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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 56:M75-M78 (2001)
© 2001 The Gerontological Society of America

Longevity and the {varepsilon}2 Allele of Apolipoprotein E

The Finnish Centenarians Study

Giovanni B. Frisonia, Jukka Louhijac, Cristina Geroldia,b and Marco Trabucchib

a Laboratory of Epidemiology and Neuroimaging, IRCCS San Giovanni di Dio–FBF, Brescia, Italy
b Alzheimer's Unit, IRCCS San Giovanni di Dio–FBF, Brescia, Italy
c Geriatric Section, Department of Medicine, Tromsø University Hospital, Norway

Giovanni B. Frisoni, Laboratory of Epidemiology and Neuroimaging, IRCCS San Giovanni di Dio\|[ndash ]\|FBF, via Pilastroni 4, I-25123 Brescia, Italy E-mail: frisoni{at}master.cci.unibs.it.

Decision Editor: John E. Morley, MB, BCh


   Abstract
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 Abstract
Methods
 Results
 Discussion
 References
 
Background. Whether and which genetic factors affect human longevity is unclear. This study assesses the association between the {varepsilon}2 allele of apolipoprotein E (APOE), a putative longevity gene, and extremely old age.

Methods. This study is based on all centenarians living in Finland in 1991. Subjects were 179 persons (28 men and 151 women) aged 100 years and older (response rate, 97%).

Results. The percentages of {varepsilon}2-allele carriers in persons aged 100 to 101, 102 to 103, and 104 years and older were 9% (10/117), 21% (9/42), and 25% (5/20; gender-adjusted p for trend = .01), respectively. The effect was particularly strong in women: 8% (8/100), 18% (6/33), and 28% (5/18; p for trend = .01) by age group, respectively. Low cell numbers prevented clear conclusions being drawn for men. Seventeen percent (30/179) of the adult Finnish population were carriers of the {varepsilon}4 allele, a figure lower than expected, and stable by age group.

Conclusions. Carriers of the {varepsilon}2 allele of APOE might be predisposed to reach extremely old age.

IT is believed that about one third to one quarter of the variation of the human life span can be attributed to genetic factors (1)(2), and a number of genes have recently been indicated as possible longevity genes (3). One of the strongest candidates is the lipid-carrying protein apolipoprotein E (APOE) (4). Three common alleles ({varepsilon}2, {varepsilon}3, and {varepsilon}4) and the rare {varepsilon}1 allele account for close to 100% of APOE's allelic variability. In normal populations, the {varepsilon}4 allele is associated with greater risk of Alzheimer's disease (5)(6), while the {varepsilon}2 allele is associated with decreased levels of serum cholesterol and lower risk of cardiovascular diseases (7), memory disturbances, and Alzheimer's disease (8)(9)(10)(11).

The effect of the {varepsilon}2 allele on longevity has been suggested by observations of its increased frequency with age (12)(13)(14)(15) and in centenarians (4)(16). Centenarians are regarded as particularly useful models to detect longevity genes (17)(18). Through selection, mortality produces changes in the phenotypic and genotypic composition of a population, such that survivors are a distinctive subgroup carrying the more resistant genotypes (19). Demographic simulations have shown that the genetic composition of a population may undergo dramatic changes in extremely old age, and a rare genotype that favors survival rapidly becomes very frequent after the age of 100 years (17). This selection hypothesis is consistent with demographic observations. Based on US census data, Riggs and Millecchia (20) showed that mortality rates after age 85 had a progressively longer doubling time, reached a plateau by age 95, and actually decreased after age 100.

We tried to test the hypothesis of the increased frequency of the {varepsilon}2 allele of APOE in centenarians using data collected in the Finnish Centenarians Study, a population-based survey involving all the centenarians living in Finland in 1991 (21).


   Methods
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 Methods
Results
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At the start of the data collection, on March 1, 1991, the Finnish population was 5.04 million, and there were 224 subjects aged 100 years and older, identified on the basis of the Finnish National Population Registry. The Finnish Registry is peculiar in that it is one of the few in the world (together with that of Japan, France, and of the other Scandinavian countries) providing accurate and complete information on birth dates of those born before 1900 (22). Medical examinations and interviews were carried out, and blood samples were drawn by one of the authors (J.L.) until the conclusion of data collection on December 31, 1991. At the time of evaluation, 185 of the 224 subjects were still alive. Of these, 4 refused to be evaluated, and blood could not be obtained in another 2 subjects. Thus, the APOE genotype was available for 179 individuals (97%) of the evaluated population. The APOE genotype was derived from the phenotype, determined by isoelectric focusing of plasma (21). A 97.5% concordance of this DNA genotyping technique was demonstrated by Kontula and colleagues (23). Further details of our study methods have been previously reported (21)(24). Carriers of the {varepsilon}2 allele were defined as those with at least one copy of the allele. This study was approved by the Ethics Committee of the Helsinki University Central Hospital.

In women, two logistic models were constructed to test the association of {varepsilon}2 carrier status with age. Model 1 had two dichotomous predictor variables (age group, 100–101 vs 102–103 years, and age group, 100–101 vs 104+ years). Model 2 had one predictor, that is, age group coded as an ordinal (1, 2, and 3) variable (test for trend). Odds ratios and a 95% confidence interval (CI) (25) were computed from the B coefficients of the logistic models. The SPSS statistical package, release 9 (SPSS, Inc., Chicago, IL), was used for the analysis.


   Results
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 Abstract
 Methods
 Results
Discussion
 References
 
The mean age of the study population was 101.2 years (SD = 1.4) in the 28 men and 101.1 years (SD = 1.5) in the 151 women. The oldest subject was a woman aged 106 years and 2 months. Gender was not differently distributed by age: women comprised 100 of 117 (86%) of those aged 100 to 101, 33 of 42 (79%) of those aged 102 to 103, and 18 of 20 (90%) of those aged 104 years and older ({chi}2 = 1.7, df = 2, p = .44).

The percentages of each genotype are shown in Table 1 . The sample was composed primarily of women. In the raw data, the frequency of the {varepsilon}2/3 genotype increased with age from 9% to 25% (Mantel-Haenszel {chi}2 test for linear association = 5.9, df = 1, p = .02), although {varepsilon}3/3 became less frequent ({chi}2 = 4.3, df = 1, p = .04). There were no subjects who carried the {varepsilon}2/4 genotype. For counts of at least 5, percentages across age groups were comparable for men and women.


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  		Table 1. Genotypic Frequencies of Apolipoprotein E in a Population of 179 Centenarians (the Finnish Centenarians Study)

 
Odds ratios from the two logistic models were computed for women (shown in Table 2 ). In model 1, women aged 102 to 103 years were 2.6 times more likely to carry the {varepsilon}2 allele compared with those aged 100 to 101 years. Those aged 104 years and older were 4.4 times more likely to carry the {varepsilon}2 allele compared with those aged 100 to 101 years. The 95% CI for this odds ratio did not include 1, indicating statistical significance. Model 2 estimates that each age increment (100–101 years to 102–103 years, and 102–103 years to 104+ years) more than doubled the frequency of the {varepsilon}2—a statistically significant result roughly consistent with model 1.


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  		Table 2. Association Between {varepsilon}2 Carrier Status and Age in a Population of 151 Centenarian Women (the Finnish Centenarians Study)

 
Carriers of the {varepsilon}2 allele were not more frequent in men (5/28, 18%) than in women (19/151, 13%; {chi}2 = 0.5, df = 1, p = .45). The low numbers of the cells of the male population (see Table 1 ) prevented further analyses.


   Discussion
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 Abstract
 Methods
 Results
 Discussion
References
 
We found that the frequency of the {varepsilon}2 allele of APOE shows a marked increase after age 100, supporting the view that the allele is related to longevity.

Although an increase of the frequency of the {varepsilon}2 allele with age has been previously reported in other elderly populations (4)(12)(13)(14)(15)(16), data on the frequency of {varepsilon}2 carriers within the group of centenarians have never been reported. Mathematical simulations of the changes in the genetic composition of large populations have shown that, starting from around age 100, longevity genes have an increased likelihood of being selected (17). Thus, the finding of a rise in frequency of the {varepsilon}2 allele with age in Finnish centenarians strengthens the idea that the allele is related to longevity.

The selection of the {varepsilon}2 allele with age has been previously shown in a relatively younger Swedish cohort (75–98 years). Corder and colleagues (12) found an increased frequency of {varepsilon}2/3 individuals with older age, and this association was more marked in men (12%, 14%, and 17% in those aged 75–79, 80–84, and 85+ years, respectively) than women (13%, 11%, and 15%, respectively). Moreover, {varepsilon}2/3 individuals had two- and fourfold lower mortality than {varepsilon}3/3 and {varepsilon}3/4 individuals (12), and {varepsilon}3/4 individuals had lower survival rates following ischemic stroke (26). These data are in agreement with other observations on the attrition of the {varepsilon}4 allele with age (4)(13)(14)(15) and with our own of low prevalence (17%) of {varepsilon}4 carriers in the Finnish centenarians. This figure is about half that expected on the basis of studies in large population samples that have shown the prevalence of {varepsilon}4 carriers in young and adult Finns is 35% to 40% (27)(28).

One other study of Japanese centenarians failed to detect any frequency increase of the {varepsilon}2 allele. Asada and colleagues (16) found that the frequency of carriers of the {varepsilon}2 allele was not significantly different from that of younger controls (9% vs 7%); however, their sample was small (N = 33). We believe that the few epidemiological studies on this issue can be accounted for by the considerable practical difficulties met by the collection of sizable and representative samples of centenarians. The proportion of centenarians is very small, even in developed countries: only 1 in 10,000 adults reach age 100, and, of these, less than 1 in 100 reaches age 110. Therefore, studies must draw subjects from large geographical areas, often nationwide. Moreover, centenarians are often in poor physical and mental condition, and the refusal rate can be as high as 30% (29). It should be noted that, although the Finnish Centenarians Study overcomes some of these methodological problems, its numbers are insufficient to assess some phenomena, such as age-related effects in men.

Some hypotheses can be proposed to explain the mechanism of the {varepsilon}2 allele's action on longevity. The hypocholesterolemia typical of middle-aged {varepsilon}2 carriers is believed to protect from atherosclerosis and vascular disease (4). However, the effect of the E2 protein isoform on serum cholesterol attenuates with age (30). Thus, it is unlikely that the increased frequency of the {varepsilon}2 allele in centenarians is mediated by its hypocholesterolemic effect.

Alternatively, the {varepsilon}2 allele might enhance the efficiency of the neuroendocrine system. The neuroendocrine system might play a key role in aging and longevity (31), and it has been shown that function of APOE is directly related to that of the hypothalamic-pituitary-adrenal axis in response to acute and chronic stresses in mice (32).

Finally, {varepsilon}2 carriers might be more resistant to the insults of aging and disease in general. In addition to being less susceptible to Alzheimer's disease, it has been shown that the brains of subjects carrying the {varepsilon}2 allele are also less susceptible to traumatic and vascular lesions (33), as well as to the chronic insults of inherited metabolic diseases (34). It has been suggested that this effect is due to the greater efficiency of the E2 protein isoform in repairing nervous tissue damage (33). However, longevity is due to successful aging, not only of the brain, but of the whole body machinery. Although it is presently unknown whether the beneficial effect of the E2 isoform extends to tissues and organs outside the nervous system, anecdotal reports indicate a surprising resistance of some centenarians to a series of adverse general medical events occurring during their lifetimes (35).


   Acknowledgments
 
This study was supported by a grant from the IRCCS San Giovanni di Dio–FBF, Brescia, Italy.

Received October 25, 1999

Accepted May 12, 2000


   References
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 Abstract
 Methods
 Results
 Discussion
 References
 

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