Study details

For the study, researchers analyzed pathological data from 3,297 brain donors and biomarkers and clinical data from 10,039 people, including over 500 people with two copies of APOE4, a gene variant that has long been known to increase a person's risk of developing Alzheimer's.

The researchers found that nearly every patient with two copies of APOE4 developed the biological pathology of Alzheimer's. By age 55, more than 95% of the patients had biological markers associated with Alzheimer's, and by age 65, nearly every patient had abnormal levels of amyloid proteins, a hallmark of Alzheimer's. Many of the patients also started developing symptoms of cognitive decline at age 65, which is younger than most patients without any form of the APOE4 variant.

"The critical thing is that these individuals are often symptomatic 10 years earlier than other forms of Alzheimer's disease," said Reisa Sperling, a neurologist at Mass General Brigham and an author on the study.

"By the time they are picked up and clinically diagnosed, because they're often younger, they have more pathology," she added.

As a result of the study, the authors suggested that having two copies of APOE4 should be considered a cause of Alzheimer's disease rather than just a risk factor.

People with two copies of APOE4, known as APOE4 homozygotes, make up around 2 to 3% of the general population but make up between 15 and 20% of people with Alzheimer's dementia, experts said. People with one copy of APOE4 make up 15 to 25% of the general population and around 50% of Alzheimer's patients.

Discussion

Establishing that two copies of APOE4 cause Alzheimer's means that thousands of people in the United States could receive an Alzheimer's diagnosis before they develop any symptoms of cognitive decline, the New York Times reports.

Experts also said the new classification would make Alzheimer's one of the most common genetic disorders in the world.

"This reconceptualization that we're proposing affects not a small minority of people," said Juan Fortea, director of the Sant Pau Memory Unit in Barcelona, Spain, and an author on the study. "Sometimes we say that we don't know the cause of Alzheimer's disease," he added, but this reclassification would mean that around 15 to 20% of cases "can be tracked back to a cause, and the cause is in the genes."

Experts noted that such a reclassification would have major implications, including encouraging the development of drugs beyond the field's current focus on treatments that reduce amyloid proteins.

Samuel Gandy, an Alzheimer's researcher at Mount Sinai, as well as other experts, noted that classifying patients as having a genetic form of Alzheimer's would likely galvanize interest in developing drugs that are safe and effective for them and add urgency to efforts to prevent cognitive decline in patients not yet exhibiting symptoms.

"Rather than say we have nothing for you, let's look for a trial," Gandy said, adding that these patients should be included in trials at younger ages.

"We have to think about how we can treat APOE4/4 carriers," Sperling said. "These individuals are desperate. They've seen [Alzheimer's disease] in both of their parents often and really need therapies. We can see that amyloid is a major driver in this population in particular, and I hope we ... find ways to treat them safely, and especially work on prevention trials."

Some experts were skeptical of the claims of the study, however.

"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. It has been known for decades that APOE4 is a strong risk factor for Alzheimer's disease," said David Curtis, a researcher at the University College London Genetics Institute. "No matter how many alleles of APOE4 one carries, the underlying disease processes seem similar across cases of Alzheimer's disease."

The study also came with limitations, including a lack of diversity, as most of the patients in the study had European ancestry.

According to Michael Greicius, a neurologist at Stanford University School of Medicine, while having two copies APOE4 greatly increases Alzheimer's risk in different ethnicities, the risk levels are different.

"One important argument against their interpretation is that the risk of Alzheimer's disease in APOE4 homozygotes varies substantially across different genetic ancestries," he said. Greicius cowrote a study that found white people with two copies of APOE4 had a 13 times greater risk of Alzheimer's than white people with two copies of APOE3, while Black people with two copies of APOE4 had a 6.5 times greater risk than Black people with two copies of APOE3.

"This has critical implications when counseling patients about their ancestry-informed genetic risk for Alzheimer's disease," he said, "and it also speaks to some yet-to-be-discovered genetics and biology that presumably drive this massive difference in risk." (Belluck, New York Times, 5/6; George, MedPage Today, 5/6; Wosen, STAT+ [subscription required], 5/6)

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