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By Genevieve Wanucha
Most cases of Alzheimer’s disease after age 65 are not caused by a specific gene, but common variants in certain genes associated with Alzheimer’s disease can either raise or lower an individual’s risk. One variation of the Apolipoprotein E (APOE) gene, called the APOE e4 allele, is the strongest risk factor for developing late-onset Alzheimer’s disease, especially for individuals who carry two copies of APOE e4.
The most common APOE allele, APOE e3, is not associated with disease risk, while APOE e2 is protective against Alzheimer’s disease. However, research in population genetics has shown that an individual’s Alzheimer’s risk associated with APOE e4 may depend on genetic ancestry. The risk from APOE e4 is higher for European populations and is lower for individuals of African ancestry.
Now, in research published in Nature Communications, researchers in the Valdmanis Lab and others in the UW ADRC have dug deep into genomes of diverse populations and identified a new gene variant near APOE e4 that is protective against Alzheimer’s disease in individuals of African ancestry.
The researchers estimate that this newly identified genetic variant is present in 60% of African Americans who carry 2 APOE e4 alleles. They found that this gene variant reduces the odds of having Alzheimer's disease compared with individuals without it.
The authors of this study are interested in the genes that neighbor APOE and may affect its biological function. This newly discovered genetic variant affects genes near APOE, providing insight into its role in health and disease.
Members of the Valdmanis Lab
Study author Paul Valdmanis, PhD, Associate Professor in the UW Division of Medical Genetics, says he was most surprised to discover that this gene variant shows a regulatory effect on microglial cells, which act as the brain’s immune system. “We know that microglia have an important role in clearing Alzheimer’s-related amyloid aggregates, as does APOE, so finding a way to connect these two key elements in disease was exciting. In retrospect, this link makes intuitive sense,” said Valdmanis.
The research relied on genetic sequence data from the 1000 Genomes Project and compared 5 African participants with APOE e4 to non-African participants with APOE e4, Africans with an APOE e3 allele, and non-Africans with an APOE e3 allele. They searched until they found a genetic variant present only in the African APOE e4 carriers.
“This study highlights the importance of studying genetic sequencing data from groups that have been historically excluded in large-scale sequencing efforts for Alzheimer's disease,” says lead author Julianna Brutman, PhD, a postdoctoral scholar in the Valdmanis Lab.
Their next step was to use the All of Us dataset and the NIA Alzheimer’s Disease Sequencing Project, collections of genetic resources to uncover genetic risk factors for Alzheimer’s disease. This analysis provided them with evidence in tens to hundreds of thousands of participants that their variant of interest conferred significant protection against Alzheimer’s disease in African or African American individuals.
“This study counters the argument that has been put forth that two APOE e4 alleles are causal for Alzheimer's disease, since in some populations this does not appear to be the case,” says Valdmanis.
The authors believe that their approach is important not only for a basic understanding of APOE e4 and Alzheimer’s risk but also for therapeutics. The study suggests that future treatments targeting APOE e4 can be designed to confer the benefits of the protective variant in individuals who lack it.
“This finding signifies the importance of understanding the genetics of Alzheimer's disease at a population-specific level,” says Brutman, “so that we can better design therapeutics to target some of these differences that we see.”
Citation:
Brutman JN, Busald T, Nizamis E, et al. A common 19 bp APOE enhancer deletion is protective against Alzheimer's disease in African Americans. Nat Commun. 2026;17(1):2237. Published 2026 Feb 2. doi:10.1038/s41467-026-68808-3 [PubMed]
Funding for this study was provided by NIH grants:
K00 NS125830/NS/NINDS NIH HHS/United States
R21AG089267/U.S. Department of Health & Human Services | National Institutes of Health (NIH)
K00NS125830/U.S. Department of Health & Human Services | National Institutes of Health (NIH)
R01NS122766/U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)
U01AG058589/U.S. Department of Health & Human Services | National Institutes of Health (NIH)
UW ADRC personnel funded by P30 AG066509/AG/NIA NIH HHS/United States were authors on this paper.
