Solving the Amyloid Paradox: Unveiling the Complex Pathogenicity of Amyloid Fibrils

More than a century ago, it was known that the accumulation of ordered protein aggregates, amyloid fibrils, accompanies several serious and still largely incurable pathologies, including Alzheimer's and Parkinson's diseases. The striking gap between decades of research identifying amyloids as one of the key drivers of neurodegeneration and the persistent lack of effective anti-amyloid therapies reveals a perplexing contradiction, which we define as the “amyloid paradox.” To address this paradox, here we summarize and analyze current perspectives on the unique properties and pathogenic mechanisms of amyloids, highlighting the variability and complexity of their biological consequences and uncovering the risks and limitations encountered in combating these aggregates. We conceptualize amyloid fibril pathogenicity as a complex cascade extending well beyond direct cytotoxicity, such as that arising from disruption of membranes and other cellular organelles. This review encompasses amyloids' disruptive effects on cellular processes and ability to trigger inflammatory responses, their resistance to degradation, capacity to regenerate after apparent destruction, tendency to propagate throughout the organism, propensity to cytotoxicity-increasing transformation, and ability to sequester and pathologically modify essential biomolecules. This integrated analysis reveals why single-target therapeutic approaches often fail and suggests that effective anti-amyloid strategies must address multiple aspects of amyloid pathogenicity simultaneously. The conceptual reframing of the threats of amyloid fibrils helps explain the origins of the amyloid paradox, enhances our understanding of these complex pathogenic agents, and provides a foundation for developing more effective and safe therapeutic strategies for neurodegenerative diseases. These strategies should address the complex and interconnected nature of amyloid pathogenicity rather than its targeting isolated aspects.