Research reveals how pollution can trigger harmful changes in the brain that lead to neurodegeneration.

Air pollution sickens and kills. In many ways. It has been found to trigger cardiovascular disease, respiratory infections, and tumors, such as lung cancer. And it is behind 4.2 million premature deaths worldwide each year. There is no doubt about its harmful potential, but science is trying to unravel the details ever more precisely to identify the exact links between pollution and various diseases. New research, published this Thursday in the journal Science , has focused on the connection between air pollution and the risk of developing dementia, a group of neurodegenerative diseases traditionally associated with aging and characterized by the destruction of memory and individual autonomy.

Specifically, the Johns Hopkins University (USA) scientists behind the study have focused on Lewy body dementia, a neurodegenerative disorder characterized by the abnormal accumulation of alpha-synuclein, a protein in the brain. These harmful deposits (Lewy bodies), hallmarks of this type of dementia and also of Parkinson's disease, are responsible for motor problems and memory loss. According to this new research, this protein may also hold a key to explaining how prolonged exposure to air pollution increases the risk of developing this type of dementia. The research provides scientific support for the potential of air pollutants to trigger disease and suggests that alpha-synuclein is a key mediator linking environmental stress with brain damage.

Xiaobo Mao, a researcher in the Department of Neurology at Johns Hopkins University and author of the study, says his intention was to delve into a large gap in knowledge, a “black box” that prevented understanding exactly how pollution damages the brain: an association between pollution and the risk of developing dementia had already been demonstrated , but “the specific molecular mechanisms were not clear.”

They focused specifically on Lewy body dementia because of its public health impact—it's the second most common neurodegenerative dementia, behind only Alzheimer's—and because its link to pollution was "a blind spot for science," he says, almost unknown. "We saw a pressing need to investigate whether this common environmental exposure could be a risk factor for this devastating and widespread disease," he explains in an email response.

The first thing the scientists did was delve into epidemiological research to confirm this association, which was already suggested in the previous scientific literature. To do so, they used data from 56 million American patients hospitalized for neurodegenerative diseases between 2000 and 2014. They focused on those with Lewy body diseases and also calculated their exposure to PM 2.5—a suspended air pollutant formed by vehicle combustion, in factories, or from the burning of materials. By cross-referencing the data, the scientists found that as exposure to these types of environmental toxins increased, so did the risk of hospitalization for these neurodegenerative diseases.

Then, in experiments with mice, they also confirmed that normal rodents exposed to these pollutants did indeed present accumulations of alpha-synuclein and ended up suffering brain atrophy, neuronal death, and cognitive decline—all hallmarks of dementia. In contrast, when mice genetically modified not to produce alpha-synuclein were exposed to the same pollutants, no significant changes were seen in the brain: neither brain atrophy nor cognitive decline. “The pollution was still present, but without its key target protein, it couldn't cause this specific type of neurodegeneration,” the researcher adds.

These scientists hypothesize that environmental toxins, such as fine PM 2.5 particles, could trigger an abnormal accumulation of alpha-synuclein, which can spread damage throughout the brain.

And they corroborated this in another experiment with mice genetically modified to produce the human version of the protein: after five months of exposure to the pollutants, the authors detected accumulations of alpha-synuclein and cognitive decline. But these harmful deposits were different from those that develop with aging: exposure to fine particles generated a different strain of alpha-synuclein.

A toxic, distinct and very aggressive strain

“We found that PM2.5 acts as a catalyst, causing the alpha-synuclein protein to misfold into a distinct and highly aggressive toxic strain. You can think of it this way: PM2.5 doesn't just damage the brain directly, but it corrupts a native protein, turning it into a super-spreader of disease, more resistant to cellular clearance and more toxic to neurons than forms of alpha-synuclein that aggregate on their own. We confirmed this effect with PM2.5 samples from the US, China, and Europe,” Mao explains.

The scientist claims that the toxic strain of alpha-synuclein identified in his mouse experiments "shares key biochemical and pathological properties with alpha-synuclein strains extracted from the cerebrospinal fluid of human patients with Lewy body dementia."

Pascual Sánchez, secretary of the Behavior and Dementia Study Group of the Spanish Society of Neurology, welcomes the results of this research, in which he did not participate, because he says it adds "more evidence that pollution can influence dementia," but urges caution in interpreting the results: just because a molecular pathway has been found that helps explain this correlation does not mean that all people exposed to air pollution will develop Lewy body dementia. "It is a risk factor, but the association is relatively mild. It's not like smoking and the risk of cancer, which is much higher. But although the absolute risk is small, the link is clear, and this study is a wake-up call," warns the neurologist, who is also director of the CIEN Foundation.

Great unknowns to be resolved

In this regard, Mao himself admits that what remains to be learned is precisely "how pollutants interact with individual genetic risk factors, since not all people exposed to pollution develop Lewy body dementia." They also don't know which specific components of PM 2.5—these particles are made up of many different chemicals—are the most harmful. He recalls that his research focused on the relationship between pollution and the need for hospitalization for Lewy body dementia, but "more research is needed to confirm the role of pollution in the initial onset of the disease."

Overall, the discovery strengthens the evidence on the impact of pollution on health and opens up new preventive and therapeutic scenarios, Mao predicts. “Reducing air pollution is a crucial strategy for protecting brain health. Future therapies could also be designed to prevent the interaction of air pollutants with alpha-synuclein or to specifically neutralize this highly toxic strain once it forms.”

Diana Esteller, a neurologist at the Hospital Clínic in Barcelona, ​​further emphasizes the impact of this study on prevention: "Anything you can do to eliminate this risk factor will be positive." And while she admits that it may also open up new therapeutic research, she points out that pharmacological development for this specific disease is "limited." "Given how common it is, it seems that Lewy body dementia has been somewhat neglected," she agrees.

Mao, for his part, assumes that the molecular pathway discovered in his research to explain this association between pollution and dementia is just one of many. “Air pollution is a complex combination that attacks the body on multiple fronts. Our study has added a crucial new piece to the puzzle, but the full picture is likely a combination of several damaging mechanisms,” he suggests.