Alzheimer’s disease (AD) is a significant public health challenge, as prevalence rises with an aging population and few, if any, treatments are effective at slowing disease progression. The vast majority of cases are late onset, and genetic sequencing reveals that these late-onset AD (LOAD) cases involve many weakly penetrant mutations that interact with environment and nondisease risk factors such as aging to induce disease onset. Current work implicates microglia, the brain’s resident immune cells, in the pathogenesis of AD—more than half of all LOAD risk genes are solely expressed in microglia and/or peripheral myeloid cells. Despite this clear association, we know shockingly little about how these mutations contribute to microglial function, or how they may accelerate AD pathogenesis. By understanding how the normal surveillance and injury response functions microglia perform change in disease conditions, either beneficially, by removing toxic proteins and cellular debris, or detrimentally by inflammation, we can better understand the contribution of genetic risk to microglial function, and the role microglia play in AD pathogenesis.
Given the complexity and diversity of microglia in health and disease, there is a critical need for ways to distinguish beneficial from detrimental microglial states over the course of AD, and to determine how specific AD-relevant mutations may affect specific microglial states or functions. However, few studies can clearly link variants to specific functional changes. We have begun to systematically profile the ways in which microglia change their response to stimuli and normal functionality in the face of genetic mutation, and to map that response back onto disease models. This understanding of the relationship between genetic variation and function will be key for understanding how LOAD mutations result in AD, and identifying treatments that can slow or reverse disease progression.