Background: Delirium is a common post-operative complication, particularly in older adults undergoing major or emergency procedures. It is associated with increased length of intensive care and hospital stay, post-operative mortality and subsequent dementia risk. Current methods of predicting delirium incidence, duration and severity have limitations. Investigation of blood and cerebrospinal fluid (CSF) biomarkers linked to delirium may improve understanding of the underlying pathophysiology, particularly with regard to the extent this is shared or distinct with underlying dementia. Together, these have the potential for development of better risk stratification tools and perioperative interventions. Methods: 200 patients over the age of 70 scheduled for surgery with routine spinal anaesthetic will be recruited from UK hospitals. Their cognitive and functional baseline status will be assessed pre-operatively by telephone. Time-matched CSF and blood samples will be taken at the time of surgery and analysed for known biomarkers of neurodegeneration and neuroinflammation. Patients will be assessed daily for delirium until hospital discharge and will have regular cognitive follow-up for two years. Primary outcomes will be change in modified Telephone Interview for Cognitive Status (TICS-m) score at 12 months and rate of change of TICS-m score. Delirium severity, duration and biomarker levels will be treated as exposures in a random effects linear regression models. PRIMED Risk has received regulatory approvals from Health Research Authority and London – South East Research Ethics Committee. Discussion: The main anticipated output from this study will be the quantification of biomarkers of acute and chronic contributors to cognitive impairment after surgery. In addition, we aim to develop better risk prediction models for adverse cognitive outcomes.