Investigation of the myelin-amyloid interplay in Alzheimer’s disease: insights from novel dsCMA imaging in mouse and human brains

Abstract Myelin deterioration impairs neural communication and may contribute to neurodegenerative diseases such as Alzheimer’s disease (AD). However, the spatiotemporal relationship between myelin degeneration and AD pathology remains unclear. We developed a novel imaging method—double-scan Cyto- and myelo-architecture (dsCMA)—that integrates multi-fluorescent labeling of cytoarchitecture and pathological markers with brightfield myelin staining on the same tissue sections. Coupled with computational tools for automated detection and quantification of amyloid-beta (Aβ) plaques and myelinated axons, dsCMA enables systematic analysis of Aβ–myelin interactions in 5xFAD mice and postmortem human AD tissues. In mice, we identified progressive, region-specific myelin disruption associated with Aβ accumulation, particularly in the hippocampus and cortex. Human samples revealed variable Aβ–myelin spatial relationships across individuals and regions, with evidence supporting a potential myelin origin for some plaques. These findings offer new insights into Aβ–myelin interplay and establish dsCMA as a scalable platform for histopathological analysis in translational and longitudinal AD research.