Alzheimer disease as a vascular disorder: nosological evidence

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J.C. de la Torre
Alzheimer Disease as a Vascular Disorder : Nosological Evidence
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Alzheimer Disease as a Vascular Disorder
Nosological Evidence
J.C. de la Torre, MD, PhD
Background—The main stumbling block in the clinical management and in the search for a cure of Alzheimer disease
(AD) is that the cause of this disorder has remained uncertain until now.
Summary of Review—Evidence that sporadic (nongenetic) AD is primarily a vascular rather than a neurodegenerative
disorder is reviewed. This conclusion is based on the following evidence: (1) epidemiological studies showing that
practically all risk factors for AD reported thus far have a vascular component that reduces cerebral perfusion; (2) risk
factor association between AD and vascular dementia (VaD); (3) improvement of cerebral perfusion obtained from most
pharmacotherapy used to reduce the symptoms or progression of AD; (4) detection of regional cerebral hypoperfusion
with the use of neuroimaging techniques to preclinically identify AD candidates; (5) presence of regional brain
microvascular abnormalities before cognitive and neurodegenerative changes; (6) common overlap of clinical AD and
VaD cognitive symptoms; (7) similarity of cerebrovascular lesions present in most AD and VaD patients; (8) presence
of cerebral hypoperfusion preceding hypometabolism, cognitive decline, and neurodegeneration in AD; and (9) con-
firmation of the heterogeneous and multifactorial nature of AD, likely resulting from the diverse presence of vascular
risk factors or indicators of vascular disease.
Conclusions—Since the value of scientific evidence generally revolves around probability and chance, it is concluded that
the data presented here pose a powerful argument in support of the proposal that AD should be classified as a vascular
disorder. According to elementary statistics, the probability or chance that all these findings are due to an indirect
pathological effect or to coincidental circumstances related to the disease process of AD seems highly unlikely. The
collective data presented in this review strongly support the concept that sporadic AD is a vascular disorder. It is
recommended that current clinical management of patients, treatment targets, research designs, and disease prevention
efforts need to be critically reassessed and placed in perspective in light of these important findings. (Stroke. 2002;33:
1152-1162.)
Key Words: Alzheimer disease 䡲dementia 䡲microcirculation 䡲risk factors 䡲vascular disorders
Alzheimer disease (AD) is an insidious disorder that
progressively ravages the brain, destroying its memory,
intellect, and dignity in the process. The main stumbling
block in the clinical management and in the search for a cure
of AD is that the cause of this disorder has remained uncertain
until now. For more than 30 years, AD has been classified and
managed as a neurodegenerative disorder,
1,2
following a
report by Roth in 1955
3
that suggested that dementia should
be classified into 2 distinct disorders according to the variable
mental changes caused by each: vascular dementia (VaD),
caused by vascular lesions, and AD, resulting from a neuro-
degenerative process.
Most investigators in the field have supported Roth’s
notion that dementing processes will differentially affect
brain structures, resulting in a consistent pattern of neuropsy-
chological deficits. Even if this notion were correct, it does
not explain the clinicopathological similarities between 2
apparently different disorders, namely, AD and VaD, despite
the fact that the latter originates from a cerebrovascular insult
and the former through some less obvious mechanism.
Consequently, according to the Diagnostic and Statistical
Manual of Mental Disorders, Fourth Edition (DSM-IV), the
presence of cerebrovascular disease in a demented individual
paradoxically excludes the diagnosis of AD, and the condi-
tion is classified instead as VaD.
2
These 2 sets of criteria for
differentiating AD from VaD and their respective diagnoses
have been based on “expert opinion” rather than a critical
review of the scientific evidence.
4
Since the first description of this disorder more than 90
years ago,
5
there has been little clarity in the pathogenic
evolution of AD, despite an enormous amount of basic and
clinical research. This situation has deferred attention to the
reduction of risk factors, optimal patient management, and
development of effective therapy that can alter the course and
the outlook of this disease. Physicians’ attitudes toward
modifying the course of AD have consequently been fatalis-
Received December 14, 2001; final revision received January 18, 2002; accepted January 25, 2002.
From the Department of Neuropathology, University of California at San Diego.
Correspondence to J.C. de la Torre, MD, PhD, Department of Pathology, University of California at San Diego, 1363 Shinly, Suite 100, Escondido,
CA 92026. E-mail jdelator@nctimes.net
© 2002 American Heart Association, Inc.
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tic, and little effort has been made to reshape the thinking that
“nothing can be done”about this illness.
More recently, however, a substantial and ever-growing
amount of evidence, discussed below, indicates that nonge-
netic AD is initiated by vascular factors that precede the
neurodegenerative process. This conclusion seems consistent
with most of the basic and clinicopathological data reported
thus far for AD and is not inconsistent with other findings that
may favor a neurodegenerative process as the cause of this
disorder.
The question of whether AD is first provoked by a
neurodegenerative process, as the prevailing paradigm main-
tains, or by premorbid vascular-related events, such as those
listed in the Table, which then propel neurodegenerative
changes mostly in the elderly, is of crucial importance.
Establishing the correct pathogenesis for this dementia could,
for example, help to unravel the exact mechanisms responsi-
ble for the cognitive failure and, in so doing, target specific
therapy to overcome or treat this disorder more effectively.
If, as we have proposed,
6–11
AD is a vascular disorder that
initiates its pathology through cerebral microvascular abnor-
malities, then its origin, clinical signs, diagnosis, and poten-
tial treatment should revolve around a “vasculopathic com-
plex”that provides its defining qualities. This vasculopathic
complex would be expected to be identified with the follow-
ing: (1) epidemiological evidence linking vascular factors to
cerebrovascular pathology that can set in motion metabolic,
neurodegenerative, and cognitive changes in Alzheimer
brains; (2) evidence that AD and VaD (defined here as a
“poststroke hypoperfusion”dementia) share similar risk fac-
tors; (3) evidence that therapy that improves cerebrovascular
insufficiency also improves AD symptoms; (4) evidence that
preclinical or prodromal detection of potential AD is possible
from direct or indirect regional cerebral perfusion measure-
ments; (5) evidence that AD clinical symptoms arise from
cerebromicrovascular pathology; (6) evidence of matching
clinical symptomatology in AD and VaD; (7) evidence
showing overlap of cerebrovascular and neurodegenerative
pathology in AD and VaD; (8) evidence that cerebral hypo-
perfusion can trigger hypometabolic, cognitive, and degener-
ative changes; and (9) evidence that AD is a heterogeneous
and multifactorial disorder due to a variety of vascular risk
factors or indicators of vascular disease.
It is not the purpose of this review to be exhaustive or to
profoundly interpret all the findings in support or contradic-
tion of its main thesis, a chore that would require consider-
ably more space than allowed here. Instead, this review will
attempt to crystallize the most relevant clinical and basic
findings that indicate that sporadic AD should be classified as
a vascular disorder.
Epidemiological Studies
A growing number of prospective, population-based epide-
miological studies have evaluated aged demented subjects
and nondemented age-matched controls with the goal of
identifying risk factors that might clarify the pathological
process leading to AD. A reassuring feature in most of these
epidemiological studies, especially the large-scale ones, is
their ability to transcend cultural barriers and historical
disease biases and generally to arrive at quite similar conclu-
sions. Most of the epidemiological data discussed here have
been reported within the last decade and deal only with
nongenetic risk factors. As a reference point, the only
suspected risk factors for AD in 1988 were aging, Down
syndrome, and persons with 1 or more relatives affected with
this disorder.
12
One of the most important of the epidemiological studies,
as judged by cohort population size, duration of follow-up,
and determinants of various risk factors associated with AD,
is the Rotterdam Study. More than 7000 elderly subjects have
been studied since 1990 in a series of reports consisting of
demented subjects and nondemented, age-matched controls.
13
The dementia group was further divided into vascular and
Alzheimer’s dementia with the use of accepted neurological,
neuroimaging, and psychological screening techniques.
13,14
On the basis of the collective data gathered by the
Rotterdam Study, it was concluded that vascular risk factors
and indicators of vascular disease, particularly in elderly
subjects, have an established association with AD.
15,16
The
risk factors for AD reported thus far in the Rotterdam Study,
many of which have been confirmed by other independent
studies, include the following: (1) diabetes mellitus,
17
(2) thrombotic episodes,
18
(3) high fibrinogen concentra-
tions,
19
(4) high serum homocysteine,
20
(5) atrial fibrilla-
tion,
16,21
(6) smoking,
22,23
(7) alcoholism,
24
(8) low level of
education,
25
and (9) atherosclerosis
26
(Table). All these
conditions have a vascular involvement and are known to
reduce cerebral perfusion.
27
Two compelling sets of data from the Rotterdam Study and
the Honolulu-Asia Study indicate that AD can develop from
vascular pathology involving atherosclerosis or hypertension.
In the Rotterdam Study, a group of 284 dementia patients
(207 with AD and the rest with VaD), all diagnosed with
varying severity of atherosclerosis (determined noninva-
sively), were compared with 928 nondemented age-matched
controls. It was found that AD and VaD severity correlated
significantly with the severity of atherosclerosis in these
Reported Risk Factors for AD Compiled From Epidemiological
Studies of Elderly Subjects
●Aging ●Thrombogenic factors
●Atherosclerosis ●ApoE4
●Stroke ●High serum homocysteine
●Diabetes mellitus ●Hypertension
●Smoking ●Hypotension
●Alcoholism ●High fibrinogen levels
●High HDL cholesterol ●Head injury/loss of consciousness
●Cardiac disease ●Menopause
●Migraine ●Lower education
●High serum viscosity ●Transient ischemic attacks
●Depression ●Microvessel pathology
●Fat intake
Note that despite the discrete etiogenesis, pathological course, and clinical
outlook of each risk factor, all are linked by 2 activities: (1) all are vascular
related and (2) all impair or reduce cerebral perfusion. It should be noted that
most of the risk factors listed are also risk factors for VaD. See text for details.
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patients.
26
Using Occam’s razor, 2 possible conclusions can
be drawn from these findings: (1) AD or VaD caused both the
atherosclerosis and the degenerative vessel wall damage
observed in these patients, or (2) atherosclerosis provoked the
development of AD or VaD, and as the vessel pathology
worsened, cognitive function deteriorated. Since the diagno-
sis of dementia had been recently made in these patients and
it is well known that atherosclerosis often requires several
decades or more to unfold, it is more likely that atheroscle-
rosis was present before AD and VaD and sparked the gradual
cognitive loss that later progressed into either dementia.
Moreover, it was observed that the frequency and severity of
AD and VaD were associated with the degree of atheroscle-
rosis. The conclusion from this study that atherosclerotic
carotid artery flow (which is known to result in chronic brain
hypoperfusion) can lead to cognitive decline much later in
life is further supported by cerebral function studies in
humans in which 1 common carotid artery is occluded for 30
minutes. In this acute clinical test, the degree of cognitive
performance wanes in direct relation to reduced cerebral
blood flow (CBF) after carotid occlusion, a dysfunction that
is reversed when occlusion is removed.
28
It has long been suspected that raised blood pressure in
midlife may precede the development of AD. Until the last
few years, little evidence had been gathered to support this
notion. A study of Japanese-American men (the Honolulu-
Asia Aging Study) with elevated blood pressure and a mean
age of 53 years reported that these individuals have a higher
risk for AD when followed for 25 years.
29,30
Elevated midlife blood pressure has been shown to in-
crease the risk of mild cognitive impairment (MCI) in older
subjects to the same degree as the presence of apolipoprotein
E-␧4 (apoE4) genotype, a genetic marker for AD and for
vascular pathology of the brain and heart.
31–38
It is important
to note that MCI is presently considered by many in the field
to be the first stage of AD when it is routinely discovered in
elderly patients. MCI is suspected in patients presenting with
only memory difficulties but no other cognitive
disability.
39–41
In another longitudinal Honolulu-Asia Aging Study,
midlife hypertension was seen to be associated 36 years later
with a significantly greater number of neurofibrillary tangles
in the hippocampus and with brain atrophy in postmortem
AD brains compared with age-matched AD brains with a
history of normal blood pressure.
30
More recently, the FINMONICA study examined midlife
blood pressure and cholesterol concentrations in the develop-
ment of MCI and AD. The FINMONICA study, which
included 1449 subjects and a 21-year follow-up, reported that
people with raised systolic pressure or high serum cholesterol
levels in midlife had a significantly higher risk of developing
MCI and, later in life, AD.
42,43
The risk for MCI or AD was
higher when both blood pressure and cholesterol levels were
high, suggesting that AD prevalence may be accelerated as
the level of cerebral perfusion decline becomes more
marked.
42
Blood pressure and cholesterol increases are also
prominent in the development of VaD.
30,44–47
Cross-cultural studies that have investigated the incidence
of hypertension in genotypically similar population groups
residing in Africa or the United States conclude that lifestyle
rather than genetics plays a more important role in the
development of high blood pressure and the risk of AD.
48
The effect of chronic cerebral hypoperfusion on human
cognition has been studied primarily in patients presenting
with carotid artery stenosis of long duration and in those who
have undergone surgical treatment to improve blood flow by
carotid endarterectomy (CEA). A review of the literature with
respect to the effects of CEA on brain function remains
controversial because CEA can promote cerebral microem-
boli even when reversing carotid artery stenosis and increas-
ing cerebral perfusion. However, it would appear that when
global brain hypoperfusion after CEA is reversed without
microembolic sequelae, cognitive ability generally improves,
but when microemboli are generated or the hypoperfused
state is not corrected after CEA, cognitive performance often
remains unchanged.
49,50
It now appears that coronary artery bypass grafting
(CABG) surgery may induce cognitive loss in as many as
50% of patients undergoing this procedure.
51
This high
prevalence of cognitive decline after CABG continues for at
least 5 years after surgery.
51
With more than 150 000 new
patients electing CABG surgery every year in the United
States,
52
the problem warrants considerable efforts in the
prevention and identification of patients at risk for postoper-
ative cognitive dysfunction.
53,54
Prospective population stud-
ies could determine whether CABG is a major risk factor for
Alzheimer’s and other dementias.
One vascular event that has received little epidemiological
attention in relation to its clinical gravity is the development
of silent stroke. It has been estimated that approximately 11
million Americans experience a silent stroke (defined as a
focal stroke without acute symptoms) every year.
55
Silent
stroke shows a higher prevalence in cigarette smokers and
subjects with atherosclerosis, conditions that are linked to AD
and to cerebral hypoperfusion.
13,14,16,22,26,56
Silent stroke may
be a “sleeping giant”in the development of AD since cerebral
perfusion is often found to be reduced in association with an
increased oxygen extraction fraction (misery perfusion) dur-
ing an attack,
57
a hemodynamic presentation typically found
in AD patients.
58,59
Additional vascular-related risk factors have been reported for
AD: migraine,
60
high intake of saturated fat,
61
presence of apoE4
allele,
33,47,57,62
transient ischemic attacks,
63
high serum choles-
terol levels,
13,16,47
depression,
64,65
alcoholism,
24,63
high serum
homocysteine levels,
20,66
menopause,
67,68
high fibrinogen con-
centrations,
19,69–71
hypotension,
72–74
ischemic stroke,
75,76
head
injury,
77–79
cardiac disease including arrhythmias,
80–86
and, most
importantly, aging.
7,87
Most of these risk factors are present not
only in the early stages of AD but often decades before any
cognitive symptoms develop.
18,22,25,26,29,42,43,46
The main point is that despite the discrete pathologies
involved in each of these risk factors (Table) and their
differential clinical course and outlook, all share 1 common
action: the reduction or impairment of optimal cerebral
perfusion.
88
When elementary statistics are used, the possi-
bility that these reported AD risk factors share a single,
common biological pathology that is due to chance alone is
highly improbable. A secondary point is that most of the
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aforementioned risk factors for AD are also risk factors for
VaD (Table). This relationship, if considered only by itself,
strongly suggests that these 2 dementias share a common
origin. When it is considered that approximately 30% of all
AD brains show some form of cerebrovascular pathology,
and pratically all AD brains reveal either periventricular
white matter lesions, microvessel degeneration, cerebral amy-
loid angiopathy, or combinations of these lesions,
89–91
the
connection between AD and VaD appears more than mere
chance. The reverse of this relationship is equally intriguing,
because approximately 40% of brains meeting the criteria for
clinical VaD diagnosis have concurrent AD pathological
deposits involving senile plaques and fibrillary tangles.
92
Moreover, difficulties in differentiating AD from VaD on
clinical grounds alone are well known,
93–96
creating the
suspicion that their pathophysiological roots are nearly
identical.
In regard to the correlations that appear to fuse these 2
dementias, a reasonable explanation for the cerebrovascular
component seen in some AD brains is that it is likely due to
“mixed”dementia, that is, pathological lesions characteristic
of AD and VaD existing comorbidly and as a separate entity
from a “pure”dementia in which only neurodegenerative
lesions (AD) or cerebrovascular lesions (VaD) are present.
However, this argument does not explain why pure AD still
retains a powerful vascular basis. For example, as shown in
the Table, many of the risk factors reported for AD, such as
atherosclerosis, cardiac disease, and diabetes, are not in
themselves cerebrovascular events characteristic of VaD. In
fact, these reported risk factors appear to convert just as easily
to VaD as they do to AD.
13–26,60–87
It should be recalled that
VaD usually arises from immediate ischemic, hemorrhagic,
hypoxic, or anoxic events, and, as seen in the Table, AD can
develop from many other conditions that might not give
exclusive rise to VaD. How AD develops from these risk
factors is controversial, but we have presented a “hemody-
namic model”in the past that offers a possible explanation of
this process and the evidence in support of its position.
6–11,88
Since it is almost certain that additional risk factors for AD
will be reported in the near future, it will be of interest to see
how many of these will exert an influence similar to those
already known to promote a reduction of cerebral perfusion.
In summary, considerable epidemiological evidence sup-
ports the concept that AD is a heterogeneous and multifac-
torial disorder with a definite vascular basis.
Pharmacological Treatments for AD
No drug treatment at the present time is truly effective in the
treatment of AD or in altering the course of this disorder.
Only 3 drugs are available in the United States for prescrip-
tive use in AD: tacrine(Cognex), donepezil (Aricept), and
rivastigmine tartrate (Exelon). All 3 act to slow the synaptic
breakdown of acetylcholine, a neurotransmitter important in
memory and learning. A fourth drug, galantamine hydrobro-
mide (Reminyl), targets “mixed”dementia, that is, VaD or
AD complicated by cerebrovascular pathology.
These treatments generally provide modest damage control
at the early stages of AD and offer minor to no improvement
at later stages of the disease. For this reason, other drug
therapies for AD have been tried. These include nonsteroidal
anti-inflammatory agents,
97,98
ginkgo biloba,
99,100
estrogen
during menopause,
67,68,101
dimethyl sulfoxide,
102
aspirin,
97,103
vitamin E,
104–106
acetyl-L-carnitine,
107,108
antihypertensive
drugs,
109
statins,
110,111
and selegiline.
112
While the biological
activity and pharmacokinetics of these compounds differ
from one another and their effect in reducing the symptoms or
delaying the progress of AD is debatable, they all share to a
degree 1 common effect: to improve or increase cerebral
perfusion.
10,113
Most (although not all) of these agents are not
known to exert a direct protective or a salvaging effect on
neural tissue after nonvascular damage of the brain. In other
words, whatever beneficial effect is obtained from their
administration in AD is not exclusively due to nerve cell
rescue or protection.
Prodromal Diagnosis of AD
Prevention of brain damage and cognitive disability in AD
patients is entirely dependent on the ability to diagnose this
disorder as early in the disease process as possible. This
strategy can salvage neurons not yet destroyed from irrevers-
ible damage and death by applying treatments that direct their
action at early neuronal protection. Such treatments need not
be strictly pharmacological (see Reference 113 for review).
There is now good evidence that the first stage of AD
begins with MCI, defined as memory deficits with preserva-
tion of other cognitive and functional activities.
39–41
Recog-
nition of MCI means that AD diagnosis and preventive
treatment can be applied much earlier than previously prac-
ticed. One technique that offers such preclinical assessment
of AD during the MCI stage is based on detection of cerebral
hypoperfusion patterns with the use of single-photon emis-
sion CT (SPECT) or positron emission tomography among
individuals complaining only of memory problems. In 1
study, subjects with memory complaints not meeting criteria
of the Alzheimer’s Disease and Related Disorders Associa-
tion for AD had their regional CBF measured with SPECT
and were separated into 2 groups. The majority of the subjects
with significant hypoperfusion of the hippocampal-
amygdaloid complex (areas linked to memory function)
converted to AD within a 3-year follow-up, while patients
with normal cerebral perfusion in these and other brain areas
did not.
114,115
Other neuroimaging studies have supported the aformen-
tioned findings. In MCI patients who later converted to AD,
the presence of temporoparietal (including hippocampal)
hypoperfusion,
116
hippocampal-parahippocampal hypoperfu-
sion,
117
and posterior cingulate hypoperfusion
118
distin-
guished this population group from non-MCI subjects.
Other markers indirectly reflecting reduced cerebral perfu-
sion are used with equal success. Positron emission tomog-
raphy, when used to measure cerebral glucose metabolism,
shows specific decline of glucose metabolic rate utilization in
the hippocampus in subjects with MCI
119,120
and in the brains
of subjects who later convert to MCI.
121
Cerebral hypome-
tabolism is often due to a lowering of cerebral perfusion.
Emission tomography is also useful in diagnosing very-
early-stage AD. With the use of SPECT image-reconstruction
technique, elderly individuals with very mild AD (or MCI)
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symptoms showed significant hippocampal hypoperfusion
compared with age-matched nondemented subjects.
122
Reduced hippocampal volume secondary to ischemic atro-
phy has been used successfully in MCI patients to identify a
population group more likely to initiate conversion to AD.
123
These studies indicate that hippocampal perfusion levels may
be a useful marker in predicting very early diagnosis of AD.
The hippocampal region is known to contain the highest
density of neurofibrillary tangles in the advanced stage of AD
and is the most damaged brain region in these patients found
at autopsy.
93
By focusing on abnormal CBF patterns or their patholog-
ical end products, these neuroimaging techniques are becom-
ing more reliable and sensitive in detecting prodromal clinical
features predictive of progressive cognitive loss and possible
unfolding of Alzheimer’s dementia. Neuroimaging tech-
niques used for the detection of chronic cerebral hypoperfu-
sion in regions linked to memory and learning are conse-
quently becoming a common diagnostic tool to identify the
earliest possible stage of disorders that may later convert to
AD. These techniques are medically attractive because they
are noninvasive, cost-effective, easily performed, informative
and, in the proper hands, provide a quantitative measure of
disease progress and the relative merit of ongoing clinical
management or treatment benefits.
AD Capillary Degeneration and
Basic Considerations
Cerebral capillary degeneration has been shown to be present
in practically all AD brains examined postmortem and in
cortical biopsy material from pathologically confirmed
AD.
124–132
The variety of these brain microvascular aberra-
tions has been catalogued since 1967
133
and may have been
first described by Tuke
134
in 1873, even before the clinical
description of AD by Alzheimer in 1907.
4
The capillary changes recorded in AD brain with the use of
light and electron microscopy consist of (1) basement mem-
brane thickening, (2) endothelial compression, (3) luminal
“buckling”and narrowing, and (4) pericyte degeneration.
These cerebral microvessel aberrations have been consis-
tently observed in AD brain tissue by a considerable number
of investigators using a variety of histological techniques.
135–143
The degenerate capillaries appear more prevalent in the
hippocampus,
136,139,142
a region that is linked to memory and
learning and is an initial target for neurofibrillary tangle
formation in AD.
144
Microvessel changes in AD brains show
no correlation to the stage of the disease (Braak I to VI), a
finding that suggests that such capillary anomalies are not a
consequence of AD pathology.
145
Brain capillary distortions do not appear to be significantly
targeted by amyloid angiopathic deposition. Ultrastructural
examination of AD tissue reveals that cerebral amyloid
angiopathy is mainly deposited in smooth muscle cells
involving cerebral arterioles but often spares capillary endo-
thelium and blood-brain barrier damage.
146–148
The exact causes of the capillary structural changes,
however, are unknown and would be difficult to demonstrate
in humans since they may involve a series of interacting
factors. Nonetheless, experiments in rodents undergoing
chronic brain hypoperfusion (with the use of bilateral carotid
artery occlusion) for 1 year have revealed that capillary
changes almost identical to those described in AD brains also
develop in these animals, with a distinct prevalence toward
the CA1 hippocampal region.
147
With the use of similar models of chronic brain hypoper-
fusion in rodents, a state mimicking MCI can be induced in
which the only behavioral outcome observed after weeks or
months is visuospatial memory impairment.
149
Rodent studies
have reported cerebral metabolic changes after chronic brain
hypoperfusion consisting of hippocampal cytochrome oxi-
dase decline (a marker of energy metabolism),
149
microtubule-associated protein-2 loss in CA1 (a marker of
protein synthesis),
150
changes in monoamine neurotransmitter
turnover,
151
reduction of postsynaptic cholinergic activity,
152
decreased brain glucose utilization,
153,154
reactive gliosis,
155
heme oxygenase expression (a marker of oxidative stress),
156
and increase in matrix metalloproteinase-2 (a marker of
vessel calcification).
157
All these changes occurred many
weeks to months before any neuronal damage or spatial
memory dysfunction was recorded, suggesting that chronic
brain hypoperfusion induces important metabolic changes,
mostly in the hippocampal area, which eventually trigger
MCI-like memory loss in rats. In these studies animals were
not observed to develop brain microinfarcts, hemorrhage,
white matter changes, or high blood pressure, but CBF, when
measured, was reduced to 25% to 33% of baseline.
158,159
Reduction of CBF can also be obtained with the intrave-
nous administration of freshly solubilized A
␤
1-40 in mice
160,161
but not with the use of the reverse peptide A
␤
40-1.
161
In
addition to the cerebral hypoperfusion observed in these
rodents, regional vasoconstriction and increased vascular
resistance are also seen, particularly in brain cortex.
160
These
findings could partly explain the negative role of amyloid
angiopathy in cerebral perfusion when the peptide is depos-
ited in AD cerebrovasculature.
These experimental findings form a basic understanding of
what happens to brain metabolic activity when aging and
cerebral hypoperfusion meld in an animal model and offer
some insight into what might be happening during the early
stages of AD, when advanced aging and brain hypoperfusion
appear to play major roles.
AD-VaD Correlates
It is commonly known that the differential diagnosis of AD
and VaD on the basis of clinical evidence is, at best, very
difficult.
94,162–164
This problem exists because of overlapping
features found in both disorders. For example, AD and VaD
share features involving cerebral hypoperfusion, white matter
changes,
165–167
pathophysiological markers,
168–172
genetic
links,
173–176
overlapping symptomatology, and diagnostic cri-
teria of dubious reliability.
177–185
Several objective clinical
criteria are presently used to distinguish AD from VaD, such
as the Alzheimer Disease Diagnostic and Treatment Centers,
National Institute of Neurological Disorders and Stroke–
Association Internationale pour la Recherche et
l’Enseignement en Neurosciences (NINDS-AIREN), DSM-
IV, and the Hachinski Ischemia Score.
186
Of these, the most
useful in differentiating VaD from AD appears to be the
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Hachinski Ischemia Score,
187
if it is assumed that mixed
pathology is minimally present.
188
The use of CT or MR
neuroimaging contributes little to characterizing either de-
mentia when white matter changes and medial temporal
atrophy are involved.
189
These findings strongly argue in
favor of the hypothesis that AD and VD are not mutually
exclusive disorders.
The similarities of the clinical presentation, pathophysiol-
ogy, and rate of cognitive decline between AD and VaD have
led to the development of treatments that appear useful to
both conditions at the level where risk factors are discovered
or during the disease process.
109,110,177,190–192
For this reason,
several pharmaceutical companies have targeted both demen-
tias using a common drug application,
110,111,191
with the
rationale that central cholinergic mechanisms are impaired in
both AD and VaD.
192
However, it is also possible that
cholinesterase inhibitors have another action aside from
increasing acetylcholine stores: that of improving CBF mod-
estly and transiently by their vasodilating innervation derived
from the nucleus basalis of Meynert.
193,194
The comorbidity of many vascular-related risk factors
makes a compelling case for AD and VaD sharing a common
origin. We and others have reviewed this phenomenon in the
past; the Table lists a series of suspected and actual vascular
risk factors found in AD and also generally in VaD.
9,15,45,96
In addition to sharing vascular risk factors, a major study
has reported the coexistence of similar neuropathological
features of AD and VaD in elderly nuns.
76
That study also
found that these elderly women required an 8-fold increase in
neurofibrillary tangles to express the same severity of demen-
tia when strategic cerebral infarctions were absent, suggesting
that patients with previous strokes require considerably less
AD pathology for dementia symptoms to appear.
Cerebral Hypoperfusion and Hypometabolism
in AD: Chicken or Egg?
The collective findings discussed thus far imply that brain
hypoperfusion probably precedes the hypometabolic and
neurodegenerative state seen in AD. This is a reasonable
assumption based on Darwinian laws of survival because it is
less likely that neurons exposed to oxidative stress and
impaired energy substrate delivery will reduce blood flow to
them to accelerate their death. Moreover, the conclusion that
brain hypoperfusion “pushes”oxidative stress, cognitive
decline, and neurodegeneration is further reinforced by the
following 6 findings. (1) Regional microvessel degeneration
is independent of AD stage severity (Braak I to VI), a finding
that indicates that these microvascular changes are not a
consequence of AD pathology.
147
(2) Regional hypometabo-
lism found in Alzheimer brains does not appear to result from
neurodegenerative damage or senile plaque formation but is
present before significant tissue pathology.
195,196
(3) Abun-
dant density of senile plaques, neurofibrillary tangles, and
neurodegenerative changes that met neuropathological crite-
ria for AD have been found in a large percentage of
cognitively normal, elderly brains at autopsy.
197
(4) The same
structural capillary aberrations seen in AD have been also
been observed in Down syndrome at a young age, when no
senile plaque or neurofibrillary tangle formation has yet
formed.
139
(5) Young patients with Down syndrome show
abnormal patterns of cerebral perfusion similar to those found
in AD at an age when senile plaques and neurofibrillary
tangles are still absent from their brains and before any
dementia symptoms are manifested.
198,199
(6) Oxidative stress
seems to precede A
␤
1-42 deposition by many years in Down
syndrome subjects who die in their teens and twenties,
200
a
finding that indicates that AD-like pathology is not the trigger
of neuronal metabolic disruption in these patients.
While it could be argued that hypometabolism in AD may
elicit microvascular changes at some point, a considerable
number of animal experiments have revealed that chronic
brain hypoperfusion can trigger oxidative stress, energy
metabolic deficits, and memory loss before any neuronal
structural pathology materializes,
149–159
whereas we are
aware of no data that demonstrate that the reverse process can
or does occur. Moreover, the recent discovery of “neuroglo-
bin”in rodent and human brain could partly explain why CA1
hippocampal neurons are exquisitely sensitive to hypoperfu-
sion and hypometabolism.
201
Neuroglobin in brain appears to
act much like myoglobin in cardiac muscle cells in that it aids
in oxygen diffusion to the mitochondria. Lower resistance by
CA1 to ischemia may be due to lower oxygen supply
resulting from less available neuroglobin, whose lowest
expression is in the hippocampus.
201
For further reading on the role of vascular pathology in
AD, the reader is referred to recently published volumes on
the subject.
202–204
Summary
Mounting clinical and experimental evidence indicates that
AD can be caused by vascular-related factors that directly
reduce cerebral perfusion to a critical level of dysfunction.
This evidence can be summarized as follows: (1) epidemio-
logical studies show that risk factors thus far described for
AD have a vascular basis; (2) most of the risk factors for AD
are also associated with VaD; (3) practically all drugs
reported to slow the development of AD improve or increase
cerebral perfusion; (4) development of AD can be predicted
preclinically by measuring regional cerebral perfusion defi-
cits; (5) clinical evidence exists that AD symptoms are related
to brain microvascular hemodynamic pathology; (6) clinical
symptomatology is similar in AD and VaD; (7) cerebrovas-
cular pathological lesions often overlap in AD and VaD; and
(8) evidence that cerebral hypoperfusion appears to precede
the hypometabolic, cognitive, and degenerative pathology
that is present in AD.
The wide range of potential vascular conditions that can
develop into Alzheimer’s dementia may help to explain the
heterogeneous and multifactorial nature of this disorder. This
review attempts to crystallize into a coherent clinical picture
the major findings in support of the proposal that identifies
AD as a vascular disorder.
Since the value of scientific evidence often revolves
around probability and chance, it is fair to conclude that the
data presented here pose a powerful statistical argument in
support of the conclusion that AD has a vasculopathic origin.
Rarely has so much verifiable information been available
de la Torre Alzheimer Disease as a Vascular Disorder 1157
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from so many different sources that point so compellingly to
the nosological origin of a disorder as in the case for AD.
This review also seeks to provide an alternative explana-
tion to that offered by conventional wisdom, which has
dominated research and clinical thinking and, through much
self-investment, has delayed potential progress in the area of
AD patient care for the past 25 years. Conventional wisdom
has not appreciably improved AD course or disease outlook,
nor has it engendered much hope that its extension into the
future management and treatment of this disorder will result
in a better quality of life for AD victims. It is the medical
community’s prime scientific responsibility, and it is in the
patients’best interest, to recognize the possibility that con-
ventional wisdom has been incorrect in the classification and
management of AD.
It is now the task of investigators and others responsible for
patient welfare to determine, in the immediate future, a
course of action that includes proper examination of the
findings presented in this review, with the intent of applying
such information to the best advantage of AD patients.
Acknowledgment
This research was supported by an investigator-initiated research
grant from the Alzheimer’s Association.
References
1. Blessed G, Tomlinson BE, Roth M. The association between quanti-
tative measures of dementia and of senile change in the cerebral grey
matter of elderly subjects. Br J Psychiatry. 1968;114:797–811.
2. American Psychiatric Association. Diagnostic and Statistical Manual of
Mental Disorders, Fourth Edition. Washington DC: American Psy-
chiatric Association; 1994:138–142.
3. Roth M. The natural history of mental disorder in old age. J Mental Sci.
1955;101:281–301.
4. McKhann G, Drachman D, Folstein R, Katzman R, Price D, Stadlan E.
Clinical diagnosis of Alzheimer’s disease: report of the
NINCDS-ADRDA Work Group under the auspices of the Department of
Health and Human Services Task Force on AD. Neurology. 1984;34:
939–944.
5. Alzheimer A. Uber eine eigenartig Erkrankung der Hirnrinde. Allg Z
Psychiatrie Psych Ger Med. 1907;64:146–148.
6. de la Torre JC, Mussivand T. Can disturbed brain microcirculation cause
Alzheimer’s disease? Neurol Res. 1993;15:146–153.
7. de la Torre JC. Impaired brain microcirculation may trigger Alzheimer’s
disease. Neurosci Behav Rev. 1994;18:397–401.
8. de la Torre JC. Critical threshold cerebral hypoperfusion causes Alzhei-
mer’s disease. Acta Neuropathol (Berl). 1999;98:1–8.
9. de la Torre JC. Critically-attained threshold of cerebral hypoperfusion:
the CATCH hypothesis of Alzheimer’s pathogenesis. Neurobiol Aging.
2000;21:331–342.
10. de la Torre JC. Hemodynamic consequences of deformed microvessels
in the brain in Alzheimer’s disease. Ann N Y Acad Sci. 1997;826:75–91.
11. de la Torre JC, Stefano GB. Evidence that Alzheimer’s disease is a
microvascular disorder: role of constitutive nitric oxide. Brain Res Rev.
2000;34:119–136.
12. Amaducci LA, Lippi A, Fratiglioni L. What risk factors are known? In:
Henderson A, Henderson H, eds. Etiology of Dementia of Alzheimer’s
Type. Plenum, NY: 1988:29–37.
13. Breteler MM. Epidemiological evidence of a connection between Alz-
heimer’s disease and vascular dementia. Neurobiol Aging. 1998;
19(suppl 4):S150. Abstract.
14. Breteler MM, Bots ML, Ott A, Hofman A. Risk factors for vascular
disease and dementia. Haemostasis. 1998;28:167–173.
15. Breteler MM. Vascular involvement in cognitive decline and dementia:
epidemiologic evidence from the Rotterdam Study and the Rotterdam
Scan Study. Ann N Y Acad Sci. 2000;903:457–465.
16. Breteler MM. Vascular risk factors for Alzheimer’s disease: an epide-
miological study. Neurobiol Aging. 2000;21:153–160.
17. Ott A, Stolk RP, Hofman A, van Harskamp F, Grobbee DE, Breteler
MM. Association of diabetes mellitus and dementia: the Rotterdam
Study. Diabetologia. 1996;39:1392–1397.
18. Ott A, Stolk RP, Hofman A, van Harskamp F, Grobbee DE, Breteler
MM. Diabetes mellitus and the risk of dementia: the Rotterdam Study.
Neurology. 1999;53:1907–1909.
19. Bots ML, van Kooten F, Haverkate F, Meijer P, Koudstaal PJ, Grobbee
D, Kluft C. Coagulation and fibrinolysis markers and risk of dementia:
the Dutch vascular factors in dementia study. Haemostasis. 1998;28:
216–222.
20. Kalmijn S, Launer LJ, Lindemans J, Bots JL, Hofman A, Breteler MM.
Total homocysteine and cognitive decline in a community based sample
of elderly subjects: the Rotterdam Study. Am J Epidemiol. 1999;150:
283–289.
21. Ott A, Breteler MM, de Bruyne MC, van Harskamp F, Grobbee DE,
Hofman A. Atrial fibrillation and dementia in a population-based study:
the Rotterdam Study. Stroke. 1997;28:316–321.
22. Ott A, Slooter AJ, Hofman A, van Harskamp F, Witteman JC. Smoking
and risk of dementia and Alzheimer’s disease in a population-based
cohort study: the Rotterdam Study. Lancet. 1998;351:1840–1843.
23. Van Duijn CM, Havekes LM, van Broeckhoven C, de Knijff P, Hofman
A. Apolipoproyein E genotype and association between smoking and
early onset Alzheimer’s disease. Br Med J. 1995;310:627–631.
24. Graves AB, van Duijn CM, Chandra V, Fratiglioni L, Heyman A, Jorm
AF, Kokmen E, Kondo K, Mortimer JA, Rocca WA, Shalat S, Soininen
H, Hofman A, for the EURODEM Risk Factors Research Group.
Alcohol and tobacco consumption as risk factors for Alzheimer’s
disease: a collaborative re-analysis of case-controlled studies. Int J
Epidemiol. 1991;20:S48–S57.
25. Ott A, Breteler MM, van Harskamp F, Claus JJ, van der Camden T,
Grobbee DE, Hofman A. Prevalence of Alzheimer’s disease and
vascular dementia association with education: the Rotterdam Study. Br
Med J. 1995;310:970–973.
26. Hofman A, Breteler MM, Bots ML, Slooter AJ, van Harskamp F.
Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alz-
heimer’s disease in the Rotterdam Study. Lancet. 1997;349:151–154.
27. de la Torre JC. Hemodynamics of deformed microvessels in Alzhei-
mer’s disease brain. Ann N Y Acad Sci. 1997;826:75–91.
28. Marshall RS, Lazar RM, Pile-Spellman J, Young W, Duong D, Joshi S,
Ostapkovich N. Recovery of brain function during induced cerebral
hypoperfusion. Brain. 2001;124:1208–1217.
29. Launer LJ, Ross GW, Petrovich H, Masaki K, Foley D, White L, Havlik
RJ. Midlife blood pressure and dementia: the Honolulu-Asia Aging
Study. Neurobiol Aging. 2000;21:49–55.
30. Petrovich H, White LR, Izmirilian G, Ross GW, Havlik R, Markesbery
W, Nelson J, Davis D, Hardman J, Foley DJ, Launer LJ. Midlife blood
pressure and neuritic plaques, neurofibrillary tangles, and brain weight
at death: the HAAS, Honolulu-Asia Aging Study. Neurobiol Aging.
2000;21:57–62.
31. DeCarli C, Miller BL, Swan GE, Reed T, Wolf PA, Carmelli D.
Cerebrovascular and brain pathologic correlates of mild cognitive
impairment in the National Heart, Lung, and Blood Institute Twin Study.
Arch Neurol. 2001;58:643–647.
32. Roses AD, Saunders AM. ApoE, Alzheimer’s disease, and recovery
from brain stress. Ann N Y Acad Sci. 1997;826:200–212.
33. Davignon J, Gregg RE, Sing CF. Apolipoprotein E polymorphism and
atherosclerosis. Atherosclerosis. 1998;8:1–21.
34. Margaglione M, Seripa D, Gravina C, Grandone E, Vecchine G,
Cappucci G. Prevalence of apolipoprotein E alleles in healthy subjects
and survivors of ischemic stroke. Stroke. 1998;29:399–403.
35. Botet JP, SentíM, Nogues X, Rubies-Prat J, Roquer J, D’Olhaberriaque
J, Olive J. Lipoprotein and apolipoprotein profile in men with ischemic
stroke. Stroke. 1992;23:1556–1562.
36. Bates HM. Apolipoproteins and coronary heart disease risk assessment.
Diagn Clin Testing. 1989;27:52–53.
37. Lehtinen S, Lehtimaki T, Sisto T, Salenius J, Nikkila M, Jokela H,
Koivula T, Eberling F, Ehnholm C. Apolipoprotein E polymorphism,
serum lipids, myocardial infarction and severity of angiographically
verified coronary artery disease in men and women. Atherosclerosis.
1995;114:83–91.
38. Saunders AM, Roses AD. Apolipoprotein E4 allele frequency, ischemic
cerebrovascular disease, and Alzheimer’s disease. Stroke. 1993;24:
1416–1417.
1158 Stroke April 2002
by guest on May 31, 2013http://stroke.ahajournals.org/Downloaded from

39. Morris JC, Storandt M, Miller JP, McKeel DW, Price JL, Rubin H, Berg
L. Mild cognitive impairment represents early stage Alzheimer’s
disease. Arch Neurol. 2001;58:397–405.
40. Shah S, Tangalos EG, Petersen R. Mild cognitive impairment: when is
it a precursor of Alzheimer’s disease? Geriatrics. 2000;55:65–68.
41. Bozoki A, Giordani B, Heidebrink JL, Berent S, Foster NL. Mild
cognitive impairments predict dementia in non-demented elderly
patients with memory loss. Arch Neurol. 2001;58:411–416.
42. Kivipelto M, Helkala EL, Hanninen T, Laakso M, Hallikainen M.
Midlife vascular risk factors and late-life cognitive impairment: a
population-based study. Neurology. 2001;56:1683–1689.
43. Kivipelto M, Helkala EL, Hanninen T, Laakso M, Hallikainen M.
Midlife vascular risk factors and Alzheimer’s disease in later life:
longitudinal, population-based study. BMJ. 2001;322:1447–1451.
44. Skoog I. The relationship between blood pressure and dementia: a
review. Biomed Pharmacother. 1997;51:367–375.
45. Skoog I. Risk factors for vascular dementia. Dementia. 1994;5:137–144.
46. Skoog I, Lernfelt B, Landahl S. A 15-year longitudinal study on blood
pressure and dementia. Lancet. 1996;347:1141–1147.
47. Notkola IL, Sulkava R, Pekkanen J, Erkinjuntti T, Ehnholm C, Kivinen
P. Serum total cholesterol, apolipoprotein E epsilon 4 allele, and Alz-
heimer’s disease. Neuroepidemiology. 1998;17:14–20.
48. Hendrie HC, Oginniyi A, Hall KS, Baiyewu O, Unverzagt F, Gureje O,
Gao S, Evans RM. Incidence of dementia and Alzheimer’s disease in 2
communities: Yoruba residing in Ibadan, Nigeria, and African American
residing in Indianapolis, Indiana. JAMA. 2001;285:739–747.
49. Lunn S, Crawley F, Harrison M, Brown MM, Newman SP. Impact of
carotid endarterectomy upon cognitive functioning: a systematic review
of the literature. Cerebrovasc Dis. 1999;9:74–81.
50. Heyer EJ, Adams D, Solomon RA, Todd G, Quest D, McMahon D,
Steneck S. Neuropsychometric changes in patients after carotid endar-
terectomy. Stroke. 1998;29:1110–1115.
51. Newman MF, Kirchner JL, Phillips-Bute B, Gaver V, Grocott H, Jones
RH, Mark D, Reves J, Blumenthal JA. Longitudinal assessment of
neurocognitive function after coronary-artery bypass surgery. N Engl
J Med. 2001;344:395–402.
52. Brillman J. Central nervous system complications in coronary artery
bypass graft surgery. Neurol Clin. 1993;11:475–495.
53. Selnes OA, Goldsborough MA, Borowicz L, Enger C, Quaskey S,
McKhann GM. Determinants of cognitive change after coronary artery
bypass surgery: a multifactorial problem. Ann Thorac Surg. 1999;67:
1669–1676.
54. Waltzer T, Herrmann M, Wallesch CW. Neuropsychological disorders
after coronary bypass surgery. J Neurol Neurosurg Psychiatry. 1997;
62:644–648.
55. Leary MC. Incidence of silent stroke in the US. Stroke. 2001;32:363.
Abstract.
56. Howard G, Wagenknecht LE, Cai J, Cooper L, Kraut M, Toole JF.
Cigarette smoking and other risk factors for silent cerebral infarction in
the general population. Stroke. 1998;29:913–917.
57. Yao H, Fujishima M. Cerebral blood flow and metabolism in silent brain
infarction and related cerebrovascular disorders. Ann Med. 2001;33:
98–102.
58. Nagata K, Buchan RJ, Yokoyama E, Kondoh Y, Sato M. Misery per-
fusion with preserved vascular reactivity in Alzheimer’s disease. Ann
N Y Acad Sci. 1997;826:272–281.
59. Tohgi H, Yonezawa H, Takahashi S, Sato N. Cerebral blood flow and
oxygen metabolism in senile dementia of Alzheimer’s type and vascular
dementia with deep white matter changes. Neuroradiology. 1998;40:
131–137.
60. Tyas SL, Manfreda J, Strain LA, Montgomery PR. Risk factors for
Alzheimer’s disease: a population-based, longitudinal study in
Manitoba, Canada. Int J Epidemiol. 2001;30:590–597.
61. Kalmijn S. Dietary fat intake and risk of incident dementia in the
Rotterdam Study. Ann Neurol. 1997;42:776–782.
62. Polvikoski T, Sulkava R, Myllykangas L, Notkola IL, Niinisto L,
Verkkoniemi A, Kainulainen K. Prevalence of Alzheimer’s disease in
very elderly people: a prospective neuropathological study. Neurology.
2001;56:1690–1696.
63. Meyer JS, Rauch G, Rauch RA, Haque A. Risk factors for cerebral
hypoperfusion, mild cognitive impairment and dementia. Neurobiol
Aging. 2000;21:161–169.
64. Devanand DP, Sano M, Tang M, Taylor S, Gurland B, Wilder D, Stern
Y, Mayeux R. Depressed mood and the incidence of Alzheimer’s
disease in the elderly living in the community. Arch Gen Psychiatry.
1996;53:175–182.
65. Geerlings MI, Schoevers RA, Beekman A, Jonker C, Deeg D.
Depression and risk of cognitive decline and Alzheimer’s disease:
results of two prospective community-based studies in the Netherlands.
Br J Psychiatry. 2000;176:568–575.
66. Diaz-Arrastia R. Hyperhomocysteinemia: a new risk factor for Alzhei-
mer’s disease? Arch Neurol. 1998;55:1–2.
67. Ohkura T, Isse K, Akazawa K, Hamamoto M, Yaoi Y, Hagino N.
Evaluation of estrogen treatment in female patients with dementia of the
Alzheimer type. Endocr J. 1994;41:361–371.
68. Waring SC, Rocca WA, Petersen RC, O’Brien OC, Tangalos EG,
Kokmen E. Postmenopausal estrogen replacement therapy and risk of
AD: a population-based study. Neurology. 1999;52:965–970.
69. Ajmani RS, Metter EJ, Jaycumar R, Ingram D, Spangler E, Abugo O,
Rifkind JM. Hemorheological changes during aging associated with
cerebral blood flow and impaired cognitive function. Neurobiol Aging.
2000;21:257–270.
70. Solerte SB, Ferrari E, Fioravanti M. Hemorheologic changes and over-
production of cytokines in mild to moderate dementia of the Alzhei-
mer’s type: adverse effects on cerebrovascular system and therapeutic
approach with pentoxifylline. Neurobiol Aging. 2000;21:271–282.
71. Fioravanti M, Ricciardi T, Cottinelli M, Sarasso B, Fontana I. Hemo-
rheologic alterations and acute-phase reaction are related to recent-onset
patients with senile dementia of the Alzheimer’s type. Neurobiol Aging.
1998;19(suppl 4):S246–S247.
72. Morrison RA, McGrath A, Davidson G, Brown JJ, Murray GD, Lever
AF. Low blood pressure in Down’s syndrome: a link with Alzheimer’s
disease? Hypertension. 1996;28:569–575.
73. Passant U, Warkentin S, Gustafson L. Orthostatic hypotension and low
blood pressure in organic dementia: a study of prevalence and related
clinical characteristics. Int J Geriatr Psychiatry. 1997;12:395–403.
74. Guo Z, Viitanen M, Fratiglioni L, Winblad B. Blood pressure and
dementia in the elderly: epidemiologic perspectives. Biomed Pharma-
cother. 1997;51:68–73.
75. Jendroska K, Hoffmann OM, Patt S. Amyloid
␤
peptide and precursor
protein (APP) in mild and severe brain ischemia. Ann N Y Acad Sci.
1997;826:401–405.
76. Snowdon DA, Greiner L, Mortimer J, Riley K, Greiner P, Markesbery
WR. Brain infarction and the clinical expression of Alzheimer disease:
the Nun Study. JAMA. 1997;277:813–817.
77. Guo Z, Cupples LA, Kurz A, Auerbach S, Volicer L, Chui H, Green RC,
Sadovnick A, Duara R. Head injury and the risk of AD in the MIRAGE
study. Neurology. 2000;54:1316–1323.
78. Plassman BL, Havlik RJ, Steffens D, Helms M, Newman T, Drosdick D,
Phillips C. Documented head injury in early childhood and risk of
Alzheimer’s disease and other dementias. Neurology. 2000;55:
1158–1166.
79. Lye TC, Shores EA. Traumatic brain injury as a risk factor for Alzhei-
mer’s disease: a review. Neuropsychol Rev. 2000;10:115–129.
80. Kilander L, Andren B, Nyman H, Lind L, Boberg M, Lithell H. Atrial
fibrillation is an independent determinant of low cognitive function: a
cross-sectional study in elderly men. Stroke. 1998;29:1816–1820.
81. Deklunder G, Roussel M, Lecroart JL, Prat A, Gautier C. Microemboli
in cerebral circulation and alteration of cognitive abilities in patients
with mechanical prosthetic heart valves. Stroke. 1998;29:1821–1826.
82. Cardiogenic dementia. Lancet. 1997;1:27–28.
83. Soneira CF, Scott TM. Severe cardiovascular disease and Alzheimer’s
disease: senile plaque formation in cortical areas. Clin Anat. 1996;9:
118–127.
84. Sparks DL, Hunsaker JC III, Scheff S, Kryscio RJ, Markesbery RJ.
Cortical senile plaques in coronary artery disease, aging and Alzhei-
mer’s disease. Neurobiol Aging. 1990;11:601–607.
85. Sparks DL. Coronary artery disease, hypertension, apoE and cholesterol:
a link to Alzheimer’s disease? Ann N Y Acad Sci. 1997;826:128–146.
86. Ott A, Breteler MM, de Bruyne MC, van Harskamp F, Grobbee DE,
Hofman A. Atrial fibrillation and dementia in a population-based study:
the Rotterdam Study. Stroke. 1997;28:316–321.
87. Martin AJ, Friston KJ, Colebatch JG, Frackowiak R. Decreases in
regional cerebral blood flow with normal aging. J Cereb Blood Flow
Metab. 1991;11:684–689.
88. de la Torre JC. Cerebral perfusion, capillary degeneration, and devel-
opment of Alzheimer’s disease. Alzheimer Dis Assoc Disord. 2000;
14(suppl 1):S72–S81.
de la Torre Alzheimer Disease as a Vascular Disorder 1159
by guest on May 31, 2013http://stroke.ahajournals.org/Downloaded from

89. Kalaria RN, Ballard C. Overlap between pathology of Alzheimer disease
and vascular dementia. Alzheimer Dis Assoc Disord. 1999;13(suppl
3):S115–S123.
90. Olichney JM, Hansen LA, Hofstetter CR, Grundman M, Katzman R.
Apolipoprotein epsilon 4 allele is associated with increased neuritic
plaques and CAA in Alzheimer’s disease and Lewy body variant. Neu-
rology. 1996;47:190–196.
91. Premkumar DR, Cohen DL, Hedera P, Friedland RP, Kalaria RN.
Apolipoprotein E e4 alleles in CAA and cerebrovascular pathology in
Alzheimer’s disease. Am J Pathol. 1996;148:2083–2095.
92. Skoog I. Vascular factors in dementia. Alzheimer Dis Assoc Disord.
1999;13(suppl 3):S106–S114.
93. Vinters HV. Cerebrovascular disease in the elderly. In: Duckett S, de la
Torre JC, eds. Pathology of the Aging Human Nervous System. New
York, NY: Oxford; 2001:58–100.
94. Groves WC, Brandt J, Steinberg M, Warren A, Rosenblatt A, Baker A,
Lyketsos CG. Vascular dementia and Alzheimer’s disease: is there a
difference? A comparison of symptoms by disease duration. J Neuro-
psychiatry Clin Neurosci. 2000;12:305–315.
95. Kalaria RN. The role of cerebral ischemia in Alzheimer’s disease.
Neurobiol Aging. 2000;21:321–330.
96. Villardita C. Alzheimer’s disease compared with cerebrovascular
dementia: neuropsychological similarities and differences. Acta Neurol
Scand. 1993;87:299–308.
97. Anthony JC, Breitner JC, Zandi P, Meyer M, Jurasova I, Norton MC,
Stone SV. Reduced prevalence of AD in users of NSAIDs and H2
receptor antagonists: the Cache County study. Neurology. 2000;54:
2066–2071.
98. Broe GA, Grayson DA, Creasey H, Waite L, Casey B, Bennett H,
Brooks W, Halliday GM. Anti-inflammatory drugs protect against Alz-
heimer’s disease at low doses. Arch Neurol. 2000;57:1586–1591.
99. Le Bars PL, Kieser M, Itil K. A 26-week analysis of a double-blind,
placebo-controlled trial of the ginkgo biloba extract Egb 761 in
dementia. Dement Geriatr Cogn Disord. 2000;11:230–237.
100. Forstl H. Clinical issues in current drug therapy for dementia. Alzheimer
Dis Assoc Disord. 2000;14(suppl 1):S103–S108.
101. Losordo DW, Isner JM. Estrogen and angiogenesis: a review. Arte-
rioscler Thromb Vasc Biol. 2001;21:6–12.
102. Groppa SA. New possibilities in the treatment of patients with Alzhei-
mer’s disease. Neurobiol Aging. 1994;15:S101. Abstract.
103. Breitner JC, Gau BA, Welsh KA, Plassman B, McDonald W, Helms M,
Anthony JC. Inverse association of anti-inflammatory treatments and
Alzheimer’s disease: initial results of a co-twin control study. Neu-
rology. 1994;44:227–232.
104. Sano M, Ernesto C, Thomas RG, Klauber M, Schafer K, Grundman M,
Woodbury P, Growdon J, Cotman CW, Pfekffer E, Schneider LS, Thal
LJ. A controlled trial of selegiline, alpha-tocopherol, or both as
treatment for Alzheimer’s disease: the Alzheimer’s Disease
Co-operative Study. N Engl J Med. 1997;336:1216–1222.
105. Reichman WE. Alzheimer’s disease: clinical treatment options. Am J
Manag Care. 2000;6(suppl 22):S1125–S1132.
106. Pettegrew JW, Levine J, McClure RJ. Acetyl-L-carnitine physical-
chemical, metabolic, and therapeutic properties: relevance for its mode
of action in Alzheimer’s disease and geriatric depression. Mol Psy-
chiatry. 2000;5:616–632.
107. Postiglione A, Soricelli A, Cicerano U, Mansi L, De Chiara S, Gallotta
G. Effect of acute administration of L-acetyl carnitine on cerebral blood
flow in patients with chronic cerebral infarct. Pharmacol Res. 1991;23:
242–246.
108. Rai G, Wright G, Scott I, Beston B, Rest J, Exton-Smith AN. Double-
blind, placebo controlled study of L-acetyl carnitine in patients with
Alzheimer’s dementia. Curr Med Res Opin. 1990;11:638–647.
109. In’t Veld BA, Ruitenberg A, Hofman A, Stricker B, Breteler MM.
Antihypertensive drugs and incidence of dementia: the Rotterdam Study.
Neurobiol Aging. 2001;22:407–412.
110. Jick H, Zornberg G, Jick SS, Seshadri S, Drachman DA. Statins and the
risk of dementia. Lancet. 2000;356:1627–1631.
111. Wolozin B, Kellman W, Ruosseau P, Celesia GG, Siegel G. Decreased
prevalence of Alzheimer disease associated with 3-hydroxy-3 methyl-
glutaryl coenzyme A reductase inhibitors. Arch Neurol. 2000;57:
1439–1443.
112. Thomas T. Monoamine oxidase-
␤
-inhibitors in the treatment of Alzhei-
mer’s disease. Neurobiol Aging. 2000;21:343–348.
113. de la Torre JC. Impaired cerebromicrovascular perfusion: summary of
evidence in support of its causality in Alzheimer’s disease. Ann N Y
Acad Sci. 2000;924:136–152.
114. Johnson KA, Jones K, Holman BL, Becker J, Spiers PA, Satlin A, Albert
MS. Preclinical prediction of Alzheimer’s disease using SPECT. Neu-
rology. 1998;50:1563–1571.
115. Johnson KA, Albert MS. Perfusion abnormalities in prodromal Alzhei-
mer’s disease. Neurobiol Aging. 2000;21:289–292.
116. Kogure D, Matsuda H, Ohnishi T, Asada T, Uno M, Kunihiro T, Nakano
S, Takasaki M. Longitudinal evaluation of early Alzheimer’s disease
using brain perfusion SPECT. J Nucl Med. 2000;41:1155–1162.
117. Okamura N, Shinkawa M, Arai H, Matsui T, Kakajo K, Maruyama M.
Prediction pf progression in patients with mild cognitive impairment
using IMP-SPECT. Nippon Ronen Igakkai Zasshi. 2000;37:974–978.
118. Rodriguez G, Vitali P, Calvini P, Bordoni C, Girtler N, Taddei G,
Mariani G, Nobili F. Hippocampal perfusion in mild cognitive
impairment. Psychiatry Res. 2000;100:65–74.
119. De Santi S, de Leon MJ, Rusinek H, Convit A, Tarshish C, Roche A.
Hippocampal formation glucose metabolism and volume losses in MCI
and AD. Neurobiol Aging. 2001;22:529–539.
120. Arnaiz E, Jelic V, Almkvist O, Wahlund L, Winblad B, Valind S,
Nordberg A. Impaired cerebral glucose metabolism and cognitive func-
tioning predict deterioration in mild cognitive impairment. Neuroreport.
2001;12:851–855.
121. de Leon M, Convit A, Wolf OT, Tarnish CY, De Santi S, Rusinek H,
Tsui W. Prediction of cognitive decline in normal elderly subjects with
2-[(18)F] fluoro-2-deoxy-D-glucose/positron-emission tomography
(FDG/PET). Proc Natl Acad Sci U S A. 2001;98:10966 –10971.
122. Jack CR, Petersen RC, Xu YC, O’Brien PC, Smith GE, Ivnik RJ, Boeve
B, Waring SC, Tangalos EG, Kokmen E. Prediction of AD with
MRI-based hippocampal volume in mild cognitive impairment. Neu-
rology. 2000;55:484–489.
123. Jack CR, Petersen RC, Xu YC, O’Brien P, Smith GE, Ivnik R, Boeve B,
Waring SC. Prediction of AD with MRI-based hippocampal volume in
mild cognitive impairment. Neurology. 1999;52:1397–1403.
124. Alexianu M, Tudorache B. Structural modifications of intracerebral
small blood vessels in various types of dementia. Rom J Neurol Psy-
chiatry. 1994;32:141–152.
125. Kalaria RN, Hedera PJ. Differential degeneration of the cerebral micro-
vasculature in Alzheimer’s disease. Neuroreport. 1995;6:477–480.
126. Claudio L. Ultrastructural features of the blood-brain barrier in biopsy
tissue from Alzheimer’s disease patients. Acta Neuropathol (Berl).
1996;91:6–14.
127. Miyakawa T, Kuramoto R. Ultrastructural study of senile plaques and
microvessels in the brain with Alzheimer’s disease and Down’s
syndrome. Ann Med. 1989:21:99–102.
128. Beskow J, Hassler O, Ottoson JO. Cerebral arterial deformities in
relation to senile deterioration. Acta Psychiatry Scand. 1971;221:
111–119.
129. Yamashita K, Miyakawa T, Katsuragi S. Vascular changes in the brains
of Alzheimer’s disease. Jpn J Psychiatry Neurol. 1991;45:79–84.
130. Scheibel AB, Duong R, Tomyasu O. Microvascular changes in Alzhei-
mer’s disease. In: Sheibel AB, ed. The Biological Substrates of Alzhei-
mer’s Disease. New York, NY: Academic Press; 1986:77–192.
131. Delacourte A, Defossez A, Persuy P, Peero MC. Observation of mor-
phological relationships between angiopathic blood vessels and degen-
erative neurites in Alzheimer’s disease. Virchows Arch. 1987;411:
199–204.
132. Perlmutter LS, Myers MA, Barron E. Vascular basement membrane
components and the lesions of Alzheimer’s disease. Microsc Res Tech.
1994;28:204–215.
133. Hassler O. Arterial deformities in senile brains. Acta Neuropathol (Berl).
1967;8:219–229.
134. Tuke JB. On the morbid history of the brain and spinal cord as observed
in the insane. Br For Med Chir Rev. 1873;51:450–460.
135. Higuchi Y, Miyakawa T, Shimoji A, Katsuragi S. Ultrastructural
changes in blood vessels in the cerebral cortex in Alzheimer’s disease.
Jpn J Psychiatry Neurol. 1987;41:283–290.
136. Fisher VW, Siddigi A, Yusufaly Y. Altered angioarchitecture in selected
areas of brains with Alzheimer’s disease. Acta Neuropathol (Berl).
1990;79:672–679.
137. Miyakawa T, Uehara Y. Observation of amyloid angiopathy and senile
plaque under a scanning electron microscope. Acta Neuropathol (Berl).
1979;48:153–156.
1160 Stroke April 2002
by guest on May 31, 2013http://stroke.ahajournals.org/Downloaded from

138. Moody DM, Brown WR, Challa VR, Ghazi-Birri H, Reboussin D.
Cerebral microvascular alterations in aging, leukoaraiosis and Alzhei-
mer’s disease. Ann N Y Acad Sci. 1997;826:103–116.
139. Buée L, Hof PR, Bouras C, Delacourte A, Perl D, Norroson J, Fillit HM.
Pathological alterations of the cerebral microvasculature in Alzheimer’s
disease and related demented disorders. Acta Neuropathol (Berl). 1994;
87:469–480.
140. Kalaria RN, Hedera P. Differential degeneration of the cerebral micro-
vasculature in Alzheimer’s disease. Neuroreport. 1995;6:477–480.
141. Kidd M. Alzheimer’s disease: an electron microscopic study. Brain.
1964;87:307–320.
142. Mancardi GL, Perdelli F, Leonardi A, Bugiani O. Thickening of the
basement membrane of cortical capillaries in Alzheimer’s disease. Acta
Neuropathol (Berl). 1980;49:79–83.
143. Ravens JR. Vascular changes in the human senile brain. In: Cervos-
Navarro J, ed. Pathology of Cerebrospinal Microcirculation. New York,
NY: Raven Press; 1974:487–501.
144. Amaral DG, Insausti R. Hippocampal formation. In: Paxinos G, ed. The
Human Nervous System. New York, NY: Academic Press; 1990:
711–755.
145. De Jong GI, Farkas E, Plass J, de la Torre JC, Luiten PGM. Cerebral
hypoperfusion yields capillary damage in hippocampus CA1 that cor-
relates to spatial memory impairment. Neuroscience. 1999;91:203–210.
146. Vinters HV, Secor DL, Read SL, Frazee JG, Tomiyasu U, Stanley T,
Ferreiro J, Akers MA. Microvasculature in brain biopsy specimens from
patients with Alzheimer’s disease: an immunohistochemical and ultra-
structural study. Ultrastruct Pathol. 1994;18:333–348.
147. De Jong GI, De Vos RAI, Janssen-Steur E, Luiten PG. Cerebrovascular
hypoperfusion: a risk factor for Alzheimer’s disease? Animal model and
postmortem human studies. Ann N Y Acad Sci. 1997;826:56–74.
148. Wisniewski HM, Vorbrodt AW, Wegiel J. Amyloid angiopathy and
blood-brain barrier changes in Alzheimer’s disease. Ann N Y Acad Sci.
1997;826:161–172.
149. de la Torre JC, Cada A, Nelson N, Sutherland RJ, Gonzalez-Lima F.
Reduced cytochrome oxidase and memory dysfunction after chronic
brain ischemia in aged rats. Neurosci Lett. 1997;223:165–168.
150. Abdollahian NP, Cada A, Gonzalez-Lima F, de la Torre JC. Cytochrome
oxidase: a predictive marker of neurodegeneration. In: Gonzalez-Lima
F, ed. Cytochrome Oxidase in Neuronal Metabolism and Alzheimer’s
Disease. New York, NY: Plenum Press; 1998:233–261.
151. Tanaka K, Wada N, Ogawa N. Chronic cerebral hypoperfusion induces
transient reversible monoaminergic changes in the rat brain. Neurochem
Res. 2000;25:313–320.
152. Ouchi Y, Tsukada H, Kakiuchi T, Nishiyama S, Futatsubachi M.
Changes in cerebral blood flow and postsynaptic muscarinic activity in
rats with bilateral carotid artery ligation. J Nucl Med. 1998;39:198–202.
153. Otori T, Katsumata T, Katayama Y, Terashi A. Measurement of regional
cerebral blood flow and glucose utilization in rat brain under chronic
hypoperfusion conditions following bilateral carotid artery occlusion.
Nippon Ika Daigaku Zasshi. 1997;64:428–439.
154. Tsuchiya M, Sako K, Yura S, Yonemasu Y. Local cerebral glucose
utilization following acute and chronic bilateral carotid artery ligation in
Wistar rats: relation to changes in local cerebral blood flow. Exp Brain
Res. 1993;95:1–7.
155. de la Torre JC, Fortin T, Park G, Butler K, Kozlowski P, Pappas B, de
Socarraz H, Saunders J, Richard M. Chronic cerebrovascular insuffi-
ciency induces dementia-like deficits in aged rats. Brain Res. 1992;582:
186–195.
156. Pappas BA, Davidson C, Bennett S, de la Torre JC, Fortin T,
Tenniswood M. Chronic ischemia: memory impairment and neural
pathology in the rat. Ann N Y Acad Sci. 1997;826:498–501.
157. Ihara M, Tomimoto H, Kinoshita M, Oh J, Noda M, Wakita H. Chronic
cerebral hypoperfusion induces MMP-2 but not MMP-9 expression in
the microglia and vascular endothelium of white matter. J Cereb Blood
Flow Metab. 2001;21:828–834.
158. Tanaka K, Wada N, Hori K, Asanuma M, Nomura M, Ogawa N.
Chronic cerebral hypoperfusion disrupts discriminative behavior in
acquired-learning rats. J Neurosci Meth. 1998;84:63–68.
159. Ni JW, Ohta H, Matsumoto K, Watanabe H. Progressive cognitive
impairment following chronic cerebral hypoperfusion induced by per-
manent occlusion of bilateral carotid arteries in rats. Brain Res. 1994;
653:231–236.
160. Suo Z, Humphrey J, Kundtz A, Sethi F, Placzek A, Crawford F, Mullan
M. Soluble Alzheimer’s beta-amyloid constricts the cerebral vasculature
in vivo. Neurosci Lett. 1998;257:77–80.
161. Niwa K, Porter VA, Kazama K, Cornfield D, Carlsson GA, Iadecola C.
A beta-peptides enhance vasoconstriction in cerebral circulation. Am J
Physiol. 2001;281:H2417–H2424.
162. Bowler JV, Eliasziw M, Steenhuis R, Munoz DG, Fry R, Merkskey H,
Hachinski VC. Comparative evolution of Alzheimer’s disease, vascular
dementia, and mixed dementia. Arch Neurol. 1997;54:697–703.
163. Ransmayr G. Difficulties in the clinical diagnosis of vascular dementia
and dementia of the Alzheimer type: comparison of clinical classifi-
cations. J Neural Transm Suppl. 1998;53:79–90.
164. Aguero-Torres H, Winblad B. Alzheimer’s disease and vascular
dementia: some points of confluence. Ann N Y Acad Sci. 2000;903:
547–552.
165. Wallin A. The overlap between Alzheimer’s disease and vascular
dementia: the role of white matter changes. Dement Geriatr Cogn
Disord. 1998;9(suppl 1):30–35.
166. Scheltens P, Korf ES. Contribution of neuroimaging in the diagnosis of
Alzheimer’s disease and other dementias. Curr Opin Neurol. 2000;13:
391–396.
167. Barber R, Scheltens P, Gholkar A, Ballard C, McKeith I, Ince P, Perry
R, O’Brien J. White matter lesions on magnetic resonance imaging in
dementia with Lewy bodies, Alzheimer’s disease, vascular dementia and
normal aging. J Neurol Neurosurg Psychiatry. 1999;67:66–72.
168. Tarkowski E, Blennow K, Wallin A, Tarkowski A. Intracerebral pro-
duction of tumor necrosis factor-alpha, a local neuroprotective agent, in
Alzheimer’s disease and vascular dementia. J Clin Immunol. 1999;19:
223–230.
169. Parnetti L, Reboldi GP, Gallai V. Cerebrospinal fluid pyruvate levels in
Alzheimer’s disease and vascular dementia. Neurology. 2000;54:
735–737.
170. Carantoni M, Zuliani G, Munari M, D’Elia K, Palmieri E, Fellin R.
Alzheimer disease and vascular dementia: relationship with fasting
glucose and insulin levels. Dement Geriatr Cogn Disord. 2000;11:
176–180.
171. Ellis RJ, Olichney JM, Thal L, Mirra S, Morris JC, Beekly D, Heyman
A. Cerebral amyloid angiopathy in the brains of patients with Alzhei-
mer’s disease: the CERAD experience, part XV. Neurology. 1996;46:
1592–1596.
172. Rosengren LE, Karlsson JE, Sjogren M, Blennow K, Wallin A. Neuro-
filament protein levels in CSF are increased in dementia. Neurology.
1999;52:1090–1093.
173. Rodriguez MT, Calella AM, Silva S, Munna E. Apolipoprotein E and
intronic polymorphism of presenilin 1 and alpha-1-antichymotrypsin in
Alzheimer’s disease and vascular dementia. Dement Geriatr Cogn
Disord. 2000;11:239–244.
174. Zhang JG, Yang JG, Lin Z, He L, Feng GY. Apolipoprotein E epsilon
4 allele is a risk factor for late-onset Alzheimer’s disease and vascular
dementia in Han Chinese. Int J Geriatr Psychiatry. 2001;16:438–439.
175. Bonarek M, Barberger-Gateau P, Letenneur L, Deschamps V, Iron A,
Dubroca B, Dartigues JF. Relationship between cholesterol, apoli-
poprotein E polymorphism and dementia: a cross-sectional analysis
from the PAQUID study. Neuroepidemiology. 2000;19:141–148.
176. Wehr H, Parnowski T, Puzynski S, Bednarska-Makaruk M, Bisko M.
Apolipoprotein E genotype and lipid lipoprotein levels in dementia.
Dement Geriatr Cogn Disord. 2000;11:70–73.
177. Tarkowski E, Ringqvist A, Blennow K, Wallin A, Wennmalm A. Intra-
thecal release of nitric oxide in Alzheimer’s disease and vascular
dementia. Dement Geriatr Cogn Disord. 2000;11:322–326.
178. Kalaria RN, Lewis HD, Thomas N, Shearman S. Brain A
␤
42 and A
␤
40
concentrations in multi-infarct dementia and Alzheimer’s disease. Soc
Neurosci Abstr. 1999;23:1114. Abstract.
179. Ballard C, O’Brien J, Morris CM, Barber R, Swann A, Neill D, McKeith
I. The progression of cognitive impairment in dementia with Lewy
bodies, vascular dementia and Alzheimer’s disease. Int J Geriatr Psy-
chiatry. 2001;16:499–503.
180. Holmes C, Cairns N, Lantos P, Mann A. Validity of current clinical
criteria for Alzheimer’s disease, vascular dementia and dementia with
Lewy bodies. Br J Psychiatry. 1999;174:45–50.
181. O’Brien JT, Paling S, Barber R, Williams ED, Ballard C, McKeith IG,
Gholkar A, Crum WR, Rossor M, Fox NC. Progressive brain atrophy on
serial MRI in dementia with Lewy bodies, Alzheimer’s and vascular
dementia. Neurology. 2001;56:1386–1388.
182. Morris JC. The nosology of dementia. Neurol Clin. 2000;18:773–788.
183. Erkinjuntti T. Clinical deficits of Alzheimer’s disease with cerebro-
vascular disease and probable VaD. Int J Clin Pract Suppl. 2001;120:
14–23.
de la Torre Alzheimer Disease as a Vascular Disorder 1161
by guest on May 31, 2013http://stroke.ahajournals.org/Downloaded from

184. Dickson DW. Neuropathology of Alzheimer’s disease and other
dementias. Clin Geriatr Med. 2001;17:209–228.
185. Wentzel C, Darvesh S, MacKnight C, Shea C, Rockwood K. Inter-rater
reliability of the diagnosis of vascular cognitive impairment at a memory
clinic. Neuroepidemiology. 2000;19:186–193.
186. Roman G. Diagnosis of vascular dementia and Alzheimer’s disease. Int
J Clin Pract Suppl. 2001;suppl 120:9–13.
187. Chui HC, Mack W, Jackson JE, Mungas D, Reed BR, Tinklenberg J,
Chang FL, Skinner K. Clinical criteria for the diagnosis of vascular
dementia: a multicenter study of comparability and interrater reliability.
Arch Neurol. 2000;57:191–196.
188. Hachinski VC, Iliff LD, Zihlka M, Du Boulay G, Mc Allister VL,
Marshall J, Russell RW, Symon L. Cerebral blood flow in dementia.
Arch Neurol. 1975;32:632–637.
189. Scheltens P, Kittner B. Preliminary results from an MRI/CT-based
database for vascular dementia and Alzheimer’s disease. Ann N Y Acad
Sci. 2000;903:542–546.
190. Guo Z, Fratiglioni L, Viitanen M, Lannfelt L, Basun H, Fastbom J,
Winblad B. Apolipoprotein E genotypes and the incidence of Alzhei-
mer’s disease among persons aged 75 years and older: variation by use
of antihypertensive medication? Am J Epidemiol. 2001;153:225–231.
191. Kittner B, Rossner M, Rother M. Clinical trials in dementia with pro-
pentofylline. Ann N Y Acad Sci. 1997;826:307–316.
192. Maelicke A. The pharmacological rationale for treating vascular
dementia with galantamine (Reminyl). Int J Clin Pract. 2001;suppl
120:24–28.
193. Ono N. Microcirculation in the brain: viewpoint of autoregulation.
Nippon Yakurigaku Zasshi. 1999;113:203–210.
194. Nordberg A. PET studies and cholinergic therapy in Alzheimer’s
disease. Rev Neurol (Paris). 1999;155(suppl 4):S53–S63.
195. Hatanpää K. Neuronal activity and early neurofibrillary tangles in Alz-
heimer’s disease. Ann Neurol. 1996;40:411–420.
196. Duara R, Barker WW, Chang J, Yoshii F. Viability of neocortical
function shown in behavioral activation state PET studies in Alzhei-
mer’s disease. J Cereb Blood Flow Metab. 1992;12:927–934.
197. Davis DG, Schmitt FA, Wekstein D, Markesbery WR. Alzheimer neu-
ropatholoic alterations in aged cognitively normal subjects. J Neuro-
pathol Exp Neurol. 1999;58:376–388.
198. Jones AM, Kennedy N, Hanson J, Fenton GW. A study in adults with
Down’s syndrome using 99Tc(m)-HMPAO SPECT. Nucl Med
Commun. 1997;18:662–667.
199. Kao CH, Wang PY, Wang SJ, Chou KT, Hsu CY, Lin WY, Liao SQ,
Yeh SH. Regional cerebral blood flow of Alzheimer’s disease-like
pattern in young patients with Down’s syndrome detected by
99Tcm-HMPAO brain SPECT. Nucl Med Commun. 1993;14:47–51.
200. Nunomura A, Perry G, Pappolla MA, Friedland RF, Hiral K, Chiba S,
Smith MA. Neuronal oxidative stress precedes amyloid-beta deposition
in Down syndrome. J Neuropathol Exp Neurol. 2000;59:1011–1017.
201. Burmester T, Weich B, Reinhardt S, Hankeln T. A vertebrate globin
expressed in the brain. Nature. 2000;407:520–523; comment 461–462.
202. de la Torre JC, Hachinski VC, eds. Cerebrovascular pathology in Alz-
heimer’s disease. Ann N Y Acad Sci. 1997;826:1–519.
203. Kalaria RN, Ince P, eds. Vascular factors in Alzheimer’s disease. Ann
N Y Acad Sci. 2000;903:1–552.
204. de la Torre JC, ed. Vascular pathophysiology in Alzheimer’s disease.
Neurobiol Aging. 2000;21:153–383.
1162 Stroke April 2002
by guest on May 31, 2013http://stroke.ahajournals.org/Downloaded from