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Topical Review

Cerebrovascular Disease, Amyloid Plaques, and Dementia

Wenyan Liu, MD; Adrian Wong, PhD; Andrew C.K. Law, MD, PhD; Vincent C.T. Mok, MD

A myloid plaques are depositions of amyloid (A) pro-

tein in the cerebral parenchyma and considered as one
of the neuropathological diagnostic hallmarks of Alzheimers
transient ischemic attack and 31.1% of patients with clinical
diagnosis of subcortical vascular dementia (VaD).24,25 These
findings are in keeping with the prevalence reported in neu-
disease (AD).1 Cerebrovascular disease (CVD) is also highly ropathological studies showing that AD pathology, including
prevalent among the elderly and is commonly found in both amyloid plaques and neurofibrillary tangles, was found
patients with AD.2 Autopsy studies conducted during the past between 25.8% and 55.6% of patients diagnosed with possible
2 decades show that amyloid plaques frequently coexist with VaD.4648
CVD, and the 2 may interact to modulate the risks and expres-
sion of clinical dementia.2 Neuropathological examinations Interactions Between CVD and Amyloid
show that between 6% and 47% individuals with dementia Plaques
had coexisting AD and CVD pathologies (Table).320 Indeed, Being the 2 commonest causes for dementia, mounting evi-
mixed pathologies may account for the majority of dementia dence shows that CVD and AD share risk factors, including
cases (38%).11 age, hypertension, diabetes mellitus, hypercholesterolaemia,
Although autopsy study is considered the gold standard ischemic heart disease, and smoking.1 Research findings on
for determining the underlying pathology of dementia, it has the relationship between CVD and amyloid accumulation are
inherent limitations with correlating pathological and clini- discussed below.
cal findings. In particular, uncertainties exist with regard to
the temporal relationship between the development of brain Neurovascular Unit and Amyloid Plaques
lesions and dementia syndrome because of the time lag Amyloid accumulation may occur a decade or more before
between dementia onset and autopsy. Moreover, the exact the emergence of clinical symptoms of cognitive decline.49
severity or extent of certain manifestations of CVD, in par- Alterations in neurovascular unit may take part in the pro-
ticular, white matter changes (WMC), is difficult to quantify cess.50 According to the 2-hit vascular hypothesis of AD,
in autopsy studies.21 Also, heterogeneity in the definition of impaired bloodbrain barrier and reduced cerebral blood
CVD lesions (eg, lacunar infarct) might contribute to incon- flow, caused by neurovascular unit dysfunction, may
sistency in assessments between neuropathologists.21 induce A accumulation in addition to direct damage to
Clinical in-vivo study investigating the relationship neurons.50,51 Apolipoprotein E-4, which is associated with
between amyloid plaques and cognitive impairment has only both cerebrovascular lesions and late-onset sporadic AD,
been made possible a decade ago with the advent of amyloid may also contribute to amyloid formation via vascular
imaging, such as Carbon-11-labeled Pittsburgh Compound B mechanisms.52 Different from the direct neurotoxic effects
(PiB) positron emission tomography (PET). Other amyloid of parenchymal amyloid plaques, amyloid deposits in
ligands, such as flutemetamol (GE-067), florbetaben (BAY- vessels are associated with cerebral amyloid angiopathy
949172, AV-1), and florbetapir (AV-45) have also become (CAA). Vascular amyloid may disrupt bloodbrain barrier
available to the market in recent years.22 Amyloid PET can function and rupture the vessels, causing the leakage of the
detect comorbid amyloid deposition in patients with high vas- serum proteins and red blood cells into brain parenchyma.
cular burden.23 We reviewed the potential interactions between Together, these series of events set the stage for the for-
CVD and amyloid plaques and their relationships with cog- mation of amyloid plaques.50 This hypothesis is supported
nitive impairment, with reference to in-vivo clinical studies by pathological observations of an preferential accumula-
using amyloid PET imaging2440 and autopsy studies measur- tion of amyloid plaques around capillaries with CAA in
ing amyloid plaques.4145 patients with AD.53 In young APP23 transgenic mouse
(a mouse model for AD), vessels deformation and attach-
Prevalence of Amyloid Plaques in Subjects ment by small amyloid deposits were found before the
With CVD presence of amyloid plaques in the parenchyma, suggesting
Using amyloid PET, AD-like PiB retention was found in that microvasculature alternations may be an early event in
29.7% of patients with incident dementia after stroke or the formation of amyloid plaques.54

Received October 15, 2014; accepted February 23, 2015.

From the Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China (W.L., A.W., V.C.T.M.); and Neural
Dysfunction Research Laboratory, Department of Psychiatry, The University of Hong Kong, Hong Kong, China (A.C.K.L.).
Correspondence to Adrian Wong, PhD, Department of Medicine and Therapeutics, 10/F Clinical Sciences Bldg, Prince of Wales Hospital, The Chinese
University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China. E-mail
(Stroke. 2015;46:1402-1407. DOI: 10.1161/STROKEAHA.114.006571.)
2015 American Heart Association, Inc.
Stroke is available at DOI: 10.1161/STROKEAHA.114.006571

Liu et al Cerebrovascular Disease, Amyloid, and Cognition 1403

Table. Pathology Findings in Dementia

Author Setting No. Mean Age, y AD+CVD (%) Pure AD (%) Pure VaD (%) LBD (%) FTD (%) Others (%)
Victoroff3 Hospital 196 d 76.6 25 (12.8%) 88 (44.9%) 9 (4.6%) 13 (6.6%) NA 61 (31.1%)
Snowdon 4
Convents 45 d 76100 21 (47%) NA NA NA NA NA
Nolan5 Hospital 87 d NA 32 (37%) 44 (50.6%) NA NA 11 (12.6%)
Seno6 Nursing home 122 d 83.68.3 14 (11%) 41 (34%) 42 (35%) NA NA 25 (20%)
Barker7 Hospital 382 d 7913 43 (11%) 159 (42%) 12 (3%) 99 (25.9%)* 21 (5.5%) 48 (12.6%)
Akatsu 8
Geriatric 158 d 81.28.3 9 (6%) 73 (46%) 34 (22%) 28 (18%) 14 (8%)
Riekse9 Community 124 d 65+ 18 (14.5%) 30 (24.2%) 8 (6.5%) NA NA 124 (54.8%)
Petrovitch10 Community 333 (120 d) 78 22 (18.3%) 37 (30.8%) 35 (29.2%) 26 (21.7%)
Schneider11 Community 141 (50 d) 87.85.6 19 (38%) 15 (30%) 6 (12%) NA 10 (20%)
(the Rush MAP)
Brunnstrm12 Hospital 524 d 80 (39102) 113 (21.6%) 220 (42%) 124 (23.7%) 1 (0.2%) 21 (4%) 45 (8.6%)
Schneider 13
Community 179 d 86.9 54 (30.2%) 76 (42.4%) 8 (4.5%) 30 (16.8%)* NA 11 (6.2%)
(the Rush ROS
and MAP)
Brayne14 Community 213 (113 d) 91.1 (81101) 25 (22.1%) 76 (67.2) 4 (3.5%) 1 (1%) NA 7 (6%)
(CC75C study)
White15 Community 443 (183 d) 7290+ 26 (14.2%) 34 (18.6%) 62 (33.8%) 20 (10.9%) 41 (22.4%)
Jellinger16 Hospital 1700 d 84.35.4 473 (27.8%) 775 (45.6%) 209 (12.3%) 158 (9.3%) NA 85 (5%)
Sinka17 Hospital 93 (86 d) 90103 17 (19.7%) 48 (55.8%) 21 (24.4%)
Echavarri 18
Hospital 200 d 78.7 (15100) 31 (16%) 52 (26%) 4 (2%) 1 (0.5%) 4 (2%) 113 (56.5%)
Grinberg19 Community 1291 (113 d) 78.39.7 15 (13.3%) 40 (35.4%) 24 (21.2%) NA NA 34 (30.1%)
Magaki20 Hospital 218 d 50100 24 (11%) 123 (56.4%) 1 (0.5%) 31 (14.2%)* 14 (6.4%) 25 (11.5%)
AD indicates Alzheimers disease; BBBABSG, Brain Bank of the Brazilian Aging Brain Study Group; CC75C, Cambridge City Over-75s Cohort; CVD, cerebrovascular
disease; d, number of patients with dementia; FTD, frontotemporal dementia; HAAS, Honolulu-Asia Aging Study; LBs, Lewy bodies; LBD, Lewy body disease; MAP, Rush
Memory and Aging Project; NA, not available; ROS, Religious Order Study; and VaD, vascular dementia.
*Including LBs+others.
Including FTD+others.
AD+others, but most are AD+CVD.

However, an unresolved issue remains on the temporal rela- Infarcts and Amyloid Plaques
tionship between the development of vascular and amyloid Most amyloid PET studies did not find significant relation-
pathologies as other potential factors, such as the overproduction ships between infarcts and amyloid deposition.27,28 In fact,
of A caused by genetic mutations in APP and presenilin genes a study showed that in patients with subcortical vascular
might also take part in the abnormal amyloid accumulation.1 cognitive impairment, the number of lacunes was negatively
related with the PiB retention ratio.29 In patients with recent
Atherosclerosis and Amyloid Plaques ischemic stroke, although a relatively increased PiB reten-
Atherosclerosis in large cerebral arteries can compromise tion was found in peri-infarct region comparing to the con-
cerebral blood flow and cause cerebral hypoperfusion. Patients tralateral mirror region, this increased regional PiB retention
with AD had a higher proportion and more pronounced athero- did not translate into a higher global PiB retention.30 In
sclerosis in the circle of Willis than those patients with non- experimental stroke models in transgenic mouse with amy-
AD dementias (except VaD) as shown in autopsy studies.41,5558 loid deposition (APPswe/PS1dE9), increase in new amy-
Moreover, there was a high concordance between the ratings loid plaques around the infarcted area was only transient, in
of atherosclerosis with amyloid plaques and CAA ratings.41 which the accumulation most probably reflected an impaired
Through [18F] AV-45 PET examination, amyloid deposition amyloid clearance pathway caused by infarcted tissue.59
in patients with dementia having unilateral carotid artery ste- Moreover, the possibility that the observed increase in local
nosis was increased. More importantly, the distribution of the PiB retention being a result of leakage of free PiB because
amyloid disposition was found to be lateralized to the side of of the bloodbrain barrier damage could not be excluded.30
stenosis.26 Together, these clinical and pathological findings Overall, thus far, there is no solid evidence of a significant
suggest that there is a shared cause between atherosclerosis interaction between cerebral infarcts and global amyloid
and amyloid deposition. burden.
1404StrokeMay 2015

WMC and Amyloid Plaques expression of dementia. It suggested that concurrent cere-
Pathogenesis of WMC could be multifactorial. Here, we bral infarcts might significantly amplify the risk and severity
specify WMC as age-related WMC, which is suggested to of dementia in patients with neuropathologically confirmed
represent incomplete infarct related to small vessel disease. AD.4 More recent studies using amyloid PET also showed
WMC is generally hypothesized to be associated with demy- converging findings. For example, PiB-positive (PiB+) sub-
elination, loss of oligodendrocytes, and axonal damage.60 cortical patients with VaD had lower cognitive performance
Findings about the relationship between WMC and amyloid than those who were PiB-negative (PiB).25 Interestingly,
accumulation seem to be inconsistent. In general, most stud- there seems to be a dynamic balance between amyloid depo-
ies showed a lack of correlation between WMC and amy- sition and CVD pathologies on the expression of demen-
loid load.2729,31,32 However, there were also studies showing tia because on a given level of cognitive impairment, less
positive relationships between WMC and amyloid.33,34 For amount of one kind of pathology is found when the amount
instance, in sporadic AD patients, WMC at baseline was sig- of other kind of pathology increases. For example, in neuro-
nificantly related to the progression of amyloid deposition in pathological studies, amyloid plaques were found to be fewer
28 months,33 suggesting that WMC might accelerate the aggre- in those with CVD lesions.4345 Among patients with post-
gation of amyloid protein produced in situ. However, the posi- stroke dementia, PiB+ patients had fewer old infarcts than
tive association between WMC and amyloid burden seemed their PiB counterparts.24,25
to be predominant in the posterior brain regions, which are Although findings from above studies raised the possibility
not the typical topography of AD but CAA.34 Another study of a synergistic effect between the 2 pathologies, other study
also reported that the volume of WMC was independently suggested that CVD largely contributed an additive, rather
related to amyloid retention in patients with CAA but not in than synergistic, effect on the expression of dementia against
patients with AD.35 On the basis of these findings, it can be the background of amyloid burden.29 Note that synergistic
speculated that WMC may be more closely linked to vascular effects between the 2 pathologies might be specific to cogni-
amyloid deposition associated with CAA rather than paren- tive domains such as visuospatial functions.39
chymal amyloid deposition characteristic of AD. Noteworthy
is that a study among cognitively normal individuals showed Contributions of Comorbid CVD and Amyloid
that gray matter regions with more WMC had lower amyloid Plaques on Expression of Dementia
deposition.36 It was hypothesized that WMC might disrupt the The amyloid hypothesis posits that the amyloid deposition
entry of misfolded proteins from white matter tracts and thus on its own is an early step in the development of cognitive
resulted in lower amyloid load in gray matter regions.36 In impairment.49 The accumulation of amyloid in the aging brain
view of these conflicting results, further investigation between causes oxidative and inflammatory effects, which lead to neu-
WMC and amyloid is warranted. ronal death and synaptic failure, and eventually result in brain
atrophy and cognitive impairment. Although the detrimental
Microbleeds and Amyloid Plaques effects of A on neuron and synapse have been observed in
The number of studies on the association of microbleeds and animal models, it remains unclear how much A deposition
amyloid burden are limited.37,38,42 Two studies revealed posi- is required to instigate the neurodegenerative process and
tive findings.37,42 In a postmortem study using immunohisto- finally results in cognitive dysfunction. Given that amyloid
chemical staining, the majority of A deposits were found to burden could be found in 20% to 30% cognitively normal
be at or near the capillary hemorrhage sites.42 The Australian older adults,62,63 the threshold of amyloid plaques for cognitive
Imaging, Biomarkers, and Lifestyle Study of Aging Research manifestation is likely to be modulated by individual differ-
group showed that the prevalence and incidence of micro- ences, such as brain and cognitive reserve, and other environ-
bleeds were both significantly higher in AD than in cogni- mental factors.49
tively normal individuals.37 However, converging evidence Concurrent CVD lesions may catalyze or trigger the onset
showed that microbleeds in AD were more linked to CAA and of clinical dementia in asymptomatic or subclinical individu-
related increased bloodbrain barrier permeability, rather than als with amyloid plaques by several ways. First, CVD may
amyloid disposition.38 Autopsy study showed that microbleeds impair cognition directly via neuronal death and synaptic
in AD with CAA were found in all brain sections, whereas failure independent of amyloid.2 According to laboratory
in AD without CAA, microbleeds were only predominate in research, the neurovascular dysfunction could cause oxida-
the central coronal sections.61 This observed discrepancy on tive stress and inflammation via nonamyloidogenic pathway,
topographical distribution of microbleeds may differentiate leading to neuronal loss.2,50 Second, according to the afore-
AD patients with and without CAA. mentioned 2-hit vascular hypothesis, the neurovascular dys-
function is also associated with an increased accumulation of
amyloid plaques.50 Third, decreased number of viable neu-
Interactions Between CVD, Amyloid Plaques
rons caused by the CVD lesions may reduce brain reserve
on Cognition
and subsequently the resilience of the brain against the
Comorbid CVD and Amyloid Plaques on detrimental effects from amyloid-mediated neurotoxicity.
Expression of Dementia Therefore, concurrent CVD lesions may lower the thresh-
The Nun study was a landmark study that revealed a con- old for clinical manifestation of cognitive impairment with
certed effect of lacunes and AD pathologies on clinical amyloid burden.
Liu et al Cerebrovascular Disease, Amyloid, and Cognition 1405

In addition to possible pathological mechanisms mentioned Conclusions and Future Directions

above, in clinical setting, the presence of concurrent CVD Autopsy and amyloid PET studies showed the existence of
may increase the likelihood for patients to receive a diagno- comorbid CVD and amyloid deposition in patients with cog-
sis of dementia. In the early stage of amyloid deposition, a nitive impairment. Underlying microvasculature alternation
diagnosis of dementia is more likely to be established in the may contribute to an early accumulation of amyloid. With
presence of deficits on multiple cognitive domains contributed aging, emergence of CVD could further affect cognition in
concurrently by frontal dysfunction associated with cerebro- those patients with preexisting amyloid by causing direct
vascular lesions.64 When the invasion of amyloid progresses neuronal damage and accelerating the amyloid deposition.
to later stage and involves in all areas of the isocortex, the Concurrent CVD may also lower the brain reserve against
superimposed cognitive dysfunction caused by CVD will be cognitive effects from amyloid disposition, and vice versa.
difficult to distinguish.65 This may be one of the reasons why Nevertheless, relationships between amyloid deposition
CVD lesions play a greater role in the development of demen- and different kinds of cerebrovascular lesions are still unclear.
tia in people with fewer amyloid plaques than those with more Longitudinal studies with repeated amyloid and MRI in
severe deposition. young subjects with high risks of CVD or AD will be help-
ful to study the evolution in the development and interactions
Comorbid CVD and Amyloid Plaques on Cognitive between CVD and amyloid deposition. In addition, the valid-
Profile of Dementia ity of neuropsychological paradigms such as intraindividual
In AD, amyloid has most robust effects on episodic memory variability measures may be examined in conjunction with the
among the cognitive domains.66 In contrast, executive dys- use of computerized testing technology as a way to differenti-
function tends to be typically more prominent in patients ate underlying pathology and predict clinical course. In clini-
with subcortical vascular disease, such as individuals exhibit- cal practice, aggressive control of risk factors of CVD will
ing lacunes and WMC, in which their effects are more pro- probably prevent or delay onset of dementia in elderly sub-
nounced on the frontosubcortical system.67 Such dissociations
jects harboring amyloid plaques. Furthermore, active lifestyle
have been demonstrated in patients with mixed pathologies.
engagement, such as physical activities and mental stimula-
For example, in patients with subcortical VaD and mild cogni-
tion has been found to be associated with reduced CVD risks
tive impairment, amyloid burden seemed to be more related
and amyloid burden.71,72 Clinical trials are needed to study the
to episodic memory decline, whereas WMC was associated
modulating effects of lifestyle intervention on clinical and
with poor executive function.25,29,39 A path analysis study
neuroimaging markers of CVD and AD for primary preven-
showed that memory deficits related to amyloid burden was
tion of dementia in our rapidly aging populations.
mediated by hippocampal atrophy, whereas WMC affected
executive function via frontal thinning.40 However, the rela-
tionships between cognitive domains and pathologies may Sources of Funding
not be straightforward. For example, WMC could also affect This work was supported by Health and Health Services Research
Fund 07080411 and Lui Che Woo Institute of Innovative Medicine.
episodic memory by affecting working memory and executive
retrieval with frontal dysfunction.40 In addition, amyloid and
CVD might influence memory and executive function inde- Disclosures
pendent of brain atrophy.40 None.
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