Sex-specific brain immunometabolism differences may underlie increased Alzheimer's risk in women

Cleveland Clinic researchers analyzed genes and brain tissue of 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 increased risk for the disease and its severity.

The findings, published in Alzheimer's and Dementia, offer important insight into developing sex-specific treatment and prevention options for Alzheimer's disease, the sixth-leading cause of death in the United States.

Our immune systems depend on communication between different cell types in our bodies, which are fueled by energy created from unique metabolic processes. As sex influences both the immune system and metabolic process, our study aimed to identify how all of these individual factors influence one another to contribute to Alzheimer's disease."

Justin Lathia, Ph.D., vice chair of the Department of Cardiovascular and Metabolic Sciences and co-author on the paper

A collaboration between researchers in the Lerner Research Institute and physicians at the Lou Ruvo Center for Brain Health in Ohio and Nevada, the team analyzed brain samples and publicly available sequencing data obtained from 469 Alzheimer's patients. They looked for changes in gene expression between males and females in immune function, cellular metabolism and communication between brain cells. They found sex-specific differences in all three areas with the notable difference in microglia – immune cells in the brain. Changes in microglia were greater in brains of female patients compared to males.

"Women are more likely to develop Alzheimer's disease, and experience faster cognitive decline compared to their male counterparts. These sex differences should be accounted for when designing medications and conducting clinical trials," said Feixiong Cheng, Ph.D., Associate Staff, Genomic Medicine Institute and lead author of the paper. "These findings build on our knowledge of each part of the systems that play into Alzheimer's and are critical to determining appropriate 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 untangle 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 further understand the link between sex and all neurodegenerative conditions.

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

Recently, Dr. Cheng has been awarded $6.3 million from the NIH to support sex-based research in Alzheimer's disease. Along with Dr. Lathia, their project, "Microglial Activation and Inflammatory Endophenotypes Underlying Sex Differences of Alzheimer's Disease" aims to identify novel peripheral-central neuroimmune mechanisms to better understand sex differences in Alzheimer's.

In addition, Drs. Cheng and Caldwell were awarded $4 million from the National Institutes of Neurological Disorders and Stroke of the NIH to further examine the role of 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 Demetia" aims to characterize protein receptors in the gut to determine if they offer potential prevention and treatment strategies for Alzheimer's disease and is supported by award #RF1NS133812.