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Acta Neuropathol (2009) 118:87–102
DOI 10.1007/s00401-009-0498-z
R EV IE W
Microvasculature changes and cerebral amyloid angiopathy
in Alzheimer’s disease and their potential impact on therapy
Roy O. Weller · Delphine Boche · James A. R. Nicoll
Received: 24 December 2008 / Revised: 8 February 2009 / Accepted: 9 February 2009 / Published online: 22 February 2009
© Springer-Verlag 2009
Abstract The introduction of immunotherapy and its ultimate success will require re-evaluation of the pathogenesis
of Alzheimer’s disease particularly with regard to the role
of the ageing microvasculature and the eVects of APOE
genotype. Arteries in the brain have two major functions (a)
delivery of blood and (b) elimination of interstitial Xuid and
solutes, including amyloid- (A), along perivascular pathways (lymphatic drainage). Both these functions fail with
age and particularly severely in Alzheimer’s disease and
vascular dementia. Accumulation of A as plaques in brain
parenchyma and artery walls as cerebral amyloid angiopathy (CAA) is associated with failure of perivascular elimination of A from the brain in the elderly and in
Alzheimer’s disease. High levels of soluble A in the brain
correlate with cognitive decline in Alzheimer’s disease and
reXect the failure of perivascular drainage of solutes from
the brain and loss of homeostasis of the neuronal environment. Clinically and pathologically, there is a spectrum of
disease related to functional failure of the ageing microvasculature with “pure” Alzheimer’s disease at one end of the
spectrum and vascular dementia at the other end. Changes
in the cerebral microvasculature with age have a potential
impact on therapy with cholinesterase inhibitors and especially on immunotherapy that removes A from plaques in
the brain, but results in an increase in severity of CAA and
no clear improvement in cognition. Drainage of A along
perivascular pathways in ageing artery walls may need to
be improved to maximise the potential for improvement of
cognitive function with immunotherapy.
R. O. Weller (&) · D. Boche · J. A. R. Nicoll
Clinical Neurosciences, University of Southampton School
of Medicine, LD74, South Laboratory & Pathology Block,
Southampton General Hospital, Southampton SO16 6YD, UK
e-mail: [email protected]
Keywords Structure and functions of normal cerebral
arteries · Perivascular drainage of A · Cerebral amyloid
angiopathy · Microvascular disease · Arteriosclerosis ·
Arteriolosclerosis · Vascular dementia · Alzheimer’s
disease · Brain homeostasis · Cholinesterase inhibitors ·
Immunotherapy
Introduction
Alzheimer’s disease is a disorder of elderly individuals and
is characterised by the failure of elimination of hyperphosphorylated tau protein from neurons and the failure of elimination of amyloid- (A) from brain parenchyma and
blood vessel walls [48]. NeuroWbrillary tangles (NFT)
within neurons in the brain are composed largely of ubiquitin and the microtubule-associated protein tau [48]. The
accumulation of neuroWbrillary tangles appears to be associated with the failure of the ubiquitin–proteasome system
to dispose of hyperphosphorylated tau from ageing neurons
[11, 46]. A accumulates mainly in the extracellular spaces
of the brain parenchyma as insoluble plaques and in the
walls of arteries and capillaries as cerebral amyloid angiopathy (CAA) [48]. The accumulation of insoluble A in the
brain and eventually the rise in levels of soluble A in Alzheimer’s disease [49, 51] reXect the failure of mechanisms
by which A is normally eliminated from the brain [92].
Advancing age is also a major risk factor for cerebrovascular disease that aVects large and small arteries supplying
the brain [31]. Cerebrovascular disease aVects two of the
major functions of cerebral arteries viz: (a) the supply of
blood to the brain and (b) the perivascular drainage of interstitial Xuid and solutes that constitutes the lymphatic drainage of the brain [90]. Both the Xow of blood and the
drainage of Xuid and solutes fail with age and these failures
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contribute to the pathogenesis of vascular dementia, CAA
and Alzheimer’s disease.
This review concentrates on how structural and functional changes in the microvasculature in the elderly interfere with the blood supply of the brain and contribute to the
failure of elimination of A from the brain in the pathogenesis of Alzheimer’s disease. We explore the concept that
age changes in cerebral arteries are a major factor not only
in (a) the pathogenesis of ischaemic lesions in the brain, but
also in (b) the pathogenesis of CAA and Alzheimer’s disease. Finally, we examine the interface between Alzheimer’s disease and vascular dementia and how age changes
in the microvasculature have an impact on current therapies
for Alzheimer’s disease, especially on immunotherapy
[16].
Structure and functions of the cerebral vasculature
Fig. 1 Normal young leptomeningeal artery in transverse section
showing a convoluted internal elastic lamina (IEL), a media of smooth
muscle cells and a thick collagenous adventitia (Adv). Klüver–Barrera
stain, bar 20 m
The cerebral vasculature has several functions that are reXected in the structure of blood vessels within the brain.
Arteries and capillaries supply blood, nutrients and inXammatory cells to the brain but their walls are also the pathways for the drainage of interstitial Xuid from the brain [17,
90].
Branches of the internal carotid and vertebral arteries
form major cerebral arteries that have relatively thin, translucent and malleable walls in young individuals [31]. Leptomeningeal arteries derived from the cerebral arteries
branch and penetrate the superWcial and deep surfaces of
the brain to supply structures in the cerebrum, cerebellum
and brain stem.
Leptomeningeal arteries
Medium-sized leptomeningeal arteries have an internal
elastic lamina, a tunica media and a Wbrous adventitia. In
young individuals, there is little Wbrous tissue separating
the endothelium from the internal elastic lamina (Fig. 1)
and very little Wbrous tissue in the media. The internal elastic lamina is highly convoluted (Fig. 1) which reXects a
lack of stiVness in young artery walls and their ability to
recoil following expansion by the pulse wave. There is a
relatively thick collagenous adventitia around leptomeningeal arteries even in children and young adults (Fig 1).
Electron microscopy reveals a thin layer of leptomeningeal
(arachnoid) cells coating the outer aspects of leptomeningeal arteries separating the adventitia from the CSF in the
subarachnoid space [66, 98] (Fig. 2). Tracer studies in
experimental animals suggest that interstitial Xuid and solutes drain from the brain along the tunicae media et adventitia of leptomeningeal arteries to cervical lymph nodes [17,
80, 90].
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Fig. 2 Normal young leptomeningeal artery in transverse section
showing the outer coating of leptomeninges (Lep) enclosing the collagenous perivascular space (PVS). Smooth muscle cells of the media
(SMC). Transmission electron micrograph, bar 20 m
Cortical arteries
Branches of leptomeningeal arteries penetrate the cerebral
cortex perpendicular to its pial surface to form arterioles
that supply cortex and subcortical white matter [24]. Those
arterioles that supply the subcortical white matter pass
through the cortical layers without branching [24]. The
walls of arterioles in the cerebral cortex are compact and
have no natural perivascular space [66, 98] (Fig. 3). Vascular endothelium surrounds the lumina of cortical arterioles
and, as there is no internal elastic lamina, the endothelial
basement membrane is fused with basement membranes of
smooth muscle cells in the tunica media. A thin sheath of
Acta Neuropathol (2009) 118:87–102
Fig. 3 A portion of the wall of a normal young cortical artery. Endothelium (Endo) lines the lumen and the tunica media is composed of
smooth muscle cells separated by basement membrane (BM). A layer
of leptomeningeal cells (Lep) separates the tunica media from the
astrocytes (Ast) of the perivascular glia limitans. There is no adventitia
or perivascular space. Transmission electron micrograph, bar 1 m
(reproduced with permission from reference [66])
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Fig. 4 Scanning electron micrograph of an artery (Art) in the basal
ganglia to show the two layers of leptomeniniges (Lep 1, Lep 2) surrounding the artery and separated by a perivascular space (PVS). Basement membrane of the glia limitans (BM), bar 250 m (reproduced
with permission from reference [65])
leptomeningeal cells, derived from the pia mater [98], separates the smooth muscle cells of the tunica media from the
astrocytes of the perivascular glia limitans [66, 98] (Fig. 3).
Arteries supplying the deep grey matter of the cerebral
hemispheres
Deep penetrating arteries arise from the circle of Willis and
its major branches at the base of the brain to supply the
deep grey matter structures comprising the basal ganglia
and thalamus [31]. These arteries diVer in their structure
from those in the cortex as they are invested by a double
layer of leptomeninges and an expandable perivascular
space (Figs. 4, 5) [65, 89]. In older individuals, the perivascular spaces in the basal ganglia are often expanded (état
lacunaire) [64]; the expansion may be great enough to
result in space occupying lesions [70].
Capillaries
Fig. 5 Diagram comparing the structure of the walls of (a) a cortical
artery with a single layer of leptomeninges—solid line (1)—that separates the glia limitans—dotted line (2) from the tunica media (3). There
is no perivascular space. b An artery from the basal ganglia in which
there is a second layer of leptomeninges (4). A perivascular space separates the two layers of leptomeninges (reproduced with permission
from reference [89])
Capillaries are the site of the blood–brain barrier for the
exchange of Xuid and solutes between the blood and the
brain and this is a major source of interstitial Xuid [1]. Capillary basement membranes also form the initial part of the
perivascular pathway for the drainage of interstitial Xuid
and solutes from the brain [17].
Endothelial cells of cerebral capillaries are almost
devoid of vesicles and joined by tight junctions (Fig. 6)
[1, 66], reXecting the presence of the blood–brain barrier
[1, 10]. Pericapillary basement membranes are in direct
contact with the narrow and restricted extracellular
(interstitial) spaces between the neuronal and glial
processes of the grey matter (Fig. 6). Interstitial Xuid and
solutes secreted by the capillary endothelium are distributed by
bulk Xow along pericapillary basement membranes to
supply nutrients to the neuropil [1]. Waste products and
soluble metabolites return in the interstitial Xuid to drain
out of the brain along basement membranes in the walls of
capillaries and arteries [17, 90]. The continuity of the
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Perivascular drainage of interstitial Xuid and solutes
from the brain
Fig. 6 A transmission electron micrograph of a capillary in the cerebral cortex from a young individual shows endothelial cells lining the
capillary lumen and joined by tight junctions (TJ). A basement membrane coats the abluminal surface of the endothelial cells and is direct
contact (asterisks) with the narrow extracellular space of the cortex,
bar 1 m (reproduced with permission from reference [66])
extracellular space with capillary basement membranes
(Fig. 6) seems to be well suited for the perivascular bulk
Xow of interstitial Xuid and solutes from the brain [1, 17].
Capillary endothelium is also a site for the absorption of
solutes from the brain into the blood. Particularly relevant
to Alzheimer’s disease is the absorption of A by receptormediated pathways involving lipoprotein receptor-related
protein-1 (LRP-1) [12, 78], p-glycoprotein [20] and receptor for advanced glycation end products (RAGE) [22].
Although absorption of A into the blood is six times faster
than drainage of A along perivascular lymphatic pathways, it appears to fail with age [12, 78].
Veins and venules
Veins in grey and white matter have a relatively large
lumen and thin walls that lack smooth muscle cells [17,
98]. These characteristics distinguish veins from arteries
and capillaries. The leptomeningeal cells around veins do
not form a complete sheath and there is a perivascular
space around veins containing a few collagen Wbres [98].
Postcapillary venules are the site for the receptor-mediated entry of inXammatory cells into the brain [10, 25].
Once through the endothelium, inXammatory cells traverse the glia limitans [47, 61] into brain tissue or accumulate in the dilated perivascular spaces around venules
and veins. Lymphocytes that enter the CNS appear to
undergo apoptosis and there is no deWned pathway for the
migration of lymphocytes from CNS parenchyma to
regional lymph nodes [90]. Lymphocytes and dendritic
cells in the CSF, however, may migrate to lymph nodes
via nasal lymphatics [34, 35].
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Approximately 140 ml of CSF and 280 ml of interstitial
Xuid comprise the extracellular Xuids associated with the
human CNS [13]. CSF in the ventricles and subarachnoid
spaces drains from the intracranial and spinal compartments via arachnoid villi and granulations and to some
extent via nasal lymphatics and along nerve roots [90].
Interstitial Xuid and solutes drain from the brain along
the walls of capillaries and arteries and this function of the
cerebral vasculature is eVectively the lymphatic drainage of
the CNS parenchyma [17, 90]. The drainage pathway for
interstitial Xuid is largely separate from the CSF in the normal CNS [80, 90]. Experimental studies have shown that
perivascular drainage of ISF and solutes out of the brain is
along the basement membranes of capillaries and arteries
[17]. When Xuorescent 3 kDa dextran or 40-kDa ovalbumin
is injected as tracer into the grey matter of the mouse brain,
they initially spread diVusely through the brain parenchyma
but almost immediately enter the basement membranes of
capillaries and arteries to drain out of the brain. Fluorescent
tracers do not appear to enter the walls of venules and veins
within the brain, so these blood vessels do not seem to be
part of the perivascular drainage system [17].
Other studies have shown that radioactive tracers and
horseradish peroxidase injected into animal brains drain
along the media and adventitia of leptomeningeal arteries to
cervical lymph nodes [80]. The rate of lymphatic drainage
of interstitial Xuid and solutes from the brain is comparable
to that of lymphatic drainage from other organs [80].
Experimental evidence in rats has shown that only 10–15%
of ISF draining from the brain leaks into the CSF [80]. This
suggests that drainage of interstitial Xuid and solutes via the
perivascular route is separate from the CSF [90].
Lymphatic drainage of the human brain
In humans, A acts as a natural tracer for perivascular
drainage [90]. The distribution of A in the basement membranes of capillary and artery walls and in the adventitia of
leptomeningeal arteries in CAA [86, 92] corresponds
exactly with the pathways outlined by tracers in the experimental studies [17, 80].
Figure 7a summarises the structure of the carotid arterial
blood supply to the cerebral cortex and identiWes the tissue
components of the artery and capillary walls that appear to
form the lymphatic drainage pathways of the human brain
[2, 38, 89, 98]. The distribution of A in CAA (Fig. 7b)
outlines the drainage pathways for solutes from the brain,
initially along the basement membranes in the walls of capillaries and arteries [17, 66] and then out of the skull along
Acta Neuropathol (2009) 118:87–102
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the adventitia of the carotid artery to lymph nodes in the
neck. Neither tracers injected into the interstitial Xuid of the
brain nor A is detectable in the walls of the carotid artery
in the neck [79, 80] which suggests that solutes draining
from the brain leave the carotid artery wall at the base of
the skull for adjacent cervical lymph nodes [80].
and the deposition of A in the tunicae media et adventitia
of cerebral arteries as CAA [81, 92].
Focal Wbrous thickening and deposition of cholesterol
and other lipids in the walls of larger cerebral arteries and
occasionally of leptomeningeal arteries constitutes atherosclerosis [31]. Functional failure of the cerebral circulation
associated with atherosclerosis results in ischaemic damage
and infarction due to thrombotic–embolic occlusion of
large or small cerebral arteries. Infarcts may be large or
small and result in strokes or in multiple small infarcts
associated with vascular dementia [31].
Arteriosclerosis is characterised by the generalised Wbrosis and stiVening of artery walls [55] and this may result not
only in a reduction of cerebral blood [26] but also in the
failure of perivascular drainage of interstitial Xuid and solutes from the brain in elderly individuals and in Alzheimer’s disease [92]. Medium-sized leptomeningeal arteries
in older people exhibit subintimal Wbrosis, Xattening of the
internal elastic lamina (Fig. 8a, b) and an increase in the
amount of Wbrous tissue in the tunica media when compared with similar arteries in the young (Fig. 1). As a result,
arteries in the elderly do not recoil in the same way as
younger vessels [55] and this may interfere with the motive
force for the perivascular lymphatic drainage of the brain
[72].
Arteriolosclerosis (lipohyalinosis, hyalinosis [31])
aVects the arterioles in the grey and white matter of the
cerebral hemispheres [81, 84]. Arterioles do not posses an
internal elastic lamina but they do show an increase in
Wbrous tissue in the tunica media with age resulting in sclerosis and stiVening of the vessel walls [31, 81]. DiVerent
regions of the brain are aVected by arteriolosclerosis in the
ageing population and in Alzheimer’s disease [81]. Arteriolosclerosis initially aVects arterioles in the basal ganglia,
then those in the cerebral white matter, cerebral and cerebellar cortices and thalamus. Arterioles in the brainstem are
aVected later [81]. Arterioles also show an increase in tortuosity with age, particularly in the white matter [54].
Capillaries in the cerebral cortex and white matter show
an increase in thickness of basement membranes with associated deposition of collagen Wbres with age and in Alzheimer’s disease [27, 28]. These changes in capillary basement
membranes may aVect blood Xow, transfer of nutrients
from blood to brain [27, 28] and the perivascular drainage
of Xuid and solutes from the brain [90, 92].
Structural changes and failure of function
in the cerebral vasculature with age
Pathophysiology of the microvasculature in Alzheimer’s
disease
The major changes that occur in the cerebral vasculature
with advancing age and in Alzheimer’s disease are Wbrosis
and stiVening of the walls of arteries and arterioles [55, 81]
The changes that occur in the cerebral microvasculature
with age have two major eVects on the brain (a) reduction
in blood supply (hypoperfusion) with resulting ischaemia,
Fig. 7 A diagrammatic summary of blood Xow and perivascular lymphatic drainage of the cerebral cortex. a Blood Xows into the brain (red
arrow) and interstitial Xuid and solutes Xow out along capillary and
artery walls (green arrow). As the carotid artery penetrates the base of
the skull it acquires an outer leptomeningeal (arachnoid) coating (dark
blue) which is reXected onto the surface of the brain as the pia mater
but also forms a sheath around arteries in the cerebral cortex. Capillaries lack a leptomeningeal coat and the capillary endothelial basement
membrane is in direct contact with the extracellular space and interstitial Xuid of the brain. Cortical arteries have no adventitia. The relatively thick collagenous adventitia around leptomeningeal arteries
(light blue layer) is continuous with the adventitial of the carotid artery
in the neck. b Cerebral amyloid angiopathy (CAA) outlines the perivascular lymphatic pathway by which interstitial Xuid and solutes
(including A) drain from the brain. A (shown as a green line) is
deposited in basement membranes of (i) capillaries, (ii) the tunica
media of cortical and (iii) leptomeningeal arteries. A also accumulates in
the adventitia of leptomeningeal arteries (iii) as part of the drainage
pathway to cervical lymph nodes
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Fig. 8 Age changes in leptomeningeal arteries. a A leptomeningeal
branch of the anterior cerebral artery from an elderly individual. The
lumen has not collapsed post mortem (cf a young artery in Fig. 1) due
to stiVness of the wall. A layer of leptomeninges (Lep) separates the
vessel wall from the CSF in the subarachnoid space. b Enlargement of
the artery wall showing Xattening of the internal elastic lamina (IEL)
and the thickness of the Wbrous adventitia (Adv). Klüver–Barrera stain.
a Bar 40 m, b Bar 25 m
and (b) failure of perivascular drainage of interstitial Xuid
associated with reduced elimination of A, the development of CAA and loss of homeostasis of the extracellular
Xuid in cerebral grey and white matter [92].
least frequently aVected. CAA appears to occur in arteries in diVerent areas of the brain in a hierarchical pattern
that follows closely the deposition of A in plaques in
brain parenchyma in Alzheimer’s disease [81]. Leptomeningeal arteries and arterioles of the cerebral neocortex
are involved in the early stages of CAA followed by
extension of CAA to arterioles in the allocortex and the
midbrain. CAA less frequently involves arteries and arterioles in the basal ganglia, and thalamus; the lower brainstem is least frequently aVected by deposition of A in
CAA [81].
The relative infrequency of A plaques and CAA in the
basal ganglia and their late appearance in Alzheimer’s disease [81] may be related to the structure of the artery walls.
Whereas there is no perivascular space around cortical arterioles (Fig. 3) [66, 98], there is an expandable perivascular
space around arteries in the basal ganglia (Figs. 4, 5) [65]
that may facilitate the drainage of interstitial Xuid and A
from the basal ganglia.
Immunocytochemistry shows the pattern of involvement
of artery and capillary walls by CAA. Smaller leptomeningeal arteries in the cerebral sulci (Fig. 9) show deposition
of A initially in the basement membranes in the tunica
media [66, 92, 95] (Fig. 10). In larger leptomeningeal arteries, A may be deposited in the adventitia (Fig. 11) as well
as in the tunica media [86].
Deposits of A are occasionally associated with the
walls of veins (Fig. 10) and arachnoid trabeculae in the subarachnoid space, especially when CAA in the arteries is
severe in patients who have received immunotherapy for
Alzheimer’s disease [16]. The mechanism for such deposition is not known, but as amyloid deposits in artery walls
Hypoperfusion
The main pathological consequences of hypoperfusion are
lacunar infarcts in the basal ganglia, microinfarcts in the
cerebral cortex, especially in the water-shed zones, and leukoaraiosis of the cerebral white matter [26, 48]. Lacunar
infarcts of the subcortical grey matter and ischaemia of the
white matter are major pathological features of vascular
dementia but they also occur in cases of mixed dementia in
which the features of Alzheimer’s disease and vascular
dementia are present in the same brain [41].
Failure of perivascular drainage
The major consequences for the elderly brain of failure of
perivascular drainage of interstitial Xuid and solutes appear
to be (a) CAA, (b) accumulation of insoluble and soluble
A in cerebral grey matter and (c) retention of Xuid in the
subcortical cerebral white matter (leukoaraiosis).
Cerebral amyloid angiopathy
Cerebral amyloid angiopathy is a feature of the ageing
brain and patients with Alzheimer’s disease [5]. It aVects
the leptomeningeal arteries most commonly; cortical
arteries are also frequently involved and capillaries are
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Fig. 9 Cerebral amyloid angiopathy (CAA). A section of Alzheimer
brain from a patient immunised with A42 showing extensive CAA of
small leptomeningeal arteries (Lep A) within a sulcus, and of cortical
arteries (Cort A). Numerous plaques of A are present in the cortex.
Immunohistochemistry for A, bar 80 m
Fig. 10 Cerebral amyloid angiopathy (CAA). Enlargement of part of
Fig. 9 showing small leptomeningeal arteries laden with A. In an
oblique section of an artery wall, A is in the basement membranes
(BM) of the tunica media. Fragments of A attached to the wall of a
vein (AV) have probably become detached from leptomeningeal
arteries. Immunohistochemistry for A, bar 80 m
tend to be brittle (Preston and Weller, unpublished observation), it is possible that fragments of A break from the surface of leptomeningeal arteries and adhere to the arachnoid
and to the walls of veins in the subarachnoid space.
Amyloid- accumulates in the basement membranes of
the tunica media of cortical arteries in the initial stages of
CAA [92]. However, in the later stages of CAA, smooth
muscle cells and their basement membranes are replaced by
A (Fig. 12). Deposition of A is seen in a linear distribution in capillary basement membranes (Fig. 12) and excrescencies of A may form on the capillary walls as globular
or Wlamentous “Drusen” [66, 73].
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Fig. 11 Cerebral amyloid angiopathy (CAA) of a medium-sized leptomeningeal artery on the surface of a gyrus. A is deposited in the
adventitia (CAA Adv). Arteries in the underlying cortex (Cort A) also
have CAA. Immunohistochemistry for A1-40, bar 40 m
Fig. 12 Cerebral amyloid angiopathy (CAA) involving a cortical
artery (Cort A) and its capillary bed (Cap CAA). Immunohistochemistry for A, bar 10 m
Pathogenesis of cerebral amyloid angiopathy
The major evidence now indicates that CAA is due to the
deposition of A in the perivascular pathways by which
interstitial Xuid and solutes drain from the brain [36, 92].
A is derived from the enzymic cleavage of the transmembrane amyloid precursor protein (APP) [76, 77] resulting in
a small pool of soluble A in normal brain [43]. Several
pathways have been identiWed for the elimination of A
from the normal brain. Enzymes, such as neprilysin and
insulin degrading enzyme that degrade A are produced by
neurons and glia and are also expressed in cerebral vessel
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walls [52]. A is also absorbed into the blood by mechanisms involving LRP-1 [12, 78], and p-glycoprotein [20].
However, enzymic degradation by neprilysin and absorption of A into the blood fail with age [53, 78]. The
decrease in neprilysin activity is associated with an increase
in CAA [53].
The perivascular route for the elimination of A appears
to function throughout life. A has been detected biochemically in the walls of cerebral arteries in individuals at the
age of 20 years and not just in the elderly [79]. Although
A is present in the walls of intracranial arteries, it is undetectable in the walls of the extracranial portion of the internal carotid artery [79]. This vascular distribution of A
supports the suggestion that A drains along perivascular
lymphatic drainage pathways in the walls of intracranial
arteries to lymph nodes in the neck [90].
Entrapment of A in the perivascular drainage pathways in
the pathogenesis of cerebral amyloid angiopathy
Evidence for entrapment of A in the perivascular drainage
pathways comes from a number of observations [36, 58, 91,
92].
1. The distribution of A in the basement membranes of
capillaries and arteries and its presence in the adventitia of leptomeningeal arteries corresponds exactly to
the distribution of tracers injected into the brain to outline perivascular lymphatic drainage pathways for the
elimination of Xuid and solutes from the brain [17, 21,
80, 90].
2. Transgenic mice that produce excessive amounts of A
only in neurons develop CAA [36]. This suggests that
A deposits in the perivascular drainage pathways are
derived from the brain [36].
3. It is not only A that accumulates in vessel walls in
CAA. A number of amyloidogenic proteins are
involved in diVerent types of CAA [67]. They include
cystatin, transthyretin, gesolin, prion protein [67] and
the amyloid deposited in the vessel walls in the British
and Danish types of dementia [45]. The variety of proteins involved suggests a common pathogenesis for the
diVerent types of CAA. Thus, there appears to be the
phenomenon of protein-elimination failure arteriopathy
(PEFA) that is common to all types of CAA [92]. In
familial CAA associated with intracerebral haemorrhage [36, 85] there are mutations in the APP gene that
involve the A peptide itself resulting in an A that is
resistant to breakdown by neprilysin [85]. In these
patients, the lack of elimination of A by neprilysin
appears to result in an overload of the perivascular
drainage system and the development of severe CAA at
an early age [85].
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Other theories for the pathogenesis of CAA
Other mechanisms for the pathogenesis of CAA have been
proposed. Scholz [73] published the Wrst comprehensive
account of the pathology of CAA in 1938 and suggested
that the amyloid in the vessel walls and the surrounding
brain was derived from the blood. This was also proposed
by Glenner [33] who Wrst isolated A from leptomeningeal
arteries with CAA. Evidence against this proposal comes
mainly from observations in transgenic mice that produce
human A only in neurons; they develop CAA [36] and a
marked increase in A in the brain is associated with
decreased clearance of A and the development of CAA
[42].
Most cells in the body produce A [77] including
smooth muscle cells in the walls of cerebral arteries [58,
95]. Although vascular smooth muscle cells may contribute
to the A load in CAA [95] they are probably not the sole
source for a number of reasons. (1) Transgenic animals
develop CAA when the A is only produced by neurons in
the brain [36], (2) patients with the British type of dementia
deposit the amyloid protein, ABri, in vessel walls as CAA
but no mRNA for ABri has been detected in cerebral vascular smooth muscle cells [45]. (3) A is deposited in the
basement membranes of capillaries that posses no smooth
muscle cells [66], (4) the highest concentration of immunocytochemically detectable insoluble A in CAA in humans
is in the smaller cerebral and leptomeningeal artery walls
and not in the larger intracranial artery walls [91]. Furthermore, A is not detectable in the walls of the extracranial
carotid arteries in the neck even in cases of CAA [79].
If the majority of A were produced by vascular smooth
muscle cells in CAA, the larger vessels with more smooth
muscle calls would be expected to develop the most severe
CAA and this is not the case.
Age changes in cerebral arteries and the pathogenesis
of CAA
Although the evidence outlined above suggests that the
pathogenesis of CAA involves the deposition of A and
other amyloids in the perivascular pathways by which interstitial Xuid and solutes drain from the brain, it does not
explain why the majority of cases of CAA occur in the elderly. Age is a major risk factor for CAA and for arteriosclerosis and other forms of cerebrovascular disease, so the
changes in arteries that occur with age may play a role in
the pathogenesis of CAA.
Theoretical studies modelling the motive force for perivascular drainage of interstitial Xuid and solutes from the
brain suggest that the contrary (reXection) wave that follows each pulse wave drives interstitial Xuid and solutes
along artery walls in the reverse direction to the Xow of
Acta Neuropathol (2009) 118:87–102
blood in the artery lumen [72]. This mechanism would
require a valve-like action to prevent back Xow of Xuid during passage of the pulse wave [72]. The nature of the valvelike action is not known. However, one possibility is that
the conformational changes in vascular basement membranes that occur as the artery walls expands during the
passage of the pulse wave and recoils during diastole may
provide the valve-like eVect. StiVening of artery walls with
age reduces the amplitude of the pulse wave and may thus
diminish the motive force for drainage of interstitial Xuid
and solutes from the brain [72]. Slowing of perivascular
drainage probably induces the formation of the A amyloid
Wbrils in the vascular basement membranes that further
impairs the drainage of Xuid and solutes from the brain
[92].
Capillary amyloid angiopathy
Capillary CAA, in which A is deposited in capillary basement membranes in Alzheimer’s disease (Fig. 12) is much
less common than CAA in cerebral and leptomeningeal
arteries. Even in cases of severe CAA aVecting leptomeningeal and cortical arteries, capillary CAA is only abundant
in about one-third of cases [60]. Capillary CAA has been
associated with a high frequency apolipoprotein E 4 genotype [82] and with Alzheimer’s disease pathology [4], but
does not correlate with CAA of leptomeningeal and cortical
arteries [3, 5, 82].
The mechanisms by which the A is deposited in the
capillary walls in the pathogenesis of capillary CAA are
unclear but may be due to an overload of A42 draining
into capillary basement membranes from degraded plaques
in the brain parenchyma [16, 93]. Capillary CAA is frequently seen as clusters of A-laden capillaries in regions
of cerebral cortex that are devoid of A plaques [60]. Serial
transverse sections of cortical arteries feeding areas of capillary CAA has revealed an association between capillary
CAA and thrombotic–embolic occlusion of cortical arteries
[93, 96]. The inverse relationship between capillary CAA
and A plaques suggests that occlusion of cortical arterioles results in focal ischaemia and destruction of the A
plaques by activated microglia. A released from the
plaques then accumulates in perivascular drainage pathways in capillary walls. A42 in Alzheimer’s disease is
predominantly in the plaques [69] and the more soluble
A40 is located in artery walls in CAA (Fig. 11). In capillary CAA it is predominantly A42 that is deposited in the
capillary walls [4]. This suggests that solubilised plaque A
may be overloading the perivascular drainage system in
capillary CAA [96].
Capillary CAA is also seen in the brains of patients with
Alzheimer’s disease who have been immunised with A42.
95
The destruction of A plaques by microglia that occurs in
these cases may also result in overloading the perivascular
drainage system [16].
Relationship of CAA to Alzheimer’s disease
Several complications are associated with CAA. The most
devastating is acute intracerebral haemorrhage associated
with sporadic or familial CAA [97]. Granulomatous inXammation may also occur in relation to amyloid laden vessels
in CAA [75].
The relationship of CAA to Alzheimer’s disease is less
certain. In community studies there is an association
between severe CAA and dementia [18] but both positive
[81] and negative [83] correlations between CAA and A
plaques in Alzheimer’s disease have been made.
Most quantitative studies of CAA are performed on histological sections of cerebrum cut in a coronal plane. These
investigations do not take account of the long drainage
pathways along artery walls. Blockage of the drainage pathways at one point along the wall of an artery by the deposition of A may have an eVect on the eYciency of drainage
of A along substantial lengths of the pathway. Examination of isolated leptomeningeal and cortical arteries [91]
has shown that amyloid deposition does not necessarily
involve the whole length of an artery and gaps in the amyloid deposition are present. This may mean that quantitation of CAA in coronal histological sections underestimates
both the amount of A in the vessel walls and its eVect on
the elimination of A from the brain.
Smaller leptomeningeal arteries are more severely
involved by CAA than the larger arteries in humans [91].
However, some transgenic mice show a pattern of involvement in which A is initially deposited in the walls of the
larger arteries near the circle of Willis [23]; then there is a
progressive spread of CAA to involve the smaller branches.
This suggests a damming back process in which the drainage channels for A in the walls of larger arteries are
blocked with subsequent deposition of A in the more
proximal parts of the drainage pathways in the walls of the
smaller arteries. Until the dynamics of CAA are fully
understood, quantitative estimates of CAA should perhaps
include the examination of isolated cerebral and leptomeningeal arteries [91].
The full eVects of CAA on the brain are poorly understood. One of the major roles of A in Alzheimer’s disease
may be the obstruction of lymphatic drainage of interstitial
Xuid and solutes from the brain. This would lead to (1) the
early deposition of insoluble plaques of A in the brain
parenchyma, (2) the eventual rise in soluble A in the cortex that correlates with cognitive decline in Alzheimer’s
disease [49, 51] and (3) the accumulation of Xuid in the
123
96
white matter in leukoaraiosis [68]. It has been suggested
that an increase in oligomeric A species is associated with
cognitive decline in Alzheimer’s disease [87]. However, it
is also possible that the rise in the level of soluble A
related to dementia in Alzheimer’s disease is a reXection of
a general failure of drainage of metabolites from the brain,
blocked by CAA. Such a general failure of drainage may
result in loss of homeostasis of the neuronal environment
and failure of neuronal function in Alzheimer’s disease.
Acta Neuropathol (2009) 118:87–102
Vascular Factors in Alzheimer’s disease
Atherosclerosis
Arteriosclerosis
Failure of perivascular
drainage of ISF and
solutes including A from
the brain
Fibrosis and
stiffening of
artery walls and
hypoperfusion
of grey and
white matter
Thromboembolic
occlusion of
arteries and
infarction
Cerebral Amyloid
Angiopathy
White matter disease in Alzheimer’s disease
and in vascular dementia
Changes in the white matter with increased signal in T2
weighted MRI images (leukoaraiosis) are frequently seen in
the elderly, in Alzheimer’s disease and in vascular dementia; such changes are associated with low cognitive performance [14, 29]. Abnormal signal suggesting an increase in
Xuid content of the white matter is seen in the periventricular regions and in the subcortical white matter [29] (see
Fig. 16). The periventricular white matter lesions may indicate a disturbance of CSF drainage and the infusion of CSF
into periventricular white matter [88, 90].
Leukoaraiosis in the subcortical white matter, however,
has been correlated with arteriolosclerosis in arteries in the
white matter and with markers of tissue hypoxia [29]. This
suggests that there is ischaemia of the white matter due to
the age changes in the arteries supplying the white matter.
Leukoaraiosis has also been correlated with amyloid
load in the brain parenchyma [19] and with severe CAA in
the leptomeningeal arteries from which the arterial supply
of the white matter arises [68]. This raises the possibility
that white matter changes in Alzheimer’s disease result
from a combination of ischaemia and a failure of Xuid
drainage along perivascular pathways blocked by the deposition of A and by Wbrosis in the walls of arteriolosclerotic
arteries in the white matter [29, 68].
Relationship between Alzheimer’s disease and vascular
dementia
Microvascular changes in the elderly brain are associated
with a spectrum of dementias ranging from vascular
dementia to Alzheimer’s disease with many cases showing
a mixed dementia with features of both Alzheimer’s disease
and of vascular dementia [41]. At one end of the spectrum
(Fig. 13), demented patients exhibit pathological changes
characteristic of Alzheimer’s disease with the accumulation
of neuroWbrillary tangles and the deposition of A as
plaques in brain parenchyma and as CAA. At the other end
of the spectrum, there are the heterogeneous pathological
123
Intracellular
accumulation of
Tau and NFTs
White Matter Lesions
(Leukoaraiosis)
Ischaemic damage to
the brain
Accumulation of insoluble and
soluble A in the brain in
Alzheimer’s disease
Vascular Dementia
Mixed dementia
Fig. 13 Relationship between age changes in the microvasculature,
Alzheimer’s disease and vascular dementia. Arteriosclerosis (and arteriolosclerosis) has two major eVects. The left hand side of the diagram
depicts the failure of perivascular drainage along the ageing arteries
resulting in cerebral amyloid angiopathy and accumulation of A in
the Alzheimer brain. The other eVect of arteriosclerosis, on the right,
is hypoperfusion. Atherosclerosis mainly has its eVect through thromboembolism of cerebral arteries and cerebral infarction. Features of both
Alzheimer’s disease and vascular dementia are present in mixed
dementia
features of vascular dementia with multifocal lacunar infarcts in the basal ganglia and thalamus with or without
larger cerebral infarcts. Ischaemic lesions are also seen in
the hippocampus and in the white matter [40]. In mixed
dementia the features of Alzheimer pathology and ischaemic lesions appear to act synergistically [40, 41]. The presence of lesions of vascular dementia results in a signiWcant
deterioration in cognitive function in the earliest stages of
Alzheimer’s disease [26].
Figure 13 illustrates how microvascular changes in the
ageing brain play an important role throughout the spectrum of Alzheimer’s disease, mixed and vascular dementias
with varying proportions of ischaemia and failure of perivascular lymphatic drainage.
Impact on therapy
Treatment of Alzheimer’s disease with cholinesterase
inhibitors is well established [32] and immunotherapy for
the clearance of A plaques from the brain is under development [37]. The changes in the microvasculature that
occur with age potentially have an impact on both forms of
therapy.
Acta Neuropathol (2009) 118:87–102
Treatment with cholinesterase inhibitors
Alzheimer’s disease is characterised not only by the accumulation of neuroWbrillary tangles and by the deposition of
A in brain parenchyma and in blood vessel walls but also
by a reduction in the cholinergic system in the brain [7, 44].
This has led to the introduction of acetylcholinesterase
inhibitors for the treatment of Alzheimer’s disease [32].
The cholinergic deWcit appears be related to the accumulation of A in the brain [7, 8, 32]. Patients with dementia
with Lewy bodies who were treated with cholinesterase
inhibitors were found to have signiWcantly reduced levels
of parenchymal A deposition [6], whereas blockade of
muscarinic receptors in patients with Parkinson’s disease
resulted in a 2.5-fold increase in the density of A plaques
[63].
One of the mechanisms by which the accumulation of
A may be associated with a cholinergic deWcit is illustrated by experimental ablation of the nucleus basalis in
rabbits by a selective immunotoxin [9]. This results in cortical cholinergic deaVerentation, and leads to deposition of
A in cerebral blood vessels (CAA) and in the perivascular
neuropil. Biochemical measurements revealed a 2.5- and 8fold elevations of cortical A40 and A42, respectively [9].
These results suggest that cholinergic deaVerentation in
Alzheimer’s disease may reduce the elimination of A
along perivascular pathways resulting in CAA and plaque
formation in the brain. So part of the eVect of treatment of
Alzheimer’s disease with cholinesterase inhibitors may be
enhanced elimination of A along perivascular drainage
pathways and their eYcacy in this way may be aVected by
age changes in the microvasculature.
Impact of age changes in the cerebral vasculature on A
immunotherapy for Alzheimer’s disease
In pursuing the amyloid hypothesis for the pathogenesis of
Alzheimer’s disease, it was found that immunization of
APP transgenic mice with A peptide could prevent or
reverse age-related A plaques accumulation [71]. Subsequent studies have conWrmed that clearance of A plaques
can occur as a result of immunotherapy in humans with
Alzheimer’s disease (Elan Pharmaceuticals AN1792) [16,
30, 37, 50, 56, 57], although there is little evidence yet that
this beneWts cognitive function [37].
The results of immunotherapy in humans are summarised in Fig. 14. In non-immunised patients with Alzheimer’s disease (Fig. 14a), there are numerous plaques of A
and neuroWbrillary tangles within neurons. Dystrophic neurites are associated with A plaques (neuritic plaques) and
neuropil threads are present in the parenchyma of the grey
matter. Following immunisation with A42 (Fig. 14b), the
97
plaques of A have been removed and their surrounding
dystrophic neurites have disappeared, but the intraneuronal
neuroWbrillary tangles and the neuropil threads remain.
Figure 15 summarises the eVects of immunisation with
A42. Plaques of A42 are removed by activated microglia
and A42 accumulates in the perivascular drainage pathways resulting in a signiWcant increase in severity of CAA.
In investigating the potential mechanisms of removal of
plaque A by immunotherapy, we hypothesised that plaque
A might be solubilised by binding of anti-A antibodies
and subsequently drain to the perivascular pathways, thus
increasing the severity of CAA [15, 16, 58]. Of relevance to
this hypothesis is the observation that A42 is predominantly localised in plaques whereas A40 is predominantly
localised in the vessel walls as CAA (Fig. 11). We therefore proposed that immunisation might result in an increase
in the amount of plaque-derived A42 in the blood vessel
walls which would be detectable by immunohistochemistry
using an A42-speciWc antibody [16]. Our observations
conWrmed that there is a substantial increase in the quantity
of A42, accompanied by A40, in the cerebral vasculature
in Alzheimer’s disease patients immunised with A compared with unimmunised Alzheimer’s disease controls [16].
This increase in CAA aVects arteries and arterioles in the
cerebral cortex and overlying leptomeninges. In some
cases, prominent capillary angiopathy was observed. A
range of post-immunization time-points were available for
study and these were consistent with a dynamic sequence of
events involving solubilisation of plaque A followed by
A accumulation in the vessel walls. A striking appearance
was observed in sections immunostained using A42-speciWc antibodies, in which plaques were absent but there was
full thickness and full circumference A accumulation
within the blood vessel walls [16], i.e. the converse of the
pattern usually seen in Alzheimer’s disease with such antibodies.
The increase in the severity of CAA [16] and of soluble
A in the brain parenchyma [62] raises the possibility that
the eVect of immunization is merely redistributing A
within the brain rather than removing A from the brain.
However, in two cases with prolonged survival of about
5 years after immunisation, there was extensive clearance
of A plaques and very little CAA, suggesting that, given
suYcient time, the plaque-derived A can be cleared from
the perivascular pathways [16]. Although the evidence has
yet to emerge, age and APOE genotype related alterations
in the blood vessels walls, are likely to inXuence the process of vascular and perivascular clearance of A after
immunization.
Studies of A immunotherapy in APP transgenic mice
with carefully selected time-points have conWrmed that
CAA severity increases as plaques are removed from the
parenchyma [94]. Passive immunisation using anti-A
123
98
Fig. 14 Changes that occur in the brain in Alzheimer’s disease following immunisation with A42. a Non-immunised patient with Alzheimer’s disease showing rounded plaques of A and associated
dystrophic neurites. Neurons contain neuroWbrillary tangles and there
Acta Neuropathol (2009) 118:87–102
are neuropil threads in the brain parenchyma. b Following immunisation with A42, the plaques of A and the dystrophic neurites have disappeared but the neuroWbrillary tangles and neuropil threads remain.
Bielschowsky stain, bars 50 m
Fig. 15 Summary diagram of
the results of immunisation with
A42 in Alzheimer’s disease.
On the left is the pathological
picture in a non-immunised patient with Alzheimer’s disease
with plaques of A42 (green)
surrounded by dystrophic neurites and microglia. Following
immunisation with A42 (right
hand panel) the plaques of A
have been removed by activated
microglia, the dystrophic neurites have disappeared, but there
is a signiWcant rise in the amount
of A42 (green) in the walls of
capillaries and arteries as the
severity of CAA increases (diagram modiWed from reference
[15])
antibodies that speciWcally bind diVerent epitopes on the
A peptide have diVerent eVects on CAA. Antibodies that
bind the N-terminal portion on the A peptide cause a
reduction in CAA severity [74]. It is unclear whether this is
a direct eVect on the A already in the vessel walls or
whether it is an eVect on the time-course of plaque-derived
A tracking through the perivascular pathway.
The APOE gene polymorphism, which is the basis of the
major genetic risk factor for sporadic Alzheimer’s disease,
seems likely to have an inXuence on the success with which
A can be removed from the brain. Although the precise
mechanism by which APOE genotype inXuences the risk of
Alzheimer’s disease remains unclear, there is evidence that
APOE chaperones A and inXuences its accumulation and
123
removal. It is already known that the relative distribution of
A between the parenchymal plaques and the cerebral vasculature is inXuenced by APOE genotype; patients with
APOE 4 have more severe CAA. Putatively, this could be
because of the known association of APOE 4 with atherosclerosis and arteriosclerosis, resulting in more marked agerelated impairment of perivascular drainage. Currently
there are few data on the role of APOE and the relevance of
the APOE gene polymorphism in post-immunotherapy A
mobilisation. However, the observation that APOE colocalises with the marked vascular accumulation of A
following immunotherapy [56], is consistent with the
mobilised A being transported or chaperoned by apoE, as
it is in Alzheimer’s disease.
Acta Neuropathol (2009) 118:87–102
99
cortex, the function of which is impaired by CAA, and
changes in the white matter. It is, therefore, possible to
hypothesise a sequence of events that occurs after immunotherapy as follows: (1) Anti-A antibodies enter the brain
and bind to plaques resulting, in the solubilisation of A.
(2) The solubilised A diVuses through the brain parenchyma and enters the perivascular drainage pathways, manifesting as increased CAA. (3) AVected blood vessels are
dysfunctional and, whether through a mechanism of ischaemia or impaired drainage of extracellular Xuid, result in
alteration of the white matter. According to this hypothesis,
the patches of white matter abnormality underlie regions of
cortex in which there has been recent or rapid solubilisation
of plaques. The hypothesis is now testable because of the
recent ability to image amyloid plaques in vivo using PIB
PET imaging [39] and it is likely that the relevant data with
which to test the hypothesis will be available soon.
Conclusions
Fig. 16 T2 weighted MRI of a patient with Alzheimer’s disease following immunisation with A42 showing high signal in the white matter of one temporal lobe. This may be due to accumulation of Xuid
resulting from blockage of perivascular Xuid drainage by an increase
in the severity of CAA (reproduced with permission from reference
[57])
A further point hinting at the role of the vasculature and
of APOE genotype in the process of post-immunisation
plaque removal comes from consideration of the side
eVects of immunotherapy that have been a cause for concern in the human clinical trials [59]. Brain imaging studies
performed on patients in both the active and the more
recent passive vaccine trials have shown focal changes in
the cerebral white matter (Fig. 16). How can this be
explained when the plaques that are being targeted by the
immunotherapy are located in the cerebral cortex?
Although the answer to this question is far from clear at this
stage, one intriguing possibility of relevance to the processes under discussion in this review relates to the known
association of severe CAA and cerebral white matter alterations [15, 68]. Much of the cerebral white matter receives
its blood supply from vessels that penetrate the brain surface from the leptomeninges, supply and pass through the
cortex into the underlying white matter [24]. According to
the perivascular drainage hypothesis [17, 90, 92] extracellular Xuid in the white matter, can drain retrogradely along
the walls of these blood vessels. This provides a potential
link between blood vessels in the leptomeninges and
This review has exposed a complex association between
microvascular changes and Alzheimer’s disease ranging
from ischaemia to impaired elimination of A from the
brain. Further understanding of such vascular factors will
clarify their impact on therapies for Alzheimer’s disease.
Acknowledgments We thank Dr. Anton Page of the Biomedical
Imaging Unit Southampton University Hospitals for preparing the Wgures for this paper. This study was supported by the Medical Research
Council and the Alzheimer Research Trust. Research Ethics Committee Approval reference 07/H0505/86.
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