What amyloid ligands can tell us about molecular polymorphism and disease

Brain-penetrant positron emission tomography imaging ligands selective for amyloid pathology in living subjects have sparked a revolution in presymptomatic biomarkers for Alzheimer's disease progression. As additional chemical structures were investigated, the heterogeneity of ligand-binding sites became apparent, as did discrepancies in binding of some ligands between human disease and animal models. These differences and their implications have received little attention. This review discusses the impact of different ligand-binding sites and misfolded protein conformational polymorphism on the interpretation of imaging data acquired with different ligands. Investigation of the differences in binding in animal models may identify pathologic processes informing improvements to these models for more faithful recapitulation of this uniquely human disease. The differential selectivity for binding of particular ligands to different conformational states could potentially be harnessed to better define disease progression and improve the prediction of clinical outcomes.