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Expansion funding identifies cause of sex-dependent vulnerability in Alzheimer’s disease

Drs. Jonathan Epp, Derya Sargin, and Dylan Terstege

“In a field where most treatments have failed and sex differences are rarely addressed, this study offers a fresh direction—one that could lead to sex-specific strategies to slow or prevent Alzheimer’s disease,” says Dr. Derya Sargin.

A research team led by Dr. Jonathan Epp, PhD, and Dr. Derya Sargin, PhD, at the University of Calgary, funded by Brain Canada and Women’s Brain Health Initiative (WBHI), has identified a potentially promising target for new Alzheimer’s disease treatments. The results were recently published in Science Advances.

What they found

The retrosplenial cortex, a region of the brain critical for a range of cognitive functions, shows early signs of dysfunction in Alzheimer’s disease. But the changes responsible for this dysfunction have been unclear – until now.

Drs. Epp and Sargin and their team looked at both mice and human brain tissue and discovered that specific brain cells in this region called parvalbumin interneurons are impaired in Alzheimer’s disease, and that changes to these cells occur to a greater extent and earlier in females compared to males. When the team stimulated these impaired brain cells in mice with an Alzheimer’s-like condition, cognitive function improved, suggesting a promising therapeutic approach.

What makes this study important is that it doesn’t just highlight a sex difference but identifies that early problems in a specific brain region and cell type may help explain why women are at greater risk of developing Alzheimer’s disease. This provides an intriguing target for future therapeutic intervention as well as a marker for potentially identifying at risk individuals.

– Dr. Jonathan Epp

“Nearly 70% of those with Alzheimer’s are women—yet most research overlooks the biological factors that put women at greater risk. By funding sex- and gender-based research, we’re not just closing a critical knowledge gap—we’re advancing smarter, more effective ways to combat brain-aging diseases that disproportionately affect women,” says Lynn Posluns, President & CEO, Women’s Brain Health Initiative.

Case in point

In a separate study also made possible with funding from Brain Canada, Dr. Epp and team recently identified that people who progress from mild cognitive impairment to Alzheimer’s disease show dysfunction in the retrosplenial cortex years before diagnosis, even without other typical markers of the disease. This change – now detectable via this newly identified marker, parvalbumin interneurons in the retrosplenial cortex – could serve as an early warning sign that helps doctors identify at-risk patients who might benefit from closer monitoring or early interventions. Given the significant uncertainty that patients with mild cognitive impairment experience, wondering whether they will or won’t acquire Alzheimer’s, which causes stress for patients and families who lack reliable answers.

“It is critical to support research that examines health differences between men, women, and gender-diverse individuals. Time and time again, studies have shown that significant differences do, in fact, exist between males and females in many areas of health care,” says Dr. Viviane Poupon, President and CEO of Brain Canada. “We are very proud to partner with Women’s Brain Health Initiative to support research that is filling this gap.”

Dr. Jonathan Epp and Dr. Derya Sargin at the University of Calgary’s Hotchkiss Brain Institute and team members Dr. Liisa Galea, Dr. Dylan Terstege and Kabirat Adigun were awarded a Brain Canada-Women’s Brain Health Initiative Expansion Grant: Considering Sex and Gender in 2022 for their project entitled Functional Connectivity and Cognitive Decline in a Mouse Model of Alzheimer’s Disease. This project built upon an Azrieli Foundation – Brain Canada Early-Career Capacity Building grant awarded to Dr. Epp in 2018. Dr. Sargin is the recipient of a Brain Canada Future Leaders in Canadian Brain Research in 2020. 

Alzheimer's | Brain Canada