Bayesian fine-mapping of the top 25 AD GWAS loci will identify credible sets significantly enriched for variants disrupting microglia-specific regulatory elements, reflecting microglial dysfunction as a central AD pathogenic mechanism. Credible sets at loci with known effector genes (APOE, TREM2, PLCG2) will be smaller (<10 variants) due to stronger functional constraints, while novel loci will have larger sets requiring integration with epigenomic data to prioritize causal variants. The highest
TREM2 signaling controls the spatial distribution of complement regulators CD55 and CD46 on synaptic membranes, determining which synapses are vulnerable to complement-mediated pruning. Under normal conditions, TREM2 activation promotes the expression and clustering of CD55/CD46 at perisomatic inhibitory synapses through DAM pathway signaling, while maintaining low regulator density at distal excitatory synapses. This creates a protective gradient where inhibitory circuits are preserved while al
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.
TREM2NeuroinflammationUnspecified Mechanism
Convergent signals
TREM2 recurs across 2 selected hypotheses with aligned directionality in neuroinflammation, unspecified mechanism.
Divergent signals
No direct polarity conflicts detected among the selected hypotheses.
Verdict Summary
5/11
dimensions won
AD fine-mapping identifies causal varian
6/11
dimensions won
TREM2-Mediated Spatial Redistribution of
Radar Chart — 10 Dimensions
Score Comparison Bars
Mechanistic
0.86
0.75
Evidence
0.72
0.33
Novelty
0.68
0.00
Feasibility
0.85
0.00
Impact
0.00
0.00
Druggability
0.00
0.70
Safety
0.00
0.50
Competition
0.00
0.80
Data
0.00
0.55
Reproducible
0.00
0.72
KG Connect
0.50
0.50
Score Breakdown
Dimension
AD fine-mapping identifies cau
TREM2-Mediated Spatial Redistr
Mechanistic
0.860
0.750
Evidence
0.720
0.325
Novelty
0.680
0.000
Feasibility
0.850
0.000
Impact
0.000
0.000
Druggability
0.000
0.700
Safety
0.000
0.500
Competition
0.000
0.800
Data
0.000
0.550
Reproducible
0.000
0.720
KG Connect
0.500
0.500
Evidence
AD fine-mapping identifies causal variants in microglia-spec
No evidence citations yet
TREM2-Mediated Spatial Redistribution of Complement Regulato
No evidence citations yet
Debate Excerpts
TREM2-Mediated Spatial Redistribution of Complemen
4 rounds · quality: 0.75
Theorist
# Therapeutic Hypotheses: Selectivity of Complement-Mediated Synaptic Elimination During Prolonged Anesthesia
---
## Hypothesis 1: Activity-Dependent Synaptic Tagging via CREB-BDNF TrkB Signaling
*...
Skeptic
# Critical Evaluation of Hypotheses for Complement-Mediated Synaptic Selectivity
## Overview
These hypotheses address a legitimate gap in understanding how C1q distinguishes between synapses for eli...
Domain Expert
# Feasibility Assessment: Selectivity Mechanisms in Anesthesia-Induced Synaptic Elimination
## Executive Summary
The central question—whether specific synapses become targets for complement-mediated...
Synthesizer
{
"ranked_hypotheses": [
{
"title": "Differential Complement Regulator Expression on Synaptic Membranes (CD55/CD46)",
"description": "Excitatory synapses on specific neuronal compart...