Apolipoprotein E O-glycosylation is associated with amyloid plaques and APOE genotype

Although the APOE 4 pound allele is the strongest genetic risk factor for sporadic Alzheimer's disease (AD), the relationship between apolipoprotein (apoE) and AD pathophysiology is not yet fully understood. Relatively little is known about the apoE protein species, including post-translational modifications, that exist in the human periphery and CNS. To better understand these apoE species, we developed a LC-MS/MS assay that simulta-neously quantifies both unmodified and O-glycosylated apoE peptides. The study cohort included 47 older in-dividuals (age 75.6 +/- 5.7 years [mean +/- standard deviation]), including 23 individuals (49%) with cognitive impairment. Paired plasma and cerebrospinal fluid samples underwent analysis. We quantified O-glycosylation of two apoE protein residues - one in the hinge region and one in the C-terminal region - and found that glycosylation occupancy of the hinge region in the plasma was significantly correlated with plasma total apoE levels, APOE genotype and amyloid status as determined by CSF A842/A840. A model with plasma glycosylation occupancy, plasma total apoE concentration, and APOE genotype distinguished amyloid status with an AUROC of 0.89. These results suggest that plasma apoE glycosylation levels could be a marker of brain amyloidosis, and that apoE glycosylation may play a role in the pathophysiology of AD.

Automated summary

Although the APOE 4 allele is highly associated with sporadic Alzheimer's disease, the mechanism of apolipoprotein (apoE) and AD pathophysiology remains unclear. This study developed a LC-MS/MS assay to measure both unmodified and O-glycosylated apoE peptides in plasma and cerebrospinal fluid (CSF). The results indicate that plasma apoE glycosylation levels correlate with total apoE levels, APOE genotype, and amyloid status, suggesting it could be a marker of brain amyloidosis and may contribute to the pathophysiology of AD.