Systematic proteomics reveals plasma NEFL as a robust predictor and pathological associate in C9ORF72-related neurodegeneration

Background: expansion and evaluated their predictive value for motor neuron disease (MND). Methods: expansions (defined as >30 repeats) and 212 age- and sex-matched controls. We screened ~3,000 proteins for associations with the continuous repeat count. The top candidate was evaluated using restricted cubic splines (RCS) to assess non-linearity and threshold effects. Its ability to independently predict MND risk was tested using regression models and a machine learning approach. Results: repeat count. Our predictive model, combining NEFL and repeat count, achieved an AUC of 0.941 with 100% sensitivity. These findings align with emerging evidence that secreted NEFL may actively modulate neuroinflammation. Conclusions: carriers.