APOE and cerebral amyloid angiopathy in community-dwelling older persons

Abstract

Both cerebral amyloid angiopathy and Alzheimer's disease pathology involve abnormal β-amyloid processing. We aim to elucidate the relationship of the apolipoprotein E (APOE) genotypes with amyloid angiopathy in the presence of variable amounts of Alzheimer's pathology. Data came from 1062 autopsied subjects from 2 community-based studies of aging. Common neuropathologies including Alzheimer's disease and amyloid angiopathy were assessed using uniform methods. APOE was genotyped by sequencing the 2 polymorphisms in codons 112 and 158 of exon 4. We examined the associations of APOE with amyloid angiopathy using ordinal logistic regression analyses, controlling for demographics and subsequently Alzheimer's and other common pathologies. Moderate to severe amyloid angiopathy was identified in 35.2% (n = 374) of the subjects; 15.3% (n = 162) of the subjects were APOE ε2 carriers; and 26.1% (n = 277) ε4 carriers. Adjusting for demographics, the presence of ε4 allele, but not ε2, was associated with more severe amyloid angiopathy. After further adjustment for Alzheimer's pathology, both ε2 (odds ratio 1.707, 95% confidence interval 1.236-2.358, p = 0.001) and ε4 (odds ratio 2.284, 95% confidence interval 1.730-3.014, p < 0.001) were independently associated with amyloid angiopathy. The results were confirmed by path analysis. Furthermore, APOE ε4 carriers, but not ε2 carriers, were more likely to have capillary amyloid angiopathy. Accounting for capillary involvement did not alter the APOE associations with amyloid angiopathy. We conclude that both APOE ε2 and ε4 alleles are associated with more severe cerebral amyloid angiopathy, and the direct effect of ε2 is masked by the allele's negative association with comorbid Alzheimer's pathology. APOE ε4, but not ε2, is associated with capillary amyloid angiopathy.

Keywords: APOE; Alzheimer's disease; Capillaries; Cerebral amyloid angiopathy.

Figure 1

illustrates representative CAA localization by the APOE genotypes. (A) shows a subject with ε3/3 genotype with sparse CAA which is confined to segmental deposition of β amyloid in only meningeal vessels, and the cortex has few β amyloid plaques. (B) shows a ε2 carrier with CAA present in meningeal and intracerebral cortical vessels, as well as few β amyloid plaques in the cortex. (C) shows a ε4 carrier with marked CAA in meningeal and intracerebral cortical vessels, as well as frequent β amyloid plaques in the cortex. Scale bar = 150 μm.

Figure 2

illustrates relationship of AD pathology, CAA and APOE genotypes. (A) and (B) show the distribution of the composite measure of AD pathology by CAA. The association of CAA with more burden of AD pathology is evident. (C) shows the percentages of moderate to severe CAA by APOE genotypes. The figure illustrates isoform-dependent pattern of APOE (i.e. ε4>ε2>ε3) in relation to CAA. (D) shows the percentages of pathologic AD diagnosis by APOE genotypes. Here, we observe a different pattern in relation to AD (i.e. ε4>ε3>ε2), as compared with CAA (C).

Figure 3

summarizes the path analysis of APOE genotypes and CAA where the model links the presence of APOE ε2 allele, and separately ε4 allele, with CAA, either directly or indirectly through an effect on AD pathology. The path coefficients (standard errors) estimate the associations of APOE genotypes with AD and subsequently CAA. All the coefficients are significant, and the result reveals that there is a significant direct effect of ε2 on CAA which is masked by the allele’s negative association with AD pathology.