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Published on: March 22, 2015
by Fredrick Kunkle for The Washington Post:
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 of those assumptions vanished, opening the way for new approaches to research and treatment.
A similar shift is underway in Alzheimer’s disease. It has long been known that more women than men get the deadly neurodegenerative disease, and now 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 have largely 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 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 to develop Alzheimer’s or other forms of dementia than men who are the same age. After 80, the risk is identical and remains similar throughout the rest of the 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, 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 — particularly those who were born before the modern feminist movement — were shut out of universities and generally relegated to menial jobs.
Women have a 70 per cent 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 per cent 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 than 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. Rocca, professor of neurology and epidemiology at the Mayo Clinic in Rochester, Minnesota. He said it’s not fully understood why, but scientists suspect the APOe4 gene appears to interact with oestrogen to create the conditions that lead to Alzheimer’s.
Oestrogen’s role in Alzheimer’s still 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 oestrogen also acts as a signalling molecule in genes, cells and organs. And it’s a critical regulator of metabolism in the female brain.
“I call oestrogen the Queen of Darwin,” said Roberta Diaz Brinton, a professor at the University of Southern California’s School of Pharmacy who helped organise the Alliance of Women in 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 oestrogen 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 II diabetes, which also is a risk factor for Alzheimer’s.
“It’s kind of like burning rubber tyres 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.”
Oestrogen has been of interest to Alzheimer’s researchers. Initially, many scientists suspected that oestrogen, owing to its anti-inflammatory effects and other properties, 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 oestrogen, 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 oestrogen-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 was perhaps 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 oestrogen and Alzheimer’s has received renewed attention.
In one recent study, written by Natalie 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 cancelled the estradiol benefit and accelerated deterioration. Premarin, an older form of oestrogen 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 oestrogen therapy appeared to play a significant role in reducing the risk of Alzheimer’s.
Women who underwent oestrogen replacement within five years of menopause seemed to reduce their chances of developing Alzheimer’s, while those who used oestrogen more than five years later had no reduced risk. Women who used oestrogen 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.
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