Changes in the brain that happen after menopause may make women vulnerable to Alzheimer's disease, recent research suggests.
The hypothesis may explain why women are twice as likely to develop Alzheimer's disease after age 65 compared with men, the researchers say. (About 17 % of women in the U.S. over age 65 have Alzheimer's, compared with 9 % of men.)
Traditionally, researchers have believed that women's increased risk of Alzheimer's disease was due to the fact that women live longer, said Roberta Diaz Brinton, a professor of pharmacology, biomedical engineering and neurology at the University of Southern California's School of Pharmacy. However, women only live about four years longer than men, and Alzheimer's develops over decades, Brinton said.
Now, research from Brinton and colleagues suggests that, as women age, their brains experience a shift in the way they use energy. A woman's risk of Alzheimer's disease may, in part, be determined by how well it adapts to this energy shift, Brinton said.
"Just like the woman is going through a reproductive shift," Brinton said, "the brain is undergoing adaptations as well."
Brinton's studies on mice have shown that, during menopause, the cell's powerhouses, called mitochondria, become less efficient at producing energy. In addition, cells start to use fuel sources other than glucose, which is a sign that the energy system is not working well, Brinton said. The brain has the highest energy requirement of any organ in the body, using 20 % of the body's fuel, she said.
In a 2011 study, Brinton and colleagues removed the ovaries of mice and found that the subsequent loss of ovarian hormones such as estrogen harmed the mitochondria.
In both people and mice, declines in the brain's energy production have been shown to precede the development of Alzheimer's disease, Brinton said.
"Over time, the reduction in the ability to generate sufficient energy for the brain leads to, ultimately, an increased risk of developing Alzheimer's disease," Brinton said.
Brinton and colleagues are now conducting a clinical trial to see if a drug that promotes estrogen activity in the brain reduces cognitive difficulties in women going through menopause. The drug does not promote estrogen activity in other parts of the body, such as the breast, where the hormone has been shown to increase the risk of cancer.
The largest trial of estrogen therapy in postmenopausal women did not find that the therapy reduced the risk of Alzheimer's disease, Brinton said. But that may be because there's a window of time when the therapy is effective, Brinton said.
"If you treat a woman at age 65, her brain is no longer estrogen-responsive," Brinton said. The time to provide an estrogen therapy for cognitive benefits could be during menopause, when women are still experiencing symptoms, Brinton said.
Brinton said changes in brain metabolism likely increase the risk of Alzheimer's disease in men as well. However, men tend to experience hormonal changes, a stage known as andropause, later in life than women, Brinton said.