We hypothesize that rare loss-of-function variants in microglial-expressed genes within the TREM2-TYROBP signaling cascade (PLCG2, TREM2, INPP5D, APOC2) capture a distinct late-onset Alzheimer's disease etiological subtype characterized by dysregulated microglial lipid sensing and enhanced synaptic pruning that is not captured by standard AD polygenic risk scores. This rare variant burden identifies individuals with enhanced microglial-driven neurodegeneration who fall below PRS risk thresholds, representing a 'microglial subtype' that may respond differently to immunomodulatory therapies. Testable prediction: combining rare variant burden scores from microglial regulatory genes with standard AD PRS will improve area under the ROC curve by >0.05 in independent cohorts and reclassify ~15-20% of cases currently missed by PRS alone.
Curated pathway from expert analysis
flowchart TD
A["PLCG2 Variant<br/>Gain of Function"]
B["TREM2-TYROBP<br/>Signaling Cascade"]
C["PLCgamma2<br/>Phospholipase Activation"]
D["Microglial<br/>Calcium Signaling"]
E["Phagocytic Activity<br/>Enhanced"]
F["PLCG2 as Modifier of<br/>TREM2 Pathogenesis"]
A --> B
B --> C
C --> D
D --> E
E --> F
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style F fill:#1b5e20,stroke:#a5d6a7,color:#a5d6a7No linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for PLCG2 yet. Search RCSB →
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 PLCG2.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF individuals are stratified by rare loss-of-function variant burden (MAF <1%) in PLCG2, TREM2, INPP5D, and APOC2 THEN combining a rare variant burden score with standard AD polygenic risk scores wil | AUC improvement >0.05 when rare variant burden is added to standard PRS; reclassification of 15-20% of LOAD cases currently classified as low-risk by PRS alone | — no observation — | pending | 0.72 |
| IF human iPSC-derived microglia or mouse models carrying rare PLCG2/TREM2/INPP5D loss-of-function variants are exposed to amyloid-beta oligomers THEN these cells will demonstrate enhanced synaptic pru | ≥30% increase in complement-mediated synaptic engulfment (C1q/C3d colocalization with synaptic markers) in microglia harboring rare loss-of-function variants fo | — no observation — | pending | 0.65 |