Chronic traumatic encephalopathy neuropathologic change is associated with highest stage limbic-predominant age-related TDP-43 encephalopathy

Traumatic brain injury (TBI) is recognized as a major risk factor for neurodegenerative disease (NDD). Autopsy studies frequently describe chronic traumatic encephalopathy neuropathologic change (CTE-NC) in individuals with histories of repetitive head impact (RHI) exposure, often with accompanying comorbid neurodegenerative proteinopathies. Of these, deposition of abnormally phosphorylated TDP-43 (pTDP-43) has been reported but the prevalence and distribution of pTDP-43 in CTE-NC and its distinction from that encountered in wider NDD are uncertain. Here, patients with a history of RHI and documented NDD (n = 30), and age-matched controls with no known TBI or RHI exposure, either with (n = 24) or without (n = 18) NDD, were identified within the CONNECT-TBI archive. Standardized brain tissue sections stained for pTDP-43 were assessed. pTDP-43 pathology prevalence was similar among RHI patients (40%) and controls with NDD (33%). pTDP-43 was typically localized (limbic-predominant age-related TDP-43 encephalopathy neuropathologic change [LATE-NC] stage 1 to 2) in amygdala and hippocampus in controls with NDD and following RHI exposure without CTE-NC. In contrast, this pathology was often widespread and of high stage (LATE-NC stage 3; P = .0045) in patients with CTE-NC. Thus, CTE-NC may be associated with more widespread pTDP-43 pathology than encountered in aging or those with NDD and no history of TBI/RHI. [Abstract copyright: © The Author(s) 2026. Published by Oxford University Press on behalf of American Association of Neuropathologists, Inc.]