Mapping tau spread to long‐range functional and structural connections along the major axes of brain organization
Bibliographic record
Abstract
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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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".