Basic Science and Pathogenesis.

Background: ApoE4 is the strongest genetic risk factor for late onset Alzheimer's Disease (AD). However, ApoE4 has also been suggested to exhibit antagonistic pleiotropy, a phenomenon by which some allelic variations of a gene promote fitness during certain periods of life but may be detrimental in others. Previous work suggests that ApoE4 carriers exhibit superior performance on executive function tasks in early and middle age, while later in life (>70 years) ApoE4 carriers experience greater cognitive decline across multiple domains. We examined this ApoE4 antagonistic pleiotropy hypothesis using a cross-species translational approach, focusing on cognitively unimpaired human adult ApoeE4 carriers and non-carriers who were within a relatively younger age range (<70 years). We complement this using knock-in mouse models that express humanized wild-type App, MAPT, and ApoE3 or ApoE4 genes. To quantify executive function in both human and mouse, we used cross-species touchscreen based Continuous Performance Task (CPT) to assess selective attention.

Method: Human participants were recruited from the PREVENT-AD program at the Douglas Research Centre. Human touchscreen CPT testing was conducted using an MS SurfacePro. Mice were tested with the same task as humans using an operant chamber platform.

Result: Our initial behavioural results suggest that ApoE4 facilitates attentional processes in both older adults and mouse ApoE4 carriers, as indexed by discrimination performance on the CPT. Further strengthening this translational pattern, we found that the facilitative effect of ApoE4 on CPT was more pronounced in female ApoE4 carriers of both species. In mice, we were able to examine this ApoE-dependent effect on attention longitudinally. Consistent with antagonistic pleiotropy hypothesis, ApoE4 female mice present a higher CPT performance early in life (6-9 months of age) when compared to ApoE3 mice, but this difference was reduced by 12 months of age.

Conclusion: Taken together, these results support the ApoE4 antagonistic pleiotropy hypothesis, whereby ApoE4 carriership confers greater attentional performance early in life in both female humans and mice. These new mouse models, in combination with fully translatable touchscreen tests of cognition, can be used to explore potential mechanisms by which ApoE4 can affect different aspects of brain function across the life span.