Association between Human Blood Metabolome and the Risk of Alzheimer's Disease

Sun, Lulu; Guo, Daoxia; Jia, Yiming; Shi, Mengyao; Yang, Pinni; Wang, Yu; Liu, Fanghua; Chen, Guo‐Chong; Zhang, Yonghong; Zhu, Zhengbao

doi:10.1002/ana.26464

Cited by 25 publications

(14 citation statements)

References 54 publications

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“…Our finding is in line with another previous study (Sun et al, 2022) that demonstrated a negative association between circulating levels of Gln and the risk of AD. In contrast, another observational study (Cui et al, 2020) showed the opposite correlation to our results.…”

Section: Discussionsupporting

confidence: 94%

“…Recently, one study using MR analysis demonstrated a negative association between circulating levels of glutamine and the risk of Alzheimer's disease (Sun et al, 2022). However, Mei Cui et al (Cui et al, 2020) found an opposite correlation to the MR study described above.…”

Section: Introductionmentioning

confidence: 93%

“…As a result of the random assignment of parental alleles during meiosis, MR is less likely to result in conventional biases arising from reverse causation and confounding (Davey Smith & Hemani, 2014). Recently, one study using MR analysis demonstrated a negative association between circulating levels of glutamine and the risk of Alzheimer's disease (Sun et al, 2022). However, Mei Cui et al (Cui et al, 2020) found an opposite correlation to the MR study described above.…”

Section: Introductionmentioning

confidence: 99%

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The causal role of circulating amino acids on neurodegenerative disorders: A two‐sample Mendelian randomization study

Cheng

Deng

2023

Journal of Neurochemistry

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Potential associations between the risk of neurodegenerative diseases and circulating levels of amino acids have been implied in both experimental research and observational studies. However, because of the confounding and reverse causality, the findings could be biased. We aimed to determine whether circulating amino acid levels have potential effects on the risk of neurodegenerative diseases through a more robust analysis. So, we performed a total of two MR analyses, a discovery two‐sample MR analysis, and a replication test, using summary‐level genome‐wide association study (GWAS) data, both with circulating levels of amino acids as exposure and risk of neurodegenerative diseases as an outcome. The potential causalities between nine amino acids (Glutamine [Glu], Leucine [Leu], Isoleucine [Ile], Phenylalanine [Phe], Valine [Val], Alanine [Ala], Tyrosine [Tyr], Histidine [His], and Glycine [Gly]) and six neurodegenerative disorders (Alzheimer's disease [AD], Parkinson's disease [PD], Multiple sclerosis [MS], Frontotemporal dementia [FTD], Lewy body dementia [DLB], Amyotrophic lateral sclerosis [ALS]) were explored in this study. According to the discovery MR analysis, 1 SD. increase in circulating levels of Gln was genetically determined to result in a 13% lower risk of AD (IVW ORSD [95% CI] = 0.872 [0.822, 0.926]; FDR = 7.46 × 10−5) while PD risk was decreased to 63% per SD. increase of circulating Leu levels (IVW ORSD [95% CI] = 0.628 [0.467, 0.843]; FDR = 0.021). Results from the replication test provide further evidence of the potential association between circulating Gln levels and AD risk (IVW ORSD [95% CI] = 0.094 [0.028, 0.311]; FDR = 9.98 × 10−4). Meanwhile, sensitivity analysis demonstrated that the significant relationships revealed by our two‐sample MR outcomes were reliable. Our analyses provided robust evidence of causal associations between circulating levels of Gln and AD risk as well as circulating Leu levels and risk of PD. However, the underlying mechanisms remain to be further investigated.image

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Section: Discussionsupporting

confidence: 94%

Section: Introductionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

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The causal role of circulating amino acids on neurodegenerative disorders: A two‐sample Mendelian randomization study

Cheng

Deng

2023

Journal of Neurochemistry

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“…This assertion was substantiated in a subsequent study investigating the correlation between sex hormones and AD risk. However, caution is advised in clinical practice, as a Phe-MR analysis by Sun et al suggested potential detrimental effects of epiandrosterone sulfate on respiratory and digestive diseases (Sun et al, 2022). Thus, while epiandrosterone sulfate may hold promise as a therapeutic target for AD, careful consideration of potential adverse side effects is essential.…”

Section: Discussionmentioning

confidence: 99%

Association of genetically predicted 486 blood metabolites on the risk of Alzheimer’s disease: a Mendelian randomization study

Yang,

Han,

et al. 2024

Front. Aging Neurosci.

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BackgroundStudies have reported that metabolic disturbance exhibits in patients with Alzheimer’s disease (AD). Still, the presence of definitive evidence concerning the genetic effect of metabolites on AD risk remains insufficient. A systematic exploration of the genetic association between blood metabolites and AD would contribute to the identification of new targets for AD screening and prevention.MethodsWe conducted an exploratory two-sample Mendelian randomization (MR) study aiming to preliminarily identify the potential metabolites involved in AD development. A genome-wide association study (GWAS) involving 7,824 participants provided information on 486 human blood metabolites. Outcome information was obtained from a large-scale GWAS meta-analysis of AD, encompassing 21,982 cases and 41,944 controls of Europeans. The primary two-sample MR analysis utilized the inverse variance weighted (IVW) model while supplementary analyses used Weighted median (WM), MR Egger, Simple mode, and Weighted mode, followed by sensitivity analyses such as the heterogeneity test, horizontal pleiotropy test, and leave-one-out analysis. For the further identification of metabolites, replication and meta-analysis with FinnGen data, steiger test, linkage disequilibrium score regression, confounding analysis, and were conducted for further evaluation. Multivariable MR was performed to assess the direct effect of metabolites on AD. Besides, an extra replication analysis with EADB data was conducted for final evaluation of the most promising findings.ResultsAfter rigorous genetic variant selection, IVW, complementary analysis, sensitivity analysis, replication and meta-analysis with the FinnGen data, five metabolites (epiandrosterone sulfate, X-12680, pyruvate, docosapentaenoate, and 1-stearoylglycerophosphocholine) were identified as being genetically associated with AD. MVMR analysis disclosed that genetically predicted these four known metabolites can directly influence AD independently of other metabolites. Only epiandrosterone sulfate and X-12680 remained suggestive significant associations with AD after replication analysis with the EADB data.ConclusionBy integrating genomics with metabonomics, this study furnishes evidence substantiating the genetic association of epiandrosterone sulfate and X-12680 with AD. These findings hold significance for the screening, prevention, and treatment strategies for AD.

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“…Mendelian randomization (MR) is an emerging approach that uses genetic variation as an instrumental variable (IV) for the exposure of interest to estimate the causal relationship between exposure and disease without confounding or reverse causality biases 10 . To date, MR studies of blood metabolites in various diseases such as epilepsy, 11 Alzheimer's disease 12 and lacunar stroke 13 have been conducted by related scholars, but MR studies of blood metabolites in COVID‐19 have not been performed. Therefore, this study used MR analysis to explore the causal relationship between blood metabolites and severe COVID‐19, providing clues to unravel the pathogenesis of COVID‐19 and thus offering new ideas for the prediction and treatment of severe COVID‐19.…”

Section: Introductionmentioning

confidence: 99%

Human blood metabolites and risk of severe COVID‐19: A Mendelian randomization study

Shang,

Qian,

Shen

et al. 2023

Eur J Clin Investigation

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BackgroundEvidence supports the observational associations of human blood metabolites with the risk of severe COVID‐19. However, little is known about the potential pathological mechanisms and the analysis of blood metabolites may offer a better understanding of the underlying biological processes.MethodsWe applied a two‐sample Mendelian randomization (MR) analysis to evaluate relationships between 486 blood metabolites and the risk of severe COVID‐19. The inverse‐variance weighted (IVW) model was used as the primary two‐sample MR analysis method to estimate the causal relationship of the exposure on the outcome. Sensitivity analyses were implemented with Cochran's Q test, MR‐Egger intercept test, MR‐PRESSO, leave‐one‐out analysis and the funnel plot.ResultsFour hunderd and eighty six metabolites were included for MR analysis following rigorous genetic variants selection. After MR analyses and sensitivity analysis filtration, we found weak evidence of an association between 3‐hydroxybutyrate (odds ratio [OR] = 1.21, 95% CI, 1.07–1.38, p = .0036) and the risk of severe COVID‐19. A series of sensitivity analyses have been carried out to confirm the rigidity of the above results.ConclusionThis study suggested a causal relationship between 3‐hydroxybutyrate and the severity of COVID‐19, thus providing novel insights into biomarkers and pathways for COVID‐19 prevention and clinical interventions.

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Association between Human Blood Metabolome and the Risk of Alzheimer's Disease

Cited by 25 publications

References 54 publications

The causal role of circulating amino acids on neurodegenerative disorders: A two‐sample Mendelian randomization study

The causal role of circulating amino acids on neurodegenerative disorders: A two‐sample Mendelian randomization study

Association of genetically predicted 486 blood metabolites on the risk of Alzheimer’s disease: a Mendelian randomization study

Human blood metabolites and risk of severe COVID‐19: A Mendelian randomization study

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