Epidemiological data showing a predisposition of women to develop
Alzheimer disease (AD) led many researchers to investigate the role of sex
steroids, namely
estrogen, in disease pathogenesis. Although there is circumstantial support for the role of
estrogen, the unexpected results of the Women's Health Initiative (WHI) Memory Study, which reported an increase in the risk for probable
dementia and impaired cognitive performance in postmenopausal women treated with a combination of
estrogen and
progestin, have raised serious questions regarding the protective effects of
estrogen. Although explanations for these surprising results vary greatly, the WHI Memory Study cannot be correctly interpreted without a complete investigation of the effects of the other
hormones of the hypothalamic-pituitary-gonadal (HPG) axis on the aging brain. Certain
hormones of the HPG axis, namely, the
gonadotropins (
luteinizing hormone and
follicle-stimulating hormone), are not only involved in regulating reproductive function via a complex feedback loop but are also known to cross the blood-brain barrier. We propose that the increase in
gonadotropin concentrations, and not the decrease in
steroid hormone (e.g.,
estrogen) production following menopause/andropause, is a potentially primary causative factor for the development of AD. In this review, we examine how the
gonadotropins may play a central and determining role in modulating the susceptibility to, and progression of, AD. On this basis, we suggest that the results of the WHI Memory Study are not only predictable but also avoidable by therapeutically targeting the
gonadotropins instead of the sex
steroids.