Project Summary/Abstract The ability to learn, consolidate and retrieve information begins to decline with normal aging, a major risk factor for Alzheimer’s Disease (AD) and dementia. The 2012 National Projections report by the U.S. Census Bureau indicates that in 2050 the population in the U.S. aged 65+ will be approximately 84 million, which will reflect 21% of the predicted U.S. total population. Also in the U.S., 16-20% of current 65+ individuals are predicted to be cognitively impaired. Understanding mechanisms of age-related cognitive decline may inform AD-related dementia and lead to the discovery of effective treatments for improving cognitive function in AD. Genomic and epigenomic studies, as well as cognitive neuroepigenetic studies, have demonstrated that alterations of the epigenome may be critically important to age- and AD-associated cognitive decline. Recent studies have also demonstrated that the epigenome, and DNA methylation in particular, may be used to distinguish chronological age from biological age. That is, the exact age of an individual (chronological age) versus the apparent age of an individual (biological age). The precise collection of patterns of DNA methylation that are used to make these distinctions in different tissue types are called ‘epigenetic clocks’. Although several epigenetic clocks have been published from mixed tissues and whole brain regions, there are no studies identifying an epigenetic clock in a brain region necessary for memory, and determining the ability of that clock to predict age-impaired or age-unimpaired cognitive performance, which would represent a major conceptual and technical innovation. In this proposal, we aim to identify an epigenetic clock in the hippocampus, a major brain region involved in learning and memory, and one that begins to decline with age and becomes even further impaired with AD pathology. Our preliminary data demonstrates our ability to develop a DNA methylation data analysis pipeline (using reduced representation bisulfite sequencing) from the hippocampus of 2 and 20 month old male and female C57BL/6 mice, which established a foundation for arriving at an epigenetic clock. In Aim 1 we proposed to identify a hippocampus epigenetic clock in wildtype male and female mice across the lifespan, and to determine how that epigenetic clock is altered in the context of AD using the 5xFAD mouse model. In Aim 2, we propose to determine the epigenetic clock can predict age-impaired versus age-unimpaired cognitive performance in wild type animals, and whether the clock may distinguish resilience versus susceptibility to cognitive decline in 5xFAD animals.