The first large-scale study to look at gene expression in brain tissue from African American donors diagnosed with Alzheimer’s disease has identified key differences and similarities between genetic drivers of diseases among Black and White patients. Published today in the Alzheimer’s & Dementia journal, results from the study could help scientists design treatments for this neurodegenerative disease that are effective across people of all ancestries.
In the U.S., the prevalence of Alzheimer’s is approximately two times higher among African Americans than among people with European ancestry. This difference is partly due to reduced access to healthcare and education, testing biases, and higher rates of risk factors such as diabetes or cardiovascular disease among the African American population. However, genetic differences are also known to contribute to this disparity. For instance, the APOE4 gene variant is more frequent in African Americans, but the risk of Alzheimer’s associated with it is lower in this population compared to those with European ancestry.
Despite these differences, the inclusion of African Americans in genomic studies of Alzheimer’s has historically been limited. Many studies have looked at differences in gene expression in brain tissue from Alzheimer’s patients, but the number of African American individuals in these studies are often unspecified or too small to pinpoint any findings that apply specifically within this patient group.
“Although risk of [Alzheimer’s disease] in African Americans has been associated with variants in several genes, the overlap of genes showing association in [European ancestry] populations is modest, and even among the overlapping genes the particular variants involved and the size of the effect on [Alzheimer’s disease] risk usually differ,” said Lindsay A. Farrer, PhD, chief of biomedical genetics at the Boston University Chobanian & Avedisian School of Medicine.
In the current study, Farrer and colleagues analyzed brain samples from 207 African American brain donors, including 125 samples from individuals confirmed to have Alzheimer’s and 82 from healthy donors. Using RNA sequencing, the team identified 482 genes that showed different levels of expression in Alzheimer’s patients compared to the healthy controls.
The largest difference was reported in the ADAMTS2 gene, which showed expression levels 1.52 times higher in Alzheimer’s cases compared to the controls. This same gene was among one of the top-ranked genes in a previous study led by Farrer in brain tissue from donors with European ancestry.
“To our knowledge, this is the first time in similarly designed [Alzheimer’s disease] genetics studies that the most significant finding was the same in both White and African Americans,” said Farrer. “The fact that expression of ADAMTS2 is significantly and substantially higher in brain tissue from both [White and Black people] with [Alzheimer’s disease] not only points to a shared biological process leading to [Alzheimer’s disease], but also elevates the priority of further research involving this gene which could determine its suitability as a potential therapeutic target.”
Another three of the top genes identified in the study on African Americans, including ITPKB, TDRKH and LINC0194 had also been reported to show similar differences among people of European ancestry, with a total of 65 genes showing common trends among both studies.
While the ADAMTS2 gene is known to have multiple functions, previous studies have shown that it reduces levels of reelin, a neuroprotective protein; low levels of reelin in the brain are associated with tau phosphorylation and amyloid plaque formation, two major hallmarks of neurodegenerative conditions such as Parkinson’s and Alzheimer’s. Based on these results, the researchers propose the inhibition of ADAMTS2 as a promising therapeutic strategy against Alzheimer’s disease with potential to be effective across diverse populations.
