Donanemab triggers acute microglial activation (ARIA-E). Patients achieving favorable M2-like phenotype show better p-tau217 normalization due to enhanced tau aggregate clearance, while persistent M1 phenotype may show biomarker dissociation. However, TSPO-PET M1/M2 specificity in humans is questionable—human microglia do not conform cleanly to the rodent M1/M2 dichotomy, and TSPO signals are non-specific for activation state.
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.
Median TPM across 13 brain regions for TREM2 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.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
No resource usage or linked notebooks recorded for this hypothesis yet.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF individuals with TREM2 R47H variant (risk genotype) and individuals with reference alleles are treated with donanemab, THEN the TREM2 R47H group will demonstrate attenuated p-tau217 reduction relat | TREM2 R47H carriers will show ≥30% less p-tau217 normalization per unit reduction in amyloid PET SUVr compared to reference allele carriers | — no observation — | pending | 0.65 |
| IF patients receiving donanemab are stratified by baseline TSPO-PET signal into high vs low microglial activation tertiles, THEN the high activation tertile will demonstrate a divergent p-tau217 traje | High TSPO-PET tertile will show ≥40% greater variance in p-tau217 reduction per unit amyloid clearance compared to low tertile, indicating biomarker dissociatio | — no observation — | pending | 0.55 |