Investigating the plasma-liver-brain axis of omega-3 fatty acid metabolism in mouse knock-in for the human apolipoprotein E epsilon 4 allele
Bibliographic record
Abstract
The metabolism of docosahexaenoic acid (DHA), an omega-3 fatty acid, is different in carriers of APOE4, the main genetic risk factor for late-onset Alzheimer's disease. The brain relies on the plasma DHA pool for its need, but the plasma-liver-brain axis in relation to cognition remains obscure. We hypothesized that this relationship is compromised in APOE4 mice considering the differences in fatty acid metabolism between APOE3 and APOE4 mice. Male and female APOE3 and APOE4 mice were fed either a diet enriched with DHA (0.7 g DHA/100 g diet) or a control diet for 8 months. There was a significant genotype × diet interaction for DHA concentration in the liver and adipose tissue. In the cortex, a genotype effect was found where APOE4 mice had a higher concentration of DHA than APOE3 mice fed the control diet. There was a significant genotype × diet interaction for the liver and hippocampal arachidonic acid (AA). APOE4 mice had 20-30% lower plasma DHA and AA concentrations than APOE3 mice, independent of diet. Plasma and liver DHA levels were significantly correlated in APOE3 and APOE4 mice. In APOE4 mice, there was a significant correlation between plasma, adipose tissues, cortex DHA and the Barnes maze and/or with a better recognition index. Moreover, higher AA levels in the liver and the hippocampus of APOE4 mice were correlated with lower cognitive performance. Our results suggest that there is a plasma-liver-brain axis of DHA that is modified in APOE4 mice. Moreover, our data support that APOE4 mice rely more on plasma DHA than APOE3 mice, especially in cognitive performance. Any disturbance in plasma DHA metabolism might have a greater impact on cognition in APOE4 carriers.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.004 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".