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APOE-ε4 genotype may play a role in an individual's susceptibility to the consequences of hypothalamic-pituitary-adrenal (HPA) axis dysregulation on cognitive function, researchers report in a study published online July 1 in the American Journal of Psychiatry.

Brian K. Lee, of Johns Hopkins University in Baltimore, and colleagues analyzed data from 962 subjects, aged 50 to 70. Participants submitted salivary cortisol samples and blood samples for APOE genotyping, and took a variety of tests in seven cognitive domains.

People with higher cortisol and one ε4 allele performed worse in language, processing speed, eye-hand coordination and executive functioning, the researchers found. People with higher cortisol and two ε4 alleles performed worse in all domains compared to those with lower cortisol and no ε4 alleles. In those with two ε4 alleles and higher cortisol, the decrements in language scores were equivalent to an additional 33.4 years of age, the report indicates.

"While the roles of both APOE and cortisol in the pathogenesis of cognitive dysfunction are still not well understood, several plausible biological mechanisms can be proposed for the cortisol-APOE interaction. APOE genotype may modify the physiological consequences of HPA axis activity.…In addition, APOE genotype may lower the neuronal threshold required for cortisol or neurotoxicants to produce neurodegenerative changes," the authors conclude. "It is also possible that cortisol may increase susceptibility of the brain to adverse events, such as the structural and functional changes mediated by apolipoprotein E."

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