Neutrophil‐Secreted Enzymes and ALS Risk: Exploring a Potential Mechanistic Link

Objective Peripheral immunity plays a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS). We previously showed that elevated neutrophil counts are associated with increased risk of ALS occurrence and faster disease progression, potentially through axonal damage. However, the mechanisms linking neutrophils to ALS occurrence remain unclear. Neutrophil‐secreted enzymes, key markers of neutrophil activity, may mediate these effects. We therefore investigated the role of neutrophil‐secreted enzymes in ALS occurrence. Methods Six neutrophil‐secreted enzymes were selected from the UK Biobank–Proteomics Platform. Cox proportional hazards regression was used to examine associations between these enzymes and ALS occurrence. Multiple sensitivity analyses were conducted to ensure robustness. Stratified analyses evaluated potential effect modifications by age, sex, and body mass index (BMI). To investigate whether neutrophil‐secreted enzymes contribute to ALS occurrence via a “dying‐back” mechanism, mediation analysis was performed to assess the indirect effect of neurofilament light chain (NfL) levels in this relationship. Results Individuals who later developed ALS showed significantly higher levels of neutrophil‐secreted enzymes prior to disease onset, suggesting that neutrophil activation occurs before ALS occurrence. Elevated enzyme levels were associated with an increased risk ALS occurrence. Furthermore, we observed a linear positive correlation between enzyme levels and NfL concentrations. Mediation analysis indicated that the effects of MPO and S100A12 on ALS onset were partially mediated through axonal injury. Interpretation Elevated neutrophil‐secreted enzymes are associated with an increased risk of ALS occurrence. This finding provides mechanistic insight into neutrophil involvement in ALS and identifies these enzymes as potential therapeutic targets. ANN NEUROL 2026