Structural changes in gray matter and white matter across the Alzheimer’s disease continuum

Abstract

Objective The pathophysiological spectrum of Alzheimer’s disease (AD) is a continuum, with the AT(N) framework defining stages based on the presence of Aβ pathology, tau pathology, and neurodegeneration. However, the spatial characteristics of gray matter (GM) and white matter (WM) changes at different stages remain insufficiently defined. This study aimed to establish a cross-sectional cohort of the AD continuum using the AT(N) staging system and systematically delineate the spatial features of GM and WM changes across this spectrum. Methods This study included subjects across the AD continuum with defined AT(N) stages [n = 178, including A-T- cognitive normal (CN), A + T- CN, A + T + CN, A + T + mild cognitive impairment (MCI), and A + T + AD subgroups]. Voxel-based morphometry (VBM) was used to assess GM volume changes. Tract-based spatial statistics (TBSS) was employed to analyze WM microstructure alterations using fractional anisotropy (FA). Group comparisons were performed to characterize the pattern of brain structural alterations across different AT(N) stages. Correlation analyses were performed to assess correlations of GM and WM changes with AD neuropathology and with cognitive function, respectively. Results A region-specific pattern of GM volume atrophy was observed: hippocampal (HIP) volume atrophy was most pronounced in the A + T- CN subgroup. The parahippocampal gyrus (PHG), amygdala (AMYG), and fusiform gyrus (FFG) showed volume atrophy in the A + T + CN subgroup. In the A + T + MCI and A + T + AD subgroups, extensive GM volume reduction involved global GM regions. For WM alterations, reduced FA values were observed in the hippocampal cingulum (CgH) at the A + T + CN stage. In A + T + MCI and A + T + AD subgroups, a broader scope of WM FA reduction was observed. Correlation analyses revealed that HIP volume was positively associated with CgH FA values and Aβ levels, while both HIP volume and CgH FA values were negatively associated with P-tau levels, and both HIP volume and CgH FA values positively correlated with global cognition and memory performance. Conclusion GM and WM alterations are widespread in the AD continuum. Early selective GM volume loss and impaired WM axonal integrity are associated with pathological processes in AD.