Tracking a decade of structural brain changes in preclinical and prodromal Alzheimer's disease: insights into amyloid-beta pathology

Alzheimers 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-{beta} (A{beta}), suggesting that A{beta}-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 A{beta} burden related to both cross-sectional levels and longitudinal changes in brain volume, cortical thickness, and cortical tissue mean diffusivity (MDT) derived from free-water corrected diffusion tensor imaging. We examined associations separately in individuals below (A{beta}-) and above (A{beta}+) the A{beta}-positivity threshold, tested for nonlinearity across all participants, and aligned structural trajectories to the estimated years from A{beta}-positivity onset. We found that higher A{beta} was associated with larger brain volume, higher cortical thickness and lower MDT in regions such as the fusiform gyrus, supramarginal gyrus, hippocampal volume, inferior parietal and middle temporal cortex in the A{beta}- group. The opposite associations were found in the A{beta}+ group. Across all participants, volume and thickness showed an inverse U-shaped relationship with A{beta}, while MDT followed a U-shaped pattern. Longitudinally, the rate of cortical thickness change showed an inverse U-shaped association with A{beta}, whereas A{beta} burden was associated with faster volume loss and greater MDT increase. When structural measures were aligned to the estimated time of A{beta} positivity onset, volume and thickness increased years before the expected A{beta} positivity onset and declined thereafter, while MDT showed no association with time relative to A{beta} positivity onset. Our results help reconcile inconsistencies across prior studies and suggest that brain structural changes related to A{beta} pathology start years before A{beta} 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.