The air in Mexico City was once so toxic that people watched as dead birds fell out of the sky. In 1992, the United Nations declared the city the most polluted in the world, with its unregulated diesel engines, factory production, fossil-fuel powered energy plants, and widespread use of internal-combustion engines, all trapped in a high-altitude, mountain-lined valley.
In 2002, toxicologist and neuropathologist Lilian Calderón-Garcidueñas, who grew up east of the metropolis and attended medical school in the city, decided to look at the brains of 40 dogs that had lived either in the city’s polluted valley or in the cleaner air of Tlaxcala, a state on its eastern edge. The results were striking: The rural dogs’ brains appeared healthy. In the brains of the city dogs, however, she saw the beginnings of neurodegeneration in puppies as young as eight months old.
The findings prompted Calderón-Garcidueñas, who has joint appointments at the University of Montana and Universidad del Valle de México in Mexico City, to begin looking at human brains. And over the last 20 years, she has grown convinced that children raised in areas like Mexico City, with air quality that rarely falls into the healthy range, are at noticeably increased risk for Alzheimer’s and other neurodegenerative conditions.
Scientists have known for decades that air pollution has effects far beyond blurred skylines and burning lungs. The fine particles and gases in polluted air have been connected to asthma, heart disease, inflammation, and a variety of other health impacts. But demonstrating that this pollutant soup can have neurodegenerative effects has proved trickier. Only recently has new research begun to paint a picture of air pollution as dangerous not only for the heart and lungs but potentially for the brain, as well.
In a 2018 study published in the journal Environmental Research, Calderón-Garcidueñas and her colleagues examined more than 200 brains of Mexico City residents who were between 11 months to 40 years old when they died. All but one of the brains they studied showed at least the beginnings of changes that scientists have previously found in the brains of people with Alzheimer’s disease. In comparison, the researchers described nine control brains that had been gathered from people who’d lived (and died) breathing clean air, as “unremarkable.”
The Mexico City studies, while intriguing, were far from definitive and limited by methodological issues, some researchers said.
“Nobody in the neuropathology world would consider this other than an indication,” said Caleb Finch, a biomedical gerontologist at the University of Southern California in Los Angeles, referring to the Mexico City studies. “It’s not something from which one can draw major conclusions.”
But he noted that further research by scientists at USC and around the world have strengthened the link between air pollution and neurodegenerative disease. Finch noted that there is now a series of papers showing that brain atrophy and cognitive disorders are directly related to how much air pollution someone has been exposed to. “Population-based studies have come into complete agreement on three continents — North America, Western Europe, and Asia — that air pollution above a certain level predicts a higher risk of dementia, particularly Alzheimer’s, and cognitive decline. That’s now proven by at least 10 major studies,” he said.
There are also a small-but-growing number of studies that suggest a connection between high levels of air pollution and Parkinson’s disease. But Ray Dorsey, a neurologist and Parkinson’s disease researcher at the University of Rochester Medical Center, noted that “almost all environmental risk factors associated with Parkinson’s have a long latency.”
“You don’t inhale pesticides or air pollution and get Parkinson’s the next day, just like you don’t smoke tobacco and get cancer the next day,” he said. “We know the disease takes decades to unfold.”
Pathways to the brain
The air we breathe is an ever-changing stew of tiny particles and noxious gasses, and it may be difficult to pin down the specific components of pollution that are involved in neurodegeneration. There is likely no single culprit. “Fifty years of work have identified 30 carcinogens in tobacco smoke — which one of them causes lung cancer? The whole package does,” said Finch, “and the chemistry of air pollution is even more complex.” The Environmental Protection Agency regulates six of the most concerning components: carbon monoxide, lead, nitrogen oxides, ozone, particulate matter, and sulfur oxides.
Researchers have placed special focus on the fine particulates known as PM2.5 — to indicate particles smaller than 2.5 microns, or 1/30th the width of a human hair — which have been shown to be especially dangerous. These particulates can be thrown up in the air by farms and factories, but the most common source of PM2.5 is the burning of fossil and bio fuels — in combustion engines, for example, or coal-fired power plants, or even from wildfires, which are becoming more frequent with climate change. Once suspended in air, the particles can be inhaled deeply into the lungs, which allows them to move into the bloodstream and beyond. These particles have been linked to inflammation, cancer, and severe cardiac and respiratory diseases, including asthma, heart attack, and stroke. The smaller the particles, the more malignant their effects.
Now work by Calderón-Garcidueñas and others has shown that these microscopic particles also enter the brain. Some probably travel through the bloodstream, but researchers believe a person’s nasal passages may provide an even more efficient route. In her research, Calderón-Garcidueñas focused specifically on the olfactory bulb when looking for early indications of neurodegenerative disease. “The nose is the front door of the brain,” Dorsey said. As someone breathes in polluted air, PM2.5 particles enter the nasal cavity and then travel directly into the brain’s olfactory bulb. That’s when neuronal cell death begins, he said.
Dorsey pointed to the fact that in both Alzheimer’s and Parkinson’s, loss of smell is an early warning sign, sometimes preceding other symptoms by 10 years or more. “Pathology of both diseases is found in the olfactory bulb and smell centers before it’s found in parts of the brain responsible for memory, and then movement,” he said.
Although the nose may be the most direct route, researchers are also uncovering a variety of other ways that air pollution can make its way to the brain. Michelle Block, an environmental neurotoxicologist at Indiana University School of Medicine in Indianapolis, has been drilling down on what she calls the lung-brain axis. By studying the inhalation of ozone, a gas that doesn’t cross the blood-brain barrier, she’s able to track other potential mechanisms for air pollution’s neurodegenerative effects.
“One of the reasons we use ozone is because it has been linked to increased risk for Alzheimer’s disease, but also because it will never ever, ever reach the brain,” Block said, making the gas a particularly good tool to investigate communication between the brain and the lungs. “It’s environmentally relevant, but it’s also mechanistically important,” she said.
Block has found that ozone inhaled into the lung triggers an immune reaction, and her lab has seen changes in populations of immune cells that communicate with the brain. She’s also homing in on the role of microglia — tiny cells in the brain that help maintain neural networks, repair injury, and eliminate dangerous brain debris like microbes, dead cells, and aggregated protein. In a healthier brain, microglia will gather around clusters of protein fragments, called plaques, and condense them; researchers believe this may limit their pathology.
“Our work showed that air pollution affects these microglia and they don’t associate with the plaques like they should,” Block said. “They don’t do their job at all, and it promotes a more pro-inflammatory environment.”
Connecting the dots
Neurodegenerative diseases become more common as people age, but assessing how much pollution someone has been exposed to is challenging. Most studies of Alzheimer’s disease have looked at environmental exposures perhaps 5 to 10 years prior to onset, said Beate Ritz, professor of epidemiology and environmental health sciences at the University of California, Los Angeles Fielding School of Public Health. In Parkinson’s, she said, relevant exposures could occur anywhere from 5 to 20 years prior to disease onset. Yet by the time someone is 60, they may have lived in 10 different homes in three different cities, and historical air-quality data can be difficult, if not impossible, to find.
Another issue has been accurately identifying patients who have Parkinson’s disease, especially since most countries don’t maintain disease registries and those databases that do exist may not use verified diagnoses. Other registries, such as the oft-used Medicare database, don’t have address histories reaching back as far as researchers require to get high-quality results.
Still, Ritz and her colleagues have managed to find at least a few countries with the quantity and quality of data they need. Denmark and Taiwan, both of which have national health systems and substantive air-pollution records, have given Ritz a trove of data to mine. In Taiwan, the researchers found a positive association between Parkinson’s risk and traffic-related air pollution (nitrogen oxide and carbon monoxide). In Denmark, the results were remarkably similar. A different research group, in South Korea, found an association between high nitrogen oxide levels and increased risk of Parkinson’s. A third group, in Canada, found that in a study of residents of Ontario, Parkinson’s was associated with high levels of air pollution, especially PM2.5.
Air pollution may also cause or exacerbate other neurodegenerative diseases. One that some neurodegenerative disease researchers think may belong in this group is amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease. The researchers note that there are tantalizing hints from both animal and epidemiological research, including a study in the Netherlands that linked long-term nitrogen oxide and PM2.5 exposures from traffic-related pollution to susceptibility to ALS. ALS, however, is a relatively rare disease and few countries maintain a disease registry for it, making data difficult to find, let alone parse.
‘Over a lifetime, it adds up’
For many neurological diseases, aligning pathology with clinical findings has sometimes been a “best guess” undertaking. The Mexico City children whose brains Calderón-Garcidueñas examined may have shown the beginnings of Alzheimer’s pathology — hyperphosphorylated tau, for instance, which has been linked to neurodegenerative disease — but they didn’t have dementia. And in older brains, post-mortem studies have shown that some people with dementia do not exhibit pathology that is as extensive as would be expected with their symptoms, while others with substantial Alzheimer’s pathology die after showing few or no symptoms at all. “We know that there’s multiple other processes going on with aging so that almost everybody over age 60 has some clear kind of pathology, even though they’re not demented,” Finch said, adding, “I’m 83, so I can speak on this with authority.”
One major defense against aging is resiliency — in the brain, this comes in the form of what scientists call cognitive reserve. Cognitive reserve refers to the brain’s ability to function, even thrive, as neurodegenerative disease progresses. And researchers believe that the best ways to improve cognitive reserve are through education, healthy lifestyles (both diet and exercise), breathing clean air, and drinking clean water.
“We’re harming populations in a way that we’re making them less resilient over their lifetime,” Ritz said.
She added, “We don’t have children who have Alzheimer’s or Parkinson’s disease,” but said she finds the presence of identifiable disease pathology in the Mexico City study deeply concerning. If an infant or toddler already shows the beginnings of hyperphosphorylated tau and other disease-linked pathology, those children will have less reserve capacity at an older age. “We’re dealing with a long-term issue,” Ritz said. “Over a lifetime, it adds up.”
If air pollution is a significant contributor to neurodegenerative disease, any solution is likely to be difficult from an economic and societal perspective. But as Dorsey sees it, the answer is straightforward. “Air pollution can be taken care of overnight, and we did the experiment,” he said. “Look at the pre- and post-pictures of New Delhi during Covid. This is tractable.”
This story is part of ongoing coverage of climate change and health, supported by a grant from The Commonwealth Fund.
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