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.
Using data from the Health and Retirement Study, a nationally representative longitudinal study of persons over age 50, this project will use genetic data and state-of-the art analytic methods to investigate the relationship between genes, early and midlife socioeconomic status, and episodic memory. Understanding the underlying genetic and gene-environment interactions associated with age-related memory decline may help to reveal the mechanisms of disease, and may also provide targets for potential intervention, treatment, and prevention.