Associations between the APOE-ε2 and APOE-ε4 alleles with resistance and resilience against Alzheimer's disease pathology

BACKGROUND: To examine associations between the APOE-ε2 and APOE-ε4 alleles and core Alzheimer's disease (AD) pathological hallmarks as measured by amyloid-β (Aβ) and tau PET in older individuals without dementia. METHOD: We analyzed data from 462 ADNI participants without dementia who underwent Aβ ([18 F]florbetapir or [18 F]florbetaben) and tau ([18 F]flortaucipir) PET, structural MRI and cognitive testing. Employing APOE-ε3 homozygotes as the reference group, associations between APOE-ε2 and APOE-ε4 carriership with global Aβ PET and regional tau PET measures (entorhinal cortex [ERC], inferior temporal cortex, and Braak-V/VI neocortical composite regions) were investigated using linear regression models. In a subset of 156 participants, we also investigated associations between APOE genotypeand regional tau accumulation over time using linear mixed models. Finally, we assessed whether Aβ mediated the cross-sectional and longitudinal associations between APOE genotype and tau. RESULT: Compared to APOE-ε3 homozygotes, APOE-ε2 carriers had lower global Aβ burden (βstd [95% confidence interval (CI)]:-0.31[-0.45,-0.16], p=0.034), but did not differ on regional tau burden (Figure-1) or tau accumulation over time (Figure-2). APOE-ε4 participants showed higher Aβ (βstd [95%CI]: 0.64[0.42,0.82], p<0.001) and tau burden (βstd range: 0.27-0.51, all p<0.006). In mediation analyses, APOE-ε4 only retained an Aβ-independent effect on tau in the ERC. APOE-ε4showed a trend towards increased tau accumulation over time in Braak-V/VI compared to APOE-ε3 homozygotes (βstd [95%CI]: 0.10[-0.02,0.18], p=0.11), and this association was fully mediated by baseline Aβ (Figure-3). CONCLUSION: Our data suggest that the established protective effect of the APOE-ε2 allele against developing clinical AD is primarily linked to resistance against Aβ deposition rather than tau pathology.