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,
The ad_genetic_risk_loci dataset identifies PLCG2 rs72824905 as a rare protective AD variant with a strong protective odds-ratio proxy. The notebook's Enrichr and GTEx analysis places PLCG2 in a microglial immune signaling module with actionable phospholipase biology. Hypothesis: partial, pathway-biased PLCG2 activation can increase microglial plaque and debris clearance while avoiding broad inflammatory gain-of-function toxicity.
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.
PLCG2Microglial DysfunctionMicroglial Immunity
Convergent signals
PLCG2 recurs across 2 selected hypotheses with aligned directionality in microglial dysfunction, microglial immunity.
Divergent signals
No direct polarity conflicts detected among the selected hypotheses.
Verdict Summary
5/11
dimensions won
Rare TREM2-TYROBP pathway variants compl
6/11
dimensions won
Calibrated PLCG2 activation can reproduc
Radar Chart — 10 Dimensions
Score Comparison Bars
Mechanistic
0.84
0.70
Evidence
0.72
0.66
Novelty
0.68
0.64
Feasibility
0.78
0.58
Impact
0.00
0.72
Druggability
0.00
0.76
Safety
0.00
0.46
Competition
0.00
0.00
Data
0.00
0.78
Reproducible
0.00
0.62
KG Connect
0.50
0.50
Score Breakdown
Dimension
Rare TREM2-TYROBP pathway vari
Calibrated PLCG2 activation ca
Mechanistic
0.840
0.700
Evidence
0.720
0.660
Novelty
0.680
0.640
Feasibility
0.780
0.580
Impact
0.000
0.720
Druggability
0.000
0.760
Safety
0.000
0.460
Competition
0.000
0.000
Data
0.000
0.780
Reproducible
0.000
0.620
KG Connect
0.500
0.500
Evidence
Rare TREM2-TYROBP pathway variants complement standard PRS b
No evidence citations yet
Calibrated PLCG2 activation can reproduce the protective rs7