The apolipoprotein E allele 4 (APOE-ε4) is established as a major genetic risk factor for cognitive decline and late-onset Alzheimer’s disease. Accumulating evidence has linked ε4 carriership to abnormal structural brain changes across the adult lifespan. To better understand the underlying causal mechanisms, we investigated the extent to which the effect of the ε4 allele on cognition is mediated by structural brain imaging markers in the population-based Age, Gene/Environment Susceptibility–Reykjavik Study (AGES-Reykjavik). This study included 4527 participants (aged 76.3 ± 5.4 at baseline) who underwent the brain magnetic resonance imaging assessment (of brain tissue volumes, white matter lesion volume, subcortical and cortical infarcts, and cerebral microbleeds) and a battery of neuropsychological tests at baseline. Causal mediation analysis was used to quantify the mediation of the ε4 effect on cognition by these MRI markers, both individually and jointly. We observed that about 9% of the total effect of ε4 carriership on cognition was mediated by white matter lesion volume. This proportion increased to 25% when total brain tissue volume was jointly considered with white matter lesion volume. In analyses separating ε4 homozygotes from ε4 heterozygotes, the effect on global cognition of specifically ε4 homozygosity appeared to be partially mediated by cerebral microbleeds, particularly lobar microbleeds. There was no evidence of mediation of the ε4 effect by cortical or subcortical infarcts. This study shows that the ε4 effect on cognition is partly mediated by white matter lesion volume and total brain tissue volume. These findings suggest the joint role of cerebral small vessel disease and neurodegeneration in the ε4-cognition relationship.

载脂蛋白 E 等位基因 4 ( APOE-ε4) 被确定为认知能力下降和迟发性阿尔茨海默病的主要遗传风险因素。越来越多的证据已将 ε4 携带与整个成人寿命期间的异常大脑结构变化联系起来。为了更好地理解潜在的因果机制，我们调查了 ε4 等位基因对认知的影响在多大程度上由基于人群的年龄、基因/环境易感性-雷克雅未克研究 (AGES-Reykjavik) 中的结构性脑成像标记介导。这项研究包括 4527 名参与者（基线时年龄为 76.3 ± 5.4 岁），他们在基线时接受了脑磁共振成像评估（脑组织体积、白质病变体积、皮质下和皮质梗塞以及脑微出血）和一系列神经心理学测试。因果中介分析用于量化这些 MRI 标记对认知的 ε4 影响的中介，包括单独和联合。我们观察到，ε4 携带对认知的总影响中约有 9% 是由白质病变体积介导的。当脑组织总体积与白质病变体积共同考虑时，这一比例增加到 25%。在将 ε4 纯合子与 ε4 杂合子分开的分析中，特别是 ε4 纯合子对整体认知的影响似乎部分由脑微出血介导，尤其是脑叶微出血。没有证据表明皮质或皮质下梗塞介导了 ε4 效应。这项研究表明，ε4 对认知的影响部分是由白质病变体积和脑组织总体积介导的。