Strongest mechanistic support among all hypotheses. TREM2-TYROBP signaling for DAM transition well-established. AL002 Phase 2 readout (2025) will be pivotal. Skeptic correctly identifies that APOE4 may act downstream of TREM2, requiring genetic epistasis studies. Expert confirms TREM2 agonism has best tractability; ABCA1 agonists problematic due to hepatotoxicity. APOE protein replacement (Voyager) and TREM2 antibodies provide multiple development paths.
Curated pathway from expert analysis
flowchart TD
A["Amyloid-beta Plaques<br/>Phospholipid Ligands"]
B["TREM2 Receptor<br/>Ligand Binding"]
C["TYROBP/DAP12<br/>ITAM Phosphorylation"]
D["SYK Kinase<br/>Activation"]
E["PLCG2<br/>IP3 + DAG Generation"]
F["Ca2+ Release<br/>Cytoskeletal Remodeling"]
G["Microglial Phagocytosis<br/>Plaque Compaction"]
A --> B
B --> C
C --> D
D --> E
E --> F
F --> G
style A fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style G fill:#1b5e20,stroke:#81c784,color:#81c784No linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for TREM2-APOE yet. Search RCSB →
Median TPM across 13 brain regions for TREM2-APOE 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 TREM2-APOE.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF Trem2 is genetically ablated in 5xFAD mice and APOE lipidation is pharmacologically enhanced, THEN DAM recruitment and amyloid clearance effects will be completely abolished in Trem2 knockout anima | Trem2 knockout mice receiving APOE lipidation therapy will show equivalent amyloid burden and DAM gene expression to Trem2 knockout vehicle controls (no rescue | — no observation — | pending | 0.55 |
| IF APOE lipidation is enhanced via ABCA1 agonism (at sub-hepatotoxic doses) or APOE protein replacement therapy in 5xFAD mice, THEN measurable increases in DAM marker genes (Trem2, Clec7a, Itgax, Lpl) | ≥30% increase in DAM signature gene expression and ≥25% reduction in insoluble amyloid-beta plaques relative to vehicle-treated controls | — no observation — | pending | 0.65 |