Amyloid PET normalizes faster than CSF p-tau217 due to differential compartment kinetics (vascular vs. neuronal). Using amyloid PET alone for stopping may prematurely halt treatment before downstream tau pathology resolution. This hypothesis remains biologically plausible but lacks outcome validation—the clinical inference (dual threshold required) is not yet supported by data showing harm from amyloid-PET-only stopping.
Curated pathway from expert analysis
flowchart TD
A["APP Full Length<br/>Membrane Protein"]
B["BACE1 Beta-Secretase<br/>Cleavage at beta-site"]
C["sAPPbeta + CTFbeta<br/>C-terminal Fragment"]
D["Gamma-Secretase Complex<br/>PSEN1/PSEN2"]
E["Abeta42 Peptide<br/>Amyloidogenic Fragment"]
F["Abeta Oligomers<br/>Toxic Aggregates"]
G["Amyloid Plaques<br/>Extracellular Deposits"]
H["ADAM10 Alpha-Secretase<br/>Non-amyloidogenic Path"]
A --> B
B --> C
C --> D
D --> E
E --> F
F --> G
A --> H
H -.->|"competes with BACE1"| B
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style E fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style G fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style H fill:#1b5e20,stroke:#81c784,color:#81c784No linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for NA yet. Search RCSB →
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 NA - Biomarker validation hypothesis.
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 patients discontinue anti-amyloid therapy based solely on amyloid PET negativity while CSF p-tau217 remains ≥1.5x baseline, THEN they will demonstrate significantly greater cognitive decline (≥1.5 | Mean annual CDR-SB decline of ≥1.5 points in the amyloid-PET-only stop group versus ≤0.8 points in the dual-threshold stop group over 24 months | — no observation — | pending | 0.35 |
| IF patients with early Alzheimer's disease receive anti-amyloid monoclonal antibody therapy and achieve amyloid PET negativity, THEN CSF p-tau217 will remain above the diagnostic threshold in at least | CSF p-tau217 remains elevated (above 23 pg/mL baseline-adjusted threshold) in ≥60% of amyloid PET-negative participants at month 12 | — no observation — | pending | 0.45 |