UCSF

Plasma neurofilament light chain (NfL) is a sensitive blood-based biomarker of neuroaxonal injury with potential value for predicting Alzheimer’s disease (AD)-related neurodegeneration. However, plasma NfL is influenced by physiological factors, including age, body mass index (BMI), and renal function. Besides, it remains unclear whether adjusted NfL measurements can predict subsequent structural brain changes during the preclinical stage of AD. Using data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), this study developed individualized plasma NfL reference distributions and evaluated their ability to predict longitudinal MRI-measured neurodegeneration. Generalized Additive Models for Location, Scale, and Shape were fitted in CU Aβ− reference participants with valid eGFR data (n=378) to derive age-, BMI-, and eGFR-adjusted NfL Z-scores. Linear mixed-effects models were then used to test whether baseline and longitudinal NfL Z-scores were associated with changes in hippocampal volume, AD-signature cortical thickness, and lateral ventricular volume among Aβ+ participants. Expected plasma NfL increased with age and lower eGFR and decreased with higher BMI. Adjusted NfL Z-scores increased progressively across the AD continuum. However, baseline NfL Z-score did not significantly predict longitudinal change in any MRI outcome in the CU Aβ+, cognitively impaired Aβ+, or Early AD Continuum cohorts. In an exploratory subset, a greater annualized increase in NfL Z-score was associated with faster hippocampal volume decline (β = −0.225, P = 0.045), although the association did not remain significant after multiple-comparison correction. These findings support physiological adjustment for individualized interpretation of plasma NfL. Although a single baseline measurement did not predict subsequent MRI change, longitudinal NfL dynamics may provide a more informative signal of ongoing neurodegeneration and warrant further evaluation in larger cohorts with more frequent repeated measurements.