Plasma metabolomic signature of healthy lifestyle, structural brain reserve and risk of dementia

Abstract Although the association between healthy lifestyle and dementia risk has been documented, the relationship between a metabolic signature indicative of healthy lifestyle and dementia risk and the mediating role of structural brain impairment remain unknown. We retrieved 136 628 dementia-free participants from UK Biobank. Elastic net regression was used to obtain a metabolic signature that represented lifestyle behaviours. Cox proportional hazard models were fitted to explore the associations of lifestyle-associated metabolic signature with incident dementia. Causal associations between identified metabolites and dementia were investigated using Mendelian randomization. Mediation analysis was also conducted to uncover the potential mechanisms involving 19 imaging-derived phenotypes (brain volume, grey matter volume, white matter volume and regional grey matter volumes). During a follow-up of 12.55 years, 1783 incident cases of all-cause dementia were identified, including 725 cases of Alzheimer's dementia and 418 cases of vascular dementia. We identified 83 metabolites that could represent healthy lifestyle behaviours using elastic net regression. The metabolic signature was associated with a lower dementia risk, and for each standard deviation increment in metabolic signature, the hazard ratio was 0.89 [95% confidence interval (CI): 0.85, 0.93] for all-cause dementia, 0.95 (95% CI: 0.88, 1.03) for Alzheimer's dementia and 0.84 (95% CI: 0.77, 0.91) for vascular dementia. Mendelian randomization revealed potential causal associations between the identified metabolites and risk of dementia. In addition, the specific structural brain reserve, including the hippocampus, grey matter in the hippocampus, parahippocampal gyrus and middle temporal gyrus, were detected to mediate the effects of metabolic signature on dementia risk (mediated proportion ranging from 6.21% to 11.98%). The metabolic signature associated with a healthy lifestyle is inversely associated with dementia risk, and greater structural brain reserve plays an important role in mediating this relationship. These findings have significant implications for understanding the intricate connections between lifestyle, metabolism and brain health.