While there is ample experimental evidence supporting the role of
estrogen in the pathogenesis of
Alzheimer disease, recent inconclusive data regarding
hormone replacement therapy (HRT), specifically, the unexpected results of the Women's Health Initiative (WHI) Memory Study has raised serious questions regarding the protective effects of
estrogen. Because of this and other inconsistencies in the
estrogen hypothesis, we propose that another
hormone of the hypothalamic-pituitary-gonadal axis,
luteinizing hormone, is a major factor in the pathogenesis of
Alzheimer disease. Specifically, we suspect that the increase in
gonadotropin concentrations, and not the decrease in
steroid hormone (e.g.,
estrogen) production following menopause/andropause, is a primary causative factor for the development of
Alzheimer disease. In this review, we examine how the
gonadotropins may play a central and determining role in modulating the susceptibility to, and progression of,
Alzheimer disease.