APP and Hyperglycemia: We have previously reported that chronic hyperglycemia not only promoted β-site cleavage of the β-amyloid (Aβ) precursor protein (APP) to increase extracellular senile plaque (SP) formation but also triggered intracellular tau hyperphosphorylation and synaptic loss in the brain, thus potentiating the cognitive dysfunction in a mouse model of combined T2DM and AD [18, 19].