Relations among CRFR1 and FKBP5 genotype, cortisol, and cognitive function in aging humans: A Project FRONTIER study.

Here we use the glucocorticoid cascade hypothesis framework to address the role of baseline cortisol on changes in cognitive function over a 3-year span in non-demented rural Americans. We also determine if genotype at 4 different single nucleotide polymorphisms (SNPs) relates to change in cognitive function. We predicted 1) over time, increases in baseline cortisol will be associated with decline in cognitive function, 2) individuals homozygous for 3 CRFR1 SNP rare alleles (AA rs110402, TT rs7209436, and TT rs242924 vs. others) will show less cognitive decline and this will be particularly pronounced in those with lower baseline cortisol, and 3) FKBP5 T carriers (TT or CT vs. CC homozygotes) will have decreased cognitive performance and this will be particularly pronounced in individuals with higher baseline cortisol. Collectively, our data do not robustly support the glucocorticoid cascade hypothesis. In several cases, higher baseline cortisol related to better cognitive performance over time, but within individuals, increased cortisol over time related to decreased performance on some cognitive domains over time. Contrary to our predictions, individuals with the rare CRFR1 haplotype (AA, TT, TT) performed worse than individuals with the common haplotype across multiple domains of cognitive function. FKBP5 genotype status had minimal impacts on cognitive outcomes. Genotype effects were largely not dependent on cortisol. The Project FRONTIER dataset is supported by Texas Tech University Health Sciences Center Garrison Institute on Aging.

Effects of early trauma and corticotropin-releasing factor receptor 1 gene polymorphism on adult visual spatial memory.

BACKGROUND: The study sought to determine the effects of earthquake on the working memory of adults who experienced earthquake either as infants or fetuses and also investigates whether earthquake exposure and corticotropin-releasing factor receptor 1 (CRHR1) variants rs242924 and rs7209436 interacted with each other in modulating working memory. METHODS: We enrolled subjects who experienced the Tangshan Earthquake as fetuses (group I) or infants (group II), as well as those who did not experience the earthquake (group III). Their working memory was measured using Brief Visuospatial Memory Test-Revised (BVMT-R) and Hopkins Verbal Learning Test-Revised (HVLT-R). Two single-nucleotide polymorphisms (SNPs) of CRHR1 rs242924 and rs7209436 were analyzed by fluorescence quantitative polymerase chain reaction (PCR). RESULTS: The study enrolled 535 subjects, including 172 subjects in group I, 176 subjects group II, and 187 subjects in group III. Both group I and II had significantly lower BVMT-R scores than group III (p < .05). Moreover, no difference was observed in HVLT-R scores among the three groups (p > .05). The allele frequency was 84.7% for AA, 82.8% for TT, 13.6% for AC, and 15.9% for TC. C gene carriers in group II (t = -4.231, p < .01) and group I (t = -3.201, p < .05) had significantly lower visual spatial memory scores than group III. Furthermore, AT gene carriers had significantly lower visual spatial memory scores than C gene carriers in group III (t = 2.215, p < .05). Moreover, there was significant interaction between earthquake exposure and CRHR1 genotype in their effects on visual spatial memory (F = 4.028, p < .05). CONCLUSIONS: Our cross-sectional study has demonstrated that infant or fetus exposure to earthquake impairs visual spatial memory during adulthood and CRHR1 polymorphisms and earthquake exposure may interact with each other to accentuate this impairment.

Interaction of early life stress and corticotropin-releasing hormone receptor gene: effects on working memory.

BACKGROUND: Early life stress (ELS) experience is associated with persisting working memory (WM) deficits; changes to the corticotropin-releasing hormone (CRH) system; and structural, functional, and epigenetic changes in the hippocampus. Single nucleotide polymorphisms in the CRH receptor 1 (CRHR1) gene interact with ELS experience to predict depression as well as neuroendocrine and neuronal reactivity. Although these findings indicate that vulnerable genotypes might also show impaired WM performance after ELS experience, no previous study investigated whether there is an interaction effect of CRHR1 polymorphisms and ELS experience on WM performance. METHODS: Subjects (N = 451) were genotyped for rs110402 and rs242924 within the CRHR1 gene. We used an n-back task to investigate the hypothesis that WM performance in healthy subjects may be subtly influenced by functional differences in CRHR1 and represents an early marker of increased vulnerability after exposure to ELS. RESULTS: Exposure to ELS had a particularly strong impact on WM performance in subjects with the common homozygous GG GG genotype, whereas only severe exposure to ELS interfered with WM accuracy in AT carriers. CONCLUSIONS: Our data indicate that specific CRHR1 polymorphisms moderate the effect of ELS experience on WM performance. Exposure to ELS in combination with a vulnerable genotype results in subtle memory deficits in adulthood, which might develop before psychopathological symptoms.