revue neurologique 169 (2013) 757764

Available online at

www.sciencedirect.com

International meeting of the French society of neurology 2013

Vascular risk factors and cognitive disorders

Facteurs de risque vasculaires et cognition
S. Debette a,*,b,c,d
a

Department of neurology, hopital Lariboisie`re, 2, rue Ambroise-Pare, 75475 Paris cedex 10, France
Inserm unit U740, universite Paris Diderot Paris 7, UFR de medecine Paris Diderot Paris 7 (site Villemin), 10, avenue
de Verdun, 75010 Paris, France
c
Paris 7 university, DHU neurovasc Sorbonne Paris-Cite, 190, avenue de France, 75013 Paris, France
d
Department of neurology, Framingham heart study, Boston university school of medicine, 72 E Concord St, Boston,
MA 02118, USA
b

info article

abstract

Article history:

Delaying the onset of dementia by just a few years could have a major impact on the

Received 18 July 2013

prevalence of the disease at the population level. Vascular risk factors are modifiable and

Accepted 22 July 2013

may offer an important opportunity for preventive approaches. Several studies have shown

Available online 12 September 2013

that diabetes, hypertension, obesity, and smoking are associated with an increased risk of

Keywords:

associations were observed mainly in studies where risk factors were assessed in midlife,

cognitive decline and dementia, but other groups have not observed such a relation. Positive
Vascular risk factors

suggesting that age is an important modulator in the relation between vascular risk factors

Hypertension

and cognition. The population attributable risk of dementia is particularly high for hyper-

Stroke

tension. Associations of vascular risk factors with cognitive decline and dementia are

Dementia

probably mediated largely by cerebrovascular disease, including both stroke and covert

Cognition

vascular brain injury, which can have additive or synergistic effects with coexisting neu-

Mots cles :

treating vascular risk factors is associated with a reduction in cognitive decline or dementia

Facteurs de risque vasculaire

risk. Of eight randomized trials testing the effect of antihypertensive agents on dementia

Hypertension

risk, only one was positive, and another in a subgroup of individuals with recurrent stroke.

rodegenerative lesions. To date, randomized trials have not convincingly demonstrated that

AVC

In most trials, cognition and dementia were secondary outcomes, follow-up was short and

Demence

treatment was initiated at an older age. No effect on cognitive decline or dementia could be

Cognition

demonstrated for statins and intensive glycemic control. Future areas of investigation could
include differential class effects of antihypertensive drugs on cognitive outcomes and
identification of high risk individuals as target population for clinical trials initiated in
midlife.
# 2013 Published by Elsevier Masson SAS.

r e s u m e
Retarder la survenue de la demence de quelques annees seulement aurait un impact
majeur sur la prevalence de cette maladie a` lechelle de la population. Les facteurs de
risque vasculaires sont modifiables et pourraient constituer une cible importante pour des
* Correspondence. Department of neurology, hopital Lariboisie`re, 2, rue Ambroise-Pare, 75475 Paris cedex 10, France.
E-mail address : sdebette@bu.edu.
0035-3787/$ see front matter # 2013 Published by Elsevier Masson SAS.
http://dx.doi.org/10.1016/j.neurol.2013.07.022

758

revue neurologique 169 (2013) 757764

strategies de prevention. Plusieurs etudes ont montre que le diabe`te, lhypertension,

lobesite, et le tabac etaient associes a` un risque accru de declin cognitif et demence, mais
dautres etudes nont pas pu mettre en evidence de telles associations. Des associations
significatives etaient observees principalement dans des etudes ou` les facteurs de risque
vasculaires etaient evalues a` un age moyen, suggerant un effet modulateur important de
lage dans la relation entre facteurs de risque vasculaires et cognition. Le risque attribuable
de demence est particulie`rement eleve pour lhypertension arterielle. Lassociation des
facteurs de risque vasculaires avec le declin cognitif et la demence est probablement mediee
principalement par la pathologie cerebrovasculaire, incluant a` la fois les accidents vasculaires cerebraux et les lesions cerebrovasculaires silencieuses , qui peuvent avoir des
` ce
effets additifs voire synergiques avec des lesions neurodegeneratives coexistantes. A
jour, les essais therapeutiques randomises nont pas demontre de facon convaincante que
traiter les facteurs de risque vasculaires etait associe a` un ralentissement du declin cognitif
et une reduction du risque de demence. Parmi huit essais therapeutiques randomises
testant leffet de traitements antihypertenseurs sur le risque de demence, seul un etait
positif ; un autre essai etait positif dans un sous-groupe dindividus avec recidive daccident
vasculaire cerebral. Dans la plupart des essais, la cognition et la demence netaient que des
crite`res de jugement secondaires, le suivi etait court et le traitement etait initie a` un age
avance. Aucun benefice des statines ou dun controle glycemique intensif na pu etre
demontre sur le declin cognitif et la demence. De futurs axes de recherche pourraient
inclure les effets differentiels de certaines classes dantihypertenseurs sur la cognition ainsi
que lidentification dindividus a` haut risque comme population cible pour des essais
therapeutiques inities dans des populations dage moyen.
# 2013 Publie par Elsevier Masson SAS.

With expanding longevity, the number of dementia cases is

increasing worldwide and is expected to triple over the next 40
years. Delaying the onset of this disease by just a few years
could have a major impact on the prevalence of dementia at
the population level (Barnes and Yaffe, 2011). To date, no
effective mechanism-based preventive strategies are available
for dementia. Vascular risk factors are modifiable and, given
the strong relationship between cerebrovascular disease and
dementia, they may offer an important opportunity for
preventive approaches. Gathering evidence for associations
between vascular risk factors and dementia and evaluating
the impact of interventions modifying vascular risk factor
exposure on cognitive decline and dementia is therefore of
paramount importance.

1.
Contribution of cerebrovascular disease to
cognitive impairment and dementia
The importance of cerebrovascular disease for cognitive
impairment and dementia is now widely recognized (Viswanathan et al., 2009; Gorelick et al., 2011). Vascular cognitive
impairment and dementia can occur after one of more strokes
(ischemic or hemorrhagic) or in the presence of silent infarcts
or diffuse subcortical cerebrovascular disease (Gorelick et al.,
2011). It is referred to as pure in the absence of Alzheimer
disease (AD) pathology or positive biomarkers for the latter
(e.g. positron emission tomography, cerebrospinal fluid
amyloid b or tau protein) (Gorelick et al., 2011). However,
the vascular contribution to cognitive disorders reaches far
beyond the concept of pure vascular cognitive decline
(Viswanathan et al., 2009). Indeed, cognitive impairment
and dementia is a continuum ranging from patients with

pure vascular dementia to patients with pure AD and

including a large majority of patients with contributions from
both Alzheimer and vascular pathologies (Viswanathan et al.,
2009). Accordingly, neuropathological correlates of cognitive
impairment in late-life are most often a mix of AD pathology
(amyloid plaques and neurofibrillary tangles) and microvascular brain damage. Moreover, in patients with AD, if
cerebrovascular disease is present concomitantly, less AD
pathology is needed to express the dementia syndrome. This
may be due to additive or even synergistic effects of
cerebrovascular damage and neurodegenerative processes
(Snowdon et al., 1997; Petrovitch et al., 2005).

2.
Association of vascular risk factors with
cognition in observational studies
Several studies have shown that diabetes, hypertension,
obesity, and smoking are associated with an increased risk of
dementia (Kivipelto et al., 2005; Whitmer et al., 2005; Anstey
et al., 2007), but other groups did not observe such a relation
(Kloppenborg et al., 2008; Barnes and Yaffe, 2011). Overall,
positive associations were observed mainly in studies where
risk factors were assessed in midlife, especially for blood
pressure and obesity, while most negative studies targeted
older populations (Kloppenborg et al., 2008; Barnes and Yaffe,
2011). In the ARIC study, the impact of vascular risk factors on
dementia was assessed in different age groups and at different
time points within the same cohort, demonstrating that age is
an important modulator, associations being stronger in
individuals aged less than 60 years when the vascular
risk factors were assessed (Alonso et al., 2009). There are
several possible explanations for these age-dependent effects.

revue neurologique 169 (2013) 757764

Epidemiological data suggest that the pathological processes

leading to the disease start operating many years before the
clinical onset (Elias et al., 2000; Jack et al., 2005), and that some
risk factors begin to exert their impact as early as midlife.
Exposure to risk factors in midlife may better capture these
effects and also better reflect cumulative lifetime exposure
that single late-life measurements. Moreover, vascular risk
factor measurements in older persons may be modified by
concomitant chronic diseases inducing weight loss, blood
pressure drop and other metabolic changes, and by concurrent
medications. Finally, associations with late-life risk factor
measurements may be modified by survival bias, due to
premature death of individuals exposed to a high risk factor
burden (Debette and Seshadri, 2009).
Recently, Barnes and Yaffe have reviewed evidence for
seven modifiable risk factors for AD (diabetes, midlife
hypertension, midlife obesity, smoking, physical inactivity,
depression, cognitive inactivity) and have calculated the
population attributable risk, i.e. the percentage of AD cases
attributable to each of these risk factors (Barnes and Yaffe,
2011). Based on this, they estimated that a 10%-reduction in all
seven risk factors could prevent 1.1 million AD cases
worldwide (Barnes and Yaffe, 2011). Of all vascular risk
factors, the population attributable risk of elevated blood
pressure for dementia is particularly high, given the high
prevalence of this condition in the general population
(Kloppenborg et al., 2008; Launer et al., 2010). In the Honolulu
Asia Aging Study, among participants who did not report
taking antihypertensive medication in midlife, 27% of
dementia cases could be attributed to systolic blood pressure
 120 mm Hg (Launer et al., 2010).
There is also important evidence that vascular risk factors
are associated with poorer cognitive performance and
accelerated cognitive decline in individuals without dementia,
the most prominent associations being observed with processing speed and executive function (Carmelli et al., 1998;
Plassman et al., 2010; Debette et al., 2011).

3.

Therapeutic trials

Few randomized trials have tested the impact of vascular risk

factor modification on the risk of dementia, mostly in
secondary analyses.
Eight randomized trials have evaluated the effect of
antihypertensive agents on dementia risk (SHEP_Cooperative_Research_Group, 1991; Forette et al., 1998; Lithell et al.,
2003; Tzourio et al., 2003; Patel et al., 2007; Diener et al., 2008;
Peters et al., 2008; Anderson et al., 2011). Only one of them, the
Syst-Eur trial, including 1238 individuals aged 65 years or
older, demonstrated a significantly reduced risk of dementia
(P = 0.04) in individuals taking nitrendipine, a calcium channel
blocker (CCB), vs. individuals taking placebo (Forette et al.,
1998). In the PROGRESS trial active treatment was associated
with reduced risks of dementia and cognitive decline in
individuals with recurrent stroke (Tzourio et al., 2003). In this
trial, patients with a history of stroke or transient ischemic
attack within five years and a wide range of blood pressure
were randomly assigned to take an angiotensin converting
enzyme (ACE) inhibitor (perindopril), associated or not with a

759

diuretic (indapamide), or placebo, stroke recurrence being the

primary endpoint (PROGRESS_collaborative_group, 2001).
In a meta-analysis combining the eight randomized trials
of antihypertensive therapy for prevention of dementia, blood
pressure lowering did not reduce the risk significantly overall
(Staessen et al., 2011). However, when combining trials by
antihypertensive drug type, the reduction in dementia risk
was significant for trials involving a diuretic or dihydropyridine CCB, but not in trials of renin system inhibitors (Staessen
et al., 2011).
In the ACCORD MIND trial, participants with type 2
high
glycated
haemoglobin
A1c
(HbA1c
diabetes,
concentrations > 7.5%), and a high risk of cardiovascular
events were randomly assigned to receive intensive glycemic
control targeting HbA1c < 6.0% or a standard strategy targeting HbA1c to 7.07.9% (Launer et al., 2011) Although baseline
levels of HbA1c were associated with lower cognitive function
(Cukierman-Yaffe et al., 2009), the primary cognitive outcome
(Digit Symbol Substitution Test score, measuring processing
speed, at 40 months) was not different between the two
treatment arms (Launer et al., 2011). In an MRI-substudy, the
intensive therapy group had significantly greater total brain
volume compared to the standard group at follow-up, and
although total brain volume declined in both groups, it
declined less in the intensive therapy group (Launer et al.,
2011).
Two trials have examined the impact of statins on
dementia or cognition. The PROSPER trial (testing pravastatin
vs. placebo) showed no difference in cognitive function (MiniMental State Examination) at four years between patients on
treatment and those on placebo (Trompet et al., 2010).
Likewise, there was no difference in incidence of dementia
nor in performance on the modified Telephone Interview for
Cognitive Status in the HPS trial (testing simvastatin vs.
placebo) (HPS_Collaborative_Group, 2002).

4.

Mechanisms

The association of vascular risk factors with cognitive decline

and dementia is most likely mediated largely by cerebrovascular disease, including both stroke and covert vascular brain
injury, which can have additive or synergistic effects with
coexisting neurodegenerative lesions. Other putative mechanisms will be discussed briefly.

4.1.

Vascular risk factors, stroke and cognition

Adverse effects of vascular risk factors on cognition can be

mediated by an increased risk of stroke and thereby poststroke cognitive decline and dementia. Of all vascular risk
factors, hypertension is the most powerful predictor of stroke,
both hemorrhagic stroke and ischemic stroke of all subtypes
(Goldstein et al., 2011), and thus also represents an important
risk factor for post-stroke dementia.
Numerous studies, both in a hospital-based (Tatemichi
et al., 1994; Andersen et al., 1996; Inzitari et al., 1998;
Pohjasvaara et al., 1998; Barba et al., 2000; Henon et al.,
2001; Klimkowicz et al., 2002; Tang et al., 2004; Zhou et al.,
2004; de Koning et al., 2005), and community setting (Kokmen

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revue neurologique 169 (2013) 757764

et al., 1996; Kase et al., 1998; Zhu et al., 2000; Ivan et al., 2004),
have shown that the incidence of dementia is substantially
increased in individuals with a history of stroke. In a recent
systematic review, the prevalence of post-stroke dementia
was estimated at 20.3% [95% CI: 18.222.5%] in hospitalizedbased studies and at 7.4% [4.810%] in population-based
studies, after excluding individuals with prestroke dementia
(Pendlebury and Rothwell, 2009).
Cerebrovascular lesions can accelerate the clinical expression of AD pathology through additive effects, by reducing the
threshold for cognitive impairment (Pasquier and Leys, 1997;
Iadecola, 2010). In addition, cerebral hypoperfusion may alter
clearance of amyloid b (Ab) peptide, thus favoring amyloid
plaque deposition, a key neuropathological feature of AD; Ab
in turn was shown to be a potent vasoconstrictor, potentially
contributing to impaired cerebrovascular regulation (Thomas
et al., 1996; Iadecola, 2004; Zlokovic, 2005). Injury to the
neurovascular unit (neurons, glia, perivascular, and vascular
cells), via vascular or neurodegenerative mechanisms, can
alter cerebral blood flow regulation, disrupt the bloodbrain
barrier, and reduce the brains repair capacity, thus further
amplifying the brain dysfunction leading to cognitive impairment (Iadecola, 2010).

4.2.
Vascular risk factors, covert vascular brain injury
and cognition
Brain imaging, especially MRI, performed in large populationbased samples has revealed that covert vascular brain injury is
very common in the elderly, suggesting that the burden of
cerebrovascular disease is far greater than suggested by the
occurrence of acute neurological events such as stroke
(Longstreth, 2005). Covert vascular brain injury, comprising
white matter hyperintensities (WMH) (Debette and Markus,
2010), covert brain infarcts (Vermeer et al., 2007), microbleeds
(Cordonnier et al., 2007), and dilated perivascular spaces (Zhu
et al., 2011), all mostly reflecting cerebral small vessel disease,
is an important mediator in the relation of vascular risk factors
with cognition.
WMH are particularly prevalent in the general population,
and increasingly so with advancing age. Over 90% of
individuals aged 80 years or more have some degree of
WMH (Debette and Markus, 2010), and the prevalence in the
late forties is already estimated around 50% (Wen et al., 2009).
Extensive WMH are associated with an increased risk of
incident dementia, according to a systematic review and
meta-analysis (HR = 1.9 [IC95%: 1.32.8]) (Debette and Markus,
2010). Associations are most prominent for vascular or mixed
dementia (Bombois et al., 2008; Debette and Markus, 2010),
although an association with increased risk of AD has also
been reported (Kuller et al., 2003). WMH also predict an
increased risk of cognitive decline (Debette and Markus, 2010;
Debette et al., 2010a), the strongest associations being
observed with executive function and processing speed
(Longstreth et al., 2005; Kramer et al., 2007; van Dijk et al.,
2008). A stronger association with cognitive impairment was
suggested for WMH in periventricular vs. deep subcortical
areas (Prins et al., 2004, 2005; Debette et al., 2007), or in
strategic regions, e. g. the anterior thalamic radiation (Duering
et al., 2011). Associations of covert brain infarcts, microbleeds,

and dilated perivascular spaces with increased dementia risk

have also been reported (Vermeer et al., 2003, 2007; Greenberg
et al., 2009; Zhu et al., 2010; Poels et al., 2012).
Several putative mechanisms could be underlying the
association between covert vascular brain injury and cognition. Direct damage of cortico-subcortical neuronal circuits
passing through the white matter could contribute to cognitive
decline, especially for tasks involving executive function and
processing speed (Mungas et al., 2005; Nordahl et al., 2006). As
discussed above, cerebrovascular lesions can also interact
with neurodegenerative AD type lesions, with reciprocal
potentiation of disease processes and synergistic deleterious
effects on cognition. In some instances, covert vascular brain
injury could also be a marker of cerebral amyloid angiopathy,
which is highly prevalent in older people, and may contribute
to age-related cognitive impairment through various mechanisms (Arvanitakis et al., 2011; Viswanathan and Greenberg,
2011; Tanskanen et al., 2012).

4.3.

Other putative mechanisms

Whereas vascular brain injury is likely the principal mediator

of associations between vascular risk factors and cognitive
impairment, other mechanisms could also play a role (Hajjar
et al., 2011). In a longitudinal MRI analysis on non-demented
participants from the Framingham Heart Study, hypertension
led to an increase in WMH load, whereas diabetes was
associated with an accelerated rate of hippocampal atrophy,
and smoking predicted an accelerated rate of WMH progression, global and hippocampal atrophy (Debette et al., 2011).
Both vascular and neurodegenerative processes could be
involved in the relation of vascular risk factors with cognition.
A few examples of putative alternative mechanisms under
investigation are listed below.
Animal studies have suggested that angiotensin II, angiotensin converting enzyme and other components of the reninangiotensin system, which play a key role in blood pressure
regulation, may directly modulate Ab production and metabolism (Selkoe, 2000; Kehoe, 2009). Angiotensin receptor
blockers (ARBs) were shown to decrease Ab oligomerization
in animal models (Wang et al., 2007; Danielyan et al., 2010),
and more recently ARB exposure was found to be associated
with less neuropathological features of AD compared to other
antihypertensive medications in a large brain autopsy series
(Hajjar et al., 2012), supporting further research in this
direction.
Mechanisms underlying the association of diabetes with
cognitive impairment could involve potentiation of AD
neuropathology, via promoting oxidative stress, and formation of toxic advanced glycation end products (Tan et al.,
2011). Insulin has also been implicated in production of the
neurotransmitter acetylcholine (Brass et al., 1992), and in tau
phosphorylation and amyloid deposition (Pasquier et al.,
2006). However, in contrast with epidemiological findings,
neuropathological studies found that diabetes is not associated with an increase in AD pathology, but with a
prominent increase in microinfarcts (Kalaria, 2009; Nelson
et al., 2009; Sonnen et al., 2009). Animal experiments have
demonstrated impaired hippocampal plasticity after nicotine exposure (Abrous et al., 2002), and suggested that

revue neurologique 169 (2013) 757764

smoking increases the severity of typical AD features,

including amyloidogenesis, inflammation and tau phosphorylation (Moreno-Gonzalez et al., 2013). Mechanisms underlying the relationship between midlife obesity, especially
central adiposity, and dementia could include inflammation
and insulin-resistance, as well as adipose-tissue derived
hormones promoting neurodegenerative processes (Lieb
et al., 2009; Debette et al., 2010b).

5.

Current limitations and perspectives

Considering the overwhelming evidence that optimal

treatment of vascular risk factors should be targeted to
reduce the burden of vascular disease, investigating the
relation of these risk factors with dementia may seem
superfluous. Indeed, one may argue that management of
these risk factors should be optimal regardless of dementia
risk, given the substantial impact on vascular disease and
life expectancy. However, several questions remain unanswered. First, while there is currently no definitive evidence
that any class of antihypertensive agents offers special
protection against stroke (Goldstein et al., 2011), recent data
suggest that there could be differential class effects of
antihypertensive drugs on cognitive outcomes (Staessen
et al., 2011). Second, time of treatment onset may matter.
Indeed, various studies have shown that associations of
vascular risk factors with cognition are strongest when
exposure is measured in midlife, whereas associations with
vascular risk factors in late-life are less consistent and may
in some cases even show inverse relationships. Thus,
prevention of dementia by blood pressure lowering drugs
may not be efficient if initiated in older individuals. Setting
up a trial in middle-aged individuals is a challenge, as it
would require large numbers and a very long period of
follow-up, unless the trial is conducted on a group of
individuals selected to be at particularly high risk
of developing dementia. Third, simulations of the expected
impact of risk factor control on cognitive disorders at the
population level need to account for competing effects due
to the reduction in vascular disease and extended lifespan,
which increases the risk of developing dementia. Finally,
identifying the mechanisms and molecular pathways by
which vascular risk factors impact cognition may lead to the
identification of novel therapeutic targets for dementia
prevention and treatment.

Disclosure of interest
The author declares that he has no conflicts of interest
concerning this article.

Acknowledgements
Stephanie Debette is a recipient of a chair of excellence from
the National Research Agency (ANR), in collaboration with the
University of Versailles Saint-Quentin-en-Yvelines and
Inserm Unit U708.

761

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