A new systematic review highlights how biomarkers, biological indicators of disease, are reshaping clinical trials for amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND). By enabling earlier and more sensitive assessments of treatment effects.

This research underscores the growing importance of biomarker-driven approaches in tackling one of the most challenging neurodegenerative diseases.

Studying the role of biomarkers in ALS research

Led by researchers at King’s College London, the review analysed 93 studies investigating biomarkers used in ALS clinical trials. These included protein markers such as neurofilament light chain (NFL), genetic markers like SOD1 and C9orf72, inflammatory molecules, and imaging techniques.

NfL emerged as the most robust and clinically useful biomarker. Elevated NfL levels in blood and cerebrospinal fluid strongly correlate with disease severity and progression, making it a powerful tool for monitoring treatment response. Trials such as RESCUE-ALS, CENTAUR, and MND-SMART have already incorporated NfL as a secondary endpoint to detect therapeutic effects earlier than traditional measures, such as survival or functional decline.

Expanding the biomarker landscape

Beyond NFL, the review highlights promising exploratory biomarkers, including:

  • Retroviral elements such as HERV-K are linked to neuroinflammation.
  • Extracellular vesicle markers carrying proteins and microRNAs associated with ALS pathology.
  • Inflammatory cytokines like IL-18 and TNF-α, which reflect immune system involvement.
  • Metabolic indicators such as uric acid and creatinine, offering insights into systemic changes.

Combining these markers in multimodal panels could provide a more comprehensive picture of disease activity and improve patient stratification in trials.

Why is this important?

Traditional ALS trials often rely on survival or functional scales, which require long observation periods and are influenced by clinical variability. Biomarkers offer objective, quantifiable measures of disease progression, enabling:

  • Adaptive trial designs that adjust in real time based on biomarker data.
  • Earlier detection of treatment effects, reducing patient exposure to ineffective therapies.
  • Personalised medicine approaches, tailoring interventions to biological profiles.

However, challenges remain, including variability in biomarker levels and the need for standardised measurement protocols. Future research will focus on validating multimodal biomarker panels and integrating them into adaptive trial frameworks.

You can read about our other blogs and news stories here or read about our research here. Also sign up to our newsletter.

Original study:
Roy T, Al-Chalabi A, Iacoangeli A, Al Khleifat A. Biomarkers in ALS trials: from discovery to clinical utility. Frontiers in Neuroscience. 28 November 2025. DOI: 10.3389/fnins.2025.1636303