Review of Advanced Drug Trials Focusing on the Reduction of Brain Beta-Amyloid to Prevent and Treat Dementia.
Review of Advanced Drug Trials Focusing on the Reduction of Brain Beta-Amyloid to Prevent and Treat Dementia.
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DOI：
10.2147/jep.s265626
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发表时间：
2022
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阿尔茨海默病 (AD) 是最常见的神经退行性疾病，通常影响 65 岁以上的患者。在这个年龄段，健康大脑中的神经元数量开始逐渐减少，但 AD 患者大脑中的神经元死亡显着增加，常常导致认知能力显着丧失。受影响的认知技能包括信息保留、识别能力和语言技能。目前，AD 只能通过死后脑活检，通过检测细胞外淀粉样蛋白 (Aβ) 斑块和细胞内过度磷酸化的 tau 神经原纤维缠结来明确诊断。由于 Aβ 斑块和 tau 蛋白缠结的水平均增加，因此这两种蛋白质被认为与疾病进展有关。尽管人们对 AD 的病因及其确切的病理学发展知之甚少，但已经研究了多种治疗形式，以确定通过靶向 Aβ 来控制 AD 症状的有效方法。这些治疗包括但不限于使用小分子改变 Aβ 单体的相互作用、减少改变 Aβ 分子合成途径的神经元回路过度激活、改善 Aβ 降解、采用被动免疫方法以及刺激患者对目标 Aβ 的主动免疫。本综述总结了当前处于临床开发 II/III 期或更高阶段的治疗干预措施，这些干预措施能够降低异常的脑 Aβ 水平，以确定哪些治疗最有可能显示出临床疗效。我们的结论是，在不久的将来，针对脑 Aβ 病理学最有希望的治疗干预措施可能是被动免疫疗法，其中以阿杜卡单抗和多南单抗为主导，并且这些药物可能与抗抑郁药和乙酰胆碱酯酶抑制剂联合使用，从而调节 Aβ 合成。
Alzheimer disease (AD) is the most common neurodegenerative disease and typically affects patients older than age 65. Around this age, the number of neurons begins to gradually decrease in healthy brains, but brains of patients with AD show a marked increase in neuron death, often resulting in a significant loss of cognitive abilities. Cognitive skills affected include information retention, recognition capabilities, and language skills. At present, AD can be definitively diagnosed only through postmortem brain biopsies via the detection of extracellular amyloid beta (Aβ) plaques and intracellular hyperphosphorylated tau neurofibrillary tangles. Because the levels of both Aβ plaques and tau tangles are increased, these 2 proteins are thought to be related to disease progression. Although relatively little is known about the cause of AD and its exact pathobiological development, many forms of treatment have been investigated to determine an effective method for managing AD symptoms by targeting Aβ. These treatments include but are not limited to using small molecules to alter the interactions of Aβ monomers, reducing hyperactivation of neuronal circuits altering Aβ’s molecular pathway of synthesis, improving degradation of Aβ, employing passive immunity approaches, and stimulating patients’ active immunity to target Aβ. This review summarizes the current therapeutic interventions in Phase II/III of clinical development or higher that are capable of reducing abnormal brain Aβ levels to determine which treatments show the greatest likelihood of clinical efficacy. We conclude that, in the near future, the most promising therapeutic interventions for brain Aβ pathology will likely be passive immunotherapies, with aducanumab and donanemab leading the way, and that these drugs may be combined with antidepressants and acetylcholine esterase inhibitors, which can modulate Aβ synthesis.