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

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.

Sex Differences in Tryptophan Metabolism: A Systematic Review Focused on Neuropsychiatric Disorders

“…Further, compared with healthy individuals, AD and depressive patients had reduced circulating levels of Tryp [ 58 , 103 , 110 , 111 ], while CFS patients exhibited similar levels [ 112 , 113 ]. Concerning sexual dimorphisms, women with MDD and AD showed a reduced availability of Tryp compared with men [ 45 , 83 , 94 , 95 ]. Further, depressive women also had lower 5-HT production [ 45 ] and a more pronounced depressive response to the depletion of this neurotransmitter precursor [ 85 , 86 ].…”

“…In contrast, for CFS both sexes had similar concentrations of this amino acid available in circulation for baseline conditions [ 42 , 87 ] and following a supplementation treatment [ 87 ]. Regarding kynurenine, some studies reported higher levels in circulation in women with AD and CFS [ 42 , 95 ], while others reported no sex differences in that metabolite for CFS and depression [ 42 , 87 ]. All these results sustained that Tryp signalling might be involved in the sexual dimorphism observed in the pathology and symptomatology of depression and AD.…”

The promise of multi-omics approaches to discover biological alterations with clinical relevance in Alzheimer’s disease

“…This suggests that specific clinical manifestations of AD could be associated with distinct biological alterations. More generally, the molecular signature of disease could differ from one patient to another, according to cognitive status, age or sex for example ( Xu et al, 2021 ). Therefore, identification of specific molecular signatures is key for (i) better understanding the mechanisms underlying the heterogeneity of AD, (ii) developing specific diagnosis tests based on multi-omics derived biomarkers and (iii) for developing patient-tailored interventions that take into account individual biological specificities.…”

“…Alterations of the lipid metabolism including oxysterols ( Gamba et al, 2019 ; Jahn et al, 2021 ), cholesterol and non-cholesterol sterols ( Popp et al, 2012 , 2013 ), eicosanoids ( Biringer, 2019 ) and other lipid groups ( Kao et al, 2020 ), have been associated with AD pathology ( Barbash et al, 2017 ). Other metabolic pathways, such as one-carbon metabolism ( Oikonomidi et al, 2016 ; Troesch et al, 2016 ; Dayon et al, 2017 ), glucose ( Arnold et al, 2018 ) and amino acid metabolism ( De Leeuw et al, 2017 ), amongst others ( van der Velpen et al, 2019 ; Xu et al, 2021 ), are also implicated in AD. Vascular factors are also part of the AD pathology ( Bowman et al, 2018 ; Nation et al, 2019 ).…”

Multivariate GWAS of Alzheimer’s disease CSF biomarker profiles implies GRIN2D in synaptic functioning

“…Both deep phenotyping (such as brain imaging and determination of CSF biomarkers) and genotyping (SNP arrays and wholeexome sequencing) were performed on a large part of EMIF-AD participants. [21][22][23] The current study utilizes the existing CSF biomarker and SNP array data and combines them with a range of statistical methods not previously employed on these data. Written informed consent was obtained for all assessment before start of the study.…”