Interplay between polygenic effects and polypharmacy on dementia: An investigation in an elderly Scottish cohort.

Abstract

INTRODUCTIONPolygenic Risk Scores for Alzheimer dementia (AD-PRS), a measure of aggregate AD genetic risk and polypharmacy have been associated with dementia. Here, we test their interactions association with future dementia among older adults without baseline neurodegenerative diagnoses. METHODSUsing Cox proportional hazards and mortality-adjusted competing risk regression models we analysed up to 17.5 years all-cause incident dementia in the Lothian Birth Cohort 1936 (n=759, 105 dementia patients). We used polypharmacy (total or nervous-system-acting medications count), AD-PRS, and their interaction as main predictors. RESULTSA non-significant interaction was found between AD-PRS and total polypharmacy (HR=1.06; p=0.15) or nervous-system-acting polypharmacy (HR=0.98; p=0.86) in shaping dementia risk. Omitting interaction, mortality-adjusted models showed significant AD-PRS prediction of dementia (HR [~]1.40; p<0.001), non-significant total (HR=1.03; p=0.49), and nervous-system-acting polypharmacy effects (HR=1.27; p=0.069). DISCUSSIONElucidating the complex interplay between polypharmacy and genetics could improve management of inappropriate medication in older adults genetically prone to dementia/AD.