Genetic variants in glutamate, Aβ and tau related pathways determine polygenic risk for Alzheimer’s disease

Abstract Synapse loss is an early event in late-onset Alzheimer’s disease (LOAD). In this study we have assessed the capacity of a polygenic risk score (PRS) restricted to synapse-encoding loci to predict LOAD. We used summary statistics from the IGAP genome-wide association meta-analysis of 74,046 subjects for model construction and tested the “Synaptic PRS” in two independent datasets of controls and pathologically-confirmed LOAD. The mean Synaptic PRS was 2.3-fold higher in LOAD compared to controls (p