Incorporating Multi-threshold Polygenic Risk in Hippocampal-based Normative Models Improves Cognitive Decline Prediction

Predicting cognitive decline using MRI measures of brain volume is challenging. Normative models capture the evolution of biomarkers over time in a healthy group, quantifying an individual’s deviation from that norm. Here, we improve the precision of normative models for hippocampal volume, a key cognitive biomarker, by integrating multi-threshold polygenic scores (PGS) that capture genetic predisposition to its variability. We built Gaussian Process Regression (GPR) models on genetic, imaging, and demographic data from 23,997 UK Biobank (UKBB) participants, validating on 3,000 out-of-sample participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the European Prevention of Alzheimer’s Disease (EPAD) cohorts. The genetically-informed models improved associations significantly across five experimental designs and 13 key neurocognitive measures, including Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR), Alzheimer’s Disease Assessment Scale (ADAS), and importantly, improving prediction of future cognitive decline. These findings underscore the value of integrating multi-threshold PGS with neuroimaging-based predictive models for improving prognostication in neurodegenerative diseases.