Sex, hormones, and Alzheimer's disease.

More women than men have Alzheimer's disease (AD). Retrospective studies suggested that hormone replacement therapy (HRT) might counteract this disparity by reducing the risk of developing dementia. However, a recent, large, prospective study revealed the puzzling result that HRT increased dementia risk. A review of the literature was conducted to generate hypotheses that might explain why more women than men have AD, and how HRT may increase dementia risk. Longer life span of women than men may be the largest factor in the preponderance of women with AD. Longer duration of disease, less vascular dementia, and less testosterone in women than men may also contribute somewhat. HRT might increase dementia risk by several mechanisms: greater risk of strokes, leading to dementia; use of medroxyprogesterone acetate and estrone, which might have somewhat different possible effects on neuronal and cerebrovascular function than may progesterone and estradiol; decrease of free testosterone which might protect against AD; a dose or delivery method perhaps producing drug levels that might lie outside a hypothetical beneficial range; and down-regulation of estrogen receptors on cholinergic neurons, possibly reducing cholinergic activity. Further study is required to discern by which of several possible mechanisms HRT increases dementia risk.