State of the Art
Hypertension and Its Role in Cognitive Function: Current
Evidence and Challenges for theFuture
Timothy M.Hughes1 and Kaycee M.Sink1
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 rand-
omized 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 hyperten-
sion 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 Alzheimers pathology to lower the pathologic threshold
at which Alzheimers signs and symptoms manifest. In addition, recent
studies of hypertension and Alzheimers biomarkers show that elevated
blood pressure and pulse pressure are associated with the extent of
brain beta amyloid (A) deposition and altered cerebral spinal fluid pro-
files of A and tau indicative of Alzheimers pathology. However, in spite
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 demen-
tia that are summarized by several excellent review articles35
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 asso-
ciations between late-life measures of BP and cognition are
less consistent, (iii) midlife hypertension likely better reflects
the long-term effect and duration of hypertensions effect
Correspondence: Kaycee M.Sink (kmsink@wakehealth.edu).
Initially submitted August 28, 2015; date of first revision September
15, 2015; accepted for publication October 6, 2015; online publication
November 11, 2015.
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 hyper-
tension should be better for cognition. We propose that future clini-
cal 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.
Keywords: Alzheimers disease; blood pressure; cognition; dementia;
hypertension; review.
doi:10.1093/ajh/hpv180
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 (A)
deposition, 2 major pathologic factors in dementia; how-
ever, (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 pro-
pose 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 thesegaps.
OVERVIEW OF STUDIES OF BP AND COGNITION
Observational studies linking BP and cognition
Several decades of observational epidemiology stud-
ies suggest that there are strong links between elevated BP
and cognitive impairment leading to dementia. The most
consistent data come from longitudinal epidemiology stud-
ies evaluating midlife BP and cognition. They show that
elevated BP in midlife is a strong, consistent risk factor for
1Department of Internal Medicine, Division of Gerontology and Geriatric
Medicine, Wake Forest School of Medicine, Winston-Salem, North
Carolina, USA.
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American Journal of Hypertension 29(2) February 2016 149
Hughes and Sink
incident cognitive impairment and dementia6,8,9 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 sup-
port for long-term temporal associations between elevated
SBP in midlife and cognitive impairment 20years 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 cogni-
tive 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 neuroimag-
ing 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, A deposition quantified by positron emission
tomography, and autopsy studies used to identify and quan-
tify the pathologic correlates of dementia.
BP is related to smaller total brain volume and regional
brain volumes in Alzheimers disease (AD) prone regions.
Arecent meta-analysis of BP and brain volume showed that
higher BP levels are associated with smaller total, corti-
cal, and hippocampal brain volumes, which was evident in
both cross-sectional and longitudinal studies.15 These asso-
ciations between high SBP and brain volume are evident
regardless of treatment with antihypertensive medications.16
While high SBP appears to be associated with brain struc-
tural abnormalities in studies of older adults, it may not be
evident across the entire adult age range17,18 or consistent
across all cognitive statuses. For example, in older adults
with mild cognitive deficits using antihypertensive medica-
tion, 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 ben-
efits 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 sug-
gests that subcortical vascular pathology on cortical neu-
ronal apoptosis underlies brain atrophy.22 The relationship
between BP and cortical gray matter volume appears to
150 American Journal of Hypertension 29(2) February 2016
be driven by cerebrovascular disease and abnormalities
in cerebral blood flow. Untreated hypertension, poorly
controlled hypertension, and high BP levels are associ-
ated 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 vol-
ume.23 Hypertension is a risk factor for cerebral small
vessel disease, which includes white matter hyperin-
tensities (WMHs), cerebral microbleeds, and lacunar
infarcts. Careful longitudinal studies show that high BP
precedes WMHs and are associated with WMH progres-
sion.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 pro-
gression of WMH in patients with evident cerebrovascu-
lar 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.3135 Large epi-
demiologic 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 stud-
ies show that elevated BP is a risk factor for silent brain infarcts
in large and small cerebral arteries,36 prevalent and incident
lacunar infarcts,3740 and cerebral microbleeds.35,41 It is specu-
lated 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 Alzheimers 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 A described as cerebral
amyloid angiopathy is emerging as an important marker of
risk for AD, microinfarction, microhemorrhage and macrohe-
morrhage 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 A plaques.4549 The frequency of AD pathology
increases with increasing SBP46 and with greater PP.50
Recent in vivo positron emission tomography studies5153
show that the extent of A deposition in the brain is posi-
tively associated with higher PP,53 SBP,52,54 and higher DBP.51
The relationships between BP and brain A were consistent
across cognitive groups (normal, mild cognitive impair-
ment, and AD),51 evident regardless of antihypertensive
therapy53,54 and could potentially be attributed to underly-
ing 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 A burden may differ by apolipoprotein E (APOE)
genotype, with the greatest A 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 (A142)).
Nation etal. have published 2 recent studies showing that ele-
vated PP is associated with increased CSF p-tau and decreased
A142 in cognitively normal older adults consistent with CSF
patterns of AD progression.56,57 Further, individuals with ele-
vated 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 A142 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 A142.60
BP LOWERING AND DEMENTIARISK
While there is ample evidence that hypertension is associ-
ated 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, summa-
rized in several systematic reviews and meta-analyses, do not
show definitive evidence that BP lowering with individual anti-
hypertensive drugs or classes has an effect on cognitive decline
or dementia.9,10,6164 Of the large RCTs, antihypertensive treat-
ment 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 low-
ering to cognition that if not properly addressed can
Hypertension and Its Role in Cognitive Function
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 cog-
nitive outcomes as the primary aims of relatively short-term
studies.
Heterogeneity and bias within BP loweringtrials
There are important distinctions to be made when evaluat-
ing and comparing RCTs of hypertension treatment, includ-
ing: 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 inter-
ventions for the primary or secondary prevention of cardio-
vascular 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 impor-
tant factor in vascular dementia but may also contributes to
cognitive dysfunction in AD.44,65 ACochrane 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 cogni-
tive 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 stud-
ies of BP across the life span show that BP and the prevalence
of hypertension peaks in late-middle age.6668 Age-related
increase in BP is associated with increases in central arte-
rial stiffness and PP.66,68 Further, the duration of hyperten-
sion 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 hyper-
tension 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 associa-
tions 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 hyperten-
sion preceding the intervention.
The effect of individual agents on BP and cognitive func-
tion is an obvious consideration given the different mecha-
nisms employed by antihypertensive classes. Using a network
meta-analysis approach, Levi Marpillat etal. determined the
American Journal of Hypertension 29(2) February 2016 151
Hughes and Sink
rank-order of benefit for each drug class on overall cogni-
tion62 and found results similar to those reported by Duron
et al.61 Benefit was highest for ARBs followed by calcium
channel blockers, -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 exist-
ing 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 car-
diovascular, cognitive, and brain structural outcomes regard-
less 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 end-
points. 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 cognition73,74 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 dec-
ades.10 Taken together these studies suggest that APOE
genotype may predict who is likely to find cognitive ben-
efit 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
Figure1. Diagram of the components contributing to arterial blood pressure, its antihypertensive targets and associated dementia-related brain out-
comes. *Proposed cardiovascular targets. ARBs, angiotensin receptor blockers; ACIs, angiotensin-converting enzymes; CCBs, calcium channel blockers.
152 American Journal of Hypertension 29(2) February 2016
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 increas-
ingly accepted that AD biomarkers of tau and A pathology
precede more salient features of neurodegeneration and cog-
nitive 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 cogni-
tive 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 hypertensioncognition study results
It is also important to consider the underlying physiology
that resting BP is intended to represent in studies of cogni-
tion (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.

In addition to circumventing these biases, ABPM offers
additional physiologic advantages over clinical BP measure-
ments. 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 reduc-
tion <10%) and extreme nocturnal dippers (night-time
SBP reduction of >20%) tend to have a greater burden of
WMH81,82 than dippers with normal nocturnal BP patterns
(night-time SBP reduction 1020%). Associations between
different ABPM parameters (circadian pattern, short-term
variability) and poorer performance scores in cognitive func-
tion tests have been reported, especially in elderly hyperten-
sives.78 Longitudinal studies using ABPM report similar and
often stronger associations between diurnal BP and cogni-
tion 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 5years of fol-
low-up.83 Higher evening DBP on ABPM was also associated
with greater risk cognitive impairment 20years 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 noc-
turnal BP abnormalities (e.g., non-dipping) are more com-
mon and have a greater impact on cognition.78
Other metrics of BP homeostasis are emerging as impor-
tant factors related to brain health and cognition in aging
adults. These include intervisit BP variability,8486 orthostatic
intolerance,87 and heart rate variability.88 In particular, inter-
visit 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 thin-
ning,84 global cognitive dysfunction,85,86 and worse psycho-
motor speed and verbal memory.86
The importance of assessing pulsatile flow from the heart to
thebrain
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 con-
text 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 avail-
able metric of convenience. PP (SBP DBP) represents the
net pulsatility during systole. Most studies use brachial BP to
Hypertension and Its Role in Cognitive Function
calculate PP, but it can be derived from any point in the vas-
culature. 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 progres-
sion over time25; abnormalities in cerebral blood flow23,24
and cerebrovascular pulstility,92 increased mean cortical A
deposition,52,53 CSF p-tau levels,56 severity of cerebrovascu-
lar 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 stiff-
ness 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 periph-
eral 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 cer-
ebral 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 ven-
tricles, 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 cogni-
tion are less consistent, (iii) midlife hypertension likely better
reflects the long-term effect and duration of hypertensions
effect on the brain which can be also be captured by measures
of arteriosclerosis (including PWV), and (iv) there is com-
pelling evidence that hypertension is associated with vascular
dysfunction and evidence of cerebrovascular disease and A
deposition, 2 major pathologic factors in dementia; however,
(v) to date, there is a lack of definitive support for pharma-
cologic 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, endothe-
lial function, microvascular recruitment, energy metabolism,
American Journal of Hypertension 29(2) February 2016 153
Hughes and Sink
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 bio-
markers related to dementia change years and decades prior
to neurodegeneration and brain atrophy most closely linked
to cognitive dysfunction; therefore, biomarkers maybe use-
ful 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 cardio-
metabolic risk factors that have been associated with pro-
gression 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 neuro-
degenerative disorders as well. For example, in patients with
Parkinsons 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 endpointsthe SPRINT trial. The
SPRINT trial was designed to determine if intensive vs.
standard BP lowering would affect the trajectory of cogni-
tive decline, brain structural abnormalities, and/or incident
dementia in middle-aged and older adults.70 The interven-
tion 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 impor-
tant question.
ACKNOWLEDGMENTS
K.M.S. is funded, in parts, by RFP NHLBI-HC-09-04,
NINDS R01 NS075107-01, NIA U01 AG022376, several
Alzheimers Disease Cooperative Studies (NIA), and is the
site PI for an industry sponsored trial of an amyloid imag-
ing agent (Navidea NAV4-02). T.M.H.is funded in parts by
NIH HHSN268201100027C and the Department of Internal
Medicine, Section on Gerontology and Geriatric Medicine.
DISCLOSURE
The authors declared no conflict of interest.
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