Biomedicines (Nov 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
- 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,
- on behalf of the European Medical Information Framework Consortium
Affiliations
- Jin Xu
- Institute of Pharmaceutical Science, King’s College London, London SE1 9NH, UK
- Rebecca Green
- Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King’s College London, London SE5 9RT, UK
- Min Kim
- Steno Diabetes Center, 2820 Gentofte, Denmark
- Jodie Lord
- Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King’s College London, London SE5 9RT, UK
- Amera Ebshiana
- Institute of Pharmaceutical Science, King’s College London, London SE1 9NH, UK
- Sarah Westwood
- Department of Psychiatry, University of Oxford, Oxford OX3 7JX, UK
- Alison L. Baird
- Department of Psychiatry, University of Oxford, Oxford OX3 7JX, UK
- Alejo J. Nevado-Holgado
- Department of Psychiatry, University of Oxford, Oxford OX3 7JX, UK
- Liu Shi
- Department of Psychiatry, University of Oxford, Oxford OX3 7JX, UK
- Abdul Hye
- Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King’s College London, London SE5 9RT, UK
- Stuart G. Snowden
- Institute of Pharmaceutical Science, King’s College London, London SE1 9NH, UK
- Isabelle Bos
- Alzheimer Center, VU University Medical Center, 1081 HV Amsterdam, The Netherlands
- Stephanie J. B. Vos
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Alzheimer Centrum Limburg, Maastricht University, 6211 LK Maastricht, The Netherlands
- Rik Vandenberghe
- Alzheimer Center, VU University Medical Center, 1081 HV Amsterdam, The Netherlands
- Charlotte E. Teunissen
- Department of Radiology and Nuclear Medicine, VU University Medical Center, 1081 HV Amsterdam, The Netherlands
- Mara Ten Kate
- Alzheimer Center, VU University Medical Center, 1081 HV Amsterdam, The Netherlands
- Philip Scheltens
- Alzheimer Center, VU University Medical Center, 1081 HV Amsterdam, The Netherlands
- Silvy Gabel
- Department of Clinical Chemistry, Neurochemistry Laboratory, Amsterdam Neuroscience, Amsterdam University Medical Centers, Vrije Universiteit, 1081 HV Amsterdam, The Netherlands
- Karen Meersmans
- Department of Neurosciences, Laboratory for Cognitive Neurology, KU Leuven, 3000 Leuven, Belgium
- Olivier Blin
- Clinical Pharmacology & Pharmacovigilance Department, Aix-Marseille University-CNRS, 13007 Marseille, France
- Jill Richardson
- Neurosciences Therapeutic Area, GlaxoSmithKline R&D, Stevenage SG1 2NY, UK
- Ellen Elisa De Roeck
- Center for Neurosciences, Vrije Universiteit Brussel, 1050 Brussels, Belgium
- Sebastiaan Engelborghs
- Reference Center for Biological Markers of Dementia (BIODEM), Institute Born-Bunge, University of Antwerp, 2000 Antwerp, Belgium
- Kristel Sleegers
- Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, University of Antwerp, 2000 Antwerp, Belgium
- Régis Bordet
- Department of Medical Pharmacology, Université de Lille, 59000 Lille, France
- Lorena Rami
- Alzheimer’s Disease and Other Cognitive Disorders Unit, Hospital Clínic of Barcelona, August Pi Sunyer Biomedical Research Institute (IDIBAPS), 08036 Barcelona, Spain
- Petronella Kettunen
- Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden
- Magda Tsolaki
- 1st Department of Neurology, AHEPA University Hospital, 546 21 Thessaloniki, Greece
- Frans R. J. Verhey
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Alzheimer Centrum Limburg, Maastricht University, 6211 LK Maastricht, The Netherlands
- Daniel Alcolea
- Sant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain
- Alberto Lleó
- Sant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain
- Gwendoline Peyratout
- Lausanne University Hospital, 1011 Lausanne, Switzerland
- Mikel Tainta
- Fundación CITA-Alzhéimer Fundazioa, 20009 San Sebastian, Spain
- Peter Johannsen
- Danish Dementia Research Centre, Rigshospitalet, 2100 Copenhagen, Denmark
- Yvonne Freund-Levi
- Department of Neurobiology, Caring Sciences and Society (NVS), Division of Clinical Geriatrics, Karolinska Institutet, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden
- Lutz Frölich
- Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany
- Valerija Dobricic
- Lübeck Interdisciplinary Platform for Genome Analytics, Institutes of Neurogenetics and Cardiogenetics, University of Lübeck, 23562 Lübeck, Germany
- Giovanni B. Frisoni
- Laboratory of Neuroimaging of Aging (LANVIE), University of Geneva, 1205 Geneva, Switzerland
- José Luis Molinuevo
- Alzheimer’s Disease and Other Cognitive Disorders Unit, Hospital Clínic of Barcelona, August Pi Sunyer Biomedical Research Institute (IDIBAPS), 08036 Barcelona, Spain
- Anders Wallin
- Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden
- Julius Popp
- Old Age Psychiatry, Department of Psychiatry, University Hospital Lausanne, 1011 Lausanne, Switzerland
- Pablo Martinez-Lage
- Center for Research and Advanced Therapies, CITA-Alzheimer Foundation, 20009 San Sebastian, Spain
- Lars Bertram
- Lübeck Interdisciplinary Platform for Genome Analytics, Institutes of Neurogenetics and Cardiogenetics, University of Lübeck, 23562 Lübeck, Germany
- Kaj Blennow
- Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, 413 45 Mölndal, Sweden
- Henrik Zetterberg
- Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, 413 45 Mölndal, Sweden
- Johannes Streffer
- Reference Center for Biological Markers of Dementia (BIODEM), Institute Born-Bunge, University of Antwerp, 2000 Antwerp, Belgium
- Pieter Jelle Visser
- Alzheimer Center, VU University Medical Center, 1081 HV Amsterdam, The Netherlands
- Simon Lovestone
- Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King’s College London, London SE5 9RT, UK
- Petroula Proitsi
- Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King’s College London, London SE5 9RT, UK
- Cristina Legido-Quigley
- Institute of Pharmaceutical Science, King’s College London, London SE1 9NH, UK
- on behalf of the European Medical Information Framework Consortium
- DOI
- https://doi.org/10.3390/biomedicines9111610
- Journal volume & issue
-
Vol. 9,
no. 11
p. 1610
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.
Keywords
