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, R. gis 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

Research output: Contribution to journalArticleAcademicpeer-review

6 Citations (Scopus)


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 languageEnglish
Article number1610
Issue number11
Publication statusPublished - 1 Nov 2021


  • Alzheimer’s disease
  • Blood
  • Metabolic pathway
  • Metabolomics
  • Sex
  • Tryptophan betaine
  • Vanillylmandelate

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