Neuroinflammation-mediated YKL-40 correlates with tau pathology and predicts longitudinal cognitive impairment and brain atrophy in Alzheimer’s disease, with hypertensive dependency
BackgroundNeuroinflammation and hypertension are involved in Alzheimer’s disease (AD). However, their independent and additive impacts on astrocytes and AD-related pathologies have not been fully explored. Hence, this study investigated whether the associations between astrocyte reactivity, measured...
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Frontiers Media S.A.
2025-08-01
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| Series: | Frontiers in Aging Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnagi.2025.1630022/full |
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| author | Ya-Yu Wang Man Zhang Shu-Jian Chen Wei Miao Zhi-Xin Wang Ya-Jun Zhou Si-Qi Yu Zhong-Wu Sun Xia Zhou Xian-Feng Yu Xiao-Qun Zhu |
| author_facet | Ya-Yu Wang Man Zhang Shu-Jian Chen Wei Miao Zhi-Xin Wang Ya-Jun Zhou Si-Qi Yu Zhong-Wu Sun Xia Zhou Xian-Feng Yu Xiao-Qun Zhu |
| author_sort | Ya-Yu Wang |
| collection | DOAJ |
| description | BackgroundNeuroinflammation and hypertension are involved in Alzheimer’s disease (AD). However, their independent and additive impacts on astrocytes and AD-related pathologies have not been fully explored. Hence, this study investigated whether the associations between astrocyte reactivity, measured by cerebrospinal fluid (CSF), Chitinase 3-like protein 1 (CHI3L1/YKL-40), and AD-related pathologies were mediated by neuroinflammation and whether these associations were modified by hypertension. We also investigated the influence of hypertension on the relationship between baseline levels of CSF YKL-40 and longitudinal changes in cognitive function and brain structures.MethodsThis study analyzed 288 participants from the AD Neuroimaging Initiative (ADNI) database. Multivariate linear regression, interaction, and subgroup analyses were conducted to explore the interrelationship between CSF YKL-40, AD biomarkers, neuroinflammation, cognitive function, and brain structures. Causal mediation analyses with 10,000 bootstrapped iterations were performed, using CSF YKL-40 as the independent variable and AD-related pathologies as the dependent variables, to explore mediation effects of neuroinflammation. Linear mixed-effects models were employed to study the associations between CSF YKL-40 and longitudinal changes in cognitive function and brain structures.ResultsHigher baseline CSF YKL-40 levels were correlated with higher p-tau, t-tau, and neuroinflammatory biomarkers (ICAM1, VCAM1, sTNFR1, and sTNFR2), but with lower entorhinal cortex volume. Interaction showed that hypertension had a moderating influence on the associations between CSF YKL-40 and p-tau and t-tau. The significant associations of CSF YKL-40 with p-tau and t-tau were partially mediated by neuroinflammatory biomarkers (ICAM1, VCAM1, sTNFR1, and sTNFR2) in the whole sample (proportions: 13.0%∼78.8%). Similarly, the partial mediation effects of VCAM1, sTNFR1, and sTNFR2 on the aforementioned associations also existed in hypertensive subgroup (proportions: 17.9%∼50.3%). Additionally, higher baseline levels of CSF YKL-40 predicted faster decline in cognitive performance and brain atrophy (volumes of whole brain, hippocampus, entorhinal cortex, and middle temporal lobe) in the whole sample. Notably, subgroup analyses showed that the associations between higher CSF YKL-40 and faster brain atrophy were pronounced in hypertensive individuals.ConclusionThese findings suggest that neuroinflammation may mediate the relationship between astrocyte reactivity, measured by CSF YKL-40, and AD-related pathologies, with significant hypertensive dependency. Furthermore, elevated baseline CSF YKL-40 levels accelerated cognitive decline and brain atrophy, particularly in hypertensive individuals. |
| format | Article |
| id | doaj-art-8c822d111d954aa99f32fa58f5756e88 |
| institution | Kabale University |
| issn | 1663-4365 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Aging Neuroscience |
| spelling | doaj-art-8c822d111d954aa99f32fa58f5756e882025-08-20T03:40:38ZengFrontiers Media S.A.Frontiers in Aging Neuroscience1663-43652025-08-011710.3389/fnagi.2025.16300221630022Neuroinflammation-mediated YKL-40 correlates with tau pathology and predicts longitudinal cognitive impairment and brain atrophy in Alzheimer’s disease, with hypertensive dependencyYa-Yu WangMan ZhangShu-Jian ChenWei MiaoZhi-Xin WangYa-Jun ZhouSi-Qi YuZhong-Wu SunXia ZhouXian-Feng YuXiao-Qun ZhuBackgroundNeuroinflammation and hypertension are involved in Alzheimer’s disease (AD). However, their independent and additive impacts on astrocytes and AD-related pathologies have not been fully explored. Hence, this study investigated whether the associations between astrocyte reactivity, measured by cerebrospinal fluid (CSF), Chitinase 3-like protein 1 (CHI3L1/YKL-40), and AD-related pathologies were mediated by neuroinflammation and whether these associations were modified by hypertension. We also investigated the influence of hypertension on the relationship between baseline levels of CSF YKL-40 and longitudinal changes in cognitive function and brain structures.MethodsThis study analyzed 288 participants from the AD Neuroimaging Initiative (ADNI) database. Multivariate linear regression, interaction, and subgroup analyses were conducted to explore the interrelationship between CSF YKL-40, AD biomarkers, neuroinflammation, cognitive function, and brain structures. Causal mediation analyses with 10,000 bootstrapped iterations were performed, using CSF YKL-40 as the independent variable and AD-related pathologies as the dependent variables, to explore mediation effects of neuroinflammation. Linear mixed-effects models were employed to study the associations between CSF YKL-40 and longitudinal changes in cognitive function and brain structures.ResultsHigher baseline CSF YKL-40 levels were correlated with higher p-tau, t-tau, and neuroinflammatory biomarkers (ICAM1, VCAM1, sTNFR1, and sTNFR2), but with lower entorhinal cortex volume. Interaction showed that hypertension had a moderating influence on the associations between CSF YKL-40 and p-tau and t-tau. The significant associations of CSF YKL-40 with p-tau and t-tau were partially mediated by neuroinflammatory biomarkers (ICAM1, VCAM1, sTNFR1, and sTNFR2) in the whole sample (proportions: 13.0%∼78.8%). Similarly, the partial mediation effects of VCAM1, sTNFR1, and sTNFR2 on the aforementioned associations also existed in hypertensive subgroup (proportions: 17.9%∼50.3%). Additionally, higher baseline levels of CSF YKL-40 predicted faster decline in cognitive performance and brain atrophy (volumes of whole brain, hippocampus, entorhinal cortex, and middle temporal lobe) in the whole sample. Notably, subgroup analyses showed that the associations between higher CSF YKL-40 and faster brain atrophy were pronounced in hypertensive individuals.ConclusionThese findings suggest that neuroinflammation may mediate the relationship between astrocyte reactivity, measured by CSF YKL-40, and AD-related pathologies, with significant hypertensive dependency. Furthermore, elevated baseline CSF YKL-40 levels accelerated cognitive decline and brain atrophy, particularly in hypertensive individuals.https://www.frontiersin.org/articles/10.3389/fnagi.2025.1630022/fullAlzheimer’s diseaseastrocyte reactivityYKL-40neuroinflammationhypertension |
| spellingShingle | Ya-Yu Wang Man Zhang Shu-Jian Chen Wei Miao Zhi-Xin Wang Ya-Jun Zhou Si-Qi Yu Zhong-Wu Sun Xia Zhou Xian-Feng Yu Xiao-Qun Zhu Neuroinflammation-mediated YKL-40 correlates with tau pathology and predicts longitudinal cognitive impairment and brain atrophy in Alzheimer’s disease, with hypertensive dependency Frontiers in Aging Neuroscience Alzheimer’s disease astrocyte reactivity YKL-40 neuroinflammation hypertension |
| title | Neuroinflammation-mediated YKL-40 correlates with tau pathology and predicts longitudinal cognitive impairment and brain atrophy in Alzheimer’s disease, with hypertensive dependency |
| title_full | Neuroinflammation-mediated YKL-40 correlates with tau pathology and predicts longitudinal cognitive impairment and brain atrophy in Alzheimer’s disease, with hypertensive dependency |
| title_fullStr | Neuroinflammation-mediated YKL-40 correlates with tau pathology and predicts longitudinal cognitive impairment and brain atrophy in Alzheimer’s disease, with hypertensive dependency |
| title_full_unstemmed | Neuroinflammation-mediated YKL-40 correlates with tau pathology and predicts longitudinal cognitive impairment and brain atrophy in Alzheimer’s disease, with hypertensive dependency |
| title_short | Neuroinflammation-mediated YKL-40 correlates with tau pathology and predicts longitudinal cognitive impairment and brain atrophy in Alzheimer’s disease, with hypertensive dependency |
| title_sort | neuroinflammation mediated ykl 40 correlates with tau pathology and predicts longitudinal cognitive impairment and brain atrophy in alzheimer s disease with hypertensive dependency |
| topic | Alzheimer’s disease astrocyte reactivity YKL-40 neuroinflammation hypertension |
| url | https://www.frontiersin.org/articles/10.3389/fnagi.2025.1630022/full |
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