May 15, 2024
Carrying the APOE-E4 gene variant, inherited from one or both parents, has long been linked to an increased risk of developing Alzheimer’s disease. Now scientists say that carrying two copies of the worrisome gene variant may represent a distinct form of inherited Alzheimer’s disease.
A study, from researchers in Spain and the United States, found that 95 percent of people who inherit two copies of the gene variant, one from each parent, show signs of Alzheimer’s disease in their brains and spinal fluid. They also tend to develop the disease at younger ages than those with other variants of the APOE gene. Rather than just being a risk factor for Alzheimer’s, inheriting two copies of APOE-E4, the findings suggest, may be an underlying cause of the disease.
“This gene has been known for over 30 years, and it was known to be associated with a higher risk of developing Alzheimer’s disease,” said study leader Dr. Juan Fortea, Director of the Memory Unit of the Neurology Service at the Sant Pau Research Institute in Barcelona. “But now we know that virtually all individuals with this duplicated gene develop Alzheimer’s biology. This is important because they represent between 2 and 3 percent of the population.” The findings were published in Nature Medicine.
Other genes have been linked to inherited forms of Alzheimer’s disease, typically in early-onset cases that appear before age 60. But most of these inherited cases are rare, accounting for fewer than 1 percent of Alzheimer’s cases overall.
The APOE-E4 gene variant is far more common. An estimated 15 to 25 percent of the general population carries one copy of the gene variant, which is present in about half of Alzheimer’s cases overall. While only 2 to 3 percent of the population carries two copies of APOE-E4, those with two copies of the gene variant account for 15 to 20 percent of Alzheimer’s cases overall.
The APOE gene is involved in making a protein that helps carry cholesterol and other types of fats in the bloodstream. The most common variant, APOE-E3, has a neutral effect on the risk of developing Alzheimer’s, while the APOE-E2 variant protects against Alzheimer’s onset.
For the new study, scientists looked at medical data from more than 10,000 men and women, over 500 of whom carried two copies of APOE-E4. They also looked at brain pathology from a dataset that included more than 3,000 brain donors. By age 55, over 95 percent of patients with two copies of APOE-E4 had brain changes and other biological markers characteristic of Alzheimer’s disease. By age 65, most had elevated levels of beta-amyloid, a toxic protein that clumps together to form the telltale brain plaques of Alzheimer’s. Many had also begun to experience memory problems and other symptoms of dementia by their mid-60s. Those without the APOE-E4 variant who developed Alzheimer’s typically didn’t start to experience significant clinical symptoms until their 70s.
Not everyone who carries two copies of the APOE-E4 gene will go on to develop memory loss and other clinical symptoms of Alzheimer’s. But the vast majority will develop brain changes typical of the disease, the study found, and many will subsequently develop symptoms.
Recognition that carrying two copies of the APOE-E4 gene variant represents a new genetic form of Alzheimer’s could open the way to develop new treatments that target the gene specifically. It could also spur research into new and better ways to prevent or delay the onset of Alzheimer’s in these patients or even guide the course of treatment. Leqembi, for example, a new drug that has been shown to modestly slow the course of Alzheimer’s, may have a heightened risk of potentially fatal side effects in people who carry two copies of the APOE-E4 gene, and some medical centers do not offer the drug to these patients.
Still, carrying two copies of APOE-E4 likely accounts for only one in six cases of Alzheimer’s disease overall. The underlying cause of most cases of Alzheimer’s disease remains unknown. Until more effective treatments are found, taking lifestyle steps to reduce risk can be an important for helping to curb Alzheimer’s onset. Being physically active, eating a heart healthy diet, maintaining a healthy weight, staying socially engaged, keeping hearing and vision intact, and not smoking have been shown to prevent up to 40 percent of known cases of Alzheimer’s disease and other forms of dementia.
By ALZinfo.org, The Alzheimer’s Information Site. Reviewed by Eric Schmidt, Ph.D. Fisher Center for Alzheimer’s Research Foundation at The Rockefeller University.
Source: Juan Fortea, Jordi Pegueroles, Daniel Alcolea, et al: “APOE4 homozygozity represents a distinct genetic form of Alzheimer’s disease.” Nature Medicine, May 6, 2024
