Associations between apolipoprotein E gene polymorphisms and Alzheimer’s disease risk in a large Chinese Han population

Figures & data

Table 1 Characteristics of subjects in AD and control groups

	AD	Control	P
Number	875	1,195
Agea (mean ± SD) (range), years	67.7±9.67 (45–97)	68.5±10.13 (48–94)	0.106
Male/female	397/478	493/702	0.062
MMSE (mean ± SD)	14.3±6.35	28.6±1.85	0.000*

Notes:

* P<0.01.

a Age at onset for AD; age at entrance for control.

Abbreviations: AD, Alzheimer’s disease; MMSE, mini-mental state examination; SD, standard deviation.

Table 2 Distribution of allele frequencies and genotypes of APOE in AD and controls

	APOE	Numbers	Genotypes (%)						Allele frequencies (%)
	Genotype		ε2ε2	ε2ε3	ε2ε4	ε3ε3	ε3ε4	ε4ε4	ε2	ε3	ε4	ε2 (+)	ε4 (+)
Total	AD (%)	875	0.5	6.2	2.5	48.5	33.0	9.4	4.8	68.1	27.1	9.1	44.9
	Control (%)	1,195	0.6	12.3	3.4	60.9	22.0	0.8	8.5	78.1	13.5	16.3	26.2
	χ^2 (P)		143.5 (3.15×10^−29)*						131.3 (3.08×10^−29)*			22.6 (2.02×10^−6)*	78.8 (6.94×10^−19)*
Male	AD	397	0.3	7.1	2.3	51.6	31.2	7.6	4.9	70.8	24.3	9.6	41.1
	Control	493	0.6	11.6	4.5	59.8	22.7	0.8	8.6	77.0	14.4	16.6	28.0
	χ^2 (P)		43.2 (3.39×10^−8)*						33.9 (4.37×10^−8)*			9.4 (0.002)*	16.8 (4.21×10^−5)*
Female	AD	478	0.6	5.4	2.7	45.8	34.5	10.7	4.7	65.8	29.5	8.8	48.1
	Control	702	0.6	12.8	2.7	61.7	21.5	0.7	8.3	78.8	12.8	16.1	24.9
	χ^2 (P)		107.5 (1.35×10^−21)*						104.9 (1.82×10^−23)*			13.3 (2.63×10^−4)*	67.8 (1.78×10^−16)*
EOAD	AD	354	0	6.5	2.8	49.7	32.5	8.5	4.7	69.2	26.1	9.3	43.8
	Control	483	0.8	11.4	4.6	60.9	21.7	0.6	8.8	77.4	13.8	16.8	26.9
	χ^2 (P)		55.2 (1.17×10^−10)*						46.5 (7.88×10^−11)*			9.6 (0.002)*	25.9 (3.61×10^−7)*
LOAD	AD	521	0.8	6.0	2.3	47.6	33.4	10.0	4.9	67.3	27.8	9.0	45.7
	Control	712	0.4	12.9	2.7	61.0	22.2	0.8	8.2	78.5	13.3	16.0	25.7
	χ^2 (P)		92.6 (1.92×10^−18)*						85.7 (2.45×10^−19)*			13.0 (3.20×10^−4)*	53.4 (2.71×10^−13)*

Note:

* P<0.01.

Abbreviations: AD, Alzheimer’s disease; APOE, apolipoprotein E gene; EOAD, early-onset AD; LOAD, late-onset AD.

Table 3 Logistic regression of APOE genotypes and allele frequencies in Alzheimer’s disease patients and controls

Total	ε2ε2	ε2ε3	ε2ε4	ε3ε3	ε3ε4	ε4ε4	ε2 (+)	ε4 (+)
P	0.994	8×10^−3*	0.682	1.ref	1.18×10^−9*	8.59×10^−15*	2.88×10^−6*	1.57×10^−18*
OR	1.01	0.64	0.90		1.90	15.93	0.52	2.30
95% CI	0.29–3.46	0.46–0.89	0.53–1.53		1.54–2.33	7.92–32.05	0.39–0.68	1.91–2.77
Male
P	0.50	0.22	0.16	1.ref	4×10^−3*	8.87×10^−6*	6×10^−3*	7.22×10^−5*
OR	0.46	0.735	0.561		1.58	11.06	0.54	1.77
95% CI	0.05–4.42	0.45–1.20	0.25–1.25		1.16–2.16	3.83–31.94	0.36–0.81	1.34–2.34
Female
P	0.61	1.8×10^−2*	0.41	1.ref	3.79×10^−8*	2.02×10^−10*	3.19×10^−4*	4.61×10^−16*
OR	1.48	0.57	1.36		2.16	20.58	0.50	2.79
95% CI	0.33–6.66	0.36–0.91	0.66–2.80		1.64–2.84	8.10–52.27	0.35–0.73	2.18–3.58
EOAD
P	1.00	0.25	0.45	1.ref	4.17×10^−4*	1.91×10^−6*	3×10^−3*	6.73×10^−7*
OR	0.00	0.74	0.74		1.80	18.83	0.52	2.10
95% CI	0	0.44–1.24	0.34–1.61		1.30–2.50	5.63–63.03	0.34–0.80	1.57–2.81
LOAD
P	0.28	2.3×10^−2*	0.82	1.ref	1.18×10^−6*	1.25×10^−9*	1.0×10^−3*	9.73×10^−13*
OR	2.30	0.60	1.09		1.94	14.41	0.53	2.41
95% CI	0.51–10.41	0.39–0.93	0.52–2.28		1.48–2.53	6.09–34.08	0.37–0.76	1.89–3.07

Note:

* P<0.01.

Abbreviations: APOE, apolipoprotein E gene; CI, confidence interval; EOAD, early-onset Alzheimer’s disease; LOAD, late-onset Alzheimer’s disease; OR, odds ratio.

Table 4 The APOE ε2 and ε4 allele dosage effect on age at onset in AD patients

	ε2 (+)		ε2 (−)		No ε2		One ε2		Two ε2
Total AAO, n	67.7±9.60	80	67.7±9.69	795	67.7±9.69	795	67.5±9.75	76	72.0±4.97	4
EOAD AAO, n	57.9±4.30	33	57.7±5.09	321	57.7±5.01	321	57.9±4.30	33	0	0
LOAD AAO, n	74.6±5.30	47	74.4±5.17	474	74.4±5.17	474	74.9±5.32	43	72.0±4.97	4
Male AAO, n	67.0±9.24	38	67.6±9.77	359	67.6±9.77	359	66.7±9.18	37	78.0	1
Female AAO, n	68.4±9.98	42	67.8±9.63	436	67.8±9.62	436	68.3±10.32	39	70.0±9.64	3
	ε4 (+)		ε4 (−)		No ε4		One ε4		Two ε4
Total AAO, n	67.9±9.80	706	68.2±10.01	1,364	67.8±9.95	482	67.6±9.69	311	67.4±7.88	82
EOAD AAO, n	58.0±5.13	155	57.6±4.93	199	57.6±4.93	199	57.6±5.20	125	59.2±4.72	30
LOAD AAO, n	73.9±5.12	238	74.9±5.18a	283	74.9±5.18	283	74.4±5.10	186	72.2±4.86b	52
Male AAO, n	67.8±9.58	163	67.3±9.82	234	67.3±9.81	234	67.6±9.85	133	68.6±8.38	30
Female AAO, n	67.5±9.17	230	68.2±10.08	248	68.2±10.08	248	67.7±9.59	178	66.7±7.57	52

Notes:

a Difference between AAO in LOAD in ε4 (+) and ε4 (−) status was significant (P=0.022).

b Difference between AAO in LOAD in carriers of one and two APOEε4 alleles was significant (P=0.006).

Abbreviations: AD, Alzheimer’s disease; AAO, age at onset; APOE, apolipoprotein E gene; EOAD, early-onset AD; LOAD, late-onset AD.

Table 5 Effect of APOE ε2 and ε4 haplotype on AD risk stratified by age

	AAO	AD (%)	Control (%)	P-value	OR (95% CI)
ε2 (+)	≤55	9 (8.0)	26 (15.8)	0.088	0.492 (0.218–1.110)
	56–60	15 (11.7)	20 (15.2)	0.572	0.810 (0.391–1.680)
	61–65	9 (7.9)	35 (18.8)	0.016*	0.382 (0.175–0.833)
	66–70	13 (10.0)	20 (12.9)	0.422	0.737 (0.349–1.554)
	71–75	16 (8.7)	6 (14.6)	0.062	0.552 (0.296–1.030)
	76–80	11 (7.9)	31 (18.6)	0.009**	0.376 (0.181–0.781)
	>80	7 (10.3)	27 (18.9)	0.027*	0.888 (0.800–0.986)
ε4 (+)	≤55	51 (45.5)	49 (29.7)	0.010*	1.954 (1.173–3.256)
	56–60	49 (38.3)	35 (26.5)	0.051	1.700 (0.998–2.896)
	61–65	55 (48.2)	46 (24.7)	5.13×10^−5**	2.817 (1.706–4.650)
	66–70	73 (56.2)	39 (25.2)	1.59×10^−7**	3.842 (2.323–6.355)
	71–75	84 (45.7)	54 (21.9)	2.99×10^−7**	3.011 (1.975–4.590)
	76–80	55 (39.6)	53 (31.7)	0.149	1.417 (0.883–2.276)
	>80	26 (38.2)	37 (25.9)	0.073	1.772 (0.948–3.314)

Notes:

* P<0.05

** P<0.01.

Abbreviations: AAO, age at onset; AD, Alzheimer’s disease; APOE, apolipoprotein E gene; CI, confidence interval; OR, odds ratio.

Table S1 Hardy–Weinberg equilibrium of APOE in AD patients and controls

APOE	AD (actual)	AD (expected)	Controls (actual)	Controls (expected)
Number	875 (%)		1,195 (%)
ε2ε2	4 (0.5)	2 (0.2)	7 (0.6) 1.0	9 (0.8)
ε2ε3	54 (6.2)	57 (6.5)	147 (12.3)	158 (13.2)
ε2ε4	22 (2.5)	22 (2.5)	41 (3.4)	27 (2.3)
ε3ε3	424 (48.5)	406 (46.5)	728 (60.9)	728 (60.9)
ε3ε4	289 (33.0)	322 (36.9)	263 (22.0)	251 (21.0)
ε4ε4	82 (9.4)	64 (7.3)	9 (0.8)	22 (1.8)
ε2	84 (4.8)		202 (8.5)
ε3	1,191 (68.1)		1,866 (78.1)
ε4	475 (27.1)		322 (13.5)
ε2 (P)	5.137 (0.399)		9.261 (0.099)

Abbreviations: AD, Alzheimer’s disease; APOE, apolipoprotein E gene.