Having two copies of a gene variant known to predispose people to Alzheimer’s may actually represent a distinct genetic form of the disease, researchers said.
The variant, known as ApoE4, has long been known to increase the risk of developing Alzheimer’s, with two copies conferring greater risk than one.
Now research has revealed that almost everyone with two copies of the variant develops Alzheimer’s disease (AD), suggesting that it is not only a risk factor, but also a cause.
“More than 95% of the individuals [with two copies of ApoE4]AD pathology has either in the brain or in the biomarkers that we analyzed,” said Dr. Juan Fortea, the co-author of the research from Sant Pau Hospital in Barcelona.
His team said the predictability of the age at which symptoms begin is similar to other genetic forms of the disease such as autosomal dominant Alzheimer’s disease (ADAD) and Alzheimer’s disease in Down syndrome (DSAD).
Dr Victor Montal, a co-author from 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 study 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 examination results from 3,297 brain donors revealed that almost all of the 273 donors with two copies of ApoE4 showed signs of Alzheimer’s in the brain.
The researchers also analyzed clinical data from more than 10,000 people, revealing that almost all of the 519 people with two copies of ApoE4 had abnormal levels of a protein involved in Alzheimer’s disease by age 65. 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 of symptom onset 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 with about 2% of the general population thought to have two copies of ApoE4, this form of Alzheimer’s constituted one of the most common diseases due to changes in just one gene.
However, with much of the data collected from people of European descent, further work is needed to examine whether the findings hold for people of different ethnicities.
Prof Reisa Sperling, a co-author of the study from Brigham and Women’s Hospital in Boston, USA, 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 the importance of further research in the area, as well as around other approaches for treatment and prevention in such individuals.
Researchers from the University of California, San Francisco and the city’s Gladstone Institutes wrote in an accompanying opinion piece that the definition of two copies of ApoE4 as a distinct genetic form of Alzheimer’s disease has important implications, because it will identify those who allow those affected to receive support through educational and counseling programs, to stimulate new avenues of research, including targeted drug development. They added that it could also lead to changes in the diagnosis and management 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, an honorary professor at University College London’s Genetics Institute.
“No matter how much [copies] of ApoE4 one carries the underlying disease processes look similar across cases of Alzheimer’s disease, suggesting that any effective treatment and prevention strategies, which have yet to be developed, will have broad applicability,” he added.
