- Alzheimer disease (AD) is a progressive neurodegenerative disease associated with accumulation of aggregated Aβ1-40/Aβ1-42 peptides in the brain. Ordered aggregates can extend into β-strand enriched fibrils, regardless of their initial native conformational states. To date, the self-assembly mechanism leading to ordered fibril formation is not fully understood. Understanding the mechanisms and the range of structural features of the aggregates are of crucial importance for effective drug design to reduce aggregate formation. The polymorphism of Aβ1-42 based on ssNMR, EM, 2D hydrogen exchange and mutational studies, was investigated using all-atom molecular dynamics simulations with explicit solvent. Open questions relate to (1) how the monomeric peptides assemble into oligomers; (2) which segments of a long peptide constitute the recognition motifs and as such playing key roles in amyloid fibril formation; (3) how the β-strands arrange relative to one another; (3) is there a favored organization between the β-sheets and if so as one would expect (4) what is it and what are the intermolecular interactions between the layers that stabilize the favored amyloid fibril organization(s) are discussed. This project has been funded in whole or in part with Federal funds from the NCI, NIH, under contract number HHSN261200800001E.