Höglund K, Kern S, Zettergren A, Börjesson-Hansson A, Zetterberg H, Skoog I, Blennow K
Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, Centre for ageing and Health, AgeCap, University of Gothenburg, Sahlgrenska University Hospital, Mölndal, Sweden.
Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Disease Research, Neurogeriatrics Division, Karolinska Institutet, Novum, Stockholm, Sweden.
Transl Psychiatry. 2017 Jan 10;7(1):e995. doi: 10.1038/tp.2016.252.
Brain autopsy and biomarker studies indicate that the pathology of Alzheimer's disease (AD) is initiated at least 10-20 years before clinical symptoms. This provides a window of opportunity to initiate preventive treatment. However, this emphasizes the necessity for biomarkers that identify individuals at risk for developing AD later in life. In this cross-sectional study, originating from three epidemiologic studies in Sweden (n=1428), the objective was to examine whether amyloid pathology, as determined by low cerebrospinal fluid (CSF) concentration of the 42 amino acid form of β-amyloid (Aβ42), is associated with biomarker evidence of other pathological changes in cognitively healthy elderly. A total of 129 patients were included and CSF levels of Aβ42, total tau, tau phosphorylated at threonine 181 (p-tau), neurogranin, VILIP-1, VEGF, FABP3, Aβ40, neurofilament light, MBP, orexin A, BDNF and YKL-40 were measured. Among these healthy elderly, 35.6% (N=46) had CSF Aβ42 levels below 530 pg ml. These individuals displayed significantly higher CSF concentrations of t-tau (P<0.001), p-tau (181) (P<0.001), neurogranin (P=0.009) and FABP3 (P=0.044) compared with amyloid-negative individuals. Our study indicates that there is a subpopulation among healthy older individuals who have amyloid pathology along with signs of ongoing neuronal and synaptic degeneration, as well as tangle pathology. Previous studies have demonstrated that increase in CSF tau and p-tau is a specific sign of AD progression that occurs downstream of the deposition of Aβ. On the basis of this, our data suggest that these subjects are at risk for developing AD. We also confirm the association between APOE ɛ4 and amyloid pathology in healthy older individuals.
脑部尸检和生物标志物研究表明，阿尔茨海默病（AD）的病理变化在临床症状出现前至少10 - 20年就已开始。这为启动预防性治疗提供了一个机会窗口。然而，这凸显了识别晚年有患AD风险个体的生物标志物的必要性。在这项横断面研究中，该研究源自瑞典的三项流行病学研究（n = 1428），目的是检查由脑脊液（CSF）中42个氨基酸形式的β - 淀粉样蛋白（Aβ42）浓度低所确定的淀粉样蛋白病理变化，是否与认知健康老年人其他病理变化的生物标志物证据相关。总共纳入了129名患者，并测量了CSF中Aβ42、总tau蛋白、苏氨酸181位点磷酸化的tau蛋白（p - tau）、神经颗粒素、VILIP - 1、血管内皮生长因子（VEGF）、脂肪酸结合蛋白3（FABP3）、Aβ40、神经丝轻链、髓鞘碱性蛋白（MBP）、食欲素A、脑源性神经营养因子（BDNF）和YKL - 40的水平。在这些健康老年人中，35.6%（N = 46）的CSF Aβ42水平低于530 pg/ml。与淀粉样蛋白阴性个体相比，这些个体的CSF中t - tau（P < 0.001）、p - tau（181）（P < 0.001）、神经颗粒素（P = 0.009）和FABP3（P = 0.044）浓度显著更高。我们的研究表明，在健康的老年人中存在一个亚群体，他们既有淀粉样蛋白病理变化，又有正在进行的神经元和突触退化迹象以及缠结病理变化。先前的研究表明，CSF中tau蛋白和p - tau蛋白增加是AD进展的一个特定标志，发生在Aβ沉积的下游。基于此，我们的数据表明这些受试者有患AD的风险。我们还证实了健康老年人中APOE ε4与淀粉样蛋白病理变化之间的关联。
