Donanemab treatment reduces amyloid-induced axonal transport deficits and endosomal trafficking impairment. Restored axonal integrity decreases the release of tau fragments and hyperphosphorylated tau species into CSF. However, this hypothesis conflates intracellular tau phosphorylation with extracellular tau release, and the primary source of CSF tau (extracellular release mechanisms including unconventional secretion, synaptic activity-dependent release, and necrotic cell death) is not adequately addressed by axonal transport mechanisms.
Curated pathway from expert analysis
flowchart TD
A["Amyloid Clearance<br/>Therapeutic Intervention"]
B["Axonal Integrity<br/>Recovery Signal"]
C["RAB GTPase Activity<br/>Axonal Transport Restoration"]
D["MAPT/Tau Function<br/>Microtubule Stabilization"]
E["CSF p-tau217<br/>Normalization"]
F["Neuronal Health<br/>Restored"]
G["Biomarker-Linked<br/>Mechanistic Validation"]
A --> B
B --> C
C --> D
D --> E
E --> F
G -.->|"confirms"| D
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style E fill:#1b5e20,stroke:#a5d6a7,color:#a5d6a7
style F fill:#1b5e20,stroke:#a5d6a7,color:#a5d6a7No linked papers recorded for this hypothesis yet.
Median TPM across 13 brain regions for MAPT, RAB GTPases 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 MAPT, RAB GTPases.
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 Donanemab treatment achieves ≥50% reduction in amyloid plaque burden (Centiloid <20) THEN CSF p-tau217 concentrations will decrease by ≥40% within 12 months post-baseline, with the temporal traject | CSF p-tau217 levels will show ≥40% reduction at 12 months, and the magnitude/timing of this reduction will correlate (r > 0.5) with concurrent NfL reduction | — no observation — | pending | 0.60 |
| IF patients are stratified at baseline by elevated CSF tau release markers (extracellular/extracellular vesicle-associated tau) versus primarily axonal damage markers THEN those with dominant axonal t | High axonal-damage/low extracellular-tau subgroup will exhibit ≥50% greater CSF p-tau217 reduction compared to high extracellular-tau subgroup | — no observation — | pending | 0.40 |