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 language | English |
|---|---|
| Pages (from-to) | 2151-2166 |
| Number of pages | 16 |
| Journal | Alzheimer's & Dementia |
| Volume | 18 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - Nov 2022 |
Keywords
- Alzheimer's disease
- APOE ε2
- APOE ε4
- lipid species
- lipidomics
- mass spectrometry
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In: Alzheimer's & Dementia, Vol. 18, No. 11, 11.2022, p. 2151-2166.
Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - APOE ε2 resilience for Alzheimer's disease is mediated by plasma lipid species
T2 - Analysis of three independent cohort studies
AU - Wang, Tingting
AU - Huynh, Kevin
AU - Giles, Corey
AU - Mellett, Natalie A.
AU - Duong, Thy
AU - Nguyen, Anh
AU - Lim, Wei Ling Florence
AU - Smith, Alex A.T.
AU - Olshansky, Gavriel
AU - Cadby, Gemma
AU - Hung, Joseph
AU - Hui, Jennie
AU - Beilby, John
AU - Watts, Gerald F.
AU - Chatterjee, Pratishtha
AU - Martins, Ian
AU - Laws, Simon M.
AU - Bush, Ashley I.
AU - Rowe, Christopher C.
AU - Villemagne, Victor L.
AU - Ames, David
AU - Masters, Colin L.
AU - Taddei, Kevin
AU - Doré, Vincent
AU - Fripp, Jürgen
AU - Arnold, Matthias
AU - Kastenmüller, Gabi
AU - Nho, Kwangsik
AU - Saykin, Andrew J.
AU - Baillie, Rebecca
AU - Han, Xianlin
AU - Martins, Ralph N.
AU - Moses, Eric K.
AU - Kaddurah-Daouk, Rima
AU - Meikle, Peter J.
N1 - Funding Information: Support was provided by the National Health and Medical Research Council (NHMRC) of Australia (no. 1101320 and 1157607). Kevin Huynh was supported by a Dementia Australia Research Foundation Scholarship and NHMRC investigator grant (1197190) . This work was also supported in part by the Victorian Government's Operational Infrastructure Support Program. The Busselton Health Study (BHS) acknowledges the generous support for the 1994/95 Busselton follow‐up studies from HealthWay, the Department of Health, PathWest Laboratory Medicine of Western Australia (WA), and the Busselton community volunteers, who assisted with data collection and the study participants from the Shire of Busselton. Funding for the AIBL study was provided in part by the study partners (Commonwealth. Scientific Industrial and Research Organization [CSIRO], Edith Cowan University [ECU], Mental Health Research institute [MHRI], National Ageing Research Institute [NARI], Austin Health, and CogState Ltd). The Australian Imaging, Biomarkers and Lifestyle (AIBL) flagship study has also received support from the NHMRC and the Dementia Collaborative Research Centre (DCRC2), as well as funding from the Science and Industry Endowment Fund (SIEF) and the Cooperative Research Centre (CRC) for Mental Health—funded through the CRC Program (Grant ID:20100104), an Australian Government Initiative. Support for the metabolomics sample processing, assays and analytics reported here was provided by grants from the National Institute on Aging (NIA); NIA supported the Alzheimer's Disease Metabolomics Consortium, which is a part of NIA's national initiatives AMP‐AD and M2OVE‐AD (R01 AG046171, RF1 AG051550, RF1 AG057452, and 3U01 AG024904‐09S4). Additional United States National Institutes of Health (NIH) support from the NIA, National Library of Medicine (NLM), and National Cancer Institute (NCI) for analysis includes P30 AG10133, R01 AG19771, R01 LM012535, R03 AG054936, R01 AG061788, K01 AG049050, and R01 CA129769. Matthias Arnold is supported by NIA grants RF1 AG057452, RF1 AG058942, RF1 AG059093, and U01 AG061359. Matthias Arnold is also supported by funding from Qatar National Research Fund NPRP8‐061‐3‐011. Kwangsik Nho is supported by NLM R01 LM012535 and NIA R03AG054936. Data collection and sharing for the Alzheimer's Disease Neuroimaging Initiative (ADNI) was supported by NIH grant U01 AG024904. ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol‐Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann‐La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd; Janssen Alzheimer Immunotherapy Research & Development, LLC; Johnson & Johnson Pharmaceutical Research & Development LLC; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health ( www.fnih.org ). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. This study was only possible with the help of the AIBL research group. The authors who made direct contribution to this study have been listed as authors in this article. Members of the AIBL group who did not participate in the analysis or writing of this report are listed here: https://aibl.csiro.au/about/aibl‐research‐team/ . Part of the data used in preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). The authors who made direct contribution to this study have been listed as authors in this article. As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wpcontent/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf . Part of the data used in preparation of this article were generated by the Alzheimer's Disease Metabolomics Consortium (ADMC). The authors who made direct contribution to this study have been listed as authors in this article. Investigators within the ADMC provided data but did not participate in analysis or writing of this report can be found at https://sites.duke.edu/adnimetab/team/ . Metabolomics data and results from the ADNI study have been made accessible through the AMP‐AD Knowledge Portal ( https://ampadportal.org ). The AMP‐AD Knowledge Portal is the distribution site for data, analysis results, analytical methodology, and research tools generated by the AMP‐AD Target Discovery and Preclinical Validation Consortium and multiple Consortia and research programs supported by the National Institute on Aging. Funding sources that contributed to the cohort studies or directly to the analyses presented in the study are described in the Acknowledgements section. The funding sources had no role in the collection, analysis, or interpretation of the data; in the writing of the report; or in the decision to submit this article for publication. Publisher Copyright: © 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.
PY - 2022/11
Y1 - 2022/11
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - APOE ε2
KW - APOE ε4
KW - lipid species
KW - lipidomics
KW - mass spectrometry
UR - http://www.scopus.com/inward/record.url?scp=85123489503&partnerID=8YFLogxK
U2 - 10.1002/alz.12538
DO - 10.1002/alz.12538
M3 - Article
C2 - 35077012
AN - SCOPUS:85123489503
SN - 1552-5260
VL - 18
SP - 2151
EP - 2166
JO - Alzheimer's & Dementia
JF - Alzheimer's & Dementia
IS - 11
ER -