Alzheimer’s disease (AD) presents a disproportionately high burden on African American (AA) communities in the United States, with incidence rates approximately double those observed in individuals of European ancestry (EA). While socio-environmental determinants, including disparities in healthcare access, educational attainment, and inherent biases within cognitive assessment methodologies, are recognized contributors to this disparity, emerging research is shedding light on the complex genetic landscape. Furthermore, the elevated prevalence of comorbidities such as cardiovascular disease and diabetes within the AA population is known to amplify the risk of developing neurodegenerative conditions like Alzheimer’s.
For decades, scientific inquiry into Alzheimer’s disease has predominantly relied on analyzing gene expression patterns within brain tissue. This involves quantifying the activity levels of genes, essentially measuring the amount of protein they are instructed to produce. However, the vast majority of this foundational research has been conducted on cohorts predominantly comprising individuals of European ancestry or mixed genetic backgrounds. Crucially, studies involving African American participants have often either omitted demographic data regarding ancestry or included sample sizes too small to yield statistically robust conclusions about genetic variations specific to this demographic group. This historical gap has significantly hindered a comprehensive understanding of AD’s genetic underpinnings across the full spectrum of human diversity.
In a landmark endeavor, representing the most extensive investigation to date utilizing brain tissue from African American donors for Alzheimer’s research, scientists at Boston University’s Chobanian & Avedisian School of Medicine have identified a substantial number of genes exhibiting altered activity in individuals diagnosed with AD compared to their healthy counterparts. A significant portion of these identified genes had not previously been implicated in Alzheimer’s disease by prior genetic studies, signaling a potential expansion of our knowledge base.
The most prominent molecular signature within this groundbreaking study emanated from the ADAMTS2 gene. Researchers observed a notable increase, approximately 1.5-fold, in the gene’s activity level within brain tissue samples obtained from individuals with autopsy-confirmed Alzheimer’s disease when contrasted with control samples. This pronounced difference immediately flagged ADAMTS2 as a gene of significant interest.
The robustness of these findings was further underscored by their consistent replication across independent research datasets. The Boston University research team meticulously analyzed gene expression data derived from post-mortem prefrontal cortex tissue samples. This comprehensive dataset comprised samples from 207 African American brain donors, of whom 125 had pathologically confirmed AD, and 82 served as controls. These invaluable samples were sourced from fourteen Alzheimer’s Disease Research Centers funded by the National Institutes of Health (NIH) across the United States, ensuring broad geographic representation and adherence to standardized collection protocols.
Within this meticulously curated African American cohort, ADAMTS2 emerged as the gene exhibiting the most statistically significant differential expression. Remarkably, this same gene also secured the top ranking in a separate, independently conducted study. This subsequent investigation, also performed by the same research group, utilized brain tissue from a substantially larger cohort of individuals of European ancestry. The EA study specifically compared gene expression profiles between individuals who exhibited confirmed Alzheimer’s pathology and clinical symptoms prior to death, and those who possessed the same pathological markers but maintained cognitive resilience throughout their lives.
"To the best of our knowledge, this marks the inaugural instance in AD genetics studies employing similarly designed methodologies where the most significant molecular finding has been identical across both White and African American populations," stated Dr. Lindsay A. Farrer, the corresponding author of the study and Chief of Biomedical Genetics at the Boston University Chobanian & Avedisian School of Medicine. This statement highlights the profound implications of discovering a shared genetic pathway, suggesting that underlying biological mechanisms of AD may transcend ancestral differences.
The implications of these discoveries are far-reaching, offering a significant stride forward in comprehending the genetic underpinnings of Alzheimer’s risk, particularly within the African American demographic. Existing scientific consensus has largely posited that the majority of identified genetic risk variants for AD are either specific to particular populations or manifest at varying frequencies across different ancestral groups. This has historically led to a fragmented understanding of AD genetics, with research often focusing on variants prevalent in European populations.
Dr. Farrer elaborated on this point, explaining, "While the risk of AD in African Americans has been associated with variations in several genes, the overlap of genes showing association in EA populations is modest. Furthermore, even among genes that do overlap, the specific variants involved and the magnitude of their impact on AD risk typically diverge." The groundbreaking finding that ADAMTS2 exhibits significantly elevated expression in the brain tissue of individuals with AD, irrespective of their ancestry—both in Black and White individuals—strongly suggests a common biological process contributing to the development of the disease. This shared pathway elevates the priority for intensive future research into ADAMTS2, with the potential to unlock its role as a novel therapeutic target.
The full findings of this pivotal study have been published online in the esteemed journal, Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association. This publication ensures that the scientific community has access to the detailed methodology, data analysis, and conclusions, facilitating further investigation and validation.
The research initiative was generously supported by a comprehensive array of grants from the National Institutes of Health (NIH), including but not limited to R01-AG048927, U01-AG058654, U54-AG052427, U19-AG068753, U01-AG062602, P30-AG072978, U01-081230, P01-AG003949, P30-AG062677, P30-AG062421, P30-AG066507, P30-AG066511, P30-AG072972, P30-AG066468, R01-AG072474, RF1-AG066107, U24-AG056270, RF1-AG082339, RF1-NS118584, P30-AG072946, P01-AG003991, P30-AG066444, P01-AG026276, P30-AG066462, P30-AG072958, and P30-AG072978. Additionally, funding was provided by awards from the Florida Department of Health, specifically 8AZ06 and 20A22. It is crucial to note that these funding bodies played no role in the design of the study, the collection or analysis of data, the interpretation of findings, the drafting of the manuscript, or the ultimate decision to submit the research for publication, ensuring the independence and scientific integrity of the work.
Several researchers involved in this study disclosed potential conflicts of interest and funding sources. Mark Logue received grants from the NIH and the Department of Veterans Affairs. Marla Gearing, Lee-Way Jin, Richard Mayeux, Richard Perrin, Shih-Hsiu Wang, and Lindsay Farrer were recipients of grants from the NIH. Melissa Murray’s contributions were supported by NIH grants; she also served as a paid consultant for Biogen Pharmaceuticals and participated in committees for the Alzheimer’s Association and the International Conference on Alzheimer’s and Parkinson’s Diseases. Thor Stein’s work was supported by grants from the NIH and the Department of Veterans Affairs, and he received an honorarium from Brown University. Andrew Teich received grants from the NIH, a contract from Regeneron Pharmaceuticals, and an honorarium from Ono Pharmaceuticals; he holds stock in Ionis Pharmaceuticals and Biogen Pharmaceuticals and served on committees for the Department of Defense and the Alzheimer’s Association. The efforts of Katarnut Tobunluepop and Zihan Wang were supported by NIH grants. Benjamin Wolozin received NIH grants, consulting fees from Aquinnah Pharmaceuticals and Abbingworth Ventures, and honoraria for various lectures; he also holds stock and is a Co-Founder and CSO of Aquinnah Pharmaceuticals Inc. The remaining authors reported no competing interests. This transparency regarding funding and potential conflicts is standard practice in scientific publishing and allows readers to assess the research within its full context.
About the Author
