Alzheimer’s disease presents a significantly disproportionate burden on African American communities within the United States, with individuals experiencing roughly double the incidence observed in their White or European-ancestry counterparts. While acknowledging the profound impact of socio-economic determinants, such as disparities in healthcare access, educational attainment, and inherent biases within cognitive assessment methodologies, scientific inquiry is increasingly delving into the biological underpinnings of this disparity. Furthermore, a higher prevalence of comorbid conditions, notably cardiovascular disease and diabetes, within the African American population is recognized as a critical exacerbating factor in Alzheimer’s risk.
Historically, much of the research focused on the genetic architecture of Alzheimer’s disease has been concentrated on cohorts of European ancestry or mixed populations. This has often resulted in a limited representation of African American participants, with data either not explicitly reported or insufficient for robust statistical analysis concerning population-specific genetic signatures. This research gap has hindered a comprehensive understanding of how genetic factors might contribute to the heightened risk and differential progression of Alzheimer’s in African Americans.
In a pioneering effort, the most extensive investigation to date utilizing brain tissue from African American donors has successfully identified a constellation of genes exhibiting altered activity patterns in individuals diagnosed with Alzheimer’s disease compared to those without the neurodegenerative condition. Conducted by scientists at the Boston University Chobanian & Avedisian School of Medicine, this comprehensive study has brought to light numerous genetic candidates previously unassociated with Alzheimer’s in prior research endeavors.
At the forefront of these discoveries, the ADAMTS2 gene has emerged with the most compelling evidence of differential expression. Analysis revealed a substantial 1.5-fold increase in the activity level of ADAMTS2 within brain tissue harvested from individuals with autopsy-confirmed Alzheimer’s pathology, in stark contrast to the tissue samples from control subjects. This finding represents a significant divergence from the typical landscape of Alzheimer’s genetic research, which has often focused on established risk genes with varying prevalence across different ancestries.
The integrity and reliability of these findings have been further substantiated by their replication across independent research datasets. The Boston University team meticulously examined gene expression profiles derived from post-mortem prefrontal cortex tissue samples obtained from a cohort of 207 African American brain donors. This group comprised 125 individuals with pathologically confirmed Alzheimer’s disease and 82 control individuals, with the valuable samples sourced from 14 federally funded Alzheimer’s Disease Research Centers spanning the United States. The consistent observation of ADAMTS2’s heightened expression in this carefully curated African American cohort underscores its potential significance.
Remarkably, ADAMTS2 was also identified as the most significantly differentially expressed gene in a separate, independently conducted study by the same research group. This subsequent investigation involved a considerably larger cohort of individuals of European ancestry and employed a similar experimental design. Crucially, it compared individuals with confirmed Alzheimer’s pathology who exhibited clinical symptoms prior to death with those who possessed the same pathological markers but demonstrated remarkable cognitive resilience throughout their lives.
"To our knowledge, this marks the first instance in similarly designed Alzheimer’s genetics studies where the most significant molecular 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 institution. This confluence of results across distinct ancestral groups and research designs is a powerful indicator of a shared biological mechanism underlying Alzheimer’s disease, irrespective of racial or ethnic background.
The implications of these findings are profound for advancing our comprehension of Alzheimer’s risk factors, particularly within the African American community. Existing research has suggested that many identified genetic variants associated with Alzheimer’s disease tend to be population-specific or exhibit disparate frequencies across different demographic groups. This has complicated the development of universal diagnostic and therapeutic strategies.
Dr. Farrer elaborated on this complexity, noting that "While the risk of Alzheimer’s disease in African Americans has been linked to variations in several genes, the overlap with genes showing association in European American populations is modest. Moreover, even among overlapping genes, the specific variants involved and the magnitude of their impact on Alzheimer’s risk typically differ." The consistent and substantial elevation of ADAMTS2 expression observed in the brain tissue of both White and Black individuals afflicted with Alzheimer’s disease not only points towards a common biological pathway culminating in the disease but also elevates the gene’s importance for future research. This heightened focus could ultimately determine its viability as a potential therapeutic target for intervention.
The groundbreaking research detailing these discoveries has been officially published online in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, a leading publication in the field. The study received robust financial support from a comprehensive array of National Institutes of Health (NIH) grants, including but not limited to R01-AG048927, U01-AG058654, U54-AG052427, U19-AG068753, and U01-AG062602, among many others. Additional funding was also provided by awards from the Florida Department of Health, specifically 8AZ06 and 20A22. It is noteworthy that the funding bodies played no role in the design of the study, the collection and analysis of data, the interpretation of findings, the writing of the manuscript, or the ultimate decision to submit the research for publication, ensuring the independence and objectivity of the scientific inquiry.
Further disclosures highlight potential conflicts of interest and affiliations among the study authors. Mark Logue reported receiving 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 all received 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 has been an active member of committees for the Alzheimer’s Association and the International Conference on Alzheimer’s and Parkinson’s Diseases. Thor Stein’s research was supported by grants from the NIH and the Department of Veterans Affairs, and he has received an honorarium from Brown University. Andrew Teich’s work benefited from NIH grants, a contract with 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 also supported by NIH grants. Benjamin Wolozin received grants from the NIH, consulting fees from Aquinnah Pharmaceuticals and Abbingworth Ventures, and honoraria for numerous lectures; he also owns stock and holds the positions of Co-Founder and CSO at Aquinnah Pharmaceuticals Inc. The remaining authors have declared no competing interests that would influence the integrity of their research. This transparency is crucial for maintaining scientific rigor and public trust in research findings.
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