Alzheimer's Disease Risk Allele APOE4 Interacts with Arsenic Exposure to Drive Microglial Dysfunction

Alzheimer's disease (AD) is influenced by both genetic risk and environmental exposures, but how these factors interact in human microglia remains unclear. Here, we investigate whether the late-onset AD risk allele APOE4 impacts microglial vulnerability to arsenite exposure. To that end, we used CRISPR/Cas9 to generate an isogenic APOE4 ^+/+ iPSC-derived transcription factor-induced microglia-like cells (iTFM). We demonstrate that APOE4 ^+/+ iTFM exhibit decreased survival following arsenite exposure, as evidenced by a lower LC₅₀ compared to APOE3 ^+/+ controls. Transcriptomic profiling identified arsenite concentration as the primary driver of gene expression changes, while genotype contributed a secondary, distinct component of the response. Weighted gene co-expression network analysis revealed genotype-dependent modules enriched for phagocytic and oxidative stress pathways, including KEAP1-NFE2L2 signaling. These transcriptomic changes were further supported by functional assays. APOE4 ^+/+ iTFM had a high proportion of phagocytic cells and altered mitochondrial phenotypes including increased mitochondrial mass, reduced membrane potential, and reduced superoxide production, all of which were further perturbed by low dose arsenite exposure. These results support a gene-environment interaction-dependent increase in microglial vulnerability via reshaping of transcriptional and functional stress responses, and provide a human cell-based framework for studying environmentally mediated microglial contributions to AD.