Background: The key pathogenic event in the onset of Alzheimer’s disease (AD) is believed to be the aggregation of the β-amyloid peptide (Aβ) into toxic oligomers. Molecules that interfere with this process may therefore act as therapeutic agents for the treatment of AD. N-methylated peptides (meptides) are a general class of peptide aggregation inhibitors that act by binding to one face of the aggregating peptide, but are unable to hydrogen bond on the other face, due to the N-methyl group. Objective(s): We optimized the structure of meptide inhibitors of Aβ aggregation, starting with the KLVFF lead sequence that is known to bind to Aβ. We varied the meptide length, N-methylation sites, acetylation and amidation of the N- and C-termini, side chain identity and chirality, via five compound libraries. Methods: Inhibitor activity was tested by Thioflavin T binding, affinity chromatography, electron microscopy and toxicity assays. Results: Optimized inhibitors were able to reverse the toxic effects of β-amyloid at nanomolar concentration on an in vitro brain slice, determined by long term potentiation. Related non-N-methylated analogues were insoluble and toxic. Light scattering and electron microscopy data suggest that the inhibitors act by inducing Aβ oligomers to aggregate into a non-toxic conformation. Conclusions: We found more potent compounds than all other known peptides, peptidomimetics and small molecule inhibitors.