In the present study, we revealed that ApoE4 intensified brain insulin signaling disruption with activated GSK‐3β, increased tau phosphorylation, increased Aβ42/Aβ40 ratio in cortex, enhanced gliosis and neuroinflammation, exacerbated synaptic damage and cognitive deficits in T2DM mice. Here, APOE is linked to type 2 diabetes mellitus.