Cardiovascular-kidney-metabolic syndrome, dementia risk, cognition, and neuroimaging outcomes

The recently defined Cardiovascular-Kidney-Metabolic (CKM) syndrome represents a critical intersection of cardiovascular, renal, and metabolic health. However, the specific relationship between CKM syndrome and dementia risk, cognitive function, and brain structure remains underexplored.

We conducted a retrospective analysis in the prospective, community-based cohort in the UK Biobank. Participants were recruited across the United Kingdom between 2006 and 2010. Follow-up began at enrollment until dementia diagnosis, death, or the censoring date (1 January 2023), whichever occurred first. The individual CKM syndrome stage was defined and categorized into five levels according to their baseline information, ranging from a healthy condition (Stage 0) to advanced clinical cardiovascular disease (Stage 4). The primary outcome was incident all-cause dementia. Multivariable Cox and linear regression models examined the associations between CKM stages and dementia risk, cognitive decline, and neuroimaging outcomes. Mediation analysis was performed to quantify how brain structural changes mediate the relationship between CKM stage and all-cause dementia incidence.

A total of 387,340 individuals were included in this analysis. Over a mean follow-up of 13.8 years, all-cause dementia was diagnosed among 249 participants in CKM Stage 0 (0.76 %), 1612 among Stage 1 (1.22 %), 3205 among Stage 2 (1.76 %), 958 among Stage 3 (6.01 %), and 1303 among Stage 4 (5.21 %). Compared to Stage 0 (the reference group), all-cause dementia risk was highest among participants in Stage 4 (HR = 1.87, 95 % CI 1.61-2.16). Neuroimaging analyses revealed significant reductions in total brain, gray matter, and hippocampal volumes, and increased white matter hyperintensity (WMH) volumes, with advancing CKM stages (all P-trend < 0.001). Mediation analyses indicated that structural brain changes, particularly WMH volume, explained up to 15.7 % of the CKM-dementia association.

CKM syndrome is associated with higher dementia risk, cognitive decline, and altered brain structure.