Later Onset of Hypertension Increased the Risk of Dementia in Mild Cognitive Impairment

Objective To investigate the effect of hypertension development on the progression of MCI for middle aged and elderly people. Methods A population-based longitudinal cognition survey of people aged 55+ was conducted. The hypertension onset age was estimated by self-reported information and medical insurance card records. In order to study the effect of later onset of hypertension on dementia, the incidence of dementia was compared between the two groups. Results A total of 277 h ypertensive mild cognitive impairment (MCI) participants without dementia were followed for 6 years. Overall, 56 MCI participants (20.22%) progressed to dementia (MCIp). The proportion of MCIp participants in the old-age onset hypertension group ( ≥ 65 years) was higher than that of middle-age onset one (27.0% vs 15.4%; X 2 = 5.538, P = 0.019). And in the old-age onset hypertension group, the proportion of MCIp without diabetes mellitus was higher than those with diabetes mellitus (24.7% vs 12.6%; X 2 = 5.321, P = 0.021), and the proportion of MCIp with increased pulse pressure was higher than those without increased pulse pressure (33.3% vs 15.4%; X 2 = 3.902, P = 0.048). However, the multivariate logistic regression analysis showed that older age was the only risk for MCIp (OR=0.732, p=0.029). Conclusions These results suggest that, later onset hypertension was harmful to cognition even in cases where the level of blood pressure maintained at 130/80 mmHg with antihypertensive management.


Background
With the advent of population aging, the population of dementia continues to rise, with approximately 47 million people in the whole world in 2015, which is expected to triple by 2050 [1]. The two most common types of dementia are Alzheimer's disease (AD) and Vascular dementia (VaD), accounting for about 80% [1][2][3]. Mild Cognitive Impairment (MCI) is an intermediate transition stage between normal aging and dementia, which is characterized by mild impairment of cognitive function without decline of daily living or social functioning, and previous studies has shown that all MCI eventually progressed to dementia (MCI progression, MCIp) after 9 years [4]. A multicenter research performed in China from 2008 to 2009 showed that the prevalence rates of MCI and dementia (> 65 years old) were as high as 20.8% and 5.14% respectively [5].
Hypertension is another disease that compromises with the abilities of daily living of the elderly [6,7]. In the recent twenty years, several studies have found that hypertension is a risk factor not only for Alzheimer's disease, but also for MCI [2,[7][8][9][10]. In a 2 years follow-up study of 385 MCI cases, Goldstein FC et al. showed that, compared to subjects without hypertension, the cognitive function (such as attention, executive function and naming) of subjects with hypertension declined signi cantly, especially those with Systolic blood pressure (SBP) ≥ 140 mmHg or Diastolic Blood Pressure (DBP) ≥ 90 mmHg [11]. In other words, hypertension is a risk factor for MCI progression. To date, there is no con rmative effect of nootropic drugs on dementia, whereas hypertension is a very important controllable vascular risk factor [2]. Therefore, it is crucial to quickly identify and manage high-risk patients with hypertension, which will prevent dementia effectively.
It has been found that the incidence of dementia is related to the age onset of hypertension. Numerous studies have shown that middle-aged hypertension is associated with increased dementia twenty or thirty years later, but it is uncertain of later onset hypertension (≥65 years) [9,12]. For example, some studies have found that hypertension is independently associated with cognitive impairment in later life, the cognitive function declining with increasing SBP, especially SBP ≥ 180mmHg [13][14][15]. In Yuan's study, the cognition declined with the increased SBP like a hockey [16]. It was also con rmed by cross-sectional survey that, in dementia group, not only the proportion of hypertension (76.5% vs 59.3%), but also the SBP level was higher than that of MCI group [15]. However, some previous studies performed ten years ago showed that hypertension does not necessarily increase the risk of dementia [2,[17][18][19][20][21][22]. A 10-year follow-up (averaging 2.8 years) study of 559 over 90 year-olds conducted by Corrada MM et al. had found that the risk of dementia in hypertensive patients aged 80 and 90 was lower than that in non-hypertensive patients [17]. Nevertheless, high SBP level was possibly associated with increased risk of dementia for <75 year-olds, and it was not the case for >80 year-olds [19][20][21][22]. Moreover, not the high SBP level, but the increased pulse pressure (PP) was negatively correlated with cognition [23].
Our previous epidemiological investigation found that MCI with newly onset hypertension (≥ 60 years old) had a higher rate of dementia. We then put forth the hypothesis that there may be a particular age (between 55 and 75 years old) when hypertension is particularly harmful to cognitive function. Our objective was to evaluate the association between later onset of hypertension and the risk of all-cause dementia in a population-based cohort of individuals.
Materials And Methods

Subjects
The current research was carried out in Pudong district in Shanghai. We analyzed the elderly with MCI (age ≥ 55 years old) who had participated in a survey from June 2011 to June 2012 (No. PKJ2010-Y26) and were successfully contacted in the later survey in 2017. All participants have signed informed consent. Only those su ciently educated, with enough audiovisual level to complete the necessary examinations were included.
According to the age onset of hypertension, the participants were divided into the old-aged group (onset age ≥ 65 years) and the middle-aged group (onset age <65 years).

MCI and dementia diagnostic criteria
MCI was diagnosed using the Petersen's diagnostic criteria: (1) the elderly consciously exhibited memory loss, especially those with memory impairment for more than 3 months; (2) the overall cognitive function is normal through the Minimental state examination (MMSE total score: illiterate subjects > 17, with primary school education > 20 points, and others > 24 point); (3) clinical dementia rating (CDR) score reached a level of 0.5; (4) Montreal cognitive assessment scale: MoCA score ≤ 26; (5) with normal function of daily life; (6) the patient did not meet the diagnostic criteria for dementia [24,25].

Diagnosis and treatment of hypertension
The diagnosis, duration, age of onset, stage and treatment of hypertension were according to elderly self-report and examination of their medical insurance card records.

Additional variables:
Other medical histories reported at the baseline visit and considered as potential confounders included stroke, transient ischemic attack, diabetes, heart disease, and depression. Heart disease included any of the following diseases or surgeries: coronary artery disease, myocardial infarction, atrial brillation or other arrhythmias, heart valve disease, congestive heart failure, coronary artery bypass, or pacemaker placement. The highest level of education attained, marital status and occupation were also recorded.

Statistical approach:
Data were analyzed using the Statistical Package for Social Sciences (version 19.0; SPSS, IBM, Chicago, IL, USA). Continuous variables were tested for normality by One-Sample Kolmogorov-Smirnov Test. Continuous variables were expressed as mean±SD or median (range) as per distribution type, and categorical data were expressed as frequency and percentages. Statistical analysis was performed using independent samples t-test for normal data and Mann-Whitney U test for non-normal data. Categorical data was analyzed by Chi-square test. The multivariate logistic regression analysis was conducted to identify the determinants of outcome of MCI following-up. A P value of less than 0.05 was considered statistically signi cant.

Follow-up outcomes of hypertensive MCI in community
There were 56 individuals (20.22%) who progressed to dementia (MCIp) while 221 (79.78) remained stable (MCIs). In comparison with MCIs, MCIp individuals demonstrated signi cantly worse performance in CDR and ADL scores (p < 0.01). Besides, MCIp individuals were more likely to be single (p = 0.022) ( Table 2), which could be both the reason and consequence of cognitive function deterioration. Next, all individuals were divided into two groups according to the onset time of hypertension: the proportion of MCIp participants in the old-age onset hypertension group (≥ 65 years) was signi cantly higher than that of middle-age onset one (27.0% vs 15.4%; X2 = 5.538, p = 0.019). However, this may be due to that the old-age onset group had a higher age compared with the middle-age onset group (77.75±6.75 vs70.45±6.41, p<0.001). In the old-age onset hypertension group, the proportion of MCIp without diabetes mellitus was higher than those with diabetes mellitus (24.7% vs 12.6%; X2 = 5.321, P = 0.021), and the frequency of MCIp with increased pulse pressure was higher than those without increased pulse pressure (33.3% vs 15.4%; X2 = 3.902, P = 0.048). This result implied that for individuals with a later onset of hypertension, increased pulse pressure does link to CI progression.

Multivariate Logistic Regression Analysis of Cognitive Function deterioration in MCI
The multivariate logistic regression model was tted to analyze the determinants of the outcome of MCI following-up (MCIp = 1, MCIs = 0). Demographic data and variables such as hypertension, age at onset of hypertension, blood pressure grouping, and pulse pressure were taken as independent variables into the model. The variables assignment of logistic regression analysis was listed in table 3. The results showed that age (P=0.029, OR = 0.732) was the only independent determinant of outcome of MCI following-up, that the patients with a younger age are the more likely to control the cognitive function (Table 4) In this prospective study of 277 mild cognitive impairment participants aged 73.48±7.47, later onset of hypertension group (≥65 years) was related to a higher dementia risk compared with middle-age. This increased risk was limited to participants who reported mean SBP was 130/80 mmHg. In addition, the differences disappeared after strati cation according to age, BMI, SBP and DBP levels. To our knowledge, our study is the rst to report the level of blood pressure and to include hypertension by age of onset.
Some researchers found that the increased risk of dementia was related to the increase of SBP in the group under 75 years old [17]. The risk of cognitive impairment increased by 1.17 times when SBP was 130-139 mmHg, however, it increased to 1.54 times when SBP was≥180 mmHg [16]. The results of 3.8-year follow-up of hypertension (n=2800) showed that incidences of MCI and dementia could decrease by 15% in intensive control of blood pressure (SBP<120 mmHg) compared with the standard control group (SB<140 mmHg) (HR = 0.85, 95% CI = 0.74-0.97, P = 0.02) [31]; moreover, statistically signi cant reduced risk of MCI and dementia can be found in the intensive group (SBP =120 mmHg) less than 75 years old [32].
The results of this study are not consistent with some results previously published. The reasons may be as follows: Firstly, the average age of the participants in this study was 73 years old with mean SBP 130/80 mmHg, 57% of them were less than 75 years old, 8 cases (2.89%) with SBP < 120 mmHg and 8 (2.89%) with SBP ≥160 mmHg. Our sample size was relatively small. Secondly, through medication management with a goal of normal range (130/80 mmHg), the proportion of MCIp was different between the two groups, suggesting that aggressive lowering of systolic blood pressure may not good for the elderly [2]. Similar ndings were found in long-term large sample study (n=1440, 8 years follow-up), the risk of dementia increased by 2.4 times when blood pressure was less than 140/90 mmHg with hypertension from middle to old age.
Furthermore, some studies have found that the relationship between the risk of dementia and the increase of SBP was not clear yet for those older than 85 years [17]. After 10 years of follow-up (average 2.8 years, n=559), Corrada MM et al. reported that the risk of dementia in newly onset hypertension aged 80+ and 90+ was lower than that in non-hypertensive patients (HR 0.54 and 0.37, P 0.04 and 0.004, respectively) [17]. The results suggested that the mechanism of hypertension in the elderly was different from that in the middle-aged cohort. Hypertension may be a result of compensatory or response of the body. That is to say, the etiology of hypertension is similar to that of dementia, but the clinical symptoms occur at different times.
In addition, the cognitive impacts of middle-aged hypertension can only be followed up and analyzed after excluding cerebrovascular accidents [21], that is to say, there is bias in the samples. The patients with middle-aged onset hypertension are too serious to detect the impact of hypertension on AD because of cerebrovascular damage such as stroke [22]. In addition, other community studies have found that middle-aged hypertension is associated with MCI and dementia at the age of 70-90 (more strongly associated with dementia) [23]. Namely, this part of the population did not go through the MCI stage and directly entered the dementia stage, which is also an aspect of sample bias.

The MCIp frequency was higher in the group without diabetes mellitus.
Another nding of our study was that for hypertensive MCI without diabetes mellitus, the rate of MCIp in the old-age group was 1.96 times higher than that in the middle-age one. One Meta-analysis also found that the predictive ability of cerebrovascular risk factors for dementia/AD in the old-age group (average age 72.3-82.5) was signi cantly reduced [33]. That is, cerebrovascular diseases such as hypertension, diabetes, hyperlipidemia did not necessarily increase the risk of dementia. A large sample survey of community-based brain magnetic resonance imaging (MRI) follow-up (n = 2367) revealed that cerebrovascular risk factors such as white matter degeneration, hypertension, diabetes, smoking were associated with aging and contributed more to dementia, although the age range of this survey was 20-90 years [19]. It should be considered that only 61 cases (22.02%) of diabetes mellitus in this study may be due to insu cient sample size, which makes it di cult to re ect statistical differences. In addition, for MCI aged 73.48 (SD=7.47), the pathogenesis of diabetes mellitus may be different from that of middle age, so the effect of diabetes mellitus on dementia is also different.

The MCIp was higher in the group with increased pulse pressure
The results of this study showed that, the MCIp was higher in the increased pulse pressure group, as compared to the normal pulse pressure group. Pulse pressure is a sign of arterial stiffness. It was found that pulse pressure was not associated with hypertension and apolipoprotein E4 but with the deposition of beta-amyloid plaques in the brain [23]. In other words, pulse pressure is closely related to aging.
Jefferson et al. used pulse wave velocity (PWV, m/sec) to measure aortic stiffness and found that the decrease of regional cerebral blood ow was related to the increase of arterial stiffness despite the existence of cerebral blood ow reserve capacity [34]. Follow-up and cross-sectional clinical studies have con rmed that increased pulse pressure increases the risk of dementia (including vascular dementia and Alzheimer's disease), which indicates that medicine may lead to occult hypotension and cerebral hypoperfusion [35].

MCIp cannot bene t from antihypertensive therapy
As for the prevention of dementia by antihypertensive therapy, some studies suggest that the risk of dementia is increased by the potential hypotension in antihypertensive therapy due to the impaired vascular regulation mechanism in the elderly [36][37][38]. A 16-week follow-up study suggested that people over 75 years old with MCI stopped taking antihypertensive drugs did not develop cognitive function deterioration [38]. They did not clarify whether all MCI cases had late-onset hypertension and their follow-up time was too short. A multicenter study found that hypertension patients over 65 years of age had a temporary increase in blood pressure four months after reducing antihypertensive medicine, but recovered to 134 mmHg in nine months, while the control group (without reducing drugs) had an increased risk of emergency hospitalization [20]. Animal experiments also suggested that sartan therapy can improve cognition in aged rats [39,40]. However, clinical studies, as well as meta-analyses, reported that although antihypertensive therapy can reduce systolic or DBP, it cannot reduce the incidence of dementia [12,17,23,41]. Together, for prevention of dementia in elderly with hypertension, a lot of exploration still need to be conducted.

Age, a risk factor for MCIp
In this study, regression analysis failed to decree age onset of hypertension, blood pressure and increased pulse pressure as risk factors for MCI deterioration, but only older age was found a risk factor. This is consistent with the results of other studies con rming that old age is the main risk factor for dementia [42].

Conclusion
Later onset hypertension was harmful to cognition even in cases where the level of blood pressure maintained at 130/80 mmHg with antihypertensive management. Those with hypertension occurring ≥ 65 years old may have a different pathogenesis from middle-aged hypertension.

Research limitations
First, 277 elderly people with hypertension in MCI community were followed up prospectively. The sample size was small, and the age distribution was uneven. The follow-up time was 6 years. There might be sample bias, and the proportion of MCIp was affected to some extent.
Secondly, the survey of occupational mental activity, post-retirement economic life, lifestyle, and other factors in MCI population with hypertension is not detailed enough, and the in uence of insu cient sample size also has some in uence on the results of the study.
Thirdly, the diagnosis of dementia in this study sample does not combine the detection of images and CSF biochemical indicators. The history and examination of hypertension are mainly provided by the community elderly and medical record card. There is no 24-hour ambulatory blood pressure monitoring, which may have some bias and have a certain impact on the objectivity of the results.

Research Signi cance
Firstly, the results of the current investigation show that MCI patients with hypertension ≥ 65 years old) with average age about 73 years old are prone to develop dementia, which suggests that comprehensive consideration should be given to antihypertensive drugs for hypertension (≥ 65 years old). Because of the different mechanisms of hypertension, maintaining blood pressure at 130/80 mmHg may not have a positive effect on the protection of cognitive function.
Secondly, this study shows that pulse pressure has a negtive effect on the protection of cognitive function. In the group of increased pulse pressure, the proportion of senile patients progressing to dementia is higher than that of middle-aged patients. This suggests that, there may be different pathogenesis of hypertension in old age patients, and the effect of increased pulse pressure on cerebrovascular is also increased with age. Therefore, increased pulse pressure may be one of the risk factors of dementia. In the future, it is necessary to expand the research sample and improve the experimental methods for further con rmation.

Declarations Ethics Approval and Consent to Participate
The research project was examined and approved by the ethics committee of the Mental Health Center of Pudong New Area, Shanghai 2017005).

Consent to publish
All the authors consent to publish.

Availability of data and materials
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing Interest
No Con ict of Interest.

Authors Contribution
HY Qin and CP Hu guided the implementation of research, collated and analyzed the data. L Wang was responsible for the quality control and logistics support of the subject. Y Guo and ZC Cao were responsible for project implementation and data entry. XD Zhao and BG Zhu were the leaders and BG Zhu was the corresponding author.