Associations of cardiovascular disease and depression with memory related disease: A Chinese national prospective cohort study

Associations of cardiovascular disease and depression with memory related disease: A Chinese national prospective cohort study

Journal of Affective Disorders 260 (2020) 11–17 Contents lists available at ScienceDirect Journal of Affective Disorders journal homepage: www.elsevi...

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Journal of Affective Disorders 260 (2020) 11–17

Contents lists available at ScienceDirect

Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad

Research paper

Associations of cardiovascular disease and depression with memory related disease: A Chinese national prospective cohort study Xue Yunlian#, Liu Guihao#, Geng Qingshan

T



Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Guangzhou, China

A R T I C LE I N FO

A B S T R A C T

Key Words: Depression Cardiovascular disease Memory related diseases

Background: Association of cardiovascular disease (CVD) or depression and memory has been studied. But hardly any studies on the association of coexistence of CVD and depression and memory. Methods: This is a prospective cohort study of a nationally representative sample of 12,272 adults aged 45 years and more who participated in the China health and retirement longitudinal study 2011 to 2015. All Variables were acquired by self-reporting questions. The associations between coexistence of CVD and depression with memory related disease (MRD) were investigated by using Cox proportional hazards regression models. Results: Among the 12,272 participants (mean age 65.69 years; 46.8% male) in this study, 56.9% no CVD or depression and 6.7% coexistence of CVD and depression. After adjustment for age, sex, marriage, living place, registered permanent residence, education level, smoking status, alcoholic intake, sleep status, nap status, social communication, health before 15 years, life satisfaction, cognitive function, and 11 chronic diseases risk factors, depression alone was significantly high risk for MRD (HR:1.64; 95% CI: 1.09–2.49); coexistence of CVD and depression increased the risk for MRD significantly higher (HR: 4.72; 95%CI: 2.91–7.64). Limitations: Diseases were all self-reported and we couldn't adjust for all the potential confounders, which might be prone to information error and residual confounding. Conclusions: In a nationally representative cohort with median 4 years of follow-up, depression alone and coexistence of depression and CVD could significantly increase the risk of MRD. Our study supports the idea of prevention of memory disease from a psycho-cardiology aspect.

1. Introduction Memory related diseases (MRD), include dementia, brain atrophy and Parkinson's disease, take great burden for adults. Data from WHO points that number of people died of Alzheimer disease and other dementias increased significantly to 2 million in 16 years and became the fifth cause of death in 2016 (WHO, 2018). Cardiovascular disease (CVD) remains the leading cause of death in China and worldwide. Fastforwarding to 1552BC, Ebers papyrus pointed that brain and heart are intimately connected (Ebbell, 1937). Over the past decades, numerous studies pointed a positive association of CVD and its risk factors with MRD (Dolan et al., 2010; Vogels et al., 2007; Hoth et al., 2008; Van Oijen et al., 2007; Lloyd-Jones et al., 2010; Ivanovs et al., 2018; Petkus et al., 2015). The intriguing link between a sick heart and MRD may be because it starts a cognitive deterioration, which led to vascular dementia. Both depression and CVD are risk factors for cognitive impairment

(Chang et al., 2013). The association of depression and decline of cognitive function is studied by many previous studies (Alexopoulos et al., 2005; Yuan et al., 2008; Darcet et al., 2016). A meta-analysis reported that depression showed poor memory for positive events, potentiated memory for negative events, and impaired recollection (Dillon and Pizzagalli, 2018). Depression is also a risk factor for CVD and can negatively affect patients with CVD (Lugoboni et al., 2005). However, less is known about the association of coexistence of CVD and depression and MRD. Studies on memory influence when both considering CVD and depression are sparse. The aim of our study was to examine the association of CVD and depression with MRD in a nationally representative cohort in China.



Corresponding author at: Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Guangzhou 510080, China. E-mail address: [email protected] (Q. Geng). # These authors contributed equally to this work. https://doi.org/10.1016/j.jad.2019.08.081 Received 2 August 2019; Received in revised form 23 August 2019; Accepted 27 August 2019 Available online 28 August 2019 0165-0327/ © 2019 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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by a doctor?”, “How did you know that you had memory-related disease through routine or CHALS physical examination, or any other?”. Participants were followed up from the date of enrollment until incidence of MRD or the end of 2015 investigation.

2. Methods 2.1. Study population The China Health and Retirement Longitudinal Study (CHARLS), conducted by the National School for Development (China Center for Economic Research), is a large-scale, multistage, ongoing, nationally representative health survey of the civilian in China (Zhao et al., 2014). Samples of households with members aged 45 and older were chosen, and a total of 17,708 individuals in 10,257 household, 450 villages nationwide, 150 counties and districts from 28 provinces were selected in the baseline 2011 year. The response rate was 80.51% in all eligible households (Zhao et al., 2014). The medical ethics committee approved the CHARLS study, and all participants were required to sign informed consent, Ethics approval for the data collection in CHARLS was obtained from the Biomedical Ethics Review Committee of Peking University (IRB00001052–11015). In this study, we used data from CHARLS 2011 and 2015. All the exposure and covariates information were acquired from CHARLS 2011. Detailed descriptions of CHARLS 2011 procedures, sampling methods have been described extensively (Yu et al., 2018; Wang et al., 2017). The respondents were followed up every two years through a face-to-face interview in their homes via computer-assisted personal interviewing (CAPI) technology. MRD was acquired from CHARLS 2015, after 4 years following up. We included 17,216 participants aged 45 years and older who were free of a history MRD at baseline. Participants with missing CESD 10 or age information were excluded. After further exclusion of participants who loss following up, 12,272 participants were included as the analytical sample (Fig. 1).

2.3. Exposure measurement CVD and depression were two interested exposure variables. CVD contained heart disease and stroke, diagnosed by two questions: “Have you ever been diagnosed with heart attack, coronary heart disease, angina, congestive heart failure, or other heart problems, or stroke by a doctor?”, “How did you know that you had heart attack, coronary heart disease, angina, congestive heart failure, or other heart problems, or stroke through routine or CHALS physical examination, or any other?”. Participants reported have heart disease or stroke was defined as CVD. Depression was detected using the scale of the Center for Epidemiological Studies Depression Scale-10 (CESD-10) (Andresen et al., 1994). CESD-10 is a useful scale which can examine different aspects of depression such as depressed mood and positive affect (Amtmann et al., 2014). It consists of ten items from the original 20 with response options of 0–3 [0 = Rarely or none of the time (less than 1 day); 1 = Some or a little of the time (1–2 days); 2 = Occasionally or a moderate amount of time (3–4 days); 3 = Most or all of the time (5–7 days)]. The time frame is “during the past week” and sum scores can range from 0 to 30, with higher scores indicating higher degrees of depressive symptoms. Depression was defined as depressed (CESD score ≥ 10) and not depressed (CESD score < 10). We found significant association between depression and CVD (r = 0.118, p < 0.001; χ2=172.278, p < 0.001). Taking the interaction of CVD and depression (p = 0.031 < 0.05) into account, all participants were categorized into four groups: group 0, no CVD or depression; group 1, CVD but no depression; group 2, no CVD but depression; and group 3, CVD and depression.

2.2. Outcome ascertainment The main outcome that we examined in this study was MRD among participants. MRD was defined as diseases related with memory (Dementia, brain atrophy, Parkinson's disease) diagnosed by a doctor, through routine or CHARLS physical examination from self-reported questions “Have you ever been diagnosed with memory-related disease

2.4. Covariate assessment Based on previous work on MRD, we also included a number of relevant covariates. Information on age, sex, marriage, living place,

Fig. 1. Flowchart of participant selection. 12

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Table 1 Baseline demographic and lifestyle characteristics, and diseases prevalence of participants (n(%)). Variables

All participants

Group 0 (no CVD or depression)

Group 1 (CVD but no depression)

Group 2 (no CVD but depression)

Group 3 (CVD and depression)

p valuea

Ageb,y Sex (%) man woman Marriage (%) married not married Living place (%) city village Registered permanent residence (%) agricultural non-agricultural others Education level (%) below primary school primary school middle school high school and above Smoking status (%) no quit smoke now Alcoholic intake (%) none little everyday much everyday Sleep status (%) 7–9h <7h >9h Nap status (%) 30–60min <30min >60min Social communication (%) no yes Health before 15 years (%) healthy unhealthy Life satisfaction (%) satisfied unsatisfied Cognitionc (score) Hypertension (%) no yes Dyslipidemia (%) no yes High blood sugar(%) no yes Cancer (%) no yes Chronic lung disease (%) no yes Liver diseasev(%) no yes Kidney disease (%) no yes Digestive disease (%) no yes ENP(%) no yes

65.69(9.36)

64.81(9.14)

68.39(9.29)

66.27(9.56)

68.08(9.24)

<0.001

5738(46.8) 6534(53.2)

3693(52.9) 3291(47.1)

354(46.2) 413(53.8)

1429(38.6) 2272(61.4)

262(32.0) 558(68.0)

<0.001

10,895(88.8) 1377(11.2)

6401(91.7) 583(8.3)

685(89.3) 82(10.7)

3131(84.6) 570(15.4)

678(82.7) 142(17.3)

<0.001

11,158(91.0) 1112(9.0)

6271(89.8) 711(10.2)

623(81.2) 144(18.8)

3530(95.4) 171(4.6)

734(89.5) 86(10.5)

<0.001

9858(80.4) 2336(19.0) 75(0.6)

5470(78.3) 1457(20.9) 54(0.8)

463(60.4) 301(39.2) 3(0.4)

3273(88.4) 412(11.1) 16(0.5)

652(79.5) 166(20.3) 2(0.2)

<0.001

5387(43.9) 2824(23.0) 2628(21.4) 1431(11.7)

2621(37.5) 1627(23.3) 1723(24.7) 1012(14.5)

264(34.4) 178(23.2) 192(25.0) 133(17.4)

2063(55.8) 825(22.3) 601(16.2) 211(5.7)

439(53.5) 194(23.7) 112(13.7) 75(9.1)

<0.001

7509(61.2) 1002(8.2) 3759(30.6)

4075(58.4) 565(8.1) 2342(33.5)

479(62.4) 105(13.7) 183(23.9)

2418(65.3) 237(6.4) 1046(28.3)

537(65.5) 95(11.6) 188(22.9)

<0.001

8247(67.2) 936(7.6) 3089(25.2)

4392(62.9) 571(8.2) 2021(28.9)

548(71.5) 60(7.8) 159(20.7)

2638(71.3) 267(7.2) 796(21.5)

669(81.6) 38(4.6) 113(13.8)

<0.001

5529(45.3) 6173(50.5) 510(4.2)

3706(53.3) 2942(42.3) 310(4.4)

379(49.5) 355(46.3) 32(4.2)

1223(33.3) 2309(62.8) 142(3.9)

221(27.1) 567(69.7) 26(3.2)

<0.001

3678(30.1) 6841(55.8) 1733(14.1)

2177(31.2) 3731(53.5) 1065(15.3)

263(34.3) 381(49.8) 122(15.9)

996(26.9) 2253(61.0) 446(12.1)

242(29.6) 476(58.2) 100(12.2)

<0.001

6028(49.1) 6244(50.9)

3209(45.9) 3775(54.1)

333(43.4) 434(56.6)

2058(55.6) 1643(44.4)

428(52.2) 392(47.8)

<0.001

9249(75.7) 2976(24.3)

5466(78.6) 1490(21.4)

607(79.1) 160(20.9)

2628(71.3) 1056(28.7)

548(67.0) 270(33.0)

<0.001

9439(84.6) 1713(15.4) 11(7)

5922(91.9) 524(8.1) 11(6)

658(91.4) 62(8.6) 12(5)

2349(72.0) 915(28.0) 9(6)

510(70.6) 212(29.4) 9(6)

<0.001

9360(76.6) 2853(23.4)

5671(81.5) 1285(18.5)

369(48.3) 395(51.7)

2900(78.9) 775(21.0)

420(51.3) 398(48.7)

<0.001

10,967(90.9) 1092(9.1)

6393(93.0) 479(7.0)

582(77.2) 172(22.8)

3372(92.9) 258(7.1)

620(77.2) 183(22.8)

<0.001

11,524(94.7) 649(5.3)

6659(96.1) 272(3.9)

665(87.8) 92(12.2)

3488(95.0) 182(5.0)

712(87.4) 103(12.6)

<0.001

12,108(99.1) 116(0.9)

6915(99.3) 46(0.7)

751(98.4) 12(1.6)

3636(98.7) 47(1.3)

806(98.6) 11(1.4)

0.002

11,050(90.3) 1187(9.7)

6517(93.5) 454(6.5)

649(85.2) 113(14.8)

3254(88.2) 435(11.8)

630(77.3) 185(22.7)

<0.001

11,727(96.1) 481(3.9)

6756(97.1) 202(2.9)

712(93.9) 46(6.1)

3509(95.5) 164(4.5)

750(91.6) 69(8.4)

<0.001

11,453(93.8) 762(6.2)

6667(95.8) 293(4.2)

696(91.8) 62(8.2)

3418(92.7) 267(7.3)

672(82.8) 140(17.2)

<0.001

9418(76.9) 2832(23.1)

5761(82.6) 1215(17.4)

571(74.5) 195(25.5)

2602(70.5) 1087(29.5)

484(59.1) 335(40.9)

<0.001

12,113(98.9) 128(1.1)

6933(99.5) 37(0.5)

760(99.4) 5(0.6)

3627(98.4) 59(1.6)

793(96.7) 27(3.3)

<0.001

<0.001

(continued on next page) 13

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Table 1 (continued) Variables

AR(%) no yes Asthma (%) no yes

All participants

Group 0 (no CVD or depression)

Group 1 (CVD but no depression)

Group 2 (no CVD but depression)

Group 3 (CVD and depression)

p valuea

8090(66.0) 4167(34.0)

5208(74.6) 1772(25.4)

480(62.7) 286(37.3)

2045(55.4) 1646(44.6)

357(43.5) 463(56.5)

<0.001

11,830(96.7) 404(3.3)

6826(98.1) 133(1.9)

735(95.8) 32(4.2)

3524(95.5) 165(4.5)

745(91.0) 74(9.0)

<0.001

Abbreviations: ENP, emotional, nervous, or psychiatric problems; AR, Arthritis or rheumatism. a P value based on χ2test. b P value based on an analysis of variance. c P value based on Kruskal–Wallis H test.

to draw a picture of 2 overlapping pentagons successfully. Respondents who draw the picture successfully can receive a score of 1, and those who fail to do so receive a score of 0. This is an overall measure of the respondent's cognitive function (Sha et al., 2018). 11 chronic diseases were studied and taken as covariates, of which some were risk factors of CVD and MRD. Hypertension, dyslipidemia (elevation of low density lipoprotein, triglycerides, and total cholesterol, or a low high density lipoprotein level), high blood sugar (including Diabetes), cancer (or malignant tumor, excluding minor skin cancers), chronic lung diseases (eg, chronic bronchitis, emphysema (excluding tumors or cancer)), liver disease (except fatty liver, tumors, and cancer), Kidney disease (except for tumor or cancer), Digestive disease (Stomach or other digestive disease, except for tumor or cancer), Emotional, nervous, or psychiatric problems (ENP), Arthritis or rheumatism (AR) and Asthma. These diseases were also defined as having been diagnosed or being told by doctors.

registered permanent residence, education level, smoking status, alcoholic intake, sleep status, nap status, social communication, health before 15 years, and life satisfaction was collected using standardized questionnaires during interviews. Marriage was classified as married and not married (included widowed, divorced, never married and separated). Living place was categorized as city or town, and village. Registered permanent residence was classified as agricultural, nonagricultural, and others. Education level was categorized as below primary school (included no formal education (illiterate), and did not finish primary school but capable of reading or writing), primary school (included Sishu/home school, and graduate from elementary school), middle school, and high school and above. Smoking status was categorized as nonsmoker, past smoker, and current smoker based on their responses to questions about smoking ever, in last interview and at present. Alcoholic intake was categorized as none, drinking much (more than once a month) and drinking little (less than once a month). Sleep status was categorized as 7 h to 9 h, <7 h, and >9 h. Nap status was categorized as 30 min to 1 h, <30 min, and >1 h. Social communication was categorized as yes (any of the following activities: interacted with friends; played Ma-jong, played chess, played cards, or went to community club; provided help to family, friends, or neighbors who do not live with you and who did not pay you for the help; went to a sport, social, or other kind of club; took part in a community-related organization; done voluntary or charity work; cared for a sick or disabled adult who does not live with you and who did not pay you for the help; attended an educational or training course; stock investment; used the Internet; other activities with friends) and no. Health before 15 years was categorized as healthy (included excellent, very good and good) and unhealthy (included fair and poor). Life satisfaction was selfrated by a five-point scale “Please think about your life-as-a-whole. How satisfied are you with it?”, and classified as satisfied (included completely satisfied, very satisfied and somewhat satisfied) and unsatisfied (included not very satisfied, and not at all satisfied). As a part of cognitive function, memory was associated with cognitive function (Anstey et al., 2001). So, cognitive function was adjusted in the association of CVD and depression and MRD. In line with the American Health and Retirement Study, this study mainly focused on three composite measures of cognitive functioning. We used the sum of three measures to represent the respondent's cognitive status as a whole, with total scores ranging from 0 to 21. The first measurement is based on Telephone Interview of Cognitive Status, involving 10 questions, including recalling today's date(month, day, year), the day of the week and season of the year, and serial 7 subtraction from 100 (up to 5 times). This dimension score is calculated on the number of correct answers, ranging from 0 to 10.The second measurement of cognition relies on word recall. It mainly tests episodic memory of cognition. After the interviewer reading a list of 10 Chinese words, the participant is asked to repeat the words in any order immediately. About 4 min later, the respondent is asked to recall the list of words again. The word recall score is based on the average of the number of correct answers, ranging from 0 to 10. The third cognitive measure is a test of the ability

2.5. Statistical analysis Means (standard deviations) or median (quartile range) are expressed for continuous variables and counts (percentiles) for categorical variables. Baseline characteristics of participants in the two groups were compared using analysis of two independent t-test for age, two independent nonparametric test for continuous variables violated normal distribution and theχ2test for categorical variables (see Table 1). ID (Incidence density) and IRR (Incidence rate ratio) were computed at unit of 100,000 person year. Kaplan–Meier estimates for the cumulative risk of CVD event were computed in the different pushup categories, compared using the log-rank test, and presented as a

Fig. 2. Kaplan–Meier curves for the cumulative risk of MRD outcome in four groups. Abbreviations: CVD: cardiovascular disease; MRD: memory related disease. 14

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Table 2 Associations of CVD and depression with incidence rate of MRD in Chinese adults aged 45 years or older. Incidence of MRD

Group 0 (no CVD or depression)

Group 1 (CVD but no depression)

Group 2 (no CVD but depression)

Group 3 (CVD and depression)

Incidences/person-yrs Unadjusted Model1 Model2 Model3 Model4

59/27,896 1(ref) 1(ref) 1(ref) 1(ref) 1(ref)

9/3056 1.4(0.69–2.81) 1.13(0.56–2.31) 1.12(0.55–2.29) 1.13(0.53–2.39) 1.04(0.48–2.23)

67/14,769 2.15(1.51–3.05) 2.17(1.52–3.11) 1.92(1.33–2.78) 1.88(1.26–2.8) 1.64(1.09–2.49)

49/3249 7.18(4.92–10.49) 6.58(4.46–9.69) 5.8(3.89–8.65) 5.34(3.43–8.31) 4.72(2.91–7.64)

Values are n or weighted hazard ratio (95% confidence interval). Model 1: adjusted for age, sex, marriage, living place, registered permanent residence, education level. Model 2: model 1+ smoking status, alcoholic intake, sleep status, nap status, social communication. Model 3: model 2 + health before 15 years, life satisfaction, cognitive function. Model 4: model 3 + Hypertension, dyslipidemia, high blood sugar, cancer, chronic lung diseases, liver disease, kidney disease, digestive disease, ENP, AR, and Asthma. Fig. 3. Hazard ratios for MRD incidence for all participants, age < 65 years old, age ≥ 65 years old, men and women. Hazard ratios were adjusted for adjusted for age, sex, marriage, living place, registered permanent residence, education level, smoking status, alcoholic intake, sleep status, nap status, social communication, health before 15 years, life satisfaction, cognitive function, hypertension, dyslipidemia, high blood sugar, cancer, chronic lung diseases, liver disease, kidney disease, digestive disease, ENP, AR, and Asthma. Horizontal lines represent 95% confidence intervals. CI = confidence interval. Group 0, no CVD or depression; Group 1, CVD but no depression; Group 2, no CVD but depression; Group 3, CVD and depression.

study. The average age of all participants was 65.69 ± 9.36 years (range, 45–101 years). Of all the participants, 5738(46.8%) were men and 6534(53.2%) were women. 56.9% (n = 6984) hadn't suffered from CVD or depression, 6.3% (n = 766) suffered from CVD but without depression, 30.2% (n = 3701) hadn't suffered from CVD but from depression, 6.7%(n = 820) both suffered from CVD and depression. During 48,970 person-years of follow-up (median follow-up 4 years; maximum follow-up 4 years), 184 participants suffered from MRD. 4 years incidence density (ID) of MRD was 211 (IRR = 1) for group 0, 295 (incidence relative risk (IRR) = 1.39) for group 1, 454 (IRR = 2.14) for group 2, and 1508 (IRR = 7.13) for group 3. As shown in Table 1, participants who suffered from both CVD and depression were more likely to be older, women, not married, and with lower education level, less smoking and alcohol intake, less sleep time and nap time, less social communication, and with more proportion of unhealthy, unsatisfied with life, had higher prevalence rate of hypertension, dyslipidemia, high blood sugar, cancer, chronic lung diseases, liver disease, kidney disease, digestive disease, ENP, AR, and Asthma. Participants who both suffered from CVD and depression had lowest MRD-free survival probability (Fig. 2) and were at higher risk for suffering from MRD. After adjustment for age, sex, marriage, living place,

Fig. 2. The associations between different CVD and depression status and incidence rate of MRD were investigated by using Cox proportional hazards regression models with the following covariates: age, sex, marriage, living place, registered permanent residence, education level (model 1); model 1 plus smoking status, alcoholic intake, sleep status, nap status, social communication(model 2); model 2 plus health before 15 years, life satisfaction, cognitive function(model 3); model 3 plus hypertension, dyslipidemia, high blood sugar, cancer, chronic lung diseases, liver disease, kidney disease, digestive disease, ENP, AR, and Asthma (model 4) (see Table 2, Fig. 3 for central illustration). We have checked model assumptions for all the analyses. All statistical analyses were conducted using survey modules of SAS software version 9.4 (SAS Institute, Cary, North Carolina). Two-sided pvalues <0.05 was considered statistically significant.

3. Results 3.1. Study population A total of 12,272 participants with average following up time 3.99 years (minimum:1 year; maximum: 4 years) were analyzed in this 15

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depressive disorder in the future than men (Li et al., 2015), which confirmed the finding that depression only was significantly associated with MRD for women instead of men in this study. The most important finding is that coexistence of CVD and depression could significantly increase the incidence risk of MRD by 372% times for all participants, 430% times for young adults with age<45 years, 373% times for older adults with age≥65 years, 305% times for men, and 439% for women compared to adults with neither CVD nor depression. This suggests that preventing depression is important for CVD people avoiding suffering from MRD, and the same for preventing CVD for depression people.

registered permanent residence, education level, participants who both suffered from CVD and depression had a 618% higher risk (hazard ratio [HR]: 7.18; 95% confidence interval [CI]: 4.92 to 10.49), who didn't suffered from CVD but with depression had a 115% higher risk (HR: 2.15; 95% CI: 1.51 to 3.05), who suffered from CVD but without depression showed no significant higher risk (HR: 1.4; 95% CI: 0.69 to 2.81) of MRD incidence compared with those who neither suffered from CVD nor depression. In the fully adjusted model, the multivariableadjusted HRs for MRD incidence for all participants who both suffered from CVD and depression was 4.72 (95% CI: 2.91 to 7.64), for only suffered from depression but not CVD was 1.64 (95% CI: 1.09 to 2.49). Only suffered from CVD but not depression still had no significant influence on the incidence rate of MRD (HR: 1.04; 95% CI: 0.48 to 2.23) (Table 2, Fig. 3). Participants who both suffered from CVD and depression had a higher risk of MRD incidence both for age older and younger than 65 years, and men and women. However, the significantly higher risk of MRD incidence for participants with depression but no CVD had only been found in women and age≥65 years (Fig. 3).

5. Study limitations First, diseases including CVD and MRD were all self-reported, which was proved to be with poor sensitivity but fairly good specificity and positive predictive values (Yuan et al., 2015), might be prone to information error. Second, cognitive dysfunction hasn't been distinguished, those who should be diagnosed as MRD but missed might brought new information error. Finally, although we have adjusted for many potential confounders, we could not completely rule out the possibility of residual confounding by unmeasured factors.

4. Discussion In this large prospective study of a nationally representative cohort with 1 to 4 years of follow-up, we found that depression was significantly associated with an increased risk of MRD incidence, the coexistence of CVD and depression could significantly increase the risk of MRD incidence twice more than depression only. The association of CVD and risk of MRD incidence hadn't been found. These associations were independent of demographic, lifestyle factors, health before 15 years, life satisfaction, cognitive function and 11 chronic diseases. To the best of our knowledge, this is the first prospective analysis of association of coexistence of CVD and depression and the risk of MRD incidence. Our findings are generally in line with previous studies on the relationship between depression and memory (Dalgleish et al., 2007; Sumner et al., 2010; Dalgleish and Werner-Seidler, 2014). But the association of CVD and memory haven't been found in this study. Another interesting finding was that coexistence of CVD and depression could greatly improve the association of MRD incidence for all participants, also the same for different age groups and sex groups. It has been widely suggested in the literature that depression negatively affects patients with CVD (Lugoboni et al., 2005; Duivis et al., 2011). The same finding was also been found in this study. We also found a significant interaction of CVD and depression and MRD. In order to distinguish the independent association of CVD and depression and the interaction of them, participants were divided into four groups. In fully-adjusted model, 25 covariates not only included the demographic and life style factors, but also contained cognitive function, life satisfaction and other chronic diseases, such as hypertension, diabetes, dyslipidemia, emotion problem, and cancer, which had been reported as risk factors of memory were considered (Winblad et al., 2016; Norton et al., 2014; Orgeta et al., 2019; Samieri et al., 2018; Williams et al., 2007; Jean-Pierre et al., 2015). As is known, memory is related with cognitive function. In this study MRD contains dementia, brain atrophy, and Parkinson's disease, which is a severe cognition decline. The association of CVD and depression and MRD also adjusted for cognitive function. Previous findings found that depressed individuals typically show poor memory for positive events, potentiated memory for negative events, and impaired recollection (Cipolli et al., 1996; Schweizer et al., 2018). Dillon also reported the mechanisms of memory disruption in depression (Dillon and Pizzagalli, 2018). We found the same association in this study for all participants, old people aged 65 and more and women, but not for young people or men. People with depression only could add the risk of MRD incidence of 116% times for old people aged 65 and more and 102% times for women compared to people with neither depression nor CVD. Women are more likely to suffer from longer terms of depression and can more easily suffer from major

6. Conclusions In this large prospective study of Chinese adults aged 45 and more, we found that coexistence of CVD and depression was significantly associated with an increased risk of incidence of MRD; depression only was significantly associated with an increased risk of incidence of MRD for women and older adults aged 65 years and more. Our study supports the important idea of psycho-cardiology that joint treatment of CVD and psychological disease. Translational outlook Further studies are needed to elucidate the biological mechanisms underlying this association to optimize the impact of a targeted intervention that might reduce incidence of MRD. Funding information Research reported in this publication was supported by the Key R & D and Planning projects of the Ministry of Science and Technology under Award Number 2018YFC2001805, the Special Funds for Scientific Research of Dengfeng Plan of Guangdong Provincial People's Hospital under Award Number DFJH201811 and the Guangdong Health Economic Association under Award Number 2019-WJMF-02. CRediT authorship contribution statement Xue Yunlian: Conceptualization, Funding acquisition, Writing original draft, Data curation, Methodology, Formal analysis. Liu Guihao: Writing - original draft, Data curation, Methodology, Formal analysis. Geng Qingshan: Conceptualization, Funding acquisition, Writing - review & editing. Declaration of Competing Interest Author has no conflicts of interests or financial disclosures relevant to this article. Acknowledgments The authors thank the participants and staff of the China Health and Retirement Longitudinal Study (CHARLS) team for their valuable contributions. 16

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Supplementary materials

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