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Anomalous self-assembly of the Aβ peptide into fibrillar amyloid deposits is strongly correlated with the development of Alzheimer's disease. Aβ fibril extension follows a template guided “dock and lock” mechanism where polymerisation is catalysed by the fibrillar ends. Using surface plasmon resonance (SPR) and quenched hydrogen-deuterium exchange NMR (H/D-exchange NMR), we have analysed the fibrillar structure and polymerisation properties of both the highly aggregation prone Aβ1–40 Glu22Gly (Aβ 40Arc ) and wild type Aβ1–40 (Aβ 40WT ). The solvent protection patterns from H/D exchange experiments suggest very similar structures of the fibrillar forms. However, through cross-seeding experiments monitored by SPR, we found that the monomeric form of Aβ 40WT  is significantly impaired to acquire the fibrillar architecture of Aβ 40Arc . A detailed characterisation demonstrated that Aβ 40WT  has a restricted ability to dock and isomerise with high binding affinity onto Aβ 40Arc  fibrils. These results have general implications for the process of fibril assembly, where the rate of polymerisation, and consequently the architecture of the formed fibrils, is restricted by conformational constraints of the monomers. Interestingly, we also found that the kinetic rate of fibril formation rather than the thermodynamically lowest energy state determines the overall fibrillar structure.

Aβ Peptide Fibrillar Architectures Controlled by Conformational Constraints of the Monomer