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

13 Citations (Scopus)


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
Pages (from-to)2151-2166
Number of pages16
JournalAlzheimer's & dementia : the journal of the Alzheimer's Association
Issue number11
Early online date25 Jan 2022
Publication statusPublished - Nov 2022


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