The air in Mexico City was once so toxic that people watched as dead birds fell out of the sky. In 1992, the United Nations declared the city the most polluted in the world, with its unregulated diesel engines, factory production, fossil-fuel powered energy plants, and widespread use of internal-combustion engines, all trapped in a high-altitude, mountain-lined valley.
In 2002, toxicologist and neuropathologist Lilian Calderón-Garcidueñas, who attended medical school in the city, looked the brains of 40 dogs that had lived either in the city’s polluted valley or in the cleaner air of Tlaxcala, a state on its eastern edge. The results were striking: The rural dogs’ brains appeared healthy. In the brains of the city dogs, however, she saw the beginnings of neurodegeneration in puppies as young as eight-months-old.
STAT reports that the findings prompted Calderón-Garcidueñas, who has joint appointments at the University of Montana and Universidad del Valle de México in Mexico City, to begin looking at human brains. And over the past 20 years, she has grown convinced that children raised in areas like Mexico City, with air quality that rarely falls into the healthy range, are at noticeably increased risk for Alzheimer’s and other neurodegenerative conditions.
Scientists have known for decades the fine particles and gases in polluted air have been connected to asthma, heart disease, inflammation and numerous other health impacts. But demonstrating that this pollutant soup can have neurodegenerative effects has proved trickier. Only recently has new research begun to paint a picture of air pollution as dangerous not only for the heart and lungs but potentially for the brain, as well.
In a 2018 study published in the journal Environmental Research, Calderón-Garcidueñas and her colleagues examined more than 200 brains of Mexico City residents aged between 11 months and 40-years-old when they died. All but one of the brains showed at least the beginnings of changes that scientists have previously found in the brains of people with Alzheimer’s disease.
In comparison, the researchers described nine control brains that had been gathered from people who had lived (and died) breathing clean air, as “unremarkable”.
The Mexico City studies, while intriguing, were far from definitive and limited by methodological issues, some researchers said.
“Nobody in the neuropathology world would consider this other than an indication,” said Caleb Finch, a biomedical gerontologist at the University of Southern California, referring to the Mexico City studies. “It’s not something from which one can draw major conclusions.”
But he said further research by scientists at USC and around the world have strengthened the air pollution and neurodegenerative disease link. Finch referred to a series of papers showing brain atrophy and cognitive disorders are directly related to a person’s air pollution exposure.
“Population-based studies are in complete agreement on three continents – North America, Western Europe and Asia – that air pollution above a certain level predicts a higher risk of dementia, particularly Alzheimer’s, and cognitive decline. That’s proven by at least ten major studies,” he said.
There are also increasing numbers of studies linking air pollution and Parkinson’s disease.
But Ray Dorsey, a neurologist and Parkinson’s disease researcher at the University of Rochester Medical Centre, said “almost all environmental risk factors associated with Parkinson’s have a long latency”.
“You don’t inhale pesticides or air pollution and get Parkinson’s the next day, just like you don’t smoke tobacco and get cancer the next day,” he said. “We know the disease takes decades to unfold.”
Pathways to the brain
The air we breathe is a stew of tiny particles and noxious gases, and it may be difficult to pin down the specific components of pollution involved in neurodegeneration. There is probably no single culprit. “Fifty years of work have identified 30 carcinogens in tobacco smoke. Which one causes lung cancer? The whole package does,” said Finch, “and the chemistry of air pollution is even more complex.”
The Environmental Protection Agency regulates six of the most concerning components: carbon monoxide, lead, nitrogen oxides, ozone, particulate matter, and sulphur oxides.
Researchers have placed special focus on the fine particulates known as PM2.5 – to indicate particles smaller than 2.5 microns, or 1/30th the width of a human hair – shown to be especially dangerous. These can be thrown up in the air by farms and factories, but the most common source is the burning of fossil and bio fuels, in combustion engines, for example, or coal-fired power plants, or even wildfires, becoming more frequent with climate change.
Once suspended in air, the particles can be inhaled deeply into the lungs, allowing them to move into the bloodstream and beyond.
These particles have been linked to inflammation, cancer, severe cardiac and respiratory diseases, including asthma, heart attack and stroke. The smaller the particles, the more malignant their effects.
Now work by Calderón-Garcidueñas and others has shown that these microscopic particles also enter the brain. Some probably travel through the bloodstream, but a person’s nasal passages may provide an even more efficient route.
In her research, Calderón-Garcidueñas focused specifically on the olfactory bulb when looking for early indications of neurodegenerative disease.
“The nose is the front door of the brain,” Dorsey said. As someone inhales polluted air, PM2.5 particles enter the nasal cavity and then travel directly into the brain’s olfactory bulb, when neuronal cell death begins.
Dorsey said that in both Alzheimer’s and Parkinson’s, loss of smell is an early warning sign, sometimes preceding other symptoms by 10 years or more. “Pathology of both diseases is found in the olfactory bulb and smell centres before it’s found in parts of the brain responsible for memory, and then movement,” he said.
Although the nose may be the most direct route, researchers are also uncovering other ways air pollution can make its way to the brain.
Michelle Block, an environmental neurotoxicologist at Indiana University School of Medicine in Indianapolis has been researching what she calls the lung-brain axis. By studying the inhalation of ozone, a gas that doesn’t cross the blood-brain barrier, she can track other potential mechanisms for air pollution’s neurodegenerative effects.
“One of the reasons we use ozone is because it has been linked to increased risk for Alzheimer’s disease, but also because it will never reach the brain,” she said, making the gas a good tool to investigate communication between the brain and the lungs. “It’s environmentally relevant, but also mechanistically important.”
Block found ozone inhaled into the lung triggers an immune reaction, and her lab has seen changes in populations of immune cells that communicate with the brain. She’s also examining the role of microglia, tiny cells that help maintain neural networks, repair injury, and eliminate dangerous brain debris like microbes, dead cells, and aggregated protein.
In a healthier brain, microglia gathers around clusters of protein fragments, called plaques, and condenses them; researchers believe this may limit their pathology.
“Air pollution affects these microglia and they don’t associate with the plaques as they should,” Block said. “They don’t do their job at all, promoting a more pro-inflammatory environment.”
Connecting the dots
Neurodegenerative diseases become more common with age, but assessing how much pollution someone has been exposed to is challenging. Most Alzheimer’s studies have looked at environmental exposures perhaps five to 10 years before onset, said Beate Ritz, professor of epidemiology and environmental health sciences at the University of California-Los Angeles Fielding School of Public Health.
In Parkinson’s, she said, exposures could occur anywhere from five to 20 years before disease onset. Yet by the time someone is 60, they may have lived in 10 homes in three cities, and historical air-quality data can be difficult, even impossible, to find.
Another issue has been accurately identifying patients with Parkinson’s, especially since most countries don’t maintain disease registries and databases that do exist may not use verified diagnoses.
Still, Ritz and colleagues have found a few countries with the quantity and quality of data they need. Denmark and Taiwan both have national health systems and substantive air-pollution records, and have given Ritz troves of data to mine.
In Taiwan, researchers found a positive association between Parkinson’s risk and traffic-related air pollution (nitrogen oxide and carbon monoxide). In Denmark, the results were similar. Another research group, in South Korea, found an association between high nitrogen oxide levels and increased risk of Parkinson’s.
A Canadian study of Ontario residents found Parkinson’s was associated with high levels of air pollution, especially PM2.5.
Air pollution may also cause or exacerbate other neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease.
The researchers said there are hints from both animal and epidemiological research, including a study in the Netherlands that linked long-term nitrogen oxide and PM2.5 exposures from traffic-related pollution to susceptibility to ALS. ALS, however, is relatively rare: few countries maintain a disease registry for it, making data difficult to find.
‘Over a lifetime, it adds up’
For many neurological diseases, aligning pathology with clinical findings has sometimes been a “best guess” undertaking. The Mexico City children whose brains Calderón-Garcidueñas examined may have shown the beginnings of Alzheimer’s pathology – hyperphosphorylated tau, for instance, which has been linked to neurodegenerative disease – but they didn’t have dementia.
And in older brains, post-mortem studies have shown some people with dementia do not exhibit pathology as extensive as would be expected with their symptoms, while others with substantial Alzheimer’s pathology die after showing few or no symptoms at all.
“We know there’re multiple other processes happening with ageing – almost everybody over 60 has some clear kind of pathology, even though they’re not demented,” Finch said, adding, “I’m 83, so I can speak on this with authority.”
One major defence against ageing is resiliency – in the brain, this comes in the form of what scientists call cognitive reserve. This refers to the brain’s ability to function, even thrive, as neurodegenerative disease progresses. And researchers believe the best ways to improve cognitive reserve are through education, healthy lifestyles (both diet and exercise), breathing clean air, and drinking clean water.
“We’re harming populations in a way that we’re making them less resilient over their lifetime,” Ritz said.
She added: “We don’t have children who have Alzheimer’s or Parkinson’s disease, but the presence of identifiable disease pathology in the Mexico City study is concerning.”
If an infant already shows the beginnings of hyperphosphorylated tau and other disease-linked pathology, those children will have less reserve capacity at an older age. “We’re dealing with a long-term issue,” she said. “Over a lifetime, it adds up.”
Study details
Alzheimer's disease and alpha-synuclein pathology in the olfactory bulbs of infants, children, teens and adults ≤ 40 years in Metropolitan Mexico City.
Lilian Calderón-Garcidueñas, Angélica González-Maciel, Rafael Reynoso-Robles, Randy Kulesza, Partha Mukherjee, Ricardo Torres-Jardón, Topi Rönkkö, Richard Doty.
Published in Environmental Research Volume 166 in 2018
Abstract
There is growing evidence that air pollution is a risk factor for a number of neurodegenerative diseases, most notably Alzheimer's (AD) and Parkinson's (PD). It is generally assumed that the pathology of these diseases arises only later in life and commonly begins within olfactory eloquent pathways prior to the onset of the classical clinical symptoms. The present study demonstrates that chronic exposure to high levels of air pollution results in AD- and PD-related pathology within the olfactory bulbs of children and relatively young adults ages 11 months to 40 years. The olfactory bulbs (OBs) of 179 residents of highly polluted Metropolitan Mexico City (MMC) were evaluated for AD- and alpha-synuclein-related pathology. Even in toddlers, hyperphosphorylated tau (hTau) and Lewy neurites (LN) were identified in the OBs. By the second decade, 84% of the bulbs exhibited hTau (48/57), 68% LNs and vascular amyloid (39/57) and 36% (21/57) diffuse amyloid plaques. OB active endothelial phagocytosis of red blood cell fragments containing combustion-derived nanoparticles (CDNPs) and the neurovascular unit damage were associated with myelinated and unmyelinated axonal damage. OB hTau neurites were associated mostly with pretangle stages 1a and 1b in subjects ≤ 20 years of age, strongly suggesting olfactory deficits could potentially be an early guide of AD pretangle subcortical and cortical hTau. APOE4 versus APOE3 carriers were 6–13 times more likely to exhibit OB vascular amyloid, neuronal amyloid accumulation, alpha-synuclein aggregates, hTau neurofibrillary tangles, and neurites. Remarkably, APOE4 carriers were 4.57 times more likely than non-carriers to die by suicide. The present findings, along with previous data that over a third of clinically healthy MMC teens and young adults exhibit low scores on an odor identification test, support the concept that olfactory testing may aid in identifying young people at high risk for neurodegenerative diseases. Moreover, results strongly support early neuroprotective interventions in fine particulate matter (PM2.5) and CDNP's exposed individuals ≤ 20 years of age, and the critical need for air pollution control.
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