Genetic studies have identified dozens of changes in DNA that are associated with risk of Alzheimer’s disease (AD). 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 extend our previous CureAlz-supported studies suggesting that such ‘noncoding’ changes in DNA affect the amounts of specific proteins that are made within microglia and other cell types in the brain. We will focus specifically on the role of a region of the genome that selectively controls expression of the BIN1 gene in microglia and contains changes in noncoding DNA sequence that are highly associated with risk for AD. As a second aim, we will define regions in the genome that control microglia functions dependent on proteins that are members of the MS4A gene family. These proteins are encoded by genes that reside in a region of the genome that also contains changes in noncoding DNA sequence that are highly associated with risk of AD. These studies have the objective of determining how MS4A proteins regulate microglia functions that promote AD. Successful completion of this work will depend on extensive collaborations with members of the CureAlz Neuroimmune Consortium. These studies are expected to enable better understanding of how noncoding changes in DNA influence the risk of AD, and may lead to identification of new therapeutic targets.