Abstract for presentation at 11th International Congress of Human Genetics

DRD4 genotype and activity level predict Alzheimers in the oldest-old

  • Deborah Grady, Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA 92697, United States
  • Maria Corrada, Department of Neurology, University of California, Orange, CA 92868, United States
  • Valentina Ciobanu, Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA 92697, United States
  • Hao-Yuan Chen, Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA 92697, United States
  • Eric Wang, Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA 92697, United States
  • Simin Hakim, Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA 92697, United States
  • Claudia Kawas, Department of Neurology, University of California, Orange, CA 92868, United States
  • Robert Moyzis, Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA 92697, United States

    • Genotyping/sequencing of 260 oldest-old individuals (90+ years of age) at the DRD4 locus was conducted. These individuals were part of the 90+ Study cohort (N=1,151), surviving participants in a 25-year population-based health survey study in Southern California. The dopamine receptor DRD4 gene was chosen for investigation based on prior studies in which a variant allele of this gene (DRD4 7R) was associated with activity level in children (Grady et al. Mol Psychiatry 8, 536-545, 2003). Strong evidence that the DRD4 7R allele has undergone recent Darwinian selection has been presented (Ding et al. PNAS 99, 309-314; 2002; Wang et al. AJHG 74, 931-944, 2004; PNAS 103, 135-140, 2006). In comparison to younger European ancestry controls (N=860), there is a 75% increase in 90+ individuals with a DRD4 7R/x genotype (0.22 versus 0.38, p<0.001), predominantly in females (0.42 versus 0.29 males, p=0.05). Allele frequencies for 10 other randomly chosen loci did not differ between the oldest-old and control populations.
    There is a strong correlation between the DRD4 7R/x genotype in this oldest-old population and activity level, as measured both 25 years ago and currently (p=0.004). We also found an association between exercise and the development of dementia. Participants who exercised 2 or more hours a day were 64% less likely to develop Alzheimers (AD) compared to participants who exercised less than 30 minutes a day (OR=0.36, 95%CI=0.14-0.94). Due to the high activity level exhibited by the DRD4 7R/x participants, however, we sorted the population by genotype. The AD association with activity was only apparent among participants with a DRD4 7R/x genotype. Among those with this genotype, participants who exercised 2 or more hours a day were 79% less likely to develop AD compared to participants who exercised less than 30 minutes a day (OR=0,21, 95% CI=0.04-1.00). In contrast, the association with exercise was not significant among those without a DRD4 7R/x genotype (OR=0.52, 95%CI=0.15-1.83). We conclude that the presence of a DRD4 7R/x genotype is associated with “protection” from dementia in the oldest-old, but only if accompanied by continuing exercise.

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