Raghavan Neha S, Dumitrescu Logan, Mormino Elizabeth, Mahoney Emily R, Lee Annie J, Gao Yizhe, Bilgel Murat, Goldstein David, Harrison Theresa, Engelman Corinne D, Saykin Andrew J, Whelan Christopher D, Liu Jimmy Z, Jagust William, Albert Marilyn, Johnson Sterling C, Yang Hyun-Sik, Johnson Keith, Aisen Paul, Resnick Susan M, Sperling Reisa, De Jager Philip L, Schneider Julie, Bennett David A, Schrag Matthew, Vardarajan Badri, Hohman Timothy J, Mayeux Richard
Department of Neurology, Columbia University Medical Center, New York, New York.
Department of Neurology, The New York Presbyterian Hospital, New York.
JAMA Neurol. 2020 Oct 1;77(10):1288-1298. doi: 10.1001/jamaneurol.2020.1760.
Genetic studies of Alzheimer disease have focused on the clinical or pathologic diagnosis as the primary outcome, but little is known about the genetic basis of the preclinical phase of the disease.
To examine the underlying genetic basis for brain amyloidosis in the preclinical phase of Alzheimer disease.
DESIGN, SETTING, AND PARTICIPANTS: In the first stage of this genetic association study, a meta-analysis was conducted using genetic and imaging data acquired from 6 multicenter cohort studies of healthy older individuals between 1994 and 2019: the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease Study, the Berkeley Aging Cohort Study, the Wisconsin Registry for Alzheimer's Prevention, the Biomarkers of Cognitive Decline Among Normal Individuals cohort, the Baltimore Longitudinal Study of Aging, and the Alzheimer Disease Neuroimaging Initiative, which included Alzheimer disease and mild cognitive impairment. The second stage was designed to validate genetic observations using pathologic and clinical data from the Religious Orders Study and Rush Memory and Aging Project. Participants older than 50 years with amyloid positron emission tomographic (PET) imaging data and DNA from the 6 cohorts were included. The largest cohort, the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease Study (n = 3154), was the PET screening cohort used for a secondary prevention trial designed to slow cognitive decline associated with brain amyloidosis. Six smaller, longitudinal cohort studies (n = 1160) provided additional amyloid PET imaging data with existing genetic data. The present study was conducted from March 29, 2019, to February 19, 2020.
A genome-wide association study of PET imaging amyloid levels.
From the 4314 analyzed participants (age, 52-96 years; 2478 participants [57%] were women), a novel locus for amyloidosis was noted within RBFOX1 (β = 0.61, P = 3 × 10-9) in addition to APOE. The RBFOX1 protein localized around plaques, and reduced expression of RBFOX1 was correlated with higher amyloid-β burden (β = -0.008, P = .002) and worse cognition (β = 0.007, P = .006) during life in the Religious Orders Study and Rush Memory and Aging Project cohort.
RBFOX1 encodes a neuronal RNA-binding protein known to be expressed in neuronal tissues and may play a role in neuronal development. The findings of this study suggest that RBFOX1 is a novel locus that may be involved in the pathogenesis of Alzheimer disease.
阿尔茨海默病的基因研究主要聚焦于临床或病理诊断这一主要结果，但对于该疾病临床前期的基因基础知之甚少。
研究阿尔茨海默病临床前期脑淀粉样变性的潜在基因基础。
设计、地点和参与者：在这项基因关联研究的第一阶段，对1994年至2019年间从6项针对健康老年人的多中心队列研究中获取的基因和影像数据进行了荟萃分析，这些研究包括：无症状阿尔茨海默病的抗淀粉样蛋白治疗研究、伯克利衰老队列研究、威斯康星州阿尔茨海默病预防登记处、正常个体认知衰退生物标志物队列、巴尔的摩纵向衰老研究以及阿尔茨海默病神经影像倡议（其中包括阿尔茨海默病和轻度认知障碍）。第二阶段旨在利用宗教团体研究和拉什记忆与衰老项目的病理和临床数据来验证基因观察结果。纳入了年龄超过50岁且有淀粉样蛋白正电子发射断层扫描（PET）影像数据及来自这6个队列的DNA的参与者。最大的队列，即无症状阿尔茨海默病的抗淀粉样蛋白治疗研究（n = 3154），是用于一项旨在减缓与脑淀粉样变性相关的认知衰退的二级预防试验的PET筛查队列。6项较小的纵向队列研究（n = 1160）提供了更多带有现有基因数据的淀粉样蛋白PET影像数据。本研究于2019年3月29日至2020年2月19日进行。
对PET影像淀粉样蛋白水平进行全基因组关联研究。
在4314名分析参与者（年龄52 - 96岁；2478名参与者[57%]为女性）中，除了APOE基因外，在RBFOX1基因内发现了一个新的淀粉样变性位点（β = 0.61，P = 3×10⁻⁹）。在宗教团体研究和拉什记忆与衰老项目队列中，RBFOX1蛋白定位于斑块周围，并且在生活中RBFOX1表达降低与更高的淀粉样β蛋白负荷（β = -0.008，P = 0.002）以及更差的认知（β = 0.007，P = 0.006）相关。
RBFOX1编码一种已知在神经组织中表达的神经元RNA结合蛋白，可能在神经元发育中起作用。本研究结果表明，RBFOX1是一个可能参与阿尔茨海默病发病机制的新位点。
