CSF p-tau217 normalization must co-occur with neurogranin (Ng) stabilization to confirm cessation thresholds. Ng reflects synaptic integrity while p-tau217 reflects neuronal injury—both must normalize to ensure treatment cessation occurs after the critical window of ongoing amyloid-induced synaptotoxicity has closed. However, neurogranin normalizes more slowly than p-tau217, making binary co-normalization requirement impractical; instead, a composite synaptic-health score should replace the binary requirement.
Curated pathway from expert analysis
flowchart TD
A["SNAP25/Synaptosomal-Associated Protein<br/>SNARE Complex Member"]
B["VAMP2 and STX1A Complex Assembly<br/>Synaptic Vesicle Docking"]
C["Neurotransmitter Release<br/>Synaptic Vesicle Fusion and Exocytosis"]
D["Tau Sequestration<br/>VAMP2 Availability Reduced"]
E["SNAP25-Tau Interaction<br/>Exocytotic Machinery Impairment"]
F["SNAP25 Disruption<br/>Synaptic Vesicle Tau Capture and Neurotransmission Failure"]
A --> B
B --> C
C --> D
D --> E
E --> F
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style F fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9aNo linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for NRGN yet. Search RCSB →
Median TPM across 13 brain regions for NRGN, SNAP25 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 NRGN, SNAP25.
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 we compute a composite synaptic-health z-score (weighted average of p-tau217 and neurogranin z-scores) from serial CSF measurements in amyloid-positive individuals receiving anti-amyloid therapy, T | Composite synaptic-health z-score accounts for ≥20% greater variance (R² increment ≥0.20) in 24-month CDR-SB change compared to p-tau217 z-score alone | — no observation — | pending | 0.65 |
| IF neurogranin normalizes to baseline reference ranges at least 6 months after p-tau217 achieves normalization in anti-amyloid-treated amyloid-positive participants, THEN the time-to-neurogranin-norma | Spearman correlation ρ ≥ 0.40 between months-to-neurogranin-normalization and months-from-treatment-to-cognitive-trajectory-inflection, with neurogranin normali | — no observation — | pending | 0.55 |