GENOMICS CORE SUMMARY Core Leader: Vivianna M. Van Deerlin, MD, PhD; Core Co-leader: Corey T. McMillan, PhD The focus of the University of Pennsylvania (Penn) Alzheimer’s Disease Research Center (ADRC) is to develop a mechanistic understanding of the still evolving complexity of Alzheimer disease (AD) and related dementias (ADRD) by studying the spectrum of disease from earliest onset through progressive stages of disease and ultimately at autopsy. Aside from rare and highly penetrant mutations that cause familial AD, several genetic factors play a critical role for risk of AD/ADRD. Also, epigenetic markers change throughout the lifespan and may contribute to AD heterogeneity by potentially providing resistance to pathology or resilience to clinical progression. The Genetics Core was first funded in 2017 to meet the Penn ADRC’s growing needs of increasing the genetic characterization of the Penn ADRC Cohort and here we propose to transition from traditional genetics to a Genomics Core. The Genomics Core will innovatively incorporate genetics and bioinformatics expertise with the goal of supporting the Penn ADRC mission by providing resources to conduct and support genomics research in collaboration with the other cores through the following Aims: (1) Extract nucleic acid from biosamples for biobanking and sharing; (2) Perform genotyping and generate polygenic risk scores to relate to pathology and downstream processes of AD; (3) Measure DNA methylation and generate epigenetic summary scores like “epigenetic clock”; (4) Screen and counsel patients for hereditary disease; and (5) Enhance diversity in research and education of genetics of AD. We will accomplish these Aims by receiving DNA from Clinical Core subjects through the Biomarker and Neuropathology Cores. DNA banking efforts will be enhanced by the diversity of subjects in the Penn Aging Brain Cohort (ABC) Study that is enriched for African Americans and the collaborating Aging Brain Cohort Dedicated to Diversity (ABCD2). We will closely collaborate with the Data Management and Statistic (DMS) Core to deposit resulting data into the Integrated Neurodegenerative Disease Database. This will enable collaborating Penn ADRC Cores, and through data sharing initiatives other internal and external investigators, to perform genetic association studies of neuroimaging, biofluid biomarkers and clinical progression with the goal of improving our understanding of the complexities and heterogeneity of AD/ADRD and identifying mechanistic candidates for novel therapies. Through these activities we will additionally contribute to the Research and Education Component (REC) by training early career scientists including fellows and junior faculty.