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<p>The apolipoprotein E (<i>APOE</i>) 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, <i>n</i> = 181) and plasma (<i>n</i> = 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 &gt; apoE3 &gt; apoE4 in the CSF and in plasma (apoE3 &gt; apoE4), with stronger effect sizes for secondary glycosylation in CSF (total glycosylation in CSF: E2 &gt; E3 (4.6%), E3 &gt; E4 (5.1%), E2 &gt; E4 (9.4%); secondary glycosylation in CSF: E2 &gt; E4 (33.1%), E3 &gt; E4 (25.4%); total glycosylation in plasma: E3 &gt; E4 (24.2%). Secondary ApoE glycosylation was reduced (8%, <i>p</i> = 0.009) in the MCI group compared with the CN group and in the progressor group compared with the non-progressor group (7%, <i>p</i> = 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.</p>

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Increased cerebrospinal fluid and plasma apoE glycosylation is associated with reduced levels of Alzheimer’s disease biomarkers

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月10日

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  • Dobrin Nedelkov,
  • Zoe E. Tsokolas,
  • Matheus Scarpatto Rodrigues,
  • Isabel Sible,
  • S. Duke Han,
  • Bilal E. Kerman,
  • Michael Renteln,
  • Wendy J. Mack,
  • Tharick A. Pascoal,
  • Hussein N. Yassine

摘要

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.