This study investigates the structural conversion of neurotoxic amyloid-β (1–42) oligomers to fibrils. The research reveals that low temperature and low salt conditions stabilize disc-shaped oligomers (pentamers) that are significantly more toxic to murine cortical neurons than protofibrils and fibrils. These neurotoxic oligomers lack the β-sheet structure characteristic of fibrils and instead consist of loosely aggregated strands with a turn conformation placing Phe19 in contact with Leu34. Using NMR spectroscopy, the study shows that the structural conversion of Aβ42 oligomers to fibrils involves the association of these loosely aggregated strands into β-sheets with parallel, in-register orientation and staggered inter-monomer contacts between Gln15 and Gly37. The study also highlights the structural differences between Aβ42 oligomers and fibrils, showing that Aβ42 fibrils have parallel, in-register β-sheets, while oligomers do not. The Phe19-Leu34 packing in Aβ42 oligomers and fibrils is consistent with the hydrophobic collapse of residues in two of the most hydrophobic stretches of the Aβ peptide. Additionally, the β-strands in Aβ42 fibrils are staggered, which is not observed in oligomers. The study further demonstrates that the conversion of Aβ42 oligomers to fibrils is associated with a reduction in neurotoxicity. The findings provide insights into the structural features of Aβ42 oligomers and fibrils, which are crucial for understanding the aggregation pathway involved in plaque formation and for the development of therapeutic and diagnostic agents.This study investigates the structural conversion of neurotoxic amyloid-β (1–42) oligomers to fibrils. The research reveals that low temperature and low salt conditions stabilize disc-shaped oligomers (pentamers) that are significantly more toxic to murine cortical neurons than protofibrils and fibrils. These neurotoxic oligomers lack the β-sheet structure characteristic of fibrils and instead consist of loosely aggregated strands with a turn conformation placing Phe19 in contact with Leu34. Using NMR spectroscopy, the study shows that the structural conversion of Aβ42 oligomers to fibrils involves the association of these loosely aggregated strands into β-sheets with parallel, in-register orientation and staggered inter-monomer contacts between Gln15 and Gly37. The study also highlights the structural differences between Aβ42 oligomers and fibrils, showing that Aβ42 fibrils have parallel, in-register β-sheets, while oligomers do not. The Phe19-Leu34 packing in Aβ42 oligomers and fibrils is consistent with the hydrophobic collapse of residues in two of the most hydrophobic stretches of the Aβ peptide. Additionally, the β-strands in Aβ42 fibrils are staggered, which is not observed in oligomers. The study further demonstrates that the conversion of Aβ42 oligomers to fibrils is associated with a reduction in neurotoxicity. The findings provide insights into the structural features of Aβ42 oligomers and fibrils, which are crucial for understanding the aggregation pathway involved in plaque formation and for the development of therapeutic and diagnostic agents.