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 replacing a backbone NH group. We optimised the structure of meptide inhibitors of Aβ aggregation, starting with the KLVFF 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. Inhibitor activity was tested by Thioflavin T binding, affinity chromatography, electron microscopy and an MTT toxicity assay. We found that inhibitors should have all-D chirality, have a free N-terminus, but an amidated C-terminus, and have large, branched hydrophobic side chains at positions 1-4, while the side chain at position 5 was less important. A single N-methyl group was sufficient. The most active compound, D-[(chGly)-(Tyr)-(chGly)-(chGly)-(mLeu)]-NH2 (SEN304), was more active than a wide range of previously reported peptide inhibitors. Its related non-N-methylated analogues were insoluble and toxic. A model for learning and memory is long term potentiation in a brain slice. While Aβ inhibits long term potentiation, SEN304 is able to reverse this toxic effect at nanomolar concentrations. SEN304 is able to reduce the concentration of Aβ oligomers by inducing their aggregation into a non-toxic morphology, as shown by light scattering, electron microscopy and gel electrophoresis.