Academic Editor: Peter A. McCullough
Hypertension is one of the most prevalent vascular risk factors and a leading cause of disability and mortality worldwide. The negative impact of hypertension on brain health is substantial. Already well-established as a risk factor for cerebrovascular disease, hypertension also has been shown to increase the risk for cognitive impairment and dementia. Mounting evidence from epidemiological studies suggests that hypertension, particularly in midlife, is associated with late-life cognitive impairment and the development of dementia. The link between late-life hypertension and cognitive function is, however, less clear. Experimental and neuroimaging studies have revealed complexities of mechanisms underlying the link between hypertension and cognitive function. Furthermore, the effect of blood pressure lowering on cognitive function, the optimal target and timing of the intervention, and the optimal antihypertensive agent in the context of cognitive function remain unclear. In this review, we discuss contemporary science on the link between hypertension and cognitive function by reviewing experimental, neuroimaging, and life-course observational studies. Furthermore, we provide a detailed review of randomized clinical trials addressing the effect of blood pressure lowering on cognitive function. Finally, unanswered questions, challenges, and other considerations for blood pressure lowering are highlighted.
Vascular risk factors and related disorders contribute to cognitive decline and Alzheimer’s disease-related dementias [1, 2]. Chronic hypertension has emerged among vascular risk factors, as a major contributor to adverse cognitive outcomes [3]. Particularly, evidence from observational studies has established a strong link between hypertension during midlife and negative cognitive outcomes in later adulthood [4, 5]. Furthermore, recent life-course observational studies have shown a link between raised blood pressure as early as young adulthood and worse cognition in midlife [6, 7].
Given that hypertension is a modifiable vascular risk factor, it represents an important target for preventive and treatment interventions to mitigate dementia risk. A number of major clinical trials has shown that lowering blood pressure reduces morbidity and mortality associated with cardiovascular diseases and stroke [8]. However, similar beneficial effects on cognition and dementia risk have not been consistently reported [3, 9, 10]. In fact, the impact of lowering blood pressure on cognitive function in older age is less clear and remains a matter of debate. Furthermore, the precise blood pressure lowering target in different age categories remains controversial as some experts suggest less stringent blood pressure lowering in the elderly to preserve cerebral autoregulation [11]. Therefore, a deeper understanding of the complex relationship between hypertension and brain structure and function is essential and will help identify potentially effective therapeutic targets.
In this review we provide discussion of the following relevant topics that link hypertension to cognitive outcomes: (1) Pathophysiology underlying the association with a focus on hypertension-induced cerebrovascular alterations and role of the renin-angiotensin system (RAS) and neuroimaging markers; (2) Observational studies across the life course; (3) Study designs and results of blood pressure lowering in randomized controlled trials (RCTs); and (4) Guidance statements, blood pressure lowering targets, and unanswered questions and challenges going forward.
The mechanisms underlying the link between hypertension and cognitive impairment are complex and diverse. Current evidence suggests that the synergistic interaction between multiple pathologic factors is likely responsible for hypertension induced cognitive impairment. A detailed review of this topic has been previously provided by the 2016 American Heart Association statement and others [3, 9, 11, 12]. Below we provide a brief summary of key points, and summarize current evidence using neuroimaging markers to elucidate the link between hypertension and cognition (Fig. 1).
Mechanisms linking hypertension with brain health. Hypertension results in cerebrovascular structural and functional alterations, disruption in the renin-angiotensin system’s function, inflammation, and oxidative stress. Such hypertension-induced alterations may compromise brain health by predisposing brain to white matter damage and cerebral small vessel disease, brain atrophy, cerebral macro- and microbleeds, brain ischemia/hypoxia, and deposition of pathologic proteins in the brain. All of the aforementioned brain lesions have been shown to negatively affect cognitive function.
The large and small cerebral vessels are the prime targets of hypertension in the brain. Hypertension results in structural and functional alterations in cerebral vessels, which, in turn, predispose brain to white matter damage, brain atrophy, cerebral macro- and microbleeds, brain ischemia and deposition of pathologic proteins. All of the aforementioned brain lesions have been shown to negatively affect cognition and increase the risk for cognitive impairment [11] (Fig. 1).
Blood flow to the brain is controlled by segmental vascular resistance in and around the brain [13]. Vessels primarily outside the brain including pial arterioles and large arteries, provide approximately 60% of the vascular resistance, and penetrating arterioles, capillaries and venules provide about 40% of the vascular resistance. When there is hypertension, cerebral vessels undergo adaptive structural changes in response to hypertension to protect downstream smaller vessels from the mechanical stress associated with increasing pressure. However, such adaptive structural changes may become maladaptive over time, resulting in various pathologies [12]. The interaction between several mechanical, humoral, and cellular factors—such as endothelial damage, inflammation, oxidative stress, and calcium deposition—are likely responsible for structural changes in cerebral vessels [14, 15]. Such structural changes in the setting of hypertension include atherosclerosis of larger cerebral arteries, arteriosclerosis, lipohyalinosis, microvascular rarefaction, hypertrophic and eutrophic vascular remodeling, and vascular stiffness [3, 11]. In particular, cerebral small arteries and arterioles are more vulnerable to the mechanical stress associated with hypertension [16, 17]. Alterations in these small vessels supplying the subcortical white matter may ultimately lead to cerebral small vessel disease (cSVD), which is a significant contributor to white matter damage, silent brain infarcts and clinically manifest lacunar strokes [3, 10, 11, 16, 17]. All these structural changes, in concert with alterations in cerebrovascular function, contribute to brain dysfunction and may ultimately lead to cognitive impairment.
Hypertension may adversely impact cerebrovascular functioning by disruption in
neurovascular coupling, cerebral autoregulation, and endothelium-dependent
mechanisms. Neurovascular coupling is a normal physiologic response to neuronal
activation that results in a localized increase in cerebral blood flow. This
mechanism is regulated by endothelial cells, neurons, astrocytes, and vascular
smooth muscle cells. Chronic hypertension has been shown to attenuate the
increase in cerebral blood flow in response to neuronal activation, thus creating
a mismatch between metabolic demand and blood flow delivery [16, 18]. Such
perfusion mismatch is thought to contribute to cognitive impairment, although
direct data examining the link between hypertension and loss of neurovascular
coupling in humans is lacking. Cerebral autoregulation, another normal
physiologic mechanism in the brain, is a regulatory mechanism that ensures
relatively constant cerebral blood flow over a wide range of blood pressure
fluctuations, which is likely mediated by neurogenic, myogenic and metabolic
mechanisms [19]. In the setting of chronic hypertension, there is a rightward
shift in the autoregulatory curve, which creates vulnerability to sudden changes
in blood pressure resulting in ischemia and increased risk for brain hemorrhage
[10, 11]. Direct data examining the link between hypertension and cerebral
autoregulation in the context of cognitive impairment in humans are warranted. A
recent study in the Coronary Artery Risk Development in Young Adults (CARDIA)
cohort showed that exposure to a higher burden of vascular risk
factors—including higher blood pressure levels—during young adulthood is
linked with worse cerebral autoregulation during midlife as measured by
transcranial Doppler ultrasound [20]. These results, albeit limited, support the
notion that impaired cerebral autoregulation is a likely early mechanism
underlying the link between higher blood pressure and negative cognitive
outcomes. Finally, hypertension has been shown to disrupt the function of
endothelial cells. Endothelial cells are critical in the regulation of
microvascular blood flow, blood-brain barrier function, and protecting the
vessels against thrombosis, atherogenesis, and accumulation of vascular amyloid
Emerging evidence supports the involvement of RAS in hypertension-induced brain injury and points toward the potential impact of drugs within this family to prevent dementia [10]. RAS is a complex system of interconnected hormones and receptors involved in the regulation of important physiologic functions such as water and electrolyte balance, hemodynamic hemostasis, and blood pressure. However, chronic activation of this system may lead to endothelial injury, oxidative stress, and inflammation, which in turn leads to various pathological conditions such as hypertension [22]. Although RAS was initially believed to be mainly localized to the systemic circulation, further research has revealed locally expressed RAS in a number of tissues including the brain [23]. In fact, all components of RAS are known to be locally produced in several brain regions and contribute to hypertension development and hypertension-induced brain injury [23, 24, 25, 26]. It has been shown that angiotensin II (Ang-II) in the brain—the main vasoactive peptide of RAS—promotes a hypertensive state by altering sympathetic neural outflow, the release of hormones involved in homeostasis regulation and inflammatory processes [24]. Ang-II in the brain is known to function through binding to two major receptors: Ang-II type I receptor (AT1) and Ang-II type II receptor (AT2). It is generally believed that the AT1 receptor mediates most of the hypertensive effects of Ang-II, while the AT2 receptor possesses opposing effects by promoting vasodilation, anti-proliferation, and increase in cerebral blood flow [23, 24, 25]. Activation of the Ang-II/AT1 axis has been shown to result in vascular remodeling, fibrosis, and vascular stiffness in the brain. In addition, Ang-II was shown to impair cerebrovascular function through its negative effects on cerebrovascular autoregulation, and inducing endothelial dysfunction and blood-brain-barrier breakdown [27, 28]. However, blockade of the AT1 receptor or angiotensin converting enzyme (ACE) was shown to reverse cerebrovascular dysfunction induced by hypertension [29] and improve endothelial cells’ barrier function via activation of AT2 receptor signaling [30, 31]. Interestingly, the AT1 receptor and ACE signaling were also linked with exacerbation of cell death in brain regions involved in cognitive function through initiating a cascade of oxidative stress processes in animal models [25]. The AT2 receptor activation, however, was shown to facilitate cognition and cell survival and possess antioxidant and anti-inflammatory functions [25]. Furthermore, experimental data suggest that the RAS in the brain may regulate processes beyond BP control including learning and memory behaviors [25]. Taken together, emerging evidence support the possible role of centrally acting RAS in hypertension-induced cognitive impairment. However, the interaction between systemic and centrally acting RAS remains largely unknown.
Given the negative effects of RAS on cerebrovascular function and structure in
the setting of hypertension, modulation of RAS has been a target to study in
relation to its impact not only on blood pressure lowering, but also on
cerebrovascular outcomes [32]. Modulation of RAS has been documented to have a
protective effect on cognitive function in various experimental models of
cognitive impairment such as Alzheimer’s disease’s (AD) models, hypertensive
animals, and post-stroke cognitive impairment [26]. In humans, observational
studies have provided evidence that RAS modulators are protective against
incident stroke [32], cognitive function, and incident dementia [25, 26]. A
meta-analysis on the impact of antihypertensive use on cognition that combined
results from both observational and RCT studies showed that Ang-II receptor
blockers (ARBs) had a greater beneficial effect on cognitive function than
Over the past few decades, neuroimaging studies have played a significant role
in advancing our knowledge about the mechanisms underlying the link between
hypertension and negative cognitive outcomes. Various neuroimaging markers,
including brain volume, radiographic markers of cSVD such as WMH, neuronal
connectivity, and brain amyloid
Neuroimaging markers of cSVD that manifest on MRI, such as WMH, lacunar infarcts, and cerebral micro-bleeds, have been all shown to have a strong relation with hypertension [9]. In particular, WMH on MRI has been established as a radiographic measure of hypertensive brain injury. Hypertension has been associated with higher WMH volume [43] and greater progression of WMH burden [44]. Moreover, WMH progression has also been associated with a greater decline in cognitive function [45]. Together, these findings suggest that white matter in the brain may be particularly vulnerable to the negative impact of hypertension. Moreover, accumulating evidence from newer imaging and analysis techniques, such as diffusion, kurtosis, free water, and myelin imaging, suggest that WMH represents the end of a continuous spectrum of white matter injury [46, 47, 48, 49, 50]. In fact, microstructural changes in normal appearing white matter may be measured long before they manifest as WMH on standard neuroimaging studies [51, 52]. Hypertension has been associated with worse white matter diffusion properties and microstructural integrity [53], and these associations appear to be largely independent of WMH volumes [54]. Similarly, accumulating evidence links cognition with white matter microstructural integrity as measured by diffusion imaging [55, 56]. In line with these, our recent results from the CARDIA cohort showed that higher exposure to SBP from young adulthood to midlife was associated with changes in diffusion properties of normal appearing white matter among middle aged adults without a significant burden of WMH [57]. Therefore, the health or integrity of the white matter, and even normal appearing white matter on MRI, may be a significant factor contributing to or leading to hypertension induced brain injury.
Finally, hypertension has been associated with AD specific markers on
neuroimaging, such as cortical thickness on MRI and amyloid
Epidemiological evidence linking hypertension and its components—SBP and DBP—with adverse cognitive outcomes is plentiful. A large number of observational studies have established a strong link between hypertension and a range of adverse cognitive outcomes [65]. Cognitive outcomes studied in relation to hypertension include cognitive function/decline, MCI, and dementia and its subtypes. While cognitive function assessed by neuropsychological tests allows capturing more subtle changes in cognitive function, MCI or dementia are clinically relevant outcomes that have stronger public health implications [10]. Hypertension has been associated with all of these cognitive outcomes [4, 5, 66, 67, 68]. In addition, a role for incident hypertension, prevalent hypertension, and prehypertension in relation to cognitive deficits has been implicated. For example, in ~3000 middle-aged participants from the Vieillissement Sante’ Travail (VISAT) study, Rouch et al. [69] showed that both prevalent and incident hypertension were linked with a steeper decline in global cognition. In the ARIC cohort, both hypertension and prehypertension were shown to increase the risk of incident dementia [70]. Similarly, ELSA-Brasil cohort results showed that hypertension and prehypertension were both associated with steeper decline in cognitive function (memory and verbal fluency) [71].
While epidemiological evidence clearly points toward a strong link between hypertension and worse cognitive outcomes, attention has been paid to the age-dependent impact of hypertension on cognition. Recently, results from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study showed that age modifies the relationship between blood pressure and cognitive change over a period spanning 8 years in older adults. It was shown that with increasing age, higher blood pressure values were associated with steeper global cognitive decline [72]. Furthermore, emerging evidence suggest that the negative impact of hypertension on cognitive outcomes may start as early as young adulthood, underscoring the need for primordial prevention of hypertension [73]. In line with this, the recent Lancet Commission statement indicates that hypertension in midlife, but not in late-life, is among the 12 potentially modifiable risk factors for dementia with a population attributable risk of 2% [74]. Given the importance of age at hypertension onset and its duration in relation to cognitive outcomes, below we summarize evidence from observational studies that focused on the relationship between hypertension—and its components—with cognitive outcomes according to different stages of life (Table 1).
Hypertension is linked with negative cognitive outcomes according to duration of hypertension and life-course time period: | |
Midlife hypertension is strongly associated with late-life cognitive impairment/dementia. | |
Young-to-midlife higher blood pressure exposure is associated with midlife cognitive impairment. | |
The association between hypertension and cognitive outcomes in late-life is complex and less consistent. | |
Distinct patterns of blood pressure changes over the life-course may be important predictors of late-life cognitive impairment. |
Substantial evidence from observational studies supports that high blood
pressure in middle aged individuals
Hypertension and higher blood pressure values (particularly SBP
Taken together, growing evidence from epidemiological studies suggests a strong
link between midlife hypertension and late-life cognitive deficits. These
findings support the notion that the duration of hypertension during midlife may
represent an important determinant of late-life cognitive deficits [9]. In line
with this, longitudinal studies have shown that a greater duration of time since
hypertension onset is associated with worse cognitive outcomes in late-life
[85, 86, 87]. Moreover, blood pressure patterns during the life-course may play an
essential role in cognitive functioning, as is discussed in section 3.3 below.
However, there remains several unanswered questions that need to be addressed in
future studies, such as (a) the optimal blood pressure level that is most
protective of cognition in late-life, (b) the precise period during which blood
pressure may be most deleterious for cognitive outcomes, and (c) the
age-dependent effect across the life course of antihypertensive treatment on
cognitive outcomes. Finally, to summarize the results of observational
prospective studies on the link between hypertension and cognitive outcomes in
midlife, it is worth noting the results of a recent systematic review and
meta-analyses [65]. In this study, 209 prospective studies published until August
2019 were identified that reported the impact of blood pressure exposure on the
risk of cognitive disorders in various stages of life, from midlife to late-life.
This meta-analysis included prospective studies of participants with normal
cognition or no MCI at baseline, resulting in ~2 million
individuals included in the meta-analyses. The mean age of participants ranged
from 35 to 93 years, and the mean duration of follow-up ranged from 1.5 to 43
years. Overall, this meta-analysis suggests that midlife blood pressure (defined
at
While most studies have focused on the link between midlife hypertension and
late-life cognition, emerging evidence suggest that high blood pressure as early
as childhood may negatively impact cognitive function. In the CARDIA study of
young to middle-aged participants from their 20s to 60s years of age, it has been
shown that cumulative years of elevated blood pressure beginning in young
adulthood have a stronger impact on cognitive function [6, 7], as compared to a
single blood pressure measurement in midlife [6]. In the same cohort, early-onset
hypertension (at
Studies on the relation between hypertension and cognitive outcomes in older
adults have reported conflicting results. While some studies have reported a
deleterious impact of hypertension on cognition, many others have failed to find
such a relation. For example, results from the Cardiovascular Health Study [90],
Framingham Heart Study [91], and Northern Manhattan study [92, 93] in older
adults 65–75 years of age suggest that hypertension is associated with a decline
in global cognition, executive function, processing speed, and memory. However,
in individuals with a mean age of 74
Hypertension in the 7th decade of life has been shown to increase the risk of
MCI [93], while no strong link between hypertension and risk of dementia has been
reported. By contrast, most studies support an association between low blood
pressure and increased risk of dementia in late-life. For example, in a pooled
analysis of adults aged 55–85 years from the Rotterdam study and the
Göteborg H-70 study, higher blood pressure was associated with reduced risk
of dementia in antihypertensive medication users [103]. The Kungsholmen project
showed similar results. Lower DBP increased the risk of dementia and AD,
especially in those taking antihypertensives or carriers of the Apolipoprotein E
(APOE) e4 allele [104]. In the Bronx Aging Study, low DBP was associated with a
2-fold higher risk of dementia and AD among adults
Only a few studies have assessed the link between hypertension and dementia subtypes, including vascular dementia among older adults [83, 103, 106, 107]. However, results are conflicting, showing both a positive relationship between hypertension and future development of vascular dementia [83, 106] or no relationship [103, 105, 107, 108]. It has been suggested that the relation between blood pressure and vascular dementia is age-dependent, such that high SBP is associated with increased risk of vascular dementia only between ages of 30 to 70, but not after 70 years of age [109]. It may be challenging to elucidate the relationship between hypertension and dementia subtypes as there is a high prevalence of mixed neuropathologies among cases of dementia [110], making such distinction between dementia subtypes difficult.
Taken together, observational evidence on the relation between blood pressure and cognitive outcomes in late-life does not show a consistent pattern. In fact, it appears that the link between blood pressure and cognition is largely dependent on the age at which blood pressure is assessed and the interval between blood pressure and outcome assessment. Furthermore, a non-linear curve may better explain the link between blood pressure and cognition in late-life. Such diverse findings in studies of older adults could be attributed to heterogeneous study populations, varied length of follow-up time, effects of specific classes of antihypertensive medications, or the confounding effect of other co-existing vascular risk factors in older adults. Finally, it should also be noted that other blood pressure components such as blood pressure variability and orthostatic hypotension may play a significant role in relation to cognitive deficits in late-life. Both blood pressure variability and orthostatic hypotension are more prevalent with increasing age and have been linked to cognitive deficits [111, 112].
In summary, taking into account the results from observational studies on
hypertension and cognitive outcomes in old age and results from a recent
meta-analysis [65] of prospective cohort studies up to August 2019, the totality
of data suggest that in late-life (defined as those
Several studies have identified the pattern of blood pressure changes over the
life-course as an important determinant of cognitive outcomes. The Adult Changes
in Thought study showed that in those aged 65–74 years who later develop
dementia, SBP is consistently high but also has a steeper decline two years prior
to dementia diagnosis [113]. However, among those aged
Few studies have focused on patterns of blood pressure starting from early
adulthood (e.g.,
In summary, current evidence suggests that there may be different patterns of blood pressure exposure from childhood to late-life in relation to cognitive outcomes. While during mid to late-life a pattern of high followed by low blood pressure appears to negatively impact cognition [121], in earlier adulthood, a pattern of consistently elevated blood pressure seems to be a dominant pattern for negative cognitive outcomes. Given that the early and middle adulthood periods are less likely to be confounded by the effect of medication use and other co-existing vascular risk factors, patterns identified in these stages of life may be prone to less observational study bias. Finally, the characterization of risk for cognitive deficits according to blood pressure patterns may need to be integrated into future risk assessment studies for better identification of those at higher risk of dementia.
As the most important contributor to the global burden of disease, one of the most important modifiable risk factors for cardiovascular disease, and one of the largest contributors to morbidity and mortality worldwide, hypertension is an ideal target for the study of preservation of cognitive function [122, 123]. In this section, we review RCT designs and results of blood pressure lowering studies to prevent cognitive impairment or decline. In addition, we discuss key systematic analyses and meta-analyses of blood pressure lowering and cognition. We first discuss two recent high impact studies that may be considered companion trials, Systolic Blood Pressure Intervention Trial Memory and Cognition in Decreased Hypertension (SPRINT MIND) and Action to Control Cardiovascular Risk in Diabetes Memory in Diabetes (ACCORD MIND).
SPRINT MIND is arguably the most influential of the blood pressure lowering
studies designed to preserve cognition. SPRINT MIND is a sub-study of a parent
study, the RCT SPRINT, and assessed the effect of intensive SBP lowering (goal:
Of the 9361 participants who had a median age of 67.9 years, of which 3332 (35.6%) were women, adjudicated dementia occurred in 149 persons in the intensive treatment group and 176 in the standard treatment group representing 7.2 versus 8.6 cases per 1000 person-years, respectively, and a hazard ratio (HR) of 0.83 (95% CI of 0.67, 1.04) [124]. The risk of MCI, however, was significantly reduced by intensive SBP lowering as there were 14.6 versus 18.3 cases per 1000 person-years, respectively, and a HR of 0.81 (95% CI of 0.69, 0.95). Similarly, the combined outcome of MCI and probable dementia were statistically significantly reduced in favor of intensive SBP lowering treatment (20.2 versus 24.1 cases per 1000 person-years and a HR of 0.85, 95% CI of 0.74, 0.97) [124]. SPRINT MIND study follow-up continued for about 3 years after the main phase study was terminated, and the SBP differences between the treatment groups favoring intensive therapy went from 13 to 6 mm Hg.
The results have been met with enthusiasm in favor of intensive SBP lowering to maintain cognitive function. Due to the early study termination of the parent study, SPRINT MIND may have been underpowered for the primary endpoint probable dementia [124]. SPRINT MIND is undergoing an extension study which may help to clarify the results in relation to an underpowered primary outcome [123]. In a prior critique of SPRINT MIND, we recommended healthy skepticism about blood pressure lowering to prevent cognitive impairment or decline based on difficulty showing a beneficial effect in many other blood pressure lowering trials (described below in other sections) [123].
In a MRI sub-study of cerebral white matter lesions and total brain volume, intensive SBP lowering was associated with a smaller increase in cerebral white matter lesion volume but a greater decrease in total brain volume, although the absolute differences were minor [125]. In a domain-specific cognition sub-study of SPRINT and a median follow-up time of 4.1 years, there was no statistically significant difference in composite scores for memory; however, there was a steeper decline of processing speed in the intensive treatment group. The differences were slight, and possibly not clinically relevant [126]. Finally, in a sub-study of AD imaging biomarkers (hippocampal volume, regional atrophy, posterior cingulate cerebral blood flow, and mean fractional anisotropy of the cingulum bundle), there was a small but statistically significant reduction in hippocampal volume that was higher in the intensive SBP treatment group, consistent with the findings for total brain volume [127].
SPRINT MIND was patterned after ACCORD MIND with the main difference being the
inclusion of patients with type 2 diabetes mellitus in the latter study [128].
ACCORD originally included an intensive glycemic arm (goal: hemoglobin A1c
[HbA1c]
The mean age of participants was 62 years, mean duration of type 2 diabetes
mellitus of 10 years, and mean HbA1c level of 8.3%, and there were no
differences in cognition at 40 months in either the intensive SBP lowering group
or fibrate treatment group [128]. However, there was a statistically significant
greater decline in total brain volume (by –4.4 cm
We now discuss Systolic Hypertension in Europe (Syst-Eur) trial [132, 133] and Perindopril Protection Against Recurrent Stroke Study (PROGRESS) [134] as less recent RCTs that provide support for lowering blood pressure in the maintenance of cognition.
4.3.1.1 Design. Syst-Eur had a vascular dementia project which investigated whether lowering
blood pressure could reduce the incidence of dementia [132]. Participants
included in the study had no dementia at baseline, were 60 years of age or older,
and had a blood pressure of 160–219 mm Hg/
4.3.1.2 Main results. Among 2418 randomized participants with a median follow-up of 2.0 years, the incidence of dementia was reduced by approximately 50% in favor of the active treatment group (7.7 versus 3.8 cases per 1000-patient years; 21 versus 11 patients; p = 0.05) [132]. The median MMSE score at baseline was 29 in both groups, and during the course of treatment the blood pressure was lower in the active treatment group (8.3 mm Hg/3.8 mm Hg). On average, MMSE scores did not change substantially in either treatment group, however, in control participants the MMSE score declined with declining DBP, but in the active treatment group, the MMSE scores had a marginal improvement with greater decline in DBP [132]. The investigators estimated that 19 cases of dementia might be prevented if 1000 hypertensive patients were treated for 5 years.
In an extended follow-up study to 3.9 years, active treatment reduced the risk
of dementia by 55% (43 versus 21 cases; p
4.3.2.1 Design. PROGRESS included 6105 participants (mean age of 64 years) with prior stroke or transient ischemic attack (TIA) [134]. The active intervention was perindopril with or without indapamide, a thiazide-like diuretic, and the comparator was placebo. The primary cognitive outcomes were dementia according to DSM-IV (the Diagnostic and Statistical Manual of Mental Disorders, fourth edition) criteria and cognitive decline defined by a drop of 3 points or more on the MMSE.
4.3.2.2 Main results. During a mean follow-up time of 3.9 years, dementia was diagnosed in 6.3% of
the participants in the active treatment group and 7.1% of those in the placebo
group (relative risk reduction 12%, 95% CI of –8%, 28%; p = 0.2)
[134]. Cognitive decline was diagnosed in 9.1% of those in the active treatment
group versus 11.0% of the placebo treatment group (risk reduction 19%, 95% CI
of 4%, 32%; p = 0.01). In the active treatment group, there was a
statistically significant reduction in the composite outcomes of recurrent stroke
with dementia (34%, 95% CI of 3%, 55%; p = 0.03) and cognitive
decline (45%, 95% CI of 21%, 61%; p
We summarize key elements of a number of RCTs that show neutral results in relation to blood pressure lowering and preservation of cognition in Table 2 (Ref. [135, 136, 137, 138, 139, 140, 141, 142, 143]).
Study name (publication date) | Participant characteristic | Intervention | Cognitive outcomes | Main results | Key conclusions |
SHEP* (1994) [135] | Active treatment with chlorthalidone (step 1), atenolol (step 2) or reserpine if atenolol contraindicated versus placebo. | Short-CARE administered at baseline and 6-month intervals for screening purposes, and once a cut-point is reached, the participant is referred for formal diagnostic evaluation. In addition, 2034 participants received a Part II evaluation of more specific cognitive tests. | Medical treatment did not cause deterioration in cognitive function in elderly persons with isolated systolic hypertension. | ||
SCOPE** (2004) [136] | Candesartan versus placebo. | Cognitive function and dementia were secondary outcomes (change in MMSE score, significant cognitive decline defined as |
Blood pressure lowering was associated with no harm in relation to cognitive outcomes, and the lack of a beneficial effect on cognition may be explained by the relatively short follow-up and small blood pressure differences between comparator groups. | ||
HYVET-COG*** (2008) [137] | Slow release indapamide with the option of adding perindopril versus placebo. | After baseline and annual MMSE administration, possible cases of dementia were defined by a fall in the MMSE score to |
There was a short follow-up period because the study was terminated early as there were significant results for the primary cardiovascular outcomes, however, the addition of the HYVET-COG data to a meta-analysis provided favorable results in support of blood pressure lowering to reduce the risk of incident dementia. | ||
PRoFESS^ (2008) [138] | MMSE was compared at 4 weeks after randomization and at the penultimate visit. | In relation to key cognitive outcomes among the various treatment groups, there was no significant difference in the median MMSE scores, the percentage of participants with a MMSE score of 24 points or less, the percentage with a drop in MMSE score of 3 points or more between 1 month and the last study visit, or in the proportion of patients with cognitive impairment or dementia (as determined by clinical impression). | Cognitive decline in patients with ischemic stroke was not affected by telmisartan or either of the antiplatelet regimens. The lack of a significant difference may be explained by the short follow-up period and relatively small reductions in blood pressure compared to other studies. | ||
ONTARGET and TRANSCEND^^(2011) [139] | The 2 trials provide different means of blocking the renin-angiotensin system (RAS). | Secondary outcomes were cognitive impairment established by investigator impression or a score of |
Although there were no clear beneficial effects of RAS blockade on cognition, persons with the lowest SBP had a greater likelihood of preservation of cognitive function though meta-regression analysis showed no clear benefits of BP lowering. Longer periods of blood pressure lowering may be necessary to achieve microcirculatory and subsequent cognitive benefit. | ||
SPS3^^^ (2012) [140, 141, 142] | Change in the Cognitive Abilities Screening Instrument (CASI) during follow-up. The CASI measures global cognition, attention, concentration, orientation, short-term memory, long-term memory, and other cognitive domains. Other cognitive tests were also administered. | The authors concluded that cognition was not influenced by either antiplatelet or blood pressure lowering therapies in relatively young participants, and future studies should focus on persons at higher risk of cognitive decline. | |||
HOPE-3* |
2 |
Digit Symbol Substitution Test (DSST), modified Montreal Cognitive Assessment (m-MoCA), and Trail Making Test. | Neither long-term blood pressure lowering nor lipid lowering significantly influenced cognitive decline. | ||
Part B at baseline and study end. | |||||
*SHEP: Systolic Hypertension in the Elderly Program Study; **SCOPE: Study
of Cognition and Prognosis in the Elderly; ***HYVET-COG: Hypertension in the Very
Elderly Trial cognitive function assessment; ^PRoFESS:
Prevention Regimen for Efffectively Avoiding Second Strokes trial;
^^ONTARGET and TRANSCEND: Ongoing Telmisartan
Alone and in Combination with Ramipril Global Endpont Trial and Telmisartan
Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular
Disease trial; ^^^SPS3:
Secondary Prevention of Small Subcortical Strokes trial;
* |
We now briefly discuss recent systematic reviews and meta-analyses of blood pressure lowering or treatment and incident dementia or cognitive impairment. We have limited our review to publications in the past several years as these studies represent the most up-to-date sources and databases.
In 2019 on the occasion of the publication of SPRINT MIND, Peters and colleagues
carried out a meta-regression analysis in light of the 8 completed RCTs that have
included different approaches to blood pressure lowering and dementia endpoints
[144]. Whereas none of the RCTs showed a clear beneficial effect, earlier studies
that had higher baseline blood pressure and those with the greatest reduction of
blood pressure from baseline might be expected to yield positive results. In
fact, the difference in SBP levels ranged from 2 to 17 mm Hg. In meta-regression
analysis (
In a separate meta-analysis published in 2020 of individual participant data from prospective cohort studies (n = 31,090 from 6 studies), Ding et al. [146] found no evidence that a specific antihypertensive medication drug class was more effective than any other in reducing the risk of dementia. In this particular analysis, the authors also concluded that those persons using a blood pressure lowering medication had a reduced risk of incident dementia (HR 0.88, 95% CI of 0.79, 0.98; p = 0.019) and AD (HR 0.84, 95% CI of 0.73, 0.97; p = 0.021) compared to those not taking blood pressure lowering medication. However, there was no association between administration of blood pressure lowering medication and incident dementia or AD in those with normal blood pressure [146].
In another publication from 2020 of 14 RCTs and 96,158 participants of which 12 addressed incidence of dementia, 8 reported decline in cognition, and 8 changes in cognitive test scores, the mean age of subjects was 69 years and approximately 42% were women [147]. At baseline, mean blood pressure was 154/83.3 mm Hg. There was a reduced risk of dementia or cognitive impairment among participants followed for a mean duration of 4.1 years and who were taking antihypertensive medication compared to controls (odds ratio 0.93, 95% CI of 0.88, 0.99; absolute risk reduction 0.39%). In addition, there was a reduction of cognitive decline (odds ratio 0.93, 95% CI of 0.88, 0.99; absolute risk reduction 0.71%), but blood pressure lowering had no beneficial effect on cognitive test scores.
Limitations of some of the above methodologies should be noted. Sub-group and meta-regression analyses from systematic reviews may be prone to ecological bias, and use of RCT data rather than observational data may be better suited to resolve some of the challenging and unanswered questions of interest.
Given that many persons who are at risk for cognitive impairment and dementia are older and have multiple cardiovascular risks, it may be reasonable to conclude that reduction of blood pressure alone may not be sufficient to reduce the risk of cognitive impairment and dementia as it may require a multi-domain approach of management of multiple risks. A recent wave of studies has answered the call for such clinical science, and the topic has been reviewed by one of us in a separate publication [148]. This is further supported by results of the recent Lancet Commission study suggesting 12 potentially modifiable risk factors for dementia: less education, hypertension, hearing impairment, smoking, obesity, depression, physical inactivity, diabetes, low social contact, excessive alcohol consumption, traumatic brain injury and air population [74]. These modifiable risk factors account for 40% of dementia cases, with a population attributable risk of 2% for hypertension alone [74]. In this context, a growing body of evidence has focused on the cumulative impact of various vascular and metabolic risk factors and their interaction on cognitive outcomes. For example, Petrova et al. [149] showed that those with diabetes type II and hypertension may have a greater cognitive decline than normotensive diabetic patients (n = 113, mean age of 56 years). Metabolic syndrome, its components, and exposure to a higher burden of vascular risk factors as defined by the American Heart Association/American Stroke Association (AHA/ASA) recommendations have been consistently linked with poor cognitive outcomes [1, 20, 150, 151, 152, 153]. Therefore, a multi-domain approach for the management of modifiable vascular and metabolic risk factors could be more effective in preventing dementia and/or its progression than a single component approach such as hypertension.
Of note, one of the studies provides promise that a multi-domain approach to prevent cognitive decline in at-risk older persons in the general population may be effective [154]. The RCT of interest is FINGER (Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability) [154]. The trial included persons 60–77 years of age who were screened using the CAIDE (Cardiovascular Risk Factors, Aging and Dementia Risk Score) to assure high enough risk (CAIDE scores were at least 6 points and cognition was at a mean level or slightly below that expected for age). The active intervention group had targeted diet, exercise, and cognitive training, and vascular risk monitoring, whereas a control group was counseled on general health advice. The primary outcome was change in cognition according to a comprehensive neuropsychological test battery (NTB). Approximately 630 participants were recruited to each intervention group.
Over a 2-year follow-up period, there was a mean change of the NTB total z-score of 0.20 in the intervention group versus 0.16 in the control group [154]. The between group differences in the NTB scores annually was 0.022 (95% CI of 0.002, 0.042; p = 0.030), and there were 7% adverse events in the intervention group (5% musculoskeletal versus 0%, respectively) versus 1% in controls. Of note, in addition to beneficial effects on overall cognition, the intervention group showed significant positive effects on executive function, processing speed, and body mass index, dietary habits, and physical activity. Such an intensive interventional program may be difficult to adopt on a wider basis. A worldwide FINGERS Network study has been implemented and is currently ongoing to seek further evidence of the influence of cardiovascular risk reduction on dementia, AD and cognitive impairment prevention in different populations [155]. Of additional note, SPRINT MIND has an ongoing multi-year extension study.
Finally, when considering multi-domain interventions, one must take into account other variables such as patient frailty, multiple comorbidities, polypharmacy, life expectancy, and patient preferences, especially in relation to values in older adults.
Observational epidemiologic study suggests that midlife hypertension is significantly associated with cognitive impairment and dementia in later life. In contrast, the larger scale RCTs which have disparate study methodology, have not consistently shown a beneficial effect of blood pressure lowering on cognition. The RCTs, however, are informative in relation to the following key points [148]: (1) Adequate sample size and follow-up time are desirable to assure that the study is adequately statistically powered; (2) In RCTs, it may be advantageous to utilize MCI and/or dementia as the primary outcome endpoint(s) rather than individual neuropsychological test domains; (3) Selection of patients at high enough cardiovascular risk seems prudent; and (4) Multi-domain interventions may be more desirable than single domain interventions (Table 3).
SBP target of 120 mm Hg for patients meeting SPRINT MIND trial eligibility criteria. | |
For patients not meeting SPRINT MIND eligibility criteria: | |
SBP target of | |
For patients not tolerant to a SBP | |
Potential risks (e.g., syncope, electrolyte imbalance) and benefits of intensive BP reduction to reduce cognitive, cardiovascular and stroke outcomes are to be considered. | |
Considerations for future BP lowering RCTs aimed at preservation of cognition: | |
Adequate sample size and follow-up time to ensure adequate statistical power. | |
Utilization of MCI and/or dementia as the primary outcome rather than individual neuropsychological tests. | |
Selection of patients with high enough cardiovascular risk. | |
Multi-domain intervention rather than a single domain intervention. |
The precise blood pressure lowering target to optimize cognition remains
somewhat elusive. For example, the main US blood pressure guidance statement
suggests that blood pressure lowering is reasonable to prevent cognitive decline
and dementia but does not set a specific blood pressure lowering target [156].
The recent Lancet Commission statement recommends treatment of hypertension to a
SBP target of
Based on clinical experience and recent guidance statements, and observational
epidemiologic data, we provide consideration of the following blood pressure
treatment targets for individual patients (Table 3): (1) For patients who meet
SPRINT MIND study eligibility criteria, it may be reasonable to aim for a SBP
target of 120 mm Hg [124]; (2) For other persons who can tolerate blood pressure
lowering, it may be reasonable to aim for a SBP lowering target of
A number of unanswered questions, challenges, and unknowns remain in relation to
blood pressure lowering to maintain cognition and serve as potential foci for
additional research. The questions and individual patient clinical circumstances
may lead to a higher blood pressure target in certain cases (e.g., SBP target of
130–160 mm Hg) [123, 158]: (1) Is it safe to lower blood pressure in very
elderly persons [159], as a number of observational epidemiologic
studies suggest a higher blood pressure may be better? (2) What should be the
blood pressure strategy if there is evidence of cognitive impairment (is blood
pressure lowering safe)? (3) State of the cerebral arteries: are we risking
causing more brain infarcts with blood pressure lowering in some persons, in deep
poorly collateralized brain areas, and can we predict who will or will not
tolerate blood pressure lowering by better understanding the mechanism of
underlying cerebral artery compromise? (4) What is the best strategy for diabetic
patients (e.g., ACC/AHA guidance: blood pressure target:
SM wrote sections 1, 2 and 3. FAS contributed to critical revision of manuscript for important intellectual content. PhBG wrote sections 4, 5 and 6. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript.
Not applicable.
We would like to thank all contributing authors and peer reviewers for their comments and suggestions.
This research received no external funding.
The authors declare no conflict of interest.