Arteriosclerosis, Thrombosis, and Vascular Biology

ATVB IN FOCUS:
Vascular Components of Cognitive Disorders
Series Editor: Mat Daemen

Epidemiology of Vascular Dementia

Nosology in a Time of Epiomics
Frank J. Wolters, M. Arfan Ikram

ABSTRACT: The notion of what qualifies as vascular dementia has varied greatly since the first mention of dementia after apoplexy
in ancient literature. Current insight points towards a multifactorial cause of cognitive decline at old age, in which vascular
components like atherosclerosis, arterio(lo)sclerosis, (micro)infarcts, and amyloid angiopathy play an important role alongside
other markers of neurodegeneration. Cerebrovascular disease will be present in most individuals with dementia, but—just like other
causes—rarely a cause on its own. The consequent limitations of nosology may be alleviated by addition of a vascular component
to the recently introduced amyloid/tau/neurodegeneration etiological classification system for dementia. Meanwhile, risk of
dementia is increased about 2-fold after stroke, and the prevention of (recurrent) stroke remains a cornerstone in the prevention
of vascular dementia. Similarly, control of cardiovascular risk factors from middle age onwards is likely to have contributed to
the reported decline in the age-specific incidence of dementia over the past decades. In conjunction with experimental studies,
large-scale observational evidence from imaging, genomics, metabolomics, and alike will continue to improve our understanding
of the underlying pathophysiological processes. To prevent ecological fallacies, such etiological studies in patients with dementia
are best served by inclusion of subjects regardless of the presumed (single) cause of their disease.

VISUAL OVERVIEW: An online visual overview is available for this article.

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Key Words:  cognitive dysfunction ◼ dementia ◼ epidemiology ◼ preventive medicine ◼ stroke

T
he causes, or even concept, of vascular demen-
tia have been subject to change ever since it first
figured in the chronicles of medicine. A proper def-
inition has long been hampered by boundaries to neu-
roanatomical and pathophysiological insight, causing
uncertainty about the prevalence and incidence of vas-
cular dementia in published literature. At present, closer
observation of patients with more elaborate testing and
use of advanced (imaging) techniques continues to
change the landscape of what is considered the vascular
contribution to cognitive decline. In this disquisition on
the epidemiology of vascular dementia, we shall review
the current concept of vascular dementia, and how this
has evolved over the years. We subsequently address the
occurrence of vascular dementia in numbers, followed by
the burden of vascular pathology in cognitive decline and
the stroke-associated risk of dementia, before ending
with perspectives for future research.
Please see www.ahajournals.org/atvb/atvb-focus
for all articles published in this series.
CHANGING DEFINITIONS IN HISTORICAL
PERSPECTIVE
“I have observed in many cases that when, the Brain being
indisposed, they have been distempered with a dullness of
mind and forgetfulness, and then afterward with a stupidity
and foolishness, they would afterward have fallen into a Pal-
sie, which I oft did predict…,” wrote Thomas Willis in 1672.1,2
His description of the march from dullness of mind and
forgetfulness to stupidity and foolishness, associated with

Correspondence to: M. Arfan Ikram, MD, PhD, Department of Epidemiology, Erasmus MC, PO Box 2040, Rotterdam 3000CA, the Netherlands. Email m.a.ikram@
erasmusmc.nl
For Sources of Funding and Disclosures, see page 1547.
© 2019 American Heart Association, Inc.
Arterioscler Thromb Vasc Biol is available at www.ahajournals.org/journal/atvb

1542 August 2019 Arterioscler Thromb Vasc Biol. 2019;39:1542–1549. DOI: 10.1161/ATVBAHA.119.311908
 Wolters and Ikram
Nonstandard Abbreviations and Acronyms
MAPT Multidomain Alzheimer Prevention Trial
TDP TAR DNA-binding protein
hemiplegia, is among the first descriptions relating stroke
to cognitive decline and dementia. In the early years of neu-
rology, apoplexy was thought to originate exclusively from
hemorrhage. It was not until the 17th century, when human
autopsies became more common that it was possible to
distinguish cerebral infarction from hemorrhage as causes
of apoplexy.3 It took additional centuries for further refine-
ment of the vascular cause of dementia. One of the first
notable descriptions of the importance of arteriolosclerosis
in dementia at old age came on the account of German
psychiatrist Emil Kraepelin, who in his 1910 textbook Psy-
chiatrie defined the arteriosclerotic psychosis,4 on the basis
of findings chiefly by Maurice Klippel, Otto Binswanger,
and Alois Alzheimer.5–7 Alzheimer and Binswanger argued
early on that these manifestations of vascular disease on
cognitive ability should be seen separate from any paresis.8
Concurrently, there were descriptions in France of multiple
lacunar infarcts because of occlusion of penetrating cere-
bral arterioles, dubbed état lacunaire, by French neurologist
Pierre Marie,9 and of diffusely widened perivascular spaces
in the basal ganglia (Virchow-Robin spaces), coined état
criblé by Maxime Durand-Fardel.10 Little did they know of
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the implications their findings would have for the present-
day definition of vascular cognitive impairment. Systematic,
in vivo identification of these lesions and their importance in
cognition depended on the development of brain imaging
techniques much later. With the introduction of computed
tomography in clinics in the 1970s, and magnetic reso-
nance imaging some years later, it also became possible
to distinguish pathological hallmarks of dementia during
life. Cerebral atrophy, (covert) infarcts,11,12 and white matter
hyperintensities were consequently identified as important
contributors leading to dementia,12,13 irrespective of clinical
symptoms of stroke. Magnetic resonance imaging and pos-
itron-emitted tomography with use of specific tracers have
subsequently allowed in vivo mapping of the process of
neurodegeneration in even greater detail. In addition, devel-
opment of more sophisticated cognitive tests has led to the
notion of different cognitive domains, including attention,
memory, language, executive function, perceptual-motor
function, and social cognition. Some of these may relate to
specific pathologies and dementia types. For example, cere-
brovascular disease has been linked to a particular decline
in executive function,14 whereas memory and learning
capacity might deteriorate earlier in the course of Alzheimer
disease. However, there is much overlap between cognitive
profiles,15 with declines in various domains across dementia
types, cautioning the assigning of nosological classifica-
tions on the basis of neuropsychological testing only.16
Arterioscler Thromb Vasc Biol. 2019;39:1542–1549. DOI: 10.1161/ATVBAHA.119.311908
Epidemiology of Vascular Dementia
Highlights
ATVB IN FOCUS - VB
• In the multifactorial cause of cognitive decline at
old age, vascular components like atherosclero-
sis, arterio(lo)sclerosis, (micro)infarcts, and amyloid
angiopathy play an important role alongside other
markers of neurodegeneration. They will be present
in most individuals with dementia, but—just like other
causes—rarely a cause on their own.
• A nosological definition of dementia, therefore, best
allows for different contributions, for example, a case
of cognitive impairment because of vascular disease
and amyloid. For research purposes, this may involve
addition of a vascular component to the recently intro-
duced amyloid/tau/neurodegeneration biomarker
classification system for dementia.
• To prevent ecological fallacies, etiological studies
in patients with dementia are best served by inclu-
sion of subjects regardless of the presumed (single)
cause of their disease.
• Prevention of (recurrent) stroke and likely control of
cardiovascular risk factors in mid-life remain a cor-
nerstone in limiting dementia due to vascular causes.
The above advances in phenotyping, involving cognitive
testing as well as imaging and other markers, have thus
helped us further in distinguishing different pathologies.
At the same time, the overlap in disease characteristics,
both on a clinical level and in pathological substrates, has
left the concept of vascular dementia ill-defined, from arte-
riosclerotic dementia as a synonym for senile dementia in
the first half of the 20th century to vascular pathologies
united under the umbrella term multi-infarct dementia in
the 1970s. The National Institute of Neurological Disorders
and Stroke–Association Internationale pour la Recher-
ché et l’Enseignement en Neurosciences criteria in 1993
attempted to resolve some of the debate and discrepancies
in literature,17 highlighting the substantial heterogeneity of
vascular dementia syndromes (eg, hemorrhagic, ischemic,
hypoxic, and small vessel disease), the variability in clinical
course, the testing of multiple cognitive domains, the value
of a temporal relationship between stroke and dementia
for a secure diagnosis, and the importance of brain imag-
ing to support clinical findings. The criteria indeed proved
more specific, although less sensitive, in diagnosis of vas-
cular dementia than the Diagnostic and Statistical Manual
of Mental Disorders IV and International Classification of
Diseases-Tenth Revision criteria.18 In subsequent years, the
notion of what should be considered vascular dementia
among clinicians, general practitioners, and mental health
physicians, however, varied substantially. The awareness
that cerebral small vessel disease contributes to cognitive
decline has led to an increasing share of the latter being
considered (partly) vascular. Although partly justified, in
fact most of dementia at old age is the consequence of
a multitude of pathologies, described in more detail below.
August 2019 1543
 Wolters and Ikram
While classifying dementia in the presence of any vascu-
lar brain injury as vascular will grossly overestimate the
ATVB IN FOCUS - VB
prevalence of vascular dementia, including in the diagnosis
only poststroke dementia or dementia in the absence of
neurodegenerative features will greatly underestimate the
importance of vascular brain injury on cognitive function.
This underlines the need for careful phenotyping of distinct
pathologies and caution in the versatile nosology of what
is arguably best captured as cognitive impairment with a
vascular contribution. Of course, even within the realm of
cerebrovascular disease one could distinguish a variety of
pathologies, as we shall discuss in more detail later.
Recent developments in dementia research have seen
the rise of a classification system for biomarkers in Alzheimer
disease, including scores for amyloid, tau, and evidence of
neurodegeneration (ie, the A/T/N classification),19 which
is open for expansion with the addition of a vascular com-
ponent score. On a conceptual level, such classification
systems with dichotomous scoring of contributing factors
are a derivative from the concept of (population) attribut-
able risks. Attributable risks can be interpreted as the pro-
portion of patients that suffer from the disease because of
the risk factor under study while acknowledging that in a
single patient multiple risk factors or pathologies could have
essentially contributed to development of disease. This phe-
nomenon is also known as synergy or positive interaction
and is present in the majority of dementia cases. In practice,
a composite measure of vascular imaging markers might be
added to the score, including white matter hyperintensities,
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lacunar infarcts, microbleeds, and perivascular spaces.20–22
Although losing some of its value in the simplification,
scores such as amyloid/tau/neurodegeneration with or
without addition of a vascular score may be useful, since
they can readily be implemented in (research) practice and
can relatively easily be further refined with the use of addi-
tional markers (eg, microinfarcts) or on the basis of continu-
ous rather than ordinal scales. However, we should be wary
of misuse of classifications with limited understanding of
pathology leading to erroneous assumptions. For example,
estimating contributions of presumed etiological factors
(eg, amyloid and small vessel disease) while including their
(common) end point in the same score (eg, neurodegenera-
tion) can lead to underestimation of etiological fractions. It
should, furthermore, be stressed that it is premature to use
such scores in clinics leading to subtype diagnosis of indi-
viduals with a disease that they possibly will never develop.
Instead of etiological subtyping, such as vascular dementia
or vascular cognitive impairment, a more accurate descrip-
tion would thus be the earlier coined term “cognitive impair-
ment with a vascular contribution” with allows expansion by
other contributions (eg, amyloid and Lewy bodies) if pres-
ent: “…and possibly also contribution X, Y and Z.”
With these limitations in the nosology in mind, we shall
proceed with what should be considered best estimates
of the burden of vascular dementia and vascular cogni-
tive impairment in the population.
1544 August 2019 Arterioscler Thromb Vasc Biol. 2019;39:1542–1549. DOI: 10.1161/ATVBAHA.119.311908
Epidemiology of Vascular Dementia
VASCULAR DEMENTIA IN NUMBERS
Vascular dementia is generally considered the second
most common subtype of dementia, after Alzheimer dis-
ease, accounting for roughly 15% to 20% of dementia
cases in North America and Europe,23,24 with somewhat
higher estimates of around 30% in Asia25,26 and develop-
ing countries.27 The reported absolute risk of dementia
after stroke varies widely, from 7% in population-based
studies of first-ever stroke in previously nondemented
individuals to over 40% in hospital-based studies of
recurrent stroke with the inclusion of prestroke demen-
tia.28 Accounting for this variation in study setting and
design, estimates are rather consistent. Large part of
the variety is thus explained by stroke severity, with the
incidence of dementia ranging from 5% at 1 year after
transient ischemic attack to 34% at 1 year after severe
stroke.29 Compared with incidence rates in the general
population, this implies that cerebrovascular events
are associated with a 3.5 to 47× increase in the risk
of dementia, and that diagnosis is brought forward by
an average 2 to 25 years depending on the severity of
the event.29,30 Reliable estimates depend on meticulous
follow-up of patients with stroke, via multiple sources
of information, to prevent high drop-out in patients with
major stroke, and overcome the inability to perform
extensive cognitive testing in many patients with apha-
sia. Moreover, estimates of vascular cognitive impairment
may be underestimated when using tools with limited
sensitivity for deficits in executive function. For example,
the Montreal Cognitive Assessment has repeatedly been
shown more sensitive to picking up vascular cognitive
impairment than the Mini-Mental State Examination.14,31
Similar to Alzheimer disease, the incidence of vascu-
lar dementia increases steeply with age, contributing to
the growing epidemic of dementia in the aging popula-
tions worldwide.32 It has nevertheless been argued that,
owing to improvement in vascular care, the incidence of
(vascular) dementia might have decreased over the past
decades. Indeed, the age-specific risk of all-cause demen-
tia in the United States and Europe has declined by about
20% per decade since the late 20th century,33–36 paral-
leled by reductions in the burden of cerebral small vessel
disease.33 Although these optimistic observations may well
be because of improved control of vascular risk factors
and treatment of vascular disease,34 various other potential
explanations also warrant further investigation (eg, educa-
tional attainment and improvements in public health), and
we should caution that the rise of obesity, diabetes mel-
litus, and on a global level hypertension do not offset the
improvements underlying the declining secular trend.37–39
Moreover, mixed results from preventive trials focusing
on multidomain intervention and cardiometabolic factors
illustrate that we still have much to learn about underly-
ing pathophysiology. Promising findings of the Scandina-
vian FINGER trial (Finnish Geriatric Intervention Study to
 Wolters and Ikram
Prevent Cognitive Impairment and Disability; a multidomain
intervention involving diet, exercise, vascular risk monitor-
ing, and cognitive training),40 and positive results of blood
pressure lowering in the SPRINT (Systolic Blood Pres-
sure Intervention Trial)-MIND trial,41 are counterbalanced
by lack of improvement following multidomain vascular
care intervention in an unselected population of elderly
Dutch people (the pre-DIVA trial [Prevention of Dementia
by Intensive Vascular Care]), as well as the French MAPT
(Multidomain Alzheimer Prevention Trial—testing similar
interventions plus omega-3 supplements).42,43 Moreover,
strict management of cardiovascular risk has not been
proven beneficial for preservation of cognitive ability in
patients after transient ischemic attack or stroke,44–46 pos-
sibly owing to the already tight secondary preventive regi-
mens in standard medical care, extensive vascular disease
at time of treatment initiation, and the generally short-
term follow-ups of these trials. The potential of (primary)
interventions nevertheless remains enormous. Preventive
efforts with generally modest effect sizes at the individual
level could greatly reduce the burden of disease at the
population level, with delays in the onset of dementia by
merely a few years expected to reduce the incidence of
dementia by as much as 50% over the next decades.47–49 It
emphasizes the need to better understand the wide range
of pathological mechanisms believed to contribute to vas-
cular cognitive impairment, and to distinguish subtypes of
cerebrovascular pathology that might have benefited from
preventive efforts over the past decades, from pathologies
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that are more resilient to current treatment regiments and
require novel treatment approaches.
We shall now move on to briefly review the epide-
miological evidence for the various vascular contribu-
tions, focusing on the implications of knowledge of
(patho)physiology on the preferred study design and
methodology.
THE VASCULAR SHARE OF DEMENTIA
The further science zooms in on vascular dementia in
contemporary studies, the more we see a multifac-
eted surface. In the vast majority of elderly individuals
who develop dementia, the brain shows a multitude of
pathologies, and even within the realm of cerebrovascu-
lar disease numerous manifestations of vascular damage
or dysfunction contribute to cognitive impairment. In the
next paragraphs, we shall describe this variety of contrib-
uting pathologies in more detail but not before zooming
in on the undiminished importance of stroke prevention
in the battle against dementia.
Stroke remains a notorious risk factor for dementia,
increasing risk about 2-fold.50 Stroke characteristics,
notably severity and location,29,51–53 account for a sub-
stantial part of the variation in risk of dementia after
stroke. However, patients may be remarkably resil-
ient against cognitive decline with even large strokes,
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Epidemiology of Vascular Dementia
depending on educational attainment and premorbid
cognitive function, preexisting medial temporal lobe atro-
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phy, family history of dementia, and comorbidities.28,29
The risk of dementia after stroke, although highest in the
subacute phase, extends to many years after stroke,53,54
suggesting either a role of cognitive reserve or shared
etiological factors contributing to, for example, cerebral
small vessel disease. Although prevention of recurrent
stroke remains vital in the prevention of poststroke
dementia,29 these findings indicate that cognitive decline
after stroke cannot be seen separate of other coexist-
ing pathologies, whether of vascular nature or otherwise.
Risk factors for poststroke dementia are, therefore, likely
to differ between early and delayed poststroke dementia,
the latter being more strongly linked to small vessel dis-
ease.53 Additional studies are needed to disentangle pro-
moters of resilience, such as educational attainment from
early (genetic or cardiovascular) risk factors, coexisting
(Alzheimer) pathology, and stroke lesion characteristics.
As mentioned, on closer inspection of the brain at
old age, it commonly shows a multitude of pathologies,
ranging from vascular pathologies like macroscopic
infarcts, microbleeds, microinfarcts and amyloid angiopa-
thy, to parenchymal amyloid and tau deposits, TDP (TAR
DNA-binding protein)-43, hippocampal sclerosis, and α-
synucleinopathies.55,56 With the median age of dementia
onset in the population over 80 years,57 this implies a
multifactorial cause of cognitive decline in virtually any
patient presenting at a nonspecialized memory clinic. In
the general population without dementia, the prevalence
of cortical infarcts (≈11% in the seventh decade to ≈35%
after age 80),58 lacunar infarcts (≈5%–≈20%),58 micro-
bleeds (≈15%–≈40%),59,60 and amyloid positivity (in likely
selected cognitively healthy individuals: ≈20%–≈40%)61
all increase with age. Indeed, at time of death, 2 or more
of aforementioned pathologies are present in 78% of indi-
viduals.55 Most of these pathologies are consistently more
prevalent in patients with dementia and associated with
dementia risk. However, set aside potential confounding,
pathologies that are associated with disease on a group
level are not necessarily involved in pathogenesis in an
individual patient, just as elevated blood pressure is not
necessarily the cause of myocardial infarction in a patient
with hypertension, and in smokers other causes than
smoking may lead to lung cancer. In the individual patient,
it thus remains challenging to pinpoint the precise causal
contribution of various pathways. With better quantification
of various markers in the future, it might become possible
to estimate the relative contributions of different patholo-
gies referenced to the (age-matched) general population.
Conversely, on a group level, the importance of various
pathologies may be better estimated. In large community-
based clinicopathological cohorts, for example, combined
measures of vascular disease accounted for 32% of the
association between age and dementia, with the remaining
68% explained by hippocampal sclerosis/TDP-43 (43%),
August 2019 1545
 Wolters and Ikram
amyloid/tau (24%), and Lewy bodies (1%).62 Even of clini-
cal Alzheimer disease cases, an estimated 30% is attribut-
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able to vascular pathologies like infarct, arteriosclerosis,
and amyloid angiopathy on postmortem examination.63 At
the same time, the share of amyloid positivity in clinical
Alzheimer disease is reported to decline with age,64 which,
presumed valid, may reflect the increased contribution of
other pathologies, including vascular disease, in what is
clinically called Alzheimer disease at an elderly age.
It is important to note here that this vascular contri-
bution to cognitive impairment has to be considered an
umbrella term, capturing diverse components that poten-
tially differ in terms of cause and (preventive) treatment.
The contribution of vascular disease to dementia is,
therefore, best captured in specific vascular components,
as part within a continuum of a wider range of pathology
leading to cognitive decline. For etiological research, this
calls for investigation of dementia without any assump-
tions of its cause, as excluding, for example, patients with
stroke from studies about Alzheimer disease may falsely
imply irrelevance of hypertension and alike in the cause
of (clinical) Alzheimer disease.65 This not only applies to
dementia cases in which stroke is the mediator between
hypertension and dementia but also to cases in which
stroke and dementia may have a shared etiological factor
(namely hypertension) via separate mechanisms.
Given the importance of vascular pathology in cognitive
decline, it may come as no surprise that vascular risk fac-
tors have been widely implicated in dementia risk. Modifi-
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able risk factors such as obesity, hypertension, smoking,
and diabetes mellitus account for ≈25% of dementia in
the population.66,67 For several of these risk factors, nota-
bly obesity and hypertension, it has been found that they
are particularly detrimental to brain health when present
from mid-life.68–71 This can reflect cumulative exposure
over time but may also relate to methodological chal-
lenges that occur when investigating risk factors at old
age or closer to disease onset. For example, reverse
causation, (pleiotropic) treatment effects, and compet-
ing risks could give rise to apparent protective effects of
smoking (because of competing risk of cardiovascular or
cancer mortality), and a spuriously absent association of
dementia with obesity (reverse causation) or hyperten-
sion (potential medication effects or reverse causation),
to name only a few. For observational studies, these chal-
lenges are best overcome by the prospective design of
cohort studies, which keep track of participants over pro-
longed periods of time. Additionally, the long lag between
exposure and disease onset implies that mid-life cardio-
vascular risk factors could be important to control for in
(cross-sectional) studies of late-life disease cause.69,71
UNRAVELING CAUSE
The precise pathophysiological link between car-
diometabolic risk factors and dementia yet remains
1546 August 2019 Arterioscler Thromb Vasc Biol. 2019;39:1542–1549. DOI: 10.1161/ATVBAHA.119.311908
Epidemiology of Vascular Dementia
undetermined. Large-scale population studies aimed at
further characterizing this link and unraveling underly-
ing mechanisms have broadly centered around 4 areas.
First, cardiovascular physiology, with the underlying pre-
sumption that cardiovascular risk factors not only cause
cognitive decline via cerebrovascular disease but may
also directly contribute to neurodegeneration. Examples
of recent focuses of study in this field include blood
pressure changes, cerebral perfusion, and the neurovas-
cular unit. Second, studies of genetics investigate the
presumption that the co-occurrence of cardiovascular
risk factors and cerebrovascular disease with neurode-
generation is because of a shared genetic basis. Third,
brain imaging, which aims to study the spatiotemporal
co-occurrence of cerebrovascular and neurodegen-
erative diseases, and recently, has highlighted reduced
white matter integrity and novel markers of small vessel
disease as areas of interest. Fourth, serum biomarkers,
with the aim of identifying a blood-based signature of
early brain damage, thereby serving risk stratification of
individuals for inclusion in trials and ultimately admin-
istration of preventive interventions. The establishment
of biobanks containing blood and cerebrospinal fluid
samples will prove important to develop and readily test
future markers for (long-term) risk stratification (rather
than prospectively having to obtain follow-up data each
time) as well as importance in etiology.47
From genetics to imaging and fluid biomarkers, current
insights are for a large part the yield of high-dimensional
data analysis since the late 1990s. Genome-wide asso-
ciation studies have since then identified variants related
to (subtypes of) stroke that provide clues to the cause of
small vessel disease. Many genetic variants for Alzheimer
disease point towards inflammation and lipid metabolism,
which may well hold implications for cerebrovascular (co)
morbidity. In addition, the recent rise of metabolomics has
led to the identification of various lipid fractions as part of
a wider blood-based signature,72 which is only expected
to increase in coming years. Similarly, large imaging stud-
ies map for example differences in brain structure and
large artery disease in relation to dementia,73,74 as well
as the aforementioned acknowledgment of various imag-
ing markers of small vessel disease in the occurrence
of dementia at a population level. As different modali-
ties are increasingly available in clinics as well as on a
population level, this provides ample opportunity for the
assessment of various contributing pathologies within
one large group of individuals.
These diagnostics could prove valuable in the search
for (mediated) interaction, between for example cere-
brovascular pathology and β-amyloid,71 in the process
leading to cognitive decline. Here, applying principles
of causal mediation analysis can aid in understanding
relative and independent contributions of factors in a
causal pathway. In causal mediation analysis, the causal
effect of an exposure on the outcome of interest can
 Wolters and Ikram
be decomposed into 4 components, covering exposure-
mediator interaction in addition to unequivocal direct and
indirect effects.75,76 When investigating interaction by
stratification, it is furthermore noteworthy that mere dif-
ferences in effect estimates between subgroups in a sin-
gle study warrant formal testing for statistical interaction
(on an multiplicative or additive scale) before any mean-
ingful conclusion about their relevance can be drawn.77
Although omics approaches have thus far mainly
been applied to detect differences in characteristics
at group level, they provide the first steps towards
personal disease signatures, with more precise sub-
type diagnosis beyond a coarse clinical cognitive phe-
notype. In due time, these could prove the first steps
towards personalized prognosis, as is already feasible
with genetic information,78 and perhaps even treatment
decisions depending on the pathways implicated within
one individual. Further technological advances in both
laboratory assessment, as well as imaging techniques,
will continue to offer new opportunities for the study
of etiology, notably of vascular origin, facilitated by
increasing volumes of data and (autodidact) algorithms
for their interpretation. However, data volumes do not
make obsolete study design and data quality manage-
ment. For example, response rates of <10% in national
biobanks caution for selection bias at least in cross-
sectional analyses,79 and firm methodological founda-
tions will prove essential obtain valid results from these
valuable biobanks and beyond.
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The findings and hypotheses originating from above-
mentioned fields of study are more extensively discussed
in the accompanying articles in this edition of the journal.
CONCLUDING REMARKS
The definition of vascular dementia has changed greatly
over the centuries. Recent decades of research have
taught us that in the vast majority of dementia cases,
vascular pathology plays a role alongside amyloid depos-
its, Lewy bodies, and others to create a complex cocktail
of pathologies, which precludes assigning a single pre-
sumed cause to any individual patient at advanced age.
Consequently, etiological study about vascular dementia
is best served by the investigation of vascular determi-
nants in dementia of any origin. The spectrum of vascular
pathologies involved in dementia has, furthermore, wid-
ened from clinical stroke, to initially more covert lesions,
including white matter hyperintensities, cerebral micro-
bleeds, microinfarcts, and perivascular spaces. While
the prevention of stroke continues to hold an important
place in the prevention of dementia, halting progress of
broader vascular pathology, notably of the arterioles and
capillaries, is the most important challenge in controlling
the vascular side of cognitive impairment and dementia.
On a population level, reports of declining incidence of
dementia in Europe and North America, possibly related
Arterioscler Thromb Vasc Biol. 2019;39:1542–1549. DOI: 10.1161/ATVBAHA.119.311908
Epidemiology of Vascular Dementia
to better control of vascular disease, along with recent tri-
als about multifactorial interventions and blood pressure
ATVB IN FOCUS - VB
control, offer reason for cautious optimism for the future.
Nevertheless, much of the vascular cause of cognitive
decline remains to be unraveled. Further study into the
independent contributions and interplay between pathol-
ogies will be essential to unravel their etiological con-
tributions in the process leading to neurodegeneration.
The possibilities for such undertakings are increasingly
provided by technological advances in genetics, metabo-
lomics, proteomics, and (preclinical) models of disease,
to name a few. In the coming years, more than ever, we
can thus reap the fruits of linking observational evidence
from patients and wider populations to the experimental
(preclinical) setting.
ARTICLE INFORMATION
Received January 4, 2019; accepted June 3, 2019.
Affiliations
From the Department of Epidemiology (F.J.W., M.A.I.) and Department of Neu-
rology (F.J.W.), Erasmus University Medical Center, Rotterdam, the Netherlands.
Disclosures
None.
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