Almost All People With Two Copies of This Genetic Variant Develop Signs of Alzheimer’s Disease, Study Finds

The research focused on a variant called APOE4 and largely looked at people of European ancestry—risk levels are different for other groups, the authors say

An MRI of a brain of a person with Alzheimer's disease
An MRI of a brain of a person with Alzheimer's disease. A new study suggests having two copies of a genetic variant called APOE4 is a cause of the disease, not just a risk factor for it. BSIP / UIG Via Getty Images

Almost all people with two copies of a genetic variant called APOE4 show signs of Alzheimer’s disease, according to a new study of people predominantly of European ancestry.

The findings suggest that people with two copies of the gene—who are called APOE4 homozygotes—have a distinct genetic form of Alzheimer’s. The research points to a need for targeted prevention strategies, clinical trials and treatments, scientists write in the paper published Monday in the journal Nature Medicine.

Alzheimer’s disease is a brain disorder that erodes memory and cognitive function. It may affect more than six million people in the United States, and it’s the seventh highest cause of death in the country.

Scientists don’t fully understand what leads to the disease. But they have identified a few genetic forms of Alzheimer’s, including an early-onset form caused by mutations in three genes, per the study. Other genetic cases are linked to Down syndrome—about half of people with Down syndrome in their 60s have Alzheimer’s.

A number of genetic variants, including APOE4, have been tied to an increased risk for the disease. But with the new paper, researchers suggest having two copies of the APOE4 variant is more than just a risk factor—it might actually be a cause.

“This reconceptualization that we’re proposing affects not a small minority of people,” lead author Juan Fortea, a neurologist at the Sant Pau Memory Unit in Spain, says to the New York Times’ Pam Belluck.

People with two copies of APOE4 make up 2 percent of the general population, according to the study. But the findings suggest that around 15 percent of people with Alzheimer’s have two copies of the variant. That means those cases “can be tracked back to a cause, and the cause is in the genes,” Fortea tells Lauran Neergaard of the Associated Press.

Not all researchers agree that people with two copies of APOE4 have a unique type of the disease.

“I do not see anything in this paper to justify the claim that carrying two copies of APOE4 represents some ‘distinct genetic form’ of Alzheimer’s disease,” David Curtis, a geneticist at University College London who did not contribute to the findings, tells the Guardian’s Nicola Davis. “No matter how many [copies] of APOE4 one carries, the underlying disease processes seem similar across cases of Alzheimer’s disease, suggesting that any effective treatment and prevention strategies, which have yet to be developed, would have broad applicability.”

To reach their conclusion, the researchers looked at data from 3,297 donated brains and 10,039 individuals. They found that 273 brain donors and 519 of the participants carried two copies of the APOE4 variant—and almost all of these people had signs of Alzheimer’s disease.

Compared to people with two copies of APOE3, a variant of the APOE gene that has no effect on Alzheimer’s risk, those with two copies of APOE4 had significantly more biomarkers of the disease after turning 55.

By the age of 65, almost all members of this group had abnormal levels of a protein called amyloid—high amounts of which is tied to Alzheimer’s—in their cerebrospinal fluid, and 75 percent of them showed abnormal amyloid levels in brain scans. Their symptoms also started at an earlier age than others—around 65 years old, on average. Symptom onset occurred in a narrow age range, making it predictable.

The study shows that people with two copies of APOE4 “meet the three main characteristics of genetically determined [Alzheimer’s disease],” the authors write: a high prevalence of the disease among the group, a predictability of symptom onset and predictable biomarkers and clinical changes.

Samuel Gandy, an Alzheimer’s researcher at Mount Sinai who did not contribute to the findings, tells Reuters’ Julie Steenhuysen that the results show people with two copies of APOE4 need to be enrolled in trials that aim to prevent the disease before symptom onset.

People with two copies of APOE4 are at heightened risk for side effects from the drug lecanemab, which is used for treating Alzheimer’s. Reisa Sperling, a study co-author and neurologist at Massachusetts General Hospital, tells the Guardian there should be further research into drugs linked to side effects, as well as studies on other strategies for treatment and prevention.

The new study notes that APOE4 poses less of a risk for Black people than white people, and since all study participants were from the U.S. or Europe and were predominantly white, future research should include more diverse populations.

“One important argument against their interpretation is that the risk of Alzheimer’s disease in APOE4 homozygotes varies substantially across different genetic ancestries,” Michael Greicius, a neurologist at Stanford University who was not involved in the work, tells the New York Times. “This has critical implications when counseling patients about their ancestry-informed genetic risk for Alzheimer’s disease,” he tells the publication, “and it also speaks to some yet-to-be-discovered genetics and biology that presumably drive this massive difference in risk.”

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