Brain Estrogen Loss Disrupts a Key Space Between Cells in Aging Females

A new study from Northwestern Medicine points to a frequently overlooked part of brain biology—the space between cells—as a potential factor in why women face higher rates of Alzheimer’s disease than men.

Nearly two-thirds of Americans with Alzheimer’s disease are women, yet the reasons for this disparity remain incompletely understood. Scientists have long suspected that declining estrogen levels after menopause play a role, but a new study published in Aging Cell offers the first evidence linking estrogen loss specifically to changes in the brain's extracellular matrix, or ECM.

Like mortar between bricks, the ECM is a network of molecules filling the spaces between brain cells. It supports cell communication and function, plays a role in memory and brain development, and makes up nearly 20% of the brain’s volume. Despite its abundance, scientists have traditionally focused on neurons and glial cells, paying far less attention to this surrounding space. 

The research team used genetically engineered mouse models that lacked aromatase—an enzyme required to produce estrogen—either throughout the body or only in the brain. By examining young and old male and female mice with and without estrogen loss, they were able to isolate effects specific to older females. They found that estrogen loss, aging, and female sex are closely linked to problems in the ECM in the hippocampus, a brain region central to learning and memory.

“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 Hong Zhao.

The findings raise the possibility of a new treatment approach—one aimed at restoring the ECM rather than targeting amyloid protein buildup, the focus of existing drugs like lecanemab and donanemab. Whether those current therapies meaningfully slow memory loss or improve daily function remains a matter of ongoing debate.

“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 Serdar Bulun. “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.”

The lab’s next step is understanding how the ECM is altered in postmenopausal women and whether that change contributes to Alzheimer's susceptibility.