, tau, TDP-43, Lewy bodies, alpha-synucleinopathy, cerebral amyloid angiopathy), suggesting there may be distinct molecular mechanisms driving disease among subsets of patients. To address these complexities we propose this administrative supplement to leverage the rich multi-omic data available in the AMP-AD consortium address to construct temporal models of AD progression. Such models will form a conceptual framework to enable the interpretation of diverse molecular data and provide a principled means to contextualize peripheral immunological and biomarker data for further study.

阿尔茨海默氏症是一种不治之症，其特征是淀粉样蛋白和tau蛋白的进行性积累 神经病理学和神经退行性变。我们并不完全了解 住院患者中枢神经系统致病的分子途径 组织，特别是作为疾病的时间阶段的函数。此外，虽然基因 协会研究已经确定了无数与AD风险相关的基因座，目前仍不清楚这些基因是如何 在疾病的特定时间阶段，风险因素通过细胞特定的途径改变AD的风险。 最后，越来越多的证据表明疾病表现的异质性，包括性别。 异质性以及神经病理异质性(例如淀粉样蛋白、tau、TDP-43、路易小体、 阿尔法-突触核素病、脑淀粉样血管病)，提示可能存在明显的分子 在患者亚群中驱动疾病的机制。为了解决这些复杂性，我们建议 这一管理补充利用了AMP-AD中提供的丰富的多组数据 该联盟致力于构建AD进展的时间模型。这样的模型将形成一个 概念框架，能够解释不同的分子数据并提供一个原则性的 为进一步研究提供外周免疫学和生物标记物数据的方法。