The role of genetic ancestry in Alzheimer’s disease: Comparative methodology, framework development and genome-wide association analysis

Abstract

Understanding the role of genetic ancestry in Alzheimer's disease (AD) is crucial for uncovering the complexities of this neurodegenerative disorder. While most studies account for global ancestry, providing a broad understanding of human genetic variation, local genetic ancestry may offer a more nuanced perspective. The objective of this project was twofold. First, we aimed to develop a comparative framework for integrating Local Ancestry Inference (LAI) in Genome-Wide Association Studies (GWAS). Then, as a proof of concept, we evaluated whether local genetic ancestry influenced the identification of genetic variants associated with endophenotypes of AD, such as hippocampal volume (HV) and cerebrospinal amyloid beta 42 (Aβ42) biomarker levels, within the ALzheimer’s and FAmilies (ALFA) cohort. The bioinformatics framework incorporated both global and local ancestry into GWAS and regional association analysis, utilizing high-resolution ancestry deconvolution methods. Despite computational challenges and limitations in data accuracy, the study demonstrates that LAI provides significant insights into genetic variants associated with AD, which are not captured by traditional GWAS methods. The findings emphasize the importance of considering local ancestry in genetic research to improve the accuracy and applicability of results across diverse populations. Keywords: Alzheimer’s disease; APOE; Genetic association studies; Genetic ancestry; local ancestry inference