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

BackgroundPoor 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.ObjectiveThis study aimed to examine whether poor CKM health is associated with a higher risk of dementia and all-cause mortality, regardless of <i>APOE4</i> carrier status.MethodsIn 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.ResultsParticipants 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 <i>APOE4</i> carrier status (p for interaction <0.001), and the relationship between CKM health and dementia was more pronounced in non-<i>APOE4</i> carriers. Moreover, there were significant additive interactions between <i>APOE4</i> carrier status and CKM health on the risk of dementia.ConclusionsPoor CKM health is independently associated with an increased risk of dementia, regardless of <i>APOE4</i> carrier status, and all-cause mortality. These findings imply that promoting CKM health may help to reduce the risk of subsequent dementia and mortality.