Investigating the Effect of APOE4 on Attention and Pattern Separation in New Mouse Models of Alzheimer’s Disease Risk
Abstract
Apolipoprotein-ε4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer’s Disease (AD). However, it has also been suggested to exhibit antagonistic pleiotropy, a phenomenon where a particular gene enhances fitness during some life stages but are detrimental in others. Research suggests that earlier in life, APOE4 carriers outperform non-carriers on tasks requiring executive function, but experience greater global cognitive decline with age. This study investigates the effect of APOE4 on cognition in humanized mouse models using the touchscreen cognition system. Our findings show that APOE4 mice exhibit better attentional performance compared to those carrying APOE3 in a murine model representing individuals at risk for AD. Furthermore, in mice representing individuals with early-onset AD, APOE4 impairs pattern separation and accelerates hippocampal amyloid deposition. These results offer insight into the dual impact of APOE4 on cognition, which will help guide future research on AD risk and progression.