Many AD drivers, such as ageing, amyloid and genetic risk factors like APOE E4, perturb synaptic homeostasis and increase neuronal excitability.70-76 Indeed, epileptiform activity in the hippocampus is a very early feature of AD.77-79 In turn, hyperactivity of the hippocampal formation exacerbates pathological lesions.80-85 However, the connection between AD lesions and the disruption of synaptic homeostasis in the entorhinal-hippocampal network has remained elusive. This evidence concerns the gene APOE and Alzheimer disease.