Increased APOE‐e4 expression is associated with reactive A1 astrocytes and may confer the difference in Alzheimer disease risk from different ancestral backgrounds: Genetics: Molecular genetics of AD and ADRD.

Background: APOEε4 is the strongest genetic risk factor for Alzheimer Disease (AD) in European populations. African local genomic ancestry (LA) surrounding the APOEε4 allele has been associated with a decreased risk for AD in African‐American (AA) carriers relative to European LA in Non‐Hispanic Whites (NHW) (Rajalbi et al 2018). Identifying the cause of this protective effect in AA could lead to therapeutic intervention lowering AD risk for European carriers of APOEε4. Method: To identify potential gene expression variations in the LA region contributing to this differential risk Single Nucleus RNA sequencing (snRNA‐seq) was performed on frozen frontal cortex from four APOEε4 homozygote AA AD patients with only African LA and four APOEε4 homozygote NHW AD patients with only European LA. SnRNA‐seq (10X Chromium platform) was analyzed using Seurat for potential differences in expression between the samples. Result: 47,113 total nuclei were sequenced at a median depth of ∼131,000 reads per cell. We detected on average ∼1800 genes per nucleus. European LA carriers had significantly more APOEε4 expressed (p < 1.8E−313) than AA patients in 17 of the 42 snRNA‐seq clusters. Cluster 21 was unique, as it was highly enriched for APOEε4 expression and contained proportionately 12‐fold more NHW nuclei than AA. Examination of the transcriptional signature of cluster 21 revealed a strong enrichment for known astrocyte‐specific markers, with significantly higher levels of GFAP, VIM, LGALS1, FGF2, and HSBP1 compared to other astrocyte clusters. Conclusion: These findings suggest that the increased risk for AD seen in NHW versus AA carriers of APOEε4 is likely due to increased APOEε4 expression in carriers with the European LA. This increased APOEε4 expression is strongly associated with a large increase in potentially reactive A1 astrocytes, supporting this as a possible mechanism for the increased risk for AD conferred by the APOEε4 allele. [ABSTRACT FROM AUTHOR]