The epidemiology of estrogen replacement therapy and Alzheimer's disease

The burden of Alzheimer's disease (AD) falls more heavily on women than men. It is hypothesized that plummeting levels of circulating estrogens after the menopause increase a 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 biological credibility of this hypothesis. Estrogen interacts with neurotrophins and neurotransmitter systems relevant to AD and in some model systems estrogen modulates synaptic plasticity. Effects on beta-amyloid and apolipoprotein E may be especially germane to putative effects. Estrogen also may blunt neurotoxic consequences of the stress response mediated by the hypothalamic-pituitary-adrenal axis, augment cerebral glucose utilization, and enhance cerebral blood flow. Clinical studies of postmenopausal women suggest beneficial estrogen effects on specific cognitive skills, and small preliminary trials of estrogen replacement in women with AD support claims of clinical meaningful efficacy. Consistent with the estrogen hypothesis, cross-sectional studies imply that postmenopausal estrogen use could be associated with a lower risk for AD. Several recent epidemiologic studies in which information 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 some from randomized, placebo-controlled, primary intervention trials. For the present, however, the issue of estrogen efficacy in lowering a woman's risk for AD remains unsettled.