Higher long-term exposure to fine particulate air pollution was associated with an increased risk for Alzheimer’s disease (AD) in older adults.

In a nationwide Medicare cohort study of nearly 28 million older adults, 5-year average PM_2.5 exposure prior to AD onset was associated with a slightly increased risk of developing AD.

Hypertension, stroke, and depression were each independently associated with an increased risk for AD; however, they explained only a small proportion of the association between air pollution and AD onset.

Investigators led by Yanling Deng, PhD, found that PM_2.5 exposure was associated with an increased risk for AD in a large national cohort, primarily through direct pathways rather than through mediation by common comorbidities. The association was modestly stronger among individuals with stroke, suggesting heightened vulnerability in this subgroup.

The study was published online on February 17 in PLoS Medicine.

Comorbidities and AD Risk

Air pollution exposure is a known risk factor for AD and for chronic conditions including hypertension, stroke, and depression, which are also linked to dementia. However, it was unclear whether it increased dementia risk indirectly — by contributing to these conditions — or through direct effects on the brain. This uncertainty also raised the possibility that individuals with vascular or other chronic health vulnerabilities might be especially susceptible to its effects.

To assess whether these conditions modify or mediate the association between air pollution and incident AD, the investigators created three distinct cohorts from the nationwide Medicare database. They included a main cohort of all participants and two additional sub-cohorts that excluded individuals with preexisting hypertension, stroke, or depression at baseline.

These sub-cohorts allowed the investigators to assess whether each condition modified or mediated the relationship between PM_2.5 exposure and incident AD.

The investigators measured 5-year average PM_2.5 exposure using residential ZIP code-level air pollution data, linked to the Medicare fee-for-service claims database and supplemented with area-level socioeconomic data.

The main cohort included 27,763,593 Medicare beneficiaries aged 65 years or older (mean age, 75.7 years; women, 57.9%; men, 42.1%; White individuals, 89.2%) between 2000 and 2018. Participants were followed for a median of 6 years. Of the total cohort, 15.9% were eligible for Medicaid.

Over the follow-up period, 2,997,902 individuals (10.8%) developed incident AD. Baseline comorbidities were common, with hypertension present in 86.9%, depression in 34.9%, and stroke in 23.2% of participants after the 5-year clean period.

The clean period was used to reduce the likelihood of misclassifying preexisting AD as a new diagnosis based on Medicare claims, though some individuals may have already had underlying disease.

Exposure to PM_2.5 was assessed using high-resolution air pollution models linked to residential ZIP code, with a mean 5-year exposure level of 10.1 μg/m³ (interquartile range [IQR], 3.8 μg/m³). Investigators used Cox proportional hazards models adjusted for age, sex, race, socioeconomic indicators, geographic region, smoking rates, BMI, healthcare access, and other confounders.

The investigators also conducted mediation and stratified analyses to evaluate whether hypertension, stroke, and depression modified or mediated the relationship between PM_2.5 exposure and AD risk.

The Impact of Stroke

Higher PM_2.5 exposure was associated with significantly increased risk for incident AD, with a hazard ratio (HR) of 1.085 (95% CI, 1.078-1.091; P < .001) per IQR increase in exposure.

Stroke modestly amplified the association between PM_2.5 exposure and AD. The association was somewhat stronger among individuals with a history of stroke (HR, 1.105; 95% CI, 1.096-1.114), suggesting increased susceptibility in this subgroup. In contrast, hypertension and depression did not meaningfully modify the strength of the association.

Although PM_2.5 exposure was associated with an increased risk for hypertension, stroke, and depression, mediation analyses showed these conditions accounted for only a small portion of the air pollution-AD association: hypertension mediated 1.6%, stroke 4.2%, and depression 2.1%.

“These findings highlight the need for air quality interventions as part of dementia prevention strategies in aging populations, especially those facing overlapping environmental and clinical vulnerabilities,” the investigators wrote, emphasizing the importance of vascular risk management and environmental health awareness among older adults.

The study’s limitations include reliance on administrative claims data and ZIP code-level exposure estimates. Nevertheless, its large sample size and robust analytic approach provide additional support for an association between air pollution and AD risk. The findings suggest that long-term exposure to fine particulate air pollution may be associated with an increased risk for AD, with potentially greater effects among older adults with a history of stroke.

Cleaner Air for Better Brain Health

In a press release from the Science Media Centre in the UK, Sheona Scales, PhD, Director of Research at Alzheimer’s Research UK, noted that the results support a more direct link between air pollution and brain health.

“People who had previously had a stroke seemed slightly more vulnerable to the effects of air pollution, while high blood pressure and depression did not account for most of the increased dementia risk. This suggests that polluted air may be affecting the brain more directly than we once thought,” Scales said.

Similarly, Mark Dallas, PhD, associate professor in cellular neuroscience at the University of Reading, Reading, England, said the findings align with growing evidence that air pollution is a modifiable risk factor for dementia.

Similarly, Dallas noted that the findings are consistent with growing evidence that suggests air pollution has a negative effect on the brain.

“Overall, the study reinforces a simple idea: what we breathe over many years can shape how our brains age,” Dallas said in the release. He added that air pollution represents a potentially modifiable risk factor for dementia.

This study was funded by the National Institutes of Health (R01 AG074357 to KS and R01 ES034175 to YL). Deng and Scales reported having no relevant financial relationships. Dallas reported receiving research funding from the MRC and the Carbon Monoxide Research Trust and being a member of the Alzheimer’s Research UK Thames Valley Network.