A multiscale closed-loop neurotoxicity model of Alzheimer’s disease progression explains functional connectivity alterations

Abstract

While the accumulation of amyloid-beta (Aβ) and hyperphosphorylated-tau (hp-tau) as two classical histopathological biomarkers are crucial in Alzheimer's disease (AD), their detailed interaction with the electrophysiological changes at the meso- and macroscale are not yet fully understood. We developed a mechanistic multiscale model of AD progression, linking proteinopathy to its effects on neural activity and vice-versa. We integrated a heterodimer model of prion-like protein propagation, and a network of Jansen-Rit electrical oscillators whose model parameters varied due to neurotoxicity. Changes in inhibition guided the electrophysiological alterations found in AD, and both Aβ and hp-tau-related inhibition changes were able to produce similar effects independently. Additionally, we found a causal disconnection between cellular hyperactivity and interregional hypersynchrony. Finally, we demonstrated that early Aβ and hp-tau depositions' location determine the spatiotemporal profile of the proteinopathy. The presented model combines the molecular effects of both Aβ and hp-tau together with a mechanistic protein propagation model and network effects within a unique closed-loop model. This holds the potential to enlighten the interplay between AD mechanisms on various scales, aiming to develop and test novel hypotheses on the contribution of different AD-related variables to the disease evolution.