Alzheimer’s disease may be inherited more often than previously known, according to a new study that paints a clearer picture of a gene long known to be linked to the common form of dementia.
The authors of the study, published Monday in the journal Nature Medicine, say that this might even be considered a distinct, inherited form of the disease and that different approaches to testing and treatment may be needed.
Among people diagnosed with Alzheimer’s, researchers recognize familial forms of the disease and sporadic cases. Most cases are thought to be sporadic, which develop 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 to be inherited, or familial.
This shifting appreciation of inherited risk, researchers say, is due to a better understanding of the role of a fourth gene that carries the blueprints to make a lipid-carrying protein called apolipoprotein E, known as APOE. APOE ferries cholesterol throughout the body and brain and is thought to play a role in depositing or sweeping away sticky beta amyloid plaques, which are one hallmark of Alzheimer’s.
There are three types of the APOE gene a person can carry. One called APOE2 is thought to be protective against the development of Alzheimer’s disease. APOE3 is thought to confer a neutral risk of the disease.
APOE4, on the other hand, is bad news. It has long been recognized that people with at least one copy of the APOE4 gene have an elevated risk of developing Alzheimer’s disease, while people with two copies had a higher risk still.
Now, researchers say APOE4 shouldn’t just be recognized as a risk factor, it should be viewed as an inherited form of the disease, virtually assuring that a person who has two copies will get the biological changes associated with Alzheimer’s disease in their brains.
Teasing out gene’s role 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 forms 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 Down syndrome-associated Alzheimer’s disease (DSAD). The study included data from nearly 3,300 brains that are stored at the National Alzheimer’s 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, similar to people with the other genetic forms of the disease, they were almost assured the diagnosis: Nearly 95% of the people in the studies with two copies of the APOE4 gene had the biology of Alzheimer’s disease 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 creation of beta amyloid plaques in the brain — having one or two copies of this gene doesn’t always lead to cognitive decline. Rarely, people can have APOE4 and have a lot of beta amyloid in their brain but not have symptoms, perhaps because of other genetic or environmental factors that protect their brains at the same time. In the large dataset of nearly 3,300 brains kept by the National Alzheimer’s Coordinating Center, for example, 273 individuals had two copies of the APOE4 gene, and 240, or 88%, had dementia.
When people with two copies of APOE4 do 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 buildup of beta amyloid and tau in their brains followed almost the same trajectory as has been noted in people with other inherited forms of the disease. Their disease was more severe earlier in life.
In all the inherited forms of the disease, “there are striking, striking similarities in the way the disease progresses and the symptoms it gets,” said lead study author Dr. Juan Fortea, a neurologist and director of the Memory Unit of the Neurology Department at Hospital de la Santa Creu i Sant Pau in Barcelona, in a news briefing.
Fortea and his co-authors argue that for these reasons, having two copies of the APOE4 gene should be considered a genetic form of the disease, not merely a risk for it.
Dr. Charles Bernick, associate medical director of the Cleveland Clinic Lou Ruvo Center for Brain Health, 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.
Shifting understanding of genetic risks
The strength of APOE4’s role in the development of Alzheimer’s wasn’t recognized earlier, the researchers think, because APOE4 also plays an important role in heart health, and they think many people with two copies of the gene probably died from cardiovascular causes before they developed Alzheimer’s. Previous studies had estimated that 30% to 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 having two copies of APOE4 assured that a person would see beta amyloid and tau build up in their brains, having just 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 semi-dominant, Fortea said. Other diseases in which genes show semi-dominance 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 don’t usually have symptoms, but they may be more likely to have heat stroke or muscle breakdown during strenuous exercise, and they can experience pain crises under certain conditions.
Classifying APOE4 as an inherited form of the disease has some big implications. First, it would mean that a far greater proportion of Alzheimer’s cases are caused by genes than has been previously understood.
Before APOE4, the only gene changes recognized to cause Alzheimer’s were associated with early-onset forms of the disease and with Down’s syndrome. They accounted for about 2% of Alzheimer’s cases, about 1 in 50.
People with two copies of the APOE4 gene make up about 15% of people who are 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, which would make it one of the most prevalent inherited diseases.
The important takeaway from the study, said Dr. Constantine Lyketsos, director of the memory and Alzheimer’s treatment center at Johns Hopkins, is that Alzheimer’s disease shouldn’t be treated as a monolith. Rather, it shows that there are different forms of the disease that need personalized treatment.
“The point is, we need to start doing precision medicine and breaking it down. Start with genetics,” said Lyketsos, who was not involved in the study.
Gene testing isn’t recommended
It is also likely to change how people who carry the APOE4 gene are diagnosed and treated.
There are tests available to determine a person’s APOE4 status, but they’re not recommended as a routine part of diagnosis. That may need to change, the study authors said.
“The consensus and the guidelines now do not recommend testing for APOE4 and that was because the consensus was that it did not help for the diagnosis,” Fortea said.
APOE testing is recommended for patients who are being evaluated to take new amyloid-clearing medications, such as lecanemab.
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Because Alzheimer’s patients with two copies of the APOE4 gene are at higher risk of serious side effects like brain swelling from these amyloid-clearing medications, some treatment centers have decided not to offer them the drugs, said study author Dr. Reisa Sperling, director of the center for Alzheimer’s Research and Treatment at Brigham and Women’s Hospital.
“I find this very problematic, given these data,” she said, noting that it would be important to do research to see whether it might be possible to find safer dosing or safer treatments for this patient group.
“For me, this just means we need to treat them earlier,” Sperling said, “and this research really suggests that we should be treating them quite early, at a younger age, and at an early stage of pathology because we know they are very, very likely to progress to impairment quickly.”
Dr. Sterling Johnson, a study author who leads the Wisconsin Registry for Alzheimer’s Prevention at the University of Wisconsin, said it would be very important for clinical trials to start to take participants’ APOE4 status into account.
“We may need to start treating these as a separate group in our research papers so that 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 kind of have not been able to before, Johnson said in the news briefing.