Alzheimer’s disease is the most common type of dementia that causes problems with memory, thinking and behavior, and so far we don’t understand this disease well enough to find a cure to help these patients. In our proposal, we want to increase our understanding of this disease by studying microglia, the resident immune cells of the brain, and a gene called TREM2 which when mutated can significantly increase the risk of developing Alzheimer’s disease. Our recent studies show that when we transplant healthy human stem cell-derived microglia carrying a normal version of TREM2 into the brain of Alzheimer mice that develop amyloid plaques (a main characteristic of this disease), human microglia near the plaques show similarities to peripheral ‘foam cells’, which are immune cells filled with lipids and linked with another disease called “atherosclerosis”. As TREM2 is a lipid-sensor expressed by microglia, we now want to study the lipid content and the reaction of human microglia that carry the TREM2 R47H mutation to amyloid plaques in this specialized mouse model, to greatly improve our understanding of how this mutation can increase Alzheimer’s risk, which will in turn allow scientists to find treatments that increase the functionality of microglia to protect our brain from the damage caused by these amyloid plaques.