Dead-Space Microdomains as Explicit Barriers to Extracellular Drug Transport in Alzheimer’s Disease

Objective The impact of dead-space (DS) microdomains on cerebral drug penetration has been demonstrated experimentally; yet computational models typically capture their effects indirectly through effective tortuosity parameters. Here, we develop an anatomically grounded framework that systematically evaluates pharmaceutical diffusion within the central nervous system (CNS). Methods A finite element (FE) model was developed with DS explicitly represented as impermeable obstructions in the extracellular space (ECS) – consistent with structural remodeling observed in Alzheimer’s disease (AD). The model was calibrated by reproducing experimental diffusion timescales and subsequently applied to quantify the geometric contribution of DS to pharmaceutical transport. Results Transport hindrance exhibited a strong dependence on molecular size. Within a representative ECS unit, the arrival of the 0.5c₀ 0.5 c 0 concentration contour at the venule was delayed by 11 s for Memantine, 14 s for Donepezil, and 80 s for Aducanumab. Spatial analyses revealed penetration delays that were not captured by domain-averaged uptake metrics. A Péclet number analysis confirmed that ECS transport for all three compounds remains diffusion-dominated under neurodegenerative conditions. Conclusions The proposed framework provides a computationally efficient foundation for predictive multiphysics modeling in the human CNS and demonstrates how local ECS obstructions can lead to therapeutic hindrance in AD.