Some of the health risks of inhaling fine and ultrafine
particles are well-established, such as asthma, lung cancer, and, most
recently, heart disease. But a growing body of evidence suggests that exposure
can also harm the brain, accelerating cognitive aging, and may even increase
risk of Alzheimer’s disease and other forms of dementia.
The link between air pollution and dementia remains
controversial—even its proponents warn that more research is needed to confirm
a causal connection and work out just how the particles might enter the brain
and make mischief there. But a growing number of epidemiological studies from
around the world, new findings from animal models and human brain imaging
studies, and increasingly sophisticated techniques for modeling PM2.5 exposures
have raised alarms. Indeed, in an 11-year epidemiological study to be published
next week in Translational Psychiatry, USC researchers will report that living
in places with PM2.5 exposures higher than the Environmental Protection
Agency’s (EPA’s) standard of 12 µg/m3 nearly doubled dementia risk in older
women. If the finding holds up in the general population, air pollution could
account for roughly 21% of dementia cases worldwide, says the study’s senior
author, epidemiologist Jiu-Chiuan Chen of the Keck School of Medicine at USC.
Deepening the concerns, this month researchers at the
University of Toronto in Canada reported that among 6.6 million people in the
province of Ontario, those living within 50 meters of a major road—where levels
of fine pollutants are often 10 times higher than just 150 meters away—were 12%
more likely to develop dementia than people living more than 200 meters away.
The field is “very, very young,” cautions Michelle Block,
a neuroscientist at Indiana University in Indianapolis. Nonetheless, it’s a
“hugely exciting time” to study the connections between pollution and the
brain, she says. And if real, the air pollution connection would give public
health experts a tool for sharply lowering Alzheimer’s risks—a welcome prospect
for a disease that is so devastating and that, for now, remains untreatable.
Demented dogs in Mexico City in the early 2000s offered
the first hints that inhaling polluted air can cause neurodegeneration.
Neuroscientist Lilian Calderón-Garcidueñas, now at the University of Montana in
Missoula, noticed that aging dogs who lived in particularly polluted areas of
the city often became addled, growing disoriented and even losing the ability
to recognize their owners. When the dogs died, Calderón-Garcidueñas found that
their brains had more extensive extracellular deposits of the protein amyloid
b—the same “plaques” associated with Alzheimer’s disease—than dogs in less
polluted cities. She went on to find similarly elevated plaque levels in the
brains of children and young adults from Mexico City who had died in accidents,
as well as signs of inflammation such as hyperactive glia, the brain’s immune
cells. Calderón-Garcidueñas’s studies didn’t have rigorous controls, or account
for the fact that amyloid b plaques don’t necessarily signal dementia. But
later work lent weight to her observations.
Those tubes of fine particles from the 110 freeway have
played a key role. In a basement lab at USC, Sioutas and his team aerosolize
the pollutants with a hospital nebulizer, then pipe the dirty air into the
cages housing lab mice that have been engineered to contain a gene for human
amyloid b. Control animals housed in the same room breathe clean, filtered air.
After a designated period—220 hours over several weeks, in a recent
experiment—the team hands the rodents over to colleagues at USC, who kill the
animals and check their brains for signs of neurodegeneration.
Caleb Finch and Todd Morgan, USC neuroscientists who
combine studies of aging and the brain, are in charge of the analysis. In mice
that breathed the dirty air, they have found, the brain’s microglia release a
flood of inflammatory molecules, including tumor necrosis factor a, which is
elevated in the brains of people with Alzheimer’s disease and has been linked
to memory loss. The pollution-exposed mice also showed other signs of brain
damage, the group has reported in several recent papers: more amyloid b than in
the control mice and shrunken and atrophied neurites, the cellular processes
that extend from neurons toward other cells.
Just how the fine airborne particles might travel from a
rodent’s nasal cavity to its brain is a mystery. But a research team led by
Günter Oberdörster at the University of Rochester in New York has used
traceable, radioactive specks of elemental carbon to demonstrate that inhaled
particles smaller than 200 nanometers can get through the delicate tissues
lining a rodent’s nasal cavities, travel along neurons, and spread as far as
the cerebellum, at the back of the brain, triggering an inflammatory reaction.
To understand what the animal studies might mean for
people, however, scientists need to correlate air pollution exposure with human
brain scans and with results from rigorous cognitive testing.
A cloudy suspension of smog particles, collected near a
Los Angeles, California, freeway, will be turned into an aerosol and piped into
tanks holding laboratory mice.
Scientists let one group of mice breath polluted air for
several weeks, while exposing another to clean air. After several weeks, they
examine the brains of both groups.
That’s not easy to do, as long-term, historical data on
pollution exposures are scarce in the United States and many other countries,
says Kimberly Gray, a program administrator at the National Institute of
Environmental Health Sciences (NIEHS) in Durham, North Carolina. But in a
September 2016 review of 18 epidemiological studies from Taiwan, Sweden,
Germany, China, the United Kingdom, and the United States, all but one showed
an association between high exposure to at least one component of air pollution
and a sign of dementia. The review, published in Neurotoxicology, included a
2012 analysis of 19,000 retired U.S. nurses, which found that the more fine
particulates the nurses were exposed to, based on monitoring data near their homes,
the faster they declined on cognitive tests. For every additional 10 micrograms
per cubic meter of air they breathed, their performance on tests of memory and
attention declined as if they had aged by 2 years, says Jennifer Weuve, an
epidemiologist at Boston University, who led the analysis.
Imaging studies also suggest that pollution attacks the
human brain. In a 2015 analysis of brain MRI scans of people enrolled in the
Framingham Heart Study, a long-term cardiovascular study in New England, researchers
at Harvard Medical School in Boston found that the closer people had lived to a
major roadway—and thus the more PM2.5 they had likely been exposed to—the
smaller their cerebral brain volume. The association held up even after
adjusting for factors such as education, smoking, diabetes, and cardiovascular
disease.
Shortly after that study was published, USC’s Chen
reported another example of brain shrinkage: In 1403 elderly women, the total
volume of white matter—the insulated nerve fibers that connect different brain
regions—decreased by about 6 cubic centimeters for every 3.5-µg/m3 increase in
estimated PM2.5 exposure, based on air monitoring data from participants’
residences for 6 to 7 years before the brain scans were taken. Chen’s white
matter findings are consistent with studies of cultured neurons, which show
that exposure to PM2.5 can cause myelin—the fatty insulation that wraps around
neuronal axons—to “peel up at the ends, like a Band-Aid,” Block says.
Older women who live in areas with high levels of
pollution (specifically fine particulate matter, which consists of extremely
small particles that can be inhaled deep in the lungs) are 92% more likely to
develop dementia than women living in cleaner-air climates, according to another
2017 study. The link was strongest in
women who had the APOE4 gene, a genetic variation that increases the risk for
Alzheimer’s disease. If these results hold true in the general population, the
study authors say, air pollution could be responsible for about 21% of dementia
cases.
“When we breathe in these tiny particles, it can trigger
inflammation throughout the body,” says Richard Isaacson, MD, director of the
Alzheimer’s Prevention Clinic at New York-Presbyterian Weill Cornell Medical
Center (who was not involved in the study). “And for certain people,
inflammation seems to be a way of pressing the fast-forward button on the
progression of Alzheimer’s disease.”
Future studies
Our future studies will look at whether these findings
also apply to men, and whether any drugs under development may provide
protection against air pollution exposure. More work is also needed to confirm
a causal relationship and to understand how air pollution enters and harms the
brain.
Brain aging from exposure to air pollution may start at
development, so we also want to look at early life exposure to air pollution in
relation to Alzheimer’s disease. We already know that obesity and diabetes are
Alzheimer’s risk factors. We also know that children who live closer to
freeways tend to be more obese, an effect that is compounded if adults in the
household are smokers.
Based on existing mouse models, one would predict that
developmental exposure to air pollution could increase risk for Alzheimer’s
disease. This is an important piece of the scientific puzzle that we’d like to
better understand.
Worldwide
Pollution Problem
Importantly, the harmful effects of air pollution are
found in populations in addition to the residents of Mexico City, corroborated
by studies of this link between Alzheimer's disease and pollution. A study in
Taiwan with more than 92,000 subjects found a dose-dependent relationship
between how much air pollution levels increased in a particular region and the
risk of residents within that region developing dementia. Specifically, with
each 10.91 parts-per-billion increase in O3 (or ozone, a common measure of air
pollution that results from traffic emissions and industrial waste), the risk
of developing Alzheimer's disease increased more than 200 percent.
And in the United States a study focused on women found
an association between exposure to high levels of air pollution and risk of
both dementia from all causes (also referred to as all-cause dementia) and
cognitive decline. These studies suggest that the negative effects of living in
areas with high pollution have real-life consequences to cognition and dementia
development in elderly populations.
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