Astrocytes can adopt multiple molecular phenotypes in the brain of Alzheimer’s disease (AD) patients. Here, we studied the associations of cerebrospinal fluid (CSF) glial fibrillary acidic protein (GFAP) and chitinase-3-like protein 1 (YKL-40) levels with brain amyloid-β (Aβ) and tau pathologies. We assessed 121 individuals across the aging and AD clinical spectrum with positron emission tomography (PET) brain imaging for Aβ ([¹⁸F]AZD4694) and tau ([¹⁸F]MK-6240), as well as CSF GFAP and YKL-40 measures. We observed that higher CSF GFAP levels were associated with elevated Aβ-PET but not tau-PET load. By contrast, higher CSF YKL-40 levels were associated with elevated tau-PET but not Aβ-PET burden. Structural equation modeling revealed that CSF GFAP and YKL-40 mediate the effects of Aβ and tau, respectively, on hippocampal atrophy, which was further associated with cognitive impairment. Our results suggest the existence of distinct astrocyte biomarker signatures in response to brain Aβ and tau accumulation, which may contribute to our understanding of the complex link between reactive astrogliosis heterogeneity and AD progression.

星形胶质细胞可以在阿尔茨海默病 (AD) 患者的大脑中采用多种分子表型。在这里，我们研究了脑脊液 (CSF) 神经胶质纤维酸性蛋白 (GFAP) 和几丁质酶 3 样蛋白 1 (YKL-40) 水平与脑淀粉样蛋白 -β (Aβ) 和 tau 病理的关联。我们使用 Aβ ([ ¹⁸ F]AZD4694) 和 tau ([ ¹⁸F]MK-6240)，以及 CSF GFAP 和 YKL-40 措施。我们观察到较高的 CSF GFAP 水平与 Aβ-PET 升高有关，但与 tau-PET 负荷无关。相比之下，较高的 CSF YKL-40 水平与升高的 tau-PET 相关，但与 Aβ-PET 负荷无关。结构方程模型显示 CSF GFAP 和 YKL-40 分别介导 Aβ 和 tau 对海马萎缩的影响，海马萎缩进一步与认知障碍相关。我们的结果表明存在不同的星形胶质细胞生物标志物特征以响应大脑 Aβ 和 tau 积累，这可能有助于我们理解反应性星形胶质细胞异质性和 AD 进展之间的复杂联系。