For the first time, researchers have identified a genetic form of late-in-life Alzheimer鈥檚 disease 鈥� in people who inherit two copies of a worrisome gene.
Scientists have long known a is one of many things that can increase people鈥檚 risk for Alzheimer's, including simply getting older. The vast majority of Alzheimer鈥檚 cases occur after age 65. But research published Monday suggests that for people who carry not one but two copies of the gene, it's more than a risk factor, it's an underlying cause of the mind-robbing disease.
The findings mark a distinction with 鈥減rofound implications,鈥� said Dr. Juan Fortea, who led the study at the Sant Pau Research Institute in Barcelona, Spain.
Among them: Symptoms can begin seven to 10 years sooner than in other older adults who develop Alzheimer鈥檚.
An estimated 15% of Alzheimer鈥檚 patients carry two copies of APOE4, meaning those cases 鈥渃an be tracked back to a cause and the cause is in the genes,鈥� Fortea said. Until now, genetic forms of Alzheimer鈥檚 were thought to be only types that strike at much younger ages and account for less than 1% of all cases.
Scientists say the research makes it critical to develop treatments that target the APOE4 gene. Some doctors won鈥檛 offer the only drug that has been shown to modestly slow the disease, Leqembi, to people with the gene pair because they鈥檙e especially prone to a dangerous side effect, said Dr. Reisa Sperling, a study co-author at Harvard-affiliated Brigham and Women鈥檚 Hospital in Boston.
Sperling hunts ways to prevent or at least delay Alzheimer鈥檚 and 鈥渢his data for me says wow, what an important group to be able to go after before they become symptomatic.鈥�
But the news doesn鈥檛 mean people should race for a gene test. 鈥淚t鈥檚 important not to scare everyone who has a family history鈥� of Alzheimer鈥檚 because this gene duo isn鈥檛 behind most cases, she told The Associated Press.
How do genetics affect Alzheimer's?
More than 6 million Americans, and millions more worldwide, have Alzheimer鈥檚. A handful of genes are known to cause rare 鈥渆arly-onset鈥� forms, mutations passed through families that trigger symptoms unusually young, by age 50. Some cases also are linked to Down syndrome.
But Alzheimer鈥檚 most commonly strikes after 65, especially in the late 70s to 80s, and the APOE gene 鈥� which also affects how the body handles fats -- was long known to play some role. There are three main varieties. Most people carry the APOE3 variant that appears to neither increase nor decrease Alzheimer鈥檚 risk. Some carry APOE2, which provides some protection against Alzheimer鈥檚.
APOE4 has long been labelled the biggest genetic risk factor for late-in-life Alzheimer鈥檚, with two copies risker than one. About 2% of the global population is estimated to have inherited a copy from each parent.
Research points to a cause for a subset of Alzheimer's
To better understand the gene鈥檚 role, Fortea鈥檚 team used data from 3,297 brains donated for research and from over 10,000 people in U.S. and European Alzheimer鈥檚 studies. They examined symptoms and early hallmarks of Alzheimer鈥檚 such as sticky amyloid in the brain.
People with two APOE4 copies were accumulating more amyloid at age 55 than those with just one copy or the 鈥渘eutral鈥� APOE3 gene variety, they reported in the journal Nature Medicine. By age 65, brain scans showed significant plaque buildup in nearly three-quarters of those double carriers 鈥� who also were more likely to have initial Alzheimer鈥檚 symptoms around that age rather than in the 70s or 80s.
Fortea said the disease's underlying biology was remarkably similar to young inherited types.
It appears more like 鈥渁 familial form of Alzheimer鈥檚,鈥� said Dr. Eliezer Masliah of the National Institute on Aging. 鈥淚t is not just a risk factor.鈥�
Importantly, not everyone with two APOE4 genes develops Alzheimer鈥檚 symptoms and researchers need to learn why, Sperling cautioned.
鈥淚t鈥檚 not quite destiny,鈥� she said.
How the new findings may affect Alzheimer's research and treatment
The drug Leqembi works by clearing away some sticky amyloid but Sperling said it鈥檚 not clear if carriers of two APOE4 genes benefit because they have such a high risk of a side effect from the drug 鈥� dangerous brain swelling and bleeding. One research question is whether they鈥檇 do better starting such drugs sooner than other people.
Masliah said other research aims to develop gene therapy or drugs to specifically target APOE4. He said it's also crucial to understand APOE4鈥檚 effects in diverse populations since it鈥檚 been studied mostly in white people of European ancestry.
As for gene tests, for now they鈥檙e typically used only to evaluate if someone鈥檚 a candidate for Leqembi or for people enrolling in Alzheimer鈥檚 research 鈥� especially studies of possible ways to prevent the disease. Sperling said the people most likely to carry two APOE4 genes had parents who both got Alzheimer鈥檚 relatively early, in their 60s rather than 80s.
___
The Associated Press Health and Science Department receives support from the Howard Hughes Medical Institute鈥檚 Science and Educational Media Group. The AP is solely responsible for all content.
