No drugs that can prevent or revert Alzheimer’s disease currently exist. Genetic studies recently have discovered that people with a genetic variant in the Phospholipase C-gamma-2 (PLC-gamma-2) gene—the “P522R” variant—are protected from Alzheimer’s disease and other dementias. The PLC-gamma-2 enzyme plays a role in brain immune cells, but exactly how the P522R variant protects against dementia in these cells is not known. Here we will use novel stem cell techniques to study how the PLC-gamma-2 P522R variants affect the function of human brain immune cells (also known as microglia). We also will compare the effect of PLC-gamma-2 P522R with other PLC-gamma-2 mutations that are known to cause immune disease. Our goal is to establish what is unique about PLC-gamma-2 P522R that drives the protective effect of this mutation against dementias. This research will help provide insight into the role of PLC-gamma-2 in Alzheimer’s disease and other dementias. The knowledge gained from our proposal can directly be applied to discover novel drugs that mimic the protective effect of the P522R variant for the treatment of Alzheimer’s disease and other dementias.