APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging

Authors

  • John C. Morris MD,

    Corresponding author
    1. Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO
    2. Department of Neurology, Washington University School of Medicine, St. Louis, MO
    3. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO
    4. Department of Physical Therapy, Washington University School of Medicine, St. Louis, MO
    5. Department of Occupational Therapy, Washington University School of Medicine, St. Louis, MO
    • Alzheimer Disease Research Center, 4488 Forest Park Avenue, Suite 160, St. Louis, MO 63108
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  • Catherine M. Roe PhD,

    1. Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO
    2. Department of Neurology, Washington University School of Medicine, St. Louis, MO
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  • Chengjie Xiong PhD,

    1. Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO
    2. Division of Biostatistics, Washington University School of Medicine, St. Louis, MO
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  • Anne M. Fagan PhD,

    1. Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO
    2. Department of Neurology, Washington University School of Medicine, St. Louis, MO
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  • Alison M. Goate PhD,

    1. Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO
    2. Department of Neurology, Washington University School of Medicine, St. Louis, MO
    3. Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO
    4. Department of Psychiatry, Washington University School of Medicine, St. Louis, MO
    5. Department of Genetics, Washington University School of Medicine, St. Louis, MO
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  • David M. Holtzman MD,

    1. Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO
    2. Department of Neurology, Washington University School of Medicine, St. Louis, MO
    3. Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO
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  • Mark A. Mintun MD

    1. Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO
    2. Department of Radiology, Washington University School of Medicine, St. Louis, MO
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Abstract

Objective

To examine interactions of apolipoprotein E (APOE) genotype with age and with in vivo measures of preclinical Alzheimer disease (AD) in cognitively normal aging.

Methods

Two hundred forty-one cognitively normal individuals, aged 45–88 years, had cerebral amyloid imaging studies with Pittsburgh Compound-B (PIB). Of the 241 individuals, 168 (70%) also had cerebrospinal fluid (CSF) assays of amyloid-beta42 (Aβ42), tau, and phosphorylated tau (ptau181). All individuals were genotyped for APOE.

Results

The frequency of individuals with elevated mean cortical binding potential (MCBP) for PIB rose in an age-dependent manner from 0% at ages 45–49 years to 30.3% at 80–88 years. Reduced levels of CSF Aβ42 appeared to begin earlier (18.2% of those aged 45–49 years) and increase with age in higher frequencies (50% at age 80–88 years) than elevations of MCBP. There was a gene dose effect for the APOE4 genotype, with greater MCBP increases and greater reductions in CSF Aβ42 with increased numbers of APOE4 alleles. Individuals with an APOE2 allele had no increase in MCBP with age and had higher CSF Aβ42 levels than individuals without an APOE2 allele. There was no APOE4 or APOE2 effect on CSF tau or ptau181.

Interpretation

Increasing cerebral Aβ deposition with age is the pathobiological phenotype of APOE4. The biomarker sequence that detects Aβ deposition may first be lowered CSF Aβ42, followed by elevated MCBP for PIB. A substantial proportion of cognitively normal individuals have presumptive preclinical AD. ANN NEUROL 2010;67:122–131

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