C1q (classical complement cascade initiator) is upregulated in AD brain and tags synapses for microglial phagocytosis via C3-CR3 signaling. This excessive, activity-independent pruning underlies early synaptic loss before plaque deposition. The hypothesis is supported by compelling mechanistic studies (Hong et al. 2016) and Annexon Pharmaceuticals' ANX005 antibody is in clinical development. The mechanism explains early cognitive decline independent of amyloid burden, addressing a critical therapeutic gap. However, the complement system has pleiotropic functions—C1q also mediates protective synaptic plasticity and immune defense. Timing is critical: blocking C1q in prodromal AD may prevent pruning while later intervention may disrupt essential CNS maintenance.
Curated pathway from expert analysis
flowchart TD
A["Complement C1Q<br/>Synaptic Tagging"]
B["C1QA C1QB C1QC<br/>Subcomponent Cascade"]
C["Microglial Phagocytosis<br/>Synapse Recognition"]
D["Early Synaptic<br/>Pruning"]
E["Cognitive Decline<br/>in Early AD"]
F["C1Q-Mediated Pruning<br/>as Driver"]
A --> B
B --> C
C --> D
D --> E
E --> F
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style E fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style F fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9aNo curated PDB or AlphaFold mapping for C1Q yet. Search RCSB →
Median TPM across 13 brain regions for C1Q 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 C1Q.
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 early cognitive decline in AD is driven by C1q-mediated synaptic pruning independent of amyloid, THEN CSF C1q concentration will positively correlate with synaptic loss markers (neurogranin, GAP-43 | Baseline CSF C1q will show r≥0.30 correlation with neurogranin and r≤-0.25 correlation with ADAS-Cog13, while showing r<0.10 correlation with amyloid PET SUVR i | — no observation — | pending | 0.65 |
| IF prodromal AD patients (MCI due to AD, amyloid-positive) receive ANX005 (anti-C1q antibody) at 60mg/kg IV weekly for 12 months, THEN synaptic integrity markers in CSF (neurogranin, SNAP-25) will rem | CSF neurogranin levels will remain within 10% of baseline in the ANX005 arm versus showing ≥15% increase (indicating synaptic loss) in the placebo arm within 12 | — no observation — | pending | 0.72 |