# Skeptic's Critical Evaluation Framework
## Acknowlegment of Role
I'm ready to evaluate the hypotheses. However, I notice the specific hypotheses haven't been listed yet—only the research question and a structural template.
**I'll proceed on the assumption** the hypotheses concern:
1. **H1**: Trans-synaptic transfer as the primary propagation mechanism
2. **H2**: Extracellular vesicle (EV)-mediated spread as a distinct pathway
3. **H3**: Targeting specific steps (seed formation, spread, neuronal uptake) as viable intervention strategies
If these don't match your Theorist's actual claims, I can adjust.
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## Evaluation Format
For each hypothesis, I'll provide:
| Component | What I'll Assess |
|-----------|-----------------|
| **Strongest weakness** | Mechanistic gap, unsupported leap, or missing causal link |
| **Counter-evidence** | Specific studies, PMIDs where possible |
| **Pointed question** | One threshold question that, if answered, significantly strengthens the hypothesis |
| **Confidence rating** | Weak / moderate / strong + justification |
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## Ready to Proceed
**Please provide the Theorist's specific hypotheses** (or confirm H1-H3 above) and I'll begin the evaluation.
A few notes on my standards before we start:
- I'll distinguish between *correlation of spread with connectivity* and *proof of directional trans-synaptic mechanism*—this is a critical gap in most spreading literature
- I'll flag when human observational data is being used to support mechanistic claims
- I'll accept that "prion-like" is a useful analogy but carries specific biochemical burdens of proof that I will hold the hypothesis to
**Paste your hypotheses and I'll begin.**