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Gene modifies effect of estrogen on cognitive decline
By Sarah DeWeerdt

Estrogen may help keep your mind young—but only if you're a woman with certain genes, according to a new study led by researchers at the University of California at San Francisco. The study, reported in the May 23 issue of Neurology, examines how a woman's genes affect her response to estrogen.

In the past, some studies have shown that taking estrogen reduces a woman's risk of Alzheimer's disease and other forms of dementia, while other research has shown no such protective effect. Another line of research has established that people who inherit a certain form of a gene called APOE (apolipoprotein E) have a higher risk of developing Alzheimer's.

"We wanted to know, if there was a protective effect of estrogen, whether or not it depended on a person's APOE status," says Kristine Yaffe, of UCSF and San Francisco Veterans Administration.

In the study, 3,393 women aged 65 or older were asked about their use of hormone replacement therapy (HRT). Researchers also tracked the women's cognitive function with a questionnaire administered yearly for 5 to 7 years, and collected blood samples to determine which form of the APOE gene each woman has.

The APOE gene codes for a protein that carries cholesterol and other fatty molecules from place to place in the body. The gene has three forms, or alleles, designated e2, e3, and e4. People who inherit at least one e4 allele have a higher risk of Alzheimer's than people who inherit only the e2 or e3 alleles. About 25 percent of people have at least one e4 allele.

Yaffe and her colleagues found that in women without an e4 allele, "estrogen was indeed protective against cognitive problems." Women currently taking estrogen had a lower rate of cognitive decline and about half the risk of developing cognitive impairment compared to women not taking estrogen.

But the effect of estrogen depended on a woman's genes, and in women with an e4 allele estrogen had no protective effect. These women had the same rate of cognitive decline and the same risk of developing cognitive impairment whether or not they took estrogen.

"The issue of estrogen as a protective mechanism has been controversial," Yaffe says. "In fact, I have been somewhat skeptical at times myself." Other differences between women who take HRT and women who don't—age, weight, educational level—could conceivably account for their different risks of cognitive decline. But Yaffe says that these results showing an interaction between estrogen and genes have diminished her skepticism. In other words, the fact that a gene can modify estrogen's protective effect suggests that the protective effect is real.

Other results from the study suggest a possible mechanism for estrogen's effect. Scientists speculate that the gradual cognitive decline common in older people may be due to a series of small, undetected strokes. Estrogen may work by diminishing atherosclerosis, the thickening and stiffening of artery walls that can lead to stroke.

Indeed, among women with the e2 and e3 alleles, those taking estrogen had less atherosclerosis in their carotid arteries, the blood vessels in the side of the neck that carry blood to the brain. But women with an e4 gene had the same amount of carotid atherosclerosis whether or not they took estrogen. However, the authors caution that this hypothesis needs more study.

Yaffe and her colleagues are continuing to explore the connection between estrogen and cognitive decline, as well as the effect of selective estrogen receptor modulators (SERMs), a class of drugs that includes the osteoporosis drug raloxifene (sold under the brand name Evista). She says it would also be interesting to know whether a woman's genes influence estrogen's effect on cardiovascular disease, osteoporosis, and other processes.

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Yaffe, K. et al. Estrogen use, APOE, and cognitive decline: Evidence of gene-environment interaction. Neurology 54, 1949-1953 (May 23, 2000).

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