This is best treated as a stratification and response-modifier hypothesis rather than a primary C1q mechanism. APOE4 may alter lipid and aggregate surfaces in ways that shift C1q interactomes toward complement-amplifying complexes, but the causal chain remains loose because ApoE biology is highly pleiotropic.
Curated pathway from expert analysis
flowchart TD
A["APOE4 Isoform<br/>Structural Instability"]
B["Impaired Lipid Loading<br/>Reduced Cholesterol Efflux"]
C["LRP1 Reduced Binding<br/>BBB Clearance Deficit"]
D["Amyloid-beta<br/>Accumulation"]
E["Synaptic Dysfunction<br/>Membrane Disruption"]
F["Neurodegeneration<br/>Cognitive Decline"]
G["APOE3 Comparison<br/>Normal Lipidation"]
A --> B
B --> C
C --> D
D --> E
E --> F
G -.->|"protective"| C
style A fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style F fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style G fill:#1b5e20,stroke:#81c784,color:#81c784No linked papers recorded for this hypothesis yet.
Median TPM across 13 brain regions for APOE,C1QA,C1QB,C1QC,TREM2,APP 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 APOE,C1QA,C1QB,C1QC,TREM2,APP.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF APP/PS1 mice crossed to APOE4 knock-in mice are compared to APP/PS1 × APOE3 knock-in mice at 9 months of age, THEN APOE4 brains will show significantly elevated (≥2-fold) membrane-bound C1q-C3 comp | APOE4 mice will have significantly higher C1q-C3 soluble complex concentrations in brain tissue homogenates (ELISA: mean > 800 pg/mg protein vs < 400 pg/mg for | — no observation — | pending | 0.58 |
| IF iPSC-derived microglia from APOE4/4 donors are compared to APOE3/3 iPSC-derived microglia in a co-culture assay with fluorescently labeled C1q protein under amyloid-beta42 challenge conditions (1 µ | APOE4 microglia C1q interactome will show preferential association with complement amplification proteins (C1R, C3, C4B) compared to APOE3 microglia which will | — no observation — | pending | 0.65 |