Early noradrenergic loss may shift inflammatory tone, amyloid clearance, and cholinergic resilience, thereby modulating the observed sequence of biomarkers. The debate supports this mainly as a stratification axis and covariate rather than a primary causal program.
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 DBH yet. Search RCSB →
Median TPM across 13 brain regions for DBH, ADRB1, ADRB2 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 DBH, ADRB1, ADRB2.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF locus coeruleus integrity is experimentally reduced via DSP-4 lesioning in 3xTg-AD mice at 3 months of age, THEN cholinergic marker deficits (ChAT activity and high-affinity choline uptake) will em | ChAT activity will decline by ≥40% and ACh release will decrease by ≥30% at 5 months post-lesion, while amyloid PET signal (${}^{11}$C-PiB) and CSF p-tau181 wil | — no observation — | pending | 0.65 |
| IF cognitively normal older adults (60-80 years) are stratified by baseline LC integrity using neuromelanin-sensitive MRI, THEN those in the low-LC integrity quartile will exhibit significantly steepe | The low-LC integrity group will show ≥1.5% annual decline in FDG-PET metabolism and ≥20% reduction in CSF ACh concentration relative to baseline by 36 months, w | — no observation — | pending | 0.55 |