Elevated Plasma Neurofilament Light Chain (NfL) in Alzheimer's Disease Screening
Elevated plasma neurofilament light chain (NfL) indicates ongoing neurodegeneration but is not specific to Alzheimer's disease, serving as a general marker of neuronal injury that becomes more pronounced in advanced dementia stages. 1
Understanding Plasma NfL as a Biomarker
- Plasma NfL is a marker of neuroaxonal injury that increases when neurons are damaged, reflecting neurodegeneration across various neurological conditions 1
- NfL can be reliably measured in both CSF and blood (plasma or serum) with sensitive assays, with blood measurements correlating well with CSF findings 1
- In Alzheimer's disease, plasma NfL shows a more modest elevation compared to other neurological conditions like amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and multiple sclerosis (MS) 1
Relationship to Alzheimer's Disease Pathology
- In familial AD mutation carriers, blood NfL levels begin to increase approximately a decade before expected clinical symptom onset, marking the beginning of neurodegeneration 1, 2
- In sporadic AD, plasma NfL correlates with both amyloid-beta and tau positivity, but this association is primarily visible at more advanced dementia stages 1, 3
- Plasma NfL increases in response to amyloid-related neuronal injury in preclinical stages but becomes more strongly related to tau-mediated neurodegeneration in symptomatic patients 3, 4
- Higher plasma NfL levels are associated with faster rates of brain atrophy and hypometabolism, particularly in regions typically affected by Alzheimer's disease 3, 4
Diagnostic and Prognostic Value
- Plasma NfL is elevated in patients with mild cognitive impairment (MCI) and AD dementia compared to cognitively normal controls, with the highest levels seen in AD dementia 5, 4
- Plasma NfL has good diagnostic accuracy for distinguishing AD dementia from controls (area under the ROC curve of 0.87), comparable to established CSF biomarkers 5
- Higher plasma NfL levels correlate with poorer cognitive performance and faster cognitive decline, particularly in memory function 2, 4
- Longitudinal increases in plasma NfL correlate with faster rates of neurodegeneration and cognitive worsening 4
Limitations and Challenges
- Plasma NfL is not specific to Alzheimer's disease and increases in many neurodegenerative conditions, limiting its use as a standalone diagnostic tool 1, 6
- NfL has a strong age relationship, making interpretation challenging, particularly in older adults (>70 years) where age-related changes may contribute to elevated levels 1
- There is considerable overlap in NfL levels between different AD disease stages, especially in sporadic AD compared to familial AD 1
- Various factors can influence plasma NfL levels, including peripheral neuropathies, body mass index (BMI), and kidney disease 1
Clinical Applications and Future Directions
- Plasma NfL is increasingly being used in clinical laboratory practice as a marker of neurodegeneration 1
- It shows promise as a monitoring biomarker to track disease progression and potentially as a measure of treatment response in clinical trials 6, 4
- In anti-amyloid antibody trials, attenuated increases of CSF NfL have been reported, though whether this translates to blood NfL remains unknown 1
- Plasma NfL has strong pre-analytical robustness, making it relatively unaffected by common variations in sample handling 1
Interpretation in Clinical Context
- When interpreting elevated plasma NfL in the context of Alzheimer's screening:
- Consider the patient's age, as NfL naturally increases with aging 1
- Evaluate for other potential causes of neurodegeneration beyond AD 1, 6
- Use in combination with other AD biomarkers (like plasma p-tau or GFAP) for improved diagnostic accuracy 1
- In patients with dementia, a high plasma NfL with normal p-tau may suggest a non-AD dementia with substantial axonal degeneration 1