Cognitive decline and the development of age-related conditions such as 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 an 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. To this end, in the first phase of the CIRCUITS consortium, we had proposed to study the impact of epigenetics on two important domains. First, to decipher the correlation of DNA methylation (DNAm) patterns in brains and buccal swabs from the same individuals examined neuropathologically at the Massachusetts Alzheimer’s Disease Research Center, and second, 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 this second phase of our CIRCUITS consortium contribution, we propose to extend this work in scope, both by increasing sample size and extending our analyses to other epigenetic domains and tissue compartments. Together, the combination of experimental data derived from this and the previous phase of our project will help to elucidate novel molecular mechanisms underlying cognitive decline and the onset of dementia, and improve our ability to develop and apply novel genetic and epigenetic biomarkers of cognitive aging.
Much like many other human traits, cognitive decline and the development of Alzheimer’s disease are determined by the concerted action of genetic, epigenetic and nongenetic factors. Epigenetics refers to changes that occur by modification of gene expression rather than alteration of the genetic code itself. It is becoming increasingly evident that variations in the DNA sequence itself do not fully explain the phenotypic picture of Alzheimer’s disease. Over the last decade, genetics research in Alzheimer’s has progressed at an unprecedented pass owing to the application of genotyping technology in the context of genome-wide association studies (GWAS). This project seeks to perform one of the largest epigenome-wide association studies to date on Alzheimer’s disease relevant neuropsychiatric phenotypes. The study will use a well-characterized cohort of healthy at-risk individuals from Germany. The study will elucidate novel molecular mechanisms underlying cognitive decline and the onset of dementia.