Higher exposure to fine particulate air pollution is associated with more severe Alzheimer’s disease pathology in the brain and faster cognitive decline, according to the largest autopsy study to date examining the relationship between air pollution and dementia-related brain changes.
Researchers at the University of Pennsylvania examined more than 600 brains donated over two decades and found that for every 1 μg/m³ increase in PM2.5 exposure before death, there was a 19 per cent increase in the odds of more severe Alzheimer’s disease neuropathologic change.
The study, published in JAMA Neurology, also found that 63 per cent of the association between higher PM2.5 exposure and greater cognitive impairment was statistically mediated by Alzheimer’s pathology, suggesting that air pollution may directly affect brain vulnerability through increased disease pathology.
Previous research on pollution and dementia has relied mostly on epidemiological studies to establish an association. The Pennsylvania team used autopsy data from the Center for Neurodegenerative Disease Research brain bank, collected from 1999 to 2022.
Exposure to pollutants
“We’re linking what we actually see in the brain with exposure to pollutants,” said Dr Edward Lee, who directs the brain bank at the University of Pennsylvania’s Perelman School of Medicine and served as senior author of the study. “We’re able to do a deeper dive.”
The researchers used high spatial resolution estimates of PM2.5 obtained from a validated prediction model to calculate one-year average exposure before death for each case. They examined 10 dementia-related neuropathologic measures representing Alzheimer’s disease, Lewy body disease, limbic-predominant age-related TDP-43 encephalopathy, and cerebrovascular disease.
Higher PM2.5 exposure showed strong associations with Alzheimer’s pathology specifically. For every 1 μg/m³ increase in PM2.5, there was a 17 per cent increase in the odds of higher Thal amyloid phase, a 20 per cent increase in Braak stage, and a 20 per cent increase in CERAD score.
The study also found a 16 per cent increase in the odds of having large infarcts. However, higher PM2.5 was not associated with increased odds of Lewy body disease stage, limbic-predominant age-related TDP-43 encephalopathy stage, or other cerebrovascular lesions including cerebral amyloid angiopathy and arteriolosclerosis.
To evaluate the relationship between PM2.5 exposure and clinical dementia severity, researchers examined a subset of 287 cases who had Clinical Dementia Rating Scale assessments within five years of death. Each 1 μg/m³ increase in PM2.5 concentration before assessment was associated with a 0.48 point increase in dementia severity scores, indicating greater cognitive and functional impairment.
The researchers used structural equation modelling to examine whether Alzheimer’s pathology mediated the relationship between pollution exposure and cognitive decline. They found that the estimated indirect effect through increasing Alzheimer’s disease neuropathologic change accounted for 63 per cent of the total association.
Reversing memory loss
“Memory loss affects more than a third of people over 70, and it’s a major risk factor for Alzheimer’s disease,” said Timothy Jarome, associate professor in the School of Animal Sciences at Virginia Tech, who led complementary studies on reversing memory loss through gene reactivation. “If we can understand what’s driving it at the molecular level, we can start to understand what goes wrong in dementia.”
The autopsy cohort was demographically skewed, with the vast majority of subjects being white, non-Hispanic, highly educated with more than a college degree, and from less disadvantaged neighbourhoods. This unrepresentative sample may limit the generalisability of the findings.
The cohort also included a large proportion of cases through research programmes enriched for Alzheimer’s dementia and did not enrol individuals with vascular dementia, which may have induced selection bias. Due to the rarity of cerebrovascular pathology in the cohort, the study likely underestimated true associations between PM2.5 and cerebrovascular disease.
“While promising, deep neural networks are far from being perfect computational models of human vision,” the researchers noted in discussing limitations of exposure modelling approaches.
The findings are consistent with prior population-based studies demonstrating associations between PM2.5 exposure and worse cognitive outcomes. The identification of Alzheimer’s pathology as a potential mediator supports the hypothesis that PM2.5 exposure is deleterious for brain maintenance pathways.
The researchers called for replication in large population-based autopsy cohorts to better understand relationships among PM2.5 exposure, cognition, and neuropathology.
