EARLY-ALS: A Multicentre Study on Presymptomatic and Prodromal Amyotrophic Lateral Sclerosis

Neurodegenerative diseases often feature a prolonged presymptomatic phase during which pathological processes evolve before overt clinical manifestation. In Amyotrophic lateral sclerosis (ALS), defining this prodromal period is critical for identifying early disease features and the optimal window for intervention, yet it remains poorly characterised. In this cross-sectional study, we compared 475 ALS patients with 285 controls recruiting across 20 ALS expert centres in Germany and Switzerland. Participants completed a structured digital questionnaire capturing prodromal complaints, healthcare utilisation, comorbidities, lifestyle factors, and weight changes during the 10 years preceding ALS symptom onset. ALS patients reported substantially higher burden of prodromal complaints than controls (OR=7.50, 95% CI 4.27-13.17; P < 0.001; Padj < 0.001), particularly neuro-motor, sensory, and pain-related symptoms. Prior to symptom onset, ALS patients more frequently consulted neurologists (OR=1.26, CI 1.10-1.44; P < 0.001; Padj = 0.007). Speech therapy consultations were significantly more common among female patients (OR = 2.35, CI 1.05-5.28; P = 0.038) and those with bulbar-onset ALS (OR = 8.67, CI 3.80-19.77; P < 0.001). Prodromal musculoskeletal dysfunction was more frequently reported by ALS patients and exhibited sex- and site-specific patterns. Herniated discs were reported more often by male ALS patients (OR=2.21, CI 1.04-4.68; P = 0.038) and by those with spinal-onset disease (OR=2.32, CI 1.38-3.93; P = 0.002). ALS patients more often completed lower secondary education (OR=1.93, CI 1.24-3.01; P = 0.004; Padj = 0.020) and were more likely to have worked in physically demanding occupations (OR=2.21, CI 1.42-3.43; P < 0.001; Padj = 0.003). Lifestyle factors differed significantly, with higher prior consumption of caffeine (OR=7.21, CI 3.27-15.89; P < 0.001; Padj < 0.001), alcohol (OR=2.25, CI 1.47-3.43; P < 0.001; Padj = 0.002), and cigarettes (OR=1.64, CI 1.20-2.24; P = 0.002) among ALS patients (Padj = 0.011). Weight trajectories differed by sex (P = 0.009), with male ALS patients showing significant loss already during the pre-onset phase (P < 0.001). These findings demonstrate that ALS is preceded by a distinct prodromal phase characterised by mild motor impairment, altered healthcare engagement, and sex- and site-specific patterns in comorbidities, lifestyle, and metabolic change. Characterising these early features of ALS may facilitate earlier diagnosis and enable timely enrolment in clinical trials.