Air pollution makes people sick and can be deadly — in many ways. It has been shown to drive cardiovascular diseases, respiratory infections, and cancers such as lung cancer. It is responsible for 4.2 million premature deaths worldwide every year. There is no doubt about its harmful potential, but science is increasingly trying to pinpoint the exact links between pollution and different illnesses. A new study, published on Thursday in Science, focuses 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 loss of memory and individual autonomy.
Specifically, researchers from Johns Hopkins University in the United States, who authored the study, focused on Lewy body dementia, a neurodegenerative disorder marked by the abnormal accumulation in the brain of a protein called alpha-synuclein. These harmful deposits (Lewy bodies), which are distinctive signs of this type of dementia and also of Parkinson’s disease, are responsible for motor problems and memory loss. And according to this new research, that protein may also hold the key to explaining how prolonged exposure to air pollution increases the risk of developing this type of dementia. The study provides scientific support for the potential of air pollutants to fuel disease and suggests that alpha-synuclein is a crucial mediator linking environmental damage to brain damage.
Xiaobo Mao, a researcher in the Department of Neurology at Johns Hopkins University and author of the study, explains that his intention was to dig deeper into a major knowledge gap — “a black box” that made it impossible to understand exactly how pollution damages the brain. The association between pollution and the risk of developing dementia had already been demonstrated, but, he notes, “the specific molecular mechanisms were not clear.”
The researchers focused specifically on Lewy body dementia because of its public health impact — it is the second most common neurodegenerative dementia, after 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 the association already suggested by earlier scientific literature. They used data from 56 million U.S. patients hospitalized with neurodegenerative diseases between 2000 and 2014. They focused on those with Lewy body-related diseases and also calculated their exposure to fine particulate matter (PM2.5) — an airborne pollutant produced by vehicle combustion, factories, or the burning of materials. When they cross-referenced the data, the scientists found that as exposure to these environmental toxins increased, so did the risk of hospital admission for these neurodegenerative conditions.
Then, in experiments with mice, they confirmed that normal rodents exposed to these pollutants developed buildups of alpha-synuclein and ultimately suffered brain atrophy, neuronal death, and cognitive decline — all hallmarks of dementia. In contrast, when the same pollutants were given to genetically modified mice that did not produce alpha-synuclein, no significant brain changes were observed: no atrophy, no cognitive decline. “The pollution was still present, but without its key target protein, it could not cause this specific type of neurodegeneration,” the researcher adds.
The scientists’ hypothesis is that environmental toxins such as PM2.5 could trigger abnormal accumulations of alpha-synuclein capable of spreading damage throughout the brain.
They confirmed this in another experiment with mice genetically modified to produce the human version of the protein: after five months of exposure to pollutants, the authors detected alpha-synuclein buildups and cognitive decline. But these harmful deposits were different from those that develop as a result of aging: exposure to fine particles generated a different strain of alpha-synuclein.
A distinct, toxic, and highly aggressive strain
“We found that PM2.5 acts as a catalyst, causing the alpha-synuclein protein to misfold into a distinct, highly aggressive, toxic strain,” says Mao. “You can think of it this way: PM2.5 doesn’t just damage the brain directly, but it also corrupts a native protein, turning it into a super-spreader of pathology, 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 U.S., China, and Europe.”
Mao claims that the toxic strain of alpha-synuclein identified in the 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. According to Sánchez, the research provides “more evidence that pollution can influence dementia.”
However, he calls for caution when it comes to 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.
Major unknowns still to solve
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.”
The researchers also don’t know which specific components of PM 2.5 —the particles are made up of many different chemicals — are the most harmful. He recalls that his research focused on the relationship between pollution and hospital admissions for Lewy body dementia, but “more research is needed to confirm the role of pollution in the initial onset of the disease.”
Even so, Mao says, the discovery strengthens the evidence on pollution’s impact on health and opens new preventive and therapeutic scenarios. “Reducing air pollution is a crucial strategy for protecting brain health,” he says. “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 Hospital Clínic in Barcelona, also highlights the preventive implications of the study: “Anything you can do to eliminate this risk factor will be positive.” And although she acknowledges that it could also spur new therapeutic research, she notes that in this particular disease, drug development is “limited.” “Given how common it is, it seems that Lewy body dementia has been somewhat neglected,” she agrees.
Mao, for his part, acknowledges that the molecular pathway identified in his research to explain the association between pollution and dementia is only one among many. He explains: “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.”
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