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Why More Women Than Men Get Alzheimer’s Disease

About two thirds of people with Alzheimer’s disease are women. Scientists have long thought the main reason why more women than men get the illness is because women tend to live longer than men, and advancing age is the primary risk factors for Alzheimer’s disease. But a new study is revisiting the hypothesis that hormonal differences, especially estrogen, between women and men might explain the highest prevalence in women. This study suggests that the hormonal changes that occur with menopause may play an important role in explaining the gender disparity.

The study found that middle-aged women are far more likely than their male peers to have brain changes that are a precursor to developing Alzheimer’s, even though symptoms like impairments in memory and thinking skills are not yet apparent.

“Our findings suggest that hormonal factors may predict who will have changes in the brain,” said study author Lisa Mosconi, of Weill Cornell Medicine in New York. “Our results show changes in brain imaging features, or biomarkers in the brain, suggesting menopausal status may be the best predictor of Alzheimer’s related brain changes in women.” The findings appeared in Neurology, the medical journal of the American Academy of Neurology.

For the study, researchers looked at 85 women and 36 men ranging in age from 40 to 65; their average age was 52. None had memory impairment of other symptoms of Alzheimer’s disease.

The researchers conducted brain scans to look for the presence of amyloid plaques, a hallmark of Alzheimer’s disease. They also measured volumes of gray and white matter in their brains, as well as brain levels of glucose (blood sugar) metabolism, a marker of brain activity.

Compared to the men, the women scored worse on all four measures, indicating that the women were at higher risk of developing Alzheimer’s disease down the road. On average, the women had 30 percent more amyloid brain plaques, 22 percent lower glucose metabolism, and 11 percent lower volume of both gray and white matter.

The men and women were similar in terms of age, heart health, family history of Alzheimer’s, years of education, smoking, diabetes and other factors that may affect dementia risk. Menopausal status was the main factor that seemed to contribute to the greater degree of brain changes seen in women.

“Our findings suggest that middle-aged women may be more at risk for the disease, perhaps because of lower levels of the hormone estrogen during and after menopause,” Dr. Mosconi said. “While all sex hormones are likely involved, our findings suggest that declines in estrogen are involved in the Alzheimer’s biomarker abnormalities in women we observed. The pattern of gray matter loss in particular shows anatomical overlap with the brain estrogen network.”

After advanced age, female sex is the major risk factor for Alzheimer’s. Postmenopausal women account for more than 60 percent of those who develop Alzheimer’s late in life.

Scientists have long thought that women were disproportionately affected by Alzheimer’s because they had a longer life expectancy than men. But other studies have suggested that other factors may play a role, including medical conditions like stroke, obesity, thyroid disease and diabetes; mental health disorders like depression and stress disorders; pregnancy and hormone issues; and lifestyle factors such as diet, exercise, smoking and engagement in intellectually stimulating activities

The researchers considered these factors, and after female sex, menopausal status was the predictor most consistently and strongly associated with brain changes indicative of later Alzheimer’s disease.

The authors note that menopause is often accompanied by neurologic symptoms like poor sleep, stress and depression, which are also risk factors for Alzheimer’s. But hormonal changes, especially of the female sex hormone estrogen, had the strongest link to the Alzheimer’s brain changes.

“Lower levels of the hormone estrogen during and after menopause” might contribute to the increased risk of Alzheimer’s in middle-aged women, Dr. Mosconi said. Women who had taken hormone replacement therapy generally showed fewer adverse brain changes than those who hadn’t, though long-term use of hormones is tied to an increased risk of heart attacks and other serious problems.

Better understanding of the links between Alzheimer’s disease and gender may be an “an important step in developing new treatments,” the authors added.

By ALZinfo.org, The Alzheimer’s Information Site. Reviewed by Marc Flajolet, Ph.D., Fisher Center for Alzheimer’s Research Foundation at The Rockefeller University.

Source: Aneela Rahman, Eva Schelbaum, Katherine Hoffman, et al: Sex-driven modifiers of Alzheimer risk: A multimodality brain imaging study. Neurology, June 24, 2020