Department of Neurology and Neurological Sciences, Stanford University, Stanford, California.
Institut du Cerveau-Paris Brain Institute-ICM, Paris, France.
JAMA. 2023 Feb 21;329(7):551-560. doi: 10.1001/jama.2023.0268.
Numerous studies have established the association of the common APOE ε2 and APOE ε4 alleles with Alzheimer disease (AD) risk across ancestries. Studies of the interaction of these alleles with other amino acid changes on APOE in non-European ancestries are lacking and may improve ancestry-specific risk prediction.
To determine whether APOE amino acid changes specific to individuals of African ancestry modulate AD risk.
DESIGN, SETTING, AND PARTICIPANTS: Case-control study including 31 929 participants and using a sequenced discovery sample (Alzheimer Disease Sequencing Project; stage 1) followed by 2 microarray imputed data sets derived from the Alzheimer Disease Genetic Consortium (stage 2, internal replication) and the Million Veteran Program (stage 3, external validation). This study combined case-control, family-based, population-based, and longitudinal AD cohorts, which recruited participants (1991-2022) in primarily US-based studies with 1 US/Nigerian study. Across all stages, individuals included in this study were of African ancestry.
Two APOE missense variants (R145C and R150H) were assessed, stratified by APOE genotype.
The primary outcome was AD case-control status, and secondary outcomes included age at AD onset.
Stage 1 included 2888 cases (median age, 77 [IQR, 71-83] years; 31.3% male) and 4957 controls (median age, 77 [IQR, 71-83] years; 28.0% male). In stage 2, across multiple cohorts, 1201 cases (median age, 75 [IQR, 69-81] years; 30.8% male) and 2744 controls (median age, 80 [IQR, 75-84] years; 31.4% male) were included. In stage 3, 733 cases (median age, 79.4 [IQR, 73.8-86.5] years; 97.0% male) and 19 406 controls (median age, 71.9 [IQR, 68.4-75.8] years; 94.5% male) were included. In ε3/ε4-stratified analyses of stage 1, R145C was present in 52 individuals with AD (4.8%) and 19 controls (1.5%); R145C was associated with an increased risk of AD (odds ratio [OR], 3.01; 95% CI, 1.87-4.85; P = 6.0 × 10-6) and was associated with a reported younger age at AD onset (β, -5.87 years; 95% CI, -8.35 to -3.4 years; P = 3.4 × 10-6). Association with increased AD risk was replicated in stage 2 (R145C was present in 23 individuals with AD [4.7%] and 21 controls [2.7%]; OR, 2.20; 95% CI, 1.04-4.65; P = .04) and was concordant in stage 3 (R145C was present in 11 individuals with AD [3.8%] and 149 controls [2.7%]; OR, 1.90; 95% CI, 0.99-3.64; P = .051). Association with earlier AD onset was replicated in stage 2 (β, -5.23 years; 95% CI, -9.58 to -0.87 years; P = .02) and stage 3 (β, -10.15 years; 95% CI, -15.66 to -4.64 years; P = 4.0 × 10-4). No significant associations were observed in other APOE strata for R145C or in any APOE strata for R150H.
In this exploratory analysis, the APOE ε3[R145C] missense variant was associated with an increased risk of AD among individuals of African ancestry with the ε3/ε4 genotype. With additional external validation, these findings may inform AD genetic risk assessment in individuals of African ancestry.
大量研究已经确定了常见的 APOE ε2 和 APOE ε4 等位基因与阿尔茨海默病（AD）风险在不同种族中的关联。在非欧洲血统人群中，关于这些等位基因与 APOE 上其他氨基酸变化相互作用的研究较少，这可能会提高针对特定种族的风险预测。
确定 APOE 特定于非洲血统个体的氨基酸变化是否调节 AD 风险。
设计、地点和参与者：病例对照研究包括 31929 名参与者，并使用一个经过测序的发现样本（阿尔茨海默病测序项目；第 1 阶段），然后是 2 个基于微阵列的 imputed 数据集，这些数据集来自阿尔茨海默病遗传联盟（第 2 阶段，内部复制）和百万退伍军人计划（第 3 阶段，外部验证）。本研究结合了病例对照、基于家庭、基于人群和纵向 AD 队列，这些队列主要在美国进行研究，其中包括 1 项美国/尼日利亚研究。在所有阶段，纳入本研究的个体均为非洲裔。
评估了两个 APOE 错义变体（R145C 和 R150H），按 APOE 基因型分层。
主要结果是 AD 病例对照状态，次要结果包括 AD 发病年龄。
第 1 阶段包括 2888 例病例（中位年龄，77[IQR，71-83]岁；31.3%为男性）和 4957 例对照（中位年龄，77[IQR，71-83]岁；28.0%为男性）。在第 2 阶段，在多个队列中，包括 1201 例病例（中位年龄，75[IQR，69-81]岁；30.8%为男性）和 2744 例对照（中位年龄，80[IQR，75-84]岁；31.4%为男性）。在第 3 阶段，包括 733 例病例（中位年龄，79.4[IQR，73.8-86.5]岁；97.0%为男性）和 19406 例对照（中位年龄，71.9[IQR，68.4-75.8]岁；94.5%为男性）。在第 1 阶段的 ε3/ε4 分层分析中，R145C 存在于 52 名 AD 患者（4.8%）和 19 名对照（1.5%）中；R145C 与 AD 风险增加相关（比值比[OR]，3.01；95%置信区间[CI]，1.87-4.85；P=6.0×10-6），并且与报道的 AD 发病年龄较早相关（β，-5.87 岁；95%CI，-8.35 至-3.4 岁；P=3.4×10-6）。在第 2 阶段（R145C 存在于 23 名 AD 患者[4.7%]和 21 名对照[2.7%]中；OR，2.20；95%CI，1.04-4.65；P=0.04）中观察到与 AD 风险增加的关联得到复制，在第 3 阶段（R145C 存在于 11 名 AD 患者[3.8%]和 149 名对照[2.7%]中；OR，1.90；95%CI，0.99-3.64；P=0.051）中也观察到了关联。在第 2 阶段（β，-5.23 岁；95%CI，-9.58 至-0.87 岁；P=0.02）和第 3 阶段（β，-10.15 岁；95%CI，-15.66 至-4.64 岁；P=4.0×10-4）中，与 AD 发病年龄较早的关联得到了复制。在其他 APOE 分层或 R150H 的任何 APOE 分层中，均未观察到 R145C 或 R150H 的显著关联。
在这项探索性分析中，APOE ε3[R145C]错义变体与非洲血统个体中具有 ε3/ε4 基因型的 AD 风险增加相关。随着额外的外部验证，这些发现可能会为非洲裔个体的 AD 遗传风险评估提供信息。
