Determine the role of atmospheric particulate matter pollutants in contributing to Lewy Body Dementia

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Project Summary There is a consensus that environmental pollutants are a risk factor for Alzheimer's Disease Related Dementias (ADRD). Emerging evidence has shown that environmental stressors (e.g., urban and roadside air pollution) contribute to dementia. Our supporting epidemiological results have determined that annual mean particulate matter (PM) pollution in the USA is significantly associated with an increased risk of first hospital admission with ADRD. We found strong evidence of linearity in concentration-response relationship at PM concentration less than 16 μg/m3 (95th percentile of the PM distribution). PM pollutants can target the central nervous system (CNS). However, what specific PM pollutants are associated with dementia and the underlying mechanisms are poorly known. One of the most common dementia is called “Lewy Body Dementia (LBD)” with the typical hallmark of αS pathology, including Dementia with Lewy body (DLB) and Parkinson's Disease with Dementia (PDD). Patients with LBD suffer from cognition and memory dysfunction, behavioral and mood symptoms (e.g., depression, anxiety, and etc.), affecting 1.4 million individuals and their families in the USA. Furthermore, 30% of the Alzheimer's disease (AD) subjects with αS pathology generally exhibit a more rapid rate of cognitive decline than subjects with AD alone. Substantial postmortem studies by Braak et al. showed the presence of αS pathology was initialized in the olfactory bulb (OB) and gastrointestinal tract, and spread to the brain following stereotypical anatomical stages, resulting in autonomic, neuropsychiatric, and cognitive dysfunction. In addition to clinical observations, emerging evidence has shown pathogenic αS spreading is a master trigger to cognitive impairment (CI) by using inoculation of recombinant αS preformed fibrils (PFF). The majority cases of αS-related dementia (LBD and ⅓ AD) are sporadic and have many causes. Braak's theory well supports the hypothesis that αS-related dementia may begin when foreign stressor (e.g., PM pollutants) enter the body via the nose/gut, induce αS aggregation and subsequent prion-like pathology spreading into the CNS, which results in ADRD. While epidemiological studies demonstrating an association of ADRD with air pollutants are relatively abundant, there is a clear unmet need for more mechanistic research. This knowledge is critical for achieving a complete understanding of the etiology of LBD and the translation of such knowledge to novel prevention and treatment strategies. This is especially important for understanding the causes of socioeconomic inequities in ADRD, and importantly, environmental toxicant risk factors are potentially modifiable.