Targeting Estrogen Receptors for the Treatment of Alzheimer’s Disease

The significantly higher incidence of Alzheimer's disease (AD) in women than in men has been attributed to loss of estrogen and a variety of related mechanisms at the molecular, cellular, and hormonal levels, which subsequently elucidate neuroprotective roles of estrogen against AD-related pathology. Recent studies have proposed that beneficial effects of estrogen on AD are directly linked to its ability to reduce amyloid-β peptides and tau aggregates, two hallmark lesions of AD. Despite high expectations, large clinical trials with postmenopausal women indicated that the beneficial effects of estrogen therapies were insignificant and, in fact, elicited adverse effects. Here, we review the current status of AD prevention and treatment using estrogens focusing on recent understandings of their biochemical links to AD pathophysiology. This review also discusses development of selective ligands that specifically target either estrogen receptor α (ERα) or ERβ isoforms, which are potentially promising strategies for safe and efficient treatment of AD.