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The strengths of our research are the long follow-up period, the high participation rate, and the measure of cognitive function over time, which made it possible to include these as time-dependent covariates in the analysis. In the present study, we did not have information on causes of death. Considering that the major cause of death in Denmark is cardiovascular diseases, this could potentially explain the observed increased mortality in the aPoe ε4 allele carriers. Previous studies have found an association between carrying the aPoe ε4 allele and cardiovascular diseases. This may also have been the case in the present study. Our population was followed from age 92–93 years, thus making the result relevant for the oldest old but not for younger persons. Consequently, this complicates a comparison with other studies on this topic but also warrants studies among younger persons. The age groups studied here further raise the problem of survival selection, perhaps weakening the association between aPoe and mortality. However, in a previous study of the Danish 1905 cohort, we did not find any attenuation of the aPoe and mortality association with age (3), on the contrary, although those findings did not exclude the possibility that the association was even stronger at younger ages than the ones studied here. Cognitive function may be considered an intermediate factor in the causal chain between aPoe genotype and mortality. Still, in the present study, stratification of the analysis by cognitive function examining the separate effect of aPoe genotype within strata gave similar results. For the individual aPoe genotypes studied here, no significant differences in mortality risk were found for persons with low or high cognitive score.

In conclusion, in this study, we did not find an overall protective effect of the aPoe ε2 allele on mortality among the oldest old, but we found a 22% increased mortality risk for aPoe ε4 allele carriers. The aPoe ε2 allele has a pro- tective effect on cognitive decline among the oldest old.

Figure 1. Cumulative mortality rates over age for different aPoe genotypes.

High cognitive score Low cognitive score All Men Women 1.8 1.8 1.8 1.4 1.4 1.4 1 1 1 0.6 0.6 0.6 0.2 0.2 0.2 APOE ε22 + ε23 APOE ε34 + ε44 APOE ε22 + ε23 APOE ε34 + ε44 APOE ε22 + ε23 APOE ε34 + ε44 ksir

from http://biomedgerontology.oxfordjournals.org/ at Bibliotheque de l'Universite Laval on July 13, 2014

Figure 2. Relative risk of dying when compared with the aPoe ε33 diplotype. Vertical lines on bars are 95% confidence intervals.

APOE (cid:31)2 carriers APOE (cid:31)4 carriers A B C Cognitive function Fluency task Forward digit span 4 4 4 3 3 3 2 2 2 1 1 1 0 0 0 1998 2001 2003 2005 1998 2001 2003 2005 1998 2001 2003 2005 Study wave Study wave Study wave D E F Backward digit span Immediate recall of 12 items Delayed recall of 12 items 4 4 4 3 3 3 2 2 2 1 1 1 0 0 0 1998 2001 2003 2005 1998 2001 2003 2005 1998 2001 2003 2005 Study wave Study wave sddOoitar sddO       ‘002 Onn Onn? Onn  002 Onn Onn? 9onnE   00g 9nNN4 Onn ONNK  00g 9nNN4 Onn 9ONNE  49002 9n04 9nNn2 9nNNE 400  oa 9004 Nn? Onn  oa 9004 Nn? 9NnNE  49002 9nNN4 Onn 9NnNE  00g 9nNN4 Onn  00g 9nNN4 Onn          00g 9004 9Nn2 9ONNK  00g 9004 9Nn2 9ONNE

at Bibliotheque de l'Universite Laval on July 13, 2014

Figure 3. Odds ratio for low cognitive score and its components over study waves when compared with the aPoe ε33 diplotype. Vertical lines on bars are 95% confidence intervals.

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