REVIEWS

A major role for cardiovascular burden

inagerelated cognitive decline
Chengxuan Qiu and Laura Fratiglioni
Abstract | The incidence of dementia and cardiovascular disease (CVD) increases with age. Current evidence
supports the role for both atherosclerosis and arteriosclerosis as a common pathophysiological ground for
the heartbrain connection in ageing. Cognitive decline and CVDs share many vascular risk factors (VRFs)
such as smoking, hypertension, and diabetes mellitus; furthermore, CVDs can contribute to cognitive
decline by causing cerebral hypoperfusion, hypoxia, emboli, or infarcts. Mixed dementia, resulting from both
cerebrovascular lesions and neurodegeneration, accounts for the majority of dementia cases among very
old individuals (75years). An accumulation of multiple VRFs, especially in middle age (4059 years of
age), can substantially increase dementia risk. The suggested declining trend in dementia risk, occurring in
parallel with the decreasing incidence of cardiovascular events in high-income countries, supports the role
of cardiovascular burden in dementia. Accordingly, strategies to promote cardiovascular health, especially if
implemented from early life, might help to delay the onset of dementia. In this Review, we discuss the literature
investigating the association of cardiovascular burden with cognitive decline and dementia over the life-course.
Qiu, C. & Fratiglioni, L. Nat. Rev. Cardiol. 12, 267277 (2015); published online 13 January 2015; doi:10.1038/nrcardio.2014.223

Introduction

Division of Aging
Research Center,
Department of
Neurobiology, Care
Sciences and
Society,Karolinska
Institutet and
Stockholm University,
Gvlegatan16,
11330Stockholm,
Sweden (C.Q., L.F.).
Correspondence to:C.Q.
chengxuan.qiu@ki.se

Dementia is a disabling syndrome of the brain that

occurs predominately among older people, and is characterized by impairments in memory and other cognitive functions. The cognitive disturbances in dementia
are severe enough to interfere with regular social and
work-related activities. Clinically, Alzheimer disease is
the most frequent type of dementia, accounting for up
to 75% of all dementia cases.1,2 However, autopsy and
neuroimaging studies have revealed that the majority
of dementia cases involve brain lesions of both cerebral
vascular aetiology (such as macroinfarcts, microinfarcts,
white matter lesions, lacunar infarcts, and cerebral
microbleeds) and degenerative aetiology (such as neuritic plaques and neurofibrillary tangles), especially
among very old people (such as those aged 75years).36
Growing evidence indicates that dementia and cardiovascular diseases (CVDs) share common vascular risk
factors (VRFs), such as smoking, hypertension, high
cholesterol, and diabetes mellitus.79 Cognitive function
in specific domains (for example, episodic memory and
perceptual speed) deteriorates naturally with age,10 but
exposure to VRFs and related CVDs might accelerate
the pace of cognitive decline. Such decline can progress
to mild cognitive impairment (MCI) and dementia at a
younger age among individuals with high cardiovascular
burden compared with those with low burden of VRFs
and related CVDs.
The main purpose of this Review is to summarize the
epidemiological evidence and potential pathophysiological
Competing interests
The authors declare no competing interests.

mechanisms that link VRFs and clinical and subclinical

CVDs to cognitive ageing from a life-course perspective.
Furthermore, we discuss the implication of this relationship on clinical practice and public health in the ageing
society. In addition to studies on population-based
cohorts, we have paid particular attention to relevant
systematic reviews and meta-analyses whenever available.

VRFs, cognitive decline, and dementia

Individual vascular risk factors
Since the early 1990s, major VRFs for cognitive impairment and dementia present in mid-to-late life have been
investigated in numerous community-based studies,
such as the Framingham Study,11 the Honolulu-Asia
Aging Study,12 the Rotterdam Study,13 the Cardiovascular
Health Study (CHS),14 and the Kungsholmen Project.15
In addition, numerous systematic reviews and metaanalyses have highlighted the association between individual VRFs (such as smoking, hypertension, obesity,
physical inactivity, and diabetes) and cognitive decline
and dementia.8,1619 In particular, systematic reviews have
revealed the age-dependent association between cardiometabolic risk factors (such as high blood pressure, high
cholesterol levels, and obesity) and cognitive impairment
and dementia.2023 The presence of these VRFs in mid-life
(4059 years of age), especially if left untreated, is associated with an elevated risk of dementia; this association is
less certain when these VRFs occur in later life (75years
of age).2023 A cumulative burden from multiple VRFs
or CVDs results in an incremental increase in the risk
of dementia.24,25 Furthermore, while excessive alcohol
consumption is associated with a fast pace of cognitive

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Key points
Evidence from multidisciplinary research indicates that vascular risk factors
(VRFs) present during young adulthood and mid-life are potential aetiological
factors for cognitive decline and dementia in later life
Cardiovascular disease and cognitive ageing (such as cognitive decline and
dementia) share similar pathogenetic processes such as atherosclerosis
andischaemia
VRFs might contribute to the development of neurodegenerative lesions
(suchas deposition of amyloid) in the brain
Clinical and subclinical cardiovascular diseases can be linked to cognitive
decline and dementia by causing cerebral hypoxia and silent brain lesions
Emerging evidence indicates that dementia in advanced age develops after a
lifelong sequence of events beginning with exposure to VRFs in youth, followed
by heart disease and cerebrovascular disease
Current interventional strategies to promote cardiovascular health might be
the most promising approach to protect the brain and maintain intact cognitive
function in ageing

decline, limited alcohol intake in middle age or later life

has been linked with reduced risk of cognitive decline
and dementia;2630 this observation is consistent with
reports that light-to-moderate alcohol consumption is
beneficial for cardiovascular health. Finally, other VRFs,
such as dietary intake of saturated fat and increased
serum concentration of inflammatory markers, might
also contribute to the increased risk of cognitive decline
and dementia, whereas protective vascular factors, such
as the Mediterranean diet, intake of dietary or supplemental antioxidants (such as vitamin C and E), postmenopausal hormonal replacement therapy, and use of
non-steroidal anti-inflammatory drugs, are suggested to
benefit cognitive function and reduce dementia risk.1,2,31
However, data from randomized clinical trials have
shown that reducing VRFs via therapeutic means (such
as drugs to control hypertension, high cholesterol levels,
and inflammation) did not improve cognitive function.32 Indeed, hormonal replacement therapy (such as
oestrogen alone, or oestrogen in addition to progestin)
in postmenopausal women aged 65years or older has
been shown to be detrimental for cognitive function.33
The gap between observational studies and clinical trials
could be largely bridged when the literature is assessed
from a life-course perspective.8 Most clinical trials that
assess the relationship between CVDs and cognitive
function consider cognitive outcome as a secondary end
point after CVDs, and have been conducted among older
people (for example, 65years) when VRFs no longer act
as risk factors fordementia.8,32

Aggregation of VRFs
Several well-established longitudinal studies conducted
in the past decade have shown that the aggregation
of VRFs in mid-life plays a critical role in cognitive
decline and cognitive impairment. A high Framingham
Cardiovascular Risk Score has been associated with
an accelerated decline in memory ability, processing
speed, executive function, and in global cognitive function.3438 Greater cumulative exposure to VRFs in young
adulthood (individuals aged 1830years) is associated
with reduced memory, processing speed, and executive
268 | MAY 2015 | VOLUME 12

function in mid-life (4355years).39 Middle-aged adults

(4044years) who had an increased summary score for
VRFs including smoking, hypertension, diabetes, obesity,
and physical inactivity, performed poorly on tests that
measured processing speed, memory, and verbal ability.40
Similar findings were reported from other population
studies that included individuals across all age ranges
from young adulthood.4146 Furthermore, two studies
conducted in the USA found that an improvement in
cardiovascular health, assessed using multiple cardiovascular metrics approved by AHA, was associated with
greater cognitive performance and a lower risk of cognitive impairment.47,48 On a global scale, an estimated
1025% reduction in seven modifiable risk factors,
five of which are VRFs, could potentially prevent up to
3million cases of Alzheimer disease.49

Predicting dementia risk with VRFs

The utility of risk scores for predicting short-term and lifetime risk of cardiovascular events has been demonstrated.50
Several composite risk scores or indices at mid-life or later
life have been developed for predicting the risk of dementia in both the general population and among individuals
with diabetes.5156 VRFs and CVDs constitute the main
measures used to devise such risk scores, with prediction
accuracy ranging from 65% to 85% (Table1).5156 In the
late-life risk score calculations, which involved modifiable VRFs and demographic features as measures of risk,
an increasing composite risk score in later life was associated with an increased risk of developing dementia in
a dose-responsive manner.51,52 As expected, both micro
vascular and macrovascular disease, and metabolic factors
are important for predicting dementia risk among older
patients with diabetes.53 Likewise, in the middle-aged population (4055years of age), aggregation of major VRFs
could predict the risk of dementia onset more than 20years
later.55,56 The Australian National UniversityAlzheimers
Disease Risk Index, which includes several self-reported
VRFs to predict dementia risk, has also been developed
and validated.54 These risk scores aim to identify middleaged or older individuals who could be at an elevated
risk for cognitive impairment or dementia, and so might
benefit from early intervention.57

CVDs, cognitive decline, and dementia

Cardiovascular disease and dementia are highly prevalent among elderly individuals. These conditions might
be related to each other owing to shared risk factors and
common pathophysiology. Indeed, epidemiological
research has provided evidence linking cognitive decline
and dementia with specific clinical cardiovascular disorders, such as coronary heart disease (CHD), atrial
fibrillation (AF), and heart failure (HF).

Coronary heart disease

Epidemiological studies have yielded mixed results on
the association between CHD and the risk of dementia.
In the record-linkage Rochester Epidemiology Project,58
no association was observed between myocardial infarction and subsequent dementia. Similarly, investigators of

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Table1 | Use of vascular risk factors to predict dementia
Study

Summary

Vascular risk factors or diseases

included in the score

Other factors included in

the score

Accuracy

Barnes etal.
200951

Population-based longitudinal CHS

(n=3,375); mean age 75years; mean
follow-up 6years

BMI, alcohol intake, coronary

bypass surgery, enlarged
ventricles, white matter lesions,
and carotid artery thickness

Age, sex, education,

ethnicity, digital substitution
score, MMSE, and APOE 4

C statistic 0.81; PPV 57%

(individuals in the top
5%score)

Reitz etal.
201052

Cohort study of US Medicare recipients

(n=1,051); mean age 76years; mean
follow-up 4.2years

Smoking, diabetes, hypertension,

HDL cholesterol level, and
waist-to-hip ratio

Age, sex, education,

ethnicity, and APOE 4

For a score >28, HR20.5

(95%CI 8.450.0)

Exalto etal.
201353

Cohort study of patients with type2

diabetes (n=29,961); mean age
71years; mean follow-up 6.7years

Microvascular disease,
cerebrovascular disease, CVD,
diabetic foot ulcers, and acute
metabolic events

Age, education, and

depression

C statistic 0.74 for

creation cohort; 0.75 for
validation cohort

Anstey etal.
201454

Three validation cohorts: Kungsholmen

Project (n=1,301; mean age 81.5years;
mean follow-up 6years), CHS (n=3,375;
mean age 75years; mean follow-up
6years), and Rush Memory and Aging
Project (n=1,164; mean age 79.8years;
mean follow-up 4years)

Smoking, alcohol intake, BMI,

diabetes, total cholesterol level,
and physical activity

Age, sex, education,

traumatic brain injury,
depression, leisure activity,
and exposure to pesticides

C statistic 0.650.73

Kivipelto etal.
200655

Population-based longitudinal CAIDE

study (n=1,409); mean age 50.4years;
mean follow-up 20years

BMI, systolic blood pressure,

totalcholesterol level, and
physicalactivity

Age, sex, education,

andAPOE 4

C statistic 0.78; PPV 9%;

NPV 98%

Exalto etal.
201456

Members in voluntary Multiphasic Health

Checkups (n=9,480); mean age
46.1years; mean follow-up 36years

Smoking, central obesity, systolic

blood pressure, total cholesterol
level, physical activity, diabetes,
and pulmonary function

Age, sex, education,

traumatic brain injury, and
depressed mood

C statistic for CAIDE score

0.75 (whole cohort) and
0.81, 0.75, and 0.74 for
Asian, white, and black
individuals, respectively

Late-life score

Mid-life score

Abbreviations: APOE, gene encoding apolipoprotein E; BMI, body mass index; CAIDE, Cardiovascular Factors, Ageing and Dementia; CHS, Cardiovascular Health Study; CVD, cardiovascular
disease; MMSE, Mini-Mental State Examination; NPV, negative predictive value; PPV, positive predictive value.

the long-term follow-up study from the Cardiovascular

Risk Factors, Ageing and Dementia (CAIDE) study did
not identify a link between CHD in mid-life or later life
and increased risk of dementia.59 By contrast, the CHS
showed that myocardial infarction or angina pectoris
was associated with a 30% increased risk of dementia,60
and that the presence of imaging markers of brain lesions
(white matter hyperintensities [WMHs] and ventricular
enlargement) could attenuate the association of CHD
with dementia. This observation suggests that brain
lesions can partly mediate the association of CHD with
cognitive decline.61 Furthermore, the WHIMS trial62
investigators found that a history of myocardial infarction could double the risk of incident dementia and MCI,
and that angina pectoris alone was associated with a 45%
increased risk of dementia or MCI. Similarly, data from
the Swedish Twin Registry 63 indicated that the risk of
dementia was doubled among patients with myocardial
infarction, particularly during the first 3years of hospitalization owing to CVDs, or among individuals who
carry the APOE 4 allele, an established genetic risk
factor for Alzheimer disease. This association cannot be
explained by shared genetic factors or early-life environmental factors. Finally, in the Rotterdam Study, clinically
undetected myocardial infarction, rather than myocardial infarction diagnosed by electrocardiography, was
associated with an increased risk of dementia in men,
but not in women, independent of clinical stroke.64

By contrast, several studies have consistently linked

CHD with either cognitive decline or impairment in
specific cognitive domains. In the Whitehall II Study 65
that enrolled young and middle-aged individuals
(3555years), a history of CHD was associated with
cognitive decline that is independent of demographics and the use of cardiovascular drugs. In addition, the
cross-sectional data from the Mayo Clinic Study of Aging
suggested that CHD was associated with non-amnestic
MCI, but not with amnestic MCI,66 which implies that
CHDand non-amnestic MCI share similar vascular
aetiologies andpathophysiological processes. The followup data confirmed this association, which occurred predominantly among women.67 Finally, the investigators in
a systematic review concluded that CHD was a risk factor
for longterm global cognitive deficits.68
The strong association between cognitive deficits and
subsequent cerebrovascular disease suggests that cognitive
impairment might be a surrogate maker for silent brain
lesions. Indeed, the link between cognitive impairment
and subsequent stroke is well documented.69 Furthermore,
investigators in numerous studies have examined the association of cognitive impairment and dementia with subsequent risk of heart disease. For example, data from the
Finnish national registry cohort study of exposure-matched
individuals suggested that patients with Alzheimer disease
were more likely to have a diagnosis of incident ischaemic heart disease compared with individuals without

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Table2 | Systematic reviews assessing the link between CVDs and cognitive impairment
Study

Summary

Outcome measures

Main findings and conclusions

Systematic review of
2casecontrol studies
and4cohort studies

Cognitive function;
impairment in
cognitive domains

Coronary heart disease affected verbal fluency, motor

speed, and global cognitive function

Kwok etal.
201176

Meta-analysis of 14
cohortstudies; age range
6184years

Dementia

Pooled RR1.98 (95%CI 1.432.73); consistent

evidence supports an association of AF with increased
incidence of dementia among patients with stroke; this
association is less certain among the general population

Eggermont
etal. 201268

Systematic review of
3casecontrol studies
and3cohort studies

Cognitive function;
cognitive impairment

AF was associated with impairment in global cognitive

function, attention, and executive function

Santangeli
etal. 201277

Meta-analysis of
8cohortstudies

Dementia

Pooled RR1.42 (95%CI 1.171.72); AF is associated

with an increased risk of dementia

Kalantarian
etal. 201378

Meta-analysis of 21 crosssectional and cohort studies,

including 7 studies of patients
with stroke

Cognitive impairment;
dementia

Pooled RR for dementia 1.38 (95%CI 1.221.56);

RRfor cognitive impairment 1.50 (95%CI 1.181.91);
AF is associated with cognitive impairment and
dementia, independent of a history of clinical stroke

Udompanich
etal. 201379

Semi-systematic review of 11
cohort studies

Cognitive impairment;
dementia

Of the 11 studies, eight reported an association of AF

with cognitive impairment or dementia, but three
studies failed to establish this link

Eggermont
etal. 201268

Systematic review of
7casecontrol studies and
1population-based study

Cognitive function;
cognitive impairment

Patients with systolic HF performed worse than healthy

control individuals on multiple cognitive domains

Hajduk etal.
201384

Systematic review of
14cohortstudies

Cognitive decline

HF was associated with rapid cognitive decline, but the

risk was modifiable by cardiac therapy

Vogels etal.
200787

Systematic review and

meta-analysis of
22cohortstudies

Cognitive impairment

Pooled OR1.62 (95%CI 1.481.79); HF was

associated with global cognitive impairment and deficits
in memory, attention, and mental flexibility

Pressler
200888

Review of the literature

published 20022007

Cognitive impairment

In the general population, HF was a correlate or predictor

of cognitive impairment; approximately 2550% of
patients with HF experienced cognitive impairment

Coronary heart disease

Eggermont
etal. 201268
Atrial fibrillation

Heart failure

Abbreviations: AF, atrial fibrillation; CVD, cardiovascular disease; HF, heart failure; RR, relative risk.

Alzheimer disease.70 Similarly, data from a follow-up study

in the middle-aged patient cohort suggested that a lower
score on global and domain-specific (such as, reasoning
and vocabulary) cognitive tests was associated with an
elevated risk of incident CHD, especially among people
with low socioeconomic status.71 By contrast, the recordlinkage study from the Rochester Epidemiology Project
demonstrated a decreased risk of incident myocardial
infarction and death due to heart disease following the
diagnosis of dementia.58 However, whether the reduced
risk of myocardial infarction was attributable to the use
of Alzheimer-related medications is unclear; findings
from the Swedish Dementia Registry study suggested an
association between the use of cholinesterase inhibitors
and a reduced risk of myocardial infarction and death.72
Finally, in the follow-up study of participants in two large
clinical trials (ONTARGET73 and TRANSCEND74) cognitive impairment was associated with an increased risk of
congestive HF, but not with coronary events.75

Atrial fibrillation
In several systematic reviews and meta-analyses an
association between AF and cognitive impairment and
270 | MAY 2015 | VOLUME 12

dementia has been identified (Table2).68,7679 AF can

increase the risk of cognitive impairment and dementia by
more than 40%, independent of clinical stroke, although
the association appears to be stronger among patients
with stroke compared with the general population (relative risk [RR]2.7 [95% CI 1.84.0] versus RR1.4 [95% CI
1.21.6]).78 Furthermore, a link between AF and memory
impairment, but not between AF and processing speed
and executive function, was proposed by investigators
from the AGES-Reykjavik Study, which was consistent
with findings that patients with AF have smaller volumes
of total brain tissue, grey matter, and white matter, but not
WMHs.80 Older adults without clinical stroke enrolled in
the CHS had accelerated global cognitive decline and
reduced processing speed following incident AF.81 In the
Finnish CAIDE study, the development of AF in later
life, but not in mid-life, was associated with a 2.5-fold
increased risk of dementia; the association was stronger
among APOE 4 non-carriers compared with APOE 4
carriers.59 Finally, while investigators of the WHIMS62 did
not link cognitive decline and dementia with AF, in the
post-hoc analysis of the large randomized controlled trials
of ONTARGET73 and TRANSCEND74 a 30% increased

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risk of cognitive decline and incident dementia among
patients with AF was obsereved.82 The latter study supports cognitive decline as a consequence of AF, even in
the absence of overt stroke.

Heart failure
Cognitive impairment and dementia are frequently
detected among older adults with HF. According to
investigators in the US Health and Retirement Study,83
the prevalence of dementia and MCI among older individuals with HF was 15% and 24%, respectively. In the
same study an association was also observed between HF
and >50% increased risk of dementia, even after adjustment for demographics and previous stroke.83 This association remains despite the under-diagnosis of cognitive
impairment and dementia among older patients with
HF;84 current screening tests (such as the Mini-Mental
State Examination) are insensitive to cognitive impairment in patients with HF.85 In addition, investigators
of a population-based study of older adults in the USA
reported a 30% increased risk for incident MCI among
patients with HF.86 In the CAIDE study, the development of HF in later life, but not in mid-life, was associated with a twofold increased risk of dementia.59 Several
systematic reviews have also linked HF with cognitive
decline and cognitive impairments (Table2). 68,84,87,88
Older patients with HF often have impaired memory,
attention span, processing speed, and executive function.
The HFrelated risk for cognitive decline can be modified with therapy aimed at improving cardiac function.84
Researchers from the Framingham Heart Study reported
an association of a low cardiac function index (defined as
low cardiac output) with poor performance in processing speed,89 whereas the investigators of the Framingham
Offspring Study showed a Ushaped relationship
between left ventricular ejection fraction (LVEF) and
cognitive performance, such that LVEF in either the
lowest or highest quintile was accompanied by poor performance in multiple cognitive domains.90 These observations imply that even subclinical cardiac dysfunction
might be a potential determinant of cognitive decline
and dementia.

Subclinical CVDs and cognitive decline

Atherosclerosis is a systemic disorder that progresses

with age and simultaneously affects medium-sized
and large-sized arteries at many anatomical sites such
asthe heart, brain, and lower extremities. Consequently,
theinvolvement of vascular beds at a given organ is
likely to be associated with the development of athero
sclerosis in other organs.91 The detection of subclinical
atherosclerosis at different organs can act as a surrogate
marker for predicting cardiovascular events. Numerous
studies have investigated the relationship between the
presence of subclinical systemic atherosclerosis and
thedevelopment of cognitive impairment and dementia.

Peripheral artery disease

A link between subclinical peripheral artery disease
(PAD), defined as an ankle-to-brachial index (ABI)

<0.9, and an increased risk of dementia has been identified in several studies,60,92,93 and supported by a systematic review.94 PAD doubles the risk of dementia among
elderly individuals living in Central Africa.95 In addition, in the Lothian Birth Cohort 1921 and 1936 studies
a lower ABI was associated with worse performance in
global cognitive function and processing speed.96 Taken
together, these results suggest that a low ABI, in addition to its role in predicting cardiovascular risk, might
indicate increased susceptibility to the development of
cognitive disorders in ageing.

Carotid atherosclerosis
In 1997, the investigators in the Rotterdam Study 97
reported a relationship between the presence of severe
carotid atherosclerosis markers (such as an increase
incarotid intimamedia thickness and carotid plaques)
and an increased risk of dementia, especially among
carriers of the APOE 4 allele. Further studies have also
demonstrated this link in both middle-aged and older
populations.98,99 In addition, data from the Framingham
Study indicated that internal carotid stenosis (50%) and
increased thickness of the intimamedia in the internal
carotid artery were often accompanied by the presence
of silent cerebral infarcts, WMHs, reduced parietal grey
matter, and cognitive impairment.100 Other studies conducted in the past twoyears have also highlighted this
association between asymptomatic carotid stenosis and
cognitive impairment.101,102
Arterial stiffness
Arterial stiffness, measured using carotid femoral pulse
wave velocity (PWV), can be a marker for subclinical
CVD risk. 103 A cross-sectional association between
increased arterial stiffness (high PWV) and poor cognitive performance has been reported in populationbased studies;104106 however, a prospective association
of PWV to cognitive decline has not been consistently
reported. The Rotterdam Study 104 investigators found
no longitudinal association between PWV and subsequent cognitive decline,104 in contrast to the Baltimore
Longitudinal Study of Aging, in which a link between
high PWV and a rapid decline in executive function, but
not in global cognitive function, was observed.107 Results
from the Health, Aging, and Body Composition Study 108
supported the association of increased arterial stiffness
with rapid cognitive decline and a greater likelihood
of cognitive impairment among community-dwelling
older adults, independent of the presence of traditional
VRFs. Furthermore, central arterial stiffness, measured
as a high aortic PWV, was accompanied by a fast decline
in global cognitive function, perceptual speed, and
verbal memory in well-functioning older adults, again
independent of major VRFs,109 suggesting that reduced
compliance of the central vasculature might contribute
to cognitive decline in ageing. The association between
arterial stiffness and cognitive dysfunction has been
consistently reported in the literature; in a systematic
review, 14 of the 15 cross-sectional studies included in
the analysis identified a link between increased arterial

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Cardiovascular risk factors
Age, smoking, sedentary lifestyle, obesity, diabetes,
hypertension, high cholesterol, hyperlipidaemia

Young adulthood
(2039 years)

Systemic subclinical atherosclerosis or arteriosclerosis

Biological mechanisms including inflammation
and oxidative stress that can occur in the heart,
brain, kidney, retina, peripheral blood vessels

Transitional age
(6074 years)

Heart diseases
Coronary heart disease,
angina pectoris, myocardial
infarction, atrial fibrillation,
heart failure

Life course

Middle age
(4059 years)

Cerebral hypoperfusion
Hypoxia
Emboli

Very old age

(75 years)

Brain lesions
Stroke, white matter lesions, lacunar
infarcts, disruption of BBB, and
neurodegeneration (plaques and tangles)

Cognitive decline, MCI, dementia

Figure 1 | The heartbrain connection in ageing and cognitive decline. The

Nature Reviews | Cardiology
schematic shows aetiological factors, pathophysiological mechanisms, and the
sequence of events over the life-course of an individual. Abbreviations: BBB,
bloodbrain barrier; MCI, mild cognitive impairment.

stiffness and poor cognitive function, and in six of the

seven longitudinal studies arterial stiffness was predictive
of cognitive decline.110

Markers for subclinical CVDs

Coronary artery calcium score, a reliable measurement of cumulative burden of coronary artery plaques,
can provide additional power to the traditional VRFs
in predicting the risk of CHD among older people.111
The relationship of coronary artery calcium with brain
lesions and cognitive dysfunction has been assessed in
several population studies. In the CHS,112 coronary artery
calcium score was associated with the presence of brain
lesions (infarcts and WMHs) and cognitive impairment;
the association appeared to be mediated by vascular
brain lesions. Furthermore, investigators in the AGESReykjavik Study 113 found that an increase in coronary
artery calcification (measured by CT) was associated
with poor performance in processing speed and executive function, and an increased likelihood of dementia.
In the Rotterdam Study,114 a larger volume ofcoronary
artery calcification was linked to lower motor and information-processing speeds, a smaller volume of total
brain tissue and grey matter, and worse microstructural
integrity of the white matter. These findings support the
potential role of coronary atherosclerosis as a marker of
cognitive impairment in older adults.
High-sensitivity cardiac troponin T (hs-cTnT), a biomarker of subclinical myocardial injury, is predictive
of both cardiac events and cerebrovascular lesions.115
The Atherosclerosis Risk in Communities study116 of
middle-aged people without clinical heart disease and
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stroke revealed that the increased levels of plasma hs-cTnT

were cross-sectionally associated with poor cognitive performance and longitudinally associated with an increased
risk of hospitalization for dementia. These observations
suggest that subclinical myocardial injury might be
accompanied by cognitive impairment and dementia.
In addition, retinal microvascular abnormalities such
as focal narrowing, arteriovenous nicking, and microhaemorrhages, represent markers of cerebral microvascular lesions, CVDs, and early-life cumulative exposure
to VRFs117119 that have been associated with cognitive
impairment and dementia.120122

Invasive cardiac procedures

Invasive surgical procedures, such as CABG surgery and
cardiac catheterization, are often performed among the
elderly. Short-term minor and temporal cognitive decline
might occur days to weeks after CABG surgery.123 Longterm mild cognitive decline has been observed up to
5years after CABG surgery, but a similar degree of cognitive decline was also reported in patients with CHD
who did not undergo bypass surgery.123 Consequently,
long-term cognitive decline after surgery is probably
related to the progression of underlying cardiovascular and cerebrovascular diseases rather than the CABG
surgery itself. Indeed, in a systematic review of ran
domized controlled trials of patients undergoing CABG
surgery, no marked difference in cognitive outcomes
before and after the procedure were observed,124 suggesting that cardiopulmonary bypass perse might not
be associated with cognitive decline. Cardiac catheter
ization has been increasingly performed in patients
with CHD, but its effect on cognition has not yet been
documented.125 In one study involving 84 patients, cognitive decline and cerebral lesions following a coronary
catheter intervention was substantially milder than the
cognitive decline observed among patients who underwent CABG surgery.126 Importantly, the methodological
variations in the assessment of cognitive function and
the management of cardiac procedures among different
centres might hamper direct comparisons across studies
and quantitative syntheses in systematic reviews.

Pathophysiological mechanisms

Population-based post-mortem and neuroimaging

studies have contributed to our understanding of the
pathophysiological mechanisms underlying the association of cardiovascular burden with cognitive decline
and dementia. Cognitive decline and the development of
dementia are largely determined by cerebral mixed vascular and neurodegenerative pathology.127129 VRFs and
clinical and subclinical CVDs might contribute to cognitive decline and dementia over the course of the lifetime through various biological and pathophysiological
pathways (Figure1).

Cerebral small vessel diseases

Cerebral small vessel diseases (SVDs), such as lacunar
infarcts, WMHs, and microinfarcts, and disruption of
the bloodbrain barrier and brain network connectivity,

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REVIEWS
owing to long-term exposure to VRFs from early life, have
emerged as important mechanisms leading to cognitive
decline and dementia in later life.129132 In addition, arterial stiffness, as a marker of CVDs, might be linked with
cognitive decline through its effect on cerebral SVDs.110,133
Neuropathological data from the UK Medical Research
Council Cognitive Function and Ageing Study134 suggested an association between ischaemic heart disease
and cerebral microinfarcts,supporting the view that
cerebral SVDs and cardiovascular lesions are interrelated
inageing.

Neurodegeneration in the brain

Post-mortem and neuroimaging studies have also linked
VRFs present in mid-life (such as hypertension and diabetes) with brain neurodegeneration (such as amyloid
deposition, and global and regional brain atrophy).135138
Investigators in the Pittsburgh compound B (PiB)PET
(a technique to image cerebral amyloid plaques invivo)
studies reported an association of the Framingham
Cardiovascular Risk Score not only with grey matter
atrophy and a thin fronto-temporal cortex, but also with
the increased burden of cerebral amyloid, as quantified
with a global PiB index (a measure of mean PiB retention in brain regions prone to amyloidosis),139141 suggesting that aggregated VRFs might be amyloidogenic.
Finally, a link between persistent AF and the presence
of neurofibrillary tangles and neuritic plaques has been
reported,142 suggesting that AF might also contribute to
neurodegenerative pathologies.
Cerebral atherosclerosis
Cerebral atherosclerosis and neurodegeneration share
common biological mechanisms, such as inflammation,
oxidative stress, and toxic amyloid peptide deposition,
and often coexists in patients with dementia and cognitive impairment. Increased burden of intracranial athero
sclerosis and cerebrovascular lesions could reduce the
threshold of Alzheimer pathology for the clinical manisfestation of dementia.143 Interestingly, findings from studies
assessing the relationship between cerebral atherosclerosis
and neurodegeneration have been not consistent; an association between cerebral atherosclerosis and Alzheimer
pathology (such as amyloid and neurofibrillary tangles)
was found in some studies,144 but not others.145,146 These
disparate findings imply that although shared aetiological
or reciprocally synergistic pathophysiological mechanisms
could promote both atherosclerotic and degenerative
lesions in the brain, they might also represent coinciding
independent processes in ageing that converge to cause
additive brain damage, thus leading to cognitive decline
and clinical manifestation of dementia.147,148
Cerebral hypoperfusion and hypoxia
The stiffening of arteries and the increase in central
pulse pressure might also result in haemodynamic stress
in the heart and the brain, potentially causing structural
brain changes, insufficient blood perfusion, and cerebral
hypoxia.149,150 In addition, reduced cardiac output, cere
bral hypoperfusion, or cerebral embolic events, owing

to haemodynamic effects of AF and HF, might pre

dispose older people to subsequent cognitive decline and
dementia.78 AF, HF, and invasive cardiac procedures can
be linked to cognitive impairment, cognitive decline, and
dementia by causing silent brain lesions.151153

Lifelong events and exposure to VRFs

Systematic reviews of epidemiological studies from a lifecourse perspective have provided convincing evidence
that the development of CVDs and late-life dementia can
be traced to VRFs present in childhood, young adulthood, and mid-life.154 Thus, cumulative exposure to
VRFs (such as diabetes, hypertension, sedentary lifestyle,
and smoking) from early life might accelerate the development of atherosclerosis and arteriosclerosis that precedes CHD, stroke, and dementia. Data from the original
and offspring cohorts of the Framingham Heart Study
revealed that the trajectory of the prevalence of hypertension was followed ~10years later by the increasing
prevalence of coronary artery disease, which was then
followed by an increased prevalence of stroke a further
~10years later.155 Vascular and neurodegenerative lesions
(for example, infarcts, WMHs, and brain atrophy) seen
in the brain, which are closely linked with age and VRFs,
can first appear in mid-life and continue to accumulate
into old age where the accrued lesions start to manifest clinically as cognitive impairment and dementia
(Figure1). In support of this lifelong sequence of events,
data from epidemiological studies demonstrated that
the mean age of onset in the general populations was
~65years for myocardial infarction, 156 ~70years for
stroke,157 and ~85years for dementia.158

Implications for public health

Despite the scientific advancements in our understanding

of the contributions of cardiovascular burden to cognitive
decline and dementia, a considerable lag remains in translating this knowledge to health care professionals and the
public. The relationship between cardiovascular diseases
and cognitive decline has several important implications
for clinical practice and public health.
Given that VRFs and clinical, subclinical, and recurrent cardiovascular events accelerate cognitive decline,
improvements in clinical management of major VRFs
and CVDs, and secondary prevention of stroke and heart
disease, could benefit cognitive function.159 Furthermore,
neurologists and cardiologists are advised to act as advocates and educators for their patients concerning the
role of maintaining cardiovascular health for healthy
brain ageing and cognitive function.160 From a public
health perspective, sufficient evidence now supports
the view that intervention and management of major
VRFs (hypertension, diabetes, obesity, and high cholesterol levels) should start from early-life and mid-life, in
combination with health education to promote healthy
lifestyles (smoking cessation or promoting physical
activity), thus reducing the risk and burden of cognitive
impairment and dementia in the community.49 However,
the current prevailing view among the public is that
dementia is an unavoidable consequence of old age, and

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REVIEWS
the potential offered by interventional measures targeted
at reducing major VRFs and CVDs for delaying the onset
of dementia is still overlooked. Evidence presented in this
Review provides a strong argument for the urgent adoption of public health measures to improve cardiovascular
health as part of a strategy to slow down cognitive decline
in ageing and delay the onset of late-life dementia.
Given the devastating nature of dementia, linking major
VRFs and CVDs to dementia might help increase the publics concern about the future development of dementia,
and increase adherence to prescribed preventive medical
regimens and lifestyle modifications.161 A modest delay in
dementia onset might be achievable through maintaining cardiovascular health in early-life and mid-life. This
is important given that almost one-quarter of Alzheimer
cases could be avoided in the general population if
dementia onset could be delayed by just 2years.162
The intervention strategies targeting major VRFs in
mid-life are based mainly on the results of observational
studies. Encouragingly, several community-based intervention studies that aim to reduce the risk of cognitive
impairment and dementia by targeting multiple VRFs
and lifestyle-related factors are being conducted among
high-risk elderly individuals (age 60years).163 Although
evidence from these intervention studies might be available soon, no evidence exists from randomized controlled
trials demonstrating that dementia onset can be postponed by minimising VRFs in mid-life. Indeed, obtaining
such evidence might not be feasible owing to the required
long duration of such a study, and the ethical issues surrounding the use of control groups in trials involving
VRFs. However, the evidence from multidisciplinary
observational studies is consistent. Importantly, evidence
linking VRFs and CVDs to cognitive decline, MCI, and
dementia adds further justification for promoting cardiovascular health at the individual and community levels
from a life-course perspective.
Emerging evidence on the time trends in occurrence
of CVDs and dementia has provided additional indirect support for reducing VRFs to lower dementia risk.
Several studies from Europe and America have suggested
a stable or declining prevalence of dementia and cognitive
impairment from the 1990s to the 2000s.164166 Numerous
studies have also provided evidence for a declining incidence of dementia.164,167,168 The trends in the prevalenceof
dementia in developed countries coincide with trends
ofimprovement in the management of unhealthy behaviours (such as, smoking and physical inactivity) and VRFs
(such as, hypertension andhigh total cholesterol levels),
and a decreased riskand delayed onset of major cardiovascular events.157,169 Theinvestigators in the Rotterdam
1.

2.

3.

Qiu, C., Kivipelto, M. & von Strauss, E.

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274 | MAY 2015 | VOLUME 12

4.

5.

Study also provided evidence suggesting that the potential

decline in the incidence of dementia might partly reflect
increased use of antithrombotic and lipid-lowering drugs,
and improvement in brain health (less brain atrophy and
SVDs).167 Likewise, in a systematic review, an upward
trend in the prevalence of dementia from the 1990s to
2010 was observed in China.170 This observation is consistent with the time trends of increasing prevalence of
major VRFs and CVDs in China.171,172 The time trends
paralleled in the occurrence of VRFs and related CVDs
followed by dementia and cognitive impairment add
further weight to the argument that dementia and cognitive decline in ageing are linked to VRFs and related
cardiac diseases.

Conclusions

Epidemiological research has provided strong evidence that VRFs are potential aetiological factors for
cognitive decline and dementia in ageing, particularly
when they start to appear in young adulthood and
mid-life. Consequently, CVDs and cognitive decline
in ageing might share similar pathogenetic processes.
Multidisciplinary research also suggests that VRFs are
associated with the development of degenerative brain
lesions (such as amyloid), and that CVDs might contribute to cognitive decline and dementia by causing
cerebral hypoxia and silent brain lesions. Indeed, clinico
pathological and neuroimaging studies have revealed
that dementia with cerebral mixed vascular and degenerative pathology represents the majority of all dementia
cases among very old people; this observation challenges
the traditional view that Alzheimer disease and vascular
dementia are distinct entities, and supports the notion
that the dementing disorders in ageing are amenable
to intervention. This Review provides a strong argument for the view that strategies to maintain cardiovascular health from mid-life onward could represent
the most promising approach to protect the brain from
cognitive decline, thus benefiting cognitive function in
ageing. Interventions to promote cardiovascular health
might also modify the course of onset and progression
of the dementing disorders that are predicted to have
a major influence on the ageing population worldwide.
Increasing our understanding the pathophysiological
pathways linking cardiovascular burden with dementia
and cognitive decline in ageing will help design preventive and therapeutic studies. Future studies might
delineate whether, and to what extent, the time trends
in dementia occurrence and cognitive impairment are
attributable to the dynamic trends in major VRFs and
cardiovascular events.

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Acknowledgements
The authors work was supported by grants from the
Swedish Research Council, the Swedish Research
Council for Health, Working Life and Welfare, and the
Karolinska Institutet, Stockholm, Sweden.
Author contributions
C.Q. researched data for the article. Both authors
contributed substantially to discussion of its content,
and to writing, reviewing, and editing the manuscript
before submission.

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