A novel mathematical and computational framework of amyloid-beta triggered seizure dynamics in Alzheimer's disease

TL;DR

This paper presents a new mathematical and computational model linking amyloid-beta accumulation in Alzheimer's disease to seizure dynamics, revealing how biochemical changes influence neuronal hyperexcitability and seizure propagation.

Contribution

The study introduces a novel ionic model incorporating amyloid-beta effects and a sophisticated numerical method to simulate seizure activity in Alzheimer's disease.

Findings

Amyloid-beta accumulation causes calcium dysregulation and hyperexcitability.

Severe alterations in calcium homeostasis lead to seizure propagation.

Biochemical inhomogeneities influence seizure wavefronts and sources.

Abstract

The association of epileptic activity and Alzheimer's disease (AD) has been increasingly reported in both clinical and experimental studies, suggesting that amyloid-$\beta$ accumulation may directly affect neuronal excitability. Capturing these interactions requires a quantitative description that bridges the molecular alterations of AD with the fast electrophysiological dynamics of epilepsy. We introduce a novel mathematical model that extends the Barreto-Cressman ionic formulation by incorporating multiple mechanisms of calcium dysregulation induced by amyloid-$\beta$, including formation of $\mathrm{Ca}^{2+}$-permeable pores, overactivation of voltage-gated $\mathrm{Ca}^{2+}$ channels, and suppression of $\mathrm{Ca}^{2+}$-sensitive potassium currents. The resulting ionic model is coupled with the monodomain equation and discretized using a $p$-adaptive discontinuous Galerkin method on polytopal meshes, providing an effective balance between efficiency and accuracy in capturing the sharp spatiotemporal electrical wavefronts associated with epileptiform discharges. Numerical simulations performed on idealized and realistic brain geometries demonstrate that progressive amyloid-\textbeta{} accumulation leads to severe alterations in calcium homeostasis, increased neuronal hyperexcitability, and pathological seizure propagation. Specifically, high amyloid-$\beta$ concentrations produce secondary epileptogenic sources and spatially heterogeneous wavefronts, indicating that biochemical inhomogeneities play a critical role in shaping seizure dynamics. These results illustrate how multiscale modeling provides new mechanistic insights into the interplay between neurodegeneration and epilepsy in Alzheimer's disease.