Biomarkers
Biomarkers are measurable indicators that tell us what’s happening inside the body. For example, blood pressure is a biomarker for heart health. In ALS, we’re lacking a suite of biomarkers to diagnose the disease, track its progression, and stratify patient populations—critical information for early intervention, evaluating the efficacy of new drugs, and pairing the right treatments to the right patients.
Since TDP-43 pathology is seen in 97% of ALS cases, it’s a desirable target for biomarker development. We’ve brought together scientists from different scientific disciplines and disease areas to crack the code on TDP-43 biomarkers. At the Annual Meeting, Wednesday’s biomarker session was one of the most dynamic, with several groups sharing both breakthroughs and hard-won lessons in measuring TDP-43.
Clarifying the Cryptic: Developing Tools to Detect Cryptic Peptides
Drs. Michael Ward (National Institute of Neurological Disorders and Stroke), Pietro Fratta (University College London) and Len Petrucelli (University of Miami) have been working together to advance cryptic peptide biomarkers. Their work confirms that a cryptic peptide called HDGFL2 appears in brain and spinal cord tissue with TDP-43 pathology, indicating its potential as a specific biomarker for disease. However, detecting and measuring cryptic peptides has proven difficult. A new collaboration between Dr. Petrucelli and Nicholas Ashton (Banner Institute) yielded a notable advancement: they have developed an ultra-sensitive test that successfully detects the HDGFL2 cryptic peptide in CSF. Critically, the test has demonstrated the ability to distinguish people with ALS from healthy controls.
Michael Ward, MD, PhD
National Institutes of Health
Leonard Petrucelli, PhD
University of Miami
Pietro Fratta, MD, PhD
University College London
A Window Inside the Cell: Tracking TDP-43 via Extracellular Vesicles
A consortium including Drs. Erez Eitan (NeuroDex, Inc.), Marta Garcia Montojo (Twilight Bioscience), Alain Prochiantz (BrainEver), and Avindra Nath (NINDS) is investigating whether extracellular vesicles (EVs) can provide insight into TDP-43 dysfunction. By analyzing EVs derived from the brain, the consortium was able to detect elevated levels of TDP-43 in ALS samples relative to healthy controls.
Erez Eitan, PhD
NeuroDex Inc.
Avindra Nath, MD
National Institutes of Health/NINDS
Alain Prochiantz, PhD
BrainEver
Marta Garcia Montojo, PhD
Twilight Bioscience
Communication Breakdown: Monitoring Loss of Synaptic Function
Perhaps the most compelling presentation came from Drs. Philip Van Damme (KU Leuven), Rosa Rademakers (VIB), and Koen Poesen (KU Leuven), who are investigating the proteins that enable and support synapses. The team observed elevated synaptic proteins called SV2A and VAMP2 in CSF from people with ALS, suggesting that the proteins are lost in the course of the disease. Additionally, the team found a corresponding decrease in SV2A in imaging of the brain region responsible for motor function. The imaging measures correlated with ALSFRS-R scores, with the decreased signal linked to higher disease progression. Supported by both fluid and imaging-based techniques, these striking findings shed light on synaptic function and could be a valuable early biomarker of disease onset.
Rosa Rademakers, PhD
Vlaams Instituut Biotechnologie (VIB)
Philip Van Damme, MD, PhD
KU Leuven
Koen Poesen, PhD
KU Leuven
Key Takeaway: Building tools to effectively track TDP-43, either directly or through indirect approaches like detecting cryptic peptides or analyzing EVs, offers scientists a clearer picture of what’s happening inside the body in the majority of ALS cases. Further, TDP-43 dysfunction isn’t unique to ALS; it’s seen in up to 50% of FTD cases and 25-50% of Alzheimer’s Disease cases. The bottom line: the tools we’re developing could improve diagnosis, monitoring, and care across neurodegenerative disease.
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March 31, 2026
