Longevity Briefs: More Evidence That Air Pollution Contributes To Dementia

Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

Dementia is currently incurable, which is why preventing dementia in the first place is paramount. Recent research suggests that around 45% of dementia cases may be preventable through lifestyle modifications. A well publicised 2024 report in The Lancet suggested that around 3% of dementia cases could be caused by pollutants in our air. One such pollutant is fine particulate matter with a diameter of 2.5 micrometers or less (PM2.5). At around 20-30 times smaller than a human hair, these particles can easily make their way into the airways and then into the blood to exert toxic effects in various organs.

One hypothesis linking PM2.5 exposure to dementia was that PM2.5 might cause proteins in the brain to misfold and aggregate into insoluble structures inside neurons, killing them. In this study, researchers investigate whether this relationships exists for Lewy body dementias (LBD). Lewy bodies are structures that form from the misfolded form of a protein called α-synuclein. Parkinson’s disease is one form of Lewy body dementia, though depending on where the Lewy bodies form, some people develop Parkinson’s disease without dementia (they have the motor symptoms of Parkinson’s disease, but their cognitive function remains mostly intact).

The discovery:

To investigate whether there was a link between PM2.5 exposure and LBD in humans, researchers analysed data from over 56 million US Medicare beneficiaries. Using their zip codes, they were able to estimate PM2.5 exposure, and found that higher chronic exposure was associated with a significant increase in risk of hospitalisation with LBD. PM2.5 exposure was also associated with risk of Parkinson’s disease without dementia, but to a lesser degree.

To see if there was a biological mechanisms that could explain this association, researchers then exposed mice to PM2.5 every other day for 10 months, and found that they developed disease similar to LBD in humans: brain atrophy, cognitive decline, and aggregations of misfolded α-synuclein in the brain. However, mice that had been genetically modified to produce no α-synuclein at all were mostly unaffected, suggesting that α-synuclein mediated the relationship between PM2.5 exposure and LBD.

Finally, researchers synthesised preformed α-synuclein aggregates in the lab and found that they could react with particulate matter, forming a new type of aggregate that was more resistant to degradation, more toxic, and aggregated faster than regular α-synuclein aggregates. They then injected these aggregates into mice that had been genetically modified to produce the human form of α-synuclein, and found that while the regular synthetic aggregates primarily caused motor problems without much cognitive impairment (similar to Parkinson’s disease without dementia), the aggregates that contained PM2.5 also caused cognitive impairment.

The implications:

This research suggests that people who live in areas with higher PM2.5 levels are more at risk of LBD, and provides a compelling explanation as to why. The motor symptoms of Parkinson’s disease are mainly due to the death of dopamine-producing neurons in a region of the brain called the substantia nigra pars compacta. Dementia usually occurs when Lewy bodies form in regions of the brain responsible for cognition. If the spread of Lewy bodies to these regions remains limited, a patient may be mostly spared from cognitive impairment. The animal findings of this study suggest that PM2.5 might aid the formation and spread of Lewy bodies by forming a more durable and toxic form of α-synuclein aggregate.

Given that there is also some evidence that particulate matter can accelerate age-related cognitive decline in otherwise healthy people, we should probably be doing what we can to limit our exposure. If you are interested in learning how you can limit your exposure to particulate matter as well as other pollutants, check out this article in which we go over 5 pollutants that might accelerate ageing and how you can avoid them.