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 At 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 Villemagne; David 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

doi:10.1002/alz.12538

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

Alzheimers Dement. 2022 Nov;18(11):2151-2166. doi: 10.1002/alz.12538. Epub 2022 Jan 25.

Authors

Tingting Wang^{1

2}, Kevin Huynh^{1

2}, Corey Giles^{1

2}, Natalie A Mellett¹, Thy Duong¹, Anh Nguyen¹, Wei Ling Florence Lim³, Alex At Smith¹, Gavriel Olshansky¹, Gemma Cadby⁴, Joseph Hung⁵, Jennie Hui^{4

6}, John Beilby⁶, Gerald F Watts^{5

7}, Pratishtha Chatterjee^{3

8

9}, Ian Martins³, Simon M Laws^{3

10

11}, Ashley I Bush¹², Christopher C Rowe^{12

13}, Victor L Villemagne^{13

14}, David Ames^{15

16}, Colin L Masters¹², Kevin Taddei³, Vincent Doré^{17

18}, Jürgen Fripp¹⁹, Matthias Arnold^{20

21}, Gabi Kastenmüller²¹, Kwangsik Nho^{22

23

24}, Andrew J Saykin^{22

24

25}, Rebecca Baillie²⁶, Xianlin Han²⁷, Ralph N Martins^{3

8

9}, Eric K Moses²⁸, Rima Kaddurah-Daouk^{20

29

30}, Peter J Meikle^{1

2

31}

Affiliations

¹ Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.
² Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, Victoria, Australia.
³ Centre for Precision Health, Edith Cowan University, Joondalup, Western Australia, Australia.
⁴ School of Population and Global Health, University of Western Australia, Perth, Western Australia, Australia.
⁵ Medical School, Faculty of Health and Medical Sciences, University of Western Australia, Perth, Western Australia, Australia.
⁶ PathWest Laboratory Medicine of Western Australia, Nedlands, Australia.
⁷ Lipid Disorders Clinic, Department of Cardiology, Royal Perth Hospital, Perth, Western Australia, Australia.
⁸ Department of Biomedical Sciences, Macquarie University, North Ryde, New South Wales, Australia.
⁹ KaRa Institute of Neurological Disease, Sydney, Macquarie Park, New South Wales, Australia.
¹⁰ Collaborative Genomics Group, School of Medical and Health Sciences, Edith Cowan University, Perth, Western Australia, Australia.
¹¹ Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia.
¹² The Florey Department of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Victoria, Australia.
¹³ Department of Molecular Imaging and Therapy, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia.
¹⁴ Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia.
¹⁵ National Ageing Research Institute, Parkville, Victoria, Australia.
¹⁶ St George's Hospital, University of Melbourne Academic Unit for Psychiatry of Old Age, Kew, Victoria, Australia.
¹⁷ The Australian e-Health Research Centre, Health and Biosecurity, CSIRO, Melbourne, Victoria, Australia.
¹⁸ Department of Molecular Imaging and Therapy, Austin Health, Melbourne, Victoria, Australia.
¹⁹ CSIRO Health and Biosecurity, Brisbane, Queensland, Australia.
²⁰ Department of Psychiatry and Behavioral Sciences, Duke University, Durham, North Carolina, USA.
²¹ Institute of Computational Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
²² Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana, USA.
²³ Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana, USA.
²⁴ Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, Indiana, USA.
²⁵ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA.
²⁶ Rosa & Co LLC, San Carlos, California, USA.
²⁷ Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
²⁸ Menzies Institute for Medical Research, University of Tasmania, Tasmania, Australia.
²⁹ Duke Institute of Brain Sciences, Duke University, Durham, North Carolina, USA.
³⁰ Department of Medicine, Duke University, Durham, North Carolina, USA.
³¹ Monash University, Melbourne, Victoria, Australia.

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.

Keywords: APOE ε2; APOE ε4; Alzheimer's disease; lipid species; lipidomics; mass spectrometry.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease* / genetics
Apolipoprotein E2 / genetics
Apolipoprotein E4 / genetics
Apolipoproteins E / genetics
Australia
Cohort Studies
Genotype
Humans

Substances

Apolipoprotein E2
Apolipoproteins E
Apolipoprotein E4

Abstract

Publication types

MeSH terms

Substances

Grants and funding