Treating Alzheimer’s disease (AD) is one of the greatest challenges we face in the coming years and has the potential to have an enormous impact on human health. Despite its importance, there still are no highly effective treatments for AD. Sequencing the genomes of subjects with AD has provided valuable information about which mutations can influence the disease, but we still don’t know what most of those mutations are doing in the brain. A better understanding of how nature influences AD would provide a guide for how to develop entirely new avenues for treatment. In this proposal, we aim to solve a major challenge facing the AD field: how do you study the effects of mutations in the brain? We plan to use two parallel strategies. First, we will develop new machine-learning tools that can predict the impact of a mutation. Second, we will continue to develop new genomic technology that allows us to measure how segments of the human genome function in the brain of a mouse. Together with other Cure Alzheimer’s Fund-funded groups, we will systematically work toward the underlying cell types, pathways, biological processes, and potential drug targets.