Brain microstructure mediates the relationship between Alzheimer's proteinopathies and memory

INTRODUCTION: We examined how amyloid beta (Aβ) and tau accumulation affected gray matter (GM) microstructural integrity and how such alterations impacted memory. METHODS: We tested voxel-wise mediation models to examine the relationships between (1) positron emission tomography-derived Aβ and tau accumulation and GM microstructural integrity assessed with neurite orientation dispersion and density imaging, (2) GM microstructural integrity and memory controlling for Aβ and tau, and (3) the indirect effect of Aβ and tau on memory through GM microstructural integrity in 194 participants with memory impairments. RESULTS: Tau had a greater impact on GM microstructure than did Aβ. GM microstructural alterations in posterior cortical regions were associated with worse memory when controlling for Alzheimer's proteinopathies. GM microstructural alterations mediated the relationship between Alzheimer's proteinopathies and memory. DISCUSSION: GM microstructural alterations have functional ramifications given their mediating effect on the relationship between Alzheimer's proteinopathies and memory and their association with worse memory beyond Alzheimer's proteinopathies.