Increased Alzheimer’s Risk During Menopause Transition

Posted March 14, 2019

3-Year Longitudinal Brain Imaging Study

The results of a 3-year longitudinal brain imaging study supported by Cure Alzheimer’s Fund and conducted by Lisa Mosconi of Weill Cornell Medical College in collaboration with Roberta Diaz Brinton at the Departments of Pharmacology and Neurology, College of Medicine, University of Arizona, Tucson are in.

The study recruited fifty-nine cognitively normal participants between the ages of forty and sixty. The researchers were interested in identifying how menopause influences changes in biomarkers for Alzheimer’s disease. Menopause is known to cause metabolic changes in the brain that may increase the risk of Alzheimer’s disease. Two-thirds of late-onset Alzheimer’s disease patients are women making the changes in the brain that accompany the menopause transition a critical area of investigation.

The participants were asked to undergo tests to assess cognitive performance as well as imaging using 11C-PiB PET to assess brain b-amyloid load. The participants included both men and women. The female participants included women who were either premenopausal, perimenopausal, or postmenopausal. The study found that in the menopausal and perimenopausal group there was a decline in an estrogen-dependent memory test as compared to men. The menopausal group exhibited the highest rate of loss in an area of the brain critical for memory known as the hippocampus as well as the greatest increase in Ab deposition.

This study sheds crucial light on the changes in the brain that are specific to women as well as the optimal window of opportunity for therapeutic intervention to prevent or delay progression of brain changes associated with the endocrine aging process.

Funding for part of this project was provided by Cure Alzheimer’s Fund to Lisa Mosconi, PH.D., Weill Cornell Medicine.

Supplemental Information:


When women undergo the transition to menopause there is a shift in the brain’s use of glucose that accompanies this change to reproductive senescence.

Estrogen is a fundamental regulator of the metabolic system of the female brain and body. Within the brain, estrogen regulates glucose transport and mitochondrial function to generate ATP. ATP refers to adenosine triphosphate, which is often called the “molecular currency of energy transfer,” and is the chemical that provides energy to drive everything from muscle contraction to action potential firing. During menopause, the decline in circulating estrogen contributes to a decline in brain cellular energy. Many researchers have proposed that the loss of estrogen after menopause could significantly contribute to cognitive decline and Alzheimer’s disease risk in women. It is worth pointing out that men also undergo age-related changes in hormones that contribute to their risk for dementia.

Based on estrogen’s positive effects on mitochondrial energy production and regulation of Ab accumulation, some researchers have concluded that estrogen replacement or hormone replacement therapy after menopause would have beneficial effects on cognition in general, and might be able to reduce the risk of Alzheimer’s disease. Epidemiological studies and clinical trials of hormone therapy and cognition have shown mixed results. The prevailing data indicate that although thus far, hormone replacement therapy cannot alter the progression of Alzheimer’s disease, it may have the potential to lower the risk of women developing Alzheimer’s disease in the first place if given early enough. Over the past two decades, approximately two-dozen observational studies have examined associations between a woman’s use of estrogen-containing hormone therapy and her risk of developing Alzheimer’s disease. Additional investigations are needed to understand the impact of hormones on dementia risk. Hormone replacement therapy has not been widely adopted in large part due to concerns over the impact on cardiovascular health.

In summary, this new imaging study supports the idea that post-menopausal hormone therapy can modulate brain bioenergetics likely leading to the maintenance of cognitive function and reduced risk of Alzheimer’s disease. Any discussion of hormone therapy as a treatment strategy should take place with a doctor as estrogen receptors exist throughout the body including the breast and ovaries and hormone therapy could increase the risk for certain types of cancers in other places in the body. More research is needed to explore exactly why women are at increased risk for developing Alzheimer’s disease and whether targeting declining estrogen levels could afford protection against the development of Alzheimer’s disease.

For further reading, the paper below summarizes what is known 10 years after the Women’s Health Initiative:

Hormone therapy, dementia, and cognition: the Women’s Health Initiative Ten Years On

A review of how estrogen regulates energy systems:

Estrogen: A master regulator of bioenergetic systems in the brain and body: