ID: h-gwas-trem2-abi3-phagocytosis-5dee99f5
Hypothesis
TREM2-ABI3 actin-phagocytosis coupling is a higher-yield AD target than either locus alone
TREM2 R47H and ABI3 rs616338 are both AD risk loci linked to microglial response, phagocytosis, and cytoskeletal remodeling.
EvidenceStrong (66%)📖 0 cit🗣 1 debates✓ 7 support✗ 1 oppose
🧪 Overview
TREM2 R47H and ABI3 rs616338 are both AD risk loci linked to microglial response, phagocytosis, and cytoskeletal remodeling. The notebook prioritizes them as a convergent module rather than isolated targets. Hypothesis: restoring TREM2-dependent lipid sensing together with ABI3-linked actin remodeling will rescue plaque engagement and debris clearance more robustly than modulating either locus alone in human iPSC-microglia.
🧬 Mechanism
🧬 Curated Mechanism Pathway
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:#81c784⚖️ Evidence
⚖️ Evidence Matrix7 supports1 contradicts
Supports
TREM2 R47H has a high AD risk odds-ratio proxy and ABI3 rs616338 is a replicated rare risk locus.
dataset:ad_genetic_risk_loci
Supports
Enrichment and druggability scoring group TREM2 and ABI3 with microglial immune/phagocytic biology.
notebook:gwas-ad-risk-loci-analysis
Supports
Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease.
Supports
Transethnic meta-analysis of rare coding variants in PLCG2, ABI3, and TREM2 supports their general contribution to Alzheimer's disease.
Supports
Examination of the Effect of Rare Variants in TREM2, ABI3, and PLCG2 in LOAD Through Multiple Phenotypes.
Supports
Deletion of Abi3/Gngt2 influences age-progressive amyloid β and tau pathologies in distinctive ways.
Supports
Microglia express ABI3 in the brains of Alzheimer's disease and Nasu-Hakola disease.
Contradicts
Joint modulation could be context-dependent and may not translate from iPSC-microglia to aged human brain microglia.
notebook:gwas-ad-risk-loci-analysis
📖 Linked Papers
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — TREM2
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for TREM2/ABI3 from GTEx v10.
💉 Clinical Trials
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.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
🏆 Tournament
🏆 Arenas / Elo
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📊 Market Indicators
7d Trend
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Stable
7d Momentum
▼ 0.7%
Volatility
Low
0.0027
Events (7d)
3
Price History
▼10.1%💾 Resource Usage
No resource usage or linked notebooks recorded for this hypothesis yet.
🔮 Predictions
🔎 Predictions vs Observations2 predictions · 0 with recorded observations
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF human iPSC-derived microglia from AD patients harboring both TREM2 R47H and ABI3 rs616338 risk alleles receive AAV-mediated combinatorial overexpression of TREM2 and ABI3 THEN plaque-associated mic | Combinatorial TREM2+ABI3 overexpression will yield ≥40% greater phagocytic index (amyloid-beta internalization + degradation) and ≥35% increase in plaque-engage | — no observation — | pending | 0.65 |
| IF TREM2-ABI3 double knockout iPSC-microglia receive rescue with TREM2+ABI3 co-expression THEN actin polymerization rates (F-actin/G-actin ratio) and podosome/phagocytic cup dynamics will show ≥50% re | F-actin/G-actin ratio measured by G-actin/F-actin in vivo assay will increase ≥50% in dual-rescue vs double KO, and ≥30% higher than TREM2-only rescue; phagocyt | — no observation — | pending | 0.55 |
🔮 Falsifiable Predictions (2)
pendingconf 65%
IF human iPSC-derived microglia from AD patients harboring both TREM2 R47H and ABI3 rs616338 risk alleles receive AAV-mediated combinatorial overexpression of TREM2 and ABI3 THEN plaque-associated microglial coverage and amyloid-beta debris clearance will increase by ≥40% compared to single-locus in
Predicted outcome: Combinatorial TREM2+ABI3 overexpression will yield ≥40% greater phagocytic index (amyloid-beta internalization + degradation) and ≥35% increase in pla
Falsification: If combinatorial treatment produces ≤15% improvement in phagocytic index compared to the superior single-locus condition, the convergent-module hypothesis is falsified and independent locus effects wi
pendingconf 55%
IF TREM2-ABI3 double knockout iPSC-microglia receive rescue with TREM2+ABI3 co-expression THEN actin polymerization rates (F-actin/G-actin ratio) and podosome/phagocytic cup dynamics will show ≥50% restoration toward WT levels and exceed single-gene rescue by ≥30% within 6 weeks.
Predicted outcome: F-actin/G-actin ratio measured by G-actin/F-actin in vivo assay will increase ≥50% in dual-rescue vs double KO, and ≥30% higher than TREM2-only rescue
Falsification: If dual rescue shows ≤20% improvement in F-actin dynamics over single-gene rescue, or actin polymerization remains <30% of WT levels, the synergistic actin-phagocytosis coupling model is falsified.
▸Metadatasource: v1_phase_c_backfill · origin_type: forge_notebook
| source | v1_phase_c_backfill |
| origin_type | forge_notebook |
| _schema_version | 1 |
📊 Evidence Profile
Evidence Balance
+0%
Certainty
0%
Debates
0
Incoming
0
Outgoing
0
0 supporting
0 contradicting
0 neutral
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