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.

Automated summary

APOE epsilon 4 carriers with African local genomic ancestry (ALA) have a lower risk for Alzheimer's disease (AD) compared to carriers with European local ancestry (ELA). The differences in APOE expression between the two ancestries may contribute to this reduced risk for AD in African carriers.