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Disentangling independent and mediated causal relationships between blood metabolites, cognitive factors, and Alzheimer’s Disease

Lord, J; Green, R; Choi, SW; Hübel, C; Aarsland, D; Velayudhana, L; Sham, P; ... AddNeuroMed; + view all (2022) Disentangling independent and mediated causal relationships between blood metabolites, cognitive factors, and Alzheimer’s Disease. Biological Psychiatry , 2 (2) pp. 167-179. 10.1016/j.bpsgos.2021.07.010. Green open access

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Abstract

Background: Education and cognition demonstrate consistent inverse associations with Alzheimer’s disease (AD). The biological underpinnings, however, remain unclear. Blood metabolites reflect the end point of biological processes and are accessible and malleable. Identifying metabolites with etiological relevance to AD and disentangling how these relate to cognitive factors along the AD causal pathway could, therefore, offer unique insights into underlying causal mechanisms. // Methods: Using data from the largest metabolomics genome-wide association study (N ≈ 24,925) and three independent AD cohorts (N = 4725), cross-trait polygenic scores were generated and meta-analyzed. Metabolites genetically associated with AD were taken forward for causal analyses. Bidirectional two-sample Mendelian randomization interrogated univariable causal relationships between 1) metabolites and AD; 2) education and cognition; 3) metabolites, education, and cognition; and 4) education, cognition, and AD. Mediating relationships were computed using multivariable Mendelian randomization. // Results: Thirty-four metabolites were genetically associated with AD at p < .05. Of these, glutamine and free cholesterol in extra-large high-density lipoproteins demonstrated a protective causal effect (glutamine: 95% confidence interval [CI], 0.70 to 0.92; free cholesterol in extra-large high-density lipoproteins: 95% CI, 0.75 to 0.92). An AD-protective effect was also observed for education (95% CI, 0.61 to 0.85) and cognition (95% CI, 0.60 to 0.89), with bidirectional mediation evident. Cognition as a mediator of the education-AD relationship was stronger than vice versa, however. No evidence of mediation via any metabolite was found. // Conclusions: Glutamine and free cholesterol in extra-large high-density lipoproteins show protective causal effects on AD. Education and cognition also demonstrate protection, though education’s effect is almost entirely mediated by cognition. These insights provide key pieces of the AD causal puzzle, important for informing future multimodal work and progressing toward effective intervention strategies.

Type: Article
Title: Disentangling independent and mediated causal relationships between blood metabolites, cognitive factors, and Alzheimer’s Disease
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.bpsgos.2021.07.010
Publisher version: https://doi.org/10.1016/j.bpsgos.2021.07.010
Language: English
Additional information: © 2021 The Authors. Published by Elsevier Inc on behalf of the Society of Biological Psychiatry. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Biomarkers; Causality; Mediation; Mendelian randomization; Polygenic scores
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science > Population Science and Experimental Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science > Population Science and Experimental Medicine > MRC Unit for Lifelong Hlth and Ageing
URI: https://discovery.ucl.ac.uk/id/eprint/10131633
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