Alzheimer’s disease multiomic signatures mediated by Cholesterol Ester Transfer Protein
Bibliographic record
Abstract
BACKGROUND: Altered lipid profiles and lipid processing genes are associated with Alzheimer's disease (AD). There is a reported genetic interaction between the AD risk gene APOE and cholesterol ester transfer protein (CETP). Mice lack functional CETP which is critical to the balance of circulating lipoproteins; this imparts cardioprotective effects and may make mice resistant to AD. Additionally, previous studies in transgenic humanized CETP (hCETP) mice have demonstrated that CETP addition in mice increases expression of AD risk genes and markers of AD pathogenicity. Together, this suggests that CETP may modify AD risk in an APOE4-dependent manner. This project aims to determine molecular pathways and signatures in AD mediated by CETP with an emphasis on molecular pathways shared with APOE as a potential disease-altering mechanism. METHODS: To identify pathways shared by CETP and APOE we created molecular networks using publicly available online tools including the AD Atlas and STRING (v12.0). The Heart and Diabetes Institute Metabolomics Laboratory Portal was leveraged to perform Genome Wide Association Study (GWAS) analysis to establish changes in lipid species abundance shared by CETP and APOE genetic variants. Transcriptional signatures in several mouse models were compared to human AD gene modules to determine pathological relevance of hCETP and APOE4 mouse models. RESULTS: Molecular networks implicated several genes as being co-expressed suggesting they may co-function with CETP and APOE. These co-expression edges included C4A/B compliment genes, PSMB8, APOJ/CLU, and APP. GWAS analysis resulted in several notable findings including that CETP variants have a strong effect on the relative abundance of phosphatidylcholine (PC) lipid species. Additionally, while APOE4 is positively associated with total PC, the common loss-of-function variant CETP I405V (rs5882) is associated with reduced PC levels. Transcriptional changes in lipid-related transgenic and MODEL-AD knock-in mouse models exhibited significant associations with immune processes. CONCLUSIONS: These findings indicate that both CETP and APOE influence total PC and are associated with molecular pathways of immune activation and amyloid biology. Overall this evidence suggests that CETP and APOE act on shared pathways, likely mediated by lipid metabolism and peripheral immunity, that contribute to AD susceptibility.
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 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".