YKL-40 Emerges as a Key Indicator of Neuroinflammatory-Driven Tau Pathology and Brain Atrophy in Alzheimer’s Disease

Alzheimer's disease (AD) is increasingly understood as a multifaceted disorder involving not only amyloid and tau pathology, but also significant contributions from neuroinflammation and vascular dysfunction. In particular, astrocyte reactivity has gained attention as both a driver and a marker of neuroinflammatory cascades that shape disease progression. One of the most promising biomarkers of reactive astrocytosis is Chitinase-3-like protein 1 (CHI3L1), or YKL-40, a glycoprotein secreted by astrocytes that regulates extracellular matrix remodeling, angiogenesis, and immune responses in the CNS.

Elevated levels of YKL-40 in cerebrospinal fluid (CSF) have been associated with tau pathology, vascular inflammation, and progressive cognitive decline. Unlike GFAP, which is more closely tied to Aβ pathology, YKL-40 appears to reflect downstream mechanisms driven by neuroinflammation and tau accumulation. Vascular risk factors, especially hypertension, may further exacerbate these processes, positioning YKL-40 at the intersection of glial biology, vascular integrity, and neurodegeneration.

With recent launch of the Quanterix Simoa^® YKL-40 assay, researchers now have access to a highly sensitive tool to explore the mechanistic and clinical value of this astrocytic marker, the marker of focus in the new publication by Wang et al. (2025).

Study Overview: Wang et al., 2025 (Front. Aging Neurosci.)

This study utilized cross-sectional and longitudinal data from 288 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) and sought to address four key research aims:

1. Assess the Relationship Between CSF YKL-40 and AD Pathology

Wang et al. found that higher CSF YKL-40 levels were significantly associated with increased levels of p-tau and t-tau, but not Aβ42. YKL-40 was also positively correlated with neuroinflammatory markers such as sTNFR1, sTNFR2, VCAM1, and ICAM1. These findings reinforce the notion that YKL-40 captures a tau-centric, inflammation-driven axis of AD pathology, rather than amyloid-related processes. A marginal association was observed between YKL-40 and reduced entorhinal cortex volume, suggesting a potential structural correlate.

2. Determine Whether Risk Factors Modify These Associations

Hypertension emerged as a critical modifier of the relationship between YKL-40 and tau pathology. Specifically, the association between YKL-40 and p-tau was significant only in hypertensive individuals, while the link with t-tau was strengthened in this group. In contrast, no moderating effects were observed for sex, age, APOE ε4 status, or Aβ status, highlighting the unique role of vascular comorbidity in amplifying astrocyte-driven neurodegeneration.

3. Investigate Neuroinflammation as a Mediating Mechanism

Mediation analyses showed that the relationship between YKL-40 and tau pathology was partially mediated by key neuroinflammatory markers, particularly VCAM1, sTNFR1, and sTNFR2. These mediating effects were strongest in hypertensive individuals, suggesting that YKL-40 may signal a glial-vascular inflammatory loop that drives tau accumulation in the context of vascular risk.

4. Evaluate the Predictive Value of YKL-40 for Cognitive Decline and Brain Atrophy

Longitudinal analyses revealed that higher baseline CSF YKL-40 predicted faster decline in multiple cognitive domains, including memory, language, and visuospatial function. Elevated YKL-40 levels were also associated with accelerated atrophy in key AD-related brain regions, the hippocampus, entorhinal cortex, middle temporal lobe, and whole brain. These effects were most pronounced in hypertensive individuals and in biomarker-positive cognitively normal subjects (A+ CN), indicating that YKL-40 may have strong prognostic value even in preclinical stages of disease.

Scientific and Clinical Implications

Collectively, these findings position YKL-40 as a distinct and mechanistically informative biomarker that reflects the convergence of astrocyte reactivity, vascular dysfunction, and tau-mediated neurodegeneration. Its ability to both signal current disease state and predict future cognitive and structural decline underscores its clinical utility for patient stratification, therapeutic monitoring, and early intervention, particularly in patients with comorbid hypertension.

Quanterix Perspective

The newly released Simoa^® YKL-40 assay now offers researchers and clinicians a critical tool to interrogate this emerging biomarker with unmatched sensitivity and reproducibility. When used alongside traditional AD biomarkers, YKL-40 adds valuable insight into the neuroinflammatory landscape of disease and may enable earlier detection of at-risk individuals, especially those with modifiable vascular risk factors. As astrocytic inflammation gains prominence in neurodegenerative research, Quanterix is proud to support the field with biomarker assays that reflect not just pathology, but biology.

Citation:

Wang Y-Y et al. Neuroinflammation-mediated YKL-40 correlates with tau pathology and predicts longitudinal cognitive impairment and brain atrophy in Alzheimer's disease, with hypertensive dependency. Front. Aging Neurosci. 17:1630022 (2025). https://doi.org/10.3389/fnagi.2025.1630022