Many studies have shown that imbalance of mineral metabolism may play an important role in Alzheimer's disease (AD) progression. It was recently reported that selenium could reverse memory deficits in AD mouse model. We carried out multi-time-point ionome analysis to investigate the interactions among 15 elements in the brain by using a triple-transgenic mouse model of AD with/without high-dose sodium selenate supplementation. Except selenium, the majority of significantly changed elements showed a reduced level after 6-month selenate supplementation, especially iron whose levels were completely reversed to normal state at almost all examined time points. We then built the elemental correlation network for each time point. Significant and specific elemental correlations and correlation changes were identified, implying a highly complex and dynamic crosstalk between selenium and other elements during long-term supplementation with selenate. Finally, we measured the activities of two important anti-oxidative selenoenzymes, glutathione peroxidase and thioredoxin reductase, and found that they were remarkably increased in the cerebrum of selenate-treated mice, suggesting that selenoenzyme-mediated protection against oxidative stress might also be involved in the therapeutic effect of selenate in AD. Overall, this study should contribute to our understanding of the mechanism related to the potential use of selenate in AD treatment.