Stepwise connectivity of the entorhinal cortex along connectomic gradients in Alzheimer's disease

The entorhinal cortex is one of the earliest sites of tau tangle deposition in Alzheimer's disease. Existing connectome studies focus on tau propagation along direct, first-order connections between brain regions, overlooking multi-step, higher-order connections that contribute to the spread of pathology in the brain. We propose a novel quantitative integration of graph theory-based stepwise connectivity with low-dimensional connectome gradient space, which reflects the brain's hierarchical organization. This allows us to elucidate multi-step connectivity between the entorhinal cortex (seed region) and the rest of the brain along the major axes of functional and structural brain organization. In this study, we included 213 participants from the Translational Biomarkers in Aging and Dementia (103 amyloid-negative cognitively normal, 35 amyloid-positive cognitively normal, and 75 cognitively impaired) with diffusion-weighted MRI, resting-state functional MRI, and 18F-MK6240 tau-PET. Through the novel integration between stepwise connectivity and connectome gradients, we observed hypoconnectivity from the entorhinal cortex to the transmodal end of the functional gradient and to the posterior end of the structural gradient. On the other hand, multi-step connections from the entorhinal cortex showed increased connectivity toward both unimodal (e.g. somatomotor) and transmodal (e.g. frontoparietal) networks of the functional gradient as well as anterior ends of the structural gradient, potentially initiating new paths for tau spread. Finally, tau-connectivity correlations shifted spatially within connectome gradient space, moving from the highest-order (default mode network/limbic) cognitive system of the functional gradient in the preclinical stage (amyloid-positive cognitively normal) to the second-highest order (frontoparietal) system in the clinical stage (cognitively impaired). In conclusion, we demonstrate widespread network reorganization of both direct and indirect, multi-step connections that are associated with patterns of tau spread in Alzheimer's disease.