Beyond the Neuron: TDP-43 and the Challenge of Pre-Analytical Quality in Platelet Biomarker Development

TAR DNA-binding protein 43 (TDP-43) is the primary pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Yet, despite two decades of intensive research, a reliable peripheral TDP-43 biomarker remains elusive. Recognizing platelets as a major blood reservoir of TDP-43 opens new diagnostic avenues but may also reveal potential vulnerabilities. In this narrative review, we first trace the evolving understanding of TDP-43 from a nuclear RNA-binding protein to a molecule whose functions and disease-associated alterations extend beyond the neuron. We then examine recent breakthroughs demonstrating that TDP-43 function is shaped by its cellular environment and how it may be uniquely concentrated in platelets. Next, we argue that pre-analytical variables, such as hemolysis, clotting, cold-chain failures, and biobank protocols, are not mere “noise” but potential confounders that distort molecular integrity and should be taken into account. Finally, we discuss the biological and methodological uncertainties surrounding platelet TDP-43 and highlight how standardized handling and systematic pre-analytical reporting can improve reproducibility and support future biomarker validation. More broadly, the methodological standards outlined in this review may extend beyond TDP-43 to other disease-related proteins that are present in platelets and similarly sensitive to pre-analytical variability.