CIRCUITS: Epigenetic Determinants of Human Cognitive Aging

Much like many other human traits, cognitive decline and the development of Alzheimer's disease (AD) are determined by the concerted action of genetic, epigenetic and nongenetic factors. Over the last decade, genetics research in AD has progressed at unprecedented pace owing to the application of high-throughput genotyping technologies in the context of genome-wide association studies (GWAS). However, it is becoming increasingly evident that variants of the DNA sequence themselves do not fully explain AD’s phenotypic picture and that other mechanisms, such as those related to epigenetics, must make substantial contributions to disease development and progression. For this project, we propose to perform one of the largest epigenome-wide association studies (EWAS) to date on AD-relevant neuropsychiatric phenotypes in an extremely well and deeply characterized cohort of healthy at-risk individuals from Berlin, Germany. In an auxiliary aim, we will correlate patterns of epigenetic variation in human brain samples with those derived from buccal swabs to facilitate the interpretation of our primary EWAS results. Together, the experimental data derived from this project will elucidate novel molecular mechanisms underlying cognitive decline and the onset of dementia.