After clinical trial failures in symptomatic Alzheimer's disease (AD), our field has moved to earlier intervention in cognitively normal individuals with biomarker evidence of AD. This offers potential for dementia prevention, but mainly low and variable rates of progression to AD dementia reduce the usefulness of trials’ data in decision making by potential prescribers. With results from several Phase 3 secondary prevention studies anticipated within the next few years and the Food and Drug Administration's recent endorsement of amyloid beta as a surrogate outcome biomarker for AD clinical trials, it is time to question the clinical significance of changes in biomarkers, adequacy of current trial durations, and criteria for treatment success if cognitively unimpaired patients and their doctors are to meaningfully evaluate the potential value of new agents. We argue for a change of direction toward trial designs that can unambiguously inform clinical decision making about dementia risk and progression.

中文翻译：

---

阿尔茨海默病的二级痴呆预防试验如何具有临床意义？


在有症状的阿尔茨海默病 (AD) 临床试验失败后，我们的领域已转向对具有 AD 生物标志物证据的认知正常个体进行早期干预。这为预防痴呆症提供了潜力，但主要是 AD 痴呆症进展率低且变化多端，降低了试验数据在潜在处方者决策中的有用性。预计未来几年内将出现多项 3 期二级预防研究的结果，并且食品和药物管理局最近认可β淀粉样蛋白作为 AD 临床试验的替代结果生物标志物，现在是时候质疑生物标志物变化的临床意义、充分性了。目前的试验持续时间，以及认知未受损的患者及其医生要有意义地评估新药的潜在价值时治疗成功的标准。我们主张改变试验设计的方向，可以明确地为有关痴呆症风险和进展的临床决策提供信息。