Part 2 of 2. (Photo: Indian schoolgirls walk to school after days off due to heavy smog in Amritsar. Credit: Narinder Nanu/AFP via Getty Images)
continuing from a previous article...
Parkinson’s disease is already the second-most common neurodegenerative disease after Alzheimer’s. Symptoms, which can include uncontrolled movements, difficulty with balance, and memory problems, generally develop in people age 60 and older, but they can occur, though rarely, in people as young as 20. Could something in the air explain the increasing worldwide prevalence of Parkinson’s? Researchers have not identified one specific cause, but they know Parkinson’s symptoms result from degeneration of nerve cells in the substantia nigra, the part of the brain that produces dopamine and other signal-transmitting chemicals necessary for movement and coordination.
A host of air pollution suspects are now thought to play a role in the loss of dopamine-producing cells, according to Emory University environmental health scientist W. Michael Caudle, who uses mass spectrometry to identify chemicals in our bodies. One suspect he’s looking at are lipopolysaccharides, compounds often found in air pollution and bacterial toxins. Although lipopolysaccharides cannot directly enter the brain, they inflame the liver. The liver then releases inflammatory molecules into the bloodstream, which interact with blood vessels in the blood-barrier. “Then the inflammatory response in the brain leads to loss of dopamine neurons, like that seen in Parkinson’s disease,” Caudle says.
More evidence comes from neuroepidemiologist Brittany Krzyzanowski, based at the Barrow Neurological Institute in Phoenix. Krzyzanowski had an “aha!” moment when she saw a map highlighting the high risk of Parkinson’s disease in the Mississippi–Ohio River Valley, including areas of Tennessee and Kentucky. At first she wondered whether the Parkinson’s hotspot was due to pesticide use in the region. But then it hit her: The area also had a network of high-density roads, suggesting that air pollution could be involved. “The pollution in these areas may contain more combustion particles from traffic and heavy metals from manufacturing, which have been linked to cell death in the part of the brain involved in Parkinson’s disease,” she said.
In a study published in Neurology in October 2023, Krzyzanowski and colleagues, using sophisticated geospatial analytic techniques, went on to show that those with median levels of air pollution have a 56 percent greater risk of developing Parkinson’s disease compared to those living in regions with the lowest level of air pollution. Along with the Mississippi-Ohio River Valley, other hotspots included central North Dakota, parts of Texas, Kansas, eastern Michigan, and the tip of Florida. People living in the western half of the U.S. are at a reduced risk of developing Parkinson’s disease compared with the rest of the nation.
As to the hotspot in the Mississippi-Ohio River Valley, Parkinson’s there is 25% higher than in areas with the lowest air particulate matter. Aside from that, Krzyzanowski and her research team noted something especially odd: Frequency of the disease rose with the level of pollution, but then it plateaued even as air pollution continued to soar. One reason could be that other air pollution-linked diseases, including Alzheimer’s, are masking the emergence of Parkinson’s; another reason could be an unusual form of PM2.5. “Regional differences in Parkinson’s disease might reflect regional differences in the composition of the particulate matter, and some areas may have particulate matter containing more toxic components compared to other areas,” Krzyzanowsk says. Tapping the tenets of exposomics, she expects to explore these issues in the months and years ahead.
The hunt is on for the connections between environmental factors and Alzheimer’s as well. USC neurogerontologist Caleb Finch has spent years studying dementia, especially Alzheimer’s disease, which affects more than six million Americans. As with Parkinson’s, Alzheimer’s numbers are rising in the United State and much of the world. Degenerative changes in neurons become increasingly frequent after the age of 60, yet half of the people who make it to 100 will not get dementia. Many factors could explain those discrepancies. Air pollution may be an important one, Finch says.
Researchers like Finch and his USC colleague Jiu-Chiuan Chen are joining forces to explore the connections between environmental neurotoxins and decline in brain health. It’s a challenging project, since air pollution levels and specific pollutants vary on fine scales and can change from hour to hour in many areas of the globe. On the basis of brain scans of hundreds of people over a range of geographic areas, this much we know: “People living in areas of high levels of air pollution and who have been studied on three continents showed accelerated arterial disease, heart attacks, and strokes, and faster cognitive decline,” Finch says.
Not everyone reacts the same way when exposed to pollutants, of course. Greatest risk for Alzheimer’s seems to hit people who have a genetic variant known as apolipoprotein E (APOE4), which is involved in making proteins that help carry cholesterol and other types of fat in the bloodstream. About 25 percent of people have one copy of that gene, and 2 to 3 percent carry two copies. But inheriting the gene alone doesn’t determine a person’s Alzheimer’s risk. Environmental exposures count too.
A recent study by Chen, Finch, and colleagues published in the Journal of Alzheimer’s Disease looked at associations between air pollution exposure and early signs of Alzheimer’s in 1,100 men, all around age 56 when the study began. By age 68, test subjects with high PM2.5 exposures had the worst scores in verbal fluency. People exposed to high levels of nitrogen dioxide (NO2) air pollution were also linked to worsened episodic memory. The men who had APOE4 genes had the worst scores in executive function. The evidence indicates that the process by which air pollution interacts with genetic risk to cause Alzheimer’s in later life may begin in the middle years, at least for men.
A separate USC study of more than 2,000 women found that when air quality improved, cognitive decline in older women slowed. When exposure to pollutants like PM2.5 and NO2 dropped by a few micrograms per cubic foot a year over the course of six years, the women in the study tested as being a year or so younger than their real age. This suggests that when exposure air pollution is lowered, dementia risk can go down.
In parallel, an international study by the Lancet Commission concluded that the risk of dementia, including Alzheimer’s, can be lowered by modifying or avoiding 12 risk factors: hypertension, hearing impairment, smoking, obesity, depression, low social contact, low level of education, physical inactivity, diabetes, excessive alcohol consumption, traumatic brain injury—and air pollution. Together, the 12 modifiable risk factors account for around 40 percent of worldwide dementias, which theoretically could be prevented or delayed.
In light of all this, Finch and Duke University social scientist Alexander Kulminski have proposed the “Alzheimer’s disease exposome” to assess environmental factors that interact with genes to cause dementia. Where medicines have failed, exposomics just might help. Studies of Swedish twins show that half of individual differences in Alzheimer’s risk may be environmental, and thus modifiable; and while vast sums of research funding have been poured into the genetic roots of the disease, it could be that altering the exposome would provide a better preventive than all the ongoing drug trials to date. Environmental toxins broadly disrupt cell repair and protective mechanisms in the brain, the researchers point out. And factors like obesity and stress contribute to chronic inflammation, which likely damages neurons’ ability to function and communicate. The research framework of the Alzheimer's disease exposome offers a comprehensive, systematic approach to the environmental underpinnings of Alzheimer's risk over individuals’ lifespans—from the time they are pre-fertilized gametes to life as a fetus in the womb to childhood and beyond.
For three decades, Rosalind Wright at Mount Sinai has wanted to trace critical problems in neurodevelopment and neurodegeneration to pollutants—from highway emissions to heavy metals to specific household chemicals and a host of other factors—but the mass of data has been overwhelming. With the advent of artificial intelligence (AI) and sophisticated neuroimaging technology, high-precision research using vast genomic databanks is finally possible. “I knew we needed to ask these kinds of questions, but I didn't have the tools to do it. Now we do and it’s very exciting,” Wright says.
Using machine learning—an AI approach to data analysis—Wright looks at giant datasets that include the precise location of an individual’s residence as well as the myriad of pollutants he or she encounters. “It's no different fundamentally from other statistical models we use,” she says. “It’s just that this one has been developed to be able to take in bigger and bigger data, more and more types of exposures.” The resulting data breakdown should tell us which factors drive which types of risk for which people. That information will help people know where they should target their efforts to reduce exposures to risky pollutants, and ultimately how to lower risk of impairment and disease, brain or otherwise.
The tools used by Wright and her colleagues are being trained on diseases like Alzheimer’s. If you put genes and the environment together, “you start to see who might be at higher risk and also what underlying mechanisms might be driving it in different ways in different populations,” Wright says. The exposome could also explains more subtle cognitive effects of pollution that may emerge over long periods, such as harms to attention, intelligence, and performance.
To address environmental brain risks, it’s important to know which pollutants are present—another target of exposomic research. In the United States, the EPA has placed stationary environmental monitors all over our major cities, conducting daily measurements of small particulates from traffic and industry, along with secondary chemicals that emerge as a result. There are also thousands of satellites all over the globe calibrating heat waves that can alter how the pollutants react with each other.
Pioneers like Wright are just starting to chart the terrain of environmental exposures that affect the brain. “As we measure more and more of the exposome, we may be able to tailor prevention and intervention strategies. New weapons include a silicone bracelet that we have in the laboratory. You wear it and it will tell us what pollutants you are exposed to,” Wright says. She also is exploring more ways to collect data on the toxins people have already encountered: “With a single strand of hair, we can tell you what you’ve been exposed to. Hair grows about a centimeter a month, so if we get a hair from a pregnant woman and she has nine centimeters of hair, we can go back a full nine months, over the entire life of the fetus. Or we can create a life-long exposome history when a child loses a tooth at age six.”
“We're designed to be pretty resilient,” Wright adds. The problem comes when the exposures are chronic and accumulative and overwhelm our ability to adapt. We’re not going to fix everything, “but if I know more about myself than before, that empowers me to think, ‘I’m optimizing the balance, and I’m intervening as best I can.’ ”
Ren Ecosystem