A plausible upstream submechanism is that lipid-poor APOE4 disrupts ABCA1 trafficking, likely via ARF6-associated endosomal retention, reducing cholesterol efflux and mature apoE lipidation. This may create a state where extracellular lipid export is impaired and ER-accessible cholesterol remains insufficient for stable SCAP-INSIG retention, but that final ER-sensing link remains inferential.
Curated pathway from expert analysis
flowchart TD
A["ABCA1<br/>Primary Target"]
B["Biological Process 1<br/>Mechanistic Step A"]
C["Biological Process 2<br/>Mechanistic Step B"]
D["Output Phenotype<br/>Disease Effect"]
A --> B
B --> C
C --> D
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style D fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9aNo linked papers recorded for this hypothesis yet.
Median TPM across 13 brain regions for ABCA1 from GTEx v10.
No clinical trials data linked to this hypothesis yet.
No curated ClinVar variants loaded for this hypothesis.
Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.
No DepMap CRISPR Chronos data found for ABCA1.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF we directly measure ER cholesterol in APOE4/4 vs APOE3/3 human cells using a genetically encoded ER-cholesterol sensor (e.g., D4H-ER or LamG-RT) or mass spectrometry of ER membrane fractions, THEN | ER cholesterol will be ≥25% lower in APOE4/4 cells vs APOE3/3 cells, with corresponding ≥40% increase in Golgi-localized SCAP fraction. | — no observation — | pending | 0.55 |
| IF we pharmacologically restore ABCA1 trafficking in APOE4-expressing cells by inhibiting ARF6 (e.g., NAV-2729 at 10 μM for 24 hours) or via forced ABCA1 overexpression, THEN cholesterol efflux to apo | Cholesterol efflux to exogenous apoE particles will increase by ≥30% relative to baseline in APOE4-expressing cells receiving ARF6 inhibition or ABCA1 overexpre | — no observation — | pending | 0.65 |