Sleep, metabolites, and global cognition: a mediation analysis of plasma metabolic profiles in the West China Health and Aging Cohort.

93 metabolites were associated with sleep characteristics and 26 were linked to cognitive outcomes in older adults.

• Cross-sectional analysis of 3888 participants aged ≥60 years from the West China Health and Aging Cohort
• 221 total plasma metabolites were analyzed for associations with both sleep characteristics and cognitive outcomes
• Cognitive function was assessed via Mini-Mental State Examination (MMSE)
• Analyses were adjusted for demographic, lifestyle, comorbidity, and medication factors

Four individual metabolites mediated between 1.67% and 3.25% of the sleep-cognition association.

• The four mediating metabolites were ketoleucine, dodecanoic acid, ribonic acid, and ortho-hydroxyphenylacetic acid
• Mediation proportions ranged from 1.67% to 3.25%
• These metabolites were identified as significant intermediaries in the relationship between sleep patterns and global cognitive function

Composite metabolite scores showed stronger mediation effects than individual metabolites, with proportions reaching up to 13.6%.

• Both unrestricted composite metabolite scores and those restricted to branched-chain amino acid (BCAA) pathways demonstrated stronger mediation effects
• Mediation proportions reached up to 13.6% for composite scores
• BCAA pathway-restricted composite scores were specifically highlighted as showing meaningful mediation

Participants with concurrent exposure to poor sleep, high genetic risk, and adverse metabolic profiles showed significantly worse cognitive outcomes than those with single or dual exposures.

• Joint associations of genetic susceptibility, sleep patterns, and metabolic profiles with cognitive function were assessed
• Effect sizes for triple concurrent exposure (poor sleep, high genetic risk, adverse metabolic profiles) exceeded those observed in single or dual exposure groups
• The analysis evaluated additive or synergistic effects across these three risk domains

BCAA metabolism was identified as a key biological pathway linking poor sleep to worse cognitive function in older adults.

• BCAA pathway-specific composite metabolite scores demonstrated notable mediation of the sleep-cognition relationship
• Ketoleucine, one of the four significant individual mediators, is a branched-chain amino acid metabolite (alpha-ketoisocaproic acid derivative)
• The authors concluded that BCAA metabolic signatures 'may serve as biological intermediaries linking poor sleep to worse cognitive function in older adults'
• The authors proposed that metabolic-based strategies could help identify populations at elevated risk of cognitive impairment