载脂蛋白E ε4、脑脊液生长相关蛋白-43与轻度认知障碍个体认知及神经变性的相关性研究

The Correlation between Apolipoprotein E ε4, Cerebrospinal Fluid Growth-Associated Pro-tein-43 and Cognition, Neurodegeneration in Mild Cognitive Impairment

摘要: 目的：载脂蛋白E ε4 (Apolipoprotein E ε4, ApoE ε4)等位基因是阿尔兹海默病(Alzheimer’s disease, AD)的危险因素之一。脑脊液生长相关蛋白-43 (Growth-Associated Protein-43, GAP-43)已成为代表突触功能障碍的潜在生物标志物。本研究旨在分析ApoE ε4、GAP-43与轻度认知障碍个体(Mild Cogni-tive Impairment, MCI)认知及神经变性的相关性。方法：根据是否携带ApoE ε4，将阿尔茨海默病神经影像学计划中(Alzheimer’s Disease Neuroimaging Initiative, ADNI)的164名MCI分为ApoE ε4携带者和ApoE ε4非携带者。分析ApoE ε4携带者与ApoE ε4非携带者的GAP-43水平，ApoE ε4是否影响GAP-43与AD核心生物标志物、认知及脑区体积之间的关系。随访阶段中GAP-43与认知及各脑区体积的关系。结果：在基线和随访阶段，与ApoE ε4非携带者相比，携带者具有更高的GAP-43水平(P < 0.01)。在基线水平，无论是否携带ApoE ε4基因，GAP-43与磷酸化tau (phosphorylated tau, p-tau)和总tau (total tau, t-tau)水平有相关性(P < 0.01)。随访阶段，ApoE ε4非携带者与携带者的GAP-43变化率与t-tau和p-tau的变化率均有相关性(P < 0.01)。基线GAP-43与随访2年后中颞体积萎缩、认知功能恶化有关(P < 0.05)。结论：在MCI中，ApoE ε4可能会影响GAP-43水平，GAP-43与认知及神经退行性变的相关性与ApoE ε4状态有关。GAP-43作为一种突触生物标志物可用于追踪MCI的进展。

Abstract: Objective: The apolipoprotein E ε4 (Apolipoprotein E ε4, ApoE ε4) allele is one of the genetic risk factors for Alzheimer’s disease (AD). Growth-Associated Protein-43 (GAP-43) has emerged as a po-tential biomarker representing synaptic dysfunction. This study aims to analyze the correlation between ApoE ε4, GAP-43 and cognitive, neurodegeneration in Mild Cognitive Impairment (MCI). Methods: We included 164 MCI in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Accord-ing to whether the subjects carried ApoE ε4, they were stratified into ApoE ε4 non-carriers (MCI ε4−) and ApoE ε4 carriers (MCI ε4+). The cerebrospinal fluid GAP-43 levels of MCI ε4− and MCI ε4+ were analyzed, whether ApoE ε4 affected the relationship between GAP-43 and AD core biomarkers, cog-nition and brain area volume, and the relationship between GAP-43 and cognition and the volume of each brain region during the follow-up stage. Results: At baseline and follow-up phases, MCI ε4+ had a higher GAP-43 level compared to MCI ε4− (P < 0.01). At baseline levels, CSF GAP-43 was asso-ciated with phosphorylated tau (p-tau) and total tau (t-tau) levels, whether or not it carried the ApoE ε4 (P < 0.01). During the follow-up phase, the rate of change of cerebrospinal fluid GAP-43 in both the MCI ε4+ group and the MCI ε4− group correlated with the rate of change of t-tau and p-tau (P < 0.01). GAP-43 in baseline cerebrospinal fluid was associated with middle temporal volume at-rophy and cognitive function deterioration after 2 years of follow-up (P < 0.05). Conclusions: In MCI, ApoE ε4 may affect cerebrospinal fluid GAP-43 levels. The correlation between cerebrospinal fluid GAP-43 and cognitive and neurodegenerative degeneration is related to ApoE ε4 status. Cerebro-spinal fluid GAP-43 can be used as a synaptic biomarker to track the progression of MCI.