To determine whether CSF synaptic biomarkers are altered in the early preclinical stage of the Alzheimer continuum and associated with Alzheimer disease (AD) risk factors, primary pathology, and neurodegeneration markers.

This cross-sectional study was performed in the Alzheimer's and Families (ALFA+) cohort, comprising middle-aged cognitively unimpaired participants. CSF neurogranin and growth-associated protein-43 (GAP-43) were measured with immunoassays, and synaptosomal-associated protein-25 (SNAP-25) and synaptotagmin-1 were measured with immunoprecipitation mass spectrometry. AD CSF biomarkers β-amyloid (Aβ)_42/40, phosphorylated tau (p-tau), and total tau and the neurodegeneration biomarker neurofilament light chain (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.

All CSF synaptic biomarkers increased with age. CSF neurogranin was higher in females, while CSF SNAP-25 was higher in APOE 4 carriers. All CSF synaptic biomarkers increased with higher Aβ load (as measured by CSF Aβ_42/40 and Aβ PET Centiloid values), and it is important to note that the synaptic biomarkers were increased even in individuals in the earliest stages of Aβ deposition. Higher CSF synaptic biomarkers were also associated with higher CSF p-tau and NfL. Higher CSF neurogranin and GAP-43 were significantly associated with higher brain metabolism but lower cortical thickness in AD-related brain regions.

CSF synaptic biomarkers increase in the early preclinical stages of the Alzheimer continuum even when a low burden of Aβ pathology is present, and they differ in their association with age, sex, APOE 4, and markers of neurodegeneration.

ClinicalTrials.gov Identifier NCT02485730.

确定脑脊液突触生物标志物是否在阿尔茨海默病连续体的早期临床前阶段发生改变，并与阿尔茨海默病 (AD) 危险因素、原发性病理学和神经退行性变标志物相关。

这项横断面研究是在阿尔茨海默氏症和家庭 (ALFA+) 队列中进行的，其中包括中年认知障碍的参与者。用免疫测定法测量脑脊液神经颗粒蛋白和生长相关蛋白 43 (GAP-43)，用免疫沉淀质谱法测量突触体相关蛋白 25 (SNAP-25) 和突触结合蛋白-1。还测量了AD CSF 生物标志物 β-淀粉样蛋白 (Aβ) _42/40、磷酸化 tau (p-tau) 和总 tau 和神经变性生物标志物神经丝轻链 (NfL)。参与者接受了结构 MRI 和氟脱氧葡萄糖和 Aβ PET 成像。一般线性模型用于测试 CSF 突触生物标志物与风险因素、Aβ 病理学、tau 病理学和神经变性标志物之间的关联。

所有 CSF 突触生物标志物都随着年龄的增长而增加。女性的 CSF 神经颗粒蛋白含量较高，而APOE 4 携带者的 CSF SNAP-25 含量较高。所有 CSF 突触生物标志物随着 Aβ 负荷的增加而增加（通过 CSF Aβ _42/40和 Aβ PET Centiloid 值测量），重要的是要注意，即使在 Aβ 沉积的最早阶段的个体中，突触生物标志物也会增加。较高的 CSF 突触生物标志物也与较高的 CSF p-tau 和 NfL 相关。较高的 CSF 神经颗粒素和 GAP-43 与较高的脑代谢显着相关，但与 AD 相关的脑区皮质厚度较低。

即使存在低 Aβ 病理负担，脑脊液突触生物标志物在阿尔茨海默病连续体的早期临床前阶段也会增加，并且它们与年龄、性别、APOE 4和神经变性标志物的关联不同。

ClinicalTrials.gov 标识符 NCT02485730。