Neurofilament light chain (NfL) has become the benchmark biomarker for ALS. But does it capture the full biological complexity of the disease?
In our new study published in Neurology: Neuroimmunology & Neuroinflammation, we used the highly sensitive NULISA multiplex platform to simultaneously quantify 131 CSF proteins in patients with sporadic ALS, C9orf72-associated ALS, and controls.
Key findings:
✅ A shared biomarker signature comprising NfL, NfH, CHIT1, CHI3L1, CCL2, and CCL3 robustly distinguished ALS from controls, reflecting not only axonal degeneration but also microglial and astrocytic activation.
✅ Combining inflammatory/glial biomarkers with neurofilaments improved diagnostic performance—particularly in C9orf72-ALS—and composite inflammatory scores correlated with disease progression.
✅ We also identified genotype-specific molecular signatures, including increased PRDX6 and ENO2 in C9orf72-ALS, suggesting that different ALS subtypes may engage distinct biological pathways.
Why does this matter clinically?
As disease-modifying therapies for ALS—including antisense oligonucleotides and other gene-targeted approaches—enter clinical practice, biomarkers must evolve beyond measuring neuronal injury alone.
A multiplex panel integrating neurodegeneration, glial activation, inflammation, and oxidative stress could help: improve patient stratification, monitor biological target engagement, distinguish therapeutic effects from treatment-induced inflammation, and provide more informative pharmacodynamic and safety biomarkers in clinical trials.
Rather than replacing neurofilaments, these data suggest that the future of ALS biomarkers lies in multidimensional molecular signatures that better reflect the underlying disease biology.