Sex-Specific Metabolic Pathways Were Associated with Alzheimer's Disease (AD) Endophenotypes in the European Medical Information Framework for AD Multimodal Biomarker Discovery Cohort
Xu J, Green R, Kim M, Lord J, Ebshiana A, Westwood S, Baird AL, Nevado-Holgado AJ, Shi L, Hye A, Snowden SG, Bos I, Vos SJB, Vandenberghe R, Teunissen CE, Kate MT, Scheltens P, Gabel S, Meersmans K, Blin O, Richardson J, De Roeck EE, Engelborghs S, Sleegers K, Bordet R, Rami L, Kettunen P, Tsolaki M, Verhey FRJ, Alcolea D, Lleó A, Peyratout G, Tainta M, Johannsen P, Freund-Levi Y, Frölich L, Dobricic V, Frisoni GB, Molinuevo JL, Wallin A, Popp J, Martinez-Lage P, Bertram L, Blennow K, Zetterberg H, Streffer J, Visser PJ, Lovestone S, Proitsi P, Legido-Quigley C, On Behalf Of The European Medical Information Framework Consortium
Resum
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.
Referència
Xu J, Green R, Kim M, Lord J, Ebshiana A, Westwood S, Baird AL, Nevado-Holgado AJ, Shi L, Hye A, Snowden SG, Bos I, Vos SJB, Vandenberghe R, Teunissen CE, Kate MT, Scheltens P, Gabel S, Meersmans K, Blin O, Richardson J, De Roeck EE, Engelborghs S, Sleegers K, Bordet R, Rami L, Kettunen P, Tsolaki M, Verhey FRJ, Alcolea D, Lleó A, Peyratout G, Tainta M, Johannsen P, Freund-Levi Y, Frölich L, Dobricic V, Frisoni GB, Molinuevo JL, Wallin A, Popp J, Martinez-Lage P, Bertram L, Blennow K, Zetterberg H, Streffer J, Visser PJ, Lovestone S, Proitsi P, Legido-Quigley C, On Behalf Of The European Medical Information Framework Consortium. Sex-Specific Metabolic Pathways Were Associated with Alzheimer's Disease (AD) Endophenotypes in the European Medical Information Framework for AD Multimodal Biomarker Discovery Cohort. Biomedicines. 2021 Nov 3;9(11):1610. doi: 10.3390/biomedicines9111610. PMID: 34829839; PMCID: PMC8615383.
