Whether the deleterious effects of APOE4 are restricted to the Alzheimer’s disease (AD) spectrum or cause cognitive impairment irrespectively of the development of AD is still a matter of debate, and the focus of this study. Our analyses included APOE4 genotype, neuropsychological variables, amyloid-βeta (Aβ) and Tau markers, FDG-PET values, and hippocampal volumetry data derived from the healthy controls sample of the ADNI database. We formed 4 groups of equal size (n = 30) based on APOE4 carriage and amyloid-PET status. Baseline and follow-up (i.e., 48 months post-baseline) results indicated that Aβ-positivity was the most important factor to explain poorer cognitive performance, while APOE4 only exerted a significant effect in Aβ-positive subjects. Additionally, multiple regression analyses evidenced that, within the Aβ-positive sample, hippocampal volumetry explained most of the variability in cognitive performance for APOE4 carriers. These findings represent a strong support for the so-called preclinical/prodromal hypothesis, which states that the reported differences in cognitive performance between healthy carriers and non-carriers are mainly due to the APOE4’s capability to increase the risk of AD. Moreover, our results reinforce the notion that a synergistic interaction of Aβ and APOE4 elicits a neurodegenerative process in the hippocampus that might be the main cause of impaired cognitive performance.

APOE4 的有害影响是否仅限于阿尔茨海默病 (AD) 谱系或导致认知障碍与 AD 的发展无关，仍然是一个争论的问题，也是本研究的重点。我们的分析包括 APOE4 基因型、神经心理学变量、淀粉样蛋白-βeta (Aβ) 和 Tau 标志物、FDG-PET 值以及来自 ADNI 数据库的健康对照样本的海马体积数据。我们形成了 4 个大小相等的组（n = 30) 基于 APOE4 携带和淀粉样蛋白-PET 状态。基线和随访（即基线后 48 个月）结果表明，Aβ 阳性是解释较差认知表现的最重要因素，而 APOE4 仅在 Aβ 阳性受试者中发挥显着作用。此外，多元回归分析证明，在 Aβ 阳性样本中，海马体积法解释了 APOE4 携带者认知表现的大部分变异性。这些发现有力地支持了所谓的临床前/前驱假说，其中指出，报告的健康携带者和非携带者之间认知表现的差异主要是由于 APOE4 增加 AD 风险的能力。此外，我们的结果强化了这样一种观点，即 Aβ 和 APOE4 的协同相互作用会引发海马中的神经退行性过程，这可能是认知能力受损的主要原因。