by Alzheimer’s disease can be inherited more often than previously known, according to a new study that paints a clearer picture of a gene that has long been known to be involved in the common form of dementia.
The authors of the study, published Monday in the journal Nature Medicine, say that even this could be considered a distinct inherited form of the disease and that different approaches to testing and treatment may be needed.
Among those diagnosed with Alzheimer’s, researchers identify familial forms of the disease and sporadic cases. Most cases are thought to be sporadic, developing later in life. Familial forms, caused by mutations in any of three genes, tend to strike earlier and are known to be rare, accounting for about 2% of all Alzheimer’s diagnoses, or about 1 in 50 cases .
Under the new paradigm, 1 in 6 cases of Alzheimer’s would be considered inherited, or familial.
This changing understanding of hereditary risk, researchers say, is due to a better understanding of the role of a fourth gene that carries the blueprints for making a lipid-carrying protein called apolipoprotein E, known as APOE. APOE supplies cholesterol throughout the body and brain and is thought to play a role in depositing or brushing away the sticky beta-amyloid plaques that are one hallmark of Alzheimer’s.
There are three forms of the APOE gene that a person can carry. One called APOE2 is thought to protect against the development of Alzheimer’s disease. APOE3 is thought to confer a neutral risk for the disease.
APOE4, on the other hand, is bad news. It has long been known that people with at least one copy of the APOE4 gene have an increased risk of developing Alzheimer’s disease, and people with two copies had an even higher risk.
Now, researchers say that APOE4 should not be recognized as a risk factor alone, it should be seen as an inherited form of the disease, almost ensuring that a person with two copies will get the biological changes associated with Alzheimer’s disease in their brain.
Teasing the role of the gene in Alzheimer’s
In the new study, researchers from Spain and the United States compared people in clinical studies who had two copies of the APOE4 gene with people who had other types of the APOE gene.
They also compared people with two copies of APOE4 to people with other inherited forms of the disease: early-onset autosomal dominant Alzheimer’s disease (ADAD) and Alzheimer’s disease associated with Down syndrome (DSAD). The study included data from nearly 3,300 brains stored at the Alzheimer’s National Coordinating Center and data from another 10,000 people who were participants in five clinical trials.
Not only were people with two copies of the APOE4 gene much more likely to develop the biological changes that lead to Alzheimer’s disease, like people with other genetic forms of the disease, they were almost certain of the diagnosis: Almost 95% of people. in the studies with two copies of the APOE4 gene the biology of Alzheimer’s disease was by the time they were 82 years old.
The study authors say that while APOE4 reliably causes the biological changes associated with the disease – the formation of amyloid beta plaques in the brain – one or two copies of this gene do not always lead to cognitive decline. Very rarely, people can have APOE4 and have a lot of beta-amyloid in their brain but not have symptoms, possibly due to genetic or other environmental factors that protect their brains at the same time.. In the large dataset of nearly 3,300 brains maintained by the National Alzheimer’s Coordinating Center, for example, 273 people had two copies of the APOE4 gene, and 240, or 88%, had dementia.
When people with two copies of APOE4 have symptoms, they tend to get them earlier than others. On average, they developed Alzheimer’s about 10 years earlier – around age 65 – than people with other forms of the APOE gene. Researchers also found that the build-up of beta-amyloid and tau in their brain followed almost the same path as observed in people with other inherited forms of the disease. Their disease was more severe earlier in life.
In all inherited forms of the disease, “there are striking, striking similarities in the way the disease progresses and the symptoms it presents,” said lead study author Dr. Juan Fortea, a neurologist and director of the Memory Unit. of the Department of Neurology at Hospital de la Santa Creu in Sant Pau in Barcelona, in a news briefing.
Fortea and his co-authors argue that, for these reasons, two copies of the APOE4 gene should be considered a genetic form of the disease, and not just a risk.
Dr. Charles Bernick, associate medical director of the Lou Ruvo Cleveland Clinic Brain Health Center, said the study showed how powerful it is to have two copies of the APOE4 gene.
“It really drives a disease process,” said Bernick, who was not involved in the study.
Changing understanding of genetic risks
The strength of APOE4’s role in the development of Alzheimer’s was not recognized earlier, according to the researchers, because APOE4 also plays an important role in heart health, and they think many people with two copies of the gene died from cardiovascular causes before they developed it. Alzheimer’s. Previous studies estimated that between 30% and 35% of people with two copies of the APOE4 gene would develop mild cognitive impairment or dementia.
Researchers say they also found a gene-dose effect. While two copies of APOE4 ensured that a person would see beta-amyloid and tau build up in their brain, one copy of the gene also increased a person’s risk – but not as much as two copies of that gene.
That would mean the APOE4 gene is semidominant, Fortea said. Other diseases in which genes show semidominance include sickle cell anemia and hypercholesterolemia. In sickle cell, for example, two copies of the gene cause sickle cell disease, but one copy causes sickle cell trait. People with sickle cell trait usually do not have symptoms, but are more likely to have heat stroke or muscle failure during strenuous exercise, and can have pain crises under certain conditions.
The classification of APOE4 as an inherited form of the disease has several major implications. First, it would mean that genes cause a much larger percentage of Alzheimer’s cases than previously understood.
Before APOE4, the only gene changes identified as causing Alzheimer’s were associated with early forms of the disease and Down syndrome. They accounted for about 2% of Alzheimer’s cases, about 1 in 50.
People with two copies of the APOE4 gene account for about 15% of people diagnosed with Alzheimer’s, or 1 in 7 cases of the disease.
About 2% of the general population carries two copies of the APOE4 gene, making it one of the most common inherited diseases.
The important takeaway from the study, said Dr. Constantine Lyketsos, director of the Alzheimer’s memory and treatment center at Johns Hopkins, is that Alzheimer’s disease should not be treated as a monolith. Rather, it shows that there are different types of the disease that require personalized treatment.
“The point is, we have to start doing accurate medicine and break it down. Start with genetics,” said Lyketsos, who was not involved in the study.
Gene testing is not recommended
It is also likely to change how people who carry the APOE4 gene are diagnosed and treated.
Tests are available to determine a person’s APOE4 status, but they are not recommended as a routine part of the diagnosis. That may need to change, the study authors said.
“The consensus and the guidelines now do not recommend testing for APOE4 and the reason for the consensus was that it did not help with the diagnosis,” Fortea said.
APOE testing is recommended for patients being evaluated for taking new amyloid-clearing medications, such as lecanemab.
Because Alzheimer’s patients with two copies of the APOE4 gene are at higher risk of serious side effects such as brain swelling from these amyloid-clearing medications, some treatment centers have decided not to offer them the drugs, said the author of the studies of dr. Reisa Sperling, director of the Alzheimer’s Research and Treatment center at Brigham and Women’s Hospital.
“This is a very big problem, given these data,” she said, noting that it would be important to conduct research to see if safer doses or treatments could be found for the patient group. this.
“To me, this means we need to treat them earlier,” Sperling said, “and this research suggests that we should be treating them early, at a younger age, and at an early stage of pathology because that we know they are. very likely to progress rapidly to impairment.”
Dr. Sterling Johnson, study author who leads the Wisconsin Alzheimer’s Prevention Registry at the University of Wisconsin, said it would be very important for clinical trials to begin to take participants’ APOE4 status into account.
“Maybe we need to treat these as a separate group in our research papers so we can really understand the relationship between amyloid and tau and symptoms” in people with two copies of the APOE4 gene, in a way that we don’t have at all. able before, Johnson said in the news briefing.
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