Mortality risk associated with acetylcholinesterase inhibitor use in Parkinson’s disease dementia according to sex and age at disease onset: a nationwide cohort study

Objectives: Dementia increases mortality risk; however, most studies evaluating acetylcholinesterase inhibitors (AChEIs) have focused on Alzheimer's disease. The survival effects of AChEIs in Parkinson's disease dementia (PDD) remain unclear. This study evaluated the association between AChEI use and mortality in PDD, stratified by sex and age at Parkinson's disease (PD) onset. Methods: This retrospective cohort study used data from the Korean National Health Insurance Service from January 2002 to December 2021. Patients diagnosed with PDD after PD onset were included. Propensity score matching (2:1) was performed to match AChEI users with non-users. Kaplan-Meier survival analyses and subgroup analyses were conducted according to sex and age at PD onset. Results: AChEI use was associated with a 24% reduction in mortality risk (HR = 0.76, 95% CI: 0.74-0.78, p < 0.001). The survival benefit persisted throughout follow-up and was more pronounced in females (HR = 0.71, 95% CI: 0.69-0.74) than in males (HR = 0.83, 95% CI: 0.80-0.86). In late-onset PDD, AChEI use was associated with a 26% reduction in mortality (HR = 0.74, 95% CI: 0.72-0.76), whereas no significant association was observed in young-onset PDD (HR = 1.02, 95% CI: 0.92-1.33, p = 0.665). Survival outcomes were comparable between donepezil and rivastigmine users. Conclusion: AChEI use improved survival in patients with PDD, particularly in females and in those with late-onset PD, with the greatest benefit observed during early and medium-term follow-up periods. These findings suggest that AChEIs may confer a survival advantage in PDD regardless of the specific agent used.