Specific atrophy patterns distinguish tau and TDP-43 pathology: a longitudinal MRI ante-mortem study.

TDP-43 pathology frequently co-occurs with Alzheimer’s disease (AD), indicative of Limbic-predominant Age-related TDP-43 Encephalopathy neuropathologic changes (LATE-NC), which is associated with more severe medial temporal lobe (MTL) atrophy and cognitive decline compared to ‘pure’ AD. As both tau and TDP-43 target overlapping MTL structures and are associated with similar clinical manifestations, disentangling their respective contributions to neurodegeneration is essential yet challenging. In this study, we investigated the differential impact of tau and TDP-43 pathologies on MTL subregions, with a focus on the anterior-to-posterior and superior–-to-inferior gradients, and amygdala subnuclei. We analyzed structural MRI data from 85 ADNI participants with autopsy-confirmed neuropathology. Participants were stratified by Braak stage (Low tau: 0–III; High tau: IV–VI) and presence of TDP-43 pathology in the MTL. The presence of TDP-43 pathology was significantly associated with hippocampal head volume (R = −0.47, P < 0.01) and all amygdala subnuclei, while tau pathology was associated with parahippocampal gyrus thickness (R = −0.41, P < 0.01) and the central nucleus of the amygdala (R = −0.32, P < 0.05). In individuals with low tau burden, TDP-43 positivity was linked to widespread MTL atrophy, excluding the parahippocampal cortex (PHC), whereas in TDP-43-negative individuals, high tau pathology was associated with atrophy in the PHC and specific amygdala nuclei. Longitudinally, TDP-43 predicted faster hippocampal head volume loss (β = −6.71 mm3/year, P < 0.001), while tau pathology was associated with greater PHC thinning (β = −0.02 mm/year, P < 0.05). These results highlight an association between TDP-43 and the volume/thickness of anterior MTL regions while tau pathology was more associated with the volume/thickness of posterior MTL. However, it also suggests a superior-to-inferior gradient, TDP-43 predominantly affecting superior regions and tau affecting inferior MTL. Taken together, these findings suggest that the hippocampal head (anterior–superior) atrophy may differentiate AD patients with or without comorbid LATE-NC.