Mapping tau spread to long‐range functional and structural connections along the major axes of brain organization

BACKGROUND: Prior studies have focused on tau spread from the entorhinal cortex along first-order (short-range) connections within anatomical brain space (seed-to-target). Here, we explore tau spread along long-range connections within a novel coordinate space called connectome gradients, which is reflective of the brain's hierarchical organization. Exploring tau spread within this new framework offers insights into long-range connectivity alterations and network susceptibility in Alzheimer's disease (AD). METHOD: We included 213 participants from TRIAD (103 A- CN, 103 A+ CN, and 75 A+ CI) with diffusion-weighted MRI, resting-state functional MRI, and 18F-MK6240 tau-PET. First, we employed graph theory-based stepwise connectivity analyses to unveil long-range connectivity patterns from the entorhinal cortex to the rest of the brain. Differences in connectivity patterns were compared between A+ vs A- groups, adjusted for age, sex, and APOE-ε4. Second, we investigated the stepwise connectivity patterns in relation to tau within a novel coordinate system spanned by the principal functional and structural connectome gradients. RESULT: In the preclinical stage (A+ CN) compared to controls (A- CN), we observed connectivity increase through functional gradient space (Figure 1A red). In the clinical stage (A+ CI), connectivity reduced from the entorhinal cortex to the transmodal end of the functional gradient (DMN/limbic; Figure 1A blue) and to the posterior end of the structural gradient (temporo-occipital; Figure 1B blue). Long-range connections from the entorhinal cortex showed increased connectivity toward the unimodal and anterior ends of the functional and structural gradient, respectively (Figure 1A, B red), potentially initiating new paths for tau spread. Indeed, tau-connectivity correlations shifted spatially within gradient space with disease progression (Figure 2), moving from the highest-order (DMN/limbic) cognitive system of the functional gradient in A+ CN to the second-highest order (frontoparietal) system in A+ CI. CONCLUSION: We employed a novel integration of stepwise connectivity and connectome gradients to enable a better understanding of how connectivity is related to tau spread along the major axes of brain organization. We observed widespread network reorganization in AD and notably that the tau-connectivity correlations shifted between major networks of the functional connectome gradient with disease progression.

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