Candidate proteomic indirect-effect signals linking dementia to probable muscle-bone fragility: a UK Biobank cohort...

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.

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.

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.

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.