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

Abstract Background Neuroinflammation is increasingly recognised as a key feature of Alzheimer’s Disease (AD) pathophysiology. Two novel markers of glial reactivity, soluble Triggering Receptor Expressed on Myeloid Cells 2 (sTREM2) and Chitinase-3-like protein 1 (YKL-40), are elevated in mild cognitive impairment (MCI) and AD. This systematic review and meta-analysis aimed to investigate their cross-sectional and longitudinal associations with established AD biomarkers, and examine how these relationships may evolve dynamically across the disease continuum. Methods A systematic literature search was conducted across Medline, Embase, PsycINFO, PubMed and Scopus (PROSPERO registration: CRD420250653864). Pooled effect sizes for the cross-sectional unadjusted ( r ) and covariate-adjusted ( r p ) correlations of sTREM2 and YKL-40 with biomarkers of AD in cerebrospinal fluid (CSF) and Positron Emission Tomography (PET) were estimated with meta-analysis. Meta-regressions assessed whether these associations varied across cognitively unimpaired (CU), MCI and AD subgroups. Longitudinal data were limited and summarised descriptively. Results A total of 42 studies for sTREM2 and 44 for YKL-40 were included in the review. Both markers showed robust positive associations with AD-specific tau pathology (pTau181) and non-specific neuronal injury (tTau, NfL) (pooled r ranging 0.31–0.55, all p < .01), including in covariate-adjusted correlations. In contrast, associations with amyloid pathology (CSF Aβ42/40 and Aβ-PET) were weaker and not significant in covariate-adjusted estimates. Longitudinal evidence suggests that glial reactivity predicts increases in soluble CSF tau pathology, yet is concurrently associated with slower accumulation of insoluble PET-detectable amyloid and tau aggregates. Notably, the strength of the glial-tau associations was strongest in CU individuals, and progressively weakened in MCI and AD, independent of age effects. Conclusions The findings indicate a preferential association of sTREM2 and YKL-40 with tauopathy and neurodegenerative processes over amyloid accumulation. Notably, the progressive attenuation of glial-pathology coupling across clinical stages may reflect a saturation or “exhaustion” of the physiological glial response with disease progression. The results offer new insights into how impaired glial reactivity may be involved in AD pathophysiology.