Bidirectional relationships between plasma tau phosphorylation markers and postoperative delirium
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PROJECT SUMMARY Post-operative delirium (POD) and Alzheimer’s disease (AD) increase the risk for one another, which suggests a bidirectional relationship between POD and AD. This relationship can be explored using new blood-based biomarkers for AD pathology, such as threonine-217 phosphorylated tau (pTau217) protein, which are poised to transform AD detection, diagnosis, and prognostication. A critical gap in our understanding of the relationship between POD and AD is how AD pathology, reflected by these biomarkers, may increase POD risk and how POD may impact the longitudinal trajectories of new AD biomarkers, and, thus, AD pathology. This application responds specifically to NOT-AG-24-030, which seeks studies that “address shortcomings of currently used [AD] biomarkers,…further [characterize AD] biomarkers,…[and/or] identify…a dementia/cognition ‘stress’ test.” We propose that elective surgery can be viewed as a “stress test” for the aging brain because surgical stress may “unmask” neurocognitive vulnerability, eg, due to AD-specific pathology, resulting in POD. Further, we propose that POD may alter the “AD clock,” a model that predicts time to onset of AD symptoms based on levels of AD biomarkers, such as pTau217. We posit that after POD, the AD clock may begin to tick—consistent with the start of accumulating AD pathology—or the clock may begin to tick faster—indicating an acceleration in AD pathological progression denoted by a faster-than-expected rise in AD biomarker levels after POD. Our rationale for studying the relationship between POD and AD-specific plasma biomarkers, ie pTau217, is to better characterize (a) the extent to which surgical stress unmasks AD-specific pathology (ie, pre-op pTau217) in POD; and (b) the extent to which POD may influence AD biomarker trajectories. These insights will enhance our ability to predict, prognosticate, and develop interventions for both POD and AD. Our objective is to determine the association between POD and pTau217 levels using our pre-existing cohort of 195 surgery patients 65y. In this unique cohort, 35% of participants had Montreal Cognitive Assessment (MoCA) scores consistent with mild cognitive impairment (MCI), and more than a third had POD. Our central hypothesis is that pre-op pTau217 levels correlate with POD (Aim 1) and that POD is associated with greater long-term increase in pTau217, reflecting faster AD pathology accumulation over months to years postop. (Aim 2). Secondary analyses will evaluate additional blood-based AD biomarkers. Sensitivity analyses will evaluate MCI and non-MCI patients separately. Successful completion of this study will (a) improve understanding of the bidirectional relationship between POD and AD; (b) advance the characterization, diagnosis, and prediction of AD and POD, using new AD plasma biomarkers and elective surgery as an AD stress test, and (c) yield evidence to guide future studies of shared AD-POD mechanisms, potential therapeutics, POD predictors (eg, pTau217) and AD prognostication (eg, via refined AD clock models). Clinically, better POD prediction can optimize allocation of limited resources for POD prevention, and improved AD prognostication can help patients and their families with future planning.
