Abstract
BACKGROUND AND OBJECTIVES: To assess whether plasma neurofilament light chain (NfL) levels are elevated before amyotrophic lateral sclerosis (ALS) diagnosis and to evaluate whether prediagnostic NfL levels are associated with metabolic alterations. METHODS: We conducted a matched case-control study nested in 3 large prospective US cohorts (the Nurses' Health Study, the Health Professionals Follow-up Study, and the Multiethnic Cohort Study) and identified 84 individuals who developed ALS during follow-up and had available plasma samples prior to disease diagnosis. For each ALS case, we randomly selected controls from those who were alive at the time of the case diagnosis and matched on birth year, sex, race/ethnicity, fasting status, cohort, and time of blood draw. We measured NfL in the plasma samples and used conditional logistic regression to estimate rate ratios (RRs) and 95% confidence intervals (CIs) for ALS, adjusting for body mass index, smoking, physical activity, and urate levels. RESULTS: Higher NfL levels were associated with a higher ALS risk in plasma samples collected within 5 years of the ALS diagnosis (RR per 1 SD increase 2.68, 95% CI 1.18-6.08), but not in samples collected further away from the diagnosis (RR per 1 SD increase 1.16, 95% CI 0.78-1.73). A total of 21 metabolites were correlated with prediagnostic NfL levels in ALS cases (p < 0.05), but none of these remained significant after multiple comparison adjustments. DISCUSSION: Plasma NfL levels were elevated in prediagnostic ALS cases, indicating that NfL may be a useful biomarker already in the earliest stages of the disease. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that plasma NfL levels are elevated in prediagnostic ALS.