A groundbreaking study on gene expression in the brains of patients of African descent with Alzheimer's disease has, for the first time on a large scale, revealed differences and parallels with affected individuals of European descent. The findings, published in the journal Alzheimer’s & Dementia, could advance the development of therapies effective regardless of ethnic background. The study underscores the need to consider more diverse data in genomic research to better combat the global burden of this neurodegenerative disease.
In the U.S., the risk of Alzheimer's is about twice as high for people of African ancestry as for individuals of European descent. This disparity is influenced not only by socioeconomic factors such as limited access to healthcare and education but also by testing biases and higher rates of risk factors like diabetes and cardiovascular disease. Genetic particularities also play a role: the APOE4 gene variant, for instance, occurs more frequently in people of African ancestry but increases the risk of Alzheimer's less in this group than in Europeans.
Despite these insights, the participation of individuals of African ancestry in Alzheimer's studies has long been minimal. Many analyses of gene expression in brain tissue include few or no samples from this population group, which skews results and makes specific patterns for affected individuals of African descent invisible. The current work closes this gap by drawing on extensive data, showing that while genetic risk factors overlap between groups, they vary in variants and impact strength.
The research team led by Lindsay A. Farrer from the Boston University Chobanian & Avedisian School of Medicine examined brain samples from 207 donors of African ancestry: 125 of these were from confirmed Alzheimer's patients, and 82 were from healthy control subjects. Using RNA sequencing, they identified 482 genes whose expression levels differed significantly between patients and healthy individuals. Particularly noteworthy was the ADAMTS2 gene, whose activity was 1.52 times higher in Alzheimer's cases than in the control group. This gene was already ranked among the leading candidates in a previous study by the same team on patients of African ancestry – a first in Alzheimer's genetics research.
This match highlights a common biological mechanism behind the disease, regardless of ancestry. Three other top genes – ITPKB, TDRKH, and LINC0194 – showed similar deviations as seen in studies of individuals of European descent, with a total of 65 genes showing comparable trends. ADAMTS2 is known for diverse functions, including the downregulation of reelin, a protective protein in the brain. Low reelin levels promote tau phosphorylation and the formation of amyloid plaques – key hallmarks of Alzheimer's and related diseases like Parkinson's.
Based on these findings, the researchers recommend prioritizing ADAMTS2 as a potential therapeutic target. Inhibiting this gene could represent a strategy that works across ethnic boundaries, mitigating plaque formation and neuronal damage. The study emphasizes that such approaches can only arise from more inclusive research that reflects the genetic diversity of the global population.
The results could revolutionize Alzheimer's therapy, especially in countries with high prevalence among minorities. Further research into ADAMTS2 is now essential to clarify its role as a drug target and prepare for clinical trials.
