Objectives. Determine the relationship between depressive symptom clusters and neuropsychological test performance in an elderly cohort of cognitively normal controls and mild Alzheimer's disease (AD). Design. Cross-sectional analysis. Setting. Four health science centers in Texas. Participants. 628 elderly individuals (272 diagnosed with mild AD and 356 controls) from ongoing longitudinal study of Alzheimer's disease. Measurements. Standard battery of neuropsychological tests and the 30-item Geriatric Depression Scale with regressions model generated on GDS-30 subscale scores (dysphoria, apathy, meaninglessness and cognitive impairment) as predictors and neuropsychological tests as outcome variables. Follow-up analyses by gender were conducted. Results. For AD, all symptom clusters were related to specific neurocognitive domains; among controls apathy and cognitive impairment were significantly related to neuropsychological functioning. The relationship between performance and symptom clusters was significantly different for males and females in each group. Conclusion. Findings suggest the need to examine disease status and gender when considering the impact of depressive symptoms on cognition.