A gene variant found almost exclusively among people of African descent appears to substantially raise the risk of Alzheimer's disease, a new study finds.
The variant is in a gene called ApoE3, and it's apparently only harmful when it exists in combination with the ApoE4 gene — a well-known risk factor for Alzheimer's.
That gene duo was present in only 1% of the nearly 32,000 individuals in the study, all of African descent. But it was tied to a nearly threefold increase in the risk of developing Alzheimer's, according to findings published Feb. 21 in the Journal of the American Medical Association.
Dr. Michael Greicius, the senior researcher on the study, pointed to one major reason the finding is important: Most of what's known about the genetics of Alzheimer's — and diseases in general — comes from studies of white people. Researchers need to learn more about any unique genetic influences on the risk of Alzheimer's in people of color.
That matters for individuals who undergo genetic testing to gauge their risk of the disease, according to Greicius, a professor of neurology at Stanford University School of Medicine, in California. Racial and ethnic ancestry should be taken into consideration, he said.
More broadly, Greicius said, the more researchers understand about the genetics of Alzheimer's, the more they'll understand the "biology" of the disease — and possibly be able to turn that into treatments.
The study focused on the ApoE gene, which comes in three forms: E2, E3 and E4. That final form has gotten most of the attention when it comes to Alzheimer's. About 20% of Americans carry at least one copy of the E4 gene, which confers an increased risk of the disease. Carrying two copies of E4 is worse still: Those individuals have roughly 10 times the risk of developing Alzheimer's as people who carry two E3s.
E3 is the most common version of the ApoE gene, found in over half of the general population. And in Alzheimer's research, Greicius said, it has generally been considered "neutral" — the reference point against which E4 and E2 (which is fairly uncommon) are compared.
But in the new study, a particular variant of E3 — known as R145C — appeared to cause trouble when paired with E4.
The findings are based on genetic data and medical records for nearly 32,000 people — mostly Black, with 3% from Nigeria. Over 4,800 had Alzheimer's disease, while the rest were mentally healthy.
Around 1% of the group carried the "bad" E3 variant plus a copy of E4. Those people were almost three times more likely to have Alzheimer's, versus individuals who carried E4 and a different variant of E3.
It's not clear why, but Greicius said this particular E3 may not, itself, cause harm. Instead, it may be unable to do its usual job of mitigating some of the harm caused by E4. That's because the E3 variant only appeared problematic when it was paired up with E4.
Plus, in separate lab work, the researchers found some clues as to what's going wrong when people carry the R145C variant: It renders their ApoE3 proteins a little weaker — less able to latch onto body cells to do their normal duties.
It's possible, the researchers speculate, that impairs E3's ability to counter the harmful effects of E4.
Recent research has hinted that while E4 is bad news when it comes to Alzheimer's risk, its impact may vary by race and ethnicity.
The new study "builds on that understanding by identifying a specific form of ApoE that increases risk in individuals of African ancestry," said Percy Griffin, director of scientific engagement at the nonprofit Alzheimer's Association.
Findings like these are critical for ongoing research, according to Griffin.
"Research study participants are often grouped by which types of the ApoE gene they carry, and the study results are then analyzed according to these groups," he said. "If the impact of the ApoE gene type differs in people of different ancestries, then those analyses may not be as accurate or generalizable as originally thought."
Meanwhile, some people do undergo genetic testing to see which ApoE forms they carry — often those with a strong family history of Alzheimer's.
And it's important, Greicius said, that doctors and genetic counselors understand that the influence of those genes can vary according to ancestry.
Greicius said that he does not recommend routine ApoE testing — a position also taken by the Alzheimer's Association. That's, in part, because ApoE is only one part of the story in the likelihood of developing Alzheimer's, which also involves non-genetic factors.
And the ApoE story, itself, is complicated. That's illustrated by the current study, and by what's known about the E4 form, according to Greicius.
Based on the existing evidence, having a "double dose" of E4 is bad for white and Black people alike, but not to the same degree. On average, it raises the risk of Alzheimer's by 15-fold among white people, and by roughly sixfold among Black people.
The bottom line is that there's a lot left to learn about the complex genetics of Alzheimer's, Greicius said.
The Alzheimer's Association has more on genes and Alzheimer's.
SOURCES: Michael Greicius, MD, MPH, professor, neurology and neurological sciences, Stanford University School of Medicine, Stanford, Calif.; Percy Griffin, PhD, director, scientific engagement, Alzheimer's Association, Chicago; Journal of the American Medical Association, Feb. 21, 2023