In both men and women, age-related loss of sex steroid hormones has been linked to an increased risk for Alzheimers disease (AD). The primary female hormone estrogen, and the primary male hormone testosterone have numerous protective effects in the brain relevant to the prevention of AD such as the promotion of neuron viability, reduction of β- amyloid accumulation and alleviation of tau hyperphosphorylation. Therefore it has been hypothesized that the precipitous loss of these hormones either through menopause or normal aging, can increase susceptibility to AD pathogenesis. This review will discuss the basic science research and epidemiological evidence largely supporting this hypothesis, as well as the estrogen-based hormone therapy clinical findings that have recently shed doubt on this theory. The complications associated with estrogen-based hormone therapy such as the inclusion of a progestogen, hormone responsiveness with age, and natural vs. synthetic hormones will be discussed. Further, we will outline the cancer risks facing both estrogen and testosterone-based hormone therapy. Most importantly, this review will discuss the present and future strategies to translate the neuroprotective properties of sex steroid hormones into safe and efficacious treatments for AD. One of the most promising translational tools thus far may be the development of selective estrogen and androgen receptor modulators. However, additional research is needed to optimize these and other translational tools towards the successful use of hormone therapies in both men and women to delay, prevent, and or treat AD.
Keywords: Estrogen, testosterone, hormone therapy, Alzheimer's disease, neuroprotection, cancer risks, progesterone, Neuron Viability, signaling pathways
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