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LOESS-based normalization workflow for targeted HDL glycoproteomics in an Alzheimer's disease cohort
Brian V Hong1, Yiyun Liu2, Armin Oloumi2
1Department of Nutrition, University of California-Davis Davis CA 95616 USA amzivkovic@ucdavis.edu.
RSC Advances
|April 30, 2026
Summary
This study developed a new method to accurately measure peptides on high-density lipoprotein (HDL) in Alzheimer's disease (AD) patients. The improved technique revealed significant differences in HDL peptides related to APOE genotype, not disease severity.
Area of Science:
- Proteomics
- Glycoproteomics
- Neurodegenerative Diseases
Background:
- High-density lipoprotein (HDL) plays a role in lipid metabolism and inflammation, but characterizing its associated peptides in Alzheimer's disease (AD) is difficult due to technical variability.
- Previous studies faced challenges in quantifying HDL-associated peptides in AD cohorts, limiting understanding of their role.
Purpose of the Study:
- To develop and validate a robust workflow for quantitative analysis of HDL-associated peptides and glycopeptides in an aging cohort.
- To investigate the association of HDL peptide profiles with Alzheimer's disease and APOE genotype.
Main Methods:
- Applied Locally Estimated Scatterplot Smoothing (LOESS)-based drift correction and internal-standard normalization to targeted multiple reaction monitoring (MRM) glycoproteomic data.
- Analyzed HDL isolates from 194 participants across the cognitive spectrum, focusing on 21 consistently detected peptide and glycopeptide features.
- Utilized APOE genotype and covariate-adjusted models for statistical analysis.
Main Results:
- The normalization workflow significantly improved analytical reproducibility, reducing coefficient of variation from 69.1% to 55.2%.
- Identified six HDL peptides with significant differences between APOE3/E3 and APOE3/E4 carriers, five of which remained significant after correction.
- Disease-related differences in HDL peptides were modest and not statistically significant after covariate adjustment within APOE3/E3 carriers.
Conclusions:
- LOESS-based drift correction and internal-standard normalization stabilize quantitative HDL glycoproteomic measurements, providing a practical framework for quality control-informed analysis.
- The study highlights significant APOE genotype-associated variations in HDL peptides, suggesting a potential link independent of AD status in this cohort.
