Monday, May 14, 2018

Air pollution as Risk Factor for Alzheimer’s

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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