Amyloid proteins, which are considered 'villains' in many neurodegenerative diseases, form enigmatic pathological strains that underlie disease pathogenesis and progression. Recent technical advances in cryogenic electron microscopy and solid-state NMR spectroscopy have enabled the high-resolution structures of full-length amyloid fibrils to be determined, initiating an era in which we have the opportunity to gain atomic-level structural understanding of pathogenic protein aggregation in neurodegenerative diseases. In this Review, we aim to explain the clinicopathological heterogeneity of neurodegenerative diseases by considering the polymorphic structures of amyloid fibrils. We decipher the structural basis for the generation of fibril polymorphs, how the fibril polymorphs differ in different disease contexts and how conformational changes alter the pathology caused by amyloid proteins during disease progression. Finally, we evaluate how this knowledge might aid clinical diagnostic and therapeutic strategies to treat neurodegenerative diseases.
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