Air Pollution as an Environmental Risk Factor for Alzheimer's Disease and Related Dementias

Abstract

Alzheimer's disease and related dementias are a leading cause of morbidity in our aging populations. Although influenced by genetic factors, fewer than 5% of Alzheimer's disease and related dementia cases are due solely to genetic causes. There is growing scientific consensus that these dementias arise from complex gene by environment interactions. The 2020 Lancet Commission on dementia prevention, intervention, and care identified 12 modifiable risk factors of dementia, including lifestyle, educational background, comorbidities, and environmental exposures to environmental contaminants. In this review, we summarize the current understanding and data gaps regarding the role(s) of environmental pollutants in the etiology of Alzheimer's disease and related dementias with a focus on air pollution. In addition to summarizing findings from epidemiological and experimental animal studies that link airborne exposures to environmental contaminants to increased risk and/or severity of Alzheimer's disease and related dementias, we discuss currently hypothesized mechanism(s) underlying these associations, including peripheral inflammation, neuroinflammation and epigenetic changes. Key data gaps in this rapidly expanding investigative field and approaches for addressing these gaps are also addressed.

Figure 1.. Gene by environment interactions.

Genetic, epigenetic, and environmental risk factors interact to promote ADRD etiology and disease progression. NOTE: ADRD, Alzheimer’s disease-related dementias. Created with BioRender.com.

Figure 2.. Composition of air pollutants.

Air pollutants consist of gaseous and particulate matter (PM) fractions with heterogenous sources, compositions, and sizes, all of which influence toxicity to the respiratory system and the brain. Created with BioRender.com.

Figure 3.. Potential mechanisms by which air pollutants promote neuroinflammation.

Schematic summary of potential pathways by which air pollutants mediate neuroinflammation. A. Direct pathway: Inhaled air pollutants infiltrate the brain parenchyma via retrograde transportation from olfactory nerve terminals into the olfactory cortex or by crossing the blood-brain barrier from the systemic circulation to directly activate microglia. B. Indirect pathway: Inhaled air pollutants cause neuroinflammation via the lung-brain axis. It is hypothesized that air pollutant-induced pulmonary inflammation leads to neuroinflammation via increased systemic inflammation and release of inflammatory mediators into the systemic circulation, which are then delivered to the brain and cross the blood brain barrier to activate innate immune cells in the brain. NOTE: ROS, reactive oxygen species; dotted arrows indicate hypothesized modes of actions; solid arrows indicate modes of actions supported by experimental evidence. Created with BioRender.com.