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CR1 is associated with amyloid plaque burden and age-related cognitive decline

Authors

  • Lori B. Chibnik PhD, MPH,

    1. Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital, Boston, MA
    2. Program in Medical and Population Genetics, Broad Institute, Cambridge, MA
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  • Joshua M. Shulman MD, PhD,

    1. Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital, Boston, MA
    2. Program in Medical and Population Genetics, Broad Institute, Cambridge, MA
    3. Clinical Investigator Training Program, Beth Israel Deaconess Medical Center–Harvard/MIT Health Sciences and Technology (in collaboration with Pfizer Inc. and Merck & Co.), Chicago, IL
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  • Sue E. Leurgans PhD,

    1. Rush Alzheimer's Disease Center, Department of Neurological Sciences, Chicago, IL
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  • Julie A. Schneider MD, MS,

    1. Rush Alzheimer's Disease Center, Department of Neurological Sciences, Chicago, IL
    2. Department of Pathology, Rush University Medical Center, Chicago, IL
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  • Robert S. Wilson PhD,

    1. Rush Alzheimer's Disease Center, Department of Neurological Sciences, Chicago, IL
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  • Dong Tran BS,

    1. Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital, Boston, MA
    2. Program in Medical and Population Genetics, Broad Institute, Cambridge, MA
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  • Cristin Aubin BS,

    1. Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital, Boston, MA
    2. Program in Medical and Population Genetics, Broad Institute, Cambridge, MA
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  • Aron S. Buchman MD,

    1. Rush Alzheimer's Disease Center, Department of Neurological Sciences, Chicago, IL
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  • Christopher B. Heward PhD,

    1. Kronos Science Laboratory, Phoenix, AZ
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  • Amanda J. Myers PhD,

    1. Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL
    2. Johnnie B. Byrd Sr. Alzheimer's Center and Research Institute,Tampa, FL
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  • John A. Hardy PhD,

    1. Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD
    2. Reta Lila Weston Laboratories, Department of Molecular Neuroscience, Institute of Neurology, Queen Square, London, UK
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  • Matthew J. Huentelman PhD,

    1. Neurogenomics Division, Translational Genomics Research Institute and Arizona Alzheimer's Consortium, Phoenix, AZ
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  • Jason J. Corneveaux BS,

    1. Neurogenomics Division, Translational Genomics Research Institute and Arizona Alzheimer's Consortium, Phoenix, AZ
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  • Eric M. Reiman MD,

    1. Neurogenomics Division, Translational Genomics Research Institute and Arizona Alzheimer's Consortium, Phoenix, AZ
    2. Banner Alzheimer's Institute and Department of Psychiatry, University of Arizona, Phoenix, AZ
    3. Department of Psychiatry, University of Arizona, Tucson, AZ
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  • Denis A. Evans MD,

    1. Rush Alzheimer's Disease Center, Department of Neurological Sciences, Chicago, IL
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  • David A. Bennett MD,

    1. Rush Alzheimer's Disease Center, Department of Neurological Sciences, Chicago, IL
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  • Philip L. De Jager MD, PhD

    Corresponding author
    1. Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital, Boston, MA
    2. Program in Medical and Population Genetics, Broad Institute, Cambridge, MA
    • Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital, 77 Avenue Louis Pasteur, NRB 168C, Boston, MA 02115
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Abstract

Objective

Recently, genome-wide association studies have identified 3 new susceptibility loci for Alzheimer's disease (AD), CLU, CR1, and PICALM. We leveraged available neuropsychological and autopsy data from 2 cohort studies to investigate whether these loci are associated with cognitive decline and AD neuropathology.

Methods

The Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP) are longitudinal studies that enroll nondemented subjects and include annual clinical evaluations and brain donation at death. We evaluated CR1 (rs6656401), CLU (rs11136000), and PICALM (rs7110631) in 1,666 subjects. We evaluated associations between genotypes and rate of change in cognitive function as well as AD-related pathology. Lastly, we used pathway analysis to determine whether relationships between single nucleotide polymorphisms and cognitive decline are mediated through AD pathology.

Results

Among our study cohort, the mean years of follow-up were 7.8 for ROS and 4.3 for MAP. Only the CR1 locus was associated with both global cognitive decline (p = 0.011) and global AD pathology (p = 0.025). More specifically, the locus affects the deposition of neuritic amyloid plaque (p = 0.009). In a mediation analysis, controlling for amyloid pathology strongly attenuated the effect of the CR1 locus on cognitive decline.

Interpretation

We found that common variation at the CR1 locus has a broad impact on cognition and that this effect is largely mediated by an individual's amyloid plaque burden. We therefore highlight 1 functional consequence of the CR1 susceptibility allele and generalize the role of this locus to cognitive aging in the general population. ANN NEUROL 2011

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