期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2009808118
关键词
Alzheimer's disease; metabolomics; causality; biomarkers; Mendelian randomization
资金
- van Geest endowment fund
- Medical Research Council (MRC) [MC_UU_00019/1, MC_UU_00019/3]
- National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London
- ADNI (NIH) [U01 AG024904]
- National Institute on Aging (NIA)
- National Institute of Biomedical Imaging and Bioengineering
- Abbott
- Alzheimer's Association
- 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.
- 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.
- Takeda Pharmaceutical Company
- Canadian Institutes of Health Research
- French National Foundation on Alzheimer's disease and related disorders
- Laboratory of Excellence program investment for the future DISTALZ grant
- Inserm
- Institut Pasteur de Lille
- Universite de Lille 2
- Lille University Hospital
- Medical Research Council [503480]
- Alzheimer's Research United Kingdom [503176]
- Wellcome Trust [082604/2/07/Z]
- German Federal Ministry of Education and Research: Competence Network Dementia Grants [01GI0102, 01GI0711, 01GI0420]
- NIH/NIA [R01 AG033193, U01 AG032984, U24 AG021886, U01 AG016976]
- NIA [AG081220]
- Age, Gene/Environment Susceptibility (AGES) Contract [N01-AG-12100]
- National Heart, Lung, and Blood Institute [R01 HL105756]
- Icelandic Heart Association
- Erasmus Medical Center
- Erasmus University
- Alzheimer's Association [ADGC-10-196728]
- 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
This study explored the causal relationship between metabolites associated with midlife cognition and AD, highlighting XL.HDL.FC, total lipids, phospholipids, and XL.HDL particle concentration as potential causal candidates. Evidence suggests that GP may also play a role in AD pathology and warrants further investigation. Understanding these relationships could inform risk reduction strategies for AD, which is believed to develop decades before symptoms appear.
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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