The polymorph selection hypothesis relates the substantial structural diversity of amyloid-β (Aβ) aggregates to their divergent toxicities. These distinct Aβ morphologies may underlie the variability in the clinical characteristics of Alzheimer’s disease. Here we examine the structural basis of the polymorph selection hypothesis. We rely on in situ atomic force microscopy (AFM) observations of Aβ42 aggregates nucleated in situ in the microscope cell and monitor their dynamics at various monomer concentrations. Six classes of Aβ42 polymorphs are characterized based on the fibrils’ mesoscopic features under identical conditions. These polymorphs coexist and their distribution appears to be concentration-dependent. We identify self-assembled misfolded oligomers that grow into amorphous aggregates and show that they do not interact with the fibrillization pathway. Time-resolved AFM images also reveal diverse secondary nucleation outcomes, selecting preferred sites on the fibril surface, which leads to fibril branching and thickening. In addition, the measured growth rates for various polymorphs exceed the expectation of uniformity within each polymorph type. These heterogeneous growth rates provide deeper insight into the molecular-level mechanisms during assembly, revealing that the conformation of monomers at the fibril tip and the difference in chemical potential of monomers, both in fibril bulk and solution, play pivotal roles in governing these dynamics. Thus, the survival of a specific polymorph during the disease progression may depend on its nucleation conditions and morphology as well as physiological factors.
