Potential Biomarkers of AD - Neurofilament Light (NfL)

Neurofilaments are a major component of the axonal cytoskeleton and are particularly abundant in myelinated axons of large caliber. Neurofilaments, although rare, are also present in cytosol and dendrites. They provide stability to the cytoskeletal structure of neurons and influence conduction velocity by controlling the caliber of axons. Neurofilaments have five subunits, neurofilament heavy, neurofilament medium, neurofilament light (NfL), α-endochain, and peripheral proteins, which differ in structure and function in the structural domains at the head and tail of the chain. Neurofilaments, especially NfL, have been used as markers of neural axonal degeneration because they are released into the cerebrospinal fluid (CSF) and bloodstream as a result of axonal injury or neuronal death.

Fig. 1 The neurofilament network in axons.¹

Over the past few years, many studies have explored the value of plasma or serum NfL as biomarkers of neurodegeneration in Alzheimer's disease (AD). In this article, Creative Biolabs describes research advances regarding the relationship between blood NfL levels and other indicators of neurodegeneration in AD. With a focus on quality, reliability, and precision, we strive to provide cutting-edge tools and services that facilitate groundbreaking discoveries in the field of AD research.

NfL as A Potential Biomarker for AD

CSF or blood levels of NfL are not specific to a particular disease. CSF or blood NfL levels are elevated in patients with a variety of neurological and neurodegenerative disorders, such as traumatic brain injury, multiple sclerosis, frontotemporal lobar degeneration, and AD. Not only that, but normal aging leads to an increase in CSF and blood NfL.

However, many studies have explored the value of CSF or blood NfL as a measure of neurodegeneration or as a diagnostic marker for AD. The findings suggest that NfL may be more useful in terms of being a biomarker for monitoring and predicting AD severity. Higher blood/CSF NfL levels were associated with lower cognitive function and more severe neurodegeneration, as well as faster cognitive decline or more severe neurodegeneration in AD patients.

For scientists, research teams, and biopharmaceutical companies studying NfL in AD, we offer some research tools. Below are some of antibody products commonly used to study NfL.

Potential of Blood NfL as a Biomarker for AD Monitoring

Some researchers have focused on correlations between serum or plasma NfL and other indicators of neurodegeneration, including cortical atrophy, cortical glucose metabolism, diffusion tensor imaging (DTI) indices, and functional magnetic resonance imaging (fMRI) indices. Studies have shown that blood NfL has the potential to be a monitoring biomarker for AD.

• Correlation between cortical atrophy and blood NfL: The findings suggest that blood NfL levels indicate the severity of MTL atrophy in the early stages of Alzheimer's disease. The whole-brain study also revealed a correlation between plasma NfL levels and cortical atrophy in brain regions, including overlapping regions of the default mode network (DMN), such as the posterior cingulate cortex, precuneus, medial frontal lobe, and superior frontal gyrus in patients with mild cognitive impairment or AD. The correlation between blood NfL and cortical atrophy appeared to vary by disease stage and Aβ load, and was region-specific, focusing on temporal and DMN regions.
• Correlation between serum NfL and brain glucose metabolism measured by FDG-PET: The results suggest that the correlation between NfL and FDG uptake appears to be more centered in brain regions susceptible to AD-related hypometabolism. Blood NfL seems to correlate more strongly with hypometabolism in regions susceptible to AD pathology compared to the degree of cortical atrophy in the same regions. Thus, AD affects glucose metabolism in cortical regions, and blood NfL levels in patients on the AD continuum may serve as an indicator of the severity of hypometabolism in cortical regions.
• Correlation between blood NfL and cerebral white matter microstructural features: There have been few studies of the relationship between blood NfL and white matter microstructural features, all of which have utilized diffusion tensor imaging (DTI) as an indicator of white matter structural integrity. The correlation between blood NfL levels and DTI measurements suggests that blood NfL levels may reflect a variety of cerebral white matter injuries that occur in AD, such as cytoskeletal instability, axonal dystrophy, and demyelination due to tau phosphorylation.

In conclusion, the available studies suggest that blood NfL holds great promise as a monitoring biomarker for the severity of current neurodegeneration in AD patients.

Potential of Blood NfL as a Prognostic and Susceptibility Marker for AD

Existing studies provide evidence that blood NfL levels consistently predict future rates of change in cortical atrophy and glucose metabolism, primarily in brain regions typically affected by AD pathology. The correlation between blood NfL and subsequent neurodegeneration is more pronounced in populations with a higher likelihood of developing AD. This raises the usefulness of blood NfL as a biomarker of AD susceptibility/risk.

How Does NfL Predict Neurodegeneration as an Early Marker of AD?

Baseline blood NfL was not associated with baseline neuroimaging markers of early neurodegeneration in AD, but blood NfL predicted subsequent rates of change in these neuroimaging markers. This finding suggests that elevated blood NfL may precede changes in neuroimaging markers. The potential of blood NfL as a marker of early neurodegeneration in AD is emphasized.

Thus, blood NfL has a great role to play, for example:

• To screen for neurodegeneration or to track neurodegeneration status
• To assess the efficacy of neurodegeneration treatments
• To predict progression of neurodegeneration in AD
• Can be used as a surrogate indicator of neuronal damage

Blood NfL is a more cost-effective, accessible and less invasive biomarker. Thus, the use of blood NfL as a biomarker of neuronal injury will advance our understanding of AD pathomechanisms and improve our prediction of disease progression.

References

1. Yuan, Aidong, Mala V. Rao, and Ralph A. Nixon. "Neurofilaments and neurofilament proteins in health and disease." Cold Spring Harbor perspectives in biology 9.4 (2017): a018309.
2. Jung, Youjin, and Jessica S. Damoiseaux. "The potential of blood neurofilament light as a marker of neurodegeneration for Alzheimer's disease." Brain 147.1 (2024): 12-25.

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