Harmonizing genotype array data to understand genetic risk for brain amyloid burden in the AMYPAD PNHS Consortium

INTRODUCTION: We sought to harmonize genotype data from the predementia AMYPAD (Amyloid Imaging to Prevent Alzheimer's Disease) Consortium, compute polygenic risk scores (PRS), and determine their association with global amyloid deposition. // METHODS: Genetic data from five AMYPAD parent cohorts were harmonized, and PRS were computed for Alzheimer's disease (AD) susceptibility, cerebrospinal fluid (CSF) amyloid beta (Aβ)42, and CSF phosphorylated tau181. Cross-sectional amyloid (Centiloid [CL]) burden was available for all participants, and regression models determined if PRS were associated with CL burden. // RESULTS: After harmonization, data for 867 participants showed that high CL burden was most strongly predicted by CSF Aβ42 PRS compared to traditional AD susceptibility PRS. // DISCUSSION: This work emphasizes the importance of data harmonization and pooling of cohorts for large-powered studies. Findings suggest a genetic predisposition to amyloid pathology that may predispose individuals early in the AD continuum. This validates the potential use of PRS in clinical (trial) settings as a non-invasive tool to assess AD risk.