Causal relationship between dementia and delirium: Insights from a bidirectional two-sample Mendelian randomization analysis

<bold>Background: </bold>Our previous study found dementia as a significant risk factor for delirium development in elderly patients with hip fracture. However, the causal relationship between dementia and delirium remains unclear. <bold>Methods: </bold>To assess the causal relationship between delirium and dementia, we conducted a bidirectional Mendelian randomization (MR) analysis. Inversevariance weighted (IVW), weighted median, MR Egger, weighted mode, and simple mode were employed to conduct the MR analysis. Heterogeneity was assessed using the Cochran Q statistic in MR-Egger and IVW methods. Horizontal pleiotropy was examined via the MR pleiotropy residual sum and outliers (MR-PRESSO) and MR-Egger intercept tests. <bold>Results: </bold>The forward MR analysis revealed a significant association between unclassified dementia (1.604 (1.326-1.941), p = 1.12 x 10(-6)), Alzheimer's disease (1.259 (1.128-1.405), p = 4.10 x 10(-5)), and dementia with Lewy bodies (1.121 (1.026-1.225), p = 0.011) with an increased risk of delirium. In the reverse MR analysis, delirium was also suggested to increase the risk of unclassified dementia (1.133 (1.066-1.204), p = 6.31 x 10(-5)) and vascular dementia (1.246 (1.075-1.444), p = 0.003). These significant results were further validated in the multivariable MR analysis. No evidence of heterogeneity or horizontal pleiotropy was observed (p > 0.05). <bold>Limitations: </bold>(1) Limited to European populations. (2) Sample population overlap between delirium and dementia. (3) Not all dementia subtypes were causally associated with delirium. <bold>Conclusions: </bold>This study provides genetic evidence supporting a causal relationship between dementia and delirium, indicating that dementia may influence the risk of delirium while delirium may also increase the risk of dementia.