Donanemab treatment causes a shift from disease-specific p-tau217 (produced via amyloid-driven kinase activation) toward physiological p-tau217 (maintained by normal neuronal activity). This isoform shift—detectable through ratio changes between disease-associated p-tau217 conformers versus total p-tau217—serves as a mechanistically validated cessation endpoint distinguishing therapeutic response from passive biomarker fluctuation. However, no validated assay currently exists to distinguish disease-specific from physiological p-tau217.
Curated pathway from expert analysis
flowchart TD
A["MAPT PTM-Modified<br/>Tau Conformers"]
B["p-tau217 Isoform<br/>Shift"]
C["Mechanistic Transition<br/>Biomarker"]
D["Neurofibrillary Tangle<br/>Formation"]
E["Neuronal Loss<br/>Progression"]
F["Isoform Shift as<br/>Mechanistic Indicator"]
G["Early Detection<br/>Therapeutic Window"]
A --> B
B --> C
C --> D
D --> E
E --> F
G -.->|"identifies"| B
style A fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style F fill:#7b1fa2,stroke:#ce93d8,color:#ce93d8
style G fill:#1b5e20,stroke:#a5d6a7,color:#a5d6a7No linked papers recorded for this hypothesis yet.
Median TPM across 13 brain regions for MAPT (PTM-modified conformers) 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 (PTM-modified conformers).
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 develop a ratio assay distinguishing disease-specific p-tau217 conformers from physiological p-tau217 using conformer-specific monoclonal antibodies in an immunoprecipitation-mass spectrometry w | Disease-specific p-tau217/total p-tau217 ratio will decrease by ≥30% in donanemab-treated amyloid-positive participants, while remaining unchanged or increasing | — no observation — | pending | 0.45 |
| IF the disease-specific p-tau217/total p-tau217 ratio serves as a valid mechanistic cessation endpoint, THEN amyloid-positive participants whose ratio decreases to <50% of baseline (indicating isoform | Participants achieving ≥50% reduction in disease-specific p-tau217/total p-tau217 ratio at Month 12 will show 25-40% slower CDR-SB progression (ΔCDR-SB <1.5 poi | — no observation — | pending | 0.35 |