Longitudinal associations of cardiovascular-kidney-metabolic syndrome with midlife or late-life mental disorders and dementia, and the mediating role of metabolomic signature

BACKGROUND: Cardiovascular-Kidney-Metabolic (CKM) syndrome assesses the interconnections among metabolic, kidney, and cardiovascular diseases, rendering significant prognostic value for age-related chronic diseases and mortality. We aimed to investigate the effects of CKM syndrome on transitions between healthy status, mental disorders, and dementia and evaluate the potential mediating role of a CKM-related metabolomic signature in these associations. METHODS: This prospective longitudinal study used UK Biobank data from 375,203 midlife and older adults at baseline and 188,018 with metabolomic information. CKM was staged from 0 to 4. Mental disorders and dementia were identified via ICD-10. Multi-state models analyzed the impact of CKM on transitions from healthy status to mental disorders and dementia. Competing risk (death) models assessed the associations of CKM with specific mental disorders and dementia. Mediation role of CKM-related metabolomic signature was evaluated. RESULTS: We show that per-stage CKM increase elevates hazards of transitioning from healthy to mental disorders (HR = 1.24[1.22-1.26]) and subsequently to dementia (HR = 1.38[1.21-1.58]), or directly to dementia (HR = 1.27[1.21-1.33]). Worsening CKM stages are associated with bipolar, depressive, and anxiety disorders; whilst only advanced stages (3/4) associated with all dementia types. The CKM metabolomic signature mediates 34.9% and 8.1% of associations of CKM with pre-dementia mental disorders and dementia, respectively. CONCLUSIONS: CKM syndrome is associated with pre-dementia mental disorders and dementia, emphasizing the need for regular monitoring and early intervention to manage CKM progression and reduce geriatric neuropsychiatric disturbances.