Objective: Cholinesterase inhibitors (ChEIs) are the mainstay treatment of Alzheimer’s dementia (AD), but their long-term effectiveness is uncertain. This study aims is to investigate whether ChEIs are associated with slower cognitive decline in AD, and decreased risk of severe dementia or death.

Methods: AD patients from the Swedish Dementia Registry (SveDem) starting on ChEIs within three months of the dementia diagnosis were included and compared to non-treated AD patients. In a propensity score matched cohort, the association between ChEI-use and cognitive trajectories assessed by MMSE scores were examined with a mixed model, and severe dementia (MMSE<10) or death as outcomes with Cox proportional hazards models.

Results: The matched cohort included 11,652 ChEI-use and 5,826 non-users. During an average of 5 years follow up, 255 cases developed severe dementia and 6,055 (35%) died. ChEI-use was associated with higher MMSE at each visit (0.13 MMSE points/year; 95% confidence interval-CI 0.06, 0.20). ChEI-use had a 27% lower risk of death (0.73; CI 0.69, 0.77) compared with non-users. Galantamine was associated with lower risk of death (0.71; CI 0.65, 0.76), lower risk of severe dementia (0.69; CI 0.47-1.00), and had the strongest effect on cognitive decline of all the ChEIs (0.18 MMSE points/year, CI 0.07, 0.28).

Conclusions: ChEIs are associated with cognitive benefits which are modest but persist over time and with reduced mortality risk, which could be explained partly by their cognitive effects. Galantamine was the only ChEI demonstrating a significant reduction in the risk of developing severe dementia.

Classification of Evidence: This study provides Class III evidence that for patients with AD, ChEIs decrease long term cognitive decline and risk of death, and that galantamine decreases the risk of severe dementia.