Serum neurofilament light chain levels are associated with all-cause mortality in the general US population

Introduction: Serum neurofilament light chain (sNfL) levels are biomarkers of neuro-axonal injury in multiple neurological diseases. Little is known on their potential role as prognostic markers in people without known neurological conditions. Objective: The aim of this study is to evaluate the association between sNfL levels and all-cause mortality in a general population setting. Methods: sNfL levels were measured in 2071 people aged 25–75 years from the general US population that participated in the 2013–2014 cycles of the National Health and Nutrition Examination Survey (NHANES). Cognitive function was evaluated in a subset of participants aged 60–75 years using the Consortium to Establish a Registry for Alzheimer’s Disease-Word Learning test, the Animal Fluency test and the Digit Symbol Substitution test. We applied Cox proportional hazard models adjusted for several potential confounders to evaluate the association between sNfL and all-cause mortality through December 2019 by linking NHANES data with data from the National Death Index. Results: In a cross-sectional analysis, higher sNfL levels were associated with worse performance in all three cognitive function tests. Over a median follow-up of 6.1 years, 85 participants died. In a multivariable model adjusted for age, sex, race-ethnicity, diabetes, chronic kidney disease, harmful alcohol consumption, cigarette smoke and prevalent cardiovascular disease, higher sNfL levels were significantly and positively associated with all-cause mortality (HR per unit increase in log-transformed sNfL: 2.46, 95% CI 1.77–3.43, p < 0.001). Results were robust when analyses were stratified according to age, sex, body mass index and kidney function. Conclusion: We found a positive association between sNfL levels and mortality in the general US population. Further studies are needed to understand the biological mechanisms underlying this association.