A molecule produced by intestinal bacteria, measurable in the blood, appears linked to Alzheimer’s disease. In a study published in Nature Communicationsteams from the University of Wisconsin–Madison followed nearly 1,200 adults and showed that higher levels of this compound went hand in hand with faster cognitive decline and biological abnormalities linked to dementia.
The researchers, led by Barbara Bendlin and Federico Rey, identify this compound as theimidazole propionate (ImP)a metabolite made when certain bacteria process the essential amino acid histidine. “Since then, we have been trying to understand how this difference in the gut perhaps leads to changes in the brain.“, explains Barbara Bendlin, who studies the link between intestinal microbiota and Alzheimer’s.
Imidazole propionate: the microbiota signal linked to memory
About ten years ago, a team of researchers led by professors Barbara Bendlin and Federico Rey from the University of Wisconsin-Madison demonstrated that the microbial communities present in the intestines of people with Alzheimer’s disease differ from those observed in healthy individuals. “Since then, we have been trying to understand how this difference at the intestinal level can lead to changes at the brain level.”explains Professor Bendlin, professor of gerontology at the Faculty of Medicine and Public Health at the University of Washington.
In a recent study, they demonstrated that a compound called imidazole propionate (ImP), produced in the intestine by certain bacteria, plays a crucial role in the brain changes associated with Alzheimer’s disease and other forms of dementia. Some people have high intestinal production of ImP, while others do not. In the Wisconsin Alzheimer’s Disease Research Center (Wisconsin ADRC) and Wisconsin Registry for Alzheimer’s Prevention (WRAP) cohort, the authors measured ImP in 1,196 adults without cognitive impairment. ImP levels increased with age, were higher in men, and remained associated with poorer performance on tests of memory and attention, aggregated into the mPACC3 score. This association persisted after taking into account several vascular risk and lifestyle factors.
The participants with the most ImP also belonged to the group where cognitive decline over the years was most marked. “And because we have the results of the cognitive tests that these volunteers took over time, we can see that the people with the highest levels of Imp also experienced much more rapid cognitive decline.”explains Federico Rey. These same elevated ImP levels were accompanied by unfavorable blood biomarkers, such as pTau‑217 and NfL.
Imidazole propionate, genetics and the brain: a link that is becoming clearer
The scientists also looked at why some people accumulate more ImP. A genetic variation (a variant of the SLC6A13 gene, rs7969761) present in 43% of participants, is associated with higher concentrations of ImP in the blood and a slightly increased risk of Alzheimer’s in large genetic studies. This same variation had already been linked to an increased risk of Alzheimer’s and this work offers a possible explanation for this link.
Animal experiments complete this picture. Chronic ImP supplementation in animal models increased amyloid-β plaques, activated astrocytes, and accelerated tau hyperphosphorylation, two main hallmarks of Alzheimer’s disease.
ImP can spread from the intestine to other parts of the body, where it is implicated in type 2 diabetes and coronary heart disease. This study shows that ImP crosses the blood-brain barrier, reaches the brain in mice and increases the accumulation of aggregates of two abnormal proteins, called beta-amyloid and tau. “This process eventually leads to neuron death, and in humans this is a key feature of Alzheimer’s disease.”explains Rey.
What to do with imidazole propionate against Alzheimer’s?
Since ImP is produced from histidine, an amino acid present in protein foods, the authors rule out the idea of a list of foods to be banned. Barbara Bendlin instead evokes another scenario.
“This could be comparable to cholesterol: people with high cholesterol take a medication, a statin, which reduces their risk of heart disease.”explains Professor Bendlin. “If we can find an inhibitor that can lower the level of ImP in the blood, this could hopefully reduce the risk of Alzheimer’s disease and slow cognitive decline in a significant number of people.”.
These results therefore do not mean that it would be enough to modify one’s diet or one’s microbiota to prevent Alzheimer’s. But they reinforce an idea that is gradually changing our view of the disease: the brain does not age in isolation. What happens in the intestine could participate, remotely, in the mechanisms that weaken neurons. It now remains to be determined whether reducing the Imp actually slows cognitive decline. It is precisely this question that researchers now want to explore, with the hope that one day, this molecule could become not only a risk marker, but also a new therapeutic target.