Background: Alzheimer’s disease (AD) shows highly variable progression rates among individuals. Plasma neurofilament light chain (NfL) has emerged as a potential biomarker of neurodegeneration. Objectives: this study aimed to evaluate the predictive value of plasma NfL in estimating the rate of clinical progression (RoP) in AD. Methods: we retrospectively analyzed 87 AD patients from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. We stratified patients into two groups based on the median RoP, which was calculated from longitudinal Mini-Mental State Examination (MMSE) score evaluations: slow decliners (SD) and fast decliners (FD). We then compared plasma NfL levels between the two groups and examined their relationship with the progression rate. Results: patients with faster decline rates had higher levels of NfL. Logistic regression (LR) analysis revealed a strong correlation between plasma NfL levels and disease progression rates. Furthermore, a multivariate model incorporating Aβ42 levels improved predictive accuracy. Conclusions: these findings suggest that plasma NfL could serve as a valuable biomarker for monitoring the progression of Alzheimer’s disease, identifying patients at greater risk of rapid decline, and optimizing therapeutic strategies and clinical management. Future studies on larger cohorts will be essential to confirm and further explore these observations.