Associations between the APOE‐ε2 and APOE‐ε4 alleles with resistance and resilience against Alzheimer's disease pathology. (1st February 2022) - Ossenkoppele, Rik
Abstract: 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‐ε4 showed 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.