Expert Review of Neurotherapeutics

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Antihypertensive agents in Alzheimer’s disease:

beyond vascular protection

Thibaud Lebouvier, Yaohua Chen, Patrick Duriez, Florence Pasquier & Régis
Bordet

To cite this article: Thibaud Lebouvier, Yaohua Chen, Patrick Duriez, Florence Pasquier & Régis
Bordet (2019): Antihypertensive agents in Alzheimer’s disease: beyond vascular protection, Expert
Review of Neurotherapeutics, DOI: 10.1080/14737175.2020.1708195

To link to this article: https://doi.org/10.1080/14737175.2020.1708195

Accepted author version posted online: 23

Dec 2019.
Published online: 27 Dec 2019.

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EXPERT REVIEW OF NEUROTHERAPEUTICS
https://doi.org/10.1080/14737175.2020.1708195

REVIEW

Antihypertensive agents in Alzheimer’s disease: beyond vascular protection

Thibaud Lebouviera,b*, Yaohua Chen b,c
*, Patrick Duriezc, Florence Pasquierb,c and Régis Bordetc
a
Inserm URM_S1172, University of Lille, Lille, France; bDISTALZ, University of Lille, Lille, France; cInserm, CHU Lille, University of Lille, Lille, France

ABSTRACT ARTICLE HISTORY

Introduction: Midlife hypertension has been consistently linked with increased risk of cognitive decline Received 2 October 2019
and Alzheimer’s disease (AD). Observational studies and randomized trials show that the use of Accepted 19 December 2019
antihypertensive therapy is associated with a lesser incidence or prevalence of cognitive impairment KEYWORDS
and dementia. However, whether antihypertensive agents specifically target the pathological process Alzheimer’s disease;
of AD remains elusive. pathology; vascular risk
Areas covered: This review of literature provides an update on the clinical and preclinical arguments factors; hypertension;
supporting anti-AD properties of antihypertensive drugs. The authors focused on validated all classes of antihypertensive agents;
antihypertensive treatments such as angiotensin-converting enzyme inhibitors (ACEi), angiotensin prevention; neuroprotection;
receptor blockers (ARB), calcium channel blockers (CCB), β-blockers, diuretics, neprilysin inhibitors, treatment
and other agents. Three main mechanisms can be advocated: action on the concurrent vascular
pathology, action on the vascular component of Alzheimer’s pathophysiology, and action on nonvas-
cular targets.
Expert opinion: In 2019, while there is no doubt that hypertension should be treated in primary
prevention of vascular disease and in secondary prevention of stroke and mixed dementia, the place of
antihypertensive agents in the secondary prevention of ‘pure’ AD remains an outstanding question.

1. Background white matter lesion, and smaller brain volumes [9]. Many stu-
dies have tried to answer the question of whether antihyper-
The total number of people with dementia worldwide in 2018
tensive agents can prevent or slow down AD. There is a wealth
is estimated at 50 million and is projected to nearly triple,
of observational studies showing that the use of antihyperten-
reaching 150 million in 2050 [1]. Around 70% of these cases
sive therapy is associated with a lesser incidence or prevalence
are attributed to Alzheimer’s disease (AD), a devastating con-
of cognitive impairment and dementia [10–16]. With the excep-
dition leading to dependence to caregivers [2]. AD thus repre-
tion of the Rotterdam Study cohort, where the decrease of the
sents an enormous strain on the health-care system,
relative risk for AD was not significant [12], most studies yielded
underlining the need for medicines that would slow progres-
the same results when separating AD from all-type dementia
sion, halt or prevent AD.
[10,12–16]. Four pivotal prospective observational studies were
Findings from observational studies have linked several
performed in population-based cohorts [13,14,16,17].
vascular risk factors (VRFs) with increased risk of late-life cog-
Interestingly, the Honolulu-Asia Aging Study and the
nitive impairment and AD (reviewed in [3]). According to
Rotterdam Study showed a positive correlation between the
a recent meta-analysis, a third of AD cases worldwide could
reduction of AD risk and duration of exposure to antihyperten-
be attributed to seven modifiable factors (low education, mid-
sive drugs, supporting a mechanistic link between antihyper-
life hypertension, midlife obesity, diabetes, physical inactivity,
tensive drug use and AD prevention [14,16].
smoking, and depression) [4]. In a longitudinal 20 year-long
In an effort to circumvent the biases of observational stu-
study gathering 1,409 middle-aged individuals, future demen-
dies, at least three randomized trials were performed to exam-
tia (fulfilling AD criteria in 80% of cases) was significantly
ine whether antihypertensive treatment prevents dementia
predicted by high age, low education, hypertension, hyperch-
± AD occurrence [18–20]. Two large placebo-controlled trials
olesterolemia, and obesity [5]. In this context, the idea that
testing different antihypertensive regimens in elderly patients
VRF treatment may also interfere with AD pathological process
with hypertension had to be stopped because of interim
was put forth [6,7].
analysis showing a reduction in stroke or mortality [18,20].
Among VRFs, hypertension, diabetes, and dyslipidemia are
Despite this premature interruption, the SYST-EUR trial, includ-
readily modifiable with established therapeutic strategies [8].
ing 2418 patients ≥60 years [18], showed a marginally signifi-
But midlife hypertension is generally viewed as one of the main
cant decrease in the incidence of dementia after a median
evitable VRF for cognitive decline and AD [2,6,7,9,10]. Midlife
follow-up of 2 years (21 cases in the placebo group, 15 of
high blood pressure (BP) was also associated with an increase of

CONTACT Prof. Régis Bordet Regis.Bordet@univ-lille.fr Faculté de Médecine, pôle recherche Département de Pharmacologie Médicale 1, Université Lille 2,
place de Verdun, Lille 59045, France
*
These authors contributed equally to this work
© 2019 Informa UK Limited, trading as Taylor & Francis Group
2 T. LEBOUVIER ET AL.
Article highlights
● Observational studies showed that the use of antihypertensive ther-
apy is associated with a lesser incidence or prevalence of cognitive
impairment and dementia, whereas randomized trials and data on
established AD are issuable.
● Action on the concurrent vascular pathology is probably the main
cause of cognitive decline reduction by antihypertensive drugs.
● Action on the vascular component of Alzheimer’s pathophysiology is
the most appealing of the possible modes of action of antihyperten-
sive drugs; several ARBs and CCBs demonstrated positive effects on
vascular amyloid clearance and alterations of vascular function in AD
models.
● Action on nonvascular targets could explain anti-AD properties of
selective antihypertensive drugs, such as CCBs with high brain pene-
tration or some ARBs with PPARγ agonist properties. Off-targets may
be detrimental as well, as was shown with ACE and neprilysin
inhibitors – even though their theoretical pro-amyloidogenic proper-
ties do not seem to be clinically meaningful.
● From this review of literature, ARBs (telmisartan in particular) and
CCBs (nilvadipine in particular) may offer the most benefit by inter-
fering in amyloid formation, breakdown and clearance, and also
improving endothelial function.
which were AD, 11 cases in the treatment group, 8 of which
were AD), a result that was confirmed by an extended open-
label follow-up of 5 years [21]. The more recent HYVET trial
included 3336 significantly older patients (≥80 years). After
follow-up of 2 years, there was no significant difference in
the rate of incident dementia between treatment and placebo
groups despite a trend toward less incident AD (78 vs. 86 cases
in the placebo group). When these data were combined in
a meta-analysis with other placebo-controlled trials of antihy-
pertensive treatment, the combined risk ratio favored treat-
ment [20]. Lately, the SPRINT-MIND trial showed that an
intensive BP control compared with standard practices did
not significantly reduce the incidence of probable dementia
[22]. No attempt to classify dementia subtype was made.
However, the authors showed a lower risk of incident mild
cognitive impairment in the intensive treatment arm (14.6 vs
18.3 cases per 1000 person-years). Moreover, an intensive BP
control was significantly associated with a smaller increase in
white matter lesion volume and a greater decrease in total
brain volume [23]. Again, the trial was terminated earlier
because of a benefit on cardiovascular event.
Data in established AD are scarcer. Some observational
studies show a slower cognitive decline in patients treated
with antihypertensive drugs [24,25], although it is not
a universal finding [26].
The putative protective effect of antihypertensive therapies
against AD is thus a topic of increasing interest. However,
antihypertensive agents are the lead stroke-preventing treat-
ment. They contribute to protect the cerebrovascular structure
from the macroscopic (e.g. white matter injury, hypoperfusion,
microbleeds) and microscopic (e.g. blood–brain barrier disrup-
tion, endothelial dysfunction, microvessel rarefaction) deleter-
ious effects induced by hypertension [27]. Although vascular
dysfunction is viewed as a major contributor to AD [28,29], it
proves extremely difficult to distinguish a possible effect
on AD pathophysiology from the known effect of antihyper-
tensive agents on the vascular burden in the brain. Yet animal
models and postmortem studies largely documented
a synergistic association between hypertension and the two
pathological hallmarks of AD, namely β-amyloid deposits and
neurofibrillary tangles, suggesting that antihypertensive
agents may also reverse AD pathophysiology [30–33].
This survey thus aims to provide an update on the clinical
and preclinical arguments supporting anti-AD properties of
antihypertensive drugs, and to review putative mechanisms
(Table 1). Our aims are to provide a comprehensive view of
a timely debate, and to inspire future therapeutic guidelines
and trials.
2. Search strategy
We searched the PubMed database for relevant articles pub-
lished between 1 January 2000 and 31 August 2019. Search
terms were ‘Alzheimer’s Disease’ OR Alzheimer OR ‘Amyloid
beta-Peptides’ AND ‘antihypertensive agents’ OR different
class of antihypertensive agents.
We searched the clinical studies and preclinical research
articles. For conciseness, we focused on validated treatments
only. The search was limited to articles in English and full
papers. Abstracts were reviewed and articles potentially meet-
ing inclusion criteria identified. Reference lists and reviews
were hand-searched.
3. Angiotensin-converting enzyme inhibitors
Angiotensin-Converting Enzyme (ACE) inhibitors are the oldest
class of drugs targeting the renin-aldosterone angiotensin
system (RAAS), and one of the most prescribed antihyperten-
sive agents. They act by binding to the active site of ACE and
interfering with the ability of the enzyme to bind to and
cleave its substrates. ACE cleaves the biologically inactive
angiotensin I into the vasoconstrictive angiotensin II [34]. It
also transforms the vasodilator bradykinin into inactive
peptides.
3.1. Preclinical studies
The case for ACE inhibitors in AD became certainly weaker
after a demonstration that ACE was an Aβ peptide-cleaving
enzyme, which was first shown in cellular models [35] and
later demonstrated at a molecular level [36]. ACE converts
Aβ43 and Aβ42 to the less aggregable Aβ41 and Aβ40 species,
respectively, and its inhibition seems to enhance Aβ deposi-
tion in the brain of amyloid-beta precursor (APP) transgenic
mice [27,28]. Conversely, mice overexpressing ACE in mono-
cytes and macrophages display a reduction of Aβ deposits and
a retention of cognitive abilities [37]. This apparent protection
from AD pathology supports an important role for ACE in Aβ
clearance, at least in the context of a transgene overexpres-
sion, and claimed against the use of centrally active ACE
inhibitors in AD.
However, the deleterious effects of ACE inhibitors were not
confirmed with two other APP transgenic lines [38].
Normalization of the excessive hippocampal ACE activity was
even beneficial to Tg2576 APP mice in one study, by decreas-
ing amyloidogenic processing of APP and formation of
 EXPERT REVIEW OF NEUROTHERAPEUTICS 3

Table 1. Effect of antihypertensive drugs on Alzheimer’s pathophysiology.

Antihypertensive drugs Preclinical studies Clinical trials Global outcome
Angiotensine-converting Absence of noxiousness
enzyme inhibitors Not sufficient data to support
a neuroprotective effect
Captopril ↓ Amyloidogenic processing ([39,41])
↓ ROS [39]
↓ Inflammation [41]
Perindopril ↓ ACE activity [40] No effect [19,43]
Angiotensin receptor Encouraging positive preclinical data
blockers Potential candidate for future trial, especially
telmisartan
Valsartan ↓ Aβ deposit [51,52]
↓ Aβ oligomerization [51,52]
Losartan ↓ Aβ deposit [51,52]
↓ Aβ oligomerization [51,52]
↓ Tau phosphorylation [59]
↓ Oxidative stress in microvessels [61]
Candesartan ↓ Aβ oligomerization [51,52] Slight effect in some cognitive domains
[66]
Telmisartan ↓ LDL-R and ApoE [55]
↑ Cerebral blood flow [53]
↓ Expression of cytokines [54,57]
↓ Glial activation [58]
Calcium channel blockers Encouraging data for a future trial, with
more selective criteria of patients
Nimodipine ↓ Calcium release [79–81] Slight effect on cognitive function [91]
↓ Amyloidogenesis [82]
↓ Expression of cytokines [88]
↓ Iron entry and toxicity [89]
Nilvadipine ↓ Amyloidogenesis [78] No effect on cognitive outcome, except for
↑ Aβ42 clearance [78,85] male APOE4 [97]
Inhibition of vasoactivity and ↑ Regional cerebral blood flow [96]
restoration of cortical perfusion [86]
Nitrendipine ↓ Amyloidogenesis [84] ↓ Incidence of dementia by 50%, especially
↓ Tau phosphorylation [84] for AD (8 vs. 15 cases) [21]
Nicardipine ↓ Iron entry and toxicity [90]
β-Blockers ↓ Hippocampal Aβ42 and [99–102] Contradictory results in cohorts, no No sufficient data to support
↓ Hyperphosphorylated tau [99–101] available clinical trial [11,105] a neuroprotective effect
Diuretics Not sufficient preclinical data, mostly results
from cohorts
Thiazide diuretics ↓ Aβ oligomerization [51] None
Potassium-sparing diuretics Raise and maintain potassium level Trend to lesser incidence [20]
In cohorts, reduction of risk to develop AD
[17,106]
Neprilysin inhibitors ↑ Aβ levels [110,111] Low brain penetration [114] Not clarified for the absence of noxiousness
α-1-Adrenoceptor Release of APOE and cytokines [115] Improve behavioral symptoms [116] Not clarified for the neuroprotective effect
antagonist (prazosin)

reactive oxygen species [39]. In a rat model of intra-
hippocampal injections of Aβ, perindopril improved learning
and memory, which correlated with decreased ACE activity
and delayed AD pathology [40]. Furthermore, ACE inhibitors
might be beneficial by reducing glial-induced inflammation,
since angiotensin II leads to unregulated inflammation by glial
activation and to inhibition of acetylcholine release. A recent
study demonstrated in vitro anti-inflammatory properties of
captopril, and reduced amyloid burden, macrophage/micro-
glia accumulation by an intranasal captopril treatment as
well [41].
3.2. Clinical trials
Human studies testing ACE inhibitors support the absence of
noxiousness of ACE inhibitors. Only one observational study in
a cohort of >6,000 demented patients in UK showed an asso-
ciation between ACE-inhibitors use and a slight increase risk of
mortality in patients with AD (adjusted HR 1.19 [95% CI
1.07;1.33] but without evidence of increased hospitalization
[42], a finding that was not replicated in other cohorts.
Perindopril was not superior nor inferior to placebo to prevent
incidence of non-stroke-related dementia [19] or continued
cognitive decline [43] in the Perindopril Protection Against
Recurrent Stroke Study (PROGRESS). In two prospective obser-
vational studies, centrally active ACE-inhibitors like perindopril
or captopril seemed to prevent cognitive decline in both
cognitively normal [44] and demented patients [45], as com-
pared with non-centrally active ACE inhibitors that do not
cross the blood–brain barrier. To further address putative pro-
amyloidogenic effects of ACE inhibitors, a cerebrospinal fluid
(CSF) study showed that ramipril inhibited ACE activity in the
CSF and improved blood pressure, but did not influence CSF
Aβ1-42 [46]. One interesting pharmacogenetics study showed
that the use of ACE-inhibitors during 1 year might slow the
cognitive decline in patients with AD, but only for APOE4
carriers of specific ACE genotypes [47].
Overall, if some caution was justified regarding the use of
ACE inhibitors in AD, available preclinical data are inconclusive
and clinical data cleared most concerns regarding their
4 T. LEBOUVIER ET AL.
experimental pro-amyloidogenic properties. This is probably
consistent with the much lower efficiency of hydrolysis of Aβ
by ACE compared to other Aβ degrading enzymes, such as
neprilysin, endothelin-converting enzyme, and insulin-
degrading enzyme (reviewed in [48]). ACE inhibitors might
also act by other pathways which are beneficial for cognition,
as shown in some preclinical studies above. As we will later
discuss, a similar debate was recently stirred up by the new
class of neprilysin inhibitors.
4. Angiotensin receptor blockers
Angiotensin receptor blockers (ARBs) act downstream of ACE
inhibitors in the RAAS. The ARBs are non-peptide compounds
that specifically block the binding of angiotensin II to the
angiotensin I receptor [34].
4.1. Preclinical studies
Most preclinical studies generally support the use of ARBs
in AD, with only rare exceptions [49,50]. The work of The
Mount Sinaï group in New York stands among the interesting
data published on ARBs in preclinical AD models [51]. By
screening 55 commonly prescribed antihypertensive drugs
looking for anti-Aβ properties in vitro, they determined that
only valsartan and losartan were capable of both lowering Aβ
and decreasing oligomerization of Aβ peptides in primary
neuronal cultures, while candesartan acted on oligomerization
only [51,52]. Going to animal models, they showed that pre-
ventive treatment of Tg2576 mice with valsartan significantly
reduced brain Aβ deposits and Aβ-mediated cognitive dete-
rioration, independently of blood-pressure lowering [52].
Unfortunately, those anti-amyloidogenic properties did not
appear to be specific to ARBs as a class, since other ARBs, like
telmisartan, did not have any in vitro effect on Aβ, and there are
no available data in vivo. In an acute mouse model of intracer-
ebroventricular injection of Aβ, telmisartan was able to reduce
amyloid deposition [53] and improve cognition [53,54], thereby
suggesting that mechanisms other than action on Aβ produc-
tion or aggregation may decrease the amyloid load. Actually,
telmisartan draws an increasing interest because of a putative
pleiotropic vascular protection. Telmisartan is indeed a partial
agonist of peroxisome proliferator-activated receptor-γ (PPARγ),
a central regulator in insulin and glucose metabolism.
Interestingly, in spontaneously hypertensive stroke resistant
rats, chronically administered telmisartan strongly reduced low-
density lipoprotein receptor (LDL-R) and ApoE expression in
neurons [55]. Since ApoE and LDL-R are key elements in the
amyloidogenic processing of APP [56], these data provide
a potential mechanism for the possible anti-amyloidogenic
properties of telmisartan. In a simpler model of intracerebral
injection of Aβ, telmisartan also enhanced cerebral blood flow
and attenuated the Aβ-induced increase in expression of cyto-
kines [53,54]. The smaller efficacy of losartan and the partial
reversion of the effects by a PPARγ antagonist supported an
added value for telmisartan [53,54]. Those beneficial effects on
cognition and cytokine release were confirmed in a rat model
combining intracerebroventricular injection of Aβ and cerebral
ischemia [57]. More recently, telmisartan was shown to reduce
glial activation [58] in the 5XFAD transgenic mouse model.
ARBs could also interfere with the AD process through tau-
mediated effects: in the rat, intracerebroventricular injections
of angiotensin II significantly increased tau phosphorylation,
an effect that was attenuated by losartan [59]. The relevance
of those findings for AD however remains doubtful, since tau
phosphorylation is a nonspecific answer to any kind of neuro-
nal insult. In line with this, losartan-induced prolonged hypo-
tension was also shown to lead to tau hyperphosphorylation
through oxidative stress [50].
Beyond the effects on AD pathology, two remarkable
studies yielded the same interesting results using different
ARBs (olmesartan and losartan) and different treatment
schemes on different APP transgenic mouse lines. Both
demonstrated that ARBs protected cognitive function and
cerebrovascular activity through decreased oxidative stress
in brain microvessels. Interestingly, those benefits occurred
without any decrease in Aβ levels and were not related to
changes in blood pressure [60,61].
4.2. Clinical trials
Observational studies on ARBs are conflicting. While
a population-based cohort study showed that ARB treatment
was associated with a reduced risk of dementia, including AD
[62], those results were not confirmed in a cohort of hyper-
tensive patients [63], raising the possibility that hypertension
was a confounding factor in the first study.
More interesting is the SCOPE trial, which included 4937
patients aged 70 to 89 years with mild-to-moderate hyperten-
sion and Mini-Mental State Examination (MMSE) score ≥24.
Double-blind treatment was initiated with candesartan or pla-
cebo, and an open-label therapy was added as needed to
control BP. While there was no difference in the whole popu-
lation of the study, the MMSE score declined less in the low
cognitive function group (MMSE 24–28) receiving candesartan
[64] (reviewed in [65]). This analysis was not pre-specified but
suggested that candesartan was able to hamper an initiated
cognitive decline, regardless of its degenerative or vascular
nature. In a cognitive sub-study performed in 257 subjects
enrolled in SCOPE, the candesartan group showed less decline
on attention and episodic memory but no difference in execu-
tive function and working memory [66]. Although caution
should be exerted, the cognitive domains on which candesar-
tan had a protective effect do not discard an effect on an AD
(rather than vascular) component.
We did not find published clinical studies on ARBs in AD,
underlining the gap between a wealth of encouraging precli-
nical data and the paucity of clinical trials in AD. Few clinical
trials are ongoing [67,68], using mostly telmisartan and losar-
tan, with an estimated study completion in 2021.
Overall, while telmisartan has certainly an interesting pro-
file, and PPARγ is a longstanding target in AD [69], its super-
iority to other ARBs remains questionable. Indeed, many ARBs
share to some extent some PPARγ agonist properties [70] and
the studies performed with valsartan, losartan, and olmisartan
on AD transgenic mice provide more compelling evidence
than the ones performed with telmisartan on short-term Aβ

injection models. Beyond the effect on Aβ pathology, which
does not seem to be shared by all ARBs, the most interesting
and consistent data are the ones addressing their positive
effects on vasculature and cognition. Interestingly in that
regard, a confidential positron electron tomography study
showed that telmisartan as compared to nimodipine increased
rCBF in 10 AD patients after 6 month-treatment [71].
5. Calcium channel blockers
Calcium ions are critical mediators of cell signaling, and cal-
cium channels are ubiquitously expressed. Far from being
specific to vascular smooth muscle cells, the L-type channels,
the primary target of calcium channel blockers (CCBs), are
heavily expressed by neurons [72,73] and may be reached by
CCBs depending on brain penetration. Hence, CCBs are good
candidates as pleiotropic drugs that could influence both
neural conduction and cerebral blood flow to circumvent AD.
The effect of CCBs in AD models has been studied since the
1990s [74]. Although a few studies have focused on verapamil
and diltiazem [75], most have been performed with CCBs of
the dihydropyridine family. Nimodipine is the most studied of
this class, because its lipophilic properties favor brain penetra-
tion. Recently, however, interesting data have emerged on
nilvadipine. Both drugs block L-type calcium channels, but
nimodipine also acts on T-type channels [72,73].
5.1. Preclinical studies
Most published work supports an action of CCBs on amyloid.
In rats, impairment of spatial memory following intracerebro-
ventricular injection of Aβ was prevented both by nilvadipine
and nimodipine treatments [76,77]. In a thorough study, Paris
et al. showed that chronic oral treatment with nilvadipine
decreased Aβ burden in the brains of transgenic PS1/APPsw
mice, and improved learning abilities and spatial memory [78].
The putative mechanisms of action of CCBs on amyloid are
threefold. The first hypothesis is that CCBs suppress Aβ-
induced calcium release. Indeed, in vitro studies suggest that
the neurotoxicity of Aβ species is mediated by an increase in
cytosolic calcium, resulting from direct or indirect stimulation
of L-type calcium channels [79]. Nimodipine was repeatedly
shown to attenuate Aβ-induced neurotoxicity [80,81].
Inhibition of amyloidogenesis is the second putative effect
of CCBs. In primary cultures expressing human APP,
a sustained high concentration of cytosolic calcium inhibited
the alpha-secretase cleavage of APP (non-amyloidogenic path-
way) and induced the production of intraneuronal Aβ42 (amy-
loidogenic pathway), a process that was prevented by
nimodipine [82]. The latter is controversial since nimodipine
was shown to increase Aβ42 production and secretion in
a different culture setting [78,83]. Paris et al. showed that
among several L-type CCBs, only nilvadipine and to a lesser
extent nitrendipine were able to lower Aβ production, inde-
pendently of their action on L-type calcium channels. This
effect might be due to inhibition of the spleen tyrosine kinase
Syk, which indirectly inhibits the β-cleavage of APP [78,84].
The third and perhaps most interesting mechanism of
action of CCBs is on brain vasculature. From the observation
EXPERT REVIEW OF NEUROTHERAPEUTICS 5
that nilvadipine treatment increased plasma Aβ level in trans-
genic animals, Paris et al. showed that some CCBs, among
which nilvadipine, were able to increase Aβ42 transcytosis
across an in vitro blood–brain barrier model, as well as to
increase brain clearance of intracranially administered human
Aβ42 [78,85]. Aβ clearance properties were independent of
blood-pressure lowering, brain penetration of the drugs and
L-type CCB inhibition, suggesting that nilvadipine acted
directly on brain endothelial and/or mural cells [84]. Beyond
its effect on Aβ transcytosis, nilvadipine was shown to inhibit
the vasoactivity elicited by Aβ in isolated human arteries and
to restore cortical perfusion levels in transgenic mice [86].
Among the additional possible mechanisms of neuropro-
tection by CCBs are inhibition of Tau hyperphosphorylation
[84,87], inhibition of Aβ-induced release of proinflammatory
cytokines by microglia [88], and prevention of iron entry
and toxicity [89,90].
5.2. Clinical studies
The dementia prevention trials performed with CCBs were
pioneered by the SYST-EUR vascular dementia sub-study,
which investigated whether a long-term treatment with
nitrendipine could reduce the incidence of dementia [18]. As
mentioned earlier, the SYST-EUR study was prematurely inter-
rupted after an interim analysis showing a 42% reduction in
the incidence of stroke in the treated group. However, 2,418
patients with a median follow-up of 2 years participated to the
sub-study. Active treatment reduced the incidence of demen-
tia by 50% (11 vs. 21 cases), and those results were confirmed
in the open-label extension study [21]. Unexpectedly, nitren-
dipine prevented more Alzheimer’s dementia (8 vs. 15 cases)
than vascular dementia (3 vs. 6 cases). The criteria used to
define vascular and Alzheimer dementias were however ques-
tionable, even at that time, and one can wonder whether AD
diagnosis would have withstood the use of brain MRI and
biomarkers.
Nimodipine has been extensively tested in dementia
patients in the 1990s. The drug has even had the privilege of
a 2005 Cochrane Review to evaluate its effects on dementia.
Of the 14 trials included in the meta-analysis, 2 trials included
only patients with AD, 9 trials included only patients with
cerebrovascular dementia (CVD), and three trials included
patients with AD, CVD, and mixed disease. In hindsight, inclu-
sion criteria are now obsolete, judgment criteria are only
clinical and study durations are too short. However,
a beneficial effect was seen on cognitive function and on
overall clinical improvement at 12 weeks with a dose of
90 mg/day. There was no effect on functional scales [91].
With the emergence of cholinesterase inhibitors, clinical
research on nimodipine was dropped in the 2000s despite
these encouraging results in short-term clinical trials. Only
one small 24-week trial showed no advantage of the combina-
tion of galantamine/nimodipine over galantamine alone [92].
Following exciting preclinical results, the rather old drug
nilvadipine has recently gained its way to clinical trials. In
a proof-of-concept case report of a mild AD patient, nilvadi-
pine elevated both the regional cerebral blood flow and the
Mini-Mental State Examination (MMSE) score [93].
6 T. LEBOUVIER ET AL.
Recapitulating the beneficial short-term effects observed
with nimodipine, a six-week, open-label study gathering 55
patients with mild to moderate AD showed that nivaldipine
was well tolerated and there was a treatment benefit on the
MMSE and executive functions [94,95]. The recent 18-month
European multicentre NILVAD trial was designed to demon-
strate a positive effect of nilvadipine, based on this encoura-
ging data. The study enrolled more than 500 people with
mild to moderate AD according to the 1984 NINCDS-ADRDA
criteria, and compared a once-daily dose of 8 mg nilvadipine
to placebo during 78 weeks [96]. The study failed to demon-
strate any effect of nilvadipine on the cognitive outcome.
However, in predefined subgroup analyses, there was less
cognitive decline in patients with MMSE >20, in males and in
APOE ε4 carriers [97]. As found in the aforementioned case-
report, a subgroup of patients in the NILVAD trial showed an
increase of cerebral blood flow in hippocampal regions [98].
Overall, CCBs show preclinical arguments favoring
a protective role against AD. This putative role does not appear
to be a drug class-effect. Only selected molecules within this
class yielded interesting results – perhaps depending on brain
penetration. The clinical outcome of CCBs are more mitigated,
and possibly specific subgroup of patients should be targeted.
6. Other antihypertensive agents
The other classes of antihypertensive agents have brought
comparatively less attention. This relative paucity of data is
due to deceptive preliminary data, absence of brain penetra-
tion or (in the case of neprilysin inhibitors) novelty of the
drug.
6.1. β-Blockers
The nonselective β-blocker propanolol has been the subject of
a few encouraging reports from a single group, showing
a reduction of cognitive impairment and hippocampal Aβ42
and hyperphosphorylated tau levels in propranolol-treated
Tg2576 mice [99]. Interestingly the results were recapitulated
in senescence-prone mice spontaneously [100] or chronic cor-
ticosterone administration [101]. Comparatively, the selective
β1 adrenergic receptor antagonist nebivolol significantly
reduced brain amyloid content but failed to improve cognitive
function [102]. However, the use of centrally acting β-blockers
is hindered by the possible involvement of beta-adrenergic
systems in learning and memory [103,104].
Clinical studies on β-blockers are confusing. In 2,212
African-American adults aged 65 years and older, centrally
acting sympatholytic agents, as opposed to other antihyper-
tensive agents, were associated with an increased risk of
diagnosis of cognitive impairment [11]. In sharp contrast
are the results from the Honolulu-Asia Aging Study, which
prospectively followed 2,197 elderly Japanese American men
during more than 15 years. In this cohort, β-blocker use as
the sole antihypertensive drug at baseline was associated
with a lower risk of cognitive impairment as compared with
men not taking any antihypertensive medications. This asso-
ciation was not found with other antihypertensive
agents [105].
6.2. Diuretics
There are few preclinical reports on diuretics in AD models.
The aforementioned high throughput screening of drugs able
to inhibit oligomerization Aβ42 showed that furosemide did
not only prevent oligomerisation in vitro but also dissociated
oligomers in the brain of Tg2576 mice [51]. Research on
furosemide did not go further to date.
Clinical trials on diuretics are mostly represented by preven-
tion trials. The aforementioned negative HYVET trial used the
potassium-sparing diuretic indapamide as the first-line treat-
ment, combined with 2 to 4 mg perindopril if needed [20].
There was however a trend toward a lesser incidence of AD in
the treated group. Likewise, in the Ginkgo Evaluation in
Memory Study (GEMS), cognitively normal persons on diuretics,
ACE inhibitors or ARBs and mild cognitive impairment patients
on diuretics had a 50% reduction in the risk of developing
dementia [106]. Last, the 3-year reduction in AD risk observed
with the antihypertensive treatment in the Cache County study
was greatest with the diuretics, and specifically potassium-
sparing diuretics [17].
6.3. Neprilysin inhibitors
Neprilysin is a ubiquitous neutral endopeptidase. Peripherally,
its inhibition increases the bioavailability of natriuretic peptides,
bradykinin, and substance P, resulting in a strong antihyperten-
sive effect through increased natriuresis and vasodilation. The
first-in-class neprilysin inhibitor sacubitril was successfully tested
in hypertension [107] and heart failure [108] in combination with
the ARB enalapril. To date, enalapril/sacubitril combination has
only been approved for heart-failure patients.
This success-story was tarnished by a warning issued in
2015 [109]. Neprilysin is indeed an Aβ-degrading enzyme.
While it is not clear to what extent neprilysin contributes to
Aβ clearance in humans, preclinical data suggest that neprilysin
deficiency increases brain Aβ levels [110] and worsens cognitive
deficits and Aβ pathology in the 5XFAD transgenic mouse
model [111]. Hence, the same questions that surrounded ACE
inhibitors years ago are currently stirring up a controversy on
neprilysin inhibitors [109,112]. Reassuring preliminary results
came recently. In a thorough study performed on cynomolgus
monkeys, a well-known AD model that spontaneously develops
brain amyloidosis, there was a significant short-term increase in
Aβ species half-life and cerebrospinal fluid levels, but levels
normalized after 2 weeks [113]. A 39-week treatment did not
affect amyloid pathology [113]. Both studies were sponsored by
the pharmaceutical company that develops sacubitril. In
humans, brain penetration of the active metabolites of sacubi-
tril was low and the drug did not change cerebrospinal fluid
levels of Aβ40 and Aβ42 [114].
6.4. α-1-Adrenoceptor antagonist and other alkaloid
drugs
With the rationale that enhanced responsiveness to norepi-
nephrine at the α-1-adrenoceptor may contribute to the
pathophysiology of dementia, the centrally-acting α-1-adreno-
ceptor antagonist prazosin was tested in vitro and in vivo.

Prazosin was able to reduce the generation of amyloid β in
neuroblastoma cells but did not influence amyloid plaque
load in transgenic APP23 mice. However, prazosin seemed to
prevent memory deficits over time, possibly through
the release of apolipoprotein E and anti-inflammatory cyto-
kines [115]. Clinically, prazosin was tested in a small double-
blind, placebo-controlled, parallel group study. The drug was
well tolerated and improved behavioral symptoms in patients
with agitation/aggression in AD [116]. Neuroprotective effects
were not tested.
Two small reports additionally showed that Reserpine,
a pleiotropic indole alkaloid drug that has been used both as
an antipsychotic and antihypertensive agent, prevents Aβ toxi-
city and increases lifespan in a C. elegans AD model [117,118]. Its
numerous side-effects probably dissuade further research in AD.
7. Discussion
Several mechanisms can be advocated when trying to under-
stand how antihypertensive agents could slow down AD pro-
gression (Figure 1). Putative mechanisms are threefold: (1)
action on the concurrent vascular pathology; (2) action on
the vascular component of Alzheimer’s pathophysiology; (3)
action on a nonvascular component.
7.1. Action on the concurrent vascular pathology
Hypertension is one of the long-known risk factors for stroke
[8,119] or silent cerebrovascular disease [120,121]. While the link
between VRFs and AD only begins to be ascertained, the relation
between AD and cerebrovascular disease has been extensively
studied in recent years [28]. AD is generally not seen as a primary
vascular disease. However, although mechanistic links remain
elusive, it is becoming obvious that the concomitance of AD
Figure 1. Putative mechanisms of action of antihypertensive drugs on Alzheimer’s disease.
EXPERT REVIEW OF NEUROTHERAPEUTICS 7
and cerebrovascular disease is something more than the mere
addition of two highly prevalent conditions. Concurrent cerebro-
vascular disease is more common in AD than in any other
neurodegenerative disease [122], occurring in at least one-third
of all cases [123]. Vascular and AD pathologies may act synergis-
tically to increase the likelihood of neuronal death – and hence
symptoms – in dementia of mixed vascular and neurodegenera-
tive etiology [122]. According to the neurovascular hypothesis
of AD, brain vascular insults might even be causative in most
late-onset sporadic forms of AD (reviewed in [124]). Incident
vascular pathology is indeed associated with a faster decline
in AD [125,126].
Logically, preventing overt strokes or silent microvascular
lesions will have a positive effect on the cognitive outcome. In
that regard, antihypertensive drugs participate to reduce the
vascular burden in AD. The PROGRESS study clearly shows that
an antihypertensive agent like perindopril protects against
post-recurrent stroke dementia, and not against dementia
without recurrent stroke [19]. Once a putative neurodegenera-
tive process has engaged, perindopril seems to be less effec-
tive [43], and any remaining activity of perindopril could be
due to the prevention of silent strokes [120].
On the other hand, the action of antihypertensive agents
might go well beyond the prevention of vascular lesions. In
the Honolulu-Asia Aging Study, antihypertensive agents abol-
ish the positive association between hypertension and hippo-
campal atrophy, which is one of the radiological hallmarks
of AD [127]. Furthermore, in a postmortem study of 291 brains
with normal brain aging or AD pathology, but no significant
cerebrovascular disease, there was substantially less AD neu-
ropathology in the medicated hypertension group than in the
non-medicated hypertension and non-hypertension
groups [128]. Thus, there are hints, but no hard evidence
from clinical studies supporting a protective effect of
8 T. LEBOUVIER ET AL.
antihypertensive drugs toward AD beyond the prevention of
cerebrovascular pathology.
7.2. Action on the vascular component of Alzheimer’s
pathophysiology
Preventing cerebrovascular events may have indirect conse-
quences on the AD process, since there are putative pathophy-
siological links between ischemic injury, aberrant
beta-amyloid processing and neuronal dysfunction [124].
Above all, the treatment of VRFs could act upstream of
a shared pathway leading to vascular pathology on the one
hand and to AD on the other [124]. Alteration of the neurovas-
cular unit and the blood–brain barrier are thought to play
a central role in AD pathophysiology and symptoms [124]. In
most AD cases, β-amyloid deposits also occur around capillaries
and in arterial walls (a condition termed cerebral amyloid angio-
pathy) [129,130]. By causing collagenous thickening and reduced
pulsatility of arteries and arterioles, hypertension could in turn
impair perivascular drainage of β-amyloid and prompt cerebral
amyloid angiopathy [131]. Vascular pathology also causes
a blood–brain barrier breakdown which may also accelerate
amyloidogenesis, and decrease brain perfusion [132]. Be they
the cause or consequence of AD, preserving blood–brain barrier
integrity and neurovascular unit function might both favor the
vascular clearance of Aβ and preserve neurovascular coupling,
whose demise is one of the earliest observable changes in AD.
Antihypertensive drugs, and particularly the ARBs and the
CCBs are interesting in that regard, because preliminary data
show positive effects on vascular amyloid clearance [78,85]
and alterations of vascular function [51,52,58,59,84,96] in AD
models. While those properties seem to be shared by several
ARBs and may represent a class-effect, only individual drugs
in the CCB class yielded positive results, probably depending
on brain penetration. Interestingly, beyond AD models, ARBs
attenuate vascular oxidative stress in chronic hypoperfu-
sion [133], and restore blood–brain barrier integrity in vitro
[134] and in vivo [135,136], in hypertensive encephalopathy
and diabetes models. Those protective effects result in
improved cognition independently of blood-pressure lower-
ing in an hypertensive rat model [135].
7.3. Action on a nonvascular component of Alzheimer’s
pathophysiology
Third, the possibility that drugs approved for hypertension may
interact with AD-related pathophysiological pathways through
mechanisms unrelated to its original therapeutic intention must
not be discarded [137,138]. The concept of drug repositioning
in AD, beyond antihypertensive agents, has been discussed in
recent reviews [139,140]. Antihypertensive agents may have
unforeseen effects on Alzheimer’s pathological process because
of an extravascular, neuroglial expression of the primary target.
The CCBs are probably the best example of such effects, since
calcium channels are also expressed by neurons. Calcium fluxes
are potentially involved in amyloidogenesis and neurodegen-
eration, providing a strong rationale to their putative protective
properties against AD.
Alternatively, drugs may act on one or several secondary
targets unrelated with the one responsible for its antihyperten-
sive effect. The PPARγ agonist properties of several ARBs [70]
fall in that category. Likewise, the possible superiority of nilva-
dipine to other CCBs in preclinical studies might be due to
targets other than L-type calcium channels, such as the tyrosine
kinase Syk [84].
Interestingly, unexpected effects may as well disfavor the
drug, as showed the controversies surrounding ACE and nepri-
lysin inhibitors, which were both suspected of promoting AD
pathology by inhibiting Aβ-degrading enzymes.
8. Expert opinion
Whether and how the treatment of hypertension (and VRFs as
a whole) hampers Alzheimer’s pathological process is a timely
issue. While many observational and interventional studies
suggest that improved control of hypertension decreases
dementia incidence, it remains doubtful whether antihyper-
tensive drugs prevent AD specifically. Definitive proof will be
hard (even impossible?) to obtain since dementia prevention
trials in hypertensive individuals are now unethical, consider-
ing that hypertension decreases the risk of cardiovascular and
cerebrovascular events – even in the oldest old [20]. The place
of antihypertensive agents in the secondary prevention of AD
is a simple question – yet remains an area of uncertainty.
Research is desperately needed to tackle the outstanding
question of the role of antihypertensive drugs in the primary
prevention of AD. The relative paucity of preclinical research
studies and the lack of state-of-the-art clinical trials testing
a vascular intervention are striking. Until now, research fund-
ing was probably the main limiting factor, because most anti-
hypertensive agents are in the public domain, and studies on
VRFs depend mostly on academic funding. On the preclinical
side, the swiftness of the publication and the state-of-the-art
techniques used in the sacubitril study recently demonstrated
the quality shift of industry-funded work [113], that could
serve as a reference to reassess the effect of the main anti-
hypertensive drugs on amyloid processing. On the clinical
side, the use of CSF biomarkers and neuroimaging (3T-MRI
and tau/amyloid PET) is eagerly awaited to assess the
effect of selected long-term antihypertensive treatment on
Alzheimer pathology and vascular burdens.
For future trials, new diagnostic criteria [141,142] and neu-
roimaging markers [143,144] should be systematically used to
better differentiate their respective action on the vascular load
and on AD pathophysiology. Above all, future trials should
answer the one question with real therapeutic implications:
should patients with AD but without major hypertension nor
cerebrovascular disease be treated with the same stringent
objectives as in secondary prevention of stroke, despite poten-
tial side effects? A drop of BP is commonly observed several
years before the onset of symptoms in late-onset dementia
[145], and BP continues to fall after the diagnosis [146]. The
effect of antihypertensive drugs should thus be carefully mon-
itored in dementia, and their overall use can be questioned,
especially in frail patients. Yet evidence of an increased risk of
orthostatic hypotension in demented patients treated with
antihypertensive drugs is lacking. In the NILVAD study, there

was no evidence of an increased risk of orthostatic hypoten-
sion, fractures, falls, syncope, or dizziness in patients with
mild-to-moderate AD, with or without hypertension, treated
by 8 mg of nilvadipine during 78-weeks [147].
Studies should include individuals with preclinical or early
prodromal AD and plan a long follow-up period. As the associa-
tion between antihypertensive drugs and AD may depend on
sex, ethnicity and genetic background (APOE status), future
therapeutic strategies will probably be personalized [148].
Recent evidence of the efficacy of polypills associating two
antihypertensive drugs (diuretic and ACE inhibitor), statin, and
aspirin came from a pragmatic trial in Iran, showing a reduction
of the risk of major cardiovascular events. These findings are
particularly important for low-income and middle-income coun-
tries and should be taken into account by the scientific commu-
nity in the conception of future trials. A combination of different
classes of antihypertensive treatment might be of interest both
at scientific and pragmatic levels, favoring an ‘efficient access’ to
treatment [149]. Last, in the big data era, large-scale observa-
tional data may further support a long-term effect of antihyper-
tensive drugs on cognition and AD.
For our current practice, although the target blood-pressure
level reduction remains to be defined, we, as others [3,150],
deem reasonable to initiate an antihypertensive treatment in
hypertensive AD patients and in AD patients with evidence of
concomitant cerebrovascular disease. From this review of litera-
ture, ARBs (telmisartan in particular) and CCBs (nilvadipine in
particular) may offer the most benefit by interfering in amyloid
formation, breakdown and clearance, and also improving
endothelial function.
Funding
This paper was not funded.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
Reviewer Disclosures
Peer reviewers on this manuscript have no relevant financial relationships
or otherwise to disclose.
ORCID
Yaohua Chen http://orcid.org/0000-0003-1778-1790
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