Stress has been extensively studied in relation to Alzheimer’s disease, and there is evidence to suggest that chronic stress may increase the risk of developing the disease. The specific effects of stress on Alzheimer’s risk, however, can differ between studies and populations. According to a new study, stress raises the levels of Alzheimer’s proteins in female brains but not in male brains. This disparity may contribute to women’s increased risk of Alzheimer’s disease.
Alzheimer’s disease affects about twice as many women as it does men. Some of this is due to age; in the United States, women outlive men by five to six years, and advanced age is the most significant risk factor for Alzheimer’s. But there’s more to it, and Alzheimer’s researchers are still looking for other reasons why women have a higher risk of the deadly neurodegenerative disease.
One such reason could be stress. According to a study conducted by researchers at Washington University School of Medicine in St. Louis, the effect of stress on the brain differs by sex, at least in mice. In stressful situations, females’ brains have higher levels of the Alzheimer’s protein amyloid beta than males’. In addition, the researchers identified a molecular pathway that is active in brain cells from female mice but not male mice, and showed that it accounts for the divergent responses to stress.
How women respond to stress versus how men respond to stress is an important area of research that has implications for not only Alzheimer’s disease but also other conditions. This study shows that reducing stress may be more beneficial for women than men, to lower the risk of Alzheimer’s disease.
Carla M. Yuede
The findings, published in the journal Brain, add to a growing body of evidence that sex influences health and disease. From cancer to heart disease to arthritis, scientists have discovered gender differences that may influence how men and women respond to efforts to prevent or treat chronic diseases.
“How women respond to stress versus how men respond to stress is an important area of research that has implications for not only Alzheimer’s disease but also other conditions,” said Carla M. Yuede, Ph.D., an associate professor of psychiatry and co-corresponding author. “The National Institutes of Health (NIH) has prioritized understanding sex differences in medicine in recent years. One area where males and females clearly differ is in their approach to stress. This study shows that reducing stress may be more beneficial for women than men, in terms of lowering the risk of Alzheimer’s disease.”
Stress is a socioeconomic risk factor, along with depression and social isolation, which together account for an estimated 8% of the risk of developing Alzheimer’s. However, gender is not taken into account in the risk calculation. Women consistently report higher levels of stress than men, and stress affects women’s bodies in a variety of ways, including cardiovascular health, immune responses, and other issues.
According to corresponding author John Cirrito, Ph.D., an associate professor of neurology; Yuede; and first author Hannah Edwards, a graduate student in Cirrito’s lab, stress may affect women’s brains differently than men’s, and these differences may help explain the sex imbalance in Alzheimer’s disease.
To find out, the researchers measured amyloid beta levels in mice brains every hour for 22 hours, beginning eight hours before the mice were stressed. According to the levels of stress hormones in their blood, the experience was equally stressful for male and female mice. However, their brain responses were not the same.
Amyloid beta levels in female mice increased significantly within the first two hours and remained elevated until the end of the monitoring period. Overall, brain amyloid levels in male mice did not change, though about 20% of them did show a delayed and weak rise in amyloid levels.
Further research revealed that the distinction is due to a cellular stress response pathway in brain cells. Corticotropin releasing factor is a hormone that is released in response to stress. Female rodent neurons absorb the stress hormone, triggering a chain of events that results in increased amyloid beta levels in the brain. Male rodent neurons, on the other hand, lack the ability to absorb the stress hormone. It is not known whether there are similar sex differences in how human neurons take up stress hormones.
“There’s a fundamental biological difference between males and females in how they respond to stress at the cellular level, in both mice and people,” Cirrito said. “We don’t think that stress is the sole factor driving the sex difference in Alzheimer’s disease. There are many other differences between men and women — in hormones, lifestyle, other diseases they have — that undoubtedly contribute in some way. But that stress is driving one aspect of this sex difference I think is very likely.”
