Genetic and Environmental Drivers of Cognitive Resilience in Aging Populations

项目摘要/摘要 阿尔茨海默病和相关痴呆(ADRD)是造成健康、社会和经济负担的主要来源。 缺乏有效的ADRD疗法或策略来预防或阻止ADRD的进展是一个重要的 人口老龄化背景下的公共卫生挑战。关注韧性，而不是疾病，可能会 提供对新的治疗和预防模式的洞察。认知能力强的人通常会保留 认知功能正常，尽管年事已高或脑部有病变。认知的基因结构 根据最近的基因组研究，韧性和阿尔茨海默氏症似乎是不同的。然而，进一步 询问认知韧性的生物学基础，包括基因和基因之间的相互作用 环境因素，对于设计有针对性的干预措施，建立老年人的认知韧性是必要的 成年人。我们假设，多组学方法可以识别新的认知韧性基因座并阐明途径 这有助于提高认知韧性，降低ADRD的风险。我们建议使用现有的基因组数据，高度- 对5000种血浆蛋白进行质量纵向测量，重复心理测量评估，以及 社区动脉粥样硬化风险(ARIC)研究中的神经成像研究 目的：(1)采用多组学方法确定认知复原力的因果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 恢复力。在目标1中，我们将进行蛋白质组范围的关联研究(Pwas)以确定相关的蛋白质。 具有认知韧性。鉴于流行病学研究中认知韧性的衡量标准存在异质性， 我们将使用心理测量学和基于成像的认知韧性定义。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识别原因标记 认知韧性。在目标2中，我们将建立并验证认知韧性的多基因风险评分(PRS)。 该研究将用于模拟遗传因素和可改变的环境因素对认知的相互作用。 恢复力。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)分子、神经和衰老流行病学方面的高级培训和(2)指导应用 这些方法在一个创新的研究问题中与人口老龄化研究的优先事项一致。与 在一支高素质和热情的导师团队的奉献下，这些目标的成功实现将 加深该领域对认知韧性决定因素的理解。此外，培训目标 嵌套在这个奖项的F99和K00阶段将为我的职业生涯做准备，在这个职业生涯中，我将领导 跨学科团队作为老龄化研究的独立调查者

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