Human Molecular Genetics

Oxford Project to Investigate Memory and Ageing (OPTIMA), University Department of Pharmacology, Mansfield Rd, Oxford OX1 3QT, UK and Radcliffe Infirmary, Woodstock Rd, Oxford OX2 6HE, UK

Received July 3, 1997; Revised and Accepted July 31, 1997

The allelic frequency of the gene for the K variant of butyrylcholinesterase (BCHE-K) was 0.17 in 74 subjects with late-onset (age >65 years) histopathologically diagnosed Alzheimer's disease (AD), which was higher than the frequencies in 104 elderly control subjects (0.09), in 14 early-onset cases of confirmed AD (0.07) and in 29 confirmed cases of other dementia (0.10). The association of BCHE-K with late-onset AD was limited to carriers of the [epsilon]4 allele of the apolipoprotein E gene (APOE), among whom the presence of BCHE-K gave an odds ratio of confirmed late-onset AD of 6.9 (95% C.I. 1.65-29) in subjects >65 years and of 12.8 (1.9-86) in subjects >75 years. In APOE[epsilon]4 carriers over 75 years, only 1/22 controls, compared with 10/24 confirmed late-onset AD cases, had BCHE-K. We suggest that BCHE-K, or a nearby gene on chromosome 3, acts in synergy with APOE[epsilon]4 as a susceptibility gene for late-onset AD.

INTRODUCTION

Butyrylcholinesterase (BChE) is expressed in most human tissues (1 ), yet its function is unknown. BChE activity in the brain increases with age over 60 years and is elevated in Alzheimer's disease (AD) (2 ,3 ). Histochemically reactive BChE is associated with amyloid plaques and neurofibrillary tangles and with amyloid angiopathy in AD (4 -8 ). We have looked for possible associations of AD with two of the more common human variants of the gene for BChE (BCHE), the atypical allele and the K variant (BCHE-K). The latter has a point mutation at nucleotide 1615 (GCA -> ACA) which changes Ala539 to threonine and the catalytic activity is reduced by a third (9 ). BCHE-K is thought to have an allelic frequency of ~0.12 in Caucasians (9 -11 ).

RESULTS

After 178 subjects had been genotyped, three control subjects out of 104 and three AD cases out of 74 were identified as heterozygotes for the atypical BCHE allele. Thus, no association was found between histopathologically confirmed AD and the atypical allele of BCHE. Two out of the six atypical BCHE heterozygotes were carriers of BCHE-K.

Altogether, 282 Caucasian subjects were genotyped for BCHE-K and for APOE alleles. BCHE-K was more common in late-onset AD cases than in early-onset AD cases, other dementias or controls (Table 1 ). For subjects aged over 65, the allelic frequency of BCHE-K was 0.09 in 104 controls and 0.17 in 74 confirmed AD cases, giving an odds ratio of AD of 2.15 (Table 2 ). Most of this association appeared to be due to subjects over 75 years old, for whom the frequency of BCHE-K was 0.08 in 68 controls and 0.19 in 36 confirmed AD cases ([chi]² with Yates' correction = 4.7; P = 0.03), giving an odds ratio of AD of 2.7 (Table 2 ). There were insufficient cases for this trend with age to reach significance, but nevertheless we thought it helpful to show data for the >75 years subgroup as well as for all subjects >65 years in Table 2 .

Taking account of an individual's carrier status for APOE [epsilon]4 produced striking results. In subjects >65 years without APOE [epsilon]4, the allelic frequency of BCHE-K was 0.14 in 22 confirmed AD cases and 0.11 in 72 controls. There was thus no association of BCHE-K with late-onset AD in subjects lacking an APOE [epsilon]4 allele. In APOE [epsilon]4 carriers, however, BCHE-K allelic frequencies in subjects aged >65 years were 0.18 in 52 confirmed AD cases and only 0.03 in 32 controls; in subjects aged >75 years the frequencies were 0.23 in 24 confirmed AD cases and 0.02 in 22 controls. These results gave odds ratios of confirmed AD of 6.9 and 12.8 for BCHE-K in APOE [epsilon]4 carriers aged >65 years and >75 years, respectively (Table 2 ). For comparison, we give in Table 3 the odds ratios of confirmed AD for APOE [epsilon]4 in BCHE-K carriers. It can be seen that an individual's BCHE-K status markedly influences the strength of the effect of APOE [epsilon]4. Table 4 shows the striking differences between cases and controls in the proportions of subjects who carry both BCHE-K and APOE [epsilon]4 alleles.

All these findings indicated an interaction between BCHE-K and APOE [epsilon]4, which we confirmed by logistic regression analysis. We fitted several logistic regression models to the data and found that a parsimonious model with only APOE [epsilon]4, BCHE-K and their interaction gave an adequate fit (residual deviance: 5.5 on 4 degrees of freedom). In this model, APOE [epsilon]4 and its interaction with BCHE-K were significantly associated with AD, but BCHE-K by itself was not.

Table 1 Allelic frequencies of BCHE-K and APOE [epsilon]4

	No. of subjects	F:M ratio	Mean agea	BCHE-K allele frequency	APOE [epsilon]4 allele frequency
Controls >65 years	104	1.26	78.1	0.09	0.16
All LOAD cases	105	1.50	80.9	0.16*	0.40**
All EOAD cases	44	1.10	65.9	0.09	0.42**
Confirmed LOAD	74	1.39	81.4	0.17*	0.41**
Confirmed EOAD	14	2.50	67.8	0.07	0.54**
Confirmed other dementia	29	0.81	76.8	0.10	0.19

LOAD and EOAD are respectively late-onset (>65 years) and early-onsetAlzheimer's disease.
For BCHE-K, each of the above groups was in exact Hardy-Weinberg equilibrium.
*P <0.03, **P <0.0001 ([chi]² with Yates' correction) versus controls.
^aAges were at death, if status confirmed, but at last clinical assessment for living subjects.

Table 2 Odds ratios of confirmed late-onset Alzheimer's disease for BCHE-K alleles

Subjects	Controls	Cases	Odds ratioa	95% C.I.
All >65 years	104	74	2.15	1.1-4.25
All >75 years	68	36	2.7	1.1-6.8
ApoE [epsilon]4 carriers >65 years	32	52	6.9	1.65-29
ApoE [epsilon]4 carriers >75 years	22	24	12.8	1.9-86

Ages in Tables 2-5 were at onset for late-onset AD cases and for controls at death, if confirmed, but at last clinical assessment if living.
^aThese odds ratios were based on alleles. The equivalent odds ratios for BCHE-K based on carriers were: 2.3, 2.6, 7.9 and 15.0.

Table 3 Odds ratios of confirmed late-onset Alzheimer's disease for APOE [epsilon]4 alleles

Subjects	Controls	Cases	Odds ratio	95% C.I.
All >65 years	104	74	3.6	2.2-5.9
All >75 years	68	36	2.8	1.4-5.5
BCHE-K carriers >65 years	17	23	12.3	2.6-58
BCHE-K carriers >75 years	11	12	15.0	1.95-115

Table 4 Proportions of controls and confirmed late-onset AD cases with both BCHE-K and APOE [epsilon]4 alleles

Subjects	Proportions with both alleles
	Controls	Cases	P*
All >65 years	2/104 (2%)	18/74 (24%)	<0.0001
All >75 years	1/68 (1%)	10/36 (28%)	<0.0001
APOE [epsilon]4 carriers >65 years	2/32 (6%)	18/52 (35%)	0.007
APOE [epsilon]4 carriers >75 years	1/22 (5%)	10/24 (42%)	0.009

*[chi]² with Yates' correction.

Table 5 Odds ratios of confirmed late-onset AD, taking subjects who had neither APOE [epsilon]4 nor BCHE-K as the reference

APOE [epsilon]4	BCHE-K	Controls	Cases	Odds ratio	95% CI
Age >65 years
-	-	57	17	Reference
-	+	15	5	1.1	NS
+	-	30	34	3.8	1.8-8.1
+	+	2	18	30.2	8.4-108
Age >75 years
-	-	36	10	Reference
-	+	10	2	0.7	NS
+	-	21	14	2.4	0.8-7.3 (NS)
+	+	1	10	36.0	6.1-211

In order to examine further the strength of the interaction between BCHE-K and APOE [epsilon]4, we give in Table 5 the odds ratios of confirmed AD for subjects with different combinations of these two genes, taking subjects who have neither gene as the reference. In subjects over 65 years, the odds ratio in those who only carry BCHE-K was 1.1 and in those with only APOE [epsilon]4 it was 3.8. This gave a predicted odds ratio of 4.2 in subjects with both genes, on the assumption of independent effects of the two genes, compared with the observed value of 30.2. In subjects over 75 years, the predicted odds ratio was 1.7, but the observed odds ratio was 36. We therefore suggest that there is strong synergy between these two alleles in late-onset AD.

DISCUSSION

That APOE [epsilon]4 is a risk factor for AD is well established (12 ,13 ). Our results are consistent with the hypothesis that BCHE-K is associated with a further increase in the risk of late-onset AD in APOE [epsilon]4 carriers. The effect could be due to linkage disequilibrium with another gene on chromosome 3, conceivably transferrin, whose C2 variant was reported to be more common in 20 clinically diagnosed AD cases than in the general population (14 ). BCHE is at 3q26.1-q26.2 (15 ), while the gene for transferrin is at 3q21-q25 (16 ). On the other hand, the effect on late-onset AD might be mediated by BCHE-K itself.

Biological plausibility

There are various potential interactions between BChE and apolipoprotein E (apoE). Both proteins are produced in quantity in the liver and secreted into the circulation (1 ,17 ). Not only apoE, but probably also BChE, interact with lipoproteins (18 ,19 ). Both proteins are found in astrocytes (20 ,21 ) and in other glia, BChE in oligodendrocytes (22 ) and apoE in microglia (23 ). Both proteins occur in AD in plaques, intra- and extracellular neurofibrillary tangles and in association with amyloid angiopathy (7 ,8 ,24 ,25 ). Furthermore, both BChE and apoE have been implicated in certain models of neurite growth (26 -31 ). In the case of apoE, there are differences between the E3 and E4 isoforms (29 -31 ) and, in the case of BChE, it has been suggested that the nature of the attached sugar residues may be important (26 -28 ). It should be noted that the K variant of BChE has an additional threonine residue at position 539, but whether this is a potential O-glycosylation site (or, indeed, a phosphorylation site) remains to be shown. Furthermore, a threonine residue has a high propensity for [beta]-sheet formation (32 ). In lysozyme, conversion of an isoleucine residue to threonine causes amyloidosis (33 ), as does conversion of an alanine residue to threonine in transthyretin (34 ).

The evidence cited provides pointers for future work to test the hypothesis that BChE and apoE may interact and that this interaction is influenced by their allelic variants.

Implications for clinical genetics

Replication of our findings is particularly important since ~6% of the Caucasian population carry both BCHE-K and APOE [epsilon]4, assuming respective allelic frequencies of 0.12 (9 -11 ) and 0.15 (17 ,35 ). Thus, subject to confirmation of our results, several millions of the elderly who carry both these genes are at high risk of developing AD, especially when aged over 75 years. As pointed out by Roses (36 ), the ability to identify such at-risk individuals has major social and ethical implications. Since APOE [epsilon]4 is an established risk factor for cardiovascular disease, it will be important to see whether carriers who also have BCHE-K are at greater risk of cardiovascular disease. Such a study would not only have clinical relevance but could also increase our understanding about the role of vascular risk factors (37 ) in the aetiology of AD.

MATERIALS AND METHODS

We examined 282 Caucasians from the Oxford region recruited into the Oxford Project to Investigate Memory and Ageing (OPTIMA) (38 ). Eighty eight were autopsy confirmed CERAD (39 ) `definite or probable' AD cases (74 late-, i.e. >65 years, and 14 early-onset), 29 were pathologically confirmed cases of other dementias (12 vascular, five Parkinson's, five non-specific neurodegeneration, three Pick's, and one each of progressive supranuclear palsy, normal pressure hydrocephalus, Huntington's and glioma), 61 were living cases diagnosed `possible AD' or `probable AD' by NINCDS/ADRDA (40 ) criteria (31 late- and 30 early-onset) and 104 were controls without cognitive impairment with CAMDEX (41 ) scores >80 (14 had died and had no AD pathology on necropsy). Subjects were genotyped blind to diagnosis, using blood samples, by PCR methods for the atypical and K variants of BCHE (42 ) and for APOE (43 ).

ACKNOWLEDGEMENTS

We especially thank all patients and volunteers, members of OPTIMA, the Department of Neuropathology (Radcliffe Infirmary), Drs M Cortina Borja, R. Clarke, I. Craig and E. Sim. This work was supported by Bristol-Myers Squibb.

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*To whom correspondence should be addressed. Tel: +44 1865 271883; Fax: +44 1865 271882; Email david.smith@pharm.ox.ac.uk
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