Alzheimer’s disease (AD) casts a disproportionately heavy shadow over the African American community in the United States, with individuals of this background experiencing the condition at approximately double the rate observed in their White or European-ancestry counterparts. While societal and systemic factors, such as disparities in healthcare access, educational attainment, and inherent biases within cognitive assessment methodologies, are acknowledged contributors to this disparity, emerging research is now illuminating the intricate biological underpinnings that may also play a significant role. Furthermore, the elevated prevalence of comorbid health conditions within the African American population, including cardiovascular disease and diabetes, is independently recognized as a potent amplifier of Alzheimer’s risk.
Historically, a substantial body of research has delved into the complexities of gene expression – the measure of how actively a gene is transcribed into proteins – within brain tissue obtained from individuals diagnosed with Alzheimer’s, contrasting these findings with those from healthy controls. However, this scientific exploration has been predominantly skewed towards populations of European ancestry or those with mixed genetic heritage. In a significant number of these prior investigations, the inclusion of African American participants was either not explicitly detailed or the sample sizes were too diminutive to permit robust and meaningful conclusions regarding genetic patterns specifically pertinent to this demographic. This oversight has created a critical knowledge gap, hindering a comprehensive understanding of Alzheimer’s pathogenesis across diverse populations.
A groundbreaking investigation, representing the most extensive study to date utilizing post-mortem brain tissue from African American donors, has successfully identified a multitude of genes exhibiting altered activity patterns in individuals affected by Alzheimer’s disease compared to their unaffected peers. Conducted by scientists at the Boston University Chobanian & Avedisian School of Medicine, this research has brought to light several genes that had not previously been implicated in Alzheimer’s disease through other genetic studies. This signifies a crucial step forward in deciphering the genetic architecture of the disease in a population group that has been historically underrepresented in such research.
Among the myriad of genes scrutinized, the ADAMTS2 gene emerged with the most compelling evidence of differential expression. The research team observed a substantial increase in the activity level of ADAMTS2, registering a 1.5-fold elevation, within the brain tissue of individuals who had been definitively diagnosed with Alzheimer’s disease through post-mortem examination, when contrasted with tissue samples from control subjects. This finding immediately positions ADAMTS2 as a gene of significant interest in the ongoing quest to understand the molecular mechanisms driving Alzheimer’s pathology.
The robustness of these findings is further amplified by their consistency across independent research endeavors. The Boston University team meticulously analyzed gene expression data derived from the prefrontal cortex of 207 deceased African American brain donors. This cohort comprised 125 individuals with pathologically confirmed Alzheimer’s disease and 82 individuals serving as controls. The meticulously collected samples originated from 14 Alzheimer’s Disease Research Centers funded by the National Institutes of Health (NIH) and were distributed across various research institutions throughout the United States, ensuring a broad and representative sample base.
The significance of ADAMTS2 was further underscored when it also ranked as the most significantly differentially expressed gene in a separate, independent study conducted by the same research group. This secondary investigation utilized brain tissue from a substantially larger cohort of individuals of European ancestry. Crucially, this independent study employed a similar methodological design, comparing individuals with confirmed Alzheimer’s pathology who exhibited clinical symptoms prior to death with those who possessed the same underlying pathology but demonstrated remarkable cognitive resilience, remaining cognitively unimpaired despite the presence of AD biomarkers. The fact that ADAMTS2 emerged as a top finding in both distinct populations, using comparable analytical approaches, lends considerable weight to its potential role in the disease process.
"To the best of our knowledge, this marks the first instance in AD genetic studies employing similarly designed methodologies where the most significant finding has been identical across both White and African American populations," stated Dr. Lindsay A. Farrer, the corresponding author and Chief of Biomedical Genetics at the Boston University Chobanian & Avedisian School of Medicine. This statement highlights the profound implications of this shared genetic signal, suggesting a potential convergence of biological pathways contributing to Alzheimer’s disease, irrespective of ancestral background.
These research outcomes represent a meaningful advancement in the scientific community’s efforts to comprehend the genetic underpinnings that contribute to Alzheimer’s risk, particularly within the African American demographic. Prior scientific consensus has indicated that many identified Alzheimer’s risk variants tend to be population-specific or manifest at varying frequencies across different ethnic groups. This has often led to a fragmented understanding of the disease, with different genetic factors being emphasized for different populations.
Dr. Farrer further elaborated on the significance of these findings, explaining, "Although the risk of AD in African Americans has been linked to variants in several genes, the overlap with genes showing associations in European American populations is generally modest. Even among those genes that do show overlap, the specific variants involved and the magnitude of their effect on AD risk typically differ." He continued, "The observation that ADAMTS2 expression is significantly and substantially elevated in brain tissue from both White and Black individuals with AD not only points towards a shared biological process that leads to AD but also elevates the priority for further research involving this gene. Such research could determine its suitability as a potential therapeutic target for Alzheimer’s disease."
The implications of this discovery are far-reaching. Identifying a common genetic factor that influences Alzheimer’s risk in both African Americans and European Americans opens up new avenues for developing universally applicable diagnostic tools and therapeutic interventions. It suggests that focusing on the functional role of ADAMTS2 could yield treatments that benefit a broader spectrum of the population affected by this devastating neurodegenerative disease. This research moves beyond simply identifying correlations to suggesting potential causal pathways that can be further investigated and potentially modulated.
The full findings of this pivotal study have been officially published online in the esteemed journal Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, making this critical information accessible to the global scientific and medical communities. The research was generously supported by a comprehensive suite of grants from the National Institutes of Health (NIH), including 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-AG026276, P30-AG066462, P30-AG072958, and P30-AG072978, alongside awards from the Florida Department of Health (awards 8AZ06 and 20A22). It is important to note that the funding entities played no role in the study’s design, the collection or analysis of data, the interpretation of results, the drafting of the manuscript, or the decision to submit it for publication, ensuring the integrity and independence of the research.
A detailed disclosure of potential competing interests for the study’s authors further underscores the transparency of the research process. 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 received NIH grants, served as a paid consultant for Biogen Pharmaceuticals, and held committee positions for the Alzheimer’s Association and the International Conference on Alzheimer’s and Parkinson’s Diseases. Thor Stein received grants from the NIH and the Department of Veterans Affairs, along with an honorarium from Brown University. Andrew Teich received NIH grants, a contract from Regeneron Pharmaceuticals, an honorarium from Ono Pharmaceuticals, holds stock in Ionis Pharmaceuticals and Biogen Pharmaceuticals, and served on committees for the Department of Defense and the Alzheimer’s Association. The contributions of Katarnut Tobunluepop and Zihan Wang were supported by NIH grants. Benjamin Wolozin received NIH grants, consulting fees from Aquinnah Pharmaceuticals and Abbingworth Ventures, honoraria for various lectures, and is a co-founder and Chief Scientific Officer of Aquinnah Pharmaceuticals Inc., holding stock in the company. The remaining authors reported no competing interests. This comprehensive reporting ensures that the scientific community can critically evaluate the research within its full context.
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