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.

FAAH genotype, CRFR1 genotype, and cortisol interact to predict anxiety in an aging, rural Hispanic population: A Project FRONTIER study.

The neurophysiological underpinnings involved in susceptibility to and maintenance of anxiety are not entirely known. However, two stress-responsive systems, the hypothalamic-pituitary-adrenal axis and the endocannabinoid system, may interact in anxiety. Here, we examine the relationship between FAAH genotype, CRFR1 genotype, baseline cortisol, and state anxiety in a rural adult population using data from Project FRONTIER. We predicted that FAAH A (AA and AC vs CC; rs324420) and three CRFR1 SNP minor alleles (rs7209436 C→ T [minor allele]; rs110402, G → A [minor]; and rs242924 G→ T [minor]), would interact to predict low baseline cortisol and low state anxiety scores. We found partial support for our prediction. In CRFR1 minor carriers, the FAAH AA or AC (vs. CC) genotype was associated with higher cortisol and with lower anxiety. In CRFR1 non-minors, those with FAAH AA or AC (vs. CC) showed decreased cortisol and higher anxiety. These results suggest that FAAH CC genotype only conveys risk for anxiety in individuals who are also carriers of the CRFR1 minor combination. FAAH genotype was significantly associated with baseline cortisol but was not independently associated with anxiety. Contrary to our predictions, baseline cortisol was negatively associated with anxiety. Lastly, we did not find any independent relationships between any of our SNPs and baseline cortisol or anxiety. These data suggest FAAH and cortisol interact to predict state anxiety, but that the relationship depends on CRFR1 genotype. The Project FRONTIER dataset is supported by Texas Tech University Health Sciences Center Garrison Institute on Aging.