Oxford Centre for Human Brain Activity, Wellcome Centre for Integrative Neuroimaging, Department of Psychiatry, University of Oxford, UK.
Department of Psychiatry, University of Oxford, UK; Oxford Health NHS Foundation Trust, Warneford Hospital, Oxford, UK.
Cortex. 2018 Jul;104:103-123. doi: 10.1016/j.cortex.2018.03.025. Epub 2018 Mar 30.
APOE-ε4 is best known as a risk factor for Alzheimer's disease (AD). Consequently, there is considerable research interest in understanding whether APOE-ε4 influences cognition in healthy adults. Despite a substantial literature reporting effects of APOE genotype on cognition, findings are inconsistent. In particular, it is challenging to separate whether cognitive deficits in APOE-ε4 carriers reflect the influence of prodromal dementia pathology ("prodromal hypothesis"), or a direct contribution of APOE genotype to individual differences ("phenotype hypothesis"). Variable methodology across studies further complicates the issue. These challenges have limited what can be learnt about the processes underlying cognitive ageing and dementia by studying the influence of APOE genotype on cognition. In this review, we focus on the two compatible neurobiological mechanisms by which APOE genotype may influence cognition in healthy adults (prodromal and phenotype). We summarise the behavioural evidence for the influence of APOE on cognition in non-demented adults and explore key methodological challenges for disentangling the cognitive effects of different neurobiological mechanisms of APOE. Evidence suggests that at least some APOE-ε4 cognitive deficits are due to early AD pathology, whilst sensitive measures of cognition are beginning to reveal subtle cognitive differences between APOE genotypes in mid-adulthood, prior to the onset of the AD prodromal period. We conclude with recommendations for future research to investigate the cognitive consequences of neurobiological processes affected by APOE and maximise the translational potential of this research.
载脂蛋白 E-ε4 是阿尔茨海默病 (AD) 的主要风险因素。因此，人们非常关注了解载脂蛋白 E-ε4 是否会影响健康成年人的认知能力。尽管有大量研究报告了载脂蛋白 E 基因型对认知的影响，但研究结果并不一致。特别是，要区分载脂蛋白 E-ε4 携带者的认知缺陷是反映前驱性痴呆病理的影响（“前驱假说”），还是载脂蛋白 E 基因型对个体差异的直接贡献（“表型假说”），这具有一定的挑战性。研究之间方法学的差异进一步使问题复杂化。这些挑战限制了通过研究载脂蛋白 E 基因型对认知的影响来了解认知老化和痴呆背后的过程。在这篇综述中，我们重点关注载脂蛋白 E 基因型可能影响健康成年人认知的两种兼容的神经生物学机制（前驱假说和表型假说）。我们总结了载脂蛋白 E 对非痴呆成年人认知影响的行为证据，并探讨了在不同神经生物学机制的认知影响中分离的关键方法学挑战。有证据表明，至少一些载脂蛋白 E-ε4 认知缺陷是由于早期 AD 病理引起的，而对认知的敏感测量开始揭示在 AD 前驱期之前的中年时期，载脂蛋白 E 基因型之间的细微认知差异。我们最后提出了未来研究的建议，以研究受载脂蛋白 E 影响的神经生物学过程的认知后果，并最大限度地发挥这项研究的转化潜力。
