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Unique Alzheimer’s disease risk loci found in African Americans

JAMA Neurology
Reuters Health - 23/10/2020 - Researchers have identified several Alzheimer's disease risk loci unique to African Americans, according to a new report.

The novel risk loci are near or within genes involved in immunity, lipid processing and intracellular-trafficking pathways, Dr. Christiane Reitz of the Taub Institute for Research on the Aging Brain at Columbia University in New York City and colleagues found.

"These results really help us to understand which kinds of mechanisms and molecular pathways are involved in African Americans and Alzheimer's disease. They point to the same pathway that we have pinpointed in non-Hispanic whites," Dr. Reitz told Reuters Health by phone.

In other diseases involving multiple genes, such as diabetes, a similar pattern has been observed, Dr. Reitz noted, with the same molecular pathway across ethnic groups, but differences in the genes involved among ethnic groups.

Over 20 modest-effect AD risk loci have been found, Dr. Reitz and her colleagues note in JAMA Neurology. But these studies were done mostly in non-Hispanic whites, and genes identified account for only 30%-40% of the genetic risk for AD, they add. Twin studies estimate AD is 60%-80% heritable.

In a previous genome-wide association study (GWAS) in African Americans participating in the Alzheimer Disease Genetics Consortium, the researchers found that ABCA7 and APOE were associated with AD risk, although the odds ratios were different than for non-Hispanic whites. A minority of the loci originally identified in studies of whites were also significantly associated with AD in African American patients.

In the current study, the authors enlarged their sample size by 37% and included data from the African Genome Resources panel, comparing 2,784 AD patients with 5,222 controls without AD. Risk loci were centered near EDEM1, near ALCAM, within GPC6, and within VRK3.

EDEM1 encodes a protein a protein that helps degrade misfolded proteins, while the ALCAM gene encodes a protein involved in immune responses. The product of the GPC6 recruits glutamatergic receptors to neuron membranes and that of VRK3 plays a role in glutamate neurotoxicity.

The researchers also identified several loci associated with rare variants and six additional loci of "suggestive significance," including ARAP1, on the endocytosis/intracellular trafficking pathways, and STARD10, involved in lipid metabolism.

In a validation study in postmortem brain tissue samples from participants in the Religious Orders Study and Rush Memory and Aging Project, two ongoing studies of aging and AD, Dr. Reitz and her team found that high ALCAM and ARAP1 expression and low GPC6 and RBFOX1 expression were associated with brain amyloid load. Higher STARD10 expression was associated with greater tau pathology burden.

Seven of the 25 loci known to be associated with AD in whites were also associated with AD in African Americans: APOE, ABCA7, TREM2, BIN1, CD2AP, FERMT2 and WWOX.

"We know that there are many, many additional genes which are involved, and those we need to identify, so this is not it. We really need to repeat this analysis with many more samples, and we know that once we do that we'll identify many more genes. It's a statistical issue, it's really a sample-size issue," Dr. Reitz said.

The findings show, she added, that "you really have to do large-scale genetic studies in each ethnic group separately."

"We are following up on in the lab with cell biology on some of these genes we identified to understand what they really do in the cell," Dr. Reitz concluded.

By Anne Harding

SOURCE: https://bit.ly/3jkxcPy JAMA Neurology, online October 19, 2020.

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