Dissecting neurodegenerative diseases, mental disorders, and short- and long-term mortality in pneumonia: genetic causality analysis and two large-scale cohorts

This investigation sought to explore the genetic correlations and causal relationships between neurodegenerative diseases (NDD) and pneumonia death (short- and long-term), and to identify the mediating role of mental disorders (MD). Comprehensive Mendelian randomization (MR) and logistic regression models were utilized to examine the causal associations between NDD and pneumonia mortality. Consequently, univariable MR (UVMR) and linkage disequilibrium score regression (LDSC) analyses after Bonferroni correction revealed that genetically predicted Alzheimer’s disease (AD) (PMR= 9.11e-4), dementia (PMR= 0.009), multiple sclerosis (MS) (PMR= 0.009), and Parkinson’s disease (PD) (PMR= 0.002) significantly increased the risk of pneumonia death, except amyotrophic lateral sclerosis (ALS) (PMR= 0.099). These findings were replicated in 38 NDD cohorts (n = 233,658) and further validated using both Bayesian-weighted MR (BWMR) and multivariable MR (MVMR) analytical approaches. However, genetically proxied NDD did not significantly increase the 28-day (short-term) pneumonia mortality risk after the Bonferroni correction. Logistic regression revealed that AD, dementia, AD + dementia, and NDD significantly increased the risk of 1-year (long-term) mortality in pneumonia, but not 28-day mortality in pneumonia. Mediation analysis further revealed that MD partially mediated the effect of NDD on the long-term mortality risk of pneumonia, with mediated proportions of 21.60%. These results highlight that intervention in NDD and the corresponding mediator will likely significantly improve long-term survival in severely ill patients with pneumonia.