Scientists claim to have found another specific genetic form of Alzheimer’s disease
Having two copies of a gene variant known to predispose people to Alzheimer’s disease could actually represent a distinct genetic form of the disease, researchers say.
The variant, known as ApoE4, has long been known to increase the risk of developing Alzheimer’s disease, with two copies carrying a greater risk than one.
Research has now shown that almost everyone with two copies of the variant will develop Alzheimer’s disease (AD), suggesting that this is not just a risk factor, but also a cause.
“More than 95% of individuals (with two copies of ApoE4) have AD pathology in the brain or in the biomarkers we analyzed,” says Dr. Juan Fortea, co-author of the study from Sant Pau Hospital in Barcelona. .
His team said the predictability of the age at which symptoms started was similar to that of other genetic forms of the disease, such as autosomal dominant Alzheimer’s disease (ADAD) and Alzheimer’s disease with Down syndrome (DSAD).
Dr. Victor Montal, co-author from the Barcelona Supercomputing Center, said the research catalyzed a paradigm shift in the understanding of the disease.
“While previously the etiology of dementia was known in less than 1% of cases, our work has now enabled the identification of causative factors in more than 15% of cases,” he said.
However, the research did not shed light on the risk of developing dementia itself for people with two copies of ApoE4.
Writing in the journal Nature Medicinethe researchers reported how postmortem results from 3,297 brain donors revealed that almost all 273 donors with two copies of ApoE4 showed signs of Alzheimer’s disease in the brain.
The researchers also analyzed clinical data from more than 10,000 people, which showed that almost all 519 people with two copies of ApoE4 at age 65 had abnormal levels of a protein involved in Alzheimer’s disease, known as amyloid beta, in their cerebrospinal fluid. and 75% had positive amyloid scans. The prevalence of biomarkers for the disease also increased with age.
The team added that the age at which symptoms started was about seven to 10 years earlier in people with two copies of ApoE4, at about 65 years, compared to those without the variant.
The researchers said that since about 2% of the general population is thought to have two copies of ApoE4, this form of Alzheimer’s is one of the most common diseases due to changes in just one gene.
However, because much of the data was collected from people of European descent, further research is needed to investigate whether the findings apply to people of different ethnicities.
Prof. Reisa Sperling, co-author of the study from Brigham and Women’s Hospital in Boston, US, said that while concerns had been raised about the use of Alzheimer’s drugs such as lecanemab in people with two copies of ApoE4, the new work showed the importance of further research in this area, as well as other approaches to treatment and prevention in such individuals.
Researchers from the University of California, San Francisco and the city’s Gladstone Institutes wrote in an accompanying op-ed that defining having two copies of ApoE4 as a distinct genetic form of Alzheimer’s disease had important consequences, from allowing that those affected received support through education and counseling programs, to stimulate new research opportunities, including targeted drug development. They added that this could also lead to changes in the diagnosis and treatment of the disease and affect the way clinical trials are designed.
Not everyone agreed with the study’s conclusions. “I see nothing in this paper to justify the claim that carrying two copies of ApoE4 represents a ‘distinct genetic form’ of Alzheimer’s disease,” said Prof. David Curtis, Honorary Professor at the Genetics Institute at University College London .
“No matter how many (copies) of ApoE4 one carries, the underlying disease processes appear similar in Alzheimer’s disease cases, suggesting that effective treatment and prevention strategies, yet to be developed, would have broad applicability, ” he added.