argument

## TREM2 Showcase Synthesis

**Core verdict:** TREM2 is a legitimate but timing-sensitive AD target requiring biomarker-guided, stage-specific therapeutic modulation.

**Mechanistic consensus:** TREM2→TYROBP→SYK→PI3K/AKT drives microglial metabolic fitness and phagocytosis. APOE is a TREM2 ligand; APOE4 reduces TREM2 binding ~50%.

**Therapeutic verdict:** TREM2 agonism is scientifically justified but INVOKE-2 failure suggests the field needs better patient selection and earlier intervention. APOE4-TREM2 co-targeting is the most promising combination strategy.

**Top hypotheses:** 1. TREM2-mediated microglial dysfunction (0.812), 2. TREM2 agonism to redirect APOE4 microglia (0.887), 3. CSF sTREM2 biomarker (0.801).