Why Aβ42 Is Much More Toxic than Aβ40

Amyloid precursor A4 (770 amino acids (aa)) dimerizes and aggregates, as do its C-terminal (99 aa) and amyloid Aβ (40,42 aa Aβ40,Aβ42) fragments. The titled question has been discussed extensively, and here it is addressed further using thermodynamic scaling theory to analyze mutational trends in structural factors and kinetics. Special attention is given to Family Alzheimer’s disease mutations in C99 outside Aβ42 centered on Aβ46. The scaling analysis is connected to extensive C99 docking simulations which included membranes (Sun et al. J. Chem. Inf. Model. 2017, 57, 1375−1387 ), thereby confirming their C99 results and extending them to A4.