Regular articleAPOE and cerebral amyloid angiopathy in community-dwelling older persons
Introduction
A prominent feature of cerebral amyloid angiopathy (CAA) is the mural deposition of β-amyloid in the walls of cerebral arteries and arterioles (Greenberg and Vonsattel, 1997). The prevalence of CAA increases with age and is commonly present in persons with Alzheimer's disease (AD) pathology (Love et al., 2009). CAA is associated with a spectrum of neurological disorders including lobar intracerebral hemorrhage (ICH) and more debatably, ischemic infarction (Arvanitakis et al., 2011b, Auriel and Greenberg, 2012, Cadavid et al., 2000, Samarasekera et al., 2012).
The genetics of sporadic CAA is largely unexplored; however, its pathophysiology suggests that mutations implicated in dysfunctional β-amyloid processing may play a role (Obici et al., 2005). The apolipoprotein E (APOE) gene is a known risk gene for late-onset AD (Roses and Saunders, 1994). The APOE isoforms differentially regulate the concentration and clearance of β-amyloid, such that brain amyloid deposition follows an isoform-dependent pattern (APOE4 > APOE3 > APOE2) (Arold et al., 2012, Castellano et al., 2011, Holtzman et al., 2000). As a result, the APOE ε4 allele markedly increases the risk of AD while the ε2 allele is protective against the disease relative to the reference ε3 allele. A recent heritability study estimates that the APOE locus contributes to 15% of ICH risk variance, and the heritability is driven by lobar ICH predominantly attributable to CAA (Devan et al., 2013). Indeed, prior literature shows that the APOE ε4 allele is associated with a higher risk of CAA (Greenberg et al., 1995, Premkumar et al., 1996), suggesting that CAA and AD may share a common biological mechanism such that APOE ε4 increases β-amyloid deposition in both brain and cerebral blood vessels. However, the association of APOE ε2 with CAA-related ICH is discordant with that of AD. The ε2 allele increases the risk for lobar ICH, and the association is stronger in cases with probable or definite CAA (Biffi et al., 2010, Tzourio et al., 2008, Valant et al., 2012). APOE ε2 carriers with lobar ICH also tend to have larger hematoma volume (Biffi et al., 2011) and an increased risk for hematoma expansion (Brouwers et al., 2012). These findings on ε2 suggest that distinct from ε4 which promotes the vascular amyloid deposition, ε2 is implicated in other vasculopathic changes leading to vessel rupture (Greenberg et al., 1998). Interestingly, an investigation on CAA burden by APOE genotypes shows that, compared with ε3/ε3, ε2 carriers have more severe CAA and parenchymal CAA in particular (Nelson et al., 2013). However, the relationship of ε2 with CAA is not clear as the association was not replicated in a more recent study using data from the National Alzheimer's Coordinating Center autopsied subjects (Serrano-Pozo et al., 2015). Notably, the latter is based on the clinical cohorts for AD, which may result in a disproportional distribution of APOE genotypes such as over-representation of ε4.
In this study, using data from >1000 autopsied subjects from the community, we investigated the relationship of the APOE genotypes and CAA in the presence of variable amounts of AD pathology. First, we examined the association of the APOE genotypes with a semiquantitative measure of CAA, adjusted for demographics and subsequently for AD and other pathologies. Because earlier literature suggests that amyloid deposition into capillary walls may represent a distinct morphological type (Thal et al., 2002), we also examined the association of APOE and CAA by capillary involvement. Next, we tested the hypothesis that there are 2 pathways that link the APOE genotypes to CAA; a direct pathway and an indirect pathway through AD pathology. The hypothesis for the indirect pathway is supported by findings from transgenic mice models that perivascular drainage pathways, rather than local production or blood uptake, are the mechanism underlying amyloid deposition in CAA, and that β-amyloid of neuronal origin is sufficient to cause cerebral neurodegeneration including CAA (Calhoun et al., 1999, Carare et al., 2008, Herzig et al., 2004, Van Dorpe et al., 2000).
Section snippets
Study cases
Brains are donated by the individuals from 2 ongoing clinical pathologic studies of aging, the Religious Orders Study and the Rush Memory and Aging Project (Bennett et al., 2012a, Bennett et al., 2012b). Participants enroll without known dementia and agree to annual clinical evaluations and brain donation after death. Both studies are approved by the Institutional Review Board of the Rush University Medical Center. An informed consent and an anatomical gift act are obtained from each
Amyloid angiopathy, AD, and other common neuropathologies
The pathologic characteristics of the study group are presented in Table 1. Briefly, more than a third (N = 374) had moderate to severe meningeal and/or parenchymal CAA, and 16% (N = 170) had capillary CAA. As would be expected, the 2 measures were highly correlated such that the capillary involvement was associated with more severe meningeal and/or parenchymal CAA (p < 0.001). About 18% of the subjects with capillary CAA (N = 31) had mild CAA in meningeal and/or parenchymal vessels.
A
Discussion
In this study, we show that both APOE ε2 and ε4 genotypes are associated with more severe CAA and the associations are independent of AD and other neuropathologies that are common in aging brain. We observe that APOE ε4, but not ε2, is associated with presence of capillary CAA. Accounting for capillary involvement did not alter the APOE associations with CAA.
The relation of APOE to CAA and CAA-related ICH has been previously reported. Earlier studies suggest that the ε2 and ε4 genotypes are
Conclusions
We investigated the relationship of the APOE genotypes, CAA, and AD pathology using genetic and neuropathologic data from >1000 postmortem human brains. We found that, the APOE ε4 and ε2 alleles were both associated with more severe meningeal and/or parenchymal CAA, and that the association of ε2 with CAA was initially masked by comorbid AD pathology. APOE ε4, but not ε2, was associated with capillary CAA. Furthermore, the associations of the APOE genotypes with CAA persisted with or without
Disclosure statement
The authors have no actual or potential conflicts of interest.
Acknowledgements
This study is supported by the National Institutes of Aging grants: P30AG10161, R01AG17917, R01AG15819, R01AG043379, R01AG34374, R01NS084965, and the Illinois Department of Public Health. The authors are thankful for the participants of the Religious Orders Study and the Rush Memory and Aging Project. The authors also thank all the staff of the Rush Alzheimer's Disease Center for their work.
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