Neurofilament light (NfL) chain levels predict clinical decline in Alzheimer's disease: A systematic review and meta-analysis

Background Regulatory approval of new investigational Alzheimer's disease (AD) therapies could be accelerated if reasonably likely surrogate endpoints could be used. Neurofilament light chain (NfL) has potential utility as a prognostic biomarker of neurodegeneration in AD. Objective To synthesize available evidence on the relationship between baseline NfL levels and longitudinal clinical decline. Methods A systematic literature review identified 19 eligible studies, contributing 37 longitudinal statistical models evaluating the association between baseline NfL (plasma or cerebrospinal fluid [CSF]) with subsequent clinical decline based on validated clinical scales including Mini-Mental State Examination (MMSE), Alzheimer's Disease Assessment Scale-Cognitive Subscale, and Clinical Dementia Rating. Results were pooled via meta-analysis, using partial correlation coefficients (PCC), separately for patient sub-groups (mild cognitive impairment, AD or combined). Results Across the AD continuum, higher baseline NfL levels were consistently associated with greater cognitive and global clinical decline in most analyses. This pattern was consistent for both plasma (pooled PCC = −0.17 [95% CI = −0.22, −0.12] for MMSE, any AD population) and CSF NfL (pooled PCC = −0.14 [95% CI = −0.24, −0.04] for MMSE, any AD population). The strength of association across multiple clinical endpoints and populations, measured by absolute value of pooled PCC, ranged from 0.13 to 0.25. Conclusions The results support the utility of NfL as a predictive biomarker for progression of clinical decline in AD patients.