How Do Amyloid Pathology and Aberrant Neuronal Activity Disrupt Plasticity and Memory in Alzheimer’s Disease?

Alzheimer’s disease (AD) is increasingly understood as a disorder of network-state and plasticity-capacity, in which amyloid-β and tau pathologies disrupt the activity-dependent mechanisms that build and stabilize memory engrams. Here, I review how amyloid-β–driven neuronal hyperactivity contributes to plasticity and memory deficits in AD. I also discuss how various cellular pathologies reinforce one another, leading to a cellular environment that is impermissive to plasticity. I relate these cellular and circuit-level disturbances to failures in memory encoding, consolidation, and recall, emphasizing the role of interference arising from coexisting hyper- and hypoactive neuronal populations. Finally, I discuss the relevance and limitations of amyloid mouse models in understanding the cognitive decline in AD.