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Age and Ageing Advance Access originally published online on February 4, 2008
Age and Ageing 2008 37(3):288-293; doi:10.1093/ageing/afn003
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Copyright © The Author 2008. Published by Oxford University Press on behalf of the British Geriatrics Society.

Association between APOE {varepsilon}2/{varepsilon}3/{varepsilon}4 polymorphism and disability severity in a national long-term care survey sample

Alexander Kulminski1, Svetlana V. Ukraintseva1, Konstantin G. Arbeev1, Kenneth G. Manton3, Junko Oshima2, George M. Martin2 and Anatoli I. Yashin1

1 Center for Population Health and Aging, Duke University Population Research Institute and Department of Sociology, Duke University, Trent Hall, Room 002, Durham, NC 27708, USA
2 Department of Pathology, University of Washington, HSB K-543, 1959 NE Pacific Ave, Seattle, WA 98195-7470, USA
3 Art and Sciences, Duke University, Trent Hall, Room 012, Durham, NC 27708, USA

Address correspondence to: Alexander Kulminski. Tel: 919-684-4962; Fax: 919-684-3861. Email: Alexander.Kulminski{at}duke.edu


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion and conclusions
 Key points
 Funding
 References
 
Background: early studies reported controversial findings on association of apolipoprotein E (APOE) polymorphism with disability.

Objective: to analyse sex-specific associations of APOE genotypes with impairments in (instrumental) activities of daily living [(I)ADL] and mortality.

Design: population-based 1999 National Long Term Care Survey (NLTCS) of the US older (65+) individuals.

Participants: genetic data are available for 1,805 individuals.

Methods: each of six genotypes of three common alleles of the APOE locus ({varepsilon}2, {varepsilon}3 and {varepsilon}4) was tested on the association with a disability index or mortality.

Results: APOE {varepsilon}3/{varepsilon}3 genotype significantly decreases odds ratio (OR) for IADL disability in males [OR = 0.48; 95% Confidence Interval (CI) 0.31–0.76] while it exhibits no association in females. The OR for ADL disability is 0.19 (CI 0.04–0.99) for {varepsilon}4/{varepsilon}4 female carriers. The {varepsilon}2/{varepsilon}3 genotype increases the chances of IADL disability for males (OR = 2.33; CI 1.28–4.25). No significant association between APOE polymorphism and mortality was found. A surprising observation was that {varepsilon}4/{varepsilon}4 female carriers have a 5.3 times lower chance of having ADL disability than non-{varepsilon}4/{varepsilon}4-carriers.

Conclusions: association of the APOE polymorphism with disability and lack of association with mortality support the view that APOE gene actions may be more significant as modulators of frailty than of longevity.

Keywords: apolipoprotein E, disability, sex differences, elderly


   Introduction
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 Abstract
 Introduction
Methods
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 Discussion and conclusions
 Key points
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 References
 
Three major polymorphic alleles of the apolipoprotein E (APOE) locus ({varepsilon}2, {varepsilon}3 and {varepsilon}4) can be presumed to play an important role in the transport of cholesterol and other lipids, although their complete biological activities [1] may involve additional mechanisms. Numerous studies have demonstrated an association of the APOE polymorphism and the risk of cognitive impairment and Alzheimer's disease (AD) as well as cardiovascular disease (CVD), including atherosclerosis and stroke [2, 3]. The APOE polymorphism has also been reported to be associated with mortality risk [4, 5]; these findings are controversial, however, as a number of recent studies did not reveal a relationship between APOE alleles and mortality [6, 7].

It was hypothesised that the APOE polymorphism might be associated with other adverse health outcomes affecting the functional status of individuals [8, 9]. This hypothesis is justified by the association of a low level of high-density lipoprotein cholesterol with disability in older individuals [10, 11], but knowledge of the association of the APOE polymorphism with disability remains limited. For example, it was shown that the APOE {varepsilon}4 allele was associated with poor functional status in community-dwelling older Americans who retained normal cognitive function [8]. Later studies of Italian octo- and nonagenarians, however, did not show such an association [12]. Moreover, while the APOE {varepsilon}4 allele was not associated with a population-wide decline in functional status in the Duke Established Populations for Epidemiologic Studies of the Elderly (EPESE) participants [13], female carriers of the APOE {varepsilon}4 allele, particularly those who had comparatively good baseline functional scores, did exhibit significant functional declines [13]. Further analyses of the EPESE data show no associations between the APOE {varepsilon}4 status and any of the five dimensions of quality of life [14]. More recently, it was shown that the APOE {varepsilon}4 polymorphism is associated with an excess of mobility limitation but not with self-reported functional limitations [9].

An interpretation of the prevalence of APOE polymorphism in samples of old versus younger individuals has suggested that APOE is a ‘longevity’ gene [15]. However, while the APOE {varepsilon}4 allele has been shown to significantly increase risks of certain disorders (e.g. CVD, AD), its effect on total mortality was not found to be substantial in recent studies [16, 17]. This suggests a possible protective effect of the APOE {varepsilon}4 allele on risks of other disorders. APOE has also been viewed as a ‘frailty’ gene rather than a ‘longevity’ gene [16, 17]. Disability is often viewed as a manifestation of stress vulnerability in older people [18]; such vulnerability is referred to as ‘frailty’ by demographers [19]. Although physiological frailty and disability are generally distinct concepts [18], they partly overlap since disability is associated with physiological frailty [18, 20]. If that is the case, a stronger association of the APOE genotypes with disability than mortality would suggest a greater impact upon frailty than upon longevity.

In this work we analyse sex-specific associations among subjects stratified by disability status and specific APOE genotypes in a sample of the 1999 National Long Term Care Survey (NLTCS) for whom biological specimens were collected. The phenotype of mortality was also investigated. We address two main questions: (i) is disability status sensitive to the APOE polymorphism? (ii) do gene actions of various genotypic variants function more as modulators of frailty rather than of longevity?


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion and conclusions
 Key points
 Funding
 References
 
Study population
The NLTCS is a nationally representative survey which provides a large set of self- and proxy-reported data (several thousands variables, depending on the NLTCS wave) on health and functioning of the US elderly with a particular focus on disabled individuals. Each of five NLTCS waves is linked to Medicare service use and vital statistics files (currently from 1982 to August, 2003). The NLTCS is considered to be one of the best designed surveys to assess chronic disability (activity limitations due to disability or health problems which require either active help or standby help, or equipment use and last 90+ days [21]) in the US elderly (65+) individuals [22]. To complete the NLTCS, a two-stage interviewing process was used. A screening interview assessing chronic disability was given to all participants randomly selected from the Medicare enrollees. A detailed interview was given to (i) those who reported at least one chronic impairment in (instrumental) activities of daily living (I)ADL, (ii) institutionalised individuals, and (iii) those who received a detailed interview in a previous survey. The 1994 and 1999 surveys also explicitly included samples of individuals who were designated for detailed interviews before being give a test on disability. Therefore, by the survey design, disabled persons are over-sampled in detailed questionnaires (for details see [21] and references therein) that provide unique opportunity to focus on such vulnerable portion of the older population.

The 1999 NLTCS with APOE information
Biospecimens were collected during 2000–2002 for a sub-sample of the 1999 NLTCS participants. A total of 2,075 blood and buccal cell samples were collected to assess the effects of selected genetic markers on human longevity and physical function. The APOE {varepsilon}2, {varepsilon}3 and {varepsilon}4 alleles were determined by the presence or absence of certain restriction sites [23]. Assays were done for 1,805 individuals. To test for the reproducibility of the genotyping, 47 peripheral blood samples (1 {varepsilon}2/{varepsilon}2; 8 {varepsilon}2/{varepsilon}3; 3 {varepsilon}2/{varepsilon}4; 20 {varepsilon}3/{varepsilon}3; 11 {varepsilon}3/{varepsilon}4; 4 {varepsilon}4/{varepsilon}4) were re-genotyped using two different methods: the original restriction digestion method [23] and an automated sequencing method [24]. The results with all three assays were concordant for each of the genotypes.

For seven individuals, information on disability was missing, and thus they were excluded from the analysis. Among the other 1,798 individuals there were 680 males (37.8%). Mean age of males was 76.4 years [standard error (SE): 0.3] and of females was 78.4 (SE: 0.2) on the date of interview. The frequencies of the APOE polymorphism were: {varepsilon}2/{varepsilon}2, n = 13, 0.7%; {varepsilon}2/{varepsilon}3, n = 243, 13.5%; {varepsilon}2/{varepsilon}4, n = 42, 2.3%; {varepsilon}3/{varepsilon}3, n = 1,127, 62.7%; {varepsilon}3/{varepsilon}4, n = 351, 19.5%; and {varepsilon}4/{varepsilon}4, n = 22, 1.2%.

Disability measures
Information on disability is assessed from the NLTCS community and institutional questionnaires. Community questionnaire covers 96.4% of the genetic sub-sample and assesses six impairments in ADL [25] (eating, getting in/out of bed, getting around inside, getting to the bathroom/using the toilet, dressing and bathing) and ten impairments associated with IADL [26] (doing heavy work, doing light work, doing laundry, cooking, shopping for groceries, getting around outside, going places outside of walking distance, managing money, making telephone calls and taking medicines). Remainder of the sample (n = 65) represents institutional population which was interviewed only on ADL impairments [21]. Since our analysis shows that inclusion/exclusion of institutionalised individuals does not significantly affect the estimates, we did not distinguish between institutional and community samples. We have found that the efficient way for analysis is to dichotomise the disability measures selecting three indicators of: (i) any disability (AnyDisb, n = 1,004, 299 males; either ADL or IADL); (ii) IADL-only disability (IADL-only, n = 252, 97 males; at least one IADL and no ADL), and (iii) ADL disability (ADL-any, n = 752, 202 males; at least one ADL irrespective of IADL). Since the IADLs reflect generally less serious disabilities, while ADLs reflect more serious disabilities [27], by selecting the latter two groups we cover disabilities with distinct severity levels [22]. A reference group was composed of non-disabled individuals (Non-dis, n = 794, 381 males).

Analysis
Statistical analyses of the data were performed using SPSS software (release 12.0, Chicago, Illinois, USA). To test the association of distinct disability groups with the APOE genotypes, we used empirical analyses (t-statistics, chi-square) and logistic regression analyses. Since the results of both these approaches were qualitatively similar, only the results of logistic models were retained. The relationship between the APOE genotypes and mortality was tested using the Cox proportional hazard regression models. Relative risks (RR) of death were calculated over the follow-up time (to August, 2003). Analyses were performed for males and females combined and then for each sex (all models were adjusted for age). In each analysis we used dichotomised indices indicating carriers of given genotype(s) as contrasted to carriers of all other genotypes (e.g. the {varepsilon}2/{varepsilon}3 genotype versus non-{varepsilon}2/{varepsilon}3 genotypes) and to carriers of the {varepsilon}3/{varepsilon}3 genotype. Genetic studies involving multiple genes/alleles often require correction for multiple testing [28]. They are necessary to examine for ‘at least one genetic effect’ among the variety of genetic factors subject to testing. Since this is obviously not the case in our study, the correction for multiple testing is not required [29].


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion and conclusions
 Key points
 Funding
 References
 
Figure 1 depicts the results of pair-wise logistic regression analyses [odds ratio; (OR)] of the associations between disability and the APOE genotypes for the entire sample. The ORs are significant for the {varepsilon}4/{varepsilon}4 genotype for more serious (ADL-any) impairments [OR = 0.15, 95% Confidence Interval (CI): 0.03–0.71] and for the {varepsilon}3/{varepsilon}3 genotype for less serious (IADL-only) impairments (OR = 0.70, CI 0.53–0.95).


Figure 1
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  		Figure 1. Logistic regression associations between the APOE genotypes and disability of different types (as defined in the text) in the sex-unstratified APOE sample. Thin bars show 95% confidence interval. Note natural log OR scale for less frequent genotypes [i.e. ORNaturalLog = ln (ORlinear)].

 
Figure 2 shows the results of the analyses for females (a,b) and males (c,d). There are no {varepsilon}4/{varepsilon}4 male carriers with disabilities. Therefore, only females are in this group in Figure 1. Logistic regression analyses show that the {varepsilon}4/{varepsilon}4 genotype significantly decreases chances of ADL impairments for females (OR = 0.19, CI 0.40–0.99).


Figure 2
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  		Figure 2. Logistic regression associations between the APOE genotypes and disability of different types (as defined in the text) for females (a, b) and males (c, d). Thin bars show 95% confidence interval. Note natural log OR scale for less frequent genotypes [i.e. ORNaturalLog = ln (ORlinear)].

 
For more frequent genotypes (Figure 2b and d) significant ORs are seen for males but not for females. Significance of the OR estimates for IADL-only group for the {varepsilon}3/{varepsilon}3 genotype in Figure 1 is attributable to the presence of males. Separating males and females results in chances of having IADL becoming lesser and highly significant for males (OR = 0.48, CI 0.31–0.76). IADL impairments make the OR for males with any disability to be significant (OR = 0.71, CI 0.51–0.97). Similar behaviour (but of opposite nature) is seen for the {varepsilon}2/{varepsilon}3 genotype. Specifically, the {varepsilon}2/{varepsilon}3 male carriers have significantly higher chances of IADL disability than the non-{varepsilon}2/{varepsilon}3 carriers (OR = 2.33, CI 1.28–4.25). Significance of the OR estimates for males with any disability are attributable to IADL impairments (OR = 1.62, CI 1.02–2.58). The results for the APOE genotypes contrasted by the {varepsilon}3/{varepsilon}3 genotype are similar (not shown here).

Finally, we tested the relationship of the APOE genotypes with mortality. The test was performed for the same conditions as in the logistic regression analysis (i.e. for males and females combined and then for males and females separately, controlling for age). We found no significant associations of mortality for carriers of any particular APOE genotype with respect to carriers of other genotypes. We also found no such associations, using as a reference group carriers of the {varepsilon}3/{varepsilon}3 genotype (Table 1). Note that the results are insensitive to the type of the reference group.


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  		Table 1. Relative risk (RR) of death with 95% Confidence Interval in parentheses for each genotype versus either other genotypes or {varepsilon}3/{varepsilon}3 genotype in a Cox proportional hazard regression model for males and females combined (M and F) and each sex (adjusted for age)

 

   Discussion and conclusions
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion and conclusions
Key points
 Funding
 References
 
The NLTCS, which is specifically designed to assess health and functioning of older individuals with disabilities, provides a unique opportunity to study the association of the APOE polymorphism with various outcomes focusing on the effect-modification by disability. In this study we examined an association of the APOE genotypes with disability of different severity and mortality to clarify two issues. First, we checked whether there is an association between a particular APOE genotype and disability. Second, we contributed to the discussion on whether APOE can be considered as a ‘longevity’ or ‘frailty’ gene [16, 17].

Unlike studies by Albert et al. [8] and in support of studies by Melzer et al. [9] and Blazer et al. [13], our analysis does not show significantly increased risks of disability in carriers of the three APOE genotypes bearing an {varepsilon}4 allele. Contrary to Albert et al. [8], our analysis reveals protection of the APOE {varepsilon}4/{varepsilon}4 genotype against disability. Specifically, non-{varepsilon}4/{varepsilon}4 female carriers have 5.3 times greater chance of having more severe (ADL) impairments than the APOE {varepsilon}4/{varepsilon}4 female carriers. We also reveal a protective function of {varepsilon}3/{varepsilon}3 and an adverse function of {varepsilon}2/{varepsilon}3 in males with less severe (IADL) disability.

Our analysis shows that the associations between the APOE polymorphism and disability involve at least three factors: the effects of genotype, severity of disability and sex. Aggregation/disaggregation of the data along these dimensions provides qualitatively different results that can partly explain the disagreement of published studies. First, we show that disaggregation of disability is important. Specifically, while certain genotypes can affect mild disability, they might be irrelevant to severe impairments (e.g. {varepsilon}3/{varepsilon}3 genotype, see Figure 1). Second, particular genotypes having the same allele can contribute to the combined effect in different ways. For example, {varepsilon}2/{varepsilon}3 carriers have larger chances of less severe disabilities (IADL), {varepsilon}3/{varepsilon}4 carriers are neutral to the presence of IADLs, and {varepsilon}3/{varepsilon}3 carriers have a significantly lower chances of IADL impairments (Figure 1). The neutral and opposite tendencies exhibited by these genotypes result in no association between less severe disability and the {varepsilon}3-allele. Finally, sex also appears to be important, revealing additional significant associations, i.e. adverse function of the {varepsilon}2/{varepsilon}3 genotype in males and neutral impact in females on less severe disability. Obviously, other factors (e.g. age and the APOE-associated diseases) might contribute to the revealed associations; those issues deserve separate study [30, 31].

Another intriguing finding is that none of the six APOE genotypes is predictive of mortality in a Cox regression analyses. Given the significance of the association of a particular APOE genotype with disability and the association of disability with frailty [20], as well as the lack of significance for association of the same genotype with mortality, support is provided for the view that APOE gene actions may be more significant as modulators of frailty than of longevity per se [16].


   Key points
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion and conclusions
 Key points
Funding
 References
 

  • Early studies generally reported no association of APOE polymorphism with disability.
  • The present NLTCS study demonstrates associations between disability and APOE genotypes.
  • Female {varepsilon}4/{varepsilon}4 carriers and male {varepsilon}3/{varepsilon}3 carriers have diminished chances of developing more serious (ADL) disabilities than the respective non-carriers.
  • The {varepsilon}2/{varepsilon}3 genotype increases the chance of less serious (IADL) impairments for males.


   Conflicts of interest
 
Each co-author asserts no proprietary interest in the results and no financial conflict of interest.


   Funding
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion and conclusions
 Key points
 Funding
References
 
The research reported in this article was supported by the grants 5U01-AG-007198, 1 R01 AG028259, 1 R01-AG-027019, 5 R01-AG-030612, and 5P01-AG-008761 from the National Institute on Aging (NIA).


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion and conclusions
 Key points
 Funding
 References
 

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Received 15 February 2007; accepted in revised form 27 September 2007.


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