What NfL does well

Neurofilament light chain (NfL) is the most extensively validated biomarker across neurodegenerative diseases. It is a structural protein released when axons are damaged, making it a direct readout of neuronal injury.

Blood levels track CSF levels at about 1:40 ratio (PMID: 37844927), meaning you can monitor axonal damage with a simple blood draw instead of a lumbar puncture. Simoa technology makes this ultrasensitive detection possible.

Disease-specific performance:

• ALS: Elevated blood NfL and phosphorylated neurofilament heavy (pNfH) are prognostic. High levels predict faster progression and shorter survival. CSF also shows elevated TDP-43, the primary pathology protein.

• Multiple sclerosis: Progressive MS shows chronic, slowly increasing serum NfL concentrations indicating sustained axonal loss. Baseline levels are better predictors of clinical progression, survival, and brain atrophy than rate of change (PMID: 36523882).

• Alzheimers: Baseline plasma NfL predicts cognitive decline and neuroimaging abnormalities, particularly in preclinical AD. It complements core CSF markers: decreased Aβ42/Aβ40 ratio and increased phosphorylated tau (p-tau) and total tau.

• Parkinsons: Decreased CSF alpha-synuclein serves as a diagnostic marker alongside elevated NfL.

The blind spot: NfL cannot tell you if treatment is working

This is the critical limitation. In spinal muscular atrophy patients receiving nusinersen, over 50% of patients without measurable clinical improvement still showed decreased NfL concentrations (PMID: 38482263).

NfL drops when axonal injury slows. But that can happen for reasons other than functional recovery:

• The drug might reduce inflammation that was driving secondary axonal damage
• The disease might naturally plateau in that patient
• Neurons might be dying less but still not functioning better

NfL is a measure of injury rate, not functional status.

Emerging complementary markers

Plasma p-tau181 and p-tau217 now provide complementary information to NfL for classifying MS subtypes and predicting disability progression (PMID: 38482263). These tau species may reflect different aspects of pathology than pure axonal injury.

GFAP (glial fibrillary acidic protein) indicates astrocyte activation and is emerging as a complementary marker, particularly in AD where it may track neuroinflammation independent of NfL.

Practical implications for clinical trials

Incorporating NfL into trial design can significantly reduce required participant numbers because it is a continuous variable that changes faster than clinical scales. But it should not be used as the sole efficacy endpoint.

A drug that lowers NfL without improving function is not necessarily working. The marker is sensitive but not specific for therapeutic benefit.

Testable predictions

1. Trials using NfL as a primary endpoint will show higher response rates than those using functional outcomes—but with weaker correlation to patient benefit
2. Combination markers (NfL + GFAP + p-tau) will outperform single markers for predicting disease course
3. NfL will prove most useful as an enrichment biomarker (selecting high-progression patients for trials) rather than an efficacy biomarker

What would change my view

If a study shows that NfL reduction correlates with functional improvement at the individual patient level (not just group averages), that would establish it as a true efficacy biomarker rather than just an injury marker.

Research synthesis via Aubrai