2180-P: Cardiovascular–Kidney–Metabolic Syndrome and Risk of Mild Cognitive Impairment and Dementia in Men and Women: Findings from the UK Biobank and All of Us

Introduction and Objective: We examined the association between the full spectrum of Cardiovascular Kidney Metabolic Syndrome (CKM) stages and the risk of mild cognitive impairment (MCI) and dementia, and whether these associations differ by sex. Methods: We analyzed 109,137 dementia-free participants with CKM from the UK Biobank (UKB) and 15,265 from All of Us (AoU). CKM stages were defined as: stage 0 (no CKM risk factors); stage 1 (adiposity); stage 2 (metabolic or kidney dysfunction); stage 3 (subclinical cardiovascular disease [CVD]); and stage 4 (clinical CVD). Advanced stages were 3-4. Outcomes, including MCI and dementia (all-cause, Alzheimer’s disease [AD], and vascular dementia), were identified using ICD codes. Cox models estimated associations between CKM stages and the outcomes overall and by sex, adjusting for age, income, education, race, smoking, alcohol intake, physical activity, social isolation, loneliness, and AD polygenetic risk score. Results: In UKB, 8.7% were in CKM stage 0, 10.3% in stage 1, 38.5% in stage 2, 25.7% in stage 3, and 16.8% in stage 4. Men had a higher prevalence of advanced CKM (stage 3-4) than women (48% vs. 36%). Over a median 13-year follow-up, compared with stages 0-1, adjusted hazard ratios (HRs) and 95% CIs for MCI were 1.23 (1.05-1.45), 1.27 (1.09-1.47), and 3.01 (2.59-3.50) across stages 2-4, respectively (P-trend=.0001); HRs for all-cause dementia were 1.13 (0.97-1.31), 1.14 (0.98-1.33), and 2.47 (2.14-2.86), respectively (P-trend<.0001). Associations between advanced CKM stages (vs. non-advanced stages) and outcomes appeared stronger in men (MCI: 1.8, 1.58-2.05 vs 1.58, 1.4-1.76; all-cause dementia: 1.66, 1.51-1.8 vs 1.55, 1.36-1.76), but sex interactions were not statistically significant. Findings in AoU were consistent. Conclusion: Men have greater advanced CKM burden. CKM stage advancement is associated with progressively higher risks of MCI and dementia, without statistically significant sex-specific differences in effect. Disclosure Y. Yoshida: None. Y. Zu: None. Y. Lu: None. X. Wu: None. Funding American Diabetes Association (7-23-JDFWH-10)