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Alzheimer disease pathology in cognitively healthy elderly: A genome-wide study |
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| Authors: | Patricia L. Kramer Haiyan Xu Randall L. Woltjer Shawn K. Westaway David Clark Deniz Erten-Lyons Jeffrey A. Kaye Kathleen A. Welsh-Bohmer Juan C. Troncoso William R. Markesbery Ronald C. Petersen R. Scott Turner Walter A. Kukull David A. Bennett Douglas Galasko John C. Morris Jurg Ott |
| Affiliation: | aDepartment of Neurology, Oregon Health & Science University, Portland, OR 97239, USA;bDepartment of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA;cDepartment of Pathology, Oregon Health & Science University, Portland, OR 97239, USA;dDepartment of Biomedical Engineering, Oregon Health & Science University, Portland, OR 97239, USA;eLaboratory of Statistical Genetics, Rockefeller University, New York, NY 10065, USA;fDepartment of Psychiatry and Medicine (Neurology), Duke University Medical Center, Durham, NC 27710, USA;gDepartment of Pathology and Neurology, Johns Hopkins University, Baltimore, MD 21205, USA;hDepartment of Pathology and Neurology, University of Kentucky, Lexington, KY 40536, USA;iDepartment of Neurology, Mayo Clinic, Rochester, MN 55905, USA;jDepartment of Neurology, University of Michigan, Ann Arbor, MI 48105, USA;kGeorgetown University Medical Center, Washington DC, 20057, USA;lNational Alzheimer Coordinating Center and Department of Epidemiology, Seattle, WA 98105, USA;mRush University Medical Center, Chicago, IL 60612, USA;nDepartment of Neurosciences, University of California at San Diego, San Diego, CA 92037, USA;oDepartment of Neurology, Washington University School of Medicine, St. Louis, MO 63108, USA;pBeijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100029, China;qDepartment of Cardiology, Oregon Health & Science University, Portland, OR 97239, USA |
| Abstract: | Many elderly individuals remain dementia-free throughout their life. However, some of these individuals exhibit Alzheimer disease neuropathology on autopsy, evidenced by neurofibrillary tangles (NFTs) in AD-specific brain regions. We conducted a genome-wide association study to identify genetic mechanisms that distinguish non-demented elderly with a heavy NFT burden from those with a low NFT burden. The study included 299 non-demented subjects with autopsy (185 subjects with low and 114 with high NFT levels). Both a genotype test, using logistic regression, and an allele test provided consistent evidence that variants in the RELN gene are associated with neuropathology in the context of cognitive health. Immunohistochemical data for reelin expression in AD-related brain regions added support for these findings. Reelin signaling pathways modulate phosphorylation of tau, the major component of NFTs, either directly or through β-amyloid pathways that influence tau phosphorylation. Our findings suggest that up-regulation of reelin may be a compensatory response to tau-related or beta-amyloid stress associated with AD even prior to the onset of dementia. |
| Keywords: | Genome-wide association study Alzheimer disease Non-demented elderly with AD neuropathology Non-demented elderly without AD neuropathology Reelinneurofibrillary tangles |
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