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.

Highlights: We developed a robust harmonization pipeline for multi-cohort genotype array data. Cerebrospinal fluid amyloid beta (Aβ)-specific polygenic risk scores (PRS) more strongly predicted global Aβ positron emission tomography burden than other PRS. Results suggest a strong genetic predisposition to early Aβ pathology. This work highlights the need for robust data harmonization and data pooling. This work also validates the potential use of PRS as a non-invasive tool to assess Alzheimer's disease risk.