The causal association between insomnia and cognitive decline: A 2-sample, 2-step multivariable Mendelian randomization study.

While there have been many observational studies to date exploring the potential causal nature of any relationship between insomnia and cognitive decline, the available evidence remains contradictory. As such, in this study, a 2-sample Mendelian randomization (MR) study was performed using publicly accessible genome-wide association study data in order to clarify the mediating effects of several variables on this link. Results were validated by performing sensitivity analyses including the Cochran Q test, the MR-Egger intercept test, the Mendelian Randomization Pleiotropy RESidual Sum and Outlier, MR Radial, and leave-one-out analyses. Based on this 2-sample MR approach, genetically predicted insomnia was found to be negatively causally associated with cognitive function (β, -0.015 [95% CI, -0.026 to -0.004]; P = .006), with this causal link remaining intact following Bonferroni correction. Risk factors relevant to cognitive function including body mass index, respiratory tract infections (RTIs), blood metabolites, and immune cells were analyzed as potential mediating factors, ultimately leading to the identification of RTIs as a significant mediator of the causal link between insomnia and cognitive function (P < .05), mediating 15.4% of this effect. Insomnia is, thus, closely associated with impaired cognition, with RTI playing a role in the interplay between the 2. Developing effective approaches to the early treatment of insomnia, together with a focus on RTIs, may, thus, improve cognition both directly and indirectly through reductions in RTI incidence.