The interplay of biochemical and biomechanical degeneration in Alzheimer’s disease

Abstract Alzheimer’s disease is an irreversible neurodegenerative disorder that manifests itself in the progressive aggregation of misfolded tau protein, neuronal death, and cerebral atrophy. A reliable diagnosis of these changes in the brain is challenging because they typically precede the clinical symptoms of Alzheimer’s disease by at least one, if not two, decades. Volumetric magnetic resonance imaging holds promise as a non-invasive biomarker for disease onset and progression by quantifying cerebral atrophy in time and space. Recent studies suggest that the patterns of brain atrophy are closely correlated with the regional distribution of misfolded tau protein; yet, to date, there is no compelling computational model to simulate the interaction of misfolded protein spreading and tissue atrophy. Here we establish a multiphysics model that couples misfolded protein spreading and tissue atrophy to explore the spatio-temporal interplay of biochemical and biomechanical degeneration in Alzheimer’s disease. We discretize the coupled bio-chemo-mechanical problem using a nonlinear finite element approach with the misfolded protein concentration and the tissue deformation as primary unknowns. In a systematic parameter study, we probe the role of the individual model parameters and compare our results against cerebral atrophy curves of patients with early onset Alzheimer’s disease. A critical link between biochemical and biomechanical degeneration is the atrophy rate, which reflects both natural aging-induced atrophy and accelerated misfolding-induced atrophy. Our simulations reveal that misfolding accelerates natural atrophy by a factor of three to five, and that regions near the hippocampus are most affected by brain tissue loss. Our quantitative model could help improve diagnostic tools, advance early detection, and, ultimately, enable early interventions to delay the onset of cognitive decline in familial or sporadic Alzheimer’s disease.

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