Abstract
<jats:p> In the pathologically and clinically heterogeneous neurodegenerative disorder amyotrophic lateral sclerosis (ALS), objective biochemical predictors of survival are essential to handle complexity in clinical trials, enrich clinical decision-making and interrogate the biology of disease progression. In this longitudinal study, we performed high-depth proximity extension assay proteomics using 1,095 samples of serum ( <jats:italic>N</jats:italic> =851) and CSF ( <jats:italic>N</jats:italic> =244) from 426 people with ALS, with orthogonal replication in an external cohort of 349 people with ALS. Age- and sex-adjusted Cox analysis identified 57 proteins in serum, including neurofilament light chain (NEFL) and peripherin, as well as five proteins in CSF, including tropomyosin 3 (TPM3) that were associated with survival (FDR-adjusted <jats:italic>p</jats:italic> ≥0.05). Penalised Cox regression identified a panel of 9 serum proteins – including NEFL, peripherin, TNF receptor superfamily member 27 (EDA2R) and calcitonin – that reflect the extent of disease as well as the progression rate, improving survival prediction compared with models using clinical parameters and NEFL. Joint modelling identified associations between the longitudinal trajectories of serum EDA2R and calcitonin with survival, highlighting their potential role in measuring disease progression. This work indicates the utility of multiple proteins reflecting diverse biological pathways in refining survival stratification and highlights systemic factors in ALS progression. </jats:p>