Association of cardiovascular-kidney-metabolic health and apolipoprotein E4 genotype with risk of dementia and mortality

Background Poor cardiovascular-kidney-metabolic (CKM) health is becoming prevalent; however, sparse data exist regarding the association of CKM health with incident dementia and all-cause mortality. Objective This study aimed to examine whether poor CKM health is associated with a higher risk of dementia and all-cause mortality, regardless of APOE4 carrier status. Methods In this prospective cohort study, 352,364 participants from the UK Biobank were included. CKM syndrome was identified as a medical condition with the presence of metabolic risk factors, cardiovascular disease, and chronic kidney disease, and was classified into five stages (stage 0 to 4). Cox proportional hazards models were applied to explore the association of CKM health with incident dementia and all-cause mortality. Results Participants in stage 2–3 and stage 4 had 1.12-fold (95% CI: 1.02–1.23, p = 0.023) and 2.18-fold (95% CI: 1.96–2.43, p < 0.001) increased risk of incident all-cause dementia compared with those in stage 0. Similarly, participants in stage 4 also had an increased risk of Alzheimer's disease (HR = 1.51, 95% CI: 1.28–1.78, p < 0.001) and vascular dementia (HR = 4.62, 95% CI: 3.54–6.03, p < 0.001). Participants in later stages were at higher risk of all-cause mortality. We found an interaction between CKM health and APOE4 carrier status (p for interaction <0.001), and the relationship between CKM health and dementia was more pronounced in non- APOE4 carriers. Moreover, there were significant additive interactions between APOE4 carrier status and CKM health on the risk of dementia. Conclusions Poor CKM health is independently associated with an increased risk of dementia, regardless of APOE4 carrier status, and all-cause mortality. These findings imply that promoting CKM health may help to reduce the risk of subsequent dementia and mortality.