The joint effect of cardiovascular-kidney-metabolic (CKM) health and genetic susceptibility on dementia remains unclear.

This prospective cohort study utilized data from the UK Biobank. CKM syndrome was characterized by the presence of metabolic risk factors, cardiovascular disease, and chronic kidney disease. We employed Cox proportional hazards models to examine the association between CKM syndrome and dementia incidence, while also investigating the influence of genetic risk via polygenic risk score (PRS) and apolipoprotein E (APOE) ε4 status. We also examined the association between CKM syndrome and cognitive function via linear regression model.

Among 331,731 participants (mean ± SD age, 56.53 ± 8.1 years; 156,762 [47.26 %] male), 4413 (1.33 %) developed dementia during a mean follow-up of 12.8 years. Advanced CKM syndrome correlated with higher risk of dementia; compared to stage 0, HRs for dementia were 1.19 (95 % CI 1.01–1.39, P = 0.036), 1.26 (95 % CI 1.09–1.45, P = 0.002), and 2.06 (95 % CI 1.77–2.39, P < 0.001) for stages 1, 2, and 3–4, respectively. Genetic susceptibility further strengthened this association, and the synergistic effect of CKM syndrome, dementia PRS, and APOE ε4 status surpasses the individual contributions of any single factor. These findings remained robust in a series of subgroups and sensitivity analyses. Individuals in the later stages of CKM syndrome demonstrated poorer performance on cognitive function tests.

Poor CKM health was independently associated with cognitive impairment and an increased risk of dementia. The association between CKM syndrome and risk of dementia could be further strengthened by genetic susceptibility.