A Systematic Review and Meta-Analysis of the Effectiveness of Acetylcholinesterase Inhibitors and Memantine in Treating the Cognitive Symptoms of Dementia

Knight, Ruth; Khondoker, Mizanur; Magill, Nicholas; Stewart, Robert; Landau, Sabine

doi:10.1159/000486546

Cited by 123 publications

(90 citation statements)

References 96 publications

(24 reference statements)

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“…Our result was in line with previous studies [54,55], suggesting that AChEIs had greater efficacy than placebo for cognition change assessment. However, with the association between APOE genotype and AD as a major risk factor, APOE ɛ4 is expected to be a potential predictor of response to treatment.…”

Section: Discussionsupporting

confidence: 93%

Effect of Apolipoprotein E ɛ4 Carrier Status on Cognitive Response to Acetylcholinesterase Inhibitors in Patients with Alzheimer’s Disease: A Systematic Review and Meta-Analysis

Cheng

Huang

Liu

2018

Dement Geriatr Cogn Disord

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Background: The apolipoprotein E ɛ4 (APOE ɛ4) genotype is the major genetic risk factor for Alzheimer’s disease (AD). However, its effect on an individual’s response to treatment is less well understood. Many studies have reported that the presence or absence of APOE ɛ4 may have influence on the therapeutic response for acetylcholinesterase inhibitors (AChEIs), but the results were inconsistent. This study performed a systematic review and meta-analysis to evaluate the association between response of treatment with AChEIs and the APOE ɛ4 carrier status. Methods: Clinical studies with AD patients reporting APOE ɛ4 genotype were included in the analysis. Cognitive outcome was measured by the change in Mini-Mental State Examination (MMSE), cognition subscales of the Alzheimer’s Disease Assessment Scale (ADAS-cog), or Cognitive Abilities Screening Instrument (CASI). A random effects model was employed to calculate the standardized mean difference (SMD) and odds ratio (OR). Results: Of the 284 screened abstracts, 38 studies were identified, 30 of which were included for meta-analysis. Continuous data for assessing the association between APOE ε4 and cognitive outcomes of AChEIs were available from 18 studies. The cognitive outcomes showed no significant difference between APOE ε4 carriers and APOE ε4 non-carriers (SMD = 0.022, 95% CI: –0.089∼0.133, p = 0.702, I² = 55.3%). Twelve studies with binary data were included, also revealing insignificant difference between the two groups (OR = 1.164, 95% CI: 0.928∼1.459, p = 0.189, I² = 16.4%). Subgroup analysis indicated that AChEIs were significantly more effective than placebo in both groups. Conclusions: APOE ɛ4 carrier status had no significant influence on the treatment response to AChEIs in patients with AD. AChEIs had a positive therapeutic effect compared with placebo regardless of APOE ε4 carrier status.

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Section: Discussionsupporting

confidence: 93%

Effect of Apolipoprotein E ɛ4 Carrier Status on Cognitive Response to Acetylcholinesterase Inhibitors in Patients with Alzheimer’s Disease: A Systematic Review and Meta-Analysis

Cheng

Huang

Liu

2018

Dement Geriatr Cogn Disord

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“…Whether an even distribution of axonal innervation across the cortex would suffice is unknown, although the evidence presented above regarding the precision of cholinergic innervation linked to function would suggest not. However, acetylcholineesterase inhibitors such as Aricept show mild to moderate efficacy even when the specificity of timing and/or neuronal response cannot be maintained by this class of drug [212,213]. Therefore, it remains to be demonstrated whether specific timing of and/or a precise location of axonal innervation and acetylcholine release in the cortex is required for efficacious neurotransmission, and whether neurotrophins or mimetics can be used to enhance cholinergic-based treatment avenues for dementia.…”

Section: Neurotrophins and Admentioning

confidence: 99%

Regulation of cholinergic basal forebrain development, connectivity, and function by neurotrophin receptors

et al. 2019

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Cholinergic basal forebrain (cBF) neurons are defined by their expression of the p75 neurotrophin receptor (p75NTR) and tropomyosin-related kinase (Trk) neurotrophin receptors in addition to cholinergic markers. It is known that the neurotrophins, particularly nerve growth factor (NGF), mediate cholinergic neuronal development and maintenance. However, the role of neurotrophin signalling in regulating adult cBF function is less clear, although in dementia, trophic signalling is reduced and p75NTR mediates neurodegeneration of cBF neurons. Here we review the current understanding of how cBF neurons are regulated by neurotrophins which activate p75NTR and TrkA, B or C to influence the critical role that these neurons play in normal cortical function, particularly higher order cognition. Specifically, we describe the current evidence that neurotrophins regulate the development of basal forebrain neurons and their role in maintaining and modifying mature basal forebrain synaptic and cortical microcircuit connectivity. Understanding the role neurotrophin signalling plays in regulating the precision of cholinergic connectivity will contribute to the understanding of normal cognitive processes and will likely provide additional ideas for designing improved therapies for the treatment of neurological disease in which cholinergic dysfunction has been demonstrated.

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“…AD pharmacotherapy is still based on the modest symptomatic efficacy showed by potentiation of cholinergic transmission achieved with cholinesterase inhibitors donepezil, rivastigmine and galantamine. Memantine is also used in AD therapy [87]. As a low-affinity antagonist of extrasynaptic NMDA receptors, the main mediators of the excitotoxic component in neuronal degeneration, memantine was suggested to have neuroprotective properties [88].…”

Section: Alzheimer's Diseasementioning

confidence: 99%

Harnessing ionic mechanisms to achieve disease modification in neurodegenerative disorders

Masi

Narducci

Mannaioni

2019

Pharmacological Research

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Progressive neuronal death is the key pathogenic event leading to clinical symptoms in neurodegenerative disorders (NDDs). Neuroprotective treatments are virtually unavailable, partly because of the marked internal heterogeneity of the mechanisms underlying pathology. Targeted neuroprotection would require deep mechanistic knowledge across the entire aetiological spectrum of each NDD and the development of tailored treatments. Although ideal, this strategy appears challenging, as it would require a degree of characterization of both the disease and the patient that is currently unavailable. The alternate strategy is to search for commonalities across molecularly distinct NDD forms and exploit these for the development of drugs with broad-spectrum efficacy. In this view, mounting evidence points to ionic mechanisms (IMs) as targets with potential therapeutic efficacy across distinct NDD subtypes. The scope of this review is to present clinical and preclinical evidence supporting the link between disruption of IMs and neuronal death in specific NDDs and to critically revise past and ongoing attempts of harnessing IMs for the development of neuroprotective treatments.

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A Systematic Review and Meta-Analysis of the Effectiveness of Acetylcholinesterase Inhibitors and Memantine in Treating the Cognitive Symptoms of Dementia

Cited by 123 publications

References 96 publications

Effect of Apolipoprotein E ɛ4 Carrier Status on Cognitive Response to Acetylcholinesterase Inhibitors in Patients with Alzheimer’s Disease: A Systematic Review and Meta-Analysis

Effect of Apolipoprotein E ɛ4 Carrier Status on Cognitive Response to Acetylcholinesterase Inhibitors in Patients with Alzheimer’s Disease: A Systematic Review and Meta-Analysis

Regulation of cholinergic basal forebrain development, connectivity, and function by neurotrophin receptors

Harnessing ionic mechanisms to achieve disease modification in neurodegenerative disorders

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