Considering the unseen links to Alzheimer’s: Air Pollution

 

By Tré LaRosa
NeuLine Health

In the first iteration of “Considering the Unseen Links to Alzheimer’s,” we reviewed the evidence for gingivitis as a significant risk factor for Alzheimer’s Disease. This time, we will be reviewing the potential connection between air pollution and Alzheimer’s. In this blog, we will look at what current research suggests about air pollution and whether or not it increases the chance one might develop Alzheimer’s, and we will also look at how contributing factors to air pollution might worsen the quality of the air, which could have implications for those already at risk of AD.

As part of understanding the factors that contribute to a condition such as Alzheimer’s where the the causes are multitudinous including genetic and environmental factors, it is important to realize that teasing out exacts, as opposed to conceptualizing patterns and generalities, is difficult for researchers and advocates. The reality is that these factors are not usually unidirectional, linear, or 100% causative; what I mean by this is that it is difficult to say “X exists and by itself entirely causes Y.” In the case of air pollution, this consideration is of particular importance, not because rates of Alzheimer’s might contribute to air pollution, but because air pollution itself is not a universally-defined concept with a singular cause.

As of now, perhaps the best definition to use for air pollution comes from the Clean Air Act which requires the EPA to set standards and monitor six common air pollutants known as “criteria air pollutants.” These pollutants are particulate matter, photochemical oxidants (including ozone), carbon monoxide (CO), sulfur oxides, nitrogen oxides, and lead. All of these pollutants are relevant to researchers as they work to discern which pollutants most contribute to the development of dementias. In a lot of the research into air pollution, you’ll see “particulate matter” emphasized. Particulate matter, as defined by the EPA, is “the term for a mixture of solid particles and liquid droplets found in the air.” Further, the EPA breaks down PM to PM10 and PM2.5. A graphic below demonstrates the scale of PM10 and PM2.5 in relation to a human hair.

https://www.epa.gov/pm-pollution/particulate-matter-pm-basics

Many factors contribute to air pollution. Even how we consider air pollution can be framed in many different ways. As air pollution is affected by weather patterns, we can consider air pollution in a regional sense, but regional air pollution does not exist in a vacuum. Neighboring regions may affect the region of focus one month, and the region of focus may affect that same neighboring region the next month due to changed weather patterns; probably most accurately is that weather patterns across regions are always affecting one another. This is what is known as bidirectional relationships. 

There are tactics to combat and control these sorts of sampling biases, but ultimately, researchers are striving to reach as close as they can get to 1 (meaning a fully fleshed out understanding of a given subject), though most researchers have accepted that it is increasingly difficult to reach that point. I’d argue most researchers are not threatened or bothered by this fact, since the core principle of science is a pursuit of knowledge and understanding and the closer we get to a collective understanding of something, we usually find more questions that need answers. Each discovery propels science forward, and some of the most exciting science is in the medical field as it not only tells us something of fundamental importance about life and existence, but medical science also improves the health of real-life human beings.

In a remarkable review of the evidence published to “The Conversation,” expert Dr. Jiu-Chiuan Chen provides a high-level view of the scale of the current research into the potential connection between air pollution and AD. I highly recommend the full article for those who are trying to get an even better grasp of the evidence, but I will sum up the major points in a few bullets below. Most of the studies reviewed are trying to parse out the preclinical, or the “silent” phase of the condition, before symptoms onset.

  • “Our latest studies show how older women who lived in locations with high levels of PM2.5 – the fine particulate matter produced by vehicles and power plants – suffered memory loss and Alzheimer’s-like brain shrinkage not seen in women living with cleaner air.”
  • Based on a report from the American Lung Association, “an estimated one in six Americans lives in counties with unhealthy levels of particle pollution.”
  • “In the first U.S.-based nationwide study to link PM2.5 exposure and cognitive impairment, published in 2017, we found older women were almost twice as likely to develop clinically significant cognitive impairment if they had lived in places with outdoor PM2.5 levels exceeding the U.S. Environmental Protection Agency’s standard than if they hadn’t. Because we worked with the Women’s Health Initiative Memory Study, which followed the participants closely, we were able to account for other dementia risk factors, such as smoking, lack of exercise and hormone therapy.
    • I added the bold emphasis myself to emphasize that researchers are always actively working to control for other risk factors to ensure they are doing their best to tease out real correlations or not.
  • For women living in locations with high levels of PM2.5, “dementia risk increased by 24% over the five years.”
  • Alzheimer’s-like brain changes were seen in women with no memory problems indicating the physical damage may be done before symptoms are obvious. In some cases, these issues were seen in women living in areas where PM2.5 levels were within the current EPA standard, thus raising concern that current EPA standards are allowing for dangerous levels. It is important to note the EPA does have the authority to strengthen air quality standards.
  • “Data from the Women’s Health Initiative Memory Study and past MRIs allowed us to look for changes across time for nearly 1,000 women. We found that as outdoor PM2.5 increased in locations where these older women lived, episodic memory declined. Approximately 10%-20% of the greater memory decline could be explained by Alzheimer’s-like brain shrinkage.”
  • “Genes also appear to play a role. Our research has shown that a critical Alzheimer’s risk gene, APOE4, interacts with air particles to accelerate brain aging. We found the environmental risk raised by long-term PM2.5 exposure was two to three times higher among older women with two copies of the APOE4 gene than among women without the gene.”
  • This discussion of genes and environment is always at the top of the researcher’s mind. One Swedish study did not find any association between genes and the environment interaction, but a study published a year later in 2020 did find an association, “with steeper rates of decline found in APOE4 carriers.”
  • Because the silent phase of dementia is thought to start decades before the manifestation of symptoms, findings from our recent studies raise concerns that air pollution exposures during mid to early life may be equally or even more important than late-life exposure.” (Bold added again by myself.

Rodent models have also been used to investigate the connection between traffic-related air pollution and dementia. The authors of one study note that a benefit of rodent models is that these models allow the researchers to eliminate other confounding variables that are rampant in humans, such as socioeconomic status and diet. The authors state: “We saw that traffic-related air pollution accelerated Alzheimer’s disease characteristics not only in the animals who express the risk gene (which we anticipated) but also in the wild type rats. We didn’t anticipate that. The big, exciting discovery is that traffic-related air pollution is a risk factor for late-onset Alzheimer’s disease. This is important because this pollution is everywhere and could explain the increased number of people impacted by Alzheimer’s disease across the world.”

Furthermore, researchers found the presence of ultrafine particles in the brains of the rat, also raising concern about how these particles, when inhaled, may directly reach the brain in humans. The rats also had reduced time of onset and accelerated disease progression. But there was another unexpected, alarming discovery: this same site produced another paper that showed traffic-related air pollution also “increased risk for changes in brain development relevant to neurodevelopmental disorders such as autism” in the rats. Rat models are not perfect models for humans, but they can often help us to notice trends and patterns that will help to better inform proposed human investigations and potential mechanisms of action to explain the proposed correlation. As another researcher put it: “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.”

Not every researcher is sold on this potential connection. From an article that I also highly recommend reading in its entirety published in Science, titled “Brain pollution: Evidence builds that dirty air causes Alzheimer’s, dementia,” the author notes “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.”

As for how these ultrafine particles might actually cause Alzheimer’s, well, it might be directly, by reaching the brain themselves, or indirectly, “by triggering the release of inflammatory molecules.” We saw a similar argument in the case of gum disease. In the graphic below from the “Brain Pollution” article, these potential mechanisms of action are shown with graphics of pollutants included.

https://www.science.org/content/article/brain-pollution-evidence-builds-dirty-air-causes-alzheimer-s-dementia

Many scientists would probably agree that science is a bit like detective work and each realm of science uses a different tactic for investigation. Epidemiological researchers compare population and datasets to look for potential connections. In the case of air pollution, researchers will look at air quality data released by the EPA then compare to rates of AD in different geographic regions. From there, they will report on the high-level population data. This data is valuable for many reasons, not least of which is that peer-reviewed papers can then inspire or guide more basic researchers to investigate the population data and whether there are deeper, possibly correlative, associations between the variables. Alzheimer’s is already a difficult disease as the field does not have an established understanding of its causes and mechanism of action. As researchers do more and more research into the broader connections between air pollution and dementia, still other researchers are investigating the potential explanations for why, if this association is indeed correlative, the independent variable (air pollution) is actually causing the dependent variable (Alzheimer’s) to develop.

The scientific process utilizes feedback mechanisms to reinforce the evidence as it accrues. As more studies, from basic science to epidemiological publications, support a claim, the stronger the claim is; just as more studies are published to refute a claim, the weaker the claim becomes. Similarly, a risk factor like air pollution is also the product of feedback loops. Air pollution, without a universally-accepted definition, is affected by a wide variety factors; commuter heavy cities are more likely to have more smog and regions in the western US are more likely to filled with smoke due to wildfires, warmer annual temperatures and deforestation may result in higher rates of pollutants in the air. As these factors are not divorced from one another, there are a series of feedback loops reinforcing and attenuating one another. 

Just as the issues that cause air pollution are bidirectional and compounding, so are the issues for those who are at risk of developing dementia. As we saw in the first “Unseen Links” blog, periodontal disease is more common in poorer individuals. In the case of air pollution, lower socioeconomic status individuals are also at increased risk because “they are more likely to live in places with higher PM2.5 exposures, such as near major roadways or ports” and “stresses linked to poverty also could amplify the effects of the toxic particles,” according to USC sociologist Jennifer Ailshire.

In the case of the particulate matter that makes up air pollution, the term “unseen” is quite literal. The evidence, while not definitive, is strong enough to suggest that we should not take the threat of even the same level of air pollution lightly. The fact that the signs currently lead us to believe that without more stringent air quality regulations, air pollution will only continue to worsen should be cause for concern for everybody, no matter if they or their loved ones have or are at risk for Alzheimer’s dementia. 

It is also important to note, as I’ve harped on already, that as Alzheimer’s has a complex, multitudinous etiology, his inherent complexity should help us to consider that the causes and effects involved in every step of the pre-diagnosis onwards for somebody with Alzheimer’s are also themselves difficult to fully understand. The fact that air pollution — and as we saw a couple of months ago, oral bacteria and periodontal disease — may increase the likelihood of somebody developing dementia including Alzheimer’s, we should be encouraged as a society to work to reduce the many different risk factors involved in the condition. We should not only work to better increase prognosis for those with AD, we should also work to improve the conditions that the evidence currently suggests is associated with the prevalence and incidence of Alzheimer’s. We should work to improve general gum health while at the same time working to improve the quality of the air. Future generations and their healthcare systems will thank us if we put these frameworks into action sooner rather than later.

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