In the current study, we combined pharmacological, molecular and cellular, electrophysiological, and behavioral techniques to study the roles of Cdk5 signaling in AD pathogenesis and how chronic metformin treatment had beneficial effects on the synaptic malfunctions and the cognitive defects in the APP/PS1 mice through the regulation of the Cdk5 signaling pathway. The gene discussed is APP; the disease is Alzheimer disease.