The role of even the strongest genetic risk factor for Alzheimer's disease (AD), the apolipoprotein E (APOE) ε4 allele, in its etiology remains poorly understood. We examined molecular signatures of AD defined as differences in linkage disequilibrium patterns between AD-affected and -unaffected whites (2673/16,246), Hispanics (392/867), and African Americans (285/1789), separately. We focused on 29 polymorphisms from 5 genes in the APOE region emphasizing beneficial and adverse effects of the APOE ε2- and ε4-coding single-nucleotide polymorphisms, respectively, and the differences in the linkage disequilibrium structures involving these alleles between AD-affected and -unaffected subjects. Susceptibility to AD is likely the result of complex interactions of the ε2 and ε4 alleles with other polymorphisms in the APOE region, and these interactions differ across races/ethnicities corroborating differences in the adverse and beneficial effects of the ε4 and ε2 alleles. Our findings support complex race/ethnicity-specific haplotypes promoting and protecting against AD in this region. They contribute to better understanding of polygenic and resilient mechanisms, which can explain why even homozygous ε4 carriers may not develop AD.

中文翻译：

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跨种族/民族的阿尔茨海默病的 APOE 区域分子特征


即使是阿尔茨海默病 (AD) 最强的遗传风险因素，即载脂蛋白 E (APOE) ε4 等位基因，其病因学中的作用仍知之甚少。我们分别检查了 AD 的分子特征，定义为受 AD 影响的白人 (2673/16,246)、西班牙裔美国人 (392/867) 和非裔美国人 (285/1789) 之间连锁不平衡模式的差异。我们重点研究了 APOE 区域 5 个基因的 29 个多态性，分别强调了 APOE ε2 和 ε4 编码单核苷酸多态性的有益和不利影响，以及 AD 影响和 - 之间涉及这些等位基因的连锁不平衡结构的差异不受影响的科目。 AD 易感性可能是 ε2 和 ε4 等位基因与 APOE 区域其他多态性复杂相互作用的结果，并且这些相互作用在不同种族/民族之间存在差异，证实了 ε4 和 ε2 等位基因的不利和有益影响存在差异。我们的研究结果支持复杂的种族/民族特异性单倍型在该地区促进和预防 AD。它们有助于更好地理解多基因和恢复机制，这可以解释为什么即使是纯合的 ε4 携带者也可能不会发展为 AD。