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.
Authors of the study, published Monday in the journal Nature Medicine, say this could even be considered a separate, hereditary form of the disease, and may require different approaches to testing and treatment.
Among people diagnosed with Alzheimer’s, researchers recognize familial forms of the disease and sporadic cases. Most cases are believed to be sporadic and develop later in life. Familial forms, caused by mutations in one of three genes, tend to strike earlier and are known to be rare. They represent about 2% of all Alzheimer’s diagnoses, or about 1 in 50 cases.
Under the new paradigm, 1 in 6 cases of Alzheimer’s disease would be considered hereditary or familial.
This changing appreciation 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 transports cholesterol throughout the body and brain and is thought to play a role in depositing or sloughing off sticky beta-amyloid plaques that are a hallmark of Alzheimer’s disease.
There are three types of APOE genes that a person can carry. One known as APOE2 is believed 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 known that people with at least one copy of the APOE4 gene have an increased risk of developing Alzheimer’s disease, while people with two copies are still at higher risk.
Now researchers say that APOE4 should not just be recognized as a risk factor – it should be seen as an inherited form of the disease, which virtually guarantees that someone who has two copies will develop the biological changes in their brain that are related with Alzheimer’s disease.
Research into the role of genes in Alzheimer’s disease
In the new study, researchers from Spain and the United States compared people in clinical trials with two copies of the APOE4 gene with people with other forms of the APOE gene.
They also compared people with two copies of APOE4 with people with other inherited forms of the disease: early autosomal dominant Alzheimer’s disease (ADAD) and Down syndrome-associated Alzheimer’s disease (DSAD). The study included data from nearly 3,300 brains stored at the National Alzheimer’s Coordinating Center and data from another 10,000 people who participated in five different 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 also virtually guaranteed a diagnosis : Nearly 95% of people in the studies with two copies of the APOE4 gene had Alzheimer’s disease biology 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 beta-amyloid plaques in the brain – having one or two copies of this gene does not always lead to cognitive decline . In rare cases, people may have APOE4 and have a lot of beta-amyloid in their brain but have no symptoms, perhaps because of other genetic or environmental factors that are simultaneously protecting their brain. For example, in the large data set of nearly 3,300 brains maintained by the National Alzheimer’s Coordinating Center, 273 individuals 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 disease about ten years earlier – around age 65 – compared to 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 in people with other inherited forms of the disease. Their illness was more severe earlier in their lives.
Across all hereditary forms of the disease, “there are striking, striking similarities in the way the disease progresses and the symptoms it presents,” says 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 i Sant Pau in Barcelona, Spain, during 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, and not just a risk for it.
Dr. Charles Bernick, associate professor of the Lou Ruvo Center for Brain Health at Cleveland Clinic, said the study was important because it really showed how powerful having two copies of the APOE4 gene was.
“It really stimulates a disease process,” says Bernick, who was not involved in the study.
Shifting understanding of genetic risk
The strength of APOE4’s role in the development of Alzheimer’s disease was not previously recognized, the researchers believe, because APOE4 also plays an important role in heart health, and they think that many people with two copies of the gene probably died of cardiovascular causes before developing. Alzheimer’s. Previous studies had estimated that 30-35% 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 ensured a person would see beta-amyloid and tau build up in their brain, having just one copy of the gene also increased a person’s risk — but not as much as having 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. For example, in sickle cell disease, two copies of the gene cause sickle cell disease, but one copy causes sickle cell disease. People with sickle cell disease typically have no symptoms, but they are more likely to experience heat stroke or muscle wasting during strenuous exercise, and under certain conditions they may experience pain crises.
Classifying APOE4 as an inherited form of the disease has some major implications. First, this would mean that a much larger proportion of Alzheimer’s cases are caused by genes than previously thought.
Before APOE4, the only gene changes recognized as causing Alzheimer’s disease were associated with early-onset forms of the disease and with Down syndrome. They were responsible 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 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 common hereditary diseases.
Gene testing is not currently recommended
It will also likely change the way people who carry the APOE4 gene are diagnosed and treated.
There are tests available to determine a person’s APOE4 status, but they are 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 with diagnosis,” Fortea said.
APOE testing is recommended for patients being evaluated to use new amyloid-clearing medications such as lecanemab.
Because Alzheimer’s patients with two copies of the APOE4 gene are at greater risk of serious side effects such as brain swelling from new amyloid-clearing drugs, 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 conduct research to see if it might be possible to find safer dosages or safer treatments for this patient group.
“To me, this just means we need to treat them earlier,” Sperling said, “and this research really suggests that we need to treat them very early, at a younger age and early in the pathology, because we know they being ill. It is very, very likely that there will be a restriction soon.”
Dr. Sterling Johnson, head of the Wisconsin Registry for Alzheimer’s Prevention at the University of Wisconsin, said it would be very important for clinical trials to take into account participants’ APOE4 status.
“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 the symptoms” in people with two copies of the APOE4 gene, in a way that we actually haven’t . previously possible, Johnson, who is also an author of the study, said in the news briefing.
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