Cardiovascular-Kidney-Metabolic Syndrome in neurological and psychiatric disorders: a large multi-national cohort study
Brain, Behavior, and Immunity, 2026
Huang Y., Li K., Yang Y., Xu Y., Gu W., Lin M., Shi W., Li J., Yang Y., Wang H.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Metabolic Diseases CVD Neurology Nephrology | Pathophysiology | Plasma |  Olink Explore 3072/384 |
Abstract
Background
Cardiovascular-Kidney-Metabolic (CKM) syndrome is a pioneering paradigm focused on multisystem homeostasis. Nevertheless, the long-term cerebral manifestations of CKM syndrome and its specific relationship with neuropsychiatric disorders remain poorly understood.
Methods
Data for the study were obtained from Health and Retirement Study, UK Biobank, China Health and Retirement Longitudinal Study, and National Health and Nutrition Examination Survey. The exposures are continuous CKM stages (stages 0–4). The main outcomes were dementia, Parkinson’s disease, depression, anxiety, and sleep disorders. Models were adjusted for demographic characteristics, lifestyle factors, and history of cancer. Proteomic signatures, brain structure, epigenetic aging, and inflammatory markers provided clues to the underlying associations.
Results
A total of 321,107 participants aged ≥45 years were included in the analysis. Advanced CKM syndrome exhibited higher risks of five disorders (Stage 4 in UK Biobank: HR, 95%CI: 1.91, 1.79–2.04 in dementia; 1.62, 1.45–1.80 in Parkinson’s disease; 1.75, 1.66–1.84 in depression; 2.33, 2.18–2.48 in sleep disorders; 1.48, 1.40–1.56 in anxiety). CKM syndrome was associated with accelerated phenotypic aging and reduced volumes in the parietal, temporal, and orbitofrontal lobes. Enrichment analysis identified the “Cytokine-cytokine receptor interaction” pathway as a top enriched pathway in both disease clusters, highlighting the central role of immune-inflammatory signaling. Inflammatory markers, phenotypic aging, and certain proteins (GDF15 and PLAUR) may partly mediate the associations of CKM syndrome with these outcomes.
Conclusions
Results of this study revealing the robust and persistent association of CKM stages with neurological and psychiatric disorders suggest that early intervention may be important for cognitive performance and emotional well-being in middle-aged and older adults.