Sex hormones, aging, and Alzheimer's disease

Abstract

A promising strategy to delay and perhaps prevent Alzheimer's disease (AD) is to identify the age-related changes that put the brain at risk for the disease. A significant normal age change known to result in tissue-specific dysfunction is the depletion of sex hormones. In women, menopause results in a relatively rapid loss of estradiol and progesterone. In men, aging is associated with a comparatively gradual yet significant decrease in testosterone. We review a broad literature that indicates age-related losses of estrogens in women and testosterone in men are risk factors for AD. Both estrogens and androgens exert a wide range of protective actions that improve multiple aspects of neural health, suggesting that hormone therapies have the potential to combat AD pathogenesis. However, translation of experimental findings into effective therapies has proven challenging. One emerging treatment option is the development of novel hormone mimetics termed selective estrogen and androgen receptor modulators. Continued research of sex hormones and their roles in the aging brain is expected to yield valuable approaches to reducing the risk of AD.

Figure 1

Interactions between age-related loss of sex hormones and risk of Alzheimer’s disease. AD pathogenesis is a multifactorial process. Lifetime exposure to a combination of identified genetic and environmental risk factors interacts with numerous normal age changes to cooperatively promote the development of AD. One important normal age change that is linked to dysfunction and disease in many tissues is loss of sex hormones, estrogens in women and testosterone in men. Age-related depletion of estrogens and testosterone may be particularly significant to development of AD since these sex hormones are established regulators of several events implicated in the disease, including beta-amyloid accumulation, tau phosphorylation, neuronal death and decreased spine density. Early intervention using estrogen- and testosterone-based therapies or synthetic hormone mimetics termed estrogen receptor modulators (SERMs) and androgen receptor modulators (SARMs) may restore lost protective functions and prevent AD.