Background <p>Neurocognitive disorders are prevalent among older surgical patients, yet their underlying mechanisms and effective interventions remain largely unknown. Studies in rodents and patients suggest a connection between olfactory impairment and perioperative neurocognitive disorder (PND). Previous work in mice demonstrates that anesthesia and surgery can lead to both olfactory impairment and cognitive deficits. Olfactory enrichment, which is also referred to as olfactory training (i.e., daily exposure to multiple odorants), may prove helpful. For example, olfactory enrichment appears to reduce PND-like behaviors in mice, possibly by mitigating anesthesia- and surgery-induced reductions in olfactory receptor neurons. Additionally, olfactory enrichment increases the volume and size of olfactory-related brain regions, such as the olfactory bulb and hippocampus, as well as changes in functional connectivity in non-surgical adults. Despite promising findings in mice, it remains unknown whether olfactory training reduces PND in surgical patients. We therefore propose a randomized clinical trial.</p> Methods and analysis <p>This sham-controlled assessor-blind randomized controlled trial will enroll 686 patients aged 65 and older who are scheduled for orthopedic Surgery expected to last at least 2h under general anesthesia. Participants will be randomized 1:1 to olfactory enrichment or sham treatment. Those assigned to the olfactory enrichment group will receive twice-daily 30-min sessions involving four distinct odors, beginning on&#xa0;1 day before surgery and continuing for three postoperative days&#xa0;during hospitalization. Patients assigned to sham treatment will follow the same schedule, but with odorless substances in the scent dispenser.</p> <p>The primary outcome is the incidence of postoperative delirium, assessed using the 3-min diagnostic interview for CAM-defined delirium (3D-CAM) on postoperative days 1, 2, and 3. Secondary outcomes include the incidence of delayed neurocognitive recovery and postoperative neurocognitive disorder, evaluated through cognitive function assessments using neuropsychological tests at baseline, 21&#xa0;days, and 6&#xa0;months after the anesthesia/surgery. Exploratory outcomes include the severity of delirium measured by the CAM-severity (CAM-S) tools, the severity of delayed neurocognitive recovery and postoperative neurocognitive disorder assessed through neuropsychological tests, evaluations of activities of daily living, plasma Tau-PT217 levels, and olfactory function.</p> Discussion <p>This is the first clinical trial to evaluate the efficacy of olfactory enrichment in geriatric patients undergoing orthopedic surgery, filling an important gap in the treatment evidence for PND.</p> Trial registration <p>The trail has been registered in ClinicalTrial.gov with the Trial Registration Number of NCT06488807. Date of registration in the primary registry: June 15, 2024. The study is anticipated to start in March 2025. The anticipated primary completion date is December 31, 2027.&#xa0;</p>