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

TL;DR

This study models the spread of Alzheimer's biomarkers in the brain using a novel reaction-diffusion system, revealing key vulnerable regions and the dominant role of tau in disease progression.

Contribution

It introduces a new bistable reaction-diffusion model to analyze AT[N] biomarker propagation and identifies critical brain regions and factors influencing AD progression.

Findings

Tau is a stronger regional risk indicator than amyloid.

Temporal lobe shows higher vulnerability to AD.

Critical regions outperform hub nodes in disease transmission.

Abstract

Background: Despite the striking efforts in investigating neurobiological factors behind the acquisition of amyloid-\b{eta} (A), protein tau (T), and neurodegeneration ([N]) biomarkers, the mechanistic pathways of how AT[N] biomarkers spreading throughout the brain remain elusive. Objectives: To disentangle the massive heterogeneities in AD progressions and identify vulnerable/critical brain regions to AD pathology. Methods: 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 Alzheimer's disease (AD) progression. We applied our model to large-scale longitudinal neuroimages from the ADNI database and studied the systematic vulnerability and criticality of brains. Results: 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. Conclusion: 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-\b{eta} and tau diffusions, disruption of metabolic balance is the most determinant factor contributing to the initiation and progression of Alzheimer's disease.