Researchers have identified a gene that they reported was linked to a 1.5 times-higher likelihood of suffering from Alzheimer’s disease.
In the first large-scale trial of brains afflicted by the disease in African American donors, scientists from Boston University zeroed in on the ADAMTS2 gene in brain tissue from those with autopsy-confirmed Alzheimer’s disease.
ADAMTS2 is crucial to the formation of collagen, which helps provide structure for tissues. Overexpression of the gene has strong links to disorders that afflict the body’s connective tissues.
It has also been implicated in neurodevelopment. Certain types of collagen, particularly in the developing brain, form a structural scaffold. By processing collagen, ADAMTS2 helps build and organize this essential framework, and disruption of this process could lead to faulty brain circuits.
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The latest research added that ADAMTS2 was the most significantly overexpressed gene in the brains of African American individuals with confirmed Alzheimer’s disease compared to those without.
In the brain, one of its key targets is Reelin. Reelin is a crucial protein for proper brain development, helping to maintain cognitive function
Typically, Reelin helps protect against the hallmarks of Alzheimer’s by reducing the formation of the tau tangles and limiting amyloid plaque formation, both of which are believed to be hallmarks of the disease. However, ADAMTS2 can impair Reelin’s protective function.
Overactive ADAMTS2 disrupts this protective pathway, leading to increased Tau and amyloid buildup, which drives cognitive decline.
Boston University scientists have identified the ADAMTS2 gene as a major factor in Alzheimer’s disease, based on a large study of brains from African American donors (stock image)
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These findings could open doors to new, targeted genetic treatments designed to inhibit or block the ADAMTS2 protein. Because the effect is the same across people of different ancestries, a drug targeting ADAMTS2 could potentially help a broad range of people.
Lowering ADAMTS2 activity could also be a strategy to prevent symptoms from developing, even in people who have early signs of the disease in their brains.
The study is also impactful in its design. Historically, most genetic research has been done on people of White/European ancestry. By focusing on an understudied group, Black Americans, the latest research ensures that future Alzheimer’s treatments and diagnostic tools will work for them too.
Alzheimer’s disease is a looming plague in America as the US population skews older by the year.
The population aged 65 and above grew from approximately 13 percent in 2010 to more than 17 percent in 2022, with forecasts suggesting it could reach nearly 21 percent of the total population by 2030.
Age is the most critical risk factor for Alzheimer’s disease. Risk of developing the disease doubles approximately every five years after the age of 65, fueling projections that the case burden will rise from the current 7 million cases to nearly 14 million by 2060.
The study’s sample included donated brain tissue from 212 African Americans, including 82 cognitively healthy people and 125 with confirmed Alzheimer’s.
Researchers compared that cohort with another study that included people of European descent to gain a better understanding of the gene’s actions in different demographics.
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Although this study only included Black participants, its most significant result aligns with the result from the separate study on White participants.
Dr Lindsay Farrer, chief of biomedical genetics at the school and corresponding author, said: ‘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.’
Tissue was sourced from the prefrontal cortex, a region particularly affected by Alzheimer’s, and scientists were able to visualize each gene and its level of activity.
They also identified genes with expression levels that were significantly different between the Alzheimer’s cases and the controls.
The primary result was the identification of ADAMTS2, which showed the strongest overexpression in Alzheimer’s cases, with its expression levels 1.52 times higher than in controls.
The same gene was also a top-ranked hit in a separate study’s computer analysis conducted on a predominantly White/European ancestry cohort, confirming its importance across ancestries.
The researchers identified 65 genes that behaved consistently across both African American and European Ancestry study groups.
This shared set included genes that were either significantly overexpressed or underexpressed in Alzheimer’s patients compared to healthy controls.
The critical finding was that the direction of change was identical in both populations; genes turned up in one group were also turned up in the other, and genes turned down were turned down in both.
The consistency across study populations indicated that these 65 genes are part of a core mechanism of Alzheimer’s disease, common across ancestral backgrounds.
Their findings were published in the journal Alzheimer’s & Dementia, the journal of the Alzheimer’s Association.
The researchers concluded: ‘The inclusion of [African American] participants in AD research is important not only to ensure that predictions made based on genetic and [genomic] data are accurate in this population, but also because of the potential it will lead to new and important advances in knowledge about AD risk that will benefit everyone.’
