We know inhaling polluted air harms our lungs—but what about our brains? According to compelling new research, pollution may put you at higher risk of being hospitalized for one of the most common types of dementia.
Lewy body dementia affects more than one million people in the United States. It has two forms: Dementia with Lewy bodies and Parkinson’s disease dementia—both caused when too much of the protein alpha-synuclein builds up in the brain and infects and kills healthy cells.
A paperpublished in Science in early September outlines a possible mechanism for how air pollution could spur toxic alpha-synuclein buildup. In a study conducted in mice, researchers found when pollution particles smaller than 2.5 micrometers in diameter, or fine particulate matter (PM2.5), interact with alpha-synuclein, the protein forms into a new strain, PM-PFF. This strain closely resembles the alpha-synuclein strains seen in Lewy body disease patients, researchers found.
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“We are among the first studies to provide a plausible mechanistic link between common environmental pollutants and the molecular pathology of Lewy body dementia,” says Xiao Wu, a study co-author and an associate professor of biostatistics at Columbia University.
To get a better picture of how this plays out in humans, the researchers further analyzed 56 million U.S. patient hospitalization records. They found people chronically exposed to fine particulate matter had a stronger associated risk of being hospitalized for both forms of Lewy body dementia.
Hong Chen, an environmental health research scientist at Health Canada who was not part of the study, says he was impressed by how the authors “triangulated” the findings on a variety of fronts. “The results are very consistent and actually complementary to each other,” Chen says. “This study provides the most compelling evidence so far in linking PM2.5 to Lewy body dementia that I’m aware of.”
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What happens when you expose mice to air pollution?
Air pollution is a known risk factor for dementia. But while scientists have attempted to identify a mechanism linking pollution to Alzheimer’s disease, there’s scarce information when it comes to Lewy body dementia. Xiaobo Mao, the lead study author and associate professor of neurology at John Hopkins University, decided to investigate.
Mao’s team took samples of fine particulate matter from China, the U.S., and the Czech Republic, and put them up the noses of mice.
Within two months, they began to see changes in the alpha-synuclein that can cause the protein to spread; this phenomenon, known as serine-129 phosphorylation, can drive Parkinson’s disease. “The disease pattern is already similar to Parkinson’s dementia,” Mao says. “That’s scary to me.”
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After 10 months of exposure, the mice showed signs of brain shrinkage, a hallmark of dementia, and had accumulated “substantial” serine-129 phosphorylation. The mice were also given a nest-building test and exhibited clear cognitive decline.
Meanwhile, the mice who had not been exposed showed no significant brain shrinkage or cognitive decline—neither did “knockout” alpha-synuclein mice, a group of mice whose alpha-synuclein genes were turned off. Instead, they appeared to be “protected,” the paper says, despite air pollution exposure. That suggests “alpha synuclein is the key driver” of dementia, not air pollution, Mao explains. Instead, air pollution may act like a catalyst that “induces the brain atrophy or Lewy body dementia.”
Other interesting findings emerged: Exposed wild mice also developed signs of Lewy body disease in the lungs and gut. Since previous studies suggest that drivers of dementia can be found in other organs and tissues beside the brain, this finding provides more potential evidence that PM2.5 is linked to Lewy body dementia progression.
Comparing mice to humans
While the mouse study results are striking, they don’t translate directly to people. “You have to understand you’re just modelling what might be going on in humans,” says Ted Dawson, a co-author and director of the John Hopkins University Institute for Cell Engineering.
For example, in the real world “we’re exposed to much lower [fine particulate matter] throughout our entire life,” whereas the mice in studies receive higher dosages in the short-term, Chen says. And unlike people, mice don’t naturally accumulate alpha-synuclein with age.
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To mimic a more real-world human scenario, researchers added a new group of mice to their experiment—“humanized” mice. These mice were modified with a human mutation that enabled alpha-synuclein growth with age. After exposing the humanized mice to air pollution for five months, these mice also demonstrated cognitive impairment.
The team went a step further and compared the genetic makeup of the new PM-PFF alpha-synuclein strain they found in mice to that of the alpha-synuclein strains found in humans. Scientists homed in on gene expression in the anterior cingulate cortex, a brain region known for emotion and cognitive processing.
Researchers found a strong correlation between the gene expression of mice with PM-PFF and people with both Parkinson’s disease dementia and dementia with Lewy bodies. However, no meaningful correlation was found in Parkinson’s disease without dementia, further suggesting air pollution plays a role in Lewy body dementia specifically. “I think this goes one step further to link the potential,” Chen says.
Does pollution raise Lewy body dementia risk in actual humans?
The last piece of the puzzle was an epidemiological study—are there similar links between air pollution and Lewy body dementia among human populations?
Wu, the biostatistician from Columbia, analyzed millions of U.S. Medicare hospital records from 2000 to 2014 and used satellite imaging to measure air pollution exposure in the zip codes where those patients lived. His team found that for every 4.14 μg/m3 of fine particulate matter exposure, the associated risk of hospitalization for Parkinson’s disease dementia increased by 17 percent, and for dementia with Lewy bodies increased by 12 percent. This could imply a stronger association between Lewy body dementia and air pollution specifically.
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Meanwhile, there was just 7 percent increased associated risk for Parkinson’s disease without dementia. Why? One hypothesis is “maybe PM 2.5 is more severe in terms of leading to the dementia outcomes,” Wu says. It could also be that Parkinson’s disease patients without dementia are less likely to land in the hospital compared to the other patients.
What’s the upshot?
While the findings are exciting, the authors note more questions need answering. For example, what other dementia subtypes might air pollution be strongly linked to?
One limitation of the study is that the exact content of the PM2.5 is unknown. Fine particulate matter can be made of toxic metals, black carbon, and a host of other substances. It’s not clear exactly which pollutant caused the PM-PFF strain, but given the study used air pollution samples taken from China, the U.S., and Europe and received similar results, this suggests there’s “obviously something common between them,” Dawson says.
Understanding the pollutants and the biological drivers behind Lewy body dementia could eventually help develop targeted interventions. However, the authors stressed their study also points toward environmental action.
“What’s in the PM2.5 that’s driving this? Is it one molecule?” Dawson asks. “Let’s say it’s one class of pollutants. That would help guide public health policy.”
Dawson says, “our conclusion should prompt, we hope, public health measures where we would begin to take air pollution seriously.”