Accelerated Progression from Mild Cognitive Impairment to Dementia in People with Diabetes

Weili Xu; Barbara Caracciolo; Hui-Xin Wang; Bengt Winblad; Lars Bäckman; Chengxuan Qiu; Laura Fratiglioni

Diabetes. 2010;59(11):2928-2935.

Abstract and Introduction

Abstract

Objective—The effect of diabetes on mild cognitive impairment (MCI) and its conversion to dementia remains controversial. We sought to examine whether diabetes and pre-diabetes are associated with MCI and accelerate the progression from MCI to dementia.
Research design and methods—In the Kungsholmen Project, 963 cognitively intact participants and 302 subjects with MCI (120 with amnestic MCI [aMCI ] and 182 with other cognitive impairment no dementia [oCIND]) age ≥75 years were identified at baseline. The two cohorts were followed for 9 years to detect the incident MCI and dementia following international criteria. Diabetes was ascertained based on a medical examination, hypoglycemic medication use, and random blood glucose level ≥11.0 mmol/l. Pre-diabetes was defined as random blood glucose level of 7.8–11.0 mmol/l in diabetes-free participants. Data were analyzed using standard and time-dependent Cox proportional-hazards models.
Results—During the follow-up period, in the cognitively intact cohort, 182 people developed MCI (42 aMCI and 140 oCIND), and 212 developed dementia. In the MCI cohort, 155 subjects progressed to dementia, the multi-adjusted hazard ratio (95% CI) of dementia was 2.87 (1.30–6.34) for diabetes, and 4.96 (2.27–10.84) for pre-diabetes. In a Kaplan-Meier survival analysis, diabetes and pre-diabetes accelerated the progression from MCI to dementia by 3.18 years. Diabetes and pre-diabetes were neither cross-sectionally nor longitudinally associated with MCI.
Conclusions—Diabetes and pre-diabetes substantially accelerate the progression from MCI to dementia, and anticipate dementia occurrence by more than 3 years in people with MCI. The association of diabetes with the development of MCI is less evident in old people.

Introduction

The impact of diabetes on cognitive function has been addressed in several studies showing that type 2 diabetes is associated with cognitive decline in aging.^[1] Furthermore, many large population-based longitudinal studies have demonstrated an increased risk of dementia in people with diabetes,^[2] but the association of diabetes with Alzheimer's disease is less evident in some studies.^[2,3] Overall, diabetes leads to a 20–70% greater decline in cognitive performance, and a 60% higher risk of dementia.^[4] Even pre-diabetes, the condition of impaired glucose regulation, has been related to cognitive decline and an increased risk of dementia,^[5,6] although a cross-sectional study found no association of impaired fasting blood glucose with cognitive function.^[7] In addition, three studies addressing the relation between diabetes and mild cognitive impairment (MCI) have also shown conflicting results.^[8–10]

MCI represents the usual transitional phase from normal cognitive function to dementia, although not all people with MCI will develop dementia.^[11] Different criteria and subdivisions of MCI have been proposed and modified over time.^[12] MCI has been subdivided into two major forms—amnestic MCI (aMCI) and other domain cognitive impairment no dementia (oCIND).^[13–15] Progression to clinically diagnosable dementia occurs at a higher rate from MCI than from unimpaired cognition; the estimated rate of conversion is approximately 30% over 3 years.^[16] However, the extent to which diabetes accelerates this progression is unclear. Only two population-based studies have addressed this issue and both showed nonsignificant effect of diabetes on the conversion from MCI to dementia.^[10,17]

Most studies that have addressed the association of diabetes with dementia included people with MCI at baseline assessment as nondemented and people with pre-diabetes with a nondiabetic group. These studies may underestimate the risk of dementia associated with diabetes. We have demonstrated that diabetes and pre-diabetes increase the risk of dementia and its main subtypes.^[5,18–20] In the present study, we sought to investigate the association of diabetes and pre-diabetes with the risk of MCI and to verify the hypothesis that diabetes and pre-diabetes may accelerate the progression from MCI to dementia.

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Table 1. Cognitively intact cohort (n = 963): characteristics by diabetes status
Characteristics	Diabetes status at baseline
Characteristics	No	Diabetes	Pre-diabetes	P value
n	877	56	30
Baseline
Age (years)	81.1 ± 4.8	80.7 ± 5.0	81.5 ± 4.8	0.913
Female	656 (74.8)	38 (67.9)	22 (73.3)	0.510
Educational level ≥8 years	398 (45.4)	17 (30.4)	15 (50.0)	0.076
MMSE score	27.6 ± 1.3	27.2 ± 1.3	27.2 ± 1.4	0.678
SBP (mmHg)	156.0 ± 21.0	161.6 ± 26.7	152.9 ± 18.8	0.024
DBP (mmHg)	81.6 ± 11.0	75.0 ± 9.3	77.1 ± 10.1	0.339
Heart disease	128 (14.6)	25 (44.6)	3 (10.0)	<0.001
Stroke	48 (5.5)	5 (8.9)	0 (0.0)	0.223
Antihypertensive drug use	389 (44.4)	33 (58.9)	11 (36.7)	0.068
Random blood glucose (mmol/l)	5.1 ± 0.94	11.7 ± 4.6	8.8 ± 0.8	<0.001
Any APOE ε4 allele†	184 (21.0)	4 (10.0)	3 (7.1)
BMI† (kg/m²)	23.5 ± 3.48	24.3 ± 3.44	24.1 ± 3.28	0.204
During 9-year follow-up
Incident dementia	192 (21.9)	13 (23.2)	7 (23.3)	0.274
Incident MCI	170 (20.9)	5 (8.9)	6 (21.2)	0.220

Data are n (%) or means ± SD. DBP, diastolic blood pressure; SBP, systolic blood pressure. †The number of subjects with missing values was 207 for APOE genotype and 94 for BMI.

Table 2. MCI cohort (n = 302): characteristics by diabetes status
Characteristics	Diabetes status at baseline
Characteristics	No	Diabetes	Pre-diabetes	P value
n	268	18	16
Baseline
MCI subtypes
aMCI	113 (42.2)	2 (12.5)	5 (27.8)
oCIND	155 (57.8)	14 (87.5)	13 (72.2)	0.035
Age (years)	82.1 ± 5.0	83.2 ± 5.3	82.6 ± 5.0	0.633
Female sex	203 (75.7)	14 (77.8)	14 (87.5)	0.555
Educational level ≥8 years	118 (44.0)	6 (33.3)	4 (25.0)	0.237
MMSE score	24.7 ± 1.7	24.1 ± 1.9	23.8 ± 1.8	0.028
SBP (mmHg)	154.0 ± 22.6	156.9 ± 27.7	150.9 ± 19.9	0.744
DBP (mmHg)	80.5 ± 10.6	80.0 ± 8.6	75.0 ± 9.3	0.127
Heart disease	47 (17.5)	6 (33.3)	2 (12.5)	0.202
Stroke	30 (11.2)	4 (22.2)	0 (0.0)	0.123
Antihypertensive drug use	109 (40.7)	12 (66.7)	8 (50.0)	0.081
Random blood glucose (mmol/l)	5.1 ± 1.0	12.2 ± 4.5	8.6 ± 0.8	<0.001
Any APOE ε4 allele†	78 (29.1)	5 (27.8)	2 (12.5)	0.296
BMI† (kg/m²)	23.9 ± 3.8	24.2 ± 4.3	24.0 ± 2.9	0.380
During 9-year follow-up
Incident dementia	137 (51.2)	11 (68.8)	7 (38.9)	0.221

Data are n (%) or means ± SD. DBP, diastolic blood pressure; SBP, systolic blood pressure. †The number of subjects with missing values was 90 for APOE genotype and 64 for BMI.

Table 3. Standardized incidence rates (per 1,000 person-years) and multi-adjusted HR and 95% CI of MCI and dementia related to diabetesand pre-diabetes in the cognitively intact cohort
Exposure status	MCI (n = 182)		Dementia (n = 212)
Exposure status	IR (95% CI)^*	HR (95% CI)†	IR (95% CI)^*	HR (95% CI)†
Baseline diabetes‡
No	39.6 (34.0–46.1)	1.00 (Reference)	49.6 (43.7–56.3)	1.00 (Reference)
Yes (diabetes and pre-diabetes)	32.7 (18.1–59.0)	1.04 (0.52–2.07)	59.8 (39.7–90.0)	1.82 (1.07–3.10)
Pre-diabetes	40.9 (18.4 to 91.1)	1.07 (0.43–2.67)	52.6 (23.7–94.7)	1.64 (1.02–3.44)
Diabetes	26.3 (10.9–63.1)	1.01 (0.37–2.77)	69.6 (41.9–15.4)	2.10 (1.08–4.07)
Baseline and follow-up diabetes§
Diabetes and pre-diabetes	34.6 (18.9–81.3)	1.06 (0.62–1.81)	72.6 (41.3–86.9)	1.81 (1.19–2.75)

IR, incidence rates. *Standardized by age, sex, and education. †Adjusted for age, sex, education, baseline MMSE score, BMI, heart disease, stroke, systolic blood pressure, diastolic bloodpressure, follow-up survival status, and APOE genotype. ‡From standard Cox models. §From time-dependent Cox models.

Table 4. Standardized incidence rates (per 1,000 person-years) and multi-adjusted HR and 95% CI of dementia and Alzheimer disease relatedto diabetes and pre-diabetes in the mild cognitive impairment cohort
Exposure status	All dementia (n = 155)		Alzheimer disease (n = 125)
Exposure status	IR (95% CI)^*	HR (95% CI)†	IR (95% CI)^*	HR (95% CI)†
Baseline diabetes‡
No	135.0 (114.2–159.6)	1.00 (Reference)	104.4 (86.0–126.8)	1.00 (Reference)
Yes (diabetes and pre-diabetes)	232.6 (146.6–369.2)	3.64 (2.05–6.45)	206.8 (126.7–337.5)	3.79 (2.02–7.11)
Pre-diabetes	281.3 (155.8–507.9)	4.96 (2.27–10.84)	225.7 (137.6–475.2)	5.73 (2.43–13.50)
Diabetes	182.9 (87.2–383.7)	2.87 (1.30–6.34)	156.7 (70.4–349.0)	2.83 (1.18–6.78)
Baseline and follow-up diabetes§
Diabetes and pre-diabetes	275.4 (150.2–370.1)	3.89 (1.69–8.32)	239.4 (138.6–330.6)	4.22 (1.57– 9.01)

IR, incidence rates. *Standardized by age, sex, and education. †Adjusted for age, sex, education, baseline MMSE score, follow-up survival status, BMI, heart disease, stroke, systolic bloodpressure, diastolic blood pressure, antihypertensive drug use, APOE genotype. ‡From standard Cox models. §From time-dependent Cox models.

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