Alzheimer’s affects about 7 million seniors in the United States—a number that keeps rising. Almost two-thirds of the Alzheimer’s cases are in women, a bias that’s puzzled researchers for some time. Part of the disparity results from women living longer. Still, Stanford University neurologist Michael Greicius points out that “women at any given age are a little bit more likely to get Alzheimer’s than men are.”
A preclinical study in the journal Aging Cell recently found a possible molecular explanation for the prevalence of Alzheimer’s in women. Typically, in studying brain cells for linkages to Alzheimer’s and other memory diseases, the focus is on the nerve cells and their companion “glial cells” that keep neurons healthy. Instead, researchers from Northwestern University found clues to memory loss in the spaces between brain cells, or “extracellular matrix.”
Prior studies had implicated the decline at menopause in female hormones, such as estrogen, in memory loss. In the new study, researchers worked with mice (as preclinical models for humans) to determine the impacts on the brain of removing estrogen. In both males and females, they blocked the enzyme that synthesizes estrogen.
Read more: “What Alzheimer’s Feels Like from the Inside”
In female mice, the estrogen loss led to memory problems, based on behavioral tests such as recognizing objects and navigating a maze. The impaired female mice also showed depressive behaviors, based on an odd but standard test of suspending them by their tails to see whether they resisted or went limp. The estrogen-deficient females spent more time immobile, while male mice suffered no such effects on memory or behavior.
“This study tells us that females—but not males—may be uniquely sensitive to loss of brain estrogen at old age, potentially contributing to an increased risk of Alzheimer’s disease,” said Hong Zhao, study author and reproductive scientist, in a press release. However, it is important to remember that the results of mouse studies do not always apply in humans.
The researchers also examined gene expression in the hippocampus, the brain area associated with memory. Estrogen deficiency altered the extracellular matrix in female mice but not in males. These spaces make up about 20 percent of brain volume and contain molecules that support nerve cells in doing their job of communicating. Without estrogen, the female mice brains experienced changes in the expression of genes for binding, inflammation, structure, and other functions of the extracellular matrix.
Depending on how well these findings extrapolate to humans, new treatment approaches could protect women’s extracellular matrices in the brain from estrogen loss. “This should motivate clinicians to be more aware of the essential role of estrogen for women’s brains,” emphasized Serdar Bulun, study author and department chair of obstetrics and gynecology at Northwestern University, “because once memory is gone, it’s gone.” 
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Lead image: vpanteon / Adobe Stock
