Pleiotropic effects of Apolipoprotein (ApoE) 4 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). Compared to ApoE4 noncarriers (ApoE4-), ApoE4 carriers (ApoE4+) exhibit earlier onset and more rapid progression of memory impairment. However, separate lines of work have suggested the opposite pattern in other cognitive domains: ApoE4+ individuals exhibit superior executive function compared to ApoE4-, but this advantage decreases with age. The antagonistic pleiotropy hypothesis proposes that ApoE4 may confer advantages to brain function at earlier ages, but these advantages become detrimental later in life. To investigate this hypothesis, we took a cross-species translational approach focusing on cognitively unimpaired human adult ApoE4+ and ApoE4-, ages 60-80 years, in combination with knock-in mouse models that express humanized wild-type App, MAPT, and ApoE3/4 genes. METHOD: To quantify executive function, we utilized the cross-species touchscreen-based Continuous Performance Task (CPT) to evaluate selective attention. Human participants were drawn from the PREVENT-AD program at the Douglas Research Centre, with testing conducted on MS SurfacePros. Mice performed the same task using an operant chamber platform. RESULT: Behavioural results suggest that ApoE4 facilitates attentional processes in both older adult 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+ of both species. In mice, we examined the ApoE-dependent effects on attention longitudinally (spanning 12 months), finding that the positive effect of ApoE4 was sustained across this interval in females, though it became less robust with age. In contrast, ApoE4 was beneficial in males only during early life. Notably, these effects were observed in the absence of detectable brain pathology CONCLUSION: These results support the antagonistic pleiotropy hypothesis, whereby ApoE4 carriership confers greater attentional performance early in life and in the absence of classical AD pathology. This effect is detectable in both sexes but is stronger and more sustained across age in females. All these patterns are conserved across humans and mice, suggesting that this cross-species translational platform is well suited to explore the mechanistic basis of ApoE4 antagonistic pleiotropy as it relates to domain-specific cognitive function.
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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) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
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".