A phosphorylation‑independent monoclonal antibody improves detection of TDP‑43 pathology across frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and limbic predominant age related TDP‑43 encephalopathy neuropathological change.

TDP-43 proteinopathies encompass frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), amyotrophic lateral sclerosis (ALS-TDP), and limbic predominant age related TDP-43 encephalopathy neuropathological change (LATE-NC). These proteinopathies exhibit subtype-specific aggregate architectures that may constrain epitope accessibility in situ. We compared a phosphorylation-independent monoclonal antibody targeting a C-terminal epitope (MAb No. 9) with the phospho-specific pSer409/410 antibody to determine whether its signal relates to regional neurodegeneration in a multicenter autopsy cohort spanning FTLD-TDP types A-C, ALS-TDP, and Alzheimer disease neuropathologic change (ADNC) with or without LATE-NC. Immunolabeling with MAb No. 9 detected pathological TDP-43 across all diagnostic groups with enhanced labeling of dystrophic neurites and thread/dot-like pathology in FTLD-TDP types A/B and in ALS-TDP. MAb No. 9 performance was equivalent to p409/410 in FTLD-TDP type C. In ADNC with stage 3 LATE-NC, MAb No. 9 revealed a greater limbic burden and labeled both α type and β type inclusions. Dual label immunofluorescence demonstrated strong spatial overlap with p409/410 but additionally highlighted fine punctate pathology. MAb No. 9 burden in FTLD-TDP type A correlated strongly with cortical neurodegeneration but showed weaker and variable associations, particularly in severely atrophic cortex. These findings indicate that filament architecture governs C-terminal epitope accessibility and that MAb No. 9 may be a complementary tool for subtype refinement, clinicopathologic correlation and translational biomarker development in TDP-43 proteinopathies.