German Center for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1, 53127, Bonn, Germany.
Department of Neurodegenerative Disease and Geriatric Psychiatry, University of Bonn Medical Center, Venusberg-Campus 1, 53127, Bonn, Germany.
Alzheimers Res Ther. 2023 Jan 12;15(1):13. doi: 10.1186/s13195-022-01118-0.
Neuroinflammation constitutes a pathological hallmark of Alzheimer's disease (AD). Still, it remains unresolved if peripheral inflammatory markers can be utilized for research purposes similar to blood-based beta-amyloid and neurodegeneration measures. We investigated experimental inflammation markers in serum and analyzed interrelations towards AD pathology features in a cohort with a focus on at-risk stages of AD.
Data of 74 healthy controls (HC), 99 subjective cognitive decline (SCD), 75 mild cognitive impairment (MCI), 23 AD relatives, and 38 AD subjects were obtained from the DELCODE cohort. A panel of 20 serum biomarkers was determined using immunoassays. Analyses were adjusted for age, sex, APOE status, and body mass index and included correlations between serum and CSF marker levels and AD biomarker levels. Group-wise comparisons were based on screening diagnosis and routine AD biomarker-based schematics. Structural imaging data were combined into composite scores representing Braak stage regions and related to serum biomarker levels. The Preclinical Alzheimer's Cognitive Composite (PACC5) score was used to test for associations between the biomarkers and cognitive performance.
Each experimental marker displayed an individual profile of interrelations to AD biomarkers, imaging, or cognition features. Serum-soluble AXL (sAXL), IL-6, and YKL-40 showed the most striking associations. Soluble AXL was significantly elevated in AD subjects with pathological CSF beta-amyloid/tau profile and negatively related to structural imaging and cognitive function. Serum IL-6 was negatively correlated to structural measures of Braak regions, without associations to corresponding IL-6 CSF levels or other AD features. Serum YKL-40 correlated most consistently to CSF AD biomarker profiles and showed the strongest negative relations to structure, but none to cognitive outcomes.
Serum sAXL, IL-6, and YKL-40 relate to different AD features, including the degree of neuropathology and cognitive functioning. This may suggest that peripheral blood signatures correspond to specific stages of the disease. As serum markers did not reflect the corresponding CSF protein levels, our data highlight the need to interpret serum inflammatory markers depending on the respective protein's specific biology and cellular origin. These marker-specific differences will have to be considered to further define and interpret blood-based inflammatory profiles for AD research.
神经炎症是阿尔茨海默病（AD）的病理标志之一。然而，外周炎症标志物是否可以用于研究，类似于基于血液的β-淀粉样蛋白和神经退行性变测量，仍未得到解决。我们研究了血清中的实验性炎症标志物，并在一个重点关注 AD 高危阶段的队列中分析了它们与 AD 病理特征的相互关系。
从 DELCODE 队列中获得了 74 名健康对照（HC）、99 名主观认知下降（SCD）、75 名轻度认知障碍（MCI）、23 名 AD 亲属和 38 名 AD 患者的数据。使用免疫测定法测定了 20 种血清生物标志物的含量。分析结果经过年龄、性别、APOE 状态和体重指数的调整，并包括了血清和 CSF 标志物水平与 AD 生物标志物水平之间的相关性。组间比较基于筛选诊断和常规 AD 生物标志物方案。将结构成像数据组合成代表 Braak 阶段区域的综合评分，并与血清生物标志物水平相关联。使用 Preclinical Alzheimer's Cognitive Composite（PACC5）评分来测试生物标志物与认知表现之间的关联。
每种实验性标志物与 AD 生物标志物、成像或认知特征的相互关系都呈现出独特的特征。血清可溶性 AXL（sAXL）、IL-6 和 YKL-40 表现出最显著的相关性。在具有病理性 CSF β-淀粉样蛋白/tau 特征的 AD 患者中，可溶性 AXL 显著升高，并与结构成像和认知功能呈负相关。血清 IL-6 与 Braak 区域的结构测量呈负相关，与相应的 IL-6 CSF 水平或其他 AD 特征无关。血清 YKL-40 与 CSF AD 生物标志物特征最一致地相关，与结构呈最强的负相关，但与认知结果无关。
血清 sAXL、IL-6 和 YKL-40 与 AD 的不同特征有关，包括神经病理学程度和认知功能。这可能表明外周血标志物与疾病的特定阶段相对应。由于血清标志物不能反映相应的 CSF 蛋白水平，因此我们的数据强调了需要根据相应蛋白质的特定生物学和细胞起源来解释炎症标志物。在进一步定义和解释 AD 研究中的基于血液的炎症谱时，需要考虑这些标志物特异性的差异。
