Ancestral genomic functional differences in oligodendroglia: implications for Alzheimer's disease

INTRODUCTION: This study investigates ancestry-specific changes in induced pluripotent stem cell (iPSC)-derived oligodendroglia genomic regulation in Alzheimer's disease (AD), addressing diversity gaps by including African, Amerindian, and European ancestries in the analysis. METHODS: We generated 12 iPSC lines from AD patients and controls with different apolipoprotein E (APOE) genotypes, APOE ε3/ ε3 and APOE ε4/ ε4, across three ancestries. Lines were differentiated into neural spheroids containing oligodendrocyte lineage cells and analyzed by single-nucleus RNA sequencing, Assay for Transposase-Accessible Chromatin with sequencing (ATACseq)APO, and High-throughput Chromosome Conformation Capture (Hi-C). RESULTS: We identified ancestry-specific differences in gene expression and chromatin accessibility of AD genome-wide association study candidate genes. APOE ε4/ ε4 carriers across all ancestries showed upregulated cholesterol biosynthesis genes with decreased myelination markers. iPSC-derived oligodendrocytes demonstrated high correlation (R² > 0.85) with human brain transcriptomes. DISCUSSION: Our findings highlight the importance of studying diverse ancestries in AD research and suggest early APOE ε4 effects on cholesterol metabolism. The validated iPSC model provides a valuable tool for investigating ancestry-specific disease mechanisms. Highlights: First study comparing iPSC-derived oligodendroglia across three ancestries. APOE ε4 carriers show upregulated cholesterol synthesis in oligodendroglia. Reduced myelin gene expression observed in APOE ε4/ε4 oligodendroglia. Ancestry-specific differences found in AD GWAS genes and chromatin states. Novel insights into oligodendrocyte biology relevant to Alzheimer’s disease.