Cortical microstructural alterations along the Alzheimer’s disease continuum and association with amyloid and tau pathology

Multi-shell diffusion MRI offers considerable potential for the noninvasive mapping of Alzheimer’s disease (AD) pathology. Longitudinal studies examining the ability of Neurite Orientation Dispersion and Density Imaging (NODDI) technology to detect early neurodegenerative changes during AD’s preclinical stage are limited. Moreover, the correlation between cortical microstructural alterations and in vivo AD pathology, specifically amyloid and tau protein accumulation, requires further investigation. In this research, we assessed cortical microstructural changes across the AD spectrum, including 61 APOE-ɛ4 negative cognitively normal subjects, 28 APOE-ɛ4 positive cognitively normal subjects, 58 individuals with mild cognitive impairment, and 24 with AD dementia, as part of the Alzheimer’s Disease Neuroimaging Initiative. Assessments were made both cross-sectionally and longitudinally. We also examined the regional relationships between amyloid deposits, tau protein accumulation, and changes in cortical NODDI microstructure associated with AD. Our findings identified reductions in the Intracellular Volume Fraction, an increased isotropic volume fraction (ISOVF), and modifications to the Orientation Dispersion Index in AD-impacted regions. Notably, these modifications were observable across the AD continuum, including during preclinical stages. ISOVF, in particular, showed a positive correlation with the presence of tau and Aβ pathology in critical brain regions, potentially indicative of underlying neuroinflammation. Changes in NODDI metrics correlated with cognitive performance, especially in memory, and were found to partially mediate the link between tau pathology and cognitive function. These comprehensive results suggest NODDI’s potential as an early biomarker for AD detection, disease progression tracking, and therapeutic intervention, contributing fresh perspectives on the disease’s pathophysiology.