At a Glance
In Wisconsin, Alzheimer’s disease (AD) is the fifth leading cause of death among those aged 65 and older. Despite decades of research, the etiology of dementia due to AD remains unknown, and there are currently no preventative or disease-modifying treatments available. The overarching goal of this project was to determine the role of the gut microbiome in AD and identify new treatment targets for the disease. This project was successful in identifying new relationships between gut and brain pathology in AD, defining how timing of microbial colonization influences the development of AD, and determining the role microbe-related metabolites may play in preclinical cognitive decline.
The Challenge
In Wisconsin, Alzheimer’s disease (AD) is the fifth leading cause of death among those aged 65 and older. Despite decades of research, the etiology of dementia due to AD remains unknown and there are currently no preventative or disease-modifying treatments available. Previous studies using mouse models have revealed that modifying the community of bacteria living in the gut, or gut microbiota, can impact the accumulation of amyloid plaques in the brain. Amyloid plaques are a hallmark of AD as they build up in brain cells and disrupt their function. In addition, researchers on this project have found that individuals with dementia caused by AD have a less diverse gut microbiome that is distinct in composition compared to cognitively healthy individuals of similar age and gender. While these results provided a strong foundation for further investigation, it remained unclear whether changes in the gut microbiome occur prior to the onset of AD and whether manipulating the gut microbiome could offer protection against the disease.
Project Goals
The overarching goal of this project was to determine the role of the gut microbiome in AD and identify new treatment targets for the disease. This goal was addressed through four specific aims:
- Determine the longitudinal relationship between gut microbiota composition and the development and progression of AD
- Identify taxa capable of modulating AD
- Test the feasibility of gut microbial manipulation in humans
- Identify microbial metabolites that can serve as novel biomarkers of AD
Results
Researchers made significant progress toward each of their aims. First, to understand the relationship between the composition of gut bacteria and the development and progression of AD, researchers acquired fecal samples from cognitively healthy participants and participants with AD over time and tested whether changes in the gut microbiome predicted changes in AD pathology through evaluation of cerebrospinal fluid (CSF) and neuroimaging markers. First, the results indicated that intestinal permeability and inflammation may play a role in AD as antibodies associated with intestinal barrier function were linked with biomarkers of AD and neurodegeneration. Second, higher levels of calprotectin, an established marker of gut inflammation, were associated with greater amyloid burden in individuals with AD. Next, researchers examined the extent to which abundances of gut microbial phyla were associated with brain volume and found a significant positive correlation between a bacterial phylum called Firmicutes and total brain volume which is consistent with previous studies of AD. Finally, higher levels of a gut microbial metabolite called phenol sulfate was associated with synaptic degeneration, indicating a potential link between the gut microbiome and the brain in AD pathology.
Researchers utilized germ-and-bacteria-free mice to investigate how the microbiome modulates AD. Researchers introduced the germ-free mice to conventionally raised, microbe-laden mice at either birth or six weeks of age to understand how the timing of colonization influences the development of AD pathology. They found that mice colonized with bacteria at birth had significantly fewer amyloid plaques compared to mice who were colonized at six weeks. These findings suggest that early microbial exposure may influence AD progression later in life.
To test the feasibility of gut microbial manipulation in humans, the researchers recruited 15 individuals with dementia due to AD and 15 healthy individuals to undergo a fecal microbiota transplant (FMT) in which healthy gut bacteria is transferred from a donor to the participants. This portion of the project was terminated during COVID-19 pandemic due to concerns about the virus being present in the stool samples used for FMT. Instead, researchers explored an alternative approach using probiotic supplementation to modify the gut microbiome and established a partnership with International Flavors & Fragrances to develop a custom probiotic for AD. A new study called “Gut-PRO Study” has been developed, though the researchers are currently seeking new funding for this project.
Lastly, the researchers examined the relationship between the metabolites produced by gut microbes and cognitive function in individuals with AD and cognitively healthy individuals. While the results of machine learning techniques to link the gut microbiome with brain imaging features are still being analyzed, the researchers also investigated whether metabolites in CSF can predict preclinical cognitive decline. 21 metabolites were linked with changes in cognitive performance. Of these, 13 were associated with improvements in performance, seven were associated with declining scores on cognitive measures and one metabolite called creatinine was associated with both improved long-term verbal memory and declining overall cognitive function. These findings suggest that gut microbe-related metabolites may play a role in preclinical cognitive decline though more research is needed to understand these effects.
Looking to the Future
The research team has leveraged their progress from this project for an NIH A1 application to continue their work. They have also received an NIH R01 award, Gut Barrier Function in Alzheimer’s Disease, to expand their research.
Lasting Impact
Researchers on this project have established a relationship with a larger consortium of investigators working on the Alzheimer’s Gut Microbiome Project, and this has led to further collaborations with world leading experts in gut microbiome and disease.
