Structural variability of apolipoprotein A-I amyloid fibrils across organs, mutations, and clinical presentations, revealed by cryo-EM.

Hereditary apolipoprotein A-I (AApoA-I) amyloidosis is a rare systemic disease caused by the deposition of amyloid fibrils formed by apolipoprotein A-I in multiple organs, leading to severe clinical outcomes. With no available therapies or diagnostic tools, defining the structure of AApoA-I fibrils is crucial to understanding disease mechanisms and guiding intervention. Using cryo-electron microscopy, we analyzed AApoA-I fibrils from the heart, kidney, liver, and spleen of patients carrying G26R, L90P, and R173P mutations. G26R fibrils, regardless of organ, exhibited untwisted morphologies and could not be resolved structurally. Conversely, L90P and R173P fibrils displayed a compact diabolo-shaped conformation in all organs analyzed. Their high-resolution maps enabled visualization of -Proline 66, which may represent a potential conformational switch during fibril formation. Our findings suggest that mutation-driven polymorphism may influence organ tropism and clinical presentation. This work advances our understanding of AApoA-I fibril assembly and provides insights toward developing targeted clinical tools.