Genetic Susceptibility for Alzheimer Disease Neuritic Plaque Pathology
Year: 2013
Type: article
Study design: Observational Study
Abstract: IMPORTANCE: While numerous genetic susceptibility loci have been identified for clinical Alzheimer disease (AD), it is important to establish whether these variants are risk factors for the underlying disease pathology, including neuritic plaques. OBJECTIVES: To investigate whether AD susceptibility loci from genome-wide association studies affect neuritic plaque pathology and to additionally identify novel risk loci for this trait. DESIGN, SETTING, AND PARTICIPANTS: Candidate analysis of single-nucleotide polymorphisms and genome-wide association study in a joint clinicopathologic cohort, including 725 deceased subjects from the Religious Orders Study and the Rush Memory and Aging Project (2 prospective, community-based studies), followed by targeted validation in an independent neuroimaging cohort, including 114 subjects from multiple clinical and research centers. MAIN OUTCOMES AND MEASURES: A quantitative measure of neuritic plaque pathologic burden, based on assessments of silver-stained tissue averaged from multiple brain regions. Validation based on β-amyloid load by immunocytochemistry, and replication with fibrillar β-amyloid positron emission tomographic imaging with Pittsburgh Compound B or florbetapir. RESULTS: Besides the previously reported APOE and CR1 loci, we found that the ABCA7 (rs3764650; P = .02) and CD2AP (rs9349407; P = .03) AD susceptibility loci are associated with neuritic plaque burden. In addition, among the top results of our genome-wide association study, we discovered a novel variant near the amyloid precursor protein gene (APP, rs2829887) that is associated with neuritic plaques (P = 3.3 × 10-6). This polymorphism was associated with postmortem β-amyloid load as well as fibrillar β-amyloid in 2 independent cohorts of adults with normal cognition. CONCLUSIONS AND RELEVANCE: These findings enhance understanding of AD risk factors by relating validated susceptibility alleles to increased neuritic plaque pathology and implicate common genetic variation at the APP locus in the earliest, presymptomatic stages of AD.
Source: JAMA Neurology
Authors: Joshua M. Shulman, Kewei Chen, Brendan T. Keenan, Lori B. Chibnik, Adam Fleisher, Pradeep Thiyyagura, Auttawut Roontiva, Cristin McCabe, Nikolaos A. Patsopoulos, Jason J. Corneveaux, Lei Yu, Matthew J. Huentelman, Denis A. Evans, Julie A. Schneider, Eric M. Reiman, Philip L. De Jager, David A. Bennett
Institutions: Baylor College of Medicine, Texas Children's Hospital, University of Arizona, Banner Alzheimer’s Institute, Broad Institute, Brigham and Women's Hospital, Harvard University, University of California San Diego, Translational Genomics Research Institute, Arizona Alzheimer’s Consortium, Rush University Medical Center
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Epidemiologic Study of Neural Reserve and Neurobiology of Aging, Neurogenomics of Alzheimer's Disease and Aging, Integrative analysis of genomic and epigenomic architecture in cognitive decline, Genetic Epidemiology of Cognitive Decline in an Aging Population Sample, Neurofibrillary Tangle-Induced Dementia in AD, Microarray Center for Research on the Nervous System, National Alzheimer's Coordinating Center, G3366490313, Genetic Variation in KIBRA and its role in Human Episodic Memory, Risk Factors for Incident Alzheimer's Disease in a Biracial Community, Exploring the Genetics of Alzheimer's Disease in Humans and Drosophila, NRI Build-out: Advancing Translational Brain Research, Risk Factors, Pathology, and Clinical Expressions of AD, Rush Alzheimer's Disease Core Center, Brain Aging & Gene Expression Patterns Using Microarrays, G6576754924, Arizona Alzheimer's Disease Core Center, National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD), Mayo Alzheimer's Disease Research Center
OpenAlex ID: W1965544005