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Background: Neurocognitive decline (NCD) is a well-documented complication associated with cardiac surgery. While several factors have been associated with NCD, there is no reliable biomarker to diagnose or differentiate post-surgical NCD. Several markers of neuronal damage have been validated in other conditions like Alzheimer’s Disease (AD), but not in the cardiac surgical population. In this study, we utilize novel multiplex biomarker assays to investigate potential biomarkers for NCD in cardiac surgery patients. Hypothesis: Neuronal degradation markers will be altered, in association with NCD. Methods: Of the 1516 patients enrolled in the parent study, Omega-3 Fatty Acids for Prevention of Post-operative Atrial Fibrillation (OPERA) trial, a subset of 115 underwent plasma collection and neurocognitive testing using forms of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Testing occurred preoperatively, on postoperative day four (POD4), and one month postoperatively (POD30). NCD was defined as a 15% change in RBANS score on POD4 vs baseline. Flash-frozen plasma samples were analyzed with multiplex assays for markers of neurodegradation. Results were analyzed using normalization, Student’s t-tests, and curves. α=0.05. Results: Of patients with definitively clear neurocognitive results (n=97), 32% had NCD (n=31). Compared with baseline, on POD4, total Tau protein (tTau) decreased in patients with NCD by an average of 3.7% vs those without (p=0.030), for whom tTau increased by 72.7%. At POD30, patients with NCD who recovered to baseline had increased tTau by 1915% vs those who didn’t recover (p=0.015), for whom tTau increased by a lesser 288%. For the same baseline vs POD30 patients, phosphorylated Tau (pTau181) increased for recovered patients vs unrecovered (p=0.004). Compared with POD4, on POD30, patients with NCD who recovered had increased pTau181 vs those who didn’t recover (p=0.014) and increased tTau vs those who didn’t recover (p=0.027). All other biomarker comparisons had no association with NCD or recovery, including BDNF, Aβ42, Aβ40, GFAP, and NfL. Conclusion: NCD and recovery after cardiac surgery appears related to markers of neuronal damage. The directionality of changes is surprising, as it displays a paradigm shift from AD and other neurodegenerative processes. These findings suggest direct neuronal damage is a major mediator of NCD and necessitate further discovery using advanced machine learning models.