THE EPIDEMIOLOGY OF ESTROGEN REPLACEMENT THERAPY AND ALZHEIMERS-DISEASE

The burden of Alzheimer's disease (AD) falls more heavily on women tha n men. It is hypothesized that plummeting levels of circulating estrog ens after the menopause increase 2 woman's risk for this disorder and, conversely, that estrogen replacement therapy may lower the risk for dementia due to AD. A number of estrogenic properties support the biol ogical credibility of this hypothesis. Estrogen interacts with neurotr ophins and neurotransmitter systems relevant to AD and in some model s ystems estrogen modulates synaptic plasticity. Effects on beta-amyloid and apolipoprotein E may be especially germane to putative protective effects. Estrogen also may blunt neurotoxic consequences of the stres s response mediated by the hypothalamic-pituitary-adrenal axis, augmen t cerebral glucose utilization, and enhance cerebral blood flow. Clini cal studies of postmenopausal women suggest beneficial estrogen effect s on specific cognitive skills, and small preliminary trials of estrog en replacement in women with AD support claims of clinically meaningfu l efficacy. Consistent with the estrogen hypothesis, cross-sectional s tudies imply that postmenopausal estrogen use could be associated with a lower risk for AD. Several recent epidemiologic studies in which in formation on estrogen replacement therapy was collected prospectively further support this contention, with a dose-response relation evident in some reports. Because estrogen users tend to differ from nonusers in a number of lifestyle characteristics, convincing demonstration of putative protective effects could best come from randomized, placebo-c ontrolled, primary intervention trials. For the present, however, the issue of estrogen efficacy in lowering a woman's risk for AD remains u nsettled.