Ramanan Vijay K, Risacher Shannon L, Nho Kwangsik, Kim Sungeun, Shen Li, McDonald Brenna C, Yoder Karmen K, Hutchins Gary D, West John D, Tallman Eileen F, Gao Sujuan, Foroud Tatiana M, Farlow Martin R, De Jager Philip L, Bennett David A, Aisen Paul S, Petersen Ronald C, Jack Clifford R, Toga Arthur W, Green Robert C, Jagust William J, Weiner Michael W, Saykin Andrew J
1 Centre for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN 46202, USA 1 Centre for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN 46202, USA 1 Centre for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN 46202, USA 4 Indiana Alzheimer Disease Centre, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
1 Centre for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN 46202, USA 4 Indiana Alzheimer Disease Centre, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Brain. 2015 Oct;138(Pt 10):3076-88. doi: 10.1093/brain/awv231. Epub 2015 Aug 11.
Brain amyloid deposition is thought to be a seminal event in Alzheimer's disease. To identify genes influencing Alzheimer's disease pathogenesis, we performed a genome-wide association study of longitudinal change in brain amyloid burden measured by (18)F-florbetapir PET. A novel association with higher rates of amyloid accumulation independent from APOE (apolipoprotein E) ε4 status was identified in IL1RAP (interleukin-1 receptor accessory protein; rs12053868-G; P = 1.38 × 10(-9)) and was validated by deep sequencing. IL1RAP rs12053868-G carriers were more likely to progress from mild cognitive impairment to Alzheimer's disease and exhibited greater longitudinal temporal cortex atrophy on MRI. In independent cohorts rs12053868-G was associated with accelerated cognitive decline and lower cortical (11)C-PBR28 PET signal, a marker of microglial activation. These results suggest a crucial role of activated microglia in limiting amyloid accumulation and nominate the IL-1/IL1RAP pathway as a potential target for modulating this process.
脑淀粉样蛋白沉积被认为是阿尔茨海默病中的一个关键事件。为了鉴定影响阿尔茨海默病发病机制的基因，我们对通过（18）F-氟代贝他吡PET测量的脑淀粉样蛋白负荷的纵向变化进行了全基因组关联研究。在白细胞介素-1受体辅助蛋白（IL1RAP；rs12053868-G；P = 1.38 × 10^(-9)）中发现了一种与较高淀粉样蛋白积累率相关的新关联，该关联独立于载脂蛋白E（APOE）ε4状态，并通过深度测序得到验证。IL1RAP rs12053868-G携带者更有可能从轻度认知障碍进展为阿尔茨海默病，并且在MRI上表现出更大的纵向颞叶皮质萎缩。在独立队列中，rs12053868-G与认知能力加速下降以及较低的皮质（11）C-PBR28 PET信号相关，（11）C-PBR28 PET信号是小胶质细胞活化的标志物。这些结果表明活化的小胶质细胞在限制淀粉样蛋白积累中起关键作用，并将白细胞介素-1/IL1RAP途径确定为调节这一过程的潜在靶点。
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