Association between IgM Anti-Herpes Simplex Virus and Plasma Amyloid-Beta Levels

ObjectiveHerpes simplex virus (HSV) reactivation has been identified as a possible risk factor for Alzheimer's disease (AD) and plasma amyloid-beta (Aβ) levels might be considered as possible biomarkers of the risk of AD. The aim of our study was to investigate the association between anti-HSV antibodies and plasma Aβ levels.
MethodsThe study sample consisted of 1222 subjects (73.9 y in mean) from the Three-City cohort. IgM and IgG anti-HSV antibodies were quantified using an ELISA kit, and plasma levels of Aβ1–40 and Aβ1–42 were measured using an xMAP-based assay technology. Cross-sectional analyses of the associations between anti-HSV antibodies and plasma Aβ levels were performed by multi-linear regression.
ResultsAfter adjustment for study center, age, sex, education, and apolipoprotein E-e4 polymorphism, plasma Aβ1–42 and Aβ1–40 levels were specifically inversely associated with anti-HSV IgM levels (β = −20.7, P = 0.001 and β = −92.4, P = 0.007, respectively). In a sub-sample with information on CLU- and CR1-linked SNPs genotyping (n = 754), additional adjustment for CR1 or CLU markers did not modify these associations (adjustment for CR1 rs6656401, β = −25.6, P = 0.002 for Aβ1–42 and β = −132.7, P = 0.002 for Aβ1–40; adjustment for CLU rs2279590, β = −25.6, P = 0.002 for Aβ1–42 and β = −134.8, P = 0.002 for Aβ1–40). No association between the plasma Aβ1–42-to-Aβ1–40 ratio and anti-HSV IgM or IgG were evidenced.
ConclusionHigh anti-HSV IgM levels, markers of HSV reactivation, are associated with lower plasma Aβ1–40 and Aβ1–42 levels, which suggest a possible involvement of the virus in the alterations of the APP processing and potentially in the pathogenesis of AD in human.

**研究目的**：现有研究证实单纯疱疹病毒（Herpes simplex virus, HSV）再激活可能是阿尔茨海默病（Alzheimer's disease, AD）的潜在危险因素，而血浆β淀粉样蛋白（amyloid-beta, Aβ）水平或可作为AD发病风险的潜在生物标志物。本研究旨在探讨抗HSV抗体与血浆Aβ水平之间的关联。
**研究方法**：本研究样本来自三城队列（Three-City cohort），共纳入1222名受试者，平均年龄为73.9岁。采用酶联免疫吸附试验（Enzyme-Linked Immunosorbent Assay, ELISA）试剂盒定量检测抗HSV IgM与IgG抗体水平，采用基于xMAP的检测技术测定血浆Aβ1–40及Aβ1–42水平。本研究采用多元线性回归对抗HSV抗体与血浆Aβ水平的关联开展横断面分析。
**研究结果**：在校正研究中心、年龄、性别、受教育程度及载脂蛋白Eε4基因多态性后，血浆Aβ1–42与Aβ1–40水平均与抗HSV IgM水平呈显著负相关（Aβ1–42：β=-20.7，P=0.001；Aβ1–40：β=-92.4，P=0.007）。在754名携带CLU与CR1相关单核苷酸多态性（single nucleotide polymorphisms, SNPs）基因分型数据的亚组受试者中，进一步校正CR1或CLU遗传标记后，上述关联未发生显著改变（校正CR1 rs6656401时，Aβ1–42的β=-25.6，P=0.002；Aβ1–40的β=-132.7，P=0.002；校正CLU rs2279590时，Aβ1–42的β=-25.6，P=0.002；Aβ1–40的β=-134.8，P=0.002）。未发现血浆Aβ1–42与Aβ1–40的比值与抗HSV IgM或IgG抗体水平存在关联。
**研究结论**：高滴度抗HSV IgM抗体作为HSV再激活的标志物，与较低的血浆Aβ1–40及Aβ1–42水平显著相关，这提示该病毒可能参与了人体淀粉样前体蛋白（amyloid precursor protein, APP）的代谢异常过程，并可能在阿尔茨海默病的人类发病机制中发挥作用。