INS and Insulin resistance: 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.