October 12, 2017
Compared to premenopausal women, perimenopausal and postmenopausal women exhibited brain hypometabolism on 18F-fluorodeoxyglucose positron-emission tomography in the same brain regions as do patients with clinical AD. The findings correlated with reductions in mitochondrial cytochrome oxidase (COX) activity.
These findings suggest a "progressively increased risk of an AD endophenotype in women who undergo the perimenopause to menopause transition and suggest that endocrine aging outweighs the effects of chronological aging in the female's brain several years, if not decades, before possible clinical symptoms emerge," the authors write.
The study was published online October 10 in PLOS One.
Window of Opportunity
"Our findings show that the loss of estrogen in menopause doesn't just diminish fertility. This study suggests there may be a critical window of opportunity, when women are in their 40s and 50s, to detect metabolic signs of higher Alzheimer's risk and apply strategies to reduce that risk," Lisa Mosconi, PhD, associate director of the Alzheimer's Prevention Clinic at Weill Cornell Medicine in New York City, said in a news release.
Female sex is the second most important risk factor for AD, after advanced age, a fact that suggests a role for estrogen in the development of the disease. Preclinical studies implicate the perimenopause-to-menopause transition as a sex-specific risk factor for AD.
"In animals, estrogenic regulation of cerebral glucose metabolism (CMRglc) falters during perimenopause. This is evident in glucose hypometabolism and decline in mitochondrial efficiency, which is sustained thereafter," the investigators write.
They assessed brain "bioenergetics" in 43 healthy, cognitively normal, nondiabetic women at different endocrine transition stages. The participants included 15 premenopausal control persons (mean age, 47 years), 14 perimenopausal women (mean age, 50), and 14 postmenopausal women (mean age, 57). Except for differences in age, the groups were comparable with respect to demographics, family history of AD, and distribution of APOE4 genotype.
CMRglc was reduced in "AD-vulnerable regions" in both perimenopausal and postmenopausal women compared to premenopausal women. These AD-vulnerable regions included the posterior cingulate and the parieto-temporal and frontal cortices. A reduction in CMRglc was correlated with a decline in mitochondrial COX activity (P < .001).
There was a gradient effect such that bioenergetic abnormalities were most pronounced in postmenopausal women. Such abnormalities occurred to an intermediate degree in perimenopausal women and were lowest in premenopausal women (P < .001).
Results were independent of age, education, and APOE genotype. In addition, perimenopausal and postmenopausal women had lower scores on standard memory tests than premenopausal women.
HRT, Antioxidants to the Rescue?
"These findings validate earlier preclinical findings and indicate emergence of bioenergetic deficits in perimenopausal and postmenopausal women, suggesting that the optimal window of opportunity for therapeutic intervention in women is early in the endocrine aging process," the investigators note.
The results "provide critical evidence for early changes in the aging female brain that are relevant to the twofold greater lifetime risk in Alzheimer's disease," senior investigator Roberta Diaz Brinton, PhD, from the University of Arizona Health Sciences in Tucson, added in the news release. "Importantly, these results indicate that we know when to intervene in the aging process to divert the potential for developing this devastating disease."
The investigators point out that none of the postmenopausal women in the study were receiving hormone replacement therapy (HRT). Studies have shown that HRT is effective at preserving CMRglc in AD regions, especially if initiated before menopause.
"Our biomarker results support further investigation of the potential efficacy of estrogen-based therapies in preventing decline in brain bioenergetic capacity in women at the perimenopausal stage," the investigators write.
Antioxidants may also have a role, Dr Mosconi told Medscape Medical News.
"We have very clearly shown that there is an energy issue in women going through perimenopause and menopause, and if the mitochondria are affected, it means there is oxidative stress in the brain, so it would be interesting to see if antioxidants could help. Maybe it's not just about giving estrogen but also maybe protecting the mitochondria when you are younger," she said.
Limitations of the study include the fact that the cohort was small and consisted of carefully screened women from the New York area. Results may differ in other populations, including women with higher body mass index, lower education levels, or those at increased risk for metabolic syndrome at earlier age. The researchers say these preliminary findings need to be replicated in community-based populations with more diversified socioeconomic and medical status.
No Clinical Implications ... Yet
Reached for comment, Walter Rocca, MD, a neurologist and epidemiologist at the Mayo Clinic in Rochester, Minnesota, said the study "is a next step in the work conducted over the years by Dr Diaz Brinton and her team. Dr Diaz Brinton has proposed that some metabolic changes related to menopause and to the decrease in sex hormone production by the ovaries may be an early step in the chain of events leading to the pathological brain changes underlying cognitive decline and dementia.
"It remains unknown whether the bioenergetic dysfunction precedes the deposition of amyloid or follows the deposition of amyloid in the most common form of late-onset dementia (late-onset Alzheimer's disease). A lot of the work supporting the hypothesis has been done in animal models or cell cultures. This paper is bridging previous laboratory work with clinical work," said Dr Rocca.
"The findings are important and should prompt further studies of the hypothesis. However, clinical applications are not yet justified," Dr Rocca added. "The new findings suggest that metabolic changes may be used as early biomarkers of dementia, and that the window of opportunity for preventive interventions may be early in life.
"However, the findings need to be replicated in larger population-based samples. As recognized by the authors, the number of women was small, and longer follow-up is needed to study the changes of biomarkers over time and to confirm the ability of the biomarkers to predict clinical dementia," he said.
The study was supported by the National Institutes of Health, the National Institute on Aging, the Department of Neurology at Weill Cornell Medical College, and the Alzheimer's Prevention Clinic, Weill Cornell Memory Disorders Program. The authors and Dr Rocca have disclosed no relevant financial relationships.