The observations in man that increased risk of AD with T2DM is APOE dependent, that insulin affects Aβ pathology in an APOE dependent manner and that in the early clinical trials with TZDs there was a stratification of effect by APOE led to the hypothesis that induced insulin resistance and subsequent treatment with TZDs in animal models would have APOE dependent effects on ‘downstream’ AD pathology, specifically tau phosphorylation. This evidence concerns the gene INS and type 2 diabetes mellitus.