PDF(Pubmed)
Abstract：
Alzheimer\'s disease typically progresses in stages, which have been defined by the presence of disease-specific biomarkers: amyloid (A), tau (T) and neurodegeneration (N). This progression of biomarkers has been condensed into the ATN framework, in which each of the biomarkers can be either positive (+) or negative (-). Over the past decades, genome-wide association studies have implicated ∼90 different loci involved with the development of late-onset Alzheimer\'s disease. Here, we investigate whether genetic risk for Alzheimer\'s disease contributes equally to the progression in different disease stages or whether it exhibits a stage-dependent effect. Amyloid (A) and tau (T) status was defined using a combination of available PET and CSF biomarkers in the Alzheimer\'s Disease Neuroimaging Initiative cohort. In 312 participants with biomarker-confirmed A-T- status, we used Cox proportional hazards models to estimate the contribution of APOE and polygenic risk scores (beyond APOE) to convert to A+T- status (65 conversions). Furthermore, we repeated the analysis in 290 participants with A+T- status and investigated the genetic contribution to conversion to A+T+ (45 conversions). Both survival analyses were adjusted for age, sex and years of education. For progression from A-T- to A+T-, APOE-e4 burden showed a significant effect [hazard ratio (HR) = 2.88; 95% confidence interval (CI): 1.70-4.89; P < 0.001], whereas polygenic risk did not (HR = 1.09; 95% CI: 0.84-1.42; P = 0.53). Conversely, for the transition from A+T- to A+T+, the contribution of APOE-e4 burden was reduced (HR = 1.62; 95% CI: 1.05-2.51; P = 0.031), whereas the polygenic risk showed an increased contribution (HR = 1.73; 95% CI: 1.27-2.36; P < 0.001). The marginal APOE effect was driven by e4 homozygotes (HR = 2.58; 95% CI: 1.05-6.35; P = 0.039) as opposed to e4 heterozygotes (HR = 1.74; 95% CI: 0.87-3.49; P = 0.12). The genetic risk for late-onset Alzheimer\'s disease unfolds in a disease stage-dependent fashion. A better understanding of the interplay between disease stage and genetic risk can lead to a more mechanistic understanding of the transition between ATN stages and a better understanding of the molecular processes leading to Alzheimer\'s disease, in addition to opening therapeutic windows for targeted interventions.
摘要：
阿尔茨海默病通常分阶段进展，这已经被定义为疾病特异性生物标志物的存在：淀粉样蛋白（A），Tau(T)和神经变性(N)。生物标志物的这种进展已经浓缩到ATN框架中，其中每个生物标志物可以是阳性(+)或阴性(-)。在过去的几十年中，全基因组关联研究表明，约有90个不同的基因座与迟发性阿尔茨海默病的发展有关。在这里，我们调查阿尔茨海默病的遗传风险是否在不同的疾病阶段同样有助于进展，或者它是否表现出阶段依赖性效应。淀粉样蛋白（A）和tau（T）状态是在阿尔茨海默病神经影像学计划队列中使用可用的PET和CSF生物标志物的组合来定义的。在312名具有生物标志物确认的A-T状态的参与者中，我们采用Cox比例风险模型来估计APOE和多基因风险评分(APOE以外)对转换为A+T-状态(65次转换)的贡献.此外，我们对290名具有A+T-状态的参与者重复了分析,并调查了转化为A+T+(45次转化)的遗传贡献.两项生存分析均根据年龄进行了调整，性别,和多年的教育。对于从A-T-到A+T-的进展，APOE-e4负荷显示出显着影响（HR=2.88；95％CI：1.70-4.89；P<0.001），而多基因风险则没有（HR=1.09；95%CI：0.84-1.42；P=0.53）。相反，对于从A+T-到A+T+的过渡，APOE-e4负担贡献降低(HR=1.6295%CI：1.05-2.51；P=0.031)，而多基因风险的贡献增加（HR=1.73；95％CI：1.27-2.36；P<0.001）。边缘APOE效应由e4纯合子（HR=2.58；95％CI：1.05-6.35；P=0.039）驱动，而e4杂合子（HR=1.74；95％CI：0.87-3.49；P=0.12）。迟发性阿尔茨海默病的遗传风险以疾病阶段依赖的方式展开。更好地理解疾病阶段和遗传风险之间的相互作用可以导致对ATN阶段之间过渡的更机械的理解。更好地了解导致阿尔茨海默病的分子过程，并为有针对性的干预措施打开治疗窗口。
