The New Alzheimer’s–Air Pollution Link

Toxic airborne particles can travel from lungs and nose to the brain, and exposure is linked to memory loss.

My first day in Mexico City was tough. The smog was so thick that I gasped for breath while climbing the stairs to my hotel room. I had braced for headaches from the high altitude and thin air, but I was not prepared for how dirty that air was or for the bloodshot eyes and burning lungs.

Declared the world's most polluted metropolis by the United Nations in 1992, greater Mexico City has worked hard to clean up its act. To some degree it has: the city is rightfully proud of its miles of bike paths and lush parks. Yet a casual glance at the smudged horizon shows that those efforts are not enough. Most days the area has levels of airborne sooty particles that greatly exceed standards set by the World Health Organization, as well as elevated amounts of other pollutants. Clogged with more than 9.6 million vehicles and an estimated 50,000 smokestacks, Mexico City stews in a toxic brew known to corrode human lungs and hearts. Now many scientists agree that this pollution also damages the brain.

In 2018 a study found lesions known to be hallmarks of Alzheimer's disease in the brains of Mexico City residents in their 30s and 40s—decades before signs of the disease normally can be detected—and tied this damage to exposure to the city's bad air. The researchers who did that work, who are from institutions in Mexico and the U.S., have also found early forms of this frightening damage in infants and young children. And Mexico City is not the only place where bad air has been linked to Alzheimer's. Just a few years ago a team of Harvard scientists released data from a large study of 10 million Medicare recipients ages 65 and older living in 50 different cities in the northeastern U.S. The researchers reported a strong correlation between exposure to specific air pollutants and a number of neurodegenerative disorders, including Alzheimer's.
Other studies in England, Taiwan and Sweden—among other countries—have turned up similar results. “Air pollution is emerging as one of the hottest areas in Alzheimer's research,” says George Perry, a neurobiologist at the University of Texas at San Antonio and editor in chief of the Journal of Alzheimer's Disease. In a field where scientists have spent decades focused on genetics and the buildup of damaged protein fragments called beta-amyloid as causes of the disease, Perry says, now many experts agree that air pollution plays a major role. This assessment is echoed by Masashi Kitazawa, a toxicologist at the University of California, Irvine, and an expert on environmental toxins. “Genetics is huge in Alzheimer's research, and for years almost no one wanted to look beyond genes,” he says. “But in the past three or four years the number of papers linking air pollution and cognitive decline has exploded.” For the most common form of Alzheimer's, known as late-onset disease, researchers now estimate that at least 40 and as much as 65 percent of the risk involves nongenetic influences such as lifestyle and harmful environmental exposure. Air pollution is one of the leading factors.
Much of this concern centers on airborne toxin-packed droplets or solid bits that are about one 30th the diameter of a human hair. Known as fine particulate matter (called PM 2.5 for its specific size), it typically comes from burning oil and gas in cars and trucks and power plants, as well as from burning coal or wood. These particles are inhaled deep into the lungs and can pass quickly into the bloodstream. Scientists have demonstrated that when PM 2.5 enters the body this way, it wreaks havoc on human respiratory and cardiovascular systems, leading to cancer, heart attacks, strokes and early deaths.

Scientists once thought that the brain was protected from similar carnage by the blood-brain barrier, a network of closely packed cells lining blood vessels of the brain that prevents toxic substances from passing from the blood into brain tissue. Unfortunately, there is now compelling evidence that PM 2.5 can and does enter the brain via two pathways. First, the particles can alter the blood-brain barrier itself to make it more permeable to pollutants. Second, the particles can bypass the barrier altogether by slipping from the nose into the olfactory nerves and then traveling to a part of the brain called the olfactory bulb. The brain, it turns out, is no more protected from the relentless assault of air pollution than is any other organ.
HIGH EXPOSURE
Much of the recent work linking poor air quality and brain disease has its roots in the early research of Lilian Caldern-Garcidueas, a physician and neuropathologist at the University of Montana. Born and raised in a town not far from Mexico City, Caldern-Garcidueas has studied the health impacts of the region's foul air for decades. In the early 2000s she examined 40 dogs roaming the most polluted parts of Mexico City and found Alzheimer's-like pathology in their brains. This discovery prompted her to look at the brains of humans who had lived in similar neighborhoods. What she saw—Alzheimer's-associated proteins in the brains of children and infants as young as 11 months—alarmed her. “Exposure to air pollution,” she wrote in 2008, “should be considered a risk factor” for Alzheimer's, in particular for those who are genetically predisposed to the disease.

Caldern-Garcidueas's conclusions have been substantiated by other scientists. Jennifer Weuve, associate professor at the Boston University School of Public Health, led one of the first U.S.-wide investigations into the link between air pollution and brain disease and published the results in 2012. “We had two hints on the relationship between the aging brain and air pollution,” she says. “The first was the impact of air pollution on the cardiovascular system—heart attacks and strokes. The brain relies on blood circulation, so naturally this raised concern that the brain, too, was being affected. The second hint was subtler. Toxicologists did some well-controlled studies of animals exposed to air with high levels of suspended particles and found that these particles got into the brain. Some of those particles contained known neurotoxins, like manganese. And we knew that couldn't be good.” 
More epidemiological evidence of an airborne-particle problem has since piled up. In 2018 the BMJ published a study of some 131,000 London residents aged 50 to 79 and concluded that those with the most exposure to air pollution were the most likely to be diagnosed with dementia over the eight years they were observed. The link was particularly strong between Alzheimer's and PM 2.5 particles. A study of nearly 100,000 residents of Taiwan found similar results. Researchers in Sweden concluded that air pollution increased dementia incidence even among people with no genetic markers for the disease. And scientists at the University of Toronto looked at 6.6 million people in the Canadian province of Ontario and found that those who lived within 50 meters of a major road, where levels of fine pollutants are very high, were 12 percent more likely to develop dementia than individuals living more than 200 meters from those same roads.

FROM AIR TO BRAIN
Of course, epidemiological studies have limits. It is unethical to ask humans to knowingly expose themselves to polluted air over a period of months or years. This restriction makes it difficult to carry out controlled studies that eliminate many factors other than air pollution that might predispose residents of some regions to Alzheimer's and other forms of dementia.

“In a perfect world, everyone would wear an air-pollution monitor so that we could get real-time data on their exposures,” Weuve says. “But this is not a perfect world. So we work with experts to build estimation models. It's not enough. In the case of Alzheimer's, it's chronic, long-term exposure that counts, and we don't even have a worldwide registry of people with Alzheimer's, let alone the resources to follow people for many years prior to their acquiring the disease. So it is quite difficult to nail down causation.” Indeed, in some regions of the world, air pollution is so bad that people die of heart disease long before they would ever show symptoms of late-onset Alzheimer's.
To get a better handle on cause and effect, scientists have turned to animal models to search for biological mechanisms that may underlie a link between cognitive decline and various types and amounts of air pollution. In 2015 neurobiologist Colin Combs, chair of the department of biomedical sciences at the University of North Dakota School of Medicine and Health Sciences and an expert on neurodegenerative disease, pumped air containing different levels of particulate pollution into cages with genetically identical mice for different time periods. More exposure, he learned, produced more damage. “What we found supports the theory that long-term exposure to airborne particulate matter has the potential to alter the brain and promote the development of early Alzheimer's-like pathology,” he says. In 2018 scientists at Cedars-Sinai Medical Center in Los Angeles and their colleagues reported that heavy metals from polluted air not only found their way into the brains of rats after just a few months but also appeared to activate genes that trigger neurodegenerative disorders and cancer.