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. 2013 Sep 1;70(9):1150-7.
doi: 10.1001/jamaneurol.2013.2815.

Genetic susceptibility for Alzheimer disease neuritic plaque pathology

Joshua M Shulman  1 , 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
Affiliations

Genetic susceptibility for Alzheimer disease neuritic plaque pathology

Joshua M Shulman et al. JAMA Neurol. .

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.

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Figures

FIGURE 1
FIGURE 1. Plot showing rs2829887 at the APP locus in association with neuritic plaque pathology
FIGURE 2
FIGURE 2. Association of rs2829887 with fibrillar amyloid in cognitively normal subjects from ADNI and the 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 PiB or AV-45 SUVR images from 114 cognitively-normal subjects in the Arizona APOE and ADNI cohorts. Analyses were adjusted for subject age, APOE ε4 genotype, and cohort membership.
See this image and copyright information in PMC

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