ARTICLE IN BRIEF
Experts offer perspective on how to interpret a special report, which found significantly more women were diagnosed with Alzheimer's disease.
At first, the fact that almost two-thirds of Americans with Alzheimer's disease are women would seem to have a simple explanation: women live longer than men (81 vs. 76 years average life expectancy in the US), and Alzheimer's disease risk increases greatly with age.
But a new special report on women and Alzheimer's disease, released by the Alzheimer's Association as part of their larger annual report, 2014 Alzheimer's Disease Facts and Figures, makes it clear that the significant gender gap in Alzheimer's almost certainly cannot be explained by life expectancy alone.
As the report notes, women aged 65 have a one in six lifetime risk of developing Alzheimer's, while men aged 65 have a one in 11 risk — a difference that can't be accounted for simply by five years increased average lifespan.
To some extent, gender differences in Alzheimer's rates may be explained by similar differences in cardiovascular disease rates. A recent analysis of data from the Framingham study — published in January in the Alzheimer's Association journal, Alzheimer's & Dementia — confirmed that men aged 45–65 have a higher rate of death from cardiovascular disease than women of the same age range. Since a high risk of cardiovascular disease is also associated with a high risk of developing Alzheimer's disease, these early heart disease deaths among men means that a significant number of men who might otherwise have gone on to develop Alzheimer's have died of heart disease before reaching age 65.
But again, the researchers on this analysis found that this effect explained only part of the difference in Alzheimer's disease rates among women and men 65 and older — perhaps 20 to 50 percent.
DIFFERENCES DUE TO RESEARCH METHODOLOGY
So what else is at play here? It's possible that these differences can all be explained by research methodology. “Several European studies showed higher incidence rates in women; however, studies in the United States did not show the difference,” Walter A. Rocca, MD, MPH, director of the Rochester Epidemiology Project at the Mayo Clinic, told Neurology Today. “The different pattern in Europe and the United States may be due to differences in the methodology used to conduct the study. On the other hand, the differences may be genuine, and may reflect a different distribution of risk and protective factors related to sex or gender across countries (or continents).”
For example, he noted, men and women have had different access to education, intellectual jobs, and other social activities across countries and over history. Important historical events, like World War II or the Cold War, may have also had a different impact on men and women in Europe and the United States.
There may also be true biological differences in Alzheimer's risk based on sex or gender, but the body of research on this subject remains relatively small — although it is growing.
Several researchers are investigating the role that differences in brain structure between men and women, hormonal differences, and differences in the molecular characteristics of cells may play in the development of Alzheimer's disease.
HORMONES/MENOPAUSE ARE FACTORS
An issue that has received particular attention is the relationship between hormone therapy in menopausal and postmenopausal women and their risk of Alzheimer's disease. Observational studies suggest that women who use hormone therapy have a reduced risk of Alzheimer's, but trials show a higher risk.
In a study published in Neurology in 2012, Peter Zandi, PhD, and colleagues with the Cache County Investigators suggested that the timing of the estrogen therapy may be key. Their population-based study found that women who used any type of estrogen therapy within 5 years after menopause had a 30 percent reduced risk of developing Alzheimer's. On the other hand, women who began estrogen therapy five years or more after menopause had no reduced risk; their findings also suggested that “opposed” estrogen-progestin compounds taken later in life might actually increase risk.
“There is also a growing body of evidence indicating that common gynecological surgeries such as bilateral oophorectomy may be related to an increased risk of dementia,” said Dr. Rocca. “Even more alarming are data suggesting that removing only one ovary (unilateral oophorectomy) or the uterus alone (conserving both ovaries) may increase the risk of women to develop dementia.” (His editorial on this topic appears in the Jan. 21 issue of Neurology.)
Another area of recent research focuses on conditions affecting women during pregnancy. Hypertensive pregnancy disorders may be linked to an increased risk of cardiovascular diseases many years after the pregnancy, and to an increased risk of dementia 10–15 years further on.
Gender and sex differences in the Alzheimer's picture are very complex, said Michelle Mielke, PhD, associate professor of epidemiology and neurology at the Mayo Clinic. “In the Mayo Clinic Study of Aging, it appears that men have a higher prevalence of mild cognitive impairment (MCI) than women, but women tend to be more likely to go on to develop dementia. And some studies suggest that women decline faster than men once they have a diagnosis of Alzheimer's. Why is that?”
Research into sex and gender differences in dementia is far behind similar research in cancer and cardiovascular disease, said Dr. Rocca. “Unfortunately, these studies focusing on women are only now being recognized and valued.”
But at least it's getting started. The National Institute on Aging (NIA) and the Department of Veterans Affairs have funded several studies on the relationship between estrogen and Alzheimer's disease.
And private funders have begun to take notice as well. In 2013, the Geoffrey Beene Foundation (with technical advice from the NIA) presented a $50,000 Innovation Award to Enrico Glaab, PhD, research associate at the Luxembourg Centre for Systems Biomedicine, University of Luxembourg, as the winner of its Global NeuroDiscovery Challenge — the first-ever challenge aimed at identifying sex differences in Alzheimer's Disease. Dr. Glaab is studying age-related sex differences in brain expression levels of tau-interacting ubiquitin-specific peptidase 9 and possible implications for Alzheimer's disease.
The results of the Neurodiscovery Challenge voting — online and open to the public — were so close that one of the sponsors, Sanofi, stepped forward and offered an additional $50,000 to fund the second-place winners. Kimberly Glass, PhD, and John Quackenbush, PhD, of the Harvard School of Public Health, will continue their study of sex-specific differences in Alzheimer's disease characterized by unique alterations in cellular network structure.
Dr. Rocca and Dr. Mielke recommend sex stratification in future Alzheimer's trials — not a feature in most trials to date. “The logic in the past has been that men and women would respond to drugs acting on the brain in the same way. If men and women are the same, developing a single drug for both of them is less expensive, and would have a larger market. Unfortunately, this approach has not worked,” Dr. Rocca said. “Studies focused on sex and gender differences may accelerate the discovery of risk and protective factors, as well as the development of new treatments.”
But for now, there are no clear answers for neurologists to give their patients about differences in Alzheimer's risk between men and women, or what might be protective.
“There's nothing we can tell women that they should do differently,” said Dr. Mielke. “The best thing we can do is reiterate what we already know about current risk factors for Alzheimer's, which is to say that what's good for your heart is also good for your brain. But we do need to make it known that yes, there are sex differences and gender differences in Alzheimer's, and much more research is required to understand them.”