Alzheimer's disease: Which type of amyloid-preventing drug agents to employ?

The current paradigm in the amyloid hypothesis brands small β-amyloid (Aβ) oligomers as the toxic species in Alzheimer's disease (AD). These oligomers are fibril-like; contain β-sheet structure, and present exposed hydrophobic surface. Oligomers with this motif are capable of penetrating the cell membrane, gathering to form toxic ion channels. Current agents suppressing precursor Aβ cleavage have only met partial success; and to date, those targeting the peptides and their assemblies in the aqueous environment of the extracellular space largely fail in clinical trials. One possible reason is failure to reach membrane-embedded targets of disease-'infected' cells. Here we provide an overview, point to the need to account for the lipid environment when aiming to prevent the formation of toxic channels, and propose a combination therapy to target the species spectrum.