TREM2 Function in Alzheimer's Disease — From Risk Variant to Therapeutic Target

SUMMARY

# TREM2 Function in Alzheimer's Disease — From Risk Variant to Therapeutic Target ## Background and Rationale TREM2 (Triggering Receptor Expressed on Myeloid cells 2) is a critical microglial receptor whose R47H variant confers 3-fold increased Alzheimer's disease (AD) risk, representing the second strongest genetic risk factor after APOE4. Despite its clinical importance, the mechanistic basis for how TREM2 R47H disrupts microglial function and promotes AD pathogenesis remains poorly understood

METHODOLOGY NOTES

Phase 1 (Weeks 1-8): Generate iPSC-derived microglia from n=20 TREM2 R47H carriers and n=20 matched controls using established protocols. Differentiate iPSCs through hematopoietic intermediates using cytokine cocktails (M-CSF, IL-34, TGF-β1, CD200). Phase 2 (Weeks 9-12): Isolate primary human microglia from fresh post-mortem tissue (n=15 R47H, n=15 controls) within 6 hours of death using CD11b+ magnetic separation. Maintain cultures in serum-free medium with M-CSF (50ng/mL) and GM-CSF (10ng/mL). Phase 3 (Weeks 13-16): Establish human cortical organoids from iPSCs and co-culture with patient-matched microglia at 1:10 ratio. Phase 4 (Weeks 17-20): Functional characterization including: phagocytosis assays using fluorescent Aβ42 oligomers (0.5μM, 2-24hr timepoints), cytokine profiling via Luminex 25-plex panel, single-cell RNA-seq (10X Genomics platform, target 5000 cells/condition). Phase 5 (Weeks 21-24): Therapeutic validation testing TREM2 agonist antibodies (4D9, AL002A at 1-10μg/mL)