Hub vulnerability and short path length to entorhinal cortex are associated with tau binding in Alzheimer’s disease: a combined MEG/PET study

Background Brain network studies have revealed that highly connected ‘hub’ regions are particularly vulnerable to Alzheimer’s disease (AD) pathology. Additionally, the ‘‘transneuronal spread” hypothesis proposes that a toxic agent (tau) propagates along shortest paths through functionally connected neurons, driven by aberrant neuronal activity. We investigate whether network characteristics as determined using magnetoencephalography (MEG) are correlated to tau pathology in the different stages of AD. Method We analysed source‐reconstructed MEG data and dynamic 100‐minutes [18F]flortaucipir PET from 57 subjects positive for amyloid‐beta (Aβ)‐pathology (preclinical AD (n = 16)), mild cognitive impairment (MCI (n = 16)) and AD dementia (n = 25)). Cognitively healthy subjects without Aβ‐pathology were included as controls (n = 25). For each subject, we obtained a network based on the alpha band amplitude envelope correlation (AEC‐c, 8‐13Hz), and theta band phase lag index (PLI, 4‐8Hz), based on the Brainnettome atlas. For each node in the network, we obtained the following measures: weighted degree, degree, betweenness centrality, eccentricity (as measures of hubness); distance to left entorhinal cortex (measure of shortest path/transneuronal spread); hub disruption index for all previous hubness measures (selective hub damage) and [18F]flortaucipir BPND. Pearson’s correlations were calculated between group averages of network measures and tau‐PET binding (FDR‐corrected). Furthermore, we analysed whether network measures of the previous disease stage correlated with [18F]flortaucipir retention in the subsequent disease stage. Result Hub regions were predominantly found in the temporal areas (Fig‐1). Higher ‘hubness’ and shorter neuronal distance to epicentre were associated to higher tau binding in all stages of the AD continuum (Fig‐2a). Disproportional disruption to hub regions in the AEC‐c alpha band was associated with increased tau binding, but the opposite effect was found for the PLI theta band (Fig‐2b). Finally, high weighted degree, degree, and betweenness centrality in the preceding disease stage were correlated with increased tau binding in subsequent disease stages (Fig‐2c). Conclusion Hub regions and transneuronal spreading are key mechanisms in the propagation of tau pathology across the AD brain. Furthermore, hubs are particularly vulnerable to tau. The insight that high neuronal activity might play a causal role in Alzheimer’s disease can have