A - 20 Association between Smoking-Related DNA Methylation Marker and Brain MRI Volumes in Older Adults

Abstract Objective Smoking is a well-established risk factor for dementia. Studies have shown that a history of smoking is linked to higher rates of cortical volume loss in older adults. However, biological mechanisms of smoking, particularly through epigenetic changes, remain poorly understood. This study investigates the association between DNA methylation markers of smoking and patterns of brain atrophy. Methods In this cross-sectional analysis, 78 participants aged 47 years and older (68% female) from the ongoing Health Brain Initiative Study were included. DNA methylation markers of smoking were quantified using a validated algorithm applied to blood samples analyzed via the 850 k EPIC array (i.e., EpiSmoking). Brain MRI variables assessed included total cortical, hippocampal, entorhinal cortex, white matter hyperintensity volumes, and machine learning-derived atrophy scores for various cortical regions. Partial correlation analysis controlled for age, sex, education, and cognitive status (normal or mild cognitive impairment). Results Higher EpiSmoking scores significantly correlated with increased atrophy in the total cerebral cortex (r = 0.27, p < 0.05), frontal (r = 0.25, p < 0.05), parietal (r = 0.20, p < 0.05), and temporal lobes (r = 0.28, p < 0.01). No significant associations were found with other brain regions. Conclusions Our findings indicate that smoking-related DNA methylation changes are linked to specific patterns of brain atrophy. These results support the theory that environmental factors, such as smoking, may negatively impact the epigenome and potentially increase the risk of dementia. However, further research with larger cohorts is necessary to validate these associations and explore the underlying mechanisms.