School of Psychology and Speech Pathology and Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia.
Brain. 2013 Jul;136(Pt 7):2201-16. doi: 10.1093/brain/awt127. Epub 2013 Jun 3.
Individuals who carry the apolipoprotein E ε4 polymorphism have an increased risk of late-onset Alzheimer's disease. However, because possession of the ε4 allele confers an increased risk for the diagnosis of dementia, it has proven problematic in older individuals to dissociate the influence of ε4 on cognitive capacity per se as distinct from its influence on clinical diagnostic status. We report a statistical approach that attempts to partial out the influence of diagnostic group membership (Alzheimer's disease, mild cognitive impairment, healthy control) from the influence of apolipoprotein ε4 genetic status on cognitive functioning. The cognitive phenotype hypothesis predicts that ε4-positive individuals will show cognitive deficits (relative to matched ε4-negative individuals) independent of the development of Alzheimer's disease. By contrast, the prodromal/preclinical Alzheimer's disease hypothesis proposes that the effect of apolipoprotein E status on cognitive performance is a function of the increased risk of dementia in individuals with the ε4 allele. We evaluated these hypotheses in the Australian Imaging, Biomarkers and Lifestyle cohort (n = 1112). We first determined whether previously reported findings concerning ε4 status and age-related neuropsychological performance could be explained by the inadvertent recruitment of people with mild cognitive impairment into the healthy control group. We then tested each diagnostic group in isolation to identify any neuropsychological patterns that may be attributed to the ε4 allele. Finally, as interactions between the ε4 allele and age have previously been reported in cognitive functioning within healthy elderly populations, we attempted to determine whether the inclusion of mild cognitively impaired individuals in the sample may drive this relationship. An extensive battery of standardized, well-validated neuropsychological tasks was administered to a final sample of 764 healthy control subjects, 131 individuals with mild cognitive impairment and 168 individuals with Alzheimer's disease. The effect of the ε4 allele on cognitive performance was assessed using a statistical mediation analysis and supplemented with Bayesian methods to address a number of the limitations associated with Fisherian/Neyman-Pearsonian significance testing. Our findings support the prodromal/preclinical Alzheimer's disease hypothesis and do not support the concept of a distinctive ε4-related cognitive phenotype.
携带载脂蛋白 E ε4 多态性的个体患晚发性阿尔茨海默病的风险增加。然而，由于 ε4 等位基因的存在会增加痴呆症的诊断风险，因此在老年个体中，将 ε4 对认知能力本身的影响与对临床诊断状态的影响区分开来一直存在问题。我们报告了一种统计方法，试图从载脂蛋白 ε4 遗传状态对认知功能的影响中分离出诊断组归属（阿尔茨海默病、轻度认知障碍、健康对照组）的影响。认知表型假说预测，ε4 阳性个体将表现出认知缺陷（相对于匹配的 ε4 阴性个体），而与阿尔茨海默病的发展无关。相比之下，前驱/临床前阿尔茨海默病假说提出，载脂蛋白 E 状态对认知表现的影响是 ε4 等位基因个体痴呆风险增加的函数。我们在澳大利亚成像、生物标志物和生活方式队列（n = 1112）中评估了这些假设。我们首先确定以前关于 ε4 状态与年龄相关神经心理学表现的研究结果是否可以通过无意中招募轻度认知障碍患者进入健康对照组来解释。然后，我们单独测试每个诊断组，以确定可能归因于 ε4 等位基因的任何神经心理学模式。最后，由于以前在认知功能正常的老年人群中报道了 ε4 等位基因与年龄之间的相互作用，我们试图确定在样本中纳入轻度认知障碍个体是否会导致这种关系。对最终样本（764 名健康对照组、131 名轻度认知障碍患者和 168 名阿尔茨海默病患者）进行了一整套标准化、经过充分验证的神经心理学测试。使用统计中介分析评估 ε4 等位基因对认知表现的影响，并辅以贝叶斯方法解决与费歇尔/内曼-皮尔逊显著性检验相关的许多限制。我们的研究结果支持前驱/临床前阿尔茨海默病假说，不支持独特的 ε4 相关认知表型的概念。
