Estrogens and hormone replacement therapy: is there a role in the preservation of cognitive function?

Alzheimer's disease affects as many as 40% of Americans over the age of 80 and, as such, is a major public health issue. Interestingly, there is a two- to threefold greater prevalence in women than in men. It has been estimated that the prevalence of Alzheimer's disease will quadruple over the next half century. There have been implications of an effect of estrogen on neurological function for many years. As long as 50 years ago a study published in the gerontology literature suggested that the administration of i.m. estrogen in a nursing home population was associated with improvement in memory and a delay in progression of memory loss. Most recently there has been great interest in the effect of estrogen on both neurons and the CNS vasculature. A study evaluating verbal memory and abstract reasoning in over 700 women without dementia demonstrated that women who had used estrogen for as little as 1 year had significant improvements in baseline cognitive testing. The pathogenesis of Alzheimer's disease and neurodementia is better understood today but remains incompletely elucidated. It has been suggested that inflammation exists both within the neurovasculature and the stroma and that beta-amyloid creates an inflammatory reaction. In Alzheimer's patients there are abnormal deposits of proteins such as beta-amyloid, presenelin, and apolipoprotein E-4. Estrogen may act as a protectant against these inflammatory mediating proteins. While a recent trial demonstrated no impact of estrogen in patients diagnosed with mild to moderate Alzheimer's, other studies have suggested that estrogen use significantly delays disease onset. One study followed over 1,100 subjects who were free of disease at trial initiation over a period of 1 to 5 years. Even short-term use of estrogen imparted protection, although longer-term estrogen use was associated with greater protection. Unfortunately, most women are unaware of the potential beneficial effect of estrogen on cognitive function. Prospective studies are under way to try to delineate how estrogen impacts Alzheimer's disease.