Structural and functional remodeling of neural networks in β-amyloid driven hippocampal hyperactivity

Early detection of Alzheimer's disease (AD) is essential for improving the patients outcomes and advancing our understanding of disease, allowing for timely intervention and treatment. However, accurate biomarkers are still lacking. Recent evidence indicates that hippocampal hyperexcitability precedes the diagnosis of AD decades ago, can predict cognitive decline. Thus, could hippocampal hyperactivity be a robust biomarker for early-AD, and what drives hippocampal hyperactivity in early-AD? these critical questions remain to be answered. Increasing clinical and experimental studies suggest that early hippocampal activation is closely associated with longitudinal β-amyloid (Aβ) accumulation, Aβ aggregates, in turn, enhances hippocampal activity. Therefore, in this narrative review, we discuss the role of Aβ-induced altered intrinsic neuronal properties as well as structural and functional remodeling of glutamatergic, GABAergic, cholinergic, noradrenergic, serotonergic circuits in hippocampal hyperactivity. In addition, we analyze the available therapies and trials that can potentially be used clinically to attenuate hippocampal hyperexcitability in AD. Overall, the present review sheds lights on the mechanism behind Aβ-induced hippocampal hyperactivity, and highlights that hippocampal hyperactivity could be a robust biomarker and therapeutic target in prodromal AD.