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Originally Published 26 May 2020
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Blood Pressure and Risks of Cognitive Impairment and Dementia: A Systematic Review and Meta-Analysis of 209 Prospective Studies

Ya-Nan Ou, Chen-Chen Tan, Xue-Ning Shen, Wei Xu, Xiao-He Hou, Qiang Dong, Lan Tan, and Jin-Tai Yu https://orcid.org/0000-0002-7686-0547 [email protected]Author Info & Affiliations
Hypertension
Volume 76, Number 1
https://doi.org/10.1161/HYPERTENSIONAHA.120.14993
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Abstract

Controversies persist regarding the association between blood pressure (BP) and the risks of cognitive impairment and dementia due to inconsistent definitions of BP exposure and varying population characteristics. Here, we searched PubMed and performed a meta-analysis of the influence of BP exposure on the risks of cognitive disorders in prospective studies. Dose-response analyses were performed to illustrate the existence of linear/nonlinear relationships. The credibility of each meta-analysis was evaluated according to the risk of bias, inconsistency, and imprecision. Of the 31 628 citations, 209 were included in our systematic review, among which 136 were eligible for the meta-analysis. Overall, stronger associations were found in midlife than late-life. Moderate-quality evidence indicated that midlife hypertension was related to a 1.19- to 1.55-fold excess risk of cognitive disorders. Dose-response analyses of 5 studies indicated that midlife systolic BP >130 mm Hg was associated with an increased risk of cognitive disorders. With regard to BP exposure in late-life, high systolic BP, low diastolic BP, excessive BP variability, and orthostatic hypotension were all associated with an increased dementia risk. Encouragingly, the use of antihypertensive medications exhibited a 21% reduction in dementia risk. The U-shaped dose-response curve indicated that the protective window of diastolic BP level was between 90 and 100 mm Hg for low risk of Alzheimer disease. The relationships between BP variables and cognitive disorders are age- and BP type-dependent. Antihypertensive medications were associated with a reduced risk of dementia. However, the optimal dose, duration, and type for preventing cognitive disorders warrant further investigation.

Introduction

Dementia is a major global health challenge, with 47 million people currently living with it, and by 2050, the number is expected to increase to 131 million according to the latest reports in 2019.1,2 Among the dementing disorders, Alzheimer disease (AD) is the most prevalent of all, contributing to 40% to 70% of all cases,3 followed by vascular dementia (VaD).4 Care and support for patients with dementia has wide-ranging consequences for families, healthcare systems, and society as a whole. However, no effective strategies are currently available. Encouragingly, growing evidence of risk factors for dementia have emerged, which shows that lifestyle and other interventions might, if implemented effectively, help delay the onset and reduce the number of people with dementia in the future. Blood pressure (BP), one of the modifiable risk factors, was reported to be linked to both clinical phenotypes of dementia5 and neuropathological changes before the onset of the disease.6 Hypertension is reported as an established risk factor for VaD.7 A clear pathogenetic pathway from hypertension to VaD, involving atherosclerosis and arteriolosclerosis with stroke and cerebral ischemia leading to a decline in cognitive function has been reported.7 Hypertension has also been regarded as a risk factor for AD, but this relationship is not clearly established.8,9
Previous meta-analyses have provided inconsistent results,8,9 probably because of the heterogeneity in population characteristics (especially age) and exposure proxies (systolic and diastolic BP [SBP and DBP]). Therefore, a subgroup analysis can help us propose personalized BP management strategies to protect cognition. Furthermore, the majority of previous meta-analyses have focused on the relationship between dementia and SBP or DBP8; the associations with other BP-related factors are not well known, such as prehypertension, BP variability (BPV), BP reduction, orthostatic hypotension (OH), and pulse pressure (PP). In addition, many studies have demonstrated that antihypertensive medications (AHMs) could modulate disease progression and cognitive decline.10,11 However, some studies have shown opposite results.12 Therefore, whether AHMs reduce the risk of cognitive disorders, the most effective medication, and where the optimal BP control window is located are still topics of debate. Thus, we aimed to perform an inclusive and comprehensive systematic review and meta-analysis of prospective observational studies to determine the relationship between BP exposure, including hypertension, BP-related variables, and AHMs, and risk of dementia and cognitive impairment (hereafter, cognitive disorders) and to determine the credibility of the evidence by conducting a detailed assessment of each meta-analysis.

Methods

Data, analytic methods, and study materials are given below. Further details are available in the Data Supplement and on reasonable request from the corresponding author.

Search Strategy and Selection Criteria

Our meta-analysis was conducted as per the guidelines proposed by the Preferred Reporting Items for Systematic Review and Meta-Analysis Statement.13 Studies were identified by searching PubMed (last date: August 27, 2019); full search strategy can be found in Text S1 in the Data Supplement. We also hand-searched the bibliographies of relevant publications.
Studies were included if they (1) were prospective observational studies (cohort, case-cohort, or nested case-control) studies; (2) investigated the relationship between BP variables/AHMs and cognitive disorders (all-cause dementia/AD/VaD/cognitive impairment); (3) included participants with normal cognition (aimed to investigate conversion to dementia/AD/VaD/cognitive impairment) or mild cognitive impairment (MCI; aimed to investigate conversion to dementia/AD) at baseline; (4) reported multivariable-adjusted effect estimates (risk ratio [RR], hazard ratio, or odds ratio) with 95% CIs or other estimates that can be converted to RR; and (5) published in English.

Data Extraction

Two researchers (Y.-N. Ou and C.-C. Tan) independently extracted the following data: first author, publication year, study design, population source, inclusion and exclusion criteria, population characteristics, BP dose, and level-specific estimates (case number, sample size, and person-years), follow-up duration, sample for analysis, case number for analysis, diagnostic criteria for cognitive outcome, and multivariable-adjusted effect estimates (at least the models were adjusted at the study level for age, gender, and educational level). In cases of disagreement, consensus was reached through joint reassessment. When more than one paper reported on the same population, only the paper with higher quality score or larger sample size was included.

Assessment of Study Quality

The quality of observational studies was assessed using a modified Newcastle-Ottawa Quality Assessment Scale (Text S2) according to selection, comparability, and outcome. Each study can obtain a maximum of one point for each numbered item within the selection (4 points) and exposure (3 points) categories. A maximum of 2 points can be given for comparability. Thus, a study can obtain between 0 and 9 points. Two reviewers independently assessed the study quality, and consensus was reached through joint reassessment.

Statistical Analysis

Meta-analyses were conducted according to (1) age (mid- and late-life with a cutoff of 65 years); (2) BP variables (hypertension, SBP, DBP, prehypertension, BPV, BP change, OH, and PP) and AHMs; and (3) cognitive outcomes (cognitive domains measured by various neuropsychological tests, dementia, and its subtypes). Consistent definitions and criteria were used to define the exposure and cognitive outcomes (Table S1). The cognitive domains measured by various neuropsychological tests were found in Table S2. A random-effects model was used to calculate the summary effect of BP on the risk of cognitive disorders. In the data transformation, such effect estimates as odds ratio and β with SE were transformed to RRs (Text S3).14 Hazard ratio was directly considered as RR. The heterogeneity among studies was estimated using the I2 statistic and Cochrane Q statistic, and I2 <40% (P>0.05) was regarded as possibly low heterogeneity.
Regarding the possible sources of heterogeneity, sensitivity analysis was also performed to assess the effect of any single study on the pooled RR by omitting each study sequentially. Univariate meta-regression analyses by population gender, ethnicity, publication year, educational level, alcohol and tobacco consumption, geographic region, follow-up duration, follow-up rate, quality score of studies, and studies controlling for cerebrovascular or cardiovascular diseases as a confounder in the model were conducted (only if the number of studies included was >10). Then, when the meta-regression found significant mediators, further subgroup analyses were performed. Publication bias was evaluated using the Egger15 and Begg16 test when at least 10 studies were available. When a statistically significant bias was found, the trim-and-fill method was used to adjust it. The meta, metagen, dosresmeta, and rms packages of R software (version 3.4.2) were used to perform all of the above analyses.
The age-stratified dose-response curves of SBP/DBP and the risk of cognitive disorders were depicted using 2-stage generalized least squares trend estimation.17,18 In the first stage, restricted cubic splines with 4 knots at percentiles 5%, 35%, 65%, and 95% of the distribution were used to evaluate a potential curve association, assuming the fixed effects model. In the second stage, we combined the study-specific estimates (SE) and the variance/covariance matrix (person-years and cases) using a random-effects model. The P value for nonlinear curve fitting was calculated by testing the null hypothesis with which the coefficient of the second spline equals zero. Furthermore, we performed a sensitivity analysis with 3 knots (10%, 50%, and 90%). If medians were not reported, we estimated the approximate medians by using the midpoint of the lower and upper bounds. Some studies reported open upper boundaries for the highest category (eg, >160 mm Hg); we multiplied the reported upper boundary by 1.25, and used this value (200 mm Hg in the example).

Assessment of the Credibility of Meta-Analyses

The creditability of each pooled result was rated as good (G), acceptable (A), suspicious (S), and poor (P) grades according to the risk of bias, inconsistency, and imprecision (Text S4). As for risk of bias, based on the weighted quality score for each meta-analysis, the influences of quality score, cumulative weight, and outlier result were assessed. Inconsistencies were detected by statistical tests, variability of point estimates, and overlapping of CI; imprecision was evaluated according to 95% CI. G grade was regarded as high quality, A represented moderate-to-high quality, and S or P grade represented low quality. The quality of dose-response meta-analyses was presented as mean±SD of quality scores of the included studies.

Results

Of the 31 628 citations yielded from the database searches (last date: August 27, 2019), 209 were included in our systematic review (Figure S11), and 136 observational studies were included in the primary meta-analysis (Figure 1), including 132 prospective cohort studies, 3 nested case-control studies, and one case-cohort study. Twelve studies were included in the dose-response analysis. Data available for the meta-analysis were collected from 2 214 814 individuals (46.6% were women). The mean age of participants ranged from 35.3 to 93.2 years, and the mean duration of follow-up ranged from 1.5 to 43 years (Table S3). The mean Newcastle-Ottawa Quality Assessment Scale quality score of the studies included in the meta-analysis was 7±1 (Table S4). Forest plots of each meta-analysis and funnel plots are shown in Figure S1 to S10. We finally ascertained 10 BP-related risk factors for cognitive disorders: hypertension, prehypertension, SBP, DBP, systolic BPV, diastolic BPV, DBP change, OH, PP, and AHMs. The abbreviations of these variables are shown in Table S5. The references of the included studies can be found in Data Supplement.
Figure 1. Flow chart of literature screening. AD indicates Alzheimer disease; and BP, blood pressure.

Evidence of Associations With Midlife BP

As for cognitive function, significant associations between midlife hypertension and global cognition (RR: 1.55 [95% CI, 1.19–2.03] I2=18%, S grade) and executive function (RR: 1.22 [95% CI, 1.06–1.41] I2=0%, A− grade), but not with memory (RR: 1.13 [95% CI, 0.98–1.30] I2=0%, A− grade; Figure 2), were revealed with low-to-moderate evidence.
Figure 2. Summary of pooled estimates of midlife blood pressure (BP) variables and the risk of cognitive disorders. Significant correlations of hypertension (HTN) in midlife with executive function and global cognition but not memory were revealed. Grade A evidence showed that an elevated risk of dementia was associated with midlife hypertension (HTN), high systolic BP (SBP), high diastolic BP (DBP), and excessive DBP change. Further stratified analysis indicated that SBP ≥140 mm Hg, DBP ≥80 mm Hg, and DBP change ≥5 mm Hg conferred 38% to 52% excess risk of dementia. AD indicates Alzheimer disease; OH, orthostatic hypotension; PP, pulse pressure; and RR, risk ratio.
As for dementia, moderate evidence showed a significantly elevated risk was associated with midlife hypertension (RR: 1.20 [95% CI, 1.06–1.35] I2=89%, A− grade), high SBP (RR: 1.54 [95% CI, 1.25–1.89] I2=0%, A− grade), high DBP (RR: 1.50 [95% CI, 1.04–2.16] I2=47%, A− grade), and excessive DBP change (RR: 1.65 [95% CI, 1.28–2.11] I2=0%, A+ grade). Further stratified analysis indicated that SBP ≥140 mm Hg, DBP ≥80 mm Hg, and DBP change of ≥5 mm Hg were related to 37% to 52% excess risk of dementia (Figure 2). Dose-response analysis showed that when SBP in midlife exceeded 130 mm Hg, the risk of cognitive impairment and dementia increased by >34% (Pmodel=0.0001, Pheterogeneity=0.3533, Pnonlinearity=8×10−5; quality score, 7±1; Figure 3).
Figure 3. Dose-response relation between midlife systolic blood pressure (SBP) and risk of cognitive disorders. The association between SBP in midlife and the risk of cognitive disorders was positive and nonlinear. When SBP is >130 mm Hg, the risk of cognitive impairment and dementia may increase by >34%. RR indicates risk ratio.
As for AD, moderate-to-high evidence showed that midlife hypertension (RR: 1.19 [95% CI, 1.08–1.32] I2=0%, A− grade) and high DBP (RR: 1.50 [95% CI, 1.06–2.12] I2=0%, G grade; Figure 2) were associated with an increased risk. Stratified analysis revealed that DBP ≥90 mm Hg was associated with a 51% increased risk of AD (RR: 1.51 [95% CI, 1.02–2.23] I2=0%, A+ grade). However, the relationship between midlife prehypertension, OH, and PP and the risk of cognitive disorders needs further investigation because of the neutral results with relatively low quality.

Evidence of Associations With Late-Life BP

A moderate level of evidence implied a neutral association between late-life hypertension and dementia (RR: 1.02 [95% CI, 0.94–1.10] I2=32%, A+ grade; Figure 4). However, meta-regression and subgroup analysis indicated that the association might vary with ethnicity (P=0.036; Figure S3). In the black population, hypertension was associated with an increased risk of dementia, whereas among the white, Asian, and mixed populations, the association was greatly weakened. There was no evidence of publication bias. Similarly, no influence of hypertension in late-life on AD was found (RR: 0.94 [95% CI, 0.84–1.05] I2=25%, A+ grade), and educational level could have been a modifying factor (P=0.025; Figure S4). Hypertensive patients had a higher risk of developing AD in the low-education group (≤6 years), whereas inconsistent results were obtained for the medium (6–12 years) and high-education (≥12 years) groups. The sensitivity analysis after excluding one study that did not exclude dementia and MCI patients at baseline revealed no association with the incidence of MCI (RR: 1.19 [95% CI, 0.98–1.43] I2=34%). Furthermore, a moderate level of evidence showed that hypertension could significantly predict the progression from MCI to all-cause dementia (RR: 1.41 [95% CI, 1.00–1.99] I2=33%; Figures S5 and S6). Hypertension doubled the risk of VaD with an RR of 2.12 (95% CI, 1.50–2.99, I2=32%; Figure S7).
Figure 4. Summary of pooled estimates of late-life blood pressure (BP) variables and the risk of cognitive disorders. Grade A evidence implied that late-life hypertension (HTN) and the risks of dementia and Alzheimer disease (AD) are unrelated. However, high diastolic BP (DBP; ≥90 mm Hg) was associated with a 23% reduced risk of dementia (Grade A). Additionally, moderate-to-high-quality evidence disclosed associations of excessive BP variability (BPV) and orthostatic hypotension (OH) with increased dementia risk in late-life. MCI indicates mild cognitive impairment.
A meta-analysis of high SBP in late-life and dementia risk showed moderate-quality evidence, with a pooled RR of 1.01 (95% CI, 0.81–1.40, I2=65%, A− grade; Figure 4). In subgroup analysis, the risk was significant only when SBP ≥180 mm Hg versus SBP <180 mm Hg (RR: 1.45 [95% CI, 1.03–2.06] I2=0%, G grade). A linear positive correlation was found between SBP and risk of dementia (Pmodel=0.0000, Pheterogeneity=0.6868, Pnonlinearity=0.16; quality score, 8±1; Figure 5A) and AD (Pmodel=0.0000, Pheterogeneity=0.6868, Pnonlinearity=0.18; quality score, 8±1; Figure 5B). Dementia risk was mildly elevated per mm Hg increase in SBP.
Figure 5. Dose-response relationship between late-life blood pressure (BP) and risk of dementia. A linear positive correlation was implied between systolic BP (SBP) and the risk of dementia/Alzheimer disease (AD; A and B). As for diastolic BP (DBP), a linear relationship with dementia was observed (C). However, a U-shaped relationship between DBP and AD was demonstrated, suggesting that 90 to 100 mm Hg might be an optimum level for the elderly (D). RR indicates risk ratio.
The protective relationship of high DBP with dementia was proven by a meta-analysis with moderate-quality evidence (RR: 0.77 [95% CI, 0.59–1.00] I2=47%, A− grade), such that when DBP ≥90 mm Hg, it conferred a 23% reduced risk of dementia. A linear relationship between DBP and dementia (Pmodel=0.0000, Pheterogeneity=0.6868, Pnonlinearity=0.29; quality score, 8±1; Figure 5C) was demonstrated, where with DBP ascending, the risk of dementia increased. A U-shaped relationship of DBP with AD (Pmodel=0.0064, Pheterogeneity=0.1783, Pnonlinearity=0.0064; quality score, 8±1; Figure 5D) was shown, suggesting that the optimal DBP level was ≈90 to 100 mm Hg for low risk of AD. Sensitivity analysis did not influence the above results.
Additionally, moderate-to-high evidence revealed an increased risk of dementia in the elderly with excessive diastolic BPV (RR: 2.09 [95% CI, 1.27–3.44] I2=57%, G grade), excessive systolic BPV (RR: 1.99 [95% CI, 1.46–2.29] I2=0%, G grade), and OH (RR: 1.26 [95% CI, 1.09–1.45] I2=32%, A+ grade; Figure 4). However, a neutral relationship between PP and dementia and AD was revealed. Sensitivity analysis did not influence the results above, and no publication bias was revealed (Figure S9).

AHMs in Late Life

As shown in Figure 6, moderate-evidence indicated that AHM users (irrespective of the agent type) had 21% lower risk of dementia than nonusers (RR: 0. 79 [95% CI, 0.70–0.89] I2=68%, A− grade). The result remained significant after lowering the heterogeneity to 28% by removing 2 studies whose population had a high smoking and drinking rate. A similar association of AD was further identified with overall use of AHMs (RR: 0.81 [95% CI, 0.72–0.91] I2=52%, A− grade), including diuretics (RR: 0.66 [95% CI, 0.54–0.81] I2=0%, A+ grade), thiazide diuretics (RR: 0.70 [95% CI, 0.54–0.91] I2=0%, A− grade), calcium-channel blockers (RR: 0.74 [95% CI, 0.58–0.93] I2=0%, A− grade), and ACE (angiotensin-converting enzyme) inhibitors (RR: 0.78 [95% CI, 0.69–0.88] I2=35%, A+ grade). Regarding the duration of use of AHMs, a high level of evidence revealed strong protective effect of using AHMs over 5 years on the risk of dementia (RR: 0.56 [95% CI, 0.37–0.86] I2=51%, G grade) and AD (RR: 0.57 [95% CI, 0.35–0.91] I2=43%, G grade). The meta-regression analysis did not show any valid moderators, and there was no evidence of publication bias (Figure S9).
Figure 6. Summary of pooled estimates of the use of antihypertensive medications (AHMs) and risk of cognitive disorders. Moderate-quality evidence indicated that AHMs could reduce the risk of dementia by 21%. Furthermore, Grade A evidence implied that reduced risk of Alzheimer disease (AD) was associated with the use of AHMs, including diuretics, ACE (angiotensin-converting enzyme) inhibitors, and calcium-channel blockers (CCBs). High-quality evidence demonstrated strong protective effects of the use of AHMs for more than 5 y on both dementia and AD. ARBs indicates angiotensin receptor blockers; BBs, beta-blockers; and RR, risk ratio.
Furthermore, moderate level of evidence showed that the use of AHMs was also related to the reduced risk of AD in patients with MCI (RR: 0.85 [95% CI, 0.80–0.90] I2=0%; Figures S5 and S6). Moreover, AHM users had a lower risk of VaD than nonusers (RR: 0.38 [95% CI, 0.15–0.94] I2=53%; Figure S7). No publication bias was revealed (Figure S9).

Rating of Evidence Levels

Specifically, as for the levels of credibility, midlife meta-analyses (SBP/DBP and dementia/AD, OH and dementia) and late-life meta-analyses (hypertension and dementia/AD, BPV and dementia, use of AHMs ≥5 years and dementia/AD) were rated at a moderate-to-high level (G and A+ levels). Analysis of cognitive impairment generally yielded results of low-grade evidence. Poor generalizability, follow-up inadequacy, and attrition were major sources of bias.

Discussion

To our knowledge, this is the largest study to conduct a comprehensive systematic review and meta-analysis of prospective studies to determine the association between hypertension, BP-related variables, and AHMs and the risk of dementia and cognitive impairment. We conducted a detailed assessment of each meta-analysis to determine the credibility of the evidence, and we conducted sensitivity analysis and meta-regression to identify the sources of heterogeneity.

Hypertension/BP-Related Exposure and Cognitive Disorders

Moderate-to-high-quality evidence supported that the relationship between BP and cognitive disorders was age- and BP type-dependent. Overall, stronger associations were found in midlife than in late-life. Specifically, midlife hypertension (both high SBP ≥140 mm Hg and DBP ≥90 mm Hg) was associated with an increased risk of dementia and AD, while late-life BP seemed to play different roles depending upon the BP type, such that high SBP and low DBP were both associated with an elevated risk of dementia. Our results are consistent with those of several previous reviews,8,9 suggesting an age-dependent effect of BP on AD; hypertension in midlife may have an adverse effect on AD; and elevated late-life BP may be related to decreased risk of AD. Nonlinear dose-response curve demonstrated that in midlife, when the SBP level went above 130 mm Hg, the risk of dementia increased, parallel with the recent hypertension guideline (BP level ≥130/80 mm Hg) from the American Heart Association. This finding helps pinpoint the crucial BP range for prevention of cognitive decline in midlife. However, inadequate data restricted the analysis of midlife DBP levels and the risk of cognitive disorders. In late-life, the dose-response relationship of SBP with AD was linearly positive. However, a recent prospective study discovered a U-shaped relationship, and the APOE allele and use of AHMs might partly modify this relationship.19 The underlying dose-response relationship between SBP and cognition requires further work. As for DBP in late life, it is important to note that although our study indicated that when late-life DBP is controlled between 90 and 100 mm Hg, the risk of AD is the lowest, antihypertensive therapy should be individualized considering diverse comorbidities. All of these analyses indicated a dose-response relationship between BP and cognitive disorders and a possible optimal BP control level. However, these results, which are based on aggregated meta-analyses, need to be interpreted with great caution since the populations of the studies may vary widely.
Previous studies showed that high PP, defined as the difference between SBP and DBP, is a predictor of dementia.20 However, no significant relationship was revealed in our analysis, neither in midlife nor late-life. Qiu et al21 found a U-shaped relationship between the level of PP and dementia incidence, which means that both higher and lower tertiles of PP were associated with an increased risk of the disease. This may partly explain the neutral relationship. An increased risk of dementia among the elderly with excessive BPV was shown with moderate-to-high-quality evidence. Additionally, moderate-to-high-quality evidence indicated that OH conferred a 1.45-fold increased risk of dementia in midlife and 1.26-fold increased risk in late life. Late-life excessive BPV might increase the risk of hypoperfusion,22 further increasing the burden on cerebral white matter, leading to small-vessel cerebrovascular disease.23 OH may lead to increased BP variability and cerebral hypoperfusion, subsequently causing or exacerbating ischemic white matter lesions.24 Furthermore, there are many other BP variables that could not be included in our meta-analysis, including high mean arterial pressure, low pulse-pressure amplification, elevated ankle BP, and high inter-arm differences in SBP, all of which were linked to a higher risk of cognitive disorders. Relevant studies concerning other BP variables are presented in the systematic review (Figure S11).

AHMs and Cognitive Disorders

Moderate-quality meta-analysis indicated that AHM users had a lower risk of dementia than nonusers among the elderly. The protective role of AHMs in cognition is evident in previous meta-analyses, including diuretics,25 calcium-channel blockers,26 and ACE inhibitor/angiotensin receptor blockers.27 A network meta-analysis based on 19 randomized trials and 11 observational studies pointed out that angiotensin receptor blockers had greater benefits than placebo on overall cognition.28 However, the huge heterogeneity in subgroup analyses reduced the credibility of the results. One meta-analysis of 9 RCTs indicated a neutral relationship between lowering of BP with medication and lifestyle changes and significant reduction in incident all-cause dementia, AD, or VaD.29 This analysis combined the effect of AHMs and lifestyle intervention. Another meta-analysis based on prospective studies and trials showed no evidence to support the benefit of one AHM class over another.30 Until now, the best type, optimal dose, and duration of AHM use for preventing cognitive disorders remain unclear.
There are several double-blind, placebo-controlled trials investigating the risks and benefits of treatment of hypertension in elders in relation to cognitive function. The HYVET-COG trial (Hypertension in the Very Elderly Trial-Cognitive Function Assessment) got null results; however, when these data were combined in a meta-analysis with 3 other published placebo-controlled trials, the combined RR favored treatment (hazard ratio, 0.87). Recently, 2 other large ongoing trials are testing the effects of BP lowering on cognition in younger adults, including the NICE (Nimodipine Preventing Cognitive Impairment in Ischemic Cerebrovascular Events; URL: https://www.clinicaltrials.gov. Unique identifier: NCT01220622) and the SPRINT-MIND (Systolic Blood Pressure Intervention Trial-Memory and Cognition In Decreased Hypertension). However, SPRINT-MIND trial showed that intensive BP control to a target of <120 mm Hg compared with a target of <140 mm Hg did not significantly reduce the incidence of dementia.31 The study may have been underpowered for this end point, due to early study termination and fewer than expected cases of dementia. Furthermore, a report in Lancet Neurology further showed that the window of intervention spans middle age, peaking in the 40s.32 Overall, the effect of BP lowering on cognition improvement in middle-aged people is expected to be confirmed by more high-quality trials.
Several high-quality meta-analyses have been published recently.25,30 Most of them targeted one BP aspect, especially the use of AHMs and one cognitive outcome, contributing to inconsistent results. Compared with previous meta-analyses, the present study had several significant advantages: (1) only longitudinal studies were included, (2) the BP-related variables were fully covered and separately explored for each domain, (3) preplanned subgroup analysis according to age and cognitive outcomes was conducted, (4) dose-response relationship between SBP/DBP level and cognitive disorders’ risk was explored, (5) meta-regression and sensitivity analysis were conducted to lower the heterogeneity of the pooled results, and (6) evidence robustness was rated by the GASP system.
Several limitations of this study should be acknowledged. First, the reported associations may not reflect the true causal effect due to the presence of selection bias, reverse causation, or misclassification of observational studies. Second, as our meta-analysis only included studies in English language published in the PubMed database, the generalizability of the findings is limited. Third, results should be interpreted with caution, given that the majority of subgroup analyses were based only on a couple of eligible studies. Fourth, the lack of data related to APOE genotypes limited the analysis and subsequent interpretation of the impact of APOE genotype on the effect of BP on cognitive disorders. Fifth, considering cerebrovascular disease might be a putative mediator between hypertension and dementia, inappropriate adjustment might have contributed to the weak associations in late life. Furthermore, given that midlife versus late-life population was stratified according to an age threshold of 65 years old manually, if the duration between BP measurement and diagnosis of dementia is too short to be fully analyzed, the results might be distorted. Last, we did not register the study in International prospective register of systematic reviews.

Perspectives

In summary, this systematic review and meta-analysis summarized the latest evidence concerning the association between BP exposure and risk of cognitive impairment and dementia. Our analysis evaluated the risk influence of midlife hypertension (high SBP/DBP), late-life high SBP, low DBP, excessive BPV, and OH on the incidence of cognitive disorders, suggesting that to prevent cognitive disorders, a multidimensional, omnidirectional, and individualized strategy for BP management is needed. Dose-response curves further provided a protective window of BP level for low risk of cognitive disorders. Moreover, moderate-to-high-quality evidence indicated that the application of AHMs might prevent the incidence of dementia. However, the optimal dose, duration of use, and best types for preventing cognitive disorders are unclear. Overall, high-quality trials with large samples and long follow-up durations are in command to provide more persuasive evidence.

Novelty and Significance

What Is New?

•
This meta-analysis summarized the latest evidence concerning the association between hypertension, blood pressure (BP)-related variables, and antihypertensive medications with the risk of dementia and cognitive impairment based on prospective studies. We conducted a detailed assessment of each meta-analysis to determine the credibility of the evidence and sensitivity and meta-regression analyses to investigate sources of heterogeneity.

What Is Relevant?

•
Controversies persist regarding the association between BP with the risk of cognitive impairment and dementia due to inconsistent definitions of BP exposure and varying population characteristics.

Summary

Our analysis evaluated the risk influence of midlife hypertension (high systolic BP/diastolic BP), late-life high systolic BP, low diastolic BP, excessive BP variability, and orthostatic hypotension on the incidence of cognitive disorders, which provided moderate-to-high-quality evidence, suggesting that to prevent cognitive disorders, a multidimensional, omnidirectional, and individualized strategy for BP management is needed.

Supplemental Material

File (hyp_hype202014993_supp2.pdf)

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Jul. 24, 2020

Ya-nan Ou

Response to comment on “Blood Pressure and Risks of Cognitive Impairment and Dementia: A Systematic Review and Meta-Analysis of 209 Prospective Studies”

We appreciate their interesting and constructive comments, and we make a response here.

The autonomic regulation of blood pressure in older adults might be impaired, and therefore elders may have all of the BP-related diseases/conditions that the authors mentioned. However, the systematic review and meta-analysis itself is a secondary analysis of studies conducted by others, thus having limited power to detect the interactive mechanisms among those variables. Nevertheless, we agree with the author that several BP variables could synergistically increase the risk of dementia.

Our study found a U-shaped non-linear relationship between DBP and AD in the elderly. Howbeit, just as we mentioned in the paper, this result, which is based on aggregated meta-analyses, needs to be interpreted with great caution since the populations of the studies may vary widely. Actually, Rajan et al. reported a U-shaped association between BP and AD.[1] In detail, lower BP was associated with modestly elevated risk of incident AD and high BPs with higher risk. We agree with the author that future studies should pay attention to the non-linear relationships when analyzing the relationship between BP level and subsequent cognitive impairment/dementia.

As for the third question, actually, we conducted this analysis with various cognitive outcomes, including cognitive impairment (global cognition, executive function and episodic memory), all-cause dementia, AD and vascular dementia (VaD). However, considering the association between blood pressure and VaD has been studied thoroughly, we didn’t regard the analysis of this association as the main analysis, and put it in the data supplement.

Again, we appreciate the authors’ comments. We hope that future studies with different designs will be the answer to their concerns.

[1] Rajan KB, Barnes LL, Wilson RS, Weuve J, McAninch EA, Evans DA. Blood pressure and risk of incident Alzheimer's disease dementia by antihypertensive medications and APOE ε4 allele. Ann Neurol. 2018;83(5):935-944. doi:10.1002/ana.25228. 

Competing Interests
None.
Jul. 22, 2020

Tomoyuki Kawada

Blood pressure, cognitive impairment and dementia

Ou et al. conducted a meta-analysis regarding the association between blood pressure (BP) and the risks of cognitive impairment and dementia in prospective studies (1). The relationships between BP variables and cognitive disorders differed in different generations and BP indicators. In addition, the use of antihypertensive medications exhibited a 21% reduction in dementia risk. I have some concerns about their study.

First, Sabayan et al. and Qin et al. independently reported that visit-to-visit variability in blood pressure was a significant predictor of subsequent cognitive decline in old subjects (2,3), but Wijsman et al. reported that the association between BP variability and cognitive impairment was not mediated by BP lowering medication (4). Although there is an advantage of anti-hypertensive medications for reducing risk of dementia, BP variables such as high systolic BP, low diastolic BP, excessive BP variability, and orthostatic hypotension would interact with each other for increased dementia risk in later life (1).

Second, Ogliari et al. reported that higher visit-to-visit systolic BP variability but not diastolic DBP variability was significantly associated with steeper functional decline in older adults (5). On this point, Ou et al. described a U-shaped relationship of diastolic BP level with 90-100 mm Hg for lower risk of Alzheimer disease (1). I suspect that a non-linear relationship should be considered between blood pressure and subsequent cognitive impairment/dementia.

Finally, Ou et al. described that BP variables would contribute differently to subsequent cognitive disorders in different generations. As there are different causes of cognitive impairment/dementia, stratified analysis by the type of dementia should be considered in the analysis.

References

1. Ou YN, Tan CC, Shen XN, Xu W, Hou X, Dong Q, Tan L, Yu J. Blood pressure and risks of cognitive impairment and dementia: A systematic review and meta-analysis of 209 prospective studies. Hypertension. 2020;76:217-225. doi: 10.1161/HYPERTENSIONAHA.120.14993

2. Sabayan B, Wijsman LW, Foster-Dingley JC, Stott DJ, Ford I, Buckley BM, Sattar N, Jukema JW, van Osch MJP, van der Grond J, van Buchem MA, Westendorp RGJ, de Craen AJM, Mooijaart SP. Association of visit-to-visit variability in blood pressure with cognitive function in old age: prospective cohort study. BMJ 2013;347:f4600. doi: 10.1136/bmj.f4600

3. Qin B, Viera AJ, Muntner P. Visit-to-visit variability in blood pressure is related to late-life cognitive decline. Hypertension. 2016;68:106-113. doi: 10.1161/HYPERTENSIONAHA.116.07494

4. Wijsman LW, de Craen AJ, Muller M. Blood pressure lowering medication, visit-to-visit blood pressure variability, and cognitive function in old age. Am J Hypertens. 2016;29:311-318. doi: 10.1093/ajh/hpv101

5. Ogliari G, Smit RA, Westendorp RG, Jukema JW, de Craen AJM, Sabayan B. Visit-to-visit blood pressure variability and future functional decline in old age. J Hypertens. 2016;34:1544-1550. doi: 10.1097/HJH.0000000000000979

Competing Interests
There is no conflict of interest to disclose.

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Hypertension
Volume 76 • Number 1 • July 2020
Pages: 217 - 225
PubMed: 32450739

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Received: 1 March 2020
Revision received: 20 March 2020
Accepted: 26 April 2020
Published online: 26 May 2020
Published in print: July 2020

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Keywords

  1. Alzheimer disease
  2. blood pressure
  3. dementia
  4. hypertension
  5. meta-analysis

Subjects

  1. Aging
  2. Epidemiology
  3. Risk Factors

Authors

Affiliations

Ya-Nan Ou*
From the Department of Neurology, Qingdao Municipal Hospital, Qingdao University, China (Y.-N.O., C.-C.T., W.X., X.-H.H., L.T.)
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Chen-Chen Tan*
From the Department of Neurology, Qingdao Municipal Hospital, Qingdao University, China (Y.-N.O., C.-C.T., W.X., X.-H.H., L.T.)
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Xue-Ning Shen
Department of Neurology and Institute of Neurology, WHO Collaborating Center for Research and Training in Neurosciences, Huashan Hospital, Shanghai Medical College, Fudan University, China (X.-N.S., Q.D., J.-T.Y.).
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Wei Xu
From the Department of Neurology, Qingdao Municipal Hospital, Qingdao University, China (Y.-N.O., C.-C.T., W.X., X.-H.H., L.T.)
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Xiao-He Hou
From the Department of Neurology, Qingdao Municipal Hospital, Qingdao University, China (Y.-N.O., C.-C.T., W.X., X.-H.H., L.T.)
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Qiang Dong
Department of Neurology and Institute of Neurology, WHO Collaborating Center for Research and Training in Neurosciences, Huashan Hospital, Shanghai Medical College, Fudan University, China (X.-N.S., Q.D., J.-T.Y.).
View all articles by this author
Lan Tan
From the Department of Neurology, Qingdao Municipal Hospital, Qingdao University, China (Y.-N.O., C.-C.T., W.X., X.-H.H., L.T.)
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Jin-Tai Yu https://orcid.org/0000-0002-7686-0547 [email protected]
Department of Neurology and Institute of Neurology, WHO Collaborating Center for Research and Training in Neurosciences, Huashan Hospital, Shanghai Medical College, Fudan University, China (X.-N.S., Q.D., J.-T.Y.).
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Notes

*
These authors contributed equally to this work.
The Data Supplement is available with this article at Supplemental Material.
Correspondence to Jin-Tai Yu, Department of Neurology and Institute of Neurology, Huashan Hospital, Shanghai Medical College, Fudan University, 12th Wulumuqi Zhong Rd, Shanghai 200040, China. Email [email protected]

Disclosures

None.

Sources of Funding

This study was supported by grants from the National Key R&D Program of China (2018YFC1314702), Shanghai Municipal Science and Technology Major Project (No.2018SHZDZX03) and ZHANGJIANG LAB, Tianqiao and Chrissy Chen Institute, and the State Key Laboratory of Neurobiology and Frontiers Center for Brain Science of Ministry of Education, Fudan University.

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