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. Instead, approximately 90% of these changes are in “noncoding” regions of DNA that used to be referred to as “junk DNA,” which made them difficult to understand. Studies carried out over the past 10 years, including work from our laboratory, have shown that this so-called junk DNA actually provides the instructions that each cell in the body uses to determine which genes to turn on. In the proposed studies, we will extend our previous CureAlz-supported studies suggesting that changes in noncoding DNA that are associated with AD affect the amounts of specific proteins that are made within microglia and other cell types in the brain. We will specifically focus 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 that are 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.