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BACKGROUND: Increased exposure to ambient air pollution, especially fine particulate matter ≤2.5 μm (PM2.5) is associated with poorer brain health and increased risk for Alzheimer’s disease (AD) and related dementias. The locus coeruleus (LC), located in the brainstem, is one of the earliest regions affected by tau pathology seen in AD. Its diffuse projections throughout the brain include afferents to olfactory areas that are hypothesized conduits of cerebral particle deposition. Additionally, extensive contact of the LC with the cerebrovascular system may present an additional route of exposure to environmental toxicants. OBJECTIVE: Our aim was to investigate if exposure to PM2.5 was associated with LC integrity in a nationwide sample of men in early old age, potentially representing one pathway through which air pollution can contribute to increased risk for AD dementia. METHODS: We examined the relationship between PM2.5 and in vivo magnetic resonance imaging (MRI) estimates of LC structural integrity indexed by contrast to noise ratio (LCCNR) in 381 men [mean age = 67.3; standard deviation (SD)= 2.6] from the Vietnam Era Twin Study of Aging (VETSA). Exposure to PM2.5 was taken as a 3-year average over the most recent period for which data were available (average of 5.6 years prior to the MRI scan). We focused on LCCNR in the rostral-middle portion of LC due to its stronger associations with aging and AD than the caudal LC. Associations between PM2.5 exposures and LC integrity were tested using linear mixed effects models adjusted for age, scanner, education, household income, and interval between exposure and MRI. A co-twin control analysis was also performed to investigate whether associations remained after controlling for genetic confounding and rearing environment. RESULTS: Multiple linear regressions revealed a significant association between PM2.5 and rostral-middle LCCNR (β= -0.16; 푝= 0.02), whereby higher exposure to PM2.5 was associated with lower LCCNR. A co-twin control analysis found that, within monozygotic pairs, individuals with higher PM2.5 exposure showed lower LCCNR (β= -0.11; 푝= 0.02), indicating associations were not driven by genetic or shared environmental confounds. There were no associations between PM2.5 and caudal LCCNR or hippocampal volume, suggesting a degree of specificity to the rostralmiddle portion of the LC. DISCUSSION: Given previous findings that loss of LC integrity is associated with increased accumulation of AD-related amyloid and tau pathology, impacts on LC integrity may represent a potential pathway through which exposure to air pollution increases AD risk. [ABSTRACT FROM AUTHOR]