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

Abstract

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 doing so. 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 knock in (apoE4-KI) mice – a model of the major genetic risk factor for AD – we found 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.

Keywords: Biomarker, sharp-wave ripple, slow gamma, Apolipoprotein E4, Alzheimer’s disease, hippocampus, CA3, learning, memory