Working memory (WM) is a collection of cognitive processes that include short term storage of task related information and manipulation of this information to facilitate the transformation of memory to action immediately. Age-related declines in WM performance have been attributed to dysfunction in dopamine and cholinergic neurotransmission. In this study, we applied a genetic approach to investigate how normal variation in genes controlling monoamine expression in PFC is linked to age-related decline in working memory. One well-studied source of genetic variation in dopamine neurotransmission occurs in the gene controlling the enzyme Catechol-O-Methyltransferase (COMT). A well-studied 158 G/A polymorphism in the COMT gene (rs4680) is non-synonymous and results in a valine-to-methionine substitution. The methionine variant is associated with a 3-4 fold lower level of enzyme activity, compared to its valine counterpart. We analyzed two measures of performance (accuracy and reaction time measures) in terms of the influence of two biological parameters (age and COMT genotype) and two spatial WM parameters (distance between the target and the probe dot, and memory load). For accuracy measures, a significant interaction of memory load x COMT x age in the "Match" task conditions was observed. For accuracy measures, we showed a significant memory load x COMT x age interaction in "match" task conditions and the age effect was most prominent in "non-match" short distance task conditions. For reaction time measures, the older val/val homozygotes showed longer reaction times than the met/met and val/met subjects. Taken together, our results support the idea that different levels of COMT enzyme activity may be optimal for different tasks and heritability of COMT becomes increasingly important in cognitive performance with advancing age. The muscarinic cholinergic M2 receptor (CHRM2) belongs to the superfamily of G- protein coupled receptors, whose roles include modulation of cholinergic transmission, neuronal excitability, synaptic plasticity and feedback regulation of acetylcholine release. The CHRM2 A1890T polymorphism (rs8191992) which located in the 3' untranslated region has been repeatedly reported to be correlated to intelligence quotient (IQ). In this study, we also analyzed two measures of performance (accuracy and reaction time measures) in terms of the influence of two biological parameters (age and CHRM2 genotype) and two spatial WM parameters (distance between the target and the probe dot, and memory load). For the accuracy measures, we showed a significant memory load x CHRM2 x age interaction in the match task conditions. This interaction showed improved accuracies for CHRM2 AT heterozygotes in high memory loads. For reaction time measures, a significant CHRM2 x age interaction was also observed. This interaction showed that the young AA homozygotes used shorter reaction times than the young AT heterozygotes and the TT homozygotes, while the older AA homozygotes used longer reaction times than the older AT heterozygotes and the TT homozygotes. The CHRM2 A1890T polymorphism also showed increased effects in non-match task conditions for older adults. Taken together, our results support the idea that the CHRM2 A1890T polymorphism associated with the performance of spatial working memory at different ages. The increased genetic effects were observed in older adults. In this study, we showed the influence of normal gene variability on working memory. We also showed the increased gene effects in older adults. However, the cellular mechanism of how did these polymorphisms effect the neuronal activity is still not clear. Muscarinic neurotransmission has been implicated to play an important role in learning, attention and in Alzheimer's disease. Thus, further research is needed in this area. Cellular and molecular studies of rs8191992 may help to elucidate the molecular mechanism of this SNP.