Association of apolipoprotein E ε2 and vasculopathy in cerebral amyloid angiopathy

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Hemorrhage related to cerebral amyloid angiopathy (CAA) appears to occur through a multistep pathway that includes deposition of β-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) ε4 allele and, unexpectedly, the APOE ε2 allele. Unlike APOE ε4, APOE ε2 does not appear to act through increased β-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.


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.


Frequency of APOE ε2 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 ε2 as well as an association between this allele and earlier age of first hemorrhage.


These data suggest that APOE ε2 and ε4 might promote CAA-related hemorrhage through separate mechanisms: ε4 by enhancing amyloid deposition and ε2 by causing amyloid-laden vessels to undergo the vasculopathic changes that lead to rupture.

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