We have shown that the interaction of amyloid proteins with surfaces presents a unique opportunity to allow the protein to assemble into aggregates at concentrations that are non-permissive for aggregation in solution. This finding eliminates a major problem with understanding the spontaneous appearance of plaques in the AD brain due to the apparent gap between known extracellular Aβ concentrations in vivo (in the low nM range) and the concentration required for spontaneous aggregation in vitro (which is in the μM range). Importantly, the on-surface aggregation is a dynamic process, so the assembled aggregate can dissociate from the surface to the bulk solution. This mechanism is confirmed by direct measurement of the concentration of Aβ-42 aggregates in solution depending on the presence of the mica surface. The data shown in Supplementary Fig. 9 demonstrate that in the presence of mica, the concentration of Aβ-42 aggregates in solution is considerably higher than in the control, and this number grows with time. As a result, these dissociated oligomers can play roles as seeds for aggregation in the bulk solution, or start a neurotoxic effect such as phosphorylation of the tau protein to initiate its misfolding and aggregation followed by neurodegeneration8. Additionally, in the vast majority of cases, we found that aggregates formed on the surface are oligomers, which are considered to be the most neurotoxic amyloid aggregates. Although the experimental data presented was for APS-mica, a very similar effect was observed for the bare mica. Additionally, we are currently performing experiments with the use of a lipid bilayer surface. Preliminary results show an even stronger on-surface aggregation effect for the lipid bilayers compared with APS and bare mica. Therefore, we posit that on-surface aggregation is a general mechanism by which neurotoxic amyloid aggregates are produced under physiological conditions.