Abstract
Introduction:
Management of midlife blood pressure and hypertension status may provide a window of intervention to mitigate cognitive decline with advancing age. The aim of this review was to investigate the relationship between midlife hypertension and cognition in midlife and later life.
Methods:
Online electronic databases were searched from their inception to May 2022. Studies assessing midlife (40–65 years) hypertension and cognition at mid and/or later-life were included. A random effects meta-analysis was deemed appropriate.
Results:
One hundred forty-nine studies across 26 countries were included. Qualitative synthesis found negative relationships between midlife hypertension and later life cognition in the domains of memory, executive function, and global cognition. Metanalytical evidence revealed midlife hypertension negatively impacts memory, executive function, and global cognition but had no observed effect on attention at midlife.
Discussion:
Hypertension at midlife has a significant negative impact on cognition in mid-life and later life, namely memory, executive function, and global cognition.
Keywords: cognition, high blood pressure, hypertension, middle-aged, midlife
BACKGROUND
The worldwide prevalence of age-related cognitive decline is a major public health concern, especially in the context of an ageing population. Globally, the number of people living with dementia and cognitive impairment is expected to rise from 24.3 million in 2001 to 81.1 million in 2040, almost doubling every 20-years [1,2]. Current evidence from the Lancet Commission on dementia prevention, intervention, and care suggests that up to 40% of all dementia cases can be linked to modifiable risk factors [3]. Identification of such risk factors and strategies to modify their negative influence on cognitive function therefore has the potential to protect and improve quality of life for a significant proportion of the global population, now and in the future.
Hypertension, which affects at least 1 billion people globally [4], has emerged as an important risk factor for cognitive deterioration and vascular dementia [5], and age of onset may impact on overall risk to brain health and function later in life [6]. Specifically, there is evidence that hypertension during midlife could accelerate brain ageing [5,7], potentially inducing premature cognitive decline via vascular and structural change [8]. Interestingly, blood pressure (BP) exceeding optimal values even in the absence of a diagnosis of hypertension during young adulthood and midlife has been found to increase the risk of cognitive impairment in later life [9]. Therefore, midlife may be the optimal time point for appropriate treatment and management of BP to mitigate the associated trajectory of cognitive decline with age. Cognitive function can be measured clinically and experimentally across several domains including but not limited to memory, attention, executive function, and global cognition. Different studies have assessed the effects of hypertension on one or more of these functions, yet there is no consensus on the impact of midlife hypertension on any of these domains at midlife or later life; the systematic analysis and meta-analysis presented here aims to address this issue.
As the world's population over the age of 60 years is expected to double by 2050 [10], there is a growing need to investigate the association between midlife hypertension and cognitive decline, including any parallels in the time course of progression of each domain, to help inform public health policy. Although midlife hypertension has the potential to increase risk of later life cognitive decline, it is unclear at what point in the lifespan this decline begins and whether it is apparent during midlife. The purpose of this systematic review was to perform an analysis of the published evidence to explore the relationship between midlife hypertension status and cognitive function at both later life and at midlife, and to assess whether any negative impact was evident across different cognitive domains.
MATERIALS AND METHODS
This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA; www.prisma-statement.org) and was recorded in PROSPERO, a registry of systematic reviews. Registration of this review can be found at https://www.crd.york.ac.uk/prospero/ (registration number: CRD42021238293). The present review is a subset analysis of the registered review.
Search strategy
Online electronic databases were searched, and relevant articles retrieved from the following: EMBASE, MEDLINE, PubMed, Web of Science, and CINAHL, from their inception to May 2022. All search strategies were conducted by a medical librarian with methodological experience and the full search strategy can be found in the supplementary file. The search strategy comprises key words, MeSH terms, common medical terms, and a combination of these including, but not limited to, middle age, midlife, cardiovascular disease, cardiovascular risk, hypertension, high BP, cognition, and cognitive defect. The search strategy focused on the inclusion of longitudinal, prospective, and follow-up studies to ensure later life cognition was captured. No search restrictions for language or publication date were implemented. The search of electronic databases was supplemented by a manual literature search of the reference lists of included studies and appropriate databases to ensure all relevant studies were captured.
The stepwise process of the search methodology can be seen in Fig. 1. All stages of the screening process were conducted independently by two reviewers (O.C.J. and C.McH.), including title and abstract screening and subsequent full text screening. Disagreements between the two reviewers were resolved through discussion. If a consensus was not achieved, a third reviewer (F.W or A.K) was consulted. Titles, abstracts, and full texts of all eligible articles were screened using Covidence (https://www.covidence.org/home).
FIGURE 1.
Flow chart of the study selection process.
Eligibility criteria
Studies were deemed eligible based on the following inclusion criteria: human participants, adults between ages of 40–65 years were classified as middle-aged (WHO definition of middle age), hypertension, and/or BP reported as an outcome measure at later life, midlife, or both for determination of the longitudinal association with midlife hypertension and cognition across domains including memory, attention, executive function, intelligence, and global cognitive functioning (see Supplementary file). Hypertension was considered an outcome of elevated BP where diagnosis by clinician, self-report, and/or by recorded BP metric in line with accepted definitions were considered eligible for inclusion and data analysis. Studies not published in the English language where a translation could not be obtained were excluded. Studies were excluded if cognitive testing was undertaken by a proxy or designated respondent, such as a friend or family member, if the participant cohorts included those with midlife dementia or any form of preexisting cognitive impairment and if studies of specific disabilities [traumatic brain injury (TBI), stroke, HIV, spinal cord injury, and so on] were associated with modifiable behavioural risk factors.
Data extraction
Data extraction was carried out in accordance with the STROBE guidelines [11], including study aims, participant characteristics, measures of cognition and cardiovascular risk factors alongside relevant outcome data as group means, standard deviation (SD), standard error (SE) of the mean, statistical significance, and precision estimates. Adults between the ages of 40 and 65 years were considered middle aged in line with the WHO definition and those beyond the age of 65 years were classified as later life participants. To prevent double reporting of data from prospective longitudinal cohorts, the most recent publication relating to each was selected as the reference study for the determination of baseline data (see Supplemental file). If uncertainties arose, the corresponding authors were contacted for further clarification. Each study was assigned a reference number and separate data collection form. To ensure accurate reporting, the data extraction pro-forma was piloted against a selection of articles. All BP values reported are classified according to the European Society of Cardiology (ESC) classification in order to determine hypertension status [12].
Risk of bias and methodological assessment
The methodological quality of included studies was evaluated using the Appraisal Tool for Cross sectional Studies (AXIS) [13]. This tool employs 20 questions to determine quality of study design and risk of bias with questions being answered as ‘Yes’, ‘No’, or ‘Unsure’. Using the method outlined by McHugh et al. [14], answers were inserted in colour coding to reflect the impact on the text, including green, positive impact on quality of study; red, negative impact on quality of study; and amber, unknown impact on quality of study. Two reviewers (O.C.J. and C.McH.) independently evaluated the included studies. Disagreements between reviewers were resolved through discussion. If a consensus was not achieved, a third reviewer (F.W or A.K) was consulted. Study quality was then classified as either low, moderate, or high.
Statistical analysis
The weighted mean for demographics, cognitive measures (cognitive-specific domains and associated neuropsychological tests), SBP, and DBP values were calculated across studies to better understand the relationship with hypertension diagnosis. Weighted means were calculated using the following formula: ∑ni=1 (xi∗wi)/∑ ni=1 wi; where ∑ denotes the sum, w denotes the weights, and x is the corresponding value [15].
Cognitive outcome measures were grouped according to cognitive domain. Qualitative analysis assessed the relationship between midlife hypertension status and cognition at later life and midlife; positive, negative, or neutral, across studies.
A random effects meta-analysis was conducted to compare the difference across each cognitive domain between two independent groups, hypertension vs. normotension. This meta-analysis was deemed appropriate to calculate the pooled summary effect of midlife hypertension on cognition at midlife across the domains of memory, attention, executive function, and global cognition. Group mean differences, 95% confidence intervals (95% CIs), and P values were calculated using Review Manager (RevMan) software ([Computer pro-gramme], Version 5.4, Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2020). Sub-grouping for meta-analyses included study design and quality. The heterogeneity between studies was established using the I2 statistic. I2 values of 25, 50, and 75% (P > 0.05) correspond to low, moderate, and high degrees of heterogeneity, respectively [16]. Where high levels of heterogeneity (I2 > 75%) were detected and a sufficient availability of studies was present, sensitivity analyses were applied, and studies were removed one by one to assess their overall influence. Studies that were removed due to the sensitivity analysis are represented by a 0.0% weight in the forest plots.
All remaining studies that were not included in our meta-analysis due to lack of available comparative data between those with and without hypertension were subject to qualitative analysis. This was undertaken based on the findings reported by the respective authors in the studies included in our review. Our intention was to provide a comprehensive synthesis of the available evidence in these areas, even when the number of eligible studies was limited for specific cognitive domains.
RESULTS
Literature search
Figure 1 displays details of the study selection. The initial search and manual search yielded 6824 records. Following the removal of duplicates and title and abstract screening, 606 full texts were screened, and 442 studies were excluded (see Fig. 1). The authors of four studies were contacted for access to full texts and were later recorded as ‘studies awaiting classification’ due to lack of response. All studies were imported in Endnote version 20 and an appropriate database was created from all extracted data in Microsoft Excel. Overall, 149 studies published between 1992 and 2022 were included.
Methodological and risk of bias assessment
Of the 149 included studies, 35 were deemed low quality, 59 moderate quality, and 55 high quality. Overall, studies were deemed of moderate-to-high quality with negative commonalities arising across several domains (see Supplementary file). The most common domains that were absent or unclear from studies included sample size justification (n = 127), categorization of nonresponders (n = 130), information about nonresponders (n = 137), clear determination of statistical significance (n = 56), discussion of limitations (n = 22), and disclosure of ethical approval or consent (n = 21).
Characteristics of included studies
Of all included studies, 131 assessed men and women, 11 assessed men only and seven assessed women only. Eighty-three studies assessed subsets of data from 12 prospective longitudinal cohorts (see Supplementary file). The remaining 66 studies assessed data from individual study cohorts. Studies were conducted across 26 countries with the top five including USA (n = 67), UK (n = 23), China (n = 7), Australia (n = 4), and Brazil (n = 4).
Participant characteristics
Studies included in this review incorporated a total of 129 274 participants, who were pooled for analysis. The weighted mean age of participants was 54.5 ± 3.9 years, weighted mean BMI was 27.19 ± 4.6 kg/m2, and weighted mean height and weight were 171.4 ± 7.1 cm and 78.7 ± 14.6 kg, respectively.
In studies that provided data according to sex (n = 56), 39 325 men and 40 678 women were included. Weighted mean BMI for men and women was 25.7 ± 3.4 and 24.5 ± 4.3 kg/m2, respectively. Weighted mean age for men was 58.9 ± 1.8 and 56.7 ± 1.9 years for women. Mean height and weight were not available.
Blood pressure and hypertension
The pooled weighted mean SBP and DBP for all participants were 130.5 ± 12.1 and 80.8 ± 7.6 mmHg, respectively. Men had a higher SBP (128.2 ± 6.2 vs. 121.8 ± 8.2 mmHg) and DBP (82.7 ± 0 vs. 77.4 ± 1.5 mmHg) compared with women.
Hypertension was most commonly defined using the ESC definition (n = 30). Alternative definitions included American Heart Association (AHA) (n = 8), use of antihypertensive medication (n = 12), and self-reported hypertension (n = 10). Seven studies did not provide a working definition (see Tables 2 and 3). A total of 46 706 participants were classified as hypertensive, with 1553 classified as prehypertensive; 3968 were taking antihypertensive medication. More women were identified as hypertensive (8423 individuals compared with 7516 men) and prehypertensive (108 individuals compared with none in the male group). A higher number of men than women reported taking antihypertensive medication (951 vs. 800). A total of 18 931 participants were normotensive, with a higher proportion of women than men reporting normal BP (2849 vs. 2682).
TABLE 2.
Summary Table of pooled weighted average for all cognitive measures and associated BP metrics at baseline (i.e., midlife).
| Cognitive variable | No. of studies | Weighted average (Mean ± SD) | Age (Mean ± SD; years) | S BP (Mean ± SD; mmHg) | SBP category status (ESC) | DBP (Mean ± SD; mmHg) | DBP category status (ESC) |
| Memory Verbal Memory | Total: n = 21 Immediate: n = 3, Delayed: n = 11, STW: n = 1, EBM: n = 2, RAVLT (Immediate & Delayed recall, Learning & Summary Score): n = 2, SRT: n = 1, ROCF (Immediate & Delayed): n = 1, CERAD (Immediate & Delayed): n = 1, CVLT (Immediate & Delayed): n = 1 WLL: n = 1 |
Immediate: Total = 9.9, men = 5.7 ± 1.1, women = 4.6 ± 1.5 Delayed: Total = 6.2 ± 1.5 men = 9.9 ± 2.9, women = 12.7 ± 3.7 STW: Total = 50.5 EBM: Total = 10, Female = 10.2 RAVLT (Immediate & Delayed recall): Total = 7.1 ± 2.7 RAVLT (Learning Score): Total = 36.8 ± 8.3 RAVLT (Summary Score): Total = 8.8 ± 3.2 SRT: Total = 34.3 ROCF (Immediate): Total = 16.1 ± 7.6 ROCF (Delayed): Total = 14.9 ± 7.8 CERAD (Immediate): Total = 7.2 ± 1.1 CERAD (Delayed): Total = 7.7 ± 1.5 CVLT (Immediate): Total = 8.8 ± 2.1 CVLT (Delayed): Total = 8.8 ± 3.2 WLL: Total = 20.5 ± 0.5 |
Total = 52.7 ± 4.8 men = 53.2 ± 4.9, women = 52.4 ± 4.5 | Total = 124.2 ± 16.8, men = 123.7 ± 15.6, females = 120.9 ± 16.8 Delayed: Total = 121.6 ± 17.1, males = 123.7 ± 15.6, females: 120.9 ± 16.8 Immediate: - STW: - EBM: - RAVLT (Immediate & Delayed recall, Learning Score): Total = 131.2 ± 16.1 SRT: Total = 134.1 ± 16.9 ROCF (Immediate & Delayed): Total = 131.2 ± 16.1 CERAD (Immediate & Delayed): Total = 127.9 ± 20.7 CVLT (Immediate & Delayed): Total = 127.9 ± 20.7 WLL: Total = 123.7 ± 17.6 |
Total = Normal, men = Normal, women = Normal Delayed: Total = Normal, men = Normal, women = Normal Immediate: - STW: - EBM: - RAVLT (Immediate & Delayed recall, Learning Score): Total = High Normal SRT: Total = High Normal ROCF (Immediate & Delayed): Total = High Normal CERAD (Immediate & Delayed): Total = Normal CVLT (Immediate & Delayed): Total = Normal WLL: Normal |
Total = 82.7 ± 10.3 Delayed: Total = 74.8 ± 10.5 Immediate: - STW: - EBM: - RAVLT (Immediate & Delayed recall, Learning Score): Total = 83.4 ± 10.7 SRT: Total = 88.8 ± 10.2 ROCF (Immediate & Delayed): Total: 83.4 ± 10.7 CERAD (Immediate & Delayed): Total = 88.8 ± 10.6 CVLT (Immediate & Delayed): Total = 88.8 ± 10.6 WLL: 77.2 ± 8.1 |
Total = Normal Delayed: Total = Optimal Immediate: - STW: - EBM: - RAVLT (Immediate & Delayed recall, Learning Score): Total = Normal SRT: Total = High Normal ROCF (Immediate & Delayed): Total = Normal CERAD (Immediate & Delayed): Total = High Normal CVLT (Immediate & Delayed): Total = High Normal WLL: Optimal |
| Episodic Memory | Total: n = 4 | Total = 5.9 ± 2.3 | Total = 51.7 ± 6.1, men = 50.3 ± 8, women = 51 ± 8.1 | – | – | – | Total = High Normal |
| Semantic Memory | Total: n = 1 |
Total = 15.6 ± 2.9 men = 15.2 ± 3.0, women = 16 ± 2.8 |
Total = 50.7 ± 8, men = 50.3 ± 8, women = 51 ± 8.1 | – | – | – | – |
| Working Memory |
Total: n = 22 DSST: n = 8 Composite Score: n = 1 CMS Score: Total: n = 1 DSB Test: n = 7 McNS: n = 1 WDS: n = 1 MIS (MoCA): n = 1 VRT: n = 1 |
DSST: Total = 47.8 ± 7.9 Composite Score: men = 6.9 ± 2.3, women = 6.9 ± 2.72 CMS Score: Total = 76.6 ± 12.9 DSB Test: Total = 6.2 ± 1.9, men = 5, women = 5.3 McNS: Total = 27.7 ± 1.9 WDS: men = 38.6 ± 3.9, women = 38.9 ± 4.7 MIS (MoCA): Total = 12.72 ± 2.4 VRT: Total = 11.3 |
Total = 52.3 ± 4.2, males = 54.2 ± 4.9, females = 56 ± 4.9 | Total = 123.4 ± 15.9, men = 123.5, women = 121.7 DSST: Total = 119.3 ± 15.6 Composite Score: men = 123.5, women = 121.7 CMS Score: - DSB Test: Total = 132.7 ± 14.8 McNS: - WDS: - MIS (MoCA): - VRT: Total = 134.1 ± 16.9 |
Total = Normal, males = Normal, females = Normal DSST: Total = Optimal Composite Score: men = Normal, women = Normal CMS Score: - DSB Test: Total = High Normal McNS: - WDS: - MIS (MoCA): Not available VRT: Total = High Normal |
Total = 77.2 ± 9.9, men = 78.3, women = 75.1 DSST: Total = 73.2 ± 9.8 Composite Score: male = 78.3, female = 75.1 CMS Score: - DSB Test: Total = 80.5 ± 9.1 McNS: - WDS: - MIS (MoCA): - VRT: Total = 88.8 ± 10.5 |
Total = Optimal, men = Optimal, women = Optimal DSST: Total = Optimal Composite Score: men = Optimal, women = Optimal CMS Score: - DSB Test: Total = High Normal McNS: - WDS: - MIS (MoCA): - VRT: Total = High Normal |
| Attention |
Total: n = 11 TMT-A: n = 10 CRT: n = 4 SiRT: n = 3 DSF Test: n = 5 5-CMT: n = 1 |
TMT-A: Total = 24.8 ± 8.4 CRT: Total = 733.4 ± 153.8 SiRT: Total = 296.5 ± 64.6 DSF Test: Total = 7.5 ± 1.9 5-CMT: Total = 370.5 |
Total = 51.9 ± 4.3, men = 56.1 ± 3.7, women = 56.5 ± 3.6 | Total = 130.5 ± 16.13 TMT-A: Total = 129.4 ± 15.9 CRT: Total = 134.1 ± 15.8 SiRT: Total = 134.8 ± 15.7 DSF Test: Total = 132.8 ± 17.1 5-CMT: Total = 129.4 ± 5.03 |
Total = High Normal TMT-A: Total: = Normal CRT: Total = High Normal SiRT: Total = High Normal DSF Test: Total = High Normal 5-CMT: Total = High Normal |
Total = 81.04 ± 9.4 TMT-A: Total = 82.4 ± 9.3 CRT: Total = 79.03 ± 8.8 SiRT: Total = 78.2 ± 8.4 DSF Test: Total = 80.4 ± 10.8 5-CMT: Total = 83.4 ± 3.2 |
Total = Normal TMT-A: Total = Normal CRT: Total = Optimal SiRT: Total = Optimal DSF Test: Total = High Normal 5-CMT: Total = Normal |
| Intelligence |
Total: n = 6 WAIS: n = 1 IQ: n = 2 MR: n = 1 |
WAIS: Total = 17 ± 3 IQ: Total = 104.08 ± 18.5 MR: Total = 18.13 |
Total = 54.7 ± 4.7 | Total = 125.7 ± 17.5 WAIS: Total = 124 ± 18 IQ: Total = 149.9 ± 13.4 MR: Total = 126.7 ± 13.7 |
Total = Normal WAIS: Total = Normal IQ: Total = Grade 1 Hypertension MR: Total = Normal |
Total = 84.4 ± 7.3 WAIS: - IQ: Total = 90.3 ± 6.9 MR: Total = 77.3 ± 6.9 |
Total = High Normal WAIS: - IQ: Total = Grade 1 Hypertension MR: Total = Optimal |
| Executive Function Letter Cancellation |
Total: n = 2 LSST: n = 1 LCCS: n = 1 |
LSST: Total = 282 LCCS: Total = 50 ± 7.3 |
Total = 52.66 ± 2.59 |
Total = 129.7 ± 17.1 LSST: Total = 134.8 ± 17.9 LCCS: Total: 118.58 ± 15.25 |
Total = High Normal LSST: Total = High Normal LCCS: Total = Optimal |
Total = 77.2 ± 9.7 LSST: Total = 77.2 ± 9.7 LCCS: - |
Total = Optimal LSST: Total = Optimal LCCS: - |
| Verbal Fluency |
Total: n = 15 WFT: n = 10 BNT: n = 2 MVT: n = 2 PFT: n = 2 SFT: n = 2 VIS (MoCA): n = 1 BeDT: n = 1 BuDT: n = 1 |
WFT: Total = 31.3 ± 8.2, men = 25.7 ± 6.4, women = 24.8 ± 6.2 BNT: Total = 27.1 ± 1.9 MVT: Men = 25.8 ± 3.7, women = 23.3 ± 5.4 PFT: men = 17.1 ± 4.3, women = 16.8 ± 4.8 SFT: men = 16.7 ± 3.9, women = 16.02 ± 4.6 VIS (MoCA): Total = 6.48 ± 0.92 BeDT: men = 12, women: 12 BuDT: men = 7, women: 6 |
Total = 52.9 ± 5.3, men = 51.2 ± 4.9, women = 52.9 ± 4.9 | Total = 123.7 ± 16.5, men = 128.7 ± 16.2, women = 122.6 ± 17 WFT: Total = 123.7 ± 16.4, men = 128.7 ± 16.2, women = 122.6 ± 17 BNT: Total = 123.7 ± 17.6 MVT: - PFT: - SFT: - VIS (MoCA): - BeDT: Total = 126.7 ± 12.9 BuDT: Total = 126.7 ± 12.9 |
Total: Normal, men: Normal, women: Normal WFT: Total = Normal, men = Normal, women = Normal BNT: Total = Normal MVT: - PFT: - SFT: - VIS (MoCA): - BeDT: Total = Normal BuDT: Total = Normal |
Total = 77.8 ± 12.1 WFT: Total = 77.8 ± 12.1 BNT: 77.2 ± 8.1 MVT: - PFT: - SFT: - VIS (MoCA): - BeDT: Total = 77.2 ± 7.8 BuDT: Total = 77.2 ± 7.8 |
Total = Optimal WFT: Total = Optimal BNT: Optimal MVT: - PFT: - SFT: - VIS (MoCA): - BeDT: Total = Optimal BuDT: Total = Optimal |
| Processing speed |
Total: n = 19 TMT-B: n = 9 TrB-A: n = 1 STIT: n = 2 WMT: n = 1 CES: n = 3 RVP (CANTAB & Isolated): n = 1 SCWT: n = 1 EIS (MoCA): n = 1 VSS: n = 1 LT: n = 1 |
TMT-B: Total = 93.9 ± 2.7 TrB-A: Total = 1.14 STIT: Total = 42.9 ± 1.5 WMT: Total = 2.25 ± 1.09 CES: Total = 57.1 ± 0.1 RVP (CANTAB): Total = 0.92, 333.61 ± 88.01 SCWT: Total = 19.1 EIS (MoCA): Total = 11.64 ± 1.42 VSS: male = 302.02 ± 74.5, female = 323.5 ± 74.5 LT: men = 39.77 ± 17.8, women = 45.51 ± 26.6 |
Total = 52.5 ± 5.1, men = 56.9 ± 3.8, women = 54.1 ± 3.5 | Total = 130.4 ± 14.6, men = 128.7 ± 16.2, women = 122.7 ± 16.9 TMT-B: Total = 131.6 ± 16.9, Female = 123.3 ± 16.3 TrB-A: Total = 138.3 ± 8.4 STIT: Total = 131.2 ± 16.1, male = 128.7 ± 16.2,female = 122.6 ± 17 WMT: Total = 133.3 ± 16.9 CES: Total = 121 RVP (CANTAB): - SCWT: male = 128.7 ± 16.2, female: 122.6 ± 17 EIS (MoCA): - VSS: Total = 138.3 ± 8.4 LT: - |
Total = High Normal, men = Normal, women = Normal TMT-B: Total = High Normal, female = Normal TrB-A: Total = High Normal STIT: Total = High Normal, male = Normal, female = Normal WMT: Total = High Normal CES: Total = Normal RVP (CANTAB): - SCWT: men = Normal, female = Normal EIS (MoCA): - VSS: Total = High Normal LT: - |
Total = 85.7 ± 8.7, women = 77.4 ± 9.34 TMT-B: Total = 87.5 ± 10.4, Female = 77.4 ± 9.34 TrB-A: Total = 86.1 ± 6.5 STIT: Total = 83.3 ± 10.7 WMT: Total = 84.1 ± 12.3 CES: Total = 76.5 RVP (CANTAB): - SCWT: - EIS (MoCA): - VSS: Total = 86.1 ± 6.5 LT: - |
Total = High Normal, women = Optimal TMT-B: Total = High Normal, female = Optimal TrB-A: Total = High Normal STIT: Total = Normal WMT: Total = Normal CES: Total = Optimal RVP (CANTAB): - SCWT: - EIS (MoCA): - VSS: Total = High Normal LT: - |
| Global Cognition |
Total: n = 23 MMSE: n = 13 MoCA: n = 7 IQCODE: n = 1 CAMCOG: n = 1 NART: n = 1 MINT: n = 1 IST: n = 1 BPP: n = 1 ACE: n = 1 HRS-CS: n = 1 CERAD: n = 1 |
MMSE: Total = 27.8 ± 0.6 MoCA: Total = 24.9 ± 3.1 IQCODE: Total = 43.38 ± 3.01 CAMCOG: Total = 90 NART: Total = 28, male = 35.13 ± 9.5, female = 35.5 ± 9.1 MINT: Total = 30.25 IST: Total = 32.4 BPP: Total = 46.9 ACE: Total = 94.9 HRS-CS: Total = 14.31 ± 4.06, male = 14.2 ± 4.15, female = 14.44 ± 3.96 CERAD: Total = 81.6 ± 0.9 |
Total = 54.5 ± 5.3, men = 58.6 ± 2.8, women = 58.2 ± 2.8 | Total = 131.5 ± 16.6 MMSE: Total = 133.2 ± 16.7 MoCA: Total = 118.3 ± 15.03 IQCODE: Total = 124.05 ± 15.6 CAMCOG: Total = 140.8 ± 19.3 NART: Total = 140.8 ± 19.3 MINT: Total = 126.7 ± 12.9 IST: - BPP: - ACE: - HRS-CS: - CERAD: Total = 119.9 ± 11.8 |
Total = High Normal MMSE: Total = High Normal MoCA: Total = Optimal IQCODE: Total = Normal CAMCOG: Total = Grade 1 Hypertension NART: Total = Grade 1 Hypertension MINT: Total = Normal IST: - BPP: - ACE: - HRS-CS: - CERAD: Total = Optimal |
Total = 81.14 ± 10.08 MMSE: Total = 82.6 ± 10.02 MoCA: Total = 72.4 ± 10.4 IQCODE: Total = 73.9 ± 9.06 CAMCOG: Total = 88.7 ± 12.6 NART: Total = 88.7 ± 12.6 MINT: Total = 77.2 ± 7.8 IST: - BPP: - ACE: - HRS-CS: - CERAD: Total = 77.2 ± 8.1 |
Total = Normal MMSE: Total = High Normal MoCA: Total = Optimal IQCODE: Total = Optimal CAMCOG: Total = High Normal NART: Total = High Normal MINT: Total = Optimal IST: - BPP: - ACE: - HRS-CS: - CERAD: Total = Optimal |
| Inductive Reasoning | Total: n = 4 | AH-4: Total = 52.02 ± 8.5. male = 49.2 ± 9.5, female = 42.9 ± 11.6 | Total = 52.56 ± 2.95, males = 49.5 ± 5.9, females = 49.86 ± 5.9 | Total = 126.6 ± 15.2, male = 122.4 ± 15.5, female = 119.6 ± 16.7 | Total = Normal, male = Normal, female = Optimal | Total = 82.4 ± 10.3 | Total = Normal |
| Psychomotor Speed | Total: n = 5 | SDMT: Total = 56.1 ± 11.2, male = 48.2 ± 13.7, female = 50.5 | Total = 52.3 ± 5.2, women = 50.01 ± 2.6 | Total = 133.8 [SE: 0.3], Female = 123.3 ± 16.3 | Total = High Normal, female = Normal | Total = 82.9 [SE: 0.2], female = 77.4 ± 9.34 | Total = Normal, female = Optimal |
| Visuospatial Organisation | Total: n = 5 BDT: n = 2 VIS MoCA: n = 1 CDT: n = 1 |
BDT: Total = 16.9 ± 0.1 VIS MoCA: Total = 6.48 ± 0.92 CDT: male = 28 ± 5, female = 55 ± 10 |
Total = 52.2 ± 5.7 | Total = 128.5 ± 16.2 BDT: Total = 131.1 ± 15.2 VIS MoCA: - CDT: - |
Total = Normal BDT: Total = High Normal VIS MoCA: - CDT: - |
Total = 82.9 ± 9.4 BDT: Total = 82.9 ± 9.4 VIS MoCA: - CDT: - |
Total = Normal BDT: Total = Normal VIS MoCA: - CDT: - |
5-CMT, Choice Movement Test; ACE, Addenbrooke's cognitive examination; AH-4, Alice Heim 4-I; BDT, Block Design Test; BeDT, Benson Delay Test; BNT, Boston Naming Test; BP, Blood Pressure; BPP, Børge Priens Prøve; BuDT, Buschke Delay Test; CAMCOG, Cambridge Cognition Examination; CANTAB, Cambridge Neuropsychological Test Automated Battery; CDT, Clock Drawing Test; CERAD, Consortium to Establish a Registry for Alzheimer's Disease; CES, Composite Executive Score; CMS, Chinese Clinical Memory Scale; CRT, Choice Reaction Time; CVLT, California Verbal Learning Test DSB, Digit Span Backwards; DSF, Digit Span Forward; DSST, Digit Symbol Substitution Test; EBM, East Boston Memory Test; EIS, Executive Index Score; HRS-CS, U.S. Health and Retirement Study Composite Score; IQ, Intelligence Quotient; IQCODE, Informant Questionnaire on Cognitive Decline in the Elderly; IST, Intelligenz-Struktur-Test; LCCS, Letter Cancellation Composite Score; LSST, Letter Search Speed Test; LT, Labyrinth Test; McNS, McNair Survey; MINT, Multilingual Naming Test; MIS, Memory Index Score; MMSE, Mini-Mental State Exam; MoCA, Montreal Cognitive Assessment; MR, Mental Rotation Test; MVT, Mill Hill Vocabulary Test; NART, National Adult Reading Test; PFT, Phonemic Fluency Test; RAVLT, Rey Auditory Verbal Learning Test; ROCF, Rey–Osterreith complex figure; RVP, Rapid Visual Processing; SCWT, Stroop Colour Word Test; SDMT, Symbol Digits Modalities Test; SFT, Semantic Fluency Test; SiRT, Simple Reaction Time; SRT, Selective Reminding Test; STIT, Stroop Test (Interference Time); STW, Spot the Word Test; TMT-A, Trail making Test Part A; TMT-B, Trail making Test Part B; TrB-A, Trail making Test Difference between Part B and A; VIS, Visuospatial Index Score; VRT, Visual Reproduction Test; VSS, Visual Search Speed; WAIS, Wechsler Adult Intelligence Scale; WDS, WAIS-IV Digit Sequencing; WFT, Word Fluency Test; WLL, Word List Learning; WMT, Word Matching Test.
TABLE 3.
Summary of all studies with negative relationships between hypertension and cognitive measures at midlife.
| Author | Year | Study design | Setting | Study quality | Participants | Cognitive variables | Relationship |
| . | 2020 | Cross sectional | ELSA; Brazil | High |
n = 5275 Age = 56.3 |
Memory, executive function, temporal orientation, and global cognition | - (Executive function and global cognition) |
| Alves de Moraes | 2002 | Longitudinal follow-up | ARIC Study; USA | Low |
n = 8058 Age = 56.7 (5.6) |
Memory and executive function | - (Memory and executive function) |
| Bangen et al. | 2013 | Cross-sectional analysis of longitudinal | Framingham Study; USA | High |
n = 1436 (men = 660, women = 775) Age = 54 (9) |
Memory, executive function, global cognition, and visuospatial organisation | - (Executive function, attention, visuospatial organisation) |
| Bayes-Marin et al. | 2020 | Longitudinal | Edad con Salud; Spain | High |
n = 633 (men = 304, women = 329) Age = 56.6 |
Memory | - (Memory) |
| Bressler et al. | 2013 | Prospective cohort study | ARIC Study; USA | Low | White: n = 8364 (men = 3859, women = 4505); African-American: n = 2083 (men = 716, women = 1367) Age: White = 57 (5.6); African-American = 55.8 (5.7) |
Memory and executive function | - (Memory and executive function) |
| Cerhan et al. | 1998 | Longitudinal cohort | ARIC Study; USA | Moderate |
N = 13913 Aged 45--64 |
Memory and executive function | - (Women only: Memory and executive function) |
| Chen et al. | 2015 | Cross-sectional analysis of longitudinal | WHAP Study; Australia | High |
n = 247 Age = 50.1 (2.6) |
Executive function, psychomotor speed, and memory | - (Executive function, psychomotor speed, memory) |
| Cui et al. | 2016 | Case--control | Guangzhou, China | Moderate |
Hypertensive: n = 278; Controls = 155 Age: Hypertensive = 54.2 (4.2); Controls = 55.8 (5.5) |
Intelligence and global cognition | - (Intelligence, global cognition) |
| de Menezes et al. | 2021 | Longitudinal follow-up | ELSA Study; Brazil | High |
n = 7063 Age = 58.9 (5.9) |
Memory, executive function, and global cognition |
- (Memory, executive function, global cognition) |
| Debette et al. | 2011 | Prospective | Framingham Study; USA | Moderate |
n = 1352 (men = 6634, women = 718) Age = 54 (9) |
Memory and executive function |
- (Executive function) |
| Derby et al. | 2021 | longitudinal study of the menopause transition | SWAN, USA | Moderate |
N = 1139 Age = 53.4 (2.6) |
Memory and executive function | - (Women only: Memory and executive function) |
| Dixon et al. | 2021 | longitudinal epidemiological study | SWAN, USA | Moderate | European American (n = 1000) African-American (n = 516) Asian American (n = 437) Age: European American = 45.95 (2.73) African American = 45.88 (2.61) Asian American = 46.11 (2.58) |
Memory and executive function | - (Memory and executive function) |
| Elkins et al. | 2005 | Prospective | ARIC Study; USA | High |
n = 12 096 (men = 12 039, women = 57) Age = 57 (5.7) |
Memory and executive function |
- (Memory) |
| Elmassry et al. | 2015 | Cross sectional | Egypt | Moderate |
Patients: n = 85 (men = 40, women = 45); Controls: n = 60 (men = 27, women = 33) Age: Patient = 43.9 (6.2); Control = 45 (9) |
Memory, executive function, and global cognition | - (Memory, executive function, global cognition) |
| Gerasimenko et al. | 2017 | Cross sectional | Ukraine | Low |
Patients: n = 102; Controls: n = 20 Age: Patients = 49.8 (0.8); Controls = 52.2 (1.9) |
Memory and global cognition | - (Global cognition) |
| Giugliano et al. | 2018 | Randomized, control trial | Pozzilli, Italy | Low |
Active Treatment: n = 18 (men = 13, women = 5); Control: n = 18 (men = 14, women = 4) Age: Active Treatment = 58.2 (8); Control = 57.9 (6.7) |
Executive function, and global cognition | - (Executive function, global cognition) |
| Gonzalez et al. | 2018 | Prospective, epidemiologic | ARIC Study; USA | Moderate |
n = 13 720 (men = 5873, women = 7397) Age = 54.1 (5.7) |
Memory, executive function, and global cognition |
- (Memory, executive function, global cognition) |
| Gottesman et al. | 2017 | Prospective | ARIC Study; USA | High |
n = 15 744 (men = 7054, women = 8690) Age = 54.2 (5.8) |
Memory, executive function, and global cognition | - (Global cognition) |
| Gottesman et al. | 2014 | Prospective | ARIC Study; USA | High | Normal BP = 4, 322 + 779 = 5101 (men = 2195, women = 2908) Pre HT = 2274 + 601 = 2,875 (men = 1388, women = 1487) HT = 3651 + 1849 = 5500 (men = 2401, women = 3099) Age: Normal BP = 55(7), Prehypertensive = 56 (8), Hypertensives 57 (8) |
Memory, executive function, and global cognition | - (Memory, executive function, global cognition) |
| Gourley et al. | 2020 | Cross-sectional | Texas; USA | Moderate |
n = 132 (men = 59, women = 73) Age = 49 (6) |
Memory, executive function, intelligence, and attention | - (Memory, executive function) |
| Gupta et al. | 2008 | Cross-sectional | Jaipur; India | Moderate |
n = 85 (men = 59, women = 26) Age = 52 (7.5) |
Memory, executive function, global cognition, and attention | - (Memory, executive function, and global cognition; Systolic hypertension: attention, executive function) |
| Hajjar et al. | 2016 | Longitudinal, | USA | Moderate |
n = 291 (men = 191, women = 400) Age = 48.8 (0.4) |
Memory, executive function, attention, global cognition, and visuospatial organisation | - (Memory, executive function) |
| Hoffmann et al. | 2021 | Longitudinal | Recall Study; Germany | High | Normal BP: n = 692 (men = 242, women = 450); Incident hypertension T1: n = 366 (men = 175, women = 191); Incident hypertension T2: n = 245 (men = 109, women = 136); Temporary hypertension: n = 329 (men = 183, women = 209); Prevalent hypertension: n = 1145 (men = 635, women = 510) Age: Normal BP = 55.2 (6.6); Incident hypertension T1 = 57.8 (7.1); Incident Hypertension T2: 56.5 (6.6); Temporary hypertension = 57.6 (7.1); Prevalent hypertension = 60.2 (7.1) |
Memory, executive function, and visuospatial organization | - (Memory) |
| Houle et al. | 2019 | Cross-sectional analysis of longitudinal | HAALSI Study; South Africa | Moderate |
n = 2059 (men = 2345, women = 2714) Age = 40--59 |
Memory, executive function, attention, global cognition, and temporal orientation | - (Memory, executive function, attention) |
| Jenkins et al. | 2021 | Longitudinal | CARDIA study; USA | Moderate |
N = 578 (men = 255, women = 323) Age: 55 (4) |
Memory, executive function, global cognition, and psychomotor speed | - (Global cognition) |
| Jia et al. | 2021 | Cross-sectional | China | Moderate | Total: N = 4923 Age: 55–64: N = 2043 |
Global Cognition | - (Global Cognition) |
| Kaffashian et al. | 2013 | Prospective | Whitehall II Study; UK | High |
n = 4374 (men = 3162, women = 1212) Age = 55.2 (5.1) |
Memory, executive function, attention, global cognition, and inductive reasoning | - (Attention, executive function, global cognition, inductive reasoning) |
| Kaffashian et al. | 2011 | Prospective | Whitehall II Study; UK | High |
n = 4827 (men = 3486, women = 1341) Age: men = 55.1 (5.9), women = 55.3 (5.9) |
Memory, executive function, attention, global cognition, and inductive reasoning | - (Global cognition) |
| Kivipelto et al. | 2001 | Prospective and cross-sectional analysis of population-based, longitudinal study with a large cohort of individuals | North Karelia Project and FINMONICA study; Finland | High | Total: N = 1449; MCI: N = 82, Without MCI: N = 1270 Age: Midlife: MCI = 51.7 (5.8); Without MCI = 50.1 (6.0) Late life: MCI = 72.8 (4.1), Without MCI = 71.0 (3.9) |
Memory, attention, executive function, and global cognition | - (Global Cognition) |
| Knopman et al. | 2001 | Longitudinal | ARIC Study; USA | Low |
n = 10 882 (men = 6978, women = 3904) Age = 56.8 (5.7) |
Memory and executive function | - (Memory, executive function) |
| Knopman et al. | 2018 | Longitudinal | ARIC Study; USA | Low |
n = 10 882 (men = 8723, women = 7137) Age = 51.4 (4.9) |
Memory and executive function |
- (Memory, executive function) |
| Knopman et al. | 2009 | Longitudinal | ARIC Study; USA | Moderate |
n = 1130 (men = 429, women = 701) Age = 59 (4.3) |
Memory and executive function | - (Memory, executive function) |
| Kovacs et al. | 2014 | Cross sectional | Hungary | Moderate | Hypertensive = 72; Controls = 85 Age: Hypertensive = 43.6; Controls = 43.6 |
Memory, executive function, attention, psychomotor speed, and visuospatial organisation | - (Attention, memory, executive function, psychomotor speed, visuospatial organisation) |
| Kumar et al. | 2008 | Cross-sectional study | PATH Through Life Project; Australia | Moderate | Diabetic individuals: N = 39; Nondiabetic individuals: N = 428 Age: Diabetic individuals = 62.62 (1.16) Nondiabetic individuals = 62.55 (1.48) |
Memory, attention, global cognition, and psychomotor speed | - (Psychomotor Speed) |
| Kumari et al. | 2005 | Longitudinal | Whitehall II Study, UK | Moderate |
N: NGT: men = 3407, women = 1334; IGT: males = 405, females = 192; Diabetes: males = 208, females = 101 Age: NGT: men = 55.1, women = 55.7; IGT: men = 58.2, women = 57.8; Diabetes: men = 57.9, women = 58.9 |
Memory, inductive reasoning, and executive function | - (Inductive reasoning, executive function) |
| Lane et al. | 2019 | Longitudinal | Insight 46; UK | High |
n = 499 (men = 255, women = 244) Age at cognitive testing = 70.7 (0.7) |
Memory, executive function, and global cognition | - (Global cognition) |
| Leong et al. | 2020 | Prospective, longitudinal | TILDA; Ireland | Moderate | Non hypertensive: n = 2280 (men = 848, women = 1432); Hypertensive w/o medication: n = 2823 (men = 1420, women = 1403); Hypertensive with medication: n = 3070 (men = 1495, women = 1595) Age: Non hypertensive = 59.5; Hypertensive w/o medication = 62.7; Hypertensive with medication = 68.1 |
Attention, Global cognition | - (Global cognition) |
| Mahinrad et al. | 2020 | Longitudinal | CARDIA Study; USA | Moderate |
n = 191 (men = 104, women = 87) Age = 56 (4) |
Memory, executive function, and attention | - (Memory, executive function, attention) |
| Olaya et al. | 2019 | Longitudinal | ELSA; UK | High |
n = 4372 (men = 2023, women = 2349) Age = 56.8 (4.1) |
Memory | - (Memory) |
| Palacios-Mendoza et al. | 2018 | Cross-sectional | Guayaquil, Ecuador | High | Diabetes: n = 142 (men = 65, women = 76); No diabetes: n = 167 (men = 116, women = 50) Age: Diabetes = 59.9 (4.2); No Diabetes = 59.9 (3.8) |
Memory, executive function, intelligence, and attention | - (Memory) |
| Pan et al. | 2018 | Longitudinal | CHARLS; China | Low |
n = 1825 (45–54 = 962, 55–64 = 863) Age = 56.9 (8) |
Memory and global cognition | - (Memory, global cognition) |
| Passos et al. | 2021 | Cross-sectional study nested within the PróSaúde cohort study | Pró-Saúde study, Rio de Janeiro, Brazil | Moderate | Total: N = 488, Male = 235, Female = 253 Age groups: 45–54 = 243 55–64 = 145 |
Memory, executive function, and global cognition | - (Memory, executive function, and global cognition) |
| Rose et al. | 2010 | Prospective, epidemiologic | ARIC Study; USA | Low | OH No = 12 050; OH Yes = 652 Age: OH No = 53.9; OH Yes = 57.3 |
Memory and executive function | - (Memory, executive function) |
| Rouch et al. | 2019 | Prospective | VISAT Cohort Study; France | Moderate |
n = 3201 Controlled hypertension: n = 83 (men = 32, women = 51); Uncontrolled hypertension: n = 223 (men = 140, women = 83); Untreated hypertension: n = 784 (men = 551, women = 233); No hypertension: n = 2111 (men = 919, women = 1192) Age: Controlled hypertension = 51.3 (9.3); Uncontrolled hypertension = 54.3 (7.7); Untreated hypertension = 48.6 (10.1); No hypertension = 42.3 (9.4) |
Memory, attention, executive function, global cognition, and psychomotor speed | - (Global cognition) |
| Sands et al. | 1992 | Longitudinal | Intergenerational Studies from IHDB, California; USA | Low |
n = 103 Age: 55.4 (3.41) |
Memory, attention, executive function, and visuospatial organisation | - (Attention) |
| Sha et al. | 2018 | Longitudinal | CHARLS; China | High | n = 9750 | Memory and global cognition | - (Global cognition) |
| Sierra et al. | 2004 | Cross sectional | Barcelona; Spain | High | Without WML: n = 37 (men = 24, women = 13); With WML: n = 23 (men = 14, women = 9) Age: Without WML = 53.9 (3.5); With WML = 55.2 (4.2) |
Intelligence, memory, and attention | - (Attention) |
| Singh-Manoux et al. | 2005 | Cross sectional analysis of longitudinal | Whitehall II Study; UK | Moderate |
n = 5838 Age: men = 43.9 (5.9), women = 44.4 (6) |
Memory, executive function, and inductive reasoning | - (Memory, executive function, inductive reasoning) |
| Suemoto et al. | 2021 | Cross-sectional analysis of longitudinal | ELSA; Brazil | High |
n = 12 271 Age: 51.3 (8.9) Poor (0–2 metrics) n = 6483 (men = 3190, women = 3293; Intermediate (3–4 metrics) n = 4757 (men = 1955, women = 2802); Optimal (5–7 metrics) n = 1031 (men = 332, women = 699) Age: Poor (0–2 metrics) = 53.4 (8.6); Intermediate (3–4 metrics) = 49.7 (8.7); Optimal (5–7 metrics) = 45.8 (7.4) |
Memory, executive function, and global cognition | - (Memory, attention, executive function, global cognition) |
| Suvila et al. | 2021 | Prospective | CARDIA Study; USA | High |
n = 2496 (men = 534, women = 1689) Age = 55.1 (3.6) |
Memory, executive function, psychomotor speed, and global cognition | - (Psychomotor speed, memory, executive function, global cognition) |
| Swan et al. | 1998 | Prospective, longitudinal | NHLBI Twin Study; USA | Moderate | n = 392; 71 MZ and 61 DZ intact pairs; 128 singletons | Memory, executive function, global cognition, and psychomotor speed | - (Global cognition, psychomotor speed) |
| Swan et al. | 1998 | Longitudinal | Western Collaborative Group Study, USA | Moderate |
n = 717 Midlife SBP categorized by Later life SBP (n = Low < 120 mmHg, Medium 120–139 mmHg, High ≥140 mmHg): Low < 120 mmHg: 73, 173, 113 Medium 120–139 mmHg: 20, 119, 165 High ≥140 mmHg: 2, 16, 36 Long-term Change in SBP midlife-to-later life: Normals (n = 553–643) High-High (n = 30–36) Decreased (n = 31–38) |
Memory, executive function, and psychomotor speed | - (SBP increase: Memory) |
| Szczesnia et al. | 2020 | Longitudinal | PURE Study; Poland | High |
n = 547 (men = 195, women = 352) Age = 56.2 (6.5) [men = 55.1 (6.8), women = 56.9 (6.3)] |
Attention, executive function, psychomotor speed, and global cognition | - (Psychomotor speed, executive function, global cognition) |
| Wang et al. | 2016 | Cross sectional | APAC Study; China | High |
n = 3048 (men = 1727, women = 1321) Age = 57.9 (11.1) |
Global cognition | - (Global cognition) |
| Wei et al. | 2018 | Cross-sectional | CHARLS; China | High | n = 6732 | Memory and global cognition | - (Memory, global cognition) |
| Wod et al. | 2018 | Cross-sectional analysis of longitudinal | MADT; Denmark | High |
n = 4132 (men = 2120, women = 2012) Age: 56.6 (men = 56.6, women = 56.6) |
Memory, executive function, and attention | - (Memory, executive function, attention) |
| Wolf et al. | 2007 | Observational | Framingham Study; USA | Low |
n = 1814 (men = 854, women = 960) Age = 52.6 (7.9) |
Memory, executive function, and visuospatial orientation | - (Memory, executive function) |
| Zhang et al. | 2019 | Cross sectional | CHARLS; China | Low | No Diabetes: n = 7151; Controlled Diabetes: n = 232; Untreated Diabetes = 185; Treated Diabetes = 241 Age: No Diabetes = 59.5 (9.5) |
Memory, executive function, and global cognition | - (Memory, executive function) |
a, AHA; b, ESC; c, self-report; d, antihypertensive medication use; e, SBP >150 mmHg or DBP >95 mmHg.
0, no association; -, negative association; +, positive association
ACE, Akershus Cardiac Examination; APAC, Asymptomatic Polyvascular Abnormalities Community; ARIC, Atherosclerosis Risk in Communities; ASCEND, A Study of Cardiovascular Events in Diabetes; Barcelona-AsIA, Asymptomatic Intracranial Atherosclerosis; BHS, Bogalusa Heart Study; BIP, Bezafibrate Infarction Prevention; BP, blood pressure; CARDIA, Coronary Artery Risk Development in Young Adults; CHARLS, China Health and Retirement Longitudinal Study; DBP, diastolic blood pressure; ELSA, Brazilian Longitudinal Study of Adult Health; ELSA, English Longitudinal Study of Ageing; HAALSI, Health and Aging in Africa; HANDLS, healthy Aging in Neighborhoods of Diversity Across the Life Span; HHP, Honolulu Heart Program; IHDB, Institute of Human Development in Berkeley; KALS, Kaohsiung Atherosclerosis Longitudinal Study; KEEPSCog, Kronos Early Estrogen Prevention cognitive; KIHD, Kuopio Ischaemic Heart Disease Risk Factor Study; MACS, Multicentre AIDS Cohort Study; MADT, Middle-Aged Danish Twins; MDCS, Malmö Diet and Cancer Study; MORGEN, Monitoring Project on Cardiovascular Disease Risk Factors; MRC, Medical Research Council; NHLBI, National Heart, Lung, and Blood Institute; NSHD, National Survey of Health and Development; PATH, Population Assessment of Tobacco and Health; PURE, prospective Urban and Rural Epidemiological; RECALL, Risk Factors, Evaluation of Coronary Calcium and Lifestyle; SBP, systolic blood pressure; Swan, Study of Women's Health Across the Nation; TILDA, The Irish Longitudinal Study on Ageing; VETSA, Vietnam Era Twin Study of Aging; VISAT, Vieillissement Santé Travail (Aging, Health and Work); WHAP, Women's Health Aging Project.
Associations between hypertension status at midlife and measures of cognition at later life
Of the 12 longitudinal study cohorts, 10 evaluated midlife hypertension and cognitive function at later life. A negative relationship was reported by qualitative analysis among domains including, memory (n = 8), executive function (n = 4), attention (n = 3), global cognition (n = 5), visuospatial organization (n = 1), and psychomotor speed (n = 1) (see Table 1).
TABLE 1.
Summary of longitudinal studies with negative or null relationship between hypertension and cognitive measures at later life.
| Ref. | Year | Setting | Study quality | Cognitive variables | Relationship |
| Anstey et al. | 2014 | PATH through Life; Australia | High | Memory, attention, executive function, global cognition, and psychomotor speed | - (Memory, attention, global cognition, psychomotor speed) |
| Bangen et al. | 2013 | Framingham Study; USA | High | Memory, executive function, global cognition, and visuospatial organisation | (Executive function, attention, visuospatial organization) |
| Bayes-Marin et al. | 2020 | Edad con Salud; Spain | High | Memory | - (Memory) |
| Brunner et al. | 2017 | Whitehall II Study; UK | Low | Global Cognition | - (Global Cognition) |
| de Menezes et al. | 2021 | ELSA Study; Brazil | High | Memory, executive function, and global cognition | - (Memory, executive function, global cognition) |
| Derby et al. | 2021 | SWAN, USA | Moderate | Memory and executive function | - (Women only: Memory and executive function) |
| Dixon et al. | 2021 | SWAN, USA | Moderate | Memory and executive function | - (Memory and executive function) |
| Hajjar et al. | 2016 | USA | Moderate | Memory, executive function, attention, global cognition, and visuospatial organisation | 0 |
| Hoffmann et al. | 2021 | Recall Study; Germany | High | Memory, executive function, and visuospatial organization | - (Memory) |
| Kazlauskaite et al. | 2020 | SWAN; USA | Moderate | Memory and psychomotor speed | - (Memory, executive function) |
| Kesse-Guyot et al. | 2015 | SU.VI.MAX study; France | High | Memory, attention, executive function, and global cognition | 0 |
| Kivipelto et al. | 2001 | North Karelia Project and FINMONICA study; Finland | High | Memory, attention, executive function, and global cognition | - (Global Cognition) |
| Leong et al. | 2020 | TILDA; Ireland | Moderate | Attention, Global cognition | - (Global cognition) |
| Lin et al. | 2020 | KALS; Taiwan | High | Global cognition, memory, executive function, visuospatial orientation and attention | 0 |
| Lutski et al. | 2019 | BIP Neurocognitive Study; Israel | High | Memory, executive function, attention, global cognition and visuospatial organization | 0 |
| Olaya et al. | 2019 | ELSA; UK | High | Memory | - (Memory) |
| Power et al., | 2017 | ARIC Study; USA | High | Memory and executive function | - (Memory, global cognition) |
| Rouch et al. | 2019 | VISAT Cohort Study; France | Moderate | Memory, attention, executive function, global cognition, and psychomotor speed | - (Global cognition) |
| Swan et al. | 1998 | NHLBI Twin Study; USA | Moderate | Memory, executive function, global cognition, and psychomotor speed | - (Global cognition, psychomotor speed) |
| Swan et al. | 1998 | Western Collaborative Group Study, USA | Moderate | Memory, executive function, and psychomotor speed | - (Global cognition) |
| Szoeke et al. | 2016 | WHAP; Australia | Moderate | Memory | (Memory) |
| Zhang et al. | 2019 | CHARLS; China | Low | Memory, executive function, and global cognition | (Memory, executive function) |
0, no association; -, negative association; +, positive association.
ACE, Akershus Cardiac Examination; APAC, Asymptomatic Polyvascular Abnormalities Community; ARIC, Atherosclerosis Risk in Communities; ASCEND, A Study of Cardiovascular Events in Diabetes; Barcelona-AsIA, Asymptomatic Intracranial Atherosclerosis; BHS, Bogalusa Heart Study; BIP, Bezafibrate Infarction Prevention; BP, blood pressure; CARDIA, Coronary Artery Risk Development in Young Adults; CHARLS, China Health and Retirement Longitudinal Study; DBP, diastolic blood pressure; ELSA, Brazilian Longitudinal Study of Adult Health, FINMONICA, Finnish Multinational Monitoring of Trends and Determinants in Cardiovascular Disease; ELSA, English Longitudinal Study of Ageing; HAALSI, Health and Aging in Africa; HANDLS, healthy Aging in Neighborhoods of Diversity Across the Life Span; HHP, Honolulu Heart Program; IHDB, Institute of Human Development in Berkeley; KALS, Kaohsiung Atherosclerosis Longitudinal Study; KEEPSCog, Kronos Early Estrogen Prevention cognitive; KIHD, Kuopio Ischaemic Heart Disease Risk Factor Study; MACS, Multicentre AIDS Cohort Study; MADT, Middle-Aged Danish Twins; MDCS, Malmö Diet and Cancer Study; MORGEN, Monitoring Project on Cardiovascular Disease Risk Factors; MRC, Medical Research Council; NHLBI, National Heart, Lung, and Blood Institute; NSHD, National Survey of Health and Development; PATH, Population Assessment of Tobacco and Health; PURE, prospective Urban and Rural Epidemiological; RECALL, Risk Factors, Evaluation of Coronary Calcium and Lifestyle; SBP, systolic blood pressure; Swan, Study of Women's Health Across the Nation; TILDA, The Irish Longitudinal Study on Ageing; VETSA, Vietnam Era Twin Study of Aging; VISAT, Vieillissement Santé Travail (Aging, Health and Work); WHAP, Women's Health Aging Project.
From the 67 independent study cohorts, 10 evaluated the relationship between midlife hypertension and later life cognition. Three studies reported negative relationships for memory and visuospatial organisation and a further three studies also found a negative relationship for executive function, global cognition, and psychomotor speed. No relationship was found between hypertension and any measure of cognition in four studies.
Findings on the relationship between midlife hypertension and later life cognition did not differ by study quality. Longitudinal studies of moderate-to-high quality reported a negative relationship between midlife hypertension and later life cognition mainly in memory, executive function, and global cognition (see Table 1).
In summary, midlife hypertension was found to negatively impact on cognitive function across multiple domains at later life assessed by qualitative analysis, irrespective of study design or quality.
Associations between hypertension and measures of cognition at midlife
Table 2 details mean pooled weighted outcomes for all measures of cognition and associated BP and hypertension values.
Conflicting findings were reported on the relationships between midlife hypertension and cognitive function at midlife by qualitative analysis (see Tables 2 and 3). A similar number of studies reported no relationship or a negative relationship for cognitive domains, including attention, memory, inductive reasoning, and visuospatial organisation. Reports of no relationship were more common in the case of intelligence (n = 5, 83%), global cognition (n = 17, 74%), and executive function (n = 25, 75%). A negative relationship was more commonly reported for psychomotor speed (n = 5, 71%).
There were no discernible differences in reported relationships between midlife hypertension and midlife cognition based on study design (individual cohorts vs. large cohorts) or by study quality (low vs. moderate vs. high) (see Tables 2 and 3).
Meta analyses
All meta-analyses performed reflect the association between midlife hypertension diagnosis and midlife cognition. There were insufficient data available for meta-analyses including later life cognition (Fig. 2). Fifteen studies across four cognitive domains (memory, executive function, attention, and global cognition) were suitable for meta-analysis. A total of 12 919 participants were classified as hypertensive and 21 342 as normotensive. High levels of heterogeneity (I2 ≥75%) was identified for all four cognitive domains. Hypertension diagnosis had a negative effect on memory compared to normotension (MD = −0.06; 95% CI = −0.20 to 0.08; I2 = 0%). Hypertension diagnosis had no effect on attention compared to normotensives (MD = 0.41; 95% CI = 0.26 to 0.56; I2 = 18%). Hypertension diagnosis had a negative effect on executive function (MD = −0.02; 95% CI = −0.08 to 0.03; I2 = 36%). Hypertension diagnosis negatively impacted global cognition compared to normotensive status (MD = −0.24; 95% CI = −0.28 to −0.21; I2 = 12%) (see Fig. 3). Study quality or study design had no influence on meta-analyses findings for all four measures (Tables 4 and 5).
FIGURE 2.
Forest plot examining the overall effect of hypertension status vs. normotension status. (a) Memory function. (b) Attention. (c) Executive function. (d) Global cognition.
FIGURE 3.
Funnel plots representing hypertensive vs. normotensive individuals and their effect on cognition in midlife. (a) Memory; (b) Attention; (c) Executive function; (d) Global cognition. SMD, standardized mean difference; SE, standard error.
TABLE 4.
Summary of studies with a null or positive relationship between hypertension and cognitive measures at midlife.
| Author | Year | Study design | Setting | Study quality | Participants | Cognitive variables |
| Babaei et al. | 2013 | RCT | Iran | Low |
n = 52 (28 patients and 24 controls) Age = 57.1 (5.9) |
Memory |
| Backestrom et al. | 2015 | Retrospective, cross-sectional | Betula Prospective Cohort Study, Sweden | Moderate |
n = 291 (men = 127, women = 164) Age = 50.7 (8) [men = 50.3 (8), women = 51 (8.1)] |
Memory |
| Bahchevanov et al. | 2021 | Cross-sectional | District of Plovdiv, Bulgaria | High |
n = 112 Without MetS: n = 67 (men = 18, women = 49) With MetS: n = 45 (men = 24, women = 21) Age: Without MetS = 49.87 (3.36) With MetS = 50.29 (3.26) |
+ (lower SBP and DBP: memory, executive function, and global cognition) |
| Boots et al. | 2015 | Cross-sectional | WRAP; USA | High |
n = 315 (men = 102, women = 213) Age = 58.58 (6.3) |
Memory, executive function, visuospatial organization, and global cognition |
| Carmichael et al. | 2019 | Community-based cohort study | Bogalusa Heart Study (BHS), USA | Low |
N = 50 Age = 48.8 (4.7) |
Memory, attention, and executive function |
| Chen et al. | 2018 | Longitudinal | ARIC-NCS Study; USA | High |
n = 12 515 (men = 5334, women = 6981) Age = 56.9 (5.7) |
Memory and executive function |
| Christman et al. | 2011 | Prospective | ARIC Study; USA | Moderate |
n = 8958 (men = 3943, women = 5015) Age = 56.5 (5.6) |
Memory and executive function |
| Cohen-Manheim et al. | 2016 | Cross-sectional | Jerusalem LRC Study; Israel | High |
n = 507 (men = 343, women = 164) Age = 49.9 (0.8) |
Memory, executive function, and attention |
| Dearborn-Tomazos et al. | 2019 | Longitudinal observational | ARIC Study; USA | Low |
n = 13 588 (men = 3000, women = 7588) Age = 54.6 (5.7) |
Memory, executive function, and global cognition |
| Dounavi et al. | 2022 | Cross-sectional analysis of longitudinal multisite study | PREVENT-Dementia study; Ireland & UK | Low | Total: N = 701 (n = 600 analysable) Age = 51.2 (5.4) |
Global cognition |
| Elbaz et al. | 2014 | Longitudinal | Whitehall II Study; UK | High |
n = 4699 (men = 3,324, women = 1375) Age = 48.6 (5.8) |
Inductive reasoning |
| Fava et al. | 2013 | Prospective longitudinal | Italy | Low | Total: n = 96 (Group A = 48, Group B = 48) Age: Group A = 53 (7), Group B = 54.6 (8.1) |
Memory, executive function, global cognition |
| Ferguson et al. | 2018 | Cross-sectional | CARDIA Study; USA | Moderate |
n = 634 (men = 305, women = 329) Age = 50.4 (3.5) |
Memory and executive function |
| Ford et al. | 2010 | Longitudinal | SWAN; USA | Moderate |
n = 2003 Age = 50 (2.6) |
Memory and psychomotor speed |
| Fuh et al. | 2007 | Matched, case–control study from a population-based cohort | Kinmen Women-Health Investigation (KIWI); Kinmen, Taiwan | Low | Normal (N = 144) Impaired glucose tolerance (N = 68) Diabetes mellitus (N = 72) Age: Normal = 47.9 (4.3) Impaired glucose tolerance = 46.8 (4.1) Diabetes mellitus = 47.9 (4.3) |
Memory, attention, and executive function |
| Gerber et al. | 2021 | Multicentre, population-based cohort study | CARDIA study, USA | Low | Overall (n = 2809); Liver attenuation: No NAFLD >51 HU (n = 2136); Mild NAFLD >40–51 HU (n = 392); Severe NAFLD ≤40 HU (n = 281) Overall Age = 50.1 (3.6); Liver attenuation: No NAFLD >51 HU = 50.0 (3.7); Mild NAFLD >40–51 HU = 50.3 (3.6); Severe NAFLD ≤40 HU = 50.5 (3.6) |
Memory and executive function |
| Haley et al. | 2010 | Cross-sectional | USA | Moderate |
n = 38 Age = 50 (6.4) |
Global cognition, intelligence, memory, attention, executive function, and psychomotor speed |
| Hossain et al. | 2020 | Cross-sectional analysis of longitudinal | HANDLS Study; USA | High |
n = 128 (men = 102, women = 126) Age: men = 57.1 (0.5), women = 56 (0.8) |
Memory, attention executive function and global cognition |
| Ihle-Hansen et al. | 2019 | Prospective | ACE Study; Norway | High |
n = 3413 (men = 1774, women = 1639) Age = 63.9 (0.65) [men = 63.9 (0.66), women = 63.9 (0.63)] |
Global cognition |
| John et al. | 2021 | Longitudinal cohort | National Child Development Study (NCDS), UK | High |
N = 3730 Age = 44 |
Memory, and executive function |
| Kazlauskaite et al. | 2020 | Longitudinal | SWAN; USA | Moderate |
n = 2149 (all women); No MetS = 1514, MetS = 635) Age = 50.7 (2.9); No MetS = 50.6 (2.8), MetS = 51.1 (3.2) |
Memory and psychomotor speed |
| Kesse-Guyot et al. | 2015 | Longitudinal (Observational Follow-up) | SU.VI.MAX study; France | High |
n = 2788 (men = 1480, women = 1308) Age at cognitive evaluation: men = 66.0 (4.5), women = 65.1 (4.6) |
Memory, attention, executive function, and global cognition |
| Kilander et al. | 2000 | Longitudinal | Sweden | Low |
n = 2322 Age = 50 years n = 1860 Age = 60 years |
+ (Low DBP: attention, executive function, psychomotor speed, and shifting capacity |
| Kohde et al. | 2012 | Cross-sectional, case--control | India | Moderate |
n = 120 (60 patients and 60 controls) Age: patients = 53.7 (6.9), controls = 52.1 (6.2) |
Attention |
| Kumar et al., | 2020 | Longitudinal | ASCEND; UK | Low |
n = 80 Age = 59 |
Global cognition, attention, executive function, memory and global cognition |
| Launer et al., | 2015 | Cross-sectional | CARDIA Study; USA | Low |
n = 680 Age = 50.3 (3.5) |
Memory and executive function |
| Lin et al. | 2020 | Longitudinal | KALS; Taiwan | High |
n = 528 Age = 53.9 (8.4) |
Global cognition, memory, executive function, visuospatial orientation, and attention |
| Liu et al. | 2022 | Prospective | Neck-Shoulder and Lumbocrural Pain Hospital and the Affiliated Hospital of Shandong University of TCM; China | Moderate | Overall: n = 156; Controls = 64, SCI = 92 Age: Controls = 57.1 (6.3); SCI = 57.6 (6.7) |
General Cognition |
| Lopez-Oloriz et al. | 2014 | Population-based | AsIA Neuropsychology Study; Spain | Low |
n = 95 Age = 59.9 (3.3) |
Executive function, psychomotor speed and global cognition |
| Lutski et al. | 2019 | Longitudinal | BIP Neurocognitive Study; Israel | High | T1: n = 588, T2: n = 337 Age: T2 = 56.6 (6.4) |
Memory, executive function, attention, global cognition and visuospatial organisation |
| Mefford et al. | 2021 | Multicenter longitudinal, prospective | CARDIA study, USA | Moderate | N = 3328 Time-averaged LDL-C levels over follow-up, mg/dl: < 100 (n = 519) 100–129 (n = 1094) 130–159 (n = 961) ≥160 (n = 754) Age: Time-averaged LDL-C levels over follow-up, mg/dl: <100 = 46.9 (3.2); 100–129 = 49.2 (3.5); 130–159 = 51.1 (3.1); ≥160 = 52.6 (2.5) |
Memory, attention, and executive function |
| Meyer et al. | 2022 | Cross-sectional analysis of longitudinal, cohort study | CARDIA study, USA | Moderate |
N = 597 Age = 55.2 (3.5) |
Memory, executive function, and global cognition |
| Moore et al. | 2014 | Longitudinal | VETSA, Thailand | High |
n = 651 (all men) Age = 55.3 (3.1) |
Executive function, memory, visuospatial organization, and intelligence |
| Nation et al. | 2016 | Longitudinal | Subset of Framingham Offspring Cohort; USA | High |
n = 549 (men = 257, women = 292) Age: 59.6 (2.7) |
Memory, attention, executive function, and visuospatial organization |
| Nunley et al. | 2017 | Prospective, observational | Pittsburgh Epidemiology of Diabetes Complications Study; USA | High |
N = 108 Age = 49.52 (7.04) |
Memory, attention, executive function, global cognition, intelligence, and psychomotor speed |
| Olaya et al. | 2017 | Longitudinal | ELSA; UK | High |
n = 5523 Age = 50--64 |
Memory |
| Palta et al. | 2019 | Prospective | ARIC Study; USA | Moderate |
No PA: n = 1996 (men = 795, women = 1201); Low: n = 774 (men = 247, women = 497); Middle: n = 669 (men = 295, women = 404); High: n = 1194 (men = 733, women = 461) Age: No PA = 59.1 (5.4); Low = 59.4 (5.6) Middle = 60.6 (5.9); High = 60.2 (5.8) |
Memory and executive function |
| Panigrahi et al. | 2021 | Cross-sectional | New Delhi, India | Moderate |
N = 80 (men = 31, women = 49) Age = 51.71 (7.15) |
Global Cognition |
| Pokharel et al. | 2019 | Prospective | ARIC Study; USA | Moderate | n = 18 222 | Memory and executive function |
| Power et al. | 2017 | Prospective | ARIC Study; USA | High |
n = 15 792 Age = 57.5 (5.7) |
Memory and executive function |
| Ravona-Springer et al. | 2020 | Prospective longitudinal | Israel Registry for Alzheimer Prevention (IRAP) study; Israel | Moderate | Total: N = 483; FH+ = 379, FH- = 104 Age: FH+ = 54.55 (6.76), FH- = 56.42 (6.19) |
Memory, executive function, and global cognition |
| Rawlings et al. | 2014 | Prospective | ARIC Study; USA | Moderate |
n = 13 351 Age = 48--67 |
Memory, executive function, and global cognition |
| Reis et al. | 2013 | Cross-sectional | CARDIA study; USA | Moderate | Total: N = 2510; Coronary artery calcified plaque: Present = 686, Absent = 1824; Abdominal aortic calcified plaque: Present = 1297, Absent = 1213 Age: Coronary artery calcified plaque: Present = 51.1 (3.3), Absent = 49.6 (3.7); Abdominal aortic calcified plaque: Present = 50.6 (3.6), Absent = 49.5 (3.7) |
Memory, attention, and executive function |
| Richards et al. | 2005 | Longitudinal | MRC NSHD, UK | Low |
n = 1764 Age = 43 and 53 |
Memory and executive function |
| Ritchie et al. | 2017 | Cross sectional | PREVENT Dementia Program; UK | Low | Non-FH: n = 107 (men = 35, women = 71); FH: n = 103 (men = 29, women = 73) Age: Non-FH = 52.7; FH = 53.3 |
Memory, executive function, visuospatial organization, and attention |
| Root et al. | 2015 | Prospective, epidemiological | ARIC Study; USA | Moderate |
n = 10 041 Age = 53.5 |
Memory and executive function |
| Salama et al. | 2019 | Cross-sectional study | Egypt | Moderate | Total: N = 186; MCI: N = 14, Normal: N = 172 Age: <50: N = 65 50 - <55: N = 64 55 - <60: N = 42 60–65: N = 15 |
Global cognition |
| Salzwedel et al. | 2019 | Prospective, observational | Germany | High |
n = 401 (men = 321, women = 80) Age = 54.5 (6.3) |
Global cognition |
| Singh-Manoux et al. | 2003 | Longitudinal | Whitehall II Study; UK | Moderate |
n = 10 308 (men = 6896, women = 3411) Age = 44.45 |
Memory, executive function, and inductive reasoning |
| Singh-Manoux et al. | 2009 | Cross-sectional and prospective follow up of longitudinal cohort study | Whitehall II study; UK | High |
n = 5292 (men = 3810, women = 1481) Age: CHD = 59.4 (5.5); No CHD = 55.2 (5.9) |
+ (Lower BP Status: memory, attention, and executive function) |
| Swan et al. | 1998 | Longitudinal | Western Collaborative Group Study, USA | Moderate |
n = 717 Midlife SBP categorized by Later life SBP (n = Low <120 mmHg, Medium 120–139 mmHg, High ≥140 mmHg): Low <120 mmHg: 73, 173, 113 Medium 120–139 mmHg: 20, 119, 165 High ≥140 mmHg: 2, 16, 36 Long-term change in SBP midlife-to-later life: Normals (n = 553–643) High-High (n = 30–36) Decreased (n = 31–38) |
+ (SBP decrease: psychomotor speed) |
| Tufvesson et al. | 2013 | Prospective | MDCS; Sweden | High |
n = 933 (men = 369, women = 564) Age = 57.5 (5.7) |
Global cognition |
| Tuligenga et al. | 2014 | Prospective, longitudinal | Whitehall II study; UK | Moderate | Total: N = 5653; Normoglycaemia (n = 4703); Prediabetes (n = 648); Newly diagnosed diabetes (n = 115); Known diabetes (n = 187) Age: Total = 54.4; Normoglycaemia = 55.1 (5.9); Prediabetes = 57.5 (6.1); Newly diagnosed diabetes 59.0 (6.1); Known diabetes = 57.4 (6.3) |
Memory, executive function, and inductive reasoning |
| Vadini et al. | 2020 | longitudinal, randomized, controlled, parallel-arm study | Italy | Moderate | Preliraglutide (n = 16) Prelifestyle (n = 16) Age: Preliraglutide = 57 (49–64); Prelifestyle = 53 (52–58) |
Memory, attention, executive function |
| Veugen et al. | 2018 | Observational, prospective | Maastricht Study; Netherlands | High |
n = 3011 (men = 1542, women = 1469 Age = 52 (5) |
Memory, executive function and attention |
| Walker et al. | 2019 | Prospective | ARIC Study; USA | High |
n = 3012 (men = 1382, women = 1630) Age = 55.5 (5.4) |
Memory, executive function and psychomotor speed |
| Wang et al. | 2018 | Prospective epidemiological | ARIC Study; USA | High | n = 13 720 | Memory, executive function, and global cognition |
| Ward et al. | 2005 | Cross-sectional | WRAP & UWM; USA | High |
n = 114 (men = 44, women = 73) Age = 54.2 (6.5) |
+ (Low DBP: Episodic Learning) |
| Whitaker et al. | 2021 | Longitudinal Cohort study | CARDIA study | Moderate |
N = 1970 (men = 822, women = 1148) Age = 45.27 (3.56) |
Memory and executive function |
| Wieczorek et al. | 2016 | Prospective study | Poland | Moderate |
n = 74 (men = 44, women = 30) Age = 59 (50–63) |
Global cognition |
| Winkler et al. | 2014 | Population based | RECALL Study; Germany | Moderate |
n = 1089 (men = 515, women = 574) Age = 58.4 (4.1) |
Memory, executive function, and visuospatial orientation |
| Yang et al. | 2018 | Prospective | MACS; USA | Moderate | n = 900 (all men) | Psychomotor speed, attention, executive function, and memory |
| Ylilauri et al. | 2017 | Prospective | KIHD; Finland | High |
n = 2497 (all men) Age = 42–60 |
Global cognition, attention executive function and memory |
| Young et al. | 2006 | Longitudinal, observational | ARIC Study; USA | Moderate |
n = 7148 (men = 3173, women = 3975) Age = 53.7 |
Memory and executive function |
| ZekiAlHazzouri et al. | 2015 | Prospective | CARDIA Study; USA | Moderate |
n = 2618 (men = 1125, women = 1493) Age = 45.3 (3.6) |
Memory and executive function |
a, AHA; b, ESC; c, self-report; d, antihypertensive medication use.
0, no association; -, negative association; +, positive association
ACE, Akershus Cardiac Examination; APAC, Asymptomatic Polyvascular Abnormalities Community; ARIC, Atherosclerosis Risk in Communities; ASCEND, A Study of Cardiovascular Events in Diabetes; Barcelona-AsIA, Asymptomatic Intracranial Atherosclerosis; BHS, Bogalusa Heart Study; BIP, Bezafibrate Infarction Prevention; BP, blood pressure; CARDIA, Coronary Artery Risk Development in Young Adults; CHARLS, China Health and Retirement Longitudinal Study; DBP, diastolic blood pressure; ELSA, Brazilian Longitudinal Study of Adult Health HAALSI, Health and Aging in Africa; ELSA, English Longitudinal Study of Ageing; HANDLS, healthy Aging in Neighborhoods of Diversity Across the Life Span; HHP, Honolulu Heart Program; KALS, Kaohsiung Atherosclerosis Longitudinal Study; KEEPSCog, Kronos Early Estrogen Prevention cognitive; KIHD, Kuopio Ischaemic Heart Disease Risk Factor Study; MACS, Multicentre AIDS Cohort Study; MADT, Middle-Aged Danish Twins; MDCS, Malmö Diet and Cancer Study; MORGEN, Monitoring Project on Cardiovascular Disease Risk Factors; MRC, Medical Research Council; NSHD, National Survey of Health and Development; PATH, Population Assessment of Tobacco and Health; PURE, prospective Urban and Rural Epidemiological; .RECALL, Risk Factors, Evaluation of Coronary Calcium and Lifestyle; SBP, systolic blood pressure; SU.VI.MAX, SUpplémentation en VItamines et Minéraux AntioXydants; Swan, Study of Women's Health Across the Nation; TILDA, The Irish Longitudinal Study on Ageing; VETSA, Vietnam Era Twin Study of Aging and; WHAP, Women's Health Aging Project.
TABLE 5.
Summary of negative relationships between hypertension and cognition at midlife by study design and quality.
| Study design | Memory | Attention | Executive function | Global cognition | Psychomotor speed | Intelligence | Visuospatial organization |
| Individual Study Cohorts | Bayes-Marin et al. (2020), Chen et al. (2015), Elmassry et al. (2015), Gourley et al. (2020), Gupta et al. (2008), Hajjar et al. (2016), Hoffmann et al. (2020), Houle et al. (2019), Kovacs et al. (2014), Palacios-Mendoza et al. (2018), Wod et al. (2018) | Houle et al. (2019), Kovacs et al. (2014), Sierra et al. (2004), Wod et al. (2018), Sands et al. (1992) | Aliberti et al. (2020), Chen et al. (2015), Elmassry et al. (2015), Giugliano et al. (2018), Gourley et al. (2020), Gupta et al. (2008), Hajjar et al. (2016), Houle et al. (2019), Kovacs et al. (2014), Wod et al. (2018) | Aliberti et al. (2020), Cui et al. (2016), Elmassry et al. (2015), Gerasimenko et al. (2017), Giugliano et al. (2018), Gupta et al. (2008), Wang et al. (2016), Rouch et al. (2019) | Chen et al. (2015), Kovacs et al. (2014) | Cui et al. (2016) | Kovacs et al. (2014) |
| Longitudinal Study Cohorts | Olaya et al. (2019), Suvila et al. (2021), Zhang et al. (2019) | - | Suvila et al. (2021), Zhang et al. (2019 | Suvila et al. (2021), Leong et al. (2020) | Suvila et al. (2021) | - | - |
| Study Quality (n = ) | Low: 9 Moderate: 12 High: 11 |
Low: - Moderate: 4 High: 3 |
Low: 8 Moderate: 13 High: 8 |
Low: 3 Moderate: 6 High: 10 |
Low: - Moderate: 1 High: 3 |
Low: - Moderate: 1 High: - |
Low: - Moderate: 1 High: 1 |
DISCUSSION
This review aimed to investigate the relationship between midlife hypertension status and cognitive function at later life and midlife. Using qualitative analysis, our results indicate mixed and inconsistent findings across all cognitive domains, but predominantly favour negative relationships between midlife hypertension and later life cognition in some but not all domains, most notably memory, executive function, and global cognition. No relationship was observed for attention, inductive reasoning, visuospatial organization, or temporal orientation. There was conflicting evidence on the relationship between hypertension and cognitive function at midlife, irrespective of study quality and study design. Though qualitative analysis suggested no relationship between hypertension and memory or global cognition at midlife, findings from our meta-analyses indicate a negative relationship for memory, executive function, and global cognition and no relationship with attention.
The finding in this review that midlife hypertension affects later life cognition is consistent with previous research [17–19], indicating accelerated cognitive decline with midlife hypertension, specifically memory, executive function, and global cognition. Growing evidence highlights the hypertension-cognition relationship is age-dependent [20,21]. Long-term hypertension spanning 25–30 years, initiated during middle-age, increases the likelihood of cognitive impairment in later life [19]. Evidence suggests elevated BP even during young adulthood can have deleterious effects on cognition among middle-aged adults [22]. Ageing plays a key role in functional adaptation to elevated BP, which precedes hypertension-induced microvascular damage and subsequent vascular cognitive impairment. Hypertension and ageing create a state of vulnerability suggested to alter hippocampal gene expression associated with cognitive decline and Alzheimer's Disease [23]. The findings presented here confirm previous reports that midlife hypertension negatively affects cognition in later life. However, our analysis reveals that select domains like memory are more notably affected than others. The hippocampus and entorhinal cortex are structures associated with learning and memory that are vulnerable to pathoanatomical and pathophysiological change in the presence of cardiovascular risk factors such as hypertension [24,25]. Impairments in working memory and the encoding of new long-term memories are reported with age-related cognitive decline [26]. Working memory declines with age are in line with the Baddeley model where processing or central executive components are negatively impacted [27]. Therefore, hypertension may limit attentional capacity, where older adults are less able to inhibit irrelevant information and cognitive correlates of efficiency and arousal become impaired with ageing, beginning as early as midlife [28–32].
Neurocognitive tests can enable subtle detection of cognitive change before observable signs and symptoms develop, acting as robust indicators of pathological ageing. Our results provide evidence of significant consequences of midlife hypertension for the time course and progression of cognitive impairment, and possible neurological comorbidities including dementia and AD [33,34]. Similar to our later life findings, meta-analysis indicated memory, executive function, and global cognition at midlife were negatively affected by hypertension. Hypertension with increasing age primarily affects specific cognitive domains, such as memory and executive function, rather than overall cognitive function. In line with this finding, hypertension status among 207 late middle-aged adults was associated with age-related decline in verbal learning and memory, although hypertension was reported in only 19% of the study population [35]. Various forms of memory are thus subject to age-related and pathological decline with the rates of change highly varied [36]. Moreover, executive function also declines with age and is accelerated in late midlife, that is, after 65 years of age [37]. Decline in executive function is believed to precede reductions in memory by up to 18 years before diagnosis of AD and cognitive impairment [38], with longitudinal evidence from women in midlife showing a mean decline of 2% per year in memory [39]. The specific reasons behind the accelerated regional decline during midlife remain unclear. However, our results are supported by several hypothesized mechanisms, including higher aortic stiffness [40,41], adaptive vascular changes in cerebral blood flow and arterial pressure, and hypertension-induced neurovascular uncoupling [5,42,43]. The precise timing and onset of pathological features and concurrent cognitive decline remain to be adequately determined. However, emphasizing midlife as a focal point for intervention could potentially yield significant benefits.
Similar to previous research, we found conflicting evidence on the impact of hypertension and cognitive function at midlife [17,18,44]. Notably, our meta-analyses indicated no relationship between hypertension and attention at midlife, contradicting those of Ou et al. [17] possibly explained by the lower number of studies included in the previous review (range: 2–4 studies) compared with 15 studies in the present review. It is probable rather than possible that in studies where no relationship was reported, negative implications consequent to hypertension are not identifiable through cognitive testing at midlife. Greater duration of time since onset of hypertension is therefore associated with increased cognitive impairment, independent of age [19,45]. Theories of cognitive ageing and dynamics of neural networks, however, postulate the most basic of cognitive functions, such as attention, are affected by age. Attention at midlife was unaffected by midlife hypertension in our review. The majority of cognitive tests tend to incorporate more than one domain of cognitive function in any given task [46]. Deficits in early processing stages may influence additional co-domains in the later processing cognitive streams ultimately affecting global cognition from midlife into later life as seen in the present review. It is well known that attention is involved in most cognitive processes, therefore any impact on attention potentially causes downstream consequences affecting the ability to complete normal daily tasks. Early evidence reports those with hypertension exhibit deficits in memory and executive function but no apparent decline in continuity of attention, similar to our present findings [47]. A decline in attention in response to a synergy between age and hypertension has been found to increase with age but did not significantly differ between those with hypertension and those without [48]. Deficits in higher order processes, like attention, in the prefrontal cortex can impact memory function in later life with significant impairment in divided attention or switching attentional focus [49–51]. This may be explained by the so-called ‘central executive control’, which has a role in virtually all cognitive functions from the allocation of attentional resources to the inhibition of irrelevant stimuli [52,53]. However, the stage from midlife onwards when cognitive changes begin to be exacerbated by the presence of hypertension, and how declining trajectories across select domains can be targeted with intervention strategies, remains to be identified at a population or an individual level.
Significant cognitive impairment should not be considered a normal part of the ageing process. As a modifiable risk factor, hypertension represents a key target for the prevention, delayed progression, and reduction of cognitive impairment in aging populations [5]. Attention at midlife was not negatively impacted by midlife hypertension as evident by meta-analysis but was affected in later life. Studies of ageing and neurocognition have reported age-related declines in attention [54–57]. Our results highlight an inconsistent relationship between hypertension at midlife and a decline in attention in later life, similar to previous reports [58–60]. Recent evidence from the National Health and Nutrition Examination Survey reports 70% of older adults are living with hypertension in comparison to just 32% of adults aged 40–59 years [61]. Management of previously untreated hypertension later in life cannot correct for the negative impact of decades of uncontrolled hypertension on cognitive function [62,63]. Hypertension may therefore contribute to, and even exacerbate, brain ageing via deterioration of neuroanatomical substrates and modulators among certain cognitive domains from midlife onwards [64–67]. Our results support the hypothesis of significant variation of age-related cognitive trajectories across several domains, which may be exacerbated with long-term exposure to hypertension across the lifespan.
There are several limitations to this study. A range of tools assessing cognitive function were broadly categorized for one or several cognitive domains. Although some tests will incorporate multiple cognitive domains, for the purpose of this review each test was organised according to core cognitive functions. We did not investigate the biological underpinnings of reported cognitive impairments, only examining the qualitative relationship between hypertension status and cognitive function. Studies were of varied design and quality and data reporting limited the ability to perform meta-analysis. Furthermore, different BP values were used across studies for the classification of hypertension. Clearer reporting of data in primary studies will enable better quality systematic analysis in the future.
CONCLUSION
The risks of midlife hypertension to cognition across the adult lifespan are of considerable concern in the context of an ageing population. The variability across cognitive domains is apparent, such that midlife hypertension adversely affected memory, executive function, and global cognition in later life, and negatively affected the same select domains of memory, executive function, and global cognition, but not attention, at midlife. Further longitudinal and prospective studies are required to determine the specific timeframe at which cognitive decline in certain domains begins to manifest from midlife onward. This will help establish a clear window of hypertension duration during which cognitive impairment and the earliest affected cognitive domains become evident.
ACKNOWLEDGEMENTS
Joyce O. C. is first author having contributed to the data extraction, write up, and editing of the manuscript. C.McH. contributed equally to data extraction, write up, and editing of the manuscript. D.M. was responsible for formulating and running the search strategy for data collection from included articles. FW was responsible for the inception of the present review article and contributed to editing the manuscript. Kelly ÁM is the project Principal Investigator and final author and contributed to editing the manuscript.
This study was funded by the Faculty of Health Sciences, Trinity College Dublin.
Consent was not necessary given the nature of this article.
Within this article, all data collected and/or analysed during this review are included throughout and in the supplementary material.
This research was exempt from local ethical approval as only published data were pooled.
Appendices and supplementary tables in this review article contain extensive data. In line with the guidelines, the authors recommend they be published in the electronic version of the Journal of Hypertension and referenced in a footnote in the print edition. A cover letter, highlights, and research in context have also been provided in support of the preliminary review by the editor.
Conflicts of interest
No potential conflict of interest is reported by the author(s).
Supplementary Material
Footnotes
Abbreviations: AHA, American Heart Association; AXIS, Appraisal Tool for Cross sectional Studies; BP, Blood Pressure; CI, Confidence Interval; ESC, European Society of Cardiology; MD, Mean Difference; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines; SD, Standard Deviation; SE, Standard Error; TBI, Traumatic Brain Injury
Supplemental digital content is available for this article.
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