SNPwatch: Genetic Variant May Impact Rate of Cognitive Decline in the Elderly

New research, published recently in the journal Neurology, has found the surprising result that a genetic variant previously associated with better cognitive function in young people appears to have the opposite effect as people get older.

Alexandra Fiocco and colleagues from the University of California, San Francisco, studied 2,858 men and women (1,679 white and 1,179 black) who were between the ages of 70 and 79 upon recruitment to the study in 1997.  All were in generally good health and had no difficulty with day-to-day activities.

Each person was given two tests at various points over an eight year follow up period: 1) the Modified Mini-Mental State Examination, a measure of global cognitive performance; and 2) the Digit Symbol Substitution Test, which measures response speed, sustained attention, visual spatial skills and set shifting, and has been reported to distinguish mild dementia from healthy aging.

The study participants’ cognitive test results were then compared with their genotypes for SNP .  This genetic variant is found in the COMT (catechol-O-methyltransferase) gene, which encodes an enzyme involved in a variety of chemical conversions in the body, including the degradation of the neurotransmitter dopamine.  The different versions of encode COMT proteins with either a valine (Val) or methionine (Met) at amino acid 158.  The Val version of COMT (G at ) is associated with higher COMT enzyme activity, and therefore lower levels of dopamine in the brain, while the Met version (A at ) is associated with lower enzyme activity and higher dopamine levels.

In experiments carried out mainly in younger people, the Met version of COMT has been shown to be associated with better cognitive function.  Fiocco, et al., however, found that it was the Val version of COMT that was associated with less cognitive decline over the course of eight years in the elders they studied.  In both white and black subjects, the Val version correlated with smaller reductions in Digit Symbol Substitution test scores.  In white subjects only, the Val version was also associated with smaller declines in Modified Mini-Mental State Examination scores.

Why might the Val version of COMT have a protective effect against cognitive decline?  The authors suggest that the higher levels of COMT activity, and thus lower levels of dopamine in the brain, associated with the Val version might be better for optimal cognitive function in older adults due to the fact that there is a reduction in dopamine receptors in the brain as people age.  In support of this, they point to data showing that the brains of people with dementia have decreased levels of COMT enzyme activity.

Results from a few other studies in older adults contradict the findings of the current report.  That, combined with the fact that the Val/Met variation in the gene appears to have opposite effects in younger people, means that much more research will be needed to truly understand the role of COMT in cognition.

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  • Chic

    What if your genotype is AG, you have both variants? What would this signify?

    Does the genotype need to be AA or GG to fit this result?

  • Great question!

    For white study subjects, each copy of the Val version of COMT (G at rs4680) reduced the amount of decline on both cognitive tests. Essentially, being AG is better than being AA, but being GG is even better.

    In the black study subjects, things weren’t so clear. First, remember there was only an effect of the COMT variation on the scores for the Digit Symbol Substitution Test. People with AG at rs4680 (one copy of each version of the gene) actually had greater declines in scores than people with AA. But people with two copies of a G had lower declines. Confusing right? Why isn’t just one copy helpful in this group as it was in the white study subjects? Well, there’s no way to no for sure, but the authors of the paper suggest that this is just an artifact of the small number of black subjects with AA at this SNP. They figure that if they had a larger sample size, they’d probably see the same linear effect they saw in the white study subjects.

  • This finding is somewhat strange, and is not consistent with the way the relationship between COMT activity and performance has been studied in the past.

    The gene COMT has been studied a lot. One common way of interpreting findings with COMT is using what’s called the “inverted-U hypothesis,” which roughly states that performance vs. COMT activity takes a roughly inverted-U shape, whereby lower or higher COMT activity than some optimal level both decrease performance. COMT activity is affected by several things: (1) genotype or haplotype in the COMT gene; (2) sex; and (3) age.

    Since overall COMT activity is affected by several different factors, and since both too much and too little COMT activity harm performance, one would expect an interaction between the various factors affecting COMT activity and performance. This has been shown before for the sex-genotype interaction[1], with boys performing best with the lowest-COMT-activity diplotypes and girls performing best with the intermediate-COMT-activity diplotypes. This is as expected: estrogen reduces COMT expression and activity, so a genotype that results in the optimal COMT activity for males would be expected to result in sub-optimal COMT activity in females.

    COMT activity is positively correlated with age (though weakly; r=.2)[2]. As a result, one would expect that as people age, those with low-COMT-activity alleles (e.g. 158Met) would gain performance on those with high-COMT-activity alleles. That’s exactly the opposite from what Fiocco et al. found.

    Alternate hypotheses:

    The article presents one, but it doesn’t make sense to me. Dopamine receptors decrease with age, which means that the versions of COMT that have higher activity (and therefore lower dopamine levels) are associated with better performance? Shouldn’t it be the other way around, whereby higher dopamine levels would be needed to compensate for the reduction in receptors?

    Another hypothesis involves oxidative stress. The catecholamine neurotransmitters are broken down by the monoamine oxidases (MAOA and MAOB) as well as COMT. Metabolism of monoamines (which includes catecholamines) via the monoamine oxidase pathway produces hydrogen peroxide, which is cytotoxic. Perhaps higher COMT activity reduces the amount of oxidation of catecholamines via MAO, which results in less hydrogen peroxide production and less oxidative stress on neurons, and therefore better neuronal function later in life.

    [1] Barnett, J. H., Heron, J., Goldman, D., Jones, P. B., & Xu, K. (2009). Effects of Catechol-O-Methyltransferase on Normal Variation in the Cognitive Function of Children. Am J Psychiatry, 166(8), 909-916. doi:10.1176/appi.ajp.2009.08081251

    [2] Chen, J., Lipska, B. K., Halim, N., Ma, Q. D., Matsumoto, M., Melhem, S., Kolachana, B. S., et al. (2004). Functional Analysis of Genetic Variation in Catechol-O-Methyltransferase (COMT): Effects on mRNA, Protein, and Enzyme Activity in Postmortem Human Brain. The American Journal of Human Genetics, 75(5), 807-821. doi:10.1086/425589

  • Monte Faul

    Is it possible that people with the Val version of the COMT have been living with low dopamine levels their whole lives and are therefore somehow better conditioned to performing mental tasks in a low-dopamine state?

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