New Alzheimer’s studies bolster evidence that women are more vulnerable to disease

“It’s not just that women are living to be older. . . . There’s something else going on in terms of biology [and] environment for women compared to men that may make them at greater risk.”
Kristine Yaffe, professor at the University of California at San Francisco

bolster evidence that women are at a higher risk, and decline faster, than men. Women who display the early signs of mental decline that can precede Alzheimer’s disease deteriorate faster than men with the same condition, a new study has found.

Another study suggests that women’s daily activities and cognitive abilities decline faster than men’s after undergoing surgery with general anesthesia. A third study has found that an abnormal protein that plays a key role in triggering Alzheimer’s accumulates at higher rates in women’s brains than in men’s.

The new research, presented this week at the Alzheimer’s Association International Conference in Washington, lends additional support to the view that women run a higher risk than men of developing Alzheimer’s disease and may be more vulnerable to its damaging effects once the illness gets going.

“The bottom line is, more and more we think there are some differences,” said Kristine Yaffe, a professor of psychiatry, neurology and epidemiology at the University of California at San Francisco. “It’s not just that women are living to be older— that’s true, and that drives some of this. But there’s something else going on in terms of biology [and] environment for women compared to men that may make them at greater risk or, if they have some symptoms, may change the progression.”

Of an estimated 5.4 million people with Alzheimer’s in the United States, about 3.4 million are female. Women have twice the lifetime risk of developing Alzheimer’s disease, which is the leading cause of dementia. The disease is progressive and incurable.

The distinguishing features of Alzheimer’s include the buildup of abnormal proteins that destroy brain cells in areas critical to memory and learning. These proteins — beta-amyloid, which forms waxy, insoluble plaques; and tau, which creates fibrous tangles — begin accumulating well ahead of symptoms such as memory loss, and advances in technology have allowed scientists to obtain images of them.

For a year or more, the Alzheimer’s Association has highlighted the disease’s disparate impact on women, both in its incidence and in the burden of caring for those who have it. The findings shared Tuesday bolster the theory that gender differences may have an effect on determining Alzheimer’s risk, perhaps because of hormonal interactions with genes, biochemistry and development in the brain.

Roberta Diaz Brinton, a professor at the University of Southern California’s School of Pharmacy, said her research has shown that women may have higher Alzheimer’s risk because estrogen has such an important effect on regulating the energy supply in the brain. At menopause, women’s bodies undergo radical transformations that can alter the brain’s ability to change glucose, a kind of sugar, into energy.

“Every cell — every single cell in your body — has a sex. The X chromosome or the XY chromosome is within all of our cells, and that very likely has an effect on cell function,” said Brinton, who helped organize the Alliance of Women Alzheimer’s Researchers, a professional interest group within the Alzheimer’s Association.

A study led by scientists at UC San Francisco explored the connection between gender and a gene whose ability to raise the risk of developing Alzheimer’s disease is already well known. The study— conducted by Duygu Tosun, an assistant professor of radiology, and others— used data from brain scans to investigate links between gender and a gene variant known as APOE4.

The gene is one of several variants that code for an apolipoprotein, a protein that shuttles cholesterol and fatty substances in the body and the brain. Having a single copy of the gene raises the risk of Alzheimer’s at least twofold; having a copy from each parent boosts the odds even higher.

The study found that men who carried the APOE4 gene had higher accumulations of beta-amyloid in their brains than men who did not. But the study’s major finding was that women had higher accumulations of the abnormal protein in their brains, regardless of whether they carried the APOE4 gene.

“This study shows women have more amyloid in their brain than men in general, and especially once the women are in the late stages where they’re having dementia. They’re going to have higher levels than men, and the APOE4 isn’t going to affect that,” said Michael W. Weiner, a radiology professor at UC San Francisco and principal investigator of the Alzheimer’s Disease Neuroimaging Initiative.
That heightened vulnerability may also affect the rate of decline among women who already show signs of dementia.

Katherine Amy Lin, an undergraduate at Duke University, said her team used data from the neuroimaging initiative to track the erosion of cognitive ability in men and women who already suffered mild cognitive impairment.

Lin, who worked with the university’s medical school, said the study examined 257 men and 141 women, mostly in their mid-70s, and their performance on cognitive tests over an eight-year period.
The study found that people with the APOE4 gene had a faster rate of decline. But after adjusting for genetic disposition and other factors, the study showed that women who suffered from mild cognitive decline saw their performance deteriorate twice as fast as men’s.

“Our findings do suggest that there is greater vulnerability to women,” Lin said. She cautioned, however, that the results are preliminary and in need of further gender-specific research.

In a similar study, Katie J. Schenning, a physician at Oregon Health & Science University in Portland, said her team explored gender differences in people who suffer cognitive decline after undergoing surgery with general anesthesia. Though most people do not experience any lasting effects from surgery involving anesthesia, recent research has found that older people are susceptible to progressive cognitive and functional decline after such procedures. Older adults receive about a third of the anesthesia administered in the United States, Schenning said.

Using data from the Oregon Brain Aging Study and a project called Intelligent Systems for Assessing Aging Changes, the team looked at 527 people, including 182 who underwent 331 procedures using general anesthesia. The average follow-up was seven years. It found that men who were exposed to general anesthesia during surgery declined faster on measures of cognitive performance and daily activity than men who had not had surgery; women who underwent surgery with anesthesia also declined faster than women who did not. But women also declined more rapidly than men. The rate was even faster for women who had multiple surgeries using anesthesia.

Women had more rapid erosion in measures of both cognition and ability to perform daily activities.
“I do want to stress that, at this time, it’s uncertain which specific surgical or anesthetic factors might contribute to postoperative cognitive or functional decline,” Schenning said. “It’s also very important to note that this is just not an effect of anesthesia itself but rather a combination of the effects of anesthesia and surgery together.” 

But Schenning also said the findings suggest that physicians should advise older patients of the risk of decline after surgery with a general anesthetic and perhaps urge them to carefully weigh whether to undergo nonessential procedures.