Effects of the aPoe ε2 Allele on Mortality and Cognitive Function in the Oldest Old

Rune Lindahl-Jacobsen,1 Qihua Tan,1 Jonas Mengel-From,1 Kaare Christensen,1,2 Almut Nebel,3 and Lene Christiansen1

1Danish Aging Research Center, Epidemiology, University of Southern Denmark, J.B. Winsløws Vej 9B, DK-5000 Odense C, Denmark. 2Department of Clinical Genetics and Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Sdr Boulevard 29, DK-5000 Odense C, Denmark.

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Address correspondence to Rune Lindahl-Jacobsen, Associate professor, Cand. Scient., PhD., Danish Aging Research Center, Epidemiology, University of Southern Denmark, J.B. Winsløws Vej 9B, DK-5000 Odense C, Denmark. Email: rjacobsen@health.sdu.dk

Some studies indicate that the aPoe ε2 allele may have a protective effect on mortality and mental health among the elderly adults. We investigated the effect of the aPoe ε2 allele on cognitive function and mortality in 1651 members of the virtually extinct Danish 1905 birth cohort. We found no protective effect of the aPoe ε2 allele on mortality compared with the aPoe ε3 allele. The point estimates indicated an increased protection against cognitive decline over time for persons with the aPoe ε2 allele. Cognitive score did not significantly modify the mortality risk of the various aPoe genotypes. We did not find a protective effect of the aPoe ε2 allele on mortality among the oldest old, but in agreement with our previous findings, we found a 22% increased mortality risk for aPoe ε4 carriers. The aPoe ε2 allele may be protective on cognitive decline among the oldest old.

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Key Words: APOE—Cognitive function—Mortality—Aging—Oldest old.

Received March 16, 2012; accepted august 22, 2012

Decision editor: Rafael de cabo, PhD

A recent large study of a Swedish cohort of persons aged more than 75 years found that dementia accounts for most of the increased mortality risk for carriers of the aPoe ε4 variant. The study also found a protective effect of the aPoe ε2 allele on mortality for women when adjusting for dementia (12). Previous cross-sectional findings in the Danish 1905 cohort suggested no significant protective effect of the aPoe ε2 allele on the level of cognitive func- tion (20).

major question in human longevity research is how genetic variation influences our life span. Twin studies have found that genetic factors account for about a quarter of the variation in human life span in contemporary Nordic populations (1,2) and that the genetic factors may have a stronger influence at the highest ages (3,4). aPoe is the most well-documented gene found to influence life span. The aPoe ε4 allele is associated with an increased mortal- ity risk throughout adulthood (5), and the effect has been found to increase with age among the oldest old (3).

Hence, overall there is still controversy whether the aPoe ε2 allele has a protective effect on mortality and mental health among the elderly adults.

The aPoe allele has previously been associated with increased risk of various diseases including Alzheimer’s disease (6) and cardiovascular diseases (7–9). Most stud- ies have focused on the negative effect of carrying the aPoe ε4 allele, and fewer studies have examined the effects of the three aPoe alleles on mortality separately. In some studies, the presence of the aPoe ε2 allele in the oldest old has been associated with a reduced risk of dementia (10), decreased cholesterol levels (11), and an overall reduced mortality (12). Other studies suggest an increased risk of specific diseases such as Parkinson disease (10,13) among aPoe ε2 allele carriers, but most studies suggest a protective effect against Alzheimer’s disease (14–17).

Here we investigated the effect of the aPoe ε2 allele on cognitive function and mortality in the Danish 1905 birth cohort from 1998 through 2010.

Methods

Study Population

The Danish 1905 Cohort Survey is a nationwide longitudinal survey consisting of all individuals born in Denmark in 1905 identified through the Danish Civil Registration System. At baseline in 1998, a total of 3,600 persons aged 92–93 years were still alive in the cohort, and 2,262 of these persons participated in the intake survey (63%). DNA is available for 1,651 of the participants.

In relation to cognitive function, the aPoe ε2 allele has previously been associated with a better memory (18,19).

The baseline interview in 1998 and successive follow-ups (2000, 2003, and 2005) consisted of a personal interview in the respondent’s home and included information on sociodemographic variables, health measures, and self- reported activities of daily living. Trained interviewers from the Danish National Institute of Social Research carried out the survey. A nonresponse analysis showed no difference between responders and nonresponders with respect to sex (women, 84% vs. 89%, p = .16), median number of hospitalizations (p = .56), or median number of bed days (p = .71) during the years 2003 and 2004 (21).

aPoe genotype and mortality rather than a possible con- founder, and separate Poisson regression models were done for each stratum of cognitive score. When analyzing mortal- ity, we used the most recently measured (eg, the last study wave where the person participated) to address cognitive score allowing participants to change group during follow- up, thus making it possible to include cognitive score as a time-dependent variable. All statistical analyses were done using SAS (version 9.2; SAS Institute Inc.).

Results

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