Although the number of persons who were homozygous for the E4 isoform was low at 1.9% (Table 2), the age-related effect observed was most prominent in E4 homozygotes, with a 70% reduction in frequency from 2.7% in persons aged 60 years or less to 0.8% in those over age 85 years (Table 2). A decreased frequency of 35% was also observed in E3/E4 heterozygotes, with a reduction from 26.8% to 17.5% recorded over the same age range (Table 2). Persons who were heterozygous for the E2/E4 genotype showed a non-significant change of 0.7% in frequency within this age range, from 3.1% to 2.4% (Table 2).

DISCUSSION

In previous studies, investigators have reported increased mortality associated with the E4 allele of the APOE gene, and this has been partly attributed to the increased risk this gene confers for Alzheimer's disease. The present study suggests that the frequency of E4 decreases with age, while the frequency of E3 increases, a finding that may partially explain the decreased mortality associated with E4. The observed decrease in E4 frequency with age was most prominent in E4 homozygotes. Although the number of homozygotes in our study was small, this result is consistent with previous studies that have reported a reduced prevalence of E4 homozygosity in centenarians (15-17).Genders Genders Genders No. % No. % No. % No. % No. % No. % No. % No. % No. % 

Age group, years 
<60 1,038 18.9 116 9.5 72 8.4 1,522 73.3 891 73.2 631 73.5 366 17.6 211 17.3 155 18.1 
61-65 1,178 19.4 194 8.2 124 9.4 70 6.8 1,801 76.4 1,004 75.7 797 77.4 361 15.3 198 14.9 163 15.8 
66-70 2,485 37.6 376 7.6 246 8.3 130 6.5 3,882 78.1 2,3037 ,74   .1   ,579   .1    ,483   .9    ,287   .4 
71-75   ,627   .3       ,382   .3      ,238   .1      ,144   .7    ,154   .2    ,483   .2    ,465   .8      ,253   .3 
76-80   ,993   .0      ,330   .3      ,219   .2      ,111   .4    ,125   .4    ,085   .4     ,354   .9     ,177   .2 
81-85     ,925   .0      ,162   .8       ,111   .2       ,51     .9     ,457    .8     ,949    .0     ,508    .8      ,231  1.2 
86-90     ,311   .3        ,41    .6         ,24    .1         ,17   .5       ,511    .2     ,323    .6     ,188   1.3       ,70   1.0 
>90        ,066   .1        ,11    .8          ,7    .8           ,4   .7       ,110    .8       ,73    .9      ,37   1.3        ,11   1.6 
Total 10,623 100 1,684 100 1,085 100 599 100 16,562 100 10,299 100 6,263 100 3,000 100 1,850 100 1,150 100 

Trend testa v2 
0.03 
0.20 
0.06 
11.3 
8.84 
3.29 
14.9 
10.2 
5.43 

P value 
0.86 
0.65 
0.80 
0.001 
0.003 
0.07 
1.13 
10^4 

Change per 5-year increaseb 

Odds ratio  
1.00  
0.99  
1.01  
1.04  
1.05  
1.04  
0.95  
0.94  
0.95  

95% confidence interval  
0.96, 1.03  
0.95, 1.04   
0.95, 1.07   
1.02, 1.07   
1.02, 1.08   
1.00, 1.08   
0.92, 0.97   
0..91, 0..98   
0.90, 0.99   

Abbreviation: APOE, apolipoprotein E gene. 
a v2 tests for trend (1 df) in APOE allele frequency with age, with adjustment for confounding by study, gender, and smoking status, were generated by means of logistic regression performed separately for each allele. 
b Change in the odds of having the allele per 5-year increase in age. 

Figure 1. Allele frequency distribution of apolipoprotein E gene (APOE) e2, e3, and e4 isoforms by age group in 10,623 subjects with European ancestry, 1990-2009.