Late-Onset Alzheimer’s Disease Polygenic Risk Profile Score Predicts Hippocampal Function

  • Author Footnotes
    1 EX and QC contributed equally to this work.
    Ena Xiao
    Correspondence
    Address correspondence to Venkata S. Mattay, M.D., Lieber Institute for Brain Development, Johns Hopkins Medical Campus, 855 North Wolfe Street, Baltimore, MD 21205.
    Footnotes
    1 EX and QC contributed equally to this work.
    Affiliations
    Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland
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  • Author Footnotes
    1 EX and QC contributed equally to this work.
    Qiang Chen
    Footnotes
    1 EX and QC contributed equally to this work.
    Affiliations
    Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland
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  • Aaron L. Goldman
    Affiliations
    Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland
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  • Hao Yang Tan
    Affiliations
    Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland
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  • Kaitlin Healy
    Affiliations
    Genes Cognition and Psychosis Program, National Institute of Mental Health Intramural Research Program, National Institutes of Health, Bethesda, Maryland
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  • Brad Zoltick
    Affiliations
    Clinical and Translational Neuroscience Branch, National Institute of Mental Health Intramural Research Program, National Institutes of Health, Bethesda, Maryland
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  • Saumitra Das
    Affiliations
    Clinical and Translational Neuroscience Branch, National Institute of Mental Health Intramural Research Program, National Institutes of Health, Bethesda, Maryland
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  • Bhaskar Kolachana
    Affiliations
    Clinical and Translational Neuroscience Branch, National Institute of Mental Health Intramural Research Program, National Institutes of Health, Bethesda, Maryland
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  • Joseph H. Callicott
    Affiliations
    Clinical and Translational Neuroscience Branch, National Institute of Mental Health Intramural Research Program, National Institutes of Health, Bethesda, Maryland
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  • Dwight Dickinson
    Affiliations
    Clinical and Translational Neuroscience Branch, National Institute of Mental Health Intramural Research Program, National Institutes of Health, Bethesda, Maryland
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  • Karen F. Berman
    Affiliations
    Clinical and Translational Neuroscience Branch, National Institute of Mental Health Intramural Research Program, National Institutes of Health, Bethesda, Maryland
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  • Daniel R. Weinberger
    Affiliations
    Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland

    Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland

    Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland

    Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland
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  • Venkata S. Mattay
    Affiliations
    Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland

    Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland

    Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland
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  • Author Footnotes
    1 EX and QC contributed equally to this work.
Published:August 24, 2017DOI:https://doi.org/10.1016/j.bpsc.2017.08.004

      Abstract

      Background

      We explored the cumulative effect of several late-onset Alzheimer’s disease (LOAD) risk loci using a polygenic risk profile score (RPS) approach on measures of hippocampal function, cognition, and brain morphometry.

      Methods

      In a sample of 231 healthy control subjects (19–55 years of age), we used an RPS to study the effect of several LOAD risk loci reported in a recent meta-analysis on hippocampal function (determined by its engagement with blood oxygen level–dependent functional magnetic resonance imaging during episodic memory) and several cognitive metrics. We also studied effects on brain morphometry in an overlapping sample of 280 subjects.

      Results

      There was almost no significant association of LOAD-RPS with cognitive or morphometric measures. However, there was a significant negative relationship between LOAD-RPS and hippocampal function (familywise error [small volume correction-hippocampal region of interest] p < .05). There were also similar associations for risk score based on APOE haplotype, and for a combined LOAD-RPS + APOE haplotype risk profile score (p < .05 familywise error [small volume correction-hippocampal region of interest]). Of the 29 individual single nucleotide polymorphisms used in calculating LOAD-RPS, variants in CLU, PICALM, BCL3, PVRL2, and RELB showed strong effects (p < .05 familywise error [small volume correction-hippocampal region of interest]) on hippocampal function, though none survived further correction for the number of single nucleotide polymorphisms tested.

      Conclusions

      There is a cumulative deleterious effect of LOAD risk genes on hippocampal function even in healthy volunteers. The effect of LOAD-RPS on hippocampal function in the relative absence of any effect on cognitive and morphometric measures is consistent with the reported temporal characteristics of LOAD biomarkers with the earlier manifestation of synaptic dysfunction before morphometric and cognitive changes.

      Keywords

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