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Gut Microbiome Changes Linked to Preclinical Alzheimer's Disease

NEW YORK – Researchers have found a link between the gut microbiome and preclinical Alzheimer's disease (AD) that could lead to the development of a cost-effect diagnostic test and new treatments.

In a cross-sectional study published in Science Translational Medicine on Wednesday, researchers from Washington University in St. Louis found several differences in gut microbiome composition between healthy people and people with preclinical AD.

"These gut microbiome markers that we have identified do a pretty good job of predicting whether an individual may have preclinical Alzheimer's disease, or not," co-corresponding author Beau Ances, a neurology professor at Washington University School of Medicine in St. Louis, told GenomeWeb.

While previous studies have shown gut microbiome perturbations in people with symptomatic AD, for this study, researchers sought to determine if there were any gut microbiome changes linked to preclinical AD, a state where people are cognitively normal but have abnormal levels of beta-amyloid and tau proteins in the brain.

For their study, the researchers enrolled 164 cognitively normal individuals. Of these individuals, 49 showed evidence of early preclinical AD, as determined by PET imaging or cerebrospinal fluid assays to detect pathogenic β-amyloid (Aβ) and tau proteins. They further collected stool samples from all the participants for fecal metagenomic sequencing and microbial profiling.

They noted several differences between the gut microbiome of healthy people versus people with preclinical AD. For instance, gut microbiomes of people with preclinical AD had higher levels of the bacterial species Dorea formicigenerans as well as more active microbial pathways involved in the degradation of the amino acids arginine and ornithine.

Meanwhile, the microbial pathway most associated with healthy individuals produced a chemical called SCFA acetate, which has been observed to not only inhibit Aβ aggregation in vitro but also protect against cognitive impairment in mice, the researchers noted.

Moreover, those changes in the gut microbiome composition of individuals with preclinical AD correlated with Aβ and tau levels but not with biomarkers of neurodegeneration. This suggests that the gut microbiome may change early in the disease process, the authors noted.

The researchers integrated these findings to improve the accuracy and sensitivity of machine learning tests to predict preclinical AD. They validated this tool in a subset of 65 participants, finding improved performance. 

While the test would need to be further validated in additional cohorts, Ances said it could become a cost-effective way of diagnosing preclinical AD, compared to PET scans, which can cost nearly $10,000. "This could make a preclinical AD test accessible to more people because collecting stool samples is very easy," Ances said.

The findings could also lead to the development of new therapeutics based on probiotics and fecal transplants.

The researcher noted, though, that their findings need to be validated in larger preclinical AD cohorts and that future studies would need to investigate if the association between gut microbiome changes and preclinical AD is causal.