For the first time, a genetic form of late-onset Alzheimer's has been identified in people who inherit two copies of a gene that has been a cause of consternation.
Scientists have long known that a gene called APOE4 is one of many factors that can increase the risk of Alzheimer's, besides simply getting older. The vast majority of Alzheimer's cases occur after the age of 65. But a study published Monday 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 the disease that afflicts the mind.
According to Dr. Juan Fortea, who led the study at the Sant Pau Research Institute in Barcelona, Spain, this is a distinction with “profound implications.”
For example: Symptoms may begin seven to 10 years earlier than in other older adults who develop Alzheimer's.
An estimated 15% of Alzheimer's patients carry two copies of APOE4, meaning those cases “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 manifested at much earlier ages and represented less than 1% of all cases.
Scientists say the research makes it essential to develop treatments that target the APOE4 gene. According to Dr. Reisa Sperling, a co-author of the study at Harvard-affiliated Brigham and Women's Hospital in Boston, some doctors do not offer the only drug shown to moderately slow the disease, Leqembi, to people with this gene pair because They are especially prone to a dangerous side effect.
Sperling is looking for ways to prevent or at least delay Alzheimer's, and “this data tells me, wow, what an important group to be able to go after before they become symptomatic.”
But the news doesn't mean people should rush to get a genetic test. “It is important not to scare everyone who has a family history” Alzheimer's because this pair of genes is not behind most cases, he told .
How does genetics affect Alzheimer's?
More than 6 million Americans, and millions more around the world, have Alzheimer's. A handful of genes are known to cause rare forms of “early onset,” mutations passed from parents to children that trigger symptoms at an unusually early age, around age 50. Some cases are also related to Down syndrome.
But Alzheimer's usually appears after age 65, especially between the late 70s and 80s, and the APOE gene, which also affects how the body manages fat, has long been known to play a role. There are three main varieties. Most people carry the APOE3 variant, which appears to neither increase nor decrease the risk of Alzheimer's. Some are carriers of APOE2, which provides some protection against Alzheimer's.
APOE4 has long been considered the greatest genetic risk factor for Alzheimer's later in life, and two copies present more risk 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 from more than 10,000 people in American and European Alzheimer's studies. They examined the symptoms and early manifestations of the disease, such as the presence of 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, according to the report 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 show early symptoms of Alzheimer's around that age rather than in their 70s or 80s.
According to Fortea, the underlying biology of the disease is very similar to that of younger hereditary types.
It looks more like “a familial form of Alzheimer's,” said Dr. Eliezer Masliah of the National Institute on Aging. “It's not just a risk factor.”
It's important to note that not all people with two APOE4 genes develop Alzheimer's symptoms, and researchers need to know why, Sperling said.
“It's not entirely 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 says it's not clear whether carriers of two APOE4 genes benefit, since they are at very high risk for a side effect of the drug: inflammation and dangerous brain bleeds. One question the research raises is whether it would be better for them to start taking these drugs earlier than other people.
According to Masliah, other research aims to develop gene therapies or drugs specifically targeting APOE4. She also noted that it is crucial to understand the effects of APOE4 in diverse populations, since it has been studied primarily in white people of European descent.
As for genetic testing, for now they are usually only used to evaluate whether someone is a candidate for Leqembi or for people enrolling in Alzheimer's research, especially studies on possible ways to prevent the disease. According to Sperling, people most likely to be carriers of two APOE4 genes had parents who suffered from Alzheimer's relatively early, in their 60s rather than their 80s.
