Hypertension and Its Role in Cognitive Function: Current Evidence and Challenges for the Future

Abstract

This review summarizes evidence from studies of blood pressure and dementia-related biomarkers into our understanding of cognitive health and highlights the challenges facing studies, particularly randomized trials, of hypertension and cognition. Several lines of research suggest that elevated blood pressure, especially at midlife, is associated with cognitive decline and dementia and that treatment of hypertension could prevent these conditions. Further, studies of hypertension and brain structure show that blood pressure is associated with several forms of small vessel disease that can result in vascular dementia or interact with Alzheimer’s pathology to lower the pathologic threshold at which Alzheimer’s signs and symptoms manifest. In addition, recent studies of hypertension and Alzheimer’s biomarkers show that elevated blood pressure and pulse pressure are associated with the extent of brain beta amyloid (Aβ) deposition and altered cerebral spinal fluid profiles of Aβ and tau indicative of Alzheimer’s pathology. However, in spite of strong evidence of biological mechanisms, results from randomized trials of antihypertensive therapy for the prevention of cardiovascular or cerebrovascular disease that include cognitive endpoints do not strongly support the observational evidence that treatment of hypertension should be better for cognition. We propose that future clinical trials should consider including dementia biomarkers and assess genetic and cardiometabolic risk factors that have been associated with progression of the underlying disease pathology to help bridge these gaps.

Hypertension is regarded as a key, modifiable risk factor for age-related dementia. It affects nearly two thirds of adults aged 65 and older in the United States.¹ Several decades of observational research studies present substantial evidence linking hypertension and elevated blood pressure (BP) to general brain health,² cognitive decline, and risk for dementia that are summarized by several excellent review articles^3–5 and meta-analyses.^6,7 Yet, a lack of supporting evidence from randomized clinical trials (RCTs) remains a critical barrier to recommending BP lowering as prevention strategy for preventing cognitive decline and dementia.

Our review is not intended to be an exhaustive review of the mass of human studies linking BP and cognition or even the much larger topic of brain health,² but instead to integrate evidence from studies of BP and dementia-related biomarkers into our understanding of cognitive health and highlight the challenges facing studies of BP and cognition. This review synthesizes the existing evidence to present the following salient conclusions: (i) the strongest evidence that BP is a risk factor for dementia and cognitive decline comes from observational studies with midlife measures of BP and late-life measures of the cognitive performance, (ii) the associations between late-life measures of BP and cognition are less consistent, (iii) midlife hypertension likely better reflects the long-term effect and duration of hypertension’s effect on the brain which can be also be captured by measures of arteriosclerosis, and (iv) there is compelling evidence that hypertension is associated with vascular dysfunction and evidence of cerebrovascular disease and beta amyloid (Aβ) deposition, 2 major pathologic factors in dementia; however, (v) there is a lack of definitive support for BP lowering to prevent dementia from randomized placebo-controlled clinical trials. This review of human studies describes the challenges of assessing the effects of hypertension and BP lowering on cognition and cognitive impairment. We propose that integrating dementia biomarkers, assessing genetic risk and including a priori cognitive endpoints into future studies of hypertension and dementia, especially RCTs, will help bridge these gaps.

OVERVIEW OF STUDIES OF BP AND COGNITION

Observational studies linking BP and cognition

Several decades of observational epidemiology studies suggest that there are strong links between elevated BP and cognitive impairment leading to dementia. The most consistent data come from longitudinal epidemiology studies evaluating midlife BP and cognition. They show that elevated BP in midlife is a strong, consistent risk factor for incident cognitive impairment and dementia^6,8,9 affecting global cognition and several cognitive domains,¹⁰ including worse performance and declines in executive function and processing speed, while associations with memory domains are less marked. In contrast, studies of late-life BP suggest that only the extremes of BP (systolic BP (SBP) >180mm Hg and diastolic BP (DBP) <70mm Hg) increase the risk for dementia.⁵ Others show that declines in BP in late life are associated with poor cognition and incident dementia.^8,11 The discrepancy between midlife and late-life BP measures and cognition may result from bias due to reverse causation wherein the physiologic declines in BP late in life may be secondary to dementia pathogenesis.¹²

Two recent longitudinal studies provide additional support for long-term temporal associations between elevated SBP in midlife and cognitive impairment 20 years later.^13,14 Although the 2 studies report different relationships between DBP and cognitive decline (linear vs. U-shaped), the relationship between midlife SBP and cognitive decline in both studies was linear and evident across several cognitive domains. Interestingly, this relationship appears to be stronger for Whites than for African-Americans.¹⁴

Supporting evidence from studies of BP and brain structural abnormalities

Supporting evidence of a relationship between BP and cognitive function comes from studies using neuroimaging and autopsy data to examine the relationship between BP and brain structural abnormalities underlying cognitive decline and dementia. This includes evidence of atrophy and cerebrovascular disease defined by magnetic resonance imaging, Aβ deposition quantified by positron emission tomography, and autopsy studies used to identify and quantify the pathologic correlates of dementia.

BP is related to smaller total brain volume and regional brain volumes in Alzheimer’s disease (AD) prone regions. A recent meta-analysis of BP and brain volume showed that higher BP levels are associated with smaller total, cortical, and hippocampal brain volumes, which was evident in both cross-sectional and longitudinal studies.¹⁵ These associations between high SBP and brain volume are evident regardless of treatment with antihypertensive medications.¹⁶ While high SBP appears to be associated with brain structural abnormalities in studies of older adults, it may not be evident across the entire adult age range^17,18 or consistent across all cognitive statuses. For example, in older adults with mild cognitive deficits using antihypertensive medication, a lower SBP, rather than a high SBP is associated with reduced volumes of thalamus, putamen, and hippocampus.¹⁹ In addition, low DBP is also associated with lower cortical thickness in older adults.²⁰ Thus, in older adults, any benefits of lowering SBP will have to be carefully balanced with potential harms of simultaneously lowering DBP. BP targets in older adults are currently controversial.²¹

While the mechanisms underlying these associations between BP and atrophy are unclear, some evidence suggests that subcortical vascular pathology on cortical neuronal apoptosis underlies brain atrophy.²² The relationship between BP and cortical gray matter volume appears to be driven by cerebrovascular disease and abnormalities in cerebral blood flow. Untreated hypertension, poorly controlled hypertension, and high BP levels are associated with a decline in cerebral blood flow.^23,24 Among older individuals with lower cerebral blood flow, low SBP and higher pulse pressure (PP = SBP – DBP, discussed in detail below) are associated with lower gray matter volume.²³ Hypertension is a risk factor for cerebral small vessel disease, which includes white matter hyperintensities (WMHs), cerebral microbleeds, and lacunar infarcts. Careful longitudinal studies show that high BP precedes WMHs and are associated with WMH progression.²⁵ This relationship is strongest among untreated hypertensive adults and those treated with inadequate control.²⁵ Uncontrolled hypertension is associated with greater WMH volume, cerebral microbleeds, and lacunar infarcts,²⁶ in some but not all studies.²⁷ In the PROGRESS study, a large secondary prevention of stroke trial, active BP lowering vs. placebo was shown to slow or stop the progression of WMH in patients with evident cerebrovascular disease²⁸ and those without.²⁹ These findings support observational studies that show reduced WMH burden for those under effective BP control.³⁰

Evidence of other forms of cerebrovascular disease are being incorporated into studies of BP and brain health.^31–35 Large epidemiologic studies such as Framingham, Cardiovascular Health Study, Rotterdam, Atherosclerosis Risk in Communities, etc. include measures of cerebrovascular disease beyond WMH, such as cerebral microbleeds, infarcts, and lacunes. These studies show that elevated BP is a risk factor for silent brain infarcts in large and small cerebral arteries,³⁶ prevalent and incident lacunar infarcts,^37–40 and cerebral microbleeds.^35,41 It is speculated that the cerebral amyloid angiopathy may be responsible for the microbleeds in the parietal lobes of the brain.⁴² Recent advances in imaging microinfarcts will likely increase our understanding of the relationship between BP and evidence of small vessel disease in the brain.⁴³

BP and evidence of Alzheimer’s disease pathology

AD often manifests as co-occurring neuropathology (e.g., a-synuclein, lewy bodies, etc.) with other neurodegenerative disorders and with evidence of cerebrovascular disease. In particular, the deposition of vascular Aβ described as cerebral amyloid angiopathy is emerging as an important marker of risk for AD, microinfarction, microhemorrhage and macrohemorrhage of the brain, and vascular cognitive impairment.⁴⁴ At autopsy, hypertensive older adults have evidence of greater AD pathology in the brain, including neurofibrillary tangles and neuritic Aβ plaques.^45–49 The frequency of AD pathology increases with increasing SBP⁴⁶ and with greater PP.⁵⁰

Recent in vivo positron emission tomography studies^51–53 show that the extent of Aβ deposition in the brain is positively associated with higher PP,⁵³ SBP,^52,54 and higher DBP.⁵¹ The relationships between BP and brain Aβ were consistent across cognitive groups (normal, mild cognitive impairment, and AD),⁵¹ evident regardless of antihypertensive therapy^53,54 and could potentially be attributed to underlying arterial stiffness.^52,54,55 While these studies controlled for antihypertensive medication use, they did not evaluate the effect of effective BP control or differences by drug class. In addition, the effect of clinically diagnosed hypertension on brain Aβ burden may differ by apolipoprotein E (APOE) genotype, with the greatest Aβ burden among clinically diagnosed hypertensive APOE-4 allele carriers.⁵³

There is also emerging data on the relationship between BP and cerebral spinal fluid (CSF) measures of AD pathology (high phosphorylated tau (p-tau) and low amyloid β (Aβ_1–42)). Nation et al. have published 2 recent studies showing that elevated PP is associated with increased CSF p-tau and decreased Aβ_1–42 in cognitively normal older adults consistent with CSF patterns of AD progression.^56,57 Further, individuals with elevated PP progressed to dementia more rapidly,⁵⁷ suggesting that pulsatile hemodynamics may be related to amyloidosis and tau-related neurodegeneration underlying dementia.⁵⁶ Another study reports longitudinal declines in mean arterial pressure in the elderly are associated increases in CSF p-tau and decline in cognition.⁵⁸ There is additional evidence that ACE protein levels and activity in CSF are associated with lower CSF Aβ_1–42 and higher p-tau levels, suggesting that modulation of the renin angiotensin system is related to AD pathology.⁵⁹ As of yet, there is scant data from RCTs on the effect of BP lowering on CSF levels of AD biomarkers. One pilot study reported that ramipril therapy inhibited CSF ACE activity and improved PP, but did not influence CSF Aβ_1–42.⁶⁰

BP LOWERING AND DEMENTIA RISK

While there is ample evidence that hypertension is associated with cognitive impairment and cerebral pathology and observational studies consistently suggest that BP lowering has potential benefit for reducing cognitive decline and dementia incidence, clinical trials of BP lowering do not strongly support the observational evidence. In general, these studies, summarized in several systematic reviews and meta-analyses, do not show definitive evidence that BP lowering with individual antihypertensive drugs or classes has an effect on cognitive decline or dementia.^9,10,61–64 Of the large RCTs, antihypertensive treatment has resulted in positive results in terms of prevention of dementia (SYST-EUR) and cognitive decline (PROGRESS, HOPE), but nonsignificant results in Medical Research Council trial, Systolic Hypertension in the Elderly Program trial, Study on Cognition and Prognosis in the Elderly, and HYpertension in the Very Elderly Trial cognitive function assessment.⁶¹ The combined result trials reporting incidence of dementia indicated no significant difference between treatment and placebo;⁶¹ and the combined results from the trials reporting change in global cognition using the Mini-Mental State Examination did not indicate a benefit from treatment, despite modest reductions in both SBP and DBP levels.⁶³ Challenges of these RCTs and for the future of hypertension research as it relates to cognition and prevention of cognitive impairment are presented below.

INHERENT CHALLENGES RELATING BP AND BP LOWERING TO COGNITION AND DEMENTIA

There are several challenges to relating BP and BP lowering to cognition that if not properly addressed can negatively bias results in both observational studies and RCTs. These challenges include, but are not limited to, when in the life course BP measures are assessed, using resting BP as a surrogate measure for complex vascular dynamics in the periphery and brain, treatment effects combined with physiologic BP declines in older adults, and the use of cognitive outcomes as the primary aims of relatively short-term studies.

Heterogeneity and bias within BP lowering trials

There are important distinctions to be made when evaluating and comparing RCTs of hypertension treatment, including: whether the BP treatment is intended for the primary or secondary prevention of vascular disease, the length of the intervention, differences between antihypertensive classes and unmeasured potential confounders that are just now being identified. First, it is important to appreciate that most hypertension treatment trials are usually designed as interventions for the primary or secondary prevention of cardiovascular disease or stroke and do not make a priori cognitive endpoints or use cognition as the primary endpoint. These studies only assess cognition as a secondary outcome, which is often underpowered.⁶⁴ However, it is now generally accepted that cerebrovascular disease is not only an important factor in vascular dementia but may also contributes to cognitive dysfunction in AD.^44,65 A Cochrane review focused specifically on individuals with no history of cerebrovascular disease and found no convincing evidence that BP lowering in late life prevents the development of dementia or cognitive impairment in hypertensive patients with no apparent prior cerebrovascular disease.⁶³

Next, the length of time the brain is exposed to elevated BP and PP is an essential factor to consider. Longitudinal studies of BP across the life span show that BP and the prevalence of hypertension peaks in late-middle age.^66–68 Age-related increase in BP is associated with increases in central arterial stiffness and PP.^66,68 Further, the duration of hypertension may be a stronger risk factor for cognitive dysfunction than age. This point is demonstrated by the AGES study⁶⁹ that recently showed having history of midlife hypertension appears to modify the relationship between late-life hypertension and brain health. Among those without history of midlife hypertension, higher SBP and DBP in late life was associated greater evidence of cerebral small vessel disease. In contrast, participants with a history of midlife hypertension, it was lower late-life DBP that was associated with smaller brain volumes and lower cognitive function.⁶⁹ Therefore the duration of hypertension is an important factor to consider for the chronicity of effect of high BP and excess pulsatile pressure on end organs and findings of protective associations between hypertension and cognition may reflect the study of persons with short duration of hypertension.⁶ Most intervention trials do not assess the duration of hypertension preceding the intervention.

The effect of individual agents on BP and cognitive function is an obvious consideration given the different mechanisms employed by antihypertensive classes. Using a network meta-analysis approach, Levi Marpillat et al. determined the rank-order of benefit for each drug class on overall cognition⁶² and found results similar to those reported by Duron et al.⁶¹ Benefit was highest for ARBs followed by calcium channel blockers, β-blockers, diuretics, and angiotensin-converting enzyme inhibitors over placebo.⁶² However, BP lowering appears to have beneficial effects on executive function regardless of antihypertensive class.⁶²

It is also possible that the goal of showing the differential effectiveness of individual drug classes may have biased existing RCTs. Previous trials test the effect of specific agents on cognition rather than assessing the effect of BP lowering itself on cognition. The ongoing SPRINT trial is the first proof of concept clinical trial to directly test BP lowering itself on cardiovascular, cognitive, and brain structural outcomes regardless of agent used to achieve randomized treatment goals.⁷⁰

There is emerging evidence that key unmeasured genetic and physiologic factors may play an important role in the effect of BP treatment on brain health and cognitive endpoints. The fact that APOE gene is the genetic risk factor for both cardiovascular disease and AD⁷¹ is often overlooked. As the primary genetic risk factor for late onset sporadic AD, carriage of the episilon 4 allele (APOE4) has broad effects on neurocognitive function and may accelerate the progression of AD pathology and cognitive decline.⁷² Recent studies show that APOE genotype moderates the association between BP and global cognition^73,74 as well as episodic memory and verbal ability.⁷³ The presence of the APOE4 allele in hypertensive adults was associated with steeper cognitive decline over the following 1⁹ to 2 decades.¹⁰ Taken together these studies suggest that APOE genotype may predict who is likely to find cognitive benefit from antihypertensive therapy and clinical trials should consider this in their design.

Finally, most studies of antihypertensive treatment have included only cognitive testing and incident impairment as secondary outcomes to existing studies without surrogate neuroimaging and biofluid markers discussed above. Relying solely on detecting cognitive decline and further expecting treatment to alter cognitive trajectories can be a challenge for short- and long-term RCTs. In AD research, it is increasingly accepted that AD biomarkers of tau and Aβ pathology precede more salient features of neurodegeneration and cognitive decline by years and even decades.⁷⁵ Therefore, RCTs testing agents that are proposed to alter the disease process can be hypothesized to alter dementia-related biomarkers early with greater impact than can be expected for cognitive endpoints in RCTs of a feasible length. Therefore, we propose that using dementia-related biomarkers underlying cognitive changes will be an essential component of future RCTs that seek to prevent dementia and modify the disease process.

Limitations of standard clinical BP measurement may influence hypertension—cognition study results

It is also important to consider the underlying physiology that resting BP is intended to represent in studies of cognition (see Figure 1). At the instant resting BP is measured, it is intended to represent the usual exposure to BP of an individual across hours and days. In the context of long-term exposure studies, this extends to make clinical BP a proxy of usual BP over weeks, years, and even decades of exposure. Resting BP is often the preferred method of choice given its accessibility, convenience, and ease of use. The approach of taking several BP measurements and then averaging reduces instrument variability; however, it is well known that clinical BP measures are susceptible to physiologic bias due to white coat hypertension or masked hypertension.^76,77 Typically both of these phenomena are identified by ambulatory BP monitoring (ABPM) and may contribute to some of the variability in serial BP measures over time in longitudinal studies.

Figure 1.

Diagram of the components contributing to arterial blood pressure, its antihypertensive targets and associated dementia-related brain outcomes. *Proposed cardiovascular targets. ARBs, angiotensin receptor blockers; ACIs, angiotensin-converting enzymes; CCBs, calcium channel blockers.

In addition to circumventing these biases, ABPM offers additional physiologic advantages over clinical BP measurements. These include: measurements averaging BP measures over a 24-hour period, diurnal patterns in BP, nocturnal assessment of BP, as well as heart rate and BP variability over the entire monitoring period. As a result, studies including 24-hour ABPM show stronger associations between ABPM-defined BP measures and dementia-related outcomes than clinical resting BP alone⁷⁸ including associations between higher 24-hour, daytime, and nighttime BP with lower gray matter volume⁷⁹ and WMH volumes.⁸⁰ Higher ABPM levels and non-dipping circadian patterns are also associated with greater WMH. Normally the BP declines as an individual sleeps. “Nocturnal non-dippers” (night-time SBP reduction <10%) and “extreme nocturnal dippers” (night-time SBP reduction of >20%) tend to have a greater burden of WMH^81,82 than “dippers” with normal nocturnal BP patterns (night-time SBP reduction 10–20%). Associations between different ABPM parameters (circadian pattern, short-term variability) and poorer performance scores in cognitive function tests have been reported, especially in elderly hypertensives.⁷⁸ Longitudinal studies using ABPM report similar and often stronger associations between diurnal BP and cognition compared with resting BP measures alone. Individuals with elevated 24-hour SBP tend to have with greater brain atrophy and greater progression of WMH over 5 years of follow-up.⁸³ Higher evening DBP on ABPM was also associated with greater risk cognitive impairment 20 years later.¹³ Taken together, these studies suggest that diurnal variations in BP are important predictors of incident cognitive impairment and white matter abnormalities indicative of brain ischemia. This is particularly important for older adults because nocturnal BP abnormalities (e.g., non-dipping) are more common and have a greater impact on cognition.⁷⁸

Other metrics of BP homeostasis are emerging as important factors related to brain health and cognition in aging adults. These include intervisit BP variability,^84–86 orthostatic intolerance,⁸⁷ and heart rate variability.⁸⁸ In particular, intervisit variability in BP is emerging as an important marker of dyshomeostasis in innate BP control with initial studies suggesting that variability in SBP over time is associated with greater atrophy, a higher rate of cortical atrophy and thinning,⁸⁴ global cognitive dysfunction,^85,86 and worse psychomotor speed and verbal memory.⁸⁶

The importance of assessing pulsatile flow from the heart to the brain

As a result of its extensive microvasculature, the brain is a high flow, low resistance organ that is continuously exposed to the mechanical forces of cardiac pulsations.⁸⁹ In the context of dementia, peripheral BP is only a surrogate marker for the degree of pulsatile energy to which the brain is exposed. In essence, arterial stiffness is the mechanism that relates the pulsatile force of the heart to the brain.⁹⁰ Arterial stiffness increases with age and is proposed to be accelerated by chronic hypertension.^67,68 PP is often used as a surrogate marker of arterial stiffness because it is often a readily available metric of convenience. PP (SBP – DBP) represents the net pulsatility during systole. Most studies use brachial BP to calculate PP, but it can be derived from any point in the vasculature. In general, a PP greater than 60mm Hg increases the risk for cerebrovascular events such as stroke. Higher PP is associated with severity of WMH⁹¹ and its progression over time²⁵; abnormalities in cerebral blood flow^23,24 and cerebrovascular pulstility,⁹² increased mean cortical Aβ deposition,^52,53 CSF p-tau levels,⁵⁶ severity of cerebrovascular disease at autopsy,⁵⁰ lower cortical gray matter volume,²³ and declines in cognition over time.⁹³ It is important to note that PP remains susceptible to the same biases as resting BP when derived from clinical BP measures.

There are additional methods to more directly assess the extent of underlying vascular stiffness. Arterial stiffness measured by pulse wave velocity (PWV) or ultrasound can be assessed locally and regionally and provides a more accurate assessment of vascular compliance and stiffness than brachial pressure alone. In essence, arterial stiffness directly relates central PP to kidneys and brain. The greater the stiffness the more pulsatile pressure is delivered to end organs. Similar to PP, PWV increases with age,^66,68 but it is not as susceptible to late-life BP declines.⁹⁴ Greater peripheral arterial stiffness, measured by PWV is a risk factor for hypertension,⁹⁵ stroke,⁹⁶ cerebral small vessel disease,^26,33 smaller brain volumes,^97,98 age-related cognitive decline,⁷ AD pathology,^54,55 and dementia.^4,7 Aortic arch PWV can also be measured with phase-contrast cardiac MR imaging.

Imaging advances in transcranial doppler ultrasound and cerebral blood flow magnetic resonance imaging may prove to be the most accurate assessment of cerebral pulsatile flow and arterial stiffness. Cerebral blood flow of the middle cerebral artery as measured by transcranial doppler ultrasound is tightly correlated with peripheral PP and the extent of arterial stiffness.²⁴ Transcranial doppler ultrasound derived measures have been associated with cognitive decline and dementia,⁹⁹ as well as smaller brain volume and larger ventricles, supporting the notion that excessive cerebral arterial pulsatility harms the brain.¹⁰⁰

CONCLUSIONS

To summarize the literature: (i) the strongest evidence that elevated BP is a risk factor for dementia and cognitive decline comes from observational studies with midlife measures of BP and late-life measures of the cognitive performance, (ii) the associations between late-life measures of BP and cognition are less consistent, (iii) midlife hypertension likely better reflects the long-term effect and duration of hypertension’s effect on the brain which can be also be captured by measures of arteriosclerosis (including PWV), and (iv) there is compelling evidence that hypertension is associated with vascular dysfunction and evidence of cerebrovascular disease and Aβ deposition, 2 major pathologic factors in dementia; however, (v) to date, there is a lack of definitive support for pharmacologic BP lowering to prevent dementia from randomized placebo-controlled clinical trials. While non-pharmacologic interventions for BP reduction were outside the scope of this review, it should be mentioned that exercise, in particular, because of pluripotent effects on the vasculature, including the regulation of vascular tone, cerebral blood flow, endothelial function, microvascular recruitment, energy metabolism, and insulin actions on the vessel (all important for brain health), could be an effective intervention for mitigating the association between hypertension and cognitive impairment.

There is growing consensus from AD studies that biomarkers related to dementia change years and decades prior to neurodegeneration and brain atrophy most closely linked to cognitive dysfunction; therefore, biomarkers maybe useful as surrogate markers of AD pathology in clinical trials. Future clinical trials should focus on controlling midlife hypertension, before arterial stiffening begins to transmit excess pulsatility to the peripheral microvsculature, and include dementia biomarkers and assess genetic and cardiometabolic risk factors that have been associated with progression of the underlying disease pathology. Though this review was focused primarily on cognitive impairment in general and mechanistic links between hypertension and AD, abnormalities in BP regulation may affect other neurodegenerative disorders as well. For example, in patients with Parkinson’s disease, orthostatic hypotension and supine hypertension are associated with worse cognitive function.

Only one clinical trial has focused on BP lowering itself and set a priori cognitive endpoints—the SPRINT trial. The SPRINT trial was designed to determine if intensive vs. standard BP lowering would affect the trajectory of cognitive decline, brain structural abnormalities, and/or incident dementia in middle-aged and older adults.⁷⁰ The intervention was stopped early (press release 9 November 2015) for cardiovascular disease benefit, before the majority of 4-year cognitive data were collected. However, efforts are now underway to collect the remaining cognitive data and we are hopeful that SPRINT may still be able to answer this important question.

DISCLOSURE

The authors declared no conflict of interest.