This study investigates the differential effects of oligomeric and fibrillar forms of amyloid-beta (Aβ) peptides on neuronal viability. The research demonstrates that oligomeric Aβ-(1-42) is significantly more toxic to neurons than fibrillar Aβ-(1-42) or unaggregated Aβ. Oligomers inhibited neuronal viability 10-fold more than fibrils and 40-fold more than unaggregated peptide, with significant inhibition observed at 10 nm. In contrast, Aβ-(1-40) remained predominantly as unassembled monomers and had less effect on neuronal viability compared to Aβ-(1-42). The study also examined the effects of mutations in Aβ, such as the Dutch (E22Q) and Arctic (E22G) mutations, on the aggregation and toxicity of Aβ. While these mutations led to increased protofibril and fibril formation, they did not consistently alter the toxicity of the peptides. However, fibrillar preparations of the mutants were more toxic than wild-type fibrils. These findings suggest that the structural and functional differences between Aβ-(1-42) and Aβ-(1-40) are significant, and that mutations can influence aggregation pathways and toxicity. The study developed two aggregation protocols to produce consistent oligomeric and fibrillar preparations of Aβ-(1-42). These protocols were used to compare the effects of different aggregation states on neuronal viability. The results showed that oligomeric Aβ-(1-42) was more toxic than fibrillar Aβ-(1-42), and that Aβ-(1-40) was less toxic than Aβ-(1-42) under the same conditions. The study also highlights the importance of distinguishing between different aggregation states of Aβ in understanding the pathogenesis of Alzheimer's disease. While the amyloid hypothesis suggests that fibrillar Aβ is toxic, the findings indicate that oligomeric forms may be more harmful. This suggests that the active species responsible for neurodegeneration in Alzheimer's disease may be oligomeric Aβ rather than fibrillar Aβ. The study underscores the need for further research to clarify the role of different Aβ aggregation states in the progression of Alzheimer's disease.This study investigates the differential effects of oligomeric and fibrillar forms of amyloid-beta (Aβ) peptides on neuronal viability. The research demonstrates that oligomeric Aβ-(1-42) is significantly more toxic to neurons than fibrillar Aβ-(1-42) or unaggregated Aβ. Oligomers inhibited neuronal viability 10-fold more than fibrils and 40-fold more than unaggregated peptide, with significant inhibition observed at 10 nm. In contrast, Aβ-(1-40) remained predominantly as unassembled monomers and had less effect on neuronal viability compared to Aβ-(1-42). The study also examined the effects of mutations in Aβ, such as the Dutch (E22Q) and Arctic (E22G) mutations, on the aggregation and toxicity of Aβ. While these mutations led to increased protofibril and fibril formation, they did not consistently alter the toxicity of the peptides. However, fibrillar preparations of the mutants were more toxic than wild-type fibrils. These findings suggest that the structural and functional differences between Aβ-(1-42) and Aβ-(1-40) are significant, and that mutations can influence aggregation pathways and toxicity. The study developed two aggregation protocols to produce consistent oligomeric and fibrillar preparations of Aβ-(1-42). These protocols were used to compare the effects of different aggregation states on neuronal viability. The results showed that oligomeric Aβ-(1-42) was more toxic than fibrillar Aβ-(1-42), and that Aβ-(1-40) was less toxic than Aβ-(1-42) under the same conditions. The study also highlights the importance of distinguishing between different aggregation states of Aβ in understanding the pathogenesis of Alzheimer's disease. While the amyloid hypothesis suggests that fibrillar Aβ is toxic, the findings indicate that oligomeric forms may be more harmful. This suggests that the active species responsible for neurodegeneration in Alzheimer's disease may be oligomeric Aβ rather than fibrillar Aβ. The study underscores the need for further research to clarify the role of different Aβ aggregation states in the progression of Alzheimer's disease.