APOLIPOPROTEIN E-EPSILON-4 ALLELES IN CEREBRAL AMYLOID ANGIOPATHY ANDCEREBROVASCULAR PATHOLOGY ASSOCIATED WITH ALZHEIMERS-DISEASE

The presence of apolipoprotein E-epsilon 4 (APOE-epsilon 4) allele has been implicated as a risk factor for Alzheimer's disease (AD). We exa mined the frequencies of APOE-epsilon 4 alleles in age-matched control s and subgroups of 190 AD subjects exhibiting cerebral amyloid angiopa thy (CAA) and other frequently associated lesions. CAA was evident in 96% of the AD subjects, which were divided into two groups, one bearin g mild or no apparent CAA and the other with moderate to severe CAA. A POE-epsilon 4 allele frequency (48%) in the latter advanced CAA group was six times higher than in those who exhibited mild CAA. In the adva nced CAA subjects, the occurrence of an epsilon 4 allele was increased by a factor of 17 (95% confidence interval, 7.56 to 38.9). This was d espite the fact that neocortical amyloid-beta plaque densities in the two groups were similar and that all of the AD subjects had met the ac cepted neuropathological criteria. We also observed that the degree of CAA severity was greatest in the group of subjects with the epsilon 4 /epsilon 4 genotype. The association between CAA and APOE-epsilon 4 wa s further implicated in two non-AD subjects among neurological control s with severe CAA, These two subjects, both homozygous for the APOE-ep silon 4 allele, were primarily diagnosed as having Creutzfeldt-Jakob d isease and Pick's disease is the absence of significant neocortical am yloid deposition. Allele frequency comparisons between neurological co ntrol subjects with CAA and those without likewise accorded a strong r elationship between the APOE-epsilon 4 allele and the presence of CAA. More remarkably, the epsilon 4 allele frequency was highly associated with AD subjects exhibiting lobar or intracerebral hemorrhage, all of whom had advanced CAA. We observed that 36% of the AD subjects had co ncomitant cerebrovascular pathology resulting from single infarcts, mu ltiple microinfarcts, ischemic white matter lesions, or petechial hemo rrhages. Although the difference in APOE genotype distribution between subjects with and without cerebrovascular lesions did not reach stati stical significance, we did note that the frequency of the epsilon 4 a llele was significantly higher in subjects with such pathology as comp ared with those without. However, we found no evidence to suggest that the acquisition of an APOE-epsilon 4 allele or one of the alleles, ep silon 2 or epsilon 3, was a factor in the occurrence of atherosclerosi s localized in the basal surface arteries. Analyses of our sample also confirm that there was a lower frequency of the APOE-epsilon 2 allele in AD subjects and that the frequency of the epsilon 4 allele in AD s ubjects with concomitant diffuse Lewy body disease was intermediate be tween controls and AD subjects. Our results suggest that the APOE-epsi lon 4 allele is a significant factor in the development of CAA in AD a nd reveal the possibility that APOE is an independent factor in CAA an d other vascular abnormalities associated with AD.