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2002, Volume 7, Number 7, Pages 768-775
Table of contents    Previous  Article  Next   [PDF]
Original Research Article
APOE-epsilon4 and APOE -491A polymorphisms in individuals with subjective memory loss
S M Laws1, R M Clarnette1, K Taddei1, G Martins1, A Paton1, J Hallmayer2, O P Almeida3, D M Groth4, S E Gandy5, H Förstl6 and R N Martins1

1Sir James McCusker Alzheimer's Disease Research Unit, Department of Surgery, University of Western Australia, Hollywood Private Hospital, Perth, Western Australia

2Department of Psychiatry and Behavioural Science, Stamford University, Palo Alto, CA, USA

3Department of Psychiatry and Behavioural Science, University of Western Australia, QEII Medical Centre, Perth, Western Australia

4School of Biomedical Science, Curtin University of Technology, Bentley, Western Australia

5Alzheimer Research Program, New York University, NS Kline Institute, Orangeburg, New York, USA

6Department of Psychiatry and Psychotherapy, Technical University of Munich, Munich, Germany

Correspondence to: Dr R Martins, Sir James McCusker Alzheimer's Disease Research Unit, University of Western Australia, Department of Surgery, Hollywood Private Hospital, Monash Avenue, Nedlands, Perth, Western Australia 6009. E-mail: rmartins@cyllene.uwa.edu.au

Abstract

The accurate clinical diagnosis of Alzheimer's disease can only be made with a high degree of certainty in specialized centres. The identification of predictive or diagnostic genetic factors may improve accuracy of disease prediction or diagnosis. One major genetic risk factor, the epsilon4 allele of the apolipoprotein E gene, is universally recognised. We have recently shown that the A allele of the apolipoprotein E, -491A/T promoter polymorphism is also an important risk factor for Alzheimer's disease in an Australian population. We designed the present study to investigate the association between apolipoprotein E genotype, -491A/T polymorphism, plasma apoE levels and the subjective experience of memory decline among 98 subjects and 49 age, gender and education-matched normal controls. An increased frequency of the epsilon4 allele of apolipoprotein E was significantly associated with the 'memory complainers' group (OR = 2.35, P = 0.02) as was the A allele of the -491A/T polymorphism (OR = 2, P = 0.02). Among all subjects, only seven individuals were homozygous for both of these alleles, and six of these seven individuals belonged to the 'memory complainers' group. This sub-group also had relatively elevated plasma apolipoprotein E levels (P < 0.01) and tended to score lower on the Mini-Mental State Examination (MMSE) and Cambridge Cognition Test. These data suggest that the epsilon4 allele of apolipoprotein E and the -491A allele are over-represented among individuals who complain of memory difficulties. Follow-up studies should clarify whether these genotypes and phenotypes are useful in the prediction and/or diagnosis of Alzheimer's disease.

Molecular Psychiatry (2002) 7, 768-775. doi:10.1038/sj.mp.4001083

Keywords

APOE-epsilon4; -491A/T; apolipoprotein E; Alzheimer's disease; memory complaints

Introduction

Dementia is defined as the loss of intellectual function1 and is typically accompanied by impairment of intellect, memory and personality.2 The most frequent cause of cognitive decline in late life is Alzheimer's disease (AD).2,3 AD accounts for 50% of all dementia worldwide, and its incidence doubles every 5 years between the ages of 65 and 85.4 The prevalence of the disease grows exponentially with aging, from 5% at age 65 to approximately 40% at age 80. The recent availability of effective symptomatic treatment for AD and the prospect of further therapeutic advances have given impetus to the early diagnosis of the disease. The relationship between memory complaints in non-demented persons and future risk of dementia has prompted numerous studies.5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27 A recent study within this cohort showed that memory complainers had worse cognitive performance than non-complainers, thus supporting the findings of other studies that suggest that subjective memory loss may be a reliable indicator of cognitive decline.28 The association of genetic susceptibility factors such as the epsilon4 allele of the apolipoprotein E gene (APOE) and the APOE -491A/T promoter polymorphism with cognitive decline may provide a starting point for the formulation of criteria for early diagnosis of AD.

Currently definitive diagnosis of AD requires histopathological examination of the brain.29 Without neuropathological data, the diagnosis of 'probable AD' is based on clinical assessment.29 Familial Alzheimer cases with early onset (ie prior to age 65) are often associated with highly penetrant autosomal dominant mutations in genes coding for presenilin-1 (PS1), presenilin-2 (PS2) or the amyloid precursor protein (APP). The more common late-onset form of the disease (LOAD) has been associated with genetic risk factors rather than deterministic mutations; the APOE-epsilon4 allele is a major genetic risk factor that has been extensively characterised.30 Numerous other phenotypes and genotypes have subsequently been linked to AD, including levels of the apoE protein31 and polymorphisms within the APOE promoter.32,33,34,35,36

We designed the present study to determine whether an association exists between subjective memory loss and APOE genotype, APOE -491A/T promoter polymorphism genotype, and/or plasma apoE levels, either singly or in combination. Here we have evaluated the APOE genotype, APOE -491A/T promoter polymorphism genotype, and plasma apoE levels in control and 'memory complainer' populations.

Methods

With approval from our institute's ethics committee, we investigated the frequency of APOE genotypes and -491 A/T polymorphism genotypes together with plasma apoE levels of apoE among 98 individuals with memory complaints (age 63.4 ± 1.0 years) and 49 age, gender and education-matched37,38 controls (age 61.3 ± 1.5 years). The 98 'memory complainers' were recruited from individuals referred to The Memory and Capacity Evaluation Unit at Osborne Park Hospital between 1996 and 1998. Additionally, advertisements were placed in local newspapers seeking people with memory complaints. Control subjects were recruited through media advertisements and by asking spouses of complainers to volunteer for the study.

An experienced geriatrician (RC) clinically reviewed all volunteers and recorded medical history and completed a physical and neurological examination. A trained nurse interviewed all subjects using the Cambridge Examination for Mental Disorders of the Elderly (CAMDEX).39 The CAMDEX includes standardised patient and informant interviews, a depression scale and a cognitive examination. The cognitive component (CAMCOG) includes tests of orientation, memory, language, praxis, attention, calculation, abstract thinking and visual perception. Scores can range from 0 to 107. A score of 80 or greater is considered to exclude dementia. The CAMCOG also includes questions that allow computation of the MMSE and the Abbreviated Mental Test Score (AMTS).40 In addition, the interviews gather demographic information and recent and remote medical history. Subjects meeting criteria for the diagnosis of dementia,41 with prior medical history of stroke, or with Mini-Mental State Examination (MMSE) score lower that 244 were excluded from the study.

Subjects with functional psychiatric disorders (such as depression) were also excluded from the study. This assessment was based on the CAMDEX, which has an algorithm that produces clinical diagnoses according to the ICD-10.

Leukocyte DNA was extracted from peripheral blood samples using standard protocols. APOE genotype was determined using the PCR protocol as described by Hixson and Vernier.42 The oligonucleotide primers, (P1) 5'-TCCAAGGAGCTGCAGGCGGCGCA-3' and (P2) 5'-ACAGAATTCGCCCCGGCCTGGTACACTGCCA-3', used were as described.43 The amplified product was digested using the restriction enzyme HhaI and electrophoresed in an 8% non-denaturing polyacrylamide gel. Gels were then stained with ethidium bromide and viewed on an UV transilluminator to reveal DNA fragments with electrophoretic migration patterns unique to each allele.43 The genotype of the APOE -491A/T polymorphism was determined via a two-stage PCR amplification, using the primers [P1 (-1017) 5'-CAA GGT CAC ACA GCT GGC AAC-3' and P2 (+406) 5'-TCC AAT CGA CGG CTA GCT ACC-3'] and nested primers ([P1 (-285) 5'-TGT TGG CCA GGC TGG TTT TAA-3' and P2 (-512) 5'-CCT CCT TTC CTG ACC CTG TCC-3'] as described.33 Amplified products were digested using the restriction enzyme DraI and visualised via ethidium bromide staining of the 8% non-denaturing polyacrylamide gels.

The quantitation of plasma apoE protein levels was performed after determining total protein concentration via the BCA method (Pierce, USA). Plasma (100 mug of total protein) were diluted 1:4 with sodium dodecyl sulfate (SDS) sample buffer (1 M Tris HCl pH 6.8, 8% w/v SDS, 4% w/v glycine), boiled for 5 min and proteins separated on 8-12% SDS-polyacrylamide gels, using recombinant human apoE4 (Panvera, USA) as a standard. Separated proteins were transferred overnight onto nitrocellulose membranes (Biorad). Membranes were incubated with blocking solution (PBS pH 7.4, 0.5% w/v casein, 10 mM NaOH) for 45 min at room temperature, and then immersed in goat anti-human apoE (dilution 1:4000) for 2 h in PBS pH 7.4, also at room temperature. Membranes were then washed three times in wash buffer (TBS-T; 10 mM Tris-HCI, pH 8.0, 150 mM NaCl, 0.05% v/v Tween 20) and immersed at room temperature, in horseradish peroxidase-conjugated rabbit anti-goat IgG (DAKO) for 1 h in TBS-T pH 8.0 (dilution 1:4000). Membranes were then washed three times before chemiluminescent visualization was carried out using ECL reagent from Amersham and exposed to Amersham ECL Hyperfilm. Developed film was analysed using a UMAX scanner, and apoE protein concentration was quantitated using NIH Image software, version 1.62.

The data were analysed using the statistical package SPSS (version 10.0). Categorical variables were investigated using the Pearson method for the analysis of contingency tables (chi2). Odds ratios were estimated from 2 ´ 2 tables and 95% confidence intervals were estimated for the odds ratio (CI). Mann-Whitney U-test was used in the analysis of continuous variables, such as the scores of the CAMCOG and MMSE, whilst the student's t-test was used in the analysis of plasma apoE protein levels.

Results

Clinical assessment (Table 1) showed that individuals who complained of memory difficulties had significantly lower MMSE (27.6 ± 0.2 vs 28.8 ± 0.2; P < 0.001, z = - 5.96) and CAMCOG (96.3 ± 0.6 vs 101.5 ± 0.5; P < 0.001; z = -5.52) scores when compared to controls. Initial analysis of plasma apoE protein levels revealed no significant difference between controls and memory complainers (P = 0.64, z = 0.47; Table 1). Genotypic distribution of both APOE and -491A/T genotype were consistent with the distribution predicted by the Hardy-Weinberg equilibrium (APOE: chi2 test; P = 0.79; -491; chi2 test; P = 1.0). Subjects with memory complaints were found to have a significant increase in the frequency of APOE-epsilon4 alleles when compared to controls (chi2 = 5.06; P = 0.02; Table 2). Odds ratio analysis showed that subjects with memory complaints were 2.35 times more likely to have at least one copy of the APOE-epsilon4 allele than controls (95% CI = 1.11-4.97). With increasing copies of the APOE-epsilon4 allele a corresponding trend for decreased CAMCOG and MMSE scores was observed in controls, but more so in the memory complainers group (Table 2).

The dataset was probed to determine whether -491A/T promoter polymorphism genotype was associated with memory complaints. Subjects with memory complaints were 1.98 times more likely to have the -491AA genotype (95% CI = 0.98-3.99), however this difference did not attain statistical significance (P = 0.055, chi2 = 3.69; Table 3). However, the presence of at least one copy of the -491A allele conferred a 2-fold increased risk of memory complaints (95% CI = 1.11-3.52; P = 0.02, chi2 = 5.47). The -491A allele had no apparent effect on cognitive performance in either the control or memory complainers groups. However, in both groups, there was a trend towards increasing plasma apoE protein levels as the -491A allele copy number increased (Table 3).

The memory complainers group was then classified on the basis of a family history of dementia (Table 4) so as to determine potential differences in the patient sample regarding the investigated polymorphisms in memory complainers with a positive family history (n = 58) for dementia and those without (n = 40). This analysis revealed that the APOE-epsilon4 allele had the strongest association with 'memory complainers' who had a family history of dementia (P = 0.01, chi2 = 7.73; OR = 2.39, 95% CI = 1.22-4.66), whereas it was no longer associated with individuals without a family history of dementia. However, the reverse was seen with the -491A/T polymorphism. In this analysis 'memory complainers' without a family history of dementia had the strongest association with the -491A allele (P = 0.02, chi2 = 5.65; OR = 2.51, 1.16-5.43), whilst it was no longer significantly associated with those who had a family history of dementia.

Homozygosity for both the -491A and APOE-epsilon4 alleles occurred in only seven of the 147 individuals (4.8%), similar to the 5% that we have previously reported.36 This genetic combination was enriched within the 'memory complainers' group, which contained six out of seven of these individuals or 6.1% of 'memory complainers' (OR = 7.68; 95% CI = 0.9-65.87; chi2 = 4.65; P = 0.03). The data were analysed to determine whether these 'dual homozygotes' had elevated apoE levels. Plasma apoE levels were found to be significantly higher in these individuals (P < 0.01, t = 2.90; Table 5) and they performed significantly more poorly than controls in both the MMSE (P < 0.01, z = 2.62; Table 5) and CAMCOG (P < 0.01, z = 2.78; Table 4). Individuals who complained of memory decline and had two copies of the -491A and APOE-epsilon4 alleles showed significantly higher apoE levels than complainers with other genotypes (P < 0.001, t = 3.57). Furthermore, these individuals also tended to have lower MMSE and CAMCOG scores (Table 5) when compared to complainers of other genotypes, although this difference was not statistically significant.

To determine whether the -491A allele distribution was different between APOE-epsilon4 carriers and non-carriers, the -491 genotypes were stratified by the presence/absence of the APOE-epsilon4 allele (Table 6). In both APOE-epsilon4 carriers and non-carriers the memory complainers group had an increased frequency of the -491AA genotype. This increased frequency was significant in APOE-epsilon4 non-carriers (OR = 2.58; 95% CI 1.07-6.22; P = 0.03; chi2 = 4.58) but failed to reach significance in carriers possibly due to the low frequency of APOE-epsilon4 carriers in this group. Comparison of the frequency of the -491AA genotype in all study participants, as well as within both control and memory complainers groups, with respect to APOE-epsilon4 carrier status, revealed no significant difference between the distribution of the genotype and allele frequencies of the -491A/T polymorphism. These observations suggest that partial linkage between the APOE-epsilon4 and -491A alleles may account for some but not all of the association of the -491A allele with memory complainers.

Discussion

Cognitive assessment determined that memory complainers had significantly lower scores on the CAMCOG and MMSE. However, it must be noted that none of the subjects included in the study reached the threshold for diagnosable dementia. The APOE-epsilon4 allele was significantly over represented amongst individuals with memory complaints, and a gene dosage effect was present, emphasising that the APOE-epsilon4 allele is the most significant marker for cognitive decline. The data are also consistent with a recent report showing an association between the APOE-epsilon4 allele and memory decline in non-demented individuals.44 However, within this group the strongest association was seen in individuals with a family history of dementia. A previous cross-sectional analysis of clinical data from this cohort28 showed no association of APOE-epsilon4 with memory complaints. A high proportion of control individuals, in this study, with a relative suffering from AD, can explain this lack of association. Further controls were subsequently recruited and individuals with AD relatives were excluded from analysis to provide a better representation of a true control population.

Analysis of -491 genotype and allele frequencies revealed a significant association of the -491A allele with the 'memory complainers' group. Once again this association seemed to be determined by a family history of dementia, however in this case it was associated with individuals without a family history of dementia. This finding suggests that the -491A allele, and subsequently apoE levels, may be an important predictive factor in individuals without a family history of dementia, whilst the APOE genotype seems more associated with a positive family history. The data also suggests that the -491A allele confers an APOE-epsilon4-independent risk for an association with memory complaints, as recently reported in AD individuals.36,45 When the combination of the -491A and APOE-epsilon4 alleles was investigated among 'memory complainers' a relationship between these two polymorphisms was observed. It is interesting to note that among the seven individuals in this study who were homozygous for both alleles, six were 'memory complainers'. However, this profile represents only a small proportion of individuals (seven out of 147 in this study), and therefore these findings must be tested in a much larger population before definitive conclusions can be drawn. The six 'memory complainers' with homozygosity of both the APOE-epsilon4 and -491A alleles showed relatively low cognitive scores. Furthermore, it should be noted that one individual excluded from this study due to the clinical diagnosis of probable AD was also homozygous for both the -491A and the APOE-epsilon4 allele. On the basis of these findings, it will be interesting to determine whether other individuals with this genotypic profile will develop clinical signs of dementia.

Another biological factor that has shown promise as a potential marker for AD is plasma apoE protein levels. The levels of this protein have been previously reported to be increased in AD,31 and this increase may be partially attributed to the presence of the -491A allele,36 which has also been independently associated with increased Abeta40, Abeta42 and total Abeta loading in AD brains.46 A recent report has shown that CSF apoE levels are elevated in AD subjects,47 providing further support for its role as an important clinical marker for this disease. However, other studies have failed to replicate this finding.48,49,50,51 Whilst consensus on this issue is yet to be reached, it is interesting to note that studies have shown that apoE deficiency virtually abolishes cerebral amyloidosis in amyloid plaque-forming transgenic mice.52,53 In the current study, plasma apoE levels were not found to be significantly elevated among 'memory complainers'. However, levels were significantly higher in the sub-group of individuals who were homozygous for both the APOE-epsilon4 and the -491A alleles. Although there was no consistent elevation of plasma apoE levels among all 'memory complainers', the merits of this biological marker should not be discounted since this cross-sectional design does not distinguish between those destined to develop cognitive decline and those who will remain cognitively intact. Longitudinal studies of this cohort are in progress to determine the usefulness of plasma apoE levels as a potential biomarker.

The data from this study support the hypothesis that homozygosity at both the -491A and APOE-epsilon4 loci may be associated with cognitive decline and may play a role in the identification of individuals at high risk for the development of AD. The data also suggest that whilst partial linkage exists, the APOE-epsilon4 and -491A alleles can independently exert risk. Unfortunately, the study did not include a task of delayed recall and, as a consequence, the data did not allow for an analysis of these factors in individuals with objective memory deficits, such as in individuals with Mild Cognitive Impairment. Due to this limitation of the study, longitudinal studies on both individuals with subjective and objective memory deficits (or MCI) should clarify the significance of these risk factors as predictors of cognitive decline leading to AD.

Acknowledgements

This project was supported by the Department of Veteran Affairs, NHMRC (Australia), the McCusker Foundation for Alzheimer's Disease Research, and US NIH Program AG10491. SM Laws is a recipient of a Dora Lush (Biomedical) postgraduate research scholarship from the NHMRC (Australia).

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Tables

Table 1 ApoE levels, MMSE and CAMCOG scores in memory-impaired and control populations matched for age and education

Table 2 APOE genotype distribution and cognitive scores in memory-impaired and control populations

Table 3 APOE -491 polymorphism genotype distribution, apoE levels and cognitive scores in memory-impaired and control populations

Table 4 Summary of APOE polymorphisms in controls and memory complainers (including those with/without family history of dementia)

Table 5 ApoE levels and MMSE and CAMCOG scores in individuals who are homozygous for both the APOE-epsilon4 and the -491A alleles

Table 6 APOE -491 A/T distribution in APOE-epsilon4 carriers and non-carriers

Received 9 October 2001; revised 13 December 2001; accepted 16 January 2002
2002, Volume 7, Number 7, Pages 768-775
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