Neha S Raghavan1,2,3,4, Logan Dumitrescu5,6, Elizabeth Mormino7, Emily R Mahoney5,6, Annie J Lee1,2,3, Yizhe Gao1,2,3, Murat Bilgel8, David Goldstein1,2,3, Theresa Harrison9, Corinne D Engelman10, Andrew J Saykin11,12, Christopher D Whelan13, Jimmy Z Liu13, William Jagust9, Marilyn Albert14, Sterling C Johnson15, Hyun-Sik Yang16,17, Keith Johnson16,17, Paul Aisen18, Susan M Resnick8, Reisa Sperling16,17, Philip L De Jager1,2,3,19,20, Julie Schneider21, David A Bennett21, Matthew Schrag5, Badri Vardarajan1,2,3,4, Timothy J Hohman5,6, Richard Mayeux1,2,3,4. 1. Department of Neurology, Columbia University Medical Center, New York, New York. 2. Department of Neurology, The New York Presbyterian Hospital, New York. 3. Taub Institute for Research on Alzheimer's Disease and The Aging Brain, Columbia University Medical Center, New York, New York. 4. The Institute for Genomic Medicine, Columbia University Medical Center, New York, New York. 5. Vanderbilt Memory and Alzheimer's Center, Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee. 6. Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tennessee. 7. Department of Neurology and Neurological Sciences, Stanford University, Stanford, California. 8. Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, Maryland. 9. Helen Wills Neuroscience Institute, University of California, Berkeley. 10. Department of Population Health Sciences, University of Wisconsin, School of Medicine and Public Health, Madison. 11. Department of Radiology and Imaging Sciences, Center for Neuroimaging, School of Medicine, Indiana University, Indianapolis. 12. Department of Medical and Molecular Genetics, School of Medicine, Indiana University, Indianapolis. 13. Research and Early Development, Biogen Inc, Cambridge, Massachusetts. 14. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland. 15. Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison. 16. Department of Neurology, Massachusetts General Hospital, Boston. 17. Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts. 18. Alzheimer's Therapeutic Research Institute, Keck School of Medicine, University of Southern California, San Diego. 19. Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, New York. 20. Cell Circuits Program, Broad Institute, Cambridge, Massachusetts. 21. Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois.
Abstract
Importance: 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. Objective: 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. Main Outcomes and Measures: A genome-wide association study of PET imaging amyloid levels. Results: 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. Conclusions and Relevance: 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.
Importance: 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. Objective: 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. Main Outcomes and Measures: A genome-wide association study of PET imaging amyloid levels. Results: 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. Conclusions and Relevance: 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.
Authors: Mehmet Ilyas Cosacak; Prabesh Bhattarai; Philip L De Jager; Vilas Menon; Giuseppe Tosto; Caghan Kizil Journal: Cells Date: 2022-05-31 Impact factor: 7.666
Authors: Dallas P Veitch; Michael W Weiner; Paul S Aisen; Laurel A Beckett; Charles DeCarli; Robert C Green; Danielle Harvey; Clifford R Jack; William Jagust; Susan M Landau; John C Morris; Ozioma Okonkwo; Richard J Perrin; Ronald C Petersen; Monica Rivera-Mindt; Andrew J Saykin; Leslie M Shaw; Arthur W Toga; Duygu Tosun; John Q Trojanowski Journal: Alzheimers Dement Date: 2021-09-28 Impact factor: 16.655
Authors: Christopher J Weber; Maria C Carrillo; William Jagust; Clifford R Jack; Leslie M Shaw; John Q Trojanowski; Andrew J Saykin; Laurel A Beckett; Cyrille Sur; Naren P Rao; Patricio Chrem Mendez; Sandra E Black; Kuncheng Li; Takeshi Iwatsubo; Chiung-Chih Chang; Ana Luisa Sosa; Christopher C Rowe; Richard J Perrin; John C Morris; Amanda M B Healan; Stephen E Hall; Michael W Weiner Journal: Alzheimers Dement (N Y) Date: 2021-12-31
Authors: Kacie D Deters; Valerio Napolioni; Reisa A Sperling; Michael D Greicius; Richard Mayeux; Timothy Hohman; Elizabeth C Mormino Journal: Neurology Date: 2021-02-10 Impact factor: 9.910
Authors: Logan Dumitrescu; Emily R Mahoney; Shubhabrata Mukherjee; Michael L Lee; William S Bush; Corinne D Engelman; Qiongshi Lu; David W Fardo; Emily H Trittschuh; Jesse Mez; Catherine Kaczorowski; Hector Hernandez Saucedo; Keith F Widaman; Rachel Buckley; Michael Properzi; Elizabeth Mormino; Hyun-Sik Yang; Tessa Harrison; Trey Hedden; Kwangsik Nho; Shea J Andrews; Doug Tommet; Niran Hadad; R Elizabeth Sanders; Douglas M Ruderfer; Katherine A Gifford; Annah M Moore; Francis Cambronero; Xiaoyuan Zhong; Neha S Raghavan; Badri Vardarajan; Margaret A Pericak-Vance; Lindsay A Farrer; Li-San Wang; Carlos Cruchaga; Gerard Schellenberg; Nancy J Cox; Jonathan L Haines; C Dirk Keene; Andrew J Saykin; Eric B Larson; Reisa A Sperling; Richard Mayeux; David A Bennett; Julie A Schneider; Paul K Crane; Angela L Jefferson; Timothy J Hohman Journal: Brain Date: 2020-08-01 Impact factor: 13.501
Authors: Hong-Hee Won; Hee Jin Kim; Hang-Rai Kim; Sang-Hyuk Jung; Jaeho Kim; Hyemin Jang; Sung Hoon Kang; Song Hwangbo; Jun Pyo Kim; So Yeon Kim; Beomsu Kim; Soyeon Kim; Jee Hyang Jeong; Soo Jin Yoon; Kyung Won Park; Eun-Joo Kim; Bora Yoon; Jae-Won Jang; Jin Yong Hong; Seong Hye Choi; Young Noh; Ko Woon Kim; Si Eun Kim; Jin San Lee; Na-Yeon Jung; Juyoun Lee; Byeong C Kim; Sang Joon Son; Chang Hyung Hong; Duk L Na; Sang Won Seo Journal: Alzheimers Res Ther Date: 2021-06-21 Impact factor: 6.982