背景:阿尔茨海默病(AD)的特征是淀粉样β(Aβ)斑块的积累,神经原纤维tau缠结,和脑实质的神经变性.这里,我们旨在(i)评估用于评估认知未受损的APOEε4纯合子中神经变性的血液和成像生物标志物的差异,杂合子,以及具有不同散发性AD风险的非携带者,和(Ii)确定不同的脑病理学(即,Aβ沉积,颞叶内侧萎缩,和脑血管病理学)有助于该样品中的血液生物标志物浓度。
方法:60个APOEε4纯合子(n=19),杂合子(n=21),非携带者(n=20)年龄从60岁到75岁,是与奥里亚生物银行(图尔库,芬兰)。参与者接受了Aβ-PET([11C]PiB),包括T1加权和T2-FLAIR序列的结构性脑MRI,和用于测量血清神经丝轻链(NfL)的血液采样,血浆总tau(t-tau),血浆N末端tau片段(NTA-tau)和血浆胶质纤维酸性蛋白(GFAP)。计算AD中Aβ积累的典型区域的[11C]PiB标准化摄取值比率。MRI图像分析区域体积,萎缩评分,和大量的白质高强度。使用单变量和多变量线性模型(未调整和针对年龄和性别调整)测试生物标志物水平的差异以及血液和成像生物标志物之间的关联。
结果:与非携带者相比,APOEε4纯合子的血清NfL浓度增加(平均21.4pg/ml(SD9.5)与15.5pg/ml(3.8),p=0.013),而其他血液生物标志物在两组之间没有差异(全部p>0.077).从成像生物标志物,与非携带者相比,APOEε4纯合子的海马体积显着降低(6.71ml(0.86)与7.2ml(0.7),p=0.029)。在整个样本中,三种测量的脑病理学对血液生物标志物水平的预测不同;血清NfL浓度与脑血管病理学和内侧颞叶萎缩有关,而血浆NTA-tau与内侧颞叶萎缩有关。血浆GFAP与内侧颞叶萎缩和Aβ病理均有显着关联。血浆t-tau浓度与任何测量的病理无关。
结论:与非携带者相比,仅在认知未受损的APOEε4纯合子中观察到血清NfL浓度增加和海马体积减少。在整个人群中,血液生物标志物的浓度以不同的方式受到不同病理的影响。
BACKGROUND: Alzheimer\'s disease (AD) is characterized by the accumulation of amyloid-β (Aβ) plaques, neurofibrillary tau tangles, and neurodegeneration in the brain parenchyma. Here, we aimed to (i) assess differences in blood and imaging biomarkers used to evaluate neurodegeneration among cognitively unimpaired APOE ε4 homozygotes, heterozygotes, and non-carriers with varying risk for sporadic AD, and (ii) to determine how different cerebral pathologies (i.e., Aβ deposition, medial temporal atrophy, and cerebrovascular pathology) contribute to blood biomarker concentrations in this sample.
METHODS: Sixty APOE ε4 homozygotes (n = 19), heterozygotes (n = 21), and non-carriers (n = 20) ranging from 60 to 75 years, were recruited in collaboration with Auria biobank (Turku, Finland). Participants underwent Aβ-PET ([11C]PiB), structural brain MRI including T1-weighted and T2-FLAIR sequences, and blood sampling for measuring serum neurofilament light chain (NfL), plasma total tau (t-tau), plasma N-terminal tau fragments (NTA-tau) and plasma glial fibrillary acidic protein (GFAP). [11C]PiB standardized uptake value ratio was calculated for regions typical for Aβ accumulation in AD. MRI images were analysed for regional volumes, atrophy scores, and volumes of white matter hyperintensities. Differences in biomarker levels and associations between blood and imaging biomarkers were tested using uni- and multivariable linear models (unadjusted and adjusted for age and sex).
RESULTS: Serum NfL concentration was increased in APOE ε4 homozygotes compared with non-carriers (mean 21.4 pg/ml (SD 9.5) vs. 15.5 pg/ml (3.8), p = 0.013), whereas other blood biomarkers did not differ between the groups (p > 0.077 for all). From imaging biomarkers, hippocampal volume was significantly decreased in APOE ε4 homozygotes compared with non-carriers (6.71 ml (0.86) vs. 7.2 ml (0.7), p = 0.029). In the whole sample, blood biomarker levels were differently predicted by the three measured cerebral pathologies; serum NfL concentration was associated with cerebrovascular pathology and medial temporal atrophy, while plasma NTA-tau associated with medial temporal atrophy. Plasma GFAP showed significant association with both medial temporal atrophy and Aβ pathology. Plasma t-tau concentration did not associate with any of the measured pathologies.
CONCLUSIONS: Only increased serum NfL concentrations and decreased hippocampal volume was observed in cognitively unimpaired APOEε4 homozygotes compared to non-carriers. In the whole population the concentrations of blood biomarkers were affected in distinct ways by different pathologies.