Lifetime Estrogen Exposure, COMT Genotype, and Cognition in Postmenopausal Women

In the future, it may be possible to slow the change in cognition associated with menopause. First, we must understand the mechanism with which different biological processes interact in order to slow this decline at the source. An important gene that plays a role in cognition and aging is the gene for catechol-o-methyltransferase, which is an enzyme that degrades dopamine in the prefrontal cortex (PFC). Different genotypes cause expression of varying amounts of the enzyme intended to degrade dopamine in the synapse. When estrogen is present in the system, transcription of COMT is inhibited. The cognitive effect of the interaction between lifetime estrogen exposure and COMT was examined in 65 healthy postmenopausal women. In this study, we tested episodic and working memory, which are associated with PFC functioning. The subjects were genotyped for the COMT SNP (single nucleotide polymorphism). An index of lifetime estrogen exposure (ILEE) was created that incorporated reproductive period (menarche to menopause), total duration of breast-feeding, total time on hormonal therapy, and time since menopause. We found that in working memory and episodic memory measures, the effects of ILEE on cognition depended on the COMT genotype. This study showed that cognition in women with the lower dopaminergic baseline gene, Val/Val, benefitted from lifetime estrogen exposure. However, cognition in women with the higher baseline dopamine gene, Met/Met, was negatively affected by lifetime estrogen. Women with the Met/Val gene were not as impacted by lifetime estrogen. These results suggest that the COMT gene should be taken into account when considering exogenous estrogen to modulate the decline of cognition