Genetic regulation of the metabolome differs by sex, Alzheimer's disease stage, and plasma biomarker status

Jaclyn M. Eissman; Min Qiao; Vrinda Kalia; Marielba Zerlin-Esteves; Dolly Reyes-Dumeyer; Angel Piriz; Saurabh Dubey; Renu Nandakumar; Annie J. Lee; Rafael A. Lantigua; Martin Medrano; Diones Rivera Mejia; Lawrence S. Honig; Clifton L. Dalgard; Gary W. Miller; Richard Mayeux; Badri N. Vardarajan

doi:10.1002/alz.70898

Genetic regulation of the metabolome differs by sex, Alzheimer's disease stage, and plasma biomarker status

Jaclyn M. Eissman, Min Qiao, Vrinda Kalia, Marielba Zerlin-Esteves, Dolly Reyes-Dumeyer, Angel Piriz, Saurabh Dubey, Renu Nandakumar, Annie J. Lee, Rafael A. Lantigua, Martin Medrano, Diones Rivera Mejia, Lawrence S. Honig, Clifton L. Dalgard, Gary W. Miller, Richard Mayeux, Badri N. Vardarajan^*

^*Corresponding author for this work

Anatomy, Physiology, and Genetics

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

1 Scopus citations

Abstract

INTRODUCTION: We investigated genetic regulators of circulating plasma metabolites to identify pathways underlying biochemical changes in clinical and biomarker-supported Alzheimer's disease (AD). METHODS: We computed metabolite quantitative trait loci (QTL) with whole-genome sequencing (WGS) and small molecule plasma metabolites from 229 older adults with clinical AD and 322 age-matched healthy controls. Unbiased associations between 6881 metabolites and 332,772 common genetic variants were tested, adjusted for age, sex, and both metabolomic and genomic principal components. RESULTS: We identified 72 SNP-metabolite associations spanning 66 genes and 12 metabolite classes, including PYROXD2/N6-methyllysine, FAAH/myristoylglycine, and FADS2/arachidonic acid. Additionally, we found differences in genetic regulation of metabolites among individuals with clinically-defined AD compared to biomarker-defined AD based on a published plasma P-tau181 cutoff. We also found more SNP-metabolite associations among males compared to females. DISCUSSION: In summary, we identified sex- and disease-specific genetic regulators of plasma metabolites, revealing unique biological mechanisms of genetic perturbations in AD. Highlights: Genetic regulators of the metabolome spanned 66 genes and 12 metabolite classes. Clinically versus biomarker-defined Alzheimer's disease (AD) affects genetic regulators of the metabolome. Most metabolite quantitative trait loci (QTLs) are not shared between males and females.

Original language	English
Article number	e70898
Journal	Alzheimer's and Dementia
Volume	21
Issue number	11
DOIs	https://doi.org/10.1002/alz.70898
State	Published - Nov 2025

Keywords

Alzheimer's disease
genetic regulation
genomics
metabolites
metabolomics
quantitative trait loci

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10.1002/alz.70898

Cite this

Eissman, J. M., Qiao, M., Kalia, V., Zerlin-Esteves, M., Reyes-Dumeyer, D., Piriz, A., Dubey, S., Nandakumar, R., Lee, A. J., Lantigua, R. A., Medrano, M., Mejia, D. R., Honig, L. S., Dalgard, C. L., Miller, G. W., Mayeux, R., & Vardarajan, B. N. (2025). Genetic regulation of the metabolome differs by sex, Alzheimer's disease stage, and plasma biomarker status. Alzheimer's and Dementia, 21(11), Article e70898. https://doi.org/10.1002/alz.70898

@article{bb1e6038b76942cbbed49e8841ef26b2,

title = "Genetic regulation of the metabolome differs by sex, Alzheimer's disease stage, and plasma biomarker status",

abstract = "INTRODUCTION: We investigated genetic regulators of circulating plasma metabolites to identify pathways underlying biochemical changes in clinical and biomarker-supported Alzheimer's disease (AD). METHODS: We computed metabolite quantitative trait loci (QTL) with whole-genome sequencing (WGS) and small molecule plasma metabolites from 229 older adults with clinical AD and 322 age-matched healthy controls. Unbiased associations between 6881 metabolites and 332,772 common genetic variants were tested, adjusted for age, sex, and both metabolomic and genomic principal components. RESULTS: We identified 72 SNP-metabolite associations spanning 66 genes and 12 metabolite classes, including PYROXD2/N6-methyllysine, FAAH/myristoylglycine, and FADS2/arachidonic acid. Additionally, we found differences in genetic regulation of metabolites among individuals with clinically-defined AD compared to biomarker-defined AD based on a published plasma P-tau181 cutoff. We also found more SNP-metabolite associations among males compared to females. DISCUSSION: In summary, we identified sex- and disease-specific genetic regulators of plasma metabolites, revealing unique biological mechanisms of genetic perturbations in AD. Highlights: Genetic regulators of the metabolome spanned 66 genes and 12 metabolite classes. Clinically versus biomarker-defined Alzheimer's disease (AD) affects genetic regulators of the metabolome. Most metabolite quantitative trait loci (QTLs) are not shared between males and females.",

keywords = "Alzheimer's disease, genetic regulation, genomics, metabolites, metabolomics, quantitative trait loci",

author = "Eissman, {Jaclyn M.} and Min Qiao and Vrinda Kalia and Marielba Zerlin-Esteves and Dolly Reyes-Dumeyer and Angel Piriz and Saurabh Dubey and Renu Nandakumar and Lee, {Annie J.} and Lantigua, {Rafael A.} and Martin Medrano and Mejia, {Diones Rivera} and Honig, {Lawrence S.} and Dalgard, {Clifton L.} and Miller, {Gary W.} and Richard Mayeux and Vardarajan, {Badri N.}",

note = "Publisher Copyright: {\textcopyright} 2025 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.",

year = "2025",

month = nov,

doi = "10.1002/alz.70898",

language = "English",

volume = "21",

journal = "Alzheimer's and Dementia",

issn = "1552-5260",

publisher = "John Wiley and Sons Inc",

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Eissman, JM, Qiao, M, Kalia, V, Zerlin-Esteves, M, Reyes-Dumeyer, D, Piriz, A, Dubey, S, Nandakumar, R, Lee, AJ, Lantigua, RA, Medrano, M, Mejia, DR, Honig, LS, Dalgard, CL, Miller, GW, Mayeux, R & Vardarajan, BN 2025, 'Genetic regulation of the metabolome differs by sex, Alzheimer's disease stage, and plasma biomarker status', Alzheimer's and Dementia, vol. 21, no. 11, e70898. https://doi.org/10.1002/alz.70898

TY - JOUR

T1 - Genetic regulation of the metabolome differs by sex, Alzheimer's disease stage, and plasma biomarker status

AU - Eissman, Jaclyn M.

AU - Qiao, Min

AU - Kalia, Vrinda

AU - Zerlin-Esteves, Marielba

AU - Reyes-Dumeyer, Dolly

AU - Piriz, Angel

AU - Dubey, Saurabh

AU - Nandakumar, Renu

AU - Lee, Annie J.

AU - Lantigua, Rafael A.

AU - Medrano, Martin

AU - Mejia, Diones Rivera

AU - Honig, Lawrence S.

AU - Dalgard, Clifton L.

AU - Miller, Gary W.

AU - Mayeux, Richard

AU - Vardarajan, Badri N.

PY - 2025/11

Y1 - 2025/11

N2 - INTRODUCTION: We investigated genetic regulators of circulating plasma metabolites to identify pathways underlying biochemical changes in clinical and biomarker-supported Alzheimer's disease (AD). METHODS: We computed metabolite quantitative trait loci (QTL) with whole-genome sequencing (WGS) and small molecule plasma metabolites from 229 older adults with clinical AD and 322 age-matched healthy controls. Unbiased associations between 6881 metabolites and 332,772 common genetic variants were tested, adjusted for age, sex, and both metabolomic and genomic principal components. RESULTS: We identified 72 SNP-metabolite associations spanning 66 genes and 12 metabolite classes, including PYROXD2/N6-methyllysine, FAAH/myristoylglycine, and FADS2/arachidonic acid. Additionally, we found differences in genetic regulation of metabolites among individuals with clinically-defined AD compared to biomarker-defined AD based on a published plasma P-tau181 cutoff. We also found more SNP-metabolite associations among males compared to females. DISCUSSION: In summary, we identified sex- and disease-specific genetic regulators of plasma metabolites, revealing unique biological mechanisms of genetic perturbations in AD. Highlights: Genetic regulators of the metabolome spanned 66 genes and 12 metabolite classes. Clinically versus biomarker-defined Alzheimer's disease (AD) affects genetic regulators of the metabolome. Most metabolite quantitative trait loci (QTLs) are not shared between males and females.

AB - INTRODUCTION: We investigated genetic regulators of circulating plasma metabolites to identify pathways underlying biochemical changes in clinical and biomarker-supported Alzheimer's disease (AD). METHODS: We computed metabolite quantitative trait loci (QTL) with whole-genome sequencing (WGS) and small molecule plasma metabolites from 229 older adults with clinical AD and 322 age-matched healthy controls. Unbiased associations between 6881 metabolites and 332,772 common genetic variants were tested, adjusted for age, sex, and both metabolomic and genomic principal components. RESULTS: We identified 72 SNP-metabolite associations spanning 66 genes and 12 metabolite classes, including PYROXD2/N6-methyllysine, FAAH/myristoylglycine, and FADS2/arachidonic acid. Additionally, we found differences in genetic regulation of metabolites among individuals with clinically-defined AD compared to biomarker-defined AD based on a published plasma P-tau181 cutoff. We also found more SNP-metabolite associations among males compared to females. DISCUSSION: In summary, we identified sex- and disease-specific genetic regulators of plasma metabolites, revealing unique biological mechanisms of genetic perturbations in AD. Highlights: Genetic regulators of the metabolome spanned 66 genes and 12 metabolite classes. Clinically versus biomarker-defined Alzheimer's disease (AD) affects genetic regulators of the metabolome. Most metabolite quantitative trait loci (QTLs) are not shared between males and females.

KW - Alzheimer's disease

KW - genetic regulation

KW - genomics

KW - metabolites

KW - metabolomics

KW - quantitative trait loci

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DO - 10.1002/alz.70898

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JO - Alzheimer's and Dementia

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