Early Hippocampal Sharp-Wave Ripple Deficits Predict Later Learning and Memory Impairments in an Alzheimer’s Disease Mouse Model

Abstract

Summary: Alzheimer’s disease (AD) is characterized by progressive memory loss, and there is a pressing need to identify early pathophysiological alterations that predict subsequent memory impairment. Hippocampal sharp-wave ripples (SWRs)—electrophysiological signatures of memory reactivation in the hippocampus—are a compelling candidate for this purpose. Mouse models of AD show reductions in both SWR abundance and associated slow gamma (SG) power during aging, but these alterations have yet to be directly linked to memory impairments. In aged apolipoprotein E4 knockin (apoE4-KI) mice—a model of the major genetic risk factor for AD—we find that reduced SWR abundance and associated CA3 SG power predicted spatial memory impairments measured 1–2 months later. Importantly, SWR-associated CA3 SG power reduction in young apoE4-KI mice also predicted spatial memory deficits measured 10 months later. These results establish features of SWRs as potential functional biomarkers of memory impairment in AD. : Currently, there are no functional biomarkers that can predict progression to Alzheimer’s disease before cognitive decline begins. Jones et al. demonstrate that sharp-wave ripple and associated slow gamma deficits predict memory impairments in aged apoE4 mice. Slow gamma deficits in young apoE4 mice predict memory impairment onset 10+ months later. Keywords: biomarker, sharp-wave ripple, slow gamma, apolipoprotein E4, Alzheimer’s disease, hippocampus, CA3, learning, memory