Introduction: Several blood-based biomarkers are associated with neuronal injury, but their utility in interventional clinical trials is unclear. This study retrospectively evaluated the utility of plasma neurofilament light (NfL) and total tau (t-tau) in an 18-month trial in mild Alzheimer's disease (AD). Methods: Correlation and conditional independence analyses and Gaussian graphical models were used to investigate cross-sectional and longitudinal relations between NfL, t-tau, and clinical scales. Results: NfL had a stronger association than t-tau with clinical scales; t-tau did not hold additional information to that given by NfL (P > 0.05 at all time points). NfL held independent information about shorter-term (3- to 6-month) progression beyond patient age and clinical scores. However, no meaningful gain in power was found when adjusting a longitudinal analysis of cognitive scores for baseline NfL. Discussion: Plasma NfL is superior to t-tau in mild AD. The ability of NfL to detect changes before clinical manifestations makes it a promising biomarker of drug response in trials of disease-modifying drugs.