Association of apolipoprotein E epsilon2 and vasculopathy in cerebral amyloid angiopathy.
OBJECTIVE
Hemorrhage related to cerebral amyloid angiopathy (CAA) appears to occur through a multistep pathway that includes deposition of beta-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) epsilon4 allele and, unexpectedly, the APOE epsilon2 allele. Unlike APOE epsilon4, APOE epsilon2 does not appear to act through increased beta-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 epsilon2 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 overrepresentation of APOE epsilon2 as well as an association between this allele and earlier age of first hemorrhage.


CONCLUSIONS
These data suggest that APOE epsilon2 and epsilon4 might promote CAA-related hemorrhage through separate mechanisms: epsilon4 by enhancing amyloid deposition and epsilon2 by causing amyloid-laden vessels to undergo the vasculopathic changes that lead to rupture.
Greenberg
S M
SM
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston 02114, USA.
Vonsattel
J P
JP
Segal
A Z
AZ
Chiu
R I
RI
Clatworthy
A E
AE
Liao
A
A
Hyman
B T
BT
Rebeck
G W
GW
D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000686:Amyloidosis / Q000235:genetics / Q000473:pathology*; D053329:Apolipoprotein E2; D001057:Apolipoproteins E / Q000235:genetics*; D002536:Cerebral Arteries / Q000473:pathology*; D002543:Cerebral Hemorrhage / Q000235:genetics / Q000473:pathology*; D015331:Cohort Studies; D005838:Genotype; D006801:Humans; D008875:Middle Aged
D053329:Apolipoprotein E2; D001057:Apolipoproteins E