定量检测神经退行性疾病患者脑脊液中的载脂蛋白 E 及其异构体。
Quantification of total apolipoprotein E and its isoforms in cerebrospinal fluid from patients with neurodegenerative diseases.
机构信息
Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
出版信息
Alzheimers Res Ther. 2020 Feb 13;12(1):19. doi: 10.1186/s13195-020-00585-7.
BACKGROUND
The human APOE gene, which codes for apolipoprotein E (apoE), has three major polymorphic alleles: ε2, ε3, and ε4 that give rise to amino acid substitutions. APOE-ε4 is a strong risk factor of sporadic Alzheimer's disease (AD) but the reason why is still unknown despite intense research for more than 20 years. The aim of the study was to investigate if the concentrations of total apoE and the specific apoE isoforms in cerebrospinal fluid (CSF) differ between various neurodegenerative diseases and control individuals, as well as among the APOE genotypes.
METHODS
Quantification of total apoE and specific apoE isoforms (E2, E3, and E4) in CSF was performed using high-resolution parallel reaction monitoring mass spectrometry. In total, 1820 individuals were involved in the study including clinically diagnosed AD patients (n = 228), cognitively unimpaired (CU) patients (n = 896), and patients with other neurodegenerative disorders (n = 696). Follow-up data was available for 100 individuals, assessed at two time points. Subjects were dichotomized based on an Aβ CSF concentration ratio cut-off into Aβ positive (Aβ+, < 0.091) and Aβ negative (Aβ-, > 0.091) groups.
RESULTS
Even though there was a significant increase of total apoE in the amyloid β-positive (Aβ+) group compared with amyloid β-negative (Aβ-) individuals (p < 0.001), the magnitude of the effect was very small (AUC = 0.55). Moreover, CSF total apoE concentrations did not differ between Aβ- CU controls and clinically diagnosed AD patients. There was a difference in concentration between isoforms in heterozygous individuals in an isoform-dependent manner (E2 < E3 < E4) (p < 0.001, AUC = 0.64-0.69), and these associations remained when dichotomizing the samples into Aβ+ and Aβ- groups (p < 0.01, AUC = 0.63-0.74). In the cohort with follow-up samples, neither total apoE nor isoform-specific apoE concentrations differed between the two time points (p > 0.05).
CONCLUSIONS
The results indicate that neither the concentrations of total apoE nor the different apoE isoforms in CSF are associated with APOE-ε4 carrier status, Aβ status, or clinical dementia diagnoses.
背景
人类载脂蛋白 E 基因（APOE）编码载脂蛋白 E（apoE），具有三个主要的多态性等位基因：ε2、ε3 和 ε4，它们导致氨基酸替换。APOE-ε4 是散发性阿尔茨海默病（AD）的一个强烈危险因素，但尽管 20 多年来进行了大量研究，其原因仍不清楚。本研究的目的是调查脑脊液（CSF）中总 apoE 浓度和特定 apoE 同工型（E2、E3 和 E4）是否在各种神经退行性疾病和对照个体之间以及在 APOE 基因型之间存在差异。
方法
使用高分辨率平行反应监测质谱法定量 CSF 中的总 apoE 和特定 apoE 同工型（E2、E3 和 E4）。共有 1820 名个体参与了这项研究，包括临床诊断的 AD 患者（n=228）、认知正常（CU）患者（n=896）和其他神经退行性疾病患者（n=696）。对 100 名个体进行了随访数据，在两个时间点进行评估。根据 Aβ CSF 浓度比值截止值将受试者分为 Aβ 阳性（Aβ+，<0.091）和 Aβ 阴性（Aβ-，>0.091）组。
结果
尽管与 Aβ 阴性（Aβ-）个体相比，淀粉样蛋白 β 阳性（Aβ+）组的总 apoE 显著增加（p<0.001），但效应幅度非常小（AUC=0.55）。此外，CSF 总 apoE 浓度在 Aβ- CU 对照和临床诊断的 AD 患者之间没有差异。在依赖同工型的方式中，杂合子个体的同工型浓度存在差异（E2<E3<E4）（p<0.001，AUC=0.64-0.69），当将样本分为 Aβ+和 Aβ-组时，这些关联仍然存在（p<0.01，AUC=0.63-0.74）。在具有随访样本的队列中，无论是总 apoE 还是同工型特异性 apoE 浓度在两个时间点之间都没有差异（p>0.05）。
结论
结果表明，CSF 中的总 apoE 浓度或不同 apoE 同工型与 APOE-ε4 携带状态、Aβ 状态或临床痴呆诊断均无关联。
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