Abstract: BACKGROUND: In recent years, multiple epidemiological studies have suggested a potential pathological link between sarcopenia and cognitive impairment. However, due to methodological limitations in traditional observational studies and difficulties in controlling confounding factors, their genetic-level causal relationship has not yet been fully elucidated. 
OBJECTIVE: To systematically analyze the causal relationship and underlying pathogenesis between sarcopenia and cognitive impairment in European populations using Mendelian randomization methods. 
METHODS: This study utilized genome-wide association study (GWAS) summary statistics for sarcopenia-related phenotypes (whole-body fat-free mass, hand grip strength, and walking pace) from the UK Biobank, as well as GWAS summary data for cognitive function from the IEU database. After stringent quality control steps, including threshold screening and linkage disequilibrium removal, a bidirectional Mendelian randomization analysis was conducted. The forward analysis treated sarcopenia-related traits as exposure factors and cognitive function as the outcome variable, while the reverse analysis swapped their causal directions. The inverse-variance weighted method served as the primary analytical approach, supplemented by the weighted median method, MR-Egger regression, and robust adjusted profile score for validation. To ensure the robustness of the findings, the study further performed heterogeneity tests and a series of sensitivity analyses. 
RESULTS AND CONCLUSION: (1) The results of the forward causal analysis using the inverse variance-weighted Mendelian randomization method indicated that total fat-free mass (odds ratio=1.091, 95% confidence interval: 1.001–1.188, P=0.045), left handgrip strength (odds ratio=1.283, 95% confidence interval: 1.077–1.527, P=0.005), right handgrip strength (odds ratio=1.220, 95% confidence interval: 1.022–1.456, P=0.027), and walking speed (odds ratio=3.069, 95% confidence interval: 1.997–4.717, P < 0.001) were all significantly positively correlated with cognitive function. (2) The results of the reverse causal analysis showed that cognitive function was only significantly positively associated with walking speed (odds ratio=1.023, 95% confidence interval: 1.004–1.043, P=0.014), with no significant association found for total fat-free mass or handgrip strength. (3) Sensitivity analyses indicated some heterogeneity in the study; however, horizontal pleiotropy was not observed. Research findings demonstrate a causal relationship between sarcopenia and cognitive impairment, suggesting that sarcopenia may serve as a predictive indicator for cognitive impairment and providing a theoretical basis for early clinical screening. Furthermore, this study, based on an international public database, offers new evidence for the association between sarcopenia and cognitive impairment in the Chinese population, which holds significant reference value for the early screening and prevention of these two conditions.

Key words: sarcopenia, cognitive impairment, bidirectional Mendelian randomization, causal relationship, muscle-brain axis, muscle mass, walking speed