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Air pollution is an established environmental hazard. It is known to be linked to both respiratory disease and that of the heart and vascular system. However, recently its association with Alzheimer's disease (AD) has been suspected and explored in many studies.

Image Credit: Melinda Nagy/Shutterstock.com

There are six primary types of air pollutants, including ozone (O3), particulate matter (PM), carbon monoxide (CO), various nitrogen oxides (NOx), sulfur dioxide (SO2), and lead. Even in the USA, over a hundred million live in areas with polluted air, which may contribute to the increasing number of people with AD.

Background

AD is a progressive, irreversible neurodegenerative disorder, the most common form of dementia among older people. There are tens of millions of affected people the world over.

While age is the best-known risk factor for AD, others include a family member with the disease, being female, having cardiovascular disease, or suffering head trauma. People with less education are at a higher risk, as are individuals with Down syndrome, the latter because of trisomy 21. This chromosome encodes the amyloid precursor protein (APP), which gives rise to beta-amyloid.  

Read here: Pollution and Alzheimer's.

Reactive Oxygen Species and Oxidative Stress

The link between AD and air pollution could be oxidative stress – a build-up of oxidizing molecules and oxidized products within the body due to the presence of excessive reactive oxygen species (ROS) that overwhelm the body's natural antioxidant capacity. ROS generation is increased in the body on exposure to air pollution, and the resultant oxidative stress may alter brain function.

Most ROS come from the mitochondrial electron chain but also from fatty acid metabolism within the peroxisomes, from phagocytic cells during their respiratory burst, and several major enzymes. ROS are key to immunity, as they destroy infectious microbes and keep oxygen levels steady within the tissues. They are also involved with the oxidizing of cell membranes, proteins, and genetic material and are thought to be fundamental to aging processes.

Aging and Oxidative Stress

Oxidative stress may underlie aging by damaging key macromolecules, including DNA. Mitochondria are the primary source of these molecules called free radicals. They are also the main targets, especially mitochondrial DNA, which naturally bears the brunt of the newly generated ROS. It is close to the ROS production site and relatively exposed, with less active repair processes than nuclear DNA.

The worst-hit cells are the highly differentiated cells that use abundant oxygen for their metabolism, including nerve cells. Aging primarily affects the brain since nerve cells are not known to regenerate or repair themselves. Moreover, the brain is rich in fatty acids, a prime target of oxidation, but is comparatively lacking in antioxidant defenses. As oxidized lipids, proteins, and DNA molecules build up in the brain, functional deterioration occurs, resulting in impaired mental and intellectual skills.

Hallmarks of AD and oxidative stress

AD begins with a slow memory decline that progresses at variable rates to severe cognitive disability and loss of independent living skills. The classic lesions of AD in the brain are beta-amyloid plaques and neurofibrillary tau tangles linked to macromolecules' oxidation.

The amyloid-beta (Aβ) peptide may be the cause or the result of the oxidative stress seen in the brains of patients with AD. In early AD, oxidation may cause the deposition of this peptide in the brain. The case may be similar for the tau tangles.

Alternatively, these may shield the brain against further damage from ROS generation. Later, however, these molecules could themselves trigger an oxidative inflammatory response, thus promoting neuronal degeneration and disease progression.

The occurrence of oxidative stress may, in this scenario, be an early biomarker of the development of AD even before the tell-tale plaques and tau tangles appear.

In about 90% of AD patients, the sense of smell is impaired early and predicts cognitive decline with age. This may be due to the loss of olfactory cells and the formation of more neurofibrillary tangles within the olfactory bulb and olfactory centers early in AD.

Oxidative stress seems to occur within the olfactory epithelium, as evidenced by lipid peroxidation, the presence of the abnormal Aβ peptide, and tau protein that makes up the neurofibrillary tangles. This could be due to air pollutants, which gain entry to the brain via the nasal mucosa.

Particulate Matter and AD

Fine particulate matter in the air, measuring less than 2.5 μm (PM2.5) each, may reach the brain via inhalation. They travel through the olfactory epithelium, through the olfactory synapses, crossing the blood-brain barrier, and interact with other particles from the lungs, for instance, and with each other.

These particles cause inflammatory mediator release, which activates an immune response against the neurons, leading to a state of systemic and respiratory inflammation beyond the antioxidant capacity of the brain. This is a state of oxidative stress.

The result is lipid peroxidation, protein oxidation, and ROS generation. This leads to the activation of redox-sensitive transcription factors such as NFκB—nuclear factor kappa-light chain-enhancer of activated B cells.

Secondly, ROS production due to these fine particles can cause direct injury to the blood-brain barrier and enhance Aβ production. Thus, air pollution causes neuroinflammation and Aβ plaques, which are linked to impaired neuronal function even before the anatomical hallmarks of AD appear – plaques and tangles.

Human studies show that people exposed to air pollution are at risk of cognitive defects and cerebrovascular damage. The risk of dementia was increased 14-fold in those with the highest annual concentration of air pollution. Brain shrinkage was also more pronounced in those exposed to air pollution.

Such pollution is also linked to the presence of tau protein and Aβ plaques in the frontal cortex. Thus, breathing polluted air over a long period can cause oxidative stress, neuroinflammation, degeneration of the neurons, Aβ formation, and thus increase the risk of AD.

Ozone and AD

Chronic ozone exposure causes brain inflammation, degeneration, vascular alterations, and the loss of hippocampus repair pathways and changes in brain plasticity in rat models. These are similar to those seen in AD patients.

Air pollution may lead to dementia in older women

Conclusion

Further research is required to understand how air pollution causes AD and what routes and mechanistic pathways, especially PM 2.5 and ozone. Synergistic or additive effects of combined pollutants in the air also deserve further study. Reducing and preventing air pollution is an urgent task to prevent the large-scale development of AD and thus the healthcare burden on healthcare practitioners worldwide.

References

  • Moulton, P. V. et al. (2021). Air Pollution, Oxidative Stress, and Alzheimer's Disease. Journal of Environmental and Public Health. https://doi.org/10.1155/2012/472751. https://www.hindawi.com/journals/jeph/2012/472751/
  • Budson, A. E. et al. (2020). Does Air Pollution Cause Alzheimer's disease? (Online) Available at https://www.health.harvard.edu/blog/does-air-pollution-cause-alzheimers-disease-2020072320627. Retrieved on 28 August 2021.
  • Carey, I. M. et al. (2018). Are Noise and Air Pollution Related to The Incidence of Dementia? A Cohort Study in London, England. http://dx.doi.org/10.1136/bmjopen-2018-022404. Available at https://bmjopen.bmj.com/content/8/9/e022404. Retrieved on 28 August 2021.
  • Wood, T. (2021). Air Quality Linked to Increased Risk of Alzheimer's. Available at https://www.ucdavis.edu/news/air-quality-linked-increased-risk-alzheimers. Retrieved on 28 August 2021.

Further Reading

  • All Alzheimer's Disease Content
  • Alzheimer’s Disease | Definition, Causes, Diagnosis & Treatment
  • Explaining Alzheimer’s to Children
  • Alzheimer’s Disease Causes
  • Alzheimer’s Disease Symptoms
More…

Last Updated: Sep 9, 2021

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.

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