A genetic risk factor found virtually exclusively among people of at least partial African ancestry substantially boosts the risk of incurring Alzheimer’s disease — but only sometimes.
February 21, 2023 - By Bruce Goldman
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,” said Michael Greicius, MD, professor of neurology and neurological sciences and the Iqbal Farrukh and Asad Jamal Professor.
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.
R145C’s presence in individuals with E2/E3 and E3/E3 genotypes conveyed no detectable added risk, the study showed. But carrying R145C substantially increased Alzheimer’s risk among those with an E3/E4 genotype.
About 30% of the individuals in the study were E3/E4. And of those E3/E4 individuals, 3% (about 1% of the entire study sample) had the R145C variant riding shotgun on their E3 allele. The R145C variant’s presence in E3/E4 individuals nearly tripled carriers’ risk of acquiring Alzheimer’s, compared with that of R145C-free E3/E4 carriers.
In addition, the R145C variant’s presence in combination with the E3/E4 genotype lowered the average age of onset of the disorder by more than five years, the study indicated.
In these E3/E4 R145C carriers, Le Guen said, “The average Alzheimer’s risk was so high, they might as well have had a E4/E4 genotype.”
While harmful, an E4/E4 genotype increases Alzheimer’s risk in an African-ancestry individual by 5 to 10 times versus the E3/E3 “reference” genotype, less than the 10- to 16-fold increased risk seen among E4/E4 individuals with a European heritage. The reasons for this are not yet known.
“R145C doesn’t increase risk in the absence of E4,” said Le Guen, “hinting that perhaps R145C wipes out some beneficial property of ApoE3 that would normally mitigate the increased Alzheimer’s risk conveyed by ApoE4.”
A weaker connection
How that might come about remains to be worked out, although there are clues. The ApoE protein does many things in the body and brain, including shuttling lipids between cells. It docks at those cells by attaching temporarily to receptors, cell-surface molecules for which the protein has an affinity.
When the researchers looked, in laboratory glassware, at ApoE3’s ability to grab onto one type of these receptor molecules, they found it had a weaker hold if it harbored the amino-acid alteration dictated by R145C’s presence on the gene encoding it.
“This confirms others’ findings of a reduced capacity of the R145C-altered ApoE3 protein version to bind to several of its natural receptors in the body, including in the brain,” Le Guen said.
It’s possible that ApoE3’s R145C-impaired ability to bind strongly to appropriate receptors is at least partly responsible for what may be its inability to compensate for the misbehavior or inadequacy of ApoE4, he said.
Meanwhile, the discovery of R145C’s ultimate consequences for the human brain adds a potential tool to the arsenal of genetic tests that physicians can use to determine patients’ Alzheimer’s risk — in this case, that of African-ancestry individuals with E3/E4 genotypes — with better precision.
“The vast majority of what we understand about human genetics has been gleaned from studies of European-ancestry individuals," Greicius said. “Thanks in large part to the National Institutes of Health’s dedicated efforts to fund more studies in non-European-ancestry individuals, that’s beginning to change.”
Other Stanford Medicine investigators as well as researchers from the Mayo Clinic, the Boston University School of Medicine, UC San Diego, Harvard Medical School, the University of Washington and the University of Camerino in Italy contributed to the work.
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, the Alzheimer’s Association, and the Iqbal Farrukh and Asad Jamal Fund.
About Stanford Medicine
Stanford Medicine is an integrated academic health system comprising the Stanford School of Medicine and adult and pediatric health care delivery systems. Together, they harness the full potential of biomedicine through collaborative research, education and clinical care for patients. For more information, please visit med.stanford.edu.