Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, Douglas Hospital, McGill University, Montreal, Québec, Canada.
Department of Neurology and Neurosurgery, McGill University, Montreal, Québec, Canada.
JAMA Neurol. 2020 Apr 1;77(4):470-479. doi: 10.1001/jamaneurol.2019.4421.
Apolipoprotein E ε4 (APOEε4) is the single most important genetic risk factor for Alzheimer disease. While APOEε4 is associated with increased amyloid-β burden, its association with cerebral tau pathology has been controversial.
To determine whether APOEε4 is associated with medial temporal tau pathology independently of amyloid-β, sex, clinical status, and age.
DESIGN, SETTING, AND PARTICIPANTS: This is a study of 2 cross-sectional cohorts of volunteers who were cognitively normal, had mild cognitive impairment (MCI), or had Alzheimer disease dementia: the Translational Biomarkers in Aging and Dementia (TRIAD) study (data collected between October 2017 and July 2019) and the Alzheimer's Disease Neuroimaging Initiative (ADNI) (collected between November 2015 and June 2019). The first cohort (TRIAD) comprised cognitively normal elderly participants (n = 124), participants with MCI (n = 50), and participants with Alzheimer disease (n = 50) who underwent tau positron emission tomography (PET) with fluorine 18-labeled MK6240 and amyloid-β PET with [18F]AZD4694. The second sample (ADNI) was composed of cognitively normal elderly participants (n = 157), participants with MCI (n = 83), and participants with Alzheimer disease (n = 25) who underwent tau PET with [18F]flortaucipir and amyloid-β PET with [18F]florbetapir. Exclusion criteria were a history of other neurological disorders, stroke, or head trauma. There were 489 eligible participants, selected based on availability of amyloid-PET, tau-PET, magnetic resonance imaging, and genotyping for APOEε4. Forty-five young adults (<30 years) from the TRIAD cohort were not selected for this study.
A main association between APOEε4 and tau-PET standardized uptake value ratio, correcting for age, sex, clinical status, and neocortical amyloid-PET standardized uptake value ratio.
The mean (SD) age of the 489 participants was 70.5 (7.1) years; 171 were APOEε4 carriers (34.9%), and 230 of 489 were men. In both cohorts, APOEε4 was associated in increased tau-PET uptake in the entorhinal cortex and hippocampus independently of amyloid-β, sex, age, and clinical status after multiple comparisons correction (TRIAD: β = 0.33; 95% CI, 0.19-0.49; ADNI: β = 0.13; 95% CI, 0.08-0.19; P < .001).
Our results indicate that the elevated risk of developing dementia conferred by APOEε4 genotype involves mechanisms associated with both amyloid-β and tau aggregation. These results contribute to an evolving framework in which APOEε4 has deleterious consequences in Alzheimer disease beyond its link with amyloid-β and suggest APOEε4 as a potential target for future disease-modifying therapeutic trials targeting tau pathology.
载脂蛋白 E ε4（APOEε4）是阿尔茨海默病最重要的单一遗传风险因素。虽然 APOEε4 与淀粉样蛋白-β 负担增加有关，但它与脑 tau 病理学的关系一直存在争议。
确定 APOEε4 是否与淀粉样蛋白-β、性别、临床状态和年龄无关，与内侧颞叶 tau 病理学有关。
设计、地点和参与者：这是一项对 2 个认知正常、轻度认知障碍（MCI）或阿尔茨海默病痴呆的志愿者的横断面队列研究：转化生物标志物在衰老和痴呆症（TRIAD）研究（数据收集于 2017 年 10 月至 2019 年 7 月）和阿尔茨海默病神经影像学倡议（ADNI）（收集于 2015 年 11 月至 2019 年 6 月）。第一个队列（TRIAD）包括认知正常的老年参与者（n=124）、MCI 参与者（n=50）和阿尔茨海默病参与者（n=50），他们接受了氟-18 标记的 MK6240 正电子发射断层扫描（PET）和 [18F]AZD4694 淀粉样蛋白-β PET。第二个样本（ADNI）由认知正常的老年参与者（n=157）、MCI 参与者（n=83）和阿尔茨海默病参与者（n=25）组成，他们接受了 [18F]flortaucipir 的 tau PET 和 [18F]florbetapir 的淀粉样蛋白-β PET。排除标准是有其他神经疾病、中风或头部外伤史。根据淀粉样蛋白-PET、tau-PET、磁共振成像和 APOEε4 基因型的可用性，选择了 489 名合格的参与者。TRIAD 队列中有 45 名年龄小于 30 岁的年轻人未被选入本研究。
APOEε4 与 tau-PET 标准化摄取值比之间的主要关联，校正年龄、性别、临床状态和新皮质淀粉样蛋白-PET 标准化摄取值比。
489 名参与者的平均（SD）年龄为 70.5（7.1）岁；171 人为 APOEε4 携带者（34.9%），489 人中 230 人为男性。在两个队列中，APOEε4 与内侧颞叶的 tau-PET 摄取增加有关，与淀粉样蛋白-β、性别、年龄和临床状态无关，经多次比较校正后（TRIAD：β=0.33；95%CI，0.19-0.49；ADNI：β=0.13；95%CI，0.08-0.19；P<0.001）。
我们的研究结果表明，APOEε4 基因型增加痴呆风险的机制涉及与淀粉样蛋白-β和 tau 聚集有关的机制。这些结果为不断发展的框架提供了依据，即在与淀粉样蛋白-β的联系之外，APOEε4 在阿尔茨海默病中具有有害后果，并表明 APOEε4 可能是针对 tau 病理学的未来疾病修饰治疗试验的潜在靶点。
