Genome-wide association studies implicate microglia in Alzheimer’s disease (AD) pathogenesis, but how microglia contribute to cognitive decline in AD is unclear. Emerging research suggest microglia, the resident macrophages of the central nervous system, to be active participants in brain wiring. One mechanism by which microglia help eliminate synapses is through the classical complement pathway (C1q, CR3/C3). Data from multiple laboratories collectively suggest that there may be an aberrant reactivation of the complement-dependent pruning pathway in multiple models of neurologic diseases including AD. These data altogether suggest that microglia participate in synaptic pathology. However, how and which synapses are targeted are unknown. Furthermore, whether microglia directly impair synaptic function is unknown. Mechanistic insight into local signals that regulate neuroglia interactions will be key to developing potential therapeutic avenues to target in disease.