Tracking a decade of structural changes in preclinical and prodromal Alzheimer’s disease: insights from amyloid-β pathology
Bibliographic record
Abstract
ABSTRACT Alzheimer’s disease (AD) pathology is typically associated with reduced brain volume and cortical thickness, interpreted as neurodegeneration. However, several cross-sectional studies in cognitively unimpaired individuals have paradoxically reported larger brain volume and thicker cortex in the presence of amyloid-β (Aβ), suggesting that Aβ–brain structure associations may not follow a simple linear pattern early in the disease. We leveraged over a decade of longitudinal data from the PREVENT-AD cohort (N=367, mean follow-up 7.17 years, range 0–11.27 years) to investigate how Aβ burden related to both cross-sectional levels and longitudinal changes in brain volume, cortical thickness, and cortical tissue mean diffusivity (MD T ) derived from free-water corrected diffusion tensor imaging. We examined associations separately in individuals below (Aβ−) and above (Aβ+) the Aβ-positivity threshold, tested for nonlinearity across all participants, and aligned structural trajectories to the estimated years from Aβ-positivity onset. We found that higher Aβ was associated with larger brain volume, higher cortical thickness and lower MD T in regions such as the fusiform gyrus, supramarginal gyrus, hippocampal volume, inferior parietal and middle temporal cortex in the Aβ− group. The opposite associations were found in the Aβ+ group. Across all participants, volume and thickness showed an inverse U-shaped relationship with Aβ, while MD T followed a U-shaped pattern. Longitudinally, the rate of cortical thickness change showed an inverse U-shaped association with Aβ, whereas Aβ burden was associated with faster volume loss and greater MD T increase. When structural measures were aligned to the estimated time of Aβ positivity onset, volume and thickness increased years before the expected Aβ positivity onset and declined thereafter, while MD T showed no association with time relative to Aβ positivity onset. Our results help reconcile inconsistencies across prior studies and suggest that brain structural changes related to Aβ pathology start years before Aβ positivity onset and follow nonlinear trajectories. These early structural changes might be due to pathological processes such as neuroinflammatory swelling early in the course of the disease.
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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 | 0.002 | 0.004 |
| 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 | 0.001 | 0.001 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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".