Nedelkov Dobrin, Tsokolas Zoe E, Rodrigues Matheus Scarpatto, Sible Isabel, Han S Duke, Kerman Bilal E, Renteln Michael, Mack Wendy J, Pascoal Tharick A, Yassine Hussein N
Isoformix Inc, Sugar Land, TX, USA.
Department of Neurology, University of Southern California, Los Angeles, CA, USA.
Alzheimers Res Ther. 2025 Jul 10;17(1):151. doi: 10.1186/s13195-025-01795-7.
The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). ApoE is glycosylated with an O-linked Core-1 sialylated glycan at several sites; however, the impact and function of this glycosylation on AD biomarkers remain unclear. We examined apoE glycosylation (total and secondary) in a cohort of cerebrospinal fluid (CSF, n = 181) and plasma (n = 178) samples from the Alzheimer's Disease Neuroimaging Initiative (ADNI) stratified into 4 groups: cognitively normal (CN), Mild Cognitive Impairment (MCI), progressors, and non-progressors based on delayed word recall performance over 4 years. We observed decreasing glycosylation (reduced % of apoE being glycosylated) from apoE2 > apoE3 > apoE4 in the CSF and in plasma (apoE3 > apoE4), with stronger effect sizes for secondary glycosylation in CSF (total glycosylation in CSF: E2 > E3 (4.6%), E3 > E4 (5.1%), E2 > E4 (9.4%); secondary glycosylation in CSF: E2 > E4 (33.1%), E3 > E4 (25.4%); total glycosylation in plasma: E3 > E4 (24.2%). Secondary ApoE glycosylation was reduced (8%, p = 0.009) in the MCI group compared with the CN group and in the progressor group compared with the non-progressor group (7%, p = 0.01). In CSF, higher apoE glycosylation was cross-sectionally associated with lower total tau (t-tau) and p-tau181. In CSF, greater apoE4 glycosylation was associated with lower t-tau and p-tau181 levels. These results indicate strong associations between apoE glycosylation and biomarkers of AD pathology independent of apoE genotype, warranting a deeper understanding of the functional role of apoE glycosylation in AD tau pathology.
载脂蛋白E（APOE）ε4等位基因是晚发性阿尔茨海默病（AD）最强的遗传风险因素。载脂蛋白E在多个位点被O-连接的核心1唾液酸化聚糖糖基化；然而，这种糖基化对AD生物标志物的影响和功能仍不清楚。我们在阿尔茨海默病神经影像倡议（ADNI）的一组脑脊液（CSF，n = 181）和血浆（n = 178）样本中检测了载脂蛋白E糖基化（总糖基化和二级糖基化），这些样本根据4年的延迟单词回忆表现分为4组：认知正常（CN）、轻度认知障碍（MCI）、病情进展者和非病情进展者。我们观察到，在脑脊液和血浆中，载脂蛋白E糖基化程度从apoE2＞apoE3＞apoE4逐渐降低（载脂蛋白E糖基化的百分比降低），在血浆中为apoE3＞apoE4，脑脊液中二级糖基化的效应大小更强（脑脊液中的总糖基化：E2＞E3（4.6%），E3＞E4（5.1%），E2＞E4（9.4%）；脑脊液中的二级糖基化：E2＞E4（33.1%），E3＞E4（25.4%）；血浆中的总糖基化：E3＞E4（24.2%）。与CN组相比，MCI组的二级载脂蛋白E糖基化降低（8%，p = 0.009），与非病情进展者组相比，病情进展者组的二级载脂蛋白E糖基化降低（7%，p = 0.01）。在脑脊液中，较高的载脂蛋白E糖基化与较低的总tau蛋白（t-tau）和磷酸化tau蛋白181（p-tau181）呈横断面相关。在脑脊液中，较高的载脂蛋白E4糖基化与较低的t-tau和p-tau181水平相关。这些结果表明，载脂蛋白E糖基化与AD病理生物标志物之间存在密切关联，与载脂蛋白E基因型无关，这需要更深入地了解载脂蛋白E糖基化在AD tau病理中的功能作用。
