3.1 The MCIp was higher in the group of onset ≥ 65 years.
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 stratification according to age, BMI, SBP and DBP levels. To our knowledge, our study is the first 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 . 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 . 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) ; moreover, statistically significant reduced risk of MCI and dementia can be found in the intensive group (SBP =120 mmHg) less than 75 years old.
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 . Similar findings 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 . 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) . 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 , 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 . 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) . 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.
3.2 The MCIp frequency was higher in the group without diabetes mellitus.
Another finding 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 significantly reduced . 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. It should be considered that only 61 cases (22.02%) of diabetes mellitus in this study may be due to insufficient sample size, which makes it difficult to reflect 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.
3.3 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 . 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 flow was related to the increase of arterial stiffness despite the existence of cerebral blood flow reserve capacity . Follow-up and cross-sectional clinical studies have confirmed 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 .
3.4 MCIp cannot benefit 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 [36-38]. 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 . 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 . 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.
3.5 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 confirming that old age is the main risk factor for dementia .
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.
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 influence of insufficient sample size also has some influence 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.
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 confirmation.