Memory decline after menopause linked to loss of estrogen production in brain

Recorded: May 30, 2026, 3 p.m.

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Memory decline after menopause linked to loss of estrogen production in brain tissue - Northwestern Now

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Memory decline after menopause linked to loss of estrogen production in brain tissue
Preclinical study findings may help explain why women are at higher risk for Alzheimer’s disease

May 27, 2026

| By
Kristin Samuelson

A new study finds that women may be uniquely sensitive to loss of brain estrogen at old age, which could help explain why they are at higher risk for Alzheimer’s disease. Getty Images

Feinberg School of Medicine
Reproductive Health

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.

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A preclinical study published in Aging Cell investigated the link between memory decline after menopause and the loss of estrogen production in brain tissue, proposing that women may be uniquely susceptible to this change, which could explain their elevated risk for Alzheimer's disease. The research examined young and old male and female mice to determine the specific effects of estrogen loss in the context of aging and female sex, focusing on the extracellular matrix (ECM), a critical, yet often overlooked, space between brain cells.

The study found a close association between estrogen loss, aging, and female sex and alterations in the ECM within the hippocampus, a brain region essential for memory formation. Scientists established that this area is rich in the ECM, which functions as a supportive scaffold facilitating cellular communication and proper brain development, constituting nearly twenty percent of the brain’s volume. This research represents the first examination of estrogen loss specifically within the context of the brain's extracellular matrix. The findings suggest that females, rather than males, may exhibit a unique sensitivity to estrogen depletion in the aging brain, thus potentially contributing to an increased susceptibility to Alzheimer’s disease.

The research underscores the vital role of estrogen in female brain function and mood, with senior author Dr. Serdar Bulun noting that estrogen is fundamentally important for memory and other mood functions. This has prompted a call for clinicians to recognize estrogen's essential role in women's brains. The mechanisms uncovered by the study suggest that estrogen loss may impact the ECM, altering the supportive environment necessary for optimal neural function and potentially inducing Alzheimer’s pathology.

Current anti-amyloid treatments for Alzheimer’s disease focus on removing amyloid protein accumulation, but the study proposes an alternative approach centered on restoring the brain’s supportive environment, the ECM, to protect memory and combat neurodegeneration. This implies that targeting the structural integrity of the brain cells might be a promising avenue for intervention.

Estrogen regulation changes significantly after menopause, as estrogen production drops sharply, leading to diminished levels in various tissues, including the brain. In female mice, estrogen is predominantly synthesized in the brain, whereas in males, it is produced largely in gonadal fat. The study further indicated that women with Alzheimer's disease may have even lower estrogen levels in the brain compared to women without the disease, reinforcing the mechanistic link proposed by the research.

While hormone replacement therapy, which restores estrogen levels, has been explored as a protective measure against Alzheimer's, clinical results have been mixed, with some studies showing cognitive benefits and others showing neutral or adverse effects, depending on the treatment regimen and timing. Consequently, the research emphasizes the need for further investigation into how estrogen influences the female brain and why estrogen loss elevates AD risk in women. Understanding these underlying mechanisms is crucial for developing safer and more effective hormone replacement strategies aimed at preventing or slowing the progression of Alzheimer's disease in women.