For the first time, researchers have identified a genetic form of Alzheimer's disease later in life, in people who inherit two copies of a worrying gene.
Scientists have long known that a gene called APOE4 is one of many things that can increase people's risk of Alzheimer's, including simply getting older. The vast majority of Alzheimer's cases occur after age 65. But research suggests that for people who carry not one but two copies of the gene, it is more than a risk factor, it is an underlying cause of this mind-stealing disease.
The findings mark a distinction with “deep implications”said Dr. Juan Fortea, who led the study at the Sant Pau Research Institute in Barcelona, Spain.
Among them: Symptoms can begin seven to ten years earlier than in other older adults who develop Alzheimer's.
It is estimated that 15% of Alzheimer's patients carry two copies of APOE4, meaning that these cases “they can be traced back to a cause and the cause is in the genes”Fortea said. Until now, it was thought that genetic forms of Alzheimer's were only types that struck at much younger ages and represented less than 1% of all cases.
Scientists say the research makes it critical to develop treatments that target the APOE4 gene. Some doctors do not offer the only drug shown to modestly slow the disease, Leqembi, to people with the gene pair because they are especially prone to a dangerous side effect, said Dr. Reisa Sperling, a co-author of the study at Harvard.
Sperling is looking for ways to prevent or at least delay Alzheimer's, and “this data to me says, wow, what an important group to be able to target before they become symptomatic.”
But the news doesn't mean people should compete for a genetic test. “It's important not to scare everyone who has a family history” of Alzheimer's because this genetic duo is not behind most cases, he said.
HOW DO GENETICS AFFECT ALZHEIMER'S?
More than 6 million Americans and millions more around the world suffer from Alzheimer's. A handful of genes are known to cause rare forms of “early appearance”, mutations passed from parents to children that trigger symptoms unusually young, around age 50. Some cases are also related to Down syndrome.
But Alzheimer's appears most frequently after age 65, especially between ages 70 and 80, and the APOE gene, which also affects how the body handles fat, has long been known to play some role. There are three main varieties. Most people carry the APOE3 variant which does not appear to increase or decrease the risk of Alzheimer's. Some carry APOE2, which provides some protection against Alzheimer's.
APOE4 has long been labeled as the biggest genetic risk factor for Alzheimer's later in life, with two copies more risky than one. It is estimated that around 2% of the world's population has inherited a copy from each parent.
RESEARCH POINTS TO A CAUSE FOR A SUBSET OF ALZHEIMER'S
To better understand the gene's role, Fortea's team used data from 3,297 brains donated for research and more than 10,000 people in Alzheimer's studies in the United States and Europe. They examined the symptoms and early features of Alzheimer's, such as sticky amyloid in the brain.
People with two copies of APOE4 accumulated more amyloid by age 55 than those with a single copy or the “neutral” variety of the APOE3 gene, they reported in the journal Nature Medicine. At age 65, brain scans showed significant plaque buildup in nearly three-quarters of the double carriers, who were also more likely to have early symptoms of Alzheimer's around that age than between 70 and 80 years old.
Fortea said the underlying biology of the disease was remarkably similar to that of young hereditary types.
It looks more like “a familial form of Alzheimer's,” said Dr. Eliezer Masliah of the National Institute on Aging. “It is not just a risk factor”.
Importantly, not all people with two APOE4 genes develop Alzheimer's symptoms, and researchers need to know why, Sperling said.
“It’s not exactly destiny,” he said.
HOW NEW FINDINGS MAY AFFECT ALZHEIMER'S RESEARCH AND TREATMENT
The drug Leqembi works by removing some of the sticky amyloid, but Sperling said it's not clear whether carriers of two APOE4 genes benefit because they are at very high risk for a side effect of the drug: dangerous inflammation and bleeding in the brain.
One research question is whether they would do better if they started taking such medications earlier than other people.
Masliah said other research aims to develop gene therapy or drugs that specifically target APOE4. She said it's also crucial to understand the effects of APOE4 in diverse populations, as it has primarily been studied in white people of European descent.
As for genetic testing, for now they are typically used only to evaluate whether someone is a candidate for Leqembi or for people enrolling in Alzheimer's research, especially studies on possible ways to prevent disease. Sperling said people most likely to carry two APOE4 genes had parents who got Alzheimer's relatively early, in their 60s rather than their 80s.
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