June 26, 2020
Loss of estrogen related to menopause may explain why women are much more likely than men to develop Alzheimer disease (AD), new research suggests.
In a study of more than 120 participants, menopausal status was the main factor contributing to higher beta amyloid (Aβ) levels, lower glucose metabolism, and lower gray matter volume (GMV) and white matter volume (WMV) in women.
"Our findings suggest that hormonal factors may predict who will have changes in the brain," study author Lisa Mosconi, PhD, associate professor of neuroscience in neurology, director of the Women's Brain Initiative, and associate director of the Alzheimer's Prevention Clinic, Weill Cornell Medicine, New York City, said in a press release.
"The 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," Mosconi added.
Hormone therapy, hysterectomy status, and thyroid disease were other factors linked to sex differences in brain biomarkers.
The findings were published online June 24 in Neurology.
After advanced age, female sex is the major risk factor for late-onset AD, the most common form of dementia. Women compose about two thirds of AD dementia patients; postmenopausal women account for more than 60% of affected individuals.
Previously, the higher proportion of women affected by AD was attributed to their longer life expectancy relative to men, but several emerging lines of evidence point to sex- and gender-specific AD risk factors.
Such factors that might more severely affect women include genetic risks, such as family history and APOE genotype; medical conditions, such as depression, stroke, and diabetes mellitus; hormone-related risks, such as menopause and thyroid disease; and factors related to lifestyle, such as smoking, diet, exercise, and intellectual activity.
The new study included 121 cognitively normal middle-aged participants aged 40 to 65 years (70% women) who had more than 12 years of education.
All participants received neuropsychological evaluations of memory function, attention, and language. They provided information on family history of late-onset AD and on personal lifestyle factors, such as smoking, diet, exercise, and intellectual activity.
Researchers examined several measures related to vascular risks, including abdominal obesity, hypertension, hyperlipidemia, insulin resistance, and type 2 diabetes status. They also collected information on thyroid function and depression.
In female patients, the investigators determined menopausal status (premenopausal, perimenopausal, and postmenopausal) through information on symptoms, such as hot flashes, mood swings, insomnia, appetite changes, loss of libido, and cognitive problems.
A number of well-established AD biomarkers were also examined, including Aβ on C-Pittsburgh compound B (PiB) positron-emission tomography (PET), neurodegeneration via glucose metabolism on 18F-fluorodeoxyglucose (FDG) PET, and GMV and WMV on MRI.
Men and women were comparable with regard to clinical and cognitive measures. That there were no differences in cognitive performance between the two groups "is not surprising," inasmuch as the effects of estrogen loss on cognition have been difficult to pinpoint with neuropsychological testing, the investigators note.
"It is well documented that across the adult lifespan, women perform better than men across several cognitive domains, especially verbal memory, and that this advantage may persist even into early AD," they add.
After adjusting for relevant confounders, PiB Aβ deposition was about 30% greater in the female group than in the male group, and FDG glucose metabolism was about 22% lower.
GMV was also about 11% lower in women than men (0.73 cm3 vs 0.8 cm3). About the same difference was seen in WMV (0.74 cm3 vs had 0.82 cm3). The differences were found in several brain regions.
P values were < .001 for age-matched women in comparison with men with regard to GMV and WMV, as well as PiB uptake and FDG uptake.
The new findings support the hypothesis that "brain biomarkers are more sensitive than cognitive tests for the detection of AD risk in asymptomatic individuals," the investigators note.
After female sex, menopausal status was the predictor most consistently and strongly associated with brain biomarker differences between women and men.
The authors note that menopause is accompanied by neurologic symptoms, such as disturbed sleep, depression, and changes in multiple cognitive domains, especially memory. Many of these symptoms are known AD risk factors.
Although all sex hormones are likely involved, the findings support the view that a decrease in estrogen level is involved in the AD biomarker abnormalities in women, the researchers write.
"The pattern of gray matter loss in particular shows anatomic overlap with the brain estrogen network, which includes estrogen receptors widely found in, among other regions, the prefrontal cortex, hippocampus, amygdala, and posterior cingulate cortex," they add.
The findings suggest that middle-aged women may be more at risk for AD, "perhaps because of lower levels of the hormone estrogen during and after menopause," said Mosconi.
After menopausal status, hormone therapy and hysterectomy status were the factors most strongly linked to brain biomarker differences between women and men.
Results showed higher FDG uptake and generally more favorable biomarker outcomes in participants who had received hormone replacement therapy compared with those who had not. Similar trends were noted in women who had undergone hysterectomy in comparison with those who hadn't.
AD biomarkers were also influenced by thyroid disease, a hormone-related risk factor for AD that is more prevalent in women. Thyroid disease predicted reduced MRI volume in women compared with men.
The authors note that there are known links between thyroid disease and an increased risk for cognitive impairment.
They add that a potential limitation of the study is that it included only healthy, middle-aged participants who did not have severe brain or cardiovascular disease. The authors emphasize that these new data preclude assessment of causality.
Larger studies that follow participants over time are needed, said Mosconi.
Commenting on the study for Medscape Medical News, Thomas Vidic, MD, who manages AD patients at his clinic in Elkhart, Indiana, and is a fellow of the American Academy of Neurology, said the investigators "drilled down" and looked closely at sex differences in brain biomarkers.
"We have seen for years that more women than men have Alzheimer's disease, and we have sort of tap danced around that," said Vidic, who was not involved with the research.
"Instead of talking about it and being anecdotal, we now have some serious biomarkers that indicate this is a phenomenon we need to understand," he said.
It's "too simplistic" to say that women should take hormone replacements to reduce dementia risk, Vidic added.
At one time, such therapy was "relatively common," but it has lost some appeal because of potential side effects, including heart-related effects, he said.
Researchers now need "to drill down even further" to determine the exact mechanism, which "is probably a lot more complicated than we ever imagined," Vidic said. "We need to invest resources into figuring out this phenomenon."
To understand the hormonal environment that influences AD and to identify the mechanism by which this occurs would be "an important step in developing new treatments," he added.
The study was supported by the National Institutes of Health, the National Institute on Aging, the Cure Alzheimer's Fund, and the Women's Alzheimer's Movement. The investigators and Vidic report no relevant financial relationships.