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很常见。从认知障碍到痴呆症的高估计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，谁会下降得最快的预测因素。在这项应用中，我们将通过使用来自健康和退休研究(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，结合最新可用的遗传数据。具体地说，这项研究将针对四个目标：目标1使用基于分子的策略来估计由所有测量的单核苷酸多态(SNPs)和罕见的功能变异(按染色体和整体解释)解释的情景记忆表现和下降的差异；目标2调查40个基因的基因水平和SNP水平的关联，这些基因具有显著和重复的证据与情景记忆、海马体体积和阿尔茨海默病有关；目标3开发情景记忆的累积遗传风险评分，并比较其预测记忆表现以及对人口统计学和社会经济变量下降的能力；目标4检查社会经济地位是否是基于分子的遗传力、基因水平的关联以及SNP水平与情景记忆和衰退的关联的修饰符。这一方法的创新之处在于，它既研究了常见的SNPs，也研究了罕见的潜在功能变异，它估计了来自无关个体的认知中的“基于分子的遗传力”，并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下降的影响。这项研究的意义在于更好地理解了1)由于可测量的基因差异而导致的记忆表现/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，以及3)社会经济因素改变遗传联系的程度。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、治疗和预防提供靶点。

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.