AD/ADRD and biological aging proteomic signatures in the etiopathology of delirium and its associated long-term cognitive decline

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Project Summary/Abstract Delirium (acute confusion), is a major complication of surgery in older patients, strongly associated with long term cognitive decline (LTCD) and Alzheimer's Disease and Related Dementias (AD/ADRD). Prevention of postoperative delirium and its long-term complications would be advanced if we could better identify at-risk patients preoperatively, and if targeted pathophysiologically-based interventions could be implemented. To address these gaps, we conducted the NIA-funded “Advancing the Understanding of Postoperative Delirium Mechanisms via Multi-Omics” R01 project and program project that funded the SAGES (Successful Aging after Elective Surgery) I and II studies. We identified and validated pre- and post-operative delirium protein signatures, demonstrating that pro-inflammatory proteins, acute phase reactants, angiogenic, and neuronal injury markers are elevated in patients who develop delirium. A model of delirium pathophysiology has emerged that stipulates a systemic pre-inflammatory state predisposes to a hyperactive inflammatory response from major surgery, leading to delirium, and potentially LTCD and AD/ADRD in individuals with a vulnerable brain. While intriguing, this model does not fully address the complex inter-relationship between delirium and AD/ADRD. For our R01 renewal, we hypothesize that AD/ADRD susceptibility and accelerated biological aging are key predisposing factors for delirium and delirium with LTCD, which in turn may increase risk for AD/ADRD. SomaScan-based plasma proteomic signatures predicting AD/ADRD up to 20 years before onset, and proteomic aging clocks, panels of plasma proteins measuring biological aging relative to chronological age, have been developed and extensively validated in large cohorts. We will use the state-of-the-art SomaScan proteomics platform that measures 7,000 proteins to test our hypotheses that AD/ADRD proteomic signatures (Aim 1) and proteomic aging clocks (Aim 2) predict postoperative delirium and delirium with LTCD. We will capitalize upon the pre- and post-operative banked specimens from SAGES I (N=560) with continuous follow-up to 72 months after major scheduled surgery, and a second, recently accrued independent cohort, SAGES II (N=400), with similar characteristics and follow-up to 18 months. We will combine proteins from the AD/ADRD and aging proteomic signatures, along with additional proteins from the 7,000 protein SomaScan covering many biological pathways, for a deep etiopathological characterization of the plasma proteome for delirium and delirium with LTCD in SAGES I (Aim 3) and independent validation of the proteomic signature for delirium using both SomaScan and ELISA with plasma from SAGES II (Aim 4). Our R01 renewal Aims will provide new insights into molecular mechanisms underlying delirium pathogenesis and its association with AD/ADRD and biological aging. This project holds great promise to develop accurate blood-based biomarkers for preoperative delirium risk prediction, postoperative prognostication of LTCD following delirium, and to lay the groundwork for targeted interventions to improve outcomes of older adults at risk of delirium.