Considering that brain response to insulin can be compromised by peripheral insulin resistance [23,25,26], but also by the APOE ɛ4 genotype in an age-dependent manner [24], and that the entorhinal cortex is especially vulnerable to impairments of brain insulin signaling [23], we posit that APOE ε4 carriers and individuals with elevated peripheral insulin resistance are likely to encounter greater challenges in estimating PI when spatial cues are lacking. This evidence concerns the gene APOE and Insulin resistance.