GeroScience ·11 Nov 2026 ·Added 12 Nov 2026

Neuronal injury and inflammatory protein signatures of postoperative delirium and cognitive decline in older adults-combining insights from post-surgical and memory clinic cohorts.

Ming Ann Sim, David A Scott, Lisbeth Anne Evered, Eugene S J Tan, Siew Pang Chan, Vera Yuan Cai, Amelia Ang, Chunmei Li, Eddie Jun Yi Chong, Will N H Loh, Narayanaswamy Venketasubramanian, Boon Yeow Tan, Saima Hilal, Mitchell K P Lai, Sophia Tsong Huey Chew, Hyungwon Choi, Arthur Mark Richards, Christopher Li Hsian Chen, Lian Kah Ti

DOI ↗

Abstract

Plasma proteomics may offer novel characterization of the longer-term inflammatory and neuronal injury alterations in older adults undergoing elective surgery, and their relations to delirium and cognitive decline. We leveraged plasma protein data from N = 616 participants across two longitudinal cohorts. Plasma proteomic profiling of 447 proteins related to inflammation and neuronal injury (Olink platform) was applied to perioperative samples (collected at baseline, postoperative day (POD)1, and POD30) from the primary Southeast-Asian surgical cohort (N = 88), followed-up for postoperative delirium. Secondary mechanistic verification of key proteins was performed within an independent Southeast-Asian memory-clinic cohort (N = 528) followed-up for 4 years with cognitive and neuroimaging assessments. In the surgical cohort, significant dysregulations were observed within 330 proteins on POD1 and 230 proteins on POD30-mapping to diverse biological processes. The protein profiles most dysregulated on POD1 related to systemic inflammation, while that on POD30 exhibited a broader profile reflecting neuronal injury (i.e., EN-RAGE, NEFL, PAEP). A twelve-protein time-course signature was concordantly altered in participants with postoperative delirium (N = 26, 30%). Secondary validation within the memory-clinic cohort further prioritized 6 of the 12 proteins associating with delirium, as additional biomarkers of brain atrophy, cerebral small vessel disease, and 4-year cognitive decline: NEFL, TNFRSF10B, PLA2G10, SLC39A14, TNFRSF10A, GGT5. Leveraging insights from surgical and memory clinic cohorts, we prioritized protein signatures exhibiting robust signals for (i) postoperative delirium, (ii) neuroimaging pathology, and (iii) 4-year cognitive decline. These proteins may represent mechanistic targets for optimizing cognitive health in older adults.