A largely overlooked space between cells in women’s brains may hold the key to understanding memory loss tied to estrogen decline after menopause, reports a new preclinical Northwestern Medicine study.

Nearly two-thirds of Americans with Alzheimer’s disease (AD) are women, but the reasons why women are more vulnerable are still not fully understood. Scientists have long theorized that the loss of estrogen after menopause may reduce the brain’s natural protection against memory loss and neurodegeneration.

In the new study, the scientists examined young and old male and female mice, with or without loss of brain estrogen, which allowed them to pinpoint the effects specifically relevant to older females. They found estrogen loss, aging and female sex are closely linked to problems in an important but frequently ignored aspect of brain biology called the extracellular matrix (ECM), which is highly abundant in the hippocampus.

“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 corresponding author Dr. Hong Zhao, research professor of obstetrics and gynecology in the division of reproductive science in medicine at Northwestern University Feinberg School of Medicine.

The findings, published in the journal Aging Cell, provide new insight into how estrogen loss may affect the aging female brain and could help explain why women are at higher risk for AD.

“We have provided some of the most compelling evidence that estrogen is so important for memory function and other mood functions in the female brain,” said senior author Dr. Serdar Bulun, chair of the department of obstetrics and gynecology at Feinberg and a Northwestern Medicine physician. “This should motivate clinicians to be more aware of the essential role of estrogen for women’s brains, because once memory is gone, it’s gone.”

Looking in the space between cells

Like the mortar between bricks, the ECM is a network of molecules that fills the spaces between brain cells. It’s important for memory, brain development and brain health, and makes up nearly 20% of the brain’s volume. ECM acts like a supportive scaffold between cells that helps brain cells communicate and function properly.

Scientists have traditionally focused on studying brain cells such as neurons and glial cells and have paid much less attention to the space between the cells. This is the first study to examine estrogen loss in the ECM.

“Our findings will hopefully motivate future studies to better understand how this matrix is altered in postmenopausal women, and how it could potentially induce susceptibility to Alzheimer’s disease,” Zhao said.

New treatment approach focused on the ECM?

Current anti-amyloid treatments for AD, such as lecanemab and donanemab, can remove the abnormal amyloid protein buildup in the brain, which is one of the main signs of the disease. But it is still unclear how much these treatments truly help slow memory loss or improve daily functioning. Some studies show small benefits, while others show little meaningful improvement.

These findings suggest a possible new treatment approach focused on restoring the brain’s supportive environment — the ECM — to help protect memory and fight this devastating disease.

Estrogen production before and after menopause

Before menopause, the ovaries are the main source of estrogen in women. After menopause, estrogen levels drop sharply, and only small amounts are produced in other parts of the body, including the brain, fat tissue, bone, muscle, blood vessels and breast tissue. In mice, estrogen is locally synthesized in the brain and gonadal fat in males, whereas in females it is produced predominantly in the brain.

Research has shown that women with AD may have even lower estrogen levels in the brain compared with women without AD. This study further supports that.

How does hormone replacement therapy factor in?

Hormone replacement therapy (HRT), which restores estrogen levels, has been studied as a possible way to protect women from AD. However, clinical studies have produced mixed results. Some studies found that HRT improved memory and cognitive function, while others showed little benefit or even harmful effects, Zhao said. These differences may depend on the type of hormone treatment used, the age when treatment begins and differences in study design.

“More research is needed to understand how estrogen affects the female brain and why estrogen loss increases AD risk in women,” Zhao said. “Understanding these mechanisms could help researchers develop safer and more effective HRT strategies to prevent or slow the progression of AD in women.”

How they conducted the study

The scientists used genetically engineered mouse models that lacked aromatase — an important enzyme needed to produce estrogen — either throughout the whole body or only in the brain. They examined how the loss of estrogen affected memory, behavior and social function in male and female mice at young and old ages. They also analyzed changes in gene expression across the entire genome in the hippocampus, a brain region essential for learning and memory, in mice with brain-specific estrogen loss at young and old ages of both sexes.

Notes

Funding for the study was provided by the National Institutes of Health.