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Research Highlights

Genetic variant specific to African ancestry is associated with increased Alzheimer’s risk

Researchers have found that having a genetic variant observed often in people of African ancestry may increase a person’s risk of developing Alzheimer’s disease. The APOE ε3[R145C] variant, present in more than 4% of African Americans and very rare in people of European ancestry, is associated with an increased risk of Alzheimer’s in adults of African ancestry who also carry a separate version of the APOE gene, called ε4. Findings from the NIA-funded study were published in JAMA.

Image of a double helix.

Researchers from Stanford University and other institutions analyzed genetic and cognitive status data sets of nearly 32,000 people of African ancestry. Data was obtained from the Alzheimer’s Disease Sequencing Project, Alzheimer’s Disease Genetics Consortium, and the Veteran’s Affairs Million Veteran Program. The researchers looked for variants of the APOE gene that distinguished Alzheimer’s cases from cognitively unimpaired participants.

Apolipoprotein E (APOE) is a gene that influences Alzheimer’s risk. It comes in several forms, and all people inherit two forms, one from each parent. The most common form is APOE ε3, which is not associated with Alzheimer’s risk. APOE ε4, however, increases risk for Alzheimer’s and this risk may be determined by ancestry. People who carry two copies of APOE ε4 and are of European descent have a higher risk than those who are of African, Hispanic, or Japanese descent. About 1% of African Americans inherit the combination ε3/ε4 with the R145C variant accompanying ε3.

In this study, the R145C variant was found to be associated with an up to three times’ increased risk of Alzheimer’s compared to participants with ε3/ε4 without the R145C variant. The increased risk was only observed when the APOE ε3[R145C] variant was paired with APOE ε4 and the risk was similar to that associated with carrying two copies of APOE ε4. Participants with APOE ε3[R145C]/ε4 also showed signs of Alzheimer’s — including faster decline on a commonly used cognitive measure — five to 10 years earlier than those without the R145C variant.

The findings of this study indicate a potential new biomarker that could be used for Alzheimer’s genetic risk assessment in individuals of African ancestry, a historically underrepresented group in Alzheimer’s genetics research. Further studies are needed to understand how the APOE ε3[R145C] variant alters the activity of the APOE gene and leads to the damage seen in the brains of people with Alzheimer’s.

This research was supported in part by NIA grants R01AG048927, RF1AG057519, U19AG068753, U01AG058654, U01AG062602, R01AG066206, R01AG060747, and P30AG066515.

These activities relate to NIH’s Alzheimer’s and Related Dementias Research Implementation Milestones:

  • 1.A, “Enable precision medicine research by supporting deep and longitudinal molecular endophenotyping of existing and new at-risk cohorts as well cohorts and/or individuals who resist disease despite high genetic risk (e.g. Down Syndrome, ApoE 4 homozygous, FAD mutation carriers). Ensure that these efforts include and prioritize molecular profiling in cohorts from special populations and patients with atypical AD and ADRD (Down Syndrome, early- and late-onset familial AD, early-onset non-autosomal dominant AD), ethnic minorities and other under-represented groups.”
  • 2.G, “Maximize the translational potential of genetics research by ensuring rapid and broad sharing of large-scale genetic/genomic data.”

Reference: Le Guen Y, et al. Association of African ancestry-specific APOE missense variant R145C with risk of Alzheimer disease. JAMA. 2023;329(7):551-560. doi: 10.1001/jama.2023.0268.

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