When Lilian Calderón-Garcidueñas discovered abundant hallmarks of Alzheimer’s disease in a batch of human brain samples a few years ago, she initially wasn’t sure what to make of it. The University of Montana neuropathologist had been studying the brains as part of her research on environmental effects on neural development, and this particular set of samples came from autopsy examinations carried out on people who had died suddenly in Mexico City, where she used to work as a researcher and physician. Although Calderón-Garcidueñas had collected much of the tissue herself while attending the autopsies in Mexico, the light-microscope slides she was analyzing had been prepared by her colleagues, so she was in the dark about what patient each sample came from.
By the end of the project, she’d identified accumulations of the Alzheimer’s disease–associated proteins amyloid-ß and hyperphosphorylated tau in almost all of the 203 brains she studied. “When I started opening envelopes to see who [each sample] belonged to . . . I was devastated,” she says. The people whose brains she’d been studying were not only adults, but teens and even children. The youngest was 11 months old. “My first thought was, ‘What am I going to do with this? What am I going to tell people?’” she says. “I was not expecting such a devastating, extreme pathology.”
Despite her shock, Calderón-Garcidueñas had a reason to be on the lookout for signs of a disease usually associated with the elderly in these samples. For the last three decades, she’d been studying the health effects of Mexico City’s notoriously polluted air—a blight that earned the capital the dubious distinction of most polluted megacity on the planet from the United Nations in 1992. During that time, she’s discovered many links between exposure to air pollution and signs of neural damage in animals and humans. Although her findings are observational, and the pathology of proteins such as amyloid-ß is not fully understood, Calderón-Garcidueñas argues that air pollution is the most likely culprit behind the development of the abnormalities she saw in her postmortem samples—plus many other detrimental changes to the brains of Mexico City’s residents.
Once controversial, the theory that air pollution damages the brain is gaining traction in the research community. Although government officials in Mexico have worked to improve air quality since the 1990s, the last couple of years have seen thick smog descend over buildings, forcing periodic school and office closures to stop people from venturing into the toxic air. And it’s not just Mexico. As the rest of the world’s urban areas and their associated congestion continue to expand, most countries are witnessing increases in airborne contaminants, from noxious gases such as nitrogen oxides and ozone to fine particulate matter such as dust, soot, and nanospheres of metals that penetrate deep into the human body. One 2018 report by the Boston-based nonprofit Health Effects Institute warned that up to 95 percent of the people on Earth were breathing unsafe air.
These trends are matched by an increasing incidence of respiratory and cardiovascular problems—consequences of the inflammation and tissue damage provoked by multiple components of air pollution. At the World Health Organization’s inaugural conference on air pollution last fall, health officials gathered to discuss data showing that dirty air is implicated in more than 7 million deaths per year, with the organization’s directorgeneral, Tedros Adhanom Ghebreyesus, declaring the situation a “silent public health emergency.” Only in the last few years, however, have researchers begun raising the alarm about links between humans’ exposure to air pollution and brain function.
Epidemiologists, psychologists, and neuroscientists are now working to fill in the gaps in knowledge of how air pollution might contribute to these less visible effects on human health, both by documenting the cognitive changes occurring in human populations exposed to air pollution, and by looking inside human and animal brains to try to decipher the underlying mechanisms. “This is the beginnings of a whole new field,” says Caleb Finch, a gerontologist at the University of Southern California (USC). “This is like tobacco research and cancer 70 years ago.”
A link between air quality and cognition
Yale School of Public Health economist Xi Chen got interested in how poor air quality can affect the brain years ago as he started thinking about pollution’s cost to human society. To date, most researchers have focused on evaluating air pollution’s effects on mortality or respiratory health. But changes to cognition and social behavior also have profound influences on a person’s daily life, from financial decision making to relationships, Chen argues. “Society can lose even more with [this] more indirect link.”
A couple years ago, Chen teamed up with colleagues in Beijing to assess such effects in adults exposed to air pollution across China. The researchers used the China Family Panel Studies—a longitudinal dataset that includes verbal and math test scores from more than 20,000 adults across the country between 2010 and 2014—and estimated air pollution exposure for each participant’s town on the days of testing using national records of nitrogen dioxide, sulfur dioxide, and particulate matter levels. They also assembled data on other variables such as daily weather and the participants’ educational background.
Air is a collective good—everyone consumes it.—Xi Chen, Yale University
The analysis revealed that the higher a person’s estimated exposure to air pollution, the greater the decline in his test scores over the study period. Less educated men over 45 years old were the worst-affected group, and verbal scores were hit harder than math scores. The large sample size and the multiple time points suggest it’s more than just a correlation, says Chen. “We are more confident to say that our finding is a causal effect of air pollution on cognitive functioning.”
The paper is just one of the latest to draw a line between chronic exposure to air pollution and lowered cognitive abilities in adults—with several studies extending the link to neurodegenerative disease. In 2017, for example, researchers in Ontario reported that people living next to roads with heavy traffic were more likely to be diagnosed with dementia. Although the researchers didn’t include pollution in their analysis, they highlighted it as a likely contributor.
That same year, USC researchers reported that elderly women of European ancestry living in areas of the US with levels of particulate matter that exceeded the US Environmental Protection Agency standard of 12 μg/m3 were 81 percent more likely to experience cognitive decline generally and 92 percent more likely to suffer dementia than if they had been living with exposure below that limit. The increased risk in polluted areas—a finding that mirrors the results from cohorts in London and Taiwan—was particularly high for people with dementia- or Alzheimer’s-associated genetic variants such as APOE Ε4, hinting that air pollution might have more-severe effects in those genetically predisposed to neurodegeneration.
Other researchers are amassing evidence of cognitive and psychiatric dysfunction in pollution-exposed younger people, whose developing brains may be particularly vulnerable. In 2016, researchers found that Swedish children and adolescents were more likely to have been prescribed psychiatric medicine if they lived in areas with high nitrogen dioxide concentrations, and research published a few months ago linked lifetime exposure to air pollution with depression and anxiety in 12-year-olds living in Ohio.
In a recent large-scale project, research psychologist Helen Fisher of King’s College London and colleagues analyzed data, collected through the UK’s Environmental-Risk Longitudinal Twin Study, on more than 2,000 children born in England and Wales in 1994 and 1995. According to results published earlier this year, nearly a third of the participants had experienced at least one psychotic episode between the ages of 12 and 18 years, and the experiences were most common among teenagers who had grown up with the highest exposure to nitrogen oxides and particulate matter.
“You’re getting . . . greater odds of having those experiences among adolescents who lived in the areas with the highest levels” of pollution, says Fisher. That’s not as high as the associations seen with, for example, childhood abuse, which is more strongly linked to psychotic experiences, she says, “but it’s a lot higher than you might think.”
Some labs have linked air pollution and brain development even earlier in life—right back to the womb. One 2014 study of 250 children born to nonsmoking African American and Dominican women in New York City found that greater prenatal exposure to polycyclic aromatic hydrocarbons (PAH), which are produced by burning fossil fuels, correlated with a higher prevalence of behavioral and cognitive abnormalities, including symptoms associated with attention-deficit/hyperactivity disorder (ADHD).
Environmental epidemiologist Jordi Sunyer of the Barcelona Institute for Global Health (ISGlobal) recently collaborated on a project that aimed to replicate the ADHD-pollution link. The study, which included data from nearly 30,000 mother-child pairs across eight separate cohorts in Europe, failed to find a pattern of ADHD incidence across regions of varying air qualities. But Sunyer’s team has found other cognitive problems in children who were exposed to air pollution during gestation and after birth. The group recently reported findings from a study of more than 2,200 children that found lower working memory scores in boys who had been exposed to greater particulate matter levels from the womb until age seven.
Of course, observational studies can’t definitively demonstrate that air pollution causes cognitive changes in humans, not least because it’s impossible to fully disentangle factors that closely correlate with air pollution, such as noise. “A lot of the associations we’re seeing are with traffic-related pollutants, particularly in cities,” Fisher says. In some cases, “it’s possible that it’s the noise of the traffic, not the actual air pollution it produces, that’s problematic.”
Several labs are trying to minimize such limitations by collecting real-time pollution levels and other environmental data, rather than estimating exposure from existing datasets. ISGlobal, for example, plans to recruit 1,200 pregnant women for an in-depth look at the connections between prenatal exposure to air pollution and childhood health. Participants will monitor their surroundings with “backpacks, sensors at home, GPS, measures of physical activity, measures of noise,” and so on, Sunyer says.
To provide a stronger assessment of air pollution’s harmful effects, researchers are also taking a more interdisciplinary approach, using magnetic resonance imaging (MRI) to look inside the brain for neurological features that can complement assessments of cognitive function. In addition, they have begun to pair epidemiological data with experimental studies in the lab to learn about the biological pathways that may underlie links between air pollution and cognition. “We have to combine studies in animals with in vitro studies in cells, with epidemiological data in humans,” says Sunyer, who recently reviewed the research in this space. “It’s the combination that has to fit.”
Ports of Entry to the Brain
Air pollution refers to a wide range of gases, liquids, and solids suspended in the atmosphere. Known to have harmful effects on the respiratory and cardiovascular systems, these contaminants are now implicated in damage to the brain—an organ exposed to the air via multiple pathways.
Mechanisms linking air pollution to brain function
By the early 2000s, Calderón-Garcidueñas had come up with a way to test her theories about air pollution’s effects on the brain. Dogs in Mexico City would be exposed to the same air as people, she reasoned, so in 2003, using brains from 40 euthanized mongrels—26 from Mexico City and 14 from the less polluted city of Tlaxcala to act as controls—Calderón-Garcidueñas and colleagues documented neuropathological differences between the animals. In particular, the team identified signs of elevated inflammation, DNA damage, degradation of the blood-brain barrier, and Alzheimer’s-type pathology in the Mexico City canines. She’s since replicated the findings using postmortem human brains and additional dogs.
Calderón-Garcidueñas’s projects were seminal examples of what is now a rapidly expanding effort to come up with mechanistic explanations linking chronic air pollution exposure with cognitive changes in humans. Such work is pointing to a key role for the related processes of neuroinflammation and oxidative stress—an overproduction of reactive oxygen species that can cause cellular damage—in response to contaminants reaching the brain via the nose or lungs. (See illustration above.) Research by Finch’s group, for example, found that cultures of rodent glial cells responded to air pollution sampled from a local freeway by activating toll-like receptor 4, a transmembrane protein involved in inflammatory signaling. And mice that inhaled the polluted air for 10 weeks showed activation of those same inflammatory pathways in the hippocampus, a brain region known for its roles in learning and memory.
In subsequent work, Finch’s group found that mouse cell lines expressing a mutated version of the gene coding for amyloid precursor protein, a peptide implicated in Alzheimer’s disease, produced greater levels of biomarkers for oxidative stress with increasing exposure to nanosize particulate matter. And last year, a team in China reported that fine particulate matter triggered oxidative stress in living rats’ neurons and led to the degradation of the myelin sheath surrounding cells’ axons. Exposed rats showed deficits in learning and memory as well as impaired sensory functions compared with controls.
This year, the US government floated plans that would reduce monitoring of air pollution and its health effects.
How such findings might translate into humans chronically exposed to air pollution is less clear, though some MRI data are consistent with the idea that dirty air promotes tissue degradation. One USC study of more than 1,400 women across the US, for example, found that a person’s estimated exposure to particulate matter was inversely correlated with her total volume of white matter—the part of the brain made up of myelin-covered nerve fibers—a decrease in which is associated with dementia. MRI studies by Calderón-Garcidueñas have also found white-matter reductions among children in Mexico City compared to matched controls living in less polluted areas.
A study carried out a couple of years ago by researchers at ISGlobal compared different regions of the brain and found that some areas might be particularly susceptible. The team reported that schoolchildren exposed to high PAH levels showed particularly stunted growth in the caudate nucleus, a region deep within the brain that is linked to behavioral disorders such as ADHD. This region already generates relatively high levels of reactive oxygen species, explains study coauthor Marion Mortamais, now at INSERM in France. “The hypothesis is that . . . the local mechanism to fight the oxidative stress is completely overwhelmed by another intrusion of oxidative stress provoked by the exposure to PAH.”
Meanwhile, Calderón-Garcidueñas has suggested that certain components of air pollution could play a direct role in Alzheimer’s pathology. In 2016, University of Texas at San Antonio researchers reported that amyloid?ß plaques in human brains contained particles of magnetite, which, thanks to their iron content and magnetic properties, can promote the production of reactive oxygen species and contribute to neurodegeneration. The study was agnostic as to the origin of these particles; they can be produced through iron metabolism in brain tissue. But when Calderón-Garcidueñas and colleagues took a closer look at magnetite identified in post-mortem brains from people in Mexico City and in Manchester, UK, they found that the particles’ crystal structures showed signatures of having been generated at high temperatures—just like magnetite particles found in traffic-related air pollution.
As researchers grapple with these issues, findings from other disciplines hint that the big picture may be even more complicated. It appears likely, for example, that air pollution can influence the brain via indirect mechanisms. Last year, a team in the Netherlands found that people exposed to air pollution for just two hours had a greater abundance of several circulating microRNAs, some of which may help drive pollution-related disease. And several studies now indicate that commensal bacteria living in the gut might influence neurodegeneration, possibly via inflammation of the gut lining. Recent research in mice shows that inhalation of particulate matter alters the microbiome’s composition within weeks.
Evidence of harm
Many of the studies on the effects of chronic exposure to air pollution are observational, making researchers wary of saying air pollution causes reduced cognitive function. Nevertheless, evidence from in vivo studies in humans and nonhuman animals, combined with in vitro research and analyses of postmortem brains, is beginning to lend support to the idea.
As researchers continue to probe the effects of air pollution, several groups are investigating whether the apparent damage can be mitigated. For example, urban green spaces are recognized by the World Health Organization (WHO) as contributors to mental health, partly because they may improve air quality. A study published this May found that silver birch, elder, and yew trees were particularly effective at soaking up fine particulate matter in a lab setting, and research by ISGlobal suggests that green spaces within and around schools could help boost cognitive development in children and enhance attention, although the mechanisms behind these effects aren’t entirely clear.
Meaningful change, however, will require more than upping air quality for a particular school or region, Chen says. It’s long-term exposure that’s associated with harm, so the solution needs to be a global reduction in air pollution, he argues—a challenge, “because we all know that air pollution has no physical boundary.” He suggests that mitigating pollution requires the same sort of mentality as tackling climate change, with international agreements that set global targets for outdoor air quality, much as they have for carbon dioxide emissions, he says. “[Air] is a collective good—everyone consumes it.”
Fortunately, the more-established literature on respiratory and cardiovascular effects of air pollution has already provided momentum to move toward such international efforts. The WHO’s air pollution conference last year resulted in the Geneva Action Agenda to Combat Air Pollution, which lays out priorities ranging from better air-quality monitoring to the provision of support for cities trying to reduce urban pollution. But countries’ adherence to such goals is voluntary and difficult to guarantee. Just this year, the US government floated plans that would reduce monitoring of air pollution and its health effects and downgrade estimates of the harm it causes. Mexico, meanwhile, has been struggling with allegations of corruption as government measures to reduce emissions are reportedly undermined by local officials and car inspection centers.
“I’m not going to give up,” Calderón-Garcidueñas says. “It’s a difficult subject, but it’s very interesting. I tell my husband that it’s probably going to be another twenty years to acknowledge what we’re doing right now.”
Clarification (October 15): The article has been updated to include the full name of Xi Chen’s home institution.
Catherine Offord is an associate editor at The Scientist. Email her at email@example.com.