Microglia, the resident immune cells of the central nervous system, exist in several different functional states. We have previously identified a group of microglial states, based on which proteins are produced in these states, that are more common in Alzheimer’s disease (AD) and thus likely to contribute to the neuroinflammation and neurodegeneration seen in AD. Microglia assume their different states in response to changes in the brain microenvironment, but the precise molecular instructions that induce the transition to disease-associated states remain largely unknown. Here, we propose to characterize the spatial association of these microglial states with brain pathologies characteristic for AD, such as amyloid plaques and neurofibrillary tangles. We then will build a novel experimental system for modeling the inflammatory microglial states in vitro. This experimental system will allow us to identify transcription factors—proteins regulating the production of groups of other proteins—that control transition into and out of inflammatory states. We also will use our in vitro system to determine the effect of silencing any of these master regulators. By identifying mechanisms that govern microglial activation, our work will reveal novel targets for pharmacological interventions aimed at curbing inflammation and restoring microglial homeostasis in AD patients.