Yann Le Guen, Ph.D. Assistant Director, Computational Biology Quantitative Sciences Unit Stanford Medicine

Stanford Study Identifies Genetic Variant Linked to Alzheimer’s in African Americans

MedicalResearch.com Interview with:

Yann Le Guen, Ph.D.Assistant Director, Computational Biology
Quantitative Sciences Unit
Stanford Medicine

Dr. Yann Le Guen

Yann Le Guen, Ph.D.
Assistant Director, Computational Biology
Quantitative Sciences Unit
Stanford Medicine

MedicalResearch.com: What is the background for this study?

Response: Apart from aging, the strongest contributing factor for late-onset Alzheimer’s disease is a specific allele of the APOE gene, which has three common alleles E2, E3, and E4. While E3 is the most common and considered as the reference, E2 is associated with decreased Alzheimer’s disease risk and E4 is associated with increased Alzheimer’s disease risk. Notably the prevalence of E4 among Alzheimer’s patient is high with about 60% of these carrying at least one E4 allele, while solely about 30% Americans carry one E4 allele. It’s worth emphasizing that individuals with an E4/E4 genotype have an exponential increased in their risk to develop AD (10 times as likely than the reference E3/E3 genotype), and individuals with an E3/E4 genotype have an intermediate risk.

Though, most studies of Alzheimer’s disease genetic have been focused on European ancestry, this is beginning to change thanks to NIH’s efforts to fund more studies in non-European ancestry individuals. Our study built on these recent efforts to assess the Alzheimer disease risk associated with an APOE variant (R145C) present in about ~4% African Americans, but extremely rare in Europeans.

MedicalResearch.com: What are the main findings?

Response:  R145C is always co-inherited with an E3 allele, thus it is only present in individuals with an E2/E3, E3/E3, or E3/E4 genotype. In E2/E3 and E3/E3 genotypes R145C’s conveyed no detectable added risk. But R145C substantially increased Alzheimer’s risk among those with an E3/E4 genotype (about 5 to 10 times compared to the reference E3/E3 genotype, and similar increase as an E4/E4 genotype). R145C was also associated with an earlier onset of the disease (about 5 years earlier when comparing E3[R145C]/E4 and E3/E4).

MedicalResearch.com: Is the variant available on commercial genetic testing?        

Response:  I do not know if this variant is available on commercial genetic testing, however, it is included in some single nucleotide polymorphisms microarrays used in research, due to its previous link with cardiovascular diseases risk. Thus, it is likely also included in commercial genetic testing.

MedicalResearch.com: What should readers take away from your report?

Response: Having an APOE genotype E3[R145C]/E4 increased one’s Alzheimer’s disease risk as much as an E4/E4 genotype. Ancestry-specific information is critical as we endeavor to practice precision medicine in an equitable fashion. Ancestry-informed precision medicine will improve healthcare for individuals from ancestral backgrounds that have traditionally been understudied in medical genetics, but the biological insights we glean from a study in any one ancestry have the potential to lead to therapies that could be helpful across ancestral backgrounds.  

MedicalResearch.com: What recommendations do you have for future research as a results of this study?

Response: The main question that remains to be answered is how E3[R145C] solely has an effect in combination with E4. R145C is known to alter some apoE’s properties/functions compared to a standard E3 allele. Our results suggest that one of these apoE3’s properties/functions is key to mitigate the risk associated to apoE4 in individuals with an E3/E4 genotype. Future research should aim at elucidating this molecular mechanism. Ultimately, this line of research will help improve our understanding of how to mitigate/compensate apoE4 misbehavior that leads to an increase Alzheimer disease pathogenesis compared to apoE3. In turns, future research in this direction could help develop apoE4 targeted therapies for Alzheimer’s disease.

MedicalResearch.com: Is there anything else you would like to add? Any disclosures?

Response: The study was funded by the National Institutes of Health (grants AG060747, AG066206, AG066515, 2R01-AG048927, RF1-AG057519, U19-AG068753, U01-SH058654 and U01-AG062602), the European Union’s Horizon 2020 Research and Innovation Program (grant No. 890650), the Alzheimer’s Association, and the Iqbal Farrukh and Asad Jamal Fund.


Le Guen Y, Raulin A, Logue MW, 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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Last Updated on February 21, 2023 by Marie Benz