Alzheimer’s disease (AD) is traditionally defined by the presence of two types of protein aggregates in the brain: amyloid plaques comprised of the protein amyloid-β (Aβ) and neurofibrillary tangles containing the protein tau. However, a large proportion (up to 57%) of AD patients also have TDP-43 aggregates present as an additional comorbid pathology. The presence of TDP-43 aggregates in AD correlates with hippocampal sclerosis, worse brain atrophy, more severe cognitive impairment, and more rapid cognitive decline. In patients with mixed Aβ, tau, and TDP-43 pathology, TDP-43 may interact with neurodegenerative processes in AD, worsening outcomes. While considerable progress has been made to characterize TDP-43 pathology in AD and late-onset dementia, there remains a critical need for mechanistic studies to understand underlying disease biology and develop therapeutic interventions. This perspectives article reviews the current understanding of these processes from autopsy cohort studies and model organism-based research, and proposes targeting neurotoxic synergies between tau and TDP-43 as a new therapeutic strategy for AD with comorbid TDP-43 pathology.

传统上，阿尔茨海默病 (AD) 的定义是大脑中存在两种类型的蛋白质聚集体：由蛋白质淀粉样蛋白 β (Aβ) 组成的淀粉样斑块和包含蛋白质 tau 的神经原纤维缠结。然而，很大比例（高达 57%）的 AD 患者也存在 TDP-43 聚集体作为额外的共病病理。AD 中 TDP-43 聚集体的存在与海马硬化、更严重的脑萎缩、更严重的认知障碍和更快的认知衰退相关。在混合 Aβ、tau 和 TDP-43 病理的患者中，TDP-43 可能与 AD 中的神经退行性过程相互作用，使结果恶化。虽然在表征 AD 和迟发性痴呆的 TDP-43 病理方面取得了相当大的进展，仍然迫切需要机械研究来了解潜在的疾病生物学并开发治疗干预措施。这篇观点文章回顾了尸检队列研究和基于模型生物的研究对这些过程的当前理解，并提出将 tau 和 TDP-43 之间的神经毒性协同作用作为一种新的治疗策略，用于治疗合并 TDP-43 病理的 AD。