Journal
JAMA NEUROLOGY
Volume 70, Issue 9, Pages 1150-1157Publisher
AMER MEDICAL ASSOC
DOI: 10.1001/jamaneurol.2013.2815
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Funding
- National Institutes of Health [R01 AG30146, P30 AG10161, R01 AG17917, R01 AG15819, K08 AG034290, C06 RR029965, R01 AG11101, P30 AG19610, R01 AG023193, R01 NS059873, P50 AG16574, U01 AG016976, U24 NS051872, P50 AG23173, K01 AG024079]
- Illinois Department of Public Health
- Kronos Life Sciences Laboratories
- state of Arizona
- Burroughs Wellcome Fund
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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 beta-amyloid load by immunocytochemistry, and replication with fibrillar beta-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 x 10(-6)). This polymorphism was associated with postmortem beta-amyloid load as well as fibrillar beta-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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