With regard to applications of this work to AD development, we propose the following model in the framework of the amyloid cascade hypothesis in which interaction of amyloidogenic polypeptides with cellular membranes plays an important role for the disease-related aggregation process. Under normal conditions, the interaction of intracellular or extracellular amyloid proteins with intracellular or extracellular membranes is weak, so small aggregates assemble. These are unstable and dissociate into monomers either on the surface or after dissociation from the membrane. A change in membrane properties leading to an increase in affinity of amyloid proteins to the membrane surface will shift the process to the formation of more stable oligomers that remain intact after dissociation from the surface, and this assembly triggers the disease-related aggregation process. This mechanism does not require elevation of the amyloid peptide concentration, and indeed the concentration of amyloid beta peptide in blood fluctuates weakly regardless of the disease state and does not differ from the controls28. Also, the Aβ clearance in late-onset AD patients drops by about one quarter29, and only a fraction of the Aβ produced is trapped in amyloid plaques30. Our model is in line with recent findings31323334 that demonstrate that the aggregation rate of amyloidogenic proteins measured in the presence of membranes of various types depends on the membrane composition and mechanical properties. Indirect support for the concept of membrane-induced aggregation comes from findings on the elevated yield of Aβ dimers in membrane-containing fractions of blood from AD patients compared with controls35. Note as well our direct observation of α-Syn on-surface assembly at nanomolar concentrations when the initial monomer was covalently bound to the surface20. Recent NMR studies on the intracellular structure of α-Syn showed that it primarily exists in cells as monomers in an essentially unstructured, compact conformation, but transient interaction of the protein with the membrane was considered9. Indeed, the on-surface assembled oligomers comprise a very small fraction of the protein mass in bulk solution, and only a fraction of the aggregates dissociate into the solution, so their detection by NMR is a challenge.