Metabolome-wide association study on ABCA7 indicates a role of ceramide metabolism in Alzheimer’s disease

Abbas Dehghan; Rui Climaco Pinto; Ibrahim Karaman; Jian Huang; Brenan R. Durainayagam; Mohsen Ghanbari; Areesha Nazeer; Qi Zhong; Sonia Liggi; Luke Whiley; Rima Mustafa; Miia Kivipelto; Alina Solomon; Tiia Ngandu; Takahisa Kanekiyo; Tomonori Aikawa; Carola I. Radulescu; Samuel J. Barnes; Gonçalo Graça; Elena Chekmeneva; Stephane Camuzeaux; Matthew R. Lewis; Manuja R. Kaluarachchi; M. Arfan Ikram; Elaine Holmes; Ioanna Tzoulaki; Paul M. Matthews; Julian L. Griffin; Paul Elliott

doi:10.1073/pnas.2206083119

Metabolome-wide association study on ABCA7 indicates a role of ceramide metabolism in Alzheimer’s disease

Abbas Dehghan, Rui Climaco Pinto, Ibrahim Karaman, Jian Huang, Brenan R. Durainayagam, Mohsen Ghanbari, Areesha Nazeer, Qi Zhong, Sonia Liggi, Luke Whiley, Rima Mustafa, Miia Kivipelto, Alina Solomon, Tiia Ngandu, Takahisa Kanekiyo, Tomonori Aikawa, Carola I. Radulescu, Samuel J. Barnes, Gonçalo Graça, Elena ChekmenevaStephane Camuzeaux, Matthew R. Lewis, Manuja R. Kaluarachchi, M. Arfan Ikram, Elaine Holmes, Ioanna Tzoulaki, Paul M. Matthews, Julian L. Griffin, Paul Elliott

Neuroscience

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

Abstract

Genome-wide association studies (GWASs) have identified genetic loci associated with the risk of Alzheimer’s disease (AD), but the molecular mechanisms by which they confer risk are largely unknown. We conducted a metabolome-wide association study (MWAS) of AD-associated loci from GWASs using untargeted metabolic profiling (metabolomics) by ultraperformance liquid chromatography–mass spectrometry (UPLC-MS). We identified an association of lactosylceramides (LacCer) with AD-related single-nucleotide polymorphisms (SNPs) in ABCA7 (P = 5.0 × 10^-5 to 1.3 × 10^-44). We showed that plasma LacCer concentrations are associated with cognitive performance and genetically modified levels of LacCer are associated with AD risk. We then showed that concentrations of sphingomyelins, ceramides, and hexosylceramides were altered in brain tissue from Abca7 knockout mice, compared with wild type (WT) (P = 0.049–1.4 × 10^-5), but not in a mouse model of amyloidosis. Furthermore, activation of microglia increases intracellular concentrations of hexosylceramides in part through induction in the expression of sphingosine kinase, an enzyme with a high control coefficient for sphingolipid and ceramide synthesis. Our work suggests that the risk for AD arising from functional variations in ABCA7 is mediated at least in part through ceramides. Modulation of their metabolism or downstream signaling may offer new therapeutic opportunities for AD.

Original language	English (US)
Article number	e2206083119
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	119
Issue number	43
DOIs	https://doi.org/10.1073/pnas.2206083119
State	Published - Oct 25 2022

Keywords

ABCA7
Alzheimer’s disease
ceramide
genome-wide association study
metabolomics

ASJC Scopus subject areas

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10.1073/pnas.2206083119

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Dehghan, A., Pinto, R. C., Karaman, I., Huang, J., Durainayagam, B. R., Ghanbari, M., Nazeer, A., Zhong, Q., Liggi, S., Whiley, L., Mustafa, R., Kivipelto, M., Solomon, A., Ngandu, T., Kanekiyo, T., Aikawa, T., Radulescu, C. I., Barnes, S. J., Graça, G., ... Elliott, P. (2022). Metabolome-wide association study on ABCA7 indicates a role of ceramide metabolism in Alzheimer’s disease. Proceedings of the National Academy of Sciences of the United States of America, 119(43), Article e2206083119. https://doi.org/10.1073/pnas.2206083119

Dehghan, A, Pinto, RC, Karaman, I, Huang, J, Durainayagam, BR, Ghanbari, M, Nazeer, A, Zhong, Q, Liggi, S, Whiley, L, Mustafa, R, Kivipelto, M, Solomon, A, Ngandu, T, Kanekiyo, T, Aikawa, T, Radulescu, CI, Barnes, SJ, Graça, G, Chekmeneva, E, Camuzeaux, S, Lewis, MR, Kaluarachchi, MR, Ikram, MA, Holmes, E, Tzoulaki, I, Matthews, PM, Griffin, JL & Elliott, P 2022, 'Metabolome-wide association study on ABCA7 indicates a role of ceramide metabolism in Alzheimer’s disease', Proceedings of the National Academy of Sciences of the United States of America, vol. 119, no. 43, e2206083119. https://doi.org/10.1073/pnas.2206083119

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title = "Metabolome-wide association study on ABCA7 indicates a role of ceramide metabolism in Alzheimer{\textquoteright}s disease",

abstract = "Genome-wide association studies (GWASs) have identified genetic loci associated with the risk of Alzheimer{\textquoteright}s disease (AD), but the molecular mechanisms by which they confer risk are largely unknown. We conducted a metabolome-wide association study (MWAS) of AD-associated loci from GWASs using untargeted metabolic profiling (metabolomics) by ultraperformance liquid chromatography–mass spectrometry (UPLC-MS). We identified an association of lactosylceramides (LacCer) with AD-related single-nucleotide polymorphisms (SNPs) in ABCA7 (P = 5.0 × 10-5 to 1.3 × 10-44). We showed that plasma LacCer concentrations are associated with cognitive performance and genetically modified levels of LacCer are associated with AD risk. We then showed that concentrations of sphingomyelins, ceramides, and hexosylceramides were altered in brain tissue from Abca7 knockout mice, compared with wild type (WT) (P = 0.049–1.4 × 10-5), but not in a mouse model of amyloidosis. Furthermore, activation of microglia increases intracellular concentrations of hexosylceramides in part through induction in the expression of sphingosine kinase, an enzyme with a high control coefficient for sphingolipid and ceramide synthesis. Our work suggests that the risk for AD arising from functional variations in ABCA7 is mediated at least in part through ceramides. Modulation of their metabolism or downstream signaling may offer new therapeutic opportunities for AD.",

keywords = "ABCA7, Alzheimer{\textquoteright}s disease, ceramide, genome-wide association study, metabolomics",

author = "Abbas Dehghan and Pinto, {Rui Climaco} and Ibrahim Karaman and Jian Huang and Durainayagam, {Brenan R.} and Mohsen Ghanbari and Areesha Nazeer and Qi Zhong and Sonia Liggi and Luke Whiley and Rima Mustafa and Miia Kivipelto and Alina Solomon and Tiia Ngandu and Takahisa Kanekiyo and Tomonori Aikawa and Radulescu, {Carola I.} and Barnes, {Samuel J.} and Gon{\c c}alo Gra{\c c}a and Elena Chekmeneva and Stephane Camuzeaux and Lewis, {Matthew R.} and Kaluarachchi, {Manuja R.} and Ikram, {M. Arfan} and Elaine Holmes and Ioanna Tzoulaki and Matthews, {Paul M.} and Griffin, {Julian L.} and Paul Elliott",

note = "Publisher Copyright: Copyright {\textcopyright} 2022 the Author(s). Published by PNAS.",

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doi = "10.1073/pnas.2206083119",

language = "English (US)",

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T1 - Metabolome-wide association study on ABCA7 indicates a role of ceramide metabolism in Alzheimer’s disease

AU - Dehghan, Abbas

AU - Pinto, Rui Climaco

AU - Karaman, Ibrahim

AU - Huang, Jian

AU - Durainayagam, Brenan R.

AU - Ghanbari, Mohsen

AU - Nazeer, Areesha

AU - Zhong, Qi

AU - Liggi, Sonia

AU - Whiley, Luke

AU - Mustafa, Rima

AU - Kivipelto, Miia

AU - Solomon, Alina

AU - Ngandu, Tiia

AU - Kanekiyo, Takahisa

AU - Aikawa, Tomonori

AU - Radulescu, Carola I.

AU - Barnes, Samuel J.

AU - Graça, Gonçalo

AU - Chekmeneva, Elena

AU - Camuzeaux, Stephane

AU - Lewis, Matthew R.

AU - Kaluarachchi, Manuja R.

AU - Ikram, M. Arfan

AU - Holmes, Elaine

AU - Tzoulaki, Ioanna

AU - Matthews, Paul M.

AU - Griffin, Julian L.

AU - Elliott, Paul

PY - 2022/10/25

Y1 - 2022/10/25

N2 - Genome-wide association studies (GWASs) have identified genetic loci associated with the risk of Alzheimer’s disease (AD), but the molecular mechanisms by which they confer risk are largely unknown. We conducted a metabolome-wide association study (MWAS) of AD-associated loci from GWASs using untargeted metabolic profiling (metabolomics) by ultraperformance liquid chromatography–mass spectrometry (UPLC-MS). We identified an association of lactosylceramides (LacCer) with AD-related single-nucleotide polymorphisms (SNPs) in ABCA7 (P = 5.0 × 10-5 to 1.3 × 10-44). We showed that plasma LacCer concentrations are associated with cognitive performance and genetically modified levels of LacCer are associated with AD risk. We then showed that concentrations of sphingomyelins, ceramides, and hexosylceramides were altered in brain tissue from Abca7 knockout mice, compared with wild type (WT) (P = 0.049–1.4 × 10-5), but not in a mouse model of amyloidosis. Furthermore, activation of microglia increases intracellular concentrations of hexosylceramides in part through induction in the expression of sphingosine kinase, an enzyme with a high control coefficient for sphingolipid and ceramide synthesis. Our work suggests that the risk for AD arising from functional variations in ABCA7 is mediated at least in part through ceramides. Modulation of their metabolism or downstream signaling may offer new therapeutic opportunities for AD.

AB - Genome-wide association studies (GWASs) have identified genetic loci associated with the risk of Alzheimer’s disease (AD), but the molecular mechanisms by which they confer risk are largely unknown. We conducted a metabolome-wide association study (MWAS) of AD-associated loci from GWASs using untargeted metabolic profiling (metabolomics) by ultraperformance liquid chromatography–mass spectrometry (UPLC-MS). We identified an association of lactosylceramides (LacCer) with AD-related single-nucleotide polymorphisms (SNPs) in ABCA7 (P = 5.0 × 10-5 to 1.3 × 10-44). We showed that plasma LacCer concentrations are associated with cognitive performance and genetically modified levels of LacCer are associated with AD risk. We then showed that concentrations of sphingomyelins, ceramides, and hexosylceramides were altered in brain tissue from Abca7 knockout mice, compared with wild type (WT) (P = 0.049–1.4 × 10-5), but not in a mouse model of amyloidosis. Furthermore, activation of microglia increases intracellular concentrations of hexosylceramides in part through induction in the expression of sphingosine kinase, an enzyme with a high control coefficient for sphingolipid and ceramide synthesis. Our work suggests that the risk for AD arising from functional variations in ABCA7 is mediated at least in part through ceramides. Modulation of their metabolism or downstream signaling may offer new therapeutic opportunities for AD.

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KW - Alzheimer’s disease

KW - ceramide

KW - genome-wide association study

KW - metabolomics

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AN - SCOPUS:85140348906

SN - 0027-8424

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JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

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M1 - e2206083119

ER -

Metabolome-wide association study on ABCA7 indicates a role of ceramide metabolism in Alzheimer’s disease

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