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Low Brain Estrogen May Boost Women's Alzheimer's Risk

It could help explain why women are slightly more prone to the disease, researchers say

MONDAY, Dec. 19, 2005 (HealthDay News) -- Low levels of estrogen in the brain may raise women's risk of developing Alzheimer's disease, new research suggests.

A report, appearing in this week's online edition of the Proceedings of the National Academy of Sciences, appears to be the first to show such an association. The findings could lead to new drug candidates to help prevent the debilitating disease, experts say.

"This will help to invigorate research in this area," said Dr. Sam Gandy, chairman of the Alzheimer's Association's Medical and Scientific Advisory Council and director of the Farber Institute for Neurosciences at Thomas Jefferson University in Philadelphia. "This will give us a reason to continue to try to work at protocols for hormone replacement therapy that might be beneficial. I'm very excited by this paper."

Experts have long noted that women are at higher risk of developing Alzheimer's than men. Although part of this can be explained by the fact that women generally live longer, that's probably not the whole picture.

"The most common hypothesis is that women have a reduction of estrogen after menopause," said Dr. Rena Li, senior author of the paper and principal scientist/associate professor at Sun Health Research Institute in Sun City, Ariz.

Indeed, epidemiological research indicates that, under some circumstances, women placed on hormone replacement therapy (HRT), experience a decline in their risk of Alzheimer's, Gandy said.

Clinical trials have been largely disappointing, however, and have not shown any preventive role for HRT, Gandy added.

There's also one more hole in the menopause theory: "If estrogen reduction is the mechanism, then all women reaching menopause should have some degree of Alzheimer's -- and that's not true," Li said.

In fact, less than a quarter of women will develop the disease.

Li speculated that estrogen could be implicated in a different way than previously theorized. Her team turned its attention to the fact that fat and brain tissue, in addition to ovarian tissue, can also produce estrogen. Ovarian tissue stops producing estrogen at menopause but this would probably not be true of other tissues, she said.

For this study, Li and her colleagues studied estrogen levels and expression of aromatase -- an enzyme involved in the production of estrogen -- in the postmortem brain tissue of female Alzheimer's patients.

As it turned out, the brains of Alzheimer's patients had much lower levels of estrogen than the brains of age- and gender-matched controls.

The researchers then crossed a strain of mice genetically engineered to develop Alzheimer's disease with a strain engineered to have estrogen deficiency in the brain. They looked for any rise in levels of beta-amyloid protein plaques -- a hallmark of Alzheimer's -- within the rodents' brain tissue.

"Once again, the story was that estrogen deficiency is associated with increased plaque load," Gandy said. "Plaques come on earlier and were more severe."

So while other researchers had focused on circulating estrogens, measured by blood levels, Li switched the focus to brain estrogen.

"The whole paper is focusing on the brain," she said. "Nobody ever looked at brain estrogen. Everybody thought of blood."

Li's team is now using the animal model it developed to screen drugs, looking for medications that can reverse the brain estrogen deficiency that induces the Alzheimer's pathology.

"The idea is if we had strong enough evidence that estrogen per se was really good for Alzheimer's, we could then work on developing estrogen molecules that were specific for the brain estrogen receptor and which would leave the peripheral estrogen metabolism alone," Gandy explained.

More information

The Alzheimer's Association can tell you more about Alzheimer's disease.

SOURCES: Rena Li, M.D., Ph.D., principal scientist/associate professor, Sun Health Research Institute, Sun City, Ariz.; Sam Gandy, M.D., Ph.D., chairman, Medical and Scientific Advisory Council, Alzheimer's Association and director, Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia; Dec. 19-23, 2005, early online edition, Proceedings of the National Academy of Sciences
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