Site-specific TREM2 cleavage fragments (N-terminal vs C-terminal ratios) serve as the primary readout for microglial priming state, with CHI3L1 (YKL-40) and neurogranin as confirmatory cascade markers that validate the temporal sequence of neuroinflammation. The mechanistic foundation centers on ADAM10/17-mediated TREM2 shedding as the proximal event that defines microglial transition from homeostatic surveillance to priming phase. This transition triggers downstream CHI3L1 expression and synaptic neurogranin release, creating a predictable biomarker sequence. The fragment ratio approach provides direct molecular specificity - different ADAM protease activities generate distinct TREM2 cleavage patterns that correspond to specific microglial activation states. CHI3L1 elevation confirms that primed microglia have initiated inflammatory signaling, while neurogranin elevation indicates that synaptic damage has begun. This three-marker panel creates a mechanistically-linked temporal map: TREM2 fragment shifts occur first during microglial state transition, CHI3L1 rises during inflammatory amplification, and neurogranin appears during synaptic vulnerability.

Site-specific TREM2 cleavage fragments (N-terminal vs C-terminal ratios) serve as the primary readout for microglial priming state, with CHI3L1 (YKL-40) and neurogranin as confirmatory cascade markers that validate the temporal sequence of neuroinflammation. The mechanistic foundation centers on ADAM10/17-mediated TREM2 shedding as the proximal event that defines microglial transition from homeostatic surveillance to priming phase. This transition triggers downstream CHI3L1 expression and synaptic neurogranin release, creating a predictable biomarker sequence. The fragment ratio approach provides direct molecular specificity - different ADAM protease activities generate distinct TREM2 cleavage patterns that correspond to specific microglial activation states. CHI3L1 elevation confirms that primed microglia have initiated inflammatory signaling, while neurogranin elevation indicates that synaptic damage has begun. This three-marker panel creates a mechanistically-linked temporal map: TREM2 fragment shifts occur first during microglial state transition, CHI3L1 rises during inflammatory amplification, and neurogranin appears during synaptic vulnerability. The approach maintains direct therapeutic relevance because TREM2 fragment ratios can guide timing of TREM2-targeted interventions, while the confirmatory markers reduce false positives from technical variability in mass spectrometry-based fragment quantification. Unlike composite scoring algorithms that obscure individual marker contributions, this hierarchical approach preserves mechanistic interpretability while providing the statistical robustness of multi-analyte measurement. The primary clinical utility lies in identifying the narrow therapeutic window when microglia are primed but synaptic damage remains reversible.