2024-05-06 18:28:55
People who carry two copies of the APOE4 gene are virtually guaranteed to develop Alzheimer’s disease and develop symptoms at an earlier age. Researchers reported this Monday in a study that could redefine these carriers as carriers of a new genetic form of the debilitating disease.
The reclassification could transform Alzheimer’s research, diagnosis and treatment methods, according to researchers, whose study was published in the journal Nature Medicine.
“What we are saying through these data is that this may be a genetic form of this disease and not just indicative of a risk factor,” study co-author Sterling Johnson of the University of Wisconsin Alzheimer’s Disease Research Center told reporters in a briefing.
Scientists have known for three decades that people with two copies of the APOE4 gene variant have a significantly higher risk of developing the disease than people with the most common version of the APOE gene, known as APOE3. About 2 to 3% of the general population or 15% of people with Alzheimer’s have two copies of the APOE4 variant.
“This study provides 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 develop Alzheimer’s earlier than people without this gene,” said Professor Tara Spires-Jones, a Alzheimer’s researcher. at the University of Edinburgh who were not involved in the study.
Dr. Juan Fortea of the University of Barcelona and his colleagues examined more than 3,000 donated brains from the US National Alzheimer’s Coordinating Center, as well as biological and clinical data from more than 10,000 people from three countries.
They found that by age 65, at least 95% of people with two copies of APOE4 – called homozygotes – had abnormal levels of a protein linked to Alzheimer’s called beta-amyloid in their spinal fluid and 75% had positive brain scans for amyloid.
Almost all APOE4 homozygotes in the study had higher amyloid levels at age 65 than people who did not have the risk variant.
The results suggest that APOE4 homozygotes meet the three main criteria for a genetic disease: almost all people with these two variants have Alzheimer’s biology, they develop symptoms at about the same rate, and the clinical and biological changes occur in a predictable order of, according to to the researchers.
Professor David Curtis of the UCL Genetics Institute, who was not involved in the research, was not convinced. “I can find nothing in this study to justify the claim that carrying two copies of APOE4 represents a ‘special genetic form’ of Alzheimer’s disease,” he said in a statement.
“Regardless of how many copies of APOE4 you carry, the underlying disease processes appear to be similar in all cases of Alzheimer’s,” he said.
EFFECTS ON TREATMENT
The findings could have implications for Eisai and Biogen’s recently approved Alzheimer’s treatment Leqembi, a drug that removes amyloid from the brain.
In clinical trials, patients with two copies of the APOE4 variant had a significantly higher incidence of brain bleeding and swelling associated with treatment. For this reason, some centers do not treat these patients, Dr. Reisa Sperling, an Alzheimer’s disease researcher at Mass General Brigham who worked on the study, said in a briefing with reporters.
The results suggest that these patients should be treated at a younger age because “we know that they are very, very likely to deteriorate quickly,” she said.
Dr. Samuel Gandy, an Alzheimer’s researcher at Mount Sinai in New York, said the findings underscore the need to include APOE4 homozygotes in studies designed to prevent the disease before they develop symptoms. Sperling is conducting such a study.
Heather Snyder of the Alzheimer’s Association said the findings, if correct, could have significant implications for how disease risk is assessed, how it is studied in clinical trials and how treatments are developed.
The new name should apply to Alzheimer’s disease which develops later in life. Other genetic forms include autosomal dominant Alzheimer’s disease, which is caused by mutations in three different genes, and Down syndrome.
A key limitation of the study is that it primarily involved people of European descent. The team said further studies are needed in people of African descent, a population in which APOE4 appears to confer a lower risk of Alzheimer’s disease. (Reporting by Julie Steenhuysen, editing by Bill Berkrot)
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