Acetylcholinesterase inhibitors and the risk of delirium – a Danish nationwide register-based cohort study

Delirium is frequent in people with dementia and is linked to adverse outcomes. Disturbed cholinergic neurotransmission is implicated in its pathophysiology. We examined whether continuous use of acetylcholinesterase inhibitors (AChEIs) is associated with a reduced risk of incident delirium in patients with dementia. Using Danish nationwide registries (2005–2024), we identified individuals ≥ 50 years initiating AChEIs. Continuous users (second prescription within 90 days) were compared with early discontinuers. Follow-up started 90 days after initiation and continued for up to 3 years. The outcome was a hospital discharge diagnosis of delirium (ICD-10 F05). Confounding was addressed using high-dimensional propensity score (hdPS) fine-stratification weighting, and Cox regression yielded hazard ratios (HRs) with 95% confidence intervals (CIs). Among 45,651 patients, 311 delirium events occurred among continuous users and 84 among early discontinuers, corresponding to incidence rates of 66 and 112 events per 10,000 person-years, respectively. The hdPS-weighted HR for delirium was 0.72 (95% CI 0.54–0.96). Results were consistent across sensitivity analyses and in patients with Alzheimer’s disease HR 0.68 (95% CI 0.48–0.96). A negative control outcome showed no association. Continuous AChEI treatment was associated with a lower risk of delirium. Findings support a potential benefit of maintaining therapy in routine dementia care, and possibly even in patients with minor intolerance to acetylcholinesterase inhibitors.