Neuroinflammation-mediated YKL-40 correlates with tau pathology and predicts longitudinal cognitive impairment and brain atrophy in Alzheimer's Disease, with hypertensive dependency

Ya-Yu WangMan ZhangShu-Jian ChenWei MiaoZhi-Xin WangYa-Jun ZhouSi-Qi YuZhongwu SunXia ZhouXian-Feng Yu^*Xiao-Qun Zhu^*

• First Affiliated Hospital of Anhui Medical University, Hefei, China

Background: Neuroinflammation 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) 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.Methods: This 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.Results: Higher 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 4 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.These 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.