Clinical Memory Research Unit, Faculty of Medicine, Lund University, Lund, Sweden.
Department of Psychiatry and Behavioral Sciences, University of California, San Francisco.
JAMA Neurol. 2021 Feb 1;78(2):229-235. doi: 10.1001/jamaneurol.2020.3780.
Although the most common recent approach in Alzheimer disease drug discovery is to directly target the β-amyloid (Aβ) pathway, the high prevalence of apolipoprotein E ε4 (APOE ε4) in Alzheimer disease and the ease of identifying ε4 carriers make the APOE genotype and its corresponding protein (apoE) an appealing therapeutic target to slow Aβ accumulation.
To determine whether the ε2 allele is protective against Aβ accumulation in the presence of the ε4 allele and evaluate how age and the APOE genotype are associated with emerging Aβ accumulation and cognitive dysfunction.
DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study used screening data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease Study (A4 Study) collected from April 2014 to December 2017 and analyzed from November 2019 to July 2020. Of the 6943 participants who were a part of the multicenter clinical trial screening visit, 4432 were adults without cognitive impairment aged 65 to 85 years who completed a fluorine 18-labeled (18F)-florbetapir positron emission tomography scan, had APOE genotype information, and had a Clinical Dementia Rating of 0. Participants who were taking a prescription Alzheimer medication or had a current serious or unstable illness that could interfere with the study were excluded.
Aβ pathology, measured by 18F-florbetapir positron emission tomography and cognition, measured by the Preclinical Alzheimer Cognitive Composite.
A total of 4432 participants were included (mean [SD] age, 71.3 [4.7] years; 2634 women [59.4%]), with a mean (SD) of 16.6 (2.8) years of education and 1512 (34.1%) with a positive Aβ level. APOE ε2 was associated with a reduction in both the overall (standardized uptake value ratio [SUVR], ε24, 1.11 [95% CI, 1.08-1.14]; ε34, 1.18 [95% CI, 1.17-1.19]) and the age-dependent level of Aβ in the presence of ε4, with Aβ levels in the APOE ε24 group (n = 115; ε24, 0.005 SUVR increase per year of age) increasing at less than half the rate with respect to increasing age compared with the APOE ε34 group (n = 1295; 0.012 SUVR increase per year of age; P = .04). The association between Aβ and decreasing Preclinical Alzheimer Cognitive Composite scores did not differ by APOE genotype, and the reduced performance on the Preclinical Alzheimer Cognitive Composite in APOE ε4 carriers compared with noncarriers was completely mediated by Aβ (unadjusted difference in composite scores between ε4 carriers and noncarriers = -0.084, P = .005; after adjusting for 18F-florbetapir = -0.006, P = .85; after adjusting for 18F-florbetapir and cardiovascular scores = -0.009, P = .78).
These findings suggest that the protective outcome of carrying an ε2 allele in the presence of an ε4 allele against Aβ accumulation is important for potential treatments that attempt to biochemically mimic the function of the ε2 allele in order to facilitate Aβ clearance in ε4 carriers. Such a treatment strategy is appealing, as ε4 carriers make up approximately two-thirds of patients with Alzheimer disease dementia. This strategy could represent an early treatment option, as many ε4 carriers begin to accumulate Aβ in early middle age.
虽然阿尔茨海默病药物发现的最新方法是直接针对β-淀粉样蛋白（Aβ）途径，但载脂蛋白 E ε4（APOE ε4）在阿尔茨海默病中的高患病率以及识别 ε4 携带者的容易程度，使得 APOE 基因型及其相应的蛋白质（apoE）成为一种有吸引力的治疗靶点，可以减缓 Aβ 的积累。
确定 ε2 等位基因在存在 ε4 等位基因的情况下是否具有保护作用，以防止 Aβ 积累，并评估年龄和 APOE 基因型如何与新出现的 Aβ 积累和认知功能障碍相关。
设计、地点和参与者：这项横断面研究使用了来自 2014 年 4 月至 2017 年 12 月的无症状阿尔茨海默病抗淀粉样蛋白治疗研究（A4 研究）的筛选数据，并于 2019 年 11 月至 2020 年 7 月进行了分析。在参加多中心临床试验筛选访问的 6943 名参与者中，有 4432 名年龄在 65 至 85 岁之间、没有认知障碍的成年人完成了氟 18 标记（18F）-florbetapir 正电子发射断层扫描，有 APOE 基因型信息，并且临床痴呆评分（Clinical Dementia Rating）为 0。正在服用处方阿尔茨海默病药物或患有当前严重或不稳定疾病可能干扰研究的参与者被排除在外。
使用 18F-florbetapir 正电子发射断层扫描评估 Aβ 病理学，使用 Preclinical Alzheimer Cognitive Composite 评估认知。
共有 4432 名参与者被纳入（平均年龄[标准差]为 71.3[4.7]岁；2634 名女性[59.4%]），平均（标准差）受教育年限为 16.6（2.8）年，1512 名（34.1%）有阳性 Aβ 水平。APOE ε2 与 Aβ 总体水平（标准化摄取值比[SUVR]，ε24 为 1.11[95%CI，1.08-1.14]；ε34 为 1.18[95%CI，1.17-1.19]）和 Aβ 与年龄相关的水平均呈负相关，ε4 存在时，APOE ε2 携带的 Aβ 水平（n=115；ε24 为每年 0.005 SUVR 增加）与 APOE ε34 携带的 Aβ 水平（n=1295；每年 0.012 SUVR 增加）相比，增加速度较慢（P=0.04）。Aβ 与认知能力下降的 Preclinical Alzheimer Cognitive Composite 评分之间的关联与 APOE 基因型无关，并且与非携带者相比，APOE ε4 携带者的 Preclinical Alzheimer Cognitive Composite 表现降低完全由 Aβ 介导（ε4 携带者和非携带者之间复合评分的差异调整后为-0.084，P=0.005；调整后 18F-florbetapir 为-0.006，P=0.85；调整后 18F-florbetapir 和心血管评分后为-0.009，P=0.78）。
这些发现表明，在存在 ε4 等位基因的情况下携带 ε2 等位基因对 Aβ 积累的保护作用对于潜在的治疗方法很重要，这些治疗方法试图通过模拟 ε2 等位基因的功能来促进 ε4 携带者的 Aβ 清除。这种治疗策略很有吸引力，因为大约三分之二的阿尔茨海默病痴呆患者携带 ε4。这种策略可能代表了一种早期治疗选择，因为许多 ε4 携带者在中年早期开始积累 Aβ。
