Table 1. Characteristics of the Different aPoe Subgroups

Variable aPoe ε22 + ε23n (%) aPoe ε34 + ε44n (%) aPoe ε33n (%) aPoe ε24n (%) Sex* Men 78 (17) 87 (19) 280 (61) 11 (3) Women 185 (16) 214 (18) 722 (63) 39 (3) Year 1998 263 (16) 301 (19) 1002 (62) 50 (3) 2000 150 (17) 150 (17) 550 (62) 34 (4) 2003 70 (18) 57 (16) 241 (63) 13 (3) 2005 38 (21) 26 (15) 113 (63) 2 (1) Fluency task (mean, standard deviation)* (12.7, 6.5) (12.4, 6.7) (12.7, 6.8) (11.6, 6.3) High 122 (16) 137 (18) 476 (63) 18 (3) Low 141 (16) 164 (19) 526 (61) 32 (4) Forward digit span (mean, standard deviation)* (4.7, 2.0) (4.4, 2.0) (4.6, 2.0) (4.3, 1.7) High 136 (17) 139 (18) 494 (63) 22 (3) Low 127 (15) 162 (20) 508 (62) 28 (3) Backward digit span (mean, standard deviation)* (3.1, 1.7) (3.1, 1.8) (3.1, 1.8) (2.9, 1.7) High 104 (15) 132 (19) 423 (62) 20 (3) Low 159 (17) 169 (18) 579 (62) 30 (3) Immediate recall (12 items) (mean, standard deviation)* (2.4, 1.8) (2.2, 1.7) (2.3, 1.8) (2.6, 1.8) High 124 (17) 126 (18) 436 (61) 29 (4) Low 139 (15) 175 (19) 566 (63) 21 (2) Delayed recall (12 items) (mean, standard deviation)* (1.0, 1.6) (0.9, 1.2) (1.0, 1.5) (0.9, 1.4) High 77 (17) 73 (16) 288 (64) 13 (3) Low 186 (16) 228 (20) 714 (61) 37 (3) Cognitive score High 122 (16) 140 (18) 484 (63) 22 (3) Low 141 (17) 161 (19) 518 (61) 28 (3) Cognitive score (mean, standard deviation) 1998 (0.2, 3.5) (−0.2, 3.3) (0.1, 3.6) (−0.2, 3.6) 2000 (−0.2, 4.2) (−0,5, 3.9) (0.2, 3.6) (−0.6, 4.4) 2003 (1.0, 3.2) (−0.6, 3.2) (0.1, 3.6) (−2.0, 2.7) 2005 (0.7, 39) (−0.4, 3.3) (0.5, 3.6) —

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*Measured at baseline in 1998.

The age and sex adjusted odds ratios for having a low cog- nitive score at study waves indicated a protective effect of carrying the aPoe ε2 allele compared with the aPoe ε33 diplotype, and the effect seemed to increase with study wave (Figure 3). In 2003, the difference between the aPoe ε2 allele compared with the aPoe ε33 diplotype reached sig- nificance with an odds ratio of 0.58 (95% CI: 0.34–0.98). The relative risk estimates for having a low cognitive function for aPoe ε4 allele carriers seemed to increase with study wave when compared with the aPoe ε33 diplotype (Figure 3A). This pattern was generally present for the dichotomized sub- components of the cognitive score even though none of these reached statistical significance (Figures 3B–3F).

The increased risk of mortality for those carrying the aPoe ε4 allele has previously been demonstrated in lon- gitudinal studies over various age groups (3,12,20,27–29), but in some studies no effect was found (30–32). Other studies have failed to observe an association between the aPoe ε4 allele carriers and mortality among the oldest old (29,33,34), whereas others again have found an increased risk (3,12). This discrepancy in findings may be the results of small-scale study populations, age differences in the study populations, and length of follow-up time or different selection criteria of the study populations.

A sex-specific effect of aPoe genotype on mortality has previously been studied (12,35,36). In a study based on the Kungsholmen Project (12) including 1,094 persons aged 75 years and older, the harmful effect of the aPoe ε4 allele was found to be stronger in men than in women, and the results suggested a protective effect of the aPoe ε2 allele on mortality in women. In our study, we did not find a stronger effect of the aPoe ε4 allele on mortality in men, and we found that the aPoe ε2 allele has no sig- nificant effect on mortality compared with persons with the aPoe ε33 diplotype. The present study population is much older at study start than the population studied in the Kungsholmen Project, and the differences in findings may

Discussion

In this study based on persons aged 93 and older, we found no significant protective effect of the aPoe ε2 allele on mortality compared with the aPoe ε3 allele. The car- riers of the aPoe ε2 allele were increasingly protected against cognitive decline over time (max at 39% at third study wave). The carriers of the aPoe ε4 allele had a 22% increased risk of dying compared with the aPoe ε33 diplo- type. Cognitive score did not significantly modify the mor- tality risk of the various aPoe genotypes.

2 A) APOE ε22 + ε23 APOE ε33 APOE ε34 + ε44 1.6 1.2 0.8 0.4 0 93 95 97 99 101 103 105 Age 2 B) Men APOE ε22 + ε23 APOE ε33 1.6 APOE ε34 + ε44 Women APOE ε22 + ε23 APOE ε33 1.2 APOE ε34 + ε44 0.8 0.4 0 93 95 97 99 101 103 105 Age 3 C) Low cognitive score APOE ε22 + ε23 2.5 APOE ε33 APOE ε34 + ε44 High cognitive score 2 APOE ε22 + ε23 APOE ε33 APOE ε34 + ε44 1.5 1 0.5 0 93 95 97 99 101 103 105 Age etar ytilatrom evitalumuCetar ytilatrom evitalumuCetar ytilatrom evitalumuC

be due to selection pressure through age, thus diminishing the effects of the aPoe ε2 allele at advanced ages. However, previously we found an increased effect for aPoe ε4 allele carriers with age in the 1905 cohort with approximately the same follow-up (3), and if genes have a stronger influence at the highest ages (3,4), it is more likely that other factors have influenced the observed discrepancy. Furthermore, there are a limited number of men alive in the present study, which makes chance an important agent in the findings.

The protective effect found for the aPoe ε2 allele on the decrease in cognitive score in this study corresponds to previous findings of a protective effect on dementia (12) and reduced decline in memory among the elderly adults (10,18,19). A recent study suggests that the aPoe ε2 allele protects against brain atrophy (37) and that this may be related to a higher concentration of synaptic proteins in the cerebral cortex (38), which may play a central role in memory and cognitive function.