The amyloid cascade hypothesis, according to which the self-assembly of amyloid-β peptide (Aβ) is a causative process in Alzheimer’s disease, has driven many therapeutic efforts for the past 20 years. Failures of clinical trials investigating Aβ-targeted therapies have been interpreted as evidence against this hypothesis, irrespective of the characteristics and mechanisms of action of the therapeutic agents, which are highly challenging to assess. Here, we combine kinetic analyses with quantitative binding measurements to address the mechanism of action of four clinical stage anti-Aβ antibodies, aducanumab, gantenerumab, bapineuzumab and solanezumab. We quantify the influence of these antibodies on the aggregation kinetics and on the production of oligomeric aggregates and link these effects to the affinity and stoichiometry of each antibody for monomeric and fibrillar forms of Aβ. Our results reveal that, uniquely among these four antibodies, aducanumab dramatically reduces the flux of Aβ oligomers.

淀粉样蛋白级联假说认为淀粉样蛋白-β 肽 (Aβ) 的自组装是阿尔茨海默病的致病过程，在过去 20 年中推动了许多治疗工作。研究 Aβ 靶向治疗的临床试验的失败已被解释为反对这一假设的证据，无论治疗剂的特征和作用机制如何，这都是极具挑战性的评估。在这里，我们将动力学分析与定量结合测量相结合，以解决四种临床阶段抗 Aβ 抗体的作用机制，即 aducanumab、gantenerumab、bapineuzumab 和 solanezumab。我们量化了这些抗体对聚集动力学和寡聚体产生的影响，并将这些影响与每种抗体对 Aβ 单体和纤维形式的亲和力和化学计量联系起来。我们的研究结果表明，在这四种抗体中，阿杜卡单抗独特地显着降低了 Aβ 寡聚体的通量。