To evaluate how age and Apolipoprotein E-ϵ4 (APOE4) status interact with APOE4-independent polygenic risk score (PRS_non-APOE), we estimated PRS_non-APOE in superagers (age ≥ 90 years, N=346), 89- controls (age 60-89, N=2,930) and Alzheimer's Disease (AD) cases (N=1,760). Employing superagers, we see a nearly five times greater odds ratio (OR) for AD comparing the top PRS_non-APOE decile to the lowest decile (OR=4.82, P=2.5x10^-6), which is twice the OR as using 89- controls (OR=2.38, P=4.6x10^-9). Thus PRS_non-APOE is correlated with age, which in turn is associated with APOE. Further exploring these relationships, we find that PRS_non-APOE modifies age-at-onset among APOE4 carriers, but not among non-carriers. More specifically, PRS_non-APOE in the top decile predicts an age-at-onset five years earlier compared to the lowest decile (70.1 vs 75.0 years; t-test P=2.4x10^-5) among APOE4 carriers. This disproportionally large PRS_non-APOE among younger APOE4-positive cases is reflected in a significant statistical interaction between APOE4 status and age-at-onset (β=-0.02, P=4.8x10^-3) as a predictor of PRS_non-APOE. Thus, the known AD risk variants are particularly detrimental in young APOE4 carriers.

中文翻译：

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载脂蛋白E-ϵ4携带者的年轻病例中多基因风险评分对阿尔茨海默氏病的影响更大

为了评估年龄和载脂蛋白E-ϵ4（APOE4）状况与不依赖APOE4的多基因风险评分（PRS _non-APOE）的相互作用，我们估算了89岁以上超龄者的PRS _non-APOE（年龄≥90岁，N = 346）。 （60-89岁，N = 2,930）和阿尔茨海默氏病（AD）病例（N = 1,760）。使用超级年龄，我们将AD的最高_非APOE位数与最低的十分位数（OR = 4.82，P = 2.5x10 ^-6）进行比较，发现AD的优势比（OR）接近五倍，这是使用89的OR的两倍-控件（OR = 2.38，P = 4.6x10 ^-9）。因此，PRS_非APOE与年龄相关，而年龄又与APOE相关。进一步研究这些关系，我们发现PRS_非APOE会改变APOE4携带者之间的发病年龄，而非非携带者之间。更具体地说，与APOE4携带者中最低的十分位（70.1对75.0岁；t检验P = 2.4x10 ^-5）相比，最高十分位中的PRS_非APOE预测发病年龄要早5年。在年轻的APOE4阳性病例中，这种比例过大的PRS _non-APOE反映在APOE4状态与发病年龄之间的显着统计学相互作用（β= -0.02，P = 4.8x10 ^-3）作为PRS _non-APOE的预测因子。因此，已知的AD风险变体对年轻的APOE4携带者尤其有害。