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 two phases of the CureAlz-funded 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 third installment of our CIRCUITS consortium contribution, we propose to extend this work by adding genome-wide DNA methylation and micro-RNA (miRNA) measurements in blood at a second timepoint. This will effectively allow us to not only analyze the levels of these two types of molecular markers, but also assess their change over time. We hypothesize that these longitudinal DNAm and miRNA expression data are even more powerful than using cross-sectional data alone to derive informative molecular biomarkers of cognitive aging.