➡ Upstream Target
alzheimers
✗ KILL CRITERIA
- ** Fine-mapping and conditional analysis reveals the AD association signal at the TREM2 locus is fully explained by a distinct causal variant in linkage disequilibrium (r² > 0.8) that does not alter TREM2 protein function, expression, or splicing, and Mendelian randomization using loss-of-function-proxy variants shows no causal effect on AD risk (IVW-OR = 1.0, 95% CI: 0.92–1.08).
- ** In multiple independent TREM2 loss-of-function models (CRISPR-Cas9 knockout in iPSC-derived microglia, Trem2−/− × 5×FAD or APP/PS1 crosses), amyloid plaque burden, soluble Aβ40/42 levels, microglial cluster density, and cognitive performance are indistinguishable from wild-type controls at 12+ months of age, with no significant effect on disease progression trajectory.
- ** Human genetic analysis of TREM2 loss-of-function carriers (nonsense, frameshift, or essential splice variants with >50% expected reduction in functional protein) shows no significant association with Alzheimer's disease risk (OR = 0.95, 95% CI: 0.88–1.03, p = 0.28), cognitive decline, or age at AD onset compared to non-carriers in cohorts >10,000 AD cases and >15,000 controls.