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What works and what does not work in Alzheimer's disease? From interventions on risk factors to anti-amyloid trials.
Journal of Neurochemistry ( IF 4.7 ) Pub Date : 2020-04-11 , DOI: 10.1111/jnc.15023
Szofia Bullain 1 , Rachelle Doody 1, 2
Affiliation  

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with no approved disease‐modifying therapy (DMT). In this review, we summarize the various past approaches taken in an attempt to find treatments capable of altering the long‐term course for individuals with AD, including: translating epidemiological observations into potential treatment options; seeking a single‐treatment approach across the continuum of AD severity; utilizing biomarkers for assessing target engagement; using biomarkers as early surrogates of clinical efficacy; and enriching study populations to demonstrate adequate placebo decline during the limited duration of clinical trials. Although targeting the amyloid‐β (Aβ) pathway has been central to the search for an effective DMT, to date, trials of anti‐Aβ monoclonal antibodies have failed to consistently demonstrate significant clinical efficacy. Key learnings from these anti‐Aβ trials, as well as the trials that came before them, have shifted the focus within clinical development programs to identifying target populations thought most likely to benefit from treatments (i.e., individuals at an earlier stage of disease). Other learnings include strategies to increase the likelihood of showing measurable improvements within the clinical trial setting by better predicting decline in placebo participants, as well as developing measures to quantify the needed treatment exposure (e.g., higher doses). Given the complexity associated with AD pathology and progression, treatments targeting non‐amyloid AD pathologies in combination with anti‐amyloid therapies may offer an alternative for the successful development of DMTs.

中文翻译:

在阿尔茨海默氏病中什么有效,什么无效?从危险因素干预到抗淀粉样蛋白试验。

阿尔茨海默氏病(AD)是一种进行性神经退行性疾病,没有经过批准的疾病缓解疗法(DMT)。在这篇综述中,我们总结了过去试图寻找能够改变AD患者长期病程的治疗方法,包括:将流行病学观察结果转化为潜在的治疗方案;在整个AD严重程度中寻求单一治疗方法; 利用生物标志物评估目标参与度;使用生物标志物作为临床疗效的早期替代物;并丰富研究人群,以证明在有限的临床试验期间有足够的安慰剂下降。尽管到目前为止,针对淀粉样β(Aβ)通路的定位对于寻找有效的DMT至关重要,抗Aβ单克隆抗体的试验未能始终显示出显着的临床疗效。从这些抗Aβ试验及其之前的试验中获得的重要经验已将临床研究计划的重点转移到了确定最可能从治疗中受益的目标人群(即处于疾病早期阶段的个体)。其他学习内容包括通过更好地预测安慰剂参与者的下降来增加在临床试验环境中显示出可衡量的改善的可能性的策略,以及制定量化所需治疗暴露量(例如更高剂量)的措施。鉴于与AD病理和进展相关的复杂性,
更新日期:2020-04-11
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