Longevity and the 2 Allele of Apolipoprotein E: The Finnish Centenarians Study

Giovanni B. Frisoni,1 Jukka Louhija,2 Cristina Geroldi,1,3 and Marco Trabucchi3

1Laboratory of Epidemiology and Neuroimaging and the 3Alzheimer’s Unit, IRCCS San Giovanni di Dio–FBF, Brescia, Italy. 2Geriatric Section, Department of Medicine, Tromsø University Hospital, Norway.

Background. Whether and which genetic factors affect human longevity is unclear. This study assesses the associa- tion between the «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 «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 5 .01), respectively. The effect was particularly strong in women: 8% (8/100), 18% (6/33), and 28% (5/18; p for trend 5 .01) by age group, respectively. Low cell num- bers prevented clear conclusions being drawn for men. Seventeen percent (30/179) of the adult Finnish population were carriers of the «4 allele, a figure lower than expected, and stable by age group.

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

based survey involving all the centenarians living in Finland in 1991 (21).

T is believed that about one third to one quarter of the variation of the human life span can be attributed to ge- netic 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 apolipo- « « protein E (APOE) (4). Three common alleles ( 2, 3, and « « 4) and the rare 1 allele account for close to 100% of « APOE’s allelic variability. In normal populations, the 4 al- lele is associated with greater risk of Alzheimer’s disease « (5,6), while the 2 allele is associated with decreased levels of serum cholesterol and lower risk of cardiovascular dis- eases (7), memory disturbances, and Alzheimer’s disease (8–11).

M ETHODS

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 Reg- istry is peculiar in that it is one of the few in the world (together with that of Japan, France, and of the other Scan- dinavian countries) providing accurate and complete infor- mation on birth dates of those born before 1900 (22). Medi- cal 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 phe- notype, 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 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.

« The effect of the 2 allele on longevity has been sug- gested by observations of its increased frequency with age (12–15) and in centenarians (4,16). Centenarians are re- garded 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 be- comes very frequent after the age of 100 years (17). This se- lection hypothesis is consistent with demographic observa- tions. 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 actu- ally decreased after age 100.

In women, two logistic models were constructed to test « the association of 2 carrier status with age. Model 1 had two dichotomous predictor variables (age group, 100–101 1 vs 102–103 years, and age group, 100–101 vs 104 years). Model 2 had one predictor, that is, age group coded as an

We tried to test the hypothesis of the increased frequency « of the 2 allele of APOE in centenarians using data col- lected in the Finnish Centenarians Study, a population-

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 statisti- cal package, release 9 (SPSS, Inc., Chicago, IL), was used for the analysis.

Table 2. Association Between 2 Carrier Status and Age in Population of 151 Centenarian Women (the Finnish

Odds Ratio (95% CI) p Age category 102–103 y 2.6 (0.8–8.0) .11 1041 y 4.4 (1.3–15.6) .02 Test for trend 2.2 (1.2–3.9) .01

R ESULTS

The mean age of the study population was 101.2 years 5 5 (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 (x2 5 1.7, 5 5 df 2, p .44).

Note: CI 5 confidence interval.