Natural killer (NK) cell activity of peripheral blood mononuclear (PBM) cells was measured in 16 subjects with mild to moderate senile dementia of Alzheimer's type (sDAT) chosen for short history of disease and no medication, and in 17 age- and sex-matched controls. Levels of cytotoxicity at baseline and after PBM cell exposure to modifiers either negative (cortisol 10(-6) M) or positive (rIL-2 650 IU/ml and rIFN-gamma 100 UI/ml, respectively) were related to indices of hypothalamic-pituitary-adrenal (HPA) function and Gottfries Bråne Rating Scale (GBS) score for mental deterioration. Spontaneous NK cell activity was not significantly different in sDAT subjects vs controls. In vitro inhibition by cortisol was lower in sDAT (P<0.05); cytokine-induced changes were greater (rIL-2, P<0.02; rIFN-gamma, P<0.05). Percent negative or positive variations from baseline significantly correlated with GBS scores (P<0.05 or less). Serum cortisol and cortisol/DHEAS molar ratio at 0800 h were significantly higher in sDAT (P<0.05 and P<0.02, respectively). Cortisol/DHEA ratio positively correlated with GBS scores (P<0.02). Moreover, the ratios of incremental area of response ACTH/cortisol and beta-endorphin/cortisol after 1 microg/kg ovine-corticotrophin-releasing hormone (o-CRH) positively correlated with percent increase of NK cell activity after rIL-2 (P<0.01). Data indicate that patients with mild cognitive impairment and short history of sDAT show abnormal responsiveness of NK cell activity to physiological modifiers while maintaining normal spontaneous activity. Furthermore, data are compatible with partial glucocorticoid resistance at the immune level. Progressing sDAT longitudinal studies are needed to address: i) the clinical applicability of these abnormalities as prognostic factors; ii) the role played by pro-opiomelanocortin (POMC)-derived peptides and adrenal androgens in the control of NK cell activity.