APOE* APOE APOE* 1 APOE APOE* APOE* APOE* 1 4 APOE APOE* APOE* APOE* APOE* 5 APOE* 6 APOE* 7 11 12 19 APOE 20 22 APOE* 20 APOE* APOE* 20 21 APOE* APOE* APOE* 20 APOE APOE APOE APOE APOE Methods Study population and procedures 23 Data collection Clinical and laboratory assessments 2 2 2 2 2 2 2 24 25 26 27 28 APOE 29 APOE APOE APOE APOE APOE APOE APOE APOE p Mortality data 30 Statistical analyses APOE 2 n APOE n APOE APOE APOE 31 32 APOE 33 Results APOE* APOE* APOE* 1 APOE* APOE* APOE* 2 APOE* 2 Table 1 APOE  APOE APOE APOE p n 782 3,369 1,457  Sex (men) 38 42 42 0.05 Age at entry (years) 68.8 (8.8) 68.9 (8.7) 68.3 (8.5) 0.14 2 26.7 (3.6) 26.4 (3.6) 26.1 (3.4) <0.01 Normal weight 34 39 40  Overweight 49 47 47 <0.05 Obese 17 14 13  Waist-to-hip ratio 0.9 (0.1) 0.9 (0.1) 0.9 (0.1) 0.18 Systolic blood pressure (mmHg) 140 (22) 140 (23) 138 (2) 0.04 Diastolic blood pressure (mmHg) 74 (11) 74 (12) 73 (11) 0.06 Hypertension 36 34 33 0.25 Total serum cholesterol (mmol/l) 6.4 (1.3) 6.6 (1.2) 6.8 (1.2) <0.001 HDL-cholesterol (mmol/l) 1.4 (0.4) 1.3 (0.3) 1.3 (0.4) <0.001 Cholesterol lowering medication 3 2 3 0.71 Hypercholesterolemia 49 60 66 <0.001 Smoking status (current) 39 35 33 0.02 Education level     Lower 43 43 45      Intermediate 43 42 40 0.21     Higher 14 15 15  Diabetes mellitus 10 10 9 0.75 p 2 1 APOE APOE* APOE* p for trend APOE p for trend APOE* APOE* APOE* p APOE p p p Fig. 1 APOE  APOE* APOE* APOE* APOE* APOE* APOE* p APOE* 2 APOE 2 p 3 APOE* 2 Fig. 2 APOE  Table 2 APOE  Follow-up Incidence rate Hazard ratio Follow-up Incidence rate Hazard ratio Deaths (py) Deaths/1,000 py (95% CI) (95% CI) Deaths (py) Deaths/1,000 py (95% CI) (95% CI) Before 80 years of age After 80 years of age All APOE*2 carriers 101 6,782 14.9 (12.3–18.1) 0.9 (0.7–1.1) 156 21,764 7.2 (6.1–8.4) 0.9 (0.8–1.1) APOE 3/3 481 28,703 16.8 (15.3–18.3)  679 95,808 7.1 (6.6–7.6)  APOE*4 carriers 198 12,693 15.6 (13.6–17.9) 1.0 (0.8–1.2) 303 41,637 7.3 (6.5–8.1) 1.2 (1.0–1.4) Total 780 48,178 16.2 (15.1–17.4)  1,138 159,209 7.1 (6.7–7.6)  Normal weight APOE*2 carriers 28 2,370 11.8 (8.2–17.1) 0.7 (0.5–0.9) 57 7,289 7.8 (6.0–10.1) 1.0 (0.8–1.4) APOE 3/3 206 11,314 18.2 (15.9–20.9)  256 38,045 6.7 (6.0–7.6)  APOE*4 carriers 78 5,080 15.4 (12.3–19.2) 1.0 (0.7–1.3) 127 17,305 7.3 (6.2–8.7) 1.3 (0.9–1.7) Total 312 18,764 16.6 (14.9–18.6)  440 62,639 7.0 (6.4–7.7)  Overweight APOE*2 carriers 59 3,305 17.9 (13.8–23.0) 1.1 (0.9–1.5) 65 11,064 5.9 (4.6–7.5) 0.9 (0.7–1.1) APOE 3/3 217 13,573 16.0 (14.0–18.3)  310 45,366 6.8 (6.1–7.6)  APOE*4 carriers 90 6,047 14.9 (12.1–18.3) 0.9 (0.7–1.2) 137 19,398 7.1 (6.0–8.4) 1.2 (1.0–1.5) Total 366 22,924 16.0 (14.4–17.7)  512 75,827 6.8 (6.2–7.4)  Obese APOE*2 carriers 14 1,107 12.6 (7.5–21.4) 1.0 (0.5–1.8) 34 3,411 10.0 (7.1–14.0) 1.0 (0.6–1.5) APOE 3/3 58 3,816 15.2 (11.7–19.7)  113 12,398 9.1 (7.6–11.0)  APOE*4 carriers 30 1,566 19.2 (13.4–27.4) 1.3 (0.9–2.0) 39 4,934 7.9 (5.8–10.8) 1.1 (0.8–1.6) Total 102 6,489 15.7 (12.9–19.1)  186 20,742 9.0 (7.8–10.4)  Hazard ratios adjusted for sex, waist-hip-ratio, smoking, education level, total serum cholesterol, HDL cholesterol hypertension and diabetes; py: person-years; CI: Confidence interval Fig. 3 APOE  APOE* APOE APOE 3 Table 3 APOE  Follow-up Incidence rate Hazard ratio Follow-up Incidence rate Hazard ratio Deaths (py) Deaths/1,000 py (95% CI) (95% CI) Deaths (py) Deaths/1,000 py (95% CI) (95% CI) Before 80 years of age After 80 years of age All APOE*2 carriers 26 6,782 3.8 (2.6–5.6) 1.0 (0.6–1.5) 41 2,103 19.5 (14.4–26.5) 1.1 (0.8–1.5) APOE 3/3 126 28,703 4.4 (3.7–5.2)  171 8,744 19.6 (16.8–22.7)  APOE*4 carriers 59 12,693 4.6 (3.6–6.0) 1.1 (0.8–1.4) 66 3,472 19.0 (14.9–24.2) 1.1 (0.8–1.4) Total 211 48,178 4.4 (3.8–5.0)  278 14,319 19.4 (17.3–21.8)  Normal weight APOE*2 carriers 5 2,370 2.1 (0.9–5.1) 0.5 (0.2–1.2) 15 663 22.6 (13.6–37.5) 1.6 (0.9–2.9) APOE 3/3 56 11,314 4.9 (3.8–6.4)  48 3,075 15.6 (11.8–20.7)  APOE*4 carriers 26 5,080 5.1 (3.5–7.5) 1.2 (0.7–1.9) 21 1,286 16.3 (10.6–25.1) 1.1 (0.6–1.8) Total 87 18,764 4.6 (3.8–5.7)  84 5,024 16.7 (13.5–20.7)  Overweight APOE*2 carriers 16 3,305 4.8 (3.0–7.9) 1.4 (0.8–2.4) 15 989 15.2 (9.1–25.2) 0.7 (0.4–1.3) APOE 3/3 51 13,573 3.8 (2.9–4.9)  92 4,035 22.8 (18.6–28.0)  APOE*4 carriers 21 6,047 3.5 (2.3–5.3) 0.8 (0.5–1.4) 35 1,619 21.6 (15.5–30.1) 1.0 (0.7–1.5) Total 88 22,924 3.8 (3.1–4.7)  142 6,643 21.4 (18.1–25.2)  Obese APOE*2 carriers 5 1,107 4.5 (1.9–10.8) 1.1 (0.4–3.4) 11 450 24.4 (13.5–44.1) 1.4 (0.7–3.1) APOE 3/3 19 3,816 5.0 (3.2–7.8)  31 1,634 19.0 (13.3–27.0)  APOE*4 carriers 12 1,566 7.7 (4.4–13.5) 1.6 (0.8–3.5) 10 568 17.6 (9.5–32.7) 1.1 (0.5–2.2) Total 36 6,489 5.5 (4.0–7.7)  52 2,651 19.6 (14.9–25.7)  Hazard ratios adjusted for sex, waist-hip-ratio, smoking, education level, total serum cholesterol, HDL cholesterol hypertension and diabetes; py: person-years; CI: Confidence interval Discussion APOE* APOE* APOE* APOE 12 APOE APOE 6 19 34 APOE 6 14 18 APOE 8 10 APOE 10 11 APOE 35 APOE APOE 36 20 22 APOE APOE* APOE APOE APOE 20 22 37 APOE APOE 20 APOE 20 22 37 APOE APOE 38 39 APOE APOE APOE* APOE APOE* APOE* APOE