Kinetic fingerprints differentiate anti-Aβ therapies

Alzheimer9s disease affects nearly 50 million people worldwide with an overall cost corresponding to more than 1% of the global economy. The amyloid cascade hypothesis, according to which the misfolding and self-assembly of the amyloid-β peptide (Aβ) into oligomeric and fibrillar aggregates is a causative pathogenic process in this disease (1,2), has driven many therapeutic efforts for the past 20 years. Failures of clinical trials investigating Aβ-targeted therapies (3-6), however, have been interpreted as evidence against this hypothesis, irrespective of the characteristics and mechanisms of action of the therapeutic agents, which have proved highly challenging to assess. Here, we bring together kinetic analysis with quantitative binding measurements to address the mechanisms of action of four clinical stage anti-Aβ antibodies, aducanumab (7), gantenerumab, bapineuzumab and solanezumab. We reveal and quantify the striking differences that these antibodies have on the aggregation kinetics and on the production of oligomeric aggregates, and link these effects to the affinity and stoichiometry of each antibody for the monomeric and fibrillar forms of Aβ. Our results uncover that, uniquely amongst these four antibodies, aducanumab (3) dramatically reduces the flux of oligomeric forms of Aβ.