Wisse Laura E M, Wuestefeld Anika, Murray Melissa E, Jagust William, La Joie Renaud
Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden.
Alzheimers Dement. 2025 Feb;21(2):e14582. doi: 10.1002/alz.14582.
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.
磁共振成像显示的海马萎缩是阿尔茨海默病（AD）的一项重要生物标志物。虽然海马萎缩被认为是由AD中的tau缠结导致的，但不同的神经病理学变化均可导致海马萎缩，尤其是TAR DNA结合蛋白43（TDP - 43）病变。在这篇叙述性综述中，我们评估了关于tau和TDP - 43病变对内侧颞叶（MTL）萎缩相对贡献的现有研究。我们报告称，即使校正了其他神经病理学变化，tau和TDP - 43神经病理学变化均与MTL萎缩存在明确关联。接下来，我们讨论了tau和TDP - 43之间潜在的协同作用以及这两种神经病理学变化影响的相对时间。最后，将探讨未来的研究方向。更好地理解tau和TDP - 43神经病理学变化之间的相互作用及其对萎缩的影响，将有助于开发针对以边缘叶为主的年龄相关性TDP - 43脑病的更特异性生物标志物，并确定在试验中测试抗tau和抗TDP - 43治疗的最佳时机。要点：tau和TAR DNA结合蛋白43（TDP - 43）病变均导致内侧颞叶萎缩。tau与TDP - 43之间存在正相关，且可能存在协同作用。tau和TDP - 43对萎缩是具有累加效应还是协同效应尚不清楚。tau和TDP - 43对萎缩影响的相对时间仍不明确。阐明tau和TDP - 43之间的相互作用将有助于改进磁共振成像生物标志物。
