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Association of apolipoprotein E ~2
and vasculopathy in cerebral
amyloid angiopathy
S.M. Greenberg, MD, PhD; J.-P.G. Vonsattel, MD; A.Z. Segal, MD; R.I. Chiu, BA; A.E. Clatworthy, BA;
A. Liao, BS; B.T. Hyman, MD, PhD; and G.W. Rebeck, PhD

Article abstract-Objective: Hemorrhage related to cerebral amyloid angiopathy (CAA) appears to occur through a
multistep pathway that includes deposition of p-amyloid in cerebral vessels and specific vasculopathic changes in the
amyloid-laden vessels, such as cracking of the vessel wall. Recent reports suggest a positive association between CAA-
related hemorrhage and both the apolipoprotein E (APOE) ~4allele and, unexpectedly, the APOE ~2 allele. Unlike APOE
~ 4APOE
, ~2 does not appear to act through increased P-amyloid deposition. We therefore sought to determine whether it
might specifically accelerate the second step in this pathway, that is, development of the vasculopathic changes that lead
to hemorrhage. Methods: To determine the role of APOE in development of vasculopathic changes, we compared APOE
genotypes in two groups of postmortem brains: 52 brains with complete amyloid replacement of vessel walls but without
vasculopathic changes, and 23 brains with complete amyloid replacement of vessels with the accompanying changes of
cracking of the vessel wall and paravascular leaking of blood. Results: Frequency of APOE ~2 was significantly greater in
the group with vasculopathy (0.09) than the group without (0.01, p = 0.03). The groups did not differ in mean age or
extent of neuritic plaques. Analysis of a clinical series of patients with CAA-related hemorrhage confirmed an overrepre-
sentation of APOE ~2 as well as an association between this allele and earlier age of first hemorrhage. Conclusions: These
data suggest that APOE ~2 and ~4 might promote CAA-related hemorrhage through separate mechanisms: €4by enhanc-
ing amyloid deposition and ~2 by causing amyloid-laden vessels to undergo the vasculopathic changes that lead to rupture.
NEUROLOGY 1998;50:961-965

Cerebral amyloid angiopathy progresses t o cerebral AD might share some mechanisms and risk factors,
hemorrhage through a specific series of pathogenic particularly those related to AP deposition, and
events. CAA itself, defined as deposition of congo- might differ in other molecular features, such as
philic material in the media of cerebral is those related to the vasculopathic changes.
common in the elderly brain. CAA-related cerebral Apolipoprotein E (APOE for gene, apoE for pro-
hemorrhage, however, occurs only in a relatively tein) has been identified as a n important risk factor
small subset of cases. Those brains that develop for AP deposition and AP-related diseases. The ~4
hemorrhage demonstrate both extensive vascular allele of APOE is associated with increased AP depo-
amyloid and a set of vasculopathic changes that can sition, increased risk of disease, and earlier onset in
include cracking and fibrinoid necrosis of the vessel both ADR-14and CAA.10J5-18 APOE ~ 2 conversely,
, ap-
wall and paravascular leaking of b l o ~ d . ~ - ~ pears to protect from senile plaques and AD.11J2J9-22
Amyloid deposited in vessels in CAA, similar to These results have led to the suggestion that apoE
amyloid in senile plaques in Alzheimer’s disease might exert both its positive and negative effects on
(AD), is composed largely of the amyloid P-peptide AD by regulation of amyloid deposition.
(AP). We have previously proposed7 that CAA and Surprisingly, however, the ~2 allele of APOE ap-
From the Department of Neurology (Drs. Greenberg, Segal, Hyman, and Rebeck, and R.I. Chiu, A.E. Clatworthy, and A. Liao) and C.S. Kubik Laboratory for
Neuropathology (Dr. Vonsattel), Massachusetts General Hospital, Harvard Medical School, Boston.
Supported by grants from the American Heart Association, Edward Mallinckrodt, Jr. Foundation, and NIH AGO0725 (S.M.G.), AG12406 (B.T.H.), and
AG14473 (G.W.R.J.
Received August 26, 1997. Accepted in final form October 20, 1997.
Address correspondence and reprint requests to Dr. Steven M. Greenberg, Massachusetts General Hospital, Wang Ambulatory Care Center 836, Boston, MA
02114.
Copyright 0 1998 by the American Academy of Neurology 961
pears to be overrepresented rather than underrepre-
sented in cases of CAA-related hemorrhage, as
demonstrated first in pathologic specimensz3 and
subsequently in a clinically defined series.18 This
striking difference from AD has raised the possibility
that apoE2 might affect molecular steps specific to
CAA such as the degenerative changes in the
amyloid-laden blood vessels. The latter possibility
leads to a specific and testable prediction: that the ~2
allele be overrepresented in cases of CAA w i t h vas-
culopathic changes such as cracking of the vessel
wall and paravascular leaking of blood, relative to
brains with extensive vascular amyloid b u t without
these vasculopathic changes.

Methods. Pathologic and clinical cases of CAA. Post-

mortem cases were chosen from the Harvard Brain Tissue
Resource Center (BTRC) at McLean Hospital (Belmont,
MA). Brains had been systematically graded for CAA se-
verity by review of 18 blocks of brain tissue, including
seven from cerebral cortical regions and one from cerebel-
lum as described in detail elsewhere.24Sections were pre-
pared with Luxol fast blue, hematoxylin and eosin, and
Congo red and examined with and without polarized light;
some sections were also immunostained for AP (6F3D,
DAKO, Carpinteria, CA 1:150) to confirm the identity of
congophilic material. Cases were graded according to the
most advanced degree of CAA present among all vessels
examined, an approach previously shown to correlate with
risk of h e m ~ r r h a g eAll
. ~ pathologic grading was performed
and recorded prior to determination of genotype.
To examine specific determinants of the vasculopathic
changes in CAA, we selected only brains with complete
amyloid replacement of vessel walls, represented by the
CAA grades of moderate or ~ e v e r e . ~Moderate
,‘~ CAA de-
notes complete replacement of the blood vessel media with
amyloid but without evident vasculopathy (figure lA),
whereas severe CAA is defined by the additional changes
of cracking of the vessel wall and at least one focus of
paravascular blood leakage (figure 1B). Seventy-five brains
were selected, including 28 from the set of pathologic cases
reported previously16(in which moderate-severe cases were
analyzed as a single group) and an additional 47 repre-
senting all other moderate-severe CAA brains received by
the BTRC between July 1993 and June 1996 with avail-
able frozen tissue for genotyping. Mean density of neuritic
plaques was estimated according to Consortium to Estab-
lish a Registry for Alzheimer’s Disease (CERAD) criteria,2s
with grade 1 = sparse density, 2 = moderate, and 3 =
severe.
Clinical analysis of APOE genotype was performed on
48 consecutive patients age 250 years with a diagnosis of
probable or definite CAA-related hemorrhage,I5 27 de-
scribed previously18 and an additional 21 consecutive pa-
tients presenting between January, 1996 and February,
1997. These patients were compared with 49 patients age
250 with probable hypertensive (HTN) hemorrhage (18
described previously,18 3 1 consecutive additional patients
from the above interval), and 87 elderly volunteers without
cerebral hemorrhage (“nohemorrhage”) presenting for rou-
tine general examination during this interval. Mean age
(fSD) of the CAA patients was 77.7 ? 8.1 years, for HTN
71.8 2 10.9, and for the no-hemorrhage patients 69.0 2
962 NEUROLOGY 50 April 1998
Figure. Examples of amyloid-laden cerebral vessels with-
out (A) and with (B) cerebral amyloid angiopathy-related
vasculopathic changes. (A) Amyloid-containing cortical
vessel with moderate involvement. The media is replaced
and thickened by amyloid, with decreased number of
smooth muscle cell nuclei. The lumen is patent. The mate-
rial in the media stains positively with Congo red or with
antibodies to AP (not shown). Hematoxylin, eosin, and
luxol fast blue, original magnification 560x. (B)Amyloid-
containing leptomeningeal vessel with severe involvement.
The media is replaced by amyloid and forms the homoge-
neous outer circle, whereas the inner circle is composed
primarily of the intima. The complete crack in the vessel
wall creates a “vessel-within-vessel”appearance. The lu-
men is patent and contains blood. Macrophages with he-
mosiderin (not distinguishable at this magnification)are
scattered near the vessel. Hematoxylin, eosin, and luxol
fast blue, original magnification 350X.
11.0. All but eight of the studied patients (four black, four
Hispanic) were white. Clinical and radiographic diagnosis
was performed as described p r e v i o u ~ l y .History
~ ~ , ~ ~of prior
dementia was ascertained by interview with family mem-
bers. Determination of diagnosis, previous dementia, and
age at first hemorrhage were recorded before analysis of
APOE genotype, performed by polymerase chain reaction
(PCR) as described previ0us1y.l~This study was performed
with approval of the institutional review board and in-
formed consent of participants or family members.
Statistical analysis. Allele frequencies (proportion of
chromosomes in which the allele was present) were com-
pared using 2 X 2 tables with Fisher’s exact test for signif-
icance. Ages of first CAA-related hemorrhage were
normally distributed (Shapiro-Francia test for normality)
Table 1 Apolipoprotein E allele frequency i n patients with Table 3 Association of apolipoprotein E E2 with CAA-related
intracerebral hemorrhage and controls vasculopathic changes

Allele Frequency Allele frequency

No.of No.of
patients €2 €3 €4 CAA pathology brains €2 €3 €4
-~

Definitdprobable 48 0.19” 0.56 0.257 Replacement of media 52 0.01 0.55 0.44

CAA hemorrhage with amyloid
Probable HTN 49 0.05 0.84 0.11 Replacement of media 23 0.09* 0.45 0.46
hemorrhage with amyloid +
No hemorrhage 87 0.09 0.84 0.07 vasculopathic changes

* p < 0.005 vs. HTN hemorrhage group, p = 0.03 vs. no hemor- * p = 0.03.
rhage group. CAA = cerebral amyloid angiopathy.
t p = 0.015 vs. HTN hemorrhage group, p < 0.005 vs. no hemor-
rhage group.
loid, APOE ~2 should be present a t greater frequency in
CAA = cerebral amyloid angiopathy; HTN = hypertension. the subset of brains with vasculopathic changes than in
brains without vasculopathy.
and compared with Student’s t-test or multivariate linear We therefore compared two groups of postmortem
regression. All significance tests were two-sided. brains, each with complete replacement of vessel walls
with amyloid: one group without evidence of vasculopathy
Results. Compared with patients with either HTN hem- (“moderate CAA,” see figure 1A) and one with the CAA-
orrhage or no hemorrhage, those with CAA-related hemor- related vasculopathic changes, such as cracking of the ves-
rhage demonstrated significantly increased frequencies of sel wall that are associated with hemorrhage (“severe
both the ~4 and ~2 alleles (table 1).In comparison with the CAA,” figure 1B). The groups did not significantly differ in
~ 3 1 genotype,
~3 the presence of one copy of either APOE ~2 age a t death (79.0 5 7.0 without vasculopathy, 78.4 ? 9.9
or ~4 increased the odds ratio for CAA-related hemorrhage with vasculopathy) or density of plaques (mean CERAD
by approximately four-fold. Allele frequencies similar to grades 2.6 +- 0.7 versus 2.650.9). Frequency of APOE ~2
those in the full CAA cohort were seen in the subgroup of was significantly greater in the brains with CAA-related
CAA patients without history of preceding dementia (0.21 vasculopathic changes than those without (table 3). APOE
for ~ 2 0.24
, for ~ 4 n, = 36) and the subgroup of CAA- €4 frequency was high in each group and did not signifi-
related hemorrhages diagnosed with definite or supporting cantly differ between brains with and without vasculo-
pathologic evidence (15) (0.15 for ~ 20.35
, for -24,n = 10). pathic changes. These results are consistent with a role for
Within the cohort of patients with definitdprobable CAA, APOE ~2 in promoting vasculopathy in CAA.
those who carried ~2 or ~4had their first hemorrhage 6 to 7
years earlier than those with the ~ 3 1 ~ genotype
3 (table 2). Discussion. The results presented offer several
“he four individuals with the EYE^ genotype demonstrated lines of evidence to suggest that APOE ~ 2like , APOE
the earliest age of onset of any genotype (67.3 2 4.0 years, ~ 4is, positively associated with CAA-related hemor-
p < 0.02 [corrected for multiple comparisons] versus ~ 3 1 ~ 3 rhage: (1) it is overrepresented among CAA cases,
patients). Multivariate analysis demonstrated independent confirming an independent series”; (2) it correlates
and significant effects of APOE E2 and APOE ~4 on earlier with age of first CAA-related hemorrhage (not seen
age of first hemorrhage. Neither allele significantly affected in a previous smaller, less stringently defined co-
age at onset in the HTN hemorrhage group (data not shown). hortl*); and (3) it is associated with CAA-related vas-
Given the specific effect of APOE ~2 on the presence and culopathy. Further series of patients will be required
onset of CAA-related hemorrhage and the absence of a before this unexpected association is fully estab-
potentiating effect of APOE ~2 on vascular amyloid deposi-
lished, as highlighted by the absence of elevated ~2
tion,15*22
we reasoned that this allele might exert its effect
by accelerating the formation of the CAA-related vasculo-
frequency in a pathologic series of 13 CAA AD +
pathic changes that lead to hemorrhage. This hypothesis
cases.16 Although ~2 may increase the risk of CAA-
predicted that among brains with extensive vascular amy- related hemorrhage, it is absent in the majority of
patients (see table 1) suggesting the existence
of other factors that can independently promote
Table 2 Apolipoprotein E genotype and age in years at first hemorrhage.
CAA-related hemorrhage
We found the frequency of APOE €2 in the overall
ApoE genotype No.of patients” Age first hemorrhage (tSD) group of pathologic cases with extensive vascular
amyloid to be relatively low (see table 3), in keeping
€3/€3 16 81.6 5 7.0 with this allele’s protective influence on amyloid dep-
€2 present 15 74.2 f 7.67 siti ion.'^,'^,^^ The frequency of 0.09 observed in
€4 present 21 75.2 f 8.6t brains with CAA-related vasculopathy was, however,
significantly greater than the frequency of ~2 seen in
* €2 and €4 subgroups both include four €21~4patients. the cases without vasculopathy, and also above the
i p < 0.02 vs. €3/€3group.
range of allele frequencies (0.005 to 0.04) reported in
CAA = cerebral amyloid angiopathy. brains with extensive amyloid deposition from Alz-
April 1998 NEUROLOGY 50 963
heimer’s d i s e a ~ e . ~These
~ J ~ - results
~~ indicate that
when ~2 is present in cases with extensive CAA, the
vessels frequently proceed to develop vasculopathic
changes, such as cracking.
The data suggest a model for apoE and CAA in
which apoE4 promotes creation of amyloid-laden ce-
rebral vessels and apoE2 causes the vessels to
progress toward rupture. This model, by postulating
an action of apoE2 specific to the CAA pathway, of-
fers a potential explanation for this allele’s overrep-
resentation in CAA-related hemorrhage but not AD.
The pathologic criteria used in the current
study-cracking of an amyloid-laden vessel wall and
paravascular leaking of blood-were chosen from
among the described CAA-related vasculopathic
changes (also including vascular ectasia, microaneu-
rysms, infiltration of inflammatory cells, and fibrin-
oid necrosis3) because of their demonstrated
association with CAA-related hemorrhage. A previ-
ous study using the same methods for analysis and
grading found severe CAA as defined here in all 13
cases of hemorrhage with full postmortem examina-
tion and no other cause of hemorrhage, but only 10 of
70 brains from patients with other neurologic or psy-
chiatric illnesses and only one of 66 elderly patients
from a general hospital autopsy ~ e r i e sThese
.~ vascu-
lopathic changes thus appear to be a necessary pre-
condition for CAA-related hemorrhage.
Differences between the AP-dependent patholo-
gies of CAA and AD might pertain to the different
effects of apoE2 on the two diseases. Vascular AP,
unlike plaque amyloid, appears to contain large
amounts of the 40 amino acid form of the ~ e p t i d e . ~ ~ - ~1995;45:1323-1328.
Further, data from cell culture suggest that cerebro-
vascular smooth muscle cells might be specifically
sensitive to the unaggregated form of AP,30the oppo-
site of findings from cultured neurons.31 ApoE is
present in vessels early in CAA,27,32 where it could
affect the aggregation or other biological properties
of AP.33,34It will therefore be interesting to explore
whether apoE2 affects specific steps relevant t o
CAA, such as maintaining AP in a state toxic to
smooth muscle cells.
Although no clear role remains for determination
of APOE genotype in the diagnosis of CAA, its asso-
ciation with CAA-related hemorrhage has several po-
tential clinical implications. Acting at different
pathogenic steps in CAA, the apoE isoforms might
identify patient subgroups with particular risks of
hemorrhage recurrence. Elucidation of the molecular
basis of vasculopathy in CAA might also identify new
and useful targets for preventative treatments.
Acknowledgments
We are grateful to Larry Cherkas for preparation of figures,
James A.R. Nicoll, MD, for sharing data prior to publication, and
the Harvard Brain Tissue Resource Center (NIH grant MWNS
31862).
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 Association of apolipoprotein E ?2 and vasculopathy in cerebral amyloid
angiopathy
S. M. Greenberg, J.-P. G. Vonsattel, A. Z. Segal, et al.
Neurology 1998;50;961-965
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