Research suggests genetics may be a cause, not just a risk, for some Alzheimer's patients

Scientists are proposing a new way to understand the genetics of Alzheimer's disease. This means that up to a fifth of patients are thought to have a genetically caused form of Alzheimer's disease.

Currently, the cause of most cases of Alzheimer's disease is not clearly identified. The new designation is study The paper, published Monday, expands the scope of treatment development efforts to include gene therapy and could influence the design of clinical trials.

And while there is currently no treatment for people at that stage, hundreds of thousands of people in the United States alone could be diagnosed with Alzheimer's disease before symptoms of cognitive decline appear if they choose. It could mean something.

Medical experts say the new classification makes this type of Alzheimer's disease one of the most common genetic diseases in the world.

“This reconceptualization that we are proposing will affect a significant minority of people,” said study author Dr. Juan Fortea, director of the Sant Pau Memory Unit in Barcelona, ​​Spain. Stated. “Sometimes people say we don't know the cause of Alzheimer's disease, but this means that in about 15 to 20 percent of cases, “we can trace the cause, and it's genetic,” he said. ”

The idea involves a gene variant called APOE4. Scientists have long known that if he inherits one copy of this mutation, he has an increased risk of developing Alzheimer's disease, and that the risk increases significantly for people who have two copies of him inherited from their parents. I was there.

of new researchThe paper, published in the journal Nature Medicine, analyzed data from more than 500 people with two copies of APOE4, which is significantly larger than previous studies. Researchers found that nearly all of these patients developed the biological pathology of Alzheimer's disease, and the two copies of APOE4 may now be considered as a cause of Alzheimer's disease, rather than just a risk factor. The authors say it should.

The study also found that patients developed Alzheimer's disease at a relatively young age. By age 55, more than 95% had biological markers associated with the disease. By age 65, nearly all had abnormal levels of a protein called amyloid, which forms the plaques in the brain that are a hallmark of Alzheimer's disease. And many began developing symptoms of cognitive decline at age 65, which is younger than most people without the APOE4 mutation.

“Importantly, these patients often develop symptoms 10 years earlier than other forms of Alzheimer's disease,” said Dr. McConlogue, a neurologist at Massachusetts General Brigham Hospital in Boston and the author of the study. said Dr. Leisa Sperling, author of .

She added: “By the time they are picked up and clinically diagnosed, they are often younger and therefore have more medical conditions.”

People with two copies, known as APOE4 homozygotes, make up 2 to 3 percent of the general population but an estimated 15 to 20 percent of people with Alzheimer's disease, experts said. People with one copy make up about 15 to 25 percent of the general population and about 50 percent of people with Alzheimer's disease.

The most common variant is called APOE3 and is thought to have a neutral effect on Alzheimer's disease risk. Approximately 75 percent of the general population has one copy of APOE3, and more than half of the general population has two copies.

Alzheimer's disease experts not involved in the study said that classifying this two-copy condition as genetically determined Alzheimer's disease could be difficult because targeting amyloid, which has recently been a major focus in the field. It said it could have a significant impact, including by accelerating drug development beyond reducing treatments.

Dr. Samuel Gandy, an Alzheimer's disease researcher at Mount Sinai in New York who was not involved in the study, said patients with two copies of APOE4 are at a much higher safety risk with anti-amyloid drugs. Ta.

When the Food and Drug Administration approves an anti-amyloid drug this group Last year, black box warning The label says the drug can cause “serious and life-threatening events” such as swelling and bleeding in the brain, especially in people who have two copies of APOE4. Some treatment centers have decided not to offer Rekenbi IV to such patients.

Dr. Gandy and other experts believe that classifying these patients as having a distinct genetic form of Alzheimer's disease will increase interest in developing safe and effective drugs for patients who do not yet have symptoms. Current efforts to prevent cognitive decline in people will become more urgent, he said. .

“Instead of saying we can't do anything, let's look for trials,” Dr. Gandy said, adding that such patients should be enrolled in trials at a younger age, given that their disease starts earlier. Ta.

In addition to working on drug development, some researchers also conduct research. gene editing It converts APOE4 into a variant called APOE2, which is thought to protect against Alzheimer's disease.Alternative gene therapy approaches under investigation Includes injection of APOE2 into the patient's brain.

The new study had several limitations, including a lack of diversity that could make the findings difficult to generalize. Most of the patients in the study had European ancestry. Dr. Michael Glacius, a neurologist at Stanford University School of Medicine who was not involved in the study, said that two copies of APOE4 also significantly increase Alzheimer's risk in other ethnicities, but at different levels of risk. .

“One important argument against their interpretation is that the risk of Alzheimer's disease in APOE4 homozygotes varies widely depending on their different genetic ancestry,” said co-author Dr. Glacius. the study As a result, white people with two copies of APOE4 have 13 times the risk of white people with two copies of APOE3, whereas black people with two copies of APOE4 have a higher risk than black people with two copies of APOE3. The risk was found to be 6.5 times greater.

“This has important implications for counseling patients about their genetic risk for Alzheimer's disease derived from their ancestry, and perhaps some of the undiscovered genetics and biology that drives this large risk difference.” '' he said.

Current genetic understanding of Alzheimer's disease suggests that less than 2% of cases are thought to be genetically caused.Some of those patients Inherited a mutation in one of three genes Symptoms may appear as early as your 30s or 40s. Another person with Down syndrome has three copies of the chromosome that contains the protein that leads to what is called Down syndrome. Alzheimer's disease associated with Down syndrome.

Dr. Sperling said the genetic mutations in these cases are thought to promote amyloid accumulation, while APOE4 is thought to prevent its removal.

Under the researchers' proposal, having one copy of APOE4 would still be considered a risk factor and would not be sufficient to cause Alzheimer's disease, Dr. Fortea said. Experts say it's unusual for the disease-causing variant to follow a genetic pattern known as “semi-dominant” where there are two copies of it, but having just one copy only increases the risk.

The new recommendations raise questions about whether people should get tested to determine if they are infected with the APOE4 variant.

Until there is a cure for people with two copies of APOE4, or treatments are tested to prevent the onset of dementia, Dr. Glacius said, “If you have no symptoms, your APOE4 My recommendation is that you should never try to figure out the situation.”

He added: “At this point it only causes sadness.”

Dr. Sperling said finding ways to help these patients can't be done quickly, adding: “These patients are in desperate situations, and I see it too often in their parents, and they really need treatment. ” he added.