New WAM Grants Support Research on Blood-Brain Barrier, Microbial Metabolites and Microglia

Research is increasingly uncovering variances between the sexes in the presentation and incidence of Alzheimer’s disease (AD), with women accounting for some 70% of cases. What underlies gender differences is not well understood, and unlocking some of these mysteries may help advance the field for everyone.

To that end, the Women’s Alzheimer’s Movement (WAM) at Cleveland Clinic — a collaboration between WAM, founded by Maria Shriver, and Cleveland Clinic — focuses on research, education, prevention and treatment for this highly elusive and prevalent disease.

WAM awards grants for some of the most promising research projects in the field. Below are the 2025 recipients and their projects.

Integrin signaling at the blood-brain barrier

Category: Established Investigator Award

Project title: Copy of X Chromosome Specific Regulation of the Blood-Brain Barrier by Integrins in Alzheimer’s Disease

Principal investigator: Antoine Louveau, PhD, Assistant Staff, Molecular Medicine in Cleveland Clinic Lerner Research Institute

AD and vascular disease are closely linked. Both disproportionately affect women, and vascular dysfunction — often a harbinger of cognitive decline — is a core feature of AD.

Using murine models, Dr. Louveau’s group previously identified a transmembrane receptor that is expressed by the cells of the blood-brain barrier. Its expression is similar in males and females, and increased expression has been associated with worse AD pathology markers in humans.

However, research in models shows that only in females is the loss of this integrin expression protective, i.e., associated with lower amyloid deposition and improved cognition. This and other evidence from Dr. Louveau’s group suggest that integrin signaling may regulate the blood-brain barrier, particularly in females.

This project, which will continue Dr. Louveau’s investigations into murine models of AD, aims to better understand the relationship between integrins and sex chromosome genes and their roles in blood-brain barrier permeability.

"These findings are expected to add to our understanding of sex disparities in AD and the importance of vascular disease in AD development and progression," says Dr. Louveau. "Insights gained from this research may one day lead to identification of a sex-specific pathway regulating AD that is amenable to treatment or prophylactic intervention."

Sex differences in microbial brain metabolites

Award: MOSH/WAM Award
Category: Internal funding

Project title: Sexual Dimorphism in Microbial Metabolites From Alzheimer’s Disease Brain

Principal investigator: Tara DeSilva, PhD, Associate Staff, Molecular Medicine in Cleveland Clinic Lerner Research Institute
Co-Principal investigator: Mark Brown, PhD, Director of Research for the Center for Microbiome & Human Health, Lerner Research Institute

The established AD risk factors of hypertension, diabetes, arteriosclerosis, obesity and hypercholesterolemia — all chronic inflammatory metabolic diseases influenced by diet — may point to a possible role of gut dysbiosis in the development of Alzheimer’s disease. Evidence indicates that the gut microbiome differs between men and women, but how that may affect cognitive dysfunction and AD pathology has not been well explored.

Dr. DeSilva’s team conducted preliminary studies that found that microbial metabolites associated with cardiovascular and cerebrovascular diseases are detectable in human postmortem brain tissue, with increased levels in the cortex of women with AD compared with men with AD. They also demonstrated similar sex-dependent differences in murine models of AD, both in brain and blood plasma. 

Their current project will further this research by exploring longitudinal expression of microbial metabolites in brain and plasma in models of AD, before and after amyloid deposition in the brain. Metabolites of interest include those found in metabolic diseases and associated with brain pathology. In addition, using postmortem tissue from some 60 brains, they will investigate sex differences of such metabolites in human AD compared to age- and sex-matched cognitively healthy controls.

“The end goal is to identify early, blood-based biomarkers predictive of Alzheimer’s risk in women and support the development of nutritional or therapeutic interventions in hopes of preventing the disease,” says Dr. DeSilva.

Role of microglia in AD pathology and treatment responses

Category: Young Investigator Award

Project title: Characterize Microglial Heterogeneities and Treatment Responses Underlying Sex Differences in Alzheimer’s Neuropathology and Brain Resilience

Principal investigator: Jielin Xu, PhD, postdoctoral fellow, Genomic Medicine in Cleveland Clinic Lerner Research Institute
Mentor: Feixiong Cheng, PhD, Staff and Director, Cleveland Clinic Genome Center

Many differences are observed between men and women with AD, but little is known about the underlying drivers of disease progression. Women are nearly twice as likely as men to develop AD and tend to experience faster cognitive decline after being diagnosed with mild cognitive impairment.

With the goal of understanding this phenomenon better, Dr. Xu is focusing on the possible role of brain inflammation and microglia — the brain’s immune cells. Evidence indicates that microglia are associated with AD and sex differences, but possible mechanisms are poorly understood.

This project aims to thoroughly characterize microglia to uncover key molecular factors that drive sex-related differences in AD progression and resilience. Unlike many studies that focus solely on individuals with cognitive impairment, Dr. Xu’s research also will include resilience cases — individuals who exhibit AD-related brain pathology but maintain normal cognitive function. Through the analysis of diverse profiles and the use of artificial intelligence tools on large-scale multi-omics datasets, the study will provide a deeper understanding of how microglia contribute to both disease and protection in a sex- and pathology-specific manner.

In addition, the project will investigate gender-specific effects of treatments targeted to microglia to advance precision-medicine approaches for the prevention or treatment of AD. To help streamline the process, Dr. Xu is particularly interested in studying established medications that target microglia with the aim of repurposing them for treating AD.  

Dr. Xu is an expert on developing and conducting novel large-scale multi-omics analyses — which can include high-throughput sequencing data from studies on genomics, proteomics, transcriptomics and metabolomics — with a special focus on AD.

This extensive basic research is anticipated to inform future translational investigations.