Researchers identify new target in the gut for reducing Alzheimer’s risk

Gut bacteria produce a common compound called imidazole propionate. Higher levels of it contribute to dementia-related changes in the brain, a study reveals.

A compound produced by bacteria in most people's digestive tract increases the risk of developing Alzheimer's disease and speeds up cognitive decline in dementia patients, making it an attractive target for a treatment that could reduce Alzheimer's risk, according to a new study.

Nearly 10 years ago, researchers led by University of Wisconsin-Madison professors Barbara Bendlin and Federico Rey discovered that the communities of microbes living in the intestines of Alzheimer's disease patients differ from those of healthy people.

"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 gerontology in the UW School of Medicine and Public Health.

In a recent study published in the journal Nature Communications, Bendlin, Rey and collaborators show that a compound called imidazole propionate (ImP) - produced in the gut by some types of bacteria - plays an important role in brain changes that result in Alzheimer's disease and related cases of dementia. Some people have guts that seem to produce a lot of ImP; some people don't.

"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."

ImP can spread from the gut to other parts of the body, where it has been implicated in type 2 diabetes and coronary artery disease. The researchers showed that ImP that reaches the brain in mice increases the build-up of clumps of two abnormal proteins, called beta-amyloid and tau.

"That process eventually results in the death of neurons, and in humans is a key feature of Alzheimer's disease," Rey says.

By looking at ImP in the blood of almost 1,200 people who have participated in the Wisconsin Registry for Alzheimer's Prevention and studies at the Wisconsin Alzheimer's Disease Research Center, the researchers found that people with high ImP levels were far more likely to also show markers of dementia-related protein and neuron dysfunction.

"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 researchers also identified a genetic variation, present in about 43% of the people in the study, linked to accumulating much higher levels of ImP in the blood. The genetic difference might affect how well the kidneys sift out ImP so that the body can get rid of it.

"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.

The most significant implication of the new study may be that ImP could represent a way to help people avoid Alzheimer's disease and related types of dementia. Unfortunately, ImP is produced by bacteria making energy from an amino acid called histidine, which is essential to human health and present in a lot of common foods - especially protein-rich ones.

"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."

But narrowing the biochemical target to a single molecule in the blood or a single genetic change opens up exciting possibilities.

"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."

Collaborators on the new study included scientists from the University of California, Los Angeles and the University of Gothenburg.

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