Abstract Brain arteriolosclerosis (B-ASC) is a cerebrovascular disease characterized by pathological thickening of the arterioles in the brain. Non-Alzheimer’s disease brain pathologies, including B-ASC, are increasingly recognized as important contributors to cognitive decline in aged individuals. In autopsy cohorts, B-ASC is found in over 50% of participants aged eighty years or older at death. B-ASC is associated with multiple other neuropathologies, including hippocampal sclerosis. Despite its clinical importance, the pathophysiology of brain arteriolosclerosis and its mechanistic relationship to other pathologies are not well understood. We have aggregated and harmonized genotype and autopsy data between four high-quality neuropathology cohorts: the National Alzheimer’s Coordinating Center (NACC), the Religious Orders Study and the Memory and Aging Project (ROSMAP), the Adult Changes in Thought Study (ACT), and the Alzheimer’s Disease Neuroimaging Initiative Neuropathology Cohort (ADNI). In preliminary genetic association and functional genomic studies using NACC participants, we identified multiple B-ASC risk loci that replicated in at least one independent cohort and established a framework for genetic studies of neuropathological endophenotypes (NPE). In Aim 1, we hypothesize that analyses employing gene expression and DNA methylation will further characterize genomic risk factors for B-ASC pathology. We will investigate the relationship between B-ASC, gene expression, and DNA methylation in the dorsolateral prefrontal cortex using ROSMAP. These analyses will be followed by computational approaches that will estimate the contribution of different cell types and predict gene expression from genotype data in other cohorts. In Aim 2, we hypothesize that B-ASC shares genomic risk with associated NPE. We will first use our established analytic pipeline to perform genetic association studies of NPE comorbid with B-ASC. We will then use statistical methods to quantify and localize shared genetic risk between B-ASC and other NPE. Findings from these studies will provide a rigorous characterization of B-ASC risk factors and relevant biological pathways. Our cross-trait analyses will help clarify B-ASC’s place in the complex web of mixed brain pathologies common in aged individuals. The mentors and collaborators I have recruited comprise an experienced and multidisciplinary team that includes two biostatisticians, a genetic epidemiologist, and an experimental neuropathologist. This NIH F30 fellowship will provide the requisite experience, knowledge, and skills necessary as preparation to the next stage in my career as a clinical researcher.