CSF TDP-43: A Novel Biomarker for Limbic-Predominant Age-Related TDP-43 Encephalopathy

Mislocalization and aggregation of transactive response DNA-binding protein 43 kDa (TDP-43) represent a neuropathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) and are increasingly recognized in Alzheimers disease (AD) and limbic-predominant age-related TDP-43 encephalopathy (LATE). However, the in vivo value of CSF TDP-43 as a biomarker and its relation to established markers remains unclear. We quantified CSF concentrations of TDP-43 using ELISA in 25 controls, 32 ALS, 9 probable LATE, and 24 AD patients. CSF TDP-43 levels differed significantly between groups, with the highest concentrations in LATE, exceeding both ALS and AD. ALS and AD showed intermediate, comparable increases versus controls. In parallel, conventional AD biomarkers (t-tau, p-tau, and amyloid-b) showed the expected AD-typical profile but remained largely unaltered in probable LATE, indicating a dissociation between TDP-43 an AD-type pathology. These findings identify CSF TDP-43 as a promising candidate biomarker for LATE, characterized by disproportionate elevation in the absence of AD-type biomarker changes, and neurodegeneration in aging populations.