Biological and clinical heterogeneity is a major challenge in research for developing new treatments for Alzheimer's disease (AD). AD may be defined by its amyloid beta and tau pathologies, but we recognize that mixed pathologies are common, and that diverse genetics, central nervous system (CNS) and systemic pathophysiological processes, and environmental/experiential factors contribute to AD's diverse clinical and neuropathological features. All these factors are rational targets for therapeutic development; indeed, there are hundreds of candidate pharmacological, dietary, neurostimulation, and lifestyle interventions that show benefits in homogeneous laboratory models. Conventional clinical trial designs accommodate heterogeneity poorly, and this may be one reason that progress in translating candidate interventions has been so difficult. We review the challenges of AD's heterogeneity for the clinical trials enterprise. We then discuss how advances in repeatable biomarkers and digital phenotyping enable novel “single-case” and adaptive trial designs to accelerate therapeutics development, moving us closer to personalized research and medicine for AD.

中文翻译：

---

个性化医疗的途径 — 利用异质性推动阿尔茨海默病临床治疗研究取得进展


生物学和临床异质性是开发阿尔茨海默病 （AD） 新疗法研究中的一个主要挑战。AD 可能由其淀粉样蛋白 β 和 tau 病理学定义，但我们认识到混合病理学很常见，并且不同的遗传学、中枢神经系统 （CNS） 和全身病理生理过程以及环境/经验因素导致了 AD 的不同临床和神经病理学特征。所有这些因素都是治疗开发的合理目标;事实上，有数百种候选的药物、饮食、神经刺激和生活方式干预在同质实验室模型中显示出益处。传统的临床试验设计对异质性的适应能力很差，这可能是在转化候选干预措施方面进展如此困难的原因之一。我们回顾了 AD 异质性对临床试验企业的挑战。然后，我们讨论了可重复生物标志物和数字表型的进步如何实现新颖的“单例”和适应性试验设计，以加速治疗开发，使我们更接近 AD 的个性化研究和医学。