Investigation of the causal relationship between osteocalcin and dementia: A Mendelian randomization study

Objective: Basic medical studies have reported an improved effect of osteocalcin on cognition. We explored the causal link between osteocalcin and dementia via the implementation of Mendelian randomization methodology.Methods: Genome-wide association studies were employed to identify single nucleotide polymorphisms (SNPs) showing significant correlations with osteocalcin. Subsequently, A two-sample Mendelian randomization analysis was conducted utilizing the inverse-variance-weighted (IVW) technique to assess the causal relationship between osteocalcin and various types of dementia, including Alzheimer's disease (AD), Parkinson's disease (PD), Lewy body dementia (LBD), and vascular dementia (VD). This approach aimed to minimize potential sources of confounding bias and provide more robust results. Multivariable MR (MVMR) analysis was conducted to adjust for potential genetic pleiotropy.Results: The study employed three SNPs, namely rs71631868, rs9271374, and rs116843408, as genetic tools to evaluate the causal association of osteocalcin with dementia. The IVW analysis indicated that osteocalcin may have a potential protective effect against AD with an odds ratio (OR) of 0.790 (95 % CI: 0.688-0.906; P < 0.001). However, no significant relationship was observed between osteocalcin and other types of dementia. Furthermore, the MVMR analysis indicated that the impact of osteocalcin on AD remained consistent even after adjusting for age-related macular degeneration and Type 2 diabetes with an OR of 0.856 (95 % CI: 0.744-0.985; P = 0.030).Conclusions: Our findings provide important insights into the role of osteocalcin in the pathogenesis of AD. Future research is required to clarify the underlying mechanisms and their clinical applications.