Abstract
We demonstrate that common genetic polymorphisms contribute to the increasing heterogeneity of cognitive functioning in old age. We assess two common Val/Met polymorphisms, one affecting the Catechol-O-Methyltransferase (COMT) enzyme, which degrades dopamine (DA) in prefrontal cortex (PFC), and the other influencing the brain-derived neurotrophic factor (BDNF) protein. In two tasks (Wisconsin Card Sorting and spatial working memory), we find that effects of COMT genotype on cognitive performance are magnified in old age and modulated by BDNF genotype. Older COMT Val homozygotes showed particularly low levels of performance if they were also BDNF Met carriers. The age-associated magnification of COMT gene effects provides novel information on the inverted U-shaped relation linking dopaminergic neuromodulation in PFC to cognitive performance. The modulation of COMT effects by BDNF extends recent evidence of close interactions between frontal and medial-temporal circuitries in executive functioning and working memory.
Highlights
Individual differences in complex phenotypes result from gene-gene and gene-context interactions (McClearn, 2006)
We hypothesized that (a) human aging magnifies the influence of the Val/ Met COMT polymorphism on executive functioning and working memory, and (b) this effect is modulated by the Val/Met Brain-Derived Neurotrophic Factor (BDNF) polymorphism
For a standard measure of executive functioning, the Wisconsin Card Sorting Test (WCST), the COMT Val allele was associated with a higher number of perseverative errors in older adults
Summary
Individual differences in complex phenotypes result from gene-gene and gene-context interactions (McClearn, 2006). COMT enzymatic activity results in degradation of dopamine (DA) and has an impact on endogenous DA levels in prefrontal cortex (PFC). A common polymorphism of the COMT gene is associated with most of the human variation in intrinsic DA levels in the PFC. The COMT single nucleotide polymorphism leads to a substitution of valine (Val) with methionine (Met) at the codon 158 on chromosome 22q11 (Val158Met). This substitution affects enzymatic activity, which is three to four times higher in Val than in Met homozygotes. Lower enzymatic activity among Met carriers leads to less frontal DA degradation and greater DA availability at the receptors (Meyer-Lindenberg et al, 2007)
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