Insomnia-Related Metabolomic Profiles Reflect Antioxidant Deficits and Relate to Cognitive Decline Through a Metabolic Risk Score in HCHS/SOL

BackgroundWe aimed to identify metabolites and create risk scores for insomnia symptoms in U.S. Hispanic/Latino adults. MethodsWe analyzed data from 6,107 participants in the Hispanic Community Health Study/Study of Latinos, split into discovery (n=3,932) and replication datasets (n=2,175). Serum metabolites and the Womens Health Initiative Insomnia Rating Scale (WHIIRS) were collected at baseline. We examined the relationships between 768 metabolites and insomnia symptoms and suspected insomnia (WHIIRS[≥]9) using the discovery dataset, followed by replication. Metabolite risk scores (MRSs) were generated with LASSO regression and evaluated for replication. We assessed the relationships of replicated metabolite measures and MRS with sleep, cognitive, and psychological traits (cross-phenotypes). FindingsNine metabolites were associated with insomnia symptoms in the discovery study, with two of these being replicated. Lower levels of hydrocinnamate and indolepropionate correlated with increased insomnia symptoms. We developed MRS for insomnia symptoms with replication. Various associations were observed between the two metabolites, 2 MRS, and cross-phenotypes. For instance, the WHIIRS MRS was associated with a higher risk of mild cognitive impairment (MCI) seven years later (OR:1.58, 95%CI:1.43-1.74 per 1 SD increase in MRS). InterpretationThe metabolomic profile associated with insomnia symptoms encompasses diet and gut microbiome metabolites. This study identified specific metabolites linked to insomnia that are also related to comorbidities, such as a higher risk of developing MCI during follow-up, suggesting a shared mechanism. FundingGrants from various National Institutes of Health and the JLH Foundation supported the work. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSInsomnia affects 30-36% of individuals, with clinical insomnia estimated at 6-10%, and it is more severe among Hispanics, who also face higher risks for cognitive decline and cardiovascular disease. While previous metabolomics studies have investigated sleep disorders, most have focused on sleep apnea or sleep duration, not insomnia. The few studies that focus on insomnia were limited by small sample sizes or co-occurring psychiatric conditions. Only two large-scale studies linked insomnia symptoms to specific metabolites, but neither examined these associations in Hispanics or their connection to cognitive decline--gaps this study aims to address using data from the HCHS/SOL cohort. Added value of this studyWe identified nine metabolites related to insomnia symptoms, with two--hydrocinnamate and indolepropionate--being replicated. We also created and validated metabolite risk scores (MRS), which predicted a higher likelihood of developing mild cognitive impairment (MCI) seven years later. These results provide new insights into the metabolic pathways connecting insomnia and cognitive decline in a high-risk Hispanic population. Implications of all the available evidenceOur findings indicate that insomnia symptoms are linked to specific metabolic changes, some of which may also play a role in cognitive decline. Identifying metabolites related to diet and the gut microbiome points to biological pathways that could be modified through lifestyle or therapeutic interventions. The metabolite risk scores (MRS) developed in this study showed links with mild cognitive impairment (MCI) over time, suggesting their potential usefulness in understanding long-term health risks associated with sleep disturbances. These results encourage further research into the role of metabolomics in sleep and cognitive health, especially in high-risk populations like Hispanics.