Risk factors for dementia are by now well known, in particular how our lifestyle choices can influence our risk for dementia. But much less is known in how much our environment potentially influences the risk for dementia. The few research studies which investigated the environmental influences on the risk for developing dementia did not find much evidence in this direction and hence environmental influences on dementia risk were seen as negligible. Not any longer.

One environmental factor has recently emerged as a risk factor for dementia – the air we breathe… or more specifically, the air pollution we breathe.

What do we mean by air pollution?

Air pollution is a very generic term, encompassing many different particles in the air – from coal fires to combustion engine exhausts to sea spray to industrial by-products to forest fires and so on. This list already highlights an important aspect that air pollution is man-made and occurs as part of natural 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 the WHO (World Health Organisation) showing that people who live in high air pollution areas have a higher rate (incidence) of respiratory conditions, including asthma or lung cancer. But not only our respiratory but also our cardiovascular system (heart and blood vessels) can be affected by air pollution as some particles can enter our blood via our lungs.

How about the brain?

Until recently, the brain was suspected to be exempted from the direct impact of air pollution. The reason is that the brain has another defence barrier which protects it from any ‘foreign molecules or particles’. And with barrier I mean literally a physical barrier – the so-called blood-brain barrier.

What is the blood-brain barrier?

The blood-brain barrier as the name gives away is a barrier between our blood and our brain. The reason for having a barrier between our blood and our brain is that our brain is such a precious organ, which needs to be protected from any toxic or foreign molecules. Any toxic or foreign molecules can create havoc in the brain and potentially severely disrupting its functioning. The solution is to have a blood-brain barrier (or as scientists like to abbreviate it BBB), which only lets certain molecules through, like our blood, while blocking others, which could be potentially harmful to the brain. It is therefore literally a physical barrier protecting our brain and highly effective. In fact, it is so effective that this efficiency can cause other problems. For example, many drugs cannot cross the blood-brain barrier, which makes it much harder for pharmaceutical companies to develop drugs which can cross the barrier and be effective in the brain.

What has this all to do with air pollution?

The key to understand is that the blood-brain barrier can block most air pollution particles – most but not all. The majority of air pollution is blocked by the blood-brain barrier but air pollution particles which are less than 2.5 micrometres in diameter (so-called <PM2.5 – particulate matter less than 2.5 micrometres) can in fact cross the blood-brain barrier. PM2.5 are indeed tiny particles, in comparison, a human hair has on average a diameter of 70 micrometres, so PM2.5 are nearly 30 times smaller in diameter than our hair, making them invisible to our eyes. Because PM2.5 is invisible and odourless it is even more dangerous, since we cannot use our senses to detect when we are exposed to it. Long-term exposure to PM2.5 has been shown for decades to be particularly bad for 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 dogs.

Researchers in Mexico City, which in the 2000s was considered one of the most polluted city by the United Nations, published a series of studies investigating how air pollution affected the brains of stray dogs in Mexico City. After the dogs had died, the researchers investigated the brains of the dogs and found significant signs of neuroinflammation (an immune reaction in the brain), as well as signs of Alzheimer’s disease pathological changes¹. Alzheimer’s disease in dogs, is that possible? Technically yes, most mammals can develop Alzheimer’s disease pathological changes in their brains – as legions of laboratory mice can attest.

The findings of this study were seen by most of the research community as incredulous, if not esoteric, including, I have to admit, myself. Many researchers thought that stray dogs were clearly not a particularly good research subject, since they might have been exposed to all kinds of toxins through their lives. So, why would air pollution 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. But that was regarded by many as fanciful, and again I have to hang my own head in shame here.

But the perception that air pollution might really have an effect on the risk for dementia changed in 2017 when Canadian researchers found in a large-scale study across the state of Ontario that people living closer to major roads had a higher risk of developing dementia². 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 re-analysing 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 studies³, researchers investigated whether over time people living in postcodes with higher PM2.5 levels would show higher levels of beta-amyloid (one key protein involved in the development of Alzheimer’s disease). They analysed 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 beta-amyloid in their brains. Similarly, the other recent study⁴ investigated brain atrophy in healthy people exposed to varying levels of PM2.5 in the US. Again, they found that the level of brain atrophy – a key measure of nerve cell loss associated with dementia – was associated with levels of PM2.5 – the higher PM2.5 the higher the 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.

How can PM2.5 exposure lead then to dementia?

The short answer is that we do not know at the moment. The main hypothesis is that PM2.5 particles cause neuroinflammation in the brain. Neuroinflammation is an immune reaction of the brain to deal with potential foreign or toxic substances entering it. The theory is that PM2.5 particles can carry on them molecules such as metal molecules which can be toxic to the nerve cells and cause a neuroinflammatory response. Neuroinflammation is a completely normal and highly protective process when it occurs occasionally. The problems emerge when the neuroinflammation occurs on a more continuous basis, which causes the immune system to go into overdrive and starting to attack its own healthy nerve cells. Long-term 2.5PM exposure could potentially cause such a continuous neuroinflammatory response in the brain, leading to long-term brain damage and fostering the development of dementia. However, I should make clear that this is currently only theory and future studies will have to provide the evidence for these hypotheses.

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 respiratory and cardiovascular disease. 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 ageing societies. The emerging link air pollution and dementia risk also resulted in an international commission changing their dementia risk factor list by adding air pollution⁵.

It is interesting to note that most air pollution studies for dementia have been conducted in the Americas, whereas I am not aware of any study in Europe or Asia so far. In particular, Asia ranks often as having some of the highest levels of PM2.5 worldwide (see Figure below), 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!

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• ¹ L. Calderón-Garcidueñas et al., Air pollution and brain damage. Toxicol. Pathol. 30, 373–389 (2002).
• ² H. Chen et al., Living near major roads and the incidence of dementia, Parkinson’s disease, and multiple sclerosis: A population-based cohort study. Lancet 389, 718–726 (2017).
• ³ L. Iaccarino et al., Association Between Ambient Air Pollution and Amyloid Positron Emission Tomography Positivity in Older Adults With Cognitive Impairment. JAMA Neurol. 2020 Nov 30
• ⁴ D. Younan et al., PM2.5 associated with gray matter atrophy reflecting increased Alzheimers risk in older women. Neurology. 2020 Nov 18
• ⁵ G. Livingston et al., Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet. 2020 Aug 8;396(10248):413-446. Epub 2020 Jul 30