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

This is the authors' abstract. We don't add key points for this paper.

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.