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.

Results

Cross-sectional Relationship between Diabetes and MCI

Among the 1,435 dementia-free participants at baseline, 337 were detected as MCI cases, including 131 aMCI and 206 oCIND. Compared with non-MCI subjects, people with MCI were older (OR 0.94, [95% CI 0.89–0.99, P = 0.015]), and had a lower level of education (<8 vs. ≥8 years, OR 2.13 [95% CI 1.35–3.38]) and MMSE score (OR 0.36 [95% CI 0.29–0.46]), and higher proportion of APOE ε4 carriers (OR 1.91 [95% CI 1.15–3.15]). The two groups showed no significant differences in terms of sex, stroke, heart disease, and blood pressure. Logistic regression analyses were performed to assess the cross-sectional relationship between diabetes and MCI based on the dementia-free subjects (n = 1,435). The multi-adjusted ORs related to diabetes or pre-diabetes were 1.32 (95% CI 0.82–1.31) for overall MCI, 1.12 (95% CI 0.67–1.20) for aMCI, and 1.03 (95% CI 0.57–1.23) for oCIND.

Nonparticipants of the Follow-up

Of the 1,435 individuals who were initially identified as free of dementia at baseline, 170 subjects were lost to the first follow-up (Fig. 1). Compared with participants, dropouts were younger, but the two groups had no significant differences in other features. Multiple logistic regression analysis showed that being a dropout had ORs of 0.94 (95% CI 0.91–0.98) for old age, 1.26 (95% CI 0.84–1.87) for female sex, 1.24 (95% CI 0.89–1.73) for low education, 1.02 (95% CI 0.94–1.09) for a lower score on MMSE (<24 vs. ≥24), 0.35 (95% CI 0.28–1.06) for diabetes, 0.69 (95% CI 0.47–1.09) for heart disease, and 0.66 (95% CI 0.45–1.08) for stroke.

Characteristics of the Two Cohorts

Of the 1,265 nondemented participants, 963 were cognitively intact and 302 had MCI, which constituted the two cohorts for longitudinal analyses. In the cognitively intact cohort, 56 subjects (5.8%) had diabetes, and 30 (3.1%) had pre-diabetes (Table 1). In the MCI cohort, 18 (6.0%) subjects had diabetes, and 16 (5.3%) were ascertained as having pre-diabetes. Among the 34 MCI subjects with diabetes or pre-diabetes, 27 (79.4%) were classified as oCIND, and 7 (20.6%) had aMCI (Table 2).

Diabetes and MCI in the Cognitively Intact Cohort

In the cognitively intact cohort, during the 9-year follow-up (4,656 person-years; mean per person = 4.8 years; maximum = 10.5 years), 182 participants developed MCI, including 42 aMCI and 140 oCIND. In addition, 212 were diagnosed with dementia, including 150 AD and 26 VaD. Table 3 shows the incidence rate standardized by age, sex, and education, and multi-adjusted HRs of MCI related to diabetes and pre-diabetes. We found no statistically significant association of either diabetes or pre-diabetes with incident MCI and its subgroups, whereas diabetes and pre-diabetes were significantly related to an increased risk of incident dementia. This association was present even when adjusting for several potential confounders, including APOE and vascular disorders. No interaction with APOE genotype or other variables was obtained.

Diabetes and Dementia in the MCI Cohort

In the MCI cohort, during the same period (1,092 person-years; mean per person = 3.6 years; maximum = 10.3 years), 155 subjects developed dementia, including 125 AD and 4 VaD. Using either standard or time-dependent Cox models, we found that diabetes and pre-diabetes were associated with an increased risk of developing dementia and AD in people with MCI after controlling for possible confounders, including APOE and vascular disorders (Table 4). Of the 125 AD subjects, 57 had aMCI and 68 had oCIND at baseline. We further performed stratified analysis according to MCI subgroups. Diabetes and pre-diabetes substantially increased the risk of progression from oCIND to dementia (HR 4.31 [95% CI 1.97–9.42]), but not from aMCI (HR 2.24 [95% CI 0.75–6.71]). However, the statistical power was limited for these stratified analyses because of the small number of people in each subgroup of MCI.

Kaplan-Meier survival analysis in people with MCI showed that the median time from baseline to dementia occurrence was 1.83 years (95% CI 2.44–4.24) in people with diabetes or pre-diabetes, and 5.01 years (95% CI 5.15–6.19) in people without such conditions. Thus, diabetes or pre-diabetes accelerated the progression from MCI to dementia by an average of 3.18 years (Fig. 2).

(Enlarge Image)

Figure 2.

Cumulative hazard for the progression from MCI to dementia by diabetes status in the MCI cohort (adjusted for age, sex, and education).

Supplementary Analyses

Similar results were obtained when we used only the incident MCI cohort that was identified at the first follow-up examination (n = 94, of whom 36 developed dementia during the next 6-year follow-up), and when we repeated the analyses among participants who survived until the time when dementia status was determined (n = 170, 136 dementia and 115 AD). Further, we performed the analyses by leaving out the participants with missing values of APOE genotype or BMI, which produced results that were the same as those from the initial analysis. Finally, in the MCI cohort, among the 34 people with either diabetes or pre-diabetes, 18 (52.9%) developed dementia and 16 (47.1%) died during the 9-year follow-up period. Diabetes and pre-diabetes were significantly associated with elevated mortality (HR 1.75 [95% CI 1.17–2.60]) after adjustment for age, sex, education, baseline MMSE score, BMI, APOE genotype, and vascular disorders.

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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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