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

NEW YORK – Researchers at Stanford University and elsewhere have linked an APOE missense variant to an increased risk of Alzheimer's disease (AD) in people with African ancestry.

"Our study is very important to sort of level the playing field and consider ancestry-specific mutations and assess the risk associated with these mutations," said Yann Le Guen, assistant director of computational biology at Stanford University and the corresponding author of a study published in JAMA on Tuesday. "The findings will help improve the [understanding of] Alzheimer’s disease risk in African Americans."

The roles of APOE alleles ε2, ε3, and ε4 in AD risk have been well established among people with European ancestry. While APOE ε4 is known to increase the risk of developing 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.

"Additional APOE missense variants have been understudied because they are present mainly in African-ancestry individuals, who are underrepresented in AD genetics studies," the authors wrote.

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 AD. These included participants in the Alzheimer Disease Sequencing Project, the Alzheimer Disease Genetic Consortium, and the Million Veteran Program.

"Since R145C is always co-inherited with an APOE ε3 allele, it is only present in individuals with an ε2/ε3, ε3/ε3, or ε3/ε4 genotype, " Le Guen said.

The study revealed that individuals with the ε3/ε4 genotype who carried the R145C mutation had an increased risk for 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 AD risk with other genotype combinations, and no link between the R150H variant and AD risk.

According to Le Guen, R145C carriers had a five to 10 times elevated 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 is telling us something important that needs further investigation," Le Guen said. "It 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."

According to Le Guen, more studies are required to find the cellular mechanism by which the R145C variant leads to increased AD risk. "Future studies that could try to flesh out the exact mechanism could potentially lead to new drug targets when the details get worked out," he said.

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.