Proitsi P, Kim M, Whiley L, Pritchard M, Leung R, Soininen H, Kloszewska I, Mecocci P, Tsolaki M, Vellas B, Sham P, Lovestone S, Powell J F, Dobson R J B, Legido-Quigley C
Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Institute of Pharmaceutical Science, King's College London, London, UK.
Transl Psychiatry. 2015 Jan 13;5(1):e494. doi: 10.1038/tp.2014.127.
There is an urgent need for the identification of Alzheimer's disease (AD) biomarkers. Studies have now suggested the promising use of associations with blood metabolites as functional intermediate phenotypes in biomedical and pharmaceutical research. The aim of this study was to use lipidomics to identify a battery of plasma metabolite molecules that could predict AD patients from controls. We performed a comprehensive untargeted lipidomic analysis, using ultra-performance liquid chromatography/mass spectrometry on plasma samples from 35 AD patients, 40 elderly controls and 48 individuals with mild cognitive impairment (MCI) and used multivariate analysis methods to identify metabolites associated with AD status. A combination of 10 metabolites could discriminate AD patients from controls with 79.2% accuracy (81.8% sensitivity, 76.9% specificity and an area under curve of 0.792) in a novel test set. Six of the metabolites were identified as long chain cholesteryl esters (ChEs) and were reduced in AD (ChE 32:0, odds ratio (OR)=0.237, 95% confidence interval (CI)=0.10-0.48, P=4.19E-04; ChE 34:0, OR=0.152, 95% CI=0.05-0.37, P=2.90E-04; ChE 34:6, OR=0.126, 95% CI=0.03-0.35, P=5.40E-04; ChE 32:4, OR=0.056, 95% CI=0.01-0.24, P=6.56E-04 and ChE 33:6, OR=0.205, 95% CI=0.06-0.50, P=2.21E-03, per (log2) metabolite unit). The levels of these metabolites followed the trend control>MCI>AD. We, additionally, found no association between cholesterol, the precursor of ChE and AD. This study identified new ChE molecules, involved in cholesterol metabolism, implicated in AD, which may help identify new therapeutic targets; although, these findings need to be replicated in larger well-phenotyped cohorts.
迫切需要鉴定阿尔茨海默病（AD）的生物标志物。目前的研究表明，在生物医学和药物研究中，将血液代谢物的关联作为功能中间表型具有广阔前景。本研究的目的是利用脂质组学鉴定一系列能够区分AD患者与对照的血浆代谢物分子。我们采用超高效液相色谱/质谱法对35例AD患者、40例老年对照和48例轻度认知障碍（MCI）个体的血浆样本进行了全面的非靶向脂质组学分析，并使用多变量分析方法鉴定与AD状态相关的代谢物。在一个新的测试集中，10种代谢物的组合能够以79.2%的准确率区分AD患者与对照（灵敏度81.8%，特异性76.9%，曲线下面积0.792）。其中6种代谢物被鉴定为长链胆固醇酯（ChEs），在AD患者中含量降低（ChE 32:0，比值比（OR）=0.237，95%置信区间（CI）=0.10 - 0.48，P = 4.19E - 04；ChE 34:0，OR = 0.152，95% CI = 0.05 - 0.37，P = 2.90E - 04；ChE 34:6，OR = 0.126，95% CI = 0.03 - 0.35，P = 5.40E - 04；ChE 32:4，OR = 0.056，95% CI = 0.01 - 0.24，P = 6.56E - 04；ChE 33:6，OR = 0.205，95% CI = 0.06 - 0.50，P = 2.21E - 03，每（log2）代谢物单位）。这些代谢物的水平遵循对照>MCI>AD的趋势。此外，我们发现胆固醇（ChE的前体）与AD之间没有关联。本研究鉴定出参与胆固醇代谢且与AD相关的新ChE分子，这可能有助于确定新的治疗靶点；不过，这些发现需要在更大的、表型良好的队列中进行重复验证。
