PDF(Pubmed)
Abstract：
Established drug therapies for Alzheimer disease (cholinesterase inhibitors and memantine) do not modify the disease course and provide only modest clinical benefit. Biomarker measures of amyloid, tau and neurodegeneration have been integral to Alzheimer disease clinical trials for biologic drugs, for patient selection and efficacy monitoring. At the time of writing, two monoclonal antibodies targeting the amyloid-beta protein (aducanumab and lecanemab) have been approved in the USA, and two agents (lecanemab and donanemab) are under evaluation by the Therapeutic Goods Administration in Australia. Clinical trials have demonstrated that monoclonal antibodies are effective at removing amyloid from the brain in people with early Alzheimer disease. Cognitive benefits are statistically significant, but do not achieve the minimal clinically important difference. Amyloid-related imaging abnormalities of vasogenic oedema and microhaemorrhages occur more frequently on treatment; although these are usually asymptomatic or transient, in some people they are serious or fatal. Targeting amyloid as a unimodal strategy is unlikely to be sufficient and future therapies may need to be multimodal, targeting multiple pathogenic pathways. The burden of dementia is greatest in the older population where mixed dementia pathology dominates; the relationship between biomarkers, clinical phenotype and pathology attenuates; and frailty and comorbidity impact cognition. This creates challenges in identifying effective therapies for the group where dementia is most prevalent.
摘要：
已建立的阿尔茨海默病药物疗法（胆碱酯酶抑制剂和美金刚）不会改变疾病进程，并且仅提供适度的临床益处。淀粉样蛋白的生物标志物测量，tau和神经变性已经成为阿尔茨海默病生物药物临床试验的组成部分，用于患者选择和疗效监测。在撰写本文时,两种针对淀粉样β蛋白的单克隆抗体（aducanumab和lecanemab）已在美国获得批准，澳大利亚治疗用品管理局正在评估两种药物（lecanemab和donanemab）。临床试验表明，单克隆抗体可有效去除早期阿尔茨海默病患者大脑中的淀粉样蛋白。认知益处具有统计学意义，但没有达到最小的临床重要差异。血管源性水肿和微出血的淀粉样蛋白相关影像学异常在治疗时发生更频繁；尽管这些通常是无症状或一过性的，在某些人中，它们是严重的或致命的。将淀粉样蛋白作为单峰策略不太可能足够，未来的治疗可能需要多模式，靶向多种致病途径。在混合痴呆病理占主导地位的老年人群中，痴呆的负担最大；生物标志物之间的关系，临床表型和病理减弱；虚弱和合并症影响认知。这在为痴呆症最普遍的群体确定有效疗法方面带来了挑战。
