Importance The APOE ε2 and APOE ε4 alleles are the strongest protective and risk-increasing, respectively, genetic variants for late-onset Alzheimer disease (AD). However, the mechanisms linking APOE to AD-particularly the apoE protein's role in AD pathogenesis and how this is affected by APOE variants-remain poorly understood. Identifying missense variants in addition to APOE ε2 and APOE ε4 could provide critical new insights, but given the low frequency of additional missense variants, AD genetic cohorts have previously been too small to interrogate this question robustly. Objective To determine whether rare missense variants on APOE are associated with AD risk. Design, Setting, and Participants Association with case-control status was tested in a sequenced discovery sample (stage 1) and followed up in several microarray imputed cohorts as well as the UK Biobank whole-exome sequencing resource using a proxy-AD phenotype (stages 2 and 3). This study combined case-control, family-based, population-based, and longitudinal AD-related cohorts that recruited referred and volunteer participants. Stage 1 included 37 409 nonunique participants of European or admixed European ancestry, with 11 868 individuals with AD and 11 934 controls passing analysis inclusion criteria. In stages 2 and 3, 475 473 participants were considered across 8 cohorts, of which 84 513 individuals with AD and proxy-AD and 328 372 controls passed inclusion criteria. Selection criteria were cohort specific, and this study was performed a posteriori on individuals who were genotyped. Among the available genotypes, 76 195 were excluded. All data were retrieved between September 2015 and November 2021 and analyzed between April and November 2021. Main Outcomes and Measures In primary analyses, the AD risk associated with each missense variant was estimated, as appropriate, with either linear mixed-model regression or logistic regression. In secondary analyses, associations were estimated with age at onset using linear mixed-model regression and risk of conversion to AD using competing-risk regression. Results A total of 544 384 participants were analyzed in the primary case-control analysis; 312 476 (57.4%) were female, and the mean (SD; range) age was 64.9 (15.2; 40-110) years. Two missense variants were associated with a 2-fold to 3-fold decreased AD risk: APOE ε4 (R251G) (odds ratio, 0.44; 95% CI, 0.33-0.59; P = 4.7 × 10-8) and APOE ε3 (V236E) (odds ratio, 0.37; 95% CI, 0.25-0.56; P = 1.9 × 10-6). Additionally, the cumulative incidence of AD in carriers of these variants was found to grow more slowly with age compared with noncarriers. Conclusions and Relevance In this genetic association study, a novel variant associated with AD was identified: R251G always coinherited with ε4 on the APOE gene, which mitigates the ε4-associated AD risk. The protective effect of the V236E variant, which is always coinherited with ε3 on the APOE gene, was also confirmed. The location of these variants confirms that the carboxyl-terminal portion of apoE plays an important role in AD pathogenesis. The large risk reductions reported here suggest that protein chemistry and functional assays of these variants should be pursued, as they have the potential to guide drug development targeting APOE.

中文翻译：

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罕见 APOE 错义变异 V236E 和 R251G 与阿尔茨海默病风险的关联。

重要性 APOE ε2 和 APOE ε4 等位基因分别是最强的保护性和增加风险的迟发性阿尔茨海默病 (AD) 的遗传变异。然而，将 APOE 与 AD 联系起来的机制——尤其是 apoE 蛋白在 AD 发病机制中的作用以及它如何受到 APOE 变异体的影响——仍然知之甚少。除了 APOE ε2 和 APOE ε4 之外，识别错义变异可以提供重要的新见解，但鉴于其他错义变异的频率较低，AD 遗传队列以前太小而无法有力地审视这个问题。目的 确定 APOE 的罕见错义变异是否与 AD 风险相关。设计，设置，与病例对照状态的参与者关联在测序发现样本（第 1 阶段）中进行了测试，并在几个微阵列推算队列以及使用代理 AD 表型的 UK Biobank 全外显子组测序资源中进行了跟进（第 2 和第 3 阶段） . 这项研究结合了病例对照、基于家庭、基于人群和纵向 AD 相关队列，招募了推荐和志愿者参与者。第 1 阶段包括 37 409 名欧洲血统或混合欧洲血统的非独特参与者，其中 11 868 名患有 AD 的人和 11 934 名对照者通过了分析纳入标准。在第 2 和第 3 阶段，475 473 名参与者被纳入 8 个队列，其中 84 513 名患有 AD 和代理 AD 的个体以及 328 372 名对照者通过了纳入标准。选择标准是队列特定的，这项研究是对基因分型的个体进行的后验研究。在可用的基因型中，排除了 76 195 个。所有数据均于 2015 年 9 月至 2021 年 11 月间检索，并于 2021 年 4 月至 2021 年 11 月间进行分析。主要结果和测量 在主要分析中，使用线性混合模型回归或逻辑回归酌情估计与每个错义变异相关的 AD 风险. 在二次分析中，使用线性混合模型回归估计与发病年龄的关联，并使用竞争风险回归估计转化为 AD 的风险。结果 初步病例对照分析共纳入 544 384 名受试者；312 476 (57.4%) 人为女性，平均（SD；范围）年龄为 64.9（15.2；40-110）岁。两个错义变异与 AD 风险降低 2 至 3 倍相关：APOE ε4 (R251G)（比值比，0.44；95% CI，0.33-0.59；P = 4.7 × 10-8）和 APOE ε3 (V236E )（比值比，0.37；95% CI，0.25-0.56；P = 1.9 × 10-6）。此外，与非携带者相比，这些变异携带者的 AD 累积发病率随着年龄的增长而增长得更慢。结论和相关性 在这项遗传关联研究中，确定了一种与 AD 相关的新变异：R251G 始终与 APOE 基因上的 ε4 共同遗传，从而降低了 ε4 相关的 AD 风险。还证实了始终与 ε3 共同遗传的 V236E 变体对 APOE 基因的保护作用。这些变体的位置证实了 apoE 的羧基末端部分在 AD 发病机制中起着重要作用。