Despite advances, the roles of genetic variants from the APOE-harboring 19q13.32 region in Alzheimer's disease (AD) remain controversial. We leverage a comprehensive approach to gain insights into a more homogeneous genetic architecture of AD in this region. We use a sample of 2,673 AD-affected and 16,246 unaffected subjects from four studies and validate our main findings in the landmark Alzheimer's Disease Genetics Consortium cohort (3,662 AD-cases and 1,541 controls). We report the remarkably high excesses of the AD risk for carriers of the ε4 allele who also carry minor alleles of rs2075650 (TOMM40) and rs12721046 (APOC1) polymorphisms compared to carriers of their major alleles. The exceptionally high 4.37-fold (p=1.34 × 10⁻³) excess was particularly identified for the minor allele homozygotes. The beneficial and adverse variants were significantly depleted and enriched, respectively, in the AD-affected families. This study provides compelling evidence for the definitive roles of the APOE-TOMM40-APOC1 variants in the AD risk.

尽管取得了进展，但来自携带APOE的 19q13.32 区域的遗传变异在阿尔茨海默病 (AD) 中的作用仍然存在争议。我们利用一种综合方法来深入了解该地区 AD 的更同质的遗传结构。我们使用来自四项研究的 2,673 名受 AD 影响和 16,246 名未受影响受试者的样本，并验证我们在具有里程碑意义的阿尔茨海默病遗传学联盟队列（3,662 名 AD 病例和 1,541 名对照）中的主要发现。我们报告了与主要等位基因的携带者相比，携带 rs2075650 ( TOMM40 ) 和 rs12721046 ( APOC1 ) 多态性的次要等位基因的 ε4 等位基因携带者的 AD 风险显着升高。异常高的 4.37 倍 ( p =1.34 × 10^-3 ) 特别确定了次要等位基因纯合子的过量。在受 AD 影响的家庭中，有益和不利的变体分别显着减少和富集。这项研究为APOE-TOMM40-APOC1变体在 AD 风险中的明确作用提供了令人信服的证据。