Genetic studies have identified dozens of changes in DNA that are associated with risk of Alzheimer’s disease. Most of these changes do not occur in the regions of DNA that code for proteins, making it difficult to understand their relationship to disease risk. In the proposed studies, we will investigate the possibility that such “noncoding” changes in DNA affect the amounts of specific proteins that are made within neurons and other cell types in the brain. Remarkably, most of the noncoding changes in DNA associated with risk of AD have been suggested to affect the amounts of proteins made by microglia, which are the main immune cells of the brain. These observations suggest that alterations in the functions of microglia contribute to the development of the most common forms of Alzheimer’s disease. The proposed studies will use powerful new experimental and computational approaches to directly examine whether DNA sequences associated with risk of AD control the production of proteins that are made by neurons and microglia. Results from these studies will enable better understanding of how noncoding changes in DNA influence the risk of AD and may lead to identification of new therapeutic targets.