Abstract
<jats:title>Abstract</jats:title> <jats:p>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss and significant clinical variability. Blood-based biomarkers offer a scalable approach to stratify patients and support therapeutic development. In a large-scale serum proteomic survival study of ALS, we analyzed 741 patients from independent cohorts in Israel and the UK to identify blood proteins linked to ALS survival. The cohorts were profiled using complementary proteomics technologies, mass spectrometry and the Olink proximity extension assay (PEA), enabling cross-cohort and cross-platform evaluation of concordant protein effects. We identified 19 serum proteins associated with ALS survival across two independent cohorts profiled using orthogonal proteomic platforms. Among these, GSN and IGFBP2 improved survival prediction and patient stratification compared to established clinical covariates and provided additional prognostic information compared to serum neurofilament light chain (NfL). These novel circulating protein biomarker candidates may improve prognostic assessment and support future precision-medicine approaches in ALS.</jats:p>