Associations Between Prediagnosis Plasma Neurofilament Light Polypeptide and Amyotrophic Lateral Sclerosis Risk in the Danish EPIC Cohort

OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a rapid time from symptoms onset to diagnosis. Elevated neurofilament light polypeptide (NfL) is well-established in symptomatic ALS and up to 5 years prediagnosis, but earlier timeframes remain understudied. We aimed to assess plasma NfL levels up to 23 years before ALS diagnosis and the relation to ALS risk. METHODS: We conducted a nested matched case-control study within the Danish EPIC cohort (baseline 1993-1997) including 166 ALS cases (diagnosed 1997-2017) and 332 controls matched on birth year and sex. Plasma samples collected 0.4 to 23.2 years (median 14.1 years) prediagnosis were analyzed for NfL using Olink Target 96. Odds ratios were estimated using conditional logistic regression. Discriminatory performance was evaluated using receiver operating characteristic curves. RESULTS: NfL levels were elevated in ALS cases relative to controls up to 14.6 years before diagnosis. Among those with blood samples collected <5, 5 to 14.6, and >14.6 years before diagnosis, the odds ratios (95% CI) for ALS per standard deviation increase in the normalized protein expression value of NfL were 3.8 (1.4-10.3), 1.7 (1.2-2.3), and 1.3 (0.9-1.7), respectively. The areas under the curve for ALS discrimination by NfL among those with blood collected <5 and 5-14.6 years before diagnosis were 0.78 and 0.63, respectively. INTERPRETATION: Plasma NfL elevation may occur significantly earlier than previously reported, indicating a much longer ALS prodrome. Assuming other biomarker changes may also occur earlier, this raises the possibility of identifying at-risk individuals early that could benefit epidemiologic analyses, clinical trials, and prevention efforts. ANN NEUROL 2026.