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Original Investigation |

Genetic Susceptibility for Alzheimer Disease Neuritic Plaque Pathology

Joshua M. Shulman, MD, PhD1,2; Kewei Chen, PhD3,4; Brendan T. Keenan, MS5,6,7; Lori B. Chibnik, PhD, MPH5,6,7; Adam Fleisher, MD3,8; Pradeep Thiyyagura, MS3,4; Auttawut Roontiva, MS3,4; Cristin McCabe, BS5,6,7; Nikolaos A. Patsopoulos, MD, PhD5,6,7; Jason J. Corneveaux, BS9; Lei Yu, PhD10; Matthew J. Huentelman, PhD9; Denis A. Evans, MD11,12; Julie A. Schneider, MD10,13; Eric M. Reiman, MD3,4,9; Philip L. De Jager, MD, PhD5,6,7; David A. Bennett, MD10,14
[+] Author Affiliations
1Departments of Neurology and Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
2Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston
3Banner Alzheimer’s Institute and Banner Good Samaritan PET Center, Phoenix, Arizona
4Department of Psychiatry, University of Arizona, Phoenix
5Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women’s Hospital, Boston, Massachusetts
6Harvard Medical School, Boston, Massachusetts
7Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts
8Department of Neurosciences, University of California, San Diego
9Neurogenomics Division, Translational Genomics Research Institute and Arizona Alzheimer’s Consortium, Phoenix
10Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, Illinois
11Rush Institute for Healthy Aging, Rush University Medical Center, Chicago, Illinois
12Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois
13Department of Pathology, Rush University Medical Center, Chicago, Illinois
14Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois
JAMA Neurol. 2013;70(9):1150-1157. doi:10.1001/jamaneurol.2013.2815.
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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.

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Figure 1.
rs2829887 at APP Locus in Association With Neuritic Plaque Pathology

Plot showing rs2829887 at the APP locus in association with neuritic plaque pathology. cM indicates centimorgans; kb, kilobases; and Mb, megabases.

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Figure 2.
Association of rs2829887 With Fibrillar Amyloid in Cognitively Normal Subjects From the Alzheimer’s Disease Neuroimaging Initiative and Arizona APOE Cohorts

Statistical map of rs2829887T association with fibrillar amyloid projected onto the medial and lateral surfaces of a standardized brain, based on joint analysis of Pittsburgh Compound B or Avid-45 standard uptake value ratio images from 114 cognitively normal subjects in the Arizona APOE and Alzheimer’s Disease Neuroimaging Initiative cohorts. Analyses were adjusted for subject age, APOE ε4 genotype, and cohort membership.

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