Multimodal structural and transcriptomic correlates of regional homogeneity across the Alzheimer’s disease continuum

Regional homogeneity (ReHo) reflects local synchronization of resting-state brain activity, but the structural and molecular correlates of ReHo across the Alzheimer’s disease (AD) continuum remain unclear. We included 421 cognitively normal participants, 226 patients with mild cognitive impairment, and 68 patients with AD. T1-weighted MRI, diffusion MRI, and resting-state functional MRI were used to quantify cortical thickness, regional streamline count, structure-function coupling (SFC), and ReHo. Disease abnormality indices were constructed across diagnostic stages using ordinal regression. Generalized linear models and repeated cross-validation were used to assess the associations of structural and coupling measures with regional ReHo. Residual ReHo after adjustment for cortical thickness, regional streamline count, and SFC was spatially associated with gene-expression maps using partial least squares regression, followed by pathway, protein interaction, and cell-type enrichment analyses. ReHo, cortical thickness, regional streamline count, and SFC showed stage-dependent and spatially heterogeneous abnormalities. Disease abnormality indices of ReHo, cortical thickness, regional streamline count, and SFC were associated with broad cognitive and functional impairment. ReHo was consistently associated with cortical thickness (β, −0.210 to −0.129; all p < 0.001), regional streamline count (β, 0.001 to 0.059; all p < 0.05), and SFC (β, 0.166 to 0.197; all p < 0.001), which jointly explained regional ReHo variance (R 2 , 0.346 to 0.371). Residual ReHo was linked to cortical gene-expression gradients enriched for neurovascular signaling, energy metabolism, proteostasis, and stage-specific astrocytic, microglial, excitatory neuronal, and inhibitory neuronal processes. ReHo alterations across the AD continuum are associated with structural, functional, and molecular features. This work advances our understanding of regional functional alterations across the AD continuum and helps inform the development of targeted intervention strategies.