Hormones over time may fight Alzheimer's
By Rita Rubin
USA Today
In the debate over the risks and benefits of men opausal hormone therapy, one of the largest remaining questions is whether it reduces the risk of Alzheimer's disease.
A report in the Journal of the American Medical Association adds to a small but growing body of evidence that the answer might be yes.
While basic biology suggests that estrogen protects brain cells against death, no one is saying that women should go on hormone therapy to reduce their Alzheimer's risk. The paper's senior author notes that similar types of studies spurred doctors to prescribe estrogen to protect against heart disease, a practice that has been abandoned in light of recent, more definitive findings.
But if subsequent trials prove that hormones decrease Alzheimer's risk, the therapy's risk-to-benefit ratio — now tilted toward the risk side more than ever before — could be greatly recast.
The new study focused on 1,889 older women in Cache County, Utah, part of a long-term investigation of genetic and environmental risk factors for Alzheimer's disease and other dementias.
The women were first screened for dementia between 1995 and 1997, when their average age was 74 1/2. They were asked if they had ever taken hormones and, if so, for how long. Researchers conducted a follow-up between 1998 and 2000.
Compared to women who had never used hormones, those who had used them were, on average, 40 percent less likely to develop Alzheimer's disease in the three-year period between their initial interview and the follow-up. The longer they were on hormone therapy, the lower their risk.
But when the researchers separated former users from current users, they found a lower risk of Alzheimer's only among former and current users who had been on hormones for more than a decade. Current users who had been on therapy for fewer than 10 years saw little, if any, benefit.
That finding, consistent with previous studies, suggests that hormone therapy may be beneficial only in the pre-symptomatic phase of Alzheimer's, which could span a decade or more.
Healthy-user bias tested
These results "offer both hope for a possible neuroprotective effect of hormone therapy and frustration that it could be difficult to determine the optimal timing of treatment," write Susan Resnick of the National Institute on Aging and Victor Henderson of the University of Arkansas in an accompanying editorial.
The findings do suggest that a critical period of use might happen to be the same time that women take hormones for relief of hot flashes and other symptoms, Resnick and Henderson write.
The new study's main limitation is that it is observational. In other words, researchers observed women who decided on their own whether to take hormones.
"This could be something that arises purely because the women who take the stuff are different in some important way from the women who don't and has nothing to do with the treatment itself," says senior author John Breitner, head of the geriatric center at the VA Puget Sound Health Care System in Seattle.
Observational studies are what led doctors and their patients to believe that estrogen protected against heart disease. It took randomized controlled trials, in which women were randomly assigned to receive either hormones or a placebo, to dispel that notion.
Scientists have attributed the discrepancy between the observational studies and the randomized trials to the "healthy user bias." In other words, women who opted to go on hormone therapy tended to be better educated and, therefore, took better care of themselves. Apparently, it was their healthier lifestyle, not hormones, that reduced their heart attack risk.
To assess the healthy user bias in their study, Breitner and his collaborators looked at whether women who took multivitamins or calcium supplements were less likely to develop Alzheimer's disease. They found no link.
"It adds to the level of confidence one might have in interpreting these data" about hormone use and Alzheimer's risk, Breitner says.
Still, he says, "We've been fooled before, thinking that observational data mean what they appear to mean and then finding out, when we do the trial, that it ain't necessarily so."
In July, the government-sponsored Women's Health Initiative halted a trial comparing estrogen plus progestin to a placebo because the risks outweighed the benefits.
While hormone users had fewer colon cancers and fractures after four years of treatment, they had more heart attacks, breast cancers, blood clots and strokes. As a result, experts are now recommending that women go on hormone therapy only for relief of severe menopause symptoms and then only on as low a dose for as short a period as possible.
The WHI trial did not include Alzheimer's disease in its risk/benefit profile. That is the focus of a spinoff study called WHIMS, which enrolled 7,480 women 65 and older from the estrogen-plus-progestin trial and an ongoing estrogen-only trial.
WHIMS participants undergo annual screening for dementia. Those who score below a certain point are examined and tested further. Researchers expect to publish the effects of estrogen plus progestin on dementia by early 2003. The effects of estrogen alone won't be known until after the end of that trial, scheduled for 2005.
More studies continue
The National Institutes of Health is funding a separate randomized trial to see if Prempro, the estrogen-plus-progestin product used in the WHI, or Premarin, which contains only estrogen, cuts Alzheimer's risk. That five-year trial, led by Mary Sano of Columbia University, plans to enroll a total of 900 women 65 and older who have a close relative with Alzheimer's disease.
