ABSTRACT Alzheimer’s disease (AD) susceptibility loci are enriched for genes implicated in the endolysosomal pathway (ELP) and lipid homeostasis (LH), and these biological processes are highly interdependent. The AD Sequencing Project (ADSP) Functional Genomics Consortium (FunGen) selected the ELP/LH pathways as high-priorities for cross-cutting, collaborative investigations, culminating in 3 applications for supplemental funding. Together, investigators from 4 distinct U01 FunGen projects will probe ELP/LH mechanisms of AD risk using a tiered strategy integrating experiments in Drosophila with both 2D and 3D human iPSC cultures. We recently showed that APOE and several other AD susceptibility / ELP genes (PICALM, CD2AP, AP2A2) participate in a common pathway involving the formation of lipid droplets (LD) within glia. Glial LD formation involves two related mechanisms. The first is a non-cell autonomous neuroprotective pathway where LD form within glia in response to elevated reactive oxygen species (ROS) in neurons. These glial LDs are composed of toxic, peroxidated lipids (LPO) produced by “stressed” neurons and these LPO are catabolized within the glia, effectively removing the LPO from the brain and protecting both cell types from ROS-induced damage. The second mechanism involving glial LD formation is a cell autonomous mechanism whereby APOE4 or loss of PICALM directly drives glial LD formation in response to stress. This causes high LD load and may be important in later-stage AD pathologic changes. We hypothesize that many other AD risk genes may participate in either one or both of these pathways, having divergent impact on AD risk, glial LD load, and neuronal oxidative stress/injury, depending on the disease stage(s) and cell type(s) affected. Here, we propose systematic functional dissection of 50 AD candidate genes, using well-established Drosophila protocols to establish cell-type specific requirements for glial LD formation, potential interactions with ROS, and resulting neurodegeneration. Gene selection will be closely coordinated with FunGen collaborators and informed by complementary, high-throughput screens considering more than 1000 genes in iPSC and Drosophila models, revealing interactions with amyloid-beta / tau-induced neurodegeneration and requirements for ELP/LH. Overall, our integrated FunGen supplemental research program will promote highly synergistic studies not otherwise possible within the scope of individual projects, revealing ELP/LH mechanisms of AD risk, identifying promising therapeutic targets, and culminating in a joint consortium manuscript.