Amyloid induced hyperexcitability in default mode network drives medial temporal hyperactivity and early tau accumulation.

In early Alzheimer's disease, amyloid-beta deposits appear throughout association cortex while tau appears in the entorhinal cortex, but why these pathologies initially arise in different locations is unclear. Using task-based fMRI and multimodal PET imaging, the authors show that Alzheimer's pathologies flip interactions between the default mode network and the medial temporal lobe from inhibitory to excitatory. The default mode network becomes hyperexcited with increasing amyloid-beta levels, which drives hyperexcitability within the medial temporal lobe, and this directed hyperexcitation predicts the rate of tau accumulation within the entorhinal cortex. The results support a model where amyloid-beta-induced disruptions to local excitatory-inhibitory balance in the default mode network drive medial temporal lobe hyperexcitability, leading to tau accumulation.

Study at a glance

Abstract

In early Alzheimer's disease (AD) β-amyloid (Aβ) deposits throughout association cortex and tau appears in the entorhinal cortex (EC). Why these initially appear in disparate locations is not understood. Using task-based fMRI and multimodal PET imaging, we assess the impact of local AD pathology on network-to-network interactions. We show that AD pathologies flip interactions between the default mode network (DMN) and the medial temporal lobe (MTL) from inhibitory to excitatory. The DMN is hyperexcited with increasing levels of Aβ, which drives hyperexcitability within the MTL and this directed hyperexcitation of the MTL by the DMN predicts the rate of tau accumulation within the EC. Our results support a model whereby Aβ induces disruptions to local excitatory-inhibitory balance in the DMN, driving hyperexcitability in the MTL, leading to tau accumulation. We propose that Aβ-induced disruptions to excitatory-inhibitory balance is a candidate causal route between Aβ and remote EC-tau accumulation.