HF diet elicited insulin resistance and impaired glucose tolerance; reduced all phospho-tau epitopes in all mice. Neither diet nor pioglitazone affected APP metabolism. In HF mice, pioglitazone was associated with reduced AT8 p-tau in APOE ε3 mice and increased AT8 p-tau in APOE ε4 mice. Here, APOE is linked to Impaired glucose tolerance.