Gut Bacterial Molecule ImP Linked to Faster Cognitive Decline in Dementia

A bacterial molecule produced in the human gut appears to accelerate Alzheimer's pathology and cognitive decline, according to a study published October 3, 2026, in Nature Communications. Among nearly 1,200 research volunteers in Wisconsin, those with the highest blood levels of imidazole propionate (ImP) showed significantly faster decline on serial cognitive testing, alongside biological markers of abnormal protein accumulation and impaired neuronal function.

The research team — led by University of Wisconsin-Madison professors Barbara Bendlin (medicine) and Federico Rey (bacteriology), with collaborators at UCLA and the University of Gothenburg — has spent nearly a decade tracing how differences in the intestinal microbiome translate into brain changes. Their earlier work established that the mix of gut microorganisms differs between people with Alzheimer's disease and healthy individuals.

"Since then, we've been trying to figure out how this difference in the gut perhaps leads to changes in the brain," says Bendlin, a professor of medicine in the UW School of Medicine and Public Health.

From gut metabolite to brain pathology

ImP is produced by certain gut bacteria as they extract energy from histidine, an essential amino acid abundant in protein-rich foods. Production varies considerably between individuals. Some people generate relatively large amounts; others very little.

"ImP-producing bacteria are present in a large fraction of people, but they're not very abundant in most people," Rey says. "But something we have learned over the years is that a microbe doesn't have to be abundant to have an impact on the host."

Once produced, ImP enters the circulation and reaches other tissues. Previous research has already linked the compound to type 2 diabetes and coronary artery disease. The new study extends its reach to the brain.

In mice, ImP reaching the brain increased accumulation of abnormal beta amyloid and tau proteins — the two hallmark pathologies of Alzheimer's disease. "That process eventually results in the death of neurons, and in humans is a key feature of Alzheimer's disease," Rey says. Readers should note the mechanism data come from animal models; the human findings rest on blood biomarkers and longitudinal cognitive testing, not on direct measurement of ImP in brain tissue.

The human cohort

The researchers analyzed blood samples from almost 1,200 people enrolled in the Wisconsin Registry for Alzheimer's Prevention and in studies conducted through the Wisconsin Alzheimer's Disease Research Center. Participants with higher circulating ImP concentrations were much more likely to show biomarkers associated with dementia-related abnormal proteins and impaired neuron function.

Because these volunteers had completed cognitive testing repeatedly over time, the team could link ImP levels to trajectories of thinking and memory. "We can see that the people with the highest ImP levels also experienced much faster cognitive decline," Rey says.

The study also identified a genetic variation associated with substantially higher ImP levels in the bloodstream. About 43% of participants carried it. The researchers suspect the variant affects how efficiently the kidneys clear ImP from blood, altering how much remains in circulation.

"This genetic variation has been associated with increased Alzheimer's risk in large genetic studies before, and now we may understand why it's connected," Rey says.

A cholesterol-style prevention target?

The most consequential implication is that ImP itself could become a modifiable target for preventing or slowing Alzheimer's disease and related dementias. Dietary reduction, however, is not straightforward. Gut bacteria make ImP while metabolizing histidine, an amino acid essential for human health and widely distributed in food.

"Generally improving your diet would probably help," Bendlin says. "But it's not as easy as saying, 'Stop eating eggs' or 'Don't eat so much red meat.' Because you need histidine, and it's all over the place."

Instead, the researchers point toward treatments that specifically lower ImP in the bloodstream. Identifying a defined molecule and a linked genetic variant gives scientists a precise target for drug development.

"It could be just like cholesterol, where people with elevated cholesterol take a drug, a statin, that reduces their risk for heart disease," Bendlin says. "If we can find an inhibitor that can help decrease the levels of ImP in the blood, that could hopefully reduce the risk of Alzheimer's and the speed of cognitive decline for a significant number of people."

For clinicians tracking dementia biomarkers, the work adds a circulating metabolite and a common renal-clearance-related variant to the growing list of peripheral factors implicated in disease trajectory. Any ImP-lowering intervention remains investigational — no therapy exists yet. The study was supported in part by the Wisconsin Partnership Program, multiple NIH grants (including R01AG070973 and R01AG083883) and the U.S. Department of Agriculture, and the next steps will likely include testing whether pharmacologically reducing circulating ImP can change amyloid, tau and cognitive outcomes in humans.