Microglial Immunometabolism Endophenotypes Implicated in Sex Differences in Alzheimer’s Disease

Sex-related differences in Alzheimer’s disease (AD) pathogenesis and disease progression may be due in part to sex-specific differences in immune responses, cellular metabolism and microglial immunometabolism, according to new Cleveland Clinic research. The findings, published in Alzheimer’s and Dementia, offer important insights for the development of sex-specific treatment and prevention options for AD.

“Women are more likely to develop Alzheimer’s disease, and they experience faster cognitive decline compared with their male counterparts,” says Feixiong Cheng, PhD, corresponding author of the research report and associate staff in Cleveland Clinic’s Genomic Medicine Institute. “Yet how cell type-specific immune responses and cellular mechanisms mediate the apparent sex differences in Alzheimer’s pathophysiology has been unclear.”

“The immune system depends on communication between different cell types fueled by energy created from unique metabolic processes,” adds co-author Justin Lathia, PhD, Vice Chair of the Department of Cardiovascular and Metabolic Sciences in Cleveland Clinic’s Lerner Research Institute. “As sex influences both the immune system and metabolic processes, our study aimed to identify how all of these individual factors influence one another to contribute to Alzheimer’s disease.”

“We hypothesized that an interplay exists between cellular metabolism and immune systems,” Dr. Cheng explains, “and that understanding this interplay, which is termed the ‘immunometabolism endophenotype,’ will be essential for improving understanding of sex differences in Alzheimer’s pathogenesis and developing individualized treatments in a sex-specific manner.”

The study in brief

The study was funded in part by a grant from the National Institutes of Health supporting the use of systems biology and multi-omics approaches to untangle the complex interactions between the immune system, inflammation, and sex-based differences in AD. It is part of an ongoing effort between investigators with Lerner Research Institute and the Cleveland Clinic Lou Ruvo Center for Brain Health to further understand the link between sex and various neurodegenerative conditions.

The researchers analyzed publicly available sequencing data obtained from the brains of 469 individuals, including 203 with AD, 117 with mild cognitive impairment, 7 with other forms of dementia and 142 controls with no cognitive impairment. 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 of these factors in the brains of male versus female AD patients, especially in microglial cells ― the immune cells that reside in the brain.

Specific findings included the following:

• Sex-specific immune metabolites, gene networks and signaling pathways were associated with AD pathogenesis and progression.
• Females with AD exhibited microglial immunometabolism endophenotypes marked by reduced glutamate metabolism and enhanced interleukin-10 pathway activity.
• Females with AD demonstrated a shift in glutamate-mediated cell-cell communications between excitatory neurons and microglia and astrocytes.

“Our results point to new understanding of the molecular basis for female predominance in AD,” the researchers conclude in their study report. They add that their findings call for independent validation in ethnically diverse cohorts to assess “a likely causal relationship of microglial immunometabolism in the sex differences in AD.”

Findings in context

“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. “This project was about figuring out how these various individual established contributors to Alzheimer’s disease fit together. Once we determine that, we can design targeted treatments to prevent the disease or halt its progression.”

The project is one of multiple research avenues Dr. Cheng’s lab is pursuing with multidisciplinary collaborators at Cleveland Clinic and beyond to understand and overcome AD on various fronts. This collective work, which has drawn more than $16 million in external grant support in 2023, is profiled in a recent Consult QD article.

“At its core, Alzheimer’s disease is a woman’s health issue,” notes one of Dr. Cheng’s collaborators, Jessica Caldwell, PhD, Director of the Women’s Alzheimer’s Movement Prevention Center at Cleveland Clinic and a co-author on the current study. “To address it, we must understand how biological sex contributes to the underpinnings of this disease. 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. We look forward to continuing this research.”

Yuan Hou, PhD, a research associate with 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.