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

Alzheimers 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