In a groundbreaking study emerging from Boston University’s Chobanian & Avedisian School of Medicine, scientists have unveiled novel genetic insights into Alzheimer’s disease (AD) among African American populations, a group markedly underrepresented in prior research. This comprehensive investigation is poised to reshape our understanding of AD’s molecular underpinnings across different ethnic backgrounds, revealing key genes with altered activity in the brains of affected individuals.
Alzheimer’s disease prevalence in African Americans is nearly twice that found in White or European-ancestry groups residing in the United States. While social determinants such as healthcare disparities, educational inequality, diagnostic bias, and increased cardiovascular and metabolic comorbidities contribute to this disparity, the genetic architecture underlying AD risk in African Americans has remained elusive. Prior gene expression studies predominantly focused on mixed or European-ancestry cohorts, often marginalizing African American participants, thus limiting statistical power to identify population-specific molecular changes.
This new research addresses this glaring gap by analyzing post-mortem brain tissue from 207 African American donors—comprising 125 individuals with pathologically confirmed AD and 82 cognitively normal controls. The tissue originated from the prefrontal cortex, a brain region critically involved in higher-order cognition and severely impacted in Alzheimer’s pathology. By deploying cutting-edge gene expression profiling technologies, the researchers quantitatively assessed the activity of thousands of genes, uncovering a suite of differentially expressed genes, many of which had previously not been associated with AD.
Among the most striking discoveries was the elevated expression of ADAMTS2, a gene encoding an extracellular matrix metalloproteinase, found at approximately 1.5 times higher levels in AD brains compared to controls. This finding held robust statistical significance and was corroborated by analysis of an independent dataset derived from a larger sample of European-ancestry individuals, verifying that ADAMTS2 upregulation is a shared hallmark of Alzheimer’s pathology across ethnicities.
The convergence of ADAMTS2 as the top-ranked gene in both populations is unprecedented in AD genetic research. It implicates common biological mechanisms driving neurodegeneration, suggesting that despite diverse genetic backgrounds and environmental exposures, fundamental pathogenic pathways may be conserved. ADAMTS2’s role in remodeling the brain’s extracellular matrix could influence amyloid plaque deposition or synaptic integrity, positing it as a compelling target for therapeutic development.
Leading the study, Dr. Lindsay A. Farrer emphasized the significance of these cross-population findings: “The overlap in gene expression changes points towards universal biological processes in AD progression. This offers hope for developing treatments with broad efficacy while underscoring the importance of including diverse populations in genetic research to capture the full spectrum of disease biology.”
The implications of population-specific versus shared genetic risk factors are profound. While many AD risk variants exhibit varying frequencies or exclusive associations within different ancestries, identifying genes like ADAMTS2 that transcend these boundaries advances the field toward unified models of neurodegeneration. It also highlights the necessity of expanding genomic studies in underrepresented groups to ensure equitable biomedical advancements.
This extensive project was undertaken with specimens sourced from 14 NIH-funded Alzheimer’s Disease Research Centers nationwide, ensuring a robust and geographically diverse sample of African American brain tissue. The methodological rigor entailed pathologically verifying diagnosis and implementing sophisticated statistical models to control for confounding factors intrinsic to post-mortem transcriptional analyses, such as RNA integrity and cellular composition.
Further analyses revealed that the molecular pathways influenced by the identified gene set encompass not only extracellular matrix remodeling but also neuroinflammation, synaptic signaling, and metabolic regulation. These interconnected pathways offer a multi-layered framework for understanding how genetic perturbations contribute to the clinical manifestations of AD, potentially informing biomarker development and stratified therapeutic interventions.
This study is among the first to deliver a high-resolution portrait of gene expression disturbances in African American Alzheimer’s brains, setting a precedent for future inclusion of diverse populations in neuroscience research. It paves the way for investigating whether modulating ADAMTS2 expression or function can mitigate disease progression or cognitive decline.
Published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, the findings mark a critical stride toward enhancing the representation of African Americans in genetic studies and aspire to reduce health disparities. The work was meticulously supported by multiple NIH grants and state-level research awards, with strict adherence to ethical standards and discrete conflict of interest disclosures, underscoring the scientific integrity of the investigation.
Given the disproportionate impact of AD on African Americans and the complex interplay of genetic and social factors, this research underscores an urgent call for broader, more inclusive scientific inquiry. Such efforts promise not only to elucidate AD’s pathobiology more comprehensively but to unlock novel avenues for diagnosis and therapy that could benefit all affected populations.
In conclusion, the identification of ADAMTS2 as a consistently dysregulated gene across diverse ancestral groups invigorates the search for shared molecular triggers underpinning Alzheimer’s neurodegeneration. It invites a paradigm shift toward integrative genetic research that embraces population diversity as fundamental rather than auxiliary, ultimately contributing to equitable health outcomes and precision medicine in neurodegenerative diseases.
Subject of Research: Cells
Article Title: Novel differentially expressed genes and multiple biological pathways for Alzheimer’s disease identified in brain tissue from African American donors
News Publication Date: 8-Oct-2025
Web References: medrxiv.org/content/10.1101/2024.11.12.24317218v1
References: Published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, DOI: 10.1002/alz.70629
Keywords: Health and medicine
