Mark Logue, PhD, a statistician with the VA Boston Healthcare System and National Center for PTSD
BOSTON — VA researchers have discovered several new genetic variants associated with Alzheimer’s disease—the most common form of dementia—in people of African ancestry.
The discovery provides potential clues about the causes of dementia in African-ancestry veterans and might lead to a better understanding of the biology and perhaps drug targets and treatments that will apply to everyone, said Mark Logue, PhD, a statistician with the VA Boston Healthcare System and National Center for PTSD who led the research.
While Alzheimer’s disease affects a higher proportion of those of African than European ancestry, most large-scale genetic studies of Alzheimer’s disease have been performed in European-Ancestry participants, said Logue. “The existing studies of African-ancestry individuals have had much smaller sample sizes,” he said, noting that this discrepancy has been identified as a major issue in genetics research. “Genetic models of Alzheimer’s disease risk using data from primarily European-ancestry cohorts wouldn’t necessarily perform well on African ancestry individuals.”
To identify genetic variants associated with Alzheimer’s disease in people of African ancestry, Logue and his colleagues turned to the Million Veteran Program (MVP). One of the world’s largest genomic databases, MVP includes genomewide genotype data as well as information on health, lifestyle and military exposures for more than 900,000 veterans.
“We first looked in the medical record and identified African-ancestry MVP participants who had been given a diagnosis of Alzheimer’s disease and related dementias,” said Logue. “Then we compared their DNA to other African ancestry MVP participants who had no history of dementia. This analysis more than doubled the sample size of the previous similar study.” To further boost their ability to detect dementia-related risk variants, they also compared the DNA of African-ancestry participants who reported in surveys that their parents had a history of dementia with those who didn’t report having parents with dementia—one of the strategies that has been used in the large-scale European ancestry studies, he said. The researchers took the results from those analyses and combined them with results from another large-scale African-ancestry Alzheimer’s disease genomewide association study performed by the Alzheimer’s Disease Genetics Consortium. “So, this study represents a huge boost in sample size and ability to detect in African-ancestry dementia risk variants compared to earlier studies,” he said.1
The result: the identification of several new variants that met the group’s strong statistical threshold for significance, Logue said.
“Many of these are in genes that had been previously identified in European ancestry studies, but the particular variant that was most strongly associated with dementia differed,” Logue said. For example, studies have found that a gene variant called APOE E4 carries the largest genetic risk for Alzheimer’s disease in people with European ancestry, but the effect of APOE E4 is half as strong in people of African ancestry.
Additionally, some of the variants were in new genes which hadn’t been identified as related to dementia risk, he said. “For several of these, we were able to find evidence that the activity of these genes may differ in the brains of Alzheimer’s disease cases by looking at the results from prior post-mortem brain studies.”
The group found differences not only between participants of African and European ancestry, but also differences between their results and prior African ancestry results, as well–a finding Logue found surprising.
He said a better understanding of dementia and its risk is particularly important as the veteran population ages. “Over half of veterans are over age 65 and at risk for dementia and other age-related difficulties,” he said. While genetics is an important factor, it is only a part of the puzzle—late-onset Alzheimer’s disease risk is influenced by both genetic and environmental factors.
“While one of our goals was increasing the knowledge about the causes of dementia in African-ancestry veterans, we also hope that these findings will lead to advances in our understanding of the underlying biology that will apply to everyone, and perhaps lead to new drug targets and treatments,” Logue said.
- Sherva R, Zhang R, Sahelijo N, Jun G, et. al. African ancestry GWAS of dementia in a large military cohort identifies significant risk loci. Mol Psychiatry. 2022 Dec 22. doi: 10.1038/s41380-022-01890-3. Epub ahead of print. PMID: 36543923.