One possible hypothesis is that, in early AD the intra-neuronal Aβ accumulation causes a mild decrease in neuron–microglia crosstalk via CX3CL1–CX3CR1 signaling that leads to an enhanced microglial phagocytosis of Aβ while resulting in tau hyper-phosphorylation. This evidence concerns the gene CX3CL1 and Alzheimer disease.