CSF synaptic biomarkers in the preclinical stage of Alzheimer’s disease and their association with MRI and PET markers of neurodegeneration: a cross-sectional study

Objective: To determine whether CSF synaptic biomarkers are altered in the early preclinical stage of the Alzheimer’s continuum and associated with Alzheimer’s disease (AD) risk factors, primary pathology, and neurodegeneration markers. Methods: Cross-sectional study in the ALFA+ cohort, comprising middle-aged cognitively unimpaired participants. CSF neurogranin and GAP-43 were measured using immunoassays and SNAP-25 and synaptotagmin-1 using immunoprecipitation mass spectrometry. AD CSF biomarkers Aβ42/40, p-tau and t-tau, and the neurodegeneration biomarker NfL were also measured. Participants underwent structural MRI, and fluorodeoxyglucose and Aβ PET imaging. General linear modeling was used to test the associations between CSF synaptic biomarkers and risk factors, Aβ pathology, tau pathology, and neurodegeneration markers. Results: All CSF synaptic biomarkers increased with age. CSF neurogranin was higher in females, while CSF SNAP-25 was higher in APOE-ε4 carriers. All CSF s...研究目标：明确阿尔茨海默病连续体早期临床前阶段的脑脊液（Cerebrospinal Fluid, CSF）突触生物标志物是否发生异常改变，以及其与阿尔茨海默病（Alzheimer’s Disease, AD）危险因素、核心病理特征及神经退行性变标志物的关联。 研究方法：本研究为基于ALFA+队列的横断面研究，纳入中年认知功能正常的参与者。采用免疫测定法检测脑脊液中神经颗粒素（Neurogranin）与生长相关蛋白43（GAP-43）的表达水平；采用免疫沉淀质谱法检测突触相关蛋白25（SNAP-25）及突触结合蛋白1（Synaptotagmin-1）的表达水平。同时检测AD相关脑脊液生物标志物β淀粉样蛋白42/40（Aβ42/40）比值、磷酸化tau蛋白（p-tau）及总tau蛋白（t-tau），以及神经退行性变标志物神经丝轻链蛋白（NfL）。所有参与者均接受结构磁共振成像（Magnetic Resonance Imaging, MRI）、氟脱氧葡萄糖及β淀粉样蛋白（Aβ）正电子发射断层扫描（Positron Emission Tomography, PET）成像检查。采用广义线性模型检验脑脊液突触生物标志物与AD危险因素、Aβ病理、tau病理及神经退行性变标志物之间的关联。 研究结果：所有脑脊液突触生物标志物均随年龄增长呈升高趋势。女性受试者的脑脊液神经颗粒素水平更高，而载脂蛋白Eε4（APOE-ε4）携带者的脑脊液SNAP-25水平更高。所有脑脊液突触...