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

Alzheimer’s Disease Neuroimaging Initiative; GERAD1 Consortium, and AddNeuroMed

doi:10.1016/j.bpsgos.2021.07.010

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

Alzheimer’s Disease Neuroimaging Initiative, GERAD1 Consortium, and AddNeuroMed

Research output: Contribution to journal › Article › peer-review

5 Citations (Scopus)

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.

Original language	English
Pages (from-to)	167-179
Number of pages	13
Journal	Biological Psychiatry Global Open Science
Volume	2
Issue number	2
DOIs	https://doi.org/10.1016/j.bpsgos.2021.07.010
Publication status	Published - Apr 2022

Keywords

Biomarkers
Causality
Mediation
Mendelian randomization
Polygenic scores

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10.1016/j.bpsgos.2021.07.010

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@article{60c9befbde574768ac9f3bd0871f6aca,

title = "Disentangling Independent and Mediated Causal Relationships Between Blood Metabolites, Cognitive Factors, and Alzheimer's Disease",

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.",

keywords = "Biomarkers, Causality, Mediation, Mendelian randomization, Polygenic scores",

author = "{Alzheimer{\textquoteright}s Disease Neuroimaging Initiative} and {GERAD1 Consortium, and AddNeuroMed} and Jodie Lord and Rebecca Green and Choi, {Shing Wan} and Christopher H{\"u}bel and Dag Aarsland and Latha Velayudhan and Pak Sham and Cristina Legido-Quigley and Marcus Richards and Richard Dobson and Petroula Proitsi",

note = "Publisher Copyright: {\textcopyright} 2021 The Authors",

year = "2022",

month = apr,

doi = "10.1016/j.bpsgos.2021.07.010",

language = "English",

volume = "2",

pages = "167--179",

journal = "Biological Psychiatry Global Open Science",

issn = "2667-1743",

publisher = "Elsevier",

number = "2",

}

TY - JOUR

T1 - Disentangling Independent and Mediated Causal Relationships Between Blood Metabolites, Cognitive Factors, and Alzheimer's Disease

AU - Alzheimer’s Disease Neuroimaging Initiative

AU - GERAD1 Consortium, and AddNeuroMed

AU - Lord, Jodie

AU - Green, Rebecca

AU - Choi, Shing Wan

AU - Hübel, Christopher

AU - Aarsland, Dag

AU - Velayudhan, Latha

AU - Sham, Pak

AU - Legido-Quigley, Cristina

AU - Richards, Marcus

AU - Dobson, Richard

AU - Proitsi, Petroula

PY - 2022/4

Y1 - 2022/4

N2 - 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.

AB - 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.

KW - Biomarkers

KW - Causality

KW - Mediation

KW - Mendelian randomization

KW - Polygenic scores

UR - http://www.scopus.com/inward/record.url?scp=85136250958&partnerID=8YFLogxK

U2 - 10.1016/j.bpsgos.2021.07.010

DO - 10.1016/j.bpsgos.2021.07.010

M3 - Article

AN - SCOPUS:85136250958

SN - 2667-1743

VL - 2

SP - 167

EP - 179

JO - Biological Psychiatry Global Open Science

JF - Biological Psychiatry Global Open Science

IS - 2

ER -

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

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