Simulations and Experiments Reveal Diverse APOE States that Inform their Pathogenicity

Mutations to the lipid transport protein Apolipoprotein E (APOE) can dramatically increase the risk of developing late‐onset Alzheimer’s Disease (AD) by up to 15‐fold, however a molecular description of why some isoforms are protective while others are pathological has remained elusive. We hypothesize that individual APOE isoforms sample distinct conformational landscapes that are modulated by the presence of lipids, and that these landscapes contain co‐existing pathological and protective states.