Using 5xFAD animals, we demonstrate that in addition to skewing the microenvironment towards the accumulation of increasingly neurotoxic Aβ species, the loss of CX3CR1 signaling in AD results in impaired microglial plaque engagement, dampened microglial Aβ phagocytosis along with impaired lysosomal activation and skewing of microglia towards a ‘degenerative’ phenotype. Here, CX3CR1 is linked to Alzheimer disease.