Neurofilament impairment in neurodegenerative diseases: pathogenesis, biomarkers and diagnostic values

Abstract

Neurofilament (NF) proteins, as integral components of the neuronal cytoskeleton, are essential for maintaining axonal structure and function. Genetic defects, aberrant post-translational modifications, and co-aggregation with other pathogenic proteins can disrupt NF homeostasis, leading to axonal injury and neuronal dysfunction. Advances in ultrasensitive detection technologies, particularly SiMoA assays, have enabled reliable quantification of NFs in both cerebrospinal fluid (CSF) and peripheral blood, substantially accelerating their clinical translation. However, current research has predominantly focused on the neurofilament light chain (NfL), with comparatively limited attention given to neurofilament medium (NfM) and heavy (NfH) chains. In this review, we comprehensively synthesize recent research findings in NfL, NfM, and NfH across major neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS). Further, we provide a multi-level analysis spanning molecular structure, pathological mechanisms, and clinical translation, while comprehensively evaluating key confounding factors and methodological challenges that influence detection outcomes. We propose that future efforts should prioritize the universal standardization of detection methods and highlight the value in precision management of neurodegenerative diseases.