Cognitive ability (i.e. memory, attention, processing, problem solving, etc) undergoes rapid growth during the first two decades of life, and then generally stabilizes until cognitive decline (and more acutely Alzheimer’s Disease and related disorders (ADRD)) occurs much later in the life course. However, it remains unclear to what extent genetic influences are consistent between cognitive development and decline. Yet, it is well documented that childhood context, experiences, and cognition are predictive of cognitive decline and even ADRD. To date, most of the genetic work on cognitive development has been based on candidate genes?which have some notable limitations. In contrast, work on genetic factors of ADRD and cognitive decline in adults has been explored in several genome-wide association studies (GWAS) of 100,000s of individuals. Thus the central purpose of this administrative supplement is to test the application of polygenic scores (PGS) and genomic regions derived from GWAS of ADRD in adults on cognitive development in childhood and adolescence. The work in this supplement will provide novel insight into the timing and biological processes involved in ADRD related genetic measures. To conduct this research we have assembled an interdisciplinary team of investigators and use the Fragile Families and Child Wellbeing Study, a population-based, birth cohort study of n=4898 children born in 1998-2000. Families were interviewed at birth and again when children were ages 1, 3, 5, 9, and 15. We use large GWAS of ADRD phenotypes to create PGS and define key gene regions in order to examine the genetic effects on cognitive development. We will examine ADRD-related PGS and gene region analysis (via Sequence Kernel Analysis Tests and Burden scores) with cognitive development (i.e. memory, verbal and math reasoning, reading comprehension, and attention) from ages 3-15. Preliminary work shows a correlation between later life polygenic predictors of AD and early life memory development (Aim 1). The specific focus on gene regions (Aim 2) provides two additional insights. First, GWAS is principally designed to find loci near causal variants. By focusing on gene regions we will facilitate deeper understanding of the biological underpinnings of ADRD genes in cognitive development. Second, although GWAS have been conducted primarily in European Ancestry populations, and typically have lower predictive value in minority samples, gene-region analyses have proven to be better suited to trans-ethnic analyses. Moreover, this work will directly address the needs of the parent R01 (funded by NIMHD to study the social epigenetic processes related to race/ethnic and SES inequalities) by discovering new gene regions to examine for differential epigenetic regulation, which could ultimately lead to improved understanding of health disparities related to AD and ADRD by race/ethnicity and SES.
Health and Human Services, Department of-National Institutes of Health
08/16/2017 to 05/31/2022