Basic Science and Pathogenesis

APOE4 is the strongest genetic risk factor for Alzheimer's disease, with differing risk across populations - European ancestry has higher risk than African ancestry. The local ancestry (LA) surrounding the APOE4 region was shown to primarily affect this risk difference, with European LA (ELA) carriers having greater APOE4 chromatin accessibility and expression than African LA (ALA) individuals. Here, we investigated whether APOE LA associates with differential expression in APOE3 allele carriers, potentially revealing ancestry-specific APOE expression regulatory mechanisms.

We performed single nuclei RNA-seq on frontal cortex (BA9) from individuals with AD, specifically 4 ELA and 4 ALA, all homozygous for APOE3 and LA. Differential expression and pathways analyses were performed using Seurat, MAST, and gProfiler.

We integrated our APOE3 data with our group's published data on APOE4 carriers of the same ancestries. We analyzed 145,551 nuclei from 25 brains (14 ELA and 11 ALA) and identified 35 cell clusters with similar cell proportions/cluster between ancestries. Contrary to our previous findings in APOE4 carriers where ELA carriers expressed significantly greater APOE4 than ALA carriers, we observed ALA APOE3 carriers express higher APOE in astrocytes and microglia than ELA carriers. Further, within the same LA, we observed greater APOE expression in APOE4 carriers than APOE3 carriers. Interestingly, we also observed significant up- and down-regulation of key AD-related pathways such as lipid response, neurogenesis, phagocytosis, nervous system development, immune response, insulin resistance, oxidative phosphorylation, among others.

Our data suggest APOE LA regulates APOE expression in an allele-specific manner. It remains unclear whether this effect is driven by the APOE allele itself or differing regulatory elements in the allele haplotypes. Overall, we observed greater APOE expression in APOE4 carriers than APOE3 carriers across cell types. Given higher APOE4 expression is associated with increased risk, lower APOE3 expression may contribute to lower risk. Altogether, this provides additional insights into the expression regulatory mechanisms in the different APOE alleles, aiding in therapeutic efforts.