Compendium on the Pathophysiology and

Treatment of Hypertension
Neurovascular and Cognitive Dysfunction in Hypertension
Epidemiology, Pathobiology, and Treatment
Costantino Iadecola, Rebecca F. Gottesman

Abstract: Hypertension has emerged as a leading cause of age-related cognitive impairment. Long known to be
associated with dementia caused by vascular factors, hypertension has more recently been linked also to Alzheimer
disease—the major cause of dementia in older people. Thus, although midlife hypertension is a risk factor for late-
life dementia, hypertension may also promote the neurodegenerative pathology underlying Alzheimer disease.
The mechanistic bases of these harmful effects remain to be established. Hypertension is well known to alter
in the structure and function of cerebral blood vessels, but how these cerebrovascular effects lead to cognitive
impairment and promote Alzheimer disease pathology is not well understood. Furthermore, critical questions
also concern whether treatment of hypertension prevents cognitive impairment, the blood pressure threshold for
treatment, and the antihypertensive agents to be used. Recent advances in neurovascular biology, epidemiology,
brain imaging, and biomarker development have started to provide new insights into these critical issues. In this
review, we will examine the progress made to date, and, after a critical evaluation of the evidence, we will highlight
questions still outstanding and seek to provide a path forward for future studies.   (Circ Res. 2019;124:1025-1044.
DOI: 10.1161/CIRCRESAHA.118.313260.)
Key Words: Alzheimer’s disease ◼ biomarkers ◼ brain blood supply ◼ dementia
◼ risk factors ◼ white matter pathology

E levated arterial blood pressure (BP) contributes signifi-

cantly to the global burden of disease, its harmful effects
Subsequent population and prospective studies clearly es-
tablished the relationship between elevated BP and cognitive
Downloaded from http://ahajournals.org by on June 30, 2019

on the brain being a major culprit.1Well established as the
leading risk factor for stroke, hypertension has also emerged
as a pathogenic factor in cognitive impairment with a vas-
cular basis and Alzheimer disease (AD)—the major causes
of dementia in the elderly.2 The harmful effects of hyperten-
sion on cognitive function were already noted at the end of
the 19th century, in patients who later developed massive
cerebral hemorrhages, but systematic investigations on the
phenomenon did not appear until the 1950s to 1960s. In par-
ticular, pioneering observations on the neuropsychological
performance of air traffic controllers with hypertension by
Spieth3 and the longitudinal study on cognitive function in
hypertensives of Wilkie and Eisdorfer4 provided initial ev-
idence that hypertension deteriorates cognition. The intro-
duction of methods to measure cerebral blood flow (CBF)
let to the discovery that individuals with hypertension have
increased cerebrovascular resistance, which correlated with
the degree of hypertensive retinopathy,5 substantiating earlier
neuropathological findings linking cerebrovascular damage
with the effects of hypertension on brain health. However,
the prevailing belief at the time was that the elevation in BP
was a beneficial compensatory mechanism aimed at main-
taining normal cerebral perfusion, and attempts to lower BP
were considered dangerous.6
impairment7 and unveiled an unanticipated link between hy-
pertension and AD8. With the development of safe and effective
antihypertensive drugs and their widespread use, during the past
several decades, a dramatic reduction in the morbidity and mor-
tality caused by cardiovascular pathologies, stroke in particular,
was observed in a number of large clinical trials.9 Surprisingly,
however, similar beneficial effects on cognition were not u-
niformly noted.10 Owing to the rapid rise in the prevalence of
age-related dementia worldwide, hypertension has received
increasing attention as a treatable condition that, if properly
controlled, could potentially stave off the onset of the cognitive
deficits. Consequently, an increasing number of studies have
focused on the mechanisms by which hypertension impairs
cognitive function, on the temporal relationships between hyper-
tension and cognitive deficits during the life course, and on the
ideal BP targets to achieve to minimize its impact on the brain.
Although this body of new knowledge has provided a deeper
insight into the relationship between hypertension and the
brain, new questions have emerged that need to be addressed.
The present review seeks to provide an assessment of
the state of the art of the effects of hypertension on cognitive
function, on the underlying structural and functional altera-
tions and their mechanisms, and on potential preventive and
therapeutic strategies to minimize them. After a critical review

From the Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York (C.I.); and Departments of Neurology (R.F.G.) and
Epidemiology (R.F.G.), Johns Hopkins University, Baltimore, MD.
Correspondence to Costantino Iadecola, MD, Feil Family Brain and Mind Research Institute, 407 E 61st St, RR-303, New York, NY 10065. Email
coi2001@med.cornell.edu
© 2019 American Heart Association, Inc.
Circulation Research is available at https://www.ahajournals.org/journal/res DOI: 10.1161/CIRCRESAHA.118.313260

1025
 1026  Circulation Research  March 29, 2019
Nonstandard Abbreviations and Acronyms
Aβ amyloid-β
ACE angiotensin-converting enzyme
AD Alzheimer disease
Ang II angiotensin II
ApoE apolipoprotein-E
APP amyloid precursor protein
ARIC Atherosclerosis Risk in Communities
AT1R angiotensin type-1 receptor
BBB blood-brain barrier
BP blood pressure
BPH blood pressure high
CBF cerebral blood flow
CCB calcium channel blocker
Cdk5 cyclin-dependent kinase-5
CSF cerebrospinal fluid
DBP diastolic blood pressure
EVA Epidemiology of Vascular Aging
GSK3β glycogen synthase kinase-3
HAAS Honolulu-Asia Aging Study
ISF interstitial fluid
LYVE1 lymphatic vessel endothelial hyaluronan receptor-1
MCI mild cognitive impairment
MRI magnetic resonance imaging
NOX nicotinamide adenine dinucleotide phosphate oxidase
PET positron emission tomography
PROGRESS Perindopril Protection Against Recurrent Stroke Study
Downloaded from http://ahajournals.org by on June 30, 2019
PVM perivascular macrophage
ROS reactive oxygen species
SBP systolic blood pressure
SHR spontaneously hypertensive rat
SVD small vessel disease
of the evidence, we will attempt to identify outstanding ques-
tions and knowledge gaps that remain to be addressed.
Impact of Hypertension on Cognition
A growing body of evidence supports the role of hyperten-
sion as a risk factor for adverse cognitive outcomes. This ev-
idence primarily comes from epidemiological studies, which
consider hypertension in communities as a risk factor for a
range of adverse outcomes, including cognitive decline (wors-
ening of cognitive function over years to decades, steeper
than expected because of age alone), mild cognitive impair-
ment (MCI; reduced function in memory, thinking, and other
cognitive domains but not impacting daily functioning), and
dementia (impairments in cognition, including memory and
other cognitive domains, but with adverse impacts on daily
functioning). Studies considering cognitive decline allow e-
valuation of change, which captures more subtle cases of
cognitive dysfunction, without requiring frank thresholds for
dementia or MCI to be met but also may be a less confounded
measure of cognitive status, allowing a more pure evaluation
of the association between hypertension and cognition.11 In
contrast, studies considering MCI and dementia as outcomes
have a stronger public health message because these concepts
are easier to define and understand, and cases of preventable
disease are easily embraced, as opposed to changes in steep-
ness of cognitive slopes. For hypertension, evidence from
epidemiological studies supports all of these outcomes: hyper-
tension is clearly associated with steeper cognitive decline,12,13
poor cognitive performance,14 as well as incident MCI15 and
dementia.16–19 Furthermore, among adults with MCI, elevated
BP is associated with increased progression and worsening
of cognition.20 Prehypertension, previously considered as a
systolic BP (SBP) <140 mm Hg, has even been reported as a
risk factor for dementia in several studies, including the ARIC
(Atherosclerosis Risk in Communities) cohort,18 in which both
midlife hypertension and prehypertension conferred a similar
risk for dementia, at about 40% higher than among individuals
with normotension. New definitions of hypertension now con-
sider SBP in this range consistent with stage 1 hypertension.21
Although epidemiological data emphasize the importance
of hypertension in the development of stroke, the impact on
cognitive outcomes appears to be independent of stroke. This
is the case when stroke is defined clinically, with similar as-
sociations when individuals with incident stroke are excluded
from analyses on cognition,7,18 but fewer studies have system-
atically excluded subclinical stroke or small vessel disease
(SVD; including white matter lesions, lacunes, and enlarged
perivascular spaces), important mediators of the impact of hy-
pertension on cognitive outcomes.
The primary focus of this review is hypertension and its com-
ponents, SBP and diastolic BP (DBP), but different components
or aspects of BP may also play an important role in dementia.
Although pulse pressure was not significantly associated with
dementia in the HAAS (Honolulu-Asia Aging Study),17 it was
associated with cognitive decline among APOE (apolipoprotein-
E)-ε4 carriers in the Framingham Offspring Study.22 Most hu-
man studies do not differentiate between primary and secondary
causes of hypertension; although most studies primarily enroll
individuals with essential hypertension, rodent models consid-
ering several mechanisms of hypertension (including modeling
renovascular hypertension along with SHRs [spontaneously hy-
pertensive rats]) have demonstrated similar cognitive deficits and
white matter hyperintensities. Orthostatic hypotension, which
occurs more frequently in individuals with hypertension, was
associated with a 54% higher risk (95% CI, 1.20–1.97), with
relationships persisting after censoring for ischemic stroke.23 In
Uppsala, Sweden, using ambulatory BP monitoring, nondip-
ping circadian BP patterns and persistently high 24-hour BP (at
70 years of age) was associated with worse cognitive perfor-
mance.24 BP variability has also been described in several stud-
ies as an important risk factor for reduced cognitive function.25
Age-Dependent Risk (Midlife Versus Late Life)
Hypertension’s impact on late-life cognitive outcomes appears
the greatest when considered in middle age. Several studies
have demonstrated cognitive decline in people aged ≥70 years
when BP is elevated in the fourth or fifth decade of life. In the
HAAS, risk of reduced cognitive function in late life increased
as midlife SBP increased,14 and elevated SBP (>140 mm Hg)
in midlife was associated with a 1.77× higher risk of dementia
at ages 71 to 93.17 Furthermore in HAAS, elevated midlife BP
 Iadecola and Gottesman   Hypertension and Cognition   1027
(DBP, especially) and decrease in plasma Aβ (amyloid-β) 1–40
interacted to increase risk of late-life dementia.26 In the National
Heart, Lung, and Blood Institute Twin Study, higher midlife
SBP was associated with steeper 10-year cognitive decline.13 In
the ARIC cohort, hypertension in midlife was associated with
steeper 20-year cognitive decline on 3 repeated cognitive tests,
without similar associations with late-life hypertension, which
was not associated with cognitive decline during the preceding
20 years.12 Other studies have failed to find an association be-
tween BP and dementia or cognitive decline,27 but this may be
because they primarily focused on BP in older adults and with
a shorter follow-up period, without evaluation of hypertension
during its maximal risk period (middle age).
Some studies have suggested a U-shaped relationship be-
tween BP and cognition, but these studies seem isolated to
studies of older adults, further reflecting the potential detri-
mental effect of midlife hypertension but perhaps even a pro-
tective effect of late-life hypertension. There is no convincing
evidence that low BP, in younger people, is associated with
bad cognitive outcomes, but several studies do suggest worse
outcomes in older individuals with low BP. In 1 study, cogni-
tive performance was worst among individuals with either SBP
<130 mm Hg or with elevated SBP (≥160 mm Hg), compared
with people at 130 to 139 mm Hg, but this cohort consisted
of adults aged 65 to 102 years.28 In an analysis including data
from the Rotterdam study and the Göteborg H-70 study, hyper-
tension in old age appeared protective: elderly adults had an
inverse association between BP and dementia, with a reduced
relative risk for dementia of 0.93 (95% CI, 0.88–0.99) per 10
Downloaded from http://ahajournals.org by on June 30, 2019
mm Hg higher SBP, but only among elderly adults taking anti-
hypertensive medications.29 In the Bronx Aging Study, adults
>75 years of age with SBP between 140 and 179 mm Hg had a
lower risk for AD (hazard ratio, 0.55; 95% CI, 0.32–0.96), and
risk for dementia was especially high in individuals with low
DBP at baseline (age >75 years).30 A U-shaped relationship
between BP and cognition was also reported in the Baltimore
Longitudinal Study on Aging, among adults >80 years of age
who had decline at both extremes of BP.31
Although most observed associations are with demen-
tia broadly defined, several studies have attempted to cap-
ture dementia subtypes. Given the lack of gold standard for
subtyping dementia, it is plausible that these etiologic clas-
sifications actually represent mixed pathogenesis, so still may
point to a role of hypertension in dementias of other types. In
the Hisayama study, midlife (more so than late life) hyper-
tension was associated with vascular dementia, but not AD,32
with similar findings in the Adult Health Study in Hiroshima,
which evaluated SBP in association with subsequent 25-
to 30-year development of vascular dementia.33 In a large
Finnish study, midlife SBP ≥160 mm Hg was associated with
a >2-fold higher risk of AD, independent of other vascular and
demographic risk factors.19
Studies using imaging surrogates for cognitive or demen-
tia status also support the importance of midlife hypertension.
In the National Heart, Lung, and Blood Institute Twin Study,
midlife SBP was associated with not only more white matter
hyperintensities in later life but also smaller brain parenchy-
mal volumes.13 Furthermore, BP appears particularly related
to atrophy in regions highly relevant for AD (the amygdala
and the hippocampus, in this case).34 Other studies have also
reported strong associations with hypertension for SVD, in-
cluding white matter hyperintensities35 and their progression.36
Hypertension During the Life Course
Although the above studies emphasize the impact of midlife
hypertension as a risk factor for cognitive decline and demen-
tia, change in BP may be relevant as well. As discussed later
in this review, BP changes are particularly important when
considering shifts that occur in an individual’s autoregula-
tory curve in response to that individual’s baseline value. In
the HAAS study, men who developed dementia had a gradual
increase in SBP from midlife to late life, with a subsequent
decrease of 1.36 mm Hg/year in late life; in addition, of the
109 participants in this subcohort who developed dementia,
the majority (58%) had had a recent fall in SBP during the pre-
ceding 6 years.37 Similar patterns were shown in the Göteborg
Longitudinal Population Study, where 70 year olds with el-
evated BP had more dementia at 79 to 85 years of age, but
many also experienced decline in BP in the years more prox-
imal to a dementia diagnosis.38 In the Framingham Offspring
Cohort, elevated midlife BP was an important risk factor for
dementia, but a steep decline in BP from midlife to late life
was associated with a 2.4× higher risk of dementia in later life
(95% CI, 1.4–4.2).39
One complicating factor in studies of BP trajectories is the
fact that BP often falls in response to incident cognitive impair-
ment and dementia, making it difficult to determine whether
the apparent relationship with recent decline in BP is actually
because of reverse causation. Studies support lower and declin-
ing BP in elderly individuals with lower cognitive performance,
some of whom went on to develop dementia,40 consistent with
this concept of reverse causation possibly playing a role. This
may also explain the above-cited Rotterdam/Göteborg H-70
result,29 where hypertension in old age appeared protective.
Studies considering brain volumes as an outcome have also
found evidence that a late-life decline in BP may be a marker
for brain volume loss, with more cortical atrophy in individuals
with a drop in DBP of >10 mm Hg over 20 years in 1 study.41 In
the ARIC study, the pattern of midlife hypertension with sub-
sequent late-life hypotension was associated with smaller brain
volumes in regions typically affected in AD.42
Persistently elevated BP, from midlife and continuing
through later life, does appear to be consistently associated
with worse cognitive outcomes: Yaffe et al,43 evaluated cu-
mulative SBP and DBP level over 25 years, finding worse
cognitive performance on several tests among individuals
with higher areas under the curve based on cumulative BP.
However, using a Mendelian randomization design, genet-
ically predicted systolic hypertension was associated with
lower risk of AD, possibly indicative of subsequent changes
in lifestyle or management in response to this elevated risk.44
Cognitive Domains Affected
Although several studies have suggested that the impact of
hypertension on cognition is global, this is mostly the case
because not all studies broadly consider several distinct cogni-
tive domains or because the most impacted domains in hyper-
tension-associated brain disease are also represented in global
 1028  Circulation Research  March 29, 2019
cognitive measures. When more detailed neuropsychological
batteries are performed and hypertension-specific effects are
considered and compared, the biggest impact of hypertension
appears to be on executive function,12 motor speed, and at-
tention,45 which are classically considered domains involved
with subcortical disease, such as typical vascular disease or
pure vascular dementia.46 Even scores on the Mini-Mental
State Examination and Montreal Cognitive Assessment, 2
global cognitive measures, although lower in individuals with
more vascular risk factors, including hypertension, are prima-
rily driven by impairments in items related to attention (for
the Mini-Mental State Examination) and visuoexecutive func-
tion (for lower scoring individuals on the Montreal Cognitive
Assessment).47
The role of memory impairments in hypertension-relat-
ed dementias is complicated by the likely overlap between
pathogeneses and the high prevalence of mixed dementias.
Although memory is more typically involved in AD-related
cognitive impairments than in vascular types of dementia,
it has been noted to have impairments in individuals with a
combination of hypertension and elevated brain amyloid
by Pittsburgh compound-B positron emission tomography
(PET).48 However, many of these studies of domain-specific
cognitive deficits are influenced by misdiagnosis or difficulty
determining pathogenesis during life. Using a study neuro-
pathologic data, domains did not differ by pathogenesis as
might be expected: individuals with pure AD neuropathology
had reduced memory scores, more so than executive function,
but individuals with cerebrovascular disease had similarly re-
Downloaded from http://ahajournals.org by on June 30, 2019
duced premorbid cognitive function in executive function and
verbal and nonverbal memory.49
In summary, epidemiological data strongly support that
hypertension is associated with worse cognitive outcomes, es-
pecially when BP is considered in midlife. A pattern of midlife
hypertension followed by later life hypotension or normoten-
sion may be especially problematic, and consideration of BP
variability not only during the course of a day but during years
and decades may be important in understanding what compo-
nents of BP are the most important in increasing risk of cogni-
tive decline, MCI, and dementia. Although hypertension may
impact all aspects of cognition, its impact is the greatest on
motor speed, attention, and executive functioning. The likely
overlap with AD pathology, however, in the large group of in-
dividuals with mixed pathology of MCI and dementia, makes
differentiation of dementia subtype on the basis of patterns of
impaired cognitive domains challenging.
Pathobiology of the Effects of Hypertension
on the Brain
The cerebral vasculature is the prime target of the deleterious
effects of hypertension on the brain. In this section, we will
briefly review basic concepts on the blood supply of the brain
and its regulation and examine how chronic hypertension af-
fects the structure and function of cerebral blood vessels.
Blood Supply of the Brain
The brain’s blood supply is provided by the internal carotid
arteries and the vertebral arteries. These extracranial vessels
enter the skull and merge the base of the brain to form the
circle of Willis, from which the major intracranial vessels
supplying the brain originate (anterior, middle, and poste-
rior cerebral arteries; Figure 1).50 Branches of these arteries
travel along the brain surface giving rise to a highly anas-
tomotic vascular network (pial arteries).50 Branches of the
pial arteries penetrate the substance of the brain (penetrating
arterioles) surrounded by a virtual space, the perivascular
space, or Virchow-Robin space,50 separating the vascular ba-
sal lamina from the astrocytic processes enveloping the brain
parenchyma (glial limitans). As the vessels get smaller, the
perivascular space disappears and the vascular basal lamina
enters in direct contact with the astrocytic foot processes,
which completely envelop the vessel’s outer surface.50 At
this level, the vessel wall includes a single layer of smooth
muscle cells resting on the endothelial basement mem-
brane.50 As the vessels transition into capillaries, the smooth
muscle cell layer becomes discontinuous and is gradually
replaced by pericytes covering ≈30% of the abluminal cap-
illary surface.51 Venules are endowed with a discontinuous
smooth muscle cell layer, which becomes more pronounced
in veins, although not as marked as in the media of arter-
ies. Recent single-cell RNA sequencing studies have started
to unveil the molecular bases of the diversity of the cellu-
lar composition of the cerebrovascular tree.52 These efforts,
still in an initial stage, will provide critical insight into the
cellular, molecular, and signaling mechanisms underlying
the segmental susceptibility to hypertension of the cerebral
vasculature.
Effects of Hypertension on Cerebrovascular
Structure
Chronic hypertension exerts a profound influence on the struc-
ture of the cerebral vasculature. These structural changes re-
flect an adaptive response to protect downstream microvessels
from the increased transmural pressure. However, this process
over time becomes maladaptive resulting in different patholo-
gies depending on the segment of the cerebrovascular tree in-
volved (Figure 1).
Large Cerebral Arteries
Hypertension is a leading risk factor for extracranial and
intracranial atherosclerosis.53 Extracranial lesions are char-
acterized by lipid accumulation in carotid and vertebral
arteries, often associated with ulceration and atheroma in-
stability and protrusions, all linked to artery-to-artery em-
bolism.54 Intracranial lesions, affecting the circle of Willis
and its major branches, have a more fibrous component,
more likely to result in local vascular occlusions and focal
ischemic stroke.55
Remodeling is an important structural change induced
by hypertension and other vascular risk factors in extra-
cranial and intracranial cerebral arteries.56 Hypertrophic
remodeling leads to increased wall thickness and reduction
in vascular lumen, with an increase in media-to-lumen ra-
tio and in the total volume of wall tissue.56 Eutrophic (in-
ward) remodeling consists of an increased media thickness,
a reduced lumen, and external diameter, without changes in
the total amount of wall tissue.56 In a recent study assessing
 Iadecola and Gottesman   Hypertension and Cognition   1029

Figure 1. Cerebrovascular anatomy and segmental pathology induced by hypertension. Large extracranial cerebral arteries (internal carotid arteries and
vertebral arteries) enter the skull and converge at the base of the brain to form the circle of Willis from which the major intracranial cerebral arteries emanate.
Downloaded from http://ahajournals.org by on June 30, 2019

Branches of these arteries form a dense anastomotic network (pial arteries and arterioles), which give rise to arterioles that dive into the substance of the
brain (penetrating arterioles). Some vessels, like the lenticulostriate arteries, arise from the circle of Willis and proximal branches and vascularize the deep
brain structures, including the white matter (WM). The predominant pathology caused by hypertension in the different segment of the cerebrovascular tree is
indicated. Because of its precarious blood supply from terminal arterioles particularly vulnerable to hypertensive damage, the subcortical WM is highly likely
to be harmed by hypoxia-ischemia. ICA indicates internal carotid artery; and MCA, middle cerebral artery.

remodeling in the carotid arteries using magnetic resonance
imaging (MRI), the pattern of remodeling varied according
to the arterial segment.57 Whereas the common carotid artery
demonstrated hypertrophy, the carotid bifurcation exhibited
eutrophic remodeling. In contrast, the internal carotid artery
exhibited a mixed pattern of inward and outer remodeling.57
Sex and comorbidities had a significant effect on the pattern
of remodeling.57
Hypertension is also associated with stiffening of large
arteries. In humans as in animal models, stiffening precedes
the development of hypertension, raising the possibility that
it may contribute to the BP elevation by reducing vascular
compliance and increasing pulse pressure.58 At the same time,
stiffening may also reduce CBF,59 deplete cerebrovascular
reserves,60 and increase the hydrodynamic impact of the ele-
vated pressure (pulsatility) on the cerebral microvasculature.61
Perhaps because of these deleterious microvascular actions,
arterial stiffening is a sensitive predictor of subsequent white
matter lesions and cognitive impairment.
Pial and Penetrating Arteries and Arterioles
These vessels are responsible for a sizable component of
the pressure drop observed between large arteries and the
cerebral capillaries50,62 and, as such, are a prime target of the
effects of chronic elevations in BP. Animal studies suggest
that hypertrophic remodeling and eutrophic remodeling
are the predominant alterations in pial and penetrating ves-
sels, stiffening being less common than in large arteries.56
These vessels are often surrounded by enlarged perivascu-
lar spaces—a hallmark of SVD.63 Particularly vulnerable
are small arteries and arterioles of the deep cortical, peri-
ventricular, and basal ganglia white matter. These vessels
arise either from the first segment of the middle cerebral
artery, for example, lenticulostriate arteries, or from termi-
nal branches of the pial arteries, and converge on the white
matter deep into the hemisphere (Figure 2).64 Because of
the limited anastomosis and collateralization among pene-
trating arterioles, their dysfunction or occlusion is particu-
larly damaging to the white matter.62,65,66 Hypertension also
induces degenerative changes of the vessel wall, including
accumulation of an amorphous material consisting of de-
generated smooth muscle and collagen (lipohyalinosis) or
infiltration of fibrin and fibrin degradation products (fibrin-
oid necrosis).67 Possibly because of their shorter length and
higher pressures, fibrinoid necrosis is more common in ba-
sal ganglia arterioles and is frequently associated with ce-
rebral hemorrhage.67 Microatheromas can also be observed
in larger arterioles, which can lead to vascular occlusion.64
Alterations are also observed in capillaries, with reduction
in their number, swelling and loss of endothelial cells and
 1030  Circulation Research  March 29, 2019

Figure 2. Cerebrovascular autoregulation and hypertension. Autoregulation keeps cerebral blood flow (CBF) relatively stable during fluctuations in blood
pressure (BP). Autoregulation was first examined by measuring CBF during stepwise changes in BP, once a steady state is reached (static autoregulation;
left). Based largely on animal data, chronic hypertension was found to shift the pressure-flow curve to the right, such that the autoregulated range moves
toward higher BP. The development of methods to assess CBF dynamically like transcranial doppler flowmetry enabled to study the flow velocity changes in
large cerebral arteries during BP transients induced by different maneuvers, for example, standing from a sitting position. As illustrated in the right, middle
cerebral artery (MCA) flow drops in sync with mean arterial pressure (MAP). But, owing to an autoregulatory drop in cerebrovascular resistance (CVR), it
recovers faster. Evidence suggests that hypertension does not impair dynamic autoregulation, except in severe hypertension (see text for further details).
Right, Data derived from Aaslid et al.69

pericytes (string vessels), tortuosity, increased thickness of Impact of Hypertension on Cerebrovascular

the basal lamina, and fibrin deposition.68 Function
Endowed with limited energy reserves, the brain is highly de-
What Causes Remodeling and Stiffening?
pendent on the timely delivery of oxygen and glucose through
Remodeling and stiffening result from interacting mechanical,
blood flow to maintain its functional and structural integrity.50
Downloaded from http://ahajournals.org by on June 30, 2019

humoral, and cellular factors, including hemodynamic stress,

endothelial dysfunction, vascular inflammation, immune cell
infiltration, and calcium deposition.70,71 Both processes are
driven by overlapping mediators, including inflammatory cy-
tokines, sex hormones, Ang II (angiotensin II), endothelin,
aldosterone, and oxidative stress.72 In addition, modifications
of the extracellular matrix play an essential role in stiffening.
Accumulation of collagen and fibronectin, elastin fragmenta-
tion by matrix metalloproteases, and the profibrotic effects of
transforming growth factor-β are critical factors in the pro-
cess.70 A deficit in endothelial NO and free radicals may play
an important role in remodeling.56,72 In the aorta, perivascu-
lar macrophages (PVM) expressing the lymphatic hyaluronan
receptor LYVE1 (lymphatic vessel endothelial hyaluronan
receptor-1) safeguard the elasticity of the vascular wall by
governing collagen content in smooth muscle cells through
hyaluronan and pericellular matrix metalloprotease-9.73
Although LYVE1+ PVMs are present also in cerebral arter-
ies,73,74 it remains unclear whether they serve a similar role in
the homeostasis of the cerebrovascular wall.
In summary, stiffening, hypertrophic remodeling, and eu-
trophic remodeling result from the concerted action of me-
chanical, cellular, and molecular factors that converge on the
vascular wall to alter its structure and composition, as well
as the balance between collagen and elastin. Intended to pro-
tect the downstream microvessels from the mechanical stress
associated with elevated pressure, these responses become
maladaptive and, in concert with the functional alterations de-
scribed in the next section, contribute to the harmful effects of
hypertension on the brain.
To this end, sophisticated neurovascular regulatory mecha-
nisms assure that the blood supply is well matched to the
brain’s regionally and temporally diverse metabolic require-
ments, balancing energy delivery with removal of unwanted
byproducts of brain activity.50 In this section, we will first re-
view these mechanisms and then examine their disruption by
hypertension.
Neurovascular Coupling and Endothelial
Regulation
Neurons, astrocytes, and vascular cells work as a single func-
tional unit (neurovascular unit) to maintain the homeostasis
of the brain’s internal milieu.50 Brain activity is a major reg-
ulator of local cerebral perfusion, such that increased synap-
tic activity leads to increases in CBF highly localized to the
activated area.50 This fundamental property of the cerebral
circulation (neurovascular coupling) results from the close in-
teraction among cells of the neurovascular unit at all levels of
the cerebrovascular tree. Although the mechanistic bases of
the hemodynamic response remain to be completely elucidat-
ed, it is now clear that neurons, astrocytes, endothelial cells,
vascular smooth muscle cells, and pericytes all participate in
this carefully orchestrated process through multiple diffusible
mediators (NO, prostanoids, adenosine, ions, etc), ion chan-
nels, and segment-specific signaling mechanisms.50 Thus, ac-
tivation of neurons deep in the substance of the brain initiates
a series of highly coordinated vascular changes that start at
the level of the capillary endothelium and are transmitted to
upstream arterioles through intramural vascular signaling re-
sulting in their relaxation. The retrograde propagation of the
 Iadecola and Gottesman   Hypertension and Cognition   1031
vasodilation ultimately involves larger vessels at the brain’s
surface, which is required to induce a vigorous increase in
flow to the activated area.50,75 Endothelial cells are important
regulator of cerebral perfusion by producing powerful vasodi-
lators, for example, NO, prostacylin, or vasoconstrictors, for
example, endothelin-1.76 These vasoactive mediators are re-
leased in response to mechanical or chemical stimuli resulting
in increased or decreased in blood flow (endothelium-depen-
dent vasodilatation or vasoconstriction).76 The endothelium is
also the site of the blood-brain barrier (BBB) governing the
bidirectional molecular exchange between brain and blood.77
Furthermore, the endothelium exerts vital trophic effects on
brain cells and contributes to maintain the health of neurons,
glia, and oligodendrocytes.78,79
Hypertension reduces resting CBF and suppresses neu-
rovascular coupling and endothelium-dependent responses.
Contrary to early observations,5 several studies have shown
focal or global reductions in resting CBF in individuals with
hypertension.80,81 In a large-scale longitudinal study of hyper-
tensives with ischemic lesions and other vascular risk factors,
a reduction in global CBF was observed with uncontrolled or
untreated hypertension but not with satisfactory BP control.82
In cognitively normal people with hypertension, but no other
risk factors or evidence of brain damage, focal reductions in
CBF were observed in the prefrontal, cingulate, temporal, and
occipital cortex,83 suggesting that the reduction in CBF may
precede the development of brain pathology. It remains un-
clear whether these reductions in CBF are a consequence of
reduced brain energy metabolism or of a direct effect of hy-
Downloaded from http://ahajournals.org by on June 30, 2019
pertension on the cerebral vasculature. Although reductions
in glucose utilization—an index of energy metabolism—have
been reported in neocortical and subcortical brain regions of
patients with well-controlled longstanding hypertension,84 it
has not been established whether CBF is also reduced in these
regions. However, in patients with severe hypertension, oxy-
gen consumption is reduced in regions with reduced CBF,81
suggesting that with disease progression, the vascular effect
could be related to reduced metabolic demands possibly re-
lated to brain dysfunction and damage.
Relatively few studies have investigated neurovascular
coupling in patients with hypertension. The cerebrocortical
CBF response produced by cognitive tasks (memory and at-
tention), assessed by O15 PET, was reduced in patients with
untreated hypertension.85 Furthermore, in patients with re-
paired aortic coarctation, in whom only pulse pressure was
significantly elevated, the flow velocity increase produced
by photic stimulation in the posterior cerebral artery, which
supplies the visual cortex, was suppressed.86 Consistent with
altered neurovascular coupling, the increase in retinal blood
flow induced by light flickering was absent in individuals
with hypertension.87 These findings, albeit limited, support
the view that neurovascular uncoupling may compromise sub-
strate delivery to the brain and render the brain more vulnera-
ble to vascular insufficiency.
Endothelial dysfunction has been studied extensively in pe-
ripheral arteries and was found to precede the elevation in BP
and, once developed, to correlate with its severity.88 Although
direct assessment of cerebral endothelial function in humans is
not feasible, inhibition of NO synthesis does not reduce retinal
flow in patients with hypertension, indicating a deficit of NO
and endothelial dysfunction.87 Furthermore, postmortem anal-
ysis of arterioles of patients with SVD, most often caused by
hypertension, showed a reduced response to the endothelium-
dependent vasodilator acetylcholine.89 Independent evidence
for endothelial dysfunction is also provided by the observation
that hypertension alters the BBB90—a property of the cerebral
microvasculature attributable to endothelial cells.77
The implications of cerebral endothelial dysfunction
for the effects of hypertension on cognition are paramount.
Endothelial dysfunction is a prelude to atherosclerosis76 and,
as mentioned above, contributes to vascular remodeling and
stiffening. Failure of endothelium-dependent vasodilation in
peripheral arteries correlates with white matter lesion bur-
den91 and microbleeds,92 whereas in a population of elderly
hypertensives with subjective memory complaints, white mat-
ter lesion burden was associated with circulating levels of von
Willebrand factor— an index of endothelial dysfunction.93
The BBB dysfunction is also likely to have a devastating ef-
fect on the brain, especially in the white matter, wherein in-
creased BBB permeability has been implicated in the damage
produced by hypertension.90
Cerebrovascular Autoregulation
Cerebrovascular autoregulation refers to the ability of brain
vessels to maintain a relatively stable CBF, despite changes
in BP within a certain range.94 Owing to cerebrovascular au-
toregulation, CBF does not follow passively the BP swings
that occur during activities of daily living, protecting the brain
from excessive CBF fluctuations. Autoregulation has tradition-
ally been assessed using stepwise changes in BP and measur-
ing the corresponding changes in CBF when a steady state is
reached (static autoregulation).95,96 In the normal state, plot-
ting the CBF change as a function of the BP changes leads to
an italic S-shaped curve with a plateau in which CBF remains
relatively stable, despite changes in BP (the autoregulated
range: 60–150 mm Hg mean BP; Figure 2).95 More recently,
methods have been developed to assess cerebrovascular per-
fusion dynamics in response to fast changes in BP (dynamic
autoregulation; Figure 2).94 These studies have shown that
during pressure changes on a timescale of seconds, blood flow
does not remain stable but follows BP until the autoregulatory
adjustments in vascular resistance counteract the BP change
(Figure 2). In general, the faster the change in BP, the less ef-
ficient is autoregulation.97
The cellular bases of autoregulation rest, in part, on the
intrinsic property of the smooth muscle cells to constrict in
response to increases in transmural pressure (the myogenic re-
sponse of Bayliss).96 Accordingly, if BP increases, the smooth
muscle cells constrict the vessels and increase vascular re-
sistance, thereby preventing the CBF increase resulting from
the increased pressure. Conversely, decreases in BP relax
the smooth muscle, reducing vascular resistance and coun-
teracting the anticipated CBF decrease. Multiple redundant
mechanisms underlie the myogenic response, including (1)
mechanosensors that modulate intracellular Ca2+ levels in re-
sponse to changes in transmural pressure; selected candidates
include: transient receptor potential channels98 and G-coupled
receptors, including AT1Rs (Ang II type-1 receptors)99 and,
 1032  Circulation Research  March 29, 2019
possibly, tissue necrosis factor receptors100; (2) amplification
of the Ca2+ signal by depolarization and opening of voltage-
gated Ca2+ channels leading to further Ca2+ entry, as well as
intracellular Ca2+ release101; (3) modulation of the Ca2+ sensi-
tivity of the contractile apparatus by regulating the balance be-
tween kinases and phosphatases responsible for myosin light
chain phosphorylation and involving Rho kinase and protein
kinase-C.102 The mechanisms regulating the vasodilatation
that occurs during BP lowering are less well understood. It
has been suggested that the vasodilatation occurring with
reduced BP may be an active phenomenon driven by meta-
bolic byproducts, such as adenosine, which accumulates as
a result of the reduced tissue oxygen tension caused by the
hypoperfusion.103
Hypertension results in the chronic adaptation of the ce-
rebral circulation to higher levels of BP, such that the au-
toregulated range of CBF is higher than in normotensive
individuals.104 The implication of this right shift of the curve
is that, if the BP is lowered to a level that would be safe in
nonhypertensive individuals, the brain would be more suscep-
tible to hypoperfusion.95 The shift of the autoregulatory curve,
first described in a baboon model105 and verified in a limited
number of hypertensive individuals, has been attributed to the
increase in vascular resistance induced by remodeling in ce-
rebral resistance vessels.95 More recent studies of dynamic
autoregulation have failed to report major alterations in the
moment-to-moment adjustments of CBF to BP changes.106–108
Rather, in patients with moderate hypertension (mean SBP,
163±11 mm Hg), an enhancement of dynamic autoregulation
Downloaded from http://ahajournals.org by on June 30, 2019
was found.109 Furthermore, lowering BP with antihypertensive
therapy did not reduce flow velocity108,109 but improved carotid
artery distensibility after 6 months of treatment.108 However, in
patients with malignant hypertension (SBP, 180–260 mm Hg),
dynamic autoregulation was altered and flow velocity fol-
lowed passively the reduction in BP during treatment with so-
dium nitroprusside,110 suggesting that severe disease can have
a profound impact on both static and dynamic autoregulation.
These observations, collectively, indicate that while hy-
pertension may shift the autoregulatory range toward higher
BPs, the compensatory adjustments taking place during BP
variations within this range are not impaired, except in ma-
lignant hypertension. In addition, in moderate hypertension,
lowering BP does not seem to lead to cerebral hypoperfu-
sion. However, autoregulation data during the life course and
in the presence of vascular comorbidities are not available.
Therefore, it remains unclear how magnitude and duration of
the BP elevation influence dynamic autoregulation and what is
the impact of antihypertensive therapy on CBF.
Perivascular Spaces, Clearance, Neuroimmune
Trafficking
The brain vascular system and surrounding structures are also
responsible for the clearance of waste products generated by
brain activity, including toxic proteins, such as Aβ and tau.111
A transvascular pathway utilizes abluminal transporters that
carry solutes through the vascular wall and drain into the cir-
culating blood.77 Other pathways are thought to use the per-
ivascular space—a site of exchange between the interstitial
fluid (ISF) and the cerebrospinal fluid (CSF)—as a conduit to
carry solutes to the brain surface. In particular, a perivascular
pathway has been proposed to travel retrogradely within the
arterial wall,112 whereas a paravascular glymphatic pathway,
involving aquaporin-4 in astrocytic end-feet, reaches the brain
surface through perivenous spaces.113 However, this field is
still in evolution, and additional evidence is needed to assess
the relative weight of these clearance pathways in health and
disease. In the end, solutes drain into the cervical lymphnodes,
probably through dural lymphatics.114 Cerebral blood vessels
and perivascular spaces are also critical for the trafficking of
immune cells in and out of the brain required to maintain im-
mune homeostasis and protect the brain from invading patho-
gens.115 Innate and adaptive immune cells enter the brain
through transvascular, meningeal, choroid plexus routes and
play a critical role in immune surveillance and in a wide va-
riety of pathologies.115 In particular, as described in the next
section, PVMs located in the perivascular space have emerged
as a critical source of reactive oxygen species (ROS) in hyper-
tension with a profound impact on neurovascular function.116
How Does Hypertension Cause Neurovascular
Dysfunction?
Several animal models have been used to investigate the
neurovascular effects of acute or chronic elevations in BP.117
Better-studied models involve administration of pressor doses
of Ang II, which induce acute elevations in BP, or administra-
tion of subpressor doses (slow-pressor Ang II hypertension),
which produce delayed elevations in BP over several days. The
slow-pressor model has gained popularity since is thought to
reflect the progressive increase in BP observed in essential hy-
pertension, although with a more compressed timescale (2–4
weeks).118 In hypertension induced by acute or chronic Ang II
administration, there is attenuation of neurovascular coupling
and endothelium-dependent responses.119–121 Interestingly, the
mechanical effects of the elevation in transmural pressure are
not required for the cerebrovascular dysfunction, at least in
the short term.119,120 Neurovascular dysfunction and cognitive
deficits have also been reported in other models of hyperten-
sion, including lifelong hypertension in SHR or mice (BPH
[BP high] mice),74 intermittent hypoxia (a model of sleep ap-
nea),122 hypertension induced by administration of deoxycorti-
costerone acetate+salt,123 eNOS inhibition, etc.117,124
The pathways mediating the neurovascular effects of hy-
pertension induced by slow-pressor Ang II administration
have been studied in some detail and involve both central
effects on the brain and peripheral effects on cerebral blood
vessels. The evidence suggests that circulating Ang II acts on
AT1R in the subfornical organs—one of the circumventricular
organs—leading to ROS-mediated production of vasopressin
from the hypothalamic paraventricular nucleus. Vasopressin,
in turn, acts on cerebral blood vessels to trigger local endo-
thelin-1 production which, in concert with circulating Ang
II, contributes to the neurovascular dysfunction by inducing
vascular oxidative stress.125 Evidence from systemic vessels
also indicates a critical role of vascular oxidative stress.126
However, how oxidative stress alters vascular function re-
mains to be defined. In Ang II hypertension, peroxynitrite—
the reaction product of NO and superoxide—is required for the
neurovascular dysfunction,127 but whether the effect depends
 Iadecola and Gottesman   Hypertension and Cognition   1033
on reduction of NO bioavailability by the reaction with super-
oxide, or on downstream effects of peroxynitrite, remains to
be established. Evidence from the Ang II hypertension model
indicates that the latter possibility is more likely because a
peroxynitrite decomposition catalyst rescues the neurovascu-
lar dysfunction.127 Peroxynitrite could alter vascular function
through several mechanisms.128 In the neurovascular dysfunc-
tion produced by Aβ, peroxynitrite-induced DNA damage ac-
tivates the DNA repair enzyme poly-ADP ribose polymerase
and leads poly-ADP ribose production, which, in turn, opens
transient receptor potential melastatin-2 channels resulting in
endothelial Ca2+ overload and dysfunction.129 However, it re-
mains to be established whether this mechanism is also in-
volved in the neurovascular effects of Ang II hypertension.
There are several potential enzymatic sources of vascu-
lar oxidative stress, including mainly mitochondrial com-
plexes, xanthine oxidase, and eNOS uncoupling—a condition
in which the enzyme generates ROS instead of NO.130,131
However, a NOX-2 containing nicotinamide adenine dinucle-
otide phosphate (NADPH) oxidase has emerged as a critical
source of the ROS involved in neurovascular dysfunction, es-
pecially in Ang II hypertension. NOX2 is present in vascu-
lar and perivascular cells in close association with AT1R.74,120
Furthermore, pharmacological inhibition or genetic deletion
of NOX2 rescues the neurovascular dysfunction in models
of hypertension.120,121,125 Other isoforms of NOX, particularly
NOX1 and NOX4, may also present in the cerebral vascula-
ture, but their cellular localization and role in neurovascular
dysfunction has not been elucidated.130
Downloaded from http://ahajournals.org by on June 30, 2019
As for the cellular source of ROS, endothelial cells, smooth
muscle cells, and pericytes have the potential to produce ROS.
However, recent data suggest that PVMs are a critical source
of the ROS initiating the vascular dysfunction in Ang II hy-
pertension. PVMs are endowed with AT1R and, as phagocytic
cells, express large amounts of NOX2 and have a greater po-
tential for ROS production than vascular cells.116 In slow-pres-
sor Ang II hypertension and in BPH mice—a genetic model
of lifelong hypertension—PVM depletion prevents vascular
oxidative stress, neurovascular dysfunction, and cognitive
impairment, as well as middle cerebral artery remodeling in
hypertensive rats.74,132 Using bone marrow transplantation to
replace PVM with bone marrow–derived macrophages lack-
ing the AT1R or NOX2 abrogates vascular oxidative stress and
neurovascular dysfunction, pointing to PVM as the cellular
site of the AT1R and NOX2.74 Because in BPH mice and in
the slow-pressor model Ang II is elevated in the circulation
but not in brain, circulating Ang II was found to cross the BBB
and gain access to PVM on the abluminal side of the vessels
(Figure 3).74 Although PVMs are unlikely to be the sole source
of vascular oxidative stress, the observation that their elimina-
tion or genetic modification blocks vascular ROS production
suggests that they are the primary source, which may trigger
oxidative chain reactions in adjacent vascular cells. Whether
PVMs are also involved in the neurovascular dysfunction in
human hypertension remain to be established. However, as
discussed in the next sections, the observation of perivascular
space abnormalities, vascular oxidative stress, and inflamma-
tion in SVD is consistent with findings emerged from animal
models implicating PVM.
In summary, experimental studies and human data indi-
cate that oxidative stress and inflammation are critical factors
in the alterations in neurovascular and endothelial function
produced by hypertension. Although other enzymatic sourc-
es cannot be excluded, NOX2 has been identified as a major
source of ROS in hypertension involving Ang II. Furthermore,
innate immune cells, the PVM in particular, have emerged as
a powerful source of vascular ROS production.
Brain Lesions Induced by Hypertension and
Their Impact on Cognition
The alterations in cerebrovascular structure and function in-
duced by hypertension described in the previous sections
predispose the brain to dysfunction and damage, which, in
turn, alters cognition. Chronic hypertension is the major risk
factor for ischemic and hemorrhagic stroke, which is asso-
ciated with a 3- to 6-fold increase in cognitive impairment,
especially when multiple strokes are involved (multi-infarct
dementia).66 Additional lesions associated with hypertension
include microinfarcts and microhemorrhages, microscopic is-
chemic or hemorrhagic lesions most common in the cerebral
cortex, which portend cognitive deficits.133–135 Hypertension is
also associated with enlarged perivascular spaces, which also
correlate with cognitive impairment.63 The expansion of the
perivascular spaces may be because of fluid stagnation and
protein accumulation reflecting impaired ISF/CSF clearance,
as well as the mechanical stresses on the perivascular tissue
by the increased pulsatility and stiffening.63 Of note, enlarged
perivascular spaces can be confused with small cavitated le-
sions (lacunae) on conventional brain imaging, and it has been
proposed that lacunes rather than enlarged perivascular spaces
correlate with cognitive impairment.136 The mechanisms of
the brain atrophy induced by hypertension remain unclear,
but (1) chronic hypoperfusion leading to neuronal loss,80 (2)
retrograde neurodegeneration from deafferentation because
of lesions in other brain regions,137 or (3) vascular oxidative
stress and inflammation,138 leading to neurovascular trophic
failure,139 are potential contributing factors.
The most common brain lesions associated with hyper-
tension are white matter lesions, especially in the frontal cor-
tex, which appear as areas of hyperintensity on T2-weighted
MRI.140 SVD is considered the major cause of white matter
disease, but the mechanisms have not been completely elu-
cidated.141 Cerebral hypoxia-ischemia because of stenosis or
occlusion of vessels feeding the white matter, which are par-
ticularly susceptible to the effect of hypertension, is consid-
ered to be a major contributor.66 In support of this hypothesis,
reduction in CBF in normal-appearing white matter and ex-
pression of hypoxic markers have been reported.142,143 Other
studies have not supported this view144,145 and have suggested
that hypoperfusion is not the cause but the consequence of
the white matter lesion.146 Inflammation, upregulation of me-
talloproteases, and increased BBB permeability in the white
matter may lead to water shift and local edema resulting in
microvascular compression and occlusion.146,147 A link be-
tween vascular health and white matter maintenance and
repair by oligodendrocyte has also been established. A pop-
ulation of oligodendrocytes associated specifically with cere-
bral blood vessels has been identified148 and oligodendrocyte
 1034  Circulation Research  March 29, 2019

Figure 3. Putative mechanisms of neurovascular dysfunction in slow-pressor Ang II (angiotensin II) hypertension, BPH (blood pressure high) mice and
deoxycorticosterone acetate+salt hypertension. Circulating or brain Ang II reaches AT1R (angiotensin type-1 receptor) in perivascular macrophage (PVM)
wherein it activates NOX2 leading the vascular oxidative stress and neurovascular dysfunction. AT1R and Nox2 are also present in other vascular cells, but
they do not seem to play a primary role in these hypertension models. The cartoon depicts a penetrating arteriole, but brain macrophages are also present
in the meninges, wherein they may play a role in pial and meningeal vessel vasomotor function and permeability. Whether PVM has a similar role in models
Downloaded from http://ahajournals.org by on June 30, 2019

of Ang II–independent hypertension remains to be established. EC indicates endothelial cell; ROS, reactive oxygen species; and SMC, smooth muscle cell.
Illustration Credit: Ben Smith.

proliferation and survival requires vascular growth factors.149
These observations have suggested an oligovascular niche es-
sential for the maintenance of white matter health. Indeed,
arrested development of oligodendrocyte precursors has been
observed human white matter in SVD resulting in faulty re-
myelination of damaged white matter (Figure 4).150
In summary, oxidative stress, hypoxia-ischemia, inflam-
mation, and BBB dysfunction are critical vascular factors
threatening the health of the subcortical white matter. There
might be regional differences on the impact of hypertension
on white matter, and the white matter of the frontal lobe may
be more susceptible.134,140 However, the mechanistic bases for
such predilection remain to be established.
How Does Hypertension Cause Cognitive
Dysfunction?
Atrophy, brain damage caused by macroinfarcts and microin-
farcts, and hemorrhages are important determinants of cogni-
tive impairment. Furthermore, infarcts strategically placed in
brain regions involved in cognition, for example, hippocam-
pus, medial thalamus, and frontal lobe, can produce cognitive
dysfunction, despite relatively small volume of damage,66,134
and the estimated functional impact of microinfarcts is greater
than anticipated by the volume of injury.151 The volume and
location of white matter lesions also correlate with the degree
and temporal evolution of cognitive dysfunction.134 These
white matter lesions may affect cognition by impairing the
connectivity between the anterior thalamus to the frontal cor-
tex.134,152 Indeed, studies using white matter tractography and
resting-state MRI have provided evidence for loss of connec-
tivity and network efficiency degradation, which correlate
with a reduction in processing speed—a typical feature of vas-
cular cognitive impairment.152 In addition, brain atrophy could
also be a contributing factor by reducing gray matter in critical
brain regions, such as hippocampus and prefrontal cortex.153
The impact of enlarged perivascular spaces on cognitive
impairment of hypertension remains uncertain. The morpho-
logical alterations of the perivascular space raise the possibil-
ity that perivascular and paravascular clearance systems may
be altered and have a role in the white matter damage.63,141
Perivascular spaces are enlarged and distorted in hyperten-
sion63—an alteration that could hamper the disposal of po-
tentially toxic byproducts of brain activity. Hypertension is
associated with Aβ and tau pathology (see Hypertension and
Alzheimer Pathology), suggesting that clearance of these
proteins may be reduced. Hypertension-induced large artery
stiffening increases pulsatility in microvessels, which has
been proposed to alter perivascular spaces and reduce ISF/
CSF clearance.63 However, a transient increase in pulsatil-
ity induced by administration of dobutamine increases CSF
clearance in mice,154 suggesting that hypertension could in-
crease ISF/CSF clearance. In support of this hypothesis, ISF
flow is increased in SHR, but such increase is associated with
greater retention of tracers at the ISF/CSF interface, indicating
 Iadecola and Gottesman   Hypertension and Cognition   1035
Figure 4. Potential mechanisms of white matter (WM) damage by
hypertension. Vascular oxidative stress and inflammation disrupt the
blood-brain barrier (BBB), induce neurovascular unit (NVU) dysfunction
and damage, and impair oligodendrocyte development and function. The
resulting alterations in tissue homeostasis, hypoxia-ischemia, reduced
brain clearance, and impaired remyelination lead to WM damage.
Downloaded from http://ahajournals.org by on June 30, 2019
a reduction in clearance.155 On the contrary, carotid ligation
reduced CSF clearance,154 suggesting a negative impact of ce-
rebral hypoperfusion and reduced pulsatility, which is relevant
to large artery stenosis or occlusion often associated with hy-
pertension. Therefore, direct evidence linking hypertension to
brain clearance pathways has not been provided, in humans as
in animal models, and additional work is needed in this area.
These observations, collectively, suggest that hypertension
may lead to cognitive impairment through several pathogenic
factors (Figure 5). Gray matter loss, loss of connectivity and
network efficiency from white matter lesions, reduced peri-
vascular clearance, and neurovascular dysfunction all have the
potential to impair brain function, but their relative impact on
cognitive processes remain to be established.
Hypertension and Alzheimer Pathology
A large body of evidence indicates that hypertension is a risk
factor for AD—a condition once considered purely a neuro-
degenerative disease. AD is characterized neuropathologi-
cally by extracellular accumulation of Aβ (amyloid plaques)
and intraneuronal aggregates of hyperphosphorylated tau
(neurofibrillary tangles).2 Aβ is derived from the proteolytic
cleavage of the APP (amyloid precursor protein) by β- and
γ-secretase enzymes.2 Vascular brain lesions similar to those
associated with vascular cognitive impairment are also present
in AD, such that mixed AD-vascular pathology is present in
the majority of AD cases diagnosed clinically.156 The recent
availability of imaging and biochemical biomarkers of AD
has provided the opportunity to investigate the relationship
Figure 5. Brain lesions produced by hypertension that underlie cognitive
impairment. Brain atrophy, microinfarcts, and microbleeds cause neuronal
loss and brain dysfunction. In addition, microinfarcts and microbleeds
disrupt brain connectivity and reduce network efficiency. Damage to
white matter lesions (WML) also degrades connectivity, especially
in thalamo-cortico networks. Alteration in perivascular spaces (PVS)
impairs brain clearance and may promote protein accumulation in brain
and vessels, and dysfunction of the neurovascular unit (NVU) leads to
vascular insufficiency and BBB damage. Potential interactions between
different pathogenic mechanisms are indicated by the dashed arrows. CBF
indicates cerebral blood flow.
between AD pathology and hypertension in vivo, in an attempt
to explore the nature, causal or incidental, of their association.
Clinical-Pathological Biomarkers of AD in
Hypertension
Although hypertension’s impact on cognition is fairly clearly
established, whether this acts directly on AD neuropathology
or simply as a parallel contributor to cognitive impairment and
dementia is still somewhat controversial.8
In the ARIC-PET study, nondemented participants with
a greater number of vascular risk factors in middle age, in-
cluding hypertension, had more elevated brain amyloid in late
life, suggesting a possible direct impact of these risk factors
on amyloid; hypertension by itself, however, was not signifi-
cantly associated with elevated amyloid so may not have an
independent role.157 Other studies have failed to find strong re-
lationships between hypertension and brain amyloid, although
many of these studied hypertension in older age. Elevated vas-
cular risk, including hypertension, was associated more with
atrophy and neurodegeneration than with brain amyloid, a-
mong 430 adults studied at >60 years of age with both tau and
amyloid PET, as well as brain MRI.158 In a neuropathologic
sample, late-life BP was not associated with brain amyloid,
but SBP was associated with neurofibrillary tangles.159
Using CSF biomarkers, the potential interaction of BP and
APOE genotype was identified on tau levels, in one memory
clinic cohort, in which hypertension was not associated with
amyloid but rather was related to tau among APOE-ε4 homo-
zygotes.160 Although not specific for AD, associations between
hypertension and regional brain atrophy also support a poten-
tial role of elevated BP in Alzheimer neurodegeneration. In
addition to the above-cited studies of elevated BP and brain
atrophy,42 midlife BP has also been associated with hippocam-
pal atrophy by MRI, with the strongest associations among
untreated hypertensives.161
 1036  Circulation Research  March 29, 2019
Figure 6. Potential mechanisms underlying the relationship between hypertension and Alzheimer disease (AD). The vascular damage produced by
hypertension leads to brain dysfunction through hypoxia-ischemia, as well as increase in Aβ (amyloid-β) production because of increased APP (amyloid
precursor protein) processing by secretase enzymes and reduced clearance of AD-related proteins. In turn, Aβ and tau alter vascular function amplifying the
deleterious vascular impact of hypertension. BBB indicates blood-brain barrier. Illustration Credit: Ben Smith. Adapted from Iadecola et al8 with permission.
Copyright ©2018, the American Heart Association.
Downloaded from http://ahajournals.org by on June 30, 2019
Association Between Hypertension and AD
Pathology: Experimental Studies
Several studies have suggested that experimental hyperten-
sion promotes Aβ accumulation and tau phosphorylation.
Hypertension, induced either by administration of Ang II,123
aortic coarctation,162,163 renal artery stenosis,162 or in genetic
models164 increases microvascular deposition of Aβ or neu-
ronal tau phosphorylation. At the same time, administration of
renin-angiotensin system blockers or AT1R genetic deletion
ameliorates amyloid deposition and behavioral dysfunction
in APP-overexpressing mice.165,166 There are several mecha-
nisms by which hypertension could worsen AD pathology
(Figure 6). As discussed in a previous section, Aβ is cleared,
in part, through vascular and perivascular pathways, and,
consequently, the vascular and perivascular dysfunction and
damage induced by hypertension could impair Aβ disposal
leading to its accumulation. On the contrary, the loss of NO
and prostacyclin bioavailability associated with vascular dys-
function may also contribute to promote amyloidogenic APP
processing and increase Aβ. Thus, NO reductions upregulate
APP and β-secretase, whereas reduction in prostacyclin may
favor amyloidogenic APP processing.167 Mediators of hyper-
tension may also promote amyloidogenic APP processing. For
example, Ang II increases APP cleavage by β- and γ-secretase
and increases Aβ production in vitro and in vivo.123,168 Less is
known about a potential effect of hypertension on tau phos-
phorylation. Endothelial NO prevents tau phosphorylation
by inhibiting Cdk5 (cyclin-dependent kinase-5)—one of the
main kinases phosphorylating tau169—and consequently the
NO deficit associated with hypertension could promote tau
phosphorylation. Central administration of Ang II induces tau
phosphorylation by activation of the tau kinase GSK3β (glyco-
gen synthase kinase-3β) via AT1R-dependent mechanisms.170
These clinical and experimental observations, collectively,
suggest that hypertension has the potential to promote AD pa-
thology by acting at different levels. However, it remains un-
clear whether hypertension is a pathogenic factor in AD, and,
conversely, whether the AD pathology associated with hyper-
tension is a contributor to the cognitive dysfunction.8
Prevention and Therapy
Given the strong and consistent associations seen in the ep-
idemiological literature between hypertension and dementia,
and given the strong biological plausibility for a link between
the two, the inevitable next question is whether treatment of
hypertension reduces risk of dementia. Certainly, this is the
major reason why the study of hypertension as a risk factor for
dementia is of particular interest: in the absence of other ways
to treat or prevent dementia and AD specifically, hypertension
is an especially appealing target.
Does Treating Hypertension Reduce
Dementia Risk?
Several epidemiological studies have considered the role of an-
tihypertensive medication treatment, although all remain sus-
ceptible to some indication bias: individuals who are prescribed
and take antihypertensives are different than people who do not,
 Iadecola and Gottesman   Hypertension and Cognition   1037
in many ways beyond which can be adjusted statistically. Thus,
clinical trials would be the ideal forum in which to test this ques-
tion, but given the above reviewed evidence that relationships
between hypertension and dementia are the strongest when hy-
pertension is considered in middle age, decades before the de-
velopment of dementia, and that clinical trials cannot randomize
and follow participants for that long duration, some reliance on
longer term observational study designs is needed to consider
these life span considerations. These studies also allow consid-
eration of age of treatment or duration of treatment, which can
extend beyond the windows allowed by clinical trials.
In several observational studies, antihypertensive medica-
tion use is associated with less cognitive decline; in the ARIC
study, participants taking antihypertensive medications had
a 20-year cognitive decline equivalent to a prehypertensive
group (higher than the normotensives but lower than untreated
hypertensives).12 In the EVA study group (Epidemiology of
Vascular Aging), treated hypertension was associated with less
cognitive decline over only 4 years compared with untreated
hypertension.171 Furthermore, duration of antihypertensive
therapy appears important in risk reduction. In the HAAS
study, per additional year of antihypertensive treatment, de-
mentia risk was lower (hazard ratio, 0.94; 95% CI, 0.89–0.99),
with the greatest reduction for individuals with treatment over
12 years in duration, with overall risk nearing that of normo-
tensives.172 In the Rotterdam study, each additional year of an-
tihypertensive use, before age 75, was associated with an 8%
reduced risk of dementia; after age 75, the additional risk was
reduced and was no longer statistically significant.173
Downloaded from http://ahajournals.org by on June 30, 2019
Trial data consists of several randomized clinical trials fo-
cusing primarily on antihypertensive therapy, with most trials
to date showing negative results, with the exception of Syst-
Eur (Systolic Hypertension in Europe),174 and the most recent
SPRINT-MIND trial (Systolic Blood Pressure Intervention
Trial-Memory and Cognition In Decreased Hypertension).175
These negative trials include those in individuals with a his-
tory of stroke, in which a Cochrane review yielded a pooled
relative risk of 0.88 (not significant) for the use of antihyper-
tensives to reduce dementia,176 as well as studies of individuals
without prior known cerebrovascular disease.177
As one of the few positive clinical trials, the Syst-Eur trial
showed that dementia-free hypertensive individuals (SBP,
160–219 mm Hg, and DBP, <95 mm Hg) aged ≥60 years who
received medications (a dihydropyridine calcium channel
blocker [CCB] plus other antihypertensive drugs as needed)
to lower BP to <150 mm Hg systolic, compared with placebo,
had less incident dementia during a median follow-up of 2
years.174 The preliminary SPRINT-MIND data175 do suggest a
benefit in progression of cerebral SVD for individuals treated
with intensive BP control versus standard control, as well as
for cognitive outcomes, but only for the combination of MCI
and dementia and not for dementia itself.
Importance of Other Comorbid Vascular Disease
and Risk Factors
Although the focus of this review is on hypertension, elevated
BP as a risk factor rarely occurs in isolation, and several risk
factors co-occurring in the same individuals may further in-
crease accelerated cognitive decline. In the Framingham
Heart Study, hypertension was associated with worse decline
in the presence of diabetes mellitus compared with its effect
in nondiabetics,178 and in the Framingham Offspring Study,
cognitive outcomes were the worst among participants with
hypertension and elevated waist-hip ratio.179 In 1449 adults
aged 65 to 79 years in Finland, the combination of SBP at
≥160 mm Hg and elevated serum cholesterol, each in midlife,
was associated with a markedly increased risk of AD (odds ra-
tio, 3.5; 95% CI, 1.6–7.9), when compared with the presence
of either risk factor alone.19
Similar relationships are seen when consideration is made
of any additional risk factor: in 8945 participants of the Kaiser
HMO (Health Maintenance Organization), an increasing num-
ber of midlife vascular risk factors was associated with ele-
vated risk of dementia in late life, with a hazard ratio of 1.27
for individuals with only 1 midlife vascular risk factor and 2.37
for 4 midlife vascular risk factors (considering smoking, hy-
pertension, hypercholesterolemia, and diabetes mellitus).16 The
CAIDE score (Cardiovascular Risk Factors Aging and Incidence
of Dementia), which considers several vascular risk factors as a
dementia risk score, including hypertension, has been reliably
associated with dementia,180 with reasonably strong predictive
power (area under the curve, 0.74).181 In parallel, better Life’s
Simple 7 scores, which consider optimal control of vascular (in-
cluding hypertension) and lifestyle risk factors, were associated
with less cognitive decline, in the ARIC study.182
As the primary genetic risk factor for AD, carriage of the
APOE-ε4 allele independently increases risk for AD, but the
combination of the ε4 genotype and hypertension may fur-
ther increase risk of AD.183 In the Personality and Total Health
Through Life study, the combination of an APOE-ε4 allele
with hypertension was associated with greater decline over 8
years in 1474 cognitively normal adults aged 60 to 64 years.184
In ARIC-PET, as cited above, although no statistically signif-
icant difference was found among APOE-ε4 carriers versus
noncarriers for risk of elevated BP on late-life brain amyloid,
there was a suggestion of more brain amyloid in individuals
with at least 1 ε4 allele, as midlife BP increased.157 This poten-
tial interaction was further supported by a study by Rodrigue
et al185 in which the combination of hypertension and at least
1 APOE-ε4 allele was associated with greater brain amyloid,
by Pittsburgh compound-B PET, with a similar pattern with
greater cortical thinning among individuals with both hyper-
tension and at least 1 ε4 allele.186
Class-Specific Effects of Antihypertensive Drugs
There are conflicting data as to the potential role of distinct an-
tihypertensive medications: in HAAS, the only antihyperten-
sive drug category when considered at mean age of 77 years,
which was associated with reduced cognitive impairment, was
β-blockers (incidence rate ratio, 0.69; 95% CI, 0.50–0.94).187
Syst-Eur primarily had a CCB-based intervention, and
showed reduction in dementia rates,174 and the PROGRESS
(Perindopril Protection Against Recurrent Stroke Study)
showed a benefit in dementia reduction among individuals
with a history of stroke or transient ischemic attack who were
treated with active therapy (perindopril [an ACE (angiotensin-
converting enzyme) inhibitor] or indapamide [a diuretic]) for
3.9 years but only among individuals who also experienced
 1038  Circulation Research  March 29, 2019
recurrent stroke.188 In the 3-City cohort study, participants
who took a combination of selective serotonin reuptake inhib-
itors with CCBs, compared with selective serotonin reuptake
inhibitors combined with other antihypertensives, had im-
proved cognitive performance, as well as improved depression
scores, at 2-year follow-up,189 with a similar beneficial effect
on cognitive decline from CCBs noted in the Newcastle 85+
Study of elderly adults, without a similar benefit from other
antihypertensives.190 This is in direct contrast to findings from
the Canadian Study of Health and Aging, in which Canadians
aged ≥65 years who took CCBs had steeper decline, meas-
ured by a modified Mini-Mental State Examination repeated
serially for 5 years, than did their counterparts who used other
antihypertensive drugs (75% on CCBs declined versus 59%
on other antihypertensive drugs).191
A growing body of evidence supports the biological im-
portance of the renin-angiotensin system and points to the
potential importance of drugs within this family for demen-
tia prevention in individuals with hypertension. Intervention
trials in SHR have shown reduced poststroke cognitive im-
pairment in rodents treated with renin-angiotensin system
modifiers (specifically candesartan—an AT1R blocker).192
The ongoing HEART (History ECG Age Risk Factors and
Troponin) phase 1B randomized controlled trial will eval-
uate the renin-angiotensin system specifically, in nonde-
mented adults at risk for AD, in which participants will be
randomized to placebo versus 1 of 2 doses of telmisartan.193
The optimal treatment regimen to prevent future cogni-
tive impairment or dementia is difficult to ascertain because
Downloaded from http://ahajournals.org by on June 30, 2019
nearly all antihypertensives have studies supporting their po-
tential benefit. Again, these are still likely confounded by
indication bias, similar to the overall issue of indication bias
regarding any antihypertensive use versus none, although to
a lesser degree (considering one antihypertensive versus an-
other may be influenced by comorbidities or demographic
characteristics but are less profoundly impacted by socioec-
onomic or other factors influencing access to medical care
more broadly).
Outstanding Questions and Future Prospects
Although the body of knowledge relating hypertension to
cognitive outcomes, dementia, and AD has expanded tremen-
dously in recent years, several key questions remain. Answers
to some of these questions, listed below, will be critical to
gain a better insight into how hypertension impacts cognitive
function and to best recommend prevention and management
strategies.
Is the Neurovascular Dysfunction Induced by
Hypertension Sufficient to Cause Cognitive
Impairment?
Hypertension induces alterations in neurovascular function,
which are thought to induce brain lesions associated with
cognitive impairment (Figure 5). However, it remains to be
established whether the neurovascular dysfunction alone
is sufficient to induced cognitive impairment. Reduced ce-
rebral perfusion, alterations in brain clearance and BBB, as
well as vascular growth factor deficiency have the potential to
alter neuronal function in metabolically active brain regions
involved in cognitive function, such as the hippocampus, en-
torinal cortex, and prefrontal cortex. A better understanding of
the natural history of the impact of hypertension on cerebro-
vascular function, network degradation, and cognition would
be needed to address this question, which is relevant to the
initiation of antihypertensive therapy. In parallel, a more nu-
anced understanding of the signaling mechanisms by which
the neurovascular dysfunction interferes with neuronal func-
tion would also be desirable. Is CBF insufficiency the major
factor? Or, are there other aspects of cerebrovascular biology,
such as trophic support by endothelial factors or perivascular
clearance, also at play?
When Does Antihypertensive Therapy Need
to be Initiated to Minimize Risk of Cognitive
Impairment?
As summarized above, the benefits of antihypertensive ther-
apy are likely to be the greatest when initiated in midlife, and
continued over decades, although preliminary results from the
SPRINT-MIND trial suggest that benefits may still be possible
with a shorter duration of antihypertensive therapy. In this re-
gard, it would be important to assess whether the appearance
of brain lesions diminishes the impact of hypertensive therapy
on cognitive health. Although difficult to study in clinical tri-
als, further consideration will need to be made of optimal age
and duration of antihypertensive therapy, and correlation with
cardiovascular and structural-functional imaging biomarkers,
to best prevent cognitive decline, MCI, and dementia.
Are There Individuals Especially Susceptible to the
Cognitive Effects of Hypertension and in Whom
More Aggressive Therapy Might Be Warranted?
Individuals with more vascular risk factors appear especially
vulnerable to hypertension, with worse outcomes among indi-
viduals with several vascular risk factors. This suggests that
individuals with other known risk factors, such as diabetes
mellitus, may need better screening of BP with a lower thresh-
old for initiation of antihypertensive therapy. This is consist-
ent with the management of vascular risk factors because they
relate to other cardiovascular outcomes. Beyond vascular
risk, there may be genetic susceptibilities, such as has been
seen with the APOE data, leading to greater risk and, there-
fore, greater potential benefit from antihypertensive therapy,
in individuals with a known risk allele or even of a particular
race or sex. Focused trials with enrollment of these higher risk
groups could identify a subgroup in whom prevention might
be especially effective.
What Class of Antihypertensives Is the Most
Effective for Prevention of Cognitive Impairment?
Although ongoing studies are directly addressing the potential
benefit of particular antihypertensives, at least on surrogate
end points, at the time of this manuscript preparation, no con-
vincing data point to a clinical difference with the use of par-
ticular antihypertensive medications. This question—whether
any antihypertensive is as effective as the next—will be crit-
ical as evidence is translated into practice. Furthermore, it is
possible that the same recommended therapeutics may not be
ideal for all individuals. Race-based differences in therapeutic
effect for distinct antihypertensives have been noted for other
 Iadecola and Gottesman   Hypertension and Cognition   1039
cardiovascular outcomes,194 and similar differences by race, or
other demographic or genetic factors, may be found for reduc-
tion of adverse cognitive outcomes.
What Are the Best Surrogate End Points or
Biomarkers for Measuring a Cerebral or Cognitive
Benefit in Treating Hypertension?
Biomarkers or surrogate end points are valuable in studying
long-term relationships as seen between hypertension and
dementia because they allow for earlier assessment of thera-
peutic effect, both for research purposes, as well as clinically,
to evaluate benefits of treatment. Ongoing studies and con-
sortia, including MarkVCID (Mark Vascular Contributions to
Cognitive Impairment and Dementia), are evaluating biomark-
ers for the vascular contribution to cognitive impairment and
dementia, which likely would be candidates for the specific
effect of hypertension on the brain as well, and may include
serum, CSF, or imaging markers to examine the contribution
from AD pathology.
Is There a Synergistic Relationship Between
Hypertension and AD Pathology?
As discussed in a previous section, there is biological plau-
sibility that hypertension and other vascular risk factors may
promote AD pathology and vice versa. However, the clinical-
pathological evidence remains contradictory. The recent de-
velopment and validation of amyloid and tau PET imaging
provides the opportunity to examine in vivo the reciprocal
interaction between markers of AD and hypertensive neuro-
pathology and their relative contribution to cognitive impair-
Downloaded from http://ahajournals.org by on June 30, 2019
ment. These findings would have important implications for
targeting treatments to the relevant pathology responsible for
the cognitive deficits in a particular individual. At the same
time, in-depth investigations on the impact of AD and hyper-
tension on vessel-associated clearance pathways would be in-
valuable to provide insight into the role of failure of Aβ and
tau disposal on disease onset and progression.
These are a few of the outstanding questions that remain
to be addressed. Answering these questions will require en-
gaging both the preclinical and clinical scientific communi-
ties in a concerted effort to advance the understanding of
how hypertension affects brain function leading to cognitive
impairment. Thus, epidemiological, biomarker, and clini-
cal-pathological studies should be closely related to basic
science efforts to unravel mechanisms and provide new tar-
gets to be tested in clinical trials. Such cooperation will be
essential for the development of new diagnostic tools and
treatment strategies for one of the most devastating health
challenges of our times.
Sources of Funding
This study was supported by National Institutes of Health grants
R37-NS089323 (C. Iadecola), R01-NS100447 (C. Iadecola), R01-
NS09544 (C. Iadecola), R01-NS/HL037853 (C. Iadecola), K24-
AG052573 (R.F. Gottesman), RF1-AG050745 (R.F. Gottesman), and
R01-AG040282 (R.F. Gottesman).
Disclosures
C. Iadecola serves on the Scientific Advisory Board of Broadview
Ventures. R.F. Gottesman is Associate Editor for the journal Neurology.
References
1. Forouzanfar MH, Liu P, Roth GA, et al. Global burden of hypertension and
systolic blood pressure of at least 110 to 115 mm Hg, 1990-2015. JAMA.
2017;317:165–182. doi: 10.1001/jama.2016.19043
2. Scheltens P, Blennow K, Breteler MM, de Strooper B, Frisoni GB, Salloway
S, Van der Flier WM. Alzheimer’s disease. Lancet. 2016;388:505–517.
doi: 10.1016/S0140-6736(15)01124-1
3. Spieth W. Cardiovascular health status, age, and psychological perfor-
mance. J Gerontol. 1964;19:277–284.
4. Wilkie F, Eisdorfer C. Intelligence and blood pressure in the aged. Science.
1971;172:959–962.
5. Kety S, Hafkenschiel J, Jeffers W, Leopold I, Shenkin H. The blood flow,
vascular resistance, and oxygen consumption of the brain in essential hy-
pertension. J Clin Invest. 1948;27:511–514.
6. Saklayen MG, Deshpande NV. Timeline of history of hypertension treat-
ment. Front Cardiovasc Med. 2016;3:3. doi: 10.3389/fcvm.2016.00003
7. Elias MF, Wolf PA, D’Agostino RB, Cobb J, White LR. Untreated
blood pressure level is inversely related to cognitive functioning: the
Framingham Study. Am J Epidemiol. 1993;138:353–364.
8. Iadecola C, Gottesman RF. Cerebrovascular alterations in alzheimer disease.
Circ Res. 2018;123:406–408. doi: 10.1161/CIRCRESAHA.118.313400
9. Moser M, Roccella EJ. The treatment of hypertension: a remarka-
ble success story. J Clin Hypertens (Greenwich). 2013;15:88–91. doi:
10.1111/jch.12033
10. Iadecola C, Yaffe K, Biller J, Bratzke LC, Faraci FM, Gorelick PB, Gulati
M, Kamel H, Knopman DS, Launer LJ, Saczynski JS, Seshadri S, Zeki
Al Hazzouri A; American Heart Association Council on Hypertension;
Council on Clinical Cardiology; Council on Cardiovascular Disease in
the Young; Council on Cardiovascular and Stroke Nursing; Council on
Quality of Care and Outcomes Research; and Stroke Council. Impact
of hypertension on cognitive function: a scientific statement from the
American Heart Association. Hypertension. 2016;68:e67–e94. doi:
10.1161/HYP.0000000000000053
11. Gottesman RF, Rawlings AM, Sharrett AR, et al. Impact of differential
attrition on the association of education with cognitive change over 20
years of follow-up: the ARIC neurocognitive study. Am J Epidemiol.
2014;179:956–966. doi: 10.1093/aje/kwu020
12. Gottesman RF, Schneider AL, Albert M, Alonso A, Bandeen-Roche K,
Coker L, Coresh J, Knopman D, Power MC, Rawlings A, Sharrett AR,
Wruck LM, Mosley TH. Midlife hypertension and 20-year cognitive
change: the atherosclerosis risk in communities neurocognitive study.
JAMA Neurol. 2014;71:1218–1227. doi: 10.1001/jamaneurol.2014.1646
13. Swan GE, DeCarli C, Miller BL, Reed T, Wolf PA, Jack LM, Carmelli D.
Association of midlife blood pressure to late-life cognitive decline and
brain morphology. Neurology. 1998;51:986–993.
14. Launer LJ, Masaki K, Petrovitch H, Foley D, Havlik RJ. The association
between midlife blood pressure levels and late-life cognitive function. The
Honolulu-Asia Aging Study. JAMA. 1995;274:1846–1851.
15. Kivipelto M, Helkala EL, Hänninen T, Laakso MP, Hallikainen M,
Alhainen K, Soininen H, Tuomilehto J, Nissinen A. Midlife vascular risk
factors and late-life mild cognitive impairment: a population-based study.
Neurology. 2001;56:1683–1689.
16. Whitmer RA, Sidney S, Selby J, Johnston SC, Yaffe K. Midlife car-
diovascular risk factors and risk of dementia in late life. Neurology.
2005;64:277–281. doi: 10.1212/01.WNL.0000149519.47454.F2
17. Freitag MH, Peila R, Masaki K, Petrovitch H, Ross GW, White
LR, Launer LJ. Midlife pulse pressure and incidence of demen-
tia: the Honolulu-Asia Aging Study. Stroke. 2006;37:33–37. doi:
10.1161/01.STR.0000196941.58869.2d
18. Gottesman RF, Albert MS, Alonso A, Coker LH, Coresh J, Davis SM,
Deal JA, McKhann GM, Mosley TH, Sharrett AR, Schneider ALC,
Windham BG, Wruck LM, Knopman DS. Associations between midlife
vascular risk factors and 25-year incident dementia in the atherosclerosis
risk in communities (ARIC) cohort. JAMA Neurol. 2017;74:1246–1254.
doi: 10.1001/jamaneurol.2017.1658
19. Kivipelto M, Helkala EL, Laakso MP, Hänninen T, Hallikainen M,
Alhainen K, Soininen H, Tuomilehto J, Nissinen A. Midlife vascular
risk factors and Alzheimer’s disease in later life: longitudinal, population
based study. BMJ. 2001;322:1447–1451.
20. Goldstein FC, Levey AI, Steenland NK. High blood pressure and cognitive
decline in mild cognitive impairment. J Am Geriatr Soc. 2013;61:67–73.
doi: 10.1111/jgs.12067
21. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/
ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for
 1040  Circulation Research  March 29, 2019
the prevention, detection, evaluation, and management of high blood
pressure in adults: executive summary: a report of the American
College of Cardiology/American Heart Association task force on clin-
ical practice guidelines. Hypertension. 2018;71:1269–1324. doi:
10.1161/HYP.0000000000000066
22. Nation DA, Preis SR, Beiser A, Bangen KJ, Delano-Wood L, Lamar
M, Libon DJ, Seshadri S, Wolf PA, Au R. Pulse pressure is associ-
ated with early brain atrophy and cognitive decline: modifying ef-
fects of APOE-ε4. Alzheimer Dis Assoc Disord. 2016;30:210–215. doi:
10.1097/WAD.0000000000000127
23. Rawlings AM, Juraschek SP, Heiss G, Hughes T, Meyer ML, Selvin
E, Sharrett AR, Windham BG, Gottesman RF. Association of ortho-
static hypotension with incident dementia, stroke, and cognitive decline.
Neurology. 2018;91:e759–e768. doi: 10.1212/WNL.0000000000006027
24. Kilander L, Nyman H, Boberg M, Hansson L, Lithell H. Hypertension
is related to cognitive impairment: a 20-year follow-up of 999 men.
Hypertension. 1998;31:780–786.
25. Sabayan B, Wijsman LW, Foster-Dingley JC, Stott DJ, Ford I, Buckley
BM, Sattar N, Jukema JW, van Osch MJ, van der Grond J, van Buchem
MA, Westendorp RG, de Craen AJ, Mooijaart SP. Association of visit-
to-visit variability in blood pressure with cognitive function in old age:
prospective cohort study. BMJ. 2013;347:f4600. doi: 10.1136/bmj.f4600
26. Shah NS, Vidal JS, Masaki K, Petrovitch H, Ross GW, Tilley C,
DeMattos RB, Tracy RP, White LR, Launer LJ. Midlife blood pres-
sure, plasma β-amyloid, and the risk for Alzheimer disease: the
Honolulu Asia Aging Study. Hypertension. 2012;59:780–786. doi:
10.1161/HYPERTENSIONAHA.111.178962
27. Shah RC, Wilson RS, Bienias JL, Arvanitakis Z, Evans DA, Bennett DA.
Relation of blood pressure to risk of incident Alzheimer’s disease and
change in global cognitive function in older persons. Neuroepidemiology.
2006;26:30–36. doi: 10.1159/000089235
28. Glynn RJ, Beckett LA, Hebert LE, Morris MC, Scherr PA, Evans DA.
Current and remote blood pressure and cognitive decline. JAMA.
1999;281:438–445.
29. Ruitenberg A, Skoog I, Ott A, Aevarsson O, Witteman JC, Lernfelt B, van
Harskamp F, Hofman A, Breteler MM. Blood pressure and risk of de-
mentia: results from the Rotterdam study and the Gothenburg H-70 Study.
Downloaded from http://ahajournals.org by on June 30, 2019
Dement Geriatr Cogn Disord. 2001;12:33–39. doi: 10.1159/000051233
30. Verghese J, Lipton RB, Hall CB, Kuslansky G, Katz MJ. Low blood
pressure and the risk of dementia in very old individuals. Neurology.
2003;61:1667–1672.
31. Waldstein SR, Giggey PP, Thayer JF, Zonderman AB. Nonlinear re-
lations of blood pressure to cognitive function: the Baltimore
Longitudinal Study of Aging. Hypertension. 2005;45:374–379. doi:
10.1161/01.HYP.0000156744.44218.74
32. Ninomiya T, Ohara T, Hirakawa Y, Yoshida D, Doi Y, Hata J, Kanba S,
Iwaki T, Kiyohara Y. Midlife and late-life blood pressure and dementia in
Japanese elderly: the Hisayama study. Hypertension. 2011;58:22–28. doi:
10.1161/HYPERTENSIONAHA.110.163055
33. Yamada M, Kasagi F, Sasaki H, Masunari N, Mimori Y, Suzuki G.
Association between dementia and midlife risk factors: the Radiation
Effects Research Foundation Adult Health Study. J Am Geriatr Soc.
2003;51:410–414.
34. den Heijer T, Launer LJ, Prins ND, van Dijk EJ, Vermeer SE, Hofman
A, Koudstaal PJ, Breteler MM. Association between blood pressure,
white matter lesions, and atrophy of the medial temporal lobe. Neurology.
2005;64:263–267. doi: 10.1212/01.WNL.0000149641.55751.2E
35. Dufouil C, de Kersaint-Gilly A, Besançon V, Levy C, Auffray E,
Brunnereau L, Alpérovitch A, Tzourio C. Longitudinal study of blood
pressure and white matter hyperintensities: the EVA MRI Cohort.
Neurology. 2001;56:921–926.
36. Gottesman RF, Coresh J, Catellier DJ, Sharrett AR, Rose KM, Coker
LH, Shibata DK, Knopman DS, Jack CR, Mosley TH Jr. Blood pres-
sure and white-matter disease progression in a biethnic cohort: athero-
sclerosis risk in communities (ARIC) study. Stroke. 2010;41:3–8. doi:
10.1161/STROKEAHA.109.566992
37. Stewart R, Xue QL, Masaki K, Petrovitch H, Ross GW, White
LR, Launer LJ. Change in blood pressure and incident dementia:
a 32-year prospective study. Hypertension. 2009;54:233–240. doi:
10.1161/HYPERTENSIONAHA.109.128744
38. Skoog I, Lernfelt B, Landahl S, Palmertz B, Andreasson LA, Nilsson L,
Persson G, Odén A, Svanborg A. 15-year longitudinal study of blood pres-
sure and dementia. Lancet. 1996;347:1141–1145.
39. McGrath ER, Beiser AS, DeCarli C, Plourde KL, Vasan RS,
Greenberg SM, Seshadri S. Blood pressure from mid- to late life
and risk of incident dementia. Neurology. 2017;89:2447–2454. doi:
10.1212/WNL.0000000000004741
40. Guo Z, Viitanen M, Winblad B, Fratiglioni L. Low blood pressure and in-
cidence of dementia in a very old sample: dependent on initial cognition.
J Am Geriatr Soc. 1999;47:723–726.
41. Heijer Td, Skoog I, Oudkerk M, de Leeuw FE, de Groot JC, Hofman A,
Breteler MM. Association between blood pressure levels over time and
brain atrophy in the elderly. Neurobiol Aging. 2003;24:307–313.
42. Power MC, Schneider AL, Wruck L, Griswold M, Coker LH, Alonso A,
Jack CR Jr, Knopman D, Mosley TH, Gottesman RF. Life-course blood
pressure in relation to brain volumes. Alzheimers Dement. 2016;12:890–
899. doi: 10.1016/j.jalz.2016.03.012
43. Yaffe K, Vittinghoff E, Pletcher MJ, Hoang TD, Launer LJ, Whitmer
R, Coker LH, Sidney S. Early adult to midlife cardiovascular risk fac-
tors and cognitive function. Circulation. 2014;129:1560–1567. doi:
10.1161/CIRCULATIONAHA.113.004798
44. Østergaard SD, Mukherjee S, Sharp SJ, et al; Alzheimer’s Disease
Genetics Consortium; GERAD1 Consortium; EPIC-InterAct Consortium.
Associations between potentially modifiable risk factors and Alzheimer
disease: a mendelian randomization study. PLoS Med. 2015;12:e1001841;
discussion e1001841. doi: 10.1371/journal.pmed.1001841
45. Goldstein FC, Hajjar IM, Dunn CB, Levey AI, Wharton W. The relation-
ship between cognitive functioning and the JNC-8 guidelines for hyper-
tension in older adults. J Gerontol A Biol Sci Med Sci. 2017;72:121–126.
doi: 10.1093/gerona/glw181
46. Smits LL, van Harten AC, Pijnenburg YA, Koedam EL, Bouwman FH,
Sistermans N, Reuling IE, Prins ND, Lemstra AW, Scheltens P, van der
Flier WM. Trajectories of cognitive decline in different types of dementia.
Psychol Med. 2015;45:1051–1059. doi: 10.1017/S0033291714002153
47. Sikaroodi H, Yadegari S, Miri SR. Cognitive impairments in patients with
cerebrovascular risk factors: a comparison of mini mental status exam and
montreal cognitive assessment. Clin Neurol Neurosurg. 2013;115:1276–
1280. doi: 10.1016/j.clineuro.2012.11.026
48. Smith EE, Muzikansky A, McCreary CR, Batool S, Viswanathan A,
Dickerson BC, Johnson K, Greenberg SM, Blacker D. Impaired mem-
ory is more closely associated with brain beta-amyloid than leuko-
araiosis in hypertensive patients with cognitive symptoms. PLoS One.
2018;13:e0191345. doi: 10.1371/journal.pone.0191345
49. Reed BR, Mungas DM, Kramer JH, Ellis W, Vinters HV, Zarow C,
Jagust WJ, Chui HC. Profiles of neuropsychological impairment in au-
topsy-defined Alzheimer’s disease and cerebrovascular disease. Brain.
2007;130:731–739. doi: 10.1093/brain/awl385
50. Iadecola C. The neurovascular unit coming of age: a journey through neu-
rovascular coupling in health and disease. Neuron. 2017;96:17–42. doi:
10.1016/j.neuron.2017.07.030
51. Armulik A, Genové G, Betsholtz C. Pericytes: developmental, physio-
logical, and pathological perspectives, problems, and promises. Dev Cell.
2011;21:193–215. doi: 10.1016/j.devcel.2011.07.001
52. Vanlandewijck M, He L, Mäe MA, et al. A molecular atlas of cell types
and zonation in the brain vasculature. Nature. 2018;80:844–480.
53. Hollander W, Prusty S, Kemper T, Rosene DL, Moss MB. The effects
of hypertension on cerebral atherosclerosis in the cynomolgus monkey.
Stroke. 1993;24:1218–1226; discussion 1226.
54. Agmon Y, Khandheria BK, Meissner I, Schwartz GL, Petterson TM,
O’Fallon WM, Gentile F, Whisnant JP, Wiebers DO, Seward JB.
Independent association of high blood pressure and aortic atherosclerosis:
a population-based study. Circulation. 2000;102:2087–2093.
55.
Qureshi AI, Caplan LR. Intracranial atherosclerosis. Lancet.
2014;383:984–998. doi: 10.1016/S0140-6736(13)61088-0
56. Hu X, De Silva TM, Chen J, Faraci FM. Cerebral vascular disease and
neurovascular injury in ischemic stroke. Circ Res. 2017;120:449–471. doi:
10.1161/CIRCRESAHA.116.308427
57. Watase H, Sun J, Hippe DS, Balu N, Li F, Zhao X, Mani V, Fayad ZA,
Fuster V, Hatsukami TS, Yuan C. Carotid artery remodeling is seg-
ment specific: an in vivo study by vessel wall magnetic resonance
imaging. Arterioscler Thromb Vasc Biol. 2018;38:927–934. doi:
10.1161/ATVBAHA.117.310296
58. Kaess BM, Rong J, Larson MG, Hamburg NM, Vita JA, Levy D,
Benjamin EJ, Vasan RS, Mitchell GF. Aortic stiffness, blood pressure
progression, and incident hypertension. JAMA. 2012;308:875–881. doi:
10.1001/2012.jama.10503
59. Jefferson AL, Cambronero FE, Liu D, Moore EE, Neal JE, Terry JG, Nair
S, Gifford KA, Hohman TJ, Bell SP, Wang TJ, Beckman JA, Carr JJ. Higher
aortic stiffness is related to lower cerebral blood flow and preserved cere-
brovascular reactivity in older adults. Circulation. 2018;138:1951–1962.
 Iadecola and Gottesman   Hypertension and Cognition   1041
60. DuBose LE, Boles Ponto LL, Moser DJ, Harlynn E, Reierson L, Pierce
GL. Higher aortic stiffness is associated with lower global cerebrovas-
cular reserve among older humans. Hypertension. 2018;72:476–482. doi:
10.1161/HYPERTENSIONAHA.118.11143
61. Schnerr RS, Jansen JFA, Uludag K, Hofman PAM, Wildberger JE, van
Oostenbrugge RJ, Backes WH. Pulsatility of lenticulostriate arteries as-
sessed by 7 tesla flow MRI-measurement, reproducibility, and applicability
to aging effect. Front Physiol. 2017;8:961. doi: 10.3389/fphys.2017.00961
62. Blanco PJ, Müller LO, Spence JD. Blood pressure gradients in cerebral
arteries: a clue to pathogenesis of cerebral small vessel disease. Stroke
Vasc Neurol. 2017;2:108–117. doi: 10.1136/svn-2017-000087
63. Brown R, Benveniste H, Black SE, Charpak S, Dichgans M, Joutel A,
Nedergaard M, Smith KJ, Zlokovic BV, Wardlaw JM. Understanding the
role of the perivascular space in cerebral small vessel disease. Cardiovasc
Res. 2018;114:1462–1473. doi: 10.1093/cvr/cvy113
64. Marinković S, Milisavljević M, Puskas L. Microvascular anatomy of the
hippocampal formation. Surg Neurol. 1992;37:339–349.
65. Blinder P, Tsai PS, Kaufhold JP, Knutsen PM, Suhl H, Kleinfeld D.
The cortical angiome: an interconnected vascular network with non-
columnar patterns of blood flow. Nat Neurosci. 2013;16:889–897. doi:
10.1038/nn.3426
66. Iadecola C. The pathobiology of vascular dementia. Neuron. 2013;80:844–
866. doi: 10.1016/j.neuron.2013.10.008
67. Rosenblum WI. Fibrinoid necrosis of small brain arteries and arteri-
oles and miliary aneurysms as causes of hypertensive hemorrhage:
a critical reappraisal. Acta Neuropathol. 2008;116:361–369. doi:
10.1007/s00401-008-0416-9
68. Brown WR, Moody DM, Thore CR, Challa VR, Anstrom JA. Vascular de-
mentia in leukoaraiosis may be a consequence of capillary loss not only
in the lesions, but in normal-appearing white matter and cortex as well. J
Neurol Sci. 2007;257:62–66. doi: 10.1016/j.jns.2007.01.015
69. Aaslid R, Lindegaard KF, Sorteberg W, Nornes H. Cerebral autoregulation
dynamics in humans. Stroke. 1989;20:45–52.
70. Iulita MF, Noriega de la Colina A, Girouard H. Arterial stiffness, cognitive
impairment and dementia: confounding factor or real risk? J Neurochem.
2018;144:527–548. doi: 10.1111/jnc.14235
71. Norlander AE, Madhur MS, Harrison DG. The immunology of hyperten-
Downloaded from http://ahajournals.org by on June 30, 2019
sion. J Exp Med. 2018;215:21–33. doi: 10.1084/jem.20171773
72. Ogola BO, Zimmerman MA, Clark GL, Abshire CM, Gentry KM, Miller
KS, Lindsey SH. New insights into arterial stiffening: does sex matter? Am
J Physiol Heart Circ Physiol. 2018;6:71.
73. Lim HY, Lim SY, Tan CK, et al. Hyaluronan receptor LYVE-1-expressing
macrophages maintain arterial tone through hyaluronan-mediated reg-
ulation of smooth muscle cell collagen. Immunity. 2018;49:1191. doi:
10.1016/j.immuni.2018.12.009
74. Faraco G, Sugiyama Y, Lane D, Garcia-Bonilla L, Chang H, Santisteban
MM, Racchumi G, Murphy M, Van Rooijen N, Anrather J, Iadecola C.
Perivascular macrophages mediate the neurovascular and cognitive dys-
function associated with hypertension. J Clin Invest. 2016;126:4674–
4689. doi: 10.1172/JCI86950
75. Longden TA, Dabertrand F, Koide M, Gonzales AL, Tykocki NR, Brayden
JE, Hill-Eubanks D, Nelson MT. Capillary K+-sensing initiates retrograde
hyperpolarization to increase local cerebral blood flow. Nat Neurosci.
2017;20:717–726. doi: 10.1038/nn.4533
76. Vanhoutte PM, Shimokawa H, Feletou M, Tang EH. Endothelial dysfunc-
tion and vascular disease - a 30th anniversary update. Acta Physiol (Oxf).
2017;219:22–96. doi: 10.1111/apha.12646
77. Sweeney MD, Zhao Z, Montagne A, Nelson AR, Zlokovic BV. Blood-brain
barrier: from physiology to disease and back. Physiol Rev. 2019;99:21–78.
doi: 10.1152/physrev.00050.2017
78. Marie C, Pedard M, Quirié A, Tessier A, Garnier P, Totoson P, Demougeot
C. Brain-derived neurotrophic factor secreted by the cerebral endothelium:
A new actor of brain function? J Cereb Blood Flow Metab. 2018;38:935–
949. doi: 10.1177/0271678X18766772
79. Tran KA, Zhang X, Predescu D, Huang X, Machado RF, Göthert JR,
Malik AB, Valyi-Nagy T, Zhao YY. Endothelial β-catenin signaling is
required for maintaining adult blood-brain barrier integrity and cen-
tral nervous system homeostasis. Circulation. 2016;133:177–186. doi:
10.1161/CIRCULATIONAHA.115.015982
80. Dai W, Lopez OL, Carmichael OT, Becker JT, Kuller LH, Gach HM.
Abnormal regional cerebral blood flow in cognitively normal eld-
erly subjects with hypertension. Stroke. 2008;39:349–354. doi:
10.1161/STROKEAHA.107.495457
81. Fujishima M, Ibayashi S, Fujii K, Mori S. Cerebral blood flow and brain
function in hypertension. Hypertens Res. 1995;18:111–117.
82. Muller M, van der Graaf Y, Visseren FL, Mali WP, Geerlings MI;
SMART Study Group. Hypertension and longitudinal changes in cere-
bral blood flow: the SMART-MR study. Ann Neurol. 2012;71:825–833.
doi: 10.1002/ana.23554
83. Beason-Held LL, Moghekar A, Zonderman AB, Kraut MA, Resnick SM.
Longitudinal changes in cerebral blood flow in the older hypertensive brain.
Stroke. 2007;38:1766–1773. doi: 10.1161/STROKEAHA.106.477109
84. Mentis MJ, Salerno J, Horwitz B, Grady C, Schapiro MB, Murphy DG,
Rapoport SI. Reduction of functional neuronal connectivity in long-term
treated hypertension. Stroke. 1994;25:601–607.
85. Jennings JR, Muldoon MF, Ryan C, Price JC, Greer P, Sutton-Tyrrell K,
van der Veen FM, Meltzer CC. Reduced cerebral blood flow response and
compensation among patients with untreated hypertension. Neurology.
2005;64:1358–1365. doi: 10.1212/01.WNL.0000158283.28251.3C
86. Wong R, Ahmad W, Davies A, Spratt N, Boyle A, Levi C, Howe P,
Collins N. Assessment of cerebral blood flow in adult patients with
aortic coarctation. Cardiol Young. 2017;27:1606–1613. doi: 10.1017/
S1047951117000920
87. Delles C, Michelson G, Harazny J, Oehmer S, Hilgers KF,
Schmieder RE. Impaired endothelial function of the retinal vascu-
lature in hypertensive patients. Stroke. 2004;35:1289–1293. doi:
10.1161/01.STR.0000126597.11534.3b
88. Daiber A, Steven S, Weber A, Shuvaev VV, Muzykantov VR, Laher I, Li
H, Lamas S, Münzel T. Targeting vascular (endothelial) dysfunction. Br
J Pharmacol. 2017;174:1591–1619. doi: 10.1111/bph.13517
89. Bagi Z, Brandner DD, Le P, McNeal DW, Gong X, Dou H, Fulton DJ,
Beller A, Ngyuen T, Larson EB, Montine TJ, Keene CD, Back SA.
Vasodilator dysfunction and oligodendrocyte dysmaturation in aging
white matter. Ann Neurol. 2018;83:142–152. doi: 10.1002/ana.25129
90. Muñoz Maniega S, Chappell FM, Valdés Hernández MC, Armitage PA,
Makin SD, Heye AK, Thrippleton MJ, Sakka E, Shuler K, Dennis MS,
Wardlaw JM. Integrity of normal-appearing white matter: influence
of age, visible lesion burden and hypertension in patients with small-
vessel disease. J Cereb Blood Flow Metab. 2017;37:644–656. doi:
10.1177/0271678X16635657
91. Hoth KF, Tate DF, Poppas A, Forman DE, Gunstad J, Moser DJ, Paul
RH, Jefferson AL, Haley AP, Cohen RA. Endothelial function and white
matter hyperintensities in older adults with cardiovascular disease.
Stroke. 2007;38:308–312. doi: 10.1161/01.STR.0000254517.04275.3f
92. Nezu T, Hosomi N, Aoki S, Kubo S, Araki M, Mukai T, Takahashi T,
Maruyama H, Higashi Y, Matsumoto M. Endothelial dysfunction is asso-
ciated with the severity of cerebral small vessel disease. Hypertens Res.
2015;38:291–297. doi: 10.1038/hr.2015.4
93. Kearney-Schwartz A, Rossignol P, Bracard S, Felblinger J, Fay R,
Boivin JM, Lecompte T, Lacolley P, Benetos A, Zannad F. Vascular
structure and function is correlated to cognitive performance and
white matter hyperintensities in older hypertensive patients with
subjective memory complaints. Stroke. 2009;40:1229–1236. doi:
10.1161/STROKEAHA.108.532853
94. Castro P, Azevedo E, Sorond F. Cerebral autoregulation in stroke. Curr
Atheroscler Rep. 2018;20:37. doi: 10.1007/s11883-018-0739-5
95. Paulson OB, Strandgaard S, Edvinsson L. Cerebral autoregulation.
Cerebrovasc Brain Metab Rev. 1990;2:161–192.
96. Lassen NA. Cerebral blood flow and oxygen consumption in man.
Physiol Rev. 1959;39:183–238. doi: 10.1152/physrev.1959.39.2.183
97. Tan CO. Defining the characteristic relationship between arterial pres-
sure and cerebral flow. J Appl Physiol (1985). 2012;113:1194–1200. doi:
10.1152/japplphysiol.00783.2012
98. Longden TA, Hill-Eubanks DC, Nelson MT. Ion channel networks in the
control of cerebral blood flow. J Cereb Blood Flow Metab. 2016;36:492–
512. doi: 10.1177/0271678X15616138
99. Mederos y Schnitzler M, Storch U, Meibers S, Nurwakagari P, Breit
A, Essin K, Gollasch M, Gudermann T. Gq-coupled receptors as
mechanosensors mediating myogenic vasoconstriction. EMBO J.
2008;27:3092–3103.
100. Kroetsch JT, Levy AS, Zhang H, Aschar-Sobbi R, Lidington D,
Offermanns S, Nedospasov SA, Backx PH, Heximer SP, Bolz SS.
Constitutive smooth muscle tumour necrosis factor regulates micro-
vascular myogenic responsiveness and systemic blood pressure. Nat
Commun. 2017;8:14805. doi: 10.1038/ncomms14805
101. Knot HJ, Nelson MT. Regulation of arterial diameter and wall [Ca2+] in
cerebral arteries of rat by membrane potential and intravascular pressure.
J Physiol. 1998;508(pt 1):199–209.
102. Jarajapu YP, Knot HJ. Relative contribution of Rho kinase and pro-
tein kinase C to myogenic tone in rat cerebral arteries in hypertension.
 1042  Circulation Research  March 29, 2019
Am J Physiol Heart Circ Physiol. 2005;289:H1917–H1922. doi:
10.1152/ajpheart.01012.2004
103. Kusano Y, Echeverry G, Miekisiak G, Kulik TB, Aronhime SN, Chen
JF, Winn HR. Role of adenosine A2 receptors in regulation of cerebral
blood flow during induced hypotension. J Cereb Blood Flow Metab.
2010;30:808–815. doi: 10.1038/jcbfm.2009.244
104. Strandgaard S. Autoregulation of cerebral blood flow in hypertensive
patients. The modifying influence of prolonged antihypertensive treat-
ment on the tolerance to acute, drug-induced hypotension. Circulation.
1976;53:720–727.
105. Strandgaard S, Jones JV, MacKenzie ET, Harper AM. Upper limit of ce-
rebral blood flow autoregulation in experimental renovascular hyperten-
sion in the baboon. Circ Res. 1975;37:164–167.
106. Birns J, Jarosz J, Markus HS, Kalra L. Cerebrovascular reactivity
and dynamic autoregulation in ischaemic subcortical white matter
disease. J Neurol Neurosurg Psychiatry. 2009;80:1093–1098. doi:
10.1136/jnnp.2009.174607
107. Traon AP, Costes-Salon MC, Galinier M, Fourcade J, Larrue V. Dynamics
of cerebral blood flow autoregulation in hypertensive patients. J Neurol
Sci. 2002;195:139–144.
108. Lipsitz LA, Gagnon M, Vyas M, Iloputaife I, Kiely DK, Sorond F,
Serrador J, Cheng DM, Babikian V, Cupples LA. Antihypertensive
therapy increases cerebral blood flow and carotid distensibility in hy-
pertensive elderly subjects. Hypertension. 2005;45:216–221. doi:
10.1161/01.HYP.0000153094.09615.11
109. Zhang R, Witkowski S, Fu Q, Claassen JA, Levine BD. Cerebral hemo-
dynamics after short- and long-term reduction in blood pressure in mild
and moderate hypertension. Hypertension. 2007;49:1149–1155. doi:
10.1161/HYPERTENSIONAHA.106.084939
110. Immink RV, van den Born BJ, van Montfrans GA, Koopmans RP,
Karemaker JM, van Lieshout JJ. Impaired cerebral autoregulation in
patients with malignant hypertension. Circulation. 2004;110:2241–2245.
doi: 10.1161/01.CIR.0000144472.08647.40
111. Tarasoff-Conway JM, Carare RO, Osorio RS, et al. Clearance sys-
tems in the brain-implications for Alzheimer disease. Nat Rev Neurol.
2015;11:457–470. doi: 10.1038/nrneurol.2015.119
112. Morris AW, Sharp MM, Albargothy NJ, Fernandes R, Hawkes CA,
Downloaded from http://ahajournals.org by on June 30, 2019
Verma A, Weller RO, Carare RO. Vascular basement membranes as path-
ways for the passage of fluid into and out of the brain. Acta Neuropathol.
2016;131:725–736. doi: 10.1007/s00401-016-1555-z
113. Nedergaard M. Neuroscience. Garbage truck of the brain. Science.
2013;340:1529–1530. doi: 10.1126/science.1240514
114. Absinta M, Ha S-K, Nair G, Sati P, Luciano NJ, Palisoc M, Louveau A,
Zaghloul KA, Pittaluga S, Kipnis J, Reich DS. Human and nonhuman
primate meninges harbor lymphatic vessels that can be visualized nonin-
vasively by mri. Elife. 2017;6:780.
115. Engelhardt B, Vajkoczy P, Weller RO. The movers and shapers in
immune privilege of the CNS. Nat Immunol. 2017;18:123–131. doi:
10.1038/ni.3666
116. Faraco G, Park L, Anrather J, Iadecola C. Brain perivascular macro-
phages: characterization and functional roles in health and disease. J Mol
Med (Berl). 2017;95:1143–1152. doi: 10.1007/s00109-017-1573-x
117. Santisteban MM, Iadecola C. Hypertension, dietary salt, and cognitive
impairment. J Cereb Blood Flow Metab. 2018;38:2112–2128.
118. Reckelhoff JF, Romero JC. Role of oxidative stress in angiotensin-
induced hypertension. Am J Physiol Regul Integr Comp Physiol.
2003;284:R893–R912. doi: 10.1152/ajpregu.00491.2002
119. Kazama K, Wang G, Frys K, Anrather J, Iadecola C. Angiotensin II
attenuates functional hyperemia in the mouse somatosensory cortex.
Am J Physiol Heart Circ Physiol. 2003;285:H1890–H1899. doi:
10.1152/ajpheart.00464.2003
120. Kazama K, Anrather J, Zhou P, Girouard H, Frys K, Milner TA, Iadecola
C. Angiotensin II impairs neurovascular coupling in neocortex through
NADPH oxidase-derived radicals. Circ Res. 2004;95:1019–1026. doi:
10.1161/01.RES.0000148637.85595.c5
121. Girouard H, Park L, Anrather J, Zhou P, Iadecola C. Angiotensin II
attenuates endothelium-dependent responses in the cerebral microcir-
culation through nox-2-derived radicals. Arterioscler Thromb Vasc Biol.
2006;26:826–832. doi: 10.1161/01.ATV.0000205849.22807.6e
122. Capone C, Faraco G, Coleman C, Young CN, Pickel VM, Anrather J,
Davisson RL, Iadecola C. Endothelin 1-dependent neurovascular dys-
function in chronic intermittent hypoxia. Hypertension. 2012;60:106–
113. doi: 10.1161/HYPERTENSIONAHA.112.193672
123. Faraco G, Park L, Zhou P, Luo W, Paul SM, Anrather J, Iadecola C.
Hypertension enhances Aβ-induced neurovascular dysfunction, promotes
β-secretase activity, and leads to amyloidogenic processing of APP. J
Cereb Blood Flow Metab. 2016;36:241–252. doi: 10.1038/jcbfm.2015.79
124. Yang Y, Kimura-Ohba S, Thompson J, Rosenberg GA. Rodent models of
vascular cognitive impairment. Transl Stroke Res. 2016;7:407–414. doi:
10.1007/s12975-016-0486-2
125. Capone C, Faraco G, Peterson JR, Coleman C, Anrather J, Milner TA,
Pickel VM, Davisson RL, Iadecola C. Central cardiovascular circuits con-
tribute to the neurovascular dysfunction in angiotensin II hypertension. J
Neurosci. 2012;32:4878–4886. doi: 10.1523/JNEUROSCI.6262-11.2012
126. Touyz RM, Briones AM. Reactive oxygen species and vascular biology:
implications in human hypertension. Hypertens Res. 2011;34:5–14. doi:
10.1038/hr.2010.201
127. Girouard H, Park L, Anrather J, Zhou P, Iadecola C. Cerebrovascular
nitrosative stress mediates neurovascular and endothelial dysfunction in-
duced by angiotensin II. Arterioscler Thromb Vasc Biol. 2007;27:303–
309. doi: 10.1161/01.ATV.0000253885.41509.25
128. Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxyni-
trite in health and disease. Physiol Rev. 2007;87:315–424. doi:
10.1152/physrev.00029.2006
129. Park L, Wang G, Moore J, Girouard H, Zhou P, Anrather J, Iadecola
C. The key role of transient receptor potential melastatin-2 chan-
nels in amyloid-β-induced neurovascular dysfunction. Nat Commun.
2014;5:5318. doi: 10.1038/ncomms6318
130. Ago T, Kuroda J, Kamouchi M, Sadoshima J, Kitazono T.
Pathophysiological roles of NADPH oxidase/nox family proteins
in the vascular system. -Review and perspective-. Circ J. 2011;75:
1791–1800.
131. Santhanam AV, d’Uscio LV, Smith LA, Katusic ZS. Uncoupling of eNOS
causes superoxide anion production and impairs NO signaling in the ce-
rebral microvessels of hph-1 mice. J Neurochem. 2012;122:1211–1218.
doi: 10.1111/j.1471-4159.2012.07872.x
132. Pires PW, Girgla SS, McClain JL, Kaminski NE, van Rooijen N,
Dorrance AM. Improvement in middle cerebral artery structure and
endothelial function in stroke-prone spontaneously hypertensive rats
after macrophage depletion. Microcirculation. 2013;20:650–661. doi:
10.1111/micc.12064
133. van Veluw SJ, Shih AY, Smith EE, Chen C, Schneider JA, Wardlaw JM,
Greenberg SM, Biessels GJ. Detection, risk factors, and functional con-
sequences of cerebral microinfarcts. Lancet Neurol. 2017;16:730–740.
doi: 10.1016/S1474-4422(17)30196-5
134. Biesbroek JM, Weaver NA, Biessels GJ. Lesion location and cognitive
impact of cerebral small vessel disease. Clin Sci (Lond). 2017;131:715–
728. doi: 10.1042/CS20160452
135. Akoudad S, Wolters FJ, Viswanathan A, de Bruijn RF, van der Lugt A,
Hofman A, Koudstaal PJ, Ikram MA, Vernooij MW. Association of ce-
rebral microbleeds with cognitive decline and dementia. JAMA Neurol.
2016;73:934–943. doi: 10.1001/jamaneurol.2016.1017
136. Benjamin P, Trippier S, Lawrence AJ, Lambert C, Zeestraten E, Williams
OA, Patel B, Morris RG, Barrick TR, MacKinnon AD, Markus HS.
Lacunar infarcts, but not perivascular spaces, are predictors of cognitive
decline in cerebral small-vessel disease. Stroke. 2018;49:586–593. doi:
10.1161/STROKEAHA.117.017526
137. Seo SW, Lee JM, Im K, Park JS, Kim SH, Kim ST, Ahn HJ, Chin J,
Cheong HK, Weiner MW, Na DL. Cortical thinning related to peri-
ventricular and deep white matter hyperintensities. Neurobiol Aging.
2012;33:1156–1167. doi: 10.1016/j.neurobiolaging.2010.12.003
138. Rosenberg GA. Extracellular matrix inflammation in vascular cogni-
tive impairment and dementia. Clin Sci (Lond). 2017;131:425–437. doi:
10.1042/CS20160604
139. Guo S, Kim WJ, Lok J, Lee SR, Besancon E, Luo BH, Stins MF, Wang
X, Dedhar S, Lo EH. Neuroprotection via matrix-trophic coupling be-
tween cerebral endothelial cells and neurons. Proc Natl Acad Sci USA.
2008;105:7582–7587. doi: 10.1073/pnas.0801105105
140. Habes M, Sotiras A, Erus G, Toledo JB, Janowitz D, Wolk DA, Shou
H, Bryan NR, Doshi J, Völzke H, Schminke U, Hoffmann W, Resnick
SM, Grabe HJ, Davatzikos C. White matter lesions: spatial heteroge-
neity, links to risk factors, cognition, genetics, and atrophy. Neurology.
2018;91:e964–e975. doi: 10.1212/WNL.0000000000006116
141. Joutel A, Chabriat H. Pathogenesis of white matter changes in cerebral
small vessel diseases: beyond vessel-intrinsic mechanisms. Clin Sci
(Lond). 2017;131:635–651. doi: 10.1042/CS20160380
142. Fernando MS, Simpson JE, Matthews F, Brayne C, Lewis CE, Barber R,
Kalaria RN, Forster G, Esteves F, Wharton SB, Shaw PJ, O’Brien JT, Ince
PG; MRC Cognitive Function and Ageing Neuropathology Study Group.
White matter lesions in an unselected cohort of the elderly: molecular
 Iadecola and Gottesman   Hypertension and Cognition   1043
pathology suggests origin from chronic hypoperfusion injury. Stroke.
2006;37:1391–1398. doi: 10.1161/01.STR.0000221308.94473.14
143. Sam K, Crawley AP, Conklin J, Poublanc J, Sobczyk O, Mandell
161. Korf ES, White LR, Scheltens P, Launer LJ. Midlife blood pressure and the
DM, Venkatraghavan L, Duffin J, Fisher JA, Black SE, Mikulis DJ.
Development of white matter hyperintensity is Ppreceded by reduced
cerebrovascular reactivity. Ann Neurol. 2016;80:277–285. doi: 10.1002/
ana.24712
144. van der Veen PH, Muller M, Vincken KL, Hendrikse J, Mali WP, van
der Graaf Y, Geerlings MI; SMART Study Group. Longitudinal re-
lationship between cerebral small-vessel disease and cerebral blood
flow: the second manifestations of arterial disease-magnetic reso-
nance study. Stroke. 2015;46:1233–1238. doi: 10.1161/STROKEAHA.
114.008030
145. Shi Y, Thrippleton MJ, Makin SD, Marshall I, Geerlings MI, de Craen
AJM, van Buchem MA, Wardlaw JM. Cerebral blood flow in small ves-
sel disease: a systematic review and meta-analysis. J Cereb Blood Flow
Metab. 2016;36:1653–1667. doi: 10.1177/0271678X16662891
146. Farrall AJ, Wardlaw JM. Blood-brain barrier: ageing and microvas-
cular disease–systematic review and meta-analysis. Neurobiol Aging.
2009;30:337–352. doi: 10.1016/j.neurobiolaging.2007.07.015
147. Maclullich AM, Ferguson KJ, Reid LM, Deary IJ, Starr JM, Seckl JR,
Bastin ME, Wardlaw JM. Higher systolic blood pressure is associated
with increased water diffusivity in normal-appearing white matter.
Stroke. 2009;40:3869–3871. doi: 10.1161/STROKEAHA.109.547877
148. Marques S, Zeisel A, Codeluppi S, et al. Oligodendrocyte heteroge-
neity in the mouse juvenile and adult central nervous system. Science.
2016;352:1326–1329. doi: 10.1126/science.aaf6463
149. Arai K, Lo EH. An oligovascular niche: cerebral endothelial cells pro-
mote the survival and proliferation of oligodendrocyte precursor cells. J
Neurosci. 2009;29:4351–4355. doi: 10.1523/JNEUROSCI.0035-09.2009
150. Back SA, Tuohy TM, Chen H, Wallingford N, Craig A, Struve J, Luo
NL, Banine F, Liu Y, Chang A, Trapp BD, Bebo BF Jr, Rao MS, Sherman
LS. Hyaluronan accumulates in demyelinated lesions and inhibits oli-
godendrocyte progenitor maturation. Nat Med. 2005;11:966–972. doi:
10.1038/nm1279
151. Summers PM, Hartmann DA, Hui ES, Nie X, Deardorff RL, McKinnon
ET, Helpern JA, Jensen JH, Shih AY. Functional deficits induced by cor-
Downloaded from http://ahajournals.org by on June 30, 2019
tical microinfarcts. J Cereb Blood Flow Metab. 2017;37:3599–3614. doi:
10.1177/0271678X16685573
152. Carnevale L, D’Angelosante V, Landolfi A, Grillea G, Selvetella G,
Storto M, Lembo G, Carnevale D. Brain MRI fiber-tracking reveals
white matter alterations in hypertensive patients without damage at con-
ventional neuroimaging. Cardiovasc Res. 2018;361:878–811.
153. Beauchet O, Celle S, Roche F, Bartha R, Montero-Odasso M, Allali G,
Annweiler C. Blood pressure levels and brain volume reduction: a sys-
tematic review and meta-analysis. J Hypertens. 2013;31:1502–1516. doi:
10.1097/HJH.0b013e32836184b5
154. Iliff JJ, Wang M, Zeppenfeld DM, Venkataraman A, Plog BA, Liao Y,
Deane R, Nedergaard M. Cerebral arterial pulsation drives paravas-
cular CSF-interstitial fluid exchange in the murine brain. J Neurosci.
2013;33:18190–18199. doi: 10.1523/JNEUROSCI.1592-13.2013
155. Bedussi B, Almasian M, de Vos J, VanBavel E, Bakker EN. Paravascular
spaces at the brain surface: low resistance pathways for cerebro-
spinal fluid flow. J Cereb Blood Flow Metab. 2018;38:719–726. doi:
10.1177/0271678X17737984
156. Azarpazhooh MR, Avan A, Cipriano LE, Munoz DG, Sposato LA,
Hachinski V. Concomitant vascular and neurodegenerative pathologies
double the risk of dementia. Alzheimers Dement. 2018;14:148–156. doi:
10.1016/j.jalz.2017.07.755
157. Gottesman RF, Schneider AL, Zhou Y, Coresh J, Green E, Gupta N,
Knopman DS, Mintz A, Rahmim A, Sharrett AR, Wagenknecht LE,
Wong DF, Mosley TH. Association between midlife vascular risk factors
and estimated brain amyloid deposition. JAMA. 2017;317:1443–1450.
doi: 10.1001/jama.2017.3090
158. Vemuri P, Lesnick TG, Przybelski SA, Knopman DS, Lowe VJ,
Graff-Radford J, Roberts RO, Mielke MM, Machulda MM, Petersen
RC, Jack CR Jr. Age, vascular health, and Alzheimer disease bio-
markers in an elderly sample. Ann Neurol. 2017;82:706–718. doi:
10.1002/ana.25071
159. Arvanitakis Z, Capuano AW, Lamar M, Shah RC, Barnes LL, Bennett
DA, Schneider JA. Late-life blood pressure association with cerebrovas-
cular and Alzheimer disease pathology. Neurology. 2018;91:e517–e525.
doi: 10.1212/WNL.0000000000005951
160. Kester MI, van der Flier WM, Mandic G, Blankenstein MA, Scheltens
P, Muller M. Joint effect of hypertension and APOE genotype on CSF
biomarkers for Alzheimer’s disease. J Alzheimers Dis. 2010;20:1083–
1090. doi: 10.3233/JAD-2010-091198
risk of hippocampal atrophy: the HonoluluAsiaAging Study. Hypertension.
2004;44:29–34. doi: 10.1161/01.HYP.0000132475.32317.bb
162. Shih YH, Wu SY, Yu M, Huang SH, Lee CW, Jiang MJ, Lin PY, Yang TT,
Kuo YM. Hypertension accelerates Alzheimer’s disease-related pathol-
ogies in pigs and 3xTg mice. Front Aging Neurosci. 2018;10:73. doi:
10.3389/fnagi.2018.00073
163. Carnevale D, Mascio G, D’Andrea I, Fardella V, Bell RD, Branchi I,
Pallante F, Zlokovic B, Yan SS, Lembo G. Hypertension induces brain
β-amyloid accumulation, cognitive impairment, and memory dete-
rioration through activation of receptor for advanced glycation end
products in brain vasculature. Hypertension. 2012;60:188–197. doi:
10.1161/HYPERTENSIONAHA.112.195511
164. Schreiber S, Drukarch B, Garz C, Niklass S, Stanaszek L, Kropf S,
Bueche C, Held F, Vielhaber S, Attems J, Reymann KG, Heinze HJ,
Carare RO, Wilhelmus MM. Interplay between age, cerebral small vessel
disease, parenchymal amyloid-β, and tau pathology: longitudinal stud-
ies in hypertensive stroke-prone rats. J Alzheimers Dis. 2014;42(suppl
3):S205–S215. doi: 10.3233/JAD-132618
165. Wang J, Ho L, Chen L, Zhao Z, Zhao W, Qian X, Humala N, Seror I,
Bartholomew S, Rosendorff C, Pasinetti GM. Valsartan lowers brain
beta-amyloid protein levels and improves spatial learning in a mouse
model of Alzheimer disease. J Clin Invest. 2007;117:3393–3402. doi:
10.1172/JCI31547
166. Royea J, Zhang L, Tong XK, Hamel E. Angiotensin IV receptors me-
diate the cognitive and cerebrovascular benefits of losartan in a mouse
model of Alzheimer’s disease. J Neurosci. 2017;37:5562–5573. doi:
10.1523/JNEUROSCI.0329-17.2017
167. d’Uscio LV, He T, Katusic ZS. Expression and processing of amyloid
precursor protein in vascular endothelium. Physiology (Bethesda).
2017;32:20–32. doi: 10.1152/physiol.00021.2016
168. Zhu D, Shi J, Zhang Y, Wang B, Liu W, Chen Z, Tong Q. Central angio-
tensin II stimulation promotes β amyloid production in Sprague Dawley
rats. PLoS One. 2011;6:e16037. doi: 10.1371/journal.pone.0016037
169. Austin SA, Katusic ZS. Loss of endothelial nitric oxide synthase
promotes p25 generation and tau phosphorylation in a murine
model of Alzheimer’s disease. Circ Res. 2016;119:1128–1134. doi:
10.1161/CIRCRESAHA.116.309686
170. Tian M, Zhu D, Xie W, Shi J. Central angiotensin II-induced Alzheimer-
like tau phosphorylation in normal rat brains. FEBS Lett. 2012;586:3737–
3745. doi: 10.1016/j.febslet.2012.09.004
171. Tzourio C, Dufouil C, Ducimetière P, Alpérovitch A. Cognitive decline
in individuals with high blood pressure: a longitudinal study in the eld-
erly. EVA Study Group. Epidemiology of Vascular Aging. Neurology.
1999;53:1948–1952.
172. Peila R, White LR, Masaki K, Petrovitch H, Launer LJ. Reducing the
risk of dementia: efficacy of long-term treatment of hypertension. Stroke.
2006;37:1165–1170. doi: 10.1161/01.STR.0000217653.01615.93
173. Haag MD, Hofman A, Koudstaal PJ, Breteler MM, Stricker BH.
Duration of antihypertensive drug use and risk of dementia: A prospec-
tive cohort study. Neurology. 2009;72:1727–1734. doi: 10.1212/01.wnl.
0000345062.86148.3f
174. Forette F, Seux ML, Staessen JA, et al. Prevention of dementia in ran-
domised double-blind placebo-controlled Systolic Hypertension in
Europe (Syst-Eur) trial. Lancet. 1998;352:1347–1351.
175. The SPRINT MIND Investigators for the SPRINT Research Group,
Williamson JD, Pajewski NM, Auchus AP, et al. Effect of intensive vs
standard blood pressure control on probable dementia. JAMA. 2019;1–9.
doi: 10.1001/jama.2018.21442
176. Zonneveld TP, Richard E, Vergouwen MD, Nederkoorn PJ, de Haan R,
Roos YB, Kruyt ND. Blood pressure-lowering treatment for preventing
recurrent stroke, major vascular events, and dementia in patients with a
history of stroke or transient ischaemic attack. Cochrane Database Syst
Rev. 2018;7:CD007858. doi: 10.1002/14651858.CD007858.pub2
177. McGuiness B, Todd S, Passmore P, Bullock R. The effects of blood pres-
sure lowering on development of cognitive impairment and dementia
in patients without apparent prior cerebrovascular disease. Cochrane
Database Systemic Reviews. 2006;19:CD004034.
178. Elias PK, Elias MF, D’Agostino RB, Cupples LA, Wilson PW, Silbershatz
H, Wolf PA. NIDDM and blood pressure as risk factors for poor cognitive
performance. The Framingham Study. Diabetes Care. 1997;20:1388–1395.
179. Wolf PA, Beiser A, Elias MF, Au R, Vasan RS, Seshadri S. Relation
of obesity to cognitive function: importance of central obesity and
 1044  Circulation Research  March 29, 2019
synergistic influence of concomitant hypertension. The Framingham
Heart Study. Curr Alzheimer Res. 2007;4:111–116.
180. Kivipelto M, Ngandu T, Laatikainen T, Winblad B, Soininen H,
Tuomilehto J. Risk score for the prediction of dementia risk in 20 years
among middle aged people: a longitudinal, population-based study.
Lancet Neurol. 2006;5:735–741. doi: 10.1016/S1474-4422(06)70537-3
181. Virta JJ, Heikkilä K, Perola M, Koskenvuo M, Räihä I, Rinne JO, Kaprio
J. Midlife cardiovascular risk factors and late cognitive impairment. Eur
J Epidemiol. 2013;28:405–416. doi: 10.1007/s10654-013-9794-y
182. González HM, Tarraf W, Harrison K, Windham BG, Tingle J, Alonso
A, Griswold M, Heiss G, Knopman D, Mosley TH. Midlife cardio-
vascular health and 20-year cognitive decline: Atherosclerosis Risk in
Communities Study results. Alzheimers Dement. 2018;14:579–589. doi:
10.1016/j.jalz.2017.11.002
183. Qiu C, Winblad B, Fastbom J, Fratiglioni L. Combined effects of APOE
genotype, blood pressure, and antihypertensive drug use on incident AD.
Neurology. 2003;61:655–660.
184. Andrews S, Das D, Anstey KJ, Easteal S. Interactive effect of APOE gen-
otype and blood pressure on cognitive decline: the PATH Through Life
study. J Alzheimers Dis. 2015;44:1087–1098. doi: 10.3233/JAD-140630
185. Rodrigue KM, Rieck JR, Kennedy KM, Devous MD Sr, Diaz-Arrastia
R, Park DC. Risk factors for β-amyloid deposition in healthy aging:
vascular and genetic effects. JAMA Neurol. 2013;70:600–606. doi:
10.1001/jamaneurol.2013.1342
186. Rast P, Kennedy KM, Rodrigue KM, Robinson PRAW, Gross
AL, McLaren DG, Grabowski T, Schaie KW, Willis SL. APOEε4
Genotype and Hypertension Modify 8-year Cortical Thinning: Five
Occasion Evidence from the Seattle Longitudinal Study. Cereb Cortex.
2018;28:1934–1945. doi: 10.1093/cercor/bhx099
187. Gelber RP, Ross GW, Petrovitch H, Masaki KH, Launer LJ, White LR.
Antihypertensive medication use and risk of cognitive impairment:
the Honolulu-Asia Aging Study. Neurology. 2013;81:888–895. doi:
10.1212/WNL.0b013e3182a351d4
Downloaded from http://ahajournals.org by on June 30, 2019
188. Tzourio C, Anderson C, Chapman N, Woodward M, Neal B,
MacMahon S, Chalmers J; PROGRESS Collaborative Group. Effects
of blood pressure lowering with perindopril and indapamide therapy
on dementia and cognitive decline in patients with cerebrovascular di-
sease. Arch Intern Med. 2003;163:1069–1075. doi: 10.1001/archinte.
163.9.1069
189. Tully PJ, Peters R, Pérès K, Anstey KJ, Tzourio C. Effect of SSRI and cal-
cium channel blockers on depression symptoms and cognitive function
in elderly persons treated for hypertension: three city cohort study. Int
Psychogeriatr. 2018;30:1345–1354. doi: 10.1017/S1041610217002903
190. Peters R, Collerton J, Granic A, Davies K, Kirkwood T, Jagger C.
Antihypertensive drug use and risk of cognitive decline in the very
old: an observational study - the Newcastle 85+ Study. J Hypertens.
2015;33:2156–2164. doi: 10.1097/HJH.0000000000000653
191. Maxwell CJ, Hogan DB, Ebly EM. Calcium-channel blockers and cogni-
tive function in elderly people: results from the Canadian Study of Health
and Aging. CMAJ. 1999;161:501–506.
192. Ahmed HA, Ishrat T, Pillai B, Fouda AY, Sayed MA, Eldahshan W,
Waller JL, Ergul A, Fagan SC. RAS modulation prevents progres-
sive cognitive impairment after experimental stroke: a randomized,
blinded preclinical trial. J Neuroinflammation. 2018;15:229. doi:
10.1186/s12974-018-1262-x
193. Wharton W, Goldstein FC, Tansey MG, Brown AL, Tharwani
SD, Verble DD, Cintron A, Kehoe PG. Rationale and Design of
the Mechanistic Potential of Antihypertensives in Preclinical
Alzheimer’s (HEART) Trial. J Alzheimers Dis. 2018;61:815–824. doi:
10.3233/JAD-161198
194. Wright JT Jr, Dunn JK, Cutler JA, Davis BR, Cushman WC, Ford CE,
Haywood LJ, Leenen FH, Margolis KL, Papademetriou V, Probstfield
JL, Whelton PK, Habib GB; ALLHAT Collaborative Research Group.
Outcomes in hypertensive black and nonblack patients treated with
chlorthalidone, amlodipine, and lisinopril. JAMA. 2005;293:1595–1608.
doi: 10.1001/jama.293.13.1595