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Wang, T.* ; Huynh, K.* ; Giles, C.* ; Mellett, N.A.* ; Duong, T.* ; Nguyen, A.* ; Lim, W.L.F.* ; Smith, A.A.T.* ; Olshansky, G.* ; Cadby, G.* ; Hung, J.* ; Hui, J.* ; Beilby, J.* ; Watts, G.F.* ; Chatterjee, P.* ; Martins, I.* ; Laws, S.M.* ; Bush, A.I.* ; Rowe, C.C.* ; Villemagne, V.L.* ; Ames, D.* ; Masters, C.L.* ; Taddei, K.* ; Doré, V.* ; Fripp, J.* ; Arnold, M. ; Kastenmüller, G. ; Nho, K.* ; Saykin, A.J.* ; Baillie, R.* ; Han, X.* ; Martins, R.N.* ; Moses, E.K.* ; Kaddurah-Daouk, R.* ; Meikle, P.J.*

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

Alzheimers Dement. 18, 2151-2166 (2022)

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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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Apoe Epsilon 2 ; Apoe Epsilon 4 ; Alzheimer's Disease ; Lipidomics ; Lipid Species ; Mass Spectrometry; Density-lipoprotein Cholesterol; Coronary-artery-disease; Natural Alkylglycerols; Cognitive Decline; Risk; Association; Dementia; Individuals; Trafficking; Degradation

ISSN (print) / ISBN 1552-5260

e-ISSN 1552-5279

Journal Alzheimer's & Dementia

Quellenangaben Volume: 18, Issue: 11, Pages: 2151-2166

Publisher Elsevier

Publishing Place New York, NY [u.a.]

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Computational Biology (ICB)

Grants Austin Health, and CogState Ltd.
Dementia Australia Research Foundation Scholarship
Victorian Government's Operational Infrastructure Support Program
Commonwealth. Scientific Industrial and Research Organization [CSIRO]
Edith CowanUniversity [ECU]
Mental Health Research institute [MHRI]
National Ageing Research Institute [NARI]
Dementia Collaborative Research Centre (DCRC2)
Science and Industry Endowment Fund (SIEF)
Cooperative Research Centre (CRC)
Qatar National Research Fund
NLM
NIA
NIH
National Health and Medical Research Council (NHMRC) of Australia