NADPH Oxidase-Related Oxidative Stress in Parkinson’s Disease-Associated Cognitive Impairment: An Evidence-Focused Review

Cognitive impairment is a major non-motor manifestation of Parkinson’s disease (PD); however, evidence linking specific NADPH oxidase (NOX) isoforms to cognition-related outcomes remains incompletely integrated. In this evidence-focused narrative review, a structured four-database search identified 12 studies for study-level synthesis: 10 rodent studies involving cognitive assessment in PD-relevant models and 2 contextual studies. The 10 core studies were appraised according to the directness with which NOX involvement was examined in relation to cognitive outcomes. The most direct experimental support centered on hippocampal NOX4- and NOX2/gp91phox-associated microglial signaling. Dentate-gyrus-targeted NOX4 knockdown attenuated learning and memory deficits, with concurrent reductions in proteinopathy-related changes. CD68-driven gp91phox knockdown similarly attenuated these deficits alongside reductions in inflammatory responses and neuronal and synaptic injury. Apocynin was classified as a NOX-targeted pharmacological intervention and improved learning and memory performance. However, its lack of target and isoform specificity precluded definitive attribution of the behavioral effect to NOX inhibition. Other studies contributed partial or supportive evidence, while complementary pathway-level evidence linked cognition-related inflammatory signaling to NOX1/NOX2 dependence. Human postmortem and canine biomarker studies have provided clinicopathological and comparative peripheral biomarker context, respectively, but they have not established a NOX–cognition relationship in human PD. Overall, the evidence suggests that NOX-related oxidative stress contributes to the development of learning and memory deficits in PD-relevant models. Because the principal NOX4 and gp91phox genetic interventions preceded model induction, the observed effects are best interpreted as protection during deficit development rather than reversal of established cognitive impairment. Cross-model validation, NOX-directed interventions initiated after cognitive impairment has been confirmed, and studies in cognitively characterized human PD cohorts are needed to establish translational relevance.