This study was designed to examine whether AD pathological phenotype in APPswe/PS1dE9 (APP/PS1) mice exposed to continuous high-fat diet predispose these murine models to metabolic dysfunction and neuropathological impairments. One-month old male APP/PS1 and C57BL/6J mice were provided with 60% high-fat diet for 6.5 months. After dietary intervention, metabolic phenotyping, cognitive behaviors, AD-related brain pathological changes and insulin signaling were compared. high fat diet induced hyperglycemia, hypercholesterolemia, and aggravated inflammatory stress in both APP/PS1 and C57BL/6J mice. Compared with C57BL/6J control mice, APP/PS1 mice showed lower glucose transporter protein expression in liver, muscle, and brain. High-fat diet caused a decrease of glucose transporter protein expression in muscle and liver but increased cortical glucose transporter protein expression in APP/PS1 mice. High-fat diet-fed APP/PS1 mice demonstrated decreased cognitive function, as well as elevated cortical soluble amyloid-β levels and APP protein expression. Decrease in cortical IR, p-IR protein expression and p-GSK3β/GSK3β ratio were observed in high-fat diet-fed APP/PS1 mice. High-fat diet caused discrepant peripheral and central nervous system metabolic phenotype in APP/PS1 and C57BL/6J mice. AD pathological phenotype might accelerate metabolic changes and cognitive impairment in APP/PS1 mice treated with HFD.