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.
| Original language | English |
|---|---|
| Article number | 1610 |
| Journal | Biomedicines |
| Volume | 9 |
| Issue number | 11 |
| ISSN | 2227-9059 |
| DOIs | |
| Publication status | Published - 11.2021 |
Funding
Funding: The present study was conducted as part of the EMIF-AD project, which has received support from the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement no. 115372, EPAD grant no. 115736, and from the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 666992. Resources of which are composed of financial contribution from the European Union’s Seventh Framework Program (FP7/2007-2013) and EFPIA companies’ in-kind contribution. The DESCRIPA study was funded by the European Commission within the fifth framework program (QLRT-2001-2455). The EDAR study was funded by the European Commission within the fifth framework program (contract no. 37670). The San Sebastian GAP study is partially funded by the Department of Health of the Basque Government (allocation 17.0.1.08.12.0000.2.454.01.41142.001.H). The Leuven cohort was funded by the Stichting voor Alzheimer Onderzoek (grant numbers #11020, #13007 and #15005). The SPIN cohort (Barcelona) has received funding from CIBERNED; Instituto de Salud Carlos III; jointly funded by Fondo Eu-ropeo de Desarrollo Regional (FEDER), Unión Europea, “Una manera de hacer Europa”; Generalitat de Catalunya; Fundació “La Marató TV3” Fundació Bancària Obra Social La Caixa; Fundación BBVA; Fundación Española para el Fomento de la Investigación de la Esclerosis Lateral Amiotrófica (FUNDELA); Global Brain Health Institute; Fundació Catalana Síndrome de Down; and Fundació Víctor Grífols i Lucas. Research at VIB-Antwerp was in part supported by the National Institute of Health (NIH), USA (grant #1R01AG068398-01) Antwerp Research Fund. H.Z. is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), the AD Strategic Fund and the Alzheimer’s Association (#ADSF-21-831376-C, #ADSF-21-831381-C and #ADSF-21-831377-C), the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2019-0228), the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), and the UK Dementia Research Institute at UCL. K.B. is supported by the Swedish Research Council (#2017-00915), the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB-201809-2016615), the Swedish Alzheimer Foundation (#AF-742881), Hjärnfonden, Sweden (#FO2017-0243), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986), the European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236), and the National Institute of Health (NIH), USA, (grant #1R01AG068398-01). P.K. is supported by the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement ALFGBG-724331 and A.W. by ALFGBG-720661. Y.F.-L. is supported by The Brain Foundation (Hjärnfonden FO2018-0315), Stohne’s Foundation (Stohnes Stiftelse), Gamla Tjänarinnor Stftelse, Stohnes Stiftelse, Särfond 31S Research Fund Region Örebro län Sweden, Familjen Kamprad Stiftelse (ref 20210034, AFA 200386). D.A. received support from Institute of Health Carlos III (ISCIII), Spain PI18/00435 and INT19/00016, and by the Department of Health Generalitat de Catalunya PERIS program SLT006/17/125. J.L. is funded by the van Geest endowment fund. R.G. is funded by the National Institute for Health Research (NIHR) Biomedical Research Centre. J.X. and C.L.-Q. thank Lundbeck Fonden for the support. The present study was conducted as part of the EMIF-AD project, which has received support from the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement no. 115372, EPAD grant no. 115736, and from the European Union?s Horizon 2020 research and innovation programme under grant agreement No. 666992. Resources of which are composed of financial contribution from the European Union?s Seventh Framework Program (FP7/2007-2013) and EFPIA companies? in-kind contribution. The DESCRIPA study was funded by the European Commission within the fifth framework program (QLRT-2001-2455). The EDAR study was funded by the European Commission within the fifth framework program (contract no. 37670). The San Sebastian GAP study is partially funded by the Department of Health of the Basque Government (allocation 17.0.1.08.12.0000.2.454.01.41142.001.H). The Leuven cohort was funded by the Stichting voor Alzheimer Onderzoek (grant numbers #11020, #13007 and #15005). The SPIN cohort (Barcelona) has received funding from CIBERNED; Instituto de Salud Carlos III; jointly funded by Fondo Europeo de Desarrollo Regional (FEDER), Uni?n Europea, ?Una manera de hacer Europa?; Generalitat de Catalunya; Fundaci? ?La Marat? TV3? Fundaci? Banc?ria Obra Social La Caixa; Fundaci?n BBVA; Fundaci?n Espa?ola para el Fomento de la Investigaci?n de la Esclerosis Lateral Amiotr?fica (FUNDELA); Global Brain Health Institute; Fundaci? Catalana S?ndrome de Down; and Fundaci? V?ctor Gr?fols i Lucas. Research at VIB-Antwerp was in part supported by the National Institute of Health (NIH), USA (grant #1R01AG068398-01) Antwerp Research Fund. H.Z. is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), the AD Strategic Fund and the Alzheimer?s Association (#ADSF-21-831376-C, #ADSF-21-831381-C and #ADSF-21-831377-C), the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen f?r Gamla Tj?narinnor, Hj?rnfonden, Sweden (#FO2019-0228), the European Union?s Horizon 2020 research and innovation programme under the Marie Sk?odowska-Curie grant agreement No 860197 (MIRIADE), and the UK Dementia Research Institute at UCL. K.B. is supported by the Swedish Research Council (#201700915), the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB-201809-2016615), the Swedish Alzheimer Foundation (#AF-742881), Hj?rnfonden, Sweden (#FO2017-0243), the Swedish state under the agreement between the Swedish government and the County Councils, the ALFagreement (#ALFGBG-715986), the European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236), and the National Institute of Health (NIH), USA, (grant #1R01AG068398-01). P.K. is supported by the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement ALFGBG-724331 and A.W. by ALFGBG-720661. Y.F.-L. is supported by The Brain Foundation (Hj?rnfonden FO2018-0315), Stohne?s Foundation (Stohnes Stiftelse), Gamla Tj?narinnor Stftelse, Stohnes Stiftelse, S?rfond 31S Research Fund Region ?rebro l?n Sweden, Familjen Kamprad Stiftelse (ref 20210034, AFA 200386). D.A. received support from Institute of Health Carlos III (ISCIII), Spain PI18/00435 and INT19/00016, and by the Department of Health Generalitat de Catalunya PERIS program SLT006/17/125. J.L. is funded by the van Geest endowment fund. R.G. is funded by the National Institute for Health Research (NIHR) Biomedical Research Centre. J.X. and C.L.-Q. thank Lundbeck Fonden for the support.The authors thank the participants and families who took part in this research. The authors would also like to thank all people involved in data and sample collection and/or logistics across the different centres.
