Uncovering the System Vulnerability and Criticality of Human Brain Under Dynamical Neuropathological Events in Alzheimer's Disease.

Abstract

Despite the striking efforts in investigating neurobiological factors behind the acquisition of amyloid-β (A), protein tau (T), and neurodegeneration ([N]) biomarkers, the mechanistic pathways of how AT[N] biomarkers spreading throughout the brain remain elusive. To disentangle the massive heterogeneities in Alzheimer's disease (AD) progressions and identify vulnerable/critical brain regions to AD pathology. In this work, we characterized the interaction of AT[N] biomarkers and their propagation across brain networks using a novel bistable reaction-diffusion model, which allows us to establish a new systems biology underpinning of AD progression. We applied our model to large-scale longitudinal neuroimages from the ADNI database and studied the systematic vulnerability and criticality of brains. Our model yields long term prediction that is statistically significant linear correlated with temporal imaging data, produces clinically consistent risk prediction, and captures the Braak-like spreading pattern of AT[N] biomarkers in AD development. Our major findings include (i) tau is a stronger indicator of regional risk compared to amyloid, (ii) temporal lobe exhibits higher vulnerability to AD-related pathologies, (iii) proposed critical brain regions outperform hub nodes in transmitting disease factors across the brain, and (iv) comparing the spread of neuropathological burdens caused by amyloid-β and tau diffusions, disruption of metabolic balance is the most determinant factor contributing to the initiation and progression of AD.