Genetic and vascular modifiers of age-sensitive cognitive skills: effects of COMT, BDNF, ApoE, and hypertension

Abstract

Several single nucleotide polymorphisms have been linked to neural and cognitive variation in healthy adults. We examined contribution of three polymorphisms frequently associated with individual differences in cognition (Catechol-O-Methyl-Transferase Val158Met, Brain-Derived-Neurotrophic-Factor Val66Met, and Apolipoprotein E epsilon4) and a vascular risk factor (hypertension) in a sample of 189 volunteers (age 18-82). Genotypes were determined from buccal culture samples, and cognitive performance was assessed in 4 age-sensitive domains?fluid intelligence, executive function (inhibition), associative memory, and processing speed. We found that younger age and COMT Met/Met genotype, associated with low COMT activity and higher prefrontal dopamine content, were independently linked to better performance in most of the tested domains. Homozygotes for Val allele of BDNF polymorphism exhibited better associative memory and faster speed of processing than the Met allele carriers, with greater effect for women and persons with hypertension. Carriers of ApoE epsilon4 allele evidenced steeper age-related increase in costs of Stroop color interference, but showed no negative effects on memory. The findings indicate that age-related cognitive performance is differentially affected by distinct genetic factors and their interactions with vascular health status.

Figure 1

Modification of age-related increase in interference costs by ApoE: steeper slope for ApoE ɛ4 carriers.

Figure 2

An illustration of BDNF genotype × Hypertension interaction for processing speed. A bar chart of scores on two tests of speed of processing: Letter Comparison (Letters, blank bars) and Pattern comparison (Patterns, cross-hatched bars). Standard errors of the means are also shown. The bar labels correspond to the presence of at least one BDNF Met allele (Met+ and Met−) and Hypertensive (H) vs. Normotensive (N) status.

Figure 3

An illustration of BDNF genotype × Sex interaction on tests of speed of processing: Letter Comparison (Letters, blank bars) and Pattern comparison (Patterns, cross-hatched bars) along with standard errors of the means. The bar labels correspond to the presence of at least one BDNF Met allele (Met+ and Met−) and Sex (Men vs. Women).

Figure 4

An illustration of Sex × Hypertension interaction for two tests of speed of processing: Letter Comparison (Letters, blank bars) and Pattern comparison (Patterns, cross-hatched bars). Standard errors of the means are also shown. The bar labels correspond to Sex (Men vs. Women) and Hypertensive (H) vs. Normotensive (N) status.

Figure 5

The effect of COMT Met158 allele on associative memory at immediate and delayed recall. Bars represent mean scores with standard errors around them.

Figure 6

The effect of BDNF Met allele on associative memory, immediate and delayed.