WWC1 genotype modulates age-related decline in episodic memory function across the adult life span

Abstract

Background: Episodic memory (EM) declines with age and the rate of decline is variable across individuals. A single nucleotide polymorphism (rs17070145) in the WWC1 gene that encodes the KIBRA protein critical for long-term potentiation and memory consolidation has previously been associated with EM performance, as well as differences in hippocampal engagement during EM tasks using functional magnetic resonance imaging (fMRI). In the current study, we explore the effect of this polymorphism on EM-related activity and cognitive performance across the adult life span using fMRI.

Methods: Two hundred thirty-two healthy, Caucasian subjects (18-89 years) completed a battery of cognitive tests, as well as an EM task during an fMRI scan.

Results: WWC1 T carriers had significantly better delayed recall performance than CC individuals (p = .006). The relationship between increasing age and recall scores (immediate and delayed) was also significantly different between WWC1 genotype groups (p = .01). In addition to the age-related decline in hippocampal formation (HF) activation (p < .05; false discovery ratesmall volume correction-HF-region of interest), we observed an age by WWC1 genotype interaction on HF activation during encoding and retrieval. The CC group showed a significant negative association between HF activity and increasing age, while no such association was observed in the T carrier group (left HF p = .04; r-z correlation difference during encoding and retrieval; right HF p = .0008; r-z correlation difference during retrieval).

Conclusions: Our results show a dynamic relationship between rs17070145 polymorphism and increasing age on neuronal activity in the hippocampal region.

Keywords: Aging; KIBRA; WWC1; episodic memory (EM); hippocampus; long-term potentiation (LTP); single nucleotide polymorphism (SNP).

Figure 1

WWC1 SNP rs17070145 genotype group differences in free recall performance. (A) In subjects over 40 years of age, T-allele carriers have better immediate free recall performance when compared to CC individuals (p=0.01). (B) T-allele carriers have better 30 minute delayed free recall performance when compared to CC individuals (entire sample, p=0.006). Group differences remain significant when restricted to individuals over 40 years of age (p=0.0008). WWC1 genotype groups have significantly different correlations between increasing age and performance on immediate (C) and delayed recall (D) (p=0.01 for both immediate and delayed recall). Raw scores were computed by summing the number of correct responses for each individual. Adult C= CC homozygotes under 40 years old, Adult T= T-allele carriers under 40 years old, Older C= CC homozygotes over 40 years old, Older T= T-allele carriers over 40 years old. * = p<0.05, age> 40

Figure 2

A & B Effect of age on hippocampal formation (HF) neuronal activity during an episodic memory task. (A) Bilateral age-related decline in HF activity during the incidental encoding session (p<0.05, k>5, hippocampal formation ROI, FDR corrected for multiple comparaisons). (B) Bilateral age-related decline in HF activity during the retrieval session (p<0.05, k>5, hippocampal formation ROI, FDR corrected for multiple comparaisons). C&D WWC1 SNP rs17070145 genotype group differences in the correlation between age and activation during an episodic memory task. (C) The WWC1 CC group (red) exhibits a negative correlation between age and left hippocampal formation neuronal activity during the encoding session, which is not observed for the T-allele carrier group (blue). Age-Activation correlation coefficient (pearsons r): CC r= −0.36, CT/TT r= −0.01; Fishers r-z: z-score=2.76, p=0.04). (D) The WWC1 CC group exhibits a negative correlation between age and right hippocampal formation neuronal activity during the retrieval session, which is not observed for the T-allele carrier group. Age-Activation correlation coefficient (pearsons r): CC r= −0.43, CT/TT r= 0.03; Fishers r-z: z-score=3.66, p=0.0008). Similar differences between WWC1 groups in the relationship between increasing age and episodic memory related activity during retrieval session were also observed in the left hippocampal formation (Age-Activation correlation coefficient (pearsons r): CC r= −0.37, CT/TT r= −0.11; Fishers r-z: z-score=2.09, p=0.04. Data not shown.)