Abstract:
Neurodegenerative disorders, including Alzheimer’s disease (AD) and related dementias (ADRD), affect over 47 million people worldwide, and this number is anticipated to reach 131.5 million by 2050. Because no medication successfully reverses the course of dementia, researchers are focusing increasing efforts on prevention by addressing potentially modifiable risk factors. Recent evidence suggests that air pollution, a ubiquitous environmental exposure, may be linked to neurodegeneration and dementia. This project aimed to advance the state of the science on this topic through biologically based epidemiological analyses. In the first aim, using a cohort from the University of Washington Alzheimer’s Disease Research Center, I evaluated the association between long and short-term PM2.5 exposure and biomarkers of vascular injury (E-selectin, vascular cell adhesion molecule-1 (VCAM-1)) in the cerebrospinal fluid (CSF). This question is important to investigate because of the growing evidence of the role of cerebrovascular disease in dementia as well as well-established linkages between air pollution and cardiovascular disease. Our analyses indicated that, among cognitively normal individuals, a 5 ug/m3 increase in 1-yr and 7-day PM2.5 exposure was associated with elevated VCAM-1 (beta (95% CI) for 1-year: 51.8 (6.5, 97.1) ng/ml; 7-day: 35.4 (9.7, 61.1) ng/ml) and that a 5 ug/m3 increase in 1-yr PM2.5 exposure was associated with elevated e-selectin (53.3 (11.0, 95.5) pg/ml). We found no consistent associations between pollution and markers of vascular injury in the CSF among cognitively impaired individuals. Overall, our results in cognitively normal individuals are aligned with prior research linking PM2.5 to vascular damage in other biofluids as well as emerging evidence of the role of PM2.5 in neurodegeneration. Our null results among cognitively impaired individuals are unsurprising, given that the influence of internal disease processes would be more important than external PM2.5 exposures in contributing to vascular injury. In the second aim, I utilized autopsy specimens to conduct a novel analysis evaluating the association between PM2.5 exposure and AD stage at death. After addressing differential selection into the autopsy cohort through inverse-probability weighting, we estimated that each 1 ug/m3 increase in 10-year average PM2.5 prior to death was associated with a suggestive increase in the odds of higher CERAD score (OR: 1.35 (0.90, 1.90)). There was no association with Braak score (OR: 0.99 (0.64, 1.47), and there was a suggestive inverse association with odds of higher simulated ABC score (OR: 0.79 (0.49, 1.19). However, for all outcomes, the confidence intervals included the null. In the third aim, I evaluated the association between long term average PM2.5 exposure and incidence of dementia (AD and all-cause). This study leveraged 40 years of exposure information based on a newly developed spatiotemporal model as well as research quality diagnosis data. We estimated that a 1 ug/m3 increase in 10-year moving average of PM2.5 was associated with a 1.16 (1.03, 1.31) increase in the hazard of all-cause dementia. Results from secondary analyses of AD-subtype dementia were slightly attenuated (1.11 (0.97, 1.27)). These results providing additional evidence of the neurodegenerative effects of PM2.5 pollution. Overall, this work advances our scientific understanding of the mechanisms and risk factors for dementia. Findings of this research can inform policies to reduce exposure to air pollution, which could decrease the burden of environmental-related dementia across the population.
URI
http://hdl.handle.net/1773/46455
