Gray matter microstructure from in vivo diffusion magnetic resonance imaging reflects post mortem neuropathology severity and clinical progression of Alzheimer's disease.

INTRODUCTION: Diffusion-weighted imaging derived mean diffusivity (MD) correlates with Alzheimer's disease (AD) biomarkers, yet its neuropathological correlates remain unclear. METHODS: Diffusion-weighted imaging, post mortem neuropathology, and cognitive performance data were obtained from the National Alzheimer's Coordinating Center (N = 97), Alzheimer's Disease Neuroimaging Initiative (N = 21), and Arizona Study of Aging and Neurodegenerative Disorders (N = 15). We examined MD associations with neuropathology, cognitive decline, and expression profiles of AD-implicated genes. RESULTS: Results revealed two latent variables-one linked to amyloid/tau, the other to vascular pathology-explaining between 70% and 16% of MD-pathology covariance, respectively. Higher MD correlated with worse cognitive performance, both cross-sectionally and up to 16 years prior to death. MD was regionally associated with Thal phase, neuritic plaque density, Braak stage (temporal/limbic), and infarcts (thalamus), and reflected gene expression patterns related to AD. DISCUSSION: In vivo MD captures distinct AD-related pathologies across brain regions and relates to cognitive trajectories and gene expression. HIGHLIGHTS: Diffusion-weighted imaging (DWI) can detect early gray matter microstructural differences in the Alzheimer's disease (AD) continuum. Mean diffusivity (MD) is associated with tau, amyloid and vascular neuropathologies. Thal amyloid phase and Braak tau score correlate with MD in temporal and limbic regions. Multivariate MD scores differentially relate to proteinopathies vs. vascular damage. MD can serve as a non-invasive biomarker to predict post mortem AD neuropathology.