APOE4 Copy Number-Dependent Proteomic Changes in the Cerebrospinal Fluid.
APOE4 Copy Number-Dependent Proteomic Changes in the Cerebrospinal Fluid.
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DOI：
10.3233/jad-200747
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
and Alzheimer’s Disease Neuroimaging Initiative
中科院分区：
文献类型：
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作者：
Berger M;Cooter M;Roesler AS;Chung S;Park J;Modliszewski JL;VanDusen KW;Thompson JW;Moseley A;Devinney MJ;Smani S;Hall A;Cai V;Browndyke JN;Lutz MW;Corcoran DL;and Alzheimer’s Disease Neuroimaging Initiative
APOE 4已被假设通过增加神经炎症来增加阿尔茨海默病的风险，尽管所涉及的具体神经炎症途径尚不清楚。表征与APOE 4拷贝数相关的脑脊液（CSF）蛋白质组学变化。我们使用调整了年龄、性别和APOE 4拷贝数的线性回归模型，以及也调整了AD临床状态或CSF Aβ、tau或p-tau水平的其他线性模型，分析了ADNI CSF样本的靶向蛋白质组数据。错误发现率用于校正多重比较校正。在所有五种模型中，增加APOE 4拷贝数与CRP肽水平的显著降低相关（每种q<0.05），并且与ALDOA、CH 3L 1（YKL-40）和FABPH肽水平的显著增加相关（每种q<0.05），除了当控制AD临床状态或神经变性生物标志物时（即， CSF tau或p-tau）。在除控制CSF Aβ水平的模型外的所有模型中，尽管无统计学显著性，但APOE 4拷贝数与测量的所有8种不同补体蛋白的所有24种肽水平之间存在一致的反向关联。对于24种不相关的肽来说，这种偶然发生的几率小于1/1600万。在所有模型中，APOE 4拷贝数增加与CSF CRP水平降低相关，在控制CSF Aβ水平时，CSF ALDOA、CH 3L 1和FABH水平升高。APOE 4拷贝数增加也可能与CSF补体途径蛋白水平降低相关，这是未来研究中的一个假设。
APOE4 has been hypothesized to increase Alzheimer’s disease risk by increasing neuroinflammation, though the specific neuroinflammatory pathways involved are unclear. Characterize cerebrospinal fluid (CSF) proteomic changes related to APOE4 copy number. We analyzed targeted proteomic data from ADNI CSF samples using a linear regression model adjusting for age, sex, and APOE4 copy number, and additional linear models also adjusting for AD clinical status or for CSF Aβ, tau, or p-tau levels. False discovery rate was used to correct for multiple comparisons correction. Increasing APOE4 copy number was associated with a significant decrease in a CRP peptide level across all five models (q < 0.05 for each), and with significant increases in ALDOA, CH3L1 (YKL-40), and FABPH peptide levels (q < 0.05 for each) except when controlling for AD clinical status or neurodegeneration biomarkers (i.e., CSF tau or p-tau). In all models except the one controlling for CSF Aβ levels, though not statistically significant, there was a consistent inverse direction of association between APOE4 copy number and the levels of all 24 peptides from all 8 different complement proteins measured. The odds of this happening by chance for 24 unrelated peptides would be less than 1 in 16 million. Increasing APOE4 copy number was associated with decreased CSF CRP levels across all models, and increased CSF ALDOA, CH3L1, and FABH levels when controlling for CSF Aβ levels. Increased APOE4 copy number may also be associated with decreased CSF complement pathway protein levels, a hypothesis for investigation in future studies.