APOE Missense Variant Linked to Increased Alzheimer’s Disease Risk in African Americans

APOE Missense Variant Linked to Increased Alzheimer’s Disease Risk in African Americans

Last Updated on March 12, 2023 by Joseph Gut – thasso

March 01, 2023 – The gene APOE codes for apolipoprotein E (Apo-E), a protein involved in the metabolism of fats in the body of mammals. A subtype is implicated in the Alzheimer’s disease and cardiovascular diseases. Recently, researchers at Stanford University and elsewhere have linked in a study published in JAMA an APOE missense variant to an increased risk of Alzheimer’s disease (AD) in people with African ancestry.Their  study is very important to sort of level the playing field and consider ancestry-specific mutations and assess the risk associated with these mutations. The findings will help improve the understanding of Alzheimer’s disease risk in African Americans, which seems rather different to that of Americans of European/Caucasian descent.

The roles of APOE alleles ε2, ε3, and ε4 in Alzheimer’s disease (AD) risk have been well established among people with European ancestry. While APOE ε4 is known to increase the risk of developing Alzheimer’s disease (AD), APOE ε2 has a protective effect. Meanwhile, APOE ε3, which is the most common allele, does not have an effect on Alzheimer’s risk.

However, there are other variants, which are inherited along with these alleles, that haven’t received as much attention. Thus, the researchers in the present study note that additional APOE missense variants have simply been understudied because they are present mainly in individuals of African ancestry, who are underrepresented in genetic studies on Alzheimer’s disease (AD).

In fact, one such variant, called R145C, is found in roughly 4 percent of African American individuals, whereas another, R150H, is less common in this group. Prior studies showed that R145C is always co-inherited with the ε3 allele, whereas R150H is always in phase with the ε2 allele.

For their study, the researchers performed a case-control study involving almost 32,000 individuals of African ancestry to see if R145C or R150H are linked with an increased risk of Alzheimer’s disease (AD). These included participants in the Alzheimer Disease Sequencing Project (ADSP), the Alzheimer Disease Genetic Consortium (ADGC), and the Million Veteran Program (MVP). The researchers found that R145C is always co-inherited with an APOE ε3 allele; therefore it is only present in individuals with an ε2/ε3, ε3/ε3, or ε3/ε4 genotype.

The study revealed that individuals with the ε3/ε4 genotype who carried the R145C mutation had an increased risk for Alzheimer’s disease (AD) among participants with the ε3/ε4 genotype. They also had an earlier onset of the disease. However, there was no association between R145C and Alzheimer’s disease (AD) risk with other genotype combinations, and no link between the R150H variant and Alzheimer’s disease (AD) risk.

Overall, R145C carriers had a five to 10 times elevated Alzheimer’s disease (AD) risk among those with the ε3/ε4 genotype compared to the reference baseline ε3/ε3 genotype, and a similar risk to participants with the ε4/ε4 genotype. This finding seems to suggest that normally, APOE ε3 does something that mitigates the risk caused by APOE ε4, but when someone carries R145C on their APOE ε3, that ability to mitigate the ε4 effect is lost. Certainly, more studies are required to find the cellular mechanism by which the R145C variant leads to increased Alzheimer’s disease (AD) risk.

Meanwhile, the researchers also noted that in the age of direct-to-consumer genetic testing, with patients approaching their physicians with their APOE genotype in hand, clinicians will need to understand AD risk in the context of specific ancestral backgrounds in order to provide the best type of counseling. Another flabbergasting aspect of this research is the following: The present big data genre of research in the US classifies patients into general terms categories like European/Caucasian ancestry or African ancestry for the African-American population. However, research in Africa begins to reveal that Alzheimer’s disease (AD) risks vary considerably across the continent (geographically speaking) and as a result, between the residing populations, with apparently very different incidences of Alzheimer’s disease (AD). While the genetics underlying these observations is not yet clear, it may nevertheless have an influence on the research on Alzheimer’s disease (AD) risk for African-Americans. African ethnicity may no more sufficient as a criteria; Perhaps you need to know from where in Africa and from which people/tribe your patient in the study is a decendent.

Overall, APOE and its alleles seem to play very different roles in health risks or sometimes in protection thereof. thasso had already some articles on aspects such as (“Rare APOE genetic variants reduce Alzheimer’s risk” (here)), or on (“Soccer Headers Might Be More Risky for APOE4 Genotype Carriers” (here)), or on (“Polygenic hazard scores in age-associated Alzheimer’s disease” (here)).

See here a short sequence on Alzheimer disease (genetics):

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Ph.D.; Professor in Pharmacology and Toxicology. Senior expert in theragenomic and personalized medicine and individualized drug safety. Senior expert in pharmaco- and toxicogenetics. Senior expert in human safety of drugs, chemicals, environmental pollutants, and dietary ingredients.

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