DIMENSIONS Autumn 1997


by Cheryl Dawes

A tantalizing connection between estrogen and Alzheimer's disease has come to light in recent years, just as the "baby boom" generation reaches the half century mark. As more women than ever are weighing the pros and cons of replacing estrogen, the female hormone their ovaries virtually cease to produce at menopause, they are asking whether protection against AD is something they should take into account.

Can a reduced risk of AD be added to the benefit side of the estrogen balance sheet, along with known protection against osteoporosis and probable protection against heart disease? Because taking estrogen also poses some risks (estrogen taken by itself is known to increase the risk of uterine cancer, and estrogen use has been linked to an increased risk of breast cancer), each woman must consider, along with her doctor, her own individual risk profile when making the decision.

Some recent studies suggest that estrogen may reduce the risk of AD by up to 50 percent. Though the evidence is suggestive, it is not yet conclusive and researchers emphasize that it is premature to add protection against AD to the list of estrogen's benefits. Randomized, placebo-controlled trials, involving a large number of subjects over an extended period of time, provide the most definitive answers in medical research. As yet, no such trials investigating the relationship estrogen and AD have been completed. The seeming of estrogen in AD has grown out of animal studies and relatively small-scale studies in post-menopausal women, with and without AD.

Cellular and molecular research has yielded strong evidence for the beneficial effects of estrogen on parts of the brain involved in learning and memory. Studies have shown that the density of dendritic spines, small projections on neurons that play an integral role in the brain's communication process, increases with estrogen use. Conversely, density of dendritic spines declines when estrogen is taken away. Other studies suggest that estrogen may protect brain cells by acting as an anti-oxidant, preventing toxic molecules called free radicals from killing neurons. Research has also shown that estrogen increases production of acetylcholine, an important brain chemical, that is reduced in people with AD.

During the past decade a small number of observational studies have looked at the relationship between estrogen and AD. The results from those studies vary considerably, says Madeline Rice, a UW graduate student whose Ph.D. research in epidemiology focuses on estrogen and cognitive decline. Most results were encouraging, but some of the studies were not properly designed to screen out other factors that may have played a role in any improvement, she explains. "Part of the problem is that, in general, estrogen users tend to be healthier than non-users," she notes. "So maybe it's some characteristic of the women that is protecting them and not the estrogen per se."

"A few early studies that were really designed to look at a variety of risk factors in addition to estrogen, didn't find any relationship between estrogen and AD," Rice notes. "Recently, a couple of epidemiological studies that focused on estrogen use prior to onset of Alzheimer's symptoms have offered good evidence for a positive relationship," says Rice. "It may be the results of observational research in humans have been certain mixed because the magnitude of the effect is small."

Measurement of how well estrogen protects memory, based on statistical analysis of memory tests, can be different from the way that protection plays out in everyday life. A memory test comparing women who are taking estrogen with those who are not may show a difference that is statistically significant, suggesting that the is protective. However, the difference might only be one point on the memory test, Rice points out. This raises the question of whether the finding is clinically relevant. Rice's research, which is part of the KAME project, a UW study of aging and memory in Japanese Americans led by Dr. Eric Larson,is looking at how estrogen affects cognitive function in women without dementia. "In our research, it appears that estrogen is protective in just certain types of memory, not every type," says Rice. "It looks like estrogen protects against decline in the type of memory that uses verbal language and perhaps abstract thinking. But other types of memory, such as visual memory, don't seem to respond to estrogen."

Currently a multi-center trial sponsored by the National Institute on Aging is studying 120 women with AD who are taking either estrogen or placebo (this study was reviewed in Dimensions, Summer 1995). Slow recruitment has delayed results of that study, which are now expected in 1999. An even larger study, which is an offshoot of the Women's Health Initiative, will compare the incidence of AD in 8,000 women taking estrogen or placebo over the course of more than six years. These studies will likely provide more definitive answers to the basic question of whether estrogen prevents or delays onset of AD, but additional studies must focus on other factors, such as whether all forms of hormone replacement therapy have a similar effect. For example, Rice points out, there is some evidence that there may be differences in the cognitive effects associated with estrogen taken alone and estrogen combined with progesterone, which is commonly given to provide protection against uterine cancer.

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