Trazodone may have a secondary low-dose mechanism through astrocyte and microglial inflammatory modulation, potentially shifting GFAP, IL-6, YKL-40, or kynurenine-pathway markers. This is the weakest surviving biological mechanism worth embedding in a trial as a secondary pharmacodynamic package, not as a lead disease-modifying hypothesis.
Curated pathway from expert analysis
flowchart TD
A["AIF1 / IBA1<br/>Allograft Inflammatory Factor 1"]
B["Microglial Activation Marker<br/>Divalent Calcium Binding"]
C["F-actin Crosslinking<br/>Membrane Ruffling and Phagocytosis"]
D["Pro-inflammatory Signaling<br/>NLRP3 and NF-kB Upregulation"]
E["Synaptic Pruning Enhancement<br/>C1q and C3 Deposition"]
F["Cytokine Release<br/>IL-1beta and TNF-alpha Secretion"]
G["AIF1 Upregulation<br/>Chronic Neuroinflammation Marker"]
A --> B
B --> C
C --> D
D --> E
D --> F
G -.->|"reflects"| D
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style D fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style G fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9aNo linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for IL6; yet. Search RCSB →
Median TPM across 13 brain regions for IL6; TGFB1; AIF1; MAPK14; MAPK8; NFKB1 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 IL6; TGFB1; AIF1; MAPK14; MAPK8; NFKB1.
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 early Alzheimer's disease patients (n≥40/arm) receive trazodone 50-100 mg/day versus placebo for 12 weeks, THEN CSF GFAP concentrations will decrease by ≥15% from baseline in the active treatment g | CSF GFAP will decrease by ≥15% from baseline in the trazodone arm compared to placebo, reflecting reduced astrocyte reactivity. | — no observation — | pending | 0.48 |
| IF early Alzheimer's disease or MCI patients (n≥60/arm) are randomized to receive trazodone 50-100 mg/day versus placebo for 12 weeks, THEN serum IL-6 levels will decrease by ≥20% from baseline in the | Serum IL-6 will show a statistically significant reduction (p<0.05) with ≥20% decrease from baseline after 12 weeks of low-dose trazodone. | — no observation — | pending | 0.55 |