Estrogen Therapy Investigated As Alzheimer’s Prevention Tool

Estrogen replacement therapy and its effects—beneficial or harmful—in postmenopausal women continues to be a scientific controversy, with much of the weight of recent research leaning heavily against hormone replacement therapy.

Yet one small preliminary study now shows that short-term use of estrogen reduces blood levels of a protein associated with Alzheimer’s disease, keeping alive a hypothesis that the hormone may have some role in improving cognition and preventing neurodegenerative disease.

In the study, published in the March-April American Journal of Geriatric Psychiatry, postmenopausal women who had Alzheimer’s disease and had never had hormone replacement therapy before experienced a significant reduction in plasma Aβ-40 after receiving short-term estrogen. Aβ-40 is a protein byproduct of processing the amyloid-precursor protein, which is believed to play an important role in the pathobiology of Alzheimer’s disease.

Amyloid is the substance that forms the plaques in brain tissue that are the hallmark of Alzheimer’s. An excess of amyloid or, conversely, inadequate clearance of amyloid in the brain is believed to be related to the processing of the amyloid precursor protein and, particularly, two of its byproducts, Aβ-40 and Aβ-42.

Study author Sanjay Asthana, M.D., told Psychiatric News that the estrogen used in the study was a patch form of the hormone known as estradiol that is more potent than the estrogen used in the past. He said that previous studies of transdermal estradiol showed that it improved memory and concentration in women with Alzheimer’s.

Biological Factors

Asthana, who is head of the section of geriatrics and gerontology at the University of Wisconsin Medical School and director of the GRECC Madison VA Medical Center in Madison, Wis., said the current study was undertaken to determine what biological factors might account for the improvements in cognition seen in earlier studies.

“We wondered whether one of the mechanisms by which estrogen improves memory is by having beneficial effects on the byproducts of the amyloid precursor protein,” he said.

Asthana explained that of the two byproducts believed to be highly associated with Alzheimer’s, Aβ-40 is particularly related to vascular changes associated with the disease. Aβ-42, the more toxic of the two, is believed to be more directly associated with the formation of plaques in the brain. The assay used in the study was not sensitive enough to detect Aβ-42 in the blood, Asthana said, so the study authors opted to look for the effects on Aβ-40.

In the study, 20 women were randomized to receive either 0.10 mg/day of transdermal estradiol or a placebo for eight weeks. They were retrospectively evaluated for whether baseline Aβ-40 values were affected by pre-study use of hormone replacement therapy (HRT). Blood samples were collected at baseline, at weeks 3, 5, and 8 during treatment, and again eight weeks after treatment ended.

What Asthana and his colleagues found was that for the group overall, there was no significant effect of estrogen on blood levels of Aβ-40, though there was a trend toward a decrease. Yet among 10 patients who were HRT-naïve, baseline Aβ-40 was higher than among those who had previously been treated with estrogen, and there was a significant reduction in Aβ-40 by the end of the study period among the four HRT-naïve patients who had received the estrodiol patch.

The results suggest, Asthana said, that levels of Aβ-40 in the previously treated patients had already been suppressed, so that short-term use of the hormone couldn’t produce an effect; longer-term use might have resulted in a reduction in the previously treated patients.

Asthana noted that the study is preliminary and needs to be replicated in much larger samples. He also said that there is no consensus on whether HRT improves cognition, and much recent evidence that HRT increases the risk of coronary events, stroke, breast cancer, and other diseases.

Questions Unanswered

“There is no definitive evidence supporting the use of this hormone for treating or preventing Alzheimer’s,” Asthana said. “There are a number of questions that need to be answered at the human level. Overall, the pendulum is swinging toward the negative.”

In an article in the May issue of the New England Journal of Medicine, researchers with the Women’s Health Initiative reported that estrogen plus progestin does not have a clinically meaningful effect on health-related quality of life.

In that study, 16,608 postmenopausal women 50 to 79 years of age with an intact uterus were randomized to estrogen or placebo. Quality-of-life measures collected at baseline, at one year, and at three years showed no significant effects on general health, vitality, mental health, depressive symptoms, or sexual satisfaction.

That study follows a blockbuster report published last summer also by the Women’s Health Initiative showing that women taking estrogen plus progestin were at increased risk for myocardial infarction, stroke, venous thromboembolism, and breast cancer. The findings prompted revisions in guidelines for HRT limiting the use to short-term relief of vasomotor symptoms or for prevention of osteoporosis.

Samuel Gandy, M.D., director of the Farber Institute of Neuroscience at the Thomas Jefferson University School of Medicine in Philadelphia, said the results of the study by Asthana are intriguing, but that the definitive answer to the question of estrogen’s effects on cognition await further research.

Gandy said the study also complements findings from some of his own research. He cited a study published in the Journal of the American Medical Association of men undergoing hormone suppression for prostate cancer, which found a rise in Aβ-40 when hormones were suppressed.

“I think these results are biochemically consistent with leading theories of how Alzheimer’s is caused, but at the end of the day you want to know whether the hormone is going to be clinically effective,” Gandy told Psychiatric News. “The cross-sectional epidemiologic data have been very promising. But the results from the [Women’s Health Initiative] heart study on estrogen are a perfect example of why you don’t want to rely on epidemiologic data.

“There had also been good reason to believe from epidemiologic data that HRT would protect against coronary disease,” Gandy continued. “But when a proper study was done, not only was there no benefit, but also there were these clotting and cancer effects. What are needed are randomized, placebo-controlled trials.”

Gandy said such trial results will be forthcoming soon. This year the Women’s Health Initiative will be releasing the first results of a five-year study looking specifically at the role of estrogen in preventing Alzheimer’s and improving cognition.

So with conflicting reports about the role of estrogen in cognition, what should clinicians do?

“Stay tuned,” Gandy said. “I continue to hold out hope that HRT will be useful in preventing Alzheimer’s. But I wouldn’t—and no one should—make that recommendation until the prospective data are available.”

An abstract of the study, “17β-Estradiol Reduces Plasma Aβ40 for HRT-Naïve Postmenopausal Women With Alzheimer Disease: A Preliminary Study,” is posted on the Web at http://ajgp.psychiatryonline.org/cgi/content/abstract/11/2/239?▪

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