Overall – Project Summary The Alzheimer’s Disease Research Center (ADRC) was founded at Wake Forest School of Medicine (WFSM) in 2016 to provide a comprehensive infrastructure for research on the pathophysiology, prevention, and treatment of AD and related disorders (ADRD). The theme of our ADRC is to better understand early transitions from normal aging to MCI and dementia, and to elucidate the role that metabolic and vascular factors play in these transitions, through coordinated research activities spanning the translational spectrum. No current therapies effectively prevent or treat the symptoms of AD. This chasm highlights the need to identify antecedent biomarkers and risk factors that predict later-life vulnerability or resilience, in order to develop strategies for prevention and early intervention. Metabolic and vascular disorders are powerful modifiable factors that may contribute to the transitions from normal aging to MCI and ADRD. Such disorders are epidemic in the Southeastern region surrounding the WF ADRC; more than 70% of adults over the age of 50 have prediabetes, diabetes, or hypertension. These disorders increase the risk of cognitive impairment and dementia through complex interactions that are poorly understood. The WF ADRC seeks to provide resources to better understand these interactions. We also seek to elucidate the multi-dimensional role that health disparities play in influencing risk for AD. We emphasize engagement of African Americans and other underrepresented groups, who are twice as likely to develop dementia, and have high rates of diabetes and vascular disease. To promote innovative research on metabolic/vascular risk and health disparities, our Outreach, Recruitment and Engagement and Clinical Cores have partnered to enroll and follow ~600 participants, carefully characterizing their vascular and glycemic status. Participants receive magnetic resonance imaging and amyloid and tau positron emission tomography overseen by the Imaging Biomarker Core. Valuable samples and data from this cohort are made widely available to the National Alzheimer’s Coordinating Center, the National Centralized Repository for AD and other investigators by the Data Management and Statistical Analysis and Neuropathology Cores, providing invaluable resources to address numerous National Alzheimer’s Project Act milestones. The Neuropathology Core has also characterized novel nonhuman primate models with methods that parallel the ADRC’s human cohort to promote translational research. Finally, the ADRC and its Research Education Component provide training relating to AD, metabolic/ vascular factors and health disparities to a diverse cadre of new researchers, and education for patients and families, health professionals, and the community. The prevalence of metabolic and vascular risk factors, their role in onset, progression, and heterogeneity of ADRDs, and the strengths of the WF ADRC in these research areas, ensure that we will make high...