Higher glycated hemoglobin amplifies the effect of apolipoprotein E epsilon 4-related cognition and olfaction impairments in type 2 diabetes

Table 1 Clinical characteristics of the cohort grouped by apolipoprotein E genotypes, mean ± SD/n (%)

Characteristics	All patients	APOE genotype		P value
		Non-APOE4 carriers	APOE4 carriers
Number of subjects	636	551	85
Age (years)	64.17 ± 7.59	64.12 ± 7.6	64.54 ± 7.57	0.6328
Gender (male, %)	234 (36.8)	204 (37)	30 (35.3)	0.7580
Glycosylated hemoglobin (%)	7.83 ± 1.86	7.87 ± 1.89	7.55 ± 1.68	0.1454
Fasting plasma glucose (mmol/L)	9.08 ± 3.56	9.13 ± 3.66	8.8 ± 2.78	0.4243
Hypertension (yes)	356 (56)	306 (55.5)	50 (58.8)	0.5700
Hyperlipidemia (yes)	127 (20)	110 (20)	17 (20)	0.9940
Coronary artery disease (yes)	70 (11)	60 (10.9)	10 (11.8)	0.8100
Diabetes duration (years)	8.39 ± 6.8	8.27 (6.56)	9.14 (8.18)	0.2756
OTS	5.41 ± 2.29	5.48 (2.23)	4.93 (2.6)	0.0383
OTS, range (0-2)	118 (18.6)	91 (16.5)	27 (31.8)	< 0.0010
OTS, range (3-5)	89 (14)	81 (14.7)	8 (9.4)	0.1950
OTS, range (6-8)	429 (67.5)	379 (68.8)	50 (58.8)	0.0700
MMSE score	27.49 ± 2.4	27.57 ± 2.4	27 ± 2.37	0.0424
CN (MMSE ≥ 27)	471 (74.1)	416 (75.5)	55 (64.7)	0.0360
CI (MMSE < 27)	165 (25.9)	135 (24.5)	30 (35.3)	0.0360

APOE4: Apolipoprotein E epsilon 4; MMSE: Mini-mental state examination; OTS: Olfactory threshold score; CN: Cognition normal; CI: Cognition impairment.

Table 2 Associations of apolipoprotein E epsilon 4 with cognitive and olfactory function analyzed by logistic regression

Outcome	Variable	Model	β	SE	Wald	P value	OR	95%CI
CI	APOE4	Model 1	0.519	0.248	4.397	0.036	1.681	1.034-2.731
	APOE4	Model 2	0.514	0.253	4.133	0.042	1.673	1.019-2.747
	APOE4	Model 3	0.596	0.258	5.353	0.021	1.815	1.095-3.007
OD	APOE4	Model 1	0.856	0.260	10.859	< 0.001	2.353	1.414-3.915
	APOE4	Model 2	0.851	0.261	10.597	0.001	2.342	1.403-3.909
	APOE4	Model 3	0.951	0.268	12.621	< 0.001	2.588	1.532-4.374

CI: Cognitive impairment; OD: Olfactory dysfunction (olfactory threshold scores ≤ 2); OR: Odds ratio; CI: Confidence interval. Model 1 includes apolipoprotein E epsilon 4. Model 2 includes apolipoprotein E epsilon 4, age, and gender. Model 3 includes apolipoprotein E epsilon 4, age, gender, hypertension, hyperlipidemia, coronary artery disease, glycated hemoglobin and diabetes duration.

Table 3 Association of glycated hemoglobin with cognitive and olfactory function analyzed by logistic regression

Outcome	Variable	Model	β	SE	Wald	P value	OR	95%CI
CI	HbA1c	Model 1	0.137	0.047	8.533	0.003	1.147	1.046-1.258
	HbA1c	Model 2	0.165	0.049	11.474	< 0.001	1.18	1.072-1.298
	HbA1c	Model 3	0.173	0.050	12.194	< 0.001	1.189	1.079-1.310
OD	HbA1c	Model 1	0.094	0.052	3.227	0.072	1.099	0.991-1.217
	HbA1c	Model 2	0.107	0.053	4.085	0.043	1.113	1.003-1.235
	HbA1c	Model 3	0.139	0.055	6.418	0.011	1.149	1.032-1.280

CI: Cognitive impairment; OD: Olfactory dysfunction (olfactory threshold scores ≤ 2); OR: Odds ratio; CI: Confidence interval. Model 1 includes glycated hemoglobin. Model 2 includes glycated hemoglobin, age, and gender. Model 3 includes glycated hemoglobin, apolipoprotein E epsilon 4, age, gender, hypertension, hyperlipidemia, coronary artery disease and diabetes duration.

Table 4 Association of glycated hemoglobin with cognitive and olfactory function analyzed by stratified regression

Subgroup	Patients	Variable	P value	CI OR (95%CI)	P value	OD OR (95%CI)
APOE4 carriers	85	HbA1c	< 0.001	2.830 (1.801-4.446)	0.013	1.479 (1.085-2.015)
Non-APOE4 carriers	551	HbA1c	0.150	1.081 (0.972-1.201)	0.136	1.095 (0.972-1.234)

APOE4: Apolipoprotein E epsilon 4; CI: Cognitive impairment; OD: Olfactory dysfunction; OR: Odds ratio; CI: Confidence interval.

Table 5 Association of apolipoprotein E epsilon 4 with cognitive and olfactory function analyzed by stratified regression

Subgroup	Patients	Variable	P value	CI OR (95%CI)	P value	OD OR (95%CI)
High HbA1c group	386	APOE4	0.003	2.599 (1.374-4.914)	0.001	2.992 (1.550-5.774)
Low HbA1c group	250	APOE4	0.544	0.747 (0.291-1.916)	0.122	2.083 (0.821-5.281)

HbA1c: Glycated hemoglobin; CI: Cognitive impairment; OD: Olfactory dysfunction; OR: Odds ratio; CI: Confidence interval.

Table 6 Interaction between apolipoprotein E epsilon 4 and glycated hemoglobin on cognitive and olfactory function

Variable	Cognitive impairment		Olfactory dysfunction (OTS ≤ 2)
	OR (95%CI)	P value	OR (95%CI)	P value
Model 1 interaction (APOE4 HbA1c)	2.667 (1.725-4.122)	< 0.001	1.489 (1.084-2.047)	0.014
Model 2 interaction (APOE4 HbA1c)	2.714 (1.747-4.216)	< 0.001	1.490 (1.084-2.049)	0.014
Model 3 interaction (APOE4 HbA1c)	2.687 (1.725-4.187)	< 0.001	1.440 (1.042-1.990)	0.027

HbA1c: Glycated hemoglobin; APOE4: Apolipoprotein E epsilon 4; OR: Odds ratio; CI: Confidence interval; OTS: Olfactory threshold score. Model 1 includes apolipoprotein E epsilon 4, glycated hemoglobin and interaction. Model 2 includes apolipoprotein E epsilon 4, glycated hemoglobin, interaction, age, and gender. Model 3 includes apolipoprotein E epsilon 4, glycated hemoglobin, interaction, age, gender, hypertension, hyperlipidemia coronary artery disease and diabetes duration.

Table 7 Joint associations and additive interactions of apolipoprotein E epsilon 4 with high glycated hemoglobin on the risk of cognitive impairment

Variables	Joint associations			Addictive interactions (APOE4 +)
	Number	APOE4 -	APOE4 +	RERI (95%CI)	AP (95%CI)
Overall CI	165
High HbA1c	111	1.291 (0.846-1.972)	3.364 (1.163-9.737)	2.308 (0.178-4.439)	0.673 (0.371-0.975)
Low HbA1c	54	0.774 (0.507-1.183)	0.297 (0.103-0.860)

HbA1c: Glycated hemoglobin; APOE4: Apolipoprotein E epsilon 4; CI: Cognitive impairment; 95%CI: 95% confidence interval; RERI: Relative excess risk due to interaction; AP: Attributable proportion.