Multi-pathway aggregation drives concentration-dependent amyloid polymorphism and time-dependent morphological evolution

Abstract

Amyloid aggregation into polymorphic fibrils is central to many neurodegenerative and systemic diseases, yet the physical origins of fibril polymorphism and time-dependent morphological evolution remain unclear. Because mature fibril morphologies are separated by high energy barriers, direct interconversion is unlikely. Here, we propose a multi-pathway aggregation model in which oligomeric nuclei with distinct sizes and chemical potentials seed different fibril morphologies. The abundance and temporal evolution of these polymorphs are governed by pathway-specific fibrillization barriers and fibril stabilities, allowing kinetically favored morphologies to dominate early but to be replaced by more stable forms over time. Differences in nucleus size further introduce concentration dependence, biasing aggregation toward different intermediates and fibril morphologies at low versus high concentrations. This framework helps rationalize the substantial concentration disparity between in vitro experiments and in vivo environments and highlights the importance of considering multi-pathway, concentration-dependent aggregation in studying amyloidosis and designing anti-amyloidosis strategies.