Alzheimer's disease (AD) is characterized by the abnormal aggregation of amyloid-beta peptide (A beta) in extracellular deposits known as senile plaques. The tyrosine residue (Tyr-10) is believed to be important in A beta-induced neurotoxicity due to the formation of tyrosyl radicals. To reduce the likelihood of cross-linking, here we designed an A beta-40 analogue (A beta-40 Y10F) in which the tyrosine residue was substituted by a structurally similar residue, phenylalanine. The aggregation rate was determined by the Thioflavin T (ThT) assay, in which A beta-40 Y10F populated an ensemble of folded conformations much quicker and stronger than the wild type A beta. Biophysical tests subsequently confirmed the results of the ThT assay, suggesting the measured increase of beta-aggregation may arise predominantly from enhancement of hydrophobicity upon substitution and thus the propensity of intrinsic beta-sheet formation. Nevertheless, A beta-40 Y10F exhibited remarkably decreased neurotoxicity compared to A beta-40 which could be partly due to the reduced generation of hydrogen peroxide. These findings may lead to further understanding of the structural perturbation of A beta to its fibrillation.