Sex-Specific Metabolic Pathways Were Associated with Alzheimer's Disease (AD) Endophenotypes in the European Medical Information Framework for AD Multimodal Biomarker Discovery Cohort

Jin Xu; Rebecca Green; Min Kim; Jodie Lord; Amera Ebshiana; Sarah Westwood; Alison L Baird; Alejo J Nevado-Holgado; Liu Shi; Abdul Hye; Stuart G Snowden; Isabelle Bos; Stephanie J B Vos; Rik Vandenberghe; Charlotte E Teunissen; Mara Ten Kate; Philip Scheltens; Silvy Gabel; Karen Meersmans; Olivier Blin; Jill Richardson; Ellen Elisa De Roeck; Sebastiaan Engelborghs; Kristel Sleegers; Régis Bordet; Lorena Rami; Petronella Kettunen; Magda Tsolaki; Frans R J Verhey; Daniel Alcolea; Alberto Lleó; Gwendoline Peyratout; Mikel Tainta; Peter Johannsen; Yvonne Freund-Levi; Lutz Frölich; Valerija Dobricic; Giovanni B Frisoni; José Luis Molinuevo; Anders Wallin; Julius Popp; Pablo Martinez-Lage; Lars Bertram; Kaj Blennow; Henrik Zetterberg; Johannes Streffer; Pieter Jelle Visser; Simon Lovestone; Petroula Proitsi; Cristina Legido-Quigley

doi:10.3390/biomedicines9111610

Sex-Specific Metabolic Pathways Were Associated with Alzheimer's Disease (AD) Endophenotypes in the European Medical Information Framework for AD Multimodal Biomarker Discovery Cohort

Jin Xu, Rebecca Green, Min Kim, Jodie Lord, Amera Ebshiana, Sarah Westwood, Alison L Baird, Alejo J Nevado-Holgado, Liu Shi, Abdul Hye, Stuart G Snowden, Isabelle Bos, Stephanie J B Vos, Rik Vandenberghe, Charlotte E Teunissen, Mara Ten Kate, Philip Scheltens, Silvy Gabel, Karen Meersmans, Olivier BlinJill Richardson, Ellen Elisa De Roeck, Sebastiaan Engelborghs, Kristel Sleegers, Régis Bordet, Lorena Rami, Petronella Kettunen, Magda Tsolaki, Frans R J Verhey, Daniel Alcolea, Alberto Lleó, Gwendoline Peyratout, Mikel Tainta, Peter Johannsen, Yvonne Freund-Levi, Lutz Frölich, Valerija Dobricic, Giovanni B Frisoni, José Luis Molinuevo, Anders Wallin, Julius Popp, Pablo Martinez-Lage, Lars Bertram, Kaj Blennow, Henrik Zetterberg, Johannes Streffer, Pieter Jelle Visser, Simon Lovestone, Petroula Proitsi, Cristina Legido-Quigley

6 Citationer (Scopus)

Abstract

BACKGROUND: physiological differences between males and females could contribute to the development of Alzheimer's Disease (AD). Here, we examined metabolic pathways that may lead to precision medicine initiatives.

METHODS: We explored whether sex modifies the association of 540 plasma metabolites with AD endophenotypes including diagnosis, cerebrospinal fluid (CSF) biomarkers, brain imaging, and cognition using regression analyses for 695 participants (377 females), followed by sex-specific pathway overrepresentation analyses, APOE ε4 stratification and assessment of metabolites' discriminatory performance in AD.

RESULTS: In females with AD, vanillylmandelate (tyrosine pathway) was increased and tryptophan betaine (tryptophan pathway) was decreased. The inclusion of these two metabolites (area under curve (AUC) = 0.83, standard error (SE) = 0.029) to a baseline model (covariates + CSF biomarkers, AUC = 0.92, SE = 0.019) resulted in a significantly higher AUC of 0.96 (SE = 0.012). Kynurenate was decreased in males with AD (AUC = 0.679, SE = 0.046).

CONCLUSIONS: metabolic sex-specific differences were reported, covering neurotransmission and inflammation pathways with AD endophenotypes. Two metabolites, in pathways related to dopamine and serotonin, were associated to females, paving the way to personalised treatment.

Originalsprog	Engelsk
Artikelnummer	1610
Tidsskrift	Biomedicines
Vol/bind	9
Udgave nummer	11
ISSN	2227-9059
DOI	https://doi.org/10.3390/biomedicines9111610
Status	Udgivet - 3 nov. 2021

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Xu, J., Green, R., Kim, M., Lord, J., Ebshiana, A., Westwood, S., Baird, A. L., Nevado-Holgado, A. J., Shi, L., Hye, A., Snowden, S. G., Bos, I., Vos, S. J. B., Vandenberghe, R., Teunissen, C. E., Kate, M. T., Scheltens, P., Gabel, S., Meersmans, K., ... Legido-Quigley, C. (2021). Sex-Specific Metabolic Pathways Were Associated with Alzheimer's Disease (AD) Endophenotypes in the European Medical Information Framework for AD Multimodal Biomarker Discovery Cohort. Biomedicines, 9(11), Artikel 1610. https://doi.org/10.3390/biomedicines9111610

Xu, J, Green, R, Kim, M, Lord, J, Ebshiana, A, Westwood, S, Baird, AL, Nevado-Holgado, AJ, Shi, L, Hye, A, Snowden, SG, Bos, I, Vos, SJB, Vandenberghe, R, Teunissen, CE, Kate, MT, Scheltens, P, Gabel, S, Meersmans, K, Blin, O, Richardson, J, De Roeck, EE, Engelborghs, S, Sleegers, K, Bordet, R, Rami, L, Kettunen, P, Tsolaki, M, Verhey, FRJ, Alcolea, D, Lleó, A, Peyratout, G, Tainta, M, Johannsen, P, Freund-Levi, Y, Frölich, L, Dobricic, V, Frisoni, GB, Molinuevo, JL, Wallin, A, Popp, J, Martinez-Lage, P, Bertram, L, Blennow, K, Zetterberg, H, Streffer, J, Visser, PJ, Lovestone, S, Proitsi, P & Legido-Quigley, C 2021, 'Sex-Specific Metabolic Pathways Were Associated with Alzheimer's Disease (AD) Endophenotypes in the European Medical Information Framework for AD Multimodal Biomarker Discovery Cohort', Biomedicines, bind 9, nr. 11, 1610. https://doi.org/10.3390/biomedicines9111610

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title = "Sex-Specific Metabolic Pathways Were Associated with Alzheimer's Disease (AD) Endophenotypes in the European Medical Information Framework for AD Multimodal Biomarker Discovery Cohort",

abstract = "BACKGROUND: physiological differences between males and females could contribute to the development of Alzheimer's Disease (AD). Here, we examined metabolic pathways that may lead to precision medicine initiatives.METHODS: We explored whether sex modifies the association of 540 plasma metabolites with AD endophenotypes including diagnosis, cerebrospinal fluid (CSF) biomarkers, brain imaging, and cognition using regression analyses for 695 participants (377 females), followed by sex-specific pathway overrepresentation analyses, APOE ε4 stratification and assessment of metabolites' discriminatory performance in AD.RESULTS: In females with AD, vanillylmandelate (tyrosine pathway) was increased and tryptophan betaine (tryptophan pathway) was decreased. The inclusion of these two metabolites (area under curve (AUC) = 0.83, standard error (SE) = 0.029) to a baseline model (covariates + CSF biomarkers, AUC = 0.92, SE = 0.019) resulted in a significantly higher AUC of 0.96 (SE = 0.012). Kynurenate was decreased in males with AD (AUC = 0.679, SE = 0.046).CONCLUSIONS: metabolic sex-specific differences were reported, covering neurotransmission and inflammation pathways with AD endophenotypes. Two metabolites, in pathways related to dopamine and serotonin, were associated to females, paving the way to personalised treatment.",

author = "Jin Xu and Rebecca Green and Min Kim and Jodie Lord and Amera Ebshiana and Sarah Westwood and Baird, {Alison L} and Nevado-Holgado, {Alejo J} and Liu Shi and Abdul Hye and Snowden, {Stuart G} and Isabelle Bos and Vos, {Stephanie J B} and Rik Vandenberghe and Teunissen, {Charlotte E} and Kate, {Mara Ten} and Philip Scheltens and Silvy Gabel and Karen Meersmans and Olivier Blin and Jill Richardson and {De Roeck}, {Ellen Elisa} and Sebastiaan Engelborghs and Kristel Sleegers and R{\'e}gis Bordet and Lorena Rami and Petronella Kettunen and Magda Tsolaki and Verhey, {Frans R J} and Daniel Alcolea and Alberto Lle{\'o} and Gwendoline Peyratout and Mikel Tainta and Peter Johannsen and Yvonne Freund-Levi and Lutz Fr{\"o}lich and Valerija Dobricic and Frisoni, {Giovanni B} and Molinuevo, {Jos{\'e} Luis} and Anders Wallin and Julius Popp and Pablo Martinez-Lage and Lars Bertram and Kaj Blennow and Henrik Zetterberg and Johannes Streffer and Visser, {Pieter Jelle} and Simon Lovestone and Petroula Proitsi and Cristina Legido-Quigley",

year = "2021",

month = nov,

day = "3",

doi = "10.3390/biomedicines9111610",

language = "English",

volume = "9",

journal = "Biomedicines",

issn = "2227-9059",

publisher = "MDPI AG",

number = "11",

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TY - JOUR

T1 - Sex-Specific Metabolic Pathways Were Associated with Alzheimer's Disease (AD) Endophenotypes in the European Medical Information Framework for AD Multimodal Biomarker Discovery Cohort

AU - Xu, Jin

AU - Green, Rebecca

AU - Kim, Min

AU - Lord, Jodie

AU - Ebshiana, Amera

AU - Westwood, Sarah

AU - Baird, Alison L

AU - Nevado-Holgado, Alejo J

AU - Shi, Liu

AU - Hye, Abdul

AU - Snowden, Stuart G

AU - Bos, Isabelle

AU - Vos, Stephanie J B

AU - Vandenberghe, Rik

AU - Teunissen, Charlotte E

AU - Kate, Mara Ten

AU - Scheltens, Philip

AU - Gabel, Silvy

AU - Meersmans, Karen

AU - Blin, Olivier

AU - Richardson, Jill

AU - De Roeck, Ellen Elisa

AU - Engelborghs, Sebastiaan

AU - Sleegers, Kristel

AU - Bordet, Régis

AU - Rami, Lorena

AU - Kettunen, Petronella

AU - Tsolaki, Magda

AU - Verhey, Frans R J

AU - Alcolea, Daniel

AU - Lleó, Alberto

AU - Peyratout, Gwendoline

AU - Tainta, Mikel

AU - Johannsen, Peter

AU - Freund-Levi, Yvonne

AU - Frölich, Lutz

AU - Dobricic, Valerija

AU - Frisoni, Giovanni B

AU - Molinuevo, José Luis

AU - Wallin, Anders

AU - Popp, Julius

AU - Martinez-Lage, Pablo

AU - Bertram, Lars

AU - Blennow, Kaj

AU - Zetterberg, Henrik

AU - Streffer, Johannes

AU - Visser, Pieter Jelle

AU - Lovestone, Simon

AU - Proitsi, Petroula

AU - Legido-Quigley, Cristina

PY - 2021/11/3

Y1 - 2021/11/3

N2 - BACKGROUND: physiological differences between males and females could contribute to the development of Alzheimer's Disease (AD). Here, we examined metabolic pathways that may lead to precision medicine initiatives.METHODS: We explored whether sex modifies the association of 540 plasma metabolites with AD endophenotypes including diagnosis, cerebrospinal fluid (CSF) biomarkers, brain imaging, and cognition using regression analyses for 695 participants (377 females), followed by sex-specific pathway overrepresentation analyses, APOE ε4 stratification and assessment of metabolites' discriminatory performance in AD.RESULTS: In females with AD, vanillylmandelate (tyrosine pathway) was increased and tryptophan betaine (tryptophan pathway) was decreased. The inclusion of these two metabolites (area under curve (AUC) = 0.83, standard error (SE) = 0.029) to a baseline model (covariates + CSF biomarkers, AUC = 0.92, SE = 0.019) resulted in a significantly higher AUC of 0.96 (SE = 0.012). Kynurenate was decreased in males with AD (AUC = 0.679, SE = 0.046).CONCLUSIONS: metabolic sex-specific differences were reported, covering neurotransmission and inflammation pathways with AD endophenotypes. Two metabolites, in pathways related to dopamine and serotonin, were associated to females, paving the way to personalised treatment.

AB - BACKGROUND: physiological differences between males and females could contribute to the development of Alzheimer's Disease (AD). Here, we examined metabolic pathways that may lead to precision medicine initiatives.METHODS: We explored whether sex modifies the association of 540 plasma metabolites with AD endophenotypes including diagnosis, cerebrospinal fluid (CSF) biomarkers, brain imaging, and cognition using regression analyses for 695 participants (377 females), followed by sex-specific pathway overrepresentation analyses, APOE ε4 stratification and assessment of metabolites' discriminatory performance in AD.RESULTS: In females with AD, vanillylmandelate (tyrosine pathway) was increased and tryptophan betaine (tryptophan pathway) was decreased. The inclusion of these two metabolites (area under curve (AUC) = 0.83, standard error (SE) = 0.029) to a baseline model (covariates + CSF biomarkers, AUC = 0.92, SE = 0.019) resulted in a significantly higher AUC of 0.96 (SE = 0.012). Kynurenate was decreased in males with AD (AUC = 0.679, SE = 0.046).CONCLUSIONS: metabolic sex-specific differences were reported, covering neurotransmission and inflammation pathways with AD endophenotypes. Two metabolites, in pathways related to dopamine and serotonin, were associated to females, paving the way to personalised treatment.

UR - http://www.scopus.com/inward/record.url?scp=85119611017&partnerID=8YFLogxK

U2 - 10.3390/biomedicines9111610

DO - 10.3390/biomedicines9111610

M3 - Journal article

C2 - 34829839

SN - 2227-9059

VL - 9

JO - Biomedicines

JF - Biomedicines

IS - 11

M1 - 1610

ER -

Sex-Specific Metabolic Pathways Were Associated with Alzheimer's Disease (AD) Endophenotypes in the European Medical Information Framework for AD Multimodal Biomarker Discovery Cohort

Abstract

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