Long-term Effects of Cholinesterase Inhibitors on Cognitive Decline and Mortality

Abstract

Objective:To investigate whether Cholinesterase inhibitors (ChEIs) are associated with slower cognitive decline in Alzheimer’s dementia, and decreased risk of severe dementia or death.Methods:Alzheimer’s dementia patients from the Swedish Dementia Registry (SveDem) starting on ChEIs within three months of the dementia diagnosis were included and compared to non-treated Alzheimer’s dementia 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-users 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 Alzheimer’s dementia, ChEIs decrease long term cognitive decline and risk of death, and that galantamine decreases the risk of severe dementia.

Identification of Novel Positive Allosteric Modulators of Neurotrophin Receptors for the Treatment of Cognitive Dysfunction

“…Currently, marketed AD therapeutics are limited to two different categories of symptomatic therapies: acetylcholinesterase inhibitors (AChEIs) and the NMDA antagonist memantines. A recent study where 11,652 Alzheimer's dementia patients using AChEIs were compared to 5826 non-AChEI users in a 5-year follow up, demonstrated that the AChEIs-users had higher MMSE and a lower mortality rate than non-users [74]. Additional studies have shown that treatment using AChEIs is associated with reduced mortality in AD patients [75,76], a reduced risk for stroke [76], and a 37% reduction of cardiovascular events in persons with dementia treated with AChEIs [77].…”

Cardiovascular Complications of Acetylcholinesterase Inhibitors in Patients with Alzheimer’s Disease: A Narrative Review

“…Although no disease-modifying treatments are available for clinical AD, AchE inhibitors have been shown to produce modest improvements in cognitive function and global function scores. 15 - 17 ) Additional analysis has also shown reduction in mortality in patients prescribed AChE inhibitors. 17 , 18 ) Three AChE inhibitors (donepezil, galantamine, and rivastigmine) have been approved by the Food and Drug Administration (FDA) to slow the progression of cognitive decline in patients with mild-to-severe AD.…”

Commentary to ‘Novel drug candidates targeting Alzheimer’s disease: ethical challenges with identifying the relevant patient population’

“…Maria Eriksdotter 1,2 The article by Gustavsson et al 1 addresses the important question how to handle new medications with focus on drug candidates that reduce Aβ or tau in the brain, for individuals with Alzheimer's disease (AD), where the need for a diseasemodifying drug is enormous.…”

“…The current medications for AD, the cholinesterase inhibitors, have been shown to be persistingly better with slower decline in treated than in untreated (Xu et al) but the decline is not halted. 2 The effects on cognition by the recently FDA-approved drug aducanumab are debatable.…”