Am J Geriatr Psychiatry. 2026 Mar 10:S1064-7481(26)00299-X. doi: 10.1016/j.jagp.2026.03.205. Online ahead of print.
ABSTRACT
OBJECTIVES: CKM syndrome may represent the coexistence of multiple risk factors for dementia; however, its large sample-based effects on the risk of specific-cause dementia and the alterations revealed by brain imaging remain unclear.
MEASUREMENTS: The 239,617 dementia-free participants from the UK Biobank were included in this study. Multivariate Cox regression analyses and stratifications were used to assess longitudinal associations. Linear regression analyses were employed to evaluate CKM-brain structure links. Sensitivity and Mendelian randomization (MR) analyses were performed to confirm the robustness of the results.
RESULTS: Over a 13.6-year median follow-up duration, 3,503 participants developed dementia that included 1,526 Alzheimer's disease (AD) and 770 vascular dementia (VaD) cases. Advanced CKM syndrome stages showed a dose-dependent risk of dementia: stage 3 (Hazard Ratio [HR] = 1.74 versus stage 0, χ² = 19.92, df = 1, p <0.001) and stage 4 (HR = 1.92, χ² = 38.52, df = 1, p <0.001). This pattern held for VaD but not AD, although CKM syndrome stage progression elevated the risk of AD by 130%. MR analysis confirmed significant associations. As a component of the CKM syndrome, metabolic disorders (MD) (abdominal obesity and metabolic syndrome) significantly elevated the risk of VaD but not that of AD. Notably, midlife adults, women, non-APOEε4 carriers, and those displaying low physical activity and education exhibited heightened susceptibility to dementia. Further, there was a spatial correlation pattern between CKM syndrome and brain atrophy (imaging biomarker of dementia): early sensorimotor-limbic shrinkage expanded to prefrontal-parietal and posterior cingulate regions, culminating in hippocampal degeneration.
CONCLUSIONS AND IMPLICATIONS: CKM syndrome stages may serve as a comprehensive predictor of dementia. Individualized monitoring of CKM factors across the lifespan of a person may mitigate progressive neurodegeneration and the risk of dementia.
PMID:41936465 | DOI:10.1016/j.jagp.2026.03.205