Dopaminergic Gene Polymorphisms Affect Long-term Forgetting in Old Age: Further Support for the Magnification Hypothesis

Abstract

Abstract■ Emerging evidence from animal studies suggests that suboptimal dopamine (DA) modulation may be associated with increased forgetting of episodic information. Extending these observations, we investigated the influence of DA-relevant genes on forgetting in samples of younger (n = 433, 20-31 years) and older (n = 690, 59-71 years) adults. The effects of single nucleotide polymorphisms of the DA D2 (DRD2) and D3 (DRD3) receptor genes as well as the DA transporter gene (DAT1; SLC6A3) were examined. Over the course of one week, older adults carrying two or three genotypes associated with higher DA signaling (i.e., higher availability of DA and DA receptors) forgot less pictorial information than older individuals carrying only one or no beneficial genotype. No such genetic effects were found in younger adults. The results are consistent with the view that genetic effects on cognition are magnified in old age. To the best of our knowledge, this is the first report to relate genotypes associated with suboptimal DA modulation to more long-term forgetting in humans. Independent replication studies in other populations are needed to confirm the observed association. ■

Dopamine and glutamate receptor genes interactively influence episodic memory in old age

“…To our knowledge, this is the first evidence of interactive effects between genes related to the DA and glutamate systems on human episodic memory. Our results are in line with recent studies showing magnification of genetic effects on cognition in old age (Colzato et al, 2013;Li et al, 2010aLi et al, , 2010bLi et al, , 2013Papenberg et al, 2013). The current findings underscore the need to investigate interactive effects of multiple genes to understand interindividual differences in episodic memory in adulthood and aging.…”

Neuromodulation and aging: implications of aging neuronal gain control on cognition

“…In humans, a recent pharmacological imaging study showed that a pharmacological dopamine agonist (levodopa) enhanced episodic memory and brain activation in older adults [69 ]. Recent behavioral genetic evidence shows that genetic predispositions of dopamine transporter (DAT1) and receptor (DRD2) genes are associated with individual differences in serial memory (Figure 4b, [70 ]) and long-term episodic memory forgetting [71], particularly in older adults. The magnification of genotype effects in old age can be computationally derived from the non-linear neuronal gain control function [31], which results in an inverted-U function relating levels of dopamine signaling and memory performance [32] that is in line with empirical evidence [34][35][36][37].…”

Aging-related magnification of genetic effects on cognitive and brain integrity

“…This could result in both additive and interactive effects, emphasizing the importance of investigating the effects of multiple genes. Several studies have investigated the joint effects of DArelated genes on executive functioning, working memory, and episodic memory in old age [66][67][68]. For example, a DRD2 polymorphism interacted with a DA transporter gene in an episodic memory task requiring recall of words in backward order [68]: carriers of genetic predispositions for more D2 receptors and higher synaptic DA levels had higher recall accuracy.…”