Associations between Nicotine Metabolites and Serum Neurofilament Light Chain Levels in the General Population

Abstract Background: Nicotine has been recognized for enhancing cognitive functions, with serum neurofilament light chain (sNfL) as a biomarker for neurological conditions. However, the relationship between nicotine and its metabolites and sNfL levels remains underexplored. This study aims to investigate the associations of serum and urine levels of cotinine and trans-3’-hydroxycotinine (hydroxycotinine) with sNfL levels in a broad population. Methods: Employing data from the National Health and Nutrition Examination Survey (NHANES) 2013-2014, this cross-sectional study used multivariable linear regression models and restricted cubic splines to examine the links between cotinine, hydroxycotinine (both in serum and urine), and sNfL levels. Results: Including individuals with an average age of 46.8 (SD=15.3) years—1069 women (weighted, 52.1%) and 984 men (weighted, 47.9%) for serum analysis, and 327 women (weighted, 49.5%) and 334 men (weighted, 50.5%) for urine analysis—the study found that sNfL levels positively correlated with serum and urine levels of cotinine and hydroxycotinine. Adjusted analyses revealed increases in sNfL levels in association with these substances, noting nonlinear associations for hydroxycotinine (serum and urine) and urine cotinine with sNfL levels. Conclusions: The findings highlight significant positive relationships between serum and urine levels of cotinine and hydroxycotinine and sNfL levels, with novel U-shaped associations observed at low levels of urine cotinine and hydroxycotinine. These results suggest a potentially beneficial effect of low-dose nicotine or its metabolites on sNfL levels, warranting further research.