The Nonlinear Relationship Between the Aggregate Index of Systemic Inflammation and Serum Neurofilament Light Chain Levels in U.S. Adults: A Cross‐Sectional Study

BACKGROUND: Systemic inflammation is linked to chronic diseases. This study examines the relationship between the aggregate index of systemic inflammation (AISI) and serum neurofilament light chain (sNfL), a marker of neuronal damage. METHODS: Data were obtained from the 2013-2014 National Health and Nutrition Examination Survey (NHANES). Participants with complete data on AISI and sNfL were included. Multiple linear regression and subgroup analyses were used to assess the association, and the nonlinear relationship was explored through smoothed curve fitting and threshold effect analyses. RESULTS: Among 2,061 adults in NHANES 2013-2014, ln AISI was positively associated with sNfL (pg/mL) (fully adjusted β = 2.78 per 1-unit increase; 95% CI: 1.41-4.15; p < 0.0001). By quartiles of ln AISI, sNfL was higher in Q4 vs. Q1 (β = 6.22, 95% CI: 3.57-8.88; p < 0.0001), whereas Q2-Q3 were not significant after full adjustment; p for trend < 0.0001. Nonlinearity analysis identified an inflection at ln AISI = 4.34: below this value the estimate was negative and nonsignificant (β = -8.82; 95% CI: -18.10-0.46; p = 0.0627), whereas above it the association was positive and significant (β = 3.55; 95% CI: 2.05-5.04; p < 0.0001; likelihood ratio p = 0.013). Effect modification was observed by age (p for interaction = 0.0068), BMI (p for interaction = 0.0174), diabetes (p for interaction = 0.0004), hypertension (p for interaction = 0.0436), alcohol use (p for interaction = 0.0133), and stroke history (p for interaction = 0.0033). CONCLUSION: In the U.S. population, higher ln AISI values were independently associated with increased sNfL levels. A nonlinear relationship was observed between ln AISI and sNfL. This suggests that AISI may represent an important marker associated with sNfL levels beyond traditional clinical factors, and further studies are needed to better explore their association and potential underlying biological mechanisms.