Association of sTREM2 and YKL-40 With Alzheimer's Disease Progression: A Systematic Review.

Neuroinflammation is recognized as a core feature of Alzheimer's disease (AD). Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) and chitinase-3-like protein 1 (YKL-40) are fluid biomarkers of microglial and astrocytic reactivity associated with AD progression. However, their coupling to amyloid and tau pathology, stage-specific roles, and prognostic utility remain unclear. This systematic review synthesized evidence from 2021 to 2025 on associations of sTREM2 and YKL-40 with AD progression. This review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. PubMed/Medical Literature Analysis and Retrieval System Online (MEDLINE), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Institute of Electrical and Electronics Engineers (IEEE) Xplore, and Web of Science were searched (Jan 2021-Dec 2025), with citation searching. Duplicates were removed using EndNote X21 (Clarivate, London, UK). Two independent reviewers screened records using the Population, Intervention, Comparison, Outcomes, and Study Design (PICOS) criteria, with disagreements resolved by a third reviewer. Original human studies measuring sTREM2 and/or YKL-40 across the AD spectrum were included. Methodological quality was assessed using the Newcastle-Ottawa Scale (NOS). Due to heterogeneity in study design and outcomes, a narrative synthesis was performed. Thirteen studies were included: seven on sTREM2, five on YKL-40, and one on both. Six were low risk of bias, and seven were moderate. Cerebrospinal fluid (CSF) sTREM2 showed a biphasic pattern across disease stages, with early potential neuroprotective associations and later correlation with cortical atrophy and cognitive decline. A sex-APOE ε4 interaction was observed, with higher levels in female carriers. YKL-40 showed weak amyloid associations but strong coupling with tau pathology and neurodegeneration, influenced by vascular risk factors. Plasma YKL-40 predicted incident dementia and cognitive decline, and serum YKL-40 differentiated early dementia from controls with good diagnostic performance. sTREM2 and YKL-40 represent biologically distinct but complementary neuroinflammatory pathways in AD. sTREM2 reflects a stage-dependent microglial response, while YKL-40 reflects tau-associated astrocytic activation modulated by vascular factors. Longitudinal studies with concurrent biomarker assessment are needed to clarify their combined prognostic value.