Researchers have reported that individuals carrying two copies of the APOE4 gene are virtually guaranteed to develop Alzheimer’s disease, often experiencing symptoms at an earlier age. The study, published in Nature Medicine, suggests that these individuals may have a distinct genetic form of the neurodegenerative disease.
“Through these data we are saying that perhaps this is a genetic form of this disease, not merely a risk factor indication,” said Sterling Johnson, co-author of the study and researcher at the University of Wisconsin’s Alzheimer’s Disease Research Center.
For over three decades, scientists have known that carrying two copies of the APOE4 gene variant significantly increases the risk of developing Alzheimer’s compared to the more common APOE3 variant. Approximately 2 to 3 percent of the population—or 15 percent of those with Alzheimer’s—have two copies of APOE4.
The study involved analysis of more than 3,000 donated brains from the U.S. National Alzheimer’s Coordinating Center and biological and clinical data from over 10,000 individuals across three countries. Led by Juan Fortea of the University of Barcelona, the research team found that by age 65, at least 95 percent of individuals with two APOE4 genes—known as homozygotes—showed abnormal levels of the Alzheimer’s-related protein beta amyloid in their spinal fluid, and 75 percent had positive brain scans for amyloid.
“This study adds compelling data to suggest that people with two copies of this gene are almost guaranteed to develop Alzheimer’s if they live long enough, and that they will develop Alzheimer’s earlier than people without this gene,” commented Professor Tara Spires-Jones of the University of Edinburgh, who was not involved in the research.
The findings indicate that APOE4 homozygotes meet the criteria for a genetic disease: widespread presence of Alzheimer’s biology among carriers, similar symptom development rates, and predictable clinical and biological progression.
However, not all experts agree with this potential reclassification. Professor David Curtis of the UCL Genetics Institute expressed skepticism, stating, “I do not see anything in this paper to justify the claim that carrying two copies of APOE4 represents some ‘distinct genetic form’ of Alzheimer’s disease. No matter how many copies of APOE4 one carries, the underlying disease processes seem similar across cases of Alzheimer’s disease.”
The potential redefinition of APOE4 homozygosity as a genetic form of Alzheimer’s could have significant implications for research, diagnosis, and treatment approaches, potentially leading to more targeted interventions for those at highest risk.
Reference(s):
People with two copies of a risk gene have genetic form of Alzheimer's
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