Amyloid plaques drive state-dependent long-range circuit reorganization in the hippocampus

Amyloid plaques are a pathological hallmark of Alzheimer’s disease, but how they drive widespread neuronal dysfunction remains unclear. While studies in anesthetized animals show that plaques drive local hyperactivity ^1,2 , it is unknown how this pathology shapes functional hippocampal maps in freely behaving animals. We combined chronic 1-photon calcium imaging, local field potential recordings, and post hoc 2-photon plaque imaging in freely behaving APP/PS1 mice across behavior and sleep to correlate real-time hippocampal activity and place coding with precise plaque topography. Here we show that plaques exert nonlocal, long-range effects on hippocampal activity that depend on plaque size, laminar position, and the animal’s behavioral state. Place cells, which encode spatial position and are normally uniformly distributed, are preferentially enriched near plaques, revealing an aberrant reorganization of plaque-adjacent neurons into the hippocampal map of space. In longitudinal experiments, pre-existing place cell locations do not predict future plaque sites, whereas hyperactivity during slow-wave sleep weakly predicts future amyloid deposition. These findings identify a mechanism by which amyloid pathology reorganizes brain circuits, degrading the functional architecture of the hippocampus and contributing to widespread dysfunction and cognitive impairment in Alzheimer’s disease.