Study Identifies Genetic Variant as a Clear Cause of Alzheimer's—Does This Mean You Should Get Tested?

Recent research suggests that some Alzheimer’s cases can be traced back to a direct genetic cause, raising questions about the future of diagnosis and treatment.

Currently, most cases of Alzheimer’s don't have an identifiable underlying cause. Still, scientists have long known that inheriting a copy of a gene variant called APOE4 can elevate the chances of a diagnosis. People with two copies, who make up 2 to 5% of the general population, are at even higher risk. 

Now, researchers are proposing that having two copies of APOE4 doesn’t just raise the odds of developing the disease but can, in fact, cause it. 

“This expands our understanding to encompass 15 to 20% of cases where we can identify a genetic cause,” Juan Fortea, PhD, who led the study at the Sant Pau Research Institute in Barcelona, Spain, told Health. “This is crucial as it opens new avenues for specific research and interventions, enhancing our grasp on the disease’s underlying mechanisms.”

The new findings, published in the journal Nature Medicine, also mean more people could receive an Alzheimer’s diagnosis before they begin to show any symptoms. Medical experts say this research will hopefully spur the development of treatments and kickstart targeted clinical trials focused on this population.

“Our findings represent more than scientific progress,” Fortea said. “They are a step towards translating hope into tangible strategies for those affected by Alzheimer's.”

Here’s how the scientists made their discovery, what it could mean for Alzheimer’s treatment, and whether experts advise testing to see if you have the genetic variant.

Researchers analyzed data from 3,297 brains donated for medical research and 10,000 people participating in U.S. and European Alzheimer’s studies.

They found that 273 people had two copies of APOE4. Of those, nearly all showed signs of Alzheimer’s in their brains. The researchers concluded that having two copies of APOE4 should now be considered a genetic form of Alzheimer’s.

The team also found that patients developed Alzheimer’s pathology relatively young.

By age 55, participants with two APOE4 copies were accumulating more amyloid, a protein that forms plaques in the brain that signal Alzheimer’s, than those with just one copy of another form of APOE—the APOE3 allele. By 65, almost all had abnormal levels of amyloid. And many started developing symptoms of Alzheimer’s at age 65, younger than most people without the APOE4 variant.

“The study beautifully demonstrates that having two copies of the APOE4 gene predictably leads to pathological changes in the brain in almost every carrier,” Jim Ray, PhD, director of the Belfer Neurodegeneration Consortium at MD Anderson Cancer Center who was not involved in the study, told Health. 

Fortea acknowledged the study had notable limitations, including that almost all participants were White. Because the risk associated with APOE varies across different ethnic backgrounds, the findings might not be universally applicable.

Ray and other experts said that the research could be a catalyst for the development of new drugs to treat people with two copies of the gene variant—both before and after they experience symptoms.

“This study argues strongly that we need therapeutics targeting the APOE4 gene for the millions of people who are at risk for AD,” he said.

No cure exists for Alzheimer’s, but some medications can temporarily improve symptoms. 

One of the more common prescriptions is Leqembi, which works to break apart some of the amyloid in the brain. Experts have been hesitant to widely prescribe the drug, however, because it carries an FDA-required black-box warning on the label that “serious and life-threatening events” like bleeding and swelling in the brain can occur, specifically in people with two copies of APOE4. 

“We are at the threshold of a new era with the advent of disease-modifying treatments, which holds significant promise for those with genetic markers linked to Alzheimer’s,” Fortea said.

The new study raises the question whether asymptomatic people should get tested to determine whether they have two copies of APOE4.

People whose parents were both diagnosed with Alzheimer’s relatively early—most likely in their 60s—are most likely to carry two APOE4 genes.

Currently, genetic tests aren’t routinely used in clinical settings to diagnose or predict the risk of developing Alzheimer’s. Many experts don’t advise it because of the complexities involved in interpreting the results. 

Fortea said she doesn’t think the new study should change anything regarding testing recommendations.

“At this stage, our findings do not advocate for changes in testing practices for Alzheimer’s,” Fortea said. “More research is needed, particularly in developing preventive treatments and accurately assessing risk, before we can offer concrete recommendations for genetic testing or counseling in the context of these findings.”

If you are curious about whether you have one or two copies of the APOE4 gene or concerned that you might, consult a doctor or genetic counselor about whether testing might be right for you.