Investigating the role of blood metabolites as biomarkers of cognitive function and dementia in the MRC 1946 British Birth Cohort

Abstract

AbstractBackgroundDecline in cognitive function in late midlife is indicative of dementia. Identifying early markers in this key phase is critical for identifying those at risk and guiding effective interventional strategies. As blood metabolites closely reflect the physiological status of an individual, they show promise as minimally invasive markers for population‐level implementation. Using the MRC 1946 British Birth Cohort, we aim to: 1) Identify blood metabolites associated with early cognitive changes relevant to dementia 2) Tease apart mediating life course factors to address key aetiological questions 3) Employ a network approach, weighted coexpression network analysis (WGCNA), to glean insights into underlying biology.MethodAt age 60‐64, levels of 1019 metabolites were quantified using liquid chromatography‐mass spectrometry (N=1740). At the same age and 5‐9 years later, four aspects of cognitive function were assessed: short‐term and delayed verbal memory, processing speed, and the Addenbrook’s Cognitive Examination‐IIII (ACE‐III). Using WGCNA, 14 modules of highly connected metabolites were identified. Linear regression models evaluated associations between metabolites/metabolite modules and cognitive outcomes, sequentially adjusting for sex, childhood cognitive ability, education, socioeconomic status (SES), lipid medication and lifestyle factors. To infer biological function, pathway analyses were conducted to identify enriched pathways within metabolite modulesResultAfter correcting for multiple testing, 154 metabolites were associated with cognitive outcomes. Many associations attenuated after adjusting for early life cognition and SES, with seven metabolites belonging to lipid, amino acid and xenobiotic families remaining. WGCNA revealed two modules, enriched in vitamin A and sphingolipid metabolism, to be positively associated with cognitive outcomes. However, after adjusting for education and childhood cognition, these associations were largely reduced. Two modules, enriched in amino acid and fatty acid metabolism, were negatively associated with cognitive outcomes, with associations of the fatty acid metabolism module remaining after adjusting for life course factors.ConclusionThese results provide support for a role for metabolites in reflecting early changes relevant to dementia, revealing insights into underlying biological mechanisms and lifelong interplay. It is hoped that these insights can be utilised to inform early diagnosis and the development of disease‐modifying treatments and interventions.