751e8bcbeee8146dfe965652008af5a5 264741.pdf ecd4a784203a6178e59c5287b7cd6721906fc381 264741.pdf c919e5bd4d06b2438db508e3d7f3fa3013acaa0050ae434db85e1905d98b2a32 264741.pdf 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 Subject: 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 4 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. Keywords: sex; Alzheimer’s disease; metabolomics; metabolic pathway; blood; vanillylmandelate; tryptophan betaine Author: 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 and on behalf of the European Medical Information Framework Consortium Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Wed Nov 24 10:51:06 2021 CET ModDate: Wed Nov 24 10:58:14 2021 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 15 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 2199603 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- HJOMHV+VnURWPalladioL-Bold Type 1 Custom yes yes no 10 0 JEXXFA+URWPalladioL-Ital Type 1 Custom yes yes no 15 0 FYIZYI+URWPalladioL-Bold Type 1 Custom yes yes no 20 0 OGSZSL+URWPalladioL-Roma Type 1 Custom yes yes no 24 0 EBFBTV+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 32 0 MCBCCI+SourceSansRoman-Regular Type 1C Custom yes yes no 54 0 MCBCCM+SourceSansRoman.613wght Type 1C Custom yes yes no 58 0 MCBCCO+SourceSansRoman-Bold Type 1C Custom yes yes no 62 0 GQQAMP+VnURWPalladioL Type 1 Custom yes yes no 74 0 KGBZDM+EURM10 Type 1 Builtin yes yes no 78 0 KWKPAT+CMSY10 Type 1 Builtin yes yes no 88 0 WBVKDJ+URWPalladioL-BoldItal Type 1 Custom yes yes no 92 0 BADTUE+PazoMath-Italic Type 1 Builtin yes yes no 96 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2023-05-27 03:21:41 CEST RepresentationInformation: 264741.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2023-03-31 11:59:23 CEST Size: 2199603 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 302 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@44c8afef Item: Title: Methods Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Children: Item: Title: Participants Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Item: Title: Clinical and Cognitive Data Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: Metabolomics Data Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: Statistical Analyses Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: Results Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Children: Item: Title: Demographics Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: Sex-Specific Association of Blood Metabolites with AD Endophenotypes Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Item: Title: Interactive Effect of APOE 4 and Sex Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: Sex-Specific Metabolites as Diagnostic Biomarkers Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: Discussion Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Children: Item: Title: Metabolites Associated with AD and Other Endophenotypes Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Item: Title: Sex-Specific Biomarkers Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@a38d7a3 Item: Title: Limitations and Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77f99a05 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@63440df3 Info: 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 Author: 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 and on behalf of the European Medical Information Framework Consortium Subject: 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 4 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. 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