Objective. The present study explores the underlying factors of cognitive abilities in relation to the expression of adiponectin and nitric oxide, fatigue, and other cofounder variables such as physical activity, diabetes, and adiposity status in healthy home-resident mature and older adults. Background. Fatigue has been shown to be correlated with many metabolic and psychiatric conditions, such as cognitive, neurological, musculoskeletal, and hormonal disorders, as well as physical and unhealthy lifestyles. Methods. A total of 85 home residents aged 50–85 years participated in this case-control study. Mental, fatigue, and pain status were assessed by the cognitive assessment (LOTCA), fatigue questionnaire (CIS20r), and pain score (0–10). VO2 max and the prevalidated global physical activity questionnaire were used to estimate physical status. The levels of adiponectin, nitric oxide (NO), and variables related to diabetes, such as blood sugar and glycated hemoglobin (HbA1c %), were assessed using ELISA and spectrophotometric immunoassays. Results. The participants were classified according to the CIS-fatigue score into two groups: the healthy group (n = 40) and the fatigue group (n = 45). In fatigued subjects, LOTCA scores as a measure of cognitive performance significantly decreased (65.97 ± 7.17;
P
= 0.01) as compared with healthy subjects (LOTCA scores, 94.2 ± 7.5). The results of cognitive performance domains (LOTCA seven-subset scores) showed a significant decrease in the scores of orientation, visual perception, spatial perception, motor praxis, vasomotor organization, thinking operations, attention, and concentration in older subjects with fatigue compared with healthy subjects. In addition, pain scores significantly increased, and the expression of both nitric oxide (NO) and adiponectin significantly reduced in older adults with fatigue as compared with healthy controls. The decline in cognitive abilities among older adults with fatigue is significantly associated with the CIS-fatigue score, sedentary lifestyle, obesity, pain status, diabetes, and reduction in the levels of nitric oxide (NO), and adiponectin. Moreover, in fatigued cases, the expression of both NO and adiponectin was significantly correlated with CIS-fatigue score, physical activity, obesity, and diabetes, which indicates its availability as diagnostic markers for cognition in mature and older adults with fatigue. Conclusion. In the present study, the data concluded that cognitive abilities were significantly associated with the lower expression of adiponectin and NO as endothelial vascular markers in association with fatigue among home-resident older adults. In addition, the reduction in cognition was significantly affected by other parameters, such as diabetes, obesity, and unhealthy sedentary life activities. Moreover, the results might recommend the use of cellular adiponectin and NO as diagnostic indicators of cognitive abilities in fatigued mature and older adults. However, more studies on larger sample sizes are required.