Sex dependent pleiotropic effects of <i>Apolipoprotein (ApoE) 4</i> on executive function in mice and humans
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".