A key Alzheimer’s gene emerges in African American brain study
Alzheimer disease (AD) affects African Americans (AA) at roughly twice the rate seen in White or European-ancestry (EA) individuals
Alzheimer disease (AD) affects African Americans (AA) at roughly twice the rate seen in White or European-ancestry (EA) individuals living in the U.S. Researchers attribute part of this disparity to social and structural factors, including unequal access to health care, differences in educational opportunities, and known biases in cognitive testing. African Americans also have higher rates of health conditions such as cardiovascular disease and diabetes, both of which increase the risk of developing AD.
Many previous studies have examined gene expression (measure of the amount of protein encoded by a gene) in brain tissue from people with Alzheimer’s compared with those without the disease. However, most of this research focused on EA or mixed-ancestry groups. In many cases, the number of AA participants was either not reported or too small to allow meaningful conclusions about genetic patterns specific to this population.
Largest Brain Study Identifies New Alzheimer’s Genes
In the largest Alzheimer’s study to date using brain tissue from African American donors, scientists at Boston University Chobanian & Avedisian School of Medicine identified numerous genes that behaved differently in people with AD compared with individuals without the disease. Many of these genes had not been previously linked to Alzheimer’s by other genetic studies.
The strongest signal came from the ADAMTS2 gene. Researchers found that its activity level was 1.5 fold higher in brain tissue from individuals with autopsy-confirmed AD than in tissue from controls.
Consistent Findings Across Independent Studies
The research team analyzed gene expression data from post-mortem prefrontal cortex tissue collected from 207 AA brain donors, including 125 individuals with pathologically confirmed AD and 82 controls. These samples came from 14 NIH-funded AD Research Centers across the United States.
ADAMTS2 stood out as the most significantly differentially expressed gene in this group. It also ranked first in an independent study (medrxiv.org/content/10.1101/2024.11.12.24317218v1) conducted by the same researchers using brain tissue from a much larger group of EA individuals. That study compared people with confirmed Alzheimer’s pathology who showed clinical symptoms before death with individuals who had the same pathology but remained cognitively resilient.
“To our knowledge, this is the first time in similarly designed AD genetics studies that the most significant finding was the same in both white and African Americans,” said corresponding author Lindsay A. Farrer, PhD, chief of biomedical genetics at the school.
Implications for Understanding Alzheimer’s Risk
The researchers say the findings represent a meaningful advance in understanding the genetic foundations of Alzheimer’s risk in African Americans. Previous evidence suggests that most known AD risk variants tend to be population-specific or occur at different frequencies across groups.
“Although risk of AD in African Americans has been associated with variants in several genes, the overlap of genes showing association in in EA populations is modest, and even among the overlapping genes the particular variants involved and the size of the effect on AD risk usually differ,” explains Farrer. “The fact that expression of ADAMTS2 is significantly and substantially higher in brain tissue from both Whites and Blacks with AD not only points to a shared biological process leading to AD, but also elevates the priority of further research involving this gene which could determine its suitability as a potential therapeutic target.”
The findings were published online in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.
The study was supported by National Institute of Health grants R01-AG048927, U01-AG058654, U54-AG052427, U19-AG068753, U01-AG062602, P30-AG072978, U01-081230, P01-AG003949, P30-AG062677, P30-AG062421; P30-AG 066507, P30-AG066511, P30-AG 072972, P30-AG066468, R01-AG072474, RF1-AG066107, U24-AG056270, P01-AG003949 , RF1-AG082339, RF1-NS118584, P30-AG072946; P01-AG003991, P30-AG066444, P01-AG026276, P30-AG066462, P30-AG072958, and P30-AG072978, as well as Florida Department of Health awards 8AZ06 and 20A22. The funding sources had no role in study design, data collection, analysis, interpretation, writing of the article, or the decision to submit it for publication.
Mark Logue received grants from the NIH and Department of Veterans Affairs. Marla Gearing, Lee-Way Jin, Richard Mayeux, Richard Perrin, Shih-Hsiu Wang and Lindsay Farrer received grants from the NIH. Melissa Murray received grants from NIH, was a paid consultant for Biogen Pharmaceuticals, and served on committees for the Alzheimer’s Association and International Conference on Alzheimer’s and Parkinson’s Diseases. Thor Stein received grants from the NIH and Department of Veterans Affairs, and an honorarium from Brown University. Andrew Teich received grants from the NIH, a contract from Regeneron Pharmaceuticals and an honorarium from Ono Pharmaceuticals, owns stock in Ionis Pharmaceuticals and Biogen Pharmaceuticals, and served on committees for the Department of Defense and the Alzheimer’s Association. The effort of Katarnut Tobunluepop and Zihan Wang was supported by NIH grants. Benjamin Wolozin received grants from the NIH, consulting fees from Aquinnah Pharmaceuticals and Abbingworth Ventures, honoraria for several lectures, and owns stock and is Co-Founder and CSO of Aquinnah Pharmaceuticals Inc. Other authors have no competing interests to report.
