Disentangling Independent and Mediated Causal Relationships Between Blood Metabolites, Cognitive Factors, and Alzheimer’s Disease

Biological Psychiatry Global Open Science

Marcus Richards¹  Shing Wan Choi²  Latha Velayudhan²  Pak Sham³  Christopher Hübel⁴  Petroula Proitsi⁵  Richard Dobson⁶  Jodie Lord⁶  Rebecca Green⁶  Dag Aarsland⁶  Cristina Legido-Quigley⁶ 

[1] Center for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway;NIHR Maudsley Biomedical Research Centre, South London and Maudsley NHS Foundation Trust, London, United Kingdom;National Centre for Register-based Research, Aarhus University, Aarhus, Denmark;Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York;Department of Psychiatry, University of Hong Kong, Hong Kong, China;Institute of Psychology, Psychiatry and Neuroscience, King’s College London, London, United Kingdom;

关键词: Biomarkers;    Causality;    Mediation;    Mendelian randomization;    Polygenic scores;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown