In this study we found within a series of prospectively characterized and clinicopathologically confirmed AD cases, ApoE ϵ4 carriers had a significantly higher percentage of “frequent” scores for plaques and tangles when using the CERAD scale when compared to ApoE ϵ4 non-carriers in several regions of the brain. These results imply that carrying the ϵ4 allele increases the density of pathologies in several brain regions. Since AD is characterized by senile plaques and tangles, our study supports previous evidence demonstrating that the presence of the ApoE ϵ4 allele is a strong contributor to increased AD pathology. However, our study also demonstrates a much more detailed continuum of AD pathology as it relates to ApoE genotype. To our knowledge, the relationship between ApoE genotype and AD pathology has not been reported in this manner before. Previous studies have reported AD pathology and ApoE ϵ4 associations in terms of odds ratios [5, 19]; however reporting this association in terms of CERAD score frequency may provide a more detailed picture of the differences in AD pathology severity between ApoE ϵ4 carriers and non-carriers. Additionally, we report this association as it relates to the distribution of CERAD pathology scores among different brain regions. In both ApoE ϵ4 carriers and non-carriers, we found that “sparse” and “moderate” plaque density scores were more prevalent in the hippocampus entorhinal regions when compared to the frontal, temporal, and parietal, regions in which “frequent” scores were more prevalent. Tangle density scores in the frontal, temporal, and parietal regions were more evenly distributed than plaque density scores within the ApoE ϵ4 carrier and non-carrier groups; however ApoE ϵ4 carriers had a higher prevalence of “frequent” scores for all brain regions when compared to non-carriers, except in the hippocampal and entorhinal areas among individuals age 90 and older where non-carriers had greater tangle pathology than carriers.
When analyzed by individual ApoE genotype, “none”, “sparse” and “moderate” plaque density scores were more prevalent among 3/3 carriers with 3/4 and 4/4 carriers having a higher prevalence of “frequent” scores among the different regions. A similar pattern was also noted for tangle density scores. There was a trend among all ApoE genotype groups for tangle pathology to be less frequent than plaque pathology in the frontal, temporal, and parietal regions. These results suggest that ApoE ϵ4 carries and non-carriers have independent neurodegenerative pathways in which plaque and tangle frequency vary among different cortical regions. Given that ApoE ϵ4 carrier status has been shown to result in differing clinical phenotypes of AD, [19–21] our results support these findings in demonstrating pathophysiologic differences between ApoE ϵ4 carriers and non-carriers.
Nagy et al.  found that, among all ApoE genotypes, 4/4 carriers displayed the greatest amount of AD pathology which is consistent with our results. In the current study, plaque and tangle pathologies increased in the genotype order 2/3<3/3<2/4<3/4<4/4 which has also been previously reported [5, 6]. Ohm et al.  showed that the mean stages for beta amyloid deposition and Braak stages for NFTs were higher in those who carried the ApoE ϵ4 allele in comparison to non-carriers [2, 5]. ApoE ϵ4 carriers not only had higher Braak NFT stages, but also an accelerated development of neurofibrillary changes [2, 5]. Additionally, those who were homozygous for the ϵ4 allele had higher mean Braak stages than ϵ4 heterozygotes.
Beffert et al.  found that subjects with AD had decreased ApoE levels in both the hippocampus and frontal cortex. However, beta amyloid levels were significantly higher in AD cases compared controls. Those with the ApoE ϵ4 allele were found to have higher levels of Aβ (1–40 and 1–42) and lower levels of ApoE compared to non-carriers of the allele. From these results, Beffert et al.  suggest that lower ApoE levels are associated with increased Aβ levels.
Richey et al.  found that ApoE bound avidly to senile plaques and NFTs in AD brains, suggesting a direct interaction between ApoE and the aggregation of Aβ and tau. It has been suggested that increased ApoE levels may be the result of a neuroprotective mechanism that is triggered in response to the formation of NFTs . If ApoE does play a protective role, then its common isoforms and their effects could vary in efficiency, with ApoE ϵ4 being the least efficient and ϵ2 the most. Beffert et al.  found decreased levels of ApoE in the hippocampus and the frontal cortex of AD brains which suggests that lower ApoE levels may make the brain more susceptible to the aggregation of AD pathology.
However, a study by Wisniewski et al.  showed that Aβ increases area ssociated with ApoE ϵ3 and ϵ4 in comparison to Aβ alone,with the ϵ4 isoform having the highest rate of increase in Aβ production. This implicates ApoE’s role as an accelerator for Aβ formation. It was also shown in vitro that the carboxyl-terminus of ApoE could, itself, form amyloid-like fibrils, which were congo-red positive and are present in senile plaques, further emphasizing its role as a pathological chaperone . Holtzman et al.  highlight the importance of ApoE lipidation status as it relates to amyloid deposition stating that decreases in ApoE lipidation lead to increased amyloid deposition through increased fibrillization of Aβ. In particular, ApoE ϵ4 is associated with greater Aβ fibrillization. Jiang et al.  state that ApoE lipidation status is important in terms of determining whether Aβ peptides are cleared from the brain or whether they fibrillize and become amyloid deposits.
Guo et al.  investigated the role of Aβ and its role as a potential neuroinflammatory stimulator in AD. The study found that ApoE ϵ3 and ApoE ϵ4 suppressed Aβ-induced endogenous ApoE levels, with ApoE ϵ4 having a more effective inhibitory action. However, it was shown that in the absence of Aβ, both of these ApoE isoforms stimulated cytokine interleukin-1β (IL-1β), a pro-inflammatory agent. Specifically, ApoE ϵ4 was associated with significantly more production of IL-1β than ApoE ϵ3. Guo et al.  concluded that overproduction of ApoE may trigger this particular pro-inflammatory response. It is also suggested that ApoE ϵ4 could be a less effective anti-inflammatory isoform compared to ϵ2 and ϵ3, explaining its association with higher risk for AD . Others have suggested that ApoE ϵ4 is associated with increased Aβ deposition and compromised neural repair mechanisms which, in conjunction, are associated with increased risk and observed pathology in AD .
One positive aspect of this study is the large sample size which allowed for differences to be seen between the different ApoE genotypes. Although the CERAD scoring scheme is commonly used to quantify AD pathology, it uses a semi-quantitative scoring system and does not provide an exact measurement of pathological densities. One weakness of our study was the low number of ApoE 2/4 carriers relative to the other genotypes so the comparisons of pathology score frequencies to the other genotypes may be somewhat biased. However, since the estimated prevalence of the ApoE 2/4 isoform is relatively low (2%)  and since the ϵ2 allele confers the lowest risk of developing AD , it would appear to be difficult to obtain a large number of these cases. The low prevalence of ϵ2 carriers in the general population may also be the reason that no ApoE 2/2 carriers were present in the sample as previous studies have estimated ϵ2 prevalence at approximately 7 to 8 percent [14, 31]. Also, the prevalence of ApoE ϵ4 carriers in this study was substantially higher than what would be expected in the general population . A meta analysis conducted by Ward et al.  found that the pooled prevalence rate of ApoE ϵ4 carriers in AD studies was 48.7% (95% CI: 46.5% - 51.0%). This suggests that AD studies are likely to have higher proportions of ApoE ϵ4 carriers relative to the general population given the role of ApoE ϵ4 as a risk factor for AD. From these results, it is not surprising that our sample also had a high proportion of ApoE ϵ4 carriers.
Another point of consideration is whether or not these results are dependent upon the proportion of different clinicopathologic subtypes of AD. Murray et al.  report that up to 25% of pathologically confirmed AD cases may be those with atypical pathologic presentations (limbic predominant [LP], hippocampal sparing [HpSp]). This study also found that the LP and HpSp subtypes were associated with ApoE ϵ4 non-carrier status, however this association was not statistically significant.
Also, the geographical area from which tissue samples were collected is relatively homogenous with respect to ethnicity and socioeconomic status so it cannot be stated that these results would apply to populations that are more ethnically and intellectually diverse.