Gene variant found in individuals of African ancestry dramatically boosts Alzheimer's risk

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Stanford Medicine scientists and their colleagues have discovered that a gene variant found almost exclusively in the genomes of individuals of African ancestry dramatically boosts Alzheimer's risk. About 4% of African Americans carry this variant.

The findings derive from a study of nearly 32,000 individuals of African ancestry (almost all of them African Americans)  published online Feb. 21 in JAMA. They reveal a significant but previously unexplored genetic factor contributing to Alzheimer's disease in African Americans, who are at slightly greater risk of developing the disorder than other ethnic populations in the United States. And they provide a window into the workings of the mysterious ApoE protein, which comes in multiple forms, one of which is the most significant known genetic risk factor for Alzheimer's disease.

The biological insights we glean from a study in any one ancestry can lead to therapies that could be helpful for all ancestral backgrounds."

Michael Greicius, MD, professor of neurology and neurological sciences and the Iqbal Farrukh and Asad Jamal Professor

Greicius is the study's senior author. The lead author is Yann Le Guen, PhD, a former postdoctoral scholar who is now an assistant director in Stanford Medicine's Quantitative Sciences Unit.

Alzheimer's outlook

As any expert will tell you, the best way to avoid Alzheimer's disease is to not get old, a tall order for most of us. Apart from aging, the biggest known risk factor for contracting Alzheimer's disease is the inheritance of a particular version of the gene coding for the protein ApoE. We can't do much about that roll of the dice, either.

Each of us inherits two copies of the ApoE gene, which comes in three versions, or alleles: E2, E3 and E4. (E1 is so rare that only a handful of people have been found to carry it.) E3, the most common ApoE allele, is considered the reference point against which relative Alzheimer's risk conveyed by the other alleles is measured. E2, while rather infrequent, is protective compared with E3. But E4 is deleterious.

About 20% of Americans, and about 60% of all Alzheimer's patients, carry at least one copy of E4. People with an E4/E4 genotype (a double dose of the high-risk ApoE4 allele) are roughly 10 times as likely to develop Alzheimer's as E3/E3 carriers are. An E3/E4 genotype (a single copy each of E3 and E4) conveys intermediate risk.

The variant found just in people of African descent, called R145C, pops up only on the E3 allele of ApoE. Yet, the study found, it appears to increase Alzheimer's risk only among those individuals whose other ApoE allele is of the E4 variety. While this variant has been studied in connection with heart disease in African Americans, it hasn't previously been implicated as an Alzheimer's risk factor.

At the molecular level, the R145C variant is a tiny shift in the ApoE gene's coding sequence, resulting in the replacement of a single protein building block, the amino acid arginine, with another one, cysteine, in the ApoE protein's sequence. This switch shifts the shape and, consequently, function of ApoE in a way that, somehow, puts an R145C carrier at increased Alzheimer's risk — but apparently only under certain conditions.

Search through genotype database

Le Guen and Greicius gained access to several databases containing the ApoE genotypes of 31,929 individuals of African descent (about 3% Nigerian, the rest African American) along with health information about those individuals. The researchers compared the genotypes of individuals diagnosed with Alzheimer's disease with those whose medical records indicated that they were free of Alzheimer's or any other form of dementia.

Source:
Journal reference:

Guen, Y.L., et al. (2023) Association of African Ancestry–Specific APOE Missense Variant R145C With Risk of Alzheimer Disease. JAMA. doi.org/10.1001/jama.2023.0268.

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