Interplay of Genetic & Socioeconomic Predictors of Memory Decline in Older Adults

描述（申请人提供）：认知障碍和衰退在老年人中普遍存在。从认知障碍到痴呆的高转化率激发了人们对识别与认知障碍及其进展相关的遗传因素的兴趣。为了更好地预防和治疗认知障碍，有必要确定哪些人会出现认知障碍，哪些人会衰退得最快。在这个应用程序中，我们将通过使用健康与退休研究（HRS）的纵向调查数据来扩展现有的研究，HRS是一个具有全国代表性的50岁以上成年人样本，并结合最新的遗传数据。具体来说，本研究将解决四个目标：目标1使用基于分子的策略来估计情景记忆表现和衰退的差异，这些差异由所有测量的单核苷酸多态性（snp）和罕见的功能变异解释，包括染色体和整体；目的2研究了40个基因在基因水平和snp水平上的关联，这些基因与情景记忆、海马体积和阿尔茨海默病对记忆表现和衰退的影响有显著和重复的证据；目标3开发情景记忆的累积遗传风险评分，并将其预测记忆表现和衰退的能力与人口和社会经济变量进行比较；目的4检验社会经济地位是否是基于分子的遗传性、基因水平关联和snp水平与情景记忆和衰退关联的修饰因子。这种方法在检查常见snp和罕见的、潜在的功能变异方面是创新的，它对不相关个体认知中的“基于分子的遗传力”的估计，以及使用最先进的基于基因的统计分析方法来检查基因区域中罕见的功能变异对种族/民族群体认知表现和认知衰退的影响。本研究的意义在于提高了对以下方面的认识：1)可归因于可测量的基因型差异的记忆表现/下降的变异比例；2)在具有全国代表性的样本中，位置候选基因对认知表现/下降的影响；3)遗传关联受社会经济因素影响的程度。研究与年龄相关的记忆衰退相关的潜在遗传和基因-环境相互作用可能有助于揭示疾病的机制，并为潜在的干预、治疗和预防提供目标。

DESCRIPTION (provided by applicant): Cognitive impairment and decline are prevalent among the elderly. The high estimated rate of conversion from cognitive impairment to dementia has fueled interest in the identification of genetic factors associated with cognitive impairment and its progression. Identifying predictors of which individuals will develop cognitive impairment and who will decline the fastest is necessary for better prevention and treatment of cognitive disorders. In this application, we will extend existing research by using longitudinal survey data from the Health and Retirement Study (HRS), a nationally-representative sample of adults over age 50, combined with newly- available genetic data. Specifically, this study will address four aims: Aim 1 uses a molecular-based strategy to estimate the variance in episodic memory performance and decline explained by all measured single- nucleotide polymorphisms (SNPs) and rare functional variants, both by chromosome and overall; Aim 2 investigates the gene-level and SNP-level associations of 40 genes that have significant and replicated evidence of association with episodic memory, hippocampal volume, and Alzheimer's Disease on memory performance and decline; Aim 3 develops a cumulative genetic risk score for episodic memory and compares its ability to predict memory performance and decline to demographic and socioeconomic variables; and Aim 4 examines whether socioeconomic status is a modifier of the molecular-based heritability, gene-level associations, and SNP-level associations with episodic memory and decline. This approach is innovative in its examination of both common SNPs as well as rare, potentially functional variants, its estimation of "molecular- based heritability" in cognition from unrelated individuals, and the use of state-of-the-art gene-based statistical analysis methods to examine the impact of rare functional variants in a gene region on cognitive performance and cognitive decline across racial/ethnic groups. The significance of this research lies in the improved understanding of 1) the proportion of variation in memory performance/decline that is attributable to measurable differences in genotype, 2) the impact of positional candidate genes on cognitive performance/decline in a nationally-representative sample, and 3) the degree to which genetic associations are modified by socioeconomic factors. Investigating the underlying genetic and gene-environment interactions associated with age-related memory decline may help to reveal the mechanisms of disease and provide targets for potential intervention, treatment, and prevention.