The interaction of genes and environment contributes to Alzheimer’s disease (AD). For example, agricultural workers, military personnel, industrial manufacturers, veterinarians, horticulturists, aircraft maintenance personnel, and pilots are all potentially at risk of occupational exposure to organophosphates (OPs), which are associated with increased risk of AD. We report here that occupational-like exposure of young animals to the OP chlorpyrifos (CPF) accelerates AD-like cognitive deficits and severe neurodegeneration in male, but not female, TgF344-AD rats, a genetic model of AD. CPF exposure also causes chronic dysregulation of brain microglial cells, while amyloid and tau pathology are not affected. Thus, microglial dysregulation after environmental toxin exposure may represent a second hit that advances the disease. Future therapies to preserve or restore normal microglia might help prevent AD in genetically vulnerable individuals exposed to CPF or other disease-accelerating environmental agents.