Healthy aging increases the cognitive effects of two genes that influence extracellular dopamine

We hypothesized that normal variation in genes influencing the bioavailability of dopamine in prefrontal cortex contribute to inter-individual differences in working memory (WM), particularly in healthy old age. To test this, 858 healthy young, middle-aged, and older people were tested on a spatial WM task and genotyped for catechol-O-methyltransferase (COMT VAL158MET) and dopamine betahydroxylase (DBH; C-1021T) single nucleotide polymorphisms (SNPs). Since these genes encode enzymes influencing levels of extracellular dopamine, important for WM, we reasoned that individuals with low activity alleles of each SNP (less efficient degradation of dopamine by COMT and less efficient conversion of dopamine to norepinephrine by DBH) would have higher levels of extracellular dopamine and therefore better WM performance. We predicted the poorest WM performance in people who are both COMT VAL/VAL and DBH C/C homozygotes, encoding enzymes with high activity. That prediction was borne out, but only in the older group under difficult discrimination. This suggests the high activity alleles of these 2 genes combine in reducing ability to manipulate information in WM among the old. Further, we predicted the best performance in people who inherited both low activity alleles. That prediction was not borne out. That we found genetic effects only among older people and not in midlife indicates that brain changes late in life heighten negative effects of chronically lower levels of extracellular dopamine due to normal genetic variation. We found that age increased the combined effect on WM of the COMT and DBH genes encoding enzymes controlling levels of extracellular dopamine.