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Mendelian randomization identifies blood metabolites previously linked to midlife cognition as causal candidates in Alzheimer’s disease

Research output: Contribution to journalArticlepeer-review

Original languageEnglish
Article numbere2009808118
JournalProceedings of the National Academy of Sciences
Volume118
Issue number16
DOIs
Published20 Apr 2021

Bibliographical note

Funding Information: This work was made possible only through generous funding from key funding bodies. P.P. is an Alzheimer's Reearch UK (ARUK) Senior Research Fellow. J.L. is funded by the van Geest endowment fund. M.R. is funded by the Medical Research Council (MRC) (MC_UU_00019/1 and MC_UU_00019/3). B.J. and R.G. are funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. This study represents independent research additionally funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley National Health Service (NHS) Foundation Trust and King's College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. A proportion of data collection and sharing for this project was also funded by the ADNI (NIH Grant U01 AG024904). ADNI is funded by the National Institute on Aging (NIA), the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Abbott; the Alzheimer's Association; the Alzheimer's Drug Discovery Foundation; Amorfix Life Sciences Ltd.; AstraZeneca; Bayer HealthCare; BioClinica, Inc.; Biogen Idec, Inc.; Bristol Myers Squibb Company; Eisai, Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd. and its affiliated company Genentech, Inc.; GE Healthcare; Innogenetics, N.V.; Janssen Alzheimer Immunotherapy Research & Development, LLC; Johnson & Johnson Pharmaceutical Research & Development, LLC; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC; Novartis Pharmaceuticals Corporation; Pfizer, Inc.; Servier; Synarc, Inc.; and Takeda Pharmaceutical Company. 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 NIH (http://www.fnih.org/). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California San Diego. ADNI data are disseminated by the Laboratory of Neuro Imaging at the University of California, Los Angeles. We also thank all providers of summary genomic data for use within this study. For the provision of International Genomics of Alzheimer's Project (IGAP), IGAP investigators within contributed to the design and implementation of IGAP and provided data but did not participate in the analysis or writing of this report. IGAP was made possible by the generous participation of the control subjects, the patients, and their families. The i-Select chip was funded by the French National Foundation on Alzheimer's disease and related disorders. The European Alzheimer's Disease Initiative was supported by the Laboratory of Excellence program investment for the future DISTALZ grant, Inserm, Institut Pasteur de Lille, Universit? de Lille 2, and the Lille University Hospital. Genetic and Environmental Risk in AD/ Defining Genetic, Polygenic and Environmental Risk for Alzheimer's Disease Consortium (GERAD/PERADES) was supported by the Medical Research Council (Grant 503480), Alzheimer's Research United Kingdom (Grant 503176), the Wellcome Trust (Grant 082604/2/07/Z), and the German Federal Ministry of Education and Research: Competence Network Dementia Grants 01GI0102, 01GI0711, and 01GI0420. Cohorts for Heart and Aging Research in Genomic Epidemiology was partly supported by NIH/NIA Grant R01 AG033193 and NIA Grant AG081220 and Age, Gene/Environment Susceptibility (AGES) Contract N01-AG-12100, National Heart, Lung, and Blood Institute Grant R01 HL105756, the Icelandic Heart Association, and the Erasmus Medical Center and Erasmus University. The Alzheimer Disease Genetics Consortium was supported by the NIH/NIA Grants U01 AG032984, U24 AG021886, U01 AG016976 and Alzheimer's Association Grant ADGC-10-196728. Funding Information: ACKNOWLEDGMENTS. This work was made possible only through generous funding from key funding bodies. P.P. is an Alzheimer’s Reearch UK (ARUK) Senior Research Fellow. J.L. is funded by the van Geest endowment fund. M.R. is funded by the Medical Research Council (MRC) (MC_UU_00019/1 and MC_UU_00019/3). B.J. and R.G. are funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. This study represents independent research additionally funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley National Health Service (NHS) Foundation Trust and King’s College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. A proportion of data collection and sharing for this project was also funded by the ADNI (NIH Grant U01 AG024904). ADNI is funded by the National Institute on Aging (NIA), the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Abbott; the Alzheimer’s Association; the Alzheimer’s Drug Discovery Foundation; Amorfix Life Sciences Ltd.; AstraZeneca; Bayer HealthCare; BioClinica, Inc.; Biogen Idec, Inc.; Bristol Myers Squibb Company; Eisai, Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd. and its affiliated company Genentech, Inc.; GE Healthcare; Innogenetics, N.V.; Janssen Alzheimer Immunotherapy Research & Development, LLC; Johnson & Johnson Pharmaceutical Research & Development, LLC; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC; Novartis Pharmaceuticals Corporation; Pfizer, Inc.; Servier; Synarc, Inc.; and Takeda Pharmaceutical Company. 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 NIH (http://www.fnih.org/). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Disease Cooperative Study at the University of California San Diego. ADNI data are disseminated by the Laboratory of Neuro Imaging at the University of California, Los Angeles. We also thank all providers of summary genomic data for use within this study. For the provision of International Genomics of Alzheimer’s Project (IGAP), IGAP investigators within contributed to the design and implementation of IGAP and provided data but did not participate in the analysis or writing of this report. IGAP was made possible by the generous participation of the control subjects, the patients, and their families. The i–Select chip was funded by the French National Foundation on Alzheimer’s disease and related disorders. The European Alzheimer’s Disease Initiative was supported by the Laboratory of Excellence program investment for the future DISTALZ grant, Inserm, Institut Pasteur de Lille, Université de Lille 2, and the Lille University Hospital. Genetic and Environmental Risk in AD/ Defining Genetic, Polygenic and Environmental Risk for Alzheimer’s Disease Consortium (GERAD/PERADES) was supported by the Medical Research Council (Grant 503480), Alzheimer’s Research United Kingdom (Grant 503176), the Wellcome Trust (Grant 082604/2/07/Z), and the German Federal Ministry of Education and Research: Competence Network Dementia Grants 01GI0102, 01GI0711, and 01GI0420. Cohorts for Heart and Aging Research in Genomic Epidemiology was partly supported by NIH/NIA Grant R01 AG033193 and NIA Grant AG081220 and Age, Gene/Environment Susceptibility (AGES) Contract N01–AG–12100, National Heart, Lung, and Blood Institute Grant R01 HL105756, the Icelandic Heart Association, and the Erasmus Medical Center and Erasmus University. The Alzheimer Disease Genetics Consortium was supported by the NIH/NIA Grants U01 AG032984, U24 AG021886, U01 AG016976 and Alzheimer’s Association Grant ADGC–10–196728. Publisher Copyright: © This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors

Abstract

There are currently no disease-modifying treatments for Alzheimer's disease (AD), and an understanding of preclinical causal biomarkers to help target disease pathogenesis in the earliest phases remains elusive. Here, we investigated whether 19 metabolites previously associated with midlife cognition-a preclinical predictor of AD-translate to later clinical risk, using Mendelian randomization (MR) to tease out AD-specific causal relationships. Summary statistics from the largest genome-wide association studies (GWASs) for AD and metabolites were used to perform bidirectional univariable MR. Bayesian model averaging (BMA) was additionally performed to address high correlation between metabolites and identify metabolite combinations that may be on the AD causal pathway. Univariable MR indicated four extra-large high-density lipoproteins (XL.HDL) on the causal pathway to AD: free cholesterol (XL.HDL.FC: 95% CI = 0.78 to 0.94), total lipids (XL.HDL.L: 95% CI = 0.80 to 0.97), phospholipids (XL.HDL.PL: 95% CI = 0.81 to 0.97), and concentration of XL.HDL particles (95% CI = 0.79 to 0.96), significant at an adjusted P < 0.009. MR-BMA corroborated XL.HDL.FC to be among the top three causal metabolites, in addition to total cholesterol in XL.HDL (XL.HDL.C) and glycoprotein acetyls (GP). Both XL.HDL.C and GP demonstrated suggestive univariable evidence of causality (P < 0.05), and GP successfully replicated within an independent dataset. This study offers insight into the causal relationship between metabolites demonstrating association with midlife cognition and AD. It highlights GP in addition to several XL.HDLs-particularly XL.HDL.FC-as causal candidates warranting further investigation. As AD pathology is thought to develop decades prior to symptom onset, expanding on these findings could inform risk reduction strategies.

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