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Background/Objectives <p>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.</p> Methods <p>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.</p> Results <p>Meta-analyses revealed that both markers showed robust positive associations with pTau181, tTau and NfL (pooled <i>r</i> = 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.</p> Conclusions <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月30日

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  • Rachael Yu,
  • Anastasia Suraev,
  • Victor Vidal,
  • Shawn Kong,
  • Robert Zachariae,
  • Laura Piccio,
  • Michael T. Heneka,
  • Sharon L. Naismith,
  • Johannes C. Michaelian

摘要

Background/Objectives

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.

Methods

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.

Results

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.

Conclusions

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.