ERβ is highly expressed in the hippocampus, mPFC, and hypothalamus (Shughrue et al., 1997; Milner et al., 2001; Milner et al., 2005; Almey et al., 2014), and its activation is associated with reduced Aβ levels and tau phosphorylation in the hippocampus (Tian et al., 2013; Xiong et al., 2015) Thus, highly selective ERβ agonists may improve memory and reduce AD risk in menopausal individuals both directly by boosting hippocampal and cortical function and indirectly by reducing hypothalamic-mediated hot flashes. This evidence concerns the gene ESR2 and Alzheimer disease.