Participant characteristics and incidence of dementia
Participant characteristics are presented in Table 1. A total of 242,237 participants were included in the analyses (77,587 [68.0%] aged over 65 years at baseline; 131,712 [54.4%] women; 140,415 [58.0%] from non-capital regions). There was a total of 7,006 (2.9%) participants who had histories of depression during the enrollment period from 2002 to 2004. There was a total of 9,680 (4.0%) participants with CVD during the same period. The demographic characteristics of the study participants and the diseases from Charlson’s Comorbidity index were set as covariates (Table 1). A total of 12,735 (5.3%) participants were newly diagnosed with dementia (AD, 9,729 [76.4%]; VD, 1,306 [10.3%]; non-AD or non-VD, 1,700 [13.3%], Table S1 in Additional file 1). There were significant differences between the groups in terms of age, sex, income level, and comorbidities (P-value < 0.05).
When the patients were classified into the four categories as shown in Fig. 1, the number of patients with newly diagnosed dementia was 7,525 (4.0 %) in the reference group (N = 190,255, 78.5%), 1,336 (6.8%) in the depression alone group (N = 19,692, 8.1%), 3,099 (11.6%) in the CVD alone group (N = 26,798, 11.1%), and 775 (14.1%) in the comorbid depression and CVD group (N = 5,492, 2.3%).
|
Study Population
|
With Dementia
|
Without Dementia
|
N
|
%
|
N
|
%
|
N
|
%
|
TOTAL
|
242,237
|
100.0
|
12,735
|
100.0
|
229,502
|
100.0
|
Age
|
|
|
|
|
|
|
50 to 64 years
|
164,650
|
68.0
|
3,345
|
26.3
|
161,305
|
70.3
|
Older than 64 years
|
77,587
|
32.0
|
9,390
|
73.7
|
68,197
|
29.7
|
Sex
|
|
|
|
|
|
|
Men
|
110,525
|
45.6
|
3,982
|
31.3
|
106,543
|
46.4
|
Women
|
131,712
|
54.4
|
8,753
|
68.7
|
122,959
|
53.6
|
Residential area a
|
|
|
|
|
|
|
Capital region
|
101,822
|
42.0
|
4,403
|
34.6
|
97,419
|
42.5
|
Non-capital region
|
140,415
|
58.0
|
8,332
|
65.4
|
132,083
|
57.6
|
Income level b
|
|
|
|
|
|
|
Low
|
65,730
|
27.1
|
3,948
|
31.0
|
61,782
|
26.9
|
Middle
|
80,753
|
33.3
|
3,683
|
28.9
|
77,070
|
33.6
|
High
|
95,754
|
39.5
|
5,104
|
40.1
|
90,650
|
39.5
|
Comorbidities
|
|
|
|
|
|
|
Myocardial infarction
|
2,332
|
1.0
|
156
|
1.2
|
2,176
|
1.0
|
Congestive heart failure
|
8,904
|
3.7
|
814
|
6.4
|
8,090
|
3.5
|
Peripheral vascular disease
|
6,661
|
2.8
|
575
|
4.5
|
6,086
|
2.7
|
Chronic pulmonary disease
|
47,871
|
19.8
|
3,232
|
25.4
|
44,639
|
19.5
|
Connective tissue disorder
|
11,761
|
4.9
|
881
|
6.9
|
10,880
|
4.7
|
Peptic ulcer
|
50,849
|
21.0
|
2,984
|
23.4
|
47,865
|
20.9
|
Mild liver disease
|
22,914
|
9.5
|
1,022
|
8.0
|
21,892
|
9.5
|
Uncomplicated diabetes
|
29,720
|
12.3
|
2,209
|
17.4
|
27,511
|
12.0
|
Complicated diabetes c
|
11,717
|
4.8
|
933
|
7.3
|
10,784
|
4.7
|
Hemiplegia
|
1,533
|
0.6
|
151
|
1.2
|
1,382
|
0.6
|
Moderate or severe renal diseases
|
1,476
|
0.6
|
96
|
0.8
|
1,380
|
0.6
|
Non-metastatic solid cancer d
|
9,382
|
3.9
|
435
|
3.4
|
8,947
|
3.9
|
Moderate or severe liver diseases
|
754
|
0.3
|
17
|
0.1
|
737
|
0.3
|
Metastatic solid cancer
|
2,805
|
1.2
|
51
|
0.4
|
2,754
|
1.2
|
Table 1
Table 1 Descriptive characteristics of the study population
a Individuals who resided in the capital city of South Korea and surrounding metropolitan cities (Seoul, Incheon, Gyeonggi-do) were classified as pertaining to a “capital region”; the others, to a “non-capital region.”
b Income levels were divided into three groups according to low (up to the 30th percentile), middle (40 to 70th percentile), and high (80 to 100th percentile) incomes.
c Diabetes complicated with retinopathy, neuropathy, renal disease
d Non-metastatic solid cancer including leukemia, lymphoma, and multiple myeloma
Independent associations of depression and CVD with increased dementia risk
In an analysis of the time-varying Cox proportional hazard model, depression was found to be associated with a 122 % increased risk of dementia (HR 2.22, 95% CI 2.12-2.33, Table 2, Fig. 2A) after adjusting for age, sex, residential area, income level, and comorbid chronic diseases, compared to participants without depression. The lag-time analyses showed that the effect of depression was significant, even after considering depression as a prodrome of dementia for up to two years (Additional file 1: Table S2). The analyses with CVD showed a similar risk increase, with a higher risk hazard for dementia onset (HR 3.12, 95% CI 3.00-3.25, Table 2, Fig. 2B). Effects which were modified according to age and sex were statistically significant in both the analyses for depression and CVD patients (P-value for the interaction was <0.0001). The effect of depression on the development of dementia was outstanding in men and in those under the age of 65, and the same was seen for the effect of CVD.
|
No Depression
|
Depression
|
No CVD
|
CVD
|
Total population
|
217,053 (89.6%)
|
25,184 (10.4%)
|
209,947 (86.7%)
|
32,290 (13.3%)
|
Dementia events
|
10,624 (4.9%)
|
2,111 (8.4%)
|
8,861 (4.2%)
|
3,874 (12.0%)
|
Person-years
|
1,777,860
|
210,499
|
1,734,836
|
253,523
|
Incidence (events/1,000 person-years)
|
5.98
|
10.03
|
5.11
|
15.28
|
Unadjusted HR in Model 1 (95% CI)
|
1 [Reference]
|
2.40 (2.29-2.51)
|
1 [Reference]
|
4.36 (4.20-4.53)
|
aHR in Model 2 (95% CI) a
|
1 [Reference]
|
2.35 (2.24-2.46)
|
1 [Reference]
|
3.26 (3.14-3.39)
|
aHR in Model 3 (95% CI) b
|
1 [Reference]
|
2.22 (2.12-2.33)
|
1 [Reference]
|
3.12 (3.00-3.25)
|
50 to 64 years
|
147,019 (89.3%)
|
17,631 (10.7%)
|
147,069 (89.3%)
|
17,851 (10.7%)
|
Dementia events
|
2,591 (1.8%)
|
754 (4.3%)
|
2,150 (1.5%)
|
1,195 (6.8%)
|
Person-years
|
1,271,789
|
152,534
|
1,276,238
|
148,084
|
Incidence (events/1,000 person-years)
|
2.04
|
4.94
|
1.68
|
8.07
|
Unadjusted HR in Model 1 (95% CI)
|
1 [Reference]
|
3.43 (3.16-3.72)
|
1 [Reference]
|
6.82 (6.35-7.32)
|
aHR in Model 2 (95% CI) a
|
1 [Reference]
|
3.24 (2.99-3.52)
|
1 [Reference]
|
6.84 (6.37-7.34)
|
aHR in Model 3 (95% CI) b
|
1 [Reference]
|
3.11 (2.86-3.37)
|
1 [Reference]
|
6.54 (6.09-7.03)
|
Older than 64 years
|
70,034 (90.3%)
|
7,553 (9.7%)
|
62,878 (81.0%)
|
14,709 (19.0%)
|
Dementia events
|
8,033 (11.5%)
|
1,357 (18.0%)
|
6,711 (10.7%)
|
2,679 (18.2%)
|
Person-years
|
506,071
|
57,965
|
458,597
|
105,439
|
Incidence (events/1,000 person-years)
|
15.87
|
23.41
|
14.63
|
25.41
|
Unadjusted HR in Model 1 (95% CI)
|
1 [Reference]
|
2.06 (1.95-2.18)
|
1 [Reference]
|
2.50 (2.39-2.62)
|
aHR in Model 2 (95% CI) a
|
1 [Reference]
|
2.04 (1.93-2.16)
|
1 [Reference]
|
2.55 (2.43-2.66)
|
aHR in Model 3 (95% CI) b
|
1 [Reference]
|
1.92 (1.81-2.04)
|
1 [Reference]
|
2.44 (2.33-2.56)
|
Men
|
102,043 (92.3%)
|
8,482 (7.7%)
|
95,637 (86.5%)
|
14,888 (13.5%)
|
Dementia events
|
3,388 (3.3%)
|
594 (7.0%)
|
2,531 (2.7%)
|
1,451 (9.6%)
|
Person-years
|
831,452
|
69,492
|
784,992
|
115,952
|
Incidence (events/1,000 person-years)
|
4.07
|
8.55
|
3.22
|
12.51
|
Unadjusted HR in Model 1 (95% CI)
|
1 [Reference]
|
3.13 (2.87-3.42)
|
1 [Reference]
|
5.69 (5.33-6.07)
|
aHR in Model 2 (95% CI) a
|
1 [Reference]
|
2.83 (2.60-3.09)
|
1 [Reference]
|
4.15 (3.88-4.42)
|
aHR in Model 3 (95% CI) b
|
1 [Reference]
|
2.69 (2.46-2.93)
|
1 [Reference]
|
3.99 (3.74-4.26)
|
Women
|
115,010 (87.3%)
|
16,702 (12.7%)
|
114,310 (86.8%)
|
17,402 (13.2%)
|
Dementia events
|
7,236 (6.3%)
|
1,517 (9.1%)
|
6,330 (5.5%)
|
2,423 (13.9%)
|
Person-years
|
946,408
|
141,007
|
949,844
|
137,571
|
Incidence (events/1,000 person-years)
|
7.65
|
10.76
|
6.66
|
17.61
|
Unadjusted HR in Model 1 (95% CI)
|
1 [Reference]
|
1.97 (1.87-2.09)
|
1 [Reference]
|
3.84 (3.67-4.03)
|
aHR in Model 2 (95% CI) a
|
1 [Reference]
|
2.19 (2.07-2.32)
|
1 [Reference]
|
2.89 (2.76-3.03)
|
aHR in Model 3 (95% CI) b
|
1 [Reference]
|
2.07 (1.96-2.19)
|
1 [Reference]
|
2.77 (2.64-2.91)
|
Table 2
Table 2 Cox regression analysis for the association between the exposure diseases and dementia
Abbreviations: HR hazard ratio, aHR adjusted hazard ratio, CI confidence interval
a Adjusted for demographic characteristics (age, sex, residential area, and income level)
b Adjusted for demographic characteristics (age, sex, residential area, and income level), other exposure diseases, and 14 comorbidities (myocardial infarction, congestive heart failure, peripheral vascular disease, chronic pulmonary disease, connective tissue disorder, peptic ulcer, mild liver disease, uncomplicated diabetes, complicated diabetes, hemiplegia, moderate or severe renal diseases, non-metastatic solid cancer, moderate or severe liver diseases, and metastatic solid cancer)
Synergistic interaction of depression and CVD on dementia risk
Compared to the participants without depression or CVD, the depression alone group (aHR 2.35, 95% CI 2.21-2.49), CVD alone group (aHR 3.25, 95% CI 3.11-3.39), and comorbid depression and CVD group (aHR 5.02, 95% CI 4.66-5.42) were significantly associated with an increased risk of dementia (Table 3). The AP due to the interaction between depression and CVD was 0.08, which was statistically significant (P-value = 0.037, Table 3 and Fig. 2C). The coexistence of the two diseases added 8% to the subsequent dementia risk determined with the sum of the individual conditions. When participants were distinguished according to their dementia subtypes, the AP due to interaction with each dementia subtype were statistically insignificant. Nevertheless, there was evidence of a synergistic effect on AD in the sensitivity analyses that used 1:2 propensity score matching (AP due to interaction 0.10, 95% CI 0.01-0.20, P-value = 0.056, Table S3). The synergistic effect between depression and CVD changed with sex, which was significant only in women. AP due to interaction among women with comorbid depression and CVD was 0.12 (P-value = 0.010, Table 3). The sensitivity analyses that used 1:1 or 1:2 propensity score matching further supported the results (Additional file 1: Table S3).
|
Risk of dementia, HR (95% CI)
|
AP due to Interaction
|
|
No Depression or CVD
|
Depression
|
CVD
|
Depression and CVD
|
AP (95% CI)
|
P -valuea
|
Model 1b
|
1 [Reference]
|
2.41 (2.27-2.55)
|
4.51 (4.32-4.70)
|
6.54 (6.08-7.05)
|
0.10 (0.02-0.17)
|
0.016
|
Model 2c
|
1 [Reference]
|
2.39 (2.26-2.54)
|
3.33 (3.19-3.47)
|
5.16 (4.79-5.56)
|
0.09 (0.01-0.16)
|
0.035
|
Model 3d
|
1 [Reference]
|
2.35 (2.21-2.49)
|
3.25 (3.11-3.39)
|
5.02 (4.66-5.42)
|
0.08 (0.01-0.16)
|
0.037
|
Dementia subtypese
|
|
|
|
|
|
|
AD
|
1 [Reference]
|
2.36 (2.21-2.52)
|
2.77 (2.63-2.91)
|
4.54 (4.15-4.95)
|
0.09 (0.00-0.18)
|
0.056
|
VD
|
1 [Reference]
|
2.13 (1.68-2.70)
|
9.75 (8.64-11.02)
|
11.98 (9.74-14.75)
|
0.09 (-0.14-0.32)
|
0.431
|
Non-AD or non-VDf
|
1 [Reference]
|
2.37 (2.02-2.78)
|
2.97 (2.64-3.35)
|
4.55 (3.68-5.62)
|
0.05 (-0.18-0.28)
|
0.696
|
Agee
|
|
|
|
|
|
|
50 to 64 years
|
1 [Reference]
|
3.46 (3.12-3.83)
|
6.93 (6.38-7.53)
|
10.10 (8.85-11.53)
|
0.07 (-0.07-0.21)
|
0.316
|
Older than 64 years
|
1 [Reference]
|
2.01 (1.87-2.16)
|
2.53 (2.41-2.66)
|
3.83 (3.50-4.21)
|
0.08 (-0.02-0.18)
|
0.126
|
Sexe
|
|
|
|
|
|
|
Men
|
1 [Reference]
|
3.16 (2.82-3.54)
|
4.31 (4.01-4.64)
|
6.71 (5.85-7.69)
|
0.04 (-0.12-0.19)
|
0.649
|
Women
|
1 [Reference]
|
2.11 (1.97-2.26)
|
2.82 (2.67-2.97)
|
4.46 (4.07-4.88)
|
0.12 (0.03-0.21)
|
0.010
|
Table 3
Table 3 Interaction analysis for depression and CVD
Abbreviations: AP attributable proportion, CVD cerebrovascular disease, AD Alzheimer's disease, VD vascular dementia, HR hazard ratio
a P value for the test of the null hypothesis that the AP = 0
b Unadjusted model
c Adjusted for demographic characteristics (age, sex, residential area, and income level)
d Adjusted for demographic characteristics (age, sex, residential area, and income level) and 14 comorbidities(myocardial infarction, congestive heart failure, peripheral vascular disease, chronic pulmonary disease, connective tissue disorder, peptic ulcer, mild liver disease, uncomplicated diabetes, complicated diabetes, hemiplegia, moderate or severe renal diseases, non-metastatic solid cancer, moderate or severe liver diseases and metastatic solid cancer)
e Subgroup analyses that are based on Model 3 (adjusted for demographic characteristics and 14 comorbidities). Age or sex was not entered as a covariate in each subgroup analysis.
f Includes dementia in other diseases classified elsewhere (F02), unspecified dementia (F03), and other degenerative diseases of the nervous system, which are not classified elsewhere (G31)