Integrating Polygenic Risk and Environmental Exposures to Uncover Biological Mechanisms Underlying Dementia in a Diverse Cohort

项目摘要 阿尔茨海默病（AD）是发达国家的主要死亡原因。超过50个基因位点 与迟发性AD风险相关，但我们仍然没有完全了解疾病的发病机制， 未能找到预防或治疗痴呆症或认知能力下降的成功解决方案。AD受影响 由遗传和环境（社会，建筑和物理）因素。了解这些之间的相互作用 遗传和非遗传因素对于解决该疾病的潜在生物学问题至关重要。许多研究 专注于识别与AD相关的遗传原因或可改变的风险因素，大多数基因- AD的环境研究仅限于单基因×单环境因素研究（主要是 关注基因APOE）。很少有研究涉及上游因素，如社会经济地位 环境空气污染与许多遗传位点（多基因）的风险相互作用， 表达和蛋白质组学变化导致AD和相关痴呆。本研究的具体目的是 到1. (F99阶段）确定与痴呆风险相关的社会，建筑和物理环境变量 和/或认知能力下降，独立于多基因风险并由多基因风险修饰; 2. (K00相）识别 转录组学和蛋白质组学特征介导环境暴露对 痴呆/认知能力下降。在我的论文阶段，我将训练多基因风险评分计算， 预测分析，混合效应建模和机器学习，以表征遗传和 AD和相关痴呆的环境决定因素。我将采用多基因风险评分方法， 旨在提高多种族人群的预测准确性。作为一名博士后，我将 将我的培训扩展到多组学数据整合和分析，以提高我们对AD风险因素的理解 和相关痴呆症的研究，以了解因果通路和 环境暴露的生物介质。这项研究将利用多民族研究， 动脉粥样硬化父母和辅助研究（梅萨邻里和老龄化，梅萨MIND和梅萨Air），a 在健康的社会决定因素的范围上，纵向队列与痴呆沿着是前所未有的 裁定和多组学数据。该奖学金申请符合NIA战略方向， 研究目标D-1“确定遗传、分子、细胞和社会/环境因素如何相互作用， 大脑健康和神经退化。”通过这项工作，我们将确定上游（政策一级） 和下游（生物机制）干预和预防点。此外，研究和 这个奖项提供的职业发展将帮助我开始我的职业生涯，作为一个独立的调查员， AD的预测和预防。

PROJECT SUMMARY Alzheimer’s disease (AD) is a leading cause of death in developed countries. Over 50 genetic loci have been associated with late-onset AD risk, yet we still do not fully understand the disease pathogenesis and have failed to find successful solutions for prevention or treatment of dementia or cognitive decline. AD is influenced by genetic and environmental (social, built, and physical) factors. Understanding the interplay between these genetic and non-genetic factors is crucial to address the underlying biology of the disease. Many studies have focused on identifying either genetic causes or modifiable risk factors associated with AD, and most gene- environment studies of AD have been restricted to single-gene x single-environmental factor studies (primarily focusing on the gene APOE). Few studies have addressed how upstream factors like socioeconomic status and ambient air pollution interact with risk across many genetic locations (polygenic) to influence gene expression and proteomic changes that lead to AD and related dementias. The specific aims of this study are to 1. (F99 phase) determine social, built, and physical environmental variables associated with dementia risk and/or cognitive decline, independent of and modified by polygenic risk and 2. (K00 phase) identify transcriptomic and proteomic signatures that mediate the effect of environmental exposure on dementia/cognitive decline. During my dissertation phase, I will train in polygenic risk score computation, predictive analysis, mixed-effect modeling, and machine learning to characterize the effects of genetic and environmental determinants on AD and related dementias. I will employ polygenic risk score methods that have been designed to improve predictive accuracy in multi-ethnic populations. As a post-doctoral fellow, I will expand my training to multi-omic data integration and analysis to move our understanding of risk factors for AD and related dementias beyond studies of association to an understanding of causal pathways and the biological mediators of environmental exposures. This research will leverage the Multi-Ethnic Study of Atherosclerosis parent and ancillary studies (MESA Neighborhood and Aging, MESA MIND, and MESA Air), a longitudinal cohort unprecedented in its scope of social determinants of health along with dementia adjudication and multi-omic data. This fellowship application aligns with the NIA Strategic Directions for Research Goal D-1 “to determine how genetic, molecular, cellular, and social/environmental factors interact for brain health and neurodegeneration.” As a result of this work, we will have identified upstream (policy-level) and downstream (biological mechanisms) points of intervention and prevention. In addition, the research and career development provided by this award will help me launch my career as an independent investigator of AD prediction and prevention.