Increased APOE ε4 expression is associated with the difference in Alzheimer's disease risk from diverse ancestral backgrounds

INTRODUCTION Apolipoprotein E (APOE) e4 confers less risk for Alzheimer's disease (AD) in carriers with African local genomic ancestry (ALA) than APOE e4 carriers with European local ancestry (ELA). Cell type specific transcriptional variation between the two local ancestries (LAs) could contribute to this disease risk differences. METHODS Single-nucleus RNA sequencing was performed on frozen frontal cortex of homozygous APOE e4/e4 AD patients: seven with ELA, four with ALA. RESULTS A total of 60,908 nuclei were sequenced. Within the LA region (chr19:44-46Mb), APOE was the gene most differentially expressed, with ELA carriers having significantly more expression (overall P