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 hereditary ALS cohorts show that some pathogenic-variant carriers may show elevated neurofilament light chain (NfL), mild motor impairment (MMI), electromyographic abnormalities, or imaging changes before clinical manifestation. Since 2022, research has shifted from detecting presymptomatic abnormalities to identifying observable prodromal 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 participants for the randomized treatment phase. Evidence remains concentrated in a few genetic subtypes, and no single marker accurately predicts individual phenoconversion. Identification requires genotype-specific natural history, serial clinical examinations and biomarker testing, with clinical utility validated in independent longitudinal cohorts and prevention trials.