In this study, we assessed the effects of ApoE ε4 genotype on Aβ and tau burden and found a greater baseline Aβ and tau burden and higher tau accumulation rate in the ε4 + group than in the ε4- group. The Aβ accumulation rate in the ε4 + group was higher in small areas in the lateral temporal cortex. In Aβ + individuals, baseline tau burden in the ε4 + group was greater in the medial temporal regions and tau accumulation rate in the ε4 + group was higher in the small regions in the basal and lateral temporal cortices compared to the ε4- group.
Transgenic mice model with neuron-specific overexpression of ApoE ε4 showed greater phosphorylated tau burden in the neocortex and hippocampus , and tau transgenic mice with human ApoE ε4 exhibited greater tau burden in the hippocampus than those with ε2 or ε3 . A postmortem study showed ε4 gene dose-dependent increase in neurofibrillary tangle (NFT) pathology and thereby greater NFT pathology in the diffuse cortical areas in the AD patients with ε4 allele than those without . Another study showed greater cortical NFT pathology only in the AD patients homozygous for ε4 allele than those with a single ε4 allele or those without the allele . Unlike these transgenic mice and human postmortem studies, human cerebrospinal fluid (CSF) biomarker studies showed no differences in the level of CSF T-tau and P-tau between the ε4 + and ε4- groups [34, 35]. Moreover, one cross-sectional tau PET study in Aβ + MCI and AD patients demonstrated that the ε4- group conversely exhibited greater tau burden in the parieto-occipital cortex than the ε4 + group . However, our study results showed greater tau burden in the medial temporal areas even in the Aβ + individuals with the ε4 allele than in those without, although the result for the hippocampus was limited by the off-target binding in the choroid plexus neighboring hippocampus. This discrepancy may be attributable to the disproportionate frequency of the ε4 allele in different subtypes of AD. The hippocampal sparing type of AD is associated with a younger age at onset, lower frequency of the ApoE ε4 allele, greater tau burden particularly in the parietal cortex, faster cortical atrophy, and faster cognitive decline than the typical AD subtype [36–39]. Therefore, we suspect that the inclusion of a greater proportion of the hippocampal sparing subtype in the study cohort diluted an effect of ε4 on tau burden or even caused contrary results.
Although there has been a report demonstrating a longitudinal increase in CSF tau in AD patients , one longitudinal tau PET study in a small number of AD patients did not find an association between the ApoE genotypes and longitudinal changes in tau burden . In our results for all Aβ ± individuals, the regional tau accumulation rate was higher in the ε4 + group in the diffuse regions in the medial and lateral temporal and parieto-occipital cortices than that in the ε4- group. Moreover, even in the Aβ + individuals, higher tau accumulation rate was observed in the ε4 + group in the small regions in the temporal cortex suggesting the impact of ApoE ε4 genotype on progressive tau accumulation.
One recent tau PET study including 325 individuals (90% cognitively-unimpaired and 10% cognitively-impaired) showed an association of ApoE ε4 with increased tau burden in the entorhinal cortex, but they lost significance after adjusting for global cortical Aβ burden . In contrast, the other study including 489 individuals with more balanced distribution of cognitive status (57% cognitively-unimpaired and 43% cognitively-impaired) demonstrated an effect of ApoE ε4 on increased tau burden in the entorhinal cortex and hippocampus, and it persisted even after adjusting for global cortical Aβ burden like our study result . Moreover, the effect of ApoE ε4 on progressive tau accumulation was replicated after adjusting for global cortical Aβ burden in our longitudinal study. Therefore, tau accumulation may be accelerated by the presence of ApoE ε4 independent of Aβ burden.
The ApoE ε4 isoform was more likely to stimulate neuronal Aβ production than the other isoforms in vitro , and transgenic mice expressing the ApoE ε4 isoform showed less effective clearance of soluble Aβ from the brain interstitial fluid . Human autopsy findings demonstrated greater Aβ burden in the ε4 + than in the ε4- group not only in AD patients , but also in the MCI patients and CU individuals . Likewise, when compared to the individuals without the ε4 allele, a greater Aβ burden was observed in the global cortex in CU and MCI patients with ε4 allele , and in the temporo-parietal cortex in AD patients with ε4 allele in the PET studies . Our study also demonstrated greater Aβ burden in the diffuse cortical areas in individuals with the ε4 allele than in those without. In contrast to the strong association between the ε4 allele and baseline Aβ burden, we found a weak effect of ApoE ε4 on progressive Aβ accumulation in small regions in the lateral temporal cortex only in all Aβ ± individuals. The Aβ accumulation rate in the Aβ + individuals was not different between the ε4 + and ε4- groups like previous studies [9, 11], suggesting an effect of the ApoE ε4 allele on Aβ deposition only in the early stage of the disease.
Interestingly, Aβ burden in the Aβ + individuals was paradoxically greater in the ε4- group than in the ε4 + group, similar to the previous 11C-PIB and 18F-fluorodeoxyglucose PET studies that demonstrated lower Aβ burden and contrarily greater cortical hypometabolism in the AD patients with ε4 allele than in those without [46, 47]. This paradoxical effect of the ApoE ε4 allele on Aβ deposition can be expected by clinical studies that found an impact of the ApoE ε4 allele on Aβ burden in CU and MCI but not in those with AD [8, 34]. Furthermore, a study with transgenic mice demonstrated enhanced Aβ aggregation by ApoE4 in the early seeding stage but not in the later Aβ growth stage . An in vitro experiment demonstrated that ApoE ε4 binds to toxic Aβ oligomers and more potently delays further aggregation of Aβ into the PET-detectable fibril form than the other ApoE isoforms . Therefore, ApoE ε4 may play an important role in Aβ accumulation in the early stages of AD pathogenesis rather than in the advanced stages and may be more likely to be exposed to toxic oligomers. Subsequently, events toward final neurodegeneration may be induced, thereby shifting the hypothetical biomarker curves for tau and neurodegeneration to the Aβ curve . It is also interesting to note that a transgenic mice model expressing both Aβ and tau exhibited a smaller number of plaque than that expressing only Aβ . Greater microgliosis and reduction of the amyloid-precursor protein-producing neurons due to greater tau accumulation in ε4 carriers may be another possible mechanism explaining the paradoxically lower Aβ burden . However, this hypothesis cannot fully explain the mechanism due to mismatch between the cortical areas with greater Aβ burden in the ε4- group and those with greater tau burden in the ε4 + group (Fig. 1).