Plasma TDP-43 is a potential biomarker for advanced limbic-predominant age-related TDP-43 encephalopathy neuropathologic change.

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is a common cause of late-onset dementia that does not yet have specific in vivo biomarkers. Here, we examine the biomarker potential of plasma TDP-43, measured using a highly sensitive Nucleic Acid Linked Immuno-Sandwich Assay (NULISA), in detecting advanced LATE-NC. Leveraging plasma TDP-43 and phospho-TDP-43 data from 50 deceased Religious Orders Study and the Rush Memory and Aging Project participants, we show that plasma TDP-43 and pTDP-43 were associated with advanced LATE-NC, especially in those with comorbid Alzheimer's disease neuropathologic change (ADNC): in the subgroup with autopsy-confirmed AD dementia (n=32), receiver operating characteristic area under the curve (AUC) for both plasma biomarkers approached 0.8. Plasma TDP-43 was also elevated in hippocampal sclerosis, a pathologic finding closely related to advanced LATE-NC. Together, our findings suggest the potential utility of plasma TDP-43 and pTDP-43 as biomarkers of LATE-NC, particularly in individuals with comorbid AD.