Layer-dependent effect of Aβ-pathology on cortical microstructure with ex-vivo human brain diffusion MRI at 7 Tesla

Background: The laminar-specific distributions of Aβ and Tau deposition in the neocortex of Alzheimer’s disease (AD) have been established. However, direct evidence about the effect of AD pathology on cortical microstructure is lacking in human studies. Methods: We performed high-resolution T2-weighted and diffusion-weighted MRI (dMRI) on fifteen ex-vivo whole-hemisphere specimens, including eight cases with an AD pathology, three cases with primary age-related tauopathy (PART) and four healthy controls (HCs). Using the diffusion tensor model, we evaluated microstructure patterns in six layers of grey matter cortex and performed MRI-histology correlation analysis across cortical layers. Results: Aβ-positive cases exhibited higher diffusivity than Aβ-negative cases (PART and HC) in selected cortical regions, particularly in the inferior frontal cortex. Both Aβ/Tau depositions and dMRI-based microstructural markers demonstrated distinct cortical layer-dependent and region-specific patterns. A significant positive correlation was observed between increased diffusivity and Aβ burden across six cortical layers, but not with Tau burden. Furthermore, the mean diffusivity in layer-V of the inferior frontal cortex significantly increased with the Amyloid stage. Conclusion: Our findings demonstrate a layer-dependent effect of Aβ-pathology on cortical microstructure of the human brain, which may be used to serve as early markers of AD pathology.