背景:尚未完全确定血浆β-淀粉样蛋白(Aβ)42/Aβ40和磷酸化的Tau181(p-Tau181)是否可以有效检测中国老年人的阿尔茨海默病(AD)病理生理以及这些生物标志物如何与星形胶质细胞反应性相关,Aβ斑块沉积,tau缠结聚合,和神经变性。
方法:我们招募了470名老年人,分析了血浆Aβ42/Aβ40,p-Tau181,胶质纤维酸性蛋白(GFAP),和神经丝光(NfL)使用Simoa平台。其中,301、195和70接受了磁共振成像,Aβ和tau正电子发射断层扫描成像。根据受试者工作特征曲线分析,使用Youden指数,通过比较Aβ-PET阴性认知未受损个体和Aβ-PET阳性认知受损患者,将血浆Aβ42/Aβ40和p-Tau181阈值定义为≤0.0609和≥2.418。为了评估使用血浆Aβ42/Aβ40(A)和p-Tau181(T)检测AD的可行性,并了解星形胶质细胞反应性如何影响这一过程,我们比较了血浆GFAP,Aβ斑块,tau缠结,血浆NfL,海马体积,不同血浆A/T分布之间的时间-metaROI皮层厚度,并使用一般线性模型探索它们之间的关系,包括年龄,性别,APOE-ε4和诊断为协变量。
结果:血浆A+/T+个体显示出最高水平的星形胶质细胞反应性,Aβ斑块,tau缠结,和轴突变性,和最低的海马体积和颞叶ROI皮质厚度。较低的血浆Aβ42/Aβ40和较高的血浆p-Tau181与较高的血浆GFAP和Aβ斑块独立且协同相关。血浆p-Tau181和GFAP浓度升高与更多的tau缠结形成直接且相互作用地相关。关于神经变性,较高的血浆p-Tau181和GFAP浓度与更多的轴突变性密切相关,通过血浆NfL测量,较低的血浆Aβ42/Aβ40和较高的血浆p-Tau181与较大的海马萎缩有关。较高的血浆GFAP水平与较薄的皮质厚度相关,并与较低的血浆Aβ42/Aβ40和较高的血浆p-Tau181显着相互作用,以预测更多的时间-metaROI皮质变薄。体素成像分析证实了这些发现。
结论:这项研究为使用血浆生物标志物检测中国社区人群中的AD提供了有价值的参考,并提供了有关星形胶质细胞反应如何促进AD进展的新见解。强调靶向反应性星形胶质细胞增生预防AD的重要性。
BACKGROUND: It is not fully established whether plasma β-amyloid(Aβ)42/Aβ40 and phosphorylated Tau181 (p-Tau181) can effectively detect Alzheimer\'s disease (AD) pathophysiology in older Chinese adults and how these biomarkers correlate with astrocyte reactivity, Aβ plaque deposition, tau tangle aggregation, and neurodegeneration.
METHODS: We recruited 470 older adults and analyzed plasma Aβ42/Aβ40, p-Tau181, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) using the Simoa platform. Among them, 301, 195, and 70 underwent magnetic resonance imaging, Aβ and tau positron emission tomography imaging. The plasma Aβ42/Aβ40 and p-Tau181 thresholds were defined as ≤0.0609 and ≥2.418 based on the receiver operating characteristic curve analysis using the Youden index by comparing Aβ-PET negative cognitively unimpaired individuals and Aβ-PET positive cognitively impaired patients. To evaluate the feasibility of using plasma Aβ42/Aβ40 (A) and p-Tau181 (T) to detect AD and understand how astrocyte reactivity affects this process, we compared plasma GFAP, Aβ plaque, tau tangle, plasma NfL, hippocampal volume, and temporal-metaROI cortical thickness between different plasma A/T profiles and explored their relations with each other using general linear models, including age, sex, APOE-ε4, and diagnosis as covariates.
RESULTS: Plasma A+/T + individuals showed the highest levels of astrocyte reactivity, Aβ plaque, tau tangle, and axonal degeneration, and the lowest hippocampal volume and temporal-metaROI cortical thickness. Lower plasma Aβ42/Aβ40 and higher plasma p-Tau181 were independently and synergistically correlated with higher plasma GFAP and Aβ plaque. Elevated plasma p-Tau181 and GFAP concentrations were directly and interactively associated with more tau tangle formation. Regarding neurodegeneration, higher plasma p-Tau181 and GFAP concentrations strongly correlated with more axonal degeneration, as measured by plasma NfL, and lower plasma Aβ42/Aβ40 and higher plasma p-Tau181 were related to greater hippocampal atrophy. Higher plasma GFAP levels were associated with thinner cortical thickness and significantly interacted with lower plasma Aβ42/Aβ40 and higher plasma p-Tau181 in predicting more temporal-metaROI cortical thinning. Voxel-wise imaging analysis confirmed these findings.
CONCLUSIONS: This study provides a valuable reference for using plasma biomarkers to detect AD in the Chinese community population and offers novel insights into how astrocyte reactivity contributes to AD progression, highlighting the importance of targeting reactive astrogliosis to prevent AD.