The disproportionately high incidence of Alzheimer’s disease (AD) among African Americans, who are affected at approximately twice the rate of individuals of European ancestry in the United States, has long been a subject of intense scientific inquiry. While social determinants of health, encompassing disparities in healthcare access, educational attainment, and potential biases within cognitive assessment methodologies, contribute significantly to this observable gap, emerging research is shedding light on potential biological underpinnings that may transcend these societal factors. Conditions such as cardiovascular disease and diabetes, which are more prevalent in the African American community, are well-established risk enhancers for AD, further complicating the landscape of understanding.
Historically, a substantial body of research investigating the molecular mechanisms of Alzheimer’s disease has centered on brain tissue analyses, meticulously comparing gene expression patterns between individuals diagnosed with the neurodegenerative condition and healthy controls. However, a critical limitation pervading much of this prior work has been the underrepresentation of African American participants. In numerous studies, the number of individuals from this demographic included in analyses was either not explicitly reported or was too limited to permit statistically robust conclusions regarding genetic variations or expression differences unique to or more pronounced within this population. This lacuna in research has hindered a comprehensive understanding of how Alzheimer’s may manifest at a genetic level across diverse ancestral groups.
A landmark investigation, representing the most extensive analysis of brain tissue from African American donors afflicted with Alzheimer’s disease to date, has recently yielded significant findings. Scientists affiliated with the Boston University Chobanian & Avedisian School of Medicine have identified a multitude of genes exhibiting altered activity in the brains of individuals with AD compared to those without the disease. Intriguingly, many of these identified genes had not previously been implicated in Alzheimer’s disease through earlier genetic studies, suggesting a potential broadening of the genetic landscape associated with the condition.
Among the newly identified genetic players, the ADAMTS2 gene emerged with the most compelling evidence of differential activity. Researchers observed a remarkable 1.5-fold increase in the expression level of ADAMTS2 within brain tissue samples obtained from individuals with autopsy-confirmed Alzheimer’s disease when contrasted with tissue from control subjects. This finding represents a notable departure from previous research that may have overlooked or been unable to detect such specific alterations due to sample limitations.
The robustness of this discovery is further underscored by its consistent appearance across independent research endeavors. The Boston University team meticulously analyzed gene expression data derived from post-mortem prefrontal cortex tissue samples generously donated by 207 African American individuals. This cohort comprised 125 individuals diagnosed with pathologically confirmed AD and 82 control subjects, with the tissue samples sourced from 14 Alzheimer’s Disease Research Centers funded by the National Institutes of Health (NIH) across the United States.
Within this extensive dataset, ADAMTS2 stood out as the gene demonstrating the most statistically significant difference in expression. Crucially, this gene also ranked as the primary finding in a parallel, independent study conducted by the same research group. This secondary investigation utilized brain tissue from a substantially larger cohort of individuals of European ancestry and compared gene expression in those with confirmed AD pathology and clinical symptoms against individuals who possessed the same pathology but remained cognitively resilient, showcasing remarkable clinical preservation despite neuropathological changes.
The convergence of findings across these two distinct cohorts, one predominantly African American and the other predominantly of European ancestry, holds profound implications. As articulated by the corresponding author, Dr. Lindsay A. Farrer, PhD, Chief of Biomedical Genetics at the Boston University Chobanian & Avedisian School of Medicine, "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." This statement highlights the unprecedented nature of the discovery and its potential to bridge previously perceived genetic divides in AD research.
These findings represent a pivotal advancement in unraveling the intricate genetic underpinnings of Alzheimer’s disease risk, particularly within the African American population. Existing evidence has suggested that many known genetic risk variants for AD are either specific to certain populations or exhibit varying frequencies across different ancestral groups. This often leads to a limited overlap in genetic associations identified in studies focusing on different racial or ethnic demographics.
Dr. Farrer further elaborated on this complexity, explaining that "Although risk of AD in African Americans has been associated with variants in several genes, the overlap of genes showing association 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." The discovery that ADAMTS2 expression is significantly and substantially elevated in the brain tissue of individuals with AD, irrespective of their ancestral background, strongly suggests a shared biological pathway contributing to the development of the disease.
The elevated activity of ADAMTS2 not only points towards a common pathophysiological mechanism but also elevates the imperative for intensified research into this specific gene. Future investigations are poised to determine its suitability as a potential therapeutic target, offering a glimmer of hope for developing more inclusive and effective treatments for Alzheimer’s disease. This shared genetic pathway could represent a critical nexus for developing interventions that benefit a broader spectrum of the population.
The groundbreaking research contributing to these insights was recently disseminated through online publication in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, a leading peer-reviewed journal in the field. The study received comprehensive financial backing from a multitude of National Institutes of Health (NIH) grants, 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, P01-AG003949, RF1-AG082339, RF1-NS118584, P30-AG072946, P01-AG003991, P30-AG066444, P01-AG003991, P30-AG066444, P01-AG026276, P30-AG066462, P30-AG072958, and P30-AG072978. Additional support was provided by awards from the Florida Department of Health, specifically 8AZ06 and 20A22. It is noteworthy that the funding entities played no role in the design of the study, the collection and analysis of the data, the interpretation of the findings, the drafting of the manuscript, or the decision to submit it for publication, ensuring the integrity and independence of the research process.
The study’s authors have disclosed various affiliations and potential conflicts of interest, meticulously documented to maintain transparency. For instance, 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 were recipients of grants from the NIH. Melissa Murray’s contributions were supported by NIH grants, and she has also served as a paid consultant for Biogen Pharmaceuticals and as a committee member for organizations such as the Alzheimer’s Association and the International Conference on Alzheimer’s and Parkinson’s Diseases. Thor Stein’s research was funded by grants from the NIH and the Department of Veterans Affairs, and he received an honorarium from Brown University. Andrew Teich’s work was supported by NIH grants, a contract from Regeneron Pharmaceuticals, and an honorarium from Ono Pharmaceuticals. He also holds stock in Ionis Pharmaceuticals and Biogen Pharmaceuticals and has 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 lectures. He also holds stock and is a Co-Founder and CSO of Aquinnah Pharmaceuticals Inc. The remaining authors have reported no competing interests. This comprehensive disclosure ensures that the scientific community can fully evaluate the research within its appropriate context.
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