Researchers at the John P. Hussman Institute for Human Genomics at the University of Miami Miller School of Medicine have found that variations in chromatin accessibility, and thus gene expression, may explain why people of European descent with APOE4 gene variants have a greater risk of developing Alzheimer’s disease than people of African descent with similar genetics. The study was published on April 10 in the journal Alzheimer's & Dementia.
“We previously showed that people with European ancestry have higher APOE4 expression than their African counterparts, but we didn’t understand why,” said Jeffery Vance, M.D., Ph.D., professor and director of the Hussman Institute’s Center for Genomic Education and Outreach and senior author on the study. “Now we know that differences in how the DNA is packaged — chromatin accessibility — contribute to these distinctions.”
Cells pack a lot of DNA into a small area — around six feet of genetic material per cell if it were unwrapped and extended. Tight packaging is a necessity, but it also impacts gene expression. Chromatin, the mixture of DNA and proteins that make up chromosomes, plays a major role in unpacking specific DNA regions to support expression. As a result, chromatin accessibility is profoundly important for both good health and disease.
In the study, the team investigated chromatin in astrocytes from 12 brains (six Europeans and six African Americans) impacted by Alzheimer’s disease. All the African Americans had inherited APOE4 from an African ancestor. Astrocytes are neural housekeeping cells that support neuronal function and many other areas. They are also deeply implicated in Alzheimer’s disease progression.
Increased Accessibility Boosts APOE4 Expression
The team found increased accessibility in European astrocytes, boosting the expression of APOE4, as well as genes associated with synapses (the space between neurons), cholesterol and astrocyte reactivity.
While these results provide insights into an important question about APOE4 function in European and African genomes, they also generate complex issues surrounding descent and health risks.
“When we look at African American ancestry, many who consider themselves Black have significant numbers of genes from European descendants,” said Katrina Celis, M.D., an associate scientist from the Hussman Institute and first author on the study. “Both African Americans and Hispanic/Latino Americans are admixed populations, with a patchwork of ancestries across each chromosome.”
As a result, people from these groups could inherit their APOE4 gene from African, European, Hispanic/Latino or Amerindian ancestors. Their Alzheimer’s disease risk from APOE4 depends on the ancestry surrounding it, which will affect their APOE4 expression.
These findings could inform clinical care, diagnostics and therapeutics. Clinicians may need to understand a patient’s ancestral profile before assessing the risks associated with their APOE4 status.
In addition, drug and diagnostics companies may want to reconsider how they conduct clinical trials, as patients may present entirely different risk profiles based on their ancestry. These new insights could also lead to better Alzheimer’s drugs.
“Because we now know there's a difference in accessibility and expression, APOE4 itself could become a therapeutic target,” said Dr. Vance. “Current options target amyloid plaques with limited success. New avenues of therapeutic intervention are needed, and APOE4 is a key target as we move ahead.”