Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK.
Scottish Biologics Facility, University of Aberdeen, Aberdeen, UK.
Transl Neurodegener. 2024 May 21;13(1):25. doi: 10.1186/s40035-024-00417-w.
The use of biomarker-led clinical trial designs has been transformative for investigating amyloid-targeting therapies for Alzheimer's disease (AD). The designs have ensured the correct selection of patients on these trials, supported target engagement and have been used to support claims of disease modification and clinical efficacy. Ultimately, this has recently led to approval of disease-modifying, amyloid-targeting therapies for AD; something that should be noted for clinical trials investigating tau-targeting therapies for AD. There is a clear overlap of the purpose of biomarker use at each stage of clinical development between amyloid-targeting and tau-targeting clinical trials. However, there are differences within the potential context of use and interpretation for some biomarkers in particular measurements of amyloid and utility of soluble, phosphorylated tau biomarkers. Given the complexities of tau in health and disease, it is paramount that therapies target disease-relevant tau and, in parallel, appropriate assays of target engagement are developed. Tau positron emission tomography, fluid biomarkers reflecting tau pathology and downstream measures of neurodegeneration will be important both for participant recruitment and for monitoring disease-modification in tau-targeting clinical trials. Bespoke design of biomarker strategies and interpretations for different modalities and tau-based targets should also be considered.
生物标志物引导的临床试验设计在探索针对阿尔茨海默病（AD）的淀粉样蛋白靶向疗法方面具有变革性。这些设计确保了在这些试验中正确选择患者，支持了靶点结合，并被用于支持疾病修饰和临床疗效的主张。最终，这最近导致了批准用于 AD 的疾病修饰、淀粉样蛋白靶向疗法；这对于正在研究针对 AD 的 Tau 靶向疗法的临床试验应该注意。在淀粉样蛋白靶向和 Tau 靶向临床试验的临床开发的每个阶段，生物标志物的使用目的都有明显的重叠。然而，在某些生物标志物的潜在用途和解释方面存在差异，特别是在淀粉样蛋白的特定测量和可溶性磷酸化 Tau 生物标志物的实用性方面。鉴于 Tau 在健康和疾病中的复杂性，至关重要的是，治疗方法针对与疾病相关的 Tau，并且同时开发适当的靶点结合测定方法。正电子发射断层扫描 Tau、反映 Tau 病理学的液体检生物标志物以及神经退行性变的下游测量结果对于 Tau 靶向临床试验中的参与者招募和监测疾病修饰都将非常重要。还应考虑针对不同模式和基于 Tau 的靶标定制生物标志物策略和解释。
