A largely overlooked space between cells in women’s brains may hold the key to understanding memory loss associated with postmenopausal estrogen decline, reports a new preclinical study from Northwestern Medicine.
Nearly two-thirds of Americans with Alzheimer’s disease (AD) are women, but it is still not fully understood why women are more vulnerable. Scientists have long theorized that the loss of estrogen after menopause may reduce the brain’s natural protections against memory loss and neurodegeneration.
In the new study, scientists examined young and old male and female mice with and without loss of brain estrogen and were able to pinpoint effects that were particularly relevant in older females. They found that declining estrogen, aging, and female gender are closely linked to problems with an important but often neglected aspect of brain biology called the extracellular matrix (ECM), which is abundant in the hippocampus.
This study shows that women, but not men, are uniquely susceptible to brain estrogen loss as they age, which may contribute to an increased risk of Alzheimer’s disease. ”
Dr. Hong Zhao, Corresponding Author, Research Professor of Obstetrics and Gynecology, Department of Reproductive Sciences, Northwestern University Feinberg School of Medicine
The study is scheduled to be published in the journal May 26 aged cells.
The findings provide new insight into how declining estrogen affects women’s brains as they age and may help explain why women are at higher risk for Alzheimer’s disease.
“We have provided some of the most convincing evidence that estrogen is critical for memory and other mood functions in the female brain,” said lead author Dr. Serdar Brun, Feinberg chair of obstetrics and gynecology and a physician at Northwestern Medicine. “This should make clinicians more aware of the important role of estrogen in women’s brains, because once memory is gone, it’s gone.”
Looking into the spaces between cells
Like the mortar between bricks, the ECM is a network of molecules that fills the spaces between brain cells. It is important for memory, brain development, and brain health and makes up almost 20% of the brain’s volume. The ECM acts like a supporting scaffold between cells, helping brain cells communicate and function properly.
Scientists have traditionally focused on studying brain cells, such as neurons and glial cells, and have paid less attention to the spaces between cells. This is the first study to examine estrogen loss in the ECM.
“Our findings are expected to motivate future studies to better understand how this matrix changes in postmenopausal women and how it potentially induces susceptibility to Alzheimer’s disease,” Zhao said.
A new therapeutic approach focused on the ECM?
Current anti-amyloid treatments, such as lecanemab and donanemab, can eliminate the buildup of abnormal amyloid proteins in the brain, one of the main symptoms of the disease. However, it is still unclear how well these treatments actually help slow memory loss or improve daily functioning. Some studies show small benefits, while others show little meaningful improvement.
These findings suggest the possibility of new therapeutic approaches focused on restoring the brain’s supportive environment, the ECM, to protect memory and combat this devastating disease.
Production of estrogen before and after menopause
Before menopause, a woman’s ovaries are the main source of estrogen. After menopause, estrogen levels drop rapidly, and other parts of the body, such as the brain, fatty tissue, bones, muscles, blood vessels, and breast tissue, produce only small amounts. In mice, estrogen is synthesized locally in the brain and gonadal fat in males, but is produced primarily in the brain in females.
Research shows that women with Alzheimer’s disease may have even lower levels of estrogen in their brains compared to women without Alzheimer’s disease. This study further supports that.
How is hormone replacement therapy considered?
Hormone replacement therapy (HRT), which restores estrogen levels, is being studied as a potential way to protect women from Alzheimer’s disease. However, clinical studies have yielded mixed results. Some studies have found that HRT improves memory and cognitive function, while others have shown little or even harmful effects, Zhao said. These differences may depend on the type of hormonal treatment used, the age at which treatment is started, and differences in study design.
“Further research is needed to understand how estrogen affects women’s brains and why decreased estrogen increases women’s risk of Alzheimer’s disease,” Zhao said. “Understanding these mechanisms may help researchers develop safer and more effective HRT strategies to prevent or slow the progression of Alzheimer’s disease in women.”
how they conducted their research
The researchers used genetically engineered mouse models that lack aromatase, a key enzyme required for estrogen production, either whole body or only in the brain. They investigated how the loss of estrogen affected memory, behavior, and social functioning in young and old male and female mice. They also analyzed genome-wide gene expression changes in the hippocampus, a brain region essential for learning and memory, in young and old mice of both sexes with brain-specific estrogen deficiency.
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Reference magazines:
Peel, North Carolina, others. (2026). Loss of brain-derived estrogen is associated with sex- and age-dependent changes in memory, emotional behavior, and hippocampal extracellular matrix gene expression. aged cells. DOI: 10.1111/acel.70551. https://onlinelibrary.wiley.com/doi/10.1111/acel.70551
