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A subset of Alzheimer’s cases may be caused by two copies of a single gene, new research shows

WASHINGTON— For the first time, researchers have identified a genetic form of late-stage Alzheimer’s disease – in people who inherit two copies of a worrisome gene.

Scientists have long known that a gene called APOE4 is one of many things that can increase the risk of Alzheimer’s disease in people, even as they simply get older. The vast majority of Alzheimer’s cases occur after age 65. But research published Monday suggests that in people who carry not just one but two copies of the gene, it is more than just a risk factor but an underlying cause of the mind-robbing disease.

The results represent a distinction with “profound implications,” said Dr. Juan Fortea, who led the study at the Sant Pau Research Institute in Barcelona. Spain.

They include: Symptoms may appear seven to 10 years earlier than in other older adults who develop Alzheimer’s disease.

An estimated 15% of Alzheimer’s patients carry two copies of APOE4, meaning these cases “can be traced to one cause, and the cause is in the genes,” Fortea said. Previously, it was thought that the genetic forms of Alzheimer’s disease were only forms that occur at much younger ages and account for less than 1% of all cases.

Scientists say the research makes developing treatments that target the APOE4 gene critical. Some doctors are not offering the only drug shown to slightly slow the disease, Leqembi, to people with the gene pair because they are particularly vulnerable to dangerous side effects, Dr. Reisa Sperling, co-author of the study at Harvard-affiliated Brigham and Women’s Hospital in Boston.

Sperling is looking for ways to prevent or at least delay Alzheimer’s, and “this data tells me, wow, what an important group it is to take care of before they become symptomatic.”

But the news doesn’t mean people should line up for genetic testing. “It’s important not to scare everyone who has a family history of Alzheimer’s disease” because this gene duo is not the cause of most cases, she told The Associated Press.

More than 6 million Americans and millions more worldwide suffer from Alzheimer’s disease. A handful of genes are known to cause rare early-onset forms, mutations that are passed down through families and trigger symptoms unusually early, at age 50. Some cases are also associated with Down syndrome.

But Alzheimer’s most commonly occurs after age 65, particularly in the late 70s to 80s, and it has long been known that the APOE gene – which also affects the way the body handles fats – is a Role play. There are three main varieties. Most people carry the APOE3 variant, which does not appear to increase or decrease the risk of Alzheimer’s disease. Some carry APOE2, which offers some protection against Alzheimer’s.

APOE4 has long been considered the biggest genetic risk factor for late-life Alzheimer’s, with two copies being more risky than one. It is estimated that about 2% of the world’s population inherited one copy from each parent.

To better understand the gene’s role, Fortea’s team used data from 3,297 brains donated for research and from over 10,000 people in US and European Alzheimer’s studies. They examined symptoms and early signs of Alzheimer’s, such as sticky amyloid in the brain.

People with two copies of APOE4 accumulated more amyloid by age 55 than people with just one copy or the “neutral” gene variant APOE3, they reported in the journal Nature Medicine. By age 65, brain scans showed significant plaque buildup in nearly three-quarters of these double carriers – who were more likely to begin showing Alzheimer’s symptoms at this age than in the 70s or 80s.

Fortea said the underlying biology of the disease is remarkably similar to young inherited forms.

It seems more like “a familial form of Alzheimer’s,” said Dr. Eliezer Masliah from the National Institute on Aging. “It’s not just a risk factor.”

Importantly, not everyone with two APOE4 genes develops Alzheimer’s symptoms, and researchers need to figure out why, Sperling warned.

“It’s not entirely fate,” she said.

The drug Leqembi works by removing some sticky amyloid, but Sperling said it’s not clear whether carriers of two APOE4 genes benefit because they are at such a high risk of a side effect of the drug – dangerous brain swelling and bleeding. One research question is whether it would be better for them to start taking such medications earlier than for other people.

Masliah said other research aims to develop gene therapies or drugs that specifically target APOE4. He said it is also important to understand the effects of APOE4 in different populations because it has been studied primarily in white people of European descent.

As for genetic testing, it is currently typically only used to assess whether someone is a candidate for Leqembi, or for people participating in Alzheimer’s research – particularly studies into possible ways to prevent the disease. Sperling said the people most likely to carry two APOE4 genes have parents who both developed Alzheimer’s relatively early, in their 60s rather than their 80s.

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The Associated Press Health and Science Department receives support from the Science and Educational Media Group of the Howard Hughes Medical Institute. The AP is solely responsible for all content.

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