Background: Cardiometabolic multimorbidity (CMM) and depression are often co-occurring in older adults and independently associated with neurodegenerative outcomes. The present study aimed to estimate the additive associations of CMM and depression on long-term cognitive trajectory in multi-regional cohorts, and to validate the generalizability of the findings in additional settings, including clinical.Methods: 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 for generalization. CMM was defined as: 1) CMM 5, ≥ 2 among hypertension, hyperlipidemia, diabetes mellitus, stroke, and heart disease and 2) CMM 3 (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. Cognition was assessed by neuropsychological testings and standardized as z-scores. Longitudinal cognition was calculated as changes in z-scores. A pooled individual participant data analysis was utilized to estimate the main and combined effects of CMM and depression and cognitive outcomes in COSMIC studies cross-sectionally and longitudinally. Stratified analyses were conducted based on baseline dementia status, demographics, and APOE genotype. Repeated analyses were performed in three external validation studies.Findings: Of the 32,450 older adults in the 14 COSMIC cohorts, we included 31,720 participants with complete data on CMM, depression and cognitive assessments for cross-sectional analyses. Among them, 23,242 who had at least 1 follow-up cognitive assessment were included in the longitudinal analyses. The three external studies for validation had 1964 participants from 3 multi-ethnic Asian elderly cohorts (community, memory, and stroke). In COSMIC, we found no interaction between CMM and depression on cognition (all Ps > 0.05). Each of CMM and depression was independently associated with cross-sectional cognitive performance and rate of change decline. Participants with both CMM and depression had lower cross-sectional cognitive performance (e.g. β=-0·20, 95%CI=(-0·25,-0·16) for CMM5(+)/depression(+)) and a faster rate of cognitive decline (e.g. β=-0·038, 95%CI=(-0·045,-0·032) for CMM5(+)/depression(+)) , compared with those without both conditions or with either alone. This combined effect remained consistent across different subgroups but was specifically evident in participants without dementia. These findings were reproduced in the three external validation studies.Interpretation: Our study demonstrated that CMM and depression each had an additive effect on cognitive decline. Targeting both cardiometabolic and psychological conditions in preventing cognitive decline could lead to greater effectiveness.Funding: National Medical Research Council (NMRC), Singapore (NMRC/CG/NUHS/2010 [grant R-184-006-184-511]); Center Grant from the National Medical Research Council Singapore (NMRC/ CG/NUHS/2010 and NMRC/CG/013/2013); and Natural Science Foundation of China (NSFC/72274170). Research reported in this publication was supported by the National Institute On Aging of the National Institutes of Health under Award Number R01AG057531. The content is solely responsibility of the authors and does not necessarily represent the officialviews of the National Institutes of Health.Declaration of Interest: We declare no competing interests.Ethical Approval: This study was approved by the National-Healthcare Group Domain-Specific Review Board and was conducted in accordance with the Declaration of Helsinki.