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We aimed to investigate the combined association of depression and vigorous physical activity (VPA) with incident CMM and to examine whether this association differed across metabolic status. This prospective cohort study included 2,661 adults aged\u2009\u2265\u200945\u00a0years without CMM at baseline (2011) from the China Health and Retirement Longitudinal Study. Participants were followed through 2020 (median follow-up: 9\u00a0years), during which 797 incident CMM cases were identified. Depression and VPA were jointly categorized into four groups. Cox proportional hazards models with multiple imputation were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Estimated glucose disposal rate (eGDR) was evaluated as a potential effect modifier using stratified analyses and interaction tests. Sensitivity analyses were performed using alternative metabolic indicators, including the triglyceride\u2013glucose (TyG) index, waist-to-height ratio (WHtR), and cardiometabolic index (CMI). Compared with participants without depression who engaged in VPA (reference), those with both depression and no VPA had the highest risk of CMM (HR 1.93, 95% CI 1.52\u20132.44), followed by those with depression but engaging in VPA (HR 1.84, 95% CI 1.41\u20132.39) and those without depression but no VPA (HR 1.52, 95% CI 1.22\u20131.89). The associations were consistent across metabolic strata defined by eGDR. No evidence of interaction was observed between depression and VPA (P for interaction\u2009&gt;\u20090.05). A dose\u2013response relationship was observed across joint exposure categories (P for trend\u2009&lt;\u20090.001). Sensitivity analyses yielded similar results. Depression and lack of VPA jointly increase the risk of CMM in middle-aged and older adults. Engagement in VPA may partially mitigate the elevated cardiometabolic risk associated with depression. These findings highlight the importance of integrated mental health and lifestyle interventions for preventing CMM.<\/jats:p>","DOI":"10.1038\/s41598-026-50014-2","type":"journal-article","created":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T01:47:57Z","timestamp":1776736077000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Joint association of depression and physical activity with incident cardiometabolic multimorbidity (CMM) among middle-aged and older adults in China"],"prefix":"10.1038","volume":"16","author":[{"given":"Zhaoxuan","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongyu","family":"Qi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lifeng","family":"Qu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guili","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiyu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5220-8132","authenticated-orcid":false,"given":"Xiwen","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,21]]},"reference":[{"issue":"8","key":"50014_CR1","doi-asserted-by":"publisher","first-page":"2615","DOI":"10.3390\/jcm14082615","volume":"14","author":"I Ioakeim-Skoufa","year":"2025","unstructured":"Ioakeim-Skoufa, I. et al. 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