Role of tau versus TDP-43 pathology on medial temporal lobe atrophy in aging and Alzheimer's disease

Hippocampal atrophy on magnetic resonance imaging is an important biomarker in Alzheimer's disease (AD). While hippocampal atrophy was thought to result from tau tangles in AD, different neuropathologies can lead to hippocampal atrophy, especially TAR DNA-binding protein 43 (TDP-43) pathology. In this narrative review, we evaluate existing studies on the relative contribution of tau and TDP-43 pathology to medial temporal lobe (MTL) atrophy. We report a clear association of both tau and TDP-43 neuropathology with MTL atrophy, even after correcting for other neuropathologies. Next, we discuss a potential synergism between tau and TDP-43 and the relative timing of the effects of both neuropathologies. Finally, avenues for future research will be discussed. A better understanding of the interplay between tau and TDP-43 neuropathologies and their effect on atrophy will help with the development of more specific biomarkers for limbic-predominant age-related TDP-43 encephalopathy and pinpointing of the optimal timing for testing anti-tau and anti-TDP-43 treatments in trials. HIGHLIGHTS: Both tau and TAR DNA-binding protein 43 (TDP-43) pathology contribute to medial temporal lobe atrophy. There is a positive association between tau and TDP-43 and potentially a synergism. It is unclear if tau and TDP-43 have an additive or synergistic effect on atrophy. The relative timing of the tau and TDP-43 effects on atrophy remains unclear. Clarifying the interplay between tau and TDP-43 will help improve magnetic resonance imaging biomarkers.