Turbulent dynamics and in silico perturbation-based measures are disrupted across biological stages of Alzheimers disease

According to the AT(N) framework, Alzheimers disease (AD) can be biologically characterised by amyloid deposition, tau pathology, and neurodegeneration, yet how these processes relate to whole-brain dynamics remains unclear. Here, we investigated these relationships and the link between whole-brain dynamics and cognitive dysfunction using multimodal neuroimaging from 145 ADNI3 participants. We combined multiscale measures of turbulent dynamics with responses to in silico perturbations obtained from whole-brain models. AD progression was characterised by a scale-dependent reorganisation of turbulent dynamics where information flow showed the strongest contribution to the dynamics-related variance in cognitive performance. Large-scale turbulence was associated with all three AT(N) components. Model-based information capability and susceptibility measures progressively decreased across AD stages and were associated with amyloid burden and regional tau deposition. Model-free features discriminated comparisons involving AD dementia, whereas adding model-based measures produced modest, metric-dependent changes in classification performance. Exploratory analyses showed spatial alignment between large-scale turbulence alterations and AD-risk gene-expression gradients, with APOE among the strongest associations in both disease-stage contrasts examined. Lastly, we found a progressive decoupling between turbulent dynamics and the E:I balance across AD stages. Together, these findings link model-based and model-free measures of whole-brain dynamics to proteinopathy, neurodegeneration, and cognitive impairment, supporting their complementary value for characterising AD progression.