Air pollution worsens Alzheimer’s brain pathology and accelerates cognitive decline

A new study published in JAMA Neurology reveals that exposure to high levels of fine particulate air pollution may worsen the progression of Alzheimer’s disease. Post-mortem analysis of brain tissue showed that individuals who lived in areas with more polluted air had a greater buildup of the toxic proteins that define the disease and experienced a faster decline in their cognitive and functional abilities compared to those with less exposure. This research provides the first direct evidence from human brain tissue linking the severity of Alzheimer’s pathology to ambient air pollution.

Alzheimer’s disease is a progressive neurodegenerative disorder that gradually destroys memory and other important mental functions. The disease is physically characterized by the abnormal accumulation of two proteins in the brain: amyloid-beta, which forms sticky plaques between nerve cells, and tau, which creates toxic tangles inside them. Together, these plaques and tangles disrupt communication between brain cells and trigger a cascade of events that leads to cell death and brain atrophy. While age and genetics, particularly the APOE ε4 gene variant, are known risk factors, scientists are increasingly looking at environmental factors that might contribute to the disease.

Previous research has suggested a connection between air pollution and an increased risk of developing dementia. Specifically, many studies have focused on fine particulate matter, known as PM2.5. These are microscopic particles, smaller than 2.5 micrometers in diameter, that are released from sources like vehicle exhaust, industrial processes, and wildfires. Because of their tiny size, they can be inhaled deep into the lungs, enter the bloodstream, and potentially cross the protective blood-brain barrier to affect the central nervous system.

Despite the growing evidence linking PM2.5 to cognitive problems, the biological mechanisms have remained unclear. Researchers at the Perelman School of Medicine at the University of Pennsylvania sought to fill this knowledge gap. They wanted to determine if there was a direct, observable relationship between a person’s exposure to PM2.5 and the actual amount of Alzheimer’s-related damage present in their brain after death. By examining brain tissue directly, which is considered the gold standard for diagnosing and staging neurodegenerative diseases, they hoped to establish a more definitive link between pollution, brain pathology, and the clinical symptoms of dementia.

To conduct their investigation, the research team utilized data from the University of Pennsylvania’s Integrated Neurodegenerative Disease database. This database contains comprehensive information from individuals who had consented to donate their brains for research upon their death. The study included 602 deceased individuals, most of whom had been diagnosed with a form of dementia, primarily Alzheimer’s disease or Parkinson’s disease with dementia.

The participants were predominantly White, highly educated, and had a median age of 78 at the time of death. For each individual, the researchers obtained their last known residential address. They then used a sophisticated and publicly available prediction model to estimate the annual average concentration of PM2.5 at that specific location for the year leading up to the person’s death. This provided a snapshot of each participant’s recent environmental exposure.

Following autopsy, a detailed neuropathological assessment was performed on each brain. Pathologists systematically measured the extent of Alzheimer’s disease neuropathologic change (ADNC). This included quantifying the amount and distribution of amyloid plaques using a measure called the Thal amyloid phase and the spread of tau tangles using the Braak stage. They also looked at the density of amyloid plaques with the CERAD score. These individual measures were combined to generate an overall ADNC level, categorized as none, low, intermediate, or high.

The pathologists also searched for evidence of other common brain pathologies associated with dementia, such as Lewy bodies (linked to Parkinson’s disease and Lewy body dementia) and various forms of cerebrovascular disease, including small strokes. For a subset of the participants who had regular clinical evaluations before their death, the researchers had access to their scores on the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB). This is a comprehensive tool used to measure the severity of dementia across six domains, including memory, judgment, personal care, and community affairs, with higher scores indicating more severe impairment.

The researchers found a strong association between higher PM2.5 exposure and more severe Alzheimer’s pathology. For every one-microgram-per-cubic-meter increase in the estimated annual PM2.5 concentration, the odds of having more advanced brain pathology rose substantially.

Specifically, the odds of having a more widespread distribution of amyloid plaques (higher Thal phase) increased by 17%, and the odds of having more advanced tau tangles (higher Braak stage) increased by 20%. The overall level of Alzheimer’s disease neuropathologic change was 19% more likely to be in a higher severity category with each unit increase in PM2.5. This connection appeared to be specific to Alzheimer’s pathology, as the researchers did not find a similar association between air pollution and the severity of Lewy body disease or another proteinopathy called LATE.

When the team examined the clinical data, the results were equally compelling. In the subgroup of individuals with available dementia severity scores, higher PM2.5 exposure was associated with worse cognitive and functional impairment. Each one-unit increase in PM2.5 was linked to a 0.48-point increase on the 18-point CDR-SB scale, a clinically meaningful difference.

For participants with multiple assessments over time, the study showed that higher pollution exposure was also associated with a faster rate of decline. To connect these findings, the researchers performed a mediation analysis. This statistical technique allowed them to explore whether the effect of air pollution on dementia symptoms was explained by the changes in the brain. They discovered that the increased Alzheimer’s pathology was a major intermediary.

The analysis estimated that about 63% of the negative impact of PM2.5 on a person’s dementia severity score was directly attributable to the worsening of amyloid and tau pathology in the brain. This suggests that air pollution does not just coincide with cognitive decline; it may actively contribute to it by accelerating the underlying disease process.

“This study shows that air pollution doesn’t just increase the risk of dementia—it actually makes Alzheimer’s disease worse,” said Edward Lee, co-director of Penn’s Institute on Aging. “As researchers continue to search for new treatments, it’s important to uncover all of the factors that contribute to the disease, including the influence of the environment in which they live.”

But the authors note some limitations of their work. The study cohort was not representative of the general population, as participants were almost all White and highly educated, which may limit the generalizability of the findings to other demographic groups. The participants were also drawn from clinical research programs focused on dementia, meaning they were already enriched for Alzheimer’s and had relatively low rates of cerebrovascular disease. This focus might have made it harder to detect any potential links between air pollution and vascular-related brain injury.

Additionally, pollution exposure was estimated based on the last known residential address and did not account for a person’s entire life history of exposure or time spent away from home. The study was also observational, so it shows an association rather than proving a direct cause-and-effect relationship.

Future research is needed to replicate these findings in larger, more diverse population-based autopsy cohorts. Mechanistic studies are also warranted to understand exactly how inhaled pollutants might damage the brain and promote the formation of plaques and tangles. Despite these limitations, the study provides strong evidence that air quality is a meaningful factor in the progression of Alzheimer’s disease.

The study, “Ambient Air Pollution and the Severity of Alzheimer Disease Neuropathology,” was authored by Boram Kim, Kaitlin Blam, Holly Elser, Sharon X. Xie,Vivianna M. Van Deerlin, Trevor M. Penning, Daniel Weintraub, David J. Irwin, Lauren M. Massimo, Corey T. McMillan, Dawn Mechanic-Hamilton, David A. Wolk, and Edward B. Lee.