Episodic memory is a polygenic trait influenced by different molecular mechanisms. We used PET and a candidate gene approach to investigate how individual differences at the molecular level translate into between-person differences in episodic memory performance of elderly persons. Specifically, we examined the interactive effects between hippocampal dopamine D2 receptor (D2DR) availability and candidate genes relevant for hippocampus-related memory functioning. We show that the positive effects of high D2DR availability in the hippocampus on episodic memory are confined to carriers of advantageous genotypes of the brain-derived neurotrophic factor ( BDNF , rs6265) and the kidney and brain expressed protein ( KIBRA , rs17070145) polymorphisms. By contrast, these polymorphisms did not modulate the positive relationship between caudate D2DR availability and episodic memory.

The dopamine (DA) system plays an important role in cognition. Accordingly, normal variation in DA genes has been found to predict individual differences in cognitive performance. However, little is known of the impact of genetic differences on the link between empirical indicators of the DA system and cognition in humans. The present work used PET with 11 C-raclopride to assess DA D2-receptor binding potential (BP) and links to episodic memory, working memory, and perceptual speed in 179 healthy adults aged 64–68 years. Previously, the T-allele of a DA D2-receptor single-nucleotide polymorphism, C957T , was associated with increased apparent affinity of 11 C-raclopride, giving rise to higher BP values despite similar receptor density values between allelic groups. Consequently, we hypothesized that 11 C-raclopride BP measures inflated by affinity rather than D2-receptor density in T-allele carriers would not be predictive of DA integrity and therefore prevent finding an association between 11 C-raclopride BP and cognitive performance. In accordance with previous findings, we show that 11 C-raclopride BP was increased in T-homozygotes. Importantly, 11 C-raclopride BP was only associated with cognitive performance in groups with low or average ligand affinity (C-allele carriers of C957T , n = 124), but not in the high-affinity group (T-homozygotes, n = 55). The strongest 11 C-raclopride BP–cognition associations and the highest level of performance were found in C-homozygotes. These findings show that genetic differences modulate the link between BP and cognition and thus have important implications for the interpretation of DA assessments with PET and 11 C-raclopride in multiple disciplines ranging from cognitive neuroscience to psychiatry and neurology.