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

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2024 · $870,666

## Abstract

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 ...

## Key facts

- **NIH application ID:** 10745347
- **Project number:** 5R01AG051658-06
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** TOWIA A. LIBERMANN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $870,666
- **Award type:** 5
- **Project period:** 2015-12-01 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10745347

## Citation

> US National Institutes of Health, RePORTER application 10745347, AD/ADRD and biological aging proteomic signatures in the etiopathology of delirium and its associated long-term cognitive decline (5R01AG051658-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10745347. Licensed CC0.

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