Alzheimer's disease (AD) is the most common cause of
dementia. After menopause, circulating levels of oestrogens decline markedly and oestrogen influences several brain processes predicted to modify AD risk. For example, oestrogen reduces the formation of
beta-amyloid, a biochemical hallmark of AD. Oestrogen effects on oxidative stress and some effects on
inflammation and the cerebral vasculature might also be expected to ameliorate risk. However, AD pathogenesis is incompletely understood and other oestrogen actions could be deleterious. Limited clinical trial evidence suggests that oestrogen
therapy, begun after the onset of AD symptoms, is without substantial benefit or harm. Observational studies have associated oestrogen-containing
hormone therapy with reduced AD risk. However, in the Women's Health Initiative Memory Study - a randomised, placebo-controlled trial of women 65 - 79 years of age - oral oestrogen plus
progestin doubled the rate of
dementia, with heightened risk appearing soon
after treatment was initiated. Based on current evidence,
hormone therapy is thus not indicated for the prevention of AD. Discrepancies between observational studies and the Women's Health Initiative clinical trial may reflect biases and unrecognised confounding factors in observational reports. Other explanations for divergent findings should be considered in future research, including effects of unopposed oestrogen or different
hormone therapy preparations and the intriguing theoretical possibility that effects of
hormone therapy on AD risk may be modified by the timing of use (e.g., initiation during the menopausal transition or early postmenopause versus initiation during the late postmenopause).