The Hypothalamic Pituitary Adrenal (HPA) axis has been implicated in the pathophysiology of a variety of mood and cognitive disorders. Neuroendocrine studies have demonstrated HPA axis overactivity in major depression, a relationship of HPA axis activity to cognitive performance, and a potential role of HPA axis genetic variation in cognition. The present study investigated the simultaneous roles HPA axis activity, clinical symptomatology, and HPA genetic variation play in cognitive performance. Patients with major depression with psychosis (PMD) and without psychosis (NPMD) and healthy controls (HC) were studied. All participants underwent a diagnostic interview and psychiatric ratings, a comprehensive neuropsychological battery, overnight hourly blood sampling for cortisol, and genetic assessment. Cognitive performance differed as a function of depression subtype. Across all subjects, cognitive performance was negatively correlated with higher cortisol, and PMD patients had higher cortisol than did NPMDs and HCs. Cortisol, clinical symptoms, and variation in genes, NR3C1 (glucocorticoid receptor - GR) and NR3C2 (minercorticoid receptor – MR) that encode for glucocorticoid and mineralcorticoid receptors, predicted cognitive performance. Beyond the effects of cortisol, demographics, and clinical symptoms, NR3C1 variation predicted attention and working memory, whereas NR3C2 polymorphisms predicted memory performance. These findings parallel the distribution of GR and MR in primate brain and their putative roles in specific cognitive tasks. HPA axis genetic variation and activity were important predictors of cognition across the entire sample of depressed subjects and healthy controls. GR and MR genetic variation predicted unique cognitive functions, beyond the influence of cortisol and clinical symptoms. GR genetic variation was implicated in attention and working memory, whereas MR was implicated in verbal memory.

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The study sample included 76 healthy older adults and 77 individuals with very mild dementia of the Alzheimer type (DAT). Semantic (animal) and letter (S and P) fluency tasks were used to examine quantitative (word generation) and qualitative (category clustering and switching) aspects of verbal fluency. The goal of the study was to evaluate the utility of fluency tasks in discriminating between healthy aging and very mild DAT. Our results indicated better performance for the healthy group than the DAT group in terms of number of words, number of clusters, number of switches, and size of clusters generated (an exception was clustering on letter S fluency). Clustering and switching variables were significantly correlated with number of words generated and therefore were not included in discriminant analysis. Discriminant analysis revealed that the combination of semantic fluency and narrative recall may be particularly useful in differentiating healthy aging from very mild DAT.