PROJECT SUMMARY The costs associated with Alzheimer's disease are estimated at over $243 billion annually in the United States. The factors involved are not fully understood, but metabolic processes play an important role. Indeed, obesity and type II diabetes are major risk factors for Alzheimer's disease. Gaining a deeper understanding of the mechanisms involved is urgent, because obesity affects 17% of children, ~30% of US adults and especially the elderly. Gene regulatory mechanisms are emerging as major drivers of human disease, but their roles in obesity and Alzheimer's disease are poorly understood. Here, we propose a study that will uncover new and important noncoding elements and gene regulatory mechanisms in the genome that underlie mammalian obesity and age-related neurodegeneration. Our study builds on our recent publication in Cell Reports (Ferris et al., 2018), in which we performed a comparative genome-wide analysis of accelerated regions (ARs) in species with highly distinctive traits to define mammalian noncoding elements that shape clinically important phenotypes. ARs are conserved genomic elements with significantly increased nucleotide substitutions in a specific lineage, typically due to selective effects. In an unpublished study, we built on our approach to uncover regulatory elements shaping mammalian obesity and neurodegeneration by studying hibernators. Hibernators evolved metabolic and behavioral adaptations that resulted in a reversible obesogenic phenotype. They also evolved neuroprotective mechanisms that prevent brain damage. We identified 2370 50bp elements in the mammalian genome that underwent parallel accelerated evolution in multiple species that independently evolved hibernation. We call these noncoding elements hibernator accelerated regions (ARs) and found a subset associated with risk loci for human obesity and Alzheimer's disease. Our study tests the hypothesis that the conserved elements impacted by hibernator ARs near obesity and Alzheimer's disease risk genes are critical regulatory elements that control gene expression in different tissues and shape obesogenic behaviors, metabolic activity and age-related neurodegeneration. Our study is significant because the results will define important new noncoding mechanisms that regulate biological processes contributing to Alzheimer's disease. In the long-term, our results are expected to help reveal improved genetic and epigenetic biomarkers and therapeutic strategies to prevent age-related obesity and neurodegeneration.