Additive Impact of Cardiometabolic Multimorbidity and Depression on Cognitive Decline: Findings from Multi‐Regional Cohorts and Generalization from Community to Clinic

Abstract Background To estimate the additive associations of cardiometabolic multimorbidity (CMM) and depression on long‐term cognitive trajectory in multi‐regional cohorts and validate the generalizability of the findings in varying clinical settings. Method Data harmonization was performed across 14 longitudinal cohort studies within the Cohort Studies of Memory in an International Consortium (COSMIC) group, spanning North America, South America, Europe, Africa, Asia, and Australia. Three external validation studies with distinct settings were employed to assess generalizability. Cross‐sectional and longitudinal analyses were conducted. CMM was defined as: 1) CMM5: ≥ 2 among hypertension, hyperlipidemia, diabetes mellitus, stroke, and heart disease and 2) CMM3 (aligned with previous studies): ≥ 2 among diabetes mellitus, stroke, and heart disease. Depression was identified using the Geriatric Depression Scale, Center for Epidemiological Studies‐Depression scale, or medical history. A one‐step individual participant data meta‐analysis was utilized to investigate associations between the co‐occurrence of CMM and depression and cognitive outcomes in the COSMIC studies. Stratified analyses were conducted based on baseline dementia status, demographics, and APOE genotype. Repeated analyses were performed in external validation studies for generalization. Result Of the 32,450 older adults in the 14 COSMIC cohorts, we included 31,243 participants with complete data on CMM, depression, and cognitive assessment for cross‐sectional analyses. Among them, 23,242 who had at least 1 follow‐up cognitive assessment were included in the longitudinal analyses. From the three external studies we included 1964 participants, representing 3 multi‐ethnic Asian elderly cohorts (community cohort, memory clinic cohort, and stroke cohort). In the COSMIC studies analysis, the co‐occurrence of CMM and depression was associated with both cross‐sectional cognitive performance (β = ‐0.20, 95%CI = (‐0.25,‐0.16) for CMM5 and depression, β = ‐0.17, (95%CI = ‐0.044,‐0.031) for CMM3 and depression), and rate of cognitive decline (β = ‐0.038, 95%CI = (‐0.25,‐0.16) for CMM5 and depression, β = ‐0.023, (95%CI = ‐0.036, ‐0.009) for CMM3 and depression). This combined effect remained consistent across different subgroups particularly among participants without dementia. These findings were reproduced in the three external validation studies. Conclusion Our study demonstrated an additive effect between CMM and depression on cognitive decline. Targeting both cardiometabolic and psychological conditions could lead to greater effectiveness in delaying or preventing cognitive decline.