Differential associations of APOE-ε2 and APOE-ε4 alleles with PET-measured amyloid-β and tau deposition in older individuals without dementia

Abstract

Purpose: 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.

Methods: 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.

Results: Compared to APOE-ε3 homozygotes, APOE-ε2 carriers had lower global Aβ burden (β_std [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 (β_std [95%CI]: 0.64 [0.42, 0.82], p < 0.001) and tau burden (β_std 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 (β_std [95%CI]: 0.10 [- 0.02, 0.18], p = 0.11), and this association was fully mediated by baseline Aβ.

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.

Keywords: APOE; Amyloid-β; Cognition; Cross-sectional; Hippocampal volumes; Longitudinal; PET; Sex interaction; Tau.

Fig. 1

Associations of APOE-ε2 and APOE-ε4 alleles with cross-sectional measures of Aβ (a) and tau burden (b-d). Tau regions studied were ERC (b), ITC (c), and Braak V-VI (d). PET measures are adjusted by age, sex, education, and diagnosis. Boxplots show median values (middle line) with lower and upper hinges corresponding to the first and third quartiles. Dots represent individual adjusted PET measures, with violin plots showing their distribution. Aβ, amyloid-β; ERC, entorhinal cortex; ITC, inferior temporal cortex; SUVR, standardized uptake value ratio. * p < 0.05; *** p < 0.001

Fig. 2

Mediation effect of Aβ on the association of APOE-ε4 with cross-sectional (top) and longitudinal (bottom) tau deposition in the ERC (a), ITC (b), and Braak V-VI (c and d). Dark green lines show the total effect of APOE-ε4 allele on tau burden, light green lines show the direct effect (i.e., without mediation), and blue lines depict the Aβ mediation effect. Path weights are only shown for significant paths and are displayed as (unstandardized) beta values with standard errors in brackets. Significance of the indirect effect was determined using bootstrapping with 5000 iterations. All models were adjusted by age, sex, education, and diagnosis. Aβ, amyloid-β; ERC, entorhinal cortex; ITC, inferior temporal cortex

Fig. 3

Associations of APOE-ε2 and APOE-ε4 alleles with longitudinal measures of regional tau accumulation. Linear slopes of tau PET SUVR change over time and their 95% confidence intervals, as determined from linear mixed models, are depicted for the different APOE genotypes and for the following regions: ERC (a), ITC (b), and Braak V-VI (c). PET measures are adjusted by age, sex, education, and diagnosis. ERC, entorhinal cortex; ITC, inferior temporal cortex. * p < 0.05