1. Sample Size, Age Distribution, and Gender Composition Among Control Subjects From Contributing in a Pooled Analysis of Variations in APOE Allele Frequencies With Age (n ¼ 10,623), 1990–2009

Age at Recruitment, First Author, Year years Location of Study No. of Subjects % Male (Reference No.) Mean (SD) Range McKay, 2009 (22) Belfast, Northern Ireland 436 74.8 (6.9) 49–102 38.1 Fritsche, 2009 (15) Regensburg, Germany 553 76.2 (5.3) 65–97 38.0 Francis, 2009 (17) Portland, Oregon (US) 272 73.9 (6.4) 60–92 44.1 van Leeuwen, 2004 (20) Rotterdam, the Netherlands 3,805 67.5 (8.3) 55–99 42.2 Bergeron-Sawitzke, 2009 (16) AREDS, US 199 77.1 (4.6) 63–88 47.2 Baird, 2006 (18) Melbourne, Australia 106 71.5 (6.5) 60–86 45.3 Hadley, 2010 (24) Philadelphia, Pennsylvania (US) 379 75.6 (7.9) 56–96 46.4 Haan, 2006 (28) WHI-SE, US 1,283 73.7 (4.7) 65–86 0 Yates, 2007 (23) Edinburgh, United Kingdom 179 73.2 (7.8) 46–92 38.5 Ennis, 2008 (25) Southampton, United Kingdom 458 70.7 (9.3) 50–91 47.8 Conley, 2005 (21) Los Angeles, California (US) 142 72.5 (8.8) 50–91 43.7 Augood, 2004 (27) EUREYE, Europe 1,935 72.4 (5.3) 65–95 45.2 Zareparsi, 2004 (19) Ann Arbor, Michigan (US) 253 76.6 (5.3) 68–92 44.3 Yates, 2007 (23) Cambridge, United Kingdom 417 75.0 (7.8) 42–96 40.0 Dandekar, 2006 (26) London, United Kingdom 206 74.9 (7.7) 52–91 40.8 Total 10,623 71.5 (7.8) 42–102 37.7

Abbreviations: APOE, apolipoprotein E gene; AREDS, Age-Related Eye Disease Study; EUREYE, European SD, standard deviation; US, United States; WHI-SE, Women’s Health Initiative Sight Exam.

17.5% recorded over the same age range (Table 2). Persons who were heterozygous for the e2/e4 genotype showed a nonsignificant change of 0.7% in frequency within this age range, from 3.1% to 2.4% (Table 2).

P ¼ 0.80). Tests of age 3 center interactions were also conducted and showed no evidence of heterogeneity in age effects by center (likelihood ratio v2 test: e2, P ¼ 0.21; e3, P 0.88; e4, P 0.38).

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

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

Table 2. Distribution of APOE Genotypes by Age Group in a Pooled Analysis of Variations in APOE Allele Frequencies With Age (n ¼ 10,623), 1990–2009

APOE Genotype Age Group, e2/e2 e2/e3 e2/e4 e3/e3 e3/e4 e4/e4 Total No. years No. %a No. % No. % No. % No. % No. % (cid:1)60 9 0.9 138 13.3 32 3.1 553 53.3 278 26.8 28 2.7 1,038 61–65 2 0.2 157 13.3 33 2.8 692 58.7 260 22.1 34 2.9 1,178 66–70 15 0.6 296 11.9 50 2.0 1,523 61.3 540 21.7 61 2.5 2,485 71–75 12 0.5 304 11.6 54 2.1 1,632 62.1 586 22.3 39 1.5 2,627 76–80 15 0.8 257 12.9 43 2.2 1,219 61.2 430 21.6 29 1.5 1,993 81–85 6 0.6 131 14.2 19 2.1 570 61.6 186 20.1 13 1.4 925 86–90 0 0.0 32 10.3 9 2.9 212 68.2 55 17.7 3 1.0 311 >90 0 0.0 11 16.7 0 0.0 44 66.7 11 16.7 0 0.0 66 Total 59 0.6 1,326 12.5 240 2.3 6,445 60.7 2,346 22.1 207 1.9 10,623

Abbreviation: APOE, apolipoprotein E gene. a Row percentage.

Table 3. Variation in APOE Allele Frequencies With Age in a Pooled Analysis (n ¼ 10,623), Overall and by Gender, 1990–2009

APOE e2 APOE e3 APOE e4 Both Both Both No. of Samples Females Males Females Males Females Males Genders Genders Genders No. % No. % No. % No. % No. % No. % No. % No. % No. % Age group, years (cid:1)60 1,038 188 9.1 116 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 1,178 194 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 2,485 376 7.6 246 8.3 130 6.5 3,882 78.1 2,303 77.4 1,579 79.1 712 14.3 425 14.3 287 14.4 71–75 2,627 382 7.3 238 7.1 144 7.7 4,154 79.1 2,671 79.2 1,483 78.9 718 13.7 465 13.8 253 13.5 76–80 1,993 330 8.3 219 8.2 111 8.4 3,125 78.4 2,085 78.4 1,040 78.3 531 13.3 354 13.3 177 13.3 81–85 925 162 8.8 111 9.2 51 7.9 1,457 78.8 949 79.0 508 78.4 231 12.5 142 11.8 89 13.7 86–90 311 41 6.6 24 6.1 17 7.5 511 82.2 323 81.6 188 83.2 70 11.3 49 12.4 21 9.3 >90 66 11 8.3 7 8.1 4 8.7 110 83.3 73 84.9 37 80.4 11 8.3 6 7.0 5 10.9 Total 10,623 1,684 7.9 1,085 8.2 599 7.5 16,562 78.0 10,299 77.8 6,263 78.2 3,000 14.1 1,850 14.0 1,150 14.4 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 1.1 3 10(cid:2)4 0.001 0.02 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.

84 82 80 78 76 74 72 18 16 APOE 2 APOE 3 14 APOE 4 12 10 8 6 60 61–65 66–70 71–75 76–80 81–85 86–90 >90 Age Category, years % ,ycneuqerF elellA