Sex and APOE ε4 genotype modify the Alzheimer’s disease serum metabolome

Matthias Arnold; Kwangsik Nho; Alexandra Kueider-Paisley; Tyler Massaro; Kevin Huynh; Barbara Brauner; Siamak MahmoudianDehkordi; Gregory Louie; M. Arthur Moseley; J. Will Thompson; Lisa St John-Williams; Jessica D. Tenenbaum; Colette Blach; Rui Chang; Roberta D. Brinton; Rebecca Baillie; Xianlin Han; John Q. Trojanowski; Leslie M. Shaw; Ralph Martins; Michael W. Weiner; Eugenia Trushina; Jon B. Toledo; Peter J. Meikle; David A. Bennett; Jan Krumsiek; P. Murali Doraiswamy; Andrew J. Saykin; Rima Kaddurah-Daouk; Gabi Kastenmüller

doi:10.1038/s41467-020-14959-w

Sex and APOE ε4 genotype modify the Alzheimer’s disease serum metabolome

Matthias Arnold, Kwangsik Nho, Alexandra Kueider-Paisley, Tyler Massaro, Kevin Huynh, Barbara Brauner, Siamak MahmoudianDehkordi, Gregory Louie, M. Arthur Moseley, J. Will Thompson, Lisa St John-Williams, Jessica D. Tenenbaum, Colette Blach, Rui Chang, Roberta D. Brinton, Rebecca Baillie, Xianlin Han, John Q. Trojanowski, Leslie M. Shaw, Ralph MartinsMichael W. Weiner, Eugenia Trushina, Jon B. Toledo, Peter J. Meikle, David A. Bennett, Jan Krumsiek, P. Murali Doraiswamy, Andrew J. Saykin, Rima Kaddurah-Daouk, Gabi Kastenmüller

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Abstract

Late-onset Alzheimer’s disease (AD) can, in part, be considered a metabolic disease. Besides age, female sex and APOE ε4 genotype represent strong risk factors for AD that also give rise to large metabolic differences. We systematically investigated group-specific metabolic alterations by conducting stratified association analyses of 139 serum metabolites in 1,517 individuals from the AD Neuroimaging Initiative with AD biomarkers. We observed substantial sex differences in effects of 15 metabolites with partially overlapping differences for APOE ε4 status groups. Several group-specific metabolic alterations were not observed in unstratified analyses using sex and APOE ε4 as covariates. Combined stratification revealed further subgroup-specific metabolic effects limited to APOE ε4+ females. The observed metabolic alterations suggest that females experience greater impairment of mitochondrial energy production than males. Dissecting metabolic heterogeneity in AD pathogenesis can therefore enable grading the biomedical relevance for specific pathways within specific subgroups, guiding the way to personalized medicine.

Original language	English (US)
Article number	1148
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-14959-w
State	Published - Dec 1 2020

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Arnold, M., Nho, K., Kueider-Paisley, A., Massaro, T., Huynh, K., Brauner, B., MahmoudianDehkordi, S., Louie, G., Moseley, M. A., Thompson, J. W., John-Williams, L. S., Tenenbaum, J. D., Blach, C., Chang, R., Brinton, R. D., Baillie, R., Han, X., Trojanowski, J. Q., Shaw, L. M., ... Kastenmüller, G. (2020). Sex and APOE ε4 genotype modify the Alzheimer’s disease serum metabolome. Nature communications, 11(1), Article 1148. https://doi.org/10.1038/s41467-020-14959-w

Arnold, M, Nho, K, Kueider-Paisley, A, Massaro, T, Huynh, K, Brauner, B, MahmoudianDehkordi, S, Louie, G, Moseley, MA, Thompson, JW, John-Williams, LS, Tenenbaum, JD, Blach, C, Chang, R , Brinton, RD, Baillie, R, Han, X, Trojanowski, JQ, Shaw, LM, Martins, R, Weiner, MW, Trushina, E, Toledo, JB, Meikle, PJ, Bennett, DA, Krumsiek, J, Doraiswamy, PM, Saykin, AJ, Kaddurah-Daouk, R & Kastenmüller, G 2020, 'Sex and APOE ε4 genotype modify the Alzheimer’s disease serum metabolome', Nature communications, vol. 11, no. 1, 1148. https://doi.org/10.1038/s41467-020-14959-w

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abstract = "Late-onset Alzheimer{\textquoteright}s disease (AD) can, in part, be considered a metabolic disease. Besides age, female sex and APOE ε4 genotype represent strong risk factors for AD that also give rise to large metabolic differences. We systematically investigated group-specific metabolic alterations by conducting stratified association analyses of 139 serum metabolites in 1,517 individuals from the AD Neuroimaging Initiative with AD biomarkers. We observed substantial sex differences in effects of 15 metabolites with partially overlapping differences for APOE ε4 status groups. Several group-specific metabolic alterations were not observed in unstratified analyses using sex and APOE ε4 as covariates. Combined stratification revealed further subgroup-specific metabolic effects limited to APOE ε4+ females. The observed metabolic alterations suggest that females experience greater impairment of mitochondrial energy production than males. Dissecting metabolic heterogeneity in AD pathogenesis can therefore enable grading the biomedical relevance for specific pathways within specific subgroups, guiding the way to personalized medicine.",

author = "Matthias Arnold and Kwangsik Nho and Alexandra Kueider-Paisley and Tyler Massaro and Kevin Huynh and Barbara Brauner and Siamak MahmoudianDehkordi and Gregory Louie and Moseley, {M. Arthur} and Thompson, {J. Will} and John-Williams, {Lisa St} and Tenenbaum, {Jessica D.} and Colette Blach and Rui Chang and Brinton, {Roberta D.} and Rebecca Baillie and Xianlin Han and Trojanowski, {John Q.} and Shaw, {Leslie M.} and Ralph Martins and Weiner, {Michael W.} and Eugenia Trushina and Toledo, {Jon B.} and Meikle, {Peter J.} and Bennett, {David A.} and Jan Krumsiek and Doraiswamy, {P. Murali} and Saykin, {Andrew J.} and Rima Kaddurah-Daouk and Gabi Kastenm{\"u}ller",

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AU - Huynh, Kevin

AU - Brauner, Barbara

AU - MahmoudianDehkordi, Siamak

AU - Louie, Gregory

AU - Moseley, M. Arthur

AU - Thompson, J. Will

AU - John-Williams, Lisa St

AU - Tenenbaum, Jessica D.

AU - Blach, Colette

AU - Chang, Rui

AU - Brinton, Roberta D.

AU - Baillie, Rebecca

AU - Han, Xianlin

AU - Trojanowski, John Q.

AU - Shaw, Leslie M.

AU - Martins, Ralph

AU - Weiner, Michael W.

AU - Trushina, Eugenia

AU - Toledo, Jon B.

AU - Meikle, Peter J.

AU - Bennett, David A.

AU - Krumsiek, Jan

AU - Doraiswamy, P. Murali

AU - Saykin, Andrew J.

AU - Kaddurah-Daouk, Rima

AU - Kastenmüller, Gabi

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Sex and APOE ε4 genotype modify the Alzheimer’s disease serum metabolome

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