From molecular aggregates to neurodegenerative networks: Integrating electron and X-ray imaging across scale

Neurodegeneration unfolds across scales, from nanometer-scale protein assemblies to millimeter-scale tissue reorganization. This review examines how electron and X-ray methods connect these levels. Single-particle cryo-electron microscopy (cryo-EM) resolves isolated molecular assemblies, cryo-electron tomography places them within native cellular environments, and volume electron microscopy maps their organization across cells and tissue. X-ray phase-contrast imaging and ptychographic tomography enable nondestructive three-dimensional mapping of cells and tissues, whereas scanning X-ray diffraction reveals molecular organization and scanning X-ray fluorescence identifies the spatial distribution of elements. We also discuss how histopathology and fluorescence guide target selection, how emerging methods extend imaging to thicker specimens, and how human postmortem tissue and experimental models provide complementary evidence. Together, these approaches form an imaging continuum linking molecular architecture, cellular pathology, and tissue-level neurodegeneration.