To investigate whether longitudinal neurofilament light chain (NfL) trajectory is associated with survival in ALS across multiple cohorts and complementary analytical frameworks.

Elevated baseline NfL predicts shorter survival in ALS, but the prognostic value of longitudinal NfL trajectory requires validation to support its use as a surrogate endpoint. The absence of NfL measurements at the time of death and through survival makes its use difficult and requires robust analytical strategies.

We analyzed longitudinal NfL and survival data from three independent ALS cohorts: the German APST ALS Data Repository, ANSWER ALS, and the HEALEY ALS Platform Trial. The primary analysis fitted a Weibull accelerated failure time model with time-varying NfL change from baseline of natural log-transformed NfL values. The secondary analysis employed joint longitudinal-survival modeling. Supportive Cox proportional hazards models with empirical Bayes (EB) slope estimates were performed across all cohorts. Sensitivity analyses used inverse probability weighting and landmark analyses.

In the primary time-varying Weibull AFT models, increasing NfL was significantly associated with shorter survival (APST: N=4,750 observations, 470 deaths, β = −0.382, SE=0.063, p < 0.0001, γ=1.54; ANSWER ALS: N=1,118 observations, 157 deaths, β = −0.639, SE=0.180, p = 0.0004, γ=1.78). Each unit increase in Δln(NfL) was associated with 32–47% shorter survival time. Secondary joint modeling confirmed the association (HR=1.10–1.12 per unit Δln(NfL), both p≤0.001). Supportive Cox EB proportional hazards analyses confirmed consistent prognostic associations across all three cohorts (all p<0.05). NfL reduction was associated with a 6–11% instantaneous mortality hazard reduction per 10% decline. Sensitivity analyses demonstrated concordant associations.

Longitudinal NfL trajectory independently predicts survival in ALS. Consistent effects across analytical frameworks and three independent cohorts support consideration of NfL trajectory as a candidate surrogate outcome measure for ALS clinical trials.