Associations between polygenic risk scores for Alzheimer's disease and postoperative delirium risk

BackgroundPostoperative delirium (POD) affects up to a third of older surgical patients, leading to significant morbidity, mortality, and potential progression to Alzheimer's disease (AD). Polygenic risk scores (PRS) capture inherited susceptibility to complex diseases, but their relevance to POD is unclear.ObjectiveWe examined whether higher AD-PRS predict increased POD risk in patients without dementia and whether sleep burden modifies this relationship.MethodsThis study included 345 414 UK Biobank participants (mean [<i>SD</i>] age: 70.1 [7.9], range: 40.4-87.6 years; 54.0% women) to identify new-onset POD, using the International Classification of Disease-10 coding within three days of surgery. Participants with mild cognitive impairment, dementia, or dementia diagnosed within one year of POD were excluded. AD-PRS was calculated as a weighted sum of genetic variants, with scores divided into quartiles due to the absence of standardized thresholds. Covariates included demographics, comorbidities, and lifestyle factors. Cox proportional hazard models were used to evaluate the relationship between AD-PRS and POD risk.ResultsA total of 1610 POD cases were identified. Compared to Q1, individuals in Q3 (HR = 1.23, 95% CI [1.07-1.42], <i>p</i> < 0.01) and Q4 (1.35, [1.18-1.56], <i>p</i> < 0.001) had progressively higher POD risk. Findings were consistent across alternate POD definitions and subgroups defined by sleep burden, sex, age, cardiovascular risk, and inflammatory markers.ConclusionsHigher AD-PRS is independently associated with greater POD risk in adults without dementia. AD genetic susceptibility may help identify high-risk surgical patients and warrants validation in prospective perioperative cohorts.