About 4 million people in the US have Alzheimer disease , and this number is projected to quadruple in the next 50 years.

Several observational studies have found that postmenopausal women taking estrogen replacement therapy have up to a 50% lower risk of developing Alzheimer disease compared to postmenopausal women not taking supplemental estrogen. Estrogen receptors are present throughout the brain, especially in areas related to learning and memory. This biological explanation, coupled with the previous studies, prompted researchers to more definitively investigate estrogen’s possible protective effects on brain functioning.

The Women’s Health Initiative Memory Study (WHIMS) evaluated the effect of estrogen, taken with progestin, on dementia and mild cognitive impairment (MCI) in women. WHIMS is the largest randomized clinical trial evaluating estrogen plus progestin (hormone replacement therapy, or HRT) on dementia.

The researchers had expected HRT to confer a protective effect on brain function. Instead, in a study published in the May 28, 2003 issue of the Journal of the American Medical Association (JAMA) , they report that women who took estrogen plus progestin had a significantly increased risk of dementia.

About the study

The women involved in WHIMS were recruited from the Women’s Health Initiative (WHI) hormone therapy trials, which studied the risks and benefits of hormone replacement therapy (HRT) for the prevention of disease. The study participants—postmenopausal women age 65 or older—were screened at the onset of the study to ensure that dementia was not present.

Of the 4,532 women participating in WHIMS, 2,229 women were randomly assigned to receive a daily dose of HRT (0.625 milligrams (mg) estrogen plus 2.5 mg progestin) and 2,303 received a placebo.

During the 4-year follow-up, cognitive function was assessed every year with the Modified Mini-Mental State Exam (3MSE), a commonly employed screening test for dementia. Women who scored below established cut points were studied further through a battery of neuro-psychological tests. Physicians experienced at diagnosing dementia then evaluated the women.

An additional study involving the same participants, also reported in this issue of JAMA ,was conducted to evaluate the effects of the combined hormone replacement therapy on global cognitive function—including memory, verbal fluency, abstract reasoning, and writing—rather than strictly dementia.

The findings

The findings were striking. Over the course of the study, 61 women were diagnosed with probable dementia—40 from the HRT group and 21 from the placebo group. This equates to twice the risk for women taking estrogen plus progestin. Risk began to increase for the women as early as one year into the study and persisted throughout the follow-up period. Alzheimer disease was the most common type of dementia in both groups, responsible for 32 of the 61 cases. The risk of developing MCI without progression to dementia was similar for the HRT and placebo groups.

The study’s authors caution that their findings need to be kept in perspective. Although the risk was doubled for women taking estrogen plus progestin, the absolute risk is relatively small. If these results were applied to a population of 10,000 women taking HRT, there would be only 23 additional cases of dementia.

In the second study, not only did estrogen plus progestin therapy not improve cognitive function when compared with placebo, but a slight worsening of cognition was seen in the estrogen plus progestin group.

How does this affect you?

The WHIMS findings strengthen the WHI Study findings—the risks of estrogen plus progestin therapy outweigh the benefits. At this point, it is hard justify the use of hormone replacement therapy over the long term. If you are currently on HRT, your first instinct may be to stop. But, do not discontinue any medication without first talking with your doctor. You may decide that replacing estrogen over the short term is still a reasonable solution for the hot flashes and other transient symptoms of menopause. When you talk with your doctor, discuss why you are on HRT and what other options may be available to you over the long term.