Presymptomatic Amyotrophic Lateral Sclerosis: From Early Biomarker Detection to Phenoconversion Prediction

Amyotrophic lateral sclerosis (ALS) usually enters diagnostic pathways after motor symptoms emerge, by which time neural injury has been ongoing. Long-term heredi-tary ALS cohorts show that some pathogenic-variant carriers may show elevated neu-rofilament light chain (NfL), mild motor impairment (MMI), electromyographic ab-normalities, or imaging changes before clinical manifestation. Since 2022, research has shifted from detecting presymptomatic abnormalities to identifying observable pro-dromal phenotypes and predicting phenoconversion timing. Operational MMI criteria, longitudinal imaging in chromosome 9 open reading frame 72 (C9orf72) expansion carriers, TAR DNA-binding protein 43 (TDP-43)-related fluid biomarkers, and plasma proteomic models spanning prediction horizons have broadened early identification. The ATLAS study, a trial of tofersen initiated in clinically presymptomatic carriers of superoxide dismutase 1 (SOD1) variants, incorporated specific SOD1 variants and within-person NfL increases into risk monitoring and used these criteria to select par-ticipants for the randomized treatment phase. Evidence remains concentrated in a few genetic subtypes, and no single marker accurately predicts individual phenoconver-sion. Identification requires genotype-specific natural history, serial clinical examina-tions and biomarker testing, with clinical utility validated in independent longitudinal cohorts and prevention trials.