Alzheimer disease pathology in cognitively healthy elderly: A genome-wide study

• Published in: Neurobiology of aging Vol. 32; no. 12; pp. 2113 - 2122
• Main Authors: Kramer, Patricia L., Xu, Haiyan, Woltjer, Randall L., Westaway, Shawn K., Clark, David, Erten-Lyons, Deniz, Kaye, Jeffrey A., Welsh-Bohmer, Kathleen A., Troncoso, Juan C., Markesbery, William R., Petersen, Ronald C., Turner, R. Scott, Kukull, Walter A., Bennett, David A., Galasko, Douglas, Morris, John C., Ott, Jurg
• Format: Journal Article
• Language: English
• Published: London Elsevier Inc 01.12.2011; Elsevier
• Subjects: Aged; Aged, 80 and over; Alzheimer disease; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Biological and medical sciences; Cell Adhesion Molecules, Neuronal - biosynthesis; Cell Adhesion Molecules, Neuronal - genetics; Cognition - physiology; Cohort Studies; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Development. Senescence. Regeneration. Transplantation; Extracellular Matrix Proteins - biosynthesis; Extracellular Matrix Proteins - genetics; Female; Fundamental and applied biological sciences. Psychology; Genome-wide association study; Genome-Wide Association Study - methods; Health Status; Humans; Internal Medicine; Longitudinal Studies; Male; Medical sciences; Nerve Tissue Proteins - biosynthesis; Nerve Tissue Proteins - genetics; Neurofibrillary Tangles - genetics; Neurofibrillary Tangles - pathology; Neurology; Non-demented elderly with AD neuropathology; Non-demented elderly without AD neuropathology; Phosphorylation - genetics; Polymorphism, Single Nucleotide - genetics; Reelin Protein; Reelinneurofibrillary tangles; Serine Endopeptidases - biosynthesis; Serine Endopeptidases - genetics; Signal Transduction - genetics; tau Proteins - genetics; tau Proteins - metabolism; Vertebrates: nervous system and sense organs; Non-demented elderly with AD neuropathology; Reelinneurofibrillary tangles; Non-demented elderly without AD neuropathology; Genome-wide association study; Alzheimer disease; Nervous system diseases; Senescence; Central nervous system disease; Degenerative disease; Cerebral disorder
• ISSN: 0197-4580; 1558-1497; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2010.01.010

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.