The results of a human study by researchers at the Washington University School of Medicine in St. Louis suggest that the gut microbiome composition of people in the earliest stage of Alzheimer’s disease (AD)—when brain changes have already started but before cognitive symptoms become apparent—differs from that of healthy people. The team’s study identified specific gut types associated with preclinical AD, and also showed that the inclusion of such microbiome features can improve the accuracy of machine learning classifiers for predicting preclinical AD status.

The overall findings suggest it may be feasible to analyze individuals’ gut microbiota to identify people who are at higher risk of developing dementia, and also point to the potential for designing microbiome-altering preventive treatments that could stave off cognitive decline.

“We don’t yet know whether the gut is influencing the brain or the brain is influencing the gut, but this association is valuable to know in either case,” said Gautam Dantas, PhD, the Conan Professor of Laboratory and Genomic Medicine. “It could be that the changes in the gut microbiome are just a readout of pathological changes in the brain. The other alternative is that the gut microbiome is contributing to Alzheimer’s disease, in which case altering the gut microbiome with probiotics or fecal transfers might help change the course of the disease.” Dantas is co-corresponding author of the team’s published paper in Science Translational Medicine, titled “Gut microbiome composition may be an indicator of preclinical Alzheimer’s disease.” In their report the team concluded “Gut microbiome  correlates of preclinical AD neuropathology may improve our understanding of AD etiology and may help to identify gut-derived markers of AD risk.”

The human gut microbiome harbors a “compositionally and functionally diverse community of microorganisms” that influences health and wellbeing, the authors noted. “These communities include >1012 bacterial cells, representing thousands of taxa that encode a vast repertoire of pathways with diverse influences on human physiology and metabolism.”

The idea of studying the connection between the gut microbiome and Alzheimer’s disease came together at a youth soccer game, where Dantas and co-corresponding author Beau M. Ances, MD, PhD, the Daniel J. Brennan Professor of Neurology, chatted while their children played. Ances treats and studies people with Alzheimer’s disease; Dantas is an expert on the gut microbiome.

Scientists already know that the gut microbiomes of people with symptomatic Alzheimer’s differ from the microbiomes of healthy people of the same age. “Several lines of evidence suggest a role for gut microbes in the evolution of AD pathogenesis,” the authors further commented. However, Ances told Dantas, nobody had yet looked at the gut microbiomes of people in the critical pre-symptomatic phase. “… knowledge about changes in the gut microbiome before the onset of symptomatic AD is limited,” the team stated in their paper.

“By the time people have cognitive symptoms, there are significant changes that are often irreversible,” said Ances.. “But if you can diagnosis someone very early in the disease process, that would be the optimal time to effectively intervene with a therapy.”

During the early stage of Alzheimer’s disease, which can last two decades or more, clumps of the proteins amyloid beta and tau start accumulate in the brain, but affected individuals do not yet exhibit signs of neurodegeneration or cognitive decline. “Considerable data suggest that an interval of at least 10 years exists between the first deposition of Aβ plaques in the brain and the first clinical signs of impairment,” the investigators noted. “Early detection of molecular hallmarks of AD pathology remains critical for implementing effective treatments.”

For their newly reported study, Dantas, Ances, and first author Aura L. Ferreiro, PhD, then a graduate student in Dantas’ lab and now a postdoctoral researcher, evaluated participants who volunteer for studies at the Charles F. and Joanne Knight Alzheimer Disease Research Center at Washington University. All of the participants in the study were cognitively normal. They provided stool, blood and cerebrospinal fluid samples, kept food diaries, and underwent tests including PET and MRI brain scans.

To distinguish participants already in the early stage of Alzheimer’s disease from those who were healthy, the researchers looked for signs of amyloid beta and tau accumulation through brain scans and cerebrospinal fluid. Of the 164 participants, 49 had signs of early Alzheimer’s.

Their analyses revealed that healthy individuals and those with preclinical Alzheimer’s disease harbored markedly different gut bacteria—in terms of the species of bacteria present and the biological processes in which those bacteria are involved—despite eating basically the same diet. “We found differing microbiome composition and microbial functional potential at the preclinical stage of AD,” the scientists stated.

These differences potentially could be used to screen for early Alzheimer’s disease, the researchers said. “The association of gut features with the definitive molecular hallmarks of early AD pathology strengthens their potential utility as complementary early-in-progression predictive biomarkers … Microbiome markers in stool might complement early screening measures for preclinical AD and generate encouraging hypotheses about potential roles of the gut in AD progression.”

For specific predictive computational models, inclusion of microbiome taxonomic features led to a more than 11% improvement in mean accuracy, and more than 27% improvement in specificity. “Gut microbiome features could enhance early screening measures to identify candidates for follow-up CSF or PET Aβ assays to verify preclinical AD status,” the team further suggested.

Ances added, “The nice thing about using the gut microbiome as a screening tool is its simplicity and ease. One day individuals may be able to provide a stool sample and find out if they are at increased risk for developing Alzheimer’s disease. It would be much easier and less invasive and more accessible for a large proportion of the population, especially underrepresented groups, compared to brain scans or spinal taps.”

The authors further concluded, “Overall, the associations we report in this study between the gut microbiome and preclinical AD status or AD markers support the existence of an enteric neuroimmune axis in neurodegenerative disease. Here, we report that such associations are established in preclinical AD, potentially positioning at least a few of these microbial species in the causal chain.” They noted that more study will be needed to validate the associations in a greater number of individuals with preclinical AD, assess causality, and determine whether the associations also extend to symptomatic AD, or whether they are succeeded by other gut microbiome or immune features associated with disease progression.”

The researchers have launched a five-year follow-up study designed to figure out whether the differences in the gut microbiome are a cause or a result of the brain changes seen in early Alzheimer’s disease.

“If there is a causative link, most likely the link would be inflammatory,” said Dantas, who is also a professor of pathology & immunology, of biomedical engineering, of molecular microbiology and of pediatrics. “Bacteria are these amazing chemical factories, and some of their metabolites affect inflammation in the gut or even get into the bloodstream, where they can influence the immune system all over the body. All of this is speculative at this point, but if it turns out that there is a causal link, we can start thinking about whether promoting ‘good’ bacteria or getting rid of ‘bad’ bacteria could slow down or even stop the development of symptomatic Alzheimer’s disease.” As the authors further noted, “… microbially at-risk populations could open new opportunities for gut-directed interventions to interdict progression to clinical AD.”

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