As the amount of particulate matter increases, so do the cases of dementia in a region. Recent studies show how the particles can travel from the lungs and nose to the brain and cause damage there.

My first day in Mexico City was tough. The smog was so thick that I was gasping for air as I climbed the stairs. I had expected a headache; the city is located on a plateau 2250 meters above sea level, and the oxygen content of the air is correspondingly lower than on the coast. However, I was surprised at how much the polluted air burned my eyes and lungs.

In 1992, the United Nations declared Mexico City to be the most polluted metropolis in the world. Since then, its administration has done a lot to improve the situation. With some successes: The city is rightly proud of its miles of cycle paths and lush parks. However, a glance at the blurred horizon reveals that the efforts are still not enough. On most days, the air contains far more soot particles than the limits recommended by the World Health Organization. There are also increased levels of other pollutants. More than 9.6 million vehicles and an estimated 50,000 factory chimneys blow their exhaust fumes into the city. These envelop the metropolis in a toxic brew that damages lungs and hearts. Many scientists now agree that the pollution even affects the nervous system.

A study published in 2018 found destruction characteristic of Alzheimer's in the brains of residents of the city. The test subjects were all under the age of 40. Normally, the first signs of the disease only appear at a much older age. Mexico City is no exception here: A few years ago, a team at Harvard University published its analysis of data on ten million US Medicare recipients over 65 who lived in 50 different cities in the north-east of the USA. The scientists had discovered a strong correlation between certain air pollutants and the incidence of several neurodegenerative diseases, including Alzheimer's disease..Further studies provided similar results. "The impact of air pollution is becoming one of the hottest areas in Alzheimer's research," explains George Perry, a neurobiologist at the University of Texas at San Antonio and editor-in-chief of the Journal of Alzheimer's Disease. Many experts have recognized that air pollution can contribute to the development of the disease, says Perry. Toxicologist Masashi Kitazawa from the University of California in Irvine confirms this assessment. "In Alzheimer's research, the effect of genes plays a big role, and for a long time almost nobody wanted to look beyond that," he says. "In the last three or four years, however, the number of papers linking air pollution and cognitive decline has exploded." In the most common form of Alzheimer's disease, which begins late in life, lifestyle and harmful environmental influences could account for 40 to 65 percent of the risk of developing the disease. Air pollution is one of the main factors.

Brain contaminated with particulate matter

Data on suspended droplets filled with toxins or solid particles with a diameter of around one-thirtieth of a human hair is particularly worrying. This particulate matter (also known as PM2_.5 due to its specific size) is typically produced by burning oil, gas, coal and wood. It is mainly emitted by cars, trucks and power stations. With every breath, the particles enter deep into the lungs and from there into the blood. In this way, PM2_.5 has devastating effects on the human respiratory and cardiovascular systems. Cancer, heart attacks, strokes and premature deaths increase with pollution levels.

"The impact of air pollution is emerging as one of the hottest areas in Alzheimer's research" George Perry

It used to be thought that the brain was protected from such an attack. After all, it has the blood-brain barrier, a layer of tightly packed cells that lines blood vessels in the brain. The barrier prevents toxic substances from seeping from the blood into the brain tissue. Unfortunately, there is convincing evidence that PM2_.5 can nonetheless enter the brain in two ways: First, the particles can alter the blood-brain barrier to make it more permeable to pollutants. Secondly, they can bypass the barrier completely by penetrating the olfactory nerve via the nose and traveling from there to the olfactory bulb. The brain, it turns out, is no better protected from the relentless onslaught of air pollution than other organs.

Early signs of Alzheimer's even in babies and toddlers

Much of the recent work linking poor air quality and brain disease builds on the research of Lilian Calderón-Garcidueñas. The neuropathologist from the University of Montana was born not far from Mexico City and grew up near the metropolis. She has been studying the health effects of pollution in the region for decades. In the early 2000s, she dissected 32 dogs that had lived in the southwest of Mexico City. She found signs of degenerative processes in their brains.

This discovery prompted her to examine people who had lived in similar neighborhoods. What she saw - deposits like those found in Alzheimer's patients in the brains of babies and young children - alarmed her. Exposure to air pollution, she wrote in 2008, should be considered a risk factor for Alzheimer's disease. This applies in particular to people who are more susceptible to the disease due to their genetic make-up.

More recent studies support Calderón-Garcidueñas' conclusions. Jennifer Weuve, associate professor at the Boston University School of Public Health, led one of the first US-wide studies on the link between air pollution and neurological diseases. She and her team published the results in 2012. "We had two indications of the link between the aging brain and air pollution," she explains. The first was the effect on the cardiovascular system: an increasing number of heart attacks and strokes. "The brain is dependent on functioning blood circulation. So of course that gave rise to concern that the brain could also be affected."

The second clue was more subtle. Toxicologists conducted several well-controlled studies on animals exposed to air with high levels of airborne particulate matter. Particles did indeed enter the brain. "Some of these particles contained known neurotoxins such as manganese. We knew this couldn't be good," says Weuve.

Data from other epidemiological studies now confirm that particulate matter is a risk factor. For a study published in 2018, researchers monitored the health of around 131,000 Londoners aged between 50 and 79 over eight years. They counted the most cases of dementia among those who were exposed to the worst air pollution. The link between Alzheimer's and PM2_{.5 particles} was particularly strong. A study of almost 100,000 people in Taiwan came to similar conclusions. Scientists at the University of Toronto analyzed data from 6.6 million people in the Canadian province of Ontario. People who lived within 50 meters of a major road had a 12 percent higher risk of dementia than those who lived more than 200 meters away.

All coincidence?

Such studies have their limitations. They do show when two factors - in this case air pollution and Alzheimer's disease - increasingly occur together. But they cannot prove whether and how they are connected. This requires studies in which organisms are specifically exposed to a suspected risk factor. However, it would be unethical to ask people to knowingly expose themselves to polluted air for months or years. But only with data from such controlled experiments can researchers determine whether air pollution makes the inhabitants of a region more susceptible to Alzheimer's or whether other factors underlie the increased cases of the disease.

"In a perfect world, everyone would wear an air pollution monitor so that we could get real-time data on their exposure to pollutants" Jennifer Weuve

"In a perfect world, everyone would wear an air pollution monitor so that we could get real-time data on their pollution levels," says Weuve. "But we don't live in a perfect world." That's why her team works with experts who create models to estimate pollution levels in a region. However, this is not enough: With Alzheimer's, it's the chronic, long-term exposure that counts. "We don't even have a global registry of Alzheimer's patients, let alone enough resources to monitor people for many years before they develop the disease." In some regions of the world, air pollution is so bad that people die of heart disease before they can ever show symptoms of late-onset Alzheimer's.

Scientists are using animal models to investigate the connection in more detail. With their help, they are also tracing biological mechanisms that could cause cognitive decline. In 2015, a team led by neurobiologist Colin Combs from the University of North Dakota pumped polluted air into cages with genetically identical mice. The researchers varied the concentration of pollutants and the duration of the treatment. The higher the exposure, the more damage they observed in the animals. "Our data support the theory that long-term exposure to airborne particulate matter alters the brain and promotes the development of early Alzheimer's-like pathology," explains Combs. In 2018, scientists at the Cedars-Sinai Medical Center in Los Angeles reported that heavy metals from polluted air penetrate the brains of rats after just a few months. The substances apparently activate genes there that promote neurodegenerative processes and cancer.

Environmental pollution damages blood vessels and thus increases the risk of Alzheimer's and other forms of dementia. The DNA of many people with late-onset Alzheimer's disease contains gene variants that make them more susceptible to the disease. Air pollution could interact with some of them and thus promote the development of the disease, explains clinical psychologist Margaret Gatz from the University of Southern California. The brains of those affected would then age faster and more of their neurons would die. "There is evidence that vascular risk factors are more dangerous for people with the _APOE4 gene variant," she explains. "However, many studies have focused on the genetic risk of the disease and virtually ignored the lifestyle and environmental component.

"What toxic substances from particulate matter do to the brain fits in well with ideas about how Alzheimer's-related damage develops. As neurotoxicologist Deborah Cory-Slechta of the University of Rochester Medical Center explains, in both animals and humans, the substances stimulate immune cells in the brain, known as microglia, to release cytokines. These signaling molecules help to control immune defense and inflammation. Under normal circumstances, this protects our brain against external invaders.

Prolonged exposure to polluted air can lead to an overproduction of pro-inflammatory cytokines and thus to chronic inflammation, resulting in the death of nerve cells. "Ultrafine particulate matter appears to be the most important factor in this process," notes Cory-Slechta.

However, it is difficult to determine which components of the particles cause the problems. "For one thing, we have very little historical data on this," explains the researcher. This makes it difficult to assess the relative concentration of pollutants in the environment. Secondly, they contain many components that can hardly be tested separately. Particulate matter in exhaust gases comprises hundreds of substances, from toxic substances such as sulphur dioxide and nitrogen oxides to respirable particles from the abrasion of brakes, tires and clutches of motor vehicles.

According to Cory-Slechta, air pollutants tend to accumulate in the brain over many years. What exactly gets there via the lungs is not yet fully understood. It is also questionable when the substances start to cause problems. "Iron, zinc, copper and other metals are needed by the brain, but only in certain quantities," she explains. "Too much iron triggers oxidative stress, which can lead to neurodegeneration. Some pollutants, such as aluminum, do not play a significant role in the brain, but tend to accumulate there and cause an inflammatory response." Not only metals are problematic. Organic pollutants could also be involved in neurodegenerative diseases, according to the neurotoxicologist.

From the sewage treatment plant to the nervous system

These include lipopolysaccharides, for example. They originally come from bacteria. They are distributed in the ambient air from waste treatment plants and other sources. They can attach themselves to tiny particles and cause an inflammatory reaction in the lungs when inhaled. In animal experiments, scientists have shown that lipopolysaccharides and other organic substances can sometimes enter the brain and trigger inflammation and subsequent neurodegeneration.

Jiu-Chiuan Chen, a physician and epidemiologist at the University of Southern California, specializes in the study of air pollutants in the brain. Although it is still debatable how the individual components work, the mixture clearly contributes to brain damage and cognitive problems, he explains. Chen was co-author of a study published in 2019 that described a link between particulate matter pollution, structural changes in the brain and memory loss in older women. He and his colleagues analyzed data from imaging techniques and cognitive tests using a mathematical model that included values from two different sources about the air quality in the living environment of the test subjects.

Weakening long-term memory

"We found that episodic memory deteriorated earlier in women with the highest exposure to pollutants," he explains. This type of long-term memory allows people to recall a past experience - including where and when it happened and what emotions the moment triggered. The losses that Chen observed in the women appeared even before the symptoms of Alzheimer's disease. Moreover, the effects were not dependent on the condition of the test subjects' cardiovascular system. People with weakening episodic memory have been shown to have a greatly increased risk of developing Alzheimer's disease.

"There are more than ten studies linking high exposure to pollutants in later life and dementia," says Chen. "The evidence is pretty convincing." Whether exposure at a young age is also a factor, on the other hand, is less clear. "Toxicologists are already conducting experiments on young animals and they are seeing pathological changes. It seems that small particles can accelerate the process of plaque formation. But we are not yet sure whether this also happens in humans." He adds that there could be a genetic component - some may be more susceptible to the effects of pollution than others. There may be a subgroup of people who are at very high risk. "Our current studies are not yet comprehensive enough to answer this question."

Some also see something good in the findings so far: they offer an opportunity to take measures to reduce the risk of many people falling ill. Epidemiologist Melinda Power from George Washington University studies modifiable risk factors for cognitive decline and dementia. "Right now, it looks like prevention by changing environmental and lifestyle factors is our best bet," she says, "and exposure to air pollution seems to be particularly important."

Epidemiologist Kelly Bakulski of the University of Michigan adds that the data make a strong case for stricter controls on air quality. "Unlike our genes, we can influence environmental factors. Removing pollutants from our environment will not have harmful effects, but many positive ones," she explains.

Lifestyle changes also help to reduce the risk of disease. "Physical activity has been shown to reduce the risk of Alzheimer's," explains Margaret Gatz. Exercise works by improving blood flow to the brain. It also increases the production of a protein called BDNF, which promotes the growth and maintenance of brain cells. We know the devastation that the disease causes. It is therefore time to take such preventive measures. "We have the means to do so," says Bakulski, "and given the risk, we need to use them."

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