Influences of a DRD2 polymorphism on updating of long‐term memory representations and caudate BOLD activity: Magnification in aging

Abstract

A number of genetic polymorphisms are related to individual differences in cognitive performance. Striatal dopamine (DA) functions, associated with cognitive performance, are linked to the TaqIA polymorphism of the DRD2/ANKK1 gene. In humans, presence of an A1 allele of the DRD2/ANKK1-TaqIA polymorphism is related to reduced density of striatal DA D2 receptors. The resource-modulation hypothesis assumes that aging-related losses of neurochemical and structural brain resources modulate the extent to which genetic variations affect cognitive functioning. Here, we tested this hypothesis using functional MRI during long-term memory (LTM) updating in younger and older carriers and noncarriers of the A1-allele of the TaqIa polymorphism. We demonstrate that older A1-carriers have worse memory performance, specifically during LTM updating, compared to noncarriers. Moreover, A1-carriers exhibited less blood oxygen level-dependent (BOLD) activation in left caudate nucleus, a region critical to updating. This effect was only seen in older adults, suggesting magnification of genetic effects on functional brain activity in aging. Further, a positive relationship between caudate BOLD activation and updating performance among non-A1 carriers indicated that caudate activation was behaviorally relevant. These results demonstrate a link between the DRD2/ANKK1-TaqIA polymorphism and neurocognitive deficits related to LTM updating, and provide novel evidence that this effect is magnified in aging.

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

“…Genetic predisposition for higher density of extrastriatal D2 receptors (DRD2 CC) was associated with better inhibition of unwanted action tendencies, an effect that was more pronounced in older than in younger adults ( Figure 5) [61]. With respect to brain functioning, another variation in the DRD2 gene showed a similar pattern of age magnification, both on brain and behavior: lower performance in long-term memory updating was found for older carriers of the allele associated with fewer D2 receptors, as compared with non-carriers [62]. In addition, older risk carriers had lower brain activity in left caudate nucleus, a region crucial for updating [63].…”

DRD2: Bridging the Genome and Ingestive Behavior

“…Being an A1 allele carrier is associated with greater impulsivity [78–84], poorer time estimation [78], steeper delayed discounting [40] poorer working memory [76, 84, 85], impaired reversal learning [74, 86, 87], impaired negative outcome learning [14, 34, 75] and poorer long term memory [88] (though see [89]).…”

“…Relatedly, it is possible that adaptations occur in response to factors other than diet, adiposity or metabolic change, such as age, poor sleep quality, chronic stress, and physical inactivity [107]. Consistent with this notion, old but not young carriers compared to non-carriers show reduced dorsal striatal response and impaired performance during a memory task [88]. …”

Influence of the DRD2/ANKK1 Taq1A polymorphism on caudate volume in older adults without dementia

“…Individuals who carry the A allele have reduced D2 receptor density in the caudate and putamen compared to non-carriers (Pohjalainen et al 1998; Jönsson et al 1999; Thompson et al 1997). The presence of the A allele has been related to worse performance on executive function tasks (Persson et al 2015; Berryhill et al 2013; Jocham et al 2009). However, as some studies have found no effect (Cerasa et al 2009) or even a reversal effect (Bartres-Faz et al 2002; Tsai et al 2002) of the Taq1A polymorphism on cognition, the association between the DRD2 gene and behavioral performance still remains unclear.…”