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.
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Curated pathway diagram from expert analysis
flowchart TD
A["Amyloid-beta Plaques
Phospholipid Ligands"]
B["TREM2 Receptor
Ligand Binding"]
C["TYROBP/DAP12
ITAM Phosphorylation"]
D["SYK Kinase
Activation"]
E["PLCG2
IP3 + DAG Generation"]
F["Ca2+ Release
Cytoskeletal Remodeling"]
G["Microglial Phagocytosis
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
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No clinical trials data available
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