Research News

A collaboration between Cleveland Clinic researchers and physicians in Cleveland and Nevada has provided much-needed insight into why women develop Alzheimer's disease at higher rates and at more severe levels than men.

Researchers found differences in brain immunometabolism, the interactions between our immune systems and the ways our cells create energy. These data are essential to developing sex-specific treatment and prevention options for Alzheimer's disease, the sixth-leading cause of death in the United States.

The team behind the paper, published in Alzheimer's & Dementia, includes systems biologists, experts in brain immunity and metabolism, gender and sex difference experts, neuropsychologists and experts at Cleveland Clinic's Women's Alzheimer's Movement Prevention Center, the first center of its kind dedicated to risk factors and preventions in women.

This expertise is important because Alzheimer's disease and associated dementias are caused by a combination of complex factors, ranging from internal genetics to external environments, says lead author Feixiong Cheng, PhD, Associate Staff, Genomic Medicine Institute.

One of these factors is related to biological sex. Individuals who are assigned female at birth are disproportionately affected by Alzheimer's disease. Not only do they develop the disease more often, making up 70% of Alzheimer's cases, but they also experience faster cognitive decline. Dr. Cheng says that researchers and drug manufacturers need to consider these differences, as well as the other ways biological sex contributes to the disease, when designing medications.

Co-author Justin Lathia, PhD, adds that biological sex doesn't just influence how an individual responds to disease; it also affects how an individual responds to a treatment.

"If you look at a bottle of Ambien, you'll see different instructions for male or female patients," he says. "Biological sex influences the way we metabolize medications. Understanding differences in metabolism will be critical in making better Alzheimer's drugs."

The team analyzed publicly available sequencing data obtained from the brains of hundreds of Alzheimer's patients. They looked for changes in gene expression that indicated differences in immune function, cellular metabolism and signaling patterns between different cells in the brain. Results indicated sex-specific differences in all three factors in brains of male versus female Alzheimer's disease patients, especially in microglial cells – the immune cells that reside in the brain.

"The more progress we make into measures to protect against Alzheimer's disease, the more we see that it can't be a one-size-fits-all approach," Dr. Cheng says. "Our knowledge of each part of the systems that play into Alzheimer's disease is critical to determining the dosages and drugs that make a difference – and what might cause unwanted side effects."

Biological systems: the whole is better than sum of its parts

The project was funded in part by a grant from the National Institutes of Health (R01AG084250) that supports the use of systems biology to untangle the complex interactions between our immune systems, inflammation and sex-based differences in Alzheimer's disease. It was one of six grants awarded to Dr. Cheng between May and September of 2023, providing a total of $16 million to support projects that study how different biological processes interact with each other.

Our immune systems depend on communication between different cell types in our bodies. Many of these communication networks rely on energy gained from specific molecules that require our cells to use unique metabolic processes.

Dr. Lathia, Vice Chair of the Department of Cardiovascular and Metabolic Sciences, further explains that our immune systems, as well as some of the molecules and metabolic processes involved in cell signaling, are influenced by sex hormones. Dr. Cheng teamed up with Dr. Lathia for his expertise in cellular metabolism, sex differences and the immune system in the brain.

"This project was about figuring out how all these individual established contributors to Alzheimer's disease fit together," Dr. Cheng says. "Once we determine that, we can design targeted treatments to prevent the disease or halt its progression." 

Drs. Cheng and Lathia teamed up with Alzheimer's experts including James Leverenz, MD, Director of the Cleveland Clinic Lou Ruvo Center for Brain Health; Jeffrey Cummings, MD, ScD, the founding director of the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas; and neuropsychologist Jessica Caldwell, PhD, ABPP/CN, Director of the Women's Alzheimer's Movement Prevention Center at Cleveland Clinic Nevada.

Opened in 2020, the Women's Alzheimer's Movement (WAM) Prevention Center is designed to reduce women's risk for Alzheimer's disease. The WAM Prevention Center is based in Cleveland Clinic Las Vegas and supports multiple federally funded research projects investigating sex-based differences in Alzheimer's disease.

"At its core, Alzheimer's disease is a woman's health issue." says Dr. Caldwell, "Research shows women are disproportionately affected in terms of numbers and caregiving burden. Studying the biological, environmental, and lifestyle factors that underlie these differences will make a huge difference in how we treat our patients."

Now that they have discovered sex differences in immunometabolism, says Dr. Caldwell, the team can further establish sex-based prevention and treatment methods for Alzheimer's disease, ensuring everyone gets the appropriate level of personalized care.

About this study

Yuan Hou, PhD, a research associate at the Cheng Lab, is the first author of this study, which was supported by the National Institute on Aging (R01AG084250) under the National Institutes of Health (NIH).