Tau-induced atrophy drives functional connectivity disruption in Alzheimer's disease

Abstract

Alzheimer's disease involves progressive tau accumulation and spread, leading to regional brain atrophy and disruption of large-scale functional networks. While tau propagation and tissue degeneration have been widely modeled, how atrophy dynamics translate into functional connectivity (FC) degradation remains unclear. Here, we develop a multiphysics framework integrating anisotropic tau reaction-diffusion, finite-deformation biomechanics, and network modeling to link tau-driven atrophy with FC changes. Model fidelity is evaluated by quantitatively comparing simulated atrophy patterns with imaging-derived measurements. Using longitudinal structural and functional MRI, we identify an approximately linear relationship between regional atrophy rates and FC change. We then construct an atrophy-informed structural network degradation matrix from model-predicted region-specific atrophy rates and embed it into a neural oscillation model to predict FC disruption. Our results show that (i) the coupled reaction-diffusion-biomechanical model reproduces observed regional atrophy, (ii) regional atrophy rates parsimoniously predict longitudinal FC changes, and (iii) the atrophy-informed degradation matrix captures the direction and relative magnitude of regional FC disruption. By converting tau-driven atrophy into predictive FC trajectories, the proposed framework offers a clinically interpretable avenue for forecasting disease progression and informing trial design.

Figures (8)

• Figure 1: An image-driven multiphysics workflow links tau propagation, atrophy, and functional network disruption. Multimodal neuroimaging data from cognitively normal (CN) and Alzheimer’s disease (AD) subjects are processed to extract functional connectivity, structural information, and regional atrophy patterns. These image-derived measures inform a biophysically motivated multiphysics framework that couples tau protein propagation dynamics with hyperelastic tissue deformation to model whole-brain atrophy. In parallel, neural-oscillation dynamics are simulated and modulated by atrophy-induced degradation. Model parameters are calibrated through data-driven fitting, and the resulting simulations are quantitatively compared with imaging-derived measures to assess correlations between simulated and experimental atrophy as well as functional connectivity changes.
• Figure 2: An anatomically resolved finite-element mesh and entorhinal seeding define the initial conditions for tau propagation.a, A hexahedral mesh distinguishes white matter (light gray) and gray matter (dark gray), and embedded fiber trajectories provide tract-informed orientations for anisotropic transport. b, Initial seeding regions in the entorhinal cortex that define the spatiotemporal onset of tau pathology. A total of 68 regions of interest—including 64 cortical regions along with the hippocampus and amygdala—are used to trace the subsequent progression.
• Figure 3: Group-level functional connectivity differs systematically between cognitively normal controls and Alzheimer’s disease.a, Group-averaged functional connectivity (FC) matrices are shown for cognitively normal (CN) and Alzheimer’s disease (AD) cohorts. b, ROI-wise changes in FC indicate an overall reduction across most regions. c, ROIs exhibiting statistically significant between-group differences (two-sample t-test, uncorrected $p<0.05$) are highlighted in the difference matrix. d, Inter-hemispheric connections derived from the significant-difference matrix reveal altered cross-hemisphere coupling, where blue indicates decreased FC and red indicates increased FC in AD relative to CN. e,f, Left and right intra-hemispheric patterns further show hemisphere-specific topological reorganization.
• Figure 4: Longitudinal atrophy rates are associated with cross-sectional functional connectivity differences.a, Longitudinal trajectories of normalized brain volume for cognitively normal (CN) and Alzheimer’s disease (AD) groups, with regression lines and confidence intervals illustrating faster atrophy in the AD cohort. b, Atrophy rates for CN and AD participants, showing a significantly accelerated decline in the AD group (***$p < 0.001$). c, Across ROIs, protein-induced increases in atrophy rate are positively correlated with FC changes ($r=0.31$, $p=0.0103$), indicating that stronger structural degeneration is accompanied by larger functional disruption.
• Figure 5: Coupled tau transport and large-deformation mechanics reproduce whole-brain atrophy and evolving protein burden. The left panel shows simulated temporal trajectories of normalized brain volume and total tau burden over a 10-year period. The right panels show representative coronal slices at 1, 4, 7, and 10 years, illustrating the spatial distribution of protein concentration. Overlaid contours depict morphological deformation relative to baseline anatomy, and the white--gray matter interface is delineated by a solid line.