The most actionable synthesis is that pathogenicity may depend more on conversion of C1q binding into classical-pathway protease activity than on C1q recognition alone. In this model, inhibiting C1r/C1s should attenuate C4/C3-mediated synapse loss and neuroinflammation while preserving some homeostatic debris sensing and cargo recognition by C1q.
This hypothesis reconciles conflicting C1q phenotypes by placing receiver-cell state downstream of a common upstream C1q-tagging event. In a competent TREM2 program, microglia clear tagged material efficiently; in TREM2-impaired states, the same substrates persist, amplifying complement and bystander synapse loss.
Convergent vs Divergent Predictions
This summary checks where the selected hypotheses point toward the same target or mechanism, and where they pull in opposite directions.
C1QAC1QBC1QCC3Neuroinflammationneurodegeneration
Convergent signals
C1QA recurs across 2 selected hypotheses with aligned directionality in neuroinflammation.
C1QB recurs across 2 selected hypotheses with aligned directionality in neuroinflammation.
C1QC recurs across 2 selected hypotheses with aligned directionality in neuroinflammation.
C3 recurs across 2 selected hypotheses with aligned directionality in neuroinflammation.
Divergent signals
No direct polarity conflicts detected among the selected hypotheses.
Verdict Summary
9/11
dimensions won
Selective blockade of classical-pathway
3/11
dimensions won
Microglial TREM2 state determines whethe
Radar Chart — 10 Dimensions
Score Comparison Bars
Mechanistic
0.79
0.81
Evidence
0.74
0.71
Novelty
0.58
0.68
Feasibility
0.86
0.72
Impact
0.88
0.73
Druggability
0.91
0.62
Safety
0.62
0.52
Competition
0.63
0.57
Data
0.77
0.70
Reproducible
0.72
0.66
KG Connect
0.50
0.50
Score Breakdown
Dimension
Selective blockade of classica
Microglial TREM2 state determi
Mechanistic
0.790
0.810
Evidence
0.740
0.710
Novelty
0.580
0.680
Feasibility
0.860
0.720
Impact
0.880
0.730
Druggability
0.910
0.620
Safety
0.620
0.520
Competition
0.630
0.570
Data
0.770
0.700
Reproducible
0.720
0.660
KG Connect
0.500
0.500
Evidence
Selective blockade of classical-pathway activation downstrea
No evidence citations yet
Microglial TREM2 state determines whether C1q-tagged substra
No evidence citations yet
Debate Excerpts
Selective blockade of classical-pathway activation
4 rounds · quality: 0.68
Persona-Theorist
1. **Synaptic C1q drives complement-dependent pruning, while microglial surface-associated C1q biases phagocyte state through receptor-specific signaling**
**Mechanism:** C1q deposited on weak ...
Persona-Skeptic
Overall skeptical read: the debate is probably mixing three separable variables that have not been cleanly orthogonalized experimentally: `location`, `ligand identity`, and `receiver-cell state`. The ...
Persona-Domain Expert
**Triage**
The ideas worth carrying forward are `6`, `5`, `1`, `2`, `4`, and `7`, in that order. I would drop `3` for now; it is too speculative to support a drug program.
The main translational poi...
Persona-Synthesizer
{"ranked_hypotheses":[{"title":"Selective blockade of classical-pathway activation downstream of C1q will reduce synaptotoxic complement amplification while preserving beneficial C1q recognition funct...
Microglial TREM2 state determines whether C1q-tagg
4 rounds · quality: 0.68
Persona-Theorist
1. **Synaptic C1q drives complement-dependent pruning, while microglial surface-associated C1q biases phagocyte state through receptor-specific signaling**
**Mechanism:** C1q deposited on weak ...
Persona-Skeptic
Overall skeptical read: the debate is probably mixing three separable variables that have not been cleanly orthogonalized experimentally: `location`, `ligand identity`, and `receiver-cell state`. The ...
Persona-Domain Expert
**Triage**
The ideas worth carrying forward are `6`, `5`, `1`, `2`, `4`, and `7`, in that order. I would drop `3` for now; it is too speculative to support a drug program.
The main translational poi...
Persona-Synthesizer
{"ranked_hypotheses":[{"title":"Selective blockade of classical-pathway activation downstream of C1q will reduce synaptotoxic complement amplification while preserving beneficial C1q recognition funct...