Innate immune signaling as a potential pathomechanistic biomarker for distinct subtypes in amyotrophic lateral sclerosis.

Stimulation of the innate immune system has been implicated in ALS and particularly in distinct monogenic forms of ALS. To address whether this is of diagnostic value, we performed a proof-of concept study using qPCR to assess the Interferon score in blood samples of genetic ALS. 56.5% of genetic ALS patients showed significant IFN activation, highest in C9orf72HRE patients (77.3%). About half of FUS-ALS (52.2%), but none of SOD1-ALS patients demonstrated pathological IFN scores. The IFN score significantly correlated with the ALSFRS-R slope and inversely with the time to severe event as a survival surrogate in this genetic ALS cohort. IFN + patients were more likely to be male, showed more rapid disease progression and higher neurofilament levels. The IFN score might have the potential as a stratification and readout tool for biomarker-guided individualized therapy in ALS.