Document Type

Article

Publication Date

9-22-2025

Comments

This article is the author’s final published version in Journal of Alzheimer's Disease Reports, Volume 9, 2025, Article number 9.

The published version is available at https://doi.org/10.1177/25424823251379878. Copyright © The Author(s) 2025.

 

Abstract

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.

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Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License

Language

English

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