Alzheimer's disease (AD) is the most common form of dementia characterized by presence of extracellular amyloid plaques (amyloid beta; Aβ) and intracellular neurofibrillary tangles composed of tau protein. Currently there are close to 50 million people living with dementia and this figure is expected to increase to 75 million by 2030 putting a huge burden on the economy due to the health care cost. Considering the effects on quality of life of patients and the increasing burden on the economy, there is an enormous need of new disease modifying therapies to tackle this disease. The current therapies are dominated by only symptomatic treatments including cholinesterase inhibitors and NMDA receptor blockers but no disease modifying treatments exist so far. After several failed attempts to develop drugs against amyloidopathy, tau targeting approaches have been in the main focus of drug development against AD. After an overview of the tauopathy in AD, this review summarizes recent findings on the development of small molecules as therapeutics targeting tau modification, aggregation, and degradation, and tau-oriented multi-target directed ligands. Overall, this work aims to provide a comprehensive and critical overview of small molecules which are being explored as a lead candidate for discovering drugs against tauopathy in AD.

阿尔茨海默病 (AD) 是最常见的痴呆形式，其特征在于存在细胞外淀粉样蛋白斑块（淀粉样蛋白 β；Aβ）和由 tau 蛋白组成的细胞内神经原纤维缠结。目前有近 5000 万人患有痴呆症，预计到 2030 年这一数字将增加到 7500 万，由于医疗保健成本，给经济带来巨大负担。考虑到对患者生活质量的影响和日益增加的经济负担，迫切需要新的疾病改善疗法来应对这种疾病。目前的疗法仅以对症治疗为主，包括胆碱酯酶抑制剂和 NMDA 受体阻滞剂，但目前尚不存在改善疾病的治疗方法。在开发抗淀粉样变药物的几次尝试失败后，tau 靶向方法一直是抗 AD 药物开发的主要焦点。在对 AD 中的 tau 病变进行概述之后，本综述总结了最近关于小分子作为靶向 tau 修饰、聚集和降解以及 tau 导向多靶标配体的治疗剂的发展的发现。总体而言，这项工作旨在提供对小分子的全面而重要的概述，这些小分子正在被探索为发现抗 AD tau 蛋白病变药物的主要候选者。