APOE ε2 resilience for Alzheimer's disease is mediated by plasma lipid species: Analysis of three independent cohort studies

Tingting Wang, Kevin Huynh, Corey Giles, Natalie A. Mellett, Thy Duong, Anh Nguyen, Wei Ling Florence Lim, Alex A.T. Smith, Gavriel Olshansky, Gemma Cadby, Joseph Hung, Jennie Hui, John Beilby, Gerald F. Watts, Pratishtha Chatterjee, Ian Martins, Simon M. Laws, Ashley I. Bush, Christopher C. Rowe, Victor L. VillemagneDavid Ames, Colin L. Masters, Kevin Taddei, Vincent Doré, Jürgen Fripp, Matthias Arnold, Gabi Kastenmüller, Kwangsik Nho, Andrew J. Saykin, Rebecca Baillie, Xianlin Han, Ralph N. Martins, Eric K Moses, Rima Kaddurah-Daouk, Peter J. Meikle

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Introduction: The apolipoprotein E (APOE) genotype is the strongest genetic risk factor for late-onset Alzheimer's disease. However, its effect on lipid metabolic pathways, and their mediating effect on disease risk, is poorly understood. Methods: We performed lipidomic analysis on three independent cohorts (the Australian Imaging, Biomarkers and Lifestyle [AIBL] flagship study, n = 1087; the Alzheimer's Disease Neuroimaging Initiative [ADNI] 1 study, n = 819; and the Busselton Health Study [BHS], n = 4384), and we defined associations between APOE ε2 and ε4 and 569 plasma/serum lipid species. Mediation analysis defined the proportion of the treatment effect of the APOE genotype mediated by plasma/serum lipid species. Results: A total of 237 and 104 lipid species were associated with APOE ε2 and ε4, respectively. Of these 68 (ε2) and 24 (ε4) were associated with prevalent Alzheimer's disease. Individual lipid species or lipidomic models of APOE genotypes mediated up to 30% and 10% of APOE ε2 and ε4 treatment effect, respectively. Discussion: Plasma lipid species mediate the treatment effect of APOE genotypes on Alzheimer's disease and as such represent a potential therapeutic target.

Original languageEnglish (US)
JournalAlzheimer's and Dementia
DOIs
StateAccepted/In press - 2022

ASJC Scopus subject areas

  • Epidemiology
  • Health Policy
  • Developmental Neuroscience
  • Clinical Neurology
  • Geriatrics and Gerontology
  • Cellular and Molecular Neuroscience
  • Psychiatry and Mental health

Fingerprint

Dive into the research topics of 'APOE ε2 resilience for Alzheimer's disease is mediated by plasma lipid species: Analysis of three independent cohort studies'. Together they form a unique fingerprint.

Cite this