Astrocyte calcium dysfunction causes early network hyperactivity in Alzheimer’s Disease

Dysfunctions of network activity and functional connectivity (FC) represent early events in Alzheimer’s disease (AD), but the underlying mechanisms remain unclear. Astrocytes regulate neuronal activity in the healthy brain, but their involvement in early network hyperactivity in AD is unknown. We show increased FC in the human cingulate cortex, several years before amyloid deposition. We found the same early cingulate FC disruption and neuronal hyperactivity in AppNL-F mice. Crucially, these network disruptions are accompanied by decreased astrocyte calcium signaling. Recovery of astroglial calcium activity normalizes neuronal hyperactivity and FC, as well as seizure susceptibility and day/night behavioral hyperactivity. In conclusion, we show for the first time that astrocytes mediate initial features of AD and drive clinically relevant phenotypes. ### Competing Interest Statement BDS is the Bax-Vanluffelen Chair for Alzheimer's Disease and is supported by the Opening the Future campaign and Mission Lucidity of KUL, Leuven University. DRT receives funding from FWO (G0F8516N, G065721N). DRT received speaker honorarium from Biogen (USA), and collaborated with GE-Healthcare (UK), Novartis Pharma Basel (Switzerland), Probiodrug (Germany), and Janssen Pharmaceutical Companies (Belgium).