Aducanumab, a human-derived antibody targeting amyloid-β (Aβ), is in Phase 3 
clinical trials for the treatment of Alzheimer's disease. Biochemical and 
structural analyses show that aducanumab binds a linear epitope formed by amino 
acids 3-7 of the Aβ peptide. Aducanumab discriminates between monomers and 
oligomeric or fibrillar aggregates based on weak monovalent affinity, fast 
binding kinetics and strong avidity for epitope-rich aggregates. Direct 
comparative studies with analogs of gantenerumab, bapineuzumab and solanezumab 
demonstrate clear differentiation in the binding properties of these antibodies. 
The crystal structure of the Fab fragment of aducanumab bound to its epitope 
peptide reveals that aducanumab binds to the N terminus of Aβ in an extended 
conformation, distinct from those seen in structures with other antibodies that 
target this immunodominant epitope. Aducanumab recognizes a compact epitope that 
sits in a shallow pocket on the antibody surface. In silico analyses suggest 
that aducanumab interacts weakly with the Aβ monomer and may accommodate a 
variety of peptide conformations, further supporting its selectivity for Aβ 
aggregates. Our studies provide a structural rationale for the low affinity of 
aducanumab for non-pathogenic monomers and its greater selectivity for 
aggregated forms than is seen for other Aβ-targeting antibodies.