Insights into Alzheimer's risk factors through waste protein transport modeling

Waste protein buildup, like amyloid-β (Aβ) plaque, in the brain’s interstitial spaces has been linked to neurodegenerative diseases such as Alzheimer’s, but the clearance mechanisms for these waste proteins are not well understood. We study the aggregation and clearance mechanisms of Aβ in the interstitial spaces of the brain through the development of a numerical model. We solve N coupled advection-diffusion-aggregation equations to model the production, aggregation, fragmentation, and clearance of N species of Aβ in a domain oriented between a penetrating arteriole and a venule. We then model various neurological conditions. We show that a sudden increase in monomer concentration, as occurs in conditions like traumatic brain injury, leads to significant plaque formation. Our results also indicate that impaired protein clearance (as occurs with aging) and fragmentation are both mechanisms that sustain large intermediate oligomer concentrations. Our results provide novel insight into several known risk factors for Alzheimer’s disease and cognitive decline, and we introduce a unique framing of Aβ dynamics as a competition between different time scales associated with production rates, aggregation rates, and clearance conditions.