Apolipoprotein E Genotype and Cerebral Amyloid Angiopathy‐related Hemorrhage

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Abstract
Following the identification of the role of the apolipoprotein E (APOE) gene polymorphism in Alzheimer's disease (AD), this gene was examined in cerebral amyloid angiopathy (CAA). As in AD, the APOEɛ4 allele was found to be associated with CAA. Lobar intracerebral hemorrhage is the major clinical manifestation of CAA. Initial studies on a small number of patients with CAA‐related hemorrhage (CAAH) identified overrepresentation of APOEɛ4. However, it became clear that confounding bias from concomitant AD and the need for pathologically confirmed cases of CAAH would also have to be considered. A larger series of pathologically confirmed cases of CAAH, also assessed for AD pathology, found a surprising overrepresentation of the APOEɛ2 allele. Because of the association between CAA and AD, it might have been predicted that patients with CAAH would have a low, rather than a high, ɛ2 frequency. The overrepresentation of APOEɛ2 was present both in patients with and without AD, whereas a high ɛ4 frequency correlated with concomitant AD. Further studies found that overrepresentation of APOEɛ2 is specific for CAAH and is not found in intracranial hemorrhages due to other causes. In CAAH, APOEɛ2 may interact with putative risk factors for hemorrhage, including antiplatelet/anticoagulant medication, minor head trauma, and hypertension. Several microvascular abnormalities in amyloid‐laden blood vessels have been assumed to antedate CAAH and increase its likelihood. APOEɛ2 has now been found to be associated with some of these vascular abnormalities, specifically a “double‐barrel” appearance and fibrinoid necrosis. The currently favored interpretation is that APOEɛ4 enhances deposition of amyloid‐β protein in the walls of cerebral blood vessels, whereas ɛ2 is a risk factor for hemorrhage from amyloid‐laden blood vessels by promoting specific “CAA‐associated vasculopathies.”