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2 and vasculopathy in cerebral amyloid angiopathyFrom 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.
Address correspondence and reprint requests to Dr. Steven M. Greenberg, Massachusetts General Hospital, Wang Ambulatory Care Center 836, Boston, MA 02114.
Objective: Hemorrhage related to cerebral amyloid angiopathy (CAA) appears to occur through a multistep pathway that includes deposition of ß-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) 
4 allele and, unexpectedly, the APOE 2 allele. Unlike APOE 4, APOE 2 does not appear to act through increased ß-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 overrepresentation 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: 4 by enhancing amyloid deposition and 2 by causing amyloid-laden vessels to undergo the vasculopathic changes that lead to rupture.
Supported by grants from the American Heart Association, Edward Mallinckrodt, Jr. Foundation, and NIH AG00725 (S.M.G.), AG12406 (B.T.H.), and AG14473 (G.W.R.).
Received August 26, 1997. Accepted in final form October 20, 1997.
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