Background: Research indicates that polygenic indices of risk of Alzheimer’s disease are linked to clinical profiles.

Objective: Given the “genetic centrality” of the APOE gene, we tested whether this held true for both APOE-ε4 carriers and non-carriers.

Methods: A polygenic hazard score (PHS) was extracted from 784 non-demented participants recruited in the Alzheimer’s Disease Neuroimaging Initiative and stratified by APOE ε4 status. Datasets were split into sub-cohorts defined by clinical (unimpaired/MCI) and amyloid status (Aβ+/Aβ-). Linear models were devised in each sub-cohort and for each APOE-ε4 status to test the association between PHS and memory, executive functioning and grey-matter volumetric maps.

Results: PHS predicted memory and executive functioning in ε4ε3 MCI patients, memory in ε3ε3 MCI patients, and memory in ε4ε3 Aβ+ participants. PHS also predicted volume in sensorimotor regions in ε3ε3 Aβ+ participants.

Conclusion: The link between polygenic hazard and neurocognitive variables varies depending on APOE-ε4 allele status. This suggests that clinical phenotypes might be influenced by complex genetic interactions.

背景：研究表明，阿尔茨海默病风险的多基因指数与临床特征相关。

目的：鉴于 APOE 基因的“遗传中心性”，我们测试了这是否适用于 APOE-ε4 携带者和非携带者。

方法：从阿尔茨海默病神经影像学计划招募的 784 名非痴呆参与者中提取多基因风险评分 (PHS)，并按 APOE ε4 状态进行分层。数据集分为由临床（未受损/MCI）和淀粉样蛋白状态（Aβ+/Aβ-）定义的亚组。在每个亚组和每个 APOE-ε4 状态中设计了线性模型，以测试 PHS 与记忆、执行功能和灰质体积图之间的关联。

结果：PHS 预测了 ε4ε3 MCI 患者的记忆和执行功能、ε3ε3 MCI 患者的记忆和 ε4ε3 Aβ+ 参与者的记忆。PHS 还预测了 ε3ε3 Aβ+ 参与者的感觉运动区域的体积。

结论：多基因危害与神经认知变量之间的联系因 APOE-ε4 等位基因状态而异。这表明临床表型可能受到复杂遗传相互作用的影响。