The TDP-43 Decade Has Begun
Why the world’s leading neurodegeneration researchers are converging on a single protein and why fluid biomarkers are the missing piece.
How should we define diseases?
For most of the past twenty years, ALS, frontotemporal dementia, and Alzheimer’s disease were treated as separate problems with separate biologies. That consensus is breaking down. At the 2026 TDP-43 Summit in Madison, Wisconsin, neuropathologists, biomarker scientists, imaging chemists, and clinical translators returned again and again to the same observation:
TDP-43 proteinopathy is the unifying driver across an enormous and underserved patient population.
The numbers are striking:
- ~97% of ALS cases show TDP-43 pathology.
- ~45% of frontotemporal dementia cases are TDP-43-driven.
- ~40% of Alzheimer’s patients over age 70 carry TDP-43 co-pathology.
- LATE (Limbic-predominant Age-related TDP-43 Encephalopathy) affects roughly a third of adults over 85 and is now recognized as a distinct, common cause of dementia.
This is no longer a rare-disease story. TDP-43 pathology occurs in over 20M people worldwide, and the leaders of the field — from Penn, UCSF, Michigan, Mayo, Rush, Banner Health, and beyond — are now openly proposing to lump these diseases together under a single biological framework:
TAN, TDP-43-Associated Neurodegeneration, modeled directly on the biological redefinitions that transformed Alzheimer’s and Parkinson’s research. The field is doing what the AD field did fifteen years ago, moving from symptoms to a biological definition based on the hallmark pathologies.
What’s working, what isn’t, and where the field is going
The summit made one thing unmistakably clear: direct measurement of TDP-43 protein in blood or CSF has not been delivered. Measurement of soluble TDP-43 in biofluids using various methods yields only a weak, inconsistent signal that cannot support clinical trials or differential diagnosis.
The field is pivoting hard toward four strategies:
- Cryptic peptides — splicing products that appear only when TDP-43 loses nuclear function. Assays that can detect HDGFL2 with ultra-high sensitivity (LOD 0.016pg/ml) show some promise in ALS CSF. With postmortem studies showing patient variability in cryptic peptide expression, there are attempts to create a panel (HDGFL2, STMN2, UNC13A, IgLON5). The involvement of non-TDP43 RNA-binding proteins in cryptic axon splicing events is starting to emerge.
- Seed amplification assays — RT-QuIC-style detection of misfolded TDP-43 conformers. Several groups show high sensitivity in CSF, demonstrating the promise of this technology that has already transformed Parkinson’s and Lewy body dementia diagnosis. However, these studies remain small and inconsistent, with one of the main challenges being the consistent production of recombinant TDP43 protein.
- PET imaging — First-in-human studies with regional signal that tracks symptoms. Multiple academic and industry groups are racing to develop competing tracers.
- Extracellular vesicle biomarkers — Repeatedly cited at the summit as one of the most promising paths forward, especially for a blood biomarker of TDP43. EVs concentrate neuronal-origin proteins and RNA, bypass the high-abundance plasma proteome that has stymied conventional approaches, and provide access to both aggregated TDP-43 and downstream cryptic peptide and RNA targets.
Sandy Barmada’s keynote on lysosomal dysfunction landed on the same point from the cell-biology side: TDP-43 fibrils accumulate inside lysosomes, and secretory autophagy releases that material into the extracellular space, which is precisely the cargo EVs carry. Biology and biomarker strategy are converging.
Where NeuroDex fits
NeuroDex was built for this moment.
Our neuron-derived EV isolation platform was developed specifically to solve the problem the summit highlighted: how to measure neuronal pathology from a peripheral blood draw, without being defeated by plasma’s high-abundance background. As the field better understands TDP43 biology and pathophysiology, creating better tools for its detection, NeuroDex is positioned to translate these into blood biomarker assays.
We are already:
- Detecting TDP-43 in blood neuron-derived EVs using multiple immune assays. Proteinase K experiments show that over 50% of TDP43 is inside EVs and that it is mostly aggregated.
- Clinical proof of concept in ALS and dementia. In ALS, we demonstrate a significant elevation that correlates with changes in the ALSRFS-R score over time. Longitudinal analysis demonstrates an increase over time. In dementia, we also demonstrate a significant increase, especially in Amyloid-negative patients
- Qualified workflows Our NDEs enrichment is a 96-well automated platform, with high specificity and reproducibility. Full method validation in a CLIA environment is targeted for the end of 2026.
What Next
- Further characterization of NDEs associated with TDP43, we are looking for further and better ways to characterize and measure TDP43. Identify its aggregate status, post-translational modification, and more. If you have novel approaches to measuring TDP43, we are happy to discuss.
- Further clinical validation, while we already measured TDP43 in over 500 ALS samples and 1000 dementia samples, more is needed to further verify its clinical performance. We are interested in testing whether TDP43 predicts ALS progression fast vs slow, response to treatments, and more. If you have a clinical cohort and a good idea for a TDP43 clinical study, we are happy to talk.
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