Butyrylcholinesterase K variant and apolipoprotein E4 genes do not act in synergy in Finnish late-onset Alzheimer's disease patients

doi:10.1016/S0304-3940(98)00453-4

Neuroscience Letters

Volume 250, Issue 1, 26 June 1998, Pages 69-71

https://doi.org/10.1016/S0304-3940(98)00453-4 Get rights and content

Abstract

Examination of the allelic frequency of the butyrylcholinesterase K (BChE-K) variant gene revealed no increase among Finnish late-onset Alzheimer's disease (AD) patients either as a whole or among a subset of AD patients carrying the ϵ4 allele of apolipoprotein E (ApoE4). In contrast, BChE-K allele frequency was significantly reduced in the Finnish AD patient group under 75 years of age carrying the ApoE4 allele when compared to the non-demented controls (χ², P<0.05). The proportion of subjects with both BChE-K and ApoE4 alleles was 14% and 41% in AD and control groups, respectively (χ², P<0.01; odds-ratio 0.22, 95% CI 0.07–0.71). These results are in contrast to a previous study on English AD patients, in which the genes for BChE-K and ApoE4 were suggested to act in synergy.

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Acknowledgements

The authors thank Ms. Marjo Heikkinen and Ms. Seija Hynynen for their excellent technical help. The study was supported by the Health Research Council of the Academy of Finland and an EVO grant (5032) of Kuopio University Hospital.

References (19)

P. Gómez-Ramos et al.
Ultrastructual localization of butyrylcholinesterase on neurofibrillary degeneration sites in the brains of aged and Alzheimer's disease patients
Brain Res.
(1994)
J. Poirier
Apolipoprotein E in animal models of CNS injury and Alzheimer's disease
Trends. Neurosci.
(1994)
H. Soininen et al.
A severe loss of choline acetyltransferase in the frontal cortex of Alzheimer patients carrying apolipoprotein ϵ4 allele
Neurosci. Lett.
(1995)
J.R. Atack et al.
Molecular forms of acetylcholinesterase and butyrylcholinesterase in the aged human central nervous system
J. Neurochem.
(1986)
C.F. Bartels et al.
DNA mutation associated with the human butyrylcholinesterase K-variant and its linkage to the atypical variant mutation and other polymorphic sites
Am. J. Hum. Genet.
(1992)
E.H. Corder et al.
Gene dose of apolipoprotein E type ϵ4 allele and the risk of Alzheimer's disease in late onset families
Science
(1993)
A.L. Guillozet et al.
Butyrylcholinesterase in the life cycle of amyloid plaques
Ann. Neurol.
(1997)
F.S. Jensen et al.
Detection of the plasma cholinesterase K variant by PCR using an amplification-created restriction site
Hum. Hered.
(1996)
L.B. Jorde
Linkage disequilibrium as a gene-mapping tool
Am. J. Hum. Genet.
(1995)

There are more references available in the full text version of this article.

Cited by (39)

Association between butyrylcholinesterase and cerebrospinal fluid biomarkers in Alzheimer's disease patients
2017, Neuroscience Letters
Citation Excerpt :
In relation to the BuChE polymorphism, our patient and control population showed a frequency of the K allele and a genotype distribution that is very similar to what has been previously described in other cohorts from Northern Spain [1], and also in the Canary Islands [18] and the United States of America [27]. On the contrary, patients from Australia [39], have shown a higher K allele frequency (24–32%), while patients from Finland [25] or China [30] have a lower reported K allele frequency (10–14%). No significant association between BuChE-K variant and AD risk was found.
The deficit of cholinergic activity is one of the main findings in Alzheimer’s disease (AD), and is related to the synthesis of acetylcholine, and the hydrolysing enzymes, acetylcholinesterase and butyrylcholinesterase (BuChE). Together with the Apolipoprotein E-ε4 allele (ApoE-ε4), the BuChE-K variant has been proposed to increase AD risk in certain populations. In addition, this polymorphism has been associated with a lower capacity to attenuate β-amyloid aggregation.
In the present study we explored the interaction of the BuChE-K variant with its activity in CSF, conventional AD biomarkers and ApoE genotype.
217 AD patients and 200 age-matched controls were genotyped for the ApoE and the BuChE-K variant. BuChE activity in CSF, as well as the levels of the CSF-AD biomarkers amyloid-beta 42 (Aβ42), total and hyperphosphorylated tau (t-tau and p-tau) were determined in 88 of these patients.
The results showed no significant differences in the BuChE-K variant distribution between patients and controls. No influence of the BuChE-K variant was seen neither in CSF BuChE activity, nor in the levels of Aβ42, t-tau and p-tau in AD patients. ApoE genotype also did not seem to influence CSF BuChE activity. Interestingly, in AD patients, an association between high CSF BuChE activity and increased levels of CSF Aβ42 was shown, particularly in ApoE-ε4 allele carriers.
In our population, the BuChE-K variant does not seem to confer risk for AD or to influence the activity of the enzyme in CSF. However, we demonstrated an association between BuChE activity, ApoE-ε4 genotype and CSF Aβ42 levels, highlighting the importance of assessing BuChE activity as a possible modulator of Aβ load in the brain.
Butyrylcholinesterase-knockout reduces brain deposition of fibrillar β-amyloid in an Alzheimer mouse model
2015, Neuroscience
Citation Excerpt :
Investigations of this BCHE variant have observed that its presence pre-empts progression of AD (Sandbrink et al., 1998; O’Brien et al., 2003). However, other studies have suggested that this variant is associated with AD (Tilley et al., 1999; Wiebusch et al., 1999; Lehmann et al., 2000; Lehmann et al., 2001; McIlroy et al., 2000) and still others have observed no association of BCHE-K variant with AD (Hiltunen et al., 1998; Kehoe et al., 1998; Singleton et al., 1998; Grubber et al., 1999; Ki et al., 1999; Yamamoto et al., 1999). This suggests that the role(s) of BChE in AD may involve other components of the disease and requires further scrutiny.
In Alzheimer’s disease (AD), numerous β-amyloid (Aβ) plaques are associated with butyrylcholinesterase (BChE) activity, the significance of which is unclear. A mouse model, containing five human familial AD genes (5XFAD), also develops Aβ plaques with BChE activity. Knock-out of BChE in this model showed diminished fibrillar Aβ plaque deposition, more so in males than females. This suggests that lack of BChE reduces deposition of fibrillar Aβ in AD and this effect may be influenced by sex.
Alanine-to-threonine substitutions and amyloid diseases: Butyrylcholinesterase as a case study
2010, Chemico-Biological Interactions
Citation Excerpt :
An on-going debate discusses BChE-K's association with the debilitated Apolipoprotein ɛ4 protein known to confer an increased risk of AD. Several reports suggested a synergy between the BChE-K and APO E4 genes in AD, while others showed the opposite [58,59]. Yet other studies argued that BCHE-K confers an increased risk of developing AD-related neuropathology which is independent of the BChE-K-ApoE association [60].
Alanine-to-threonine (A to T) substitutions caused by single nucleotide polymorphisms (SNPs) occur in diverse proteins, and in certain cases these substitutions induce self-aggregation into amyloid fibrils or aggregation in other amyloidogenic proteins. This is compatible with the inverse preferences of alanine to form helices and of threonine to support β-sheet structures, which are crucial for amyloid fibrils formation. Our interest in these mutations was initiated by studying the potential effects of the A539T substitution in the butyrylcholinesterase BChE-K variant on amyloid fibrils formation in Alzheimer's disease. Other examples are, Parkinson's disease (PD), where A53T α-synuclein occurs in Lewy bodies and familial amyloid polyneuropathy (FAP), where an A25T substitution appears in transthyretin (TTR). In peripheral organs, an A34T substitution is found in the light chain immunoglobulin genes of patients with systemic amyloidosis and in familial hypercholesterolemia, an A370T substitution occurs in the LDLR regulator of cholesterol homeostasis. That such substitutions appear in proteins with important cellular functions suggests that they confer antagonistic pleiotropy, providing added value at an earlier age but causing damages and inducing amyloid diseases later on. This, in turn, may explain the evolutionary selection and preservation of these substitutions. The structural effect of residue substitutions and in particular A to T substitutions in amyloidogenic diseases thus merits further attention.
Emerging hypotheses regarding the influences of butyrylcholinesterase-K variant, APOE ε4, and hyperhomocysteinemia in neurodegenerative dementias
2009, Medical Hypotheses
Non-enzymatic functions of butyrylcholinesterase (BuChE) include prevention of the aggregation of amyloid-beta peptide (Aβ) in a concentration-dependent manner. This is mediated by the C-terminus of the protein, distal from the enzymatic site. The BuChE-K variant polymorphism lowers expression of BuChE protein and/or alters C-terminal activity. In combination with factors that increase production or reduce elimination of Aβ, and/or increase susceptibility to Aβ toxicity – such as the apolipoprotein E (APOE) ε4 allele and/or hyperhomocysteinemia – BuChE-K may accelerate cholinergic synaptic and neuronal damage and cognitive decline. Aβ-mediated damage to ascending cholinergic pathways may be further accentuated by Lewy body and/or cerebrovascular disease. As the disease advances and functioning cholinergic synapses disappear, both the rapid cognitive decline and response to cholinesterase inhibitor therapy in individuals with these factors may diminish. Non-enzymatic functions of the BuChE protein, APOE ε4 status and hyperhomocysteinemia influence the progression of pathology, symptom expression, and response to cholinesterase inhibition in a stage-specific manner in neurodegenerative disorders associated with Alzheimer, Lewy body and vascular pathology.
Butyrylcholinesterase K variant associated with higher enzyme activity in the temporal cortex of elderly patients
2008, Neuroscience Letters
There is evidence to suggest an involvement of the K variant of the butyrylcholinesterase gene (BCHE) in dementia. We have examined the relationship between BCHE genotype and butyrylcholinesterase (BuChE) activity in autopsy brain tissue. We studied 164 autopsy cases, 144 with dementia and 20 controls, including 13 K homozygotes and 48 K heterozygotes, from three centres: Newcastle, Oxford and London. Mean BuChE activity in temporal cortex was 37% higher in K homozygotes than in wild-type homozygotes. Linear regression analysis, controlling for gender, diagnosis, age at death and study centre, showed that the number of BCHE-K alleles was associated with increasing BuChE activity (p = 0.009).
Molecular basis of succinylcholine sensitivity in a prairie Hutterite kindred and genetic characterization of the region containing the BCHE gene
2007, Molecular Genetics and Metabolism
The tetrameric glycoprotein butyrylcholinesterase (BChE; EC 3.1.1.8) is one of two enzymes that hydrolyze choline esters. The controlling gene (BCHE) is comprised of four coding exons and is located on chromosome 3q26. Based on BChE activity measurements in the presence and absence of dibucaine, usual (designated U) and atypical (designated A) gene products have been distinguished. Homozygotes for the A gene product are at risk for prolonged apnea following exposure to the surgical anesthetics succinylcholine or mivacurium. In this report, we detail biochemical and molecular investigations of succinylcholine sensitivity in a prairie Hutterite kindred. Our results establish that BChE activities in the family members are impacted by two distinct BCHE mutations, namely, c.209A>G p. D70G and c.1615G>A p. A539T. However, homozygotes for the c.209A>G mutation (i.e., atypical or A) are the only individuals whose BChE activity could lead to adverse reactions to succinylcholine. Interestingly, haplotype analysis of the chromosomal region containing BCHE indicates that the c.209A>G mutation is carried on a unique haplotype, suggesting that it was likely introduced into the population only once. Conversely, the c.1615G>A mutation is carried on various haplotypes and was likely introduced into the population more than once.

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Butyrylcholinesterase K variant and apolipoprotein E4 genes do not act in synergy in Finnish late-onset Alzheimer's disease patients

Abstract

Section snippets

Acknowledgements

Brain Res.

Trends. Neurosci.

Neurosci. Lett.

Molecular forms of acetylcholinesterase and butyrylcholinesterase in the aged human central nervous system

J. Neurochem.

DNA mutation associated with the human butyrylcholinesterase K-variant and its linkage to the atypical variant mutation and other polymorphic sites

Am. J. Hum. Genet.

Gene dose of apolipoprotein E type ϵ4 allele and the risk of Alzheimer's disease in late onset families

Science

Butyrylcholinesterase in the life cycle of amyloid plaques

Ann. Neurol.

Detection of the plasma cholinesterase K variant by PCR using an amplification-created restriction site

Hum. Hered.

Linkage disequilibrium as a gene-mapping tool

Am. J. Hum. Genet.