Apolipoprotein E Genotype and the Diagnostic Accuracy of Cerebrospinal Fluid Biomarkers for Alzheimer Disease
Apolipoprotein E Genotype and the Diagnostic Accuracy of Cerebrospinal Fluid Biomarkers for Alzheimer Disease
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DOI：
10.1001/jamapsychiatry.2014.1060
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发表时间：
2014-10-01
期刊：
影响因子：
25.8
通讯作者：
Hansson, Oskar
中科院分区：
文献类型：
--
作者：
Lautner, Ronald;Palmqvist, Sebastian;Hansson, Oskar
重要性几项研究表明，载脂蛋白E(APOE)epsilon 4等位基因调节脑脊液(CSF)中β-淀粉样蛋白42(Aβ42)的水平。这种影响是否次要于APOE epsilon 4等位基因与皮质Aβ沉积的关联，或者APOE epsilon 4是否独立于Aβ病理直接影响脑脊液Aβ42水平尚不清楚。目的评估APOE基因是否影响脑脊液生物标志物对阿尔茨海默病(AD)的诊断准确性，特别是Aβ42水平，以及APOE epsilon 4与脑脊液生物标志物的相关性是否取决于皮质Aβ状态。设计、设置和参与者我们从瑞典、芬兰和德国的4个不同中心收集了数据。队列A包括1345名年龄在23~99岁的基线脑脊液样本，包括309名AD患者、287名先兆AD患者、399名稳定性轻度认知障碍患者、99名AD以外的痴呆患者和251名对照。队列B包括105名非痴呆的年轻人(年龄20-34岁)，可获得脑脊液样本。队列C包括118名年龄在60-80岁之间、有轻度认知症状的患者，他们接受了氟美他莫F18([F-18]flumetamol)正电子发射断层扫描、淀粉样蛋白成像和脑脊液扫描。主要结果和测量不同诊断组以及皮质摄取[F-18]氟美他莫的患者脑脊液中Aβ42、总tau和磷酸化tau水平与APOE epsilon 2/epsilon 3/epsilon 4基因多态性的关系。尽管如此，AD患者的脑脊液中Aβ42的水平与对照组和轻度认知损害稳定型患者相比仍有差异，即使按APOE基因进行分层时也是如此(P<；.001至P=.006)。多因素Logistic回归分析显示，脑脊液中Aβ42和apoE epsilon 4基因水平是AD诊断的独立预测因素。在队列B中，载脂蛋白E epsilon 4携带者状态不影响脑脊液中Aβ42的水平。此外，当在队列C中对[F-18]氟美他莫的皮质摄取进行分层时，APOE epsilon 4基因不影响脑脊液中Aβ42的水平。这一结果在阿尔茨海默病神经成像倡议(ADNI)的一个队列中重复，使用碳11标记的匹兹堡化合物B扫描。结论脑脊液中Aβ42的水平与AD的诊断和皮质Aβ蓄积密切相关，与APOE基因无关。所有APOE基因型脑脊液Aβ42水平的临界值应该是相同的。
IMPORTANCE Several studies suggest that the apolipoprotein E (APOE) epsilon 4 allele modulates cerebrospinal fluid (CSF) levels of beta-amyloid 42 (A beta 42). Whether this effect is secondary to the association of the APOE epsilon 4 allele with cortical A beta deposition or whether APOE epsilon 4 directly influences CSF levels of A beta 42 independently of A beta pathology remains unknown.OBJECTIVE To evaluate whether the APOE genotype affects the diagnostic accuracy of CSF biomarkers for Alzheimer disease (AD), in particular A beta 42 levels, and whether the association of APOE epsilon 4 with CSF biomarkers depends on cortical A beta status.DESIGN, SETTING, AND PARTICIPANTS We collected data from 4 different centers in Sweden, Finland, and Germany. Cohort A consisted of 1345 individuals aged 23 to 99 years with baseline CSF samples, including 309 with AD, 287 with prodromal AD, 399 with stable mild cognitive impairment, 99 with dementias other than AD, and 251 controls. Cohort B included 105 nondemented younger individuals (aged 20-34 years) with CSF samples available. Cohort C included 118 patients aged 60 to 80 years with mild cognitive symptoms who underwent flutemetamol F 18 ([F-18] flumetamol) positron emission tomography amyloid imaging and CSF tap.EXPOSURES Standard care.MAIN OUTCOMES AND MEASURES Cerebrospinal fluid levels of A beta 42 and total and phosphorylated tau in relation to the APOE epsilon 2/epsilon 3/epsilon 4 polymorphism in different diagnostic groups and in cases with or without cortical uptake of [F-18] flutemetamol.RESULTS The CSF levels of A beta 42 but not total and phosphorylated tau were lower in APOE epsilon 4 carriers compared with noncarriers irrespective of diagnostic group (cohort A). Despite this, CSF levels of A beta 42 differed between participants with AD when compared with controls and those with stable mild cognitive impairment, even when stratifying for APOE genotype (P < .001 to P = .006). Multiple binary logistic regression revealed that CSF levels of A beta 42 and APOE epsilon 4 genotype were independent predictors of AD diagnosis. In cohort B, APOE epsilon 4 carrier status did not influence CSF levels of A beta 42. Moreover, when stratifying for cortical uptake of [F-18] flutemetamol in cohort C, APOE epsilon 4 genotype did not influence CSF levels of A beta 42. This result was replicated in a cohort with individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI) using carbon 11-labeled Pittsburgh Compound B scanning.CONCLUSIONS AND RELEVANCE Cerebrospinal fluid levels of A beta 42 are strongly associated with the diagnosis of AD and cortical A beta accumulation independent of APOE genotype. The clinical cutoff for CSF levels of A beta 42 should be the same for all APOE genotypes.