Department of Neurology, National Neuroscience Institute, Singapore.
Duke-NUS Graduate Medical School, Singapore.
Eur J Neurol. 2020 Nov;27(11):2292-2296. doi: 10.1111/ene.14290. Epub 2020 May 25.
Accumulated failures in Alzheimer's disease (AD) clinical trials have highlighted an urgent need to identify additional biomarkers involved in AD. Recently, mounting evidence reported that autoantibodies are ubiquitous in human sera. However, it is unknown whether autoantibodies are upregulated in amyloid-tau biomarker-confirmed AD.
A total of 40 subjects with mild dementia (Clinical Dementia Rating = 1) were stratified into AD (n = 16) and non-AD (n = 24) groups according to their cerebrospinal fluid levels of tau and Aβ . Their sera were collected and analyzed using a microarray containing > 1600 potential human autoantigens. Autoantibodies that were present exclusively in the AD group were identified and selected using the penetrance-based fold change method with the following criteria: penetrance fold change ≥ 2, frequency ≥ 15% and frequency = 0%.
All controls and samples passed the quality control criteria and were further used for biomarker analysis. Six autoantibodies with elevated responses to the following autoantigens were found exclusively in the AD group: nucleosome assembly protein 1-like 3 (31.3%, 5/16 subjects) and microtubule-associated protein 4, pantothenic acid kinase 3, phosphoinositide-3-kinase regulatory subunit 1, protein tyrosine phosphatase type IVA member 1 and SRY (sex-determining region Y)-box 15 (all 18.8%, 3/16 subjects).
Although some identified autoantigens are linked to AD and cognitive dysfunction, the increased autoantibody levels have not been reported in AD. Autoantibodies may provide deeper insights into the pathogenesis of AD and serve as diagnostic biomarkers; their corresponding antigens can be further studied to assess their potential as therapeutic targets.
阿尔茨海默病（AD）临床试验的屡屡失败凸显了确定其他参与 AD 的生物标志物的迫切需要。最近，越来越多的证据表明，自身抗体在人类血清中普遍存在。然而，尚不清楚自身抗体是否在淀粉样蛋白-tau 生物标志物确诊的 AD 中上调。
根据脑脊液中 tau 和 Aβ水平，将 40 名轻度痴呆（临床痴呆评定量表=1）患者分为 AD 组（n=16）和非 AD 组（n=24）。收集并分析他们的血清，使用包含>1600 种潜在人类自身抗原的微阵列。使用基于通透性的倍数变化方法，根据以下标准鉴定和选择仅存在于 AD 组中的自身抗体：通透性倍数变化≥2，频率≥15%，频率=0%。
所有对照和样本均通过质量控制标准，并进一步用于生物标志物分析。发现 6 种自身抗体对以下自身抗原的反应升高，仅存在于 AD 组：核小体装配蛋白 1 样 3（31.3%，16 名受试者中有 5 名）和微管相关蛋白 4、泛酸激酶 3、磷酸肌醇 3-激酶调节亚基 1、蛋白酪氨酸磷酸酶 IVA 成员 1 和性别决定区 Y-框 15（均为 18.8%，16 名受试者中有 3 名）。
尽管一些鉴定出的自身抗原与 AD 和认知功能障碍有关，但 AD 中并未报道自身抗体水平升高。自身抗体可能为 AD 的发病机制提供更深入的见解，并作为诊断生物标志物；其相应的抗原可以进一步研究，以评估其作为治疗靶点的潜力。
