Short Trends and Associated Factors of Cognitive Impairment in a Population at High Cardiovascular Risk

Background: It has been proposed that some risk factors of cardiovascular disease (CVD) are associated with and contribute to the development of all cause of dementia. Our aim was to examine the short trends and associated factors of cognitive impairment among a eastern Chinese population at high risk of CVD. Methods: We used a convenience sampling strategy to select 7 subdistricts in Zhejiang province, which was a part of China Patient-Centered Evaluative Assessment of Cardiac Events (PEACE) project. Participants in 2018 (n=3089) and in 2020 (n=3082) at high risk of CVD in Zhejiang province with registry for the PEACE Project. Participants completed 3+ neuropsychological evaluations including of Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA) and Hospital Anxiety and Depression Scale (HAD) tests. Age-, gender- standardized prevalence rates were calculated based on the sixth population census for population of China. Cox proportional hazards regression models to estimate hazard ratios (HR) for the associations between the risk for all-cause dementia. Trial registration number was NCT02536456. Results: There was an increase prevalence of dementia and MCI among the individuals at high risk of CVD between 2018 and 2020. It showed that older age, lower education levels, having a medical history of hypertension, stroke and diabetes, having the family history of hypertension, heavy drinking, depression, and obesity were associated with dementia, while female might be a protective factor for dementia. Conclusion: More population-based strategies should be focusing on modiable risk factors of dementia, such as CVD risk factors.


Background
Dementia has been considered as a public health priority as it commonly leads to increase in terms of disability, mortality, and cost [1,2]. The number is expected to reach 152 million by 2050, with about 60 to 70% of them suffering from Alzheimer's disease (AD). Mild cognitive impairment (MCI) is identi ed as an intermediate state that cognitive impairment does not reach the threshold for dementia diagnosis, which is associated with increased risk of dementia [3,4]. Some studies suggest that key cardiovascular risk factors, such as hypertension, diabetes, and hypercholesterolemia in uence the incidence of dementia [5][6][7].
As the country with the world's largest population, China is facing substantial challenges in ageing population, of which increasing numbers will have some degree of dementia and cardiovascular disease (CVD). At present, there are about 10 million AD patients in China, and it is estimated that by 2050, the number of patients will exceed 40 million.
Zhejiang province is located in eastern China, people that aged 60 or above accounted for 21.77% of the total population by the end of 2017 [4,8]. And the incidence of CVD among the participants with high risk of CVD is about 3.9% in 2014 to 2016, and is expected to increase to 5% by 2021 [9]. But there are few epidemiological data available on dementia in eastern China, which taking into account of CVD risk factors.
Our study explores the short trends and associated factors of dementia prevalence among population at high CVD risk in eastern China for the years 2018 and 2020.

Population
It is a population-based closed cohort assembled in April 2018 and June 2020 in Zhejiang province, representative of dwellers 55 years or more at high risk of CVD. This project is part of the China Patient-Centered Evaluative Assessment of Cardiac Events (PEACE) Million Persons Project, which has been described previously [10].
Then participants were given cognitive function evaluation and diagnosis. The criteria of high risk of CVD had been described previously [10,11]. The baseline sample was initially interviewed in 2018 (N = 3500), and the replenishment sample was interviewed in 2020, with 1724 of whom were continuing and the others interviewed for the rst time. The central ethics committee at the China National Center for Cardiovascular Disease (NCCD) and Zhejiang hospital approved this project. Written informed consent is obtained from all literate participants without cognitive decline on entry into the project. And for illiterate participants or ones with cognitive decline, their informed consent is obtained from their literate legally authorized representatives. Trial registration number: NCT02536456.

Assessments
The cognitive function evaluation was carried out by a multidisciplinary team comprised of a nurse and a neurologist. Participants were classi ed into three categories: normal cognitive function, MCI and dementia. Screening was performed using the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), the Hospital Anxiety and Depression Scale (HAD) tests [12]. Participants who scored below the MMSE cutoff points of 20 for 0-2 years, 23 for 3-6 years and 27 for 7 years or more of schooling were considered as positive results, which had the tendency of dementia [13]. Participants who scored less than the MoCA cutoff points of 1.5 standard deviations (SD) or more below age-and education-adjusted norms were considered as MCI [14]. HAD tests included two sub-scales of anxiety (A) and depression (D), the sub-scale of anxiety and depression was abnormal with a score below 8 [15].
The con rmed diagnosis of dementia was conducted among the subjects with positive results of MMSE test. The diagnostic criteria of dementia used the Chinese guidelines for the diagnosis and treatment of dementia and cognitive impairment [16]. There were no questionnaires or measures used in our study require a license in order to administer them.

Statistical analysis
Characteristics, cognitive function status of participants were summarized using percentages or means and SD, and they were compared by Student's t tests and X 2 tests, respectively. Age-, gender-standardized prevalence rates were calculated based on the population distribution of China in 2010 (the sixth population census for population of China) [17].
We used Cox proportional hazards regression models to estimate hazard ratios (HR) and 95% CIs for the associations between the risk for all-cause dementia. Crude regression models were rst used to assess the risk factors associated with dementia among population at high risk of CVD, then adjusted regression models were used to ascertain the risk factors considering the main effects of sociodemographic characteristics. 2-sided signi cance tests were used for all analyses, with statistical signi cance set at P < 0.05. SAS 9.2 (SAS Institute Inc., Cary, NC, USA) for data management and analysis.

Characteristics of the population
The characteristics of the population matched cohort were displayed in Table 1. A total of 3500 residents were enrolled in this project in 2018, and 3089 ones completed the survey. The replenishment sample was interviewed in Prevalence trend of dementia and MCI Table 2 displayed the prevalence and adjusted prevalence of individuals in each cognitive function category strati ed by age groups (55-64 years, 65-74 years, and ≥ 75 years) in 2018 and 2020. The data showed an increase prevalence of dementia among the individuals aged 55 years or older at high risk of CVD between 2018 and 2020 (8.68% in 2018 compared with 10.15% in 2020, P < 0.05). The prevalence of MCI also increased signi cantly across the 2 cohorts from 22.04-25.46% (P < 0 .05). And the data showed an increase trend of dementia and MCI prevalence with the increase of age (P < 0.05).  (BMI = 18.5-24.9 kg/ m²) were associated with dementia, while female (AHR = 0.57, 95% CI: 0.41-0.78) might be a protective factor for dementia.  b Model 2 showed the multivariate models adjusted by age, gender and education levels.

Discussion
Among eastern Chinese population aged 55 years or more at high risk of CVD, we found high dementia prevalence, and the prevalence of dementia and MCI increased over the short period of 2018 to 2020. Coupled with the fact that older age, low education levels, stroke, diabetes, hypertension and depression were signi cant risk factors, which were consistent with other studies [18,19].
Compared with the 2018 cohort, the 2020 cohort had a higher prevalence of dementia and MCI at every age range. The age-gender adjusted prevalence of dementia was 10.15% in 2020, which was about twice as high compared to the general population aged 65 or older in China (5.14%), according to the national epidemiological survey [4]. It was also higher than that of the general population in Zhejiang province (4.9%), but lower than the nursing homes (40.6%) [15]. The age-gender adjusted prevalence of MCI was 25.46%, which was also higher than that of the general population in Zhjiang province [4,15].
To our knowledge, ours was one of very few surveys of dementia prevalence and trend in a population at high risk of CVD. The prevalence of CVD risk factors of this study population was relatively high. Hypertension was present almost half of the study population in 2018 and 2020, double of the global age standardized prevalence of hypertension [20,21]. The mean total cholesterol (TC) of our study was 5.33 mmol/L in 2020, which was higher than that of the general population (4.63 mmol/L). The stroke prevalence of 4.7% in 2018 and 4.0% in 2020 was higher than that of 2.8% among the general Chinese population aged 40 years or more [22]. Furthermore, the prevalence of regular exercises of 11.3% in 2018 and 13.7% in 2020 was relatively low, compared with that of 33.9% of Chinese residents [22]. The smoking rate of nearly 30% in 2020 among men in the study was high, while it was about 0.36% for women. And the high prevalence of alcohol abuse of more than half among men in 2020 was also of great concern and needed to be addressed.
Many factors had been associated with a risk for dementia. Consistent with previous investigations in China and other countries, our study con rmed that older age, lower education levels, heavy drinking were a strong risk factor for dementia in populations at high risk of CVD [4,23,24]. Prevalence of dementia had been found to be higher in women than men in some regions but not in all [14]. In our survey, being female was a protective factor for dementia. Obesity was associated with an increased risk of dementia, consistent with the hypothesis that obesity triggering vascular dementia decreased not only blood supply to the brain, but also increased fat cells that damaged the brain white matter leading to loss of cognitive and intellectual behaviors [25].
In addition, CVD including of diabetes, stroke and hypertension were important risk factors of dementia showed in this study. Other studies found that persons with diabetes had an increased risk for all cause dementia [14]. Meanwhile, some studies showed that stroke doubled the chances of developing dementia [26,27]. Preventing diabetes, stroke, hypertension and reducing cardiovascular risk factors would be an effective way to reduce the dementia burden.
It should be mentioned that depression was a strong risk factor for dementia among this survey population. Evidence suggested that cerebrovascular changes might constitute a link between depression and dementia, it was not only epidemiologically but also biologically plausible that depression increased dementia risk [28]. Further research was needed to investigate whether successful prevention and antidepressive treatment of depression decreased the risk of dementia.

Strengths And Weaknesses
Some limitations needed to be mentioned in this study. The intervals between the two surveys were relatively short.
Additional cohort survey data should be required in the future. Furthermore, the sample size was relatively small, a larger scale, larger sample size and longer period of study which including of more collected information are needed in the further.
Despite these limitations, the strengths included that it was one of very few surveys about dementia prevalence and prevalence trend among a population at high risk of CVD in eastern China. And the study was a part of the PEACE Million Persons Project, which providing regional representative data at a population level in eastern China.

Conclusion
In conclusion, cognitive impairment is highly prevalent among elderly at high risk of CVD in eastern China, and the Availability of data and material The data sets used or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests
The authors have no con ict of interest to report. Authors' contributions Substantial contributions to the conception or design of the work: Z P, Y J; Acquisition, analysis, or interpretation of data for the work: Y L; Drafting the work for important intellectual content: H S, X X, H Y, X C, Y C.
All authors read and approved the nal version of the manuscript.