Resolve: TREM2-Deficient Microglia as Drivers of Amyloid Plaque Toxicity in Alzheimer's Disease

Challenge generated from hypothesis h-44b1c9d415 (composite_score=0.817). Target gene/pathway: TREM2. Source hypothesis: TREM2-Deficient Microglia as Drivers of Amyloid Plaque Toxicity in Alzheimer's Disease. ## Falsifiable Predictions 1. TREM2-KO microglia show >50% reduction in amyloid-beta uptake vs WT in primary culture phagocytosis assay. 2. TREM2 agonist treatment (AL002c or equivalent) restores amyloid plaque clustering (IBA1+ processes) to WT levels (>40% increase vs TREM2-KO). 3. PS19 tau mouse crossed with TREM2-KO shows >30% increase in tau burden vs PS19 alone at 9 months. 4. TREM2 agonist reduces CSF tau (p-tau181) by >20% in humanised TREM2-R47H knock-in mouse model after 8 weeks.