Data-driven Stochastic Model for Quantifying the Interplay Between Amyloid-beta and Calcium Levels in Alzheimer's Disease

Abstract

The abnormal aggregation of extracellular amyloid-$\beta \left(A\beta \right)$ in senile plaques resulting in calcium $\left({Ca}^{+2}\right)$ dyshomeostasis is one of the primary symptoms of Alzheimer's disease (AD). Significant research efforts have been devoted in the past to better understand the underlying molecular mechanisms driving $A\beta$ deposition and ${Ca}^{+2}$ dysregulation. Importantly, synaptic impairments, neuronal loss, and cognitive failure in AD patients are all related to the buildup of intraneuronal $A\beta$ accumulation. Moreover, increasing evidence show a feed-forward loop between $A\beta$ and $C{a}^{+2}$ levels, i.e. $A\beta$ disrupts neuronal $C{a}^{+2}$ levels, which in turn affects the formation of $A\beta$. To better understand this interaction, we report a novel stochastic model where we analyze the positive feedback loop between $A\beta$ and ${Ca}^{+2}$ using ADNI data. A good therapeutic treatment plan for AD requires precise predictions. Stochastic models offer an appropriate framework for modelling AD since AD studies are observational in nature and involve regular patient visits. The etiology of AD may be described as a multi-state disease process using the approximate Bayesian computation method. So, utilizing ADNI data from 2-year visits for AD patients, we employ this method to investigate the interplay between $A\beta$ and $C{a}^{+2}$ levels at various disease development phases. Incorporating the ADNI data in our physics-based Bayesian model, we discovered that a sufficiently large disruption in either $A\beta$ metabolism or intracellular ${Ca}^{+2}$ homeostasis causes the relative growth rate in both ${Ca}^{+2}$ and $A\beta$, which corresponds to the development of AD. The imbalance of $C{a}^{+2}$ ions causes $A\beta$ disorders by directly or indirectly affecting a variety of cellular and subcellular processes, and the altered homeostasis may worsen the abnormalities of ${Ca}^{+2}$ ion transportation and deposition. This suggests that altering the ${Ca}^{+2}$ balance or the balance between $A\beta$ and ${Ca}^{+2}$ by chelating them may be able to reduce disorders associated with AD and open up new research possibilities for AD therapy.

Keywords: Alzheimer’s disease; Bayesian inference; Ca+2 dysregulation; Neurodegenrative disorders; amyloid β peptide; approximate Bayesian computation; data-driven models; feedback mechanisms and control; neuroscience; stochastic modelling.