The network degeneration hypothesis suggests that tau pathology in AD spreads in a manner similar to infectious prions, following the characteristic network architecture of the brain. However, the compatibility of the network-based model of tau pathology spreading and the neuropathological Braak stage model is not well understood.

To determine the relationship between pathological tau deposition in Alzheimer’s disease (AD), functional connectivity in the healthy brain, and the Braak stages of neuropathological tau deposition.

Using the tau PET tracer [18F]AV-1451, we performed a voxel-wise group comparison (SPM12, p<0.05) between 15 patients with AD and 15 age-matched healthy controls. We obtained the peak five clusters of tau-tracer uptake, using each to create a seed-based functional connectivity network with a dataset of 198 resting state fMRI images of healthy control subjects. We performed spearman correlations between t-scores of tau deposition and functional connectivity in each network and repeated these correlations within each individual Braak stage.

The peak five tau clusters, in order of maximal t-score, were located in consecutive Braak stages. Functional connectivity levels, using each peak tau cluster as a seed, correlated significantly and positively with significant tau deposition levels. Multiple correlations were significantly stronger within individual Braak stages, including within stages both more and less advanced than the stage containing the respective tau peak.

The location of peak tau clusters within consecutive Braak stages supports the Braak stage model. Positive correlations between pathological tau and healthy functional connectivity support the network degeneration hypothesis of tau spreading. Thus, our results find compatibility between the Braak stage model and the network degeneration model. Further, the strengthening of many correlations within Braak stages both more and less advanced than the stage containing the tau peak supports that tau spreading is influenced by the functional connectedness of all areas affected by tau pathology.