Cumulative Estrogen Exposure May Be Protective Against Alzheimer’s

Menopause carries with it a variety of uncomfortable symptoms, including hot flashes, mood swings, bladder problems, and sexual issues. As if those weren’t enough, it’s also associated with shrinkage of brain gray matter. However, a new study finds that the more estrogen exposure you’ve had throughout your life, the less you may be impacted by this shrinkage.

Researchers from Weill Cornell Medicine and the University of Arizona conducted an observational study of nearly 100 women around the age of 50 to better understand menopause, decreases in gray matter, estrogen, and how they may be linked. Throughout the study, the team observed the shrinkage in question, as well as the fact that more estrogen-exposing experiences like pregnancy or hormone therapy seemed to counteract it. Their findings were published in the journal Neurology.


Dr. Lisa Mosconi, senior author and director of the Weill Cornell Women’s Brain Initiative, says, “Our findings suggest that while the menopause transition may bring vulnerability for the female brain, other reproductive history events indicating greater estrogen exposure bring resilience instead.”

This study built on knowledge obtained in prior research by Mosconi, which found stark changes in the brain during menopause. Namely, that in addition to gray matter shrinkage, the brain’s connectivity and energy metabolism were also impacted. These differences were especially strong in areas of the brain that relate to higher-order cognitive processes and are the most impacted by Alzheimer’s. Between the time frame of these changes and the fact that about two-thirds of Alzheimer’s patients are women, there’s a theory that estrogen loss may have something to do with the risk of developing the disease. Mosconi’s team then hypothesized that greater estrogen exposure could protect the brain.

To investigate this possible link, the research team analyzed 99 women between the ages of 46 and 58, along with a comparison group of 29 men of roughly the same age. The study found that perimenopausal and postmenopausal women had significantly lower gray matter volume than premenopausal women and the male subjects. The areas impacted included the hippocampus, entorhinal cortex and temporal lobe regions, which are hit hard by Alzheimer’s.


However, women with greater estrogen exposure saw higher gray matter volume in areas affected by Alzheimer’s and aging. This included women with a longer reproductive span, those who had had more children, and those who had used hormone replacement therapy.

The findings suggest that estrogen may be protective against Alzheimer’s, but further research is needed.

Eva Schelbaum, first author and research assistant in Mosconi’s lab, says, “We’re hoping now to get further into the details of these links between estrogen and gray matter volume, for example by comparing the effects of surgical menopause and spontaneous menopause, and by focusing specifically on certain types of estrogen exposure, such as menopause hormone therapy. The goal as always is to understand why Alzheimer’s affects more women than men, and how we can reduce that risk.”


The team explains that if estrogen’s role is better understood, doctors could suggest medical and lifestyle changes to reduce women’s risk of Alzheimer’s or other cognitive changes related to aging.

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