Anel Frederick

Ancestry-related Differences in Chromatin Accessibility and Gene Expression of APOE ε4 Are Associated with Alzheimer’s Disease Risk

In this study, we explored why the APOE ε4 gene increases Alzheimer’s disease risk more strongly in people with European ancestry than in those with African ancestry. We analyzed brain tissue from individuals with Alzheimer’s disease who all carried two copies of APOE ε4 but differed in their local genetic ancestry around the APOE gene. Our results showed that APOE ε4 was more active in brains with European local ancestry, especially in astrocytes, a type of support cell in the brain. We found that this increased activity was linked to greater chromatin accessibility, meaning the DNA near APOE ε4 was more open and easier to turn on in European ancestry brains. These ancestry-related differences were not limited to APOE alone but extended across the genome. Genes with increased accessibility in European ancestry astrocytes were involved in processes such as synaptic function, cholesterol handling, and astrocyte reactivity. In the discussion, we suggest that these molecular differences help explain why APOE ε4 confers higher Alzheimer’s disease risk in people with European ancestry compared to those with African ancestry. Our findings highlight that genetic risk depends not only on which variant a person carries, but also on ancestry-specific regulation of gene activity. This work underscores the importance of studying multiple ancestries to fully understand Alzheimer’s disease biology and to ensure that genetic insights are relevant to all populations

Rajabli F, Seixas AA, Akgun B, Adams LD, Inciute J, Hamilton KL, Whithead PG, Konidari I, Gu T, Arvizu J, Golightly CG, Starks TD, Laux R, Byrd GS, Haines JL, Beecham GW, Griswold AJ, Vance JM, Cuccaro ML, Pericak-Vance MA. African Ancestry Individuals with Higher Educational Attainment Are Resilient to Alzheimer’s Disease Measured by pTau181. J Alzheimers Dis. 2024;98(1):221-229. doi: 10.3233/JAD-231116. PMID: 38393909; PMCID: PMC11091636.