Nearly a decade ago, a research team led by University of Wisconsin-Madison professors Barbara Bendlin and Federico Rey found that the mix of microorganisms living in the intestines 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.

A Gut Molecule With Effects Beyond the Intestines

In a recent study published in the journal Nature Communications, Bendlin, Rey and their collaborators focused on imidazole propionate (ImP), a compound produced by certain bacteria in the gut. Their findings suggest that ImP may contribute to brain changes involved in Alzheimer's disease and related forms of dementia.

ImP production varies considerably from person to person. Some people appear to generate relatively large amounts, while others produce very little.

"ImP-producing bacteria are present in a large fraction of people, but they're not very abundant in most people," says Rey, a UW-Madison professor of bacteriology. "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 in the gut, ImP can enter the circulation and reach other parts of the body. Previous research has linked the compound to type 2 diabetes and coronary artery disease.

The new study suggests that its effects may also extend to the brain. In mice, researchers found that ImP reaching the brain increased the accumulation of abnormal beta amyloid and tau proteins, two major hallmarks associated with 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.

Higher ImP Levels Linked to Faster Cognitive Decline

The researchers then examined blood samples from almost 1,200 people enrolled in the Wisconsin Registry for Alzheimer's Prevention and studies conducted through the Wisconsin Alzheimer's Disease Research Center.

Participants with higher concentrations of ImP in their blood were much more likely to show biological markers associated with abnormal proteins and impaired neuron function in dementia.

Because the volunteers had also completed cognitive testing over time, the researchers were able to compare ImP levels with changes in thinking and memory.

"And because we have the results of cognitive tests these volunteers took over time, we can see that the people with the highest ImP levels also experienced much faster cognitive decline," Rey says.

The team also discovered a genetic variation associated with substantially higher levels of ImP in the bloodstream. About 43% of the people in the study carried this variation.

Researchers suspect the genetic difference may influence how effectively the kidneys remove ImP from the blood, affecting how much of the compound 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 Potential New Target for Alzheimer's Prevention

One of the most important possibilities raised by the findings is that ImP itself could become a target for preventing or slowing Alzheimer's disease and related dementias.

However, reducing ImP through diet alone may not be straightforward. Gut bacteria produce the compound while generating energy from histidine, an amino acid that is essential for human health and found in many foods, particularly foods rich in protein.

"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."

Rather than trying to eliminate histidine from the diet, the researchers say the discovery could eventually lead to treatments that specifically reduce ImP levels in the bloodstream.

Identifying a particular molecule and a related genetic variation gives scientists a more precise target to investigate.

"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."

Scientists from the University of California, Los Angeles and the University of Gothenburg also contributed to the study.

This research was supported in part by grants from the Wisconsin Partnership Program and the National Institutes of Health (R01AG070973, R01AG083883, R01AG092220, R21AG089348, R01HL168493, R01DK143650 and U54HL170326) and the U.S. Department of Agriculture (WIS03073).