Prodromal Elevation of DNA Damage and Cell Cycle Biomarkers HRAS and CHEK2 in Amyotrophic Lateral Sclerosis

Background: Pre-symptomatic biomarkers that reflect upstream pathogenic processes in amyotrophic lateral sclerosis (ALS) are urgently needed to enable earlier diagnosis and trial enrichment. Methods: Using longitudinal plasma proteomics from the UK Biobank Pharma Proteomics Project, we analyzed pre-diagnostic samples from 23 individuals who later developed motor neuron disease (MND). Mixed-effects regression models evaluated protein trajectories relative to years before diagnosis. Results: As expected, neurofilament light (NfL) demonstrated a progressive rise approaching clinical onset. Exploratory proteome-wide analysis identified two additional markers—CHEK2, a DNA damage–response kinase, and HRAS, a regulator of MAPK/ERK cell-cycle signaling—that showed linear elevation beginning up to 10 years before diagnosis. Genetic analyses revealed no germline association between CHEK2 or HRAS variants and ALS risk, suggesting state-dependent biological activation rather than inherited susceptibility. Conclusion: These findings provide early human evidence that DNA damage–response and cell-cycle pathways are systemically activated during the ALS prodrome; they precede structural neuroaxonal injury marked by NfL, CHEK2 and HRAS, and merit further evaluation as components of multi-marker risk models for early disease detection and therapeutic stratification.