Association of the dihydrolipoamide dehydrogenase gene with Alzheimer's disease in an Ashkenazi Jewish population

Authors

  • Abraham M. Brown,

    Corresponding author
    1. Burke Medical Research Institute, 785 Mamaroneck Ave, White Plains, New York
    2. Department of Biochemistry, Weill Medical College of Cornell University, New York, New York
    • Dementia Research Service, Burke Medical Research Institute, 785 Mamaroneck Avenue, White Plains, NY 10605.
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  • Derek Gordon,

    1. Laboratory of Statistical Genetics, Rockefeller University, New York, New York
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  • Hsinhwa Lee,

    1. Burke Medical Research Institute, 785 Mamaroneck Ave, White Plains, New York
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  • Michael Caudy,

    1. Burke Medical Research Institute, 785 Mamaroneck Ave, White Plains, New York
    2. Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York
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  • John Hardy,

    1. Laboratory of Neurogenetics, National Institute of Neurological Diseases and Stroke, Bethesda, Maryland
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  • Vahram Haroutunian,

    1. Department of Psychiatry, Mount Sinai School of Medicine
    2. Bronx VA Medical Center, Bronx, New York
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  • John P. Blass

    1. Burke Medical Research Institute, 785 Mamaroneck Ave, White Plains, New York
    2. Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York
    3. Department of Medicine, Weill Medical College of Cornell University, New York, New York
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Abstract

Abundant biochemical evidence links deficient activity of mitochondrial α-ketoglutarate dehydrogenase with neuropathologically confirmed Alzheimer's disease (AD). Reduced α-ketoglutarate dehydrogenase activity has also been associated with anti-mortem measures of clinical disability. One of the genes encoding this complex, namely, DLD, lies within a chromosome 7 region that is in linkage disequilibrium with AD. We therefore examined the hypothesis that variation in DLD is associated with AD risk. Denaturing HPLC was used to search for sequence variations in the coding and flanking regions of all exons of DLD, but no abundant variants that alter protein sequence were found. However, four common SNPs were identified and genotyped in a case-control series of 297 Caucasians from New York City, including 229 residents of a Jewish nursing home. Logistic regression analysis was performed for the four-locus DLD genotype, sex, and ApoE4 status to determine the association of these independent variables with AD. Significant associations with AD were observed for ApoE4 (P < 10−6) and sex combined with DLD genotype (P = 0.013). The association with the DLD genotypes appears only in the male population in both the Caucasian series (P = 0.0009, n = 83) and the Ashkenazi Jewish subseries (P = 0.017, n = 49). The DLD genotype appears to operate independently of APOE in conferring AD risk. © 2004 Wiley-Liss, Inc.

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