Abstract: Objective To investigate the prognostic value of serum nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) and thioredoxin-interacting protein (TXNIP) in patients with Alzheimer disease (AD). Methods A total of 112 patients with AD who were admitted to Yulin Hospital, the First Affiliated Hospital of Xi'an Jiaotong University, from January 2022 to March 2023 were enrolled as an AD group. Meanwhile, another 105 healthy elderly individuals undergoing physical examination were selected as a control group. The levels of NOX4 and TXNIP between the two groups were compared by independent-sample t tests. Pearson correlation analysis was conducted to assess the associations of NOX4 and TXNIP with Mini-Mental State Examination (MMSE) scores, amyloid-β protein (Aβ42), and total tau protein (T-tau). Multivariate logistic regression was conducted to identify independent risk factors for poor prognosis in AD patients. Receiver operating characteristic (ROC) curves were plotted to evaluate the predictive value of serum NOX4 and TXNIP levels for adverse outcomes in AD patients. Results The AD group showed remarkably higher levels of serum NOX4 and TXNIP and lower MMSE scores than the control group (P<0.05). Pearson correlation analysis revealed that serum NOX4 and TXNIP levels were negatively correlated with Aβ42 and MMSE scores, and positively correlated with T-tau (P<0.05). MMSE score, disease duration, NOX4, and TXNIP were identified as independent risk factors for poor prognosis in AD patients. ROC curve analysis showed that the area under the curve (AUC) of combined NOX4 and TXNIP detection was significantly higher than that of either marker alone. Conclusions Serum NOX4 and TXNIP levels are associated with cognitive function in AD patients and can be used to evaluate and predict adverse prognosis, which is of great clinical significance for guiding clinical treatment and nursing care.