Pharmacotherapeutic combinations for the treatment of Alzheimer’s disease

Alzheimer’s disease (AD) is the most common form of dementia, and four medications are currently available as symptomatic therapies: three cholinesterase inhibitors (ChEI) and memantine. In June 2021, aducanumab was approved in the United States under an accelerated approval pathway as the first novel putative disease-modifying therapy (p-DMT) targeting the <i>β</i>-amyloid (A<i>β</i>) cascade in the brain. The combination of several monotherapies to address the multifactorial pathogenesis of neurodegenerative diseases is an anticipated next step. The cholinergic hypothesis and the amyloid cascade hypothesis have been proposed as explanations for the pathogenesis of AD. Given the limited effectiveness of monotherapies based on these hypotheses, approaches using combination therapy are attempting to address the complexity of AD pathogenesis, including putative causative proteins-related neurodegeneration, neurotransmitters, and neuroinflammation, in a comprehensive manner. The efficacy of an initial or add-on combination approach to counteracting neurodegenerative processes and functional deterioration has been investigated. The combination of symptomatic therapies with approved anti-dementia medicines (one ChEI and memantine) has been found to be functionally effective for a moderately severe disease stage. Furthermore, combination strategies involving p-DMTs, symptomatic therapies, and neuro-regeneration may be useful in the future.

阿尔茨海默病（Alzheimer’s disease, AD）是最常见的痴呆类型，目前已有4种药物作为症状性治疗手段获批上市，分别为3种胆碱酯酶抑制剂（cholinesterase inhibitors, ChEI）和美金刚。2021年6月，阿杜卡玛单抗（aducanumab）通过加速批准通道在美国获批，成为首个靶向大脑内β淀粉样蛋白（β-amyloid, Aβ）级联反应的新型潜在疾病修饰治疗（putative disease-modifying therapy, p-DMT）。针对神经退行性疾病多因素发病机制，采用多种单药联合治疗是学界预期的下一研究方向。胆碱能假说与淀粉样蛋白级联假说曾被用于阐释阿尔茨海默病的发病机制，但基于这两类假说开发的单药治疗效果有限，因此联合治疗策略被尝试用于全面覆盖阿尔茨海默病发病机制的复杂性——包括潜在致病蛋白相关的神经退行性变、神经递质异常与神经炎症等。研究人员已对初始联合或附加联合方案对抗神经退行性进程与功能衰退的疗效展开了探索。现有研究显示，将症状性治疗与获批的抗痴呆药物（1种胆碱酯酶抑制剂联合美金刚）联用，在中重度疾病阶段可实现有效的功能改善。此外，未来或可采用包含潜在疾病修饰治疗、症状性治疗与神经再生干预的联合策略。