ABSTRACT The goal of this proposal is to advance our understanding of the genetic etiology of Alzheimer disease (AD) risk in understudied and underserved populations. AD is the leading cause of dementia in the elderly and occurs in all ethnic and racial groups, but most genetic studies for AD have been performed in non-Hispanic Whites (NHW) of European ancestry. This is problematic, as much smaller studies in African Americans (AA), who have a higher prevalence of AD compared to NHW, have already revealed differences in risk effect sizes in known loci (e.g., APOE; ABCA7), indicating multiple unique patterns of risk. Genetic ancestry (including variability in allele risk frequencies and population specific variants modifying known and novel risk loci), in addition to environmental/cultural factors and their interactions with genetic risk, likely underlies part of this heterogeneity. With only a small number of the whole genome sequences in the Alzheimer’s Disease Sequencing Project (ADSP) coming from AA, increased sample sizes and multiple study designs are needed to elucidate risk in diverse ancestral populations. Family studies provide a powerful complementary design to case- control studies that can enhance risk prediction and the detection of novel rare risk variants. Filling these critical gaps using genetic tools will enhance our understanding of AD risk and provide the basis for identifying prevention strategies and druggable targets. Including ancestral populations from Africa in particular a unique cohort of multiplex African AD families enables dissecting risk not only in African populations but also among all populations with AF ancestry. Our efforts will allow for improved disease prediction, prevention, diagnosis, and treatment through precision medicine, in AA, African, and other African admixed populations.