A gene associated with Alzheimer's disease appears especially dangerous to women and may be one reason that more women than men are diagnosed with the disease.
The gene, known as APOE4, increases the risk of developing Alzheimer's in both sexes. But a study published Monday in the Annals of Neurology found that the gene had only a minimal effect on men, while in women it nearly doubled the risk of developing Alzheimer's or a related condition called mild cognitive impairment.
"We believe that there is an increased risk for Alzheimer's in women, and it may be that APOE4 is playing a sizable role in this," says Michael Greicius, one of the study's authors and head of the Stanford Center for Memory Disorders.
Women make up nearly two-thirds of the 5 million people in the U.S. diagnosed with Alzheimer's. One reason is that women are more likely than men to live long enough to develop the disease. But there have been hints that factors beyond longevity could be contributing to the disparity, Greicius says.
Studies dating to the 1990s have suggested that one of these factors could be the APOE4 gene. About 15 percent of the general population carries the gene, but about 50 percent of people diagnosed with Alzheimer's have it. The gene variant is just one risk factor for Alzheimer's, but scientists say it seems to be an important one.
Greicius and his colleagues reviewed medical records of more than 8,000 older people. Some had the APOE4 gene, some didn't. The records — many of them part of a data set funded by the National Institute on Aging — showed which people developed Alzheimer's disease over a three- or four-year period.
And when it came to the subset of people who carry the APOE4 gene, Greicius says, there was a clear pattern. Men with the gene were only slightly more likely to develop Alzheimer's, while women with the gene faced 1.8 times the risk compared with other women.
The finding is important for researchers of Alzheimer's, who will need to figure out why the gene affects women more than men, Greicius says. But until there's a way to slow or stop the disease, he says, there's still no compelling reason for most people to find out whether they carry the gene.
The current study does not settle the question of whether women as a group are more likely to develop Alzheimer's than men who are the same age, says Michelle Mielke, a psychiatric epidemiologist at the Mayo Clinic. But it does add to the evidence that risk factors for Alzheimer's can be different for men and women, something "we haven't really looked at very closely," she says.
For example, researchers are only beginning to understand the role of the hormone estrogen in Alzheimer's, Mielke says. Some studies have suggested that when a woman's estrogen levels decline after menopause, her brain becomes more vulnerable to Alzheimer's.
"What is interesting in relation to this paper is that animal and cellular studies suggest that there is an interaction between APOE4 and estrogen," Mielke says. "So that may possibly be explaining the findings we're seeing here in humans."
Someday, understanding how Alzheimer's is different in men and women could lead to different drugs or preventive treatments, Mielke says. But at the moment, she says, the advice remains the same for men and for women concerned about the disease.
"We say what's good for your heart is good for your brain," she says. "So exercise, controlling hypertension, cholesterol, eating right, doing physical activities are all important for your cognitive function."
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Researchers say a gene could help explain why Alzheimer's disease affects more women than men. The gene increases the risk of developing Alzheimer's in both sexes, but a new study shows the increase is much more pronounced in women. NPR's Jon Hamilton explains.
JON HAMILTON, BYLINE: Women make up nearly two thirds of the people in the U.S. diagnosed with Alzheimer's. Michael Greicius, who studies memory disorders at Stanford, says that's something researchers have been wondering about for decades.
MICHAEL GREICIUS: And the question has always been is that simply an effect of, you know, the fact that women tend to live longer, they have increased longevity? Or is it that plus something else? And the jury is a little bit out still.
HAMILTON: Several large studies in the U.S. and Europe haven't settled the issue. So, Greicius and a team of researchers decided to take a different approach. They focused on men and women who carry a gene variant called APOE4 that puts them at high risk of developing Alzheimer's. Greicius says in the general population, about 15 percent of people have at least one copy of the APOE4 gene.
GREICIUS: And then, in Alzheimer's disease, the numbers are more like, you know, 50 or 60 percent. So it's really over-represented in Alzheimer's disease population.
HAMILTON: The team reviewed medical records of more than 8,000 older people. Some had the APOE4 gene. Some didn't. The records, many of them part of a data set funded by the National Institute on Aging, showed which people developed Alzheimer's disease over a three or four year period. And Greicius says when it came to the subset of people who carry the APOE4 gene, there was a clear pattern.
GREICIUS: In men there was really no increased risk in conversion over those three or four years that we followed them. Whereas in women the risk bumped up about twofold.
HAMILTON: Women with the gene were 1.8 times more likely than other women to develop Alzheimer's, or what's known as mild cognitive impairment. Greicius says the finding offers at least one reason, other than age, that women may be more vulnerable to Alzheimer's.
GREICIUS: Even when you control for their increased longevity, we believe that there is an increased risk for Alzheimer's in women. It may be that APOE4 is playing a sizeable role in this, but there are probably also other factors that contribute to this increased risk in women.
HAMILTON: Greicius says the finding about APOE4 is important for Alzheimer's researchers. But he still doesn't see any compelling reason for most of his patients, men or women, to find out whether they carry the gene.
GREICIUS: We've had a few people in their mid 50s come in that have one or two copies of the APOE4 gene, they're perfectly healthy, and they're asking us, what do we make of this?
HAMILTON: Greicius says he expects that question to become more common as the cost of genetic testing continues to decline.
Michelle Mielke, an Alzheimer's researcher at the Mayo Clinic, has high praise for the new study. But she says it still doesn't prove that women as a group are at greater risk for Alzheimer's.
MICHELLE MIELKE: What this highlights is that there are different risk factors for men and women. And in the field, we haven't really looked at that very closely.
HAMILTON: For example, Mielke says researchers are only beginning to understand the importance of factors like estrogen. She says some studies have suggested that when a woman's estrogen levels decline after menopause, her brain becomes more vulnerable to Alzheimer's.
MIELKE: What is interesting in relation to this paper is that particularly animal and cellular studies suggest that there is an interaction between APOE4 and estrogen. And so, that may possibly be explaining the findings we're seeing here in humans.
HAMILTON: In other words, it's the combination of lower estrogen levels and carrying the APOE4 gene that puts some women at risk.
Mielke says someday, understanding how Alzheimer's is different in men and women could lead to different drugs or preventive treatments. But at the moment, she says the advice for men and women concerned about the disease remains the same.
MIELKE: We say what's good for your heart is good for your brain. So exercise is good, controlling hypertension, cholesterol, eating right, doing physical activities, I think, are all important for your cognitive function.
HAMILTON: The new research appears in the Annals of Neurology. Jon Hamilton, NPR News.
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