Investigating the Effect of Apolipoprotein E4 on Attention Following Repeated Mild Traumatic Brain Injuries in hAPP and hMapt mice

Alzheimer’s disease (AD) is a neurodegenerative disorder, marked by cognitive decline influenced by genetic and environmental risk factors. The APOE4 allele, the strongest genetic risk factor for late-onset AD, provides cognitive benefits in young carriers but impairs cognition in older age. APOE4 also worsens outcomes following traumatic brain injury (TBI), an environmental AD risk factor, though long-term effects are less known. Using a humanized mouse model, we assessed long-term cognitive outcomes post-TBI. Our methods included: (i) knock-in mice expressing wildtype APP, tau, and APOE4 without mutations; (ii) a repetitive closed-head mild TBI model with translatable rotational forces; and (iii) a rodent touchscreen continuous performance task (CPT) akin to clinical CPTs. Results showed that APOE4 mice outperformed APOE3s in attention tasks only in females, but better attention was lost post-TBI. The attentional changes indicated that while APOE4 can confer benefits, it accelerates cognitive decline when combined with TBI and female sex.