The brain is composed of many different cells that are tightly interconnected during health and disease. Astrocytes are integral to the normal function of the healthy brain—providing nutrients to neurons and microglia. In the AD brain, we identified that microglia become reactive and release factors that cause astrocytes to become reactive, ultimately leading to neuron death. The activation of microglia is, in part, due to a lack of release of cholesterol from astrocytes (which normally provide cholesterol to maintain microglia in a healthy state). Two risk alleles for AD, Clusterin (CLU) and Apolipoprotein E (APOE), are involved in this cholesterol transport, are highly expressed by astrocytes and are integral for normal brain health. Here we will investigate the role of AD-associated mutations in CLU and APOE and determine how they change the function of astrocytes and, in turn, how this affects microglia. These studies will connect the whole genome studies of AD risk factors with known astrocyte-microglia function, providing understanding of this glial-immune axis important for the health of neurons. We predict these results will provide insights and novel targets for future therapy development.