BPS2026 – Glymphatic clearance efficiency of Aβ monomers and oligomers: A multiphysics FEM study

Numerous studies report a correlation between the functional decline of the glymphatic system in Alzheimer's disease and amyloid-beta (Aβ) accumulation. In this study, a multiphysics finite element model quantitatively analyzes the clearance efficiency difference between Aβ monomers and oligomers, which vary in molecular weight and effective diffusion coefficients, under normal and disease conditions. The model framework comprises three distinct domains representing the subarachnoid space (SAS), the perivascular space (PVS), and the brain parenchyma. This multiphysics approach models the SAS as creeping flow, incorporates pulsatile viscoelastic flow in the PVS to simulate arterial pulsation, and treats the parenchyma as a poroelastic medium to couple tissue deformation with interstitial fluid and solute transport. At the PVS-parenchyma interface, aquaporin-4 (AQP4) function is represented by a hydraulic conductivity model (normal: 1.0 × 10 −6 m/s; diseased: 5.0 × 10 −7 m/s). The model is parameterized with a parenchymal porosity of 0.2 and permeability of 2.25 × 10 −14 m 2 ; a PVS flow driven by a 1.2 Hz arterial pulsation and a mean pressure difference of 66.7 Pa (0.5 mmHg) between the SAS and the lymphatic drainage pathway; and effective diffusion coefficients of 6.23 × 10 −11 m 2 /s for monomers and 2.16 × 10 −11 m 2 /s for oligomers. Simulation results showed that under normal conditions, oligomer clearance efficiency was approximately 55% lower than that of monomers. In the disease state, characterized by reduced hydraulic conductivity, this disparity increased to 75%, leading to a local peak parenchymal accumulation of 40 μmol/m 3 . Thus, this study demonstrates the potential of this in silico model to serve as a valuable tool for investigating the biophysical origins of glymphatic dysfunction in Alzheimer's disease and for predicting the efficacy of future therapies designed to improve cerebral waste clearance.