Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Department of Biostatistics, New York University School of Global Public Health, New York, New York, USA.
Alzheimers Dement. 2024 Oct;20(10):7384-7394. doi: 10.1002/alz.14063. Epub 2024 Sep 6.
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. HIGHLIGHTS: Alzheimer's disease is diverse in its clinical features, course, risks, and biology. Typical randomized controlled trials are exclusive and necessarily large to attain arm comparability with broad outcomes. Repeated blood biomarkers and digital tracking can improve outcome measure precision and sensitivity. This enables the use of novel "single-case" and adaptive trial designs for inclusivity, rigor, and efficiency.
生物和临床异质性是开发阿尔茨海默病（AD）新疗法研究的主要挑战。AD 可以通过其淀粉样蛋白β和 tau 病理学来定义，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/经验因素促成了 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，有数百种候选药物、饮食、神经刺激和生活方式干预措施在同质的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，这可能是候选干预措施转化进展如此困难的原因之一。我们回顾了 AD 对临床试验企业的异质性的挑战。然后，我们讨论了可重复的生物标志物和数字表型如何使新的“单病例”和适应性试验设计能够加速治疗开发，使我们更接近 AD 的个性化研究和医学。要点：阿尔茨海默病在其临床特征、病程、风险和生物学方面存在多样性。典型的随机对照试验是排他性的，并且为了实现广泛结果的手臂可比性，规模必然很大。重复的血液生物标志物和数字跟踪可以提高结果测量的精度和灵敏度。这使我们能够使用新的“单病例”和适应性试验设计来提高包容性、严谨性和效率。
