Soluble amyloid oligomers may injure cholinergic terminals via CHRNA7-linked calcium dysregulation, making cholinergic dysfunction an early downstream readout of amyloid toxicity. This remains mechanistically plausible but is not a strong lead translational thesis.
Curated pathway from expert analysis
flowchart TD
A["Amyloid<br/>Accumulation"]
B["Alpha7 Nicotinic<br/>Receptor Dysfunction"]
C["CHRNA7<br/>Synaptotoxicity"]
D["Cholinergic<br/>Terminal Loss"]
E["Cognitive<br/>Impairment"]
A --> B
B --> C
C --> D
D --> E
style A fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style E fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9aNo linked papers recorded for this hypothesis yet.
Median TPM across 13 brain regions for APP, CHRNA7 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 APP, CHRNA7.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF human iPSC-derived cholinergic neurons are exposed to soluble amyloid-β oligomers (500 nM, 24-72 hours) THEN cholinergic terminal integrity (measured by VAChT puncta density and ChAT activity) will | Significant reduction in cholinergic terminal markers (VAChT puncta: 40-60% decrease; ChAT activity: 30-50% decrease) that is rescued by CHRNA7 blockade | — no observation — | pending | 0.55 |
| IF APP/PS1 transgenic mice are treated with a selective CHRNA7 positive allosteric modulator (PAM) starting at 3 months of age (pre-plaque) and continuing for 6 months THEN cholinergic terminal densit | Cholinergic terminal preservation in CHRNA7 PAM-treated APP/PS1 mice; VAChT density maintained at 85-100% of wild-type levels vs. 60-70% in vehicle-treated APP/ | — no observation — | pending | 0.45 |