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

2021; Multidisciplinary Digital Publishing Institute; Volume: 9; Issue: 11 Linguagem: Inglês

10.3390/biomedicines9111610

2227-9059

Jin Xu, Rebecca Green, Min Kim, Jodie Lord, Amera A. Ebshiana, Sarah Westwood, Alison L. Baird, Alejo 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 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 Dobričić, Giovanni B. Frisoni, José Luís Molinuevo, Anders Wallin, Julius Popp, Pablo Martínez‐Lage, Lars Bertram, Kaj Blennow, Henrik Zetterberg, Johannes Streffer, Pieter Jelle Visser, Simon Lovestone, Petroula Proitsi, Cristina Legido‐Quigley,

Stress Responses and Cortisol

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.