"Something in the Air": Air Pollution and Dementia Risk

Risk factors for dementia are by now well established, with particular lifestyle factors/choices shown to have a significant impact on the development of dementia. However, much less is known in how much our environment potentially influences the risk for dementia. To date, the few research studies investigating the impact of environmental hazard on future dementia incidence seem to indicate little evidence in this direction, confirming the notion that environmental influences on dementia risk should be regarded as negligible. Not any longer.

Recent findings suggest that there is at least one significant environmental risk factor for dementia—air pollution.

Air pollution is a very generic term, encompassing many different particles in the air—ranging from naturally occurring air pollution by non-man-made forest fires and sea spray to man-made coal fires, combustion engine exhausts, and industry by-products. The list already highlights an important aspect that air pollution occurs due to natural and man-made processes. However, since the industrial revolution, man-made air pollution has by far exceeded 'natural air pollution' by several factors. This increased man-made air pollution has been shown for decades to impact on our health. Not surprisingly, our lungs carry the heaviest burden of air pollution with WHO reports demonstrating that people from high air pollution areas have a higher incidence of respiratory conditions, such as asthma or lung cancer.

Until recently, the brain was suspected to be exempted from the direct impact of air pollution, due its blood-brain barrier, which effectively filters any foreign molecule before they enter the brain. The blood-brain barrier blocks, therefore, most air pollution particles—most but not all. Specifically, air pollution particles which are less than 2.5 micrometers in diameter (so-called PM2.5, particulate matter less than 2.5 micrometers) can in fact cross the blood-brain barrier. PM2.5 are so small; in comparison, a human hair has on average a diameter of 70 micrometers, so PM2.5 are nearly 30 times smaller in diameter than our hair, and they can cross the blood-brain barrier in addition to being invisible as well as odorless to our senses. Because PM2.5 is invisible and odorless, it can be considered even more dangerous to us being exposed to it, since we cannot use our senses to detect when we are exposed to it. Long-term exposure to PM2.5 is known to be particularly detrimental to our respiratory and cardiovascular system. But the insight that it might also cross the blood-brain barrier only emerged in the 2000s and was first discovered not in humans but in dogs.

Researchers in Mexico City, which in the 2000s was considered one of the most polluted cities by the United Nations, published a series of studies investigating how air pollution affected the brains of stray dogs in Mexico City [1]. After the dogs had died, the researchers investigated the brains of the dogs and found significant signs of neuroinflammation, as well as amyloid plaques and tau fibrils. However, the conclusion of these findings that there was a direct association between air pollution and 'Alzheimer-like' changes, as the authors called it, was regarded with incredulity by some. In particular, the examined stray dogs were clearly not ‘well-controlled’ research subjects, since they might have been exposed to a variety of toxins through their lives, which could have caused their brain pathology. Why would air pollution, therefore, be a particular factor in causing these 'Alzheimer-like' changes in the dogs? The researchers argued that the dogs spend most of their lives along busy streets in Mexico City at the height of the car exhausts, making it more likely that the PM2.5 air pollution caused by the combustion engines was responsible for their brain changes since PM2.5 can cross the blood-brain barrier.

The notion that there might be a direct association between air pollution caused by combustion engine exhausts and dementia was confirmed in 2017. Canadian researchers reported in an epidemiological study across the state of Ontario that people living closer to major roads had a higher risk of developing dementia [2] than those living further away from major roads. These results even held true when controlling for many confounding factors, highlighting that being exposed to greater combustion engine exhaust, which distribute a significant amount of PM2.5, could increase the risk for dementia in older people. Two studies in 2020 confirmed and extended these findings further, by reanalyzing existing longitudinal data in the US. Both studies were interested in whether higher long-term PM2.5 exposure not only increased the risk for dementia but also was associated with dementia-specific changes in the brain in humans. In one of the studies [3], the authors investigated whether people living in postcodes with known higher PM2.5 levels would show higher levels of amyloid-beta over time. The authors analyzed amyloid PET scans for those people and indeed found that people who lived long-term in postcodes with higher PM2.5 had higher levels of amyloid-beta in their brains. Similarly, the other recent study [4] investigated brain atrophy in healthy people exposed to varying levels of PM2.5 in the US. Again, the authors found that the level of brain atrophy—a key measure of nerve cell loss associated with dementia—was associated with levels of PM2.5. In essence, the higher PM2.5, the more significant the level of brain atrophy. Both findings show that not only PM2.5 air pollution is a likely risk factor for dementia but causes specific changes in the brains of people, leading them likely to develop dementia in the future.

What is then the pathophysiological mechanism which leads to PM2.5 exposure increasing future risk for dementia?

The short answer is that we do not know—yet. The main hypothesis is that PM2.5 particles causes neuroinflammation in the brain but the exact mechanism how this would occur are not clear. For example, is it the actual PM2.5 particles which cause this neuroinflammation or are the PM2.5 particles mere ‘vectors’ for other molecules they might carry such as metals, which are known to cause a neuroinflammatory response? Another key question is to how long such exposure to excessive PM2.5 would lead to chronic neuroinflammation and hence an increased for dementia. It is by now well-established that chronic inflammation in the body can increase the risk for dementia, for example due to arthritis. Is a similar process happening with PM2.5 air pollution leading to chronic neuroinflammation? The recent studies seem to suggest this but there is clearly a need for further corroboration of this evidence and more mechanistic explanation of these theories.

Where does this leave us?

Air pollution has been a target of the WHO and the UN for many decades as many people die due to its impact on our respiratory and cardiovascular health. However, its potential impact on the risk for dementia makes clear that air pollution has even far more ranging impact on public health, in particular for aging societies. The emerging link air pollution and dementia risk also resulted in an international commission changing their dementia risk factor list by adding air pollution [5].

It is interesting to note that most air pollution studies for dementia have been conducted in the Americas, whereas, to my knowledge, there are no scientific studies on air pollution in Europe or Asia so far. In particular, Asia ranks often as having some of the highest levels of PM2.5 worldwide which clearly could have an effect on their dementia incidence in the future once the societies age further. The other interesting point is as to whether some of these air pollution dementia risk effects are reversible. For example, would moving away from high PM2.5 areas reduce our risk for dementia, and if so when should we do this? Alternatively, should there be even tighter environmental controls for PM2.5 since it has such significant health impacts on multiple levels? Finally, air pollution and PM2.5 have been shown to vary seasonally with commonly higher levels in winter than summer and would these seasonal changes make a difference to dementia risk?

All open questions but one thing is clear, air pollution as an environmental risk factor for dementia is here to stay!

Please follow my blog for further dementia science insights: https://dementiascience.org/ (Twitter: @DementiaScience).

[1] Calderón-Garcidueñas L, Azzarelli B, Acuna H, Garcia R, Gambling TM, Osnaya N, Monroy S, DEL Tizapantzi MR, Carson JL, Villarreal-Calderon A, Rewcastle B (2002) Air pollution and brain damage. Toxicol Pathol 30, 373-389.
[2] Chen H, Kwong JC, Copes R, Tu K, Villeneuve PJ, van Donkelaar A, Hystad P, Martin RV, Murray BJ, Jessiman B, Wilton AS, Kopp A, Burnett RT (2017) Living near major roads and the incidence of dementia, Parkinson’s disease, and multiple sclerosis: A population-based cohort study. Lancet 389, 718–726.
[3] Iaccarino L, La Joie R, Lesman-Segev OH, Lee E, Hanna L, Allen IE, Hillner BE, Siegel BA, Whitmer RA, Carrillo MC, Gatsonis C, Rabinovici GD (2021) Association between ambient air pollution and amyloid positron emission tomography positivity in older adults with cognitive impairment. JAMA Neurol 78, 197-207.
[4] Younan D, Wang X, Casanova R, Barnard R, Gaussoin SA, Saldana S, Petkus AJ, Beavers DP, Resnick SM, Manson JE, Serre ML, Vizuete W, Henderson VW, Sachs BC, Salinas JA, Gatz M, Espeland MA, Chui HC, Shumaker SA, Rapp SR, Chen JC; Women's Health Initiative (2020) PM2.5 associated with gray matter atrophy reflecting increased Alzheimer’s risk in older women. Neurology, doi: 10.1212/WNL.0000000000011149
[5] Livingston G, Huntley J, Sommerlad A, Ames D, Ballard C, Banerjee S, Brayne C, Burns A, Cohen-Mansfield J, Cooper C, Costafreda SG, Dias A, Fox N, Gitlin LN, Howard R, Kales HC, Kivimäki M, Larson EB, Ogunniyi A, Orgeta V, Ritchie K, Rockwood K, Sampson EL, Samus Q, Schneider LS, Selbæk G, Teri L, Mukadam N (2020) Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet 396, 413-446.


Related: Read about the new book Alzheimer's Disease and Air Pollution here or click the visual below! 

Alzheimer's Disease and Air Pollution book