Neuroinflammatory markers sTREM2 and YKL-40 in association with Alzheimer's disease pathology: a systematic review and meta-analysis

Neuroinflammation is increasingly recognised as a key feature of Alzheimer's Disease (AD) pathophysiology. Markers of glial reactivity, sTREM2 and YKL-40, are elevated in mild cognitive impairment (MCI) and AD, but their associations with core pathology across these stages have not yet been systematically investigated. This systematic review and meta-analysis examined their cross-sectional and longitudinal associations with core pathological biomarkers of AD, and examine how these relationships may evolve dynamically across the disease continuum.

A systematic literature search conducted across Medline, Embase, PsycINFO, PubMed and Scopus (PROSPERO: CRD420250653864) identified 42 studies for sTREM2 and 44 for YKL-40 that were included in this study.

Meta-analyses revealed that both markers showed robust positive associations with pTau181, tTau and NfL (pooled r = 0.31-0.55), including in covariate-adjusted correlations. In contrast, associations with Aβ pathology (CSF Aβ42/40, Aβ-PET) were weaker and not significant in covariate-adjusted estimates. Meta-regression analyses revealed that glial-tau associations were strongest in cognitively unimpaired (CU) individuals, and progressively weakened in MCI and AD, independent of age effects. Longitudinal data were limited and summarised descriptively; glial reactivity predicts increases in soluble CSF hyperphosphorylated tau pathology, yet is concurrently associated with slower accumulation of insoluble PET-detectable amyloid and tau aggregates.

Our findings indicate that sTREM2 and YKL-40 preferentially associate with tauopathy and neurodegeneration over pathological Aβ accumulation. The progressive attenuation of glial-pathology coupling may reflect glial saturation or "exhaustion" with disease progression, offering new insights into how impaired glial responses may be involved in AD pathophysiology.