This study investigates the effects of different forms of amyloid-β (Aβ) peptides on neuronal viability. The authors developed two aggregation protocols to produce stable oligomeric and fibrillar preparations of Aβ-(1-42). They found that oligomeric Aβ-(1-42) significantly reduced neuronal viability 10-fold more than fibrillar species and ~40-fold more than unaggregated peptide, with oligomeric Aβ-(1-42)-induced inhibition significant at 10 nm. Aβ-(1-40) remained predominantly as unassembled monomers under the same conditions and had a much less effect on neuronal viability. The study also applied these aggregation protocols to Aβ-(1-42) with the Dutch (E22Q) and Arctic (E22G) mutations, which are known to increase the rate of fibril formation and reduce Aβ-(1-42) levels, respectively. While the mutations did not consistently change the toxicity of oligomeric Aβ-(1-42), fibrillar preparations of both mutants were more toxic than wild-type Aβ-(1-42). These findings suggest that both fibril structure and the presence of fibrils may be more toxic than oligomers in certain genetic backgrounds. The study highlights the importance of distinguishing between different forms of Aβ in understanding their role in Alzheimer's disease.This study investigates the effects of different forms of amyloid-β (Aβ) peptides on neuronal viability. The authors developed two aggregation protocols to produce stable oligomeric and fibrillar preparations of Aβ-(1-42). They found that oligomeric Aβ-(1-42) significantly reduced neuronal viability 10-fold more than fibrillar species and ~40-fold more than unaggregated peptide, with oligomeric Aβ-(1-42)-induced inhibition significant at 10 nm. Aβ-(1-40) remained predominantly as unassembled monomers under the same conditions and had a much less effect on neuronal viability. The study also applied these aggregation protocols to Aβ-(1-42) with the Dutch (E22Q) and Arctic (E22G) mutations, which are known to increase the rate of fibril formation and reduce Aβ-(1-42) levels, respectively. While the mutations did not consistently change the toxicity of oligomeric Aβ-(1-42), fibrillar preparations of both mutants were more toxic than wild-type Aβ-(1-42). These findings suggest that both fibril structure and the presence of fibrils may be more toxic than oligomers in certain genetic backgrounds. The study highlights the importance of distinguishing between different forms of Aβ in understanding their role in Alzheimer's disease.