Neurofilament light chain (NfL) as a biomarker for neurodegeneration: Protein biology, detection methods, and clinical applications

Neurofilaments are vital structural components of neurons and play a central role in preserving axonal architecture and function. Among these, neurofilament light chain (NfL) has emerged as a sensitive biomarker of neuroaxonal injury. This chapter delineates the molecular organisation of neurofilaments, tracing their hierarchical assembly from coiled-coil dimers to mature filaments, and emphasises their contribution to axonal stability, calibre regulation, and intracellular transport. It further examines how perturbations in neurofilament homeostasis reflect neuronal damage across a broad spectrum of neurological disorders. Advances in analytical technologies, particularly ultrasensitive immunoassays such as Sioma and ELISA, have enabled robust quantification of NfL in cerebrospinal fluid and blood, facilitating its translation from experimental research into clinical practice. The diagnostic and prognostic relevance of NfL is examined across neurodegenerative, inflammatory, traumatic, and vascular diseases of the nervous system, with particular focus on Alzheimer's and Parkinson's diseases, highlighting its utility for disease monitoring and assessing treatment response. A discussion of clinical factors to consider when assessing NfL for disease diagnosis, along with its current challenges, is provided to draw attention to additional research. Through mechanistic insights spanning protein biology, clinical findings, and biomarker science, this chapter highlights NfL as a robust and non-invasive indicator of neuroaxonal injury applicable across distinct aetiologies. It posits that the systematic incorporation of NfL measurements into clinical workflows may refine nosological classification, enhance diagnostic and prognostic precision, and improve risk stratification at both individual and cohort levels, whilst informing evidence-based therapeutic decision-making and longitudinal patient management across a wide spectrum of neurological conditions.