Because no protective effect was seen with therapy that had not been initiated at least several years prior to onset of clinical symptoms, hormonal intervention is probably most effective before significant neuronal damage has occurred. In the continuing discussion on risks and benefits of hormone replacement therapy, it would seem that the greatest likelihood of cognitive protection comes when replacement therapy is begun early in menopause.

"Our findings, along with other recent work, suggest that hormone replacement therapy may be effective for the primary prevention of Alzheimer's disease--if not for its treatment," write the authors, drawn from a number of American medical centers.

The researchers compared the rates of Alzheimer's disease between 1995 and 2000 in 1,357 men and 1,889 women, all elderly, in Cache County, Utah. They found that women who had taken replacement therapy for at least a decade were 2.5 times less likely than women who had never used replacement therapy to develop Alzheimer's disease. The lower rate among the long-term hormone replacement therapy users was comparable with that of the men in the study.

The study also looked at the use of calcium supplements and multivitamins to see if these have a preventive effect, but none was found. In fact, the researchers do not rule out the possibility that the lower Alzheimer's rate among the long-term replacement therapy users was due to some factor other than the hormonal treatment itself.

Until very recently, hormone replacement therapy with estrogen and progestin was the treatment of choice for menopausal women who needed relief from symptoms such as hot flashes and mood swings. Based on brain-imaging studies, replacement therapy had also been thought to slow mental decline and stall the onset of Alzheimer's disease, although clinical trials on this issue had produced mixed results. The therapy was associated with a small increase in the risk for uterine and breast cancer, but many if not most clinicians believed that benefits outweighed risks.

This perception was challenged in July when the National Heart, Lung, and Blood Institute stopped a major clinical trial after finding significantly increased rates of breast cancer and cardiovascular disease in women taking replacement therapy compared with women on placebo. Soon after, a report in The Lancet showed an increased risk of breast cancer, stroke, and thrombolic events for women on hormone replacement therapy.

The current study suggests that hormone replacement therapy may help prevent mental decline, but it raises questions about the window of effectiveness. The authors theorize that estrogen, like non-steroidal anti-inflammatory drugs, may exert a protective effect against Alzheimer's only before extensive damage occurs in the brain.

In an accompanying editorial, Doctors Susan Resnick and Victor Henderson noted that the results are promising for a brain-protective effect of hormonal therapy, but the findings also demonstrate that it may be difficult to determine the best timing of treatment.