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Alzheimer's disease is more likely to be inherited than previously known, according to a new study that sheds more light on a gene known to be associated with common dementia.
Authors of the study, published Monday in the journal Nature Medicine, say it may be considered a distinct, genetic disorder that may require different diagnostic and treatment approaches.
Among people with Alzheimer's, researchers understand Familial forms of the disease and rare cases. Most cases are considered to be rare, and develop later in life. Familial forms caused by mutations in any of the three genes tend to strike early and are known to be rare, accounting for about 2% of Alzheimer's diagnoses, or about 1 in 50 cases.
Under the new paradigm, 1 in 6 Alzheimer's cases are considered hereditary or familial.
Appreciation of this hereditary risk, According to researchers, the role of a fourth gene in making apolipoprotein E, a lipid-carrying protein known as ApoE, is better understood. APOE metabolizes cholesterol in the body and brain and is thought to play a role in depositing or clearing sticky beta amyloid plaques, one of the hallmarks of Alzheimer's.
over there There are three types A person can carry the APOE gene. One called APOE2 is thought to prevent Alzheimer's disease. APOE3 is considered to be an independent risk factor for the disease.
APOE4, on the other hand, is bad news. It has long been known that people who have at least one copy of the APOE4 gene are more likely to develop Alzheimer's disease, while people who have two copies. It was still high risk..
Now, researchers say that APOE4 shouldn't just be recognized as a risk factor, the disease should be seen as inherited, actually confirming the person who has it. Two copies find biological changes in the brain associated with Alzheimer's disease.
In the new study, researchers from Spain and the United States compared people in a clinical study with two copies of the APOE4 gene to people with other copies 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 (ADD) and Down syndrome-associated Alzheimer's disease (DSD). The study included data from nearly 3,300 brains stored at the National Alzheimer's Coordinating Center and another 10,000 people who participated in five clinical trials.
Not only are people with two copies of the APOE4 gene more likely to develop the biological changes that lead to Alzheimer's disease, similar to people with other genetic forms of the disease, but they are also warranted for the diagnosis: nearly 95% of people. In studies with two copies of the APOE4 gene, they had the biology of Alzheimer's disease at the age of 82.
The authors of the study concluded that APOE4 reliably causes biological changes associated with the disease – the formation of beta amyloid 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 other genetic or environmental factors that are protecting their brain at the same time.. In a cohort of nearly 3,300 brains collected by the National Alzheimer's Coordinating Center, for example, 273 individuals had two copies of the APOE4 gene, and 240, or 88 percent, had dementia.
People with two copies of APOE4 develop symptoms earlier than others. On average, they develop Alzheimer's 10 years earlier — at age 65 — than other people with the APOE gene. Researchers also found that the build-up of beta amyloid and tau in their brains followed a similar pattern seen in people with other forms of the disease. Their illness was very serious earlier in their lives.
Of all the inherited forms of the disease, “there are striking similarities in the way the disease develops and the symptoms they experience,” said Dr. Juan Fortea, MD, neurologist and director of the neurology department's memory unit. At the Hospital de la Santa Cruz i Sant Pau in Barcelona, in a news briefing.
Forti and his co-authors argue that for these reasons, having two copies of the APOE4 gene should be considered a genetic feature rather than just a risk factor for the disease.
Dr. Charles Bernick, associate medical director of the Cleveland Clinic's Lou Ruvo Center for Brain Health, said the study showed how powerful having two copies of the APOE4 gene can be.
Bernick, who wasn't involved in the study, said it “really leads to a disease process.”
Changing the perception of genetic risks
APOE4's role in the development of Alzheimer's was previously unknown, the researchers say, because APOE4 also plays an important role in heart health, and they thought many people with two copies of the gene would likely die from cardiovascular disease. Alzheimer's. Previous studies About 30% to 35% of people with two copies of the APOE4 gene develop mild cognitive impairment or dementia.
Researchers also found a gene-size effect. While having two copies of APOE4 makes a person more likely to develop beta amyloid and tau build-up in their brain, having just one copy of the gene increases a person's risk — but not two copies of that gene.
That means the APOE4 gene is partially dominant, Fortea said. Other diseases in which genes show partial dominance include sickle cell anemia and hypercholesterolemia. For example, in sickle cell, two copies of a gene cause sickle cell disease, but one copy causes sickle cell trait. People with sickle cell trait often have no symptoms, but They can be more During intense exercise, they may experience heat stroke or muscle wasting and in some cases, pain crises.
Classifying APOE4 as an inherited form of disease has some big implications. First, this means that a far greater proportion of Alzheimer's cases are caused by genes than previously understood.
Before APOE4, the only gene mutations known to cause Alzheimer's were those associated with early forms of the disease and Down's syndrome. They account 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 with Alzheimer's, or about 1 in 7 cases of the disease.
About 2% of the population carries two copies of the APOE4 gene, making it one of the most common hereditary diseases.
Dr. Constantine Likesos, director of the Johns Hopkins Memory and Alzheimer's Center, said the important takeaway from the study is that Alzheimer's disease should not be treated as a monolith. Rather, it shows that there are different types of disease that require individualized treatment.
“The main thing is that we have to make the right medicine and start breaking it down. Start with genetics of lyketose, which is not involved in the research.
It may also 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 are. Not recommended As part of a routine examination. That may need to change, say the study authors.
“Consensus and guidelines do not currently recommend testing for APOE4, and this is because consensus does not support the diagnosis,” Fortea said.
APOE testing is recommended for patients being evaluated for new amyloid scavenging drugs. lecanemab.
Because Alzheimer's patients with two copies of the APOE4 gene are at increased risk of serious side effects from these amyloid-clearing drugs, such as brain swelling, some medical centers have decided not to give the drug, said study author Dr. Raysa Sperling. Alzheimer's Research and Treatment Center at Brigham and Women's Hospital.
“Given these data, I find that very problematic,” she said, adding that research is needed to determine if there is a safe dose or safe treatment for this patient group.
“To me, that means we need to treat them earlier,” Sperling said, “and this research suggests that we need to catch them at an early age and at an early stage of pathology because we know they're there.” It is more likely to progress to disability very quickly.
Study author Dr. Sterling Johnson, who leads the Alzheimer's Prevention Program at the University of Wisconsin-Madison, said it's important that clinical trials start taking participants' APOE4 status into account.
“We may need to start treating these as separate groups in our research to really understand the relationship between amyloid and tau and symptoms,” in a way that we don't in people with two copies of the APOE4 gene. “It's been done before,” Johnson said in a news release.