The Use of Cholinesterase Inhibitors Across All Stages of Alzheimer’s Disease

Abstract

Current pharmacological therapy for Alzheimer's disease (AD) includes the cholinesterase inhibitors (ChEIs) donepezil, rivastigmine, and galantamine and the N-methyl D-aspartate receptor antagonist memantine. Based on the results of randomized controlled trials and several meta-analyses, ChEIs appear to show modest but statistically significant improvements on several measures, including cognition and global functioning. Given their modest effects, there is a lack of consensus among clinicians regarding issues related to initiation, optimal duration, and discontinuation of ChEI therapy across the spectrum of AD. There is evidence from long-term observational controlled studies that early initiation and persistent exposure to AD therapy lead to delays in nursing home admission and significantly slower rates of cognitive and functional impairment. In the moderate to severe stages of AD, therapeutic trials of higher dose ChEIs and the addition of memantine are recommended for patients who are no longer responding to lower doses. While side effects are generally mild and gastrointestinal in nature, these events can lead to significant morbidity in more susceptible patients with advanced disease. Patients should thus be regularly monitored for any potential serious side effects of ChEI therapy, which also may include syncope and bradycardia. At the terminal stages of AD, such as when patients become hospice eligible, attempts to cautiously discontinue all medications not necessary for quality of life, including AD drugs, should be made.

A Real-world Analysis of Treatment Patterns for Cholinesterase Inhibitors and Memantine among Newly-diagnosed Alzheimer’s Disease Patients

“…This study did not attempt to define the causal direction of this relationship. Evidence from long-term observational controlled studies supports the early initiation and persistent exposure to AD therapy for delaying nursing home admission and significantly decelerating rates of cognitive and functional impairment [10]. For moderate-to-severe AD patients who are no longer responding to lower doses, therapeutic trials of higher dose AChEIs in combination with memantine are recommended [10].…”

“…Evidence from long-term observational controlled studies supports the early initiation and persistent exposure to AD therapy for delaying nursing home admission and significantly decelerating rates of cognitive and functional impairment [10]. For moderate-to-severe AD patients who are no longer responding to lower doses, therapeutic trials of higher dose AChEIs in combination with memantine are recommended [10]. Side-effects of AChEI therapy are largely mild and gastrointestinal but can lead to significant morbidity in patients with advanced disease [10].…”

“…For moderate-to-severe AD patients who are no longer responding to lower doses, therapeutic trials of higher dose AChEIs in combination with memantine are recommended [10]. Side-effects of AChEI therapy are largely mild and gastrointestinal but can lead to significant morbidity in patients with advanced disease [10]. Patients who initiated treatment with a monotherapy were mostly between the ages of 75–84 and had more severe comorbidities but had similar AD-related disease severity scores to those who were treated with a combination therapy (results not presented).…”

“…A multicenter, natural history study of 201 AD patients demonstrated that AchEI use was associated with delays in reaching the functional end point (Blessed Dementia Rating Scale score ≥10) and mortality [8]. In general, AChEIs are safe compounds, and side-effects are limited to gastrointestinal symptoms [9, 10] but can lead to significant morbidity in patients with advanced disease [10]. Memantine is an N -methyl- d -aspartate (NMDA) receptor antagonist which has been proved to improve cognition and behavior in moderate-to-severe AD [11].…”

Long-Term Effects Of Combined Treatment With Memantine And Donepezil On Alzheimer's Disease Patients: 72-Week Study

“…When the metabolizing enzyme is suppressed, acetylcholine (Ach) activity is increased, and cognitive functions improve in turn [6]. In addition, NMDA receptor antagonists regulate glutamatergic neurons activities that facilitate synaptic plasticity and neuronal growth and differentiation, thereby enhancing cognition, learning, and memory [1,7].…”