Salvadó, GemmaGrothe, Michel JGroot, ColinMoscoso, AlexisSchöll, MichaelGispert, Juan DomingoOssenkoppele, RikAlzheimer’s Disease Neuroimaging Initiative2023-02-092023-02-092021-02-01http://hdl.handle.net/10668/17078To 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. We analyzed data from 462 ADNI participants without dementia who underwent Aβ ([18F]florbetapir or [18F]florbetaben) and tau ([18F]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 genotype and 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. 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 or tau accumulation over time. APOE-ε4 participants showed higher Aβ (βstd [95%CI]: 0.64 [0.42, 0.82], p 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.enAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/APOEAmyloid-βCognitionCross-sectionalHippocampal volumesLongitudinalPETSex interactionTauAgedAllelesAlzheimer DiseaseAmyloid beta-PeptidesApolipoprotein E2Apolipoprotein E4Cross-Sectional StudiesGenotypeHumansPositron-Emission Tomographytau Proteinsresearch article33521872open access10.1007/s00259-021-05192-81619-7089PMC8175302https://link.springer.com/content/pdf/10.1007/s00259-021-05192-8.pdfhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175302/pdf