Variability of AChE, BChE, and ChAT genes in the late‐onset form of Alzheimer's disease and relationships with response to treatment with Donepezil and Rivastigmine

Abstract

Several factors are believed to give rise to the late onset sporadic form of Alzheimer's disease (LOAD). We have studied the variation at the genes of three enzymes of the cholinergic system: acetylcholinesterase, butyrylcholinesterase, and choline acetyltransferase. The single nucleotide polymorphisms (SNPs) examined were: AChE rs2571598, BChE rs1355534, BChE rs1803274, and ChAT rs2177369. The sample for the case-control study was 471 LOAD patients aged 60 years or older, and 254 subjects with no neurodegenerative disorders as the control group. A significant difference in the genotype distribution between patients and controls was observed only for ChAT rs2177369, showing that the G/G genotype was to be considered a risk factor with respect to the G/A + A/A genotypes (odds ratio = 1.56; 95% Confidence Interval = 1.10-2.22; P = 0.01). Though indicating a significant association with AD onset, our results are far from definitive since contrast with the ones reported by other authors in a previous case-control study, and call for further investigations. Among patients, 171 took part in an observational study concerning the possible role of the genetic composition on the efficacy of treatment with Donepezil and Rivastigmine. We related the SNPs of the above cited genes with cognitive status measured by MMSE. Carrying an allele or a genotype of these SNPs does not seem to play a relevant role in the response to treatment with the two cholinesterase inhibitors, though some significant results were found associated with the AChE A/A genotype that had the best response when treated with Rivastigmine.

Effect of apolipoprotein E and butyrylcholinesterase genotypes on cognitive response to cholinesterase inhibitor treatment at different stages of Alzheimer's disease

“…One other report found that BCHE genotype did not influence response to ChEI treatment. 50 However, only change in MMSE was reported and not disease severity, making comparison with previous reports and this study difficult. A recent study has suggested an explanation for these seemingly incongruous findings.…”

“…49 Another report suggested no difference in response to donepezil or rivastigmine treatment according to BCHE genotype. 50 Further investigation of the response to ChEI therapy across a range of AD severities associated with APOE and BCHE genotypes is warranted. 29 The objective of this study was to determine whether APOE or BCHE genotype predicts cognitive response to ChEI therapy.…”

Association of the Choline Acetyltransferase Gene with Responsiveness to Acetylcholinesterase Inhibitors in Alzheimer’s Disease

“…Thus, the cholinergic system is a logical target for pharmacogenomic studies. There have been several studies on possible associations between genetic polymorphisms of cholinergicrelated genes and the therapeutic effect of AChEIs [10,11]. However, there are limitations as follows in those previous studies.…”

“…In the present study we have examined the polymorphic variations of the genes encoding 3 enzymes involved in the synthesis, transport, and metabolism of acetylcholine in the cholinergic system ( • ▶ Fig. 1) [11,12]. Choline acetyltransferase (ChAT) encoded by the gene CHAT synthesizes acetylcholine, using choline and acetyl-CoA as substrates [11].…”

“…1) [11,12]. Choline acetyltransferase (ChAT) encoded by the gene CHAT synthesizes acetylcholine, using choline and acetyl-CoA as substrates [11]. The choline transporter (ChT) catalyzes the uptake of choline from the extracellular space to the neuronal cytoplasm, and is encoded by SLC5A7 [12].…”