Air pollution might also interact directly with variants of certain genes associated with Alzheimer's, prompting the acceleration of brain aging and neurodegeneration in people who are already genetically susceptible. Not all people with late-onset Alzheimer's have these genetic markers, but many do, and the one-two punch of a gene-environment interaction seems to be particularly potent. Clinical psychologist Margaret Gatz of the University of Southern California explains that damage to the vascular system from pollution and other factors is associated with an increased risk of Alzheimer's and other forms of dementia, especially in people who have a genetic tendency to acquire the disease. “There's a good deal of evidence that vascular risk factors are more dangerous for carriers of the APOE4 variant of the APOE gene,” she says. “And for this and other reasons, a lot of research has focused on the genetic risk of the disease and all but overlooked the lifestyle and environmental component.”
What toxic substances found in air pollutants do when they get to the brain fits well with several ideas about the way Alzheimer's-related damage develops. Neurotoxicologist Deborah Cory-Slechta of the University of Rochester Medical Center says that in both animals and humans, these pollutants prompt the release of cytokines from microglia cells, the resident immune sentinels in the brain. Cytokines are signaling molecules that help to regulate immunity and inflammation. Under normal circumstances, this response can help protect the brain against outside invaders. But chronic exposure to polluted air can result in the overproduction of proinflammatory cytokines and chronic inflammation that leads to nerve cell death. “Ultrafine particles seem to be the most important factor in this process,” Cory-Slechta says.
She also notes that it is hard to zero in on specific components of these particles. “For one thing, we have very little historical data on them, so it's hard to judge their relative levels in the environment. For another, they contain lots of different substances that we tend to clump together,” making it difficult to know what specifically is causing the negative effect.
Particle pollution from the burning of fossil fuels and other sources contains hundreds of substances, ranging from noxious gases such as sulfur dioxide and nitrogen oxide to the dust emitted from automobile and truck brakes, tires and clutches. Cory-Slechta says that these pollutants tend to accumulate in the brain over many years, which might help explain why Alzheimer's is typically a disease of old age. But, she adds, there are still many unknowns about what exactly gets into the brain from the air—it's not clear that all these substances make it inside—and when those that do cause trouble. “What we do know is that iron, zinc, copper, and other metals are required by the brain, but at a specific level. What happens when that level is exceeded?” she asks. “We know that too much iron can lead to oxidative stress and neurodegeneration. We also know that some pollutants, like aluminum, play no essential role in the brain yet tend to accumulate there and provoke an inflammatory response. Frankly, I think we should be taking a closer look at that. And it's not just metals. Organic contaminants might also be involved in neurodegenerative disease.”
One type of such organic pollutants are lipopolysaccharides, large molecules released from bacteria spewed from waste-treatment plants and other sources. Scientists have found these molecules can latch onto particulates and, when inhaled, provoke an inflammatory response in the lungs. In animal studies, lipopolysaccharides and other organic matter have also been shown to provoke inflammation and related cognitive degeneration in the brain.
PARTICLES AND MEMORY LOSS
Jiu-Chiuan Chen, a physician and epidemiologist at the University of Southern California, specializes in the study of airborne pollutants in the brain and says that although the impact of individual substances is still under debate, the overall effect of the mix is clearly related to brain damage and cognitive problems. Chen was co-author of a study published last year in the journal Brain that found clear links among fine-particle pollution, structural changes in the brain and memory loss in older women. Chen and his collaborators used neuroimaging and cognitive tests to measure brain changes and memory, plus a mathematical model that incorporated two sources of environmental air-quality data.
“What we found was that women with the highest exposure to pollutants showed an early decline in episodic memory,” he says. This type of long-term memory involves recalling a previous experience along with the time and place of the event and associated emotions. The decline Chen detected in these women appeared preclinically—before any actual symptoms of Alzheimer's—and was independent of the subjects' cardiovascular status. Alzheimer's research has established that people with a decline in episodic memory have a very high risk of developing the full-blown disease later in life.
“There are more than 10 studies that link late-life exposure to air pollution and dementia,” Chen says. “The evidence there is quite compelling. Whether exposure in early life is also a factor, we don't know. But in animal studies, toxicologists start exposure in early life, look at the pathological changes and see problems. It looks like small particles can accelerate the amyloid-deposit process, but we're not yet sure whether this happens in humans. And there might be a genetic component involved—that is, some people might be more susceptible than others to the effect of pollution. There might be a subgroup of individuals who are particularly susceptible and might be at greater risk. We don't yet have enough power in our studies to address this question, but I believe we will.”
While the disease remains a horror facing millions of people around the globe, there is some encouraging news in these discoveries about air pollution, several scientists say: people can take action to diminish the hazards. Most drugs so far have not helped patients, says George Washington University epidemiologist Melinda Power, who focuses on identifying modifiable risk factors for cognitive decline and dementia. ”So at the moment, prevention through the reduction of environmental and lifestyle factors looks like our best bet,” she says. “And air-pollution exposure is looking [like it could be] very important.”
The evidence about brain damage is a strong argument for stricter air-quality controls, says University of Michigan epidemiologist Kelly Bakulski. “This is a really hopeful area,” he says. “Unlike our genes, environmental factors are things we can control—removing these pollutants from our communities will have no ill and many positive impacts.”
In addition, Gatz says that simple changes in how we live can help. “Physical exercise is shown to reduce risk,” she says, both because it increases blood flow to the brain and because it increases levels of brain-derived neurotrophic factor, a protein that promotes the growth and maintenance of brain cells.