Effect of butyrylcholinesterase genotype on the response to rivastigmine or donepezil in younger patients with Alzheimer's disease.
ABSTRACT A randomized double-blind trial evaluated the efficacy and tolerability of rivastigmine, an inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), and donepezil, an AChE-selective inhibitor, in patients with Alzheimer's disease over a 2-year period. A retrospective analysis showed differential responses to cholinesterase inhibitors (ChE-Is) in patients younger than 75 years. This analysis investigated the effect of BuChE genotype on response to ChE-I therapy in these patients. In a retrospective analysis, patients younger than 75 who had consented to pharmacogenetic analysis were divided into groups according to BuChE genotype. Efficacy measures were the Severe Impairment Battery (SIB), Neuropsychiatric Inventory (NPI), Global Deterioration Scale (GDS), Mini-Mental State Examination (MMSE) and the Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale (ADCS-ADL). Changes on efficacy parameters were calculated for rivastigmine-treated and donepezil-treated patients in both groups. Of 114 (34.1%) patients younger than 75 who were successfully assessed for BuChE genotype, 76 (66.7%) were homozygous for wild-type BuChE, and 38 (33.3%) carried at least one BuChE K-variant allele. Wild-type BuChE carriers showed significantly greater responses to rivastigmine than to donepezil on the SIB, ADCS-ADL, GDS and NPI. No significant between-treatment differences in efficacy were observed in BuChE K-variant carriers, although adverse events were more frequent in rivastigmine-treated patients. In this retrospective analysis, Alzheimer's disease patients younger than 75 with wild-type BuChE exhibited differential efficacy to rivastigmine, while BuChE K-variant carriers experienced similar long-term treatment effects with both agents. These differences may reflect rivastigmine's ability to inhibit BuChE and AChE.
SourceAvailable from: Agneta Nordberg[Show abstract] [Hide abstract]
ABSTRACT: Objective: To examine the role of butyrylcholinesterase (BuChE) in cholinergic signaling and neurologic conditions, such as Alzheimer's disease (AD). The rationale for inhibiting cholinesterases in the management of AD, including clinical evidence supporting use of the dual acetylcholinesterase (AChE) and BuChE inhibitor rivastigmine, is discussed. Data Sources: PubMed searches were performed using butyrylcholinesterase as a keyword. English-language articles referenced in PubMed as of September 2011 were included. Study Selection and Data Synthesis: English-language articles related to BuChE considered to be of clinical relevance to physicians were included. English-language articles specifically related to AChE were not included, as the role of AChE in cholinergic signaling and the underlying pathology of AD is well documented. Reference lists of included publications were used to supplement the search. Results: AChE and BuChE play a role in cholinergic signaling; BuChE can hydrolyze acetylcholine and compensate for AChE when levels are depleted. In the AD brain, AChE levels decrease, while BuChE levels are reportedly increased or unchanged, with changes becoming more pronounced during the disease course. Furthermore, BuChE genotype may influence AD risk and rate of disease progression. Strategies that increase acetylcholine levels (eg, cholinesterase inhibitors) demonstrate symptomatic efficacy in AD. Rivastigmine has proven cognitive efficacy in clinical trials, and data suggest that its action is mediated, in part, by inhibition of BuChE. Retrospective analyses of clinical trials provide evidence that BuChE genotype may also influence treatment response. Conclusions: AChE-selective inhibitors and a dual AChE and BuChE inhibitor demonstrate symptomatic efficacy in AD. Mounting preclinical and clinical evidence for a role of BuChE in maintaining normal cholinergic function and the pathology of AD provides a rationale for further studies investigating use of rivastigmine in AD and the influence of BuChE genotype on observed efficacy.01/2013; 15(2). DOI:10.4088/PCC.12r01412
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ABSTRACT: Cholinesterase enzymes metabolize acetylcholine (ACh). Inhibition of acetylcholinesterase (AChE) in damaged but functional cholinergic synapses in the brains of dementia patients increases intrasynaptic ACh. This enhances cholinergic neurotransmission and improves cognition. There is a window of opportunity for this symptomatic treatment effect that opens and closes during the course of dementia depending on when significant synaptic damage occurs. Cholinesterases also metabolize extrasynaptic ACh with butyrylcholinesterase (BuChE) apparently playing the major dynamic role in extracellular ACh homeostasis. Extracellular ACh plays a key regulatory role in controlling the reactivity and functional states of non-excitable cells, such as neuroglia. Current inhibitors of cholinesterases (ChEIs) have similar effects on intrasynaptic ACh, but differ markedly in abilities to upregulate extracellular AChE, inhibit BuChE, and influence the fibrilization of amyloid-β peptides. Importantly, ChEIs can have detrimental disease modifying effects in particular individuals characterized by age, gender, and genotype. In contrast, preliminary evidence suggests that the right dose of the right ChEI in the right patient might significantly slow the progression of neurodegenerative processes. For a particular patient, understanding the condition of cholinergic synapses and the reactivity and functional status of neuroglia could allow administration of appropriate ChEI therapy for symptomatic and disease modifying benefits.Journal of Alzheimer's disease: JAD 11/2014; DOI:10.3233/JAD-142268 · 3.61 Impact Factor
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ABSTRACT: CHRNA7 encodes the α7 nicotinic acetylcholine receptor subunit, which is important to Alzheimer's disease (AD) pathogenesis and cholinergic neurotransmission. Previously, CHRNA7 polymorphisms have not been related to cholinesterase inhibitors (ChEI) response. Mild to moderate AD patients received ChEIs were recruited from the neurology clinics of three teaching hospitals from 2007 to 2010 (n = 204). Nine haplotype-tagging single nucleotide polymorphisms of CHRNA7 were genotyped. Cognitive responders were those showing improvement in the Mini-Mental State Examination score ≧2 between baseline and 6 months after ChEI treatment. AD women carrying rs8024987 variants [GG+GC vs. CC: adjusted odds ratio (AOR) = 3.62, 95% confidence interval (CI) = 1.47-8.89] and GG haplotype in block1 (AOR = 3.34, 95% CI = 1.38-8.06) had significantly better response to ChEIs (false discovery rate <0.05). These variant carriers using galantamine were 11 times more likely to be responders than female non-carriers using donepezil or rivastigmine. For the first time, this study found a significant association between CHRNA7 polymorphisms and better ChEI response. If confirmed by further studies, CHRNA7 polymorphisms may aid in predicting ChEI response and refining treatment choice.PLoS ONE 12/2013; 8(12):e84059. DOI:10.1371/journal.pone.0084059 · 3.53 Impact Factor