APOE4 has long been considered the most influential genetic risk for developing Alzheimer’s. A new study takes it a step further, positing that people with two copies of the gene are already living with a unique genetic form of the disease.
Alzheimer’s disease affects one in 10 people over the age of 65. One of the strongest genetic risk factors for developing the disease is the APOE4 gene variant — 25 percent of people are APOE4 heterozygous (they carry one copy of the variant), while 2 percent are homozygous, meaning they carry two copies. It’s rare to carry two copies, but this small group pulls a lot of weight in the broader population of people living with Alzheimer’s: One in every six people with Alzheimer’s is E4 homozygous.
Compared to other variants of the gene like APOE3, the APOE4 variant makes it harder for the brain to clear out beta-amyloid plaques. While many people who have these plaques develop the symptoms of Alzheimer’s, others remain cognitively healthy — and scientists aren’t sure why yet.
People who are E4 homozygous will have a much higher chance of developing the disease — it is far from inevitable. Estimates vary, but carrying two copies of APOE4 means as much as a 60 percent chance of being diagnosed with Alzheimer’s during one’s lifetime.
However, based on new research, some scientists are proposing to redefine being homozygous for APOE4 as a genetic cause — rather than a risk factor — for developing the biological hallmarks of Alzheimer’s disease. Under the controversial, newly proposed definition, Alzheimer’s can be defined solely by biomarkers like beta-amyloid or tau, even in the absence of any symptoms. The American Geriatrics Society wrote that the proposal would lead to over-diagnosis of Alzheimer’s, leading more people to treatments with “limited benefit and high potential for harm.” The society also noted that the financial ties to drugmakers on the committee making these recommendations was “wholly inappropriate.”
In other words, this specific, small set of researchers doesn’t consider people with two copies of ApoE4 to be “at high risk” of developing Alzheimer’s biomarkers in the brain: Rather, they would argue that there is a certainty of these biomarkers developing at some point in the future.
Here’s why they’re making the case that double ApoE4 is equivalent to a guarantee of Alzheimer’s disease: Researchers looked at data from more than 13,336 participants to assess the impact of the APOE4 gene. According to findings published in Nature Medicine in 2024, 95 percent of E4 homozygous participants developed beta-amyloid protein plaques in their brains by age 65. This group also developed memory symptoms an average of 10 years earlier than non-E4 homozygous study participants.
People with two copies of the ApoE4 variant also experienced a sequence of biomarker changes in the brain, an increase in amyloid and tau in the brain as well as shrinkage of the hippocampus which is important for memory, similar to other genetic forms of Alzheimer’s and Down syndrome.
For these reasons, the researchers concluded, having two copies of APOE4 met the criteria for having a genetic form of the disease — though people may have this form and be asymptomatic for years, decades, and possibly even throughout their lives.
“I think this is a somewhat contentious claim because it rests on the assumption that Alzheimer’s disease can be defined entirely by the presence of biomarkers and independent of clinical symptoms,” Neurologist Madhav Thambisetty, a senior investigator at the National Institute on Aging, told Being Patient.
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Dr. Juan Fortea, a neurologist at the Sant Pau Research Institute in Barcelona, who led the study, told Being Patient that some people might develop the hallmark biomarkers in the brain without experiencing cognitive decline.
“It is crucial to note that developing the biological markers of Alzheimer’s does not necessarily equate to developing clinical symptoms of dementia,” Fortea said.
He added that researchers can’t accurately estimate the exact risk of developing the symptoms of Alzheimer’s for people who are homozygous, though he mentioned it would likely be high.
Fortea noted, “These findings might not be universally applicable,” because most of the study participants were of white European descent.
In other ethnicities, carrying two copies of this gene may not increase the risk quite as much. For example, one study found no link between APOE4 and Alzheimer’s risk in a population of American Indians while another found that APOE4 conferred less of a risk for Black compared to white populations.
Meanwhile, studies of people of East Asian descent found that they have an even higher risk of developing Alzheimer’s than white Europeans.
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The study’s limitations
Other researchers who commented on the study on AlzForum pointed to limitations in the study design that could have biased the results.
The study used a biobank to compare the health information of people who had already developed Alzheimer’s to controls. In contrast, some studies that follow individuals over time to see who develops Alzheimer’s usually find a smaller lifetime risk due to APOE4, ranging from 30 to 60 percent.
Should people get genetic testing for the APOE4 gene?
The Barrow Neurological Institute’s Dr. Marwan Sabbagh, who was not involved in the study, said genetic testing for APOE4 is becoming more commonplace.
Knowing APOE4 status helps patients and doctors determine the potential risks and benefits of receiving anti-amyloid treatments, like recently approved Alzheimer’s drug Leqembi. (People who carry one or two copies of the APOE4 gene are at a much higher risk of developing brain swelling or brain bleeds while on drugs of this kind. In the study detailing the findings of the Phase 3 trial, the small subgroup of participants homozygous for APOE4 didn’t appear to benefit from the drug. )
So, Sabbagh and other neurologists may use genetic testing as part of their workflow for symptomatic patients.
Fortea said this heightened risk of ARIA is, in the research group’s opinion, further evidence “of the distinctiveness of this new genetic form of Alzheimer’s disease.”
However, many experts don’t necessarily recommend going off to get APOE4 genetic testing to people who are asymptomatic of Alzheimer’s. The guidelines written by the American College of Medical Genetics and the National Society of Genetic Counselors Testing lay out multiple reasons:
- Carrying one or two copies of the APOE4 gene doesn’t necessarily mean someone will develop the symptoms of Alzheimer’s.
- There is a lack of preventative options for people who test positive.
- Understanding what testing positive means isn’t straightforward: The risk differs based on ethnicity, gender, and other factors and these risks also vary widely between different studies.
Virginia Tech researcher Doris Zallen told Being Patient in a Live Talk that finding out your APOE4 status also has ripple effects on others. Since the gene is inherited, your APOE4 status reveals information about your relatives, siblings, children, or parents who may not have wanted to know their status in the first place.
Sabbagh and Thambisetty noted that there is still no reason to test patients who are cognitively healthy or asymptomatic for the APOE4 gene. However, studying these carriers could help scientists better understand the biology of Alzheimer’s disease.
Thambisetty’s research group recently discovered differences in protein levels in young APOE4 carriers that occurred before the age of symptom onset and used this information to zero in on new drugs to test as treatments.
“I believe that focusing our search on abnormalities in biological pathways in young APOE4 carriers is a promising approach to discovering novel Alzheimer’s disease treatments,” he said.
What’s next for APOE4 research?
Fortea and Sabbagh agree this study provides more support for designing clinical trials based on APOE4 status, which could help find precise drugs that would work better for this subpopulation of patients.
Since APOE4 carriers may benefit less from anti-amyloid drugs like Leqembi, and are at greater risk of side effects, drugmakers are developing treatments specifically for them.
Alzheon is completing a Phase 3 trial of its drug, valiltramiprosate, in patients with two copies of the APOE4 gene. The company expects to present results later this year. Lexeo Therapeutics is in the early stages of testing a new genetic therapy to see whether it can edit out the risk by turning the APOE4 variant into APOE2, which doesn’t pose an increased risk of Alzheimer’s disease.
