Alzheimer Prevention Program, Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, C/ Wellington, 30 08005, Barcelona, Spain.
IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.
Eur J Nucl Med Mol Imaging. 2021 Jul;48(7):2212-2224. doi: 10.1007/s00259-021-05192-8. Epub 2021 Feb 1.
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.
We analyzed data from 462 ADNI participants without dementia who underwent Aβ ([F]florbetapir or [F]florbetaben) and tau ([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 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 (β [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 [95%CI]: 0.64 [0.42, 0.82], p < 0.001) and tau burden (β 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 [95%CI]: 0.10 [- 0.02, 0.18], p = 0.11), and this association was fully mediated by baseline Aβ.
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.
研究载脂蛋白 E（APOE）ε2 和 ε4 等位基因与核心阿尔茨海默病（AD）病理标志物（通过淀粉样蛋白-β[β]和 tau PET 测量）之间的关联，这些标志物在没有痴呆的老年个体中存在。
我们分析了 462 名 ADNI 参与者的数据，这些参与者没有痴呆，他们接受了 Aβ[F]florbetapir 或[F]florbetaben 和 tau[F]flortaucipir PET、结构 MRI 和认知测试。以 APOE-ε3 纯合子作为参考组，使用线性回归模型研究 APOE-ε2 和 APOE-ε4 携带者与全球 Aβ PET 和区域性 tau PET 测量（内嗅皮层[ERC]、下颞叶皮层和 Braak-V/VI 新皮质复合区域）之间的关联。在 156 名参与者的一个亚组中，我们还使用线性混合模型研究了 APOE 基因型与区域 tau 随时间的积累之间的关联。最后，我们评估了 Aβ 是否介导了 APOE 基因型与 tau 之间的横断面和纵向关联。
与 APOE-ε3 纯合子相比，APOE-ε2 携带者的全球 Aβ 负担较低（β[95%置信区间（CI）]：-0.31[-0.45，-0.16]，p=0.034），但区域性 tau 负担或 tau 随时间的积累没有差异。APOE-ε4 参与者的 Aβ 更高（β[95%CI]：0.64[0.42，0.82]，p<0.001）和 tau 负担（β 范围：0.27-0.51，均 p<0.006）。在中介分析中，APOE-ε4 仅在 ERC 中保留了与 Aβ 无关的 tau 效应。与 APOE-ε3 纯合子相比，APOE-ε4 显示出在 Braak-V/VI 中随时间增加 tau 积累的趋势（β[95%CI]：0.10[-0.02，0.18]，p=0.11），并且这种关联完全由基线 Aβ 介导。
我们的数据表明，APOE-ε2 等位基因对发生临床 AD 的保护作用主要与抵抗 Aβ 沉积有关，而与 tau 病理无关。
