Years ago, many scientists assumed that a woman’s heart worked pretty much the same as a man’s. But as more women entered the male-dominated field of cardiology, many such assumptions vanished, opening the way for new approaches to research and treatment.
A similar shift is underway in the study of Alzheimer’s disease. It has long been known that more women than men get the deadly neurodegenerative disease, and an emerging body of research is challenging the common wisdom as to why. Although the question is by no means settled, recent findings suggest that biological, genetic and even cultural influences may play heavy roles.
Of the more than 5 million people in the United States who have been diagnosed with Alzheimer’s, the leading cause of dementia, two-thirds are women. Because advancing age is considered the biggest risk factor for the disease, researchers largely have attributed that disparity to women’s longer life spans. The average life expectancy for women is 81 years, compared with 76 for men.
Yet “even after taking age into account, women are more at risk,” said Richard Lipton, a physician who heads the Einstein Aging Study at Albert Einstein College of Medicine in New York.
With the number of Alzheimer’s cases in the United States expected to more than triple by 2050, some researchers are urging a greater focus on understanding the underlying reasons women are more prone to the disease and on developing gender-specific treatments.
The area of inquiry has been growing in part because of a push by female Alzheimer’s researchers, who have formed a group to advocate for a larger leadership role in the field and more gender-specific research.
“Scientific workforce diversity is very important because it’s much more likely to shape the research agenda,” said Hannah Valantine, the chief officer for scientific workforce diversity at the National Institutes of Health and a professor at Stanford University’s medical school.
Running counter to the longevity argument, Lipton’s research suggests that women who are 70 to 79 years old are twice as likely as men the same age to develop Alzheimer’s or other forms of dementia. After 80, the risk is identical and remains similar throughout the rest of life, Lipton said.
Differences in risk for cardiovascular disease may explain some of the disparity, he said. Men are more likely to die of chronic heart disease, high blood pressure or diabetes before they would develop Alzheimer’s. Those who survive may have more robust cardiovascular systems that help prevent dementia.
Other variables and theories are at work, such as educational attainment and susceptibility to depression and other ailments that affect women more than men. People with limited education appear to be at higher risk for dementia than those with advanced degrees. Women in the susceptible age group, many born before the modern feminist movement, often were shut out of universities and generally relegated to menial jobs.
Women have a 70 percent risk of developing depression in their lifetime compared with men, and a study published last year in the British Journal of Psychiatry found a link between depression late in life and dementia.
Researchers have focused on sex-specific genetic causes, particularly a specific gene variant, known as APOe4, which is found in about 20 percent of the population. Men and women have about the same chances of carrying the gene, which produces a protein in the liver that transports cholesterol and fatty acids in the body. The risk is 10 times higher for those who have two copies of the gene.
But research suggests that the APOe4 gene confers its Alzheimer’s risk unevenly in women. A recent study led by Michael Greicius, medical director of Stanford Medical School’s Center for Memory Disorders, found that women with the APOe4 gene were twice as likely to get Alzheimer’s as women who did not carry the gene. Yet the risk factor appeared to be little different between men who had the APOe4 gene and those who did not.
“We have now seen again and again that women that have [APOe4] have a much higher risk of getting Alzheimer’s than men of the same age who don’t have the gene,” said Walter A. Rocca, professor of neurology and epidemiology at the Mayo Clinic in Rochester, Minn. He said it’s not fully understood why, but scientists suspect the APOe4 gene appears to interact with estrogen to create the conditions that lead to Alzheimer’s.
Estrogen’s role in Alzheimer’s remains something of a mystery. The steroidal hormone, which is produced in a woman’s ovaries and adrenal glands, is mostly known for its critical role in promoting female sex characteristics and reproduction. But estrogen also acts as a signaling molecule in genes, cells and organs. And it’s a critical regulator of metabolism in the female brain.
“I call estrogen the Queen of Darwin,” said Roberta Diaz Brinton, a professor at the University of Southern California’s School of Pharmacy who helped organize the Alliance of Women Alzheimer’s Researchers (AWARE), a professional interest group within the Alzheimer’s Association. She is pursuing clinical trials on a neurosteroid called allopregnanolone that holds promise for regenerating damaged brain tissue.
Brinton thinks the critical moment occurs after menopause, when a women’s estrogen levels drop, triggering a cascading series of effects. Among them is a radical decline in the brain’s ability to burn glucose for energy. Without glucose as a source of fuel, the brain shifts to a backup energy system that burns ketone bodies, which are compounds produced from carbohydrates and fat in the liver.
The backup energy system keeps brain circuits running, but at a cost. It is not as efficient and creates byproducts that ultimately damage brain cells. Brinton said this is the same fuel system seen in Type 2 diabetes, which also is a risk factor for Alzheimer’s.
“It’s kind of like burning rubber tires instead of propane,” said Suzanne Craft, a professor of gerontology and geriatric medicine at Wake Forest University’s School of Medicine and a founder of AWARE whose research concerns the way problems with metabolism can damage the brain. “You’ll get heat, but you’ll get a lot of toxic byproducts as well,” she said.
Estrogen has been of interest to Alzheimer’s researchers. Initially, many scientists suspected that because of its anti-inflammatory effects and other properties, estrogen might benefit brain health. Research also has found that the risks of dementia rise for women whose ovaries were removed.
But then the Women’s Health Initiative, a 15-year clinical trial involving tens of thousands of women, was stopped midway after researchers discovered that administering synthetic estrogen, along with progestin, increased the risk of breast cancer, heart disease and other circulatory disorders in postmenopausal women. The same clinical trial also found that older women — ages 65 to 79 — who received estrogen-only hormone therapy ran a higher risk of developing dementia, including Alzheimer’s.
Craft and others said those unexpected results temporarily derailed interest in the effect of hormones on the brain — an outcome that perhaps was exacerbated by human bias.
“I think the movement away from more understanding of hormones in the brain may arguably be partly due to the disproportionate number of men in higher echelons of Alzheimer’s research,” Craft said.
In recent years, however, the search for a possible link between estrogen and Alzheimer’s has received renewed attention.
In one recent study, written by Natalie L. Rasgon, director of the Stanford Center for Neuroscience in Women’s Health, researchers found that administering the hormone estradiol soon after menopause appeared to prevent deterioration in key areas of the brains of women at risk of dementia. Yet the same study found that combining estradiol with progestin canceled the estradiol benefit and accelerated deterioration. Premarin, an older form of estrogen therapy mixed with substances derived from mares and used by women in the Women’s Health Initiative, also appeared to accelerate deterioration.
Earlier this year, Rocca reported on several studies that suggest that the timing of hormone therapy is critically important to brain health. A 2012 study by Peter P. Zandi, a researcher at Johns Hopkins University’s Bloomberg School of Public Health, also found that the timing of estrogen therapy appeared to play a significant role in reducing the risk of Alzheimer’s.
Women who underwent estrogen replacement within five years of menopause seemed to reduce their chances of developing Alzheimer’s, while those who used estrogen more than five years later had no reduced risk. Women who used estrogen alone or with progestin late in life increased their risks of dementia, the study found.
In the search for understanding hormones’ role as a possible sex-specific cause of Alzheimer’s, Kimberly Glass and John Quackenbush, researchers at the Harvard School of Public Health, think clues might be found in subtly different ways men’s and women’s genes code for the same proteins.
Using complex computational models, the two are exploring whether sex-based differences in the body alter the way genes transcribe molecular codes to create proteins. Their work suggests that in women with Alzheimer’s, the cells have fewer possible pathways between transcribing and building proteins, especially in metabolism-related networks.
“Women and men swim in different hormonal oceans, and that hormonal environment could be one of the factors for understanding the difference in risk,” Quackenbush said.