Inter-network functional connectivity increases by beta-amyloid and may facilitate the early stage of tau...

Alzheimer's disease (AD) is pathologically marked by tau tangles and beta-amyloid (Aβ) plaques. It has been hypothesized that Aβ facilitates spread of tau outside of the medial temporal lobe (MTL), but exact mechanism of this facilitation remains unclear. We aimed to test the hypothesis that abnormal Aβ induces an increase in inter-network functional connectivity, which in turn induces early-stage tau elevation in limbic network. Our study used 18F-Florbetaben Aβ positron emission tomography (PET), 18F-MK6240 tau-PET, and resting-state functional magnetic resonance imaging (rs-fMRI) from 489 healthy unimpaired older adults, including 46 with longitudinal data. We found significant correlations between tau in limbic network and Aβ in distinct functional networks. We then demonstrated that Aβ+ /Tau- participants exhibited elevated inter-network functional connectivity of the limbic network. Finally, our longitudinal results showed that annual increases in inter-network functional connectivity between limbic network and default mode and control networks were linked to annual tau elevation in limbic network, primarily modulated by Aβ+ individuals. Understanding this early brain alteration in response to pathologies could guide treatments early in disease course.