A Longitudinal Model for Tau Aggregation in Alzheimer’s Disease Based on Structural Connectivity

Abstract

Tau tangles are a pathological hallmark of Alzheimer’s disease (AD) with strong correlations existing between tau aggregation and cognitive decline. Studies in mouse models have shown that the characteristic patterns of tau spatial spread associated with AD progression are determined by neural connectivity rather than physical proximity between different brain regions. We present here a network diffusion model for tau aggregation based on longitudinal tau measures from positron emission tomography (PET) and structural connectivity graphs from diffusion tensor imaging (DTI). White matter fiber bundles reconstructed via tractography from the DTI data were used to compute normalized graph Laplacians which served as graph diffusion kernels for tau spread. By linearizing this model and using sparse source localization, we were able to identify distinct patterns of propagative and generative buildup of tau at a population level. A gradient descent approach was used to solve the sparsity-constrained optimization problem. Model fitting was performed on subjects from the Harvard Aging Brain Study cohort. The fitted model parameters include a scalar factor controlling the network-based tau spread and a network-independent seed vector representing seeding in different regions-of-interest. This parametric model was validated on an independent group of subjects from the same cohort. We were able to predict with reasonably high accuracy the tau buildup at a future time-point. The network diffusion model, therefore, successfully identifies two distinct mechanisms for tau buildup in the aging brain and offers a macroscopic perspective on tau spread.