Jiashu Yue, Jian Huang, Tongtong Zhang, Qianying Hao, Gang Liu, Huizhong Bai, Yu Jiang, Yunqiao Zhou, Jinyu Li, Xiaohong Mu
In the UK Biobank, algorithmically ascertained dementia status was associated with bone fragility, functional trajectories, and baseline probable sarcopenia-related phenotypes. Time-updated analyses supported elevated postdiagnosis bone risks, with the strongest estimates near the time of diagnosis. EGFR and EBI3/IL27 were the most consistently supported candidate circulating indirect-effect signals for the recorded dementia status-probable sarcopenia association. CKB met the prespecified observed-sample criteria but showed lower selection stability and was retained as exploratory; individual proportions mediated were modest.
BACKGROUND: The systemic impact of dementia on musculoskeletal health remains poorly characterized. We investigated associations of algorithmically ascertained dementia status with bone fragility, functional trajectories, and low grip strength-defined probable sarcopenia, and explored candidate circulating proteomic indirect-effect signals for these associations.
METHODS: In a prospective UK Biobank cohort of 151,751 participants (median follow-up 15.1 years), dementia status was defined from algorithmically derived diagnosis records spanning linked follow-up. Descriptive fixed group-status models evaluated associations with incident osteoporosis and fracture, longitudinal grip-strength and physical-activity trajectories, and baseline probable sarcopenia and probable osteosarcopenia proxy. A time-updated Cox analysis assigned person-time before and on the recorded diagnosis date to the reference state and person-time strictly after that date to the exposed state. In a proteomic subcohort (n = 16,652; Olink Explore 3,072), two-stage screening of 2,923 proteins identified candidate protein signals; these were then evaluated using exploratory, model-based indirect-effect analyses with bootstrap resampling.
RESULTS: In time-updated models, all-cause dementia after diagnosis was associated with osteoporosis (HR = 1.78, 95% CI 1.43-2.20) and fracture (HR = 3.68, 95% CI 2.34-5.77), with estimates strongest within 0-2 years after diagnosis and attenuated thereafter. For descriptive context, fixed group-status analyses of recorded dementia ascertainment status showed associations with osteoporosis (HR = 2.31, 95% CI 2.06-2.59) and fracture (HR = 3.13, 95% CI 2.27-4.31), accelerated grip decline (β = -0.317 kg/year, p = 1.3 × 10-5), and higher baseline odds of probable sarcopenia (OR = 1.41, 95% CI 1.23-1.61). Under the prespecified observed-sample criteria, EGFR (proportion mediated [PM] = 8.7%), EBI3/IL27 (PM = 5.9%), and CKB (PM = 3.8%) had modest indirect-effect estimates. Across the age-adjusted first-stage screen and the 500-resample full-pipeline bootstrap, EGFR and EBI3/IL27 were the most consistently supported signals; CKB showed lower joint selection stability and was classified as exploratory.
CONCLUSION: In the UK Biobank, algorithmically ascertained dementia status was associated with bone fragility, functional trajectories, and baseline probable sarcopenia-related phenotypes. Time-updated analyses supported elevated postdiagnosis bone risks, with the strongest estimates near the time of diagnosis. EGFR and EBI3/IL27 were the most consistently supported candidate circulating indirect-effect signals for the recorded dementia status-probable sarcopenia association. CKB met the prespecified observed-sample criteria but showed lower selection stability and was retained as exploratory; individual proportions mediated were modest.