In conclusion, the present findings that apoE4 stimulates diabetic-related effects, such as an increase in glucose tolerance and insulin resistance and a decrease in insulin secretion, which are associated with further downstream distinct brain pathologies, and that apoE3 under pro-diabetic conditions of the HFD induces similar pathological changes, suggest that diabetic mechanisms play an important role in mediating the effects of apoE4 on brain pathology. Here, APOE is linked to Insulin resistance.