Genetic and Environmental Drivers of Cognitive Resilience in Aging Populations

项目概要/摘要 阿尔茨海默病和相关痴呆症（ADRD）是健康，社会和经济负担的主要来源。 缺乏有效的ADRD治疗或策略来预防或阻止ADRD进展， 人口老龄化背景下的公共卫生挑战。注重恢复力而不是疾病， 提供对新型治疗和预防模式的深入了解。认知复原力强的人通常会保留 正常的认知功能，尽管高龄或大脑病理。认知的遗传结构 根据最近的基因组工作，恢复力和阿尔茨海默病似乎是不同的。但进一步 询问认知弹性的生物学基础，包括遗传和 环境因素，是必要的，以设计有针对性的干预措施，建立认知弹性在老年人 成年人了我们认为，多组学方法可以识别新的认知弹性位点，并阐明途径 促进认知恢复力和降低ADRD风险。我们建议使用现存的基因组数据，高- 对5,000种血浆蛋白质进行质量纵向测量，重复进行心理测量评估， 在社区动脉粥样硬化风险（ARIC）研究中， 目的：（1）采用多组学方法确定认知弹性的致病基因座和生物标志物， 社区居住的老年人和（2）分解认知的遗传和环境驱动因素 resilience.在目标1中，我们将进行蛋白质组关联研究（PWAS）， 认知恢复力。鉴于流行病学研究中认知弹性测量的异质性， 我们将使用基于心理测量和成像的认知弹性定义。我们还将鉴定蛋白质 数量性状基因座，进行精细定位，并使用孟德尔随机化来确定 认知复原力在目标2中，我们将建立并验证认知弹性的多基因风险评分（PRS）。 PRS将用于模拟遗传和可改变的环境因素对认知功能的相互作用。 resilience.这个奖项将支持我向老龄化研究的过渡以及我的近期和长期目标 通过（1）在分子，神经和衰老流行病学的高级培训和（2）指导应用 这些方法是一个创新的研究问题，与人口老龄化研究的优先事项一致。与 一个高素质和热情的导师团队的奉献精神，这些目标的成功完成将 加深该领域对认知弹性决定因素的理解。此外，培训目标 嵌套在这个奖项的F99和K 00阶段将准备我的职业生涯中，我将领导一个 跨学科团队作为一个独立的研究人员在老龄化研究

PROJECT SUMMARY/ABSTRACT Alzheimer's disease and related dementias (ADRD) are major sources of health, social, and economic burden. The lack of effective ADRD therapies or strategies to prevent or stop ADRD progression presents a significant public health challenge in the context of aging populations. A focus on resilience, instead of disease, may provide insight into novel treatment and prevention modalities. Cognitively resilient individuals typically retain normal cognitive function despite advanced age or brain pathology. The genetic architectures of cognitive resilience and Alzheimer's disease appear distinct based on recent genomic work. However, further interrogation of the biologic basis of cognitive resilience, including the interplay between genetic and environmental factors, is necessary to design targeted interventions that build cognitive resilience in older adults. We posit that a multi-omics approach can identify novel cognitive resilience loci and elucidate pathways that promote cognitive resilience and lower the risk of ADRD. We propose to use extant genomic data, high- quality longitudinal measurements of 5,000 plasma proteins, repeat psychometric assessments, and neuroimaging in the Atherosclerosis Risk in Communities (ARIC) study to accomplish the following specific aims: (1) employ a multi-omic approach to identify causal loci and biomarkers for cognitive resilience in community-dwelling older adults and (2) decompose the genetic and environmental drivers of cognitive resilience. In Aim 1, we will conduct a proteome-wide association study (PWAS) to identify proteins associated with cognitive resilience. Given heterogeneity in the measure of cognitive resilience in epidemiologic studies, we will use psychometric and imaging-based definitions of cognitive resilience. We will also identify protein quantitative trait loci, perform fine-mapping, and use Mendelian Randomization to identify causal markers of cognitive resilience. In Aim 2, we will build and validate a polygenic risk score (PRS) for cognitive resilience. The PRS will be applied to model the interplay of genetic and modifiable environmental factors on cognitive resilience. This award will support my transition to aging research and my immediate and long-term goals through (1) advanced training in molecular, neuro-, and aging epidemiology and (2) the mentored application of these methods in an innovative research question aligned with priorities in population aging research. With the dedication of a highly qualified and enthusiastic team of mentors, the successful completion of these aims will deepen the field's understanding of the determinants of cognitive resilience. Further, the training objectives nested in the F99 and K00 phases of this award will prepare me for a career in which I will lead an interdisciplinary team as an independent investigator in aging research