The lack of unequivocal benefit of estrogen therapy on cognitive function is surprising, considering that estrogen receptors α and β (ERα and ERβ) are found throughout the hippocampus and cortex, the two brain regions most implicated in Alzheimer Disease (AD; Shughrue and Merchenthaler, 2000), and that estrogen is effective in lowering brain amyloid-β (Aβ) levels in ovariectomized transgenic mice that overexpress Aβ (e.g., Levin-Allerhand et al., 2002; Carroll et al., 2007). The gene discussed is ESR2; the disease is Alzheimer disease.