Apolipoprotein E (ApoE) ε4 has a strong influence on the development of sporadic Alzheimer’s disease in many ethnic populations. However, ApoE ε4 is neither necessary nor sufficient for the development of Alzheimer’s disease, suggesting that other genes increase the risk of Alzheimer’s disease. One such new candidate is the butyrylcholinesterase (BChE) gene (BCHE).1 BChE is associated with senile plaques (SPs) and neurofibrillary tangles (NFTs). Lehmannet al recently reported that the K variant of BCHE (BCHE-K) was associated with the development of Alzheimer’s disease, especially in ApoE ε4 carriers older than 75 years.1 A possible mechanism as to how BCHE-K is related to Alzheimer’s disease under the influence of ApoE ε4 is the acceleration of Alzheimer type neuropathological changes. IfBCHE-K has an effect on the development of Alzheimer’s disease in ApoE ε4 carriers, the formation of Alzheimer type neuropathological changes may be accelerated byBCHE-K in the ApoE ε4 carriers.

We have examined genotypes of BCHE and ApoE, and densities of the senile plaques (SPs), with dystrophic neurites (NPs), and neurofibrillary tangles NFTs in the brains from 51 patients with Alzheimer’s disease and 90 non-demented subjects from a postmortem series of Japanese. Clinical and postmortem diagnosis of Alzheimer’s disease was carried out as described previously.2 The densities of Alzheimer type neuropathological changes were quantified by averaging the counts of those in the hippocampus and superior temporal gyrus. Genotypes ofBCHE and ApoE in all patients were determined as described elsewhere.1 2 Genotypic and allelic distributions of BCHE were analysed by χ² test. The densities of the SPs, NPs, and NFTs, and ages at onset and durations of illness were compared amongBCHE genotypes with the Kruskal-Wallis test or Mann-Whitney U test in total subjects, those with Alzheimer’s disease, and non-demented subjects. We also examined these relations in the subgroups divided by the ApoE ε4 status or the age of 75 years. Statistical significance was defined as two tailed probabilities of <0.05.

There were no significant differences in the frequency ofBCHE-K genotypes or alleles between patients with Alzheimer’s disease (0.16 in allele frequency) and non-demented subjects (0.18), and in the total subjects, ApoE ε4 carriers or non-ApoE ε4 carriers, although a strong association of ApoE ε4 alleles with Alzheimer’s disease was found in this population (p=0.004). Genetic association of BCHE-Kgenotypes with sporadic Alzheimer’s disease was non-significant in all subjects older than 75 years, the ApoE ε4 carriers older than 75 years, and non-ApoE ε4 carriers older than 75 years. There was no genetic association of BCHE-K with the densities of the SPs, NPs, or NFTs in the hippocampus and superior temporal gyrus in the total subjects, in the Alzheimer’s disease or non-demented groups, or with ages at onset or duration of illness in Alzheimer’s disease. However, when we divided total subjects into two subgroups with different ApoE ε4 status, there was significant association between BCHE-K and the density of the SPs and NPs in the superior temporal gyrus(STG) in the ApoE ε4 carriers (SPs, p=0.04; NPs, p=0.03, data not shown). Further, we analysed the correlation between BCHE-K and the densities of the SPs, NPs, and NFTs in the hippocampus and superior temporal gyrus in the ApoE ε4 carriers older than 75 years and non-ApoE ε4 carriers older than 75 years (table). There was a significant genetic association of BCHE-Kwith the densities of the SPs, NPs, and NFTs in the STG in the ApoE ε4 carriers older than 75 years. There was a decrease of severity of Alzheimer type neuropathological changes withBCHE-K. A similar trend was seen in the hippocampus though this did not reach significance.

Our results showed that BCHE-K might have no effect on the development of sporadic Alzheimer’s disease even in the ApoE ε4 carriers or subjects older than 75 years. By contrast with a significant genetic association in patients confirmed at postmortem in the British population,1 there was no correlation in the Japanese population. Although our sample size was small, there were not even trends for a positive association in our study, suggesting that the lack of association was not due to small sample size. The frequency of BCHE-K in our Japanese control population was 0.18. This was not significantly different from that in the British population examined by Russ et al(0.20).3 However, the frequency ofBCHE-K in the British control population reported by Lehmann et al was 0.09, which was significantly lower than our results (p=0.04).1 These findings indicate that the frequency ofBCHE-K and its genetic linkage with the development of Alzheimer’s disease would be different among sample populations.

Our neuropathological study disclosed a significant association ofBCHE-K with Alzheimer type neuropathological changes in the ApoE ε4 carriers older than 75 years, but not in the non-ApoE ε4 carriers. Lehmann et al showed that BCHE-K was strongly associated with the development of Alzheimer’s disease in the ApoE ε4 carriers older than 75 years.1 Analyses of the same subgroup of ApoE ε4 carriers older than 75 years increased statistical significance in both our studies and that of Lehmann et al. This suggests that BCHE-K as a genetic marker is linked with formation of Alzheimer type neuropathological changes or development of Alzheimer’s disease in the ApoE ε4 carriers older than 75 years. However, a decrease of the severity of Alzheimer type neuropathological changes with BCHE-K in our study was not expected because Lehmann et alshowed an increase in frequency of theBCHE-K allele in Alzheimer’s disease.1 Singleton et al also reported that BCHE-K was not associated with the densities of the SPs and NFTs, even in the ApoE ε4 carriers.4 In addition, BCHE-Kwas not related to the development of Alzheimer’s disease in the ApoE ε4 carriers in our study. Russ et al 3 and Singleton et al 4 also showed a lack of association betweenBCHE-K and the development of Alzheimer’s disease. However, Hiltunen et al showed thatBCHE-K had a protective effect on the development of Alzheimer’s disease in ApoE ε4 carriers younger than 75 years.5 The effects ofBCHE-K on the Alzheimer type neuropathological changes or development of Alzheimer’s disease are different among studies, suggesting that the significant genetic association in the studies by Lehmann et al,1 Hiltunen et al,5 and ourselves might be linkage disequilibrium with relevant variability in BCHE or other adlacent gene on chromosome 3, and thatBCHE-K does not play a direct part in the pathogenesis of Alzheimer’s disease.