1 Human aging magnifi es genetic effects on executive functioning and working memory

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 infl uencing the brain-derived neurotrophic factor (BDNF) protein. In two tasks (Wisconsin Card Sorting and spatial working memory), we fi nd that effects of COMT genotype on cognitive performance are magnifi ed 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 magnifi cation 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