Scientists are proposing a new way of understanding the genetics of Alzheimer’s disease that would mean up to a fifth of patients would be considered to have a genetically-caused form of the disease.
Currently, the vast majority of Alzheimer’s cases do not have a clearly identified cause. The new definition, proposed in a study published Monday, could broaden the scope of efforts to develop treatments, including gene therapy, and affect the design of clinical trials.
It could also mean that hundreds of thousands of people in the United States alone could, if they choose, receive an Alzheimer’s diagnosis before they show symptoms of cognitive decline, although there are currently no treatments for people at this stage.
The new classification would make this type of Alzheimer’s disease one of the most common genetic disorders in the world, medical experts said.
“This reconnection that we propose does not affect a small minority of people,” said Dr. Juan Fortea, study author and director of the Sant Pau Memory Unit in Barcelona, Spain. “Sometimes we say we don’t know the cause of Alzheimer’s disease,” but, he said, that would mean that about 15 to 20 percent of cases “can be traced to a cause, and the cause is in the genes. “
The idea involves a gene variant called APOE4. Scientists have long known that inheriting one copy of the variant increases the risk of developing Alzheimer’s, and that people with two copies, inherited from each parent, have a greatly increased risk.
The new study, published in the journal Nature Medicine, analyzed data from more than 500 people with two copies of APOE4, a much larger pool than in previous studies. The researchers found that almost all of these patients developed the biological pathology of Alzheimer’s, and the authors say that two copies of APOE4 should now be considered a cause of Alzheimer’s disease — not just a risk factor.
The patients also developed Alzheimer’s disease relatively young, according to the study. By age 55, more than 95 percent had biological markers associated with the disease. By age 65, nearly all had abnormal levels of a protein called amyloid that forms plaques in the brain, a hallmark of Alzheimer’s disease. And many began developing symptoms of cognitive decline at age 65, younger than most people without the APOE4 variant.
“Crucially, these individuals are often symptomatic 10 years earlier than other forms of Alzheimer’s disease,” said Dr. Reisa Sperling, a neurologist at Mass General Brigham in Boston and an author of the study.
He added, “By the time they’re picked up and diagnosed clinically, because they’re often younger, they have more pathology.”
People with two copies, known as APOE4 homozygotes, make up 2 to 3 percent of the general population but are estimated to make up 15 to 20 percent of people with Alzheimer’s dementia, experts said. People with one copy make up about 15 to 25 percent of the general population and about 50 percent of dementia patients with Alzheimer’s.
The most common variant is called APOE3, which appears to have a neutral effect on Alzheimer’s risk. About 75 percent of the general population has one copy of APOE3, and more than half of the general population has two copies.
Alzheimer’s experts who were not involved in the study said that classifying the two-copy condition as genetically determined Alzheimer’s disease could have important implications, including spurring drug development beyond the field’s recent heavy focus on treatments that target and reduce amyloid.
Dr. Samuel Gandy, an Alzheimer’s researcher at Mount Sinai in New York who was not involved in the study, said patients with two copies of APOE4 faced much higher safety risks from anti-amyloid drugs.
When the Food and Drug Administration approved the anti-amyloid drug Leqembi last year, it required a black box warning on the label saying the drug can cause “serious and life-threatening events,” such as swelling and bleeding in the brain, especially for people with two copies of APOE4. Some treatment centers have decided not to offer Leqembi, an intravenous infusion, to such patients.
Dr. Gandy and other experts said that classifying these patients as having a distinct genetic form of Alzheimer’s would spur interest in developing drugs that are safe and effective for them and would add urgency to current efforts to prevent cognitive decline in people who do not yet have symptoms. .
“Instead of saying we don’t have anything for you, let’s look for a trial,” Dr. Gandy said, adding that such patients should be included in trials at younger ages given how early their pathology begins.
In addition to trying to develop drugs, some researchers are investigating gene editing to convert APOE4 into a variant called APOE2, which appears to protect against Alzheimer’s disease. Another gene therapy approach being studied includes the APOE2 injection in the brain of patients.
The new study had some limitations, including a lack of diversity that could make the findings less generalizable. Most patients in the study were of European descent. While two copies of APOE4 also significantly increase Alzheimer’s risk in other ethnicities, the levels of risk differ, said Dr. Michael Greicius, a neurologist at Stanford University School of Medicine who was not involved in the research.
“An important argument against their interpretation is that the risk of Alzheimer’s disease in APOE4 homozygotes varies significantly between different genetic backgrounds,” said Dr. Greicius, who wrote a study found that whites with two APOE4 copies had a 13-fold greater risk than whites with two APOE3 copies, while blacks with two APOE4 copies had a 6.5-fold greater risk than blacks with two APOE3 copies.
“This has critical implications when counseling patients about their genetic risk for Alzheimer’s disease based on their ancestry,” he said, “and also speaks to some genetics and biology that have yet to be discovered that possibly drive this huge risk difference.”
According to the current genetic understanding of Alzheimer’s disease, less than 2 percent of cases are thought to be genetically caused. Some of these patients inherited a mutation in one of three genes and they may develop symptoms as early as their 30s or 40s. Others are people with Down syndrome, who have three copies of a chromosome that contains a protein that often leads to what is called Alzheimer’s disease associated with Down syndrome.
Dr. Sperling said the genetic alterations in these cases are thought to fuel the amyloid build-up, while APOE4 is thought to interfere with the clearance of the amyloid build-up.
Under the researchers’ proposal, having one copy of APOE4 would continue to be considered a risk factor, not enough to cause Alzheimer’s, Dr. Fortea said. It’s unusual for diseases to follow this genetic pattern, called “semidominance,” with two copies of a disease-causing variant but one copy only increasing the risk, experts said.
The new recommendation will raise questions about whether people should be tested to see if they have the APOE4 variant.
Dr. Greicius said that until there are treatments for people with two copies of APOE4 or trials of treatments to prevent them from developing dementia, “My recommendation is if you don’t have symptoms, you definitely shouldn’t know about your APOE status.”
He added: “It will only cause grief at this point.”
Finding ways to help these patients can’t come soon enough, Dr. Sperling said, adding, “These people are desperate, they’ve seen it in both their parents often, and they really need treatments.”