Complex non-Markovian dynamics and the dual role of astrocytes in Alzheimer's disease development and propagation.

Alzheimer's disease (AD) is a common neurodegenerative disorder nowadays. Amyloid-beta (Aβ) and tau proteins are among the main contributors to the AD progression. In AD, Aβ proteins clump together to form plaques and disrupt cell functions. On the other hand, the abnormal chemical change in the brain helps to build sticky tau tangles that block the neuron's transport system. Astrocytes generally maintain a healthy balance in the brain by clearing the Aβ plaques (toxic Aβ). However, overactivated astrocytes release chemokines and cytokines in the presence of Aβ and react to pro-inflammatory cytokines, further increasing the production of Aβ. In this study, we construct a mathematical model that can capture astrocytes' dual behavior. Furthermore, we reveal that the disease progression depends on the current time instance and the disease's earlier status, called the "memory effect," making non-Markovian processes an appropriate approach. We consider a fractional order network mathematical model to capture the influence of such memory effects on AD progression. We have integrated brain connectome data into the model and studied the memory effect, the dual role of astrocytes, and the brain's neuronal damage. Based on the pathology, primary, secondary, and mixed tauopathies parameters are considered in the model. Due to the mixed tauopathy, different brain nodes or regions in the brain connectome accumulate different toxic concentrations of Aβ and tau proteins. Finally, we explain how the memory effect can slow down the propagation of such toxic proteins in the brain, decreasing the rate of neuronal damage.