In years past, a small body of research hinted that hormone-replacement therapy (HRT)-a daily regimen of estrogen, sometimes in combination with a synthetic hormone called progestin-might help to relieve the memory loss and other symptoms of Alzheimer's disease, which afflicts an estimated 4 million people in the United States. Several teams of scientists put this idea to a decisive test in 2000.
Unfortunately, their findings have dimmed estrogen's prospects as an Alzheimer's treatment. But at the same time, the negative results have not completely severed the link between estrogen and Alzheimer's. Even though the hormone may not be able to treat women already diagnosed with Alzheimer's, hope persists that the hormone may help prevent or delay its onset.
Weighing risks and benefits
Many women who experience hot flashes and other symptoms choose HRT. In addition to relieving the immediate symptoms of menopause, taking estrogen reduces the risk for osteoporosis. It may also reduce heart disease in women, although it should be noted that the most recent studies on this question have cast estrogen's cardiac benefits somewhat in doubt. On the downside, estrogen can raise the risk of breast cancer. The amount of the increased risk, however, is still unclear. In the end, the decision to take HRT involves balancing the expected benefits against the potential risks.
And as if the decision was not already complicated enough, a new factor has emerged: estrogen's effects on the brain. Laboratory studies on animals and cultured tissue have showed that the hormone supports and protects brain cells. For one thing, it boosts levels of acetylcholine a chemical, important to memory, that declines in people with Alzheimer's disease. Estrogen also appears to reduce the formation of a protein called beta amyloid, which is found in the form of clumps or "plaques" in the brains of people with Alzheimer's.
Before 2000, a handful of studies suggested that supplemental estrogen might slightly improve memory or other mental skills in women with Alzheimer's disease. But these studies were generally small and short-term, offering results that fell short of establishing estrogen as an effective treatment for Alzheimer's. Then three new studies were announced. The longest and largest of these was published in the Journal of the American Medical Association (JAMA).
Putting estrogen to the test
Led by Ruth Mulnard, RN, of the Institute for Brain Aging and Dementia at the University of California (Irvine), the JAMA study involved 120 women over the age of 60 who had been diagnosed with Alzheimer's disease. The women were given either estrogen or an inactive placebo pill for a year, and tested for changes in memory, mood, language ability, and other brain functions harmed by Alzheimer's. If estrogen worked, the researchers expected that women taking it would decline less than the women in the placebo group.
They did not. Of the 97 women who completed the study, the ones on estrogen did not improve significantly; nor was their rate of decline any slower than the women taking the placebo. Two other studies besides the JAMA study were published in 2000, involving smaller groups of women who were tested for shorter periods of time. These, too, found no clear evidence that hormone therapy remedies the symptoms of Alzheimer's.
To Victor Henderson, MD, a neurologist at the University of Southern California in Los Angeles who led one of the smaller studies, the message seemed clear. "I think that probably in terms of treatment of women who already have Alzheimer's, it's unlikely that estrogen by itself will have any important effects," he says.
But these three negative studies are not the last word on estrogen and Alzheimer's. Henderson and others think it's possible, in principle, that estrogen could help to boost the effects of conventional Alzheimer's medications, such as donepezil (brand name Aricept) and others coming on the market. Estrogen, like these medications, raises the level of the neurotransmitter acetylcholine in the brain. It is possible that their combined effect might be greater than that of either alone, Henderson explains.
So far, the only backing for this estrogen-as-booster hypothesis comes from two clinical trials of Alzheimer's drugs. An analysis of the data after the studies concluded revealed that a small (and not statistically significant) number of women who happened to be on estrogen during the trials seemed to improve more than women not on estrogen. But this is just an observation, and quite possibly a meaningless coincidence, Henderson cautions. "It doesn't prove that estrogen made the difference, but it raises the possibility that maybe it did," he says.
An ounce of prevention...
Although estrogen by itself may not be an effective Alzheimer's treatment, some studies suggest that it may help to delay or prevent Alzheimer's in women who do not yet have the disease. In one recent study, 472 women were followed for 16 years as part of the Baltimore Longitudinal Study of Aging (BLSA). Some of the women were on hormone-replacement therapy, some were not. In 1997, the end of the study period, the researchers discovered women on HRT were nearly 50 percent less likely to have developed Alzheimer's.
Had estrogen prevented Alzheimer's? Right now, nobody is certain. The BLSA findings offer only an intriguing observation: that in a particular group of 472 women, those individuals who were on hormone therapy showed lower rates of Alzheimer's. It did not, however, conclusively prove that the estrogen was responsible. The result could have been due to diet, inherited genes, or the fact that women who actively choose HRT tend to be more healthy on average-perhaps because they have better access to health care, or are more diligent about maintaining their health.
Three large and rigorous studies are now underway-two in the United States and one in Britain-that will help answer the question of whether estrogen prevents or delays Alzheimer's disease. Results from the new studies, which assign HRT to women at random and check for any reduction in rates of Alzheimer's, will be reported in the next few years.
Alzheimer's disease is currently incurable. If it turns out that estrogen can prevent Alzheimer's-or even delay its onset for a few years-it would probably become a major factor in the decision women face about whether to begin HRT. However, it is also possible that the next crop of studies will further weaken the link between estrogen and Alzheimer's. If so, it would provide yet another example of how often the promising results of small preliminary studies are shot down by large, well-designed clinical trials.
In the meantime, women would be wise to focus on the risks and benefits of hormone-replacement therapy for which there is some relatively firm scientific backing-namely, cancer, osteoporosis, and heart disease.
"Estrogen Replacement Therapy for Treatment of Mild to Moderate Alzheimer's Disease: A Randomized Controlled Trial," by Ruth A. Mulnard and others. Journal of the American Medical Association, Vol. 283, No. 8 (February 23, 2000), pp. 1007-1015.
"Effects of estrogen on cognition, mood, and cerebral blood flow in AD: a controlled study," by P.N. Wang and others. Neurology, Vol. 54, pp. 2061-2066.
"Estrogen for Alzheimer's disease in women: randomized, double-blind, placebo-controlled study," by V.W. Henderson and others. Neurology, Vol. 54, p. 295.
The National Institute on Aging (NIA) offers a comprehensive and easily understandable primer about menopause, including a concise explanation of the known risks and benefits associated with hormone replacement therapy. Browse the publication, "Menopause" at: http://www.nih.gov/nia/health/pubs/menopause.