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,
Radar Chart — 10 Dimensions
Score Comparison Bars
Mechanistic
0.84
Evidence
0.72
Novelty
0.68
Feasibility
0.78
Impact
0.00
Druggability
0.00
Safety
0.00
Competition
0.00
Data
0.00
Reproducible
0.00
KG Connect
0.12
Score Breakdown
Dimension
Rare TREM2-TYROBP pathway vari
Mechanistic
0.840
Evidence
0.720
Novelty
0.680
Feasibility
0.780
Impact
0.000
Druggability
0.000
Safety
0.000
Competition
0.000
Data
0.000
Reproducible
0.000
KG Connect
0.118
Evidence
Rare TREM2-TYROBP pathway variants complement standard PRS b