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

Introduction Apolipoprotein E (APOE) epsilon 4 confers less risk for Alzheimer's disease (AD) in carriers with African local genomic ancestry (ALA) than APOE epsilon 4 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 epsilon 4/epsilon 4 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 < 1.8E(-317)) in 24 of 32 cell clusters. The transcriptome of one astrocyte cluster, with high APOE epsilon 4 expression and specific to ELA, is suggestive of A1 reactive astrocytes. Discussion AD patients with ELA expressed significantly greater levels of APOE than ALA APOE epsilon 4 carriers. These differences in APOE expression could contribute to the reduced risk for AD seen in African APOE epsilon 4 carriers.