Cleveland Clinic research finds sex differences in immune response and metabolism drive Alzheimer’s disease

• The findings provide new insight into why women are more likely to develop the disease and offer potential sex-specific approaches to prevention and treatment.

1 December 2023, CLEVELAND: Cleveland Clinic researchers analysed genes and brain tissue from patients with Alzheimer’s and found that differences in brain immunometabolism (the interactions between the immune system and the ways cells create energy) may contribute to women’s higher risk of the disease and its severity.

The results, published in the journal Alzheimer’s and Dementia, provide important information for developing sex-specific treatment and prevention options for Alzheimer’s disease, the sixth leading cause of death in the United States.

“Our immune system relies on communication between the different types of cells in our body, which are fuelled by the energy generated by unique metabolic processes,” explains Justin Lathia, Ph.D., vice chair of the Department of Cardiovascular and Metabolic Sciences and co-author of the study.

“Because sex influences both the immune system and metabolic processes, our study set out to identify how all these individual factors influence each other to contribute to Alzheimer’s disease.”

In collaboration with researchers from the Lerner Research Institute and physicians from the Lou Ruvo Center for Brain Health in Ohio and Nevada, the team analysed brain samples and publicly available sequencing data from 469 patients with Alzheimer’s. They looked for changes in gene expression between men and women in immune function, cell metabolism and communication between brain cells. They found sex-specific differences in all three areas, with a notable difference in microglia, the brain’s immune cells. The changes in microglia were greater in women’s brains than in men’s.

“Women are more likely to develop Alzheimer’s disease and experience faster cognitive decline than their male counterparts. These sex differences must be taken into account when designing medicines and running clinical trials,” says Feixiong Cheng, Ph.D., of the Genomic Medicine Institute and lead author of the paper. “These findings expand our knowledge of every part of the systems involved in Alzheimer’s and are essential for determining the right treatments.”

This study was funded in part by a grant from the National Institutes of Health (R01AG084250) that supports the use of systems biology and multi-omics approaches to unravel the complex interactions between our immune systems, inflammation and sex-based differences in Alzheimer’s disease. It is part of an ongoing effort between Cleveland Clinic and the Women’s Alzheimer’s Movement (WAM) to better understand the relationship between sex and all neurodegenerative diseases.

“At its core, Alzheimer’s disease is a women’s health issue. To address it, we must understand how biological sex contributes to the foundations of this disease,” said Jessica Caldwell, Ph.D., director of the WAM Prevention Center at Cleveland Clinic and another co-author of the paper. “These findings confirm that we need to look at sex differences in how body and brain systems communicate in order to truly offer women personalised care, and we look forward to continuing this research.”

Recently, Dr. Cheng received 6.3 million dollars from the National Institutes of Health (NIH) to support sex-based research into Alzheimer’s disease. Together with Dr. Lathia, his project “Microglial activation and inflammatory endophenotypes underlying sex differences in Alzheimer’s disease” aims to identify new peripheral-central neuroimmune mechanisms to better understand sex differences in Alzheimer’s disease.

In addition, Drs. Cheng and Caldwell received 4 million dollars from the NIH’s National Institute of Neurological Disorders and Stroke to further examine the role of the microbiome-gut-brain axis in Alzheimer’s disease.

Their project, “Dark GPCR Signaling Underlying the Microbiome Gut Brain Axis for Alzheimer’s Disease and Related Dementia”, aims to characterise protein receptors in the gut to determine whether they offer potential prevention and treatment strategies for Alzheimer’s disease, and is supported by award #RF1NS133812.

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About Cleveland Clinic

Cleveland Clinic is a nonprofit multispecialty academic medical centre that integrates clinical and hospital care with research and education. Located in Cleveland, Ohio, it was founded in 1921 by four renowned physicians with a vision of providing outstanding patient care based on the principles of cooperation, compassion and innovation. Cleveland Clinic has pioneered many medical breakthroughs, including coronary artery bypass surgery and the first face transplant in the United States.  

U.S. News & World Report consistently names Cleveland Clinic as one of the nation’s best hospitals in its annual “America’s Best Hospitals” survey. Among Cleveland Clinic’s 72,500 employees worldwide are more than 5,050 salaried physicians and researchers, and 17,800 registered nurses and advanced practice providers, representing 140 medical specialties and subspecialties.  Cleveland Clinic is a 6,500-bed health system that includes a 173-acre main campus near downtown Cleveland, 21 hospitals, more than 220 outpatient facilities, and locations in northeast Ohio; southeast Florida; Las Vegas, Nevada; Toronto, Canada; Abu Dhabi, UAE; and London, England.

In 2021, there were 10.2 million outpatient visits, 304,000 hospital admissions and observations, and 259,000 surgeries across Cleveland Clinic’s health system. Patients came for treatment from every state and 185 countries.  

Visit us at clevelandclinic.org. Follow us at twitter.com/ClevelandClinic. News and resources available at newsroom.clevelandclinic.org.

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