ESR1 and Alzheimer disease: Since Yan et al. [62] observed that peripheral 17β-estradiol treatment activates the estrogen receptor α and the downstream PI3K/Akt/Foxo1 signaling, recovering insulin sensitivity and glucose metabolism, one cannot exclude a role for the increased brain estradiol levels in this delay in AD-like neuropathology in 3xTg-AD female mice (as further discussed by Yang et al. [40]).